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UBC Theses and Dissertations

Metal-alkyne complex initiated cyclization reactions : enesulfonamides and enecarbamates as nucleophiles Harrison, James Tyler 2007

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M E T A L - A L K Y N E C O M P L E X INITIATED CYCLIZATION ENESULFONAMIDES AND E N E C A R B A M A T E S AS  REACTIONS:  NUCLEOPHILES  by  Tyler James Harrison  B.Sc. (Hons.), Simon Fraser University, 2001  A THESIS S U B M I T T E D IN P A R T I A L F U L F I L L M E N T OF T H E R E Q U I R E M E N T S F O R T H E D E G R E E OF  D O C T O R OF P H I L O S O P H Y  in  T H E F A C U L T Y OF G R A D U A T E STUDIES (Chemistry)  T H E U N I V E R S I T Y OF BRITISH C O L U M B I A July 2007 © Tyler James Harrison, 2007  11  Abstract The use of enesulfonamides and enecarbamates as 71-nucleophiles has been investigated in the context of metal catalyzed cycloisomerization reactions with a tethered alkyne and the results of these investigations are presented. This dissertation is divided into 5 chapters. Chapter 1 provides an overview of the evolution and development in the field of transition metal catalyzed cycloisomerization reactions with primary focus on the use of platinum, silver and gold catalysts.  Chapter 2 discloses investigations into the platinum(II) and silver(I) salt catalyzed cycloisomerization of 1,2,3,4-tetrahydropyridine derivatives with an alkyne moiety tethered at the 4-position of the ring. Reaction of these substrates in the presence of catalytic quantities of metal salts resulted in the formation of five-membered rings in 20-88% yield. The resultant dienes were efficiently reacted in situ in Diels-Alder cycloadditions, triethylsilane reductions and hydrogenation reactions. A series of enesulfonamides were reduced to the resulting piperidine derivatives with catalytic quantities of silver(I) trifluoromethanesulfonate and an equivalent of triethylsilane in 82-98% yield, whereas the alkyne moieties o f these enyne substrates were hydrosilylated in the presence of platinum(II) chloride and triethylsilane.  Chapter 3 discloses the silver(I) and gold(I) catalyzed formation of pyrrole rings from a variety of 4-pentyn-1 -ones. The conversion of 4-pentyn-1 -ones and a suitable primary amine into the corresponding pyrrole rings was investigated with 19 examples. Catalysis by silver(I) trifluoromethanesulfonate provided pyrroles with yields ranging 1-92%. Catalysis by either P P h ^ A u C l - A g O T f or P P h 3 - A u C l - A g O T f gold(I) catalyst systems afforded pyrrole products in 27-88% yield.  Chapter 4 discloses a high yielding and operationally straightforward synthesis of the bread aroma compound 6-acetyl-1,2,3,4-tetrahydropyridine. The desired target is obtained via a 3-pot, 4-step sequence in 59% overall yield.  Chapter 5 discloses the platinum(II) catalyzed carbocyclization of 1,2,3,4tetrahydropyridine derivatives with an alkyne tethered at the 3-position of the ring to form quaternary carbon centers within spiro-fused five-membered rings. The effects ofN-  Ill  functionalization, heterocycle size and alkyne-functionalization were investigated with 20 different substrates. Successful reactions provided spiro-fused five-membered rings in 50-83% yield. The position of the resultant double bond was strictly controlled by the use of either P t C ^ or P t C b - A g O T f catalyst systems. Controlled formation of the double bond migration product by use o f the P t C ^ - A g O T f catalyst system enabled a 4-step conversion to a 2:1 mixture of the natural products isonitramine and nitramine. Substrates containing an aryl-substituted alkyne proceeded via a one-step cycloisomerization/Friedel-Crafts tandem process to afford tetracyclic scaffolds in 65-78% yield, where initial attack of the n-nucleophile onto the metal complexed alkyne favors a 6-endo mode of cyclization. This chemistry proved promising for application to natural product total synthesis in model studies towards the tricyclic core o f fawcettidine.  IV  Table of Contents Abstract  ii  Table of Contents  iv  List of Tables  vii  List of Figures  i*  List of Schemes  xi  List of Charts  xvi  List o f Abbreviations and Symbols  xvii  Acknowledgements  xxi  Foreward References  xxiii xxv  C h a p t e r 1: P l a t i n u m , S i l v e r a n d G o l d S a l t C a t a l y z e d C y c l o i s o m e r i z a t i o n R e a c t i o n s : A Review  1  1.1 Introduction  2  1.2 Historical Perspective  2  1.3 Reactions Catalyzed by Platinum  7  1.3.1 Platinum catalyzed C - C bond formation  7  1.3.2 Platinum catalyzed C - 0 bond formation  19  1.3.3 Platinum catalyzed C - N bond formation  21  1.4 Reactions Catalyzed by Silver  22  1.4.1 Silver catalyzed C - C bond formation  22  1.4.2 Silver catalyzed C - 0 bond formation  25  1.4.3 Silver catalyzed C - N bond formation  26  1.5 Reactions Catalyzed by Gold  28  1.5.1 Gold catalyzed C - C bond formation  29  1.5.2 Gold catalyzed C - 0 bond formation  32  1.5.3 Gold catalyzed C - N bond formation  34  1.6 Bransted A c i d Catalysis  34  1.7 Conclusion  36  1.8 References  37  V  C h a p t e r 2: P t ( I I ) o r A g ( I ) S a l t C a t a l y z e d C y c l o i s o m e r i z a t i o n s a n d T a n d e m C y c l o a d d i t i o n s Forming Functionalized Azacyclic Arrays  50  2.1 Introduction  51  2.2 Synthesis of Substrates  52  2.3 Reaction of Substrates  67  2.3.1 Cycloisomerization Reactions  68  2.3.2 Diels-Alder Cycloadditions  75  2.3.3 Limitations of the Cycloisomerization Process  80  2.3.4 Reduction of Enesulfonamides  87  2.3.5 Hydrosilylation of Alkynes  89  2.3.6 Mechanistic Considerations  91  2.4 Conclusion  95  2.5 Experimental  96  2.5.1 General Experimental  96  2.5.2 Synthesis of Substrates  97  2.5.3 Cycloisomerization Reactions  146  2.5.4 Diels-Alder Cycloaddition Reactions  160  2.5.5 Limitations of the Cycloisomerization Process  177  2.5.6 Reduction of Enesulfonamides  187  2.5.7 Hydrosilylation of Alkynes  190  2.6 References C h a p t e r 3: P y r r o l e Synthesis C a t a l y z e d b y A g O T f o r C a t i o n i c A u ( I ) C o m p l e x e s  195 198  3.1 Introduction...  199  3.2 Synthesis of Substrates  203  3.3 Reaction of Substrates  206  3.4 Investigations Into Precatalyst Identity  216  3.5 Conclusion  220  3.6 Experimental  221  3.6.1 General Experimental  221  3.6.2 Synthesis of Substrates  221  3.6.3 Reaction of Substrates  233  VI  3.7 References  251  C h a p t e r 4: A n E x p e d i t i o u s , H i g h - Y i e l d i n g C o n s t r u c t i o n o f t h e F o o d A r o m a 6-Acetyl-l,2,3,4-tetrahydropyridine  Compounds  and 2-Acetyl-l-pyrroline  4.1 Introduction  254  255  4.2 Previous Synthetic Routes to 6-Acetyl-l,2,3,4-tetrahydropyridine and 2-Acetyl-pyrroline 255 4.3 Construction of 6-acetyl-l,2,3,4-tetrahydropyridine and 2-acetyl-l-pyrroline  260  General experimental  267  4.5 References  274  C h a p t e r 5: PIatinum(II)-CataIyzed Cyclizations F o r m i n g Q u a t e r n a r y C a r b o n Centers U s i n g E n e s u l f o n a m i d e s , E n e c a r b a m a t e s o r E n a m i d e s as N u c l e o p h i l e s  276  5.1 Introduction  277  5.2 Synthesis of Substrates  279  5.3 Reaction of Substrates  288  5.4 Conclusion  305  5.5 Experimental  306  5.5.1 General Experimental  306  5.5.2 Synthesis of Substrates  306  5.5.3 Reaction of Substrates  338  5.6 Reference Concluding Remarks  355 357  Appendix A :  Selected Spectra for Chapter 2  359  Appendix B:  Selected Spectra for Chapter 3  414  Appendix C :  Selected Spectra for Chapter 4  439  Appendix D:  Selected Spectra for Chapter 5  444  Appendix E :  X-ray Crystallographic Data  483  VII  List o f Tables  T a b l e 2.2.1:  Functionalization of alkyne 2 . 1 9  56  T a b l e 2.2.2:  Palladium catalyzed allylic alkylation of 2 . 6 3  63  T a b l e 2.3.1:  Cycloisomerization reactions with platinum(II) chloride  69  T a b l e 2.3.2:  Optimization study performed with enesulfonamide 2 . 3 0  71  T a b l e 2.3.3:  Cycloisomerization reactions using [dppb PtOH] (BF )2 as catalyst 4  72  T a b l e 2.3.4:  Cycloisomerization reactions using A g O T f as catalyst  75  T a b l e 2.3.5:  Effect of heterocycle size on the cycloisomerization of enesulfonamides  82  T a b l e 2.3.6:  Attempted cycloisomerization of enesulfonamides onto tethered alkenes  83  T a b l e 2.3.7:  Attempted cycloisomerization of nitrile 2 . 7 7  84  T a b l e 2.3.8:  Cycloisomerization studies involving deuterated enesulfonamide 2 . 6 1  93  T a b l e 2.5.1:  N M R data for 2 . 8 5  148  T a b l e 2.5.2:  C O S Y Data for 2 . 8 5  149  T a b l e 2.5.3:  'Ft Selective N O E Data for 2 . 8 5  150  T a b l e 2.5.4:  C O S Y Data for 2 . 8 7 - Z . . .  155  T a b l e 2.5.5:  ' H Selective N O E Data for 2 . 8 7 - Z  156  T a b l e 2.5.6:  ' H Selective N O E Data for 2.S7-E  156  T a b l e 2.5.7:  N M R Data for 2.91  162  T a b l e 2.5.8:  C O S Y Data for 2.91  163  T a b l e 2.5.9:  Selective N O E Data for 2.91  164  2  T a b l e 2.5.10:  N M R Data for 2 . 9 2  168  T a b l e 2.5.11:  C O S Y Data for 2 . 9 2  169  T a b l e 2.5.12:  ' H Selective N O E Data for 2 . 9 2  170  T a b l e 2.5.13:  N M R Data for C  171  T a b l e 2.5.14:  C O S Y Data for C  172  T a b l e 2.5.15:  ' H Selective N O E Data for C  173  T a b l e 2.5.16:  ' H Selective T O C S Y Data for C  173  T a b l e 2.5.17:  C O S Y Data for 2 . 1 0 1  185  T a b l e 2.5.18:  ' H Selective N O E Data for 2 . 1 0 1  186  Vlll  T a b l e 3.3.1:  Screen of catalysts for the conversion of 5-heptyn-2-one ( 3 . 3 1 ) into pyrrole 3 . 3 2 a  210 T a b l e 3.3.2:  Screen of primary amines for the conversion of 5-heptyn-2-one into pyrroles.... 212  T a b l e 3.3.3:  Examples of silver(I) or gold(I) catalyzed formation of pyrrole containing bicycles  with benzylamine T a b l e 3.3.4:  214  Silver(I) or gold(I) catalyzed pyrrole formation of carbamate containing  homopropargyl ketones with benzylamine Table 3.4.1: P 3 I  N M R data of precatalyst mixtures in C D C 1  215 3  217  T a b l e 3.4.2:  Investigations into the possible identity of the gold precatalyst species  219  Table 4.3.1:  Comparison of synthetic routes to heterocycle 4.1  266  T a b l e 5.2.1:  Functionalization of the alkyne terminus of enesulfonamide 5 . 1 0  284  T a b l e 5.2.2:  Construction of enamide substrates 5 . 4 9 - 5 . 5 2  286  T a b l e 5.3.1:  Evaluation of metal salts on the cyclization reaction of enesulfonamide 5 . 1 0  291  T a b l e 5.3.2:  Platinum(II) catalyzed cycloisomerization of aryl-substituted alkynes  297  T a b l e 5.3.3:  Platinum(II) catalyzed cycloisomerization of enamides 5 . 4 9 - 5 . 5 2 and 5 . 5 4 for  fawcettidine related model studies T a b l e E . 1:  X-ray Crystallographic Experimental Data  302 484  IX  List of Figures  F i g u r e 2.1.1:  General representation of the desired metal catalyzed cyclization event  51  F i g u r e 2.2.1:  General structure of required substrates  52  F i g u r e 2.2.2:  Retrosynthetic analysis for nitrile containing substrate  61  F i g u r e 2.3.1:  Structures of cycloisomerization products  69  F i g u r e 2.3.2:  Observed selective N O E for diene  70  F i g u r e 2.3.3:  Protonation of enesulfonamide  2.85  2.30  with Bronsted acid  74  F i g u r e 2.3 4 : Proposed tandem cycloisomerization/Diels-Alder cycloaddition sequence  76  F i g u r e 2.3.5:  Transition state depiction for the Diels-Alder cycloaddition  77  F i g u r e 2.3.6:  Comparison of possible transitions states for the Diels-Alder cycloaddition of  diene 2 . 8 5 and cyclopentenone  79  F i g u r e 2.3.7:  Proposed steric interactions involved with dienophile approach  79  F i g u r e 2.3.8:  Illustration of Diels-Alder cycloaddition with unisomerized diene  80  F i g u r e 2 . 3 . 9 : Observed selective N O E correlations for enesulfonamide 2.101 F i g u r e 2.3.10:  87  Proposed cycloisomerization accompanied by in situ hydride reduction  88  F i g u r e 2.5.1:  O R T E P representation of the solid-state structure of 2 . 9 1  164  F i g u r e 2.5.2:  O R T E P representation of the solid-state structure of  A  165  F i g u r e 2.5.3:  O R T E P representation of the solid-state structure of  2.95  177  F i g u r e 3.1.1:  Pyrrole containing natural products  F i g u r e 3.3.1:  Double bonds of nucleophile and electrophile are exocyclic to the ring that is  199  being formed for substrates possessing the alkyne tether at the 4-position of a tetrahydropyridine ring system F i g u r e 3.3.2:  206 Proposed metal catalyzed cycloisomerization reaction for endocyclic enamines 207  F i g u r e 3.4.1:  Gold-chloride bond lengths for both two and three coordinate complexes in the  solid-state F i g u r e 4.1.1: (4.2)  217 Structures of 6-acetyl-1,2,3,4-tetrahydropyridine  (4.1)  and 2-acetyl-1-pyrroline 255  X  F i g u r e 5.1.1:  General schematic representation of cycloisomerization reactions of 1,6-enynes  containing an enamine derivative F i g u r e 5.1.2:  277  Proposed generation of quaternary carbon centers in a cycloisomerization event 278  F i g u r e 5.1.3:  Proposed metal catalyzed carbocyclization with alcohol additive  278  F i g u r e 5.1.4:  Structural representation of fawcettidine  279  F i g u r e 5 . 3 . 1 : Illustration of proposed steric interaction between the alkynyl methyl moiety and the enesulfonamide ring F i g u r e 5.3.2:  295  Illustration of proposed steric clashing between the alkynyl arene moiety and the  p-toluenesulfonyl group F i g u r e 5.3.3:  299  Comparative differences in double bond geometry of cyclized products for iodo-  and aryl-substituted alkynes  300  F i g u r e 5 . 3 . 4 : M M 2 calculations for methyl-substituted cis- and ^rarcs-fused tricyclic models 302 F i g u r e 5.3.5:  Proposed path of decomposition for homoallyl-substituted enamide  Cope-aza-Prins sequences  5.51  via aza303  F i g u r e 5.5.1:  O R T E P representation of the solid-state structure of 5 . 6 8  346  F i g u r e 5.5.2:  O R T E P representation of the solid-state structure of 5 . 6 9 a  348  F i g u r e 5.5.3:  O R T E P representation of the solid-state structure of  348  5.69b  XI  List of Schemes S c h e m e 1.2.1:  Malone and coworkers: rhodium catalyzed cycloisomerization of diallyl ether... 3  S c h e m e 1.2.2:  Sakai and coworkers: cycloisomerization of 4-penten-1-al systems catalyzed by  Wilkinson's catalyst S c h e m e 1.2.3:  3  Grigg and coworkers: effects of catalyst and solvent on the cycloisomerization of  1 ,«-dienes  4  S c h e m e 1.2.4:  Trost and Lautens: palladium catalyzed cycloisomerization of 1,6-enynes  4  S c h e m e 1.2.5:  Grigg and coworkers: rhodium catalyzed cycloisomerizations of 1,6-enynes  5  S c h e m e 1.2.6:  Blum and coworkers: platinum catalyzed cycloisomerization of allyl propargyl  ethers  5  S c h e m e 1.2.7:  Murai and coworkers: PtCi2 catalyzed cycloisomerization of 1,6-enynes  6  S c h e m e 1.2.8:  Fiirstner and coworkers: formal synthesis of streptorubin B  6  S c h e m e 1.3.1.1:  Effect of a heteroatom in the enyne tether  S c h e m e 1.3.1.2:  Echavarren and coworkers: use of allylsilanes and allylstannanes in  7  carbocyclization reactions S c h e m e 1.3.1.3:  8  Formation of bicyclo[4.1.0]heptenes observed for substrates possessing both  allylsilanes and heteroatoms in the enyne tether S c h e m e 1.3.1.4:  8  Investigations with respect to modification of the nucleophilicity of the alkene  or alkyne S c h e m e 1.3.1.5:  9 Murai and coworkers: trapping of a carbenoid intermediate with an  intramolecular olefin S c h e m e 1.3.1.6:  10  Contemporary mechanistic explanation for transition metal catalyzed  cycloisomerizations of 1,6-enynes  11  S c h e m e 1.3.1.7:  Alkoxycyclization of 1,6-enynes  S c h e m e 1.3.1.8:  Echavarren and coworkers: proposed mechanism for alkoxycyclization of 1,6-  enynes S c h e m e 1.3.1.9:  13  13 Fiirstner and coworkers: proposed equilibrium for cyclobutenyl cation  S c h e m e 1.3.1.10:  14  Fiirstner and coworkers: cyclobutenes by P t C ^ catalyzed cycloisomerization 14  S c h e m e 1.3.1.11:  Malacria and coworkers: cycloisomerization of 1,6-enynes containing  oxygenation at the propargylic position  15  Xll  S c h e m e 1.3.1.12:  Cycloisomerization of 1,5-enyne derivatives  S c h e m e 1.3.1.13:  Kozmin and coworkers: cyclohexadienes via platinum catalyzed  cycloisomerization S c h e m e 1.3.1.14:  PtCb catalyzed hydroarylation of alkynes  S c h e m e 1.3.1.15:  Yamamoto and coworkers: platinum catalyzed cycloisomerization via C - H  insertion mechanism S c h e m e 1.3.2.1:  S c h e m e 1.3.2.2:  Barluenga and coworkers: tandem hydroalkoxylation-Prins cyclization  S c h e m e 1.3.2.3:  Fiirstner and coworkers: benzofuran synthesis via intramolecular  carboalkoxylation  17  18  19 19  20  Kirsch and coworkers: construction of 3(2//)-furanones via P t C b catalyzed  cycloisomerization of 3-butyn-l-ones S c h e m e 1.3.3.1:  Platinum(II) catalyzed addition of nitrogen nucleophiles to alkynes  S c h e m e 1.4.1.1:  Toste and coworkers: formation of naphthyl ketones via silver(I) catalyzed  cycloisomerization of 1,6-diynes S c h e m e 1.4.1.2:  17  Widenhoefer and coworkers: platinum catalyzed intramolecular  hydroalkoxylation of alkenes  S c h e m e 1.3.2.4:  16  20 21  23  Kirsch and coworkers: silver(I) catalyzed propargyl-Claisen rearrangement in  the synthesis of 2//-pyrans  23  S c h e m e 1.4.1.3:  Rhee and Krische: silver(I) promoted alkyne-carbonyl coupling reactions  24  S c h e m e 1.4.1.4:  Kozmin and coworkers: silver(I)-promoted cyclobutene formation  24  S c h e m e 1.4.2.1:  Olsson and Claesson: silver(I) catalyzed cycloisomerization of allenic alcohols 25  S c h e m e 1.4.2.2:  Marshall and coworkers: silver(I) catalyzed synthesis of furans  S c h e m e 1.4.2.3:  He and coworkers: silver(I) catalyzed intramolecular addition of carboxylic  acids and alcohols to alkenes S c h e m e 1.4.3.1:  25  26  Gallagher and coworkers: diastereoselective intramolecular hydroamination of  allenes  26  S c h e m e 1.4.3.2:  Knolker and coworkers: pyrrole construction via oxidative cyclization  27  S c h e m e 1.4.3.3:  Yamamoto and coworkers: silver(I) catalyzed addition of imines to alkynes . 27  S c h e m e 1.4.3.4:  Cui and He: silver(I)-mediated cyclization by C - H activation  28  S c h e m e 1.5.1.1:  Toste and coworkers: gold(I) catalyzed Rautenstrauch rearrangement  31  S c h e m e 1.5.1.2:  Hashmi and coworkers: gold catalyzed phenol synthesis  31  Xlll  S c h e m e 1.5.1.3:  Rossi and coworkers: gold catalyzed synthesis of pyridines  32  S c h e m e 1.5.1.4:  Shi and He: gold(III) catalyzed arene C - H functionalization  32  S c h e m e 1.5.2.1:  Hashmi and coworkers: evidence for the reductive elimination of a gold(IIl)  species  33  S c h e m e 2.2.1:  Synthesis of toluenesulfonyl protected allylic methyl ether  S c h e m e 2.2.2:  Synthesis of tert-buty] carbamate protected allylic methyl ether  53  2.6  53  2.11  S c h e m e 2 . 2 . 3 : Synthesis of bromides as described by Holmes and coworkers  54  S c h e m e 2.2.4:  Copper(I) catalyzed Grignard addition to allylic methyl ether  2.6  55  S c h e m e 2.2.5:  Copper(I) catalyzed Grignard addition to allylic methyl ether  2.11  55  S c h e m e 2 . 2 . 6 : Construction of methyl-substituted cycloisomerization substrate 2 . 2 8  55  S c h e m e 2 . 2 . 7 : Construction of ynoates 2 . 3 9 , 2 . 4 0 and 2 . 4 1  57  S c h e m e 2.2.8:  Construction of a substrate with a heteroatom in the alkyne tether  58  S c h e m e 2 . 2 . 9 : Construction of dihydropyrrole substrate 2 . 5 1 S c h e m e 2.2.10:  Construction of deuterated ynoate  59  60  2.61  S c h e m e 2 . 2 . 1 1 : Lindlar's reduction of ynoate 2 . 3 0  60  S c h e m e 2 . 2 . 1 2 : Synthesis o f allylic acetate 2 . 6 3  61  S c h e m e 2 . 2 . 1 3 : Construction of tert-buty\ carbamate-protected allylic acetate  62  S c h e m e 2.2.14:  Allylic alkylation control experiments  64  S c h e m e 2 . 2 . 1 5 : Apparent dichotomy of reaction pathways for the reaction of allylic acetate 2 . 6 3 64 S c h e m e 2.2.16:  Allylic alkylation of enecarbamate  S c h e m e 2.2.17:  Background reaction for the allylic alkylation of enecarbamate  S c h e m e 2.2.18:  Alkylation of enesulfonamide  2.73  65  2.72  66  2.72  with bromoacetonitrile  66  S c h e m e 2 . 2 . 1 9 : Failed attempt to construct a stable 1,4-dihydropyridine substrate  66  S c h e m e 2 . 2 . 2 0 : Construction o f 1,4-dihydropyridine 2 . 8 1  67  S c h e m e 2.3.1:  Double bond isomerization of  S c h e m e 2.3.2:  Diels-Alder cycloaddition with diene  2.87-Z  with either heat or platinum(II) catalyst. 73 76  2.85  S c h e m e 2 . 3 . 3 : Cyclization/Diels-Alder cycloaddition reaction of enesulfonamide 2 . 3 0 S c h e m e 2.3.4:  Cyclization/Diels-Alder cycloaddition reaction of enesulfonamide  2.30  77 with  cyclopentenone  78  S c h e m e 2 . 3 . 5 : Cycloisomerization of enecarbamate 2 . 4 0  80  XIV  S c h e m e 2.3.6:  Cycloisomerization of allylic ether  81  2.45  S c h e m e 2 . 3 . 7 : Attempted intermolecular Michael addition  84  S c h e m e 2.3.8:  Cycloisomerization as a method for six-membered ring formation  S c h e m e 2.3.9:  Procedure for the formation of six-membered rings from enesulfonamide  85 86  2.30  S c h e m e 2 . 3 . 1 0 : Cycloisomerization-hydrogenation of enesulfonamide 2 . 1 9  86  S c h e m e 2 . 3 . 1 1 : Synthesis of deoxyrhexifoline via cycloisomerization-hydrogenation of 1,4-  dihydropyridine 2.81  87  S c h e m e 2 . 3 . 1 2 : Silver(I) catalyzed reduction of enesulfonamide 2 . 3 0  88  S c h e m e 2 . 3 . 1 3 : Silver(l) catalyzed reduction of selected enesulfonamides  89  S c h e m e 2 . 3 . 1 4 : Platinum(II) catalyzed hydrosilylation of ynoate 2 . 3 0  90  S c h e m e 2 . 3 . 1 5 : Platinum(II) catalyzed hydrosilylation of selected alkynes  90  S c h e m e 2.3.16:  Proposed mechanistic scheme based upon literature precedent  91  S c h e m e 2 . 3 . 1 7 : Possible mechanistic pathway for silver(I) catalyzed cycloisomerization of enesulfonamide 2 . 3 0  92  Scheme 3.1.1:  Grigg and Savic: palladium catalyzed pyrrole synthesis  S c h e m e 3.1.2:  Toste and coworkers: gold(l) catalyzed pyrrole synthesis from homopropargyl  azides S c h e m e 3.1.3:  200  200 K e l ' i n and coworkers: copper(I) catalyzed pyrrole synthesis from alkynyl imines 201  S c h e m e 3.1.4:  Odom and coworkers: pyrrole construction from 1,4- or 1,5-diynes  S c h e m e 3.1.5:  Robinson and coworkers: pyrrole synthesis via silver(I) catalyzed  hydroamination  202  S c h e m e 3.1.6:  Kirsch and coworkers: synthesis of pyrroles from propargyl enol ethers  S c h e m e 3.2.1:  Synthesis of 2-substituted enesulfonamides and p-toluenesulfonyl containing  homopropargyl ketones S c h e m e 3.2.2:  201  202  203  Synthesis of 2-substituted enecarbamates and tert-buty\ carbamate containing  homopropargyl ketones  204  S c h e m e 3.2.3:  Deprotection of carbamate  S c h e m e 3.2.4:  Synthesis of propargyl cyclohexanones  3.20  in basic methanol 3.22  and  3.24  205 via alkylation of  cyclohexanone  205  S c h e m e 3 . 2 . 5 : Synthesis of propargyl cyclopentanones 3 . 2 6 and 3 . 2 7  205  XV  S c h e m e 3.2.6:  Acid promoted deprotection of tert-butyl carbamates  3.15  and  206  3.21  S c h e m e 3 . 3 . 1 : Attempted cycloisomerization of enesulfonamide 3 . 1 2  207  S c h e m e 3 . 3 . 2 : Attempted cycloisomerization of enecarbamate 3 . 1 8  208  S c h e m e 3.3.3:  Pyrrole synthesis from ketone  209  3.19  S c h e m e 3 . 3 . 4 : Cyclization of imines 3 . 2 8 and 3 . 2 9  216  S c h e m e 4 . 2 . 1 : Biichi and Wiiest: synthesis of 6-acetyl-1,2,3,4-tetrahydropyridine  256  S c h e m e 4.2.2:  De Kimpe and Stevens: synthesis of 6-acetyl-1,2,3,4-tetrahydropyridine  257  Scheme 4.2.3:  De Kimpe and Stevens: synthesis of 6-acetyl-1,2,3,4-tetrahydropyridine  258  S c h e m e 4 . 2 . 4 : Synthesis of methyl ketone function of 4.2 by organometallic addition to a methyl ester  258  S c h e m e 4 . 2 . 5 : Hofmann and Schieberle: synthesis of 6-acetyl-1,2,3,4-tetrahydropyridine  259  S c h e m e 4.2.6:  Duby and Huynh approach to 2-acetyl pyrroline  260  Scheme 4.3.1:  Retrosynthetic analysis for substrates analogous to  S c h e m e 4.3.2:  Proposed route to the construction of 2-acetyl heterocycles  261  3.17  261  S c h e m e 4 . 3 . 3 : Synthesis of 6-acetyl-1,2,3,4-tetrahydropyridine 4.1  262  S c h e m e 4 . 3 . 4 : Mechanism for the formation of cyclic lactam 4 . 2 6  262  Scheme 4.3.5:  Optimized synthetic route for the construction of  264  4.1  S c h e m e 4 . 3 . 6 : Application of the developed strategy to the synthesis of 4.2 S c h e m e 4.3.7:  Condensation reaction of  S c h e m e 4.3.8:  Rationale for the production of keto-imine  S c h e m e 5.2.1:  First generation synthesis of enesulfonamide  S c h e m e 5.2.2:  Synthetic route to the construction of enesulfonamides  S c h e m e 5.2.3:  Synthetic route to the construction of tert-butyl carbamate  S c h e m e 5.2.4:  Synthetic route to the construction of methyl carbamate  S c h e m e 5.2.5:  Construction of indole substrates  S c h e m e 5.2.6:  Synthetic route to the construction of enamide  4.29  does not lead to ketal formation  5.24  and  265 265  4.31  279  5.2 5.7, 5.10 5.18  5.21  5.15  280 281 281  283  5.32  Synthetic route to heterocycle precursor, 8-ketoester  and  282  5.25.  S c h e m e 5 . 2 . 7 : Functionalization of the alkyne terminus of enamide 5 . 3 2 S c h e m e 5.2.8:  264  5.44  S c h e m e 5 . 2 . 9 : Synthesis of non-commercially available amines 5 . 4 6 and 5 . 4 8  284 285 286  S c h e m e 5 . 2 . 1 0 : Functionalization of the alkyne terminus of allyl-substituted enamide 5.49... 287  XVI  S c h e m e 5.3.1:  Initial conditions attempted for cyclization of enesulfonamide  S c h e m e 5.3.2:  Optimized conditions for the platinum(II) catalyzed cyclization of  5.10  288  enesulfonamide 5 . 1 0 and corresponding aminal reduction  289  S c h e m e 5 . 3 . 3 : One-pot cyclization-reduction procedure  290  S c h e m e 5 . 3 . 4 : Platinum(II) catalyzed cyclization of enesulfonamide 5 . 1 0 in the presence of water  292  S c h e m e 5.3.5:  A c i d catalyzed alkene isomerization of methylenecyclopentane  S c h e m e 5.3.6:  Conversion of cyclopentene  S c h e m e 5.3.7:  Evaluation of substrate scope for the quaternary carbon center forming  5.57  5.56  293  to a mixture of nitramine and isonitramine . 294  platinum(II) catalyzed cyclization reaction  295  S c h e m e 5 . 3 . 8 : Attempted cyclization of indoles 5.24 and 5 . 2 5  296  S c h e m e 5.3.9:  Proposed mechanism for formation of tetracycles  5.69-5.71  S c h e m e 5 . 3 . 1 0 : Attempted cycloisomerization of 1,3-enyne 5 . 3 8 Scheme 5.3.11: S c h e m e 5.3.12:  Proposed cycloisomerization of enamides for fawcettidine model studies  298 300  301  Attempted ring-closing metathesis to form tetracyclic skeleton of fawcettidine 303  S c h e m e 5 . 3 . 1 3 : Attempted cycloisomerization of allene 5 . 5 3  304  List of Charts  C h a r t 1.5.1.1:  Gold catalyzed transformations that reexamine reactions previously explored  under platinum catalysis  29  List of Abbreviations and Symbols  5  chemical shift in parts per million  Ac  acetyl, acetic  Anal.  analysis (combustion analysis)  aq  aqueous  atm  atmosphere (pressure)  Bn  benzyl  Boc  ter?-butyloxycarbonyl  BOM  benzyloxymethyl  bp  boiling point  br  broad  Bu  butyl  BuLi  butyllithium  °C  degrees Celcius  calcd  calculated  cod, C O D  cyclooctadiene  COSY  correlation spectroscopy  CSA  10-camphorsulfonic acid  Cy  cyclohexyl  d  doublet (NMR spectroscopy), day(s) (t  2D  two dimensional  dba  dibenzylideneacetone  DBU  l,8-diazabicyclo[5.4.0]undec-7-ene  DIBA1-H  diisobutylaluminum hydride  dig  digonal  DIPEA  AVV-diisopropylethylamine  DMA  A^A'-dimethylacetarnide  DMAP  4-(AyV-dimethylamino)pyridine  DMF  A^N-dimethylformamide  DMS  dimethyl sulfide  DMSO  dimethyl sulfoxide  XV111  dppb  1,4-bis(diphenylphosphino)butane  dppm  bis(diphenylphosphino)methane  dppp  1,4-bis(diphenylphosphino)propane  dr  diastereomeric ratio  E  entgegen (configuration)  ee  enantiomeric excess  EI  electron ionization  endo  endocyclic  eq  equation  equiv  equivalents  ESI  electrospray ionization  Et  ethyl  EWG  electron withdrawing group  exo  exocyclic  g  gram  h  hour  HMBC  heteronuclear multiple bond correlation  HMQC  1  Hz  hertz  i  iso  IR  infrared (spectroscopy)  J  coupling constant  k  kilo (10 )  L  litre  LDA  lithium diisopropylamide  lit.  literature  m  multiplet (NMR spectroscopy), milli (10~ )  ra-CPBA  meto-chloroperbenzoic acid  M  parent mass (mass spectra) or molar, moles per liter (concentration),  H-detected heteronuclear multiple quantum coherence  3  3  metal (mechanism) or mega (JO ) 6  Me  methyl  Met  metal  xix  min  minute  u  micro (10~ )  MM2  molecular mechanics level 2  mol  mole  MOM  methoxymethyl  mp  melting point  Ms  mesyl, methanesulfonyl  MS  mass spectrometry  n  normal (nomenclature)  NMR  nuclear magnetic resonance  NOE  nuclear Overhauser effect  NR  no reaction  ORTEP  Oak Ridge thermal ellipsoid plot  OTf  triflate, trifluoromethanesulfonate  p  para  p  pico (Iff )  %  percent (parts per hundred)  Ph  phenyl  pH  -log[H ]  PNB  para-nitrobenzoate  ppm  parts per million  Pr  propyl  pyr  pyridine  Q  quaternary  rt  room temperature  s  singlet  SEM  2-(trimethylsilyl)ethoxymethyl  SM  starting material  SN 1  substitution nucleophilic unimolecular  SN2  substitution nucleophilic bimolecular  t  triplet (NMR spectroscopy), time (time)  t  tertiary  6  12  +  TBAF  tetra-«-butylammonium fluoride  TBDPS  ter?-butyldiphenylsilyl  TBS  fer/-butyldimethylsilyl  Temp  temperature  Tf  trifluoromethanesulfonyl  TFA  trifluoroacetic acid  THF  tetrahydrofuran  TLC  thin layer chromatography  TMS  trimethylsilyl, tetramethylsilane  trig  trigonal  Ts or p-Ts  tosyl, p-toluenesulfonyl  UBC  University of British Columbia  Z  zusammen  (configuration)  XXI  Acknowledgements First and foremost, I wish to thank my Ph.D. research supervisor, Professor Gregory Dake, for his intellectual guidance and mentorship, in addition to his assistance in the preparation of this manuscript. Over the past five and a half years, Greg has skillfully unveiled the fascinating world of organic chemistry to me. There was never any hesitation on his part, in giving up his time to discuss chemistry or other interests. I am grateful to him for his commitment to excellence and the way in which that attitude has influenced my own perspectives. Greg's continued support, both moral and intellectual, throughout the successes, hardships and failures of this work is greatly appreciated.  For additional assistance in the proofreading of this thesis I graciously acknowledge Professor David Perrin and Dr. Alan Kaller. The considerable effort and care they took as editors, and the resulting suggestions, ideas and criticisms, exceeded my expectations and were very much appreciated. I claim responsibility for any errors or deficiencies that remain.  I would like to thank all of the members of the Dake research group, past and present, Michael, Mike, Erik, Paul, Leah, Melissa, Jaqueline, Jenn, Krystle, Julien, Jenny, Amir, Eggy, Roh, Dave, Helen and Montserrat for their comradery and for making my time in the lab enjoyable.  It is difficult to expect a spouse or significant other to endure the relationship gauntlet that is graduate school. Anita has stood by me throughout the good times, hard times, reward and stresses o f graduate school with her gentle reminders that there is life beyond chemistry. Fortunately, her commitment and devotion to us transcend her patience for chemistry. I am proud and thankful to now call her my wife.  I owe a great deal to my parents, Greg and Darcy, for their continued support in whatever 1 have found interesting throughout my life, for teaching me kindness, generosity and consideration and for their love. Thank you to my sister Caitlin and my brother Travis whom I have cherished growing up with and I'm quite certain that I have never expressed just how much they mean to me.  XXII  I have been fortunate to have developed many friendships at U B C . A special thanks is extended to Dr. Paul Hurley, Dr. Jay Read and Dr. Wayne Chou for their friendship and advice over the years and for making late nights working in the lab tolerable. I sincerely hope this bond persists long after my time at U B C . I would like to thank Dr. Alan Kaller for his advice and guidance early on in my training and I am grateful for his friendship and continued support. 1 have known Matthew Higgins and Greg Pare for as long as I can remember and I feel fortunate and thankful that they remain close friends despite the inevitable neglect of the outside world that accompanies graduate school.  Last, but not least, I thank the staff of the N M R Laboratory, Mass Spectrometry Laboratory, Microanalysis Laboratory and Mech. Shop for their continual assistance. A special thank you goes to Ken Love for his kindness and generosity. Financial support from both the Natural Sciences and Engineering Research Council (NSERC) and from the University of British Columbia throughout my graduate studies was invaluable and greatly appreciated.  XX111  Fo reward At the most elementary of assessments, the field of organic chemistry is composed of and relies on the symbiotic relationship between two subfields, namely, target oriented synthesis and the development of new methodologies. As new and more complex molecules are isolated from Nature, chemists rise to the challenge to construct these molecules from commercially available materials. More often than not, however, the state of the art reactions and techniques available to chemists are not sufficient to tackle the synthetic problem at hand and the development of new synthetic methods is required to meet the goals of natural product synthesis. Advancements in the synthetic tools that are available alter strategies for total synthesis and enable chemists to tackle increasingly more complex structures. In this way, the endeavor of total synthesis is in a constant state of evolution.  Organic synthesis is a rare field that blends precise science with fine art.  1  Atoms must be  placed precisely in the correct position in order to assemble the desired target, but how one gets to the target is left up to the artistic integrity, creativity and imagination of the scientist. The practicing of organic synthesis relies heavily on a practical deftness and technical ability delicately balanced with a mental ingenuity, decision making ability and analysis that is difficult to emulate by automation. It is none too surprising that the field still thrives in the information age when other occupations have been rendered obsolete by the efficiencies of modern technology.  Garry Kasparov is often regarded as the greatest chess player of all time. However, in 1997, the I B M supercomputer, Deep Blue, defeated Kasparov in a 6 game match, marking the first time a computer was able to better a world-class human opponent in a chess tournament. While computers may be tireless and exhaustive in their approach to problem solving, they lack the ability to reason. Humans have exceptional abilities at perception, judgment and reason that enable us to dramatically stream-line the problem solving process. Computers of today have massive computing power as a result of vast technological advances, but it is unreasonable to expect computers to become creative simply by making them faster.  Perhaps the most well-developed program for computer-aided synthetic design is L H A S A (Logic and Heuristics Applied to Synthetic Analysis), which can generate reasonable synthetic  XXIV  routes for small molecules. Its handling of complex molecules and stereoselective syntheses, however, is somewhat limited. Organic chemistry has most probably endured the rigors of 2  change because of the difficulty computers have with retrosynthetic analysis and machines do not yet possess the practical deftness required to carry out research-related lab work. Programs have been written that can defeat world class chess masters, but current programs for computeraided synthetic design cannot generate the "best" synthetic route to a complex synthetic target. Fortunately, a trained synthetic organic chemist can produce multiple routes to a target, of which a select few may be suitable for practical application.  The 20 century witnessed extraordinary advances in both synthetic methods and synthetic th  design and was accompanied by the widespread embracing of transition metals by organic chemists as catalysts for organic reactions. When considering how far organic chemistry has 3  evolved over the last two centuries, one has to wonder how it has lasted as a science and how much could possibly be left to discover. In order to answer that question, one needs not look at how far we have come, but instead, must consider how far we have left to go. As defined by Professor Paul Wender in reference to the synthesis of complex target molecules, " A n ideal synthesis is generally regarded as one in which the target molecule (natural or designed) is prepared from readily available, inexpensive starting materials in one simple, safe, environmentally acceptable, and resource-effective operation that proceeds quickly and in quantitative yield".  4  Presently, it is not uncommon for a complex target total synthesis to  require 30-40 steps and to end up with an overall yield as low as <1 %. With the abovementioned standards in mind, it becomes excruciatingly clear that our current standards for synthesis are far from ideal.  5  We must strive to develop new reactions and sequences that  allow for a dramatic increase in target-relevant complexity i f we are to move towards the next level of sophistication in organic synthesis and it is becoming clear that transition metals may play a valuable role in that growth.  Organic chemistry has undergone a great deal of progressive change with respect to not only what has been accomplished, but more importantly with respect to its capabilities and the possibility of what it can accomplish. Granted, today we have very powerful tools at hand, the likes of which chemists of past would be very envious. The work, however, does not appear to have become easier over time since with more powerful tools comes the ability to tackle  X  X  V  increasingly more difficult problems. The field is driven by the seemingly endless flow of molecular architectures from Nature ' and the more complex the synthetic target, the more 6  7  development we are forced to make with respect to methodology. With improved synthetic tools, we are able to tackle even more complicated synthetic problems. Despite the seemingly perpetual nature of this cycle, it is abruptly discontinued without advancements in synthetic methods.  References 1.  Nicolaou, K . C ; Vourloumis, D.; Winssinger, N . ; Baran, P. S. Angew. Chem. Int. Ed.  39, 44-122. 2.  Todd, M . H . Chem. Soc. Rev.  3.  Krische, M . J. Tetrahedron  4.  Wender, P. A . Chem. Rev. 1 9 9 6 , 96, 1-2.  5.  Wender, P. A . ; Handy, S. T.; Wright, D . L . Chem. Ind. London 1 9 9 7 , 765-768.  6.  Nicolaou, K . C. J. Org. Chem.  2005,  70, 7007-7027.  7.  Nicolaou, K . C. J. Med. Chem.  2005,  48, 5613-5638.  2005,  2005,  34, 247-266.  61, 6169-6170.  2000,  Chapter 1: Platinum, Silver and Gold Salt Catalyzed Cycloisomerization Reactions: A Review  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  2  1.1 Introduction The skeletal reorganization of 1 ,«-enynes and dienes has received a great deal of attention in the chemical literature since the mid-1990s. Although the quantity of publications relating to this type of transformation has blossomed in recent years, the development of this field dates back to the early 1970s. The term commonly used to describe the cyclization of 1 ,«-enynes and dienes is cycloisomerization.  For the purposes of this review, cycloisomerization  will be  defined as a reaction where a section of an organic molecule containing at least one unsaturated carbon-carbon bond is isomerized with concomitant loss of at least one site of unsaturation and no formal loss or gain of any atoms, and is accompanied by the formation of one or more rings.  1  The body of research in this field has grown considerably since the late 1990s and this thesis will not provide a comprehensive review of this topic. Interested readers are directed to the abundance of reviews that have appeared in the literature " in addition to specific reviews 1  17  on p l a t i n u m ' and g o l d " catalyzed cycloisomerizations. While reactions involving P d , " 18  Rh, " 38  44  Ru, " 45  19  50  20  Co, "  lanthanides, ' " 72 76  51  78  54  Ni,  Hg, " 79  84  24  5 5  25  Fe, ' 5 6  In, ' ' 7 3  8 5  5 7  8 6  Ir, < 58  Zr, ' 7 3  59  8 7  Zn, '  6 1  Al, "  Ti, '  8 9  Ga, "  6 0  8 8  6 2  90  6 5  92  Hf,  64  W, ' 9 3  Re, 9 4  66  Cu, "  Ca,  67  95  70  Sc, " 71  73  37  Y, ' " 7 2  7 4  7 6  are known, they will  not be discussed here. This synopsis will instead focus on reactions involving either platinum, gold or silver. The chapter will begin with a historical perspective addressing the evolution of cycloisomerization reactions. This will be followed by the main body of the chapter which will be broken up into sections based on the type of metal being used to catalyze the given bond formation. Each of these sections are further broken up into subsections based on the nature of the bond that is being formed.  1.2 Historical Perspective The first transition metal catalyzed 1,6-diene cycloisomerization was reported by Malone and coworkers in 1971 while trying to synthesize rhodium complexes of allyl alcohol.  96  The  authors found that when diallyl ether was heated with a catalytic amount o f allyl alcohol in the presence of RI1CI3 3H2O or rhodium complex 1.1, a cyclization event took place (Scheme 1.2.1). The proposed mechanism involves generation of a rhodium hydride intermediate under the reaction conditions giving rise to hydrometallation of one of the alkene moieties of diallyl ether.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  3  A subsequent carbometallation of the other alkene closed the five-membered ring and finally (3hydride elimination afforded alkene 1.2. The authors did not report a yield.  1.1 S c h e m e 1.2.1:  Malone and coworkers: rhodium catalyzed cycloisomerization of diallyl ether  During studies towards the synthesis of the prostaglandins in 1972, Sakai and coworkers used Wilkinson's catalyst in benzene at room temperature for the cycloisomerization of 4penten-l-al systems to provide cyclopentanones along with cyclopropane byproducts (Scheme  Wilkinson's catalyst = Rh(PPh ) CI 3  R2  S c h e m e 1.2.2:  R2  3  R2  Sakai and coworkers: cycloisomerization of 4-penten-l-al systems catalyzed by  Wilkinson's catalyst It was not until 1984 that Grigg and coworkers reported an extensive study on the cycloisomerization of 1,6-, 1,7- and 1,8-dienes catalyzed by palladium and rhodium salts (Scheme 1.2.3)/° Diene 1.3 was selectively cyclized in acidic chloroform to methylene cyclopentanes 1.4 and 1.5 in the presence of catalytic amounts of palladium salts or Wilkinson's catalyst respectively. Alternatively, the cyclization of diene 1.3 using acidic ethanol as solvent afforded a mixture of alkene isomers 1.5 and 1.6. Importantly, no cyclization events were observed in acidic media in the absence of metal salts.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  4  Scheme 1.2.3: Grigg and coworkers: effects of catalyst and solvent on the cycloisomerization of \ ,ndienes  Trost and Lautens described the first transition metal catalyzed cycloisomerization of \,nenynes in their seminal 1985 report (Scheme 1.2.4)." The required 1,6-enynes (1.7) were prepared via palladium(O) catalyzed allylic alkylation of a variety of allylic acetates with propargyl malonate. Cycloisomerization of enyne 1.7 with catalytic amounts of (PPh3)2Pd(OAc)2 in benzene afforded alkenyl cyclopentane 1.9 and is believed to proceed through metallocyclopentene intermediate 1.8. Alternatively, the desired alkenyl cyclopentanes could be obtained directly from the allylic acetates in a two-step, one-pot procedure in good yield.  5 mol % (PPh ) Pd(OAc) 3  0  A  c  2  5 mol % PPh  Na 5 mol % (PPh ) Pd  benzene, 66 °C  55-90%  50-85%  3  4  1.7  1.8  5 mol % (PPh ) Pd 5 mol % Pd(OAc) THF, reflux 68% (R = H) 3  4  2  Na  2  3  E = C0 CH 2  3  Scheme 1.2.4: Trost and Lautens: palladium catalyzed cycloisomerization of 1,6-enynes  In 1988, Grigg and coworkers reported on the cycloisomerization o f 1,6-enynes in the presence of catalytic amounts of Wilkinson's catalyst resulting in the formation of methylene cyclohex-2-enes 1.10 (Scheme 1.2.5)  100  Chapter 1. Cycloisomerizations catalyzed by Pt, Ag and Au Salts  E,  5 mol % Rh(PPh ) CI  E,  E  C H C N , 80 °C  E'  3  3  3  5  62-83%  1.10 S c h e m e 1.2.5: Grigg and coworkers: rhodium catalyzed cycloisomerizations of 1,6-enynes  The first platinum catalyzed cycloisomerization was reported by Blum and his group in 1995 (Scheme 1.2.6).  101  Blum showed that allyl propargyl ethers could be converted into 3-  oxabicyclo[4.1.0]hept-4-enes 1.11 with catalytic amounts of platinum(lV) in varying yield depending on the nature of Ri and R . Platinum(IV) chloride catalyzed cycloisomerization of 2  1,6-enynes was later revisited by Oh and coworkers.  102  o 20-97%  1.11  S c h e m e 1.2.6: Blum and coworkers: platinum catalyzed cycloisomerization o f allyl propargyl ethers  Shinji Murai is often regarded as a pioneer in the field of transition metal catalyzed skeletal rearrangements of 1 ,«-enynes. The initial report from Murai and coworkers in 1994 demonstrated the efficiency of [RuCl (CO)3] as a catalyst for 1,6- and 1,7-enyne 2  2  1 A-l  cycloisomerizations.  It was in 1996 that Murai first reported examples using P t C l as a  catalyst in the skeletal reorganization of l,n-enynes (Scheme 1.2.7).  2  104  As illustrated in Scheme  1.2.7 (eq 1), the migration of the phenyl substituted olefinic terminal carbon (boxed in) onto the alkyne terminal carbon affords products formally resembling olefin metathesis products and is clearly a different outcome in comparison to previously reported cycloisomerizations (see Scheme 1.2.4, Scheme 1.2.5, and Scheme 1.2.6). Murai's deuterium labeling experiment given in Scheme 1.2.7 (eq 2) indicates that two mechanistic paths must be accessible under the reaction conditions. Anomalous side products, such as diene 1.13 were observed, in addition to the formal metathesis-type products ( 1 . 1 2 ) , for substrates that contained alkyl-substituted alkynes (Scheme 1.2.7, eq 3). The skeletal rearrangement product 1.13 results from a formal insertion of the terminal olefinic carbon into the alkyne C - C bond. Murai also commented on the ability of P t C l to react with a broader range of substrates compared with Ru-, Rh- and other 2  Pt -based cycloisomerization catalysts.  Chapter 1. Cycloisomerizations  6  catalyzed by Pt, Ag and Au Salts  (8:1)  Scheme 1.2.7: Murai and coworkers: P t C l catalyzed cycloisomerization of 1,6-enynes 2  In 2001, Inoue and coworkers showed that with cationic platinum complexes such as [Pt(dppp)(PhCN)2j(BF4)2, enyne cycloisomerizations could be run at room temperature in chloroform as opposed to at 80 °C in toluene, as was necessary for PtCb.  streptorubin B  Scheme 1.2.8: Fiirstner and coworkers: formal synthesis of streptorubin B  The first use o f a platinum catalyzed cycloisomerization in a synthesis was reported by Fiirstner and coworkers in 1998 in formal syntheses of streptorubin B and metacycloprodigiosin (Scheme 1.2.8). ' 105  106  Treatment of enyne 1.14 with 5 mol % P t C l at 50 °C in toluene resulted 2  in a smooth cycloisomerization event to afford ring expanded diene 1.15 in 79% yield. Diene 1.15 was manipulated further to complete a formal synthesis of streptorubin B . In order to obtain diene 1.15 free from impurities in the cycloisomerization o f enyne 1.14, the alkyne terminus was substituted with an electron withdrawing group. Although this review will not focus on synthetic applications, interested readers are directed to related reactions in the elegant syntheses of (-)-cubebol by Fiirstner  107  and Fehr.  108  Chapter 1. Cycloisomerizations  7  catalyzed by Pt, Ag and Au Salts  1.3 Reactions Catalyzed by Platinum Given the evolution of this field as outlined in Section 1.2, it becomes clear that cycloisomerizations are not only capable of providing significant increases in structural complexity from relatively simple starting materials, but are "atom economical" and have been shown to be scalable and operationally simple. Platinum(II) chloride has proven to be a special catalyst for these transformations and as such, has garnered a great deal of interest since Murai's initial report of its use for cycloisomerizations in 1996. The majority of these skeletal reorganizations of l,n-enynes involve the formation and cleavage of C - C bonds and that is where this review will commence.  1.3.1 Platinum catalyzed C - C bond formation While studying cycloisomerization reactions of 1,6-enynes catalyzed by PtCl2, Furstner observed that seemingly similar substrates can give rise to entirely different cyclization products (Scheme 1.3.1.1). " 109  111  Cycloisomerizations of 1,6-enynes with all-carbon tethers selectively  gave alkenyl cyclopentenes (Scheme 1.3.1.1, eq 1). Yamamoto and coworkers used PtBr2 to synthesize the analogous alkenyl cyclohexenes from 1,7-enynes." When there is a heteroatom 2  in the enyne tether, the product of the cycloisomerization is a bicyclo[4.1.0]heptene derivative (Scheme 1.3.1.1, eq 2 and eq 3). This observation has proven to be general.  E  / — =  5mol%PtCI  2  E  / - - / ^  (D E = C 0 E t (91%) 2  E = S 0 P h (96%) 2  (2)  (3)  S c h e m e 1.3.1.1: Effect of a'heteroatom in the enyne tether  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  8  Echavarren and coworkers investigated transition metal catalyzed carbocyclizations involving the internal attack of mild nucleophilic reagents such as allylsilanes and allylstannanes onto alkynes using catalytic amounts of platinum salts in alcoholic solvent or acetone (Scheme 1.3.1.2).  113-115  In addition to platinum salts, these investigations were also  carried out with a variety of alternative metal salts.  116  The cyclization event was tolerant of  substitution on both the alkyne terminus (Ri) and olefinic carbon ( R 2 ) , producing fivemembered rings in moderate to good yield with selective Z-alkene geometry. The products result from the formal addition of the allylsilane or allylstannane to the alkyne followed by protodemetallation. N o metathesis-type products or skeletal bond reorganization products were observed. The reaction was also useful for generating six-membered rings from the corresponding 1,7-enyne, but in these cases the allylstannane containing substrates were found to be much more reactive than the allylsilane containing substrates.  E  y  ^  R  5mol%PtCI  l  C H 3 O H or acetone reflux 43-94%  E /—\ R  Y  2  E = C 0 C H , S0 Ph  R, = H, Ph  Y = Si(CH ) , SnBu  R = H, C H  2  3  3  3  V  2  2  3  2  "  ^  *  1  E 1 2  3  Scheme 1.3.1.2: Echavarren and coworkers: use of allylsilanes and allylstannanes in carbocyclization reactions  Fiirstner and coworkers discovered that even with the increased nucleophilicity of an allylsilane, 1,6-enynes possessing a heteroatom in the enyne tether still gave rise to bicyclo[4.1.0]heptenes (Scheme 1.3.1.3). ' 109  5 mol % PtCI  2  toluene, 80 °C Si(CH ) 3  110  Ts-N  \—<LA^^  S i ( C H 3 ) 3  76% 3  Scheme 1.3.1.3: Formation of bicyclo[4.1.0]heptenes observed for substrates possessing both allylsilanes and heteroatoms in the enyne tether  Yamamoto and coworkers have also reported on their investigations of the addition of allylstannanes to unsaturated C - C bonds using zirconium, aluminum and hafnium catalysts. ' 117  118  Other groups have investigated the modification of the nucleophilicity of the alkene moiety  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  9  of the enyne or diene (Scheme 1.3.1.4). Widenhoefer and coworkers have reported on the use of indoles in platinum catalyzed cycloisomerizations (eq j ) coworkers have used both enol ethers and furans (eq 2 ) .  1 1 9 - 1 2 2  while Echavarren and  Malacria and coworkers have  1 2 3 - 1 2 6  investigated the use of enynamides in platinum catalyzed cycloisomerization reactions (eq 3 ) .  127  (3-Dicarbonyl functions have been used as nucleophiles in platinum(II) catalyzed additions to alkenes by Widenhoefer and coworkers (eq 4), in both intra-  129  and intermolecular  130  fashion.  See work by Maresca and coworkers on the platinum catalyzed addition of P-dicarbonyl functions to ethylene. ' 13  1)  2 mol % PtCI 5 mol % HCI  Widenhoefer et al.  2  1,4-dioxane, 60 °C, 24 h 92%  2)  Echavarren et al.  CH 0 C. 3  5 mol % PtCI  2  CH 0 C 3  2  2  OCH,  3  \^yOCH  2  97%  3  H3CO  Ts  Ts  3)  2  CH 0 C  C H 3 O H , reflux, 17 h  CH 0 C 3  H,C  5 mol % PtCI  Malacria et al.  2  toluene, 80 °C 98%  H-,C 4)  Widenhoefer et al.  H C  O  O  1 mol % [PtCI (CH =CH )] 2  CH,  2  2 mol % EuCI  2  H C  2  O  O  3  3  3  H C  CH  3  3  HCI (1 equiv) 1,4-dioxane, 90 °C, 18 h  CH  3  85%  S c h e m e 1.3.1.4: Investigations with respect to modification of the nucleophilicity of the alkene or alkyne  In a 1998 report, Murai speculated that these transition metal catalyzed cycloisomerizations may proceed via a carbenoid intermediate and he proposed trapping such a carbenoid intermediate with a tethered olefin (Scheme 1.3.1.5).  132  In this elegant study, Murai proposed  an initial r\ -metal complex 1.17 which forms an intermediate slipped, polarized r\ -metal complex 1.18 that proceeds to cyclopropanate the proximal alkene to give cyclopropyl metal carbenoid 1.19. He argued that the resulting metal carbenoid, that would typically give rise to further rearrangement products, could be trapped by an appropriately placed alkene, as shown in  Chapter I. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  10  Scheme 1.3.1.5. What Murai observed was the formation of tetracyclo[6.4.0.0'' 0 ' ]-undecane 9  2 4  derivatives 1.20 as predicted. Future studies would argue against the formation of an intermediate ri'-metal-alkyne complex, but Murai displayed tremendous insight nonetheless as will be discussed below.  4 mol % PtCI  2  toluene, 80 °C, 1 h 61% E = C0 Et  1.16  1.20  2  1.17  1.19  1.18  S c h e m e 1.3.1.5: Murai and coworkers: trapping of a carbenoid intermediate with an intramolecular olefin  The mechanism of transition metal catalyzed cycloisomerization reactions has been probed extensively since the late 1990s as those in the field attempted to gain a fundamental understanding of what was happening in their reaction vessels. Over the course of these investigations, many distinctly different mechanisms have been proposed to explain the vast array of reaction products observed. Fortunately, there has emerged a unifying mechanistic scheme that accounts for the observed diversity (Scheme 1.3.1.6).  Platinum(II) and related late transition metal centers have long been known to interact with alkynes to form highly electrophilic complexes that are regarded as non-classical carbocations with carbene-like character. ' 133  134  The metal center may coordinate with the alkyne selectively  ( B ) or with the alkyne and the alkene simultaneously (A), but both complexes are most probably in equilibrium with one another. The metallocyclopentene pathway invoked by Trost and coworkers would emanate from complex A . For Z = carbon, a cyclization event takes place to generate metal carbenoid D as observed by Murai (Scheme 1.3.1.5). This cyclization is currently believed to occur in a single step from a polarized r] -metal complex and not from an 2  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  11  intermediate slipped r\ '-metal complex as proposed by M u r a i . ' ' 4  I 7  1 3 5  '  1 3 6  Deformation of the r\ -  complex, resembling slippage of the bound metal along the axis of the alkyne, is believed to accompany ligand activation and enhance the electrophilicity of the complex. The question of whether intermediates such as D more closely resemble a "metal-bound carbene" or a "metalstabilized carbocation" remains unresolved and even high-level computational studies have failed to provide an unambiguous answer.  p  17  o  S c h e m e 1.3.1.6: Contemporary mechanistic explanation for transition metal catalyzed cycloisomerizations of 1,6-enynes  In the absence of a sufficient trapping mechanism, the highly electrophilic metal carbenoid D undergoes a 1,2-alkyl migration to give ring expanded cyclobutane I. For reviews on  2  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  metallocarbenes see publications by M c K e r v e y  137  and Padwa.  12  138  Fragmentation of I to alkene  K followed by elimination of the metal salt affords the metathesis-type product, diene L . Conversely, elimination of the metal salt from cyclobutane I would produce cyclobutene J , which has been shown by Echavarren not to be an intermediate en route to diene L via electrocyclic ring opening.  Alternatively, I could undergo a second 1,2-alkyl shift to give  cyclopropyl cation M from which a simple fragmentation would produce metal carbenoid N . The electrophilicity of the metal carbenoid would induce a 1,2-hydride shift providing O , which upon elimination of the metal salt, affords the bond reorganization product, diene P .  For Z = oxygen or nitrogen, the initially formed r] -metal complex B is sufficiently 2  electrophilic that the heteroatom induces a 1,2-hydride shift to give stabilized cation E . Formation of metal locyclobutane G followed by elimination of the metal salt affords bicyclo[4.1.0]heptene H . This mechanism adequately explains the propensity for 1,6-enynes containing a heteroatom in the tether to give bicyclo[4.1.0]heptene products.  135  theoretical investigation into the mechanism of this transformation by Soriano  A recent 139  suggests that  an alternative mechanism may be operating.  Shortly after Echavarren's initial report on the use of allylsilanes and allylstannanes in carbocyclization reactions, he and his coworkers discovered a unique cyclization event that could be achieved by reacting 1,6-enynes with catalytic amounts of P1CI2 in alcoholic solvent (Scheme 1 . 3 . 1 . 7 ) .  135  '  140,42  A n equivalent of alcohol is incorporated into the molecule during  the cyclization and this type of transformation has been appropriately labeled alkoxycyclization. The corresponding carbocyclization using water is called hydroxy cyclization.  Alkoxycyclization is favored over formation of bicyclo[4.1.0]heptenes when oxygen is present in the enyne tether (Scheme 1.3.1.7, eq 2). Six-membered ring formation is observed in certain cases and can even be obtained as the sole reaction product (eq 3). Although these transformations are highly diastereoselective (Scheme 1.3.1.7, eq 1), a 2004 report by Genet and coworkers showed that they can be made enantioselective by adding 25 mol% AgSbFe and 1530 m o l % of the chiral ligand (i?)-Ph-BINEPINE to the reaction conditions, affording alkoxycyclization products in up to 85% ee\  143  Chapter J. Cycloisomerizations  13  catalyzed by Pt, Ag and Au Salts  Scheme 1.3.1.7: Alkoxycyclization of 1,6-enynes  The alkoxycyclization can also be explained mechanistically with cyclopropyl platinum carbenoid intermediates (Scheme 1.3.1.8). Cyclopropyl platinum carbenoid T is sufficiently electrophilic that nucleophilic attack of the cyclopropane ring by water or alcohol is favored over rearrangement. This attack can occur along path a or path b in Scheme 1.3.1.8. Path a leads to six-membered ring intermediate U , which upon protodemetallation affords methylene cyclohexane derivative V . Path b leads to five-membered ring intermediate W , which also undergoes protodemetallation to afford methylene cyclopentane derivatives X .  M i i  M  / \ /  metallocyclopentene pathway  Scheme 1.3.1.8: Echavarren and coworkers: proposed mechanism for alkoxycyclization of 1,6-enynes  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  14  Although it is not a true cycloisomerization, Widenhoefer and coworkers have published a series of reports on the cyclization/hydrosilylation of 1,6-diynes, 1,6-enynes and 1,6-dienes with Pt(II), ' 144  145  Pd(II)  146  '  147  and R h ( I )  148  '  149  based precatalyst systems whereby a molecule of  trialkylsilane is incorporated into the cyclized product.  Fiirstner and coworkers were interested in producing cyclobutenes via cycloisomerization. ' 150  They set out to show that invoking pivotal intermediate cyclobutane I  151  (Scheme 1.3.1.6) was, in fact, plausible and they proposed that I should be in equilibrium with Y and Z (Scheme 1.3.1.9).  151  They further argued that i f R possessed enough cation stabilizing  character, then perhaps cyclobutenes could be coaxed out of the cycloisomerization process.  M~  M  M  ctr — air—ctr; I  Y  R  Z  R  H  S c h e m e 1.3.1.9: Fiirstner and coworkers: proposed equilibrium for cyclobutenyl cation  When the R substituent was made to be an electron rich aryl group (giving rise to a stabilized benzylic cation and under these conditions), cyclobutenes could be obtained without interference of side products resulting from further rearrangements (Scheme 1.3.1.10).  1.21  1.22  1.23  5 mol % PtCI toluene, 80 °C 1 atm CO 84% „ 2  S c h e m e 1.3.1.10: Fiirstner and coworkers: cyclobutenes by PtCh catalyzed cycloisomerization  Enynes such as 1.21 were treated with catalytic amounts of PtCi2 in toluene at 80 °C under 1 atm of carbon monoxide to give cyclobutenes such as 1.26. The proposed mechanism  Chapter 1. Cycloisomerizations catalyzed by Pt, Ag and Au Salts  15  involves generation of a cyclopropyl platinum carbenoid intermediate 1.22 that then rearranges to cyclobutenyl cation 1.24. Direct elimination of the metal salt in 1.23 or 1.24 would generate a highly strained double bond. The authors claim that the observed alkene isomer does not result from an isomerization process from such a strained alkene, but by the more favorable formal proton loss from 1.24, followed by protodemetallation.  Malacria and coworkers have reported a series of studies on the cycloisomerization of enynes containing oxygenation at the propargylic position (Scheme 1.3.1.1 1 ) .  152-154  The authors  found that when OA"(Scheme 1.3.1.11) is either a hydroxy or ether function, tetracyclic products 1.28 are obtained, similar to that previously described by Murai (Scheme 1.3.1.5). When OX'xs an ester function, the metal-alkyne complex 1.27 is attacked by the heteroatom to give metal carbenoid intermediate 1.30 with migration of the ester group. Finally, reaction of the metal carbenoid with one of the alkenes gives a mixture of cyclopropanation products 1.31 (62-88%) and 1.32 (5-10%).  1.32  1.31  minor  major  Scheme 1.3.1.11: Malacria and coworkers: cycloisomerization of 1,6-enynes containing oxygenation at the propargylic position  The groups of M a l a c r i a ,  155  '  156  Furstner  157  and Nishibayashi  158  have reported on the  platinum catalyzed cycloisomerization of 1,5-enynes as a means to access bicyclo[3.1 .Ojhexane  Chapter I. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  16  structures (Scheme 1.3.1.12). It was found that i f the oxygen at the 3-position of enyne 1.33 is sufficiently nucleophilic (3-hydroxy or 3-methoxy functions), it can induce a 1,2-hydride shift onto the electrophilic metal-alkyne complex 1.34, providing metal carbenoid intermediate 1.35. A final cyclopropanation affords cyclopentanone equivalent 1.36. When OX is an ester function, the metal-alkyne complex undergoes a nucleophilic attack by the carbonyl oxygen (1.37)  resulting in ester migration and formation of metal carbenoid  1.39.  A final  cyclopropanation affords enol ester 1.40. For a theoretical investigation into the mechanism of these transformations see work by S o r i a n o .  136  '  159  Sarpong and coworkers have used propargyl  acetates in an interesting rearrangement with a tethered epoxide in the construction of cyclopentenones  160  R  1.37 Scheme  1.3.1.12:  1.39  2  1.40  Cycloisomerization of 1,5-enyne derivatives  In 2006, rCozmin and coworkers showed that i f the 3-position of the 1,5-enyne is a quaternary center rather than an oxygenated center, platinum catalyzed cycloisomerization affords cyclohexadienes (Scheme 1.3.1.13).  161  Kozmin has also investigated the cyclization of  siloxyalkynes with arenes, alkenes and alkynes under catalysis by Bronsted acid.  I 6 2  "  1 6 4  Chapter 1. Cycloisomerizations  5 mol % PtCI  Ri 2  toluene, 80 °C  R  63-82%  R  17  catalyzed by Pt, Ag and Au Salts  2  2  R-, = C H , Ph, alkyl 3  R = H, C H , Ph, Ar, OTIPS 2  3  R , R = alkyl 3  4  Scheme 1.3.1.13: Kozmin and coworkers: cyclohexadienes via platinum catalyzed cycloisomerization  Gagne and coworkers have used 1,6-dienes in platinum catalyzed cycloisomerizations to form cyclohexenes and bicyclo[4.1.0]heptenes  while Malacria and coworkers have used 1,6  165  allenynes to construct cyclohexenes and bicyclo[4.3.0]nonenes.  166  Cycloisomerization via hydroarylation of an alkyne has been studied by the groups of Murai,  167  Fiirstner, ' 168  169  Sames, ' 170  171  and Echavarren  172  and affords ready access to six  membered ring containing products (Scheme 1.3.1.14).  OCH  8 mol % PtCI  1) Murai et al.  ^  //  2  E  / = ( 0 C H  3  A  toluene, 80 °C  OCHo  2)  E  3  4 h, 82%  OCH  5 mol % PtCI  Fiirstner era/.  3  2  toluene, 80 °C 20 h, 89%  cm CH 3)  3  Sames et al.  5 mol % PtCI  2  toluene, 80 °C 87%  CH  3  Scheme 1.3.1.14: P t C l catalyzed hydroarylation of alkynes 2  For publications describing intermolecular platinum catalyzed hydroarylation of alkynes, see work by F u j i w a r a  173  '  174  and Kitamura.  175  Chapter 1. Cycloisomerizations  50% (100%  (100% d)  Scheme  catalyzed by Pt, Ag and Au Salts  18  d)  1.3.1.15: Yamamoto and coworkers: platinum catalyzed cycloisomerization via C - H insertion  mechanism  In some reports, platinum catalyzed hydroarylation of alkynes is referred to as C-H activation,  even though it would appear mechanistically to proceed via attack of an electron rich  arene onto an electron deficient metal-alkyne complex followed by rearomatization (see Scheme 1.3.1.14). In work by Sarpong  176  and Yamamoto,  177  the authors claim that the cyclization  proceeds via a platinum carbene C - H insertion process (Scheme 1.3.1.15). The proposed mechanism involves treatment of 1,7-enyne 1.41 with PtBr providing metal carbenoid 1.42 via 2  coordination to both the alkene and alkyne. A carbene insertion into the C-Hb bond gives rise to the cyclized indene  1.43.  Substituted naphthalenes  cycloisomerization are common byproducts.  (1.44)  resulting from 1,7-enyne  In support of the C - H activation mechanism, the  authors showed that a substrate deuterated at the benzylic position afforded the corresponding indene product with 100% deuterium incorporation at the 2-position. The alkyl group attached to the benzylic position was required to be allyl, as both vinyl and homoallyl analogues were not reactive under these conditions.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  1.3.2 Platinum catalyzed C-O bond formation In 2004, Widenhoefer and coworkers reported the platinum(II) catalyzed intramolecular hydroalkoxylation of alkenes (Scheme 1.3.2.1).  178  The alkene moiety is sufficiently activated  by the platinum(II) complex that it experiences intramolecular nucleophilic attack by the alcohol. Protodemetallation of the metal salt then affords the cyclic ether in good yield. The authors observe 5-exo (eq 1, eq 3), 6-endo (eq 2) and 6-exo (eq 4) modes of cyclization depending on the nature of alkene substitution and found that addition of an electron-deficient phosphine ligand was required for optimum yields.  Conditions: 1 mol % [PtCI (H C=CH )] , 2 mol % P(p-C H CF ) , dichloroethane, 70 °C, 16-48 h 2  2  2  2  6  4  3  3  Scheme 1.3.2.1: Widenhoefer and coworkers: platinum catalyzed intramolecular hydroalkoxylation of alkenes  In 2006, Barluenga and coworkers designed a platinum catalyzed 6-exo intramolecular addition of an alcohol onto an alkyne whereby the resulting enol ether was consumed in an in situ Prins-type cyclization affording oxo-bridged bicyclic compounds in high yield (Scheme 1.3.2.2).  179  Substitution of methanol by acetic acid in the reaction provided access to the  corresponding acetate.  Scheme 1.3.2.2: Barluenga and coworkers: tandem hydroalkoxylation-Prins cyclization  19  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  20  In 2005, Fiirstner and coworkers reported on the intramolecular carboalkoxylation of alkynes (Scheme 1.3.2.3).  180  The authors found that when or^o-alkynyl phenol derivatives  1.45 were treated with catalytic amounts of PtCh, the substrates underwent an intramolecular 5endo  mode of cyclization via nucleophilic attack of the ether oxygen onto the metal complexed  alkyne; The R 2 alkyl group was then transferred to the 3-position o f the resulting benzofuran 1.46. This transformation was found to be both high yielding and tolerant of a wide variety of alkyl groups at both R] and R 2 .  1.45  1.46  R-i = alkyl, Ph, aryl, cyclopropyl R = allyl, benzyl, aryl, MOM, BOM, SEM 2  Scheme 1.3.2.3: Fiirstner and coworkers: benzofuran synthesis via intramolecular carboalkoxylation  The groups of O h  1 8 1  and K i r s c h  182  have reported on the platinum catalyzed  cycloisomerization of 3-butyn-l-ones in the construction of furans and furanones, respectively. Treatment of 3-butyn-l-ones 1.47 with catalytic amounts of metal salts promotes attack of the carbonyl oxygen onto the metal complexed alkyne  (1.48)  followed by ring contraction  afford 3(2/f)-furanones 1.50 in good yield (Scheme 1.3.2.4).  Ph Ph  Ph  Ph M O  1.47  1.48  1.49  1.50  Conditions: 5 mol % PtCI , 0.03 M in toluene, 80 °C, 90 min, 93% 2  Scheme 1.3.2.4: Kirsch and coworkers: construction of 3(2//)-furanones via P t C ^ catalyzed cycloisomerization of 3-butyn-1 -ones  (1.49)  to  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  21  1.3.3 Platinum catalyzed C - N bond formation 1 oi  Platinum catalyzed hydroamination of alkenes has been known since the late 1960s.'" In recent years, Widenhoefer and coworkers have reported on the intramolecular intermolecular ' 185  186  184  and  hydroamination of olefins with both amine and carboxamide functions.  Tilley and coworkers have also published work on the platinum(II) catalyzed intermolecular hydroamination o f alkenes using sulfonamides  Ph-NH  Ph  CH,  2)  2  20 mol % PtCI  1) Kirsch et al.  2  dichloroethane 60 °C,100 h  5 mol % PtCI  Uemura et al.  187  anisole  2  R +  80 °C  CH  3  81-98%  Scheme  1.3.3.1:  Platinum(II) catalyzed addition of nitrogen nucleophiles to alkynes  The groups o f both Kirsch and Uemura have investigated the platinum catalyzed addition of nitrogen nucleophiles to alkynes (Scheme 1.3.3.1). Kirsch and coworkers used 4-pentyn-1-ones to generate imines in situ which then cyclized onto the platinum complexed alkyne moiety (eq 1). Uemura and coworkers developed conditions for platinum catalyzed intramolecular carboaminations of alkynes (eq 2). The ./V-acyl group was observed to migrate to the 3-position of the indole product, in preference to the A'-alkyl group, in an analogous fashion to the work of Fiirstner (Scheme 1.3.2.3).  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  22  1.4 Reactions Catalyzed by Silver Silver(I) salts have been used since the late 1960s in the bond reorganization of highly strained ring s y s t e m s , ' 16  188-192  but only in recent years have these metal salts attracted interest as  catalysts in cycloisomerization events. Despite these discoveries, however, publications involving silver catalyzed cycloisomerizations are still relatively uncommon when compared to the number of reports involving the more electronegative platinum (II), gold(I) and gold(III) salts. Silver has an electronegativity value of 1.93 on the Pauling scale whereas that of platinum is 2.28 and that of gold is 2.54  and this trend appears to translate into the ability of these  metals to activate C - C unsaturated bonds.  1.4.1 Silver catalyzed C - C bond formation Examples of carbon nucleophiles in silver(I) catalyzed cycloisomerization reactions are relatively rare in comparison to its use in catalyzing carbon-heteroatom bond formation. A recent report by Toste and coworkers illustrates the silver catalyzed cycloisomerization of 1,6diynes providing naphthyl ketones in good yield (Scheme 1.4.1.1).  194  Diynes 1.51 were treated  with 5 mol % of AgSbFe and 2 mol % PPh3 in dichloromethane for 11 h. Complexation of the metal to the alkyne bearing a propargylic acetate resulted in a [3,3]-sigmatropic rearrangement to give allenyl acetate 1.52. Complexation of the metal with the other alkyne moiety resulted in the addition of the allenyl acetate function onto the alkyne in a 6-endo-d\g mode of cyclization (1.53)  to provide naphthyl derivative  1.54.  The authors then invoke an equivalent of water to  liberate ketone 1.55 and release the catalytic metal species via protodemetallation. Magnesium oxide is added to the reaction as an acid scavenger in order to prevent acetic acid from "consuming" the silver catalyst. While the authors do state that the reaction is air and moisture tolerant, they do not give the results of running the reaction under anhydrous conditions and make no statements regarding the necessity of water for catalyst turnover.  Chapter 1. Cycloisomerizations  1.55  catalyzed by Pt, Ag and Au Salts  1.54  23  1.53  1.52  Scheme 1.4.1.1: Toste and coworkers: formation of naphthyl ketones via silver(I) catalyzed cycloisomerization of 1,6-diynes  Kirsch and coworkers developed a route to 2//-pyrans via a cascade sequence featuring a silver(I) catalyzed propargyl-Claisen rearrangement followed by a 6rc-oxaelectrocyclization (Scheme 1.4.1.2).  195  Treatment of propargyl vinyl ethers 1.56 with catalytic amounts of  silver(I) salts promoted a [3,3]-sigmatropic rearrangement (propargyl-Claisen rearrangement) to give allene 1.57. Addition of catalytic amounts of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), efficiently isomerized the allenyl moiety to the enoate 1.58, which spontaneously cyclized to afford 2//-pyrans of general structure 1.59 in 50-90% yield.  O  ,  i  ^ C 0 E t [3,3]-sigmatropic rearrangement 2  1  1  base-catalyzed isomerization R3  \  C0 Et 2  R  electrocyclization  0  I,C0 Et 2  2  R3  1.57  1.56  1.58  1.59  Conditions: a) 5 mol % AgSbF , CH CI , rt, 1 h; b) 5 mol % DBU, 30 min 6  2  2  Scheme 1.4.1.2: Kirsch and coworkers: silver(l) catalyzed propargyl-Claisen rearrangement in the synthesis of 2//-pyrans  A directly analogous strategy was applied by Kirsch in the synthesis of pyrrole rings from propargyl vinyl ethers 1.56 and primary amines.  196  Chapter 1. Cycloisomerizations  24  catalyzed by Pt, Ag and Au Salts  Silver(I) salts have recently been used to promote the formation of four-membered rings. Rhee and Krische disclosed their results on the use of alkynes as synthetic equivalents to stabilized Wittig reagents (Scheme 1.4.1.3).  197  The authors propose that treatment of substrates  such as 1.60 with 10 mol % AgSbF6 gives rise to oxetane formation 1.61 followed by spontaneous cycloreversion to give enone 1.62. Importantly,  1 3  C N M R studies revealed that  addition of AgSbFg to an equimolar solution of 1-phenyl-1-propyne and isobutyraldehyde resulted in significant upfield shifts of the alkyne signals in the  l 3  C N M R spectrum, while the  aldehyde chemical shifts remained essentially unchanged. This result is provided as support for a mechanism whereby oxetane formation is initiated by a metal-alkyne complex as opposed to a metal-aldehyde complex. These reactions were also promoted by both boron trifluoride-diethyl etherate and tetrafluoroboric acid and in many cases, provided reaction products in comparable yields to reactions promoted by silver(I).  O Ts-N  /  ^ ^  P  h  formal [2+2] 10 mol % AgSbF  X  0  Ph  cycloreversion  Ts-N  /~~~rr^ Ph 11  6  CH CI , rt 2  2  1.60  1.61  1.62  Scheme 1.4.1.3: Rhee and Krische: silver(I) promoted alkyne-carbonyl coupling reactions  In 2004, Kozmin and coworkers published a route to cyclobutenes via a silver(I) promoted formal [2+2] cycloaddition of siloxy alkynes to enones and enoates (Scheme 1.4.1.4).  198  The  authors propose a mechanism where activation of the carbonyl by silver(I) initiates 1,4-addition of the nucleophilic siloxy alkyne resulting in a stepwise [2+2] cycloaddition providing cyclobutenes 1.63 in good yield.  OTIPS  .0' Ml  pp 1  R l  5 mol % AgNTf CH CI ,rt 2  2  TIPSO,  +  2  *  T  I  P  S  ^  C  68-90%  1.63 Scheme 1.4.1.4: Kozmin and coworkers: silver(I)-promoted cyclobutene formation  Chapter 1. Cycloisomerizations catalyzed by Pt, Ag and Au Salts  25  1.4.2 Silver catalyzed C-O bond formation In 1979, Olsson and Claesson disclosed their results on the silver(I) catalyzed intramolecular addition of alcohols to allenes to provide 2,5-dihydrofurans and 5,6-dihydro-2//pyrans in moderate yield (Scheme 1.4.2.1).  199  OH 3 mol % AgBF  4  CHCI , rt, 48 h 3  '  61%  ^—OH 8 mol % A g N 0  3  3:2 acetone:water C a C 0 rt, 54 h 3  69%  Scheme 1.4.2.1: Olsson and Claesson: silver(I) catalyzed cycloisomerization of allenic alcohols Marshall and his group have reported their efforts in the silver(I) catalyzed synthesis of 2,5dihydrofurans  200  and have made significant investigations into the silver(I) catalyzed synthesis  of furans from both allenones ' 201  C H 7  1  5  —=—/  10 mol % AgNQ /silica 5  C H 7  //  3  /— C Hn H  and alkynyl allylic a l c o h o l s  202  °  hexanes, rt, 1 h  C  7 15  '  204  (Scheme 1.4.2.2).  ^ O  H  203  C  5 11 H  96%  /  1 5  *=•=(  20 mol % AgNQ  )^C H 6  0  1 3  //  3  acetone, <1 h  C H 7  l 5  \\  --^ /^C H 0  6  1 3  90%  Scheme 1.4.2.2: Marshall and coworkers: silver(I) catalyzed synthesis of furans Marshall and Bennett also demonstrated that the conversion of alkynyl allylic alcohols into furans was achievable with a variety of bases, including potassium ter/-butoxide, potassium hydride and potassium hydroxide.  205  He and coworkers have recently disclosed a set of related studies on the silver(I) catalyzed intramolecular addition of carboxylic acids and alcohols to alkenes (Scheme 1.4.2.3).  206  The  use of silver(I) trifluoromethanesulfonate efficiently catalyzes the cycloisomerization reaction giving rise to S-exo-, 6-endo- and 6-exo- modes of cyclization and provides the corresponding  Chapter I. Cycloisomerizations  26  catalyzed by Pt, Ag and Au Salts  cyclic ethers and lactones in high yield. Bronsted acids are also reported to effect the same transformations.  207  Conditions: 5 mol % AgOTf, 1,2-dichloroethane, 83 °C, 15 h  S c h e m e 1.4.2.3: He and coworkers: silver(I) catalyzed intramolecular addition of carboxylic acids and alcohols to alkenes  1.4.3 Silver catalyzed C-N bond formation The silver(I) catalyzed intramolecular hydroamination of allenes has been known since the early 1980s in work by Arseniyadis and c o w o r k e r s . ' 208  revisited this transformation employing o x i m e s ,  210  209  Gallagher and coworkers then  carbamates and sulfonamides  211  as  nucleophiles. In 1992, Gallagher disclosed investigations into the diastereoselective intramolecular hydroamination of allenes, mediated by a tethered sulfoxide moiety with substoichiometric quantities of silver(I) trifluoromethanesulfonate (Scheme 1.4.3.1).  212  (96% d.e.)  S c h e m e 1.4.3.1: Gallagher and coworkers: diastereoselective intramolecular hydroamination of allenes  Knolker and coworkers developed an oxidative cyclization of homopropargyl amines mediated by stoichiometric amounts of silver(I) acetate giving rise to pyrroles in good yield (Scheme 1.4.3.2).  213,214  27  Chapter J. Cycloisomerizations catalyzed by Pt, Ag and Au Salts  1.1 equiv AgOAc  ,NH  CH CI , rt, 14 h 2  2  71% ^Si(CH ) 3  3  Scheme 1.4.3.2: Knolker and coworkers: pyrrole construction via oxidative cyclization  In a related study, Rutjes and coworkers used homopropargyl amines in the construction of 2,5-disubstituted pyrrolines.  215  Yamamoto and coworkers reported an interesting silver(I)  catalyzed intramolecular addition of an imine onto an alkyne in the synthesis of 1,2dihydroisoquinolines (Scheme 1.4.3.3)  216 Ph  ,Ph  Ph  3 mol % AgOTf 1,2-dichloroethane, 80 °C 93%  Scheme 1.4.3.3: Yamamoto and coworkers: silver(I) catalyzed addition of imines to alkynes •  • 2 1 7  Intermolecular silver(I) catalyzed hydroamination of alkynes has also been investigated. 219  220 221  A number of groups have demonstrated the viability of Bronsted acid catalyzed intraand intermolecular  222  '  hydroamination.  In 2004, C u i and He reported a silver(I)-mediated cyclization via a C - H insertion mechanism (Scheme 1.4.3.4).  223  This methodology was shown to provide both five and six-  membered rings in good yield. The authors claim that the mechanism proceeds by generation of a silver nitrene that then inserts into the appropriate C - H bond five or six atoms away.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  28  Conditions: 4 mol % AgN0 , 4 mol % ffiu tpy, 1.5 equiv Phl(OAc) , C H C N , 82 °C 3  3  2  3  Scheme 1.4.3.4: Cui and He: silver(I)-mediated cyclization by C - H activation  This same catalyst system was also used by the He group in the efficient aziridination of alkenes with tosylamide. ' 224  225  1.5 Reactions Catalyzed by Gold Gold is a precious metal that has been known to humankind for at least 5000 years. Our fascination with gold is deeply routed in cultural history.  23  There are many misconceptions  surrounding gold, such as that gold is the most valuable of all metals. Gold is indeed a rare element, but so are other precious metals like palladium, platinum and rhodium. For many years gold had been considered to be inert and chemically useless, but a quick perusal of the recent literature will demonstrate just how forcefully this doctrine is being overthrown. Gold has an extraordinary ability to act as a soft, carbophilic Lewis acid, allowing for the formation of new C-C, C-O, C - N and even C-S  '  bonds by nucleophilic attack of these activated  22  complexes.  Homogeneous catalysis by gold complexes has experienced a sharp increase in  the number of publications since 2003 and interest in this field appears to be unwavering. The immense impact that gold has had on the field of cycloisomerization reactions in recent years warrants its inclusion in this review. However, the use of gold complexes in my thesis work is minimal and discussion of this area will be kept to a brief summary with the intent of providing a tool of reference rather than an in-depth analysis.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  29  1.5.1 Gold catalyzed C-C bond formation Many of the reported platinum(II) catalyzed processes mentioned in Section 1.3 were later revisited in the context of gold catalysis. The primary difference observed between the use of platinum(II) and gold(I)/(III) catalyst systems is the temperatures required to achieve the desired transformation. A given transformation that is run with platinum at 80 °C can quite often be run at room temperature with a suitable gold catalyst. The publications resulting from the revisiting of previous methodologies in the context of gold catalysis will not be discussed here, but the corresponding citations are provided below in Chart 1.5.1.1 as a reference.  C h a r t 1.5.1.1: Gold catalyzed transformations that reexamine reactions previously explored under platinum catalysis  Trapping o f the gold-carbenoid:  1,6-Enyne cycloisomerizations: R  J  =  Met  Met and/or z  Ri Echavarren, 2004  228  Echavarren, 2005  Echavarren, 2006  229  For use of ene-ynamides, see: Cossy, 2006  2  1,5-Enyne cycloisomerizations:  Alkoxycyclizations: Met  *  Z  ROH  and/or  a  7  OR  Echavarren, 2006 ' 233  238  Met  / — \ >—R  -  R  R  Toste, 2006 '  234  0  o  R  Echavarren, 2005  Toste, 2004 , Toste, 2005 236  235  237  239  Gold catalyzed hydroarylation: ^ . . . . . .  Friedel-Crafts-like cyclizations: /  ( Y )  —  Met  -R  Echavarren, 2005  172  Youn, 2006  He, 2004 '  243  He, 2005  Reetz, 2003  245  L i , 2006  242  230, 2 3 !  244  246  2  2  Echavarren, 2005  — z Ri  R  2  Chapter 1. Cycloisomerizations  30  catalyzed by Pt, Ag and Au Salts  Cycloisomerizations with enol silyl ethers:  Cycloisomerizations with indoles:  OTBS  O  '^V'N  Echavarren, 2006  247  Widenhoefer, 2006  Toste, 2006  248  Gold catalyzed Conia-Ene reaction: o o  o Met  Toste, 2004 ' 250  Li, 2004  251  Met  2  Gold catalyzed ring expansions:  O  Rf  Toste, 2005  Met  Toste, 2005  252  0  Ph  2  2  Propargyl Claisen rearrangement:  Cyclohexadiene formation:  R  Toste, 2004  255  Kirsch, 2005  2  Kozmin, 2004  256  257  Kozmin, 2005  258  From allenynes, see: Malacria, 2006'  Gold catalyzed carboalkoxylation:  Toste, 2006'  Both gold(I) and gold(III) complexes display reactivity with regard to activating carboncarbon unsaturated bonds towards nucleophilic attack. In many cases it can be difficult to determine the oxidation state of the catalytically active species.  22  Common catalyst systems for  gold(III) employ either A u C h alone or A u C b in combination with 1-3 molar equivalents of a silver(I) salt as a co-catalyst. Common silver(I) salts that are used include AgOTf, AgSbFe, A g P F , A g O A c , A g B F , A g C 1 0 , A g N 0 and A g N T f . Presumably, the role of the silver(I) salt 6  4  4  3  2  is one of counterion metathesis with the gold chloride and concomitant precipitation of A g C l . The identity of the counter ion can have a dramatic effect on the reactivity of the gold catalyst.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  31  The most often used complex of gold(I) is P P h A u C l , with or without the addition of a 3  silver(I) salt. The primary way to modify the catalyst reactivity is by exchange of the counter ion (ie: use of a different silver(I) salt), but the catalyst can also be modified by altering the ligand. A wide variety of phosphine ligands as well as a few examples of iV-heterocyclic carbene l i g a n d s  233  '  261  have been used in gold complexes. Notable alternative gold catalyst  systems include [(PPh Au) 0]X, ( P P h ) A u C H + H X and the digold(I) complex [dppmAu ]X 3  3  3  3  2  2  where X is a non-coordinating counterion. For recent investigations into the modification of gold(I) catalyst systems, see the work of Gagosz.  In 2005, Toste and coworkers  263  262  used P P h A u C l - A g O T f as the catalyst system in an 3  interesting gold catalyzed Rautenstrauch rearrangement, giving rise to the formation of cyclopentenones under a mild set of conditions (Scheme 1.5.1.1).  2-5 mol% Ph PAuOTf  0^/%^-R  3  C H C N , rt  / R-i  3  \  R  264  2  3  Scheme 1.5.1.1: Toste and coworkers: gold(I) catalyzed Rautenstrauch rearrangement  For other gold catalyzed processes involving propargylic esters, see work by Malacria, Furstner,  266  Nolan  267  and Zhang.  265  268  Hashmi and coworkers have reported the gold catalyzed synthesis of phenols, initiated by a [4+2] cycloaddition of a furan and a tethered alkyne (Scheme 1.5.1.2).  ^—> O  J  2 mol % AuCI N - T s ~~  [4*2]  3  C H C N , rt  J  3  97%  N-Ts  ,0  •ffQ O T A  '  N-Ts  M  Scheme 1.5.1.2: Hashmi and coworkers: gold catalyzed phenol synthesis  Ts'  Chapter 1. Cycloisomerizations  32  catalyzed by Pt, Ag and Au Salts  Rossi and coworkers have developed a gold catalyzed annulation of ketones with 2*7 I  propargylamine in the construction of pyridines (Scheme 1.5.1.3).  Condensation of  propargyl amine and a suitable ketone, followed by equilibration to the corresponding enamine, allows for a gold catalyzed addition of the enamine onto the metal-complexed alkyne in a 6endo-d\g fashion. Subsequent aromatization affords the product pyridine. O Ri  HN 2  ] R  2  5  m  o  ) %  N a A u C  | . H o 4  2  ethanol, reflux, 12 h 15-96%  2  N ^ i  2  R," R  2  Scheme 1.5.1.3: Rossi and coworkers: gold catalyzed synthesis of pyridines  In 2004, Shi and He reported the gold(III) catalyzed direct functionalization o f arenes with alkyl inflates (Scheme 1.5.1.4).  272  The authors claim that an aryl-gold(III) intermediate is  involved and that this organometallic reagent appears to react with the alkyl triflate in an S N 2 fashion.  5 mol % AuCI 15 mol % AgOTf 3  1,2-dichloroethane, 120 °C 90%  Scheme 1.5.1.4: Shi and He: gold(lll) catalyzed arene C - H functionalization  1.5.2 Gold catalyzed C-O bond formation Hydration o f alkynes is one of the earliest uses of gold catalysts in the formation of C - 0 273  bonds  274 277  and remains an active area of research today.  "  In an analogous fashion to the  processes discussed previously in sections 1.3.2 and 1.4.2, gold complexes have been reported to catalyze the intramolecular addition of alcohols onto a l k y n e s ,  278  as well as the intermolecular versions of these transformations. '  '  282 283  984  addition of oxygen nucleophiles from ketones, 988  carbamates, reported.  980  1,2-diketones  98S  '  279  alkenes  280  and allenes.  The gold catalyzed  09.ft  aldehydes,  987  carboxylic acids,  900901  and carbonates  '  onto alkynes and allenes have also been  28  Chapter I. Cycloisomerizations  5 mol % AuCI  OP  3  CH CN  OH  3  1.64  Proposed  33  catalyzed by Pt, Ag and Au Salts  Cl  1.65  1.66  47%  10%  1.67 1%  Mechanism.  Au" . 1  R  / = • =  R OH  R>  Au"  R  1  * +  Au"  r R  protodemetallation  R O-  Q  ;  H  R,  >0 1.65  1.68 ligand exchange O Au  R  R  ir  o  R'  - Au' O  R  R  O ^  1.66 Scheme 1.5.2.1: Hashmi and coworkers: evidence for the reductive elimination of a gold(III) species  Gold and platinum are known to be reluctant to participate in redox catalytic cycles. In 2006, Hashmi and coworkers reported the first evidence for the reductive elimination of a gold species (Scheme 1.5.2.1).  292  When allenyl alcohol 1.64 was treated with catalytic amounts of  gold(III) chloride, the major product obtained was the S-endo-tng cyclization product 1.65. However, the formation of dihydrofuran 1.65 was also accompanied by the formation of dimer 1.66. The authors propose a mechanism where the initially formed organometallic 1.68 can either undergo protodemetallation to afford dihydrofuran 1.65 or may experience a ligand exchange with another equivalent of 1.68 providing a gold(III) species that can deliver the dimer 1.66 and gold(I) upon reductive elimination. Such a reductive process would liberate 2 equivalents of HC1 in addition to gold(I) and this would help to explain the detection of small amounts of vinyl chloride 1.67. The authors then tested this transformation with PPIi3AuNTf2 in dichloromethane at room temperature and observed essentially quantitative conversion of 1.64 to  1.65.  34  Chapter 1. Cycloisomerizations catalyzed by Pt, Ag and Au Salts  1.5.3 Gold catalyzed C-N bond formation Gold catalysts are extremely efficient at activating carbon-carbon unsaturated bonds for nucleophilic attack and nitrogen heteroatoms are suitable nucleophiles for this purpose. Sections 1.3.3 and 1.4.3 demonstrated the C - N bond forming processes that can be carried out with platinum and silver complexes respectively. Gold catalysts are proficient at promoting many of the same as well as directly analogous C - N bond forming transformations.  293 297  Gold catalyzed addition of nitrogen nucleophiles to alkynes is known in both intraand intermolecular  298  fashions. Similarly, gold catalyzed addition of nitrogen nucleophiles to  alkenes in both i n t r a -  261  '  299  "  302  and intermolecular ' 303  304  fashions as well as both intra-  305  and  intermolecular . addition to allenes has been reported and interested readers are directed to 306  pertinent publications.  1.6 Bronsted Acid Catalysis When using transition metal salts as catalysts for organic transformations, one must always be mindful of the possible hydrolysis reaction of the metal salt with water or alcohol. Water may be generated during a reaction by a process such as condensation or may simply be present adventitiously and this water has the potential to interact with a metal salt in a hydrolysis process to generate a protic species.  M  +  +  H 0  M(OH) +  2  A n early report by Furstner in 2 0 0 1  110  H  +  and a report by Krische in 2005  1 9 7  demonstrated  that for some transformations, both BF3 OEr.2 and HBF4 were viable catalyst replacements for P1CI2. This does not mean that protons are necessarily being generated from the metal salt, but as pointed out by Furstner, this more probably indicates a related mechanistic pathway.  The role o f Bransted acid catalysis in reported metal catalyzed cycloisomerizations remains an ongoing debate in the field. Spencer and coworkers provided evidence that Bronsted acids are efficient catalysts for the Michael addition of nitrogen nucleophiles to a,P-unsaturated  Chapter I. Cycloisomerizations  ketones.  '  catalyzed by Pt, Ag and Au Salts  The groups of Hartwig  '  and He  35  have found that trifluoromethanesulfonic  acid (triflic acid) is capable of catalyzing intramolecular hydroalkoxylations and hydroaminations of unactivated olefins. On the other side of the debate, Kobayashi and coworkers have discovered during their investigations into aldol reactions in aqueous media that many metal salts and even some metal triflates are quite stable in w a t e r . ' 310  311  Hydrolysis equilibria have been examined for silver(I). This work provides an interesting perspective on this debate.  Ag  +  H 0  Ag(OH) +  H 0  +  2  2  = ^  312  Ag(OH)  + H  +  log K =-12 ± 0 . 3  Ag(OH) " + H  +  log K =-24 ± 0 . 1  2  These measurements were obtained using NO3" as the counterion. The nitrate ion is a weak base, as is the trifluoromethanesulfonate ion and according to the equilibrium constants provided above, the acid base equilibria should lie far to the left. As a consequence, the generation of a strong acid such as trifluoromethanesulfonic acid by hydrolysis of a silver(I) salt should be minimal. While coordination of water to silver(I) does increase the acidity of water, it is questionable as to whether enough trifluoromethanesulfonic acid would be generated under cycloisomerization conditions as claimed by Hartwig.  Nonetheless, it is important to run control experiments to probe for the possibility of acid catalysis. Many researchers report control experiments where the reaction is run a) in the absence of metal salts, b) with added acid in the absence of metal salts or c) with metal salts in the presence of an added base in order to probe for the viability of Bransted acid catalysis. While arguments for both sides of the debate can be made, have been made and most likely will continue to be made, the existence of related mechanistic pathways for Lewis acids and Bransted acids should not be ruled out.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  36  1.7 Conclusion Despite the veritable force with which the chemistry community has plunged into the field of transition metal catalyzed cycloisomerization reactions and the considerable volume of resulting publications, active researchers believe that the field is still in its infancy. While the evolution of cycloisomerization reactions can be traced back to the early 1970s, it has only been within recent years that research in the field has begun to intensify and these reactions remain far from perfectly understood. There appears to be no doubt that these transformations are capable of providing significant increases in structural complexity from relatively simple starting materials, are "atom economical" and are operationally simple to carry out. One of the main drawbacks of this chemistry, however, is that it can be difficult to predict the product outcome for a given substrate and this can make application of the chemistry in a total synthesis challenging. Current efforts in the field are focused on further developing the predictability of these reactions so that synthetic chemists may draw upon these transformations at will and implement them in the arena of total synthesis. With these goals in mind, and in addition to making these transformations enantioselective, there appears to be an abundance of discoveries left for investigators just so inspired.  Chapter 1. Cycloisomerizations  catalyzed by Pt, Ag and Au Salts  1.8 References 1.  Lloyd-Jones, G . C. Org. Biomol. Chem. 2 0 0 3 , 7,215-236.  2.  Zhang, L . ; Sun, J.; Kozmin, S. A . Adv. Synth. Catal. 2 0 0 6 , 348, 2271 -2296.  3.  Nieto-Oberhuber, C ; Lopez, S.; Jimenez-Nunez, E.; Echavarren, A . M . Chem. Eur. J.  2006,  72, 5916-5923.  4.  Bruneau, C. Angew. Chem. 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"Pt(ll) or Ag(I) Salt Catalyzed Cycloisomerizations and Tandem Cycloadditions Forming Functionalized Azacyclic Arrays" Org. Lett. 2004, 6, 5023-5026. 1  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  51  2.1 Introduction Dating back to the pioneering work of Stork, ' the alkylation of enamines has remained a 1  2  fundamental method for the formation of C - C bonds in organic synthesis. ' The use of 3 4  enamines as rc-nucleophiles has been well documented in reactions with alkyl halides, acyl halides and suitable Michael acceptors. While most enamines are so reactive that they are generally prepared and reacted in situ, 7V-acyl, iV-carbamyl and N-sulfonyl enamines serve as valuable enamine analogues that are stable enough to be isolated, purified and handled. The nucleophilicity of enamides, enecarbamates and enesulfonamides have been demonstrated by their ability to undergo nucleophilic addition to aldehydes, ' acid chlorides, ' ketenes, 5 6  ketones and i m i n e s . ' ' 10  1  12  7  8  9  The use of enecarbamates has been explored in  hydroboration/oxidation reactions, ' as nucleophiles in Prins cyclizations and via additions to 7 13  para-quinone methides.  15  14  Reports of transition metal catalyzed processes involving enamines " 16  18  19 20  and /V-functionalized analogues, '  however, remain surprisingly scarce and most commonly  involve nucleophilic addition of the enamine function onto a metal-rc-allyl intermediate. " 21  23  Natural product alkaloid total synthesis is highly beneficial with regard to student training, the discovery of new reactions and the production of biologically active molecules. The development of methodologies that manipulate nitrogen containing organic fragments resulting in an increase in molecular complexity are highly valuable for this purpose. Given the emerging field of transition metal catalyzed cycloisomerization reactions, as discussed in Chapter 1 of this thesis, and the use of metal complexed carbon-carbon unsaturated bonds as electrophiles, one should be able to take advantage of the nucleophilicity of enecarbamates and enesulfonamides for use as nucleophiles in the addition to such complexes. If an alkyne was connected to an enecarbamate or enesulfonamide by a suitable tether, then the addition of an electrophilic metal species could initiate a cyclization event (Figure 2.1.1).  EWG  EWG  EWG  Figure 2.1.1: General representation of the desired metal catalyzed cyclization event  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  52  M y Ph.D. research project commenced with the above proposal in mind as a valuable tool for alkaloid synthesis. The remainder of this chapter will be primarily divided into three sections. The following section will deal strictly with the synthesis of substrates used in these investigations with the following section reserved for a discussion of the reaction of substrates. The final section will disclose experimental procedures for the reactions discussed herein.  2.2 Synthesis of Substrates In the interest of forming five- and six-membered rings, substrates were required that contained an /V-functionalized enamine with an alkyne tethered four or five carbons away from the P-position of the enamine function respectively (Figure 2.2.1).  EWG  EWG  Figure 2.2.1: General structure of required substrates  Substrates were constructed from 5-valerolactam 2 . 1 , as adapted from the method of Shono and coworkers (Scheme 2.2.1).  24  Protection of the lactam nitrogen afforded p-toluenesulfonyl  imide 2 . 2 . Reduction with diisobutylaluminum hydride, followed by elimination of the resulting aminol gave enesulfonamide 2 . 4 . Regioselective methoxybromination of the enamine moiety and elimination of the bromide ion with l,8-diazabicyclo[5.4.0]undec-7-ene afforded allylic methyl ether 2 . 6 in good yield.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  53  i) n-BuLi THF, -78 °C N  DIBAI-H  ii) TsCI  i  H  N  87%  2.1  CH CI , -78 °C 2  2  N  OH  Ts  Ts  2.2  2.3 MsCI, Et N DMAP CH CI , rt 71% 3  2  DBU N  i  OCH  DMF, 90 °C 3  83%  Ts  a  Br  N  NaOMe, Br  0  2  CH3OH  OCH3  82%  Ts  Ts  2.5  2.6  2  2.4  Scheme 2.2.1: Synthesis of toluenesulfonyl protected allylic methyl ether 2.6  This synthetic route was easily adapted to the construction of the tert-buiy\ carbamate protected analogue, 2.11 (Scheme 2.2.2). The /V-functionalization of 8-valerolactam 2.1 could be carried out at -78 °C with «-butyllithium followed by addition of di-ter/-butyl dicarbonate as in Scheme 2.2.1, but from a practical perspective, stirring lactam 2.1 with di-tert-butyl dicarbonate and a catalytic amount of D M A P in acetonitrile at room temperature was an experimentally less demanding set of conditions for the formation of imide 2 . 7 . Upon reduction of imide 2 . 7 , aminol 2.8 was dehydrated by azeotropic distillation in benzene using catalytic amounts of jc-toluenesulfonic acid to afford enecarbamate 2 . 9 . This acid catalyzed dehydration provided enecarbamate 2 . 9 in superior yield relative to elimination of the corresponding mesylate under basic conditions. Methoxybromination followed by elimination of the bromide afforded allylic methyl ether 2 . 1 1 .  Boc Q, DMAP  DIBAI-H  2  N 1  ^O  H  C H C N , rt  N  83%  Boc  3  2.1  ^0  CH CI , -78 °C  N  84%  Boc  2  2  2.7  OH  2.8 p-TsOHH 0 benzene reflux 88% 2  NaOMe, Br  DBU N  Boc  2.11  OCH3  DMF, 90 °C 87%  N l Boc  2.10  OCH, 3  CH3OH  94%  2  N Boc  2.9  Scheme 2.2.2: Synthesis of tert-buty\ carbamate protected allylic methyl ether 2.11  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  54  Cycloisomerizations  The alkyne portion of the substrates was introduced to allylic methyl ethers 2.6 and 2.11 via a copper(I) catalyzed S N 2 ' addition of an appropriate Grignard reagent. The requisite alkyl bromides were prepared through known chemistry following the method described by Holmes and coworkers (Scheme 2.2.3).  25  The dianion of 3-butyn-l-ol ( 2 . 1 2 ) or 4-pentyn-l-ol (2.15)  was generated in the presence of 2 equivalents of «-butyllithium. Quenching of the dianion with 2.5 equivalents of chlorotrimethylsilane afforded the bis-silyl protected species from which alcohols 2 . 1 3 and 2 . 1 6 were produced by cleavage of the trimethylsilyl ether with aqueous acid. Tosylation of the alcohol followed by displacement of the tosylate with bromide ion afforded bromides 2 . 1 4 and 2 . 1 7 in good yield. This procedure was easily carried out on 30 g of alcohols 2.12  or 2 . 1 5 .  i) n-BuLi (2 equiv)  .  THF,-78°C H  ii) Si(CH ) CI (2.5 equiv)  0  3  3  ^ S , ( C H H  O  3  )  3  1 ) T s  C I . pyr. C H ^ I *  2) NaBr, D M F , 60 °C  ^>n  „.,„  rt B  r  ,  H  ./Si(CH ) 3  3  '  iii) 1N HCI  2.12 2.15  (n = 1) (n = 2 )  2.13 2.16  ( 9 4 % , n = 1) ( 9 9 % , n = 2)  2.14 2.17  ( 7 3 % , n = 1) (75%, n = 2)  Scheme 2.2.3: Synthesis of bromides as described by Holmes and coworkers  The Grignard reagent formed from bromides 2 . 1 4 and 2 . 1 7 underwent smooth addition to the 4-position of tetrahydropyridine 2.6 in the presence of catalytic amounts of copper(I) bromide-dimethyl sulfide complex at-13 °C and provided enesulfonamides 2 . 1 8 and 2 . 2 0 in good yield (Scheme 2.2.4). Performing this reaction at lower temperatures resulted in a sluggish reaction, while higher temperatures interrupted the reaction progress, most likely due to decomposition of the cuprate reagent. Evidence for the formation of 2 . 1 8 and 2 . 2 0 was provided by the disappearance of the singlet at 3.36 ppm in the ' H N M R spectrum of 2.6 due to the methyl ether and the appearance of a 9-proton singlet at 0.1 ppm in the product *H N M R spectrum. In addition, the 2-proton multiplet at 5.65-5.85 ppm in the ' H N M R spectrum of 2.6 corresponding to the 2 alkene protons, gives way to two doublets at 6.61 and 4.86 ppm indicating the presence of the polarized double bond of the enesulfonamide function. Deprotection of alkynes 2 . 1 8 and 2 . 2 0 in basic methanol afforded key intermediates 2 . 1 9 and 2.21 as evidenced by the disappearance of the upfield trimethylsilyl singlet and the appearance of the alkyne proton triplet at 1.88 ppm in the ' H N M R spectrum.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  2.6  2.18 2.20  Cycloisomerizations  55  2.19 2.21  (86%, n = 1) (82%, n = 2)  (94%, n = 1) (99%, n = 2)  Scheme 2.2.4: Copper(I) catalyzed Grignard addition to allylic methyl ether 2.6  The above procedure was also directly applicable to the construction of enecarbamates 2.23 and 2 . 2 5 from allylic methyl ether 2.11 (Scheme 2.2.5).  ,Si(CH ) 3  3  BrMg^M^T 'N  OCHj  Boc  15 mol % CuBrSMe  " (CH ) si  3  N  2  3  K  2  C 0  3  CH OH 3  THF, -13 °C  2.11  2.22 2.24  (94%, n = 1) (92%, n = 2)  2.23 2.25  (97%, n = 1) (99%, n = 2)  Scheme 2.2.5: Copper(I) catalyzed Grignard addition to allylic methyl ether 2.11  Rather than functionalize the alkyne of substrate 2 . 2 3 with a methyl group, it was found advantageous to introduce that functionality with the copper(I) catalyzed Grignard addition of 2 . 2 7 to allylic methyl ether 2.6, providing enesulfonamide 2 . 2 8 in good yield (Scheme 2.2.6). The requisite bromide 2 . 2 7 was readily prepared in two steps from 3-pentyn-l-ol 2 . 2 6 .  1) TsCI, pyr, CH CI , rt, 75% 2  HO'  2  2) NaBr, DMF, 60 °C, 92%  2.26  2.6  2.27  2.28  Scheme 2.2.6: Construction of methyl-substituted cycloisomerization substrate 2.28  The key enesulfonamide intermediate 2 . 1 9 was typically functionalized by deprotonation of the alkyne with n-butyllithium at -78 °C followed by quenching with an appropriate electrophile (Table 2.2.1, entries 2-6, 8). The formation of products by this method were almost always  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  56  accompanied by recovery of some starting material. It was not until later in my graduate research that it was discovered that the recovery of starting material was due to incomplete deprotonation and that complete deprotonation of the alkyne could be accomplished at -42 °C (dry ice/acetonitrile temperatures). Alternatively, Sonogashira conditions were employed for 26  the formation of substrates 2.29 and 2 . 3 5 (entries 1, 7).  Table 2.2.1: Functionalization of alkyne 2.19  Conditions N  i  Ts  2.19 Entry  Conditions  Product  Yield (%)  2.29  87  2.30  74  2.31  66  2.32  65  i) n-BuLi, E t 0 , -78 °C ii) C I C 0 P h  2.33  51  i) n-BuLi, E t 0 , -78 °C ii) P h O C N  2.34  49  2.35  72  2.36  55  i) n-BuLi, THF, -78 °C; C 0 ii) C I C O C ( C H ) , Et N iii) D-BuLi + 2-oxazolidinone, T H F  2.37  44  i) n-BuLi, E t 0 , -78 °C ii) CICOPh  2.38  54  Phi, PdCI (PPh ) , Cul, E t N H  -i-Ph  2  3  2  2  O  XKO C H  i) n-BuLi, E t 0 , -78 °C ii) C I C 0 C H 2  3  3  O  xKC H  2  a  i) n-BuLi, T H F , - 7 8 °C ii) ZnCI , T H F iii) AcCI, T H F 2  3  O  A ~N/ X  i) n-BuLi, E t 0 , -78 °C ii) C I C O N ( C H ) 2  3  2  -C=N O  0 CI  OTBS  PdCI (PPh ) , Cul, E t N , C H C I 2  ^>  3  2  3  2  2  i) n-BuLi, E t 0 , -78 °C ii) C I C O C ( C H ) 2  X  O  2  2  OTBS  X  O  3  2  3  \__/  2  3  3  3  o 10  X  "Reported yields are isolated yields  2  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed Cycloisomerizations  57  The alkynyl ester 2 . 3 9 was derived from 1,7-enyne 2.21 in analogous fashion to the construction of ynoate 2 . 3 0 (Scheme 2.2.7). The tert-b\xty\ carbamate protecting group was stable to these reaction conditions, affording enecarbamates 2 . 4 0 and 2 . 4 1 in reasonable yield.  x 2.21 2.23 2.25  (n = 2, X = Ts) (n = 1, X = Boc) (n = 2, X = Boc)  x 2.39 2.40 2.41  (62%, n = 2, X = Ts) (67%, n = 1, X = Boc) (65%, n = 2, X = Boc)  Scheme 2.2.7: Construction of ynoates 2.39, 2.40 and 2.41  A new substrate was constructed containing an oxygen heteroatom in the enyne tether that was ultimately derived from propargyl alcohol (Scheme 2.2.8). The synthetic route focused on the manipulation of enesulfonamide 2.4 through an alkoxybromination with propargyl alcohol followed by base-mediated elimination of bromide 2 . 4 2 to give allylic propargyl ether 2 . 4 3 . Rearrangement in the presence of catalytic amounts of boron trifluoride-diethyl etherate afforded the desired enesulfonamide 2 . 4 4 in reasonable yield. Through careful optimization, however, it was discovered that 2.44 could be obtained in 81% yield in only one step from 2.6 via a Yb(OTf)3 induced S N 2 ' addition of propargyl alcohol. Ytterbium(III) triflate is a mild enough Lewis acid that it does not catalyze the addition of propargyl alcohol across the enesulfonamide double bond. The use of other Lewis acids, including B  F  3  OEr.2  afforded bis-  addition product 2 . 4 6 . Functionalization of alkyne 2.44 proceeded smoothly to give ynoate 2 . 4 5 in 7 3 % yield.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed i)  0  NBS THF, -78 °C  Cycloisomerizations  Br  DBU DMF, 90 °C  I  Ts  48%  ~H' i  78%  O  Ts  2.42  Ts  58  2.43  2.4  1 mol % B F O E t THF 3  2  74%  30 mol % BF OEt 3  N i  O  2 mol % Yb(OTf) THF  2  N i  HO  Ts  Ts  2.46  2.6  OCH  3  3  12 equiv 81%  N i Ts  2.44 i) f-BuLi THF, -78 °C ii) C I C 0 C H 2  3  73%  C0 CH 2  3  Scheme 2.2.8: Construction of a substrate with a heteroatom in the alkyne tether  A dihydropyrrole substrate was constructed from the known a,(3-unsaturated lactam 2A1  1  28  with similar chemistry to that used for the construction of tetrahydropyridine 2 . 3 0 (Scheme 2.2.9). However, instead of introducing the alkyne tether with a copper catalyzed S N 2 ' Grignard addition, the tether was introduced via cuprate addition to a,|3-unsaturated lactam 2.47 to give lactam 2 . 4 8 in 27% yield.  29  Deprotection of the alkyne with basic methanol at this stage  afforded ring opened methyl ester 2 . 5 2 . Proceeding to enesulfonamide 2 . 4 9 via the previously described reduction/elimination protocol followed by deprotection o f the alkyne afforded the desired enesulfonamide 2 . 5 0 in good yield without complication. Functionalization of alkyne 2 . 5 0 proceeded smoothly to give ynoate 2.51 in 71% yield.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Si(CH ) 3  9^  Si(CH )  3  3  Mg + 2.14 TMSCI  1) DIBAI-H CH CI , -78 °C  CuBrSMe THF, -78 °C  2) MsCI, Et N DMAP, CH CI  2  2  2  27%  2  55%  2.49  2.48  2.47  3  3  2  Ts  59  Cycloisomerizations  K C0 2  3  CH OH 3  83%  C0 CH 2  3  2.52  2.50 i) f-BuLi THF, -78 °C i) C I C 0 C H 71% 2  3  C0 CH 2  3  S c h e m e 2.2.9: Construction of dihydropyrrole substrate 2.51  Deuteration at the P-position of enesulfonamide 2 . 3 0 was accomplished following the chemistry outlined in Scheme 2.2.1 and Scheme 2.2.4, starting from deuterated lactam 2.53 (Scheme 2.2.10). The deuterated lactam 2.53 was easily obtained by treating 5-valerolactam (2.1) with potassium carbonate in deuterium oxide at reflux for seven days giving rise to complete deuteration of the a-protons of the lactam and partial deuteration of nitrogen after the workup.  30  Evidence for deuteration is supported by the absence of the 2-proton signal at 2.3  ppm in the ' H N M R spectrum of 8-valerolactam and a peak in the ESI mass spectrum of 2 . 5 3 corresponding to 101. Residual deuteration on nitrogen was inconsequential since the next step involved protection as the p-toluenesulfonyl imide 2 . 5 4 . Deuterium was then carried through the synthetic pathway without complication, affording ynoate 2.61 in high yield with 90% deuteration at the 3-position of the ring. Evidence for deuteration at the 3-position was supported by the greatly diminished signal at 4.78 ppm in the ' H N M R spectrum of 2.61  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  60  corresponding to the more shielded P-position of the enamine function. Signals in the ESI mass spectrum of 2.61 corresponded to a mass of 348 in accordance with the deuterated compound.  Or  2  3  2  reflux, 7 d  N'  ) n-BuLi THF, -78 °C  a  K C0 , D 0  N i H  31%  DIBAI-H  )TsCI  N  k  85%  0  CH CI , -78 °C 2  N^L)H  2  97%  Ts  2.53  2.1  A  Ts  2.55  2.54  MsCI, Et N DMAP, C H C I 56% 3  2  Si(CH ) 3  2.14  Mg + 3  CuBrSMe  Br DBU  2  THF, -13 °C  N  t  85%  NaOCH , Br 3  C l °  DMF  OCH,  N  87%  2.59  OCH  3  CH OH 3  94%  2  N Ts  2.56  2.57  2.58  K C0 CH OH 95%  -  Ts  Ts  2  2  3  3  i) f-BuLi THF, -78 °C ii) C I C 0 C H  N I  2  C0 CH 2  3  3  76%  Ts  2.61  2.60  Scheme 2.2.10: Construction of deuterated ynoate 2.61  Synthesis of Z-enoate 2.62 was easily accomplished via reduction of ynoate 2 . 3 0 by hydrogenation in the presence of Lindlar's catalyst and quinoline ' 31  C0 CH 2  C0 CH 2  3  32  (Scheme 2.2.11).  3  5 % Pd/CaCQ (Pb) 3  quinoline EtOAc, H , 2 h 2( g )  85%  2.30  2.62  Scheme 2.2.11: Lindlar's reduction of ynoate 2.30  With the desire to construct a substrate containing an enesulfonamide tethered to a nitrile rather than an alkyne, a new synthetic pathway that did not involve cuprate reagents was explored in order to introduce the nitrile function. Alkylation of a functionalized malonate with  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  61  bromoacetonitrile appeared to be a suitable strategy (Figure 2.2.2). It was proposed that such a malonate could be formed from an appropriate allylic ester via a palladium rc-allyl intermediate.  OR  or ~N'  ^OR  EWG  "N' EWG  Figure 2.2.2: Retrosynthetic analysis for nitrile containing substrate  Treatment of allylic methyl ether 2.6 with glacial acetic acid at room temperature for 5-10 minutes afforded 4-acetoxy tetrahydropyridine 2 . 6 3 in 78% yield (Scheme 2.2.12).  OAc glacial acetic acid N 1 Ts  2.6  OCH  * 3  10min 7  8  %  N i Ts  2.63  Scheme 2.2.12: Synthesis of allylic acetate 2.63  A t the time that this chemistry was being explored, sulfonamide 2.6 was used in the construction of a variety of substrates. In the interest of preserving this material that took five steps to make, investigations began into the synthesis of allylic acetate 2 . 6 3 or an analogous compound that could be made from cheap and readily available starting materials. Pyridine was chosen as a suitable, cheap starting material (Scheme 2.2.13).  Unfortunately, />toluenesulfonyl chloride was unreactive with pyridine, but benzyl chloroformate reacted with pyridine in the presence of a hydride source to give dihydropyridine 2 . 6 5 . This material was not stable for extended periods of time so enecarbamate 2 . 6 5 was immediately reduced with sodium borohydride and trifluoroacetic acid to give alkene 2 . 6 6 in low yield. Epoxidation with m - C P B A afforded epoxide 2 . 6 7 . A l l attempts to ring open the epoxide via elimination with base failed, resulting in unidentified decomposition products. Presumably, decomposition proceeded through deprotonation of a benzylic proton on the benzyl carbamate moiety. This side reaction was avoided by exchanging the benzyl carbamate protecting group with a tert-buty\ carbamate via hydrogenation of epoxide 2 . 6 7 in the presence  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  62  Cycloisomerizations  of di-fe/t-butyl dicarbonate, affording te/t-butyl carbamate 2 . 7 0 in 82% yield. Elimination of epoxide 2 . 7 0 with lithium diisopropylamide then proceeded smoothly to give allylic alcohol 2.71 in 85% yield. Facile conversion of the alcohol into acetate 2 . 7 2 could be carried out with either acetyl chloride and base or glacial acetic acid.  Alternatively, epoxide 2 . 7 0 was easily prepared from pyridine and di-ter/-butyl dicarbonate via sequential reduction to alkene 2 . 6 9 followed by epoxidation with m - C P B A . A s expected, the reduction of diene 2 . 6 8 was sensitive to the identity of the acid employed. Camphorsulfonic acid was the only acid that was found to enable the production of alkene 2 . 6 9 in appreciable amounts.  OH CBzCI, NaBH  P  4  C H O H , 0 °C 3  CBz  2.64  LDA m-CPBA  NaBH , TFA 4  toluene, 0 °C 22% over 2 steps  0 CBz  CH2CI2  N  N  39%  CBz  CBz  2.67  2.66  2.65  Boc 0, 5 wt % Pd/C 2  H (g), EtOAc 2  82%  Boc Q, NaBH 2  C H 3 O H , 0 °C  4  o N  2.64  Boc  2.68  NaBH , CSA 4  benzene, 0 °C 37% over 2 steps  9 Boc  m-CPBA CH2CI2  N Boc  81%  2.69  2.70 LDA THF, -78 °C 85%  OAc  OH AcCI, Et N 3  N Boc  2.72  CH2CI2 58%  N Boc  2.71  S c h e m e 2.2.13: Construction of tert-buty\ carbamate-protected allylic acetate  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  63  With allylic acetates 2.63 and 2.72 in hand, reaction with malonate anion through a metal TCallyl intermediate could be attempted. No reaction was observed with the sodium salt of dimethyl malonate in refluxing T H F with 3 mol % P d ( P P h 3 ) 4 with or without added phosphine, or with 5 mol % (PPh3)3RhCl. However, upon treating allylic acetate 2.63 with 2.5 mol % Pd2(dba) and 10 mol % tricyclohexylphosphine, a mixture of two products were obtained 3  (Table 2.2.2). The desired 4-substituted enesulfonamide 2.73 was obtained in 65% yield as the major product along with 2,4-disubstituted piperidine 2.74 in 25% yield as the minor product. Attempts to optimize this ratio by changing the phosphine ligand to triphenylphosphine or 1,4bis(diphenylphosphino)butane resulted in the exclusive formation of disubstituted piperidine 2.74.  Table 2.2.2: Palladium catalyzed allylic alkylation of 2.63  O OAc  CH 0 3  / U v  O g^0CH3 ©  Na  2.5 mol % Pd (dba) Phosphine THF, reflux  N i  2  Ts  3  2.73  2.63  2.74 E = C0 CH 2  Phosphine  Equiv  Yield 2.73  PCy  3  10 mol %  65%  25%  PPh  3  10 mol %  0  67%  5 mol %  0  74%  dppb  a  3  Yield 2.74  a  "Reported yields are isolated yields.  No evidence for the formation of a 2-substituted tetrahydropyridine analogue was observed and the question arose as to whether piperidine 2.74 was derived from the 2- or 4monosubstituted precursor. Some insight into this question was gained by treating enesulfonamide 2.73 with the exact reaction conditions in which piperidine 2.74 was formed exclusively and in the highest yield (Scheme 2.2.14). Remarkably, no reaction was observed under these conditions and this result would seem to indicate that the formation of 2.74 does not  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  64  Cycloisomerizations  proceed through 2.73. B y default, the formation of 2.74 most probably proceeds through initial substitution at the 2-position of the piperidine ring (Scheme 2.2.15).  0 C H  0  3  /  O ^ g ^ O C H  U  3  © Na  Wo Reaction  2.5 m o l % P d ( d b a ) 2  3  5 mol % dppb THF,  2.73 O  C H  reflux  O  0 ' ^ g ^ 0 C H /  3  3  © Na  0  No Reaction  2.5 m o l % P d ( d b a ) 2  10 m o l % P C y  I  Ts  THF,  2.4  3  3  reflux  Scheme 2.2.14: A l l y l i c alkylation control experiments  If initial substitution occurs at the 4-position, the reaction appears to stop at enesulfonamide 2.73. N o reaction was observed for enesulfonamide 2.4, indicating that the enesulfonamide function itself is not reactive under these conditions. Initial substitution at the 2-position of the piperidine ring should lead to the 2-substituted tetrahydropyridine shown in Scheme 2.2.15, which would not normally be expected to be reactive under these conditions. C H  C H  3  0  2  C ^ C 0  C H  2  3  0  2  C  v  C 0  2  C H  3  3  2.73 N'  I  Ts  K _ b  er^ °2 C  C  |  C 0  2  C H  H  3 C H  3  ,  N  ,  Ts  ^ C 0 C 0  2  2  C H  C H  3  3  0  2  C ^ , C 0  2  C H  3  C 0  3  Ts  C 0  2.74 Scheme 2.2.15: Apparent dichotomy of reaction pathways for the reaction of allylic acetate 2.63  2  2  C H  C H  3  3  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  65  Cycloisomerizations  This mysterious result was further compounded upon subjecting enecarbamate 2.72 to the established reaction conditions where 2-substituted tetrahydropyridine 2 . 7 5 was formed exclusively in 91% yield (Scheme 2.2.16). The 3-proton singlet from the acetate function at 1.84 ppm in the ' H N M R spectrum of 2.72 is no longer visible in the product spectrum, which displays a 6-proton singlet at 3.70 ppm from the malonate moiety. Substitution at the 4-position of 2.72 would have produced an enecarbamate similar to 2 . 7 3 . The 'IT N M R spectrum of 2 . 7 5 displays a 2-proton multiplet centered at 5.8 ppm indicating a non-conjugated alkene, whereas the a-proton of an enecarbamate is usually observed at 6.5-7.0 ppm and the (3-proton of an enecarbamate is usually observed at 4.8-5.0 ppm, indicating a polarized double bond. The C 1 3  N M R spectrum of the product also supports the proposed product structure, displaying two closely spaced alkene signals at 125 ppm and 127 ppm, indicating a non-conjugated alkene.  THF, reflux, 1.5 h  2.72  91%  2.75 E = C0 CH 2  3  Scheme 2.2.16: A l l y l i c alkylation of enecarbamate 2.72  In the reaction of 2 . 6 3 with malonate anion in the presence of Pd(PPh3)4, no reaction was observed, so there was no background reaction operating. In light of the counterintuitive result obtained for enecarbamate 2 . 7 2 , it was necessary to determine whether this reactivity was due to the metal catalyst or simply from a background reaction. In the event, stirring 2 . 7 2 in the presence of the sodium salt of the anion of dimethyl malonate in refluxing T H F over 8 hours produced a 43% yield of a 3:1 mixture of two compounds with the major component being alkene 2 . 7 5 (Scheme 2.2.17). The minor component was not separable from 2 . 7 5 , but the H !  N M R spectrum is consistent with the structure of enecarbamate 2 . 7 6 . The seemingly innocuous exchange of enecarbamate 2.72 for enesulfonamide 2.63 in this reaction gave rise to some rather unexpected and confusing results.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed O OAc  3  3  THF, reflux, 8 h  N  43%  Boc  Boc  66  O  CH 0^g^0CH © Na  N  Cycloisomerizations  2.72  E  2.75  2.76  (3:1) E = C0 CH 2  3  Scheme 2.2.17: Background reaction for the allylic alkylation of enecarbamate 2.72  Nevertheless, with enesulfonamide 2.73 in hand, alkylation with bromoacetonitrile proceeded smoothly to afford nitrile 2.77 in 88% yield (Scheme 2.2.18).  5 equiv NaH BrCH CN THF, rt 2  88% E = C0 CH 2  3  Scheme 2.2.18: Alkylation of enesulfonamide 2.73 with bromoacetonitrile  Initial attempts to construct a substrate containing a 1,4-dihydropyridine moiety tethered to an alkyne involved the cuprate addition to a methyl carbamate functionalized pyridinium salt (Scheme 2.2.19). Not entirely unexpected was the observed instability of the resulting enecarbamate. Concentration of the crude reaction mixture resulted in the appearance of aromatic signals in the ' H N M R spectrum, greatly complicating attempts to characterize these compounds. The observed instability was magnified for the corresponding 1,4-dihydropyridine that was functionalized with a trifluoromethanesulfonyl group.  CIC0 CH 2  Mg +  3  CuBrSMe  1 O^OCH Cl  Si(CH )  2.14  3  3  spontaneous  aromatization  2  THF 3  highly unstable  Scheme 2.2.19: Failed attempt to construct a stable 1,4-dihydropyridine substrate  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  67  Since aromatic signals were observed en route to decomposition of these compounds, it was proposed that expulsion of the methoxycarbonyl function was likely occurring. The protecting group was then exchanged for benzyl in an attempt to counteract this effect. The desired 1,4dihydropyridine 2.81 was prepared from pyridinium salt 2 . 7 9 via cuprate addition to the 4position of the ring (Scheme 2.2.20).  75%  2.78  Bn  2.79 Mg + 2.14 CuBrSMe THF, -42 °C 2  2.81  2.80  Scheme 2.2.20: Construction of 1,4-dihydropyridine 2.81  The methyl ester moiety of methyl nicotinate 2 . 7 8 that is carried through the synthesis presumably provides some stabilization to the electron rich 7i-system of dihydropyridines 2 . 8 0 and 2 . 8 1 . Both 2 . 8 0 and 2.81 were easily handled, stable to triethylamine washed silica gel and characterized without difficulty.  2.3 Reaction of Substrates The prepared substrates were subjected to a variety of cycloisomerization conditions, both well precedented and exploratory, in order to test the abilities and limitations of enesulfonamides and enecarbamates to act as nucleophiles in metal catalyzed cycloisomerization reactions. A t the outset of my graduate research, the field of metal catalyzed. cycloisomerizations was in its infancy and it was unknown 1) whether these substrates would be  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  68  Cycloisomerizations  reactive with regard to a cycloisomerization event and 2) i f they were reactive, whether the product distributions would be predictable and controlled.  2.3.1 Cycloisomerization Reactions In 2001, gold and silver salts were not yet popularized for use as catalysts in cycloisomerization reactions. Enesulfonamides  2.18-2.19  and  2.28-2.35  were initially subjected  to the cycloisomerization conditions originally reported by Murai: platinum(II) chloride in toluene at 80 °C (Table 2.3.1).  33  Trimethylsilyl-substituted alkyne 2 . 1 8 displayed no reactivity,  even after prolonged heating (entry 1). Conversely, unfunctionalized alkyne 2 . 1 9 was the most reactive substrate (entry 2), requiring only 50 °C to fully consume the starting material in only a few hours to provide diene 2.82 with migration of the double bond into the newly formed fivemembered ring (Figure 2.3.1). A 3-proton singlet is observed at 1.74 ppm in the ' H N M R spectrum of the product diene. Although low yielding (20% yield), this reaction appeared by thin layer chromatography to proceed without significant decomposition and the low yield of diene 2 . 8 2 may be a result of an inherent instability towards isolation in neat form. Further handling of diene 2 . 8 2 , resulted in expedient decomposition. Diene 2 . 8 3 , derived from internal alkyne 2 . 2 8 displayed increased stability to isolation, but the exocyclic alkene also appears to have migrated into the newly formed five-membered ring leaving an exocyclic ethyl group (entry 3). Evidence for this double bond migration is provided by the 3-proton triplet at 1.08 ppm in the ' H N M R spectrum of diene 2 . 8 3 . Phenyl substitution of the alkyne produced a 1:1 mixture of exocyclic alkene-double bond migration products 2.84b  (2.84)  (entry  4).  Diene  2.84a  were the first products where the R-group had the ability to conjugate with the diene  and n-  system and consequently, was the first example where the double bond was observed to remain exocyclic to an appreciable extent.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  69  Table 2.3.1: Cycloisomerization reactions with platinum(II) chloride  10 mol % PtCI  2  toluene, 80 °C  N i Ts  N i Ts b  Entrv  Substrate  R  Time (h)  1  2.18  TMS  15  -  NR  -  2  2.19  H  3  2.82  20  0:1  3  2.28  CH  2  2.83  58  0:1  4  2.29  Ph  4.5  2.84  52  1:1  5  2.30  CO2CH3  0.75  2.85  69  1:0  6  2.31  COCH  2  2.86  70  1:0  7  2.32  CON(CH )  7  2.87  62  1:0  8  2.33  C0 Ph  1  2.88  61  1:0  9  2.34  CN  40  2.89  88  1:0  10  2.35  CO(2-OTBS-C H )  1.3  2.90  63  1:0  a  3  b 3  3  b 2  2  b  6  4  Product  Yield  Ratio a:b  "Performed at 50 °C. 5 mol % PtCl? was used. Obtained as a 1:1 mixture of double bond isomers. NR = no reaction. c  .CH-, CH  3  N 1  N fs  Ts  2.83  2.82  2.84  O OCH  CH-J  3  6N1 ^ Ts  2.85  N 1  N 1  Ts  Ts  2.86  N Ts  2.88  2.87 OTBS  CN CN N I Ts  N I Ts  2.89  2.90  Figure 2.3.1: Structures of cycloisomerization products  C  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  70  These preliminary results (entries 1 -4) seemed to indicate that a conjugating R-group was able to keep the double bond exocyclic to the newly formed ring. It was proposed that a more electron withdrawing R-group might afford the exocyclic alkene selectively and avoid the formation of double bond migration products. With this in mind, substrates 2 . 3 0 - 2 . 3 5 were subjected to the reaction conditions (entries 5-10), providing dienes 2 . 8 5 - 2 . 9 0 with excellent control over double bond regiochemistry and increased stability to isolation and handling. This finding supported the idea that conjugating /v-groups are better able to keep the double bond from migrating into the ring.  A l l protons were assigned for diene 2 . 8 5 based on a ' H - ' H C O S Y 2D N M R experiment and both alkenyl protons showed a strong N O E correlation to each other (Figure 2.3.2). In all cycloisomerization examples, the alkyne carbon signals that typically appeared at 75-95 ppm in the  1 3  C N M R spectrum of the starting materials, were replaced by two additional alkene signals  at 100-130 ppm from the newly formed diene.  Figure 2.3.2: Observed selective N O E for diene 2.85 This observed reactivity in a cyclization event was a significant breakthrough in that it demonstrated the ability of enesulfonamides to act as nucleophiles in a cycloisomerization reaction. Not only did the formation of a five-membered ring take place, but the products appeared to be structurally predictable with no observed rearrangement products. Methyl ester 2 . 3 0 provided the best combination of substrate reactivity and product stability. For these reasons, it was chosen for an optimization study to test the effects of different platinum catalysts (Table 2.3.2). N o reaction was observed using C O D PtCb (entries 1-2) or dppb'PtCh (entries 34) as the precatalyst, while only minor conversion to cyclized product was observed with K2P1CI4 or K2P1CI6 in D M F (entries 6 and 8). The phenanthroline-platinum hydroxide dimer showed no reactivity as a cycloisomerization catalyst (entries 9-10), but the 1,4-  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  bis(diphenylphosphino)butane-platinum hydroxide dimer  71  gave rise to a 59% yield of cyclized  product in toluene at 80 °C in only 30 minutes (entry 11).  In light of this successful result, a series of solvent optimization experiments (not shown) revealed that dichloromethane and chloroform were suitable solvents for cycloisomerization with this platinum dimer catalyst, providing diene 2.85 in 86% and 80% yield, respectively (Table 2.3.2, entries 13-14). Under these conditions, reactions could be run at a comparatively mild 40-60 °C instead of the 80 °C previously required with platinum(II) chloride. The reaction was viable with catalyst loadings anywhere from 10 mol % and greater down to the 1 or 2 mol % range.  Table 2.3.2: Optimization study performed with enesulfonamide 2.30 ,C0 CH 2  I  I  Ts  Ts  2.30  3  2.85  Entry  Catalyst  Solvent  Temp (°C)  Time (h)  1  CODPtCb  toluene  80  3  NR  2 3  dppbPtCI  2  K PtCU 2  80  3  ' NR  toluene  80  3  NR  DMF  80  3  NR  toluene  80  3  NR  DMF  80  3  30% conversion  toluene  80  3  NR  DMF  80  3  Trace  6 7  K PtCI 2  6  ab  DMF  4 5  Yield (%)  8 9  [phen PtOH] (BF )  2  toluene  80  2  NR  10  [phen PtOH] (BF )  2  CH CI  40  2  NR  11  [dppbPtOH] (BF„)  2  toluene  80  0.5  59  12  [dppb PtOH] (BF )  2  DMF  80  2  NR  13  [dppb PtOH] (BF )  2  40  0.25  86  14  [dppb PtOH] (BF )  2  61  0.25  80  2  2  4  4  2  2  2  2  4  4  4  2  CH CI 2  CHCI  2  2  3  "Reported yields are isolated yields. N R = no reaction. b  phen =  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  72  Cycloisomerizations  These optimized conditions (entries 13-14) were then applied to enesulfonamides  2.28-2.38  (Table 2.3.3). Methyl or phenyl substituted alkynes (entries 1-2) cyclized in only moderate yield and produced products with double bond migration as observed in Table 2.3.1. Ynoates and ynones reacted efficiently (entries 3-4, 6), providing the cyclized diene in good yield and without migration of the exocyclic alkene. Nitrile 2 . 3 4 reacted sluggishly under the reaction conditions (entry 7), but afforded a complex mixture that I was not able to characterize.  Table 2.3.3: Cycloisomerization reactions using [dppb PtOH] (BF ) as catalyst 2  R I  N  [dppb.Pt0H] (BF ) 2  4  4  2  2  solvent, reflux  J  I Ts  Entry  Substrate  R  1  2.28  CH  2  2.29  Ph  3  2.30  C0 CH  4  2.31  COCH  5  2.32  CON(CH )  6  2.33  7  2.34  mol % Cat.  Solvent  Time (h)  Product  5%  CHCb  2  2.83  39%  0:1  5%  CHCI  2  2.84  47%  1:1  6%  CH CI  0.25  2.85  86%  1:0  8%  CHCI  3  4  2.86  54%  1:0  5%  CHCI  3  4  2.87  57%  1:0  C0 Ph 2  5%  CH CI  1  2.88  75%  1:0  CN  5%  CHCI  22  2.89  Complex mixture  17%  CH CI  3  2.90  NR  18%  CHCI  3  5  50% conversion  5%  CHCI  3  7  decomposition  17%  CHCI3  3.5  decomposition  2  9  2.36  10  2.37  11  2.38  3  COC(CH ) 3  0  3  0 II  II  -\  2  3  2  2  2  2  3  Ratio a:b  3  b  OTBS i  II  2.35  3  3  0  8  3  Yield  N  0  COPh  2  2  "Reported yields are isolated yields. Obtained as structure a as a 1:1 mixture of double bond isomers. Product ratios were determined by integration of signals in ' H N M R spectra. b  c  Ketone 2 . 3 5 did not undergo a reaction and only starting material was recovered. Pivaloyl alkyne 2 . 3 6 appeared to react slowly, giving rise to signals in the ' H N M R spectrum of the isolated material that are consistent with a cyclized diene, but was also accompanied by significant decomposition. Imide 2 . 3 7 and ketone 2 . 3 8 (entries 10-11) appeared to react according to thin layer chromatography, but all attempts to isolate and characterize the product  c  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  73  were unsuccessful, presumably due to instability of the product diene. Catalyst loadings were typically used at 5-8 mol %. For substrates that displayed little or no reactivity, higher catalyst loadings were used in an attempt to force a reaction (entries 8-9, 11). In these cases, the highest catalyst loading used has been reported in Table 2.3.3.  Cyclization of ynamide 2 . 3 2 afforded a 1:1 mixture of double bond isomers 2 . 8 7 - Z and 2.87b-2i  that were separable and isolable. The double bond geometry was established by N M R  spectroscopy and was confirmed by isomerization of 2 . 8 7 - Z into 2 . 8 7 - 2 ? (Scheme 2.3.1). The interconversion was found to be possible with just heat, but was more facile in the presence of metal catalyst.  o r'^Y^^V  /  Conditions A or B is  2.87-E  2.87-Z A) CHCI , reflux, 15 Ii, 50% conversion 3  B) [dppb'Pt0H] (BF )2, CHCI , reflux, 15 h, 100% conversion 2  4  3  Scheme 2.3.1: Double bond isomerization of 2.87-Z with either heat or platinum(II) catalyst  The question of acid catalysis arose for reactions run with the platinum hydroxide dimer due to the presence of O - H bonds in the bridging hydroxo ligands and is a legitimate concern depending on the acidity of those protons. Sharp and coworkers disclosed their results on the deprotonation of these hydroxo ligands, but the lithium salt of hexamethyldisilazane was found to be the only base suitable for this transformation. '  34 35  Despite the reports of Sharp and  coworkers, the bridging hydroxo ligands are generally referred to as basic in nature and are readily protonated by carboxylic acids and hydroperoxides. " 36  40  In the preparation of [dppb'PtOH] (BF )2, the source of the B F counterions is silver(I) 2  tetrafluoroborate.  4  4  A s a control experiment, the cycloisomerization of ynoate 2 . 3 0 was carried  out using 30 mol % AgBF4 as the precatalyst and, somewhat surprisingly, resulted in the formation of diene 2 . 8 5 in 31% yield. Carrying out the reaction with HBF4 produced none of the desired products, but only unidentifiable decomposition products. The use of silver(I) trifluoroacetate produced 2 . 8 5 in good yield and silver(I) trifluoromethanesulfonate afforded the  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  74  Cycloisomerizations  cyclized product cleanly and in 75% yield in dichloromethane. This was an extraordinary result at the time as it represented the first example of a silver(I) salt to efficiently catalyze a cycloisomerization reaction forming a C - C bond. Carbon-carbon bond forming silver(I) catalyzed cycloisomerization reactions reported in the literature prior to this were low yielding and/or used high catalyst loadings. " 41  43  Running the reaction with trifluoromethanesulfonic acid  resulted only in unidentifiable decomposition products with no starting material or product diene recoverable. Enamines and related structures are sensitive to acid " 44  46  and it is not  unexpected that Bransted acid failed to catalyze this transformation. Decomposition of the starting material was likely initiated by protonation at the (3-position of the enesulfonamide. Upon protonation, the nucleophilic species for the cycloisomerization reaction is suppressed (Figure 2.3.3).  CO CH 2  Ts  C0 CH  3  2  3  Ts  Figure 2.3.3: Protonation of enesulfonamide 2.30 with Bransted acid  The cycloisomerization reaction was carried out in the presence of catalytic amounts of silver(I) trifluoromethanesulfonate to investigate the generality of this precatalytic species (Table 2.3.4). N o reaction was observed at all for alkynes substituted with methyl (entry 1), phenyl (entry 2) or trimethylsilyl (not shown) resulting in clean recovery o f starting material in all cases. Substrates containing alkynes substituted with an ester, ketone or nitrile functional group all gave rise to smooth formation of cyclized product in high yield (entries 3-4, 6-7). From a qualitative perspective, these cycloisomerization reactions proceeded faster in chlorinated solvents such as dichloromethane, but reactions carried out in tetrahydrofuran proceeded more cleanly. For very reactive substrates such as ynoates 2 . 3 0 and 2 . 3 3 , a 4:1 T H F chlorinated solvent mixture seemed to be optimal. For less reactive substrates, chlorinated solvent was used without the addition of a co-solvent.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  75  Cycloisomerizations  Ynamide 2 . 3 2 reacted very sluggishly (entry 5), providing a 1:1 mixture of double bond isomers in only 31% yield. Ketone 2 . 3 5 was consumed during the reaction (entry 8), but only a complex mixture was recovered. Pivaloyl alkyne 2 . 3 6 appeared to react, albeit slowly, giving rise to signals in the ' H N M R spectrum of the isolated material that are consistent with a cyclized diene (entry 9).  Table 2.3.4: Cycloisomerization reactions using A g O T f as catalyst  Product  Yield (%)  Ratio a:b  2%  4  2.83  NR  -  19  2.84  NR  -  4.5  2.85  99  1:0  1%  4  2.86  99  1:0  4%  69  2.87  31  1:1  C0 Ph 2  1%  5  2.88  94  1:0  CN  4%  71  2.89  99  1:7.7  2%  24  Complex mixture  2%  15  85% conversion  R  1  2.28  CH  2  2.29  Ph  2%  3  a  2.30  CO2CH3  2%  4  2.31  COCH3  5  2.32  CON(CH )  6  2.33 2.34 2.35  9  2.36  3  3  2  OTBS i  0  8  b  Time (h)  Substrate  7  Ts  a  mol % Cat.  Entry  b  Ts  II  COC(CH ) 3  3  cd  e  4:l THF-CH2O2 used as solvent. 4 : l THF-1,2-dichloroethane used as solvent. °Reported yields are isolated yields. N R = no reaction. Product ratios determined by integration of signals in ' H N M R spectra.  a  b  d  c  2.3.2 Diels-Alder Cycloadditions Dienes of type 2 . 8 5 are confined to the s-cis conformation and it is not surprising that these types of systems have been efficiently used in Diels-Alder cycloaddition reactions with electron deficient dienophiles. " 47  50  In fact, treating diene 2 . 8 5 with acrolein in the presence of catalytic  amounts of boron trifluoride-diethyl etherate at low temperature gave rise to a Diels-Alder cycloaddition providing highly functionalized tricyclic scaffolds in high yield (Scheme 2.3.2).  Chapter 2. Pt(II) orAg(I) Salt Catalyzed  ,C0 CH 2  76  Cycloisomerizations  H  3  ,C0 CH  3  ,C0 CH  3  2  B F OEt , CH CI , -78 °C  I  3  2  2  2  Ts 86%  2.85  ,C0 CH 2  I H » Ts CHO  2.91  3  2  B F OEt , CH CI , -78 °C 3  2  2  2  Ts  2.85  93%  2.92  Scheme 2.3.2: Diels-Alder cycloaddition with diene 2.85  Due to the instability of dienes 2 . 8 3 - 2 . 9 0 , however, a judicious decision was made to prepare them in situ and possibly avoid an unnecessary isolation step. A tandem cycloisomerization/Diels-Alder cycloaddition sequence was envisioned that would forgo the isolation and handling of diene 2 . 8 5 (Figure 2.3 4).  2.30  2.85  Figure 2.3 4: Proposed tandem cycloisomerization/Diels-Alder cycloaddition sequence  In the event, the cycloisomerization of enesulfonamide 2 . 3 0 was carried out at 40 °C in dichloromethane with catalytic amounts of either [dppb PtOH]2(BF4)2 or A g O T f until the reaction was judged complete by thin layer chromatography. A t this point, the reaction vessel was cooled to -78 °C and acrolein or a-methylacrolein was added followed by boron trifluoride-diethyl etherate and the reaction was stirred at -78 °C until no diene was detected by thin layer chromatography. Workup and purification afforded the desired tricycle in good yield (Scheme 2.3.3). This one-pot sequence allowed for an expedient conversion of the relatively simple monocyclic starting material to a highly functionalized tricyclic framework possessing multiple handles for further synthetic manipulation.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  C0 CH 2  i) 4 mol % [dppb PtOH] (BF ) 2  3  4  H  2  CH CI , 40 °C 2  77  Cycloisomerizations  ,C0 CH  3  ,C0 CH  3  2  2  ii) cool to -78 °C  N  iii) acrolein; B F O E t  Ts  3  ' H » Ts CHO  2  74%  2.30  C0 CH 2  2.91  i)4 mol % [dppbPtOH] (BF ) CH CI , 40 °C 2  3  2  4  ii) cool to -78 °C iii) a-methylacrolein; B F O E t  N Ts  H  2  2  2  3  2  75%  2.30  2.92  Scheme 2.3.3: Cyclization/Diels-Alder cycloaddition reaction o f enesulfonamide 2.30  The major product in the formation of tricycles 2.91 and 2.92 corresponded to the expected e«cfo-addition product from approach of the dienophile to the convex face of the diene (Figure 2.3.5). The endo-add\t\on product from the concave face of the diene was usually formed as the minor product. Tricycle 2.91 contains an acidic proton a to the aldehyde function and partial epimerization of the aldehyde during the reaction with BF3  OEt.2  was observed. Formation of a  quaternary carbon center in 2.92 eliminated the possibility for epimerization.  H-- =0 F  H - ^ O  Figure 2.3.5: Transition state depiction for the Diels-Alder cycloaddition  Cycloisomerization of enesulfonamide 2.30, followed by Diels-Alder cycloaddition with 2cyclopenten-l-one afforded a 61% yield of a 6:1 mixture of two compounds with connectivity consistent with 2.93 (Scheme 2.3.4). In an attempt to obtain crystalline material, ketone 2.93 was reduced with DIBA1-H to diol 2.94 and functionalized with p-nitrobenzoyl chloride to give bis-PNB ester 2.95 as a white solid. Ester 2.95 was recrystallized by the technique of vapor diffusion using 1,2-dichloroethane and a 1:1 mixture of hexanes-petroleum ether to obtain a single crystal sample. The relative stereochemistry of 2.95 was confirmed by X-ray crystallographic analysis, which indicated an exo-addition product with approach of the dienophile from the concave face of the diene.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  78  PNBO  2.95 Scheme 2.3.4: Cyclization/Diels-Alder cycloaddition reaction of enesulfonamide 2.30 with cyclopentenone  Although exo-addition from the concave face of the diene is opposite to that observed for acrolein and a-methylacrolein, cyclopentenone is a very different dienophile as it possesses a CH2 a to the carbonyl. The C - H bonds from this CH2 extend both above and below the plane of the five-membered ring and offer a very different kind of steric environment to that provided by acrolein or a-methylacrolein (Figure 2.3.6). The increased steric bulk associated with the aCH2 of cyclopentenone may hinder an enJo-orientation of addition and favor an exo-addition. However, this effect does not explain why 2-cyclopenten-l-one approaches the diene from the concave face preferentially over the convex face.  Chapter 2. Pt(II) orAg(I) Salt Catalyzed  Cycloisomerizations  79  Exo addition from concave face H  H  Figure 2.3.6: Comparison of possible transition states for the Diels-Alder cycloaddition of diene 2.85 and cyclopentenone  Cyclopentenone also differs from acrolein and a-methylacrolein in that it is forced into an s-trans orientation by the nature of the ring and there may be important steric interactions of the coordinated Lewis acid with the toluenesulfonyl group on the nitrogen of the diene (Figure 2.3.7). It is possible that such an effect could be responsible for approach of the dienophile occurring from the concave face of the diene. While these suggestions may be plausible, with only three examples of Diels-Alder cycloadditions involving diene 2 . 8 5 , broad generalizations about mechanism and transition state structures are not appropriate at this time. Further investigations are required to gain a deeper understanding of this reaction. H  Figure 2.3.7: Proposed steric interactions involved with dienophile approach  The stereochemistry at C6 of tetracycle  2.95  (designated in Scheme  2.3.4)  is inconsistent  with the relative stereochemistry associated with an exo-addition from the concave face of the diene. Two transformations had been carried out from ketone 2 . 9 3 en route to ester 2 . 9 5 and it is unclear exactly how this configuration would have arisen from ynoate 2 . 3 0 . One option  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  80  would involve a Diels-Alder cycloaddition to a diene that failed to isomerize during the cycloisomerization event, even though this had not been observed previously (Figure 2.3.8).  H  Figure 2.3.8: Illustration of Diels-Alder cycloaddition with unisomerized diene During the Lewis acid catalyzed Diels-Alder cycloaddition o f diene 2.85 with acrolein, partial epimerization of the resulting aldehyde function was observed at temperatures as low as -78 °C. The Diels-Alder cycloaddition of diene 2.85 with cyclopentenone required temperatures of 0 °C in order to proceed and a second possibility is that the ester epimerized during the Diels-Alder cycloaddition in the presence of boron trifluoride-diethyl etherate at comparatively warmer temperatures. A third possibility is that the ester function epimerized during the reduction of ketone 2.93 to diol 2.94 with diisobutylaluminum hydride.  2.3.3 Limitations of the Cycloisomerization Process The cycloisomerization of enesulfonamides was shown to work well with substrates possessing an electron withdrawing group on the alkyne moiety. However, in order to test the scope o f this transformation, reactions were carried out on a series of substrates that were modified in other aspects. Enecarbamate 2.40 smoothly cyclized to diene 2.96 in high yield with both platinum(II) and silver(I) salts (Scheme 2.3.5). The Lewis acidity of these precatalysts did not pose a detriment to the acid sensitive tert-butyl carbamate group.  Boc  Boc  2.40  2.96  5 mol % PtCI , toluene, 80 °C, 2 h 2 mol % AgOTf, THF-CH CI , 60 °C, 1.5 h 2  2  2  80% 91%  Scheme 2.3.5: Cycloisomerization of enecarbamate 2.40  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  81  Cycloisomerizations  Allylic ether 2 . 4 5 also displayed good stability under the Lewis acidic reaction conditions, affording diene 2 . 9 7 in 75% yield (Scheme 2.3.6). Given the propensity for the formation of double bond migration products, the formation of a furan in this step would not have been unexpected. However, the formation of diene 2 . 9 7 is evidenced by two signals at 7.30 ppm and 5.92 ppm in the ' H N M R spectrum that each integrate to 1H, in analogous fashion to the other dienes products that were previously prepared. In contrast, only one alkenyl signal would be expected from the corresponding furan. Additional evidence for the diene is provided by two doublets at 5.08 ppm and 4.62 ppm that each integrate to 1-proton representing the diastereotopic allylic CH2 next to oxygen. Each doublet has a coupling constant of 16.5 Hz, indicating geminal proton coupling. Conversely, i f a furan were to have formed, the corresponding CH2 next to nitrogen and next to the ester function would no longer be diastereotopic and would be expected to produce 2H-proton singlets in the ' H N M R spectrum. Attempts to isomerize diene 2 . 9 7 to the corresponding furan with prolonged heating in the presence of 5 mol % silver(I) trifluoromethanesulfonate were surprisingly unsuccessful resulting only in the recovery of starting material.  Y  n  r  H  ou on 2  V  N T'  s  2.45  3  2mol%AgOTf . |  4 ; 1  T  H  F  C  H  2  C  2  reflux, 3.5 h 75%  P~V  /""V/COoCHa f*Y  5  N i« 1 s  2.97  m  o  1  %  A  9°  /C0 CH 2  3  T f  4:1 THF-CH CI reflux, 22 h 2  2  N is  Not Formed  Scheme 2.3.6: Cycloisomerization of allylic ether 2.45 In order to investigate the effect of the size of the heterocycle on the cycloisomerization, substrates possessing an ensulfonamide within five- and seven-membered rings were studied (Table 2.3.5). Both synthesis of substrate and the corresponding cycloisomerization of enesulfonamide 2 . 9 8 was carried out by fellow Dake group member Jennifer Kozak and is included in this thesis for the sake of comparison. Dihydropyrrole 2.51 displayed excellent reactivity, with the starting material being completely consumed in only 2 hours (entry 1). The reaction appeared by thin layer chromatography to proceed to a single product with minimal decomposition and signals observed between 5-7 ppm in the corresponding crude *H N M R spectrum may indicate a product diene. A l l attempts to isolate and characterize the product, however, were unsuccessful, presumably due to the instability of the bicyclo[3.3.0]octadienyl  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  82  Cycloisomerizations  system. Cycloisomerization of enesulfonamide 2 . 9 8 afforded a 1:1 mixture of isomers in 75% yield (entry 3).  Table 2.3.5: Effect of heterocycle size on the cycloisomerization of enesulfonamides  ^^C0 CH  X  2  AgOTf  3  (  4:1 THF-CH CI reflux, time 2  Ts  7  XX/C0 CH 2  3  u  +{  2  Ts'  ^ C0 CH /  2  Ts'  a  b  Entry  Substrate  n  Time (h)  Result  Ratio a:b  1  2.51  1  2  decomposition  -  -  2  2.30  2  4.5  99% yield  1:0  2.85  2.98  3  4  75% yield  1:1  2.99  3  a  3  b  Product  This substrate was synthesized and the corresponding cyclization reaction was carried out by Dake group member Jennifer Kozak. Product ratios determined by integration of H N M R signals. a  b  !  Attempts to cyclize enesulfonamides onto metal-alkene complexes were largely unsuccessful (Table 2.3.6). Heating alkene 2 . 1 0 0 in an appropriate solvent with either [dppb P t O H ] ( B F ) or A g O T f resulted in no observed reaction and only clean starting material 2  4  2  was recovered (entries 1-2). Prolonged heating of alkene 2 . 1 0 0 in toluene in the presence of 8 mol % platinum(II) chloride gave rise to a - 2 0 % conversion to enesulfonamide 2 . 1 0 1 along with significant amounts of decomposition products (entry 3). Enoate 2 . 6 2 showed no reactivity with catalytic amounts o f silver(I) trifluoromethanesulfonate, and only starting material was recovered (entry 4). Heating Z-alkene 2.62 in toluene in the presence o f 10 mol % platinum(II) chloride afforded only the isomerized /i-alkene 2 . 1 0 2 in 84% yield with no sign of a cyclization event taking place (entry 5). The alkenyl signals from the enesulfonamide in the *H N M R spectrum of 2 . 6 2 remained essentially unchanged in the product. The a-proton of the enoate moiety is a doublet with a coupling constant of 11.4 H z in the starting material *H N M R spectrum and is a doublet with a coupling constant of 15.6 H z in the product spectrum, indicating isomerization to an ^-double bond. In light of the work by Widenhoefer and coworkers on the cyclization of indoles tethered to alkenes, the observed lack of reactivity for enesulfonamides tethered to alkenes was surprising.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed Cycloisomerizations  83  Table 2.3.6: Attempted cycloisomerization of enesulfonamides onto tethered alkenes R  a Entry  Substrate  1  2.100  3  R  Conditions  Result"  Ratio a:b  Product  H  8 mol % [dppb PtOH] (BF ) , C H C I , reflux, 5 h  NR  -  -  2  2  4  2  2  2  2.100  H  5 mol % AgOTf, 1,2-dichloroethane, reflux, 18 h  NR  -  -  3  2.100  H  8 mol % PtCI , toluene, 80 °C, 14 h  20 % conversion  1:0  2.101  4  2.62  C0 CH  5 mol % AgOTf, 4:1 THFC H C I , reflux, 4 h,  NR  -  -  10 mol % PtCI , toluene, 80 °C, 14 h  84% yield  0:1  2.102  2  2  3  2  5  2.62  CO2CH3  2  2  "Alkene 2.100 was graciously provided by former Dake group member Roh-Eul Yoo. N R = no reaction. b  Given the success of cycloisomerization reactions involving enesulfonamides and alkynes, it was proposed that a tethered nitrile might also display good reactivity for this transformation (Table 2.3.7). Nitrile 2.77 was subjected to the typical reaction conditions of 2 mol % silver(I) trifluoromethanesulfonate in a mixture of 4:1 THF-CH2CI2 at reflux, but no reaction was observed (entry 1). Increasing the catalyst loading of silver(I) trifluoromethanesulfonate to 30 mol % (entry 3), 140 mol % (entry 6) or 300 mol % (entry 8) also failed to produce any reaction. The use of ytterbium(III) trifluoromethanesulfonate (entry 2), silver(I) tetrafluoroborate (entry 4) or platinum(II) chloride (entries 5, 7) all produced no reaction of any kind and in all cases, only starting material was recovered. The lack of reactivity of nitrile 2.77 was truly frustrating, unexpected and poorly understood.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  84  Table 2.3.7: Attempted cycloisomerization of nitrile 2.77  Ts  T  2.77  a  Entry  Conditions  1  2 mol % AgOTf, 4:1 T H F - C H C I , reflux 5 h  NR  2  10 mol % Yb(OTf) , THF, reflux, 8 h  NR  3  30 mol % AgOTf, 4:1 T H F - C H C I , reflux, 4 h  NR  4  30 mol % A g B F , 4:1 T H F - C H C I , reflux, 4 h  NR  5  30 mol % PtCI , toluene, 80 °C, 8 h  NR  6  140 mol % AgOTf, toluene, 80 °C, 8 h  NR  7  140 mol % PtCI , toluene, 80 °C, 8 h  NR  8  300 mol % AgOTf, 4:1 T H F - C H C I , reflux 5 h  NR  Result " 3  2  2  3  2  4  2  2  2  2  2  2  2  In all cases, recovery of starting material was observed. ^NR = no reaction  In an attempt to bring about an intermolecular Michael addition, enesulfonamide 2.4 was added slowly to a refluxing solution of 2 mol % silver(I) trifluoromethanesulfonate and phenylpropynoic acid methyl ester in dichloromethane (Scheme 2.3.7). However, only dimer 2 . 1 0 3 was ever recovered from the reaction in addition to a 92% recovery of the alkynoate.  o  ^ ' Ts N  2.4  Ph  =  C0 CH 2  3  2 mol% AgOTf CH CI , reflux, 1.5 h 2  2  6  3  %  2.103  Scheme 2.3.7: Attempted intermolecular Michael addition Formation of six-membered rings via platinum(II) catalyzed cycloisomerization reactions required prolonged heating to observe any conversion to product. Enesulfonamides 2.21 and 2 . 3 9 reacted sluggishly with platinum(II) chloride and afforded reaction products in poor yield whose ' H N M R spectra are consistent with the tentatively assigned structures of azadecalines 2 . 1 0 4 and 2 . 1 0 5 (Scheme 2.3.8). N o reaction was observed with the use of silver(I) trifluoromethanesulfonate or [dppb PtOH]2(BF4)2 as the precatalyst species. The reaction of tert-buty\ carbamate 2.41 under the same reaction conditions lead to a 60% mass recovery of a  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  85  2.7:1 mixture of starting material and a second compound that is tentatively described as diene 2.106. In all cases where platinum(II) chloride was used in a reaction that required heating for prolonged periods of time, it was found necessary to use degassed solvent and an inert gas atmosphere. Screw cap pressure tubes were used to ensure that no air could enter the reaction vessel during heating. Straying from these precautions usually led to the reaction stopping prematurely.  60% (2.7:1 mixture of 2.41:2.106)  2.41  B  o  c  2.106  Scheme 2.3.8: Cycloisomerization as a method for six-membered ring formation In order to circumvent the poor reactivity described above, the following procedure was developed as a means to obtain the desired azadecaline ring system (Scheme 2.3.9). A two-step, one-pot protocol for the cycloisomerization of enesulfonamide 2.30 followed by in situ reduction of the resultant diene with triethylsilane and trifluoroacetic acid afforded tetrasubstituted alkene 2.107 in 78% yield. The ESI mass spectrum of 2.107 was found to contain a peak corresponding to a mass of 349. The  1 3  C N M R spectrum displayed only 2  alkenyl signals (in addition to the signals associated with the toluenesulfonyl group and the methyl ester) and 9 aliphatic carbon signals. The signals in the ' r i N M R spectrum were assigned with a 2D C O S Y experiment and the allylic protons next to nitrogen were present as two doublets at 4.43 ppm and 2.83 ppm, both with coupling constants o f 13.2 H z , indicating  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  86  geminal coupling. Cyclopentene 2 . 1 0 7 was used to access a cyclohexenone ring via a classical ozonolysis-annulation sequence, affording azadecaline 2 . 1 0 9 in high yield. Enone 2 . 1 0 9 appears to exist in the tautomeric form illustrated in Scheme 2.3.9 as evidenced by the presence of 9 non-aliphatic signals in the  l 3  C N M R spectrum and the presence of both the enol proton  broad singlet at 13.1 ppm and a singlet at 7.23 ppm in the ' H N M R spectrum corresponding to the alkenyl proton a to nitrogen.  2.30  2.107  2.108  2.109  Scheme 2.3.9: Procedure for the formation of six-membered rings from enesulfonamide 2.30  The cycloisomerization-reduction protocol that was used for the formation of alkene 2 . 1 0 7 enabled the isolation of compounds that exhibited superior stability when compared to dienes 2.83-2.90.  Diene  2.82  was previously found to be particularly unstable, but application of this  procedure to enesulfonamide 2 . 1 9 resulted in complete and rapid decomposition of diene 2 . 8 2 . Performing the acid addition step at -78 °C or using C S A as the acidic species did not improve this result. Hydrogenation was proposed as a non-acidic alternative reduction. Fortunately, cycloisomerization of enesulfonamide 2 . 1 9 with platinum(II) chloride in toluene at 60 °C, followed by cooling of the reaction mixture to 0 °C, addition of palladium on carbon and stirring under an atmosphere of hydrogen gas afforded enesulfonamide 2 . 1 0 1 in 63% yield (Scheme 2.3.10). This result lends credence to the notion that the corresponding cycloisomerization proceeds well and that the low observed yield is due to issues with isolation and handling.  2.19  2.82  Scheme 2.3.10: Cycloisomerization-hydrogenation of enesulfonamide 2.19  2.101  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  87  Protons were assigned for enesulfonamide 2.101 based on a 2D C O S Y experiment and relative stereochemistry was determined by selective N O E studies (Figure 2.3.9). NOE  Figure 2.3.9: Observed selective NOE correlations for enesulfonamide 2.101 Dihydropyridine 2.81 proved to be much less reactive than enesulfonamide 2 . 1 9 and displayed no sign of reaction until the mixture was heated to reflux temperatures in toluene. In this case, however, cycloisomerization was accompanied by aromatization of the 1,4dihydropyridine ring system. B y employing the previously developed in situ hydrogenation protocol (Scheme 2.3.10), monoterpene alkaloid deoxyrhexifoline 2 . 1 1 0 was produced in 22% yield (Scheme 2.3.11). Deoxyrhexifoline was isolated from the mountain flower Castilleja rhexifolia in 1984 and the ' H N M R spectrum of 2 . 1 1 0 is consistent with the data provided in this report. ' 51  C H  3  0  2  C ^ ^  52  "  "H" Rn  i)10mol%PtCI toluene, reflux, 1 h 2  ii) 5 wt% Pd/C, H , 15 h 2  22%  2.81  °  C H  3  0  2  C ^ ^ ~N  deoxyrhexifoline  2.110  Scheme 2.3.11: Synthesis of deoxyrhexifoline via cycloisomerization-hydrogenation of 1,4dihydropyridine 2.81  2.3.4 Reduction of Enesulfonamides Tandem cycloisomerization-reduction procedures were developed that rendered isolable and stable products from reactions where the analogous diene was too unstable to be useful. The reaction conditions for the two steps were sufficiently compatible that both steps could be carried out sequentially in the same reaction vessel. It was then proposed that the cycloisomerization reaction could be carried out in the presence of a suitable hydride source,  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  88  giving rise to an in situ reduction without ever generating a diene, thus potentially further increasing product yields (Figure 2.3.10).  F i g u r e 2.3.10: Proposed cycloisomerization accompanied by in situ hydride reduction  Stirring enesulfonamide 2 . 3 0 in dichloromethane with 2 mol % silver(I) trifluoromethanesulfonate in the presence of NaBFL; or NaCNBH3 effectively inhibited cyclization and resulted in the recovery of starting material. Remarkably, when the cycloisomerization was carried out in the presence of triethylsilane, clean reduction of the enesulfonamide moiety was observed in preference to cyclization, affording piperidine 2 . 1 1 1 in 98% yield (Scheme 2.3.12). The alkyne moiety remained unmolested as evidenced by signals at 13  73 and 89 ppm in the  C N M R spectrum. This was an unexpected result given the electrophilic  nature of ynoates and their susceptibility to Michael addition, especially in the presence of a late transition metal species.  C0 CH 2  3  S c h e m e 2.3.12: Silver(I) catalyzed reduction of enesulfonamide 2.30  The silver ion appears to be mimicking a proton in a reaction that is commonly run with an acid such as trifluoroacetic acid. However, when enesulfonamide 2 . 3 0 was reduced with triethylsilane in the presence of silver(I) trifluoromethanesulfonate and two equivalents of calcium hydride, piperidine 2.111 was isolated in 90% yield, negating the possibility of acid catalysis.  This transformation worked well with unfunctionalized enesulfonamide 2 . 4 , unsubstituted alkyne 2 . 1 9 , nitrile 2 . 7 7 and ynoate 2 . 3 9 (Scheme 2.3.13). Importantly, no reaction was observed upon treating enesulfonamide 2.4 with triethylsilane in the absence of metal salts.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  89  1)  3)  2.77  2.114  2.39  2.115  Conditions: 3 mol % AgOTf, Et SiH (1.5 equiv), CH CI , rt, 3-5 h 3  2  2  Scheme 2.3.13: Silver(I) catalyzed reduction of selected enesulfonamides  Literature precedent suggests that the metal species should interact with the alkyne moiety. In light of the silver(I) catalyzed dimerization of enesulfonamide 2.4 (Scheme 2.3.7) and silver(I) catalyzed reduction of enesulfonamides, it appears that silver(I) interacts with the enesulfonamide preferentially over the alkyne function. Reduction of the enesulfonamide was an unexpected event and equates to the formal addition of two hydrogen atoms across the double bond. The reaction was run with 1.5 equivalents of triethylsilane, but the source of a full equivalent of H to complete the reduction is still unknown. The glassware used for these +  experiments was flamed dried in vacuo and the solvents and triethylsilane were distilled prior to use. Even i f all of the silver(I) trifluoromethanesulfonate added to the reaction (3 mol %) was in fact all hydrolyzed to trifluoromethanesulfonic acid, that would still only account for 3 mol % H . +  2.3.5 Hydrosilylation of Alkynes Given the unanticipated discovery of the silver(I) catalyzed reduction of enesulfonamides, the corresponding experiment was carried out with platinum(II) as a comparison. In predictable fashion, enesulfonamide 2.30 produced hydrosilylation product 2.116 when treated with 5 mol % platinum(II) chloride and triethylsilane in toluene at 60 °C (Scheme 2.3.14).  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  90  Cycloisomerizations  Scheme 2.3.14: Platinum(II) catalyzed hydrosilylation of ynoate 2.30  This transformation was found to be general, affording the cw-hydrosilylation products (Ealkenes) in good to excellent yield (Scheme 2.3.15). Double bond geometry of alkenyl silanes 2.117-2.126  was determined by comparison to reported data and by analysis of coupling  constants in ' H N M R spectra.  2.120  2.121  2.122  2.123  5 10  2.124  2.125  2.126  5)  Conditions: A) 5 mol % PtC , toluene, 60 °C, 10 min-1 h 2  B) 5 mol % PtCI , CH CI , reflux, 2-5 h 2  2  2  Scheme 2.3.15: Platinum(Il) catalyzed hydrosilylation of selected alkynes  While neither silver(I) nor platinum(II) produced a cyclization event in the presence of triethylsilane, the results of these experiments suggest that the cycloisomerizations catalyzed by silver(I) and platinum(II) are operating via two different mechanistic pathways. Platinum(ll) appears.to activate the alkyne moiety while results involving silver(I) indicate an activation of the enesulfonamide function.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  91  Cycloisomerizations  2.3.6 Mechanistic Considerations The proposed mechanistic pathway for metals such as platinum(II) involve coordination of the metal salt to the electron rich alkyne function A (Scheme 2.3.16). This metal-alkyne complex may undergo nucleophilic attack by the enesulfonamide to give iminium ion intermediate B or the reaction may proceed via cyclopropanation to give cyclopropyl metal carbenoid intermediate C . Due to the nucleophilicity of the nitrogen heteroatom lone pair, however, cyclopropane C would most probably fragment to give iminium ion B . Elimination to give enesulfonamide D and protodemetallation would afford diene E . Isomerization to diene F was demonstrated experimentally.  EWG ring expansion  G  H  I  Scheme 2.3.16: Proposed mechanistic scheme based upon literature precedent The proposed mechanistic pathway from enesulfonamide A to diene F appears to be the most straightforward option. Alternatively, i f enesulfonamide A was treated as a standard 1,6enyne similar to many of the all-carbon tethered 1,6-enynes discussed in Chapter 1 of this thesis, then application of the currently accepted mechanism for metal catalyzed cycloisomerizations predicts that cyclopropyl metal carbenoid C would undergo ring expansion to cyclobutane G before it could fragment to iminium ion B . Fragmentation of the cyclobutane ring would give  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed Cycloisomerizations  92  iminium ions B or H . Elimination of the metal species from H would, hypothetically, produce diene I. A major fault with the mechanistic pathway to diene I includes the generation of a potentially strained bridgehead double bond. Dienes such as I were not observed as was proved by the successful Diels-Alder cycloaddition reaction of diene F and was confirmed by X-ray crystallographic analysis of the product.  Silver(I) catalysts appear to preferentially interact with the enesulfonamide function and the mechanism proposed in Scheme 2.3.16 does not explain such observations. If enesulfonamide J interacted with silver(I) to give iminium ion K, then elimination of a proton would give silversubstituted enesulfonamide L , which may or may not be protonated ( M ) (Scheme 2.3.17). Carbometallation of the alkyne function with the alkyl silver species would provide alkenyl silver species N that upon protodemetallation would afford diene O.  t  Ts  M Scheme 2.3.17: Possible mechanistic pathway for silver(I) catalyzed cycloisomerization of enesulfonamide 2.30  In both o f the mechanisms proposed in Scheme 2.3.16 and Scheme 2.3.17, the proton at the P-position o f the enesulfonamide is transferred to the a-position o f the enoate. This proposal was investigated with a substrate that was deuterated at that particular position. Enesulfonamide 2.61 was treated with 2 mol % silver(I) trifluoromethanesulfonate in THF-CH2CI2 at reflux (entry 1) and afforded the desired diene in 88% yield with 25% deuterium incorporation at the alkenyl position. The percentage deuterium incorporation was determined by integration of signals in the ' H N M R spectrum. When the reaction was conducted in deuterated  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  93  Cycloisomerizations  dichloromethane, it gave similar results with 50% deuterium incorporation in the product diene (entry 2). In order to make sure that no deuterium was transferred from the solvent, nondeuterated substrate 2.30 was cyclized with silver(I) trifluoromethanesulfonate in deuterated dichloromethane, affording diene 2.85 in 90% yield with 0% deuterium incorporation, ruling out the solvent as a proton source (entry 3).  Table 2.3.8: Cycloisomerization studies involving deuterated enesulfonamide 2.61  Ts  Ts  2.61  d-2.85 Conditions  1  2 mol % AgOTf, 4:1 T H F - C H C I , reflux, 3.5 h  88%  25%  2  2 mol % AgOTf, C D C I , reflux, 1 h  81%  50%  2 mol % AgOTf, C D C I , reflux, 1 h  90%  0%  4  7 mol % AgOTf, C D C I , reflux, 0.5 h  50%  30%  5  2 mol % AgOTf, toluene, 80 °C, 2 h  80%  30%  6  2 mol % AgOTf, C D C I , reflux, 1 h  76%  40%  7  5 mol % PtCI , toluene, 80 °C, 3 h  72%  30%  3  2  2  a  Yield  d-lncorporation  Entry  2  2  2  2  2  2  2  2  2  b  c  2.30 used as starting material. Reported yields are isolated yields. Percentage deuterium incorporation was determined by integration of signals in the ' H N M R spectrum.  a  b  Both column chromatography and shaking the N M R sample with D2O did not affect the percent deuterium in the product. No observed correlation of %d-incorporation was observed whether silver(I) trifluoromethanesulfonate was weighed out as a solid from the glove box (entry 4) or introduced as a solution in toluene (entries 1-3,5) or d -toluene (entry 6). The amount of deuterium incorporated into the product was not consistent from reaction to reaction and did not appear to either change with the use of platinum(II) or silver(I) or depend on the identity o f the solvent. Deuterium incorporation could not be detected in any other signals in the 'l-l N M R spectrum, arguing against an intramolecular proton transfer during the reaction. Strict measures were taken during the set up of these reactions to exclude water. CD2CI2 was distilled over calcium hydride and glassware was washed with D 0 and flame dried in vacuo. 2  Since deuterium incorporation was only ever observed at one position and did not exceed 25-  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  94  50%, there was a significant amount of protonated diene produced that requires the presence of an adventitious proton source.  Unfortunately, the investigations using deuterated substrate 2.61 did little to provide any definitive answers about mechanism, but did manage to raise some interesting questions about proton transfer during this reaction. If only 25-50 % of the deuterium is transferred in an intramolecular fashion, then where does the rest of the deuterium go and where does the other 50-75 mol % H come from? The mechanism of this transformation is clearly not well +  understood at this time and requires further investigation.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  95  2.4 Conclusion The platinum(II) and silver(I) salt catalyzed cycloisomerization reactions of enesulfonamide and enecarbamate containing 1,6-enynes are an effective tool for the formation of five-membered rings. These experiments mark the first uses of these rc-nucleophiles in enyne cycloisomerizations and they displayed good reactivity, providing product dienes with control of double bond geometry and predictable product molecular structure.  Silver(I) salts were found to catalyze the facile formation of five-membered rings. These experiments represent the first uses of silver(I) salts as effective catalysts for enyne cycloisomerization reactions involving C - C bond formation.  Formation of six-membered rings under these cycloisomerization conditions were not easily accomplished, but this temporary roadblock was overcome with a developed cycloisomerization-reduction protocol to form a cyclopentene ring that was easily converted to a six-membered ring in a 2-step ozonolysis-annulation sequence.  The highly functionalized nature of the cycloisomerization product dienes provided useful handles for further manipulation ranging from Diels-Alder cycloadditions to acid catalyzed reductions and hydrogenations that could often be performed sequentially with the cycloisomerization in a "one-pot" procedure. These "one-pot" sequential reaction sequences allowed for a rapid construction of complex bi- and tricyclic scaffolds and avoided the isolation of relatively unstable intermediates. A cycloisomerization-hydrogenation sequence leading to the conversion of 1,4-dihydropyridine 2.81 to bicycle 2.110 completed a 4-step total synthesis of the natural product deoxyrhexifoline.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  96  Cycloisomerizations  2.5 Experimental 2.5.1 General Experimental A l l reactions were performed under an atmosphere of dry nitrogen. Glassware was flamedried prior to use. Glass syringes and stainless steel cannulae and needles used for handling anhydrous solvents and reagents were oven dried, cooled in a desiccator and flushed with dry nitrogen prior to use. Plastic syringes were flushed with dry nitrogen prior to use. Thin layer chromatography (TLC) was performed on DC-Fertigplatten SIL G-25  UV254  pre-coated T L C  plates. Column chromatography was performed on Silicycle ultra pure silica gel (40-63 |am, 230-400 mesh). Triethylamine washed silica gel has been stirred with triethylamine prior to packing and then sequentially flushed with polar solvent component and the solvent system of choice. Melting points were performed using a Mel-Temp II apparatus (Lab devices U S A ) and are uncorrected. Proton nuclear magnetic resonance ( ' i i N M R ) spectra and carbon nuclear magnetic resonance ( C N M R ) spectra were both recorded in deuterochloroform (unless 13  otherwise indicated) using either a Bruker A V - 3 0 0 , a Bruker WH-400 or a Bruker AV-400 spectrometer. Chemical shifts are reported in parts per million (ppm) and are referenced to the centerline of deuterochloroform (5 7.24 ppm ' H N M R ; 77.0 ppm  1 3  C N M R ) . Coupling constants  (/values) are given in Hertz (Hz). Fluorine nuclear magnetic resonance ( F N M R ) spectra l9  were recorded on a Bruker A V - 3 0 0 spectrometer and are referenced to the centerline of  CFCI3  ( 5 0 ppm). L o w resolution mass spectra were recorded by the Microanalytical Laboratory at the University of British Columbia on an Agilent HP 1100 spectrometer for electrospray ionization (ESI). Microanalyses were performed by the Microanalytical Laboratory at the University of British Columbia on a Fisions C H N - 0 Elemental Analyzer Model 1108.  Common reagents or materials were purchased from commercial sources and purified using established procedures.  53  Tetrahydrofuran and diethyl ether were distilled from sodium  benzophenone ketyl under an atmosphere of dry argon prior to use. Dichloromethane, 1,2dichloroethane, triethylamine, acetonitrile, pyridine, diisopropylamine and toluene were distilled from calcium hydride prior to use. A^N-dimethylformamide was dried by storing over flame dried 4 A molecular sieves three times over three successive days. Petroleum ether consisted of the 45-60 °C boiling point fraction. Solutions of n-BuLi and / - B u L i were purchased from  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  97  commercial sources and standardized by titration with a solution of /V-benzylbenzamide in tetrahydrofuran.  54  A p H 8 buffered solution of ammonium chloride was prepared by the  addition of 50 m L of concentrated ammonium hydroxide to 900 m L o f an aqueous saturated ammonium chloride solution.  2.5.2 Synthesis of Substrates  2.1  2.2  l - ( T o l u e n e - 4 - s u l f o n y l ) - p i p e r i d i n - 2 - o n e (2.2)  To a solution of 11.2 g 8-valerolactam (2.1) (113 mmol) in 150 m L T H F at -78 °C was added 73 m L of a solution of n-BuLi (1.63 M in hexanes, 119 mmol) dropwise. The reaction mixture was stirred for 1 h before the addition of 23.7 g of p-toluenesulfonyl chloride (124 mmol) in 150 m L of T H F and the resulting white suspension was allowed to stir and warm to rt overnight. The reaction mixture was diluted with 120 m L of dichloromethane and washed sequentially with water followed by a saturated aqueous brine solution. The combined aqueous washes were extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude pale yellow powder. Trituration with diethyl ether afforded 24.8 g (87 %) of the title compound 2.2 as a white powder, mp = 143-145 °C (lit. 144-145 °C). IR (film): 1684, 1350, 1173 cm" . ' H N M R (400 M H z , C D C b ) : 8 7.88 (d, J= 8.2 Hz, 2H), 7.28 1  (d, J= 8.2 H z , 2H), 3.88 (t, J= 6.1 Hz, 2H), 2.40 (s, 3H), 2.39 (t,J = 7.0 H z , 2H), 1.84-1.92 (m, 2H), 1.71-1.80 (m, 2H). 2.2 has been prepared previously, see: Casamitjana, N . ; Lopez, V . ; Jorge, A . ; Bosch, J.; Molins, E.; Roig, A . Tetrahedron 2000, 56, 4027-4042.  a  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  I  o  0  OH  Ts  Ts  2.2  2.3  98  Cycloisomerizations  Ts  2.4  l - ( T o l u e n e - 4 - s u l f o n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n e (2.4)  To a solution of 27.1 g of 2.2 (107 mmol) in 350 m L of dichloromethane at-78 °C was added 150 m L of a solution of diisobutylaluminum hydride (1 M in hexanes, 150 mmol) dropwise over 1.5 h. Stirring was continued at -78 °C for 1 h. The reaction was carefully quenched with 38 mL of p H 8 buffered aqueous ammonium chloride solution and allowed to stir and warm to rt for 1 h. To the reaction was added 50 g of magnesium sulfate and stirring was continued at rt for an additional hour. The resulting white suspension was filtered through Celite and concentrated by rotary evaporation in vacuo to afford 26.3 g of 2.3 as a white powder, mp = 125.5-128 °C. IR (fdm): 3469, 2950, 1329, 1159 cm" . ' H N M R (400 M H z , CDC1 ): 5 7.70 (d, J= 8.2 H z , 1  3  2H), 7.27 (d, J= 8.2 H z , 2H), 5.52 (s, 1H), 3.49-3.59 (m, 1H), 3.08 (td, J= 12.2 Hz, 2.8 Hz, 1H), 2.38-2.48 (m, 1H), 2.39 (s, 3H), 1.40-1.84 (m, 6H). 2.3 has been prepared previously, see: 1) Ahman, J.; Somfai, P. Tetrahedron 1992, 48, 9537-9544. 2) Kokotos, C . G . ; Aggarwal, V . K . Chem. Commun. 2006, 2156-2158.  To a solution of 26.3 g of 2.3 (103 mmol), 0.63 g of D M A P (5.2 mmol) and 43 m L of triethylamine (309 mmol) in 400 m L of dichloromethane cooled to 0°C was added 12 m L of methanesulfonyl chloride (155 mmol). The reaction was let stir and warm to rt for 15 h. The dark orange solution was quenched with 100 mL of a saturated aqueous solution of ammonium chloride. The aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed with a saturated aqueous brine solution, dried over magnesium sulfate and concentrated by rotary evaporation in vacuo to afford a crude red syrup. Purification of the crude material by column chromatography on triethylamine washed silica gel (10:1 hexanes:ethyl acetate) afforded 18.0 g (71 % over 2 steps) of the title compound 2.4 as a white solid, mp = 52-54 °C. IR(film): 1650, 1340, 1167 cm" . *H N M R (400 M H z , CDC1 ): 5 7.64 (d, J= 8.2 H z , 2H), 7.28 1  3  (d,J= 8.2 Hz, 2H), 6.62 (dt, J= 8.2 Hz, 1.8 Hz, 1H), 4.94 (dt, J = 8.2 Hz, 4.0 Hz, 1H), 3.313.37 (m, 2H), 2.40 (s, 3H), 1.88 (tdd, J= 6.1 Hz, 4.0 H z , 2.1 H z , 2H), 1.63 (quintet, J= 5.8 Hz, 2H).  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  99  2.4 has been prepared previously, see: Ahman, J.; Somfai, P. Tetrahedron 1992, 48, 9537-9544.  Ts  Ts  Ts  2.4  2.5  2.6  6 - M e t h o x y - l - ( t o l u e n e - 4 - s u l f o n y l ) - l , 2 , 3 , 6 - t e t r a h y d r o p y r i d i n e (2.6)  Sodium metal (1.79 g, 78.2 mmol) was added to 350 m L of methanol and stirred until no traces of sodium remained. To this solution was sequentially added 16.5 g of 2.4 (69.8 mmol) in 50 m L of methanol and 4.0 m L of bromine (78.1 mmol) to give an orange solution that was stirred for 50 min at rt. After concentration of the solution in vacuo by one half, 400 m L of diethyl ether was added. This mixture was washed with 100 m L of water. The aqueous wash was extracted with 100 m L of ether. The combined organic fractions were washed with an aqueous saturated brine solution, dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude orange powder. Careful trituration using diethyl ether afforded 19.5 g (82%) o f 2.5 as a white powder, mp - 105-107 °C . IR (film): 2952, 1598, 1334, 1163 cm" . ' H N M R (400 M H z , CDCI3): 5 7.82 (d, J = 8.2 Hz, 1  2H), 7.26 (d, J = 8.2 Hz, 2H), 5.26 (d, J = 2.1 H z , 1H), 4.29 - 433 (m, 1H), 3.38 (s, 3H), 3.28 3.34 (m, 1H), 3.04 ( d t , J = 12.8 Hz, 2.8 Hz, 1H), 2.39 (s, 3H), 2.14 - 2.26 (m, 1H), 1.67-1.85 (m, 2H), 1.36 (d, J = 14.0 H z , 1H).  I 3  C N M R (75 M H z , CDC1 ): 5 144.9, 138.3, 130.8, 129.3, 3  87.9, 57.4, 49.7, 41.3, 27.8, 23.0, 20.6. M S (ESI): 370 ( M ( B r ) + N a ) , 372 ( M ( B r ) + Na ). 79  +  81  +  To a solution o f 8.59 g of 2.5 (24.7 mmol) in 100 m L of D M F was added 4 m L of 1,8diazabicyclo[5.4.0] undec-7-ene (26.7 mmol) and the reaction mixture was stirred at 90 °C for 20 h. The resulting yellow solution was diluted with 400 m L of diethyl ether and washed sequentially with water followed by a saturated aqueous brine solution. The organic phase was dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude pale yellow solid. Purification of the crude material by column chromatography on triethylamine washed silica gel (6:1 hexanes:ethyl acetate) afforded 5.45 g (83 %) of the title compound 2.6 as a white solid, mp = 55.5-57 °C.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  100  Cycloisomerizations  IR (film): 2934, 1598, 1336, 1162 cm" . ' H N M R (400 M H z , CDC1 ): 5 7.66 (d, J = 8.2 Hz, 1  3  2H), 7.22 (d, J = 7.9 Hz, 2H), 5.73 - 5.84 (m, 2H), 5.24 (d, J = 3.7 H z , 1H), 3.67 - 3.74 (m, 1H), 3.36 (s,3H), 3.20-3.31 (m, 1H), 2.36 (s, 3H), 1.70- 1.77 (m,2H).  1 3  C N M R (75 M H z ,  CDC1 ): 8 144.7, 139.8, 131.0, 130.7, 128.4, 125.9, 82.5, 56.8, 38.9, 24.5, 22.9. M S (ESI): 236 3  ( M - OCH3), 290 ( M + Na ). Anal. Calcd for C i H i N 0 S : C , 58.40; H , 6.41; N , 5.24. Found: +  3  7  3  C, 58.11; H , 6.35; N , 5.45.  2 . 1  2  .  7  2-Oxo-piperidine-l -carboxylic acid  tert-butyl  ester (2.7)  To a solution of 1.02 g of 8-valerolactam (2.1) (10.3 mmol) in 20 m L of acetonitrile was added 122 mg of D M A P (1.0 mmol) followed by a solution of 2.50 g of di-tert-butyl dicarbonate (11.5 mmol) in 10 m L of acetonitrile. The colorless reaction mixture was stirred at rt for 2 h. The resulting orange reaction mixture was concentrated by rotary evaporation in vacuo and the resulting oil was taken up in diethyl ether. The mixture was sequentially washed with an aqueous I N HCI solution followed by a saturated aqueous brine solution. The organic phase was dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (4:1 hexanes:ethyl acetate) afforded 1.71 g (83 %) of the title compound 2.7 as a white crystalline solid, mp = 31-33 °C. (lit. 32-34 °C). IR (neat): 2979, 1771, 1718 cm" . ' H N M R (400 M H z , CDCI3): 8 3.50-3.57 (m, 2H), 2.34-2.44 1  (m, 2H), 1.66-1.76 (m, 4H), 1.40 (s, 9H).  1 3  C N M R (75 M H z , CDCI3): 8 171.0,152.4, 82.4,  46.0, 34.6, 27.7, 22.5, 20.2. 2.7 has been prepared previously, see: Williams, G . D.; Pike, R. A . ; Wade, C . E . ; Wills, M . Org. Lett. 2 0 0 3 , 5, 4227-4230.  ex  Chapter 2. Pt(II) orAg(I) Salt Catalyzed  *  C ^ O H  101  Cycloisomerizations  "  0  Boc  Boc  Boc  2.7  2.8  2.9  3,4-Dihydro-2//-pyridine-l-carboxylic acid  tert-butyl  ester (2.9)  To a solution of 1.90 g of 2.7 (9.6 mmol) in 50 m L of dichloromethane at -78 °C was added 14 m L of a solution of diisobutylaluminum hydride (1 M in hexanes, 14 mmol) dropwise. Stirring was continued at -78 °C for 1 h. The reaction was carefully quenched with 4 m L of p H 8 buffered aqueous ammonium chloride solution and allowed to stir and warm to rt for 1 h. To the reaction was added 8 g of magnesium sulfate and stirring was continued at rt for an additional hour. The resulting white suspension was filtered through Celite and concentrated by rotary evaporation in vacuo to afford 1.74 g of a crude colorless syrup. Purification of the crude material by column chromatography on triethylamine washed silica gel (4:1 hexanes:ethyl acetate) afforded 1.61 g (84 %) of 2.8 as a colorless oil. IR (neat): 3426, 2942, 1679 c m . *H N M R (400 M H z , CDC1 ): 8 5.63 (s, 1H), 3.60-3.79 (bm, 4  3  1H), 3.01 ( t d , J = 12.9 H z , 2.7 H z , 1H), 1.25-1.85 (m, 7H), 1.37 (s,9H).  1 3  C N M R (100 M H z ,  CDC1 ): 5 155.2, 79:9, 74.3, 39.0, 30.5, 28.2, 24.7, 17.7. 3  2.8 has been prepared previously, see: Dieter, R. K . ; Sharma, R. R. J. Org. Chem. 1996, 61, 4180-4184.  A solution of 1.22 g of 2.8 (6.1 mmol) and 35 mg of p-toluenesulfonic acid (0.18 mmol) in 30 m L of benzene was heated at reflux with a Dean-Stark trap for 20 minutes. The resulting yellow suspension was diluted with diethyl ether and sequentially washed with a saturated aqueous sodium bicarbonate solution followed by a saturated aqueous brine solution. The organic phase was dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude colorless oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (10:1 hexanes:ethyl acetate) afforded 0.98 g (88 %) of the title compound 2.9 as a colorless oil. IR (neat): 1703, 1653 cm" . ' H N M R (400 M H z , CDC1 ): 5 6.62-6.84 (m, 1H), 4.70-4.89 (m, 1  3  1H), 3.45-3.65 (m, 2H), 1.94-2.01 (m, 2H), 1.70-1.83 (m, 2H), 1.44 (s, 9H). 2.9 has been prepared previously, see: Dieter, R. K . ; Sharma, R. R. J. Org. Chem. 1996, 61, 4180-4184.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  0  102  Cycloisomerizations  N  Boc  Boc  Boc  2.9  2.10  2.11  OCH  3  6-Methoxy-3,6-dihydro-2.fl -pyridine-l-carboxyIic acid r  tert-butyl  ester (2.11)  Sodium metal (0.14 g, 6.3 mmol) was added to 40 m L of methanol and stirred until no traces of sodium remained. To this solution was sequentially added 0.98 g of 2.9 (5.4 mmol) in 10 mL of methanol and 0.29 m L of bromine (5.7 mmol) to give a yellow solution that was stirred for 2 h at rt. After concentration of the reaction mixture in vacuo to approximately 4 m L , the resulting yellow/white suspension was taken up in diethyl ether and washed with water. The aqueous phase was extracted with diethyl ether and the combined organic phases were washed with an aqueous saturated brine solution, dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude pale yellow oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (10:1 hexanes:ethyl acetate) afforded 1.49 g (94%) of 2 . 1 0 as a colorless o i l . IR(neat): 2976, 1699 cm" . ' H N M R (400 M H z , CDC1 ): 5 5.20-5.55 (m, 1H), 4.24 (s, 1H), 1  3  3.65-4.10 (m, 1H), 3.21 (s, 3H), 2.71-2.96 (m, 1H), 2.15-2.27 (m, 1H), 1.78-2.04 (m, 2H), 1.43 (s, 9H), 1.34-1.47 (m, 1H).  I 3  C N M R ( 7 5 M H z , CDCI3): 8 154.8, 85.2, 80.2, 54.7, 49.5, 37.0,  28.2, 26.9, 19.3. M S (ESI): 316 ( M ( B r ) + N a ) , 318 ( M ( B r ) + N a ) . Anal. Calcd for 79  +  81  +  C i i H o B r N 0 : C , 44.91; H , 6.85; N , 4.76. Found: C, 45.30; H , 6.58; N , 5.06. 2  3  2.10 has been reported previously, see: Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura, Y. Tetrahedron Lett. 1990, 31, 6385-6386.  To a solution of 1.38 g of 2 . 1 0 (4.7 mmol) in 50 m L of D M F was added 1 m L of 1,8diazabicyclo[5.4.0] undec-7-ene (6.7 mmol) and the reaction mixture was stirred at 90 °C for 20 h. The resulting yellow solution was diluted with diethyl ether and washed sequentially with water followed by a saturated aqueous brine solution. The organic phase was dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (10:1 hexanes:ethyl acetate) afforded 0.87 g (87 %) of the title compound 2.11 as a colorless oil. IR (film): 2932, 1702 cm" . ' H N M R (400 M H z , CDCI3): 8 5.93 (s, 1H), 5.70 (s, 1H), 5.20-5.47 1  (m, 1H), 3.80-4.15 (m, 1H), 3.29 (s, 3H), 2.87-3.11 (m, 1H), 2.03-2.23 (m, 1H), 1.81-1.99 (m,  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  1H), 1.43 (s,9H).  1 3  103  Cycloisomerizations  C N M R ( 1 0 0 M H z , C D C l ) : 5 154.9, 154.3, 129.8, 129.4, 125.3, 124.9, 3  79.6, 55.2, 36.6, 35.1, 28.2, 24.6. M S (ESI): 236 ( M + Na ). +  2.11 has been reported previously, see: Shono, T.; Terauchi, J.; Ohki, Y.; Matsumura, Y. Tetrahedron Lett. 1990, 31, 6385-6386.  2.13  2.12  4 - T r i m e t h y I s i I y l - b u t - 3 - y n - l -ol (2.13)  To a solution of 15 mL of 3-butyn-l-ol  (2.12)  (196 mmol) in 900 m L of T H F at-78 °C was  added 260 m L of a solution of ft-butyllithium (1.6 M in hexanes, 416 mmol) dropwise over 30 min. The yellow suspension was stirred at -78 °C for 45 min before 65 m L of chlorotrimethylsilane (512 mmol) was added dropwise over 30 min. The reaction was stirred for an additional hour before being allowed to stir and warm to rt. To the reaction was added 300 m L of an aqueous I N HCI solution and the resulting biphasic mixture was stirred at rt for 1 h. The aqueous phase was extracted two times with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated by rotary evaporation in vacuo to afford a crude yellow liquid. Purification of the crude material by distillation under reduced pressure afforded 26.4 g (94%) of the title compound 2 . 1 3 as a colorless liquid, bp = 48 °C, 0.6 mmHg (///. 72 °C, 12 mmHg). IR (neat): 3338, 2960, 2178 cm" . ' H N M R (400 M H z , CDC1 ): 5 3.65-3.73 (m, 2H), 2.48 (t, J 1  3  = 6.3 H z , 2H), 1.75 ( t , J = 6 . 4 Hz, 1H), 0.14 (s, 9H). 2.13 has been prepared previously, see: 1) Davison, E . C ; Forbes, I. T.; Holmes, A . B . ; Warner, J. A . Tetrahedron 1996, 52, 11601-11624. 2) Dobbs, A . P.; Jones, K . ; Veal, K . T. Tetrahedron 1998, 54, 2149-2160.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Si(CH ) 3  Si(CH )  3  3  HO'  104  Cycloisomerizations  Si(CH ) 3  3  3  Br  TsO'  2.13  2.14  ( 4 - B r o m o - b u t - l - y n y l ) - t r i m e t h y l - s i l a n e (2.14)  To a solution of 27.7 g of 2.13 (195 mmol) and 39.7 g of p-toluenesulfonyl chloride (208 mmol) in 300 m L of dichloromethane cooled to 0 °C was added 39 m L of pyridine (482 mmol). The reaction was let stir and warm to rt for 24 h. The resulting reaction mixture was washed with an aqueous I N HC1 solution (4 x 100 mL). The combined aqueous phases were extracted with dichloromethane.  The combined organics were dried over sodium sulfate and concentrated by  rotary evaporation in vacuo to afford a crude pale yellow oil. Purification of the crude material by column chromatography on a plug of silica gel (10:1—»6:1 hexanes:ethyl acetate) to afford toluene-4-sulfonic acid 4-trimethylsilyl-but-3-ynyl ester as a colorless oil. IR (neat): 2961, 2181, 1599 c m . H N M R (400 M H z , CDC1 ): 5 7.78 (d,J = 8.2 H z , 2H), 7.33 -1  ]  3  (d, J = 8.2 H z , 2H), 4.06 (t, J= 7.3 H z , 2H), 2.57 (t, J= 7.3 H z , 2H), 2.43 (s, 3H), 0.10 (s, 9H). toluene-4-sulfonic acid 4-trimethylsilyl-but-3-ynyl ester has been prepared previously, see: Davison, E. C ; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron 1996, 52, 11601-11624.  To a solution of the tosylate in 250 m L of D M F was added 24.5 g of NaBr (238 mmol) and the reaction was stirred at 60 °C for 2 h. The resulting yellow suspension was diluted with diethyl ether and washed with water. The aqueous phase was extracted with diethyl ether. The combined organic phases were washed with a saturated aqueous brine solution, dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude yellow liquid. Purification of the crude material by passing through a silica gel plug with petroleum ether eluant followed by distillation under reduced pressure afforded 29.4 g (73% over 2 steps) of the title compound 2 . 1 4 as a colorless liquid, bp = 68 °C, 7 mmHg (lit. 14-16 °C, 20 mmHg). IR (neat): 2961, 2178, 1251 cm" . H N M R (400 M H z , CDCI3): 8 3.40 (t, J= 7.5 Hz, 2H), 2.75 1  ]  (t, J = 7 . 5 Hz, 2H), 0.13 (s, 9H). 2.14 has been prepared previously, see: 1) Davison, E. C ; Forbes, I. T.; Holmes, A. B.; Warner, J. A. Tetrahedron 1996, 52, 11601-11624. 2) Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron 1998, 54, 2149-2160.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  2.15  105  Cycloisomerizations  2.16  5 - T r i m e t h y I s i I y l - p e n t - 4 - y n - l - o l (2.16)  Following the analogous procedure as for the formation of 2 . 1 3 using 15 m L of 2 . 1 5 (161 mmol), 230 m L of a solution of «-butyllithium (1.53 M in hexanes, 352 mmol), 1L of T H F and 52 m L of chlorotrimethylsilane afforded 25.4 g (99%) of the title compound 2 . 1 6 as a colorless liquid, bp = 82 °C, 3 mmHg (lit. 118-120, 22 mmHg). IR (neat): 3349, 2958, 2176, 1250 cm"'. ' H N M R (400 M H z , CDC1 ): 8 3.70-3.78 (m, 2H), 2.33 3  (t, .7=7.0 H z , 2H), 1.75 (quintet, J= 6.1 Hz, 2H), 1.54 (s, 1H), 0.12 (s, 9H). 2.16 has been prepared previously, see: Davison, E. C ; Forbes, I. T.; Holmes, A . B.; Warner, J. A . Tetrahedron 1996, 52, 11601-11624.  HO  ^  Si(CH ) 3  ^  TsO  3  ^Si(CH ) 3  ^Si(CH )  3  3  2.16  3  2.17  ( 5 - B r o m o - p e n t - l - y n y l ) - t r i m e t h y l - s i l a n e (2.17)  Following the analogous procedure as for the conversion o f 2 . 1 3 into the corresponding ptoluenesulfonate using 25.4 g of 2 . 1 6 (162 mmol), 37.7 g of p-toluenesulfonyl chloride (198 mmol), 300 m L of dichloromethane and 31 m L of pyridine (383 mmol) afforded toluene-4sulfonic acid 5-trimethylsilyl-pent-4-ynyl ester as a colorless oil. IR (neat): 2960, 2177, 1599 cm"'. ' H N M R (400 M H z , CDCI3): 8 7.78 (d, J= 8.5 Hz, 2H), 7.32 (d, J= 8.5 H z , 2H), 4.11 (t, J= 6.1 Hz, 2H), 2.43 (s, 3H), 2.26 (t,J= 6.9 H z , 2H), 1.82 (quintet, J = 6 . 6 H z , 2H), 0.08 (s, 9H). toluene-4-sulfonic acid 5-trimethylsilyl-pent-4-ynyl ester has been prepared previously, see: Davison, E. C ; Forbes, I. T.; Holmes, A . B.; Warner, J. A . Tetrahedron 1996, 52, 11601-11624.  Following the analogous procedure as for the formation of 2 . 1 4 using toluene-4-sulfonic acid 5trimethylsilyl-pent-4-ynyl ester, 250 mL of D M F and 20.0 g of NaBr (194 mmol) afforded 26.3 g (75% over 2 steps) of the title compound 2 . 1 7 as a colorless liquid, bp = 73 °C, 4 mmHg (///. 66 °C, 4 mmHg). IR (neat): 2961, 2177, 1250 cm"'. ' H N M R (400 M H z , CDC1 ): 8 3.49 (t, J= 6.4 H z , 2H), 2.39 3  (t, J= 6.7 H z , 2H), 2.02 (quintet, J= 6.7 H z , 2H), 0.12 (s, 9H).  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  106  2.17 has been prepared previously, see: Davison, E . C ; Forbes, I. T.; Holmes, A . B . ; Warner, J. A . y  Tetrahedron 1996, 52, 11601-11624.  Ts  Ts  2.6  2.18  l - ( T o l u e n e - 4 - s u l f o n y l ) - 4 - ( 4 - t r i m e t h y l s i l y l - b u t - 3 - y n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n e (2.18)  To a suspension of 1.23 g of magnesium (50.5 mmol) in 35 m L o f T H F was added 3.47 g of 2 . 1 4 (16.9 mmol). The reaction mixture was stirred for 70 min to give a forest green solution. This solution was transferred dropwise to a cold (-78 °C) suspension of 1.51 g o f 2.6 (5.63 mmol) and 139 mg of copper bromide-dimethyl sulfide complex (0.67 mmol) in 15 m L of T H F . The green suspension was stirred at-15 °C for 10 h, then stirred at rt for 12 h. The black reaction mixture was diluted with diethyl ether and washed successively with a p H 8 buffered saturated aqueous solution of ammonium chloride until the organic phase became translucent and the aqueous layer no longer turned blue. The combined aqueous washes were extracted with diethyl ether (twice). The combined organic fractions were dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (8:1 hexanes:ethyl acetate) afforded 1.74 g (86 %) of the title compound 2 . 1 8 as a colorless oil that solidified upon storage in the freezer, mp = 52-54 °C. IR(film): 2657,2173, 1645, 1353, 1249, 1167 cm" . ' H N M R (400 M H z , CDCI3): 8 7.64 (d, J 1  = 8.2 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 6.61 (dd, J = 8.6 Hz, 2.1 Hz, 1H), 4.86 (dd, J = 8.6 Hz, 3.1 Hz, 1H), 3.47 ( d d d , J = 11.9 Hz, 6.7 Hz, 3.4 Hz, 1H), 3.19 (ddd, J = 12.2 Hz, 9.5 H z , 3.1 Hz, 1H), 2.40 (s, 3H), 2.17 ( t , J = 9.3 Hz, 2H), 2.10 - 2.20 (m, 1H), 1.72- 1.80 (m, 1H), 1.221.50 (m, 3H), 0.10 (s, 9H).  1 3  C N M R (75 M H z , CDC1 ): 8 143.8, 135.2, 129.9, 127.2, 125.0, 3  112.1, 106.7,85.2,42.5,34.6,30.7,26.8,21.7, 17.4,0.28. Anal. Calcd for CigHzyNC^SSi: C , 63.11; H , 7.53; N , 3.87. Found: C, 63.31; H , 7.67; N , 4.06.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Si(CH ) 3  107  Cycloisomerizations  3  N i Ts  fs  2.18  2.19  4 - B u t - 3 - y n y l - l - ( t o l u e n e - 4 - s u l f o n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n e (2.19)  To a solution of 1.74 g of 2 . 1 8 (4.82 mmol) in 45 m L of methanol was added 1.34 g of potassium carbonate (9.73 mmol). The reaction mixture was stirred at rt for 14 h. Concentration by rotary evaporation in  vacuo  resulted in a yellow residue to which 100 m L of diethyl ether  was added. The solution was washed with water and a saturated aqueous brine solution. The combined aqueous washes were back extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated by rotary evaporation in  vacuo  to afford a  crude yellow syrup. Purification by column chromatography on triethylamine washed silica gel (6:1 hexanes:ethyl acetate) afforded 1.31 g (94%) of the title compound 2 . 1 9 as a colorless syrup that crystallized in the freezer, mp = 53-54.5 °C. IR (film): 3285, 2926, 1646, 1352, 1166 cm" . ' H N M R (400 M H z , CDCI3): 8 7.60 (d, J = 8.2 1  Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.59 (dd, J = 8.2 Hz, 1.8 Hz, 1H), 4.83 (dd, J = 8.2 Hz, 2.4 Hz, 1H), 3.46 ( d d d , J = 12.2 Hz, 6.7 Hz, 3.4 Hz, 1H), 3.15 (ddd, J= 12.2 Hz, 9.8 Hz, 3.1 Hz, 1H), 2.37 (s, 3H), 2.11 - 2.20 (m, 1H), 2.10 (tt, J = 7.3 Hz, 2.4 Hz, 2H), 1.88 (t, J = 2.8 Hz, 1H), 1.69- 1.78 (m, 1H), 1.23-1.48 (m, 3H).  1 3  C N M R (75 M H z , CDC1 ): 8 145.1, 136.3, 3  131.2, 128.4, 126.3, 113.2,85.1,70.2,43.7,35.6,31.6,28.1,23.0, 17.2. Anal. Calcd for C,6H N02S: C, 66.40; H , 6.62; N , 4.84. Found: C, 66.75; H , 6.71; N , 4.81. 19  Ts  Ts  2.6  2.20  Si(CH ) 3  3  l - ( T o l u e n e - 4 - s u l f o n y l ) - 4 - ( 5 - t r i m e t h y l s i I y l - p e n t - 4 - y n y l ) - l , 2 3 , 4 - t e t r a h y d r o p y r i d i n e (2.20)  Following the analogous procedure as for the formation of 2.18 using 1.23 g of magnesium (50.8 mmol), 3.74 g o f 2 . 1 7 (17.1 mmol), 35 m L of T H F , 1.50 g o f 2.6 (5.62 mmol) in 15 m L of T H F and 140 mg of copper bromide-dimethyl sulfide complex (0.-68 mmol) afforded 1.73 g (82%) of the title compound 2.20 as a pale yellow syrup.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  108  Cycloisomerizations  IR(neat): 2954, 2173, 1646 cm" . ' H N M R (400 M H z , CDCI3): 5 7.64 (d, J= 8.2 Hz, 2H), 7.28 1  (d, J= 8.2 H z , 2H), 6.59 (dd, J= 8.6 H z , 2.1 Hz, 1H), 4.86 (dd, J= 8.6 H z , 2.4 H z , 1H), 3.51 ( d d d , J = 12.2 H z , 6.1 H z , 3.4 Hz, 1H), 3.15 (ddd, J= 12.2 H z , 9.8 H z , 3.1 H z , 1H), 2.40 (s, 3H), 2.14 (t, .7=7.0 Hz, 2H), 1.95-2.07 (m, 1H), 1.69-1.79 (m, 1H), 1.46 (quintet, J= 7.5 Hz, 2H), 1.20-1.36 (m, 3H), 0.10 (s, 9H).  1 3  C N M R (75 M H z , CDCI3): 5 145.0, 136.4, 131.1, 128.5,  125.9, 114.1, 108.4,86.2,43.9,36.3,32.4,28.5,27.1,23.0,21.2,  1.5. Anal. Calcd for  C oH29N0 SSi: C , 63.95; H , 7.78; N , 3.73. Found: C, 63.55; H , 7.73; N , 3.98. 2  2  2.20  2.21  4 - P e n t - 4 - y n y l - l - ( t o l u e n e - 4 - s u l f o n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n e (2.21)  Following the analogous procedure as for the formation of 2 . 1 9 using 1.73 g o f 2 . 2 0 (4.61 mmol), 1.29 g of potassium carbonate (9.34 mmol) and 45 m L of methanol afforded 1.39 g (99%) of the title compound 2.21 as a pale yellow oil. IR (neat): 3290, 2941, 1646 cm" . ' H N M R (400 M H z , CDC1 ): 8 7.60 (d, J= 8.4 Hz, 2H), 7.25 1  3  (d,J= 8.2 Hz, 2H), 6.55 (dd, J= 8.6 H z , 2.1 Hz, 1H), 4.82 ( d d , / = 8.6 H z , 2.8 H z , 1H), 3.47 (ddd, J= 11.9 Hz, 6.4 H z , 3.4 Hz, 1H), 3.11 (ddd, .7 = 12.2 H z , 9.8 H z , 3.1 H z , 1H), 2.36 (s, 3H), 2.08 (td, .7=7.0 Hz, 2.4 Hz, 2H), 1.92-2.02 (m, 1H), 1.87 (t, .7=2.8 H z , 1H), 1.65-1.75 (m, 1H), 1.43 (quintet, J= 7.6 Hz, 2H), 1.17-1.34 (m, 3H).  1 3  C N M R (75 M H z , CDCI3): 5 145.0,  136.3, 131.1, 128.4, 125.9, 114.0, 85.5, 70.0, 43.9, 36.2, 32.4, 28.5, 26.9, 22.9, 19.8. Anal. Calcd for C , H , N 0 S : C , 67.29; H , 6.98; N , 4.62. Found: C, 67.36; H , 6.99; N , 4.78. 7  2  2  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Si(CH ) 3  N  OCH  109  Cycloisomerizations  3  N  3  Boc 2.11  Boc  Boc  2.22  2.23  4 - B u t - 3 - y n y l - 3 , 4 - d i h y d r o - 2 / / - p y r i d i n e - l - c a r b o x y l i c a c i d tert-butyl  ester (2.23)  Following the analogous procedure as for the formation of 2 . 1 8 using 0.504 g of magnesium (20.7 mmol), 1.45 g of 2 . 1 4 (7.05 mmol), 15 m L of T H F , 0.486 g of 2.11 (2.28 mmol) in 8 mL of T H F and 59 mg of copper bromide-dimethyl sulfide complex (0.29 mmol) afforded 0.66 g (94%) of 2.22 as a pale yellow syrup.  Following the analogous procedure as for the formation of 2 . 1 9 using 0.65 g of 2.22 (2.11 mmol), 0.50 g o f potassium carbonate (3.62 mmol) and 20 m L o f methanol afforded 0.48 g (97%o) of the title compound 2 . 2 3 as a colorless oil. IR(film): 3303,2934, 1703, 1649 cm" . H N M R (400 M H z , CDC1 ): 8 6.65-6.87 (m, 1H), 1  ]  3  4.62-4.83 (m, 1H), 3.58-3.76 (m, 1H), 3.37 ( d d d , / = 12.8 Hz, 9.5 H z , 3.4 Hz, 1H), 2.27-2.35 (m, 1H), 2.24 (td,J=7.3 Hz, 2.6 Hz, 2H), 1.94 (t, 7 = 2 . 6 Hz, 1H), 1.82-1.94 (m, 1H), 1.40-1.63 (m, 3H), 1.46 (s,9H).  1 3  C N M R (100 M H z , CDC1 ): 8 152.0, 125.3, 108.6,83.9,80.5,68.6, 3  39.9, 34.4, 30.7, 28.3, 27.4, 15.9. M S (ESI): 258 ( M + Na ). +  2.11  2.24  2.25  4-Pent-4-ynyl-3,4-dihydro-2//-pyridine-l-carboxylic acid  tert-butyl  ester (2.25)  Following the analogous procedure as for the formation o f 2 . 1 8 using 0.304 g o f magnesium (12.5 mmol), 0.727 g of 2 . 1 7 (3.32 mmol), 9 m L of T H F , 0.296 g of 2.11 (1.39 mmol) in 6 m L of T H F and 37 mg of copper bromide-dimethyl sulfide complex (0.18 mmol) afforded 0.41 g (92%) of 2 . 2 4 as a colorless syrup.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  110  Following the analogous procedure as for the formation of 2 . 1 9 using 0.40 g of 2 . 2 4 (1.24 mmol), 0.38 g of potassium carbonate (2.75 mmol) and 15 m L o f methanol afforded 0.30 g (99%) of the title compound 2 . 2 5 as a colorless oil. IR (film): 3304, 2938, 1703, 1649 cm" . H N M R (400 M H z , CDC1 ): 8 6.62-6.86 (m, 1H), 1  !  3  4.64-4.83 (m, 1H), 3.60-3.78 (m, 1H), 3.34 (ddd, J= 12.8 H z , 9.5 H z , 3.4 H z , 1H), 2 . 1 8 ( t d , J = 7.0 H z , 2.6 H z , 2H), 2.08-2.18 (m, 1H), 1.93 (t, .7=2.6 H z , 1H), 1.80-1.93 (m, 1H), 1.52-1.63 (m, 2H), 1.46 (s, 9H), 1.34-1.50 (m, 3H).  1 3  C N M R ( 1 0 0 M H z , CDC1 ): 8 152.0, 124.9, 109.4, 3  84.2, 80.5, 68.4, 40.5, 35.0, 31.3, 28.3, 27.8, 25.8 18.5. M S (ESI): 272 ( M + N a ) . +  2.26  2.27  5 - B r o m o - p e n t - 2 - y n e (2.27)  To a solution of 5.1 m L of 3-pentyn-l-ol 2 . 2 6 (55.3 mmol) and 15.8 g of/j-toluenesulfonyl chloride (83.0 mmol) in 100 m L of dichloromethane at 0 °C was added 9 m L of pyridine (111 mmol). The reaction was let stir and warm to rt for 24 h. The resulting reaction mixture was washed with an aqueous I N HCI solution. The combined aqueous phases were extracted with dichloromethane. The combined organics were dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification o f the crude material by column chromatography on a plug of silica gel (10:1—>6:1 hexanes:ethyl acetate) to afford 9.90 g (75%) o f toluene-4-sulfonic acid pent-3-ynyl ester as a colorless oil. IR (neat): 2922, 1599, 1362 cm" . ' H N M R (400 M H z , CDC1 ): 8 7.78 (d, J= 8.2 H z , 2H), 7.33 1  3  (d, J= 8.2 Hz, 2H), 4.04 (t,J= 7.3 Hz, 2H), 2.46 (t o f quartets, J= 7.3 H z , 2.4 Hz, 2H), 2.43 (s, 3H), 1.69 (t, .7=2.4 H z , 3H). toluene-4-sulfonic acid pent-3-ynyl ester has been prepared previously, see: 1) Ren, X . F.; Turos, E.; Lake, C. H.; Churchill, M . R. J. Org. Chem. 1995, 60, 6468-6483. 2) Collins, C. J.; Hanack, M . ; Stutz, H.; Auchter, G.; Schoberth, W. J. Org. Chem. 1983, 48, 5260-5268.  To a solution of 3.18 g of the tosylate (13.4 mmol) in 60 m L of D M F was added 4.12 g of NaBr (40.0 mmol) and the reaction was stirred at 60 °C for 3 h. The resulting yellow suspension was diluted with diethyl ether and washed with water. The aqueous phase was extracted with diethyl  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  111  Cycloisomerizations  ether. The combined organic phases were washed with a saturated aqueous brine solution, dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude colorless liquid. Purification of the crude material by distillation under reduced pressure afforded 1.81 g (92%) of the title compound 2 . 2 7 as a colorless liquid, bp = 85 °C, 20 mmHg (lit. 64-67 °C, 40 mmHg). IR (neat): 2920, 1439, 1272, 1213 cm"'. *H N M R (400 M H z , CDCI3): 8 3.39 (t,J= 7.3 Hz, 2H), 2.67 (t o f quartets, J = 7.3 H z , 2.4 Hz, 2H), 1.77 (t,J= 2.4 Hz, 3H). 2.27 has been prepared previously, see: Lubell, W . D . ; Jamison, T. F.; Rapoport, H . J. Org. Chem. 1990, 55,3511-3522.  2.6  2.28  4-Pent-3-ynyl-l-(toluene-4-sulfonyl)-l,2,3,4-tetrahydropyridine  (2.28)  Following the analogous procedure as for the formation of 2 . 1 8 using 0.269 g of magnesium (11.1 mmol), 0.526 g of 2 . 2 7 (3.58 mmol), 8 m L of THF, 0.307 g of 2.6 (1.15 mmol) in 4 m L of THF and 33 mg of copper bromide-dimethyl sulfide complex (0.16 mmol) afforded 0.273 g (78%) of the title compound 2 . 2 8 as a white solid, mp = 102-104 °C. IR (film): 2921, 1645, 1352, 1166 cm" . ' H N M R (400 M H z , CDCI3): 8 7.62 (d, J = 8.2 Hz, 1  2H), 7.27 (d, J = 8.2 H z , 2H), 6.58 (dd, J = 8.2 Hz, 1.8 Hz, 1H), 4.84 (dd, J = 8.2 Hz, 3.1 Hz, 1H), 3.46 ( d d d , y = 12.2 Hz, 6.7 Hz, 3.4 Hz, 1H), 3.16 (ddd, J = 12.2 Hz, 9.5 Hz, 3.1 Hz, 1H),  2.38 (s, 3H), 2.10 - 2.19 (m, 1H), 2.03 - 2 . 1 0 (m, 2H), 1.69 - 1.78 (m, 1H), 1.69 (t, J = 2.4 Hz, 3H), 1.20-1.44 (m, 3H).  1 3  C N M R (75 M H z , CDC1 ): 8 145.0, 136.4, 131.1, 128.5, 126.1, 3  113.6, 79.7, 77.4, 43.8, 36.2, 31.7, 28.1, 22.9, 17.5, 4.8. Anal. Calcd for C H i N 0 S : C, 67.29; 1 7  H , 6.98; N , 4.62. Found: C , 67.04; H , 7.02; N , 4.85.  2  2  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  fs  "fs  2.19  2.29  112  Cycloisomerizations  4 - ( 4 - P h e n y l - b u t - 3 - y n y l ) - l - ( t o l u e n e - 4 - s u l f o n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n e (2.29)  To a solution of 254 mg of 2 . 1 9 (0.88 mmol) and 0.12 m L of iodobenzene (1.07 mmol) in 3.5 mL of diethylamine was added 22 mg of bis(triphenylphosphine)palladium dichloride (0.031 mmol) and 5.5 mg of copper(I) iodide (0.029 mmol) in one portion. The reaction mixture was stirred in the dark for 7 h. After filtration through a short silica gel plug using dichloromethane as eluant, the solution was concentrated by rotary evaporation in vacuo to afford a crude orange semi-solid. Purification of the crude material by column chromatography on triethylamine washed silica gel (8:1 hexanes:ethyl acetate) afforded 0.28 g (87 %) of the title compound 2 . 2 9 as a yellow solid that turned pale orange upon standing, mp = 77-81 °C. IR (film): 2926, 1645, 1352, 1166 cm" . ' H N M R (400 M H z , CDCI3): 8 7.64 (d, J = 8.2 Hz, 1  2H), 7.22-7.35 (m, 7H), 6.64 ( d d , J = 8 . 6 Hz, 2.1 Hz, 1H),4.91 (dd, J = 8.6 Hz, 3.1 Hz, 1H), 3.51 ( d d d , J = 11.9 Hz, 6.4 Hz, 3.4 Hz, 1H), 3.20 ( d d d , J = 12.2 H z , 9.5 H z , 3.1 Hz, 1H), 2.39 (s, 3H), 2.36 (dd, 7 = 7.3 Hz, 2.1 H z , 2H), 2.19 - 2.29 (m, 1H), 1.76- 1.85 (m, 1H), 1.53 ( q , J = 7.3 Hz, 1H), 1 . 4 6 ( q , J = 7 . 3 H z , 1H), 1.31-1.41 (m, 1H).  1 3  C N M R (75 M H z , CDC1 ): 8 3  145.1, 136.4, 132.9, 131.2, 129.6, 129.1, 128.5, 126.3, 125.1, 113.4, 90.7, 82.5,43.8,35.9,35.6, 31.9, 28.2, 23.0, 18.2. Anal. Calcd for C22H23NO2S: C, 72.30; H , 6.34; N , 3.83. Found: C, 72.13; H , 6.44; N , 4.04.  co CH 2  is  is  2.19  2.30  3  5 - [ l - ( T o l u e n e - 4 - s u l f o n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n - 4 - y l ] - p e n t - 2 - y n o i c a c i d m e t h y l ester (2.30)  To a solution of 0.53 g of 2 . 1 9 (1.83 mmol) in 18 m L of diethyl ether at-78 °C was added 1.3 mL of a solution of n-butyllithium (1.53 M in hexanes, 2.03 mmol) dropwise. The reaction was stirred at-78 °C for 45 min. before 0.73 m L of methyl chloroformate (9.45 mmol) was added.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  113  Cycloisomerizations  The reaction was stirred at -78 °C for an additional 20 min before being warmed to rt for 1 h. The reaction mixture was diluted with diethyl ether, and washed sequentially with water followed by an aqueous saturated brine solution. The combined aqueous washes were extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (6:1 hexanes:ethyl acetate —> 4:1 hexanes:ethyl acetate) afforded 0.4721 g (74 %) of the title compound 2 . 3 0 as a colorless syrup that crystallized in the freezer, mp = 67.5-70 °C. IR(neat): 2951, 2237, 1713, 1645 cm" . ' H N M R (400 M H z , CDC1 ): 5 7.63 (d,J = 8.2 Hz, 1  3  2H), 7.29 (d, J = 8.2 H z , 2H), 6.63 (dd, J = 8.2 Hz, 1.8 Hz, 1H), 4.82 (dd, J = 8.2 H z , 2.4 Hz, 1H), 3.72 (s, 3H), 3.48 (ddd, 7 = 12.2 Hz, 6.7 Hz, 3.4 Hz, 1H), 3.17 (ddd, 7 = 12.2 Hz, 9.5 Hz, 3.1 Hz, 1H), 2.41 (s, 3H), 2.30 (td, 7 = 7 . 3 Hz, 1.8 Hz, 2H), 2.12 - 2.21 (m, 1H), 1.72- 1.81 (m, 1H), 1.48- 1.56 (m,2H), 1.26- 1.37 (m, 1H).  1 3  C N M R (75 M H z , CDCI3): 5 155.4, 145.2,  136.2, 131.2, 128.4, 126.7, 112.5,90.1,74.7, 54.0,43.6, 34.6,31.7,28.0,23.0, 17.4. Anal. Calcd for C i H i N 0 S : C, 62.23; H , 6.09; N , 4.03. Found: C, 62.31; H , 6.21; N , 4.38. 8  2.19  2  4  2.31  6 - [ l - ( T o l u e n e - 4 - s u I f o n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n - 4 - y l ] - h e x - 3 - y n - 2 - o n e (2.31)  To a solution of 0.12 g of 2 . 1 9 (0.42 mmol) in 1.5 m L of T H F at-78 °C was added 0.27 m L of a solution o f tt-butyllithium (1.61 M in hexanes, 0.44 mmol) dropwise. After the reaction mixture was stirred for 2 h at-78 °C, a slurry of 61 mg of zinc chloride (0.446 mmol) in 1.8 m L of T H F was added. The reaction mixture was stirred at -78 °C for 15 min before being warmed to - 4 0 °C for 45 min. The reaction mixture was then added dropwise to a solution of 0.1 m L of acetyl chloride (1.41 mmol) in 1.8 m L of T H F at -40 °C. The reaction mixture was stirred at-40 °C for 1 h, then warmed to rt and stirred for 2 h. The reaction mixture was diluted with diethyl ether, and washed sequentially with water followed by an aqueous saturated brine solution. The combined aqueous washes were extracted with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a  Chapter 2. Pt(II) or Ag(l) Salt Catalyzed  Cycloisomerizations  114  crude yellow oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (6:1 hexanes:ethyl acetate —> 4:1 hexanes:ethyl acetate) afforded 83 mg (74 %) of the title compound 2.31 as a yellow oil. IR (film): 2210, 1674, 1354, 1166 cm" . ' H N M R (400 M H z , CDC1 ): 8 7.57 (d, J= 8.2 Hz, 1  3  2H), 7.24 (d, J= 8.2 H z , 2H), 6.57 (dd, J= 8.6 Hz, 2.1 Hz, 1H), 4.78 (dd, J= 8.6 H z , 3.1 H z , 1H), 3.43 (ddd, J= 12.2 Hz, 6.4 Hz, 3.4 H z , 1H), 3.12 (ddd, J= 12.2 H z , 9.5 H z , 3.1 Hz, 1H), 2.40 (s, 3H), 2.30 ( t , J = 7.3 Hz, 2H), 2.26 (s, 3H), 2 . 1 0 - 2 . 1 8 (m, 1H), 1.70- 1.80 (m, 1H), 1.45 (dd, .7 = 13.4 H z , 7.0 Hz, 1H), 1.37(dd,/ = 13.7 H z , 7.3 H z , 1H), 1.26- 1.34 (m, 1H).  1 3  C  N M R (75 M H z , CDC1 ): 8 186.1, 145.2, 136.1, 131.2, 128.4, 126.6, 112.6, 94.3,83.0, 43.6, 3  34.7, 34.1, 31.7, 28.0, 22.9, 17.6. M S (ESI): 354 ( M + N a ) . +  C0N(CH ) 3  is  2  is  2.19  2.32  5-[l-(Toluene-4-sulfonyl)-l,2,3,4-tetrahydropyridin-4-yl]-pent-2-ynoic acid dimethylamide (2.32)  Following the analogous procedure as for the formation of 2 . 3 0 using 0.197 g of 2 . 1 9 (0.68 mmol), 0.43 m L of a solution of «-butyllithium (1.66 M in hexanes, 0.71 mmol), 7 m L of diethyl ether and 0.38 m L of dimethylcarbamoyl chloride (4.1 mmol) afforded a crude orange oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (2:3 hexanes:ethyl acetate) afforded 0.160 g (65%) of the title compound 2 . 3 2 as a colorless oil. IR (neat): 2927, 2225, 1636, 1396 cm" . ' H N M R (400 M H z , CDC1 ): 8 7.57 (d, J = 8.2 Hz, 1  3  2H), 7.25 (d, J = 8.2 H z , 2H), 6.57 (dd, J = 8.2 H z , 1.8 Hz, 1H), 4.79 (dd, J = 8.2 H z , 3.1 Hz, 1H), 3.43 (ddd, J = 12.2 Hz, 6.7 Hz, 3.4 Hz, 1H), 3.07 - 3.17 (m, 1H), 3.04 (s, 3H), 2.82 (s, 3H), 2.32 (s, 3H), 2.23 (dt, .7=7.3 Hz, 1.5 H z , 2H), 2.08 - 2.17 (m, 1H), 1.68- 1.76 (m, 1H), 1.42(dd,J= 13.4 H z , 7.3 Hz, 1H), 1.34(dd,J= 13.4 Hz, 7.3 H z , 1H), 1.22- 1.32 (m, 1H). N M R (75 M H z , CDC1 ): 8 155.9, 145.2, 136.1, 131.2, 128.4, 126.5, 112.7, 93.3,75.9, 43.6, 3  39.7, 35.3, 34.9, 31.7, 28.0, 22.9, 17.6. M S (ESI): 383 ( M + Na ). +  1 3  C  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  115  C0 Ph 2  2.19  2.33  5 - [ l - ( T o l u e n e - 4 - s u l f o n y l ) - l , 2 , 3 ? 4 - t e t r a h y d r o p y r i d i n - 4 - y l ] - p e n t - 2 - y n o i c a c i d p h e n y l ester (2.33)  Following the analogous procedure as for the formation of 2 . 3 0 using 99 mg of 2 . 1 9 (0.34 mmol), 0.25 m L of a solution of n-butyllithium (1.62 M in hexanes, 0.41 mmol), 4 m L of diethyl ether and 0.17 m L of phenyl chloroformate (1.4 mmol) afforded a crude colorless oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (6:1 hexanes:ethyl acetate) afforded 72 mg (51 %) of the title compound 2 . 3 3 as a white solid, mp = 89-91 °C. IR (film): 2927, 2231, 1729 cm" . H N M R (400 M H z , CDC1 ): 5 7.63 (d, J= 8.2 Hz, 2H), 7.34, 1  !  3  (t, J= 7.9 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.20 (t, J= 7.3 H z , 1H), 7.08 (d,J=  7.6 Hz, 2H),  6.64 ( d d , y = 8 . 6 Hz, 1.8 Hz, 1H), 4.82 ( d d , J = 8 . 6 Hz, 3.1 Hz, 1H), 3.48 ( d d d , J = 11.9 Hz, 6.4 H z , 3 . 4 Hz, l H ) , 3 . 1 8 ( d d d , y = 11.9 Hz, 9.5 Hz, 3.1 Hz, l H ) , 2 . 3 8 ( s , 3H), 2.33 (td, J= 7.3 Hz, 1.5 H z , 2H), 2 . 1 2 - 2 . 1 9 (m, 1H), 1.71-1.80 (m, 1H), 1.39- 1.56 (m, 2H), 1.25-1.35 (m, 1H). 1 3  C N M R (75 M H z , CDCI3): 5 153.3, 151.5, 145.3, 136.2, 131.3, 131.0, 128.5, 127.8, 126.7,  122.8, 112.5, 92.7, 74.5, 43.6, 34.5, 31.7, 28.0, 23.0, 17.5. M S (ESI): 432 ( M + N a ) . +  Ts  Ts  2.19  2.34  5-[l-(Toluene-4-sulfonyl)-l,2,3,4-tetrahydropyridin-4-yl]-pent-2-ynenitrile  (2.34)  Following the analogous procedure as for the formation of 2.30 using 0.489 g of 2 . 1 9 (1.69 mmol), 1.04 m L of a solution of «-butyllithium (2.44 M in hexanes, 2.54 mmol), 8.5 m L of diethyl ether and 0.37 m L of phenyl cyanate (3.41 mmol) afforded a crude orange o i l . Purification of the crude material by column chromatography on triethylamine washed silica gel (3:1 hexanes:ethyl acetate) afforded 0.263 g (49%) of the title compound 2.34 as a yellow gum.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  116  Cycloisomerizations  IR (film): 2927, 2315, 2262, 1646 cm" . ' H N M R (400 M H z , CDC1 ): 8 7.61 ( d , J = 8 . 2 H z , 1  3  2H), 7.28 (d, J= 8.2 H z , 2H), 6.62 (dd, J= 8.2 Hz, 2.1 Hz, 1H), 4.77 (dd, J= 8.2 Hz, 2.7 Hz, 1H), 3.47 ( d d d , J = 12.2 Hz, 6.4 Hz, 3.4 Hz, 1H), 3.15 (ddd, J= 12.2 H z , 9.5 H z , 3.1 Hz, 1H), 2.39 (s, 3H), 2.30 (td, .7=7.3 Hz, 1.8 Hz, 2H), 2.08 - 2.17 (m, 1H), 1.69- 1.79 (m, 1H), 1.51 (td, J= 13.7 Hz, 7.0 Hz, 1H), 1.44 (td, J= 13.7 H z , 7.3 Hz, 1H), 1.24- 1.34 (m, 1H).  1 3  CNMR  (75 M H z , C D C 1 ) : 5 145.3, 136.1, 131.2, 128.4, 127.0, 111.8, 106.5,88.1,57.1,43.6, 34.1,31.8, 3  27.9, 23.0, 17.6. M S (ESI): 337 ( M + Na ). +  O  OH  O  OTBS  2-(tert-Butyl-dimethyl-siIyloxy)-benzoic acid  terf-butyl-dimethyl-silyl  ester  To a stirred solution of 5.12 g of salicylic acid (37.0 mmol) and 20 m L of triethylamine (143 mmol) in 200 m L of dichloromethane at rt was added 12.5 g of /erf-butyldimethylchlorosilane (83.1 mmol) and the resulting white reaction mixture was stirred for 21 h. The resulting purple reaction mixture was diluted with 300 m L of toluene and concentrated by rotary evaporation in vacuo to a volume of approximately 70 mL before being filtered through Celite. Concentration by rotary evaporation in vacuo afforded a crude brown oil. Purification of the crude material by column chromatography on a plug of silica gel (50:1 petroleum ethendiethyl ether) afforded 13.1 g (97%) of the title compound as a colorless oil. IR(film): 2932, 1713, 1601, 1485 cm" . ' H N M R (400 M H z , CDC1 ): 5 7.72 (dd, 7 = 7 . 6 Hz, 1.8 1  3  Hz, 1H), 7.32 (ddd, J= 8.2 H z , 7.3 Hz, 1.8 Hz, 1H), 6.93 (td, .7=7.9 Hz, 1.2 Hz, 1H), 6.86 (dd, J= 8.2 Hz, 0.9 Hz, 1H), 0.99 (s, 9H), 0.98 (s, 9H), 0.33 (s, 6H), 0.19 (s, 6H).  1 3  C N M R (75  M H z , CDC1 ): 5 166.6, 157.3, 134.3, 133.0, 125.6, 123.1, 122.1, 27.3, 27.2, 19.9, 19.2, -2.9, 3  3.3. M S (ESI): 367 ( M + H ) , 389 ( M + Na ). Anal. Calcd for +  Found: C, 62.42; H , 9.63.  +  C I Q H ^ C ^ :  C , 62.24; H , 9.35.  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  117  OTBS N Ts  Ts  2.19  2.35  l-[2-(tert-Butyl-dimethyl-silyloxy)-phenyl]-5-[l-(toluene-4-sulfonyl)-l,2,3,4t e t r a h y d r o p y r i d i n - 4 - y l ] - p e n t - 2 - y n - l - o n e (2.35)  To a solution o f 1.02 g o f 2-(ter/-butyl-dimethyl-silyloxy)-benzoic acid  te^butyl-dimethyl-silyl  ester (2.79 mmol) in 17 m L of dichloromethane was added 3 drops o f D M F . The reaction was cooled to 0 °C and 0.30 m L of oxalyl chloride (3.44 mmol) was added dropwise. The reaction was stirred at 0 °C for 1 h before being allowed to stir and warm to rt over 15 h. The resulting bright yellow reaction mixture was concentrated to dryness to give 750 mg (99%) o f 2-(tertbutyl-dimethyl-silyloxy)-benzoyl chloride as a bright yellow semi-solid.  To a solution o f 15.1 mg of bis(triphenylphosphine)palladium dichloride (0.022 mmol) and 4.1 mg copper(I) iodide (0.022 mmol) in 1 mL of triethylamine (degassed using freeze-pump-thaw procedure) was added a solution o f 750 mg of 2-(ter?-butyl-dimethyl-silyloxy)-benzoyl chloride (2.78 mmol) in 2 m L o f a 1:1 mixture of triethylamine and dichloromethane. A solution of 207 mg o f 2 . 1 9 (0.715 mmol) in 2 m L of triethylamine was added and the reaction mixture was stirred in the dark for 24 h. To the reaction mixture was added 1 m L of methanol and it was concentrated by rotary evaporation in vacuo. The resulting red residue was taken up in dichloromethane and washed sequentially with a saturated aqueous solution o f sodium bicarbonate followed by a saturated aqueous brine solution. The organic phase was dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a dark brown crude residue. Purification of the crude residue by column chromatography on triethylamine washed silica gel (6:1 hexanes:ethyl acetate -> 4:1 hexanes:ethyl acetate) afforded 269 mg (72 %) of the title compound 2 . 3 5 as a yellow oil. IR (film): 2931, 2210, 1651, 1479 cm" . ' H N M R (400 M H z , CDC1 ): 5 7.84 (dd, J= 7.9 Hz, 1  3  1.8 Hz, 1H), 7.63 ( d , y = 8.2 Hz, 2H), 7.36 (ddd, J= 8.2 Hz, 7.3 H z , 1.8 H z , 1H), 7.29 (d,J = 8.2 H z , 2H), 6.97 ( t d , J = 7.6 H z , 0.9 Hz, 1H), 6.84 (dd, J= 8.2 H z , 0.9 Hz, 1H), 6.63 (dd, J = 8.2 Hz, 1.8 Hz, 1H),4.85 (dd, 7 = 8 . 2 Hz, 3.1 H z , 1H), 3.49 (ddd,J= 11.9 H z , 6.7 Hz, 3.4 Hz, 1H), 3.17 (ddd, J= 12.2 Hz, 9.46 H z , 2.7 Hz, 1H), 2.40 (s, 3H), 2.38 ( d d , J = 7.3 Hz, 1.5 Hz, 2H), 2 . 1 5 - 2 . 2 5 (m, 1H), 1.74- 1.83 (m, 1H), 1.56 (td, J= 13.4 H z , 7.0 H z , 1H), 1.48 (td, J =  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  118  13.4 Hz, 7.3 Hz, 1H), 1.28- 1.39 (m, 1H), 0.98 (s, 9H), 0.19 (s, 6H).  1 3  C N M R (75 M H z ,  CDC1 ): 5 178.9, 157.0, 145.2, 136.2, 135.5, 134.0, 131.2, 130.7, 128.4, 126.6, 122.9, 122.3, 3  112.7, 95.2, 83.3, 43.6, 34.9, 31.8, 28.0, 27.2, 22.9, 19.8, 18.0, -2.8. M S (ESI): 546 ( M + Na ). +  Ts  Ts 2.36  2.19  2,2-Dimethyl-7-[l-(toluene-4-sulfonyl)-l,2,3,4-tetrahydropyridin-4-yl]-hept-4-yn-3-one (2.36)  Following the analogous procedure as for the formation of 2 . 3 0 using 0.217 g of 2 . 1 9 (0.752 mmol), 0.45 m L of a solution of «-butyllithium (1.66 M in hexanes, 0.747 mmol), 7 m L of diethyl ether and 0.6 m L of pivaloyl chloride (4.87 mmol) afforded a crude yellow syrup. Purification of the crude material by column chromatography on triethylamine washed silica gel (5:1 hexanes:ethyl acetate) afforded 0.155 g (55%) o f the title compound 2 . 3 6 as a yellow syrup. IR(film): 2970, 2211, 1667, 1166 cm" . ' H N M R ( 4 0 0 M H Z , CDC1 ): 8 7.62 (d, .7=8.2 Hz, 2H), 1  3  7.28 ( d , y = 8 . 2 Hz, 2H), 6.62 ( d d , J = 8 . 2 H z , 2.1 Hz, 1H),4.83 ( d d , J = 8 . 2 Hz, 3.1 Hz, 1H), 3.47 ( d d d , J = 12.2 Hz, 6.7 Hz, 3.4 Hz, 1H), 3.17 (ddd, J= 12.2 Hz, 9.5 Hz, 3.1 H z , 1H), 2.39 (s,3H), 2.33 ( t d , J = 7.3 Hz, 1.5 Hz, 2H), 2.11-2.20 (m, 1H), 1.71-1.80 (m, 1H), 1.51 ( t d , J = 13.7 Hz, 7.0 Hz, 1H), 1.45 (td, .7= 13.7 Hz, 6.7 Hz, 1H), 1.27-1.37 (m, 1H), 1.12 (s,9H).  I 3  C  N M R (75 M H z , CDC1 ): 6 195.5, 145.2, 136.2, 131.2, 128.4, 126.6, 112.6, 95.9, 80.5, 45.9, 3  43.6, 34.9, 31.8, 28.0, 27.4, 22.9, 17.7.  M S (ESI):  374 ( M + H ) , 396 ( M + Na ). Anal. Calcd +  for C i H 7 N 0 S : C, 67.53; H , 7.29; N , 3.75. Found: C, 67.16; H , 7.29; N , 4.05. 2  2  3  +  Chapter 2. Pt(II) or Ag(I) Salt Catalyzed  Cycloisomerizations  119  .0  N  fs  Ts  2.19  2.37  3-{5-[l-(Toluene-4-suIfonyl)-l,2,3»4-tetrahydropyridin-4-yl]-pent-2-ynoyl}-oxazoIidin-2one (2.37)  To a solution of 40 mg of 2.19 (0.14 mmol) in 3 m L of T H F at-78 °C was added 0.065 m L of a solution of «-butyllithium (2.28 M in hexanes, 0.15 mmol) dropwise. The reaction was stirred at -78 °C for 40 min before a stream of CO2 (> was continuously bubbled through the reaction g  at -78 °C for 15 min to rt for 1 h. Dry T H F was added as necessary. The resulting cloudy reaction mixture was cooled to -78 °C and 18 u L of pivaloyl chloride (0.15 mmol) was added followed by 20 u L o f triethylamine (0.14 mmol) and stirring was continued at-78 °C for 15 min, 0 °C for 45 min, and -78 °C for 15 min. To this reaction mixture was added a cold (-78 °C), premixed solution of 16 mg of 2-oxazolidinone (0.18 mmol) and 0.07 m L of a solution of /j-butyllithium (2.28 M in hexanes, 0.16 mmol) in 1 m L of T H F . The reaction mixture was allowed to stir and warm to rt for 17 h. The resulting pale yellow reaction mixture was taken up in a 3:1 ethyl acetate-water mixture. The organic layer was washed with a saturated aqueous brine solution . The combined aqueous phases were extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated by rotary evaporation in vacuo to afford a crude pale yellow film. Purification of the crude material by column chromatography on triethylamine washed silica gel (1:1 hexanes:ethyl acetate) afforded 24.4 mg (44%) of the title compound 2 . 3 7 as a colorless residue. IR (film): 2926, 2224, 1791, 1661 cm" . *H N M R (400 M H z , CDCI3): 8 7.63 (d,J= 8.2 Hz, 1  2H), 7.28 ( d , J = 8.2 H z , 2H), 6.62 (dd, J= 8.2 H z , 2.1 Hz, 1H), 4.84 (dd,J = 8.2 Hz, 2.8 Hz, 1H), 4.37 (t, J= 8.2 H z , 2H), 3.99 (t, J= 8.2 Hz, 2H), 3.48 (ddd, J= 12.2 H z , 6.4 Hz, 3.4 Hz, 1H), 3.19 (ddd, J= 12.2 Hz, 9.5 Hz, 3.1 Hz, 1H), 2.40 (s, 3H), 2.38-2.43 (m, 2H), 2.19-2.31 (m, 1H), 1.74-1.82 (m, 1H), 1.41-1.60 (m, 2H), 1.22-1.36 (m, 1H).  I 3  C N M R (75 M H z , CDC1 ): 8 3  153.4, 152.1, 145.1, 136.3, 131.2, 128.4, 126.5, 112.7, 99.0, 75.0, 63.3,43.7,43.6, 34.4,31.6, 27.9, 22.9, 18.0. M S (ESI): 425 ( M + Na ). +  Chapter 2. Pt(Il) or Ag(I) Salt Catalyzed  is  is  2.19  2.38  120  Cycloisomerizations  l - P h e n y l - 5 - [ l - ( t o l u e n e - 4 - s u I f o n y l ) - l , 2 , 3 , 4 - t e t r a h y d r o p y r i d i n - 4 - y l ] - p e n t - 2 - y n - l - o n e (2.38)  Following the analogous procedure as for the formation of 2 . 3 0 using 0.212 g of 2 . 1 9 (0.734 mmol), 0.44 m L of a solution of n-butyllithium (1.66 M in hexanes, 0.730 mmol), 7 m L of diethyl ether and 0.5 m L of benzoyl chloride (4.31 mmol) afforded a crude yellow oil. Purification of the crude material by column chromatography on triethylamine washed silica gel (4:1 hexanes:ethyl acetate) afforded 0.156 g (54%) of the title compound 2 . 3 8 as a pale yellow oil. IR (film): 2925, 1642, 1267, 1166 cm" . ' H N M R (400 M H z , CDC1 ): 5 8.04-8.09 (m, 2H), 7.63 1  3  (d, J= 8.5 Hz, 2H), 7.57 (tt, J= 7.6 Hz, 1.2 Hz, 1H), 7.44 (t, J= 7.6 H z , 2H), 7.29 (d, J= 8.5 Hz, 2H), 6.65 ( d d , J = 8 . 6 Hz, 2.1 Hz, 1H), 4.87 ( d d ,