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Synthesis of chiral ferrocenylphosphine complexes of rhodium (I) and their use as catalysts for homogeneous… Yeh, Eshan 1977

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SYNTHESIS OF CHIRAL FERROCENYLPROSPHINE COMPLEXES OF RHODIUM(I)' AND THEIR USE AS CATALYSTS FOR HOMOGENEOUS ASYMMETRIC HYDROGENATION by ESHAN YEH = B.Sc., Fu Jen University, Taiwan Republic of China 1971 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry) We accept th i s thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA August, 1977 /~\ Eshan Yeh, 1977 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an advanced d e g r e e at the U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d by the Head o f my Depar tment o r by h i s r e p r e s e n t a t i v e s . I t i s u n d e r s t o o d t h a t c o p y i n g o r p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Depa r tment The U n i v e r s i t y o f B r i t i s h C o l u m b i a 2075 Wesbrook Place Vancouver, Canada V6T 1W5 - 11 -ABSTRACT The present work was directed toward the synthesis of a new c h i r a l c a t a l y s t f o r asymmetric homogeneous hydrogenation. E f f i c i e n t ways to synthesize the ferrocenylphosphlne ligands (R,S)- and (S,R)-c<-[2-diphenylphosphlnoferrocenyl]ethyldlme-thylamlne ((R,S)- and (S.R)-FcNP) and t h e i r c a t i o n i c rhodium complexes [(dlene)Rh(-)FcNP] A were developed. Struct u r a l / data f o r the ligand and models of i t s metal complex have been used to r a t i o n a l i z e the stereochemical approach of the subs-trate to the metal complex, and hence predict the absolute configuration of the product. The rate of c a t a l y t i c hydrogenation i s dependent on the substrate as i s the o p t i c a l y i e l d of the product alkane. High o p t i c a l y i e l d s are obtained when <*-aceta.midocinnamlc-acid i s hydrogenated:at.1 atm E? and 32° • - I l l -T A B L E OF CONTENTS page Abstra.ct H Table of Contents H i L i s t of Figures v L i s t of Tables v i Abbreviations. v*-5-Acknowledgements v i i i Introduction 1 General Review 1 Present Studies 17 Experlmental ' 21 General 21 Hydrogenation Apparatus " 22 Experimental Procedure for A Typical Gas Uptake Experiment 22 I s o l a t i o n of Hydrogenation Products 25 Preparation of Acetylferrocene 25 Preparation of cUFerrocenylethanol 26 Preparation of cx-Ferrocenylethyl Acetate 27 Preparation of N, N-Dimethyl-o(-Ferrocenyl-ethylamine 27 Resolution of N,N-Dlmethyl -o i-Ferrocenyl-ethylamine 28 - Iv -Preparation of (S,R)- and (R.S)-FcNP 30 Preparation of [(NED)RhCl] 2 31 Preparation of [(C0D)RhGlJ 2 31 Preparation of [ (CgH^jRhCl J 2 31 Preparation of [Rh(C0) 2Cl] 2 32 Preparation of (Acac)Rh(COD) 32 Preparation of [ (FcNP)Rh (CO)Cl] 33 Preparation of (PcNP)Nl(CO)^ 3^ Preparation of (. (NBD)Rh(FcNP)] +PF 6~ 3^ Preparation of [(COD)Rh(FcNP)] +C10^" 35 Preparation of [ (COD)Rh (FcNP) ] +BF^~ 36 Preparation of [(NBD)Rh(FcNP)] +C10^" 36 Preparation of [(COD)Rh((-)-FcNP)] +B(C 6H 5)^~ 37 Results and Discussion 38 Synthesis of the C h i r a l Phosphine Ligands ( + )-. (-)-FcNP 38 Synthesis of Metal Complexes of the FcNP Ligand ^3 Asymmetric Homogeneous Hydrogenations (I) . C a t a l y t i c Precursors and C a t a l y t i c P r i n c i p l e s ^7 (II) . C a t a l y t i c Hydrogenation of Olefins ^8 General Conclusions and Recommendations f o r Future Work 6k Blbiography 66 - V -LIST OP FIGURES pa.ge 1. A proposed mechanism f o r hydrogenation by Wilkinson's c a t a l y s t . 3 2. E a r l y examples of homogeneous a.symmetrlc hydrogenation. 8 3. A model f o r the c o r r e l a t i o n of the s t e r e o -chemistry of r e d u c t i o n products with t h a t of the c h i r a l llga.nd. 10 k. Reaction of a. t e r t i a r y phosphine with a t r o -p i c a c i d to produce a. phosphobetaine s a l t . 10 5. Asymmetric homogeneous hydrogena.tion with a. neomenthyldiphenylphosphine (KMDPP) c a t a l y s t . 12 6. The enantiomeric r e l a t i o n s h i p of (R,S)-and (S,R)-FcNP. 20 7. A schematic drawing of the c a t a l y t i c hydrogenation apparatus. 23 8. The apparatus used to prepare•[Rh(GOj^ClJg• 3 2 9. Ferrocene d e r i v a t i v e s w i t h p l a n a r c h l r a l i t y . - 38 10. Tota.l s y n t h e s i s of the c h i r a l f e r r o c e n y l -phosphlne (+)- and (-)-FcNP. 40 11. Absolute c r y s t a l l o g r a . p h l c s t r u c t u r e of (S,R)-FcNP„ - *<4 12. P r e p a r a t i o n of i o n i c rhodium complexes with the FcNP l i g a n d . ' 4-6 13. Prochlra.l <x ,/9-unsaturated e a r b o x y l i c a c i d substra.tes used l n t h i s study. 50 1*4-. A proposed i n t e r m e d i a t e l n which the s i -re face of the s u b s t r a t e i s d i r e c t e d towards the metal complex with (R,S)-FcNP as the llga.nd. 57 15. A proposed i n t e r m e d i a t e i n which the r e -s i f a ce of the s u b s t r a t e i s d i r e c t e d towards the metal complex with (R,S)-FcNP as the l i g a n d , 58 LIST OF TABLES Asymmetric hydrogena.tions o f ol-a.cyla.mldo-a c r y l i c a c i d s w i t h the s o l u b l e DIOP c a t a l y s t . Asymmetric hydrogenation of cx-a.ceta.mldo-cinnamlc a c i d with the FcNP-Rh c a t a l y s t . Asymmetric hydrogenation of o(-a.ceta.mido-a c r y l i c a c i d with the FcNP-Rh c a t a l y s t . The I n f l u e n c e of s o l v e n t s on the r e d u c t i o n of (E)-o(-methylcinnamlc a c i d by the Rhodi'um-(+)-NMDPP c a t a l y s t system. Asymmetric hydrogenation of oC-acylamido-a c r y l i c a c i d s by Rh-complex with o-a.nisyl-c yclohexylmethylphosphine as the l i g a n d . Hydrogenation r a t e s o f v a r i o u s o l e f i n s c a t a l y z e d by Rh-DIOP a.nd Rh-ACMP complexes. Asymmetric hydrogena.tions c a t a l y z e d by (3,R)-BPPFA-Rh complex. - v l l -ABBREVIATIONS Acac acetylacetonate ACMP o-anlsylcyclohexylmethylphosphine atm atmosphere 3PPFA d-1',2-bls(dlphenylphosphlnoferrocenyl)ethyl-dimethylamine COD 1,5-cyclooctadlene DIOP 2 , 3 -0-isopropylldene -2 ,3-dihydroxy-l f 4-bls-(dlphenylphosphino )buta.ne DOPA 3- (3i4—dihydroxyphenyl)-alanine e.e. enantiomeric excess FcN racemic mixture of N,N-dlmethyl-o(-ferrocenyl-ethylamlne (t)-FcN o p t i c a l l y active FcN FcNLl unlsolated l i t h i a t e d product of FcN, which also i s the precursor of FcNP FcNP racemic mixture of cU (2-diphenylphosphlno-ferrocenyl)ethyldimethylamine (±)-FcNP o p t i c a l l y active FcNP IR infrared K molar NBD norbornadlene (Cr,Hg) NKDPP neomenthyldlphenylphosphlne NMR nuclear magnetic resonance ppm parts per m i l l i o n TEF tetrahydrofuran TMS tetramethyl silane - v i i l -ACKNOWLEDGEMENTS I am much indebted to Dr. W. R. Cullen f o r his guidance and continual encouragement during the course of this work. Without his he l p f u l advice and assistance this task would have been much more d i f f i c u l t . I would also l i k e to express my gratitude to my wife, whose confidence and u n f a i l i n g support throughout the course of this study were an unmeasurable contribution. Sincere thanks are also due to Dr. B. R. James f o r many valable discussions, and the technical s t a f f of t h i s department fo r assistance. T am grateful to The University of B r i t i s h Columbia, and to the National Research Council of Canada, f o r f i n a n c i a l support. - 1 -INTRODUCTION General Review The search f o r and creation of a system which can pro-duce o p t i c a l a c t i v i t y l n chemical compounds has long been a goal of the preparative chemist, since the deliberate pro-duction of asymmetry i s an important problem from both the theo r e t i c a l and p r a c t i c a l point of view. In the case of many compounds i t i s only one enantiomer which i s useful l n bio-l o g i c a l systems, and examples are found, f o r example, i n pharmaceuticals (1), food additives (2), and perfumes (3). In 18^8, Pasteur f i r s t succeeded i n separating the two enantiomeric forms of sodium ammonium tartarate with the aid of forceps and a magniflng lens which i n i t i a t e d much e f f o r t i n developing methods of c h i r a l synthesis. Most early r e s u l t s showed either low o p t i c a l y i e l d or the need f o r large quan-t i t i e s of o p t i c a l l y active reagents (5i6), consequently many chemists transfered t h e i r attention to b i o l o g i c a l systems involving enzymes (7); f o r only enzymes could convert o p t i -c a l l y inactive substances into o p t i c a l l y active compounds l n p r a c t i c a l l y 100^  o p t i c a l purity without the help of large quantities of o p t i c a l l y active reagents (7). In 1956, Akaborl, Sakurai, Izumi and F u j i i , succeeded i n the asymmetric hydrogenation of various oxime and oxazolone de r i a t i v e s ; o p t i c a l y i e l d s of up to 35% were obtained. They used a heterogeneous c a t a l y s t consisting of meta l l i c palladium - 2 -drawn out on s i l k ( 8 ) . The o p t i c a l purity of the product was found to be dependent on the o r i g i n of the s i l k f i b r o i n and i t s chemical pretreatment, and even worse t h e i r r e s u l t s were not reproducible. In another heterogeneous system, Raney ni c k e l was modified with amino acids and other chira.l rea-gents to give catalysts that were used to e f f e c t asymmetric hydrogenation (9 ) . However, i t was found that the o p t i c a l p u r i t i e s of the products were very dependent on pH and the method of c a t a l y s t preparation. Over the past two decades, many pioneering studies d i -rected towards c a t a l y t i c asymmetric synthesis, mostly i n homogeneous systems, have been undertaken. Most of the work is summarized i n some review a r t i c l e s and books ( 1 0 ) . Since the f i r s t report by Wilkinson and co-workers l n 1965 (11,12) concerning the c a t a l y t i c a c t i v i t y of solutions of [(CgH^)^P]^RhCl with respect to hydrogenation, extensive mechanistic studies have been c a r r i e d out on this system ( 1 3 ) . However, the d e t a i l e d picture i s s t i l l somewhat cont r o v e r s i a l ( 1 ^ , 1 5 ) . Wilkinson and co-workers postulated a mechanism based on k i n e t i c data f o r the hydrogenation of o l e f i n s . This i s outlined i n Figure 1 (16) . This mechanism involves the dissociated, solvent saturated species (Ph^P^RhCl(S) as a key intermediate. It was envisioned that the rate-determining step could be either one or both of the two paths shown i n Figure l i ( i ) attack of o l e f i n on the dihydro complex, the k' path, or "ny-. {V?hj)jBhCl + Solvent (S) (PPh 3) 2RhCl(S) + PPh 3 (PPh 3) 2RhCl(S) + H 2 Ki E 2 ( P P h 3 ) 2 R h C l ( 3 ) o l e f i n k' o l e f i n k" (PPh 3) 2RhCl(olefin) • (PPh^) 2RhCl(S) + p a r a f f i n Figure 1. A proposed mechanism for hydrogenation by Wilkinson's c a t a l y s t . dride route" ( l ' l ) ; ( l i ) attack of hydrogen on the o l e f i n complex, the k" path, or "unsaturate route" (l'l-). I t was found that both pathways are possible and the actual mechanism is dependent on the choice of the substrate (l ' J - , 16,17). Contrary to the postulates of V/llkinson, Tolman et a l . found that the RhCl(PPh^)-^ complex does not d i s s o c i a t e into RhC'l(PPh^)2 to a s p c c t r o s c o p i c a l l y detectable extent, but i s i n equilibrium with the chlor i n e bridged dimer [RhCl(PPh^) 2] 2 (15), This dirner, which reacts with R 2 to form K 2 [RhCl (PPh^ ) 2 J 2 1_, was proved to be a. good homogeneous hydrogenation c a t a l y s t PPh q PPho CI K K / \ / Rh Rh PPh^ CI H -> PPh^ for the reduction of cyclohexene and ethylene. The major paths for the hydrogenation of cyclohexene are outlined i n the following scheme: ^ [RhCl (PPh. )oW rf2RhCl(PPh~)2 k l H 2 k - l k2«2 P - 1 1 0\l2LRhCl(PPh 3)2J2 1 0 , 2 H 2 R h C l ( P P h 3 ) £ and the actual c a t a l y s t s are dihydrides of b i s ( t r i p h e n y l -phosphlne)rhodium species. - 5 -In spite of the differences i n opinion about the precise mechanism, three points on which there i s a general agreement can be emphasized. 1. At some point i n the c a t a l y t i c cycle one phosphine ligand i s dissociated, a.nd Rg i s activated by the formation of metal-R bonds. Dlmerlzation to [RhCl (PPlr^ ) 2 ] g also occurs a f t e r the phosphine d i s s o c i a t i o n . 2. An intermediate (or at l e a s t an activated complex) exists i n which phosphine, hydrogen, and o l e f i n are a l l coordinated to the metal. 3. The hydrogens are transfered successively from the central metal to the coordinated substrate which forms meta.l-a l k y l bond f i r s t a.nd then the lea.ving product. Hydrogen a c t i v a t i o n i s l a r g e l y dependent on the coordi-nation number and e l e c t r o n i c configuration of the metal. P r a c t i c a l l y a l l meta.l complexes which are hydrogenation ca-6 8 t a l y s t s have a d to d configuration. Coordlnatively satu-rated complexes are unreactive unless the ligands present are l a b i l e i n s o l u t i o n . Thus i t i s obvious that hydrogenation catalysts are quite s e n s i t i v e to solvents, substrate and ligand properties. Halpern (18) has noted three mechanisms of a c t i v a t i o n i n homogeneous hydrogenation: (1) h e t e r o l y t i c s p l i t i n g ; ( i i ) homolytlc s p l i t i n g ; ( i l l ) dihydride formation by oxidative addition. Of these, the dihydride formation appears to be the most commonly encountered. Px>th (1) and ( i l l ) involve oxidative-addition of hydrogen to the metal complex. The - 6 -dihydride formation Involves the addition of two hydrogen atoms, which increases the oxidation state of metal by two; whereas one hydrogen atom i s added to the metal a f t e r hemoly-t i c s p l i t t i n g of hydrogen, which causes the oxidation number of the metal to Increase by one. The general order of re-a c t i v i t y of metals increases from Ni to Fe, and from Fe to Os (18). Ligands such as phosphines and carbon monoxide which have both donor and acceptor properties s t a b i l i z e the metal-hydrogen bond. Formation of a. hydride Involves either, i n t e -r a c t i o n of the IsS bonding Hg o r b i t a l with a vacant metal d o r b i t a l , or attack of an empty ls6 anti-bonding Kg o r b i t a l upon a f i l l e d metal d or d-hybrld o r b i t a l . In the case of rhodium complexes the second a l t e r n a t i v e seems favored since [Rh(Ph2PCH2CH2PPh2)2]C1 f a l l s to add Hg while the more basic complexes, e.g., [Ir(Ph2PCE 2CH2PPh 2) 2]C1 and [Rh(MegPCHgCHg-PMeg)g]Cl d o (19). (The greater the b a s i c i t y of the metal center the larger and more available are the d o r b i t a l s . ) For a given metal ion, r e a c t i v i t y i s enhanced by ligands which are more e f f e c t i v e i n s t a b i l i z i n g high oxidation states of the central metal, e.g., PPh3, rather than CO. Thus, f o r example, the r e a c t i v i t y order toward H 2 i s Rh(PPh^)^Cl > RhCl(CO)(PPh 3) 2. It has been generally accepted that coordination of the unsaturated substrate at a vacant s i t e on the metal i s nece-ssary for homogeneous hydrogenation to proceed. This substrate a c t i v a t i o n through Tr-olefln coordination r e s u l t s i n a l e -ssening of the double bond character of the substrate and also maintains the o l e f i n i n a. favorable position for hydrogen transfer. In asymmetric hydrogenation of a. p r o c h l r a l substrate the a c t i v a t i o n of the substrate seems to be a key step i n pro-ducing the c h i r a l product. (Indeed models show that the abso-lute configuration of the product can be predicted i f the geo-metry of the bound o l e f i n i s taken into consideration.) The l a s t process i n the hydrogenation reaction i s the transfer of hydrogen from, the metal to the Tr-coordinated subs-trate . This i s generally regarded as a. two step hydride trans-f e r . . . At about the same time Wilkinson reported his v e r s a t i l e c a t a l y s t , other groups had been working on the preparation and configura.tiona.l c o r r e l a t i o n of c h i r a l phosphines (20-2*4-). Realizing the p o s s i b i l i t y of combining both streams of resea.rch Horner et a l . (2 5) hypothesized that a. Wllkenson type catalyst with c h i r a l phosphines as liga.nds should show asymmetric ca-t a l y t i c behavior. Horner's suggestion was put into practice by Knowles and Sabacky i n 1968 (26). Knowles used P*PhHePr- as a c h i r a l l i -gand to make complexes of the type R h L ^ C l ^ (where L* i s the c h i r a l ligand) which were used i n the hydrogenation of atropic acid and ita.conic a c i d . The reduction conditions and results -are indicated i n Figure 2, Although the structure of the active ca.talyst i s not known, Knowles and Sabacky (26) su-ggested that the octahedral d^ Rh(III) complexes might y i e l d a square-planar d^ Rh(I) complexes on reduction with H 2, which would be coordinatlvely unsaturated and would behave Ph / HOOC atropic acid L ^ R h C l - ^ 20 atm K o , 60 benzene-EtOH-Et^N P h — C H — C H ^ COOH 15% e.e 0 (S) H 2 C = C N ^CEgCOOH C O O H L * o R h C l 3 20 atm Ii2, 60 benzene-EtOE-Et^N C H o — C H — C H o C O O H 3 , 2 COOH i Itaconic acid )% e,e L* = P*PhMePr-Figure 2. Early examples of homogeneous asymmetric hydrogenation (26). - 9 -In a manner s i m i l a r to Wilkinson's c a t a l y s t . Horner et a l . ( 2 7 ) used a. c a t a l y s t prepared i n s i t u from (S)_ ( + )-methylphenyl-n-propylphosphine and [Rh (1 , 5-hexa.diene ) Cljg i n benzene, a. procedure designed to give neutral, square planar Rh(I) complexes of the type R h L ^ C l . They envisaged the structure of the intermediate state as i n Figure 3 to explain the (S ) - ( + ) - 2-phenylbutane (7-8% e.e.) obtained from o<-ethylstyrene and the (R)-( + )-l~methoxy-l-phenylethane (3-^% e.e.) obtained from 1-methoxystyrene. During studies of the hydrogenation of atropic acid with the P*MePhPr--Rh(I) system, Knowles' group (28) found that when the L/Rh r a t i o was increased from 2 to 8, the hydroge-na.tlon reaction rate and o p t i c a l purity increased to a. maximum. This wa.s quite peculiar since l t had been established that excess ligand lowers the a c t i v i t y of a. Wilkinson-type c a t a l y s t by competing with substrate f o r vacant coordination s i t e s on the metal. It was eventually found that" l t was the formation of a phosphobetalne by the reaction of atropic acid with any ligand i n excess of 2 equivalents per equivalent" of rhodium, which influenced the rate and o p t i c a l y i e l d . Associated with this was the conversion of the substrate to the carboxylate a.nlon (Figure k). It was also found (28) that i n the presence-of trlethyla.mine and using L/Rh = 2 a. t h i r t y - f o l d rate increase was observed, compared with the ra.te without triethylamine. An increased o p t i c a l purity (28%, e.e.) was also obtained. In 1 9 7 1 * both Morrison's and Kagan's groups showed that i n order to obtain asymmetric reduction using rhodium phosphine - 10 -(Pro S) (Pro fi) R = methyl or methoxy group. Fi g u r e 3 . A model f o r the c o r r e l a t i o n of the stereochemis-t r y o f r e d u c t i o n products with t h a t of the c h i r a l l i g a n d ( 2 7 ) . Ph L + H 2C=G OOH -* L — C Ho C HG 0 0 Ph phosphobetalne LH" CH 2GHC00H'E 2C=c: Ph .Ph C H 2 = C L Ph "C00H •ohosnhobetslne sa.lt F i gure *K Reac t i o n of a. t e r t i a . r y phosphlne w i t h a t r o p i c a c i d to produce a. phosphobetalne sa.lt. - 11 -complexes the c h i r a l center does not have to be on phosphorus. Thus Morrison et a l . (29) prepared t h e i r c a t a l y s t i n s i t u by the reaction of (+)-neomenthyldlphenylphosphlne (NMDPP) with rhodium (I) complexes of ethylene or dlene i n ethanol-benzene. This c a t a l y s t , thought to be Rh(NMDPP)jCl, was used to reduce (E)-/S-methylcinnamic a c i d i n the presence of t r i e -thylamine. The r e s u l t i n g 3-phenyl-butanoic acid contained a 6l% e.e. of the S isomer (Figure 5). Reduction of ef-ethylsty-rene gave only 7% e.e. and l t was suggested that t h i s was due to the lack of b i f u n c t i o n a l interactions through both the : . carboxylase anion and o l e f i n i c bond (29,30). Kagan and Dang used the dlphosphine, (-')-2,3-0-isopro-pylldene-2,3-dihydroxy-l,^-bis(diphenylphosphino)butane ( ( - ) -DIOP), 2, derived from (+)-ethyl tartarate, to prepare, In Ph 2PH 2C • 0 H 2 s i t u , a complex represented by [Rh(-)-DIOPClS], where S i s the solvent (31»32). This s o l u t i o n catalyzed the reduction of alkenes at room temperature and atmospheric pressure. Thus o!-acetamidocinna.mic a c i d was reduced to (R)-N-acetyl-phenylalanlne with an o p t i c a l y i e l d of 72%, the chemical y i e l d being 95%* They att r i b u t e d the high s t e r e o s e l e c t i v i t y H-C H . fh 3 \ / [Rh(CH ?=CE 9)pCl] . NMDPP | > C 1 7 t H qC—C—CH 2COOH / \ 2 0 atm K 2, 6 0 ° | Ph COOH benzene-EtOri-Et^N H (E)-£-methylcinnamic 6l% e.e. (S) a c i d NMDPP = H-jC- ,,,'i< \—=3Pri = > PPh 2 PPh 2 fx: i Figure 5 . Asymmetric homogeneous hydrogenation w i t h a neomenthyldiphenyl-phosphlhe (NMDPP) c a t a l y s t (29). - 13 -of this reduction to the conformational r i g i d i t y of the trans-fused dloxolane ri n g and also to the presence of the rhodium-containing chelate r i n g . Stereochemical control through par-t i c i p a t i o n of the carboxylic acid function of the substrate also seemed to be indicated since hydrogenation of methyl cX-phenylacrylate gave methyl-2-phenylpropa.noate of the R c o n f i -guration l n only 7% e.e. (31). Later, i t was found that a substrate containing the enamlde group could be hydrogenated NECOCEo with high o p t i c a l y i e l d (32). For example, CEoCE=c" J NPh was hydrogenated to afford a 7&% o p t i c a l y i e l d . Table 1 shows the results obtained by Kagan et a l . with DIOP as the ligand in the hydrogenation of <X-a.cyla.midoacryllc acids. They found that the Rh-(-)-DIOP c a t a l y s t gave the unnatural R or D-amino acid derivatives, whereas L-amino acid derivatives could be obtained with the (+)-DIOP c a t a l y s t . In 1972, Knowles and co-workers (30.33-36) synthesized c h i r a l o-anlsylcyclohexylmethylphosphlne (ACMP) This 2 (+)-(R)-ACMP ligand gave complexes with rhodium, which were very e f f e c t i v e catalysts f o r the reduction of o(-a.cylamidoacrylic acids. Op-t i c a l y i e l d as high as 90% were obtained. Catalysts prepared Table 1. Asymmetric Kydrogenations of oi-Acyla.midoa.crylic Acids with the Soluble DIOP Catalyst (32). R'HC= NHCOR R'CEgCHIfflCOH R' COOK R COOH Conversion Optical y i e l d {%) H Ph p-OK-phenyl p-OE-phenyl 1-0 3H 7 CE. CH. CB CH. Ph Ph 96 95 92 97 95 98 73 72 80 79 62 22 a[Rh] = 3 mM; P = 1.1 atm; room temperature. (-)-DIOP-Rh complex gives D amino acid derivatives; (+)-DIOP-Rh complex gives L. - 15 -from ( + )-ACMP give L-a.mlno acid derivatives, and (-)-ACMP give D-amino acid d e r i v a t i v e s . In 1975 > they obtained an enantio-meric excess of 9&% l n the reduction of <*-a.cyla.midoacryllc acids using a. new c h i r a l d i ( t e r t i a r y phosphine) 4 as the 11-gand (37). The c a t a l y t i c species was believed to be i n the cat i o n l c form. They found that the high o p t i c a l y i e l d s ob-tained with this chelating ligand were not sensitive to tem-perature and pressure change. While d i f f e r e n t kinds of "Wilkinson type" catalysts were being developed, Osborn and his co-workers were working on cat i o n l c rhodium systems. These proved to be useful as hy- . drogenatlon and h y d r o s l l y l a t i o n catalysts (37i39-^0 • They have the formula [(diene)Rh I^]"* and are e f f i c i e n t at 25° and 1 atm of E2. They are easy to make i n large numbers since L can vary widely and can be i s o l a t e d for physical studies. These cationlc. c a t a l y t i c systems are very v e r s a t i l e , for example, some w i l l reduce alkynes s p e c i f i c a l l y to c i s o l e f i n s (*+3), chelating dlenes to monoenes (*J-3)p and ketones to alco-hols (39,^1,^*0. Knowles used his asymmetric ligands, ACMP - 16 -2 and d i ( t e r t i a r y phosphine) 4, to make cati o n l c rhodium com-plexes which catalyzed the reduction of <X-acyla.mldoacrylic acids giving o p t i c a l y i e l d s as high as 96% (33.37). In l a t e r studies, however, Knowles found that the i n s i t u preparation of rhodium (I) catal y s t s gave the same re s u l t s as using the c r y s t a l l i n e , a i r stable, c a t i o n l c complexes [Rh(1,5-cyclo-octadlene)(ACHP)] +BF4~ or BPh^~ (33). In these l a t t e r experi-ments the ca t a l y s t was prepared by adding the phosphine ligands to al c o h o l i c solutions of [Rh(diene)C1] 2. Two ligands per rhodium were shown to give optimum r e s u l t s , just as expected for the formation of c a t i o n l c complex species. In 1976, Kagan prepared a c a t i o n l c rhodium complex with (+)-DIOP as the ligand. An o p t i c a l y i e l d of 92% was attained ln the asymmetric reduction of N-acetyl-l-phenyl-l-aminopropene (4-6). A tentative hydrogenation intermediate £ was proposed as follows but with l i t t l e substantlatloni Complexes of Co and Ru have also been used f o r the asym-metric hydrogenation of p r o c h i r a l o l e f i n s (^7.^-8); but most results are not very s a t i s f a c t o r y . However, recently an op-- 17 -t i c a l y i e l d of 60% f o r the hydrogenation of tX-acetamidoacrylic a d d has been obtained using [RugCl^DIOP)^] as the c a t a l y s t (W. Present Studies Since the discovery of ferrocene i n 1951 (50i51)» there have been many investigations of the chemistry of t h i s sand-wich compound, e s p e c i a l l y r e l a t i n g to i t stereochemistry (52-56). This i n t e r e s t was due i n part to the recognition that ferrocene derivatives are c h i r a l i f one r i n g c a r r i e s two d i f f e r e n t substltuents X and Y. 6 and £ a r e two cases In Fe Y which this may happen and should be noticed that these com-pounds are o p t i c a l l y active even though there i s no center of asymmetry but only a planar element of c h l r a l l t y . A study by Ugl and co-workers (57) found that ferrocene derivatives with a. plane of c h l r a l l t y e xhibit a strong asymmetric inducing power, without having large s t e r i c bulk close to the reactive s i t e . This i s In contrast with the asymmetrically inducing s t e r i c templates that contain only central elements of c h l -r a l l t y , where one extremely bulky group, a. medium sized group, a small group and the reactive s i t e usually constitute the four ligands of the inducing central c h i r o l d ( 5 8 - 6 2 ) . At the begining of the present study, i t was decided to attempt the synthesis of (+)- a.nd (-)-(2-diphenylphosphino-ferrocenyl)ethyldimethyla.mines ((+)-vand (-)-FcNP) and use them as asymmetric ligands i n rhodium complexes. It was expected that (+)- and (-)-FcNP would be easy to prepare be-cause l t had been shown that l i t h i a t i o n of (R)-N,K-dimethyl-1-ferrocenylethyla.mine ((R)-FcN) with butyllithium i n ether-hexane affords only the ortho l i t h i a t i o n products ( 5 5 i 6 3 ) » which consists of a 9 6 : ^ mixture of (R,R)- and (R,3)-FcNLl a.s mea.sured by ga.s chromatography following treatment with trimethylchlorosilane ( 5 5 ) . Thus treatment of the l l t h l a t e d products with chlorodiphenylphosphine would be expected to y i e l d (R,3)-FcNP (96%) a.nd (R.R)-FcMP (k%). The o v e r a l l reaction i s shown i n the following scheme: F e \ H/' 3 d » F e \ H 3 2 ^ < 0 > P ( C 6 H 5 ) 2 -C! J (R.R)-FcKLi (R,3)~-FcNP ^ X ^ > N ( C K 3 ) 2 P ( C 6 E 5 ) 2 N ( C H 3 ) / g \ / N ( C H 3 ) ; CH 3 (R.S)-FcNLl (R,R)-FcNP - 19 -The same scheme applied to the (S)-isomer of N,N-dime-thyl-l-ferrocenylethylamine should afford 96% of (S,R)-FcNP and k% (S,S)-FcNP. It i s very i n t e r e s t i n g to note from F i -gure 6 that (R.S)-FcNP and (S.R)-FcNP, instead of being dlastereomers of each other, are enantiomers. A prelimina.ry communication has described ligand (o,R)-FcNP and i t s use i n a. rhodium complex to catalyze the hydro-s l l y l a t i o n of ketones (64-). It i s of intere s t to study the hydrogenation of p r o c h i r a l substrate with both (3,R)- and (R,S)-FcNP as the c a t a l y s t ligand a.nd one aim of the present work was to prepare and i s o l a t e the cat a l y s t or cat a l y s t precursor, l n order to determine i t s s o l i d state structure. This would be of value l n v i s u a l i z i n g the reaction Interme-diate which i n turn would help i n r a t i o n a l i z i n g the configu-r a t i o n of the reduction products. * 0 re P ( C 6 H 5 ) 2 c ^ N ( C H 3 ) 2 H * (H 3G) 2N (H 5C 6) 2P (S.R)-FcNP M(CH 3) 2 <s> (R,S)-FcNP Figure 6. The enantiomeric r e l a t i o n s h i p of (R,3)- and (S,R)-FcNP. - dl -EXPERIMENTAL General Unless otherwise s p e c i f i e d a l l chemicals were purchased from commercial sources and were used as received. In p a r t i c u l a r , dry d i e t h y l ether was obtained from Malllnckrodt and was used without further drying. Tetrahydro-furan (THF) was d i s t i l l e d from LiAlK^ and was stored under nitrogen over molecular sieves. Benzene was refluxed over potassium wire and stored under nitrogen over molecular sieves. Ethanol was d i s t i l l e d from LiAlE/4 and was stored under nitrogen over molecular sieves. Spectro grade methanol from MCB and reagent grade lsobutanol from AMACHEM were used without p u r i f i c a t i o n but were vacuum degassed before use. Hydrogen was obtained from Canadian Liquid A i r and was passed through a "Deoxo" c a t a l y t i c p u r l f e r before use. Conductivity measurements were made i n nitromethane at 25 0 with Wayne Kerr Universal Bridge B221A. Infrared spectra were measured on a Perkln-Elmer hyi spectrometer. Carbonyl frequencies were measured on a Unlcon 3P1100 Infrared Spectrophotometer. Spectra were c a l i b r a t e d using a polystyrene f i l m . NMR measurements were made on either Varian Model HA-100 or T-60 Instruments operating at room temperature. Chemical s h i f t s are given i n ppm downfleld from i n t e r n a l TMS. Optical rotations were measured on a Perkln-Elmer l 4 l polariraeter. The sodium-D l i n e of wave length 589 nm was used - 22 -as the monochromatic l i g h t source. An o p t i c a l c e l l of 1 cm path length was used. Melting points were determined using a. Gallenkamp Melting Point apparatus and are reported without correction. A l l microanalyses were done by Mr. Peter Borda of this department. Hydrogenation Apparatus The apparatus used f o r hydrogenation i s shown schema-t i c a l l y i n Figure 7. The reaction f l a s k A consists of two -• compartments Al and A2, which are used to accommodate substrate and ca t a l y s t respectively. The U-shaped o i l manometer was f i l l e d with butyl phthalate which has n e g l i g i b l e vapor pressure. A measuring burette I of volume.50 ml and length about 90 cm was mounted on the l i n e at one end and at the other end was connected to the mercury reservior C, The reaction f l a s k was thermostated i n a. p a r a f f i n o i l bath l n - _ sulated with polystyrene foam. Constant temperature was maintained by JUMO-MSD.B.P. thermoregulator and JUMOGKT10-0 relay control u n i t . Heating was supplied by a 25 watt elon-gated l i g h t bulb. A 3* magnetic s t i r r e r was used i n the thermostat bath and a 0.5' magnetic s t i r r e r was used i n the reaction f l a s k A. Experimental procedure f o r a t y p i c a l gas uptake experiment The ca t a l y s t precursor and the substrate were measured out to to,l mg and placed In A2 and Al respectively. The Figure 7. A schematic drawing of the c a t a l y t i c hydrogenation apparatus. - 2k -flask A was evacuated and f i l l e d with Ng. Cap 1 was opened and 10 ml of solvent was added while f l u s h i n g with nitrogen. Cap 1 was closed and the s o l u t i o n (substrate and solvent) was degassed by pumping f o r a few seconds. E was closed and the reaction l i n e was evacuated through H while F was open and G closed. A was frozen with l i q u i d nitrogen and E opened to remove a l l a i r from the reaction f l a s k . E was closed, the nitrogen coolant was removed and nitrogen gas was admitted to the rest of the l i n e up to tap E. The gas i n l e t G was closed and E was open to l e t nitrogen into A. E was closed and the frozen solvent was thawed. Flask A was t i l t e d to wash the catalyst precursor into A and the mixture was s t i r r e d to obtain complete s o l u t i o n . The s o l u t i o n (substrate, solvent and c a t a l y s t ) was frozen again. A was evacuated and then thawed again a f t e r c l o s i n g E. The f l a s k was thermostrated to the required temperature and hydrogen was admitted into the l i n e up to E. The gas i n l e t G was closed and E was opened to admit Hg to the whole system at a. pressure less than 1 atm„ After thermal equilibrium had been reached (this was checked by c l o s i n g F and observing any change l n the o i l l e v e l s of the manometer.) G was opened to admit more hydrogen u n t i l the mercury l e v e l s of I and C were the same and F was closed. Any gas uptake was accompanied by a. r i s e i n the l e v e l of the o i l manometer. The pressure loss was compensated by r a i s i n g the mercury res e r v o i r u n t i l the two o i l column were leveled again. The mercury l e v e l of the measuring burette was monitored as a function of time. No attempt was made to - o -correct the data, f o r any contribution from the solvent vapor to the pressure. Isolation of hydrogenation products N-Acetylphenylalanlne The product, a f t e r pumping o f f the solvent, was washed with k ml of dlchloromethane three times. N-acetylphenylalanlne v i s Insoluble l n CHgClg and i n this way the product was separated from c a t a l y s t without a l -tering i t s form. ( R e c r y s t a l l i z a t i o n from water could r e s u l t i n enrichment of one ena.ntlomer and an a r t i f i c i a l l y high o p t i c a l y i e l d . ) N-Acetylalanlne The mixture was dissolved l n 10 ml of water a f t e r the solvent had been removed by pumping.. It was then f i l t e r e d through c e l l t e twice. The product was obtained a f t e r freeze drying the aqueous so l u t i o n . Preparation of Acetylferrocene (65) Ferrocene (93 St 0.5 mole) was dissolved i n ^00 ml of dry dlchloromethane i n a 1 1 f l a s k equipped with a 2 i n . mag-netic s t i r r i n g bar and f i t t e d with a drying tube (Ca.Cl 2). Acetyl chloride (k-J g, 0.55 mole) was added. The f l a s k was then immersed i n an ice water bath of 0 - 5 ° . Anhydrous a l u -minum chloride (67 g, 0.5 mole) was added i n about 10 portions with 2-5 min. between each portion to allow heat exchange. The reaction was vigorous and the color of the sol u t i o n changed from red-brown to deep wine-red. The reaction mixture was s t i r r e d f o r 2 hours as the ice water bath gradually warmed to room temperature. The reaction mixture was hydrolyzed by the slow addition of 100 ml cold water l n 5 ml portions while the whole f l a s k was immersed i n cold water bath. An a d d i t i o n a l 120 ml of water was then added more r a p i d l y . The cold water bath was removed and about 50 ml of fr e s h l y prepared 10$ aqueous Na 23 20ij. s o l u t i o n was added dropwlse with s t i r r i n g u n t i l the upper la y e r changed color from brown to cream-yellow. The s o l u t i o n was s t i r r e d for about one hour u n t i l the odor of 50 2 was undetectable. The reaction mixture was separated and the aqueous l a y e r extracted three times with 100 ml portion of dlchloromethane. The organic extracts were combined and washed with 100 ml of 5% aqueous NaOE so l u t i o n and 100 ml of saturated aqueous NaCl so l u t i o n . The s o l u t i o n was-dried-over-anhydrous f^CO^ over-night, f i l t e r e d , and the solvent was evaported to give 110 g (95%) of the orange s o l i d product, mp 8 7 ° . ( l i t . mp 8 5 - 8 6 ° ( 6 5 ) ) Preparation of a-Ferrocenylethanol (65) Acetylferrocene (25 g, 0.11 mole) was dissolved i n anhydrous ether (500 ml) l n a *4—necked 1 1 f l a s k equipped with a r e f l u x condenser, nitrogen i n l e t , magnetic s t i r r e r and dropping funnel. The solution was s t i r r e d and slowly treated dropwise with a suspension of 2.2 g of L1A1% l n ether and then heated under r e f l u x for two hours. The excess of LiAlH^ was destroyed by the slow addition ('!•") of ethyl acetate and • the r e s u l t i n g reaction mixture was treated with a saturated s o l u t i o n containing 30 g of NH/J.C1 l n water. After being s t i r r e d 0.5 hour at 0 ° , the reaction mixture was f i l t e r e d and the organic layer separated. The ether s o l u t i o n was washed twice with water and then concentrated to dryness to y i e l d 22.5 g of a. yellow s o l i d , rap 7^°« This product was pure enough to use d i r e c t l y but a portion of i t was recry-s t a l l i z e d from n-heptane to give yellow needles, mp 79° ( l i t . mp "78-79 ° (65)).-Preparation of a-Ferrocenylethyl Acetate (65) d-Ferrocenylethanol (69 g. 0.3 mole) and acetic acid (20 ml, 0.33 mole) were dissolved l n 500 ml of reagent grade benzene and placed i n a 1 1 round bottom f l a s k f i t t e d with a water separator (Dean and Stark trap), and a re f l u x condenser with a drying tube on top. Some b o i l i n g chips were added and the s o l u t i o n was refluxed overnight. The reaction mixture was cooled, decanted from the b o i l i n g chips, and evaporated to a f f o r d about 80 g of a dark red-brown o i l . The product was not p u r i f i e d and was used d i r e c t l y . Preparation of N, N-Dlmethyl-cx-Ferrocenylethylamlne (65) cx-Ferrocenylethyl acetate (68 g, 0,25 mole) was dissolved i n about 1*1-00 ml of methanol i n a 21 c o n i c a l f l a s k to which was added 2*1-0 ml of 2$% aqueous dimethylamine. The mixture was s t i r r e d f o r three days at room temperature. - 28 -The solvent was evaporated leaving a dark o i l y residue which s t i l l contained some water. This was s t i r r e d with a mixture of 300 ml Q»5% aqueous phosphoric a c i d and 100 ml of ether. The layers were separated and the a c i d aqueous so l u -t i o n was washed with 100 ml of ether to remove neutral by-products. The dark green a c i d i c s o l u t i o n of the amine was neutralized by cautious addition of NagCO^, allowing the effervescence to subside before each subsequent addition. The process was continued u n t i l no more effervescence was observed and by that time the dark green s o l u t i o n had turned yellow-brown. The amine was extracted with three 100 ml portions of dlchloromethane and washed with 100 ml of water, dried over KgCO^ (MgSO^ cannot be used) and evaporated to give about 50 g of a dark red-brown o i l which was rap i d l y vacuum d i s t i l l e d to avoid decomposition, bp. 118V0.5 mmHg ( l i t . l20°/2 mmHg ( 6 5 ) ) . The y i e l d was about h$ g. Resolution of N, N-Dlmethyl-ot-Ferrocenylamlne (65) The racemlc amine (25.7 g, 0.1 mole) and 15 g of R~(+)-t a r t a r l c acid were each dissolved l n 50 ml of methanol l n 250 ml f l a s k s . Both fl a s k s were Immersed i n a hot water bath at about 55 ° f o r about 10 min. to reach thermal e q u i l i -brium. The t a r t a r i c a c i d s o l u t i o n was then poured into the amine solut i o n while s t i r r i n g . The temperature of the bath was allowed to f a l l at a. rate of 2-5°/hour. Occasional scratching the f l a s k with a. glass rod was required to a i d s o l i d formation. S t i r r i n g was continued overnight and - i j y -about 15 g of the • (-)-amine tartarate was c o l l e c t e d . The mother l i q u o r was set aside for l a t e r use. The tartarate s a l t was a.dded to about 50 ml of 20% aqueous NaOH sol u t i o n in a separatory funnel and the amine extracted with three 25 ml portions of dichloromethane. The amine solution was dried over K2CO-3 and evaporated to give the o p t i c a l l y active amine as dark o i l . The amine thus obtained a.nd 5«55 g of t a r t a r i c acid, each l n 25 ml of rae.tha.nol. were mixed and. seeded. as above'" to a.fford the amine ta.rtarate s a l t . This affords 9 g of o p t l -25 c a l l y active (-)-amlne, [cx] D -12 (c 1, 95;! ethanol), ( l i t . [ o t j ^ -1*4-° (c 1, 95$ ethanol) ( 65 ) ) when treated with base as above. The mother l i q u o r from the f i r s t c r y s t a l l i z a t i o n was concentrated to about one-fourth of i t s o r i g i n a l volume. Diethyl ether was a.dded slowly to the solu t i o n u n t i l p r e c i -p i t a t i o n wa.s complete. The mixture was l e f t at 0° overnight and 24 . 3 g of ( + )-amine tartarate wa.s c o l l e c t e d . The ( + )-amine tartarate c r y s t a l s were r e c r y s t a l l i z e d by d i s s o l v i n g them i n about 30 ml of hot water followed by the addition of about 300 ml acetone. Fine needle c r y s t a l s of the (+)-amlne tartarate were obtained l n t h i s modified way. O p t i c a l l y pure (+)-amlne, [ > ] D 5 1^.5° ( c 1. 95% ethanol) ( l i t . 1*1- ( 65 ) ) was obtained from the tartarate as described above for the (-)-isomer. - 30 -Preparation of (S.H)- and (R.S)-FcKP (66,67) At 23°, 10 g of (R)-(+)-FcN was dissolved l n 60 ml anhy-drous d i e t h y l ether l n a two-necked 250 ml round bottom flask equipped with a magnetic s t i r r e r and a r e f l u x condenser. To this solution was added dropwise 21 ml of 2.2 M n - b u t y l l i -thlum l n n-hexane. The reaction was s l i g h t l y exothermic and the color of the mixture changed from red-brown to orange red. After s t i r r i n g 1.5 hours, the mixture was slowly treated with 17.5 ? of chlorodiphenylphosphine. This reaction was very exothermic and the color turned to yellow with the pre-c i p i t a t i o n of L i C l . The mixture was refluxed f o r 2 hours and then cooled to room temperature. An aqueous s l u r r y of NaHC03 ( 80 ml) was added to the reaction mixture very slowly while s t i r r i n g . The mixture was s t i r r e d for about 20 min. to hy-drolyze the product. The s o l i d was f i l t e r e d o f f and washed with d i e t h y l ether u n t i l a l l the orange yellow compound had been dissolved. The ether layer was separated, added to the washings and dried over MgSO^. After evaporating to dryness, the dark brown o i l was cooled to k' overnight to a f f o r d a brown yellow s o l i d which was r e c r y s t a l l i z e d from ethanol to y i e l d 6 g of brown yellow c r y s t a l s of (R,3)-(-)-FcNP, mp 136°, L>Jp" -36k" (c 0 .^2, ethanol). (3)-(-)-FcN was treated i n the same manner to y i e l d (3,R)-(+)-FcNP, mp 135°, l*^ +36l.^°( c 0.3^1, ethanol), ( l i t . mp 139°, L * ] ^ 5 +36l° (c 0.6, EtOK), (6k)). Anal. Calc. For C 2 6H 2 8FcNPi C, 70.7; H, 6.35; N, 3.17. Found: C, 70.^ ; K, 6.33; N, 3.1^. 1H NMR (CDCl^) 1.17 (d, - 31 -J=7 Hz, C-CK 3), 1.80 (s, N(CK 3) 2), 3.9 (s, FeCy^) , 3.5-^.5 (m, FeC^Ify mixed with C-E), 6.9-7.85(m, CgH^). The NMR and analytic data were obtained from the racemic mixture. Preparation of [(NBD)RhCl] 3 (68) Rhodium t r i c h l o r i d e trlhydrate (0 .7 g) was dissolved i n 95% ethanol (10 ml) l n a 100 ml Schlenk tube and 2 ml of nor-bornadiene (C^Eg) was added to the solut i o n . The tube was flushed with nitrogen and sealed with a serum cap. A y e l -low pr e c i p i t a t e appeared about 15 minutes a f t e r the reactants had been mixed. The reaction mixture was s t i r r e d f o r two days. The yellow deposit was Isolated and r e c r y s t a l l i z e d from chloroform-petroleum ether to give fine yellow c r y s t a l s . Preparation of [(CQD)RhCl] 2 (69) In a 100 ml three-necked round bottom f l a s k was dissolved rhodium t r i c h l o r i d e trlhydrate (1 g) and 1,5-cyclooctadlene (2 ml) in 30 ml of 95% ethanol. The solution was heated and refluxed for 3 hours. The orange yellow c r y s t a l l i n e product was f i l t e r e d and washed with ethanol and then r e c r y s t a l l i z e d from acetic acid to afford orange yellow crystals.' Preparation of [ (CgK^, )RhC112 (70) Rhodium t r i c h l o r i d e trlhydrate (1 g) was dissolved i n 99.5# ethanol (20 ml) l n a 100 ml Schlenk tube. Cyclooctene (3 g) was added to the soluti o n and the mixture was sealed under nitrogen, and was kept at room temperature for.three days. A red brown s o l i d was formed (0.85 g). The product was i s o l a t e d and washed with a small quantity of absolute ethanol, then dried and stored under nitrogen i n the r e f r i -gerator (T<5°). CO Preparation of FBh(C0) 2C1] 3 (71) , An.apparatus, shown as Figure 8, with a porous disk (medium porosity) was set up l n the fume hood. Rhodium t r i c h l o r i d e t r i -hydrate (1 g) was pulverized and placed on the top of the disk. The apparatus was flushed slowly with CO and Immersed l n an o i l bath maintained at 96-100°. The water vapor which condensed at the top of the tube was removed occasionally with absor-bent cotton. Orange red c r y s t a l s of pro-duct sublimed to about half way up the tube. VJhen the re-action was completed, (about k hours) the apparatus was removed from the o i l bath and cooled. The c r y s t a l s were scraped from the reaction vessel to give about 0.75 g of pure product, mp 1 2 ^ - 1 2 6 ° ( l i t . 12^4-125° ( 7 D ) . The c r y s t a l s were stored l n a r e f r i g e r a t o r (T<-5°)» Figure 8. Preparation of (Acac)Rh(COD) (72) A mixture of [(COD)RhCl] 2 (O .76I g), d i e t h y l ether (17 ml) - 33 -and acetylacetone (0 .6 l ml) In a 200 ml Schlenk tube with a magnetic s t i r r i n g bar was c h i l l e d to -78° and a sol u t i o n of 1 g of KOH i n 3.3 ml of water added dropwlsely. The mixture was warmed to 0 C with s t i r r i n g , and l a t e r , a. further 17 ml of d i e t h y l ether was added. This mixture was s t i r r e d at 0° f o r 0.5 hour. The ether was separated, f i l t e r e d and c h i l l e d to -78" again. The yellow c r y s t a l s which pr e c i p i t a t e d were separated and dried. The f i l t r a t e was concentrated and c h i l l e d again and more c r y s t a l s were deposited, mp 125°. Anal. Calc. for. C 1 3H 1 9 0 2Rh: C , 50.3; E, 6.13; Found: C, 50.*+; H, 6.b0%. Preparation of f (FcMP)Rh(CO)Cl] (91) [Rh(CO) 2Cl] 2 ( 0 . 1 3 ' g ) was dissolved i n 2 .5 ml of benzene. In a 100 ml Schlenk tube. On addition of 25 ml of benzene containing 0.3 g of FcNP, CO was evolved and the colour changed from orange yellow to red. The sol u t i o n was evaporated under vacuum to dryness and a yellow brown s o l i d remained. The s o l i d was dissolved In a minimum quantity of degassed CH 2C1 2 and d i e t h y l ether was slowly a.dded u n t i l s l i g h t turbu-lence was seen. The mixture was cooled to 5° and s o l i d formed in about one hour. The solvent was removed a.nd the s o l i d product was washed with ether, and r e c r y s t a l l i z e d from ben-zene, mp 124-125°. V(C0), 1990 cm"1 (cyclohexane). Anal. Calc. for Co^E^ClFeNOPRh: C, 58.2; H, 4 .99; N, 2.05; CI, 5.21. Found: C, 58.1; H , 5.10; N, 1.80; CI, 5.08$. *H NMR (CDC1-,) - ji* -1.25' (d, J=7 Hz, C-CH 3), 2.47 (s, M-CH3), 3.1*4-. (s, N-CK 3), 3.79 (s, FeC^H^), 3.9-4-.7 (m, F e C ^ mixed with G-R), 6.9-7.9 (m, CgH^). Preparation of (FcNP)Nl(C0) 3 (73) FcNP (3.4 g, 7.7-mmole) was dissolved i n 33 ml of d i e t h y l ether i n a. 3-necked, 100 ml f l a s k equipped with a. r e f l u x con-denser, nitrogen i n l e t , and magnetic s t i r r e r . The solution was- heated i n an e f f i c i e n t fume hood to the reflux temperature a.nd Nl(CO). (1.31 g, 7.7 mmole) was a.dded to the solution. 4 The rea.ction mixture wa.s refluxed for 30 minutes, then l t wa.s cooled to room temperature. An orange yellow s o l i d was formed which wa.s wa.shed with d i e t h y l ether to afford 3.1 g of orange yellow c r y s t a l s , mp 135°. Anal. Calc. For Cp^EggFeNNiO-^P: C, 59.6; H, 4.79; N, 2.40. Found: C, 59.4,.. H, 4.83; N, 2.44;$. y(CO), 1980, 2000, 2060 cm"1 (cyclohexane). Preparation of .[ (NBD) Rh (FcNP) 'l*PFg" (7*0 [(NBD)RhCll (250 mg, O.56 mmole) dissolved' i n 8 ml C.E. d 0 0 and FcNP (0.685 £» 1*55 mmole) dissolved i n 2 ml THF were com-bined together i n a. 100 ml Schlenk tube, and to this mixture wa.s a.dded NH^PF^ (0.171 g) i n acetone. The fine p r e c i p i t a t e , which formed Immediately, was f i l t e r e d and washed with d i c h l o -romethane. After concentrating the f i l t r a t e and washings un-der reduced pressure, two phases formed. The turbid bottom phase was is o l a t e d and further concentrated to about half i t s - 35 -volume. Red so l i d s separated at thi s time and more came out a f t e r standing 12 hours at room temperature. If no s o l i d pre-c i p i t a t e d , etha.nol was added very slowly u n t i l a s l i g h t tur-bulence wa.s seen then a drop of d i e t h y l ether was added. The mixture was cooled to ^ ° overnight to aff o r d a. red s o l i d which was washed with d i e t h y l ether and dried. The s o l i d was re-c r y s t a l l i z e d from a minimum quantity of dlchloromethane by the addition of ethanol and d i e t h y l ether and red fine c r y s t a l s resulted, mp 192° (decomp.). Anal. Calc. f o r C^H^FeFgNPoRh: C, 50.7; H, b.6l; N, 1.79. Found: C, ^7.7; H, 4.73; N, l.k8$. A=72.3 ohm"1cm"1M~1. XH NMR (CDCl^) 1.78 (d, J=6.k Kzy C-CH3), 2.1*2 (s, N-CRj), 3 .19 (s, N-CH3), 3 . 6 l (s, FeC^Ec), 1.^6 (s, methylene), >. 16 • (s, methine.), k.kk (m, F e C ^ ) , 7-8.5 (m, CgH^) Preparation of f (COD)Rh (FcNP) ^ ClO)," (7^) Rh(COD)(acac) (250 mg, 0.81 mmole) was placed l n a Schlenk tube Into which 3 ml of TKF and 115 mg (approximately 1 drop) of 70^ HCIO^ i n 1 ml of THF was added under an Ar atmosphere. Ad-d i t i o n of FcNP (800 mg, 1.81 mmole) changed the color of the sol u t i o n from yellow to orange-red. The solvent was removed and the resultant s o l i d dissolved l n a. minimum quantity of b o i l i n g 957= ethanol, cooled to room temperature, and stored at k" f o r four hours, A dark s o l i d formed. The s o l i d was is o l a t e d and washed with ether. The s o l i d was r e c r y s t a l l i z e d from ethanol to y i e l d ora.nge-red c r y s t a l s , mp 185° (decomp.). Anal, Calcd. f o r C^H^ ClFeNO^PRhj C, 55.2j H, 5.41; N, 1.89. - 36 -Found: C # 5^,6; H, 5-09; N, 1 .90$. A = 73.6 phrn era M . Prepara t i o n of [ (COD) Rh (FcNP) ;i*BF^~ (74,75) To a. Schlenk tube purged with N 2 was added. [_(C0D)RhCl] o (0.246 g, 5 mmole) followed by 3 ml of methanol with s t i r r i n g . FcNP (0.53 g» 1.2 mmole) d i s s o l v e d i n about 10 ml of metha.nol was added to the mixture. A f t e r s t i r r i n g f o r 20 min, the s l u r r y had. become an ora.nge-red s o l u t i o n . NE^BF^ (0.14 g) i n 1,6 ml of H 2 0 was added while s t i r r i n g , and an orange-red s o l i d p r e c i p i t a t e d . This wa.s separated, washed with 1 ml of H 20 and 1 ml of methanol, and r e c r y s t a . l l i z e d from ethanol. These f i n e orange-red c r y s t a l s were washed with d i e t h y l ether and d r i e d under reduced pressure, mp 190° (decomp.). Recrys-t a l l i z a t i o n could also be achieved by d i s s o l v i n g the s o l i d i n a minimum q u a n t i t y of CE 2C1 2 and adding ethanol. Anal. Calcd, f o r C^^E^gBF^FeNPRh: C, 55.2; E, 5.4-1; N, 1 .89. Found: C, 55.2; H, 5.31; N, 1 .89$. A=73.9 ohm"1cm~1H"1. 1 E NMR (CDCl^) 1 .01-I. 61 (m, methylene), 1.87 (d, J=6.2 Hz, C-CE^), 2.71 (s, N - C E 3 ) , 3.30 (s, N - C H 3 ) , 3.56 (s, F e C 5 E 5 ) , 4.16-4.46 ( l n . - F e C ^ mixed with C-H), 5.06 (s, o l e f i n ) , 5 .61 (s, o l e f i n ) , 7.06-7^6 (m, C 6 H 5 ) . Prepa r a t i o n of. [ (NBD)Rh (FcNP) 1*010)," (74) [(NBD)RhClJ 2 (130 mg, 0.28 mmole) was d i s s o l v e d i n 4 ml of benzene l n a Schlenk tube to which was added FcNP (0.3564 g, 0.81 mmole), and a. s o l u t i o n of NaClO^ (86.9 mg) i n 1 .3 ml - 37 -of TKF. The suspension was further s t i r r e d for 5 min. "before 2 ml of d i e t h y l ether was added to complete the p r e c i p i t a t i o n . The s o l i d was separated, washed with 2,5 ml of benzene and 2,5 ml of d i e t h y l ether, and dried. The yellow s o l i d was dissolved i n 1 ml of dlchloromathane and f i l t e r e d to remove s o l i d impurities. After adding ethanol and d i e t h y l ether to the f i l t r a t e a. yellow s o l i d formed which turned into orange brown c r y s t a l s a f t e r storing at 0" for 12 hours, mp 190° (de-comp.) Anal. Calcd. for C^H^ClFeNO^PRh: C, 53.8; H , 4.89; N, 1.90. Found: C, 53.5; H, 4,84; N, 1.83$. Preparation of [ (COD )Rh ( (-)-FcNP) 1 * 5 ( 0 ^ ) J ;~ . (74 ) [(C0D)RhClj 2 (0.1255 g, 0.25 mmole) was dissolved i n methanol i n a. Schlenk tube under argon. To this was added FcNP (0.4484 g, 1.06 mmole) and the mixture was s t i r r e d . More methanol was added to dissolve any remaining s o l i d . Solid sodium tetraphenylborate (0,1095 g) was added and s t i r r i n g was continued f o r 10 min. The ora.nge yellow s o l i d • which prec i p i t a t e d was f i l t e r e d and washed with benzene and di e t h y l ether and dried under reduced pressure, mp 150-15 2 ° (decomp.). Anal. Calcd. for C^H^BFeNPRhi C, 71.7; H, 6,22; N, 1.44. Found: C, 71.4; H, 6.10; N, 1.44,%'. A=50.13 - 1 - 1 - 1 ohm cm M - 33 -RESULTS AND DISCUSSION Synthesis of The C h i r a l Phosphine Ligands ( + )-. (-)-FcNP As mentioned i n the Introduction, l t was decided to attempt the synthesis of c h i r a l ferrocenylphosphine ligands ((R,S)- and (S ,R)-ot-[2-diphenylphosphinof e r r o c e n y l ] e t h y l d i -methylamlne or (R,3)- and (3,R)-FcNP) which not only have an asymmetric center at carbon but also have planar c h l r a l l t y . In addition, this ligand would contain a heavy ferrocene group which might show some s t e r i c and electronic effects i n asymmetric hydrogenation reactions. The precursors of the ligands ((R)- and (3)-FcN) and related compounds have been studied extensively by Ugi and his co-workers (54,55i57,7&). Ferrocene derivatives with more than two d i f f e r e n t substltuents i n one r i n g have planar c h l -r a l l t y which cannot be described by the usual R and S nomen-clature (58,59t77). The following modification of the nomen-clature has been suggested by Ugi (55(b))for t h i s type of compound and w i l l be used i n t h i s t h e s i s . In Figure 9i the Viewed from above Figure 9. Ferrocene derivatives with planar c h l r a l l t y - 39 -observer looks along th axis of the parent ferrocene rings with the dlsubstituted r i n g directed towards him. The c o n f i -guration of the substituted ferrocene Is termed "R" i f the ligands X and Y descend i n p r i o r i t y l n the shortest clockwise arc. ("Priority" here has the same meaning as used f o r the usual R,S nomenclature). Likewise, i f the p r i o r i t y ascends ln a clockwise d i r e c t i o n , the planar c h i r a l i t y Is "S". I f d i f f e r e n t types of c h i r a l i t y a.ppear i n one compound, e.g., X and Y contain central c h i r a l elements, R and 3 symbols w i l l r e f e r to these various types of c h i r a l i t y i n the order cen-tral>a.xial>planar. For example, i n Figure 9 i f X = - C L J and OH * i r W e 2 Y=-C. then i t w i l l be refered to as (S,R,3) ( 4 5 ) . The f i r s t 3 refers to the c h i r a l i t y of Y which has higher p r i o r i t y than X which has c h i r a l i t y R. The t h i r d 3 i s the planar c h i -r a l i t y of whole molecule. If Y=P(C^H^), as In the desired ligand, FcNP, then i t Is (R,S). The preparative sequence f o r the c h i r a l ferrocenylphos-phlne (FcNP) i s sketched l n Figure 10. Both ferrocene and o(-acetylferrocene are commercially ava i l a b l e . oC-Ferrocenylethanol i s obtained by the reduction of o/-acetylf errocene. Although Ugi (65) reported the reduc-ti o n with both lithiu m aluminum hydride (LiAlK^) and sodium bis(2-methoxyethoxy)aluminum hydride (commercially known as " V l t r l d e " ) , i t has been found i n the present studies that V i t -rlde i s not as active as LiAlH^ and chromatographic separation is required a f t e r reduction. Thus about 65$ of the o<-acetyl-ferrocene i s reduced by V i t r i d e , but more than 95$ reduction - 4-0 -0 H GH J - C l < S > - C - C H 3 L i A 1 E u TJ -P i ^ Fe > < ^ Z J N > A1C1 3/CH 2C1 2 < S > ferrocene acetylferrocene ether < Q > CE~CH 3 KOAc/CgEg Fe w-ferrocenylethanol < Q > C H — C K 3 t : : , K e „/cn^OH <J2>—C,h C E 3 resolution ?e OAO - ' 3 ft i ( 0 ! l ) 2 (H-)-tertorlo < ^ T > < ^ > a c l i • f e r r o c e n y l acetate FcN r * P — C F —C*E—CH- r i Fe I e t h e / F e L l N(CE 3) 2 e t h e r < s > 3 2 <e> (l')-FcN FcNLi (unl sola ted) <C,V> c*H—CH 3 F e \ N(GH 3) 2 < § > PPh 2 (+)-FcNP ure 10. Total synthesis of the c h i r a l ferrocenylphosphine (+)- and (-)-FcNP. - ki -Is attained i f LiAlE/j, Is used. cx-Ferrocenyldimethylamlne i s obtained by nucleophilic displacement of the a.cetate group by dlmethylamlne i n aqueous methanol following treatment of o(-ferrocenyletha.nol with acetic acid ( 6 5 ) . Instead of getting amide and alcohol In the reaction of the carboxyate ester with the amine ( 7 8 ) , the amlnolysls proceeds with the a l k y l a t i o n of the amine and cleavage of the carboxylic a c i d . This i s because the a-ferrocenylethyl carbonium ion i s so stable that carboxylase anion i s a. s u f f i c i e n t l y good leaving group to provide f o r i t s formation ( 6 5 ) . The resolution of N,N-dlmethyl-o<-f errocenylethylamlne with (R)-(+)-ta.rtarlc acid gives high y i e l d s of both antipodes a f t e r three recrystalllza.tions from t h e i r respective amine t a r t a -rates. L i t h i a t i o n of (+)-N,K-dimethyl-^-ferrocenylethylamlne ((+)-FcN) with n-butylllthlum i n d i e t h y l ether-hexane as shown i n a scheme on page 18 affords.only.the two ortho sub-s t i t u t e d products, FcNLi, i n a. r a t i o of 9 6 : 4 as measured by chromatography following treatment with trimethylchlorosllane It was also found (?6) that the major Isomer reacts with anisaldehyde to give j3. The absolute configuration of t h i s ( 5 5 , 6 3 ) . 8 - 42 -complex was determined by crystallographic techniques and the results show that the configuration about the a.mine-substituted carbon i s R and that (H-)-FCN has the R absolute configuration. Thus the marked difference between the two ortho positions with respect to l l t h i a t i o n apparently results from s t e r i c repulsion between the methyl•group-on the asymmetric carbon and the cyclopentadiene r i n g and a.lso the s t a b i l i z a t i o n of the l i t h i a t e d derivative by coordination with the amino group,, Thus l l t h i a t i o n of (R)-(+)-FcN affords p r a c t i c a l l y pure (R, R) -FcNLl, and (3)-(-)-FcN y i e l d s p r a c t i c a l l y pure (S,3)-FcNLl, the a.ntlpode of (R,R)-FcNLi. Using a "more a.ctive reagent, further l i t h l a , t i o n w i l l occur i n the unsubstituted ri n g (64). This second l l t h i a t i o n i s s i m i l a r to that of ferrocene i t s e l f which undergoes l l t h i a t i o n less r e a d i l y than the amine (63,79-81). Thus Kumada et a l . ( 8 1 ) . l i t h i a t e d ferrocene with n-butyllithlum-N,N,N',N'-tetramethylethylenediamine (THEDA) to give 1,1'-dillthioferrocene which was.condensed with chlorodimethylphosphlne to give 1,1'-bis(dimethylphosphlno)-ferrocene and has been used to prepare metal complexes (81).' In the present i n v e s t i g a t i o n the dlphenylphosphino derivative of ferrocenylethylamlne was formed by the rea.ction of FcNLi with chlorodiphenylphosphine i n ether. The r e s u l t i n g mixture was hydrolyzed by a.dding an aqueous sl u r r y of sodium bicarbonate arid the product was extracted into the ether phase. The ferrocenylphosphine-ether phase wa.s c a r e f u l l y dried with MgSCij. and, a f t e r evaporating the solvent, the pro-duct was obtained as brown yellow s o l i d which was r e c r y s t a l -- 43 -11zed from ethanol three times to afford c r y s t a l l i n e phos-phine in a y i e l d about 35%, At about the same time t h i s work was i n i t i a t e d an independent i d e n t i c a l synthesis of the same ligand by Japanese workers was described (64). They i s o l a t e d the phosphine by alumina-column chromatography and p u r i f i e d i t by r e c r y s t a l l i z a t i o n from ethanol (50%), Figure 11 shows the absolute crystallographic structure of (3,R)-FcNP (95) . S i g n i f i c a n t features about the structure are as follows: ( i ) the methyl group on the asymmetric carbon . Is directed away from the cyclopentadlene ring ; t h i s confirms the absolute configuration of the s t a r t i n g amine discussed • before (p. 4 l ) j ( i i ) the cyclopentadlene rings are eclipsed whereas In parent ferrocene they are staggered. Synthesis of Metal Complexes of the FcNP Ligand Some i n i t i a l attempts to prepare complexes of FcNP with compounds of Ni, Pt and Pd were l a r g e l y unsuccessful. The only well characterized products, apart from the c a t i o n l c rhodium complexes to be described next, were (FcNP)Ni (CO)^ and (FcNP)-Rh(CO)Cl. The former was obtained by d i r e c t reaction of the ligand with 111(00)^ i n d i e t h y l ether solution. FcNP + Nl(CO)^ > (FcNP)Ni (CO)^ + CO This complex which was characterized by microanalysis, shows IR absorption of carbonyl groups at 1980, 2000 and 2060 cm"1. Most Ni(C0)^ complexes show only two such bands so ap-parently the bulky FcNP coordinated to the n i c k e l destroys Figure 11. Absolute c r y s t a l l o g r a D h l c (S,R)-FcNP ( 9 5 ) . s t r u c t u r e of - 45 -the l o c a l C^ v symmetry. The complex Eh(FcNP)(CO)Cl was obtained by reacting Rh 2(CO)^Cl 2 with FcNP i n benzene. The IR spectrum shows one Rh 2(CO) 2Cl 2 + 2FcN? • 2Rh(FcNP) (C0)C1 + 2CO carbonyl absorption band at 1990 cm - 1. This compound crys-t a l l i z e s with one benzene molecule of solvation as indicated by microanalysis and the HER spectrum. In the free ligand, the chemical s h i f t of the N-methyl hydrogens i s 1.80 ppm ( s i n g l e t ) ; but the comnlex shows two absorptions (2.4-7 and 3.1^ pnm) of the equal area. Thus l n t h i s complex FcNP acts as a bidentate ligand with both N and P coordinated to the rhodium. The chloride and carbonyl group are c i s to 'each other. A l -though Rh(PPh^) 2(C0)C1 has the trans configuration, l t i s not unusual to f i n d the c i s Rh(C0)Cl moiety l n chelate derivatives I 1 (P-P)Rh(C0)Cl ((P-P) = Ph 2P(CH 2) 2PPh 2 (82), Ph2PC=Cpph2 (CF 2 )^ (83)). The general methods of synthesis of the io n i c rhodium com-plexes are based on the published methods (7^) with minor mo-d i f i c a t i o n s . These preparative sequences are summarized In Figure 12 . The preparation of the o p t i c a l l y active complexes simply involved the same procedures but o p t i c a l l y active FcNP was used instead of racemic FcNP. The equivalent co n d u c t i v i t i e s of four of the compounds, [ (COD)Rh (FcNP) ] +BF^~ , [ (NBD)Rh (FcNP ) j +PF^~, [ (COD)Rh (FcNP) J +G10 and [(COD)Rh((-)-FcNP] BPh^ have been measured. A l l these - k-6 -[Rh(NBD)Cl] 2 FcNP, NB^PF 6 C 6E 6/THF FcNP, NaClO/j, [ (NBD )'Rh (Fc NP) ] + P F 6 " •* [ (NBD) Rh (Fc NP) j +C10^ C 6H 6/TBF [Rh(C0D)Cl], a c e t y l a c e t o n e ( C 2 E 5 ) 2 0 (acac)Rh(COD) EC 10; FcNP/TEF + *• [ (C OD) R h (Fc NP ) ] +C10^" FCNP, C 2 E 5 O E FcNP, NaPFg CH 2C1 2 [ (COD ) Rh (Fc NP) j +BF^--> [ (COD) Rh (Fc NP) j +PF. FcNP, NaBPfy CH^OH [ (COD) Rh (Fc !>JP) j + 5 ( C 6 K 5 ) Fl g u r e 12. P r e p a r a t i o n of I o n i c rhodium complexes with the FcNP l i g a n d . - k7 -are i n the range of ?4 ohm" cm"iM"1 except one ([(COD)Rh((-)-FcNP)] +BPh i (~), which i s 50.13 ohm"1cm~1M~1. The NMR spectrum of [(NBD)Rh(FcNP)j +PF^~ shows that the amino group of FcNP i s c o o r d i n a t e d to the metal with two ab-s o r p t i o n s due to the N-methyl hydrogens a t 2,42 and 3.19 ppm, compared with the s i n g l e t of the f r e e l i g a n d a t 1,80 ppm. In the case o f [(COD)Rh(FcMP)] +BF^~, the two bands due to the methyl groups a.re found a t 2.71 a.nd 3-30 ppm.. The NMR data, as w e l l as the elemental a n a l y s i s suggested tha.t only one FcNP liga.nd per rhodium Is found i n a l l the i o n i c complexes even though attempts to prepare complexes with two FcNP l i g a n d s per rhodium were made by u s i n g excess l i g a n d . Asymmetric Homogeneous Eydrogena.tlons ( I ) . C a t a l y t i c P r e c u r s o r s and C a t a l y t i c P r i n c i p l e s In the pre v i o u s s e c t i o n , the p r e p a r a t i o n and. some pro-p e r t i e s of the c a t a l y s t p r e c u r s o r s , [(diene)Rh(1)-FcNPJ +A (A~; PFg~, BF^~, ClO^" a.nd B(CgP, J^""), have been" d e s c r i b e d . Here the word " p r e c u r s o r " i s used because l t has been w e l l -documented (86) that c a t i o n complexes [ ( d i e n e ) R h L n J + A ~ (diene: norbornadiene o r 1,5-cyclooc ta.diene; A": PF^~, BF^~ or C l O ^ - ; -LJ a. t e r t i a r y phosphine, a r s i n e (n=2 or 3) or a c h e l a t i n g d l -(t e r t i a . r y phosphine) ( n = l ) ) , r e a c t r e a d i l y with molecule hy-drogen (1 atm, 25°) i n s o l u t i o n (acetone o r a l c o h o l ) ; diene i s q u a n t i t a t i v e l y reduced to alkane and ca.ta.lytlca.lly a c t i v e - 48 -complexes o f formula. [RhL H^j" 1 a r e t h e r e b y g e n e r a t e d i n s i t u . n 2 T h i s k i n d o f c a t a . l y s t p r e c u r s o r o f f e r s s e v e r a l n o t a b l e advan-tages o v e r the i n s i t u p r e p a r e d W i l k i n s o n type c a t a l y s t s . Some a r e as f o l l o w s : (1) the complexes can be p r e p a r e d and i s o l a t e d e a s i l y ; ( i i ) the d i e n e i s c o m p l e t e l y reduced and e-l i m l n a t e d from the c o o r d i n a . t i o n sphere o f rhodium; thus a v a -cancy i s l e f t f o r the b i n d i n g o f hydrogen and the s u b s t r a t e to be reduced; ( i l l ) the r e a c t i o n pathway does not i n v o l v e d i s s o c i a t i o n o f a. l i g a n d and thus the r e a c t i o n s a r e much l e s s s o l v e n t dependent. In. the p r e s e n t - w o r k l t has been o b s e r v e d t h a t l n a.lco-h o l l c s o l u t i o n s , [ ( d i e n e )Rh ( (±)-FcI\ip)] r e a c t s w i t h hydrogen (1 atm, 32 ) i n the absence of s u b s t r a t e . The b r i g h t y e l l o w c o l o r f a d e s t o p a l e y e l l o w l n a few m i n u t e s ; t h i s i s •presu-mably due t o the f o r m a t i o n of [Rh (.(±-)-Fo'NP)K23x]+, where S i s the s o l v e n t . ( I I ) . C a t a l y t i c F y d r o g e n a t l o n o f O l e f i n s Knowles and co-workers ( 3 3 ) r e p o r t e d t h a t a c t i v e c a t a l y t i c s o l u t i o n s can be p r e p a r e d i n s i t u by m i x i n g [ (1 ,.5-hexadiene)-R h C l ] 2 o r even R h C l - j ' 3 H 2 0 w i t h c h i r a l l i g a n d s , L*, i n a l c o h o l i c s o l u t i o n and the r e s u l t s a r e i d e n t i c a l w i t h t h e s e o b t a i n e d u s i n g the c r y s t a l l i n e complexes [ (COD).RhL* 2] +B(CgH^ o r BF^"". However', i n the p r e s e n t s t u d y , l t was d e c i d e d t o use the w e l l - c h a r a c t e r i z e d complexes [ ( d i e n e ) R h ( +)-FcMP] +A~ t o c a t a l y z e the h y d r o g e n a t i o n o f o l e f i n s . The p r o c h l r a l s u b s t r a t e s which were i n v e s t i g a t e d a r e - 49 -l i s t e d l n Figure 1 3 . The extent of reaction was monitored using a simple gas uptake apparatus and was checked by de-termining the NMR spectrum of the f i n a l reaction products. Table 2 and 3 show the res u l t s obtained f o r the homogeneous hydrogenation of rt-acetamidocinnamic acid and <tf-acetamldo-a c r y l i c acid respectively, using cat i o n l c c h i r a l Rh-FcNP complexes as c a t a l y s t precursors. High o p t i c a l y i e l d s are obtained i n the case of o(-acetamidoclnnamic acid and the results seem to be Independent of the diene as expected. The anion except f o r BfCgE^)^" plays l i t t l e role on the o p t i c a l y i e l d although i t seems that c a t a l y s t precursors with ClO^" or PFg~ as anion give f a s t e r rates. The use of BtCgE^Oz* " as counterlon l n rhodium complexes has been discussed by Osborn (84) and Bennett (85). They found that one of the a.rene rings of the tetraphenylborate coordinates to the metal via a. h°* i n -teraction to form a complex shown as 9_, where L i s trl p h e n y l -phosphine, following hydrogen treatment of the cati o n l c com-' plex in solution. A s i m i l a r i n t e r a c t i o n of one arene ring L L 1 - 50 -C6E<; E O I « C-CK c = c H ^ ^COOE H i x. \ / E O I » IJ—C-CH-E COOH ot-Acetamidocinnamlc A c i d * o(-Aceta.midoacrylic Acld') C 6 H 5 / C 6 H 5 \ / C = G / \ E CODE E C 6 H 5 / \ E COOH ot-Ph.enylclnna.mic Acid Atropic Acid H COOH / \ C 6H 5 C E 3 CH, C^H COOH 6*5 H o(-Methylcinna.mic Acid 0-Me thylc innamlc Ac i d * These two substrates have been most i n t e n s i v e l y studied because they belong to a. class of compounds which are amino acid precursors. Figure 1 3 . Prochlral oc.,/9-unsaturated earboxylic acid substrates used i n thi s study. Table 2 . Asymmetric Hydrogenation of c*-Aceta.midocinnamic Acid with the FcNP-Rh C a t a l y s t 9 • Catalyst precursor Solvent Time (hr) Conver-sion {%) Optical . y i e l d (%) h Configu r a t i o n [ (COD)Rh( (- )-FcNP) JCIO^ methanol 2 5 91 80 3 [ (COD)Rh ( (+)-FcNP)]Cl(fy methanol 2 5 93 73 R [(COD)Rh((-)-FcNP)jBF^ ethanol 40 83 75 3 [ (NBD)Rh ( ( - )-FcNP) ]C10^ methanol 2 5 93 78 5 [ (COD)Rh( (-r)-FcNP)]BF^ ethanol 48 91 83 R [(NBD)Rh((+)-FcNP)]PF 6 isopropanol 48 96 80 R [(NBD)Rh((+)-FcNP)]PF 6 ethanol 22 : 88 84 R [ (COD)Rh( (-)-FcNP) JB(C 6H 5)^ methanol c c c _c 3 R e a c t i o n s were carried, out at 1 atm K 2 and 32° . The c o n c e n t r a t i o n of the c a t a l y s t ' was l . O x l O - 3 M and the s u b s t r a t e l . O x l O - 1 M. ^ O p t i c a l y i e l d s are c a l c u l a t e d on the b a s i s of reported values f o r the o p t i c a l l y pure compounds: N - a c e t y l - ( E ) - p h e n y l - a l a -n i n e , L*] 2/' -51.8 (c 1, EtOi:) (92); N - a c e t y l - (S ) - p h e n y l a l a n i n e , +46.0 (c 1, EtOH) ( 9 3 ) . 0The r e a c t i o n r a t e was too low to be measured. Table 3. Asymmetric Hydrogenation of <X-Acetamidoacrylic Acid with the FcNP-Rh C a t a l y s t 3 . Conver- Optical Configu-Catalyst precursor Solvent Time (hr) slon (,%) y i e l d (%)° r a t i o n [(COD)Rh((-)-FcNP)]BF^ methanol 7 100 58 S [(COD)Rh((+)-FcNP)JCIO^ methanol 7 100 55 R [ (COD)Rh( (-)-FcNP) jClOjj, methanol 6 100 43 3 [ (COD)Rh ( (-)-FcNP)]B(CgH^)24. methanol 92 90 26 3 aReactions were ca r r i e d out at 1 atm H 2 and 32°C. The concentration of the c a t a l y s t was 1.0xl0~3 i«i and the substrate 'l.OxlO - 1 M. ^Optical y i e l d s were calculated on the basis of reported value f o r the o p t i c a l l y pure, compound: N-acetyl-(R)-ala.nine , L aJD +66.5 ( c 2, K 20) (94) j1 the pure (S)-isomer was assumed to ha.ve the same degree of o p t i c a l r o t a t i o n with opposite d i r e c t i o n . - 53 -with the metal may happen in. the present instance a f t e r [(C0D)Rh((-)-FcNP)] +3Ph^~ reacts with hydrogen. The rate of hydrogenation of <*-a.ceta.midoacryllc acid using [.(COD)Rh-((-)-FcNP)] +BPh^~ a.s the ca t a l y s t i s about one-thirteenth the rate of tha.t when the anion i s BF/j.-; and the o p t i c a l y i e l d of N-acetylalanine i s half the value when [(COD)Rh((-)-FcMP)] H"BF^ -i s used as the.catalyst (see Table 3). Also, when L(COD)Rh-((-)-FcNP)] +BPh^~ was used to ca.talyze the hydrogenation of <x-acetamidocinnamic acid, the reaction rate was so low that no hydrogen uptake was detected. In contrast, -Knowles and co-workers found that [(COD)Rh((t)-ACMP) 2J +B(CgE^)^- i s as good a ca.ta.lyst a.s the same cation used with 3F^~ or PF^~ as the anion at 3.7 atm (75) and 0.7 atm (3'3). It i s d i f f i c u l t to account for the differences. In the ca.se of the cati o n i c rhodium complexes i t seems that the composition of the solvent i s not an important va-r i a b l e In determining the hydrogenation reaction rate and product o p t i c a l purity (75), and i n the present study, metha-nol, ethanol and. isopropa.nol were used. In contrast, i n a study of Wilkinson type c a t a l y s t s , Hasler (38). showed.that solvent composition of benzene-ethanol (1:1, v/v) gives the best results (high chemical and o p t i c a l y i e l d s ) when [(+)-NMDPPj^RhCl i s used to catalyze the hydrogenation of (E)-<x-methylcinna.mic aci d . When the r a t i o was changed to 3:1 (ben-zene-ethanol), only Q3% i s reduced, and the o p t i c a l y i e l d i s 2% lower (compared with 100$ reduction i n 2k hours i f 1:1 benzene-ethanol solvent i s used). If pure benzene i s used, only 13$ reduction a f t e r 24 hours i s achieved; and i n 2-buta-none, reduction takes place to the extent of 40$ and the op-t i c a l purity of the product drops to 26.5$ e.e. from 60$ e.e. obtained i n 1:1 benzene-ethanol. The res u l t s are summarized ln Table 4 . Table 3 shows that the reaction rates f o r the hydroge-nation of cx-acetamldoacryllc acid are about four times fa s t e r than the rates for the hydrogenation of o(-acetamidocInna.mic acid (see Table 4 ) , but the o p t i c a l y i e l d s of N-acetylalanlne produced are much lower. Again, [ (COD)Rh(-)-FcNP]+B(CgH<- )^~ is peculiar with regard to both reaction rate and o p t i c a l y i e l d ; thus l t takes 9 2 hours to achieve 95$ hydrogenation (estimated fron the NMR spectrum) and the o p t i c a l y i e l d i s only 26$ . In the hydrogenation of both c<-a.ceta.midoclnnamlc acid and rt-acetamidoacryllc acid, c a t a l y s t s with (+)-FcNP as the ligand always give products with the R configuration whereas-: catalysts with (-)-FcNP give the S configuration. E a r l i e r , Kagan and Sinou (46) postulated the reaction Intermediate shown as ^  ( p . l 6 ) to account f o r the re s u l t s of many homo-geneous c a t a l y t i c hydrogenatlons of -acylamidoacrylic acids using DIOP as the asymmetric ligand. The major feature i s that the acetyl oxgen atom as well as the double bond i s co-ordinated to the rhodium. This ensures that the o l e f i n Is held In a r i g i d o r i e n t a t i o n so that when the hydrogen on the rhodium i s transfered to the prochira.l carbon atom i n the next step of the reaction, l t i s transferred s t e r e o s p e c i f l c a l l y . Ta.ble 4. The Influence of Solvents on the Reduction of (E)-O(-Methylcinnamic Acid by the Rhodium-(+)-NMDPP Catalyst System (38). Solvent Reduction {%) Yield {%) Configuration Optical y i e l d {%) 1:1 benzene-ethanol 100 90.3 R . 6 0 . 0 3:1 benzene-ethanol 83 67.0 R 58.0 benzene 13 2-butanone 40 - R 26.5 1:1 benzene-ethanol 3 100 71.0 R 56.3 In this experiment 25 mmole of substrate and 25 mmole of triethyia.mine were used. - 5 6 -In one experiment (88) an i n s i t u c a t a l y s t prepared, from C(C2H2j.^2 R h C 1 ^ 2 a n d ( H*)~ D T 0 P v , a s used to c a t a l y z e the hydro-g e n a t i o n of N-a.cetyl-ot-phenyl ethylamine i n both e t h a n o l and. benzene as s o l v e n t s . Both the r e a c t i o n s gave about the same o p t i c a l y i e l d s (42.5 and kh% r e s p e c t i v e l y ) but d i f f e r e n t con-f i g u r a t i o n s were o b t a i n e d . T h i s phenomenon was a s c r i b e d to a change of mecha.nism (87)» the argument being t h a t i n pure ben-zene the enamlde would be c o o r d i n a t e d to rhodium o n l y by i t s double bond. In the. presence of a l c o h o l , d i s s o c i a t i o n of Rb-C l bond c o u l d occur to g i v e a c a t I o n i c s p e c i e s which would then intera.ct with both the double bond and the amide group of the enamlde. Intermediates of the type shown a.s _5 c a n a l s o be used to e x p l a i n the r e s u l t s o b t a i n e d d u r i n g the present i n v e s t i g a t i o n . On t h i s b a s i s two i n t e r m e d i a t e s can be dra.wn a.s i n F i g u r e 14 and F i g u r e 15 when (R,3)-(-)-FcNP i s the l i g a n d . The diene (NBD or COD), which was c o o r d i n a t e d to the metal, has r e a c t e d with hydrogen to form the alka.ne and has l e f t the c o o r d i n a t i o n sphere. The va.ca.nt s i t e s are occupied by the s u b s t r a t e which forms both a. metal o l e f i n bond and a metal amide bond. The two faces of the s u b s t r a t e double bond are s p e c i f i e d as f o l l o w s : when the s u b s t r a t e molecule i s dra.wn as 10., then 1 A - 57 -H Figure 14. A proposed i n t e r m e d i a t e i n which the s i - r e face of the s u b s t r a t e i s d i r e c t e d towards the metal complex with (R,S)-FcNP as the l i g a n d . - 58 -Figure 15 . A proposed i n t e r m e d i a t e i n which the r e - s i face of the s u b s t r a t e i s d i r e c t e d towards the metal complex with (R,3)-FcNP as the l i g a n d . - 59 -" s i " Is assigned (89) to the face around Cl according to the usual p r i o r i t y rule, and "re" i s assigned to the face around C2 (when viewed from above the page). The face facing the viewer i s c a l l e d the s i - r e face. In Figure l4 the s i - r e face of the substrate i s directed towards the metal a.nd three s t e r i c repulsions are apparent j one i s the repulsion between the phenyl groups of the sub-strate and the ligand; the second i s between the phenyl group of the substrate a.nd the cyclopentadlene ring; the t h i r d i s between the carboxylic group and the methyl groups on the l i -gand nitrogen. In the case shown i n Figure 15 i n which the r e - s i face of the substrate approaches the ca.ta.lyst, these s t e r i c re-pulsions are minimized. From th i s analysis i t can be seen that hydrogen transfer to the coordinated o l e f i n i n the more favored case (Figure 15) w i l l give a. product with the S configuration. When (S,R)-(+)-FcNP i s considered, the more stable i n t e r -mediate which can be constructed i s the mirror image of the intermediate shown i n Figure 15. This w i l l a fford products of configuration R. When the substrate i s cx-acetamidoacryllc acid, s i m i l a r Intermediates can be constructed. However, since the phenyl group i s repla.ced by a. hydrogen atom, the only stereochemical control i s the repulsion between the carboxylic group on the substrate and the methyl groups on the ligand nitrogen. This accounts for the re s u l t s that Rh-(+)-FcNP complexes s t i l l give - 60 -products predominantly with configuration R and Rh-(~)-FcNP complexes give predominantly S; but with lower o p t i c a l y i e l d . Table 5 l i s t s the r e s u l t s Knowles et a l . obtained (30,3^) when d i f f e r e n t tf-acylamidoacryllc acids were hydrogenated using cationic rhodium complexes with 2 a s the ligand. It i s seen that higher o p t i c a l y i e l d s are obtained i f R^  i s a bulky substituent. In t h i s case the methoxy group on the ligand Is believed to form a hydrogen bond with the amide group of the coordinated substrate, which would account for the ste-reochemical control (3*0« It seems u n l i k e l y that an i n t e r -mediate of the type shown i n Figure 15 would account f o r the r e s u l t s since two separate phosphines would not give the ste-r i c bulk associated with the si z e and r i g i d i t y of the chelated FcNP ligand. In the present i n v e s t i g a t i o n , attempts to hydrogenate four other substrates: atropic acid, «-phenylcinna.mic ac i d , and <*-, /9-methylclnnamic acids.were made-using [(C0D)Rh(+)-OCK (+)-(R)-ACMP 2 Table 5. Asymmetric Hydrogenation of <x-Acylamidoacrylic Acids by Rh-complex with o-Anisylcyclohexylmethylphosphlne as the Ligand (30). ^COOH ^NHCOHg * HjCHg. COOH 1 — C — H 1 NECORg R l R2 Optical y i e l d •{%) Resulting amino acid 3-MeO-4-OH-C6H3 Ph 90 L-DOPA 3-MeO-4-OH-C6H^ Me 88 L-DOPA C 6 H 5 Me 85 L-phenylalanlne C6 H5 Ph 85 L-phenylalanine p-Cl-CgH^ Me 77 p-chloro-L-phenylalanine 3-(l-Ac-indolyl) Me 80 L-tryptophan E Me ' 60 L-alanine - 62 -FcN^J^BF^" as the c a t a l y s t precursor. No hydrogen uptake was observed a f t e r two days. A possible explanation i s that these prochiral o l e f i n s lack the amide group which, i n the presence of the bulky FcNP ligand, i s indispensable to bind the sub-strate before hydrogen transfer. This pattern i s also found i n the cationlc rhodium c a t a l y s t using ACMP 3_ as the ligand ( 7 5 ) . where simple o l e f i n s are reduced at a rate about one-tenth the rate of cx-acetamldocinnamic a c i d (Table 6)» A s i m i l a r ligand, (3,R)-BPPFA, 11. (64) has been used to produce a c a t a l y s t i n s i t u f o r the hydrogenation of crt-acyla-midoacrylic acids at 50 atm hydrogen presure and room tempera-ture ( 9 0 ) . The r e s u l t s are shown i n Table 7. In t h i s case i t was postulated that a t t r a c t i v e i n t e r a c t i o n between an un-coordinated amino group on the ligand and the carboxylic group on the substrate contributes to the asymmetric induction. Yovevev, ln view of the present r e s u l t s , the amino group could be expected to coordinate to rhodium and thus the reaction intermediate could be s i m i l a r i n structure to that su^rested above for the FcNP complexes. - 63 -Table 6 . Hydrogenation Rates of Various Olefins Catalyzed by Rh-DIOP and Rh-ACMP complexes ( 3 1 , 3 2 , 7 5 ) Catalyst ligand Substrate Approx, r e l , . r a t e AC MP <*-a.ceta.mldoclnnamic acid 1 DIOP a-a.ceta.mldocinna.mic acid 2 AC MP cycloocta.dlene-. < , 1 ACMP n o r b o r n a d i e n e . 5 -ACMP 1-octene . . 5 - AC MP ot-phenylacryllc a d d < . 1 Table 7 . Asymmetric Hydrogenation Catalyzed by (S,R)-3PPFA-Rh Complex8 ( 9 0 ) . Olefin Solvent Optical y i e l d {%) (Configuration) PhCE=C (IMHCOMe )COOH Ac 0-KeO Me OH 9 3 ( 3 ) E 20/EtOH ( 1 / D 92 (S) H20/Me.OH ( 1 / D 8 9 (S) KeOH 8 (S) EtOH 38 (S) H20/MeOK ( 1 / 3 ) 8 7 (S) EtOH 36 ( 3 ) H 2 O/MeOH ( 1 / 2 ) 8 6 (s) K20/MeOK ( 3 A ) 52 (S) !T(H ?) = 50 atm; (S,R)-BPPFA/Rh = 1 . 2 / 1 ; Rh/Substrate = 0 . 5 mol%. - 64 -GENERAL CONCLUSIONS AMD RECOMMENDATIONS FOR FUTURE WORK The most Important f i n d i n g of th i s work i s that the c h i -r a l Rh-FcNP complexes catalyze the hydrogenation of a class of compounds which are amino acid precursors i n high o p t i c a l y i e l d and under mild conditions (32° and 1 atm Hg). The highest o p t i c a l y i e l d i s 84$ which i s comparable to the best results (85$) obtained with a Rh-ACMP complexes and i s better than the results (72$) obtained with a. Rh-DIOP complexes as ca t a l y s t . The ligand i s f a i r y e a s i l y to prepare (about ten steps from the s t a r t i n g material to both (+)- and (-)-FcNP) and to Isolate i n o p t i c a l l y pure form and the complexes L(diene)Rh-(Ij-FcNPj^A" which can be Isolated i n c r y s t a l l i n e form are believed to be the c a t a l y s t precursors. When the Rh-FcNP complexes are used to catalyze the hy-drogenation of a,/3-unsaturated acids, the rate i s found to be very low. It seems that the present c a t a l y t i c system Is good for the hydrogenation of cx-acylamldoacrylic acids and, I f the proposed intermediate i s correct, other enamides. There are many di r e c t i o n s f o r further work l n the area of asymmetric reactions i n which the c a t a l y s t contains asym-metric ligands which are ferrocene d e r i v a t i v e s . One would be to modify both rings of ferrocene to obtain ligands with more than two donor s i t e s . An example was prepared, recently (64) as follows s - 65 -P^Nph, a ? -•5 l L 1 J ^ P P h ? < § > 2 fe) < 5 ™ 2 G 1 < 0 > P P h 2 This could coordinate to metals using the two phosphorus atoms leaving the amino group free to i n t e r a c t with the bound substrate. A s i m i l a r procedure could y i e l d a v i n y l group on the second r i n g to give a derivative which could be polymerized to y i e l d an o p t i c a l l y active polymeric ligand which could be used i n supported c a t a l y s t systems. Other reactions such as h y d r o s i l y l a t l o n are catalyzed by Rh complexes and complexes of ligand such as FcNP should be investigated with respect to the addition of 31-H to C=C, C=0, and C=N bonds. In addition, the asymmetric hydrogenation. of C=0 and C=N bonds should be studied. - 66 -BIBLQGRAPHY 1. a) A. H. Beckett, Progr. Drug Res., 1, 455 (1959); b) P. 3. Porto^hese, J . Pharm. 3 c l . , 865 (1966); c) p. 3. Portoghese and D. L. Larson, J . Pharm. 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