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Direct carbonylation of aromatic semi-carbazones and azines Millward, Stewart 1963

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DIRECT CARBONYIATION OF AROMATIC SEMICARBAZONES AND AZINES by STEWART MILLIARD B.Sc, University of Br i t i s h Columbia, I 9 6 0 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in the Department of Chemistry We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA June, 1 9 6 3 To be presented before the XIX International Congress of Pure and Applied Chemistry at London, England, July, 1 9 6 3 In presenting th i s thesis in p a r t i a l fulf i lment of the requirements for an advanced degree at the Univers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make i t free ly avai lable for'.reference and study. I further agree that per-mission for extensive copying of this thesis for scholarly purposes may be granted by the Head of my Department or by his representatives,. It i s understood that copying, or p u b l i -cat ion of this thesis for f i n a n c i a l gain sha l l not be allowed without my written permission. Department of The Univers i ty of B r i t i s h Columbia,: Vancouver 8, Canada. / / Date JOfstl  i A B S T R A C T Benzophenone semicarbazone reacted with carbon monoxide at about 300 atmospheres and at 235-2U50 i n the presence of preformed dicobalt octacarbonyl as catalyst to yield 3-phenylphthalimidine (XXXVII), 3-phenyl-2-(N-benzhydrylcarboxamido)phthalimidine (XXXI?), N,W-dibenzhydrylurea (XXXV), and W-benzhydrylurea (XXXVI). At 200-220° benzophenone semicarbazone gave N-benzhydrylurea (XXXVI),, benzophenone azine (XXXVIIl), and benzophenone ij.-benzhydrylsemicarbazone (XXXJX). When the reaction temperature was further reduced to 175-180°, benzophenone semicarbazone did not produce the carbonylation product obtained i n the second experiment but only the degradation and reduction products, XXXVIIl and XXXIX respectively. Carbonylation of benzophenone azine (XXXVIIl) at 235-2Ji5° produced 3-phenylphthalimidine (XXXVIl), whereas carbonylation of benzophenone U-benzhydrylsemicarbazone at the same temperature yielded 3-phenylphthalimidine and 3-phenyl-2-(N-benzhydryl-carboxaraido)phthalimidine (XXXIV).. An independent synthesis of the latter compound and of benzophenone U-benzhydrylsemicarbazone, both in good yield, has been carried out. When benzaldehyde semicarbazone was carbonylated at 200-220° only the degradation product, benzaldehyde azine (XLIl) was formed. Increasing the temperature to 235-2U£° did not alter the course of the reaction. Carbonylation of benzaldehyde azine at 235>-2U5° yielded 2-benzylphthalimidine (XLVIIl), phthalimidine (L), and 2-(N-benzyl-carboxamido)phthalimidine (XLVI). The significance of the presence of i i phthalimidine and 2-(N-benzylcarboxaraido)phthalimidine in the carbonylation products of benzaldehyde azine i s discussed i n regard to the mechanism of the cyclization reaction* A mechanism i s proposed fo r the cyclization reaction and evidence is presented i n support of the proposal. The ureido group (-NHCONHj,) or i t s degradation products has been shown to have an inhibitory effect on the catalytic activity of dicobalt octacarbonyl. An independent synthesis of 2-(N-benzyIcarboxamido)phthalimidine i s also reported. TABLE OF CONTENTS Page Introduction 1 Direct Carbonylation of Aromatic Semicarbazones and Azines 35 Experimental A. General Considerations 6£ B, Carbonylation of Benzophenone Semicarbazone at 21*0° 66 C - Chromatographic Separation of the Products from B 66 D. Characterization of the Products from B 66 1.. Diphenylmethane (XXXII) 66 2- 1,1,2,2-Tetraphenylethane (XXXIII) 68 3., Reduction of Tetraphenylethylene i n Sodium and Liquid Ammonia 68 k » 3:-Pbenyl-2:- (N-benzhydrylcarboxamido )phthalimidine (XXXIV) 69 5* Exchange Reaction of 3-Phenyl-2-(N-benzhydryl-carboxamido )phthalimidine with Beuterium Oxide 70 6. Synthesis of 3-Rhenyl-Z'-(N-benzhydrylcarbox-amido)phthalimidine a) Diphenylacetylchloride 70 b) Benzhydrylisocyanate 70 c) Condensation of Benzhydrylisocyanate with 3-Phenylphthalimidine 71 7* N,N'-dibenzhydrylurea (XXXV) 72! 8* Synthesis of NjN'-dibenzhydrylurea 72 9.; N-benzhydrylurea (XXXVI) 72 10* Synthesis; of N-benzhydryiurea 73 E* 3-Phenylphthalimidine (XXXVII) 73 i v Page; F* Blue Cobalt Complex 7U G* Carbonylation of Benzophenone Semicarbazone at 200-22.00 7k H» Characterization of the Products from G 1. Benzophenone Azine (XXXVIII) 76 2!..- Synthesis of Benzophenone Azine 76 3 . Benzophenone U-benzhydrylsemicarbazone (XXXTX) 76 k* Synthesis of Benzophenone U-benzhydrylsemi-carbazone 77 a) Benzhydrylamine 77 b) Condensation of Benzhydrylamine with Benzophenone Semicarbazone 77 I. Carbonylation of Benzophenone Semicarbazone at 175-180° 78 J. Chromatographic Separation of the Products from I 78 K- Carbonylation of Benzophenone Azine at 21*0° 79 L. Carbonylation of Benzophenone U-benzhydrylsemicarbazone at 2lt0° 82 M.. Carbonylation of Benzaldehyde Semicarbazone at 215-22.0° 82 N* Chromatographic Separation of the Products from M 8I4. 0.. Carbonylation of Benzaldehyde Semicarbazone at 21*0° 89 P» Chromatographic Separation of the Products from 0 89 Q.. Characterization of the Products from M and 0 1. Bibenzyl (XLI) 91 2. Benzaldehyde Azine (XLII) 91 3 . Synthesis of Benzaldehyde Azine 91 k. Compound XLIII 92: 5. Compound XLIV 92 V Page R» Carbonylation of Benzaldehyde Azine at 2I4.O0 93 S. Chromatographic Separation of the Products from R 93 T.. Characterization of the Products from R 1. Bibenzyl (XLl) 98 2. Compound XLV 98 3. 2-(N-benzylcarboxaMdo)phthalimidine (XLVl) 98 i i . Synthesis of 2-(N-benzylcarboxaraido)phthalimidine a) Preparation and Characterization of Benzylisocyanate 98 b) Condensation of Benzylisocyanate with Phthalimidine 99 5". Compound XXVII 99 6.. 2:-Benzylphthalimidine (XLVIII) 100 7- Compound X L 3 X 100 8. Phthalimidine (L) 101 9- Compound LI 101 Bibliography 103 AGKNOl'fLED GEMENTS Many thanks are due to Dr. Alex Rosenthal for giving me the opportunity to work under his expert guidance and for his encouragement and patience during the course of this research project. Thanks are due also to I. A. M. for the many hours she spent i n preparing this manuscript for presentation. This research was supported by a grant from the Petroleum Research Fund administered by the American Chemical Society. Grateful acknowledgement i s hereby made to the donors of said fund. v i LIST CF CHARTS Page I. Carbonylation of Benzophenone Phenylhydrazone 13 I I . Carbonylation of Azobenzenes 1U III.. Carbonylation of it-Methylbenzophenone Phenylhydrazone 15 TV. Carbonylation of Aromatic Aldehyde Phenylhydrazones 17 V. Reaction of Acetylenes with Iron and Cobalt Carbonyls 26 VI*-- Studies on the Mechanism of the Cyclization Reaction 32i VII. Mechanism of Carbonylation of Benzaldehyde 1-Phenylhydrazone-l-Nl5 33!, VIII.. Carbonylation of Benzophenone Semicarbazone at 2I4O0 37 IX* Carbonylation of Benzophenone Semicarbazone at 175-180° and 200-220° UO X:. Carbonylation of Benzophenone Azine and Benzophenone U-benzhydrylsemicarbazone at 2l;0° I4.Z! XI* Carbonylation of Benzaldehyde Semicarbazone U7 XII. Carbonylation of Benzaldehyde Azine at 2I4.O0 50 XIII* Proton Magnetic Resonance Spectra of Compound LI 52' V 1 X LIST OF TABLES Page I.- Chromatographic Separation of Material B from the Carbonylation of Benzophenone Semicarbazone at 2k0° 67 I I . Chromatographic Separation of Material D from the Carbonylation of Benzophenone Semicarbazone at 200-22:0° 75 III. Chromatographic Separation of the Products from the Carbonylation of Benzophenone Semicarbazone at 175-180° 80 IV. Chromatographic Separation of the Products from the Carbonylation of Benzophenone U-benzhydrylsemi-carbazone at 2l|.0° 83 V. Chromatographic Separation of Material E from the Carbonylation of Benzaldehyde Semicarbazone at 215-220° 85 VI. Chromatographic Separation of Material F from the Carbonylation of Benzaldehyde Semicarbazone at 215-22.0° 86 VII. Chromatographic Separation of Material F after Extraction with Petroleum Ether (b.p. 30-60°) 87 VIII* Chromatographic Separation of Material H from the Carbonylation of Benzaldehyde Semicarbazone at 2ii0° 90 3X. Chromatographic Separation of the Material Extracted from the Black Solid (J) from the Carbonylation of Benzaldehyde Azine at 2k0 9k X!* Chromatographic Separation of the Greemsh-black Solid (K) from the Carbonylation of Benzaldehyde Azine at 2k9° 95 XI* Rechromatography of the F i r s t Fraction from the Chromatography of Material K. 97 I N T R O D U C T I O N Reactions involving carbon monoxide, hydrogen, organic substrates and metal carbonyl catalysts have become so extensive during the last decade that i t has become necessary to classify them for purposes of discussion and to l i m i t the discussion to the pertinent category. Further i t i s regrettably necessary to avoid discussion of such related topics as the chemistry of metal carbonyls, their organo-metallic derivatives, and their use in polymerization reactions except where germane to the present topic. Such terms as the oxo process, hydroformylation,, carbonylation, carboxylation, disproportionation, direct carbonylation, and cyclization reactions of carbon monoxide have found frequent use i n the literature. The use of the term Oxo arose as a result of the pioneering work, in the application of metal carbonyls to organic syntheses, carried out by W. Reppe and his co-workers at I. G. Farben during the Second World War ( 1 , 2 ) . One of the main results of this work was the Oxo process f o r the conversion of olefins into the homologous aldehydes or alcohols by reaction with synthesis gas (a mixture of CO and Hg) and a cobalt catalyst (3,U,5>,6), added as preformed dicobalt octacarbonyl, a cobalt salt or as the reduced metal. Other catalysts such as iron and nickel ( 7 , 8 ) , rhodium and iridium have also been used. The lat t e r two have been advocated (9) as allowing the reaction to be carried out at a lower temperature than with cobalt. -2-Since this reaction may be visualized as entailing the addition of the elements of formaldehyde (H-CHO) across the double bond i t is also referred to as the hydroformylation reaction. 100-120° RCH*CHR' + CO + Hg RCHgCCH) (R')CHO Insofar as the products of such reactions are primarily aldehydes, the term hydroformylation is preferable. The temperatures normally employed in the hydroformylation reaction are in the region 100-120° while at higher temperatures, 150-180°, subsequent reduction of the aldehyde to a primary alcohol occurs. Carbon.monoxide-hydrogen pressures of 200-300 atmospheres are typical-1^0-180° RCH=GHR' + CO + 2fl2 »• RCHgCCHKR^HgOH The direction of addition seems to be governed largely by steric effects (10) the aldehyde group being attached preferentially to the less hindered end of the double bond. Additionally, the proportion of branched chain aldehyde appears to increase at higher reaction temperatures (11). There are a number of reviews of the hydroformylation of olefins, with the most recent being that of C. ¥. Bird (12.). The fundamental, and from a commercial point of view the most . important, carboxylation reaction is typified by the exothermic conversion of acetylene to acrylic acid, in 95% yield, by the reaction of acetylene with nickel carbonyl under aqueous acidic conditions, at about U0° (13,.1U)» In the presence of other compounds possessing active hydrogen, for example, alcohols, amines, etc., the corresponding derivatives of acrylic acid are obtained. The synthesis of ethylacrylate by this route can be represented as follows:: -3-UCgHg + N i C C O ) ^ + U E t O H + 2HG1 * - UCH 2 =CHCOOEt + N i C l g + Hg T h i s r e a c t i o n c a n b e a c h i e v e d b y t h e a d d i t i o n o f a s t o i c h i o m e t r i c amount o f n i c k e l c a r b o n y l ( s t o i c h i o m e t r i c m e t h o d ) o r , b y c a r r y i n g o u t t h e c o n v e r s i o n u n d e r a n a t m o s p h e r e o f c a r b o n m o n o x i d e i n t h e p r e s e n c e o f a c a t a l y t i c amount o f n i c k e l c a r b o n y l ( c a t a l y t i c m e t h o d ) . I n b o t h c a s e s i t a p p e a r s t h e n i c k e l c a r b o n y l f u r n i s h e s c a r b o n m o n o x i d e a n d b e c a u s e t h e s y n t h e s i s r e s u l t s i n t h e f o r m a t i o n o f a n a c i d o r i t s d e r i v a t i v e s ( i . e . a d d i t i o n o f t h e e l e m e n t s o f f o r m i c a c i d , H-COOH), t h e s y n t h e s i s h a s b e e n c a l l e d c a r b o x y l a t i o n . A w i d e v a r i e t y o f s o l v e n t s y s t e m s (15) h a s b e e n e m p l o y e d s u c c e s s f u l l y i n c l u d i n g p r i m a r y , s e c o n d a r y a n d t e r t i a r y a l c o h o l s , a c e t o n e , m e t h y l e t h y l k e t o n e , d i o x a n e , t e t r a h y d r o f u r a n , e t h y l a c e t a t e , p y r i d i n e a n d a n i s o l e . However w a t e r must b e p r e s e n t a n d i n a n h y d r o u s a l c o h o l i c s o l v e n t s o n l y much r e d u c e d y i e l d s o f a c i d s a r e o b t a i n e d . M o s t o f t h e c a r b o x y l a t i o n r e a c t i o n s r e p o r t e d i n t h e l i t e r a t u r e h a v e b e e n c a r r i e d o u t i n a q u e o u s e t h a n o l a n d t h e p r o d u c t i s t h e e t h y l e s t e r , f o r m e d b y s u b s e q u e n t e s t e r i f i c a t i o n o f t h e a c i d . T h e e f f i c i e n c y o f , a n d t h e p r e c i s e c o n d i t i o n s f o r , t h e c a r b o x y l a t i o n r e a c t i o n d e p e n d o n t h e i n d i v i d u a l a c e t y l e n e a n d i t h a s b e e n p o s s i b l e t o d i v i d e s u b s t i t u e n t s i n t o two c l a s s e s : ( A ) t h o s e w h i c h f a c i l i t a t e c a r b o x y l a t i o n : a l k y l j a r y l j -CHgOHj, -CHgOAcj -CHROAcj -CHgCHgOHj -CHoCHtCH^ XOH)* - C H p C H o C ^ O H j a n d ( B ) t h o s e w h i c h h i n d e r c a r b o x y l a t i o n : Hj -CHROHj -CRoOHj - C R g O A c j - C R ^ C C C I ^ O H j - A c j -COOHj - C O g E t . T h u s i n a n a c e t y l e n e XC=CY i f b o t h X a n d Y b e l o n g t o c l a s s A t h e r e a c t i o n i s s m o o t h . S i m i l a r l y i f X comes f r o m A a n d Y f r o m B t h e r e a c t i o n p r o c e e d s smoothly with the formation of YCH=CXC02H,, but i f both X and Y come from group B the reaction is not exothermic and gives only a low yield of unsaturated acid after prolonged heating (12)* Gf course, acetylene reacts smoothly, where X = Y - K. In general, the addition of the elements of formic acid is always cis and obeys the Markownikoff rule (16), The following equations illustrate these rules: fr>0+ COOH H-C3C-C 2H- + CO — — HgC-C^ H^0+ H .COOH R-C=C-CoH< + CO C=cf 2 ^ R X C 2 H 5 The carboxylation reaction particularly lends itself to the synthesis of <*- -methylenic acids as illustrated by the synthesis of the antibiotic, <=< -methylenebutyrolactone (17) • ^ ^ C H 2 HOCHgCE^ C^ CH ' • *~ CHg C 0 Vinylacetylenes are not very readily carboxylated but the reaction appears to be catalyzed by pyridine (18). The products of these reactions are the subject of considerable controversy (12,Hi,,18,19,20). Attempts to carboxylate diacetylenes were unsuccessful (16). Acetylene can be carboxylated with dicobalt octacarbonyl in methanol at 95° and a carbon monoxide pressure of 25>0 atmospheres to give as the major product, dimethyl succinate (21), or in the presence of aniline the -5-d i a n i l i d e (22). The reaction i s complicated however by the formation of at least nine side products (23,214.).. Co 2(C0 )o HC=CH + MeOH + CO s- MeOOC(CHo)~COOMe 95° When o l e f i n s are reacted with n i c k e l carbonyl under aqueous acid conditions the products are saturated acids. The conditions f o r the o l e f i n s are i n general more stringent than f o r acetylenes (12).. Thus f o r the stoichiometric method, temperatures around 160° at pressures of about 50 atmospheres of carbon monoxide are normally employed,, while c a t a l y t i c a l l y , temperatures i n the region of 250° and carbon monoxide pressures of around 200 atmospheres are used (25,26,27). Cobalt and i r o n carbonyls have also been employed but the l a t t e r p a r t i c u l a r l y appears to be less e f f e c t i v e and cobalt tends to cause more side reactions (25). The d i r e c t i o n of addition of the elements of formic acid to olef i n s does not appear to be as selective as with acetylenes. Alcohols may be used i n place of o l e f i n s but a higher temperature and the addition of a n i c k e l halide are necessary* Secondary and t e r t i a r y alcohols react at 275° and primary at 300° (28)* The reaction generally appears to proceed v i a the o l e f i n . Phenyl substituted alcohols appear to undergo p r e f e r e n t i a l hydrogenolysis to the parent hydrocarbon* Carboxylic acid derivatives such as, esters (26,29,30), thioesters (26 ,30), amides (26,29,30,31), or anhydrides (26,32,33) are obtained by conducting the reaction i n the presence of the appropriate alcohol, t h i o l , amine or carboxylic a c i d . -6-Treatment'of an aryl halide with nickel carbonyl, aqueous acid, and carbon monoxide at temperatures around 300° and pressures of about 600 atmospheres gives the corresponding benzoic acid (3k) • Apart from nickel carbonyl the use of iron (35) and cobalt carbonyls (3kt3$) also have been reported* A number of modifications to the general procedure have been employed. Thus, the corresponding esters are obtained i f an anhydrous alcohol (36,37)*. or lower ester (36,38),; such as methylformate is used as reaction medium* Amides or nitr i les are the products in the presence of formamide, urea, or oxamide (39)* The aroyl fluoride is formed by the use of sodium fluoride under anhydrous conditions (UO). The disproportionation of benzoic anhydrides to phthalic anhydrides and benzene occurs when the former is heated with nickel carbonyl at 325°, and a carbon monoxide pressure of 100 atmospheres (iil,ii2:). O Similarly, N,N-dibenzoylaniIine disproportionates into N-phenylphthalimide and benzene (!»!)• N i ( C O ) A O ..-7-When phthalic anhydride is treated with hydrogen and dicobalt octacarbonyl i t is converted quantitatively to benzoic acid (1|3)» Primary or secondary amines undergo carbonylation by reaction with a wide variety of metal carbonyls forming the N-formyl derivatives and ureas (lhJ26ihk>k5)* Many of these reactions take place at room temperature and atmospheric pressure. Ni(CO). PhNHg- -—»- PhNHCHO + PhNHCONHPh (CH^gNH + Co2(CO)8 - (CH^NCHO + [ (CH 3) 2N] £0 Alkyl tertiary amines are reported (lli , 2 6 ) to give N,N-diaIkylformamidesj the fate of the alkyl group is not reported. Aryl tertiary amines on (CH3)3N + [Co(CO)J (CH3)2NCHO the other hand react as shown, where R is an alkyl group-PhNR2 + Co2(CO)Q' *-PhN(R)COR The reversible nature of urea formation has been shown by the conversion of urea to hydrazine using iron, cobalt, nickel, molybdenum, or tungsten metal at temperatures from I4O to 15>0° depending on the metal (I46)* When iron i s used, semicarbazine is formed as a major by-product. Conversely, hydrazine hydrate reacts with iron pentacarbonyl at k$° under 900 atmospheres of carbon monoxide to give semicarbazine while at 100° and 500 atmospheres of carbon monoxide, both urea and semicarbazine are formed (1*7)-- 8 - ' metal U5° 900 atm. 100° 500 atm. *- HgNNHCONH^  • HgNDONHg The reversible nature of this reaction i f further demonstrated by the exchange of "^CO with N.N'-diphenylurea at 230° in the presence of dicobalt octacarbonyl (1+3) •> Murahashi and Horiie (U8.lr9.50,51) have shown that azobenzenes are converted in part to diarylureas when reacted with dicobalt octacarbonyl,, carbon monoxide and hydrogen. Rosenthal and co-workers (52) reacted benzaldoxime to give NjN'-dibenzylurea (35$) and N-benzylurea (10$)* Analogous products were obtained from the oxime of 2-acetylnaphthalene (53)* Ureas have also been obtained in low yields from aniline (1U,,5U), aliphatic phenylhydrazones (5U)» aromatic semicarbazones (55)> ketazines (56) and nitriles (57) using cobalt carbonyl and high purity carbon monoxide (containing 0*0U# hydrogen). Carbonylation reactions with metal carbonyls and carbon monoxide have afforded a variety of heterocyclic compounds from substrates containing carbon-nitrogen double bonds as in Schiff bases, oximes, hydrazones, ketazines and semicarbazonesj nitrogen-nitrogen double bonds as in azobenzenes, and carbon-nitrogen triple bonds as in nitr i les . Ph-N=N-Ph (PhNH)2C0 -9-When anils, such as benzalaniline are reacted with dicobalt octacarbonyl in benzene at 200-230° and carbon monoxide pressures in the range 100 to 200 atmospheres, the products are 2-phenylphthaliraidines (50,58,59,60,61). A wide variety of Schiff bases have been employed in this reaction. Iron pentacarbonyl also catalyzes the reaction although Q ^ N P h 2 0 0 - 2 3 0 ° o less effectively while no reaction occurred with nickel carbonyl (50,62), although its use is claimed in a patent ( 6 l ) . The reaction is inhibited by polar solvents, such as ethanol, tetrahydrofuran and water (50,62). In the presence of hydrogen, the anils are reduced to the corresponding 130° PhCH=NPh <- PhCHpNHPh C0:H 1:1 80$ amines (50,51). The latter reference (5l) also reports the reaction of benzonitrile and benzylcyanide with synthesis gas and cobalt carbonyl to give a small quantity of amines (mixtures of primary and secondary ones) revealing that reduction of nitriles would be difficult to realize and no reaction product was obtained in which carbon monoxide had been. involved. More recently, however, Rosenthal and co-workers (57) have reacted the nitriles at a higher temperature (about 250°) with carbon monoxide and a carefully controlled amount of hydrogen in the presence of cobalt carbonyl to yield phthalimidines, amides and ureas. Thus when benzonitrile was reacted with carbon monoxide at 235° in the presence of catalytic amounts of dicobalt octacarbonyl and pyridine, the product -10-was N-benzylphthalimidine. The use of organic bases, such as pyridine, was reported to be effective in increasing the rate of the hydroformylation reaction (63) and was also used to catalyze the carboxylation of vinyl-acetylenes (18).' When small amounts of hydrogen were added to the reaction, system, the yield of N-benzylphthalimidine was increased and sym-dibenzylurea was also produced. Benzylcyanide, under similar conditions gave the corresponding disubstituted urea, secondary amine and mono-substituted amide. PhCHgCN (FhCHgCHgNlOgCO + [phCCR^g] ^ NH + PhCHgC-NHCHgCHgPh Aromatic ketoximes gave 3-substituted phthalimidines when reacted with carbon monoxide - hydrogen £°8:1.J> j pressures of 300 atmospheres and temperatures around 250°, in the presence of preformed dicobalt octacarbonyl (6U). R = CH3-, C 6 H r , CgHgCHg--11-The oxime of 2-acetylnaphthalene gave a small amount of 3-methylbenzo-. phthalimidine (I) and a large amount of benzoquinoline (II) plus ureas. -(2-naphthyl) l C H 3 X " JL Formation of II was later shown to be independent of the presence of carbon monoxide, hydrogen and dicobalt octacarbonyl ( 6 5 ) . Reaction of the 0 - and N-methyl derivatives of aromatic ketoximes with carbon monoxide and hydrogen at 220° in the presence of cobalt carbonyl similarly gave 3-substituted phthalimidines ( 6 6 ) . Under similar conditions 2-benzil-N,N1-dimethyldioxime gave tetraphenylpyrazine - a remarkable trans-formation ( 6 6 ) * Ph-C-C-Ph II II ^ Phif^Sph Thus the attempts to prepare 2-bydroxyphthalimidines via this route were unsuccessful. As mentioned earlier, the aromatic aldoximes are reported to give mono and disubstituted ureas under the above conditions ( 5 2 ) . At about the same time however, Murahashi (59) reported that benzaldoxime gave o benzamide when reacted at 220--230 with carbon monoxide and cobalt catalyst.. -12--Murahashi (5l) also reported that benzaldehyde phenylhydrazone did not give any definite products when reacted with synthesis gas at ,. 200 atmospheres and temperatures of 120-130°. Rosenthal and Weir later showed that both aromatic ketone (67) and aromatic aldehyde phenylhydrazones (68) undergo cyclization with high purity carbon monoxide, i n the presence of preformed dicobalt octacarbonyl at o temperatures of 190 to 250 . Thus when benzophenone phenylhydrazone was reacted with carbon monoxide at 275 atmospheres and at 230 - 21+0° (Chart I ) , 3-phenyl-phthalimidine-N-carboxyanilide (III) was obtained i n 70$ y i e l d * When the reaction temperature was reduced to 210-220°, a mixture of 3-phenylphthalimidine (IV) and 3-phenylphthalimidine-N-carboxyanilide (III) was obtained. When the temperature was reduced to 190-200°,: only 3-phenylphthalimidine (IV) was obtained. The same temperature dependence of the number of carbon monoxide entities incorporated into the product was observed by Murahashi and co-workers (U9,69) wherein they showed that azobenzene reacts under 150 atmospheres of carbon monoxide to form indazolone (V) at 190°, and 3-phenyl-2,ij.-dioxo-l,2,3,i|--tetrahydroquinazoline (VI) at 230° (Chart II).: When li-methylbenzophenone phenylhydrazone was treated with carbon monoxide at 230° under the same conditions, a mixture of 3-(p-tolyl)-phthalimidine-N-carboxyanilide (VII) and 3-phenyl,6-methylphthaIimidine-N-carboxyanilide (VIII) were obtained i n approximately equal yield (Chart III) (67)* These results differed from the observations of Murahashi and co-workers (69) on the effect' of substituents on carbon monoxide ring-closure reactions i n substituted azobenzenesj here the -13-K Ph NCNHPh 0 ° 1 ( 7 0 % ) 230 240° CO + mixture of oils 2 0 % >JHP 12% H Ph IH+ mixture of oils 30% 12(50%) 190 200° CO I Z +black solid + mixture of 2 5 % . 5 0 % oils 20% C H A R T I : C A R B O N Y L A T I O N O F B E N Z O P H E N O N E - P H E N Y L H Y D A Z O N E C H A R T H . C A R B O N Y L A T I O N O F A Z O B E N Z E N E S NHPh 511(20%) m(20°/o) 3 0 % C H A R T UL : C A R B O N Y L A T I O N O F 4 - M E T H Y L B E N Z O P H E N O N E P H E N Y L H Y D R A Z O N E -16-cyclization always occurred on the substituted ring (Chart I I ) . In general, the aromatic aldehyde phenylhydrazones gave more complex product mixtures, with lower yields of cyclic products, than the aromatic ketone phenylhydrazones (68). When aromatic aldehyde phenylhydrazones were reacted under similar conditions to the ketone phenylhydrazones, the major product was N-phenylphthaliraidine (JX) i n $0% y i e l d (Chart 17) (68). The m-tolylhydrazone of benzaldehyde under similar conditions, yielded N-(m-tolyl), phthalimidine (X), while the 1-naphthaldehyde phenylhydrazone afforded a mixture of 2-phenylbenz £ e j isoindolin-l-one (XI), sym-diphenylurea, and naphthonitrile (Chart IV).. The attempts to form a six-membered heterocyclic system by carbonylation have f a i l e d . Thus phenylbenzylketoxime gave only 3-benzylphthalimidine (61;), • PhCH 2 CPh ^ ^ f T m " while dibenzylketoxLme ( 7 0 ) gave 3$% yield of N-formyl derivative and 60% of the secondary amine as shown: COrHp Il9:l| H H (PhCH2)2C = NOH 1 ^ *~ (PhCH2)2C-NCHO + (PhCH2)2NH 220 - 230° Methyl-^ -phenylethyl ketoxime ( 7 0 ) gave similar products. -17-C HART W. : C A R B O N Y L A T ION O F A R O M A T I C ALDEHYDE P H E N Y L H Y D R A Z O N E S -18-When the phenylhydrazone of dibenzylketone (70) was reacted with carbon monoxide at 235°, no six-membered ring was formed but 2-benzyl-3-phenylindole was isolated i n about $0% yield along with a small amount of diphenylurea* PhCHoCCHoPh >• L [T^R7+ (PhNH)?C0 II 235° S ^ N / D Z NNHPh H When phenylacetaldehyde phenylhydrazone (68) was reacted under similar conditions, the only isolable products were mono- and sym-diphenylurea (68). Murahashi and co-workers (59) also reported that the a n i l of phenylacetaldehyde f a i l e d to cyclize-In reviewi then, we have seen that both alcohols and aldehydes can be produced under the oxo conditions and that, when aldehydes are the principle product, the term hydroformylation i s preferred. The latter involves the addition of the elements of formaldehyde (CO + = HCHO) across an acetylenic or olefinic linkage. Similarly, i n carboxylations, the elements of formic acid (CO * E^O = HCOOH) are pictured as adding across the unsaturated linkage giving rise to carboxylic acids and hence the name, carboxylation. When amines are carbonylated with metal carbonyls the synthesis i s referred to as formylation i n view of the product formed, namely N-formyl compounds. Reactions involving the insertion of carbon monoxide between two N atoms, or between a ring carbon and a side chain N (as i n the oximes) with subsequent ring formation, are called carbonylation reactions or insertion reactions. The term cyclization i s , of course, self-explanatory.. -19-Mechanism of Carbonyl Insertion Reactions The f i r s t mechanisms proposed for the carbonylation reactions which accounted for many of the observed results involved a cyclopropanone or cyclopropenone intermediate. I t has however, become increasingly obvious that such an explanation i s untenable* The f i n a l disproof was provided by a study of the reactions of the recently prepared diphenylcyclopropenone under carboxylation conditions (71). Thus, i n the absence of nickel carbonyl i t was found to be perfectly stable under the acidic conditions used for carboxylating diphenylacetylerie, even when nickel chloride was present.. In the presence of nickel carbonyl, conversion to trans e*L -phenylcinnamic acid occurred. That this took place via diphenylacetylene was demonstrated by the ready decarbonylation of diphenylcyclopropenone with nickel carbonyl i n benzene. 0 A Ni(CO), H COOH PhC = CPh ^- Ph6=C Ph There i s now less mystery about the ways by which hydrogen and carbon monoxide are transferred to organic molecules by transition metals. An appropriate starting point for a discussion of metal carbonyls and related complexes as catalytic intermediates i n organic syntheses i s the reaction between MeMn(CO)^ and carbon monoxide (72).. When MeMn(CO)^ i s treated with carbon monoxide at room temperature and elevated pressure,, carbon monoxide i s inserted between methyl and manganese and the corresponding acetyl complex Me,CO»Mn(CO)^, i s formed. On heating, carbon monoxide i s given off and MeMn(CO)^ formed again. -20-35 atm MeMh(CO),, + CO — Me'CO'Mn(CO) The fact that a carbon metal <r bond can be formed, and that carbon monoxide can be inserted between metal and carbon, contributes greatly to our understanding of reactions catalysed by metal carbonyls. Further interesting information came from the carbonylation of gave after decarbonylation, methylmanganese pentacarbonyl s t i l l retaining a l l of the original carbon -llj.. These observations indicate a mechanism in which the carbon monoxide residue inserted i s one originally bonded to manganese and the overall reaction may be envisioned as occurring v ia a metal to carbon migration of the methyl group. Whether or not the insertion of the carbonyl group and the coordination of another carbon monoxide molecule to the manganese atom are concerted processes i s uncertain* The generality of this reaction was demonstrated (72) by the conversion of 7T -cyclopentadienylmethyldicarbonyliron to the corresponding acetyl compound by treatment with carbon monoxide at ljj,Q atmospheres and 125°: methylmanganese pentacarbonyl with ^ 0 when the carbonyl group inserted lit was found not to contain any carbon -lU* Additionally, C H ^ * C0»Mn(C0)^ Me*Fe(C0)2 *- Me,C0"Fe(C0)2 CO Alsos CH3»Mo(C0)3 CO Me*C0«Mo(C0) -21-It was subsequently shown that methyl, ethyl, benzyl (73) and a l l y l (7k) tetracarbonylcobalt compounds also undergo reversible carbonylation to the corresponding acyltetracarbonyl cobalt compounds. CO R*Co(CO), = ^ RCOCo(CO)) -GO 4 A related reaction which sheds some light on the function of metal carbonyls as catalytic intermediates i s the exchange of carbonyl groups with certain^organic compounds catalysed by cobalt carbonyl (U3)-Thus when phthalic anhydride i s treated with carbon monoxide in the " presence of CogfaO^ at elevated pressure and temperature the carbonyl groups i n the anhydride exchange with carbon monoxide in the gas phase.., This exchange may be^  explained by the annexed sequence of reactions (7£)» znr This elimination and insertion i s plausible i n view of the reaction: Me M n ( G O k + C O ±r MeCOMn(CO), -22-Although i t i s unnecessary to explain the exchange of carbon monoxide by elimination of carbon monoxide to form XIII, the latter seems l i k e l y i n view of the fact that when hydrogen i s present i n this system, benzoic acid i s formed quantitatively according to: H The formation of benzoic acid may be accounted for by hydrogenolysis of the intermediate XIII* A variety of mechanisms have been proposed over the years to account for the products of the hydroformylation reactionj most however ignore the riowpproven interraediacy of cobalt hydrocarbonyl i n the reaction. Under normal hydroformylation conditions dicobalt octacarbonyl i s converted rapidly to cobalt hydrocarbonyl (76). However i n the presence of an olefin, no cobalt hydrocarbonyl i s detectable un t i l hydroformylation i s complete* Furthermore i t i s found (77) that cobalt hydrocarbonyl reacts rapidly with olefins at room temperature and pressure absorbing carbon monoxide and giving as products an aldehyde and dicobalt octacarbonyl i n accordance with the equation: 2HCo(C0)k + CO + olefin »- Co 2(CO) 8 + aldehyde Additional circumstantial evidence i s provided by the observation that the rate of this reaction with various olefins (77) parallels the - 2 3 -relative rates at which the same olefins undergo hydroformylation (10). On the basis of these observations the sequence of equations (a)—*-(d) f a i r l y accurately summarizes the pathway of hydroformylation (12). (a) Co^CO)^ + Hg »- 21130(00)^ (b) HCo(CO)^ + RCH-CHg —>~ RCHgCHgCoCCO)^ (c) RCHgCHgCotCO)^ + CO *• RCI^CHgCOCoCCO) (d) RCHgCHgCOCotCO)^ + HCotCO)^ *- RCHgCHgCHO + Co 2(C0) g Step (b) i s probably a multi-step process, e.g. H RCH RCH | || + HCo(CO), || •» Co(CO) + CO CH 4 CHg H RCH •Co(C0)3 + CO • »- RCHgCH2Co(CO)^ CH 2 H or RCH co ->-co(co)3 »- [RCH2CH2CO(CO) ] CHg, The carbonyl insertion reaction has also been formulated (73) as proceeding RCH2CH2Co(C0)^ „ RCH2CH2C0Co(C0). with the latter acyltricarbonylcobalt complex being reduced to products by hydrogen. However the evidence for this process i s based on the successful reduction of an acyltetracarbonylcobalt compound by hydrogen at 2^°: a process which was completely inhibited by a high pressure of -2U-carbon monoxide. It was suggested that the entity actually reduced i s the acyltricarbonylcobalt complex and the reported observations are explained, on the basis of the equilibria i RCOCo(CO)3 RCo(CO)^ RCOCo(CO)3 + CO ^ RCOCo(CO)^ The. formation of hydrocarbons i n the hydroformylation reaction i s readily envisioned i n terms of the reaction, RCo(CO)^ + HCo(CO)^ >*- RH + Co 2(CO) Q competing with prior carbonyl insertion. This i s very well illustrated by the hydroformylation of nuclear substituted benzyl alcohols where electron-withdrawing substituents favored hydrocarbon formation (78). We r e c a l l here also, the reluctance of trifluoromethyl-pentacarbonylmanganese to undergo carbonyl insertion reactions (72)-The kinetics of the carboxylation of olefins (72) roughly parallels those of the hydroformylation reaction (79). Hydrolysis of an acyltetracarbonylcobalt complex is;a l i k e l y proposal, e.,g., € j RCOCo(CO)j+ + HgO RCOOH + HCo(CO)^ Acetylene reacts with nickel carbonyl i n benzene at 80° forming indan-l-one„ presumbaly via formation of the cyclopentadienone dimer (80). -2:5-Diphenylacetylene, under similar conditions i s converted to tetraphenylcyclopentadienone together with hexaphenylbenzene (71)-Ph Ph p|_^5l PhCEECPh + N i ( C O ) 4 _ P H < - > p h ^ p h 0 Ph The most extensively investigated reaction of this type i s that of iron carbonyls with diphenylacetylene under non-aqueous conditions (81, 82, 83). The reaction i s carried out in benzene either by irradiating the refluxing solution and iron pentacarbonyl, heating with iron dodecacarbonyl, or st i r r i n g with iron enneacarbonyl at room temperature. Some tetraphenylcyclopentadienone i s formed directly and isolated as i t s iron tricarbonyl complex (XIV) (Chart V). Other complexes are also formed, including XV and XVI, which are readily converted to tetraphenylcyclopentadienone or i t s iron tricarbonyl complex by irradiation, heating with carbon monoxide, reaction with bromine i n acetic acid, or reduction with lithium aluminum hydride. The cyclopentadienone ring i s also formed when diphenyl-:or dimethyl- acetylene i s irradiated with "7C -cyclopentadienylcobalt dicarbonyl, the product being the complex XVII (Chart V) (81;). The primary step i n these reactions seems to occur via an i n i t i a l dissociation of the metal carbonyl to a coordinatively unsaturated species which then coordinates with the substrate* Dissociation of M(CO)n M(CO) n_ 1 + CO -26-C H A R T Y : : R E A C T I O N O F A C E T Y L E N E S WITH IRON A N D C O B A L T C A R B O N Y L S -27-metal carbonyls i s known to occur under irradiation by ultraviolet li g h t and as already noted, some reactions show a marked temperature dependence or are aided by irradiation. The subsequent reaction of the substrate metal carbonyl complex then may be S C 0>n-l M ( C O ) n - 1 R C H C H 2 + X + — RCHCH2X where X may be a proton or an incipient allylcarbonium ion as i n a modification, of the carboxylation of acetylenes. This accounts for the observed over-all cis-addition of formic acid i n the carboxylation of acetylenes (16). Alternatively the complex may react i n an analogous way with another olefin or acetylene molecule, e.g. .M[C°)n-l M(CO) n - 1 R C r f " : " CH0 + RCH*=CH„ RHC' CHR ir, -  *• RHC2 2 \ / HgC ^ QHg Such a scheme entailing essentially carbanionic addition would account for the apparent absence of skeletal rearrangements i n the carbonylation reactions of bicyclo ^2.2»lj heptadiene (85, 12). Carbonyl insertion then can be envisioned as occurring i n the normal way. -2.8-In consideration of the products of these reactions, the cleavage of the acyl metal carbonyl complexes may be generalized as: RCOM(CO) _ + Y" *- RGOY + M(CO) . n—1 n—l where Y~, for example, may be a hydride ion as i n hydroformylation,. hydroxide ion in carboxylation, or fluoride ion as i n formation of aroyl fluorides. The metal subcarbonyl thus produced i s then available, for further reaction with another molecule of substrate, thus providing a chain reaction or, for combination with a carbon monoxide molecule. The f i r s t mechanism proposed for the cyclization reactions of azo compounds and Schiff bases was that proposed by Horiie and Murahashi in I960 ( 8 6 ) * These workers showed that the more electronegative the C=N or N=N bond was, the easier the reaction proceeded and reasonably conceived two alternative methods for the attachment of the catalyst on the reactive centre of the substrate. The f i r s t was the attachment of cobalt carbonyl across the 7T -bond of C-N or M=N i n much the same manner as Wender and co-workers (87) had postulated for the oxo reaction when olefins and cobalt carbonyl were reacted (XVTIl) and which had been isolated from cobalt carbonyl and acetylene (XTX). R R Hq—dH HC—CH (C 0^ o-Co(C0)3 (CO^ Co-G>(CO)3 s XVIII XIX In this case a steric requirement should necessarily be considered as was used to explain the observed differences i n reaction velocity for -2.9-various olefins. Such a complex i s shown in XX and XXI, for Schiff bases and azo compounds respectively Ph \ Co(CO)3 (COjCa—Co(C0)3 : i These workers demonstrated that the reaction of benzaldehyde a n i l , acetophenone and benzophenone-anils showed no difference i n the velocity and no ste r i c a l l y hindered effect of the phenyl group was discernible.' Hence the formation of this type of complex (XX) could hardly be acceptable. Their alternative method was the attachment of cobalt carbonyl to the lone pair of nitrogen giving rise to a complex which could act as; an intermediate for the reaction.. To test this hypothesis they reacted several benzal anils with ortho-substituents i n the aniline ring i n the belief that a steric factor might be observed (see asterisks in XXII) Using benzal ani l as the standard, the reaction velocity was increased when a methyl group was substituted i n the para-position and decreased tjhen a methyl group was substituted i n the ortho-position. In the ortho, H XXII - 3 0 -ortho-disubstituted reactions the diethyl was more effective than dimethyl in decreasing the reaction velocity. Thus i n spite of having a methyl group of promoting action the fact i s that i n the case of ortho-substituted anils there was a marked lower conversion. On the other hand the reduction of the a n i l double bond with synthesis gas and cobalt carbonyl goes smoothly even where the substituents i n the ortho position showed greatest resistance to the formation of phthalimidines and no distinct steric effect was observed. They concluded from this that the clear distinction of both reactions indicated a fundamental difference i n catalytic behaviour and explained the formation of indazolone and phthalimidine as follows: 1) Some kind of complex formation occurred at f i r s t between a lone pair of the nitrogen atom of the a n i l or of azo-double bond, and here a steric effect was operative. 2) The formation of the N-CO bond was then stabilized by formation of a five-membered ring with the carbon atoms of the benzene nucleus and simultaneous transfer of a hydrogen atom from the ortho position of benzene to the unsaturated bond of C=N or N=N. Complex Complex The nature of the complex and the mode of addition of as well as the overall electronics of the complex remained i n obscurity. -31". It was apparent from the products of the carbonylation of the aromatic aldehyde phenylhydrazones (Chart IV) that a nitrogen atom: had been s p l i t out of the substrate sometime during the reaction (68). The fact that the meta-tolyl hydrazone of benzaldehyde afforded only N-(m-tolyl)phthalimidine (X.), suggested that the substituent on the phthalimidine nitrogen was derived from the substrate and not from the solvent (benzene). Furthermore, the meta-tolyl group must not come free during the rearrangement, otherwise the structural integrity of the N-substituent would not have been retained. Elimination of the iraino nitrogen was confirmed when benzaldehyde 1-phenylhydrazone-l-(XXIII) reacted under similar condition to give N-phenyl-phthalimidine-N 1^ (XXIV) containing 91-$% enriched nitrogen (Chart V i ) . Confirmation that these reactions proceeded via an intramolecular mechanism was provided by a cross-over experiment involving 1-naphthaldehyde phenylhydrazone and benzaldehyde-meta-tolylphenylhydrazone i n which the only cyclized products were XI and X (Chart V i ) . To explain these observations, Rosenthal and Weir (68) proposed a mechanism which involved the splitting out of ammonia after cyclization had occurred (Chart V H ). The f i r s t step involves the formation of a sigma bond between cobalt carbonyl and the lone pair on nitrogen (XXVI) when the substrate i s i n the tautomeric form (XXV). The latter was based on the observations of Connor (88) who showed that the phenylhydrazones of aldehydes and ketones rapidly tautomerize to benzene azoalkanes. After carbon monoxide from the metal carbonyl i s inserted between the nitrogen and the cobalt atom (89) to give the intermediate CHART 2 1 : STUDIES ON T H E M E C H A N I S M O F T H E C Y C L I Z A T I O N R E A C T I O N H. ^N-MPh H H H C Q » f^ C>»IPh Co2(CO)8 k^J CO PhC=NNPh HG=0 XXIX C H A R T MECHANISM O F B E N Z A L D E H Y D E m C A R B O N Y L A T I O N O F I - P H E N Y L H Y D R A Z O N E --3U-XXVII, cyclization of the carbon monoxide to the aromatic ring occurs to yi e l d the intermediate XXVIII. Alternatively the assumption that the attack of dicobalt octacarbonyl on the phenylhydrazone gives the N-formyl compound (XXIX), which then undergoes cyclization to yi e l d labelled N-phenylphthalimidine (XXX), i s based on the fact that amines gave formamides with dicobalt octacarbonyl (90) and aniline yields form-anilide and N^N'-diphenylurea with nickel carbonyl (llj.).< It i s then suggested that hydrogenolysis of the C-N bond i n XXVIII would take place easily because of the activating effect of the benzylic group. -35-Direct Carbonylation of Aromatic Semicarbazones and Azines The synthesis of phthalimidines and N-carboxyanilide derivatives of phthalimidines by the direct incorporation of one and two carbon monoxide units into aromatic ketoximes and phenylhydrazones, respectively, have been previously reported (61i, 67). Because the kind of products obtained was dependent on temperature we hoped to obtain information on the mechanism of the cyclization reaction by a further study of the direct carbonylation of other substrates containing the imino group (but containing different substituents on the nitrogen).. This thesis i s a report of the results of a study of the carbonylation of aromatic imino compounds containing the ureido (-NHCONILj), ureylene (-NHCONH-), and imino (-N=CC ) groups attached to the nitrogen of the C=N group. In particular, benzophenone semicarbazone, benzaldehyde semicarbazone, benzophenone U-benzhydrylsemicarbazone, benzophenone azine and benzaldehyde azine were carbonylated under a variety of reaction conditions. The azines were included i n this study since i t i s known that benzophenone semicarbazone decomposes above i t s melting point to yield benzophenone azine ( 9 1 ) . It was also desirable to establish the generality of the rearrangement with subsequent loss of the imino nitrogen as was observed for the aromatic aldehyde phenylhydrazones (68). The ureido and ureylene groups were chosen as i t was believed that these might have a greater tendency to coordinate with the catalyst than the aniline group of the phenylhydrazones studied previously (67, 68)., -36-Benzophenone semicarbazone reacted with carbon monoxide at about 300 atmospheres and at 235-2U50 i n the presence of preformed dicobalt octacarbonyl to give a mixture of reduction and carbonylation products (these are shown i n Chart VIII) which were separated by chromatography on alumina- Most of the product crystallized directly out of the reaction mixture as a blue crystalline material (designated as A i n the experimental)- This material was extracted with ethanol to give a mixture of ethanol soluble compounds which were then chromatographed to yi e l d NjN'-dibenzhydrylurea (XXXV) and 3^phenyl-phthalimidine (XXXVIl). The structures of both of these substances were established by direct comparison with authentic samples of N,N'-dibenzhydrylurea (92) and 3-phenylphthalimidine (93) respectively. The f i l t r a t e remaining after the removal of the blue material A was evaporated to dryness and the residue (material B i n the experimental) then fractionated by alumina chromatography (see Table I i n the experimental). Diphenylmethane (XXXII, 9% yield), was characterised by direct comparison (mixed melting point and infrared) with an authentic sample of diphenylmethane obtained from the Eastman Kodak Co.. 1,1,2,2-Tetraphenylethane (XXXIII, 2% yield) was characterised f i r s t by comparison of the infrared spectrum of XXXIII with that of 1,1,2,2-tetraphenylethane l i s t e d i n the Sadtler Standard Spectra (9h) then by direct comparison (mixed melting point and infrared) with an authentic sample of 1,1,2,2-tetraphenylethane, prepared by reducing tetraphenylethylene with sodium metal i n l i q u i d ammonia solution (95)• -37-NHCONH' 240° CO Co2(CO)8 Ph2CH2+Ph2CHCHPh2 + [Ph2CHNH]2CO + X X X I f ( 9 % ) 2 M ( 2 ° / o ) 2 X S ? ( 2 5 % ) Ph2CHNHCONH2 + T J! NH". + 2 X X V I ( 7 % ) X X X V I I (2 5 % ) K P h ' j [ ^ : C O N H C H P h 2 + blue complex ^ 0 XXXIV (8°/o) 2 6 % C H A R T YK-C A R B O N Y L A T I O N O F B E N Z O P H E N O N E S E M I C A R B A Z O N E AT 2 4 0 ° -38-Compound XXXI? was unequivocally assigned the structure of 3-phenyl-2:-(W-benzhyd^ylcarboxamido)phthalimidine on the following basis: (l) infrared analysis showed the presence of carbonyls at 1681; and 1700 cm-"'" and a secondary N-H (st) at 3260 cm"1 in excellent agreement with the spectrum of the previously reported N-carboxyanilide of 3-phenylphthalimidine (Compound III - Chart I) (67)J (2) refluxing compound XXXI? i n 99% deuterium oxide gave a substance, the infrared spectrum of which indicated the presence of an N-D group (see experimental section)- Furthermore, the carbonyl absorption atI1700 cm""'" in compound XXXI? was lowered to 1695 cm""'" i n the deuterated product, presumably due to secondary isotope effects. The latter observation strongly suggested that the carbonyl was juxtaposed with the secondary N-Hj (3) proton magnetic resonance analyses of the compound suggested a structure similar to that of 3-phenylphthalimidine-N-carboxyanilide (absorption at ^ equal to 6.09 and 6.20 indicated the presence of the two benzylic hydrogens; comparison of the n. m. r . spectrum of XXXI? with that of 3-phenylphthalimidine-N-carboxyanilide established that the peak at 6. 20 was due to the ^C v at the 3-position H of the phthalimidine structure). The structure of XXXI? was then confirmed by direct comparison with an authentic sample of 3-phenyl-2-(N-benzhydrylcarbosamido)phthalimidine, prepared by the condensation of 3-phenylphthalimidine with benzhydrylisocyanate according to previously described procedures (67, 96, 97). Compound XXX?I was compared with an authentic sample of N-benzhydryl-urea (98), prepared by the condensation of benzhydrylisocyanate with ammonia, and shown to be the same. - 3 9 -¥hen the reaction temperature was reduced to 1 7 5 - 1 8 0 ° , benzophenone semicarbazone did not cyclize with carbon monoxide but pyrolyzed and was reduced to y i e l d two major products (see Chart EC), one of which was readily characterized as benzophenone azine (XXXVIII).. This assignment of structure i s i n accord with that of Borsche and Merkwitz (91) who f i r s t reported that the thermal decomposition of benzophenone semicarbazone yielded benzophenone azine (also called diphenylketazine). Comparison with an authentic sample prepared according to the method of Borsche and Merkwitz, confirmed the structure. On the basis of elemental, infrared and proton magnetic resonance studies, i t appeared that the second product (compound XXXIX i n the experimental) was benzophenone U-benzhydrylsemicarbazone. As expected, hydrolysis of the latter i n dilute sulfuric acid yielded benzophenone (isolated as the 2,U-dinitrophenylhydrazone). Vindication of the assigned structure was obtained by condensing benzhydrylamine with benzophenone semicarbazone to yield ammonia and benzophenone k-benzhydrylsemicarbazone (identical i n melting point and infrared to compound XXXLX). At an intermediate temperature of 200-220°, benzophenone semicarbazone afforded the same reduction products as was obtained at 1 7 5 - 1 8 0 ° , and i n addition N-benzhydrylurea (see Chart IX). It i s noteworthy that these reactions therefore indicate that carbonylation of the semicarbazone to yield a urea takes place between 180-220°. The fact that benzophenone azine and benzophenone U-benzhydryl-semicarbazone were present i n the product of the 200-220° experiment -Uo-175-180° Co2(CO)8 • P h 2 C H 2 + Ph 2 CHCHPh 2 + S E E I 2 X 3 1 ( 6 % ) X X X Ul (1%) 3 5 % Ph2C=NNHCONHCHPh2 + XXX1X(16%) Ph2c=N-N-CPh2 + blue complex XXX VIII (24%) (19%) NHCO NH' 200-220° Co2(CO)8 P h 2 C H 2 + Ph 2C=N-N=CPh 2 + xxxi(4%) xxxviimo%) Ph2C=NNHCONH€HPh2 "+ Ph 2 CHNHCONH 2  XXXIX (11%) XXX VI (4%) X X X 3 5 % blue complex 11% C H A R T J X C A R B O N Y L A T I O N O F B E N Z O P H E N O N E S E M I C A R B A Z O N E AT 1 7 5 - 1 8 0 ° & 200-220° -hl-but were not i n that of the higher temperature one, suggested that one or both of these substances might be the reactive intermediates i n the direct ring closure reactions to yield the phthalimidines. In order to test this hypothesis, both of these substances were carbonylated at 235-2U50 (see Chart X). Benzophenone azine yielded only 3-phenylphthalimidine, whereas benzophenone U-benzhydrylsemicar-bazone afforded both 3-phenylphthalimidine and 3~phenyl-2:-(N-benzhydryl-carboxamido)phthalimidine» Since some unreacted benzophenone azine remained after i t had been treated with carbon monoxide at 235-2U!?0, but none was present when benzophenone semicarbazone or benzophenone U-benzhydrylsemicarbazone was carbonylated at the same temperature for the same time i t appeared that stronger complexing had occurred between the semicarbazones and the catalyst than between benzophenone azine and the catalyst, which f a c i l i t a t e d the cyclization reaction to yie l d the phthalimidines. That strong complexing had occurred between the ureido and ureylene groups and the catalyst i s undoubtedly true, particularly i n view, of the experiments with the benzaldehyde semicarbazones (to be discussed l a t e r ) . However, benzophenone azine gave a much larger yield of cyclized product than the ketone semicarbazones. Hence the presence of unreacted azine may just be the manifestation of fewer side reactions. The fact that diphenylmethane and 1,1,2,2-tetraphenylethane were present i n the reaction products strongly suggests that benzhydryl free radicals were produced probably by thermal decomposition of benzophenone azine. Pyrolysis of the latter might be expected to yield molecular Ph2C=N-N=CPh2 XXXVIII 240° CO H Ph ^ N H + X X X V  XXXVII (80°/o) Ph2C=NNHCONHCHPh2 XXXIX 240C CO Q^NH + Q^CONHCHPh 2 +  XXXVII (70%) X X X I X (6%) •p-Ph 2 CH 2 . + Ph 2 CO + Ph 2CHNHCONH 2  XXXII (23%) X Q 7 % ) ^ X X V ( 2 2 % ) CHART X : C A R B O N Y L A T I O N O F B E N Z O P H E N O N E A Z I N E AND B E N Z O P H E N O N E 4 - B E N Z H Y D R Y L S E M I C A R ' B A Z O N E AT 240° -U3-nitrogen and benzhydryl free radicals. Combination of two benzhydryl free radicals, followed by reduction, would then yield 1,1,2,2-tetra-phenylethane. Abstraction of hydrogen from the substrate or reaction with cobalt hydrocarbonyl could give diphenylmethane. On the other hand, reduction of benzophenone azine to benzhydrylamine, followed by hydrogenolysis of the latter would also give diphenylmethane. It can:be noted here that the normal product of decomposition of azo-bis-diphenylmethane, when warmed in benzene at 1$°}, is tetraphenylethane (99). The presence of ammonia in the high pressure reaction system is manifest from the studies of Borsche and Merkwitz (91) on the pyrolysis of benzophenone semicarbazone and i t is well known that metal carbonyls undergo characteristic and quite general reactions with nucleophilic reagents. Thus, the direct addition of water to dicobalt octacarbonyl demonstrates the readiness with which cobalt carbonylhydride is formed (100)$ and a similar mode of reaction is followed when ammonia is used for hydrolysis. Further, dilute solutions obtained by these hydrolytic reactions have strong reducing properties (101).. In the light of these considerations, i t i s not surprising that reduction products were isolated from the carbonylation of benzophenone semicarbazone (m.p. 161)°) PhgCHNHNHCHFhg * PhuCHDHPh. 3Co2(C0)8 + UHgO liHCo(CO)^ + Co(0H)2 + UCO -hh-at temperatures above i t s melting point and i n the presence of dicobalt octacarbonyl.-Thus, although the mechanism of formation of benzophenone h-benzhydrylsemicarbazone i s obscure, i t i s probable that benzophenone azine was reduced by the carbonyl hydride v i a some type of hydrogen transfer process similar to that envisaged by Natta, Pino and E r c o l i ( 1 0 2 ! ) , to yield benzhydrylamine, which subsequently condensed with a molecule of benzophenone semicarbazone to yi e l d benzophenone k-benzhydrylsemicarbazone (XXXTX)* The ammonia released i n the condensation reaction would then be available for reaction with dicobalt octacarbonyl to provide more carbonyl hydride. The cr e d i b i l i t y of the condensation reaction was demonstrated when an authentic sample of benzophenone U-benzhydrylsemicarbazone was prepared i n good yield (7li/0, by heating benzhydrylamine i n the presence of benzophenone semicarbazone. The po s s i b i l i t y of inserting a carbonyl between nitrogen and cobalt i s supported by the fact that diphenylurea undergoes exchange with carbon monoxide at elevated temperatures (U3)« When hydrogen i s added to this system, diphenylurea gives aniline and i n view of the fact that cobalt carbonylhydride is formed from dicobalt octacarbonyl (PhNH^ C O + C O 2 ( C 0 ) Q ^ PhNHCo(CO), + PhNHCOCo(CO) -U5-and hydrogen, the following reaction seems likely;; PhNHGo(CO)^ + HCo(CO)^ t > PhNHg + Co 2(CO) g In view of these considerations, the last step in the reduction of benzophenone azine might be considered to be: PhgCHNHCoCCO)^ + HCo(CO)^ -y- •> PhgCHNHg + Co 2(GO) g or, alternatively, the aminotetracarbonylcobalt complex could undergo rearrangement to the acyl derivative. Ph2CHNHCo(CO)^ + CO , ? Pl^CHNHCOCoCCO)^ Nucleophilic attack by ammonia or dibenzhydrylamine w i l l now give rise to the mono- and di-substituted ureas respectively* It should be PhgCHMHCOCoCCO)^ + NHj »~ PhgCHNHGONHg + HCoCCO)^ PhgCHNHCOCoCCO)^ + PhgCHNHg *~ PhgCHNHCONHCHPhg + HCoCCO)^ pointed out that the formation of tetramethyl urea has been observed when dicobalt octacarbonyl was treated with an excess of dimethylamine (90) and.: i t has been suggested that tetramethylurea was formed by "aminolysis" 1 of the acyl complex according to (75):; (CH3)2WH + Co2,(C0)g > (CH3)2NCo(CO)jit + HCoCCO)^ (CH3)2NCo(CO)^ > (CH3)2NCOCo(CO)3 (CH3)2NC0Co(C0)3 + HN(CH3)2 *• (CH3)2NCON(CH3)2 + HCo(CO)3 -1*6-The ease with which the carbonyl becomes inserted between nitrogen and cobalt (once the nitrogen-metal sigma bond i s formed) i s evidenced by the fact that the above reaction occurs at room temperature. The genesis of benzophenone azine (XXXVIII) i s readily envisioned as a rupture of the pyrolytic N-N bond with subsequent recombination of homologous rad i c a l s ^ 2Ph2C=N|NH30NH2 - [ ZPhgON'] «- PhgC-N-N-CPhg XXXVIII Benzaldehyde semicarbazone reacted under 300 atmospheres of carbon monoxide and at 200-220° i n the presence of preformed dicobalt octacarbonyl (see Chart XI) to give a product which consisted largely of a blue solid (designated as E i n the experimental). The blue solid was removed by f i l t r a t i o n , then washed exhaustively with absolute ethanol. Removal of the ethanol under reduced pressure afforded a crystalline substance which was chromatographed on alumina to y i e l d a small amount (less than 1% yield) of bibenzyl (XLI), a large amount (lk% yield) of benzaldehyde azine (XLII) and a mixture of syrups (6% by weight)* The f i l t r a t e remaining after removal of the blue solid (E) was evaporated to dryness (the odor of benzaldehyde was detected) and the residue (material F i n the experimental) then fractionated by alumina chromatography (see Table VI) to yield bibenzyl (XLI) (6% yield) benzaldehyde azine (XLII) (k0% yield) and a mixture of unidentified substances (5$ by weight).. -U7-PhCH=NNHCONH' 200-220° Co2(CO)8 X L 1 I ( 5 4 % ) •xn"(6%) 39% N + P h C H p ^ + blue c o m p l e x XOT(63%) XL I (3%) 4 0 % 235 245° Co 2(C0) 8 PhC H=NNHCONH< C HART XL C A R B O N Y L A T I O N O f B E N Z A L D E H Y D E S E M I C A R B A Z O N E - U 8 -Bibenzyl was expected as a product i n this reaction by analogy with the experiments with the ketone semicarbazones and was readily characterized by direct comparisone with an authentic sample.. Elemental andlinfrared analysis, and the ease of hydrolysis i n dilute acid to y i e l d benzaldehyde, indicated that compound XLII was benzaldehyde azine. Final proof of structure was provided by the preparation of authentic benzaldehyde azine according to the method of Thiele ( 1 0 3 ) . The fact that no product was identified i n which carbon monoxide had been incorporated suggested that the ureido group of benzaldehyde semicarbazone had complexed so effectively with the catalyst as to inhibit i t s a b i l i t y to bring about either carbonylation or cyclization., In support of this i s the fact that benzaldoxime underwent reaction under similar condition to yield the carbonylation products, sym-and monobenzylureas i n 35$ and 10$ y i e l d respectively ( 5 2 ) . Further, the aromatic aldehyde phenylhydrazones underwent reaction with carbon monoxide under similar conditions to afford the cyclization product, N-phenylphthalimidine (See Chart I?) ( 6 8 ) . Additional support for this hypothesis was provided when benzaldehyde semicarbazone was reacted under similar conditions, but at a temperature of 2i|0°, to yi e l d benzaldehyde azine i n 63$ y i e l d * Thus there was no change i n the course of the reaction and the yi e l d of the major product,, benzaldehyde azine (XEII) was increased by about 10$. -U9-There can be l i t t l e doubt that the formation of benzaldehyde azine came about by rupture of the pyrolytic N-N bond of the substrate. Thermal decomposition of benzaldehyde azine would then be expected to give rise to molecular nitrogen and benzylidene free radicals. Combination of two benzylidene free radicals followed by reduction would account for the formation of bibenzyl. It seemed advisable at this stage, to carbonylate the benzaldehyde azine, particularly i n view of the large yield of cyclized product afforded by the carbonylation of benzophenone azine. It was also desirable to carbonylate an aldimine substrate which could not tautomerize to the azo form as i t was thought that the products from such a reaction might shed some light on the mechanism of the cyclization process. Thus, benzaldehyde azine was carbonylated at 2h0° yielding largely cyclization and possibly some carbonylation products accompanied by a small amount of bibenzyl (Chart XII). The reaction product consisted of a black solid (designated as J i n the experimental) which was removed by f i l t r a t i o n and extracted with methanol i n a Soxhlet apparatus. Removal of the methanol by evaporation under reduced pressure, afforded a green solid which was subsequently chromatographed on alumina (See Table IX) to yi e l d a white solid (Compound LI), which melted at 255-256° with decomposition.. Elemental analysis showed that compound LI had an empirical formula C^Rg^Cv, (see experimental) and a singular molecular weight (Rast) 2 4 0 ° C o 2 ( C O ) 8 P h C H 2 C H 2 P h + ~XTV + xna%) 1% H H N C O N H C H 2 P h E f f l ( 5 ° / o ) H H ^ I C H 2 P h + X L I X + XE2E(16%) 6% O ~C(13%) + black solid + XL 14% 5 % C H A R T X E : C A R B O N Y L A T I O N O F B E N Z A L D E H Y D E A Z I N E AT 2 4 0 ° - 5 1 -determination afforded a value of 587* The molecular weight was incon-sistent with the rest of the data on compound LI. When heated with either concentrated sulfuric acid or concentrated sodium hydroxide, carbon dioxide and ammonia respectively, was evolved. Preliminary evidence suggested the tentative formulation of the following structure for compound LI: Benzodiaz ^ 2 ,Uj epine-dione-1,3 Proton magnetic resonance analyses (see experimental) were consistent with the above structure (the n. m. r. spectra are reproduced i n Chart XIII). Infrared absorptions at 3380 and 3220 cm"1 indicated the presence of two different mono-substituted amide functions; the one at 3380 cm"! being a non-bonded NH and the one at 3220 cm"!, a bonded NH absorption. The CO-NH-CO group shows a single bonded amide NH absorption i n the 3200 cm"1 region similar to cyclic lactams (lOli). Although not very much work has been done on the six or more membered ring systems, evidence indicates that the carbonyl absorptions of amide groups included i n large ring systems are essentially similar to normal amides ( 10U). Further, i n six membered ring systems, Edwards and Singh (105) found that secondary lactams absorb at 1665 cm and the fusion of an additional ring did not alter the frequency appreciably. They made the additional observation that at,p unsaturation (6) ( INTEGRAL) ( 17.72 i/l a) Dimethylsul foxide A 2) 4 8 0 7 5 8 Jl b.) Deuter io-ch loro form 4 8 7 > (2) (4) ( INTEGRAL) (2) 3.01 768 j£ | 6 / ^ c.)Trifluoroacetic anhydride j\ IK II — i — i — i — i — i i — i — i — i — \ — i — i — « — i — | — i — i — i — i — — i — i — i — i — | — i — t — i — i — i — i — i — i — i — i — i — i — i — i — C H A R T ML: PROTON M A G N E T I C RESONANCE S P E C T R A O F C O M P O U N D I T -53-does not lower the carbonyl frequency. Also, the carbonyl absorptions at 1730 and 1650 cm"-'- for 3-phenyl-2,U-dioxo-l,2,3,U-tetrahya^oquinazoline (Compound VI, Chart II) are consistent with the formulation of LI (70).. The tentative structure suggested for compound LI might be expected in view of the dihydrophthalazinone intermediate (Compound XXVIII, Chart VII) proposed by Rosenthal and Weir as a result of their studies on the mechanism of the cyclization reaction ( 68 ) . Thus, rupture of the N-N bond, insertion of carbon monoxide (as observed by Murahashi and co-workers (U9) and by Rosenthal and co-workers (67)), and hydrogenolysis of the benzyl group either before or after carbon monoxide insertion, would give rise to the structure tentatively assigned to compound LI.. A survey of the literature soon revealed that the benzodiaz £ 2,u] epine-dione-1,3 series of compounds were not known and consideration of possible routes for synthesizing an authentic sample were complicated with experimental d i f f i c u l t i e s . The f i l t r a t e remaining after removal of the black solid J was evaporated to dryness and the residue (material K i n the experimental) fractionated by alumina chromatography (see Tables X and XI i n the experimental) to yi e l d bibenzyl (XLI, 1% yield), a white solid designated as compound XLV (l% by weight), 2-(N-benzylcarboxamido) phthalimidine (XLVI, $% y i e l d ) , 2-benzylphthalimidine (XLVIII, 16% y i e l d ) , a green solid (XLIX,6% by weight), phthalimidine (L, 13% yield), and a grey solid (12;? by weight), which was not investigated. -5u-As compounds XLV and XLVII showed no carbonyl absorptions in the infrared, no further work was done on them, while attempts to elucidate the structure of Compound XXIX were unsuccessful. The structure of 2-(N-benzylcarboxamido)phthalimidine (XLVI) was suggested by virtue of the similarity between the infrared spectrum of XXVI and that of 3-phenyl-2.-(N-benzhydrylcarboxamido)phthalimidine isolated from the carbonylation of the benzophenone semicarbazones. Unequivocal proof was supplied by direct comparison of compound XLVI with an authentic sample of 2(N-benzylcarboxamido)phthalimidine, prepared by condensing benzylisocyanate with phthalimidine (55, 67, 96, 106). It can be pointed out here that this i s the f i r s t time a carboxamide derivative of phthalimidine has been isolated from the carbonylation of the aromatic aldimine type of substrate. The significance of this find w i l l be discussed when the mechanism of the cyclization process i s considered i n more det a i l . On the basis of the work of Rosenthal and Weir (68) on the aromatic aldehyde phenylhydrazones, the expected product from the carbonylation of benzaldehyde azine would be 2-benzylphthalimidine (XXVIII). The melting point of XLVIII was identical to that reported i n the literature for 2-benzyphthalimidine (59)• Elemental, infrared and proton magnetic resonance analyses were also consistent with the assigned structure (see experimental). The infrared spectrum of XLVIII and that of an authentic sample of 2-benzylphthalimidine (57), prepared according to the method described by Murahashi and co-workers (59)* were identical. -55-Assignment of the phthalimidine structure to compound L was suggested by infrared and elemental analyses* Absorptions, i n the infrared region at 3190 cm"1 and 1670 cm 1 were consistent with the observed absorptions at 3180 and 1668 cm"1 for the N-H and carbonyl respectively, of 3-phenylphthalimidine isolated from the carbonylation of benzophenone azine* Further, as the reaction proceeded in part* i n a manner analogous to the ketone semicarbazones (as evidenced by the isolation of 2-(N-benzylcarboxamido)phthalimidine) i t seemed probable that some phthalimidine might be produced here also. Final proof was provided by direct comparison with an authentic sample of phthalimidine ( 118)* Before applying the mechanism deduced by Rosenthal and Weir (see Chart VII) (68) to the carbonylation reactions carried out by the author, there are a few points about their mechanism which require: further c l a r i f i c a t i o n . The f i r s t criticism i s the assumption made by these workers that the phenylhydrazones tautomerize to the azo form prior to complexing with the catalyst* This assumption was admittedly based on the observations of O'Connor ( 8 8 ) who showed that the phenyl-hydrazones of aldehydes and ketones rapidly tautomerize, in solution,, to benzene azoalkanes. It should be pointed out however that O'Connor worked with alkyl phenylhydrazones and that one could argue f a i r l y convincingly i n favor of the azo tautomer, even in the absence of O'Connor's observations. Thus the azo tautomer can extend the conjugation of the benzene ring with a concomitant increase i n resonance energy for the system as a whole. -56-This argument, however, f a l l s f l a t when applied to aromatic aldehyde phenylhydrazones, and particularly when applied to the phenylhydrazone of benzophenone. Further, i f i t was the azotautomer that underwent complexing with the metal carbonyl then one needs to ask himself why the indazolones and quinazolones (see Chart II) did not appear i n the product, as demonstrated by Murahashi and co-workers (h9) when azobenzenes were reacted under similar conditions. Additional evidence0 against the proposed azo tautomer was supplied from the results of the carbonylation of benzaldehyde azine (XXXII, see Chart XII) which afforded N-benzylphthalimidine (XLVIIl), analogous to the N-phenyl-phthalimidine (XXX, Chart VII) produced under similar conditions from benzaldehyde phenylhydrazone (68). Since benzaldehyde azine cannot tautomerize i t seemed unlikely that the azo tautomer was the complexing species. Considering the fact that dimethylformamide and tetramethylurea are formed merely by dissolving Co2(C0)g i n dimethylamine at room temperature, a reasonable proposal for the f i r s t step i n the cyclization process i s the reaction of dicobalt octacarbonyl with the aniline NH to form a sigma bond between nitrogen and cobalt, maintaining the "inert" gas configuration on cobalt.. H NHPh Co2(CO)ft , ^ V S ^ N R h ^ Co(CO)A Rearrangement of the latter complex to the acyl form i s a well established process and in view of the reaction with amines at room -57-temperature, probably occurs very easily once the nitrogen-metal sigma bond i s formed. What happens next i s the interesting "organic part" and i s somewhat obscure.. However, in view of the products formed i t i s d i f f i c u l t to propose an alternative to attack by the carbonyl carbon atom at the ortho position of the benzene nucleus. An electromeric effect may be operative here which would explain why, i n the absence of conjugation with the aromatic nucleus, cyclization does not occur* The stoichiometry to this point i s , c n H P h c ^ c o ) B + c o -The presence of carbonylhydride at this stage of the reaction provides a clue as to what happens next but before proceeding i t i s necessary to make an historical digression to review the work of, Rowe (107) and Vaughan (108, 109) as corroborating evidence for subsequent proposals* The r' -phthalazone-phthalazone or Rowe rearrangement (107) involves the transformation of a ¥-phthalazone (LIl) into a phthalazone (LIIl) i n - £ 8 -R t-Ar acid, solution at 180°. Rowe discarded a mechanism involving ring contraction to an isoindolone structure (LIV) even though he isolated such a compound i n some of his studies because, he argued, rr 150° R= CH3 H + 180c urn when R of LII = H, the intermediate LIV could not form. An alternative course of rearrangement proposed by Vaughan (108) was closely related to Rowe's discarded mechanism but obviated the d i f f i c u l t y of the intermediate LIV, when R=H, by postulating a carbonium ion derived from isoindalone. The alternative mechanism proceeded through the intermediate formation of a five membered ring, followed by a second rearrangement enlarging the ring to six members again. The formulation of Vaughan's proposals are outline below- He later validated his proposals with experimental proof using isotopes (10°)• -59-The driving force i n i t i a t i n g the formation of the intermediate LV may be considered an attack of a proton on the nitrogen carrying the aryl group, thus displacing the C +, which subsequently ejects the original proton. CH 2 LV • H * ' Q^JNHAr R =CH 3 0 E2L J3L O L The isotopic studies carried out by Vaughan and co-workers (109) involved i n part, the heating of 3-aryl-li,-methyl- V -phthalazone (LVIl),, with excess N 1^ i n the two position, at 180° i n acid solution to form 2-aryl-U-methylphthalazone (LVIIl) enriched with at the three position. The chemical method used by Vaughan to determine the position of the enriched nitrogen was based on the fact that, on reduction, both <p -phthalazones and phthalazones afford chiefly W-substituted -60-isoindolones (otherwise known as phthalimidines) (LTX). r T T o r r n T Zn HC! hAr + NH 4 CI TJX We now return to the stoichiometric equation, j^VNslNHPh + Co2(CO)8 + CO fiPh+2HCo(C0)A and consider the attack of a proton on the nitrogen carrying the aryl group, with subsequent displacement of the carbonyl carbon followed by attack of the carbonium ion on the imino nitrogen giving rise to the carbonium ion intermediate IXI: NHPh This i s reasonable i n view of the fact that cobalt hydrocarbonyl i s a strong acid (110) and the experimental evidence for the acidic properties were demonstrated by Murahashi and co-workers ($9) when they reacted benzaldoxime at 220-230° to give benzamide, presumably -61-by a Beckmann rearrangement. Transfer of a hydride ion, as suggested by Gaetz and Orchin ( i l l ) and as envisaged by Natta and co-workers (102), w i l l result i n the formation of the intermediate IXII.. Hydrogenolysis of IXII affords the 3-substituted phthalimidines (IXIII) while at higher temperatures (required to rupture the N-N bond) carbonylation occurs to form the carboxamide derivatives (IXIV). HCo(CO) [Co(C0 ) J Hydrogenolys is Carbonylation 200° 235° k:0NHPh XTV In the opinion of the author, the course of the reaction w i l l be governed primarily by the position of the equilibrium between IX and IXI. R groups which can stabilize the formation of the carbonium ion IXI (such as a phenyl group) w i l l s h i f t the equilibrium i n favor of IXI, while those which cannot (such as H) w i l l favor the formation of IX* In the latter case, reduction of the phthalazone (IX) to the N-substituted phthalimidine i s the expected course of the reaction i n H Ph 4HG>(CQ rXJPh+ [2Cc2(C08+NH3] -62-view of the chemistry of phthalazones (106) and particularly i n view of the fact that dilute solutions of cobalt hydrocarbonyl show strong reducing properties (101). Further, the ammonia produced here can perpetuate the reaction by production of more hydrocarbonyl (101). Thus the experiments of Rosenthal and Weir (see Chart VII) (68), and Vaughan and co-workers (109) using isotopes, are complimentary. When R of IX has intermediate stabilizing a b i l i t y both IX'. and LXI are present i n the reaction medium and the products observed for the carbonylation of acetophenone phenylhydrazone are i n agreement with this postulation (67)• Additional support for the proposed equilibrium between LX and LXI i s provided by the results of the carbonylation of benzaldehyde azine (see Chart XII). The i n i t i a l step i n this reaction may be considered the addition of cobalt hydrocarbonyl across one of the C=N linkages to form IXV. PhCH=N-N=:HCPh -63-Cyclization follows the proposed pathway to yield IXVT, which exists i n equilibrium with the carbonium ion LXVII. K H L X V H 2 P h rxvr Reduc t ion r K H CXVT Q r t l N H C H 2 P h ^ + [ C o 2 ( C O ) 8 ] QnjcH 2Ph EEHd6%) Hyd rogenoly s i s Carbonylat io n i K H H k H H " "Oc|H Cx|^CH2ph L ( 1 3 ° / o ) X L V r ( 5 ° / o ) -6U-To the extent that this research was directed toward determining the tendency of various substituents on the imino group to coordinate with the catalyst, the following statement can be made: When substrates containing the ureido group on the imino nitrogen of aromatic imino compounds are subjected to carbonylation conditions, they undergo thermal decomposition and the products of the latter process inhibit the catalytic action of cobalt carbonyl-The blue complex isolated from the carbonylation of ureido-substituted imino substrates, but not from substrates substituted with ureylene or imino groups (see experimental), suggests a relationship between the cobalt carbonyl and the ureido substituent or i t s degradation products. That the catalyst was inhibited, as mentioned above, was shown by subsequent carbonylation of the thermal decomposition products. Thus, while benzaldehyde semicarbazone did not afford a product in which carbon monoxide had been directly incorporated, benzaldehyde azine did undergo reaction to form products i n which carbon monoxide had played a r o l e . Under the conditions of the cyclization reaction,, benzophenone semicarbazone afforded a low yi e l d (33%) of cyclized products while the thermal decomposition and reduction products (benzophenone azine and benzophenone It-benzbydrylsemicarbazone respectively) afforded, under similar conditions, 80% and 76% yields, respectively, of cyclized product--65-A.. General Considerations a) The high pressure equipment has been described previously (6I4.). b) In every carbonylation experiment, preformed dicobalt octacarbonyl (112) was used, and high purity carbon monoxide containing 0»Q1% hydrogen, supplied by the Matheson Co*, East Rutherford, N. J., was added to an i n i t i a l pressure of about 2100 p.s.i.. at room temperature. c) The aluminum oxide (calcined) "Analar" was procured from the B r i t i s h Drug Houses (Canada) Ltd., Toronto l l * . d) A l l melting points were obtained on a Leitz heating stage and are uncorrected. e) The infrared analyses were done by Mrs. Z e l l of this Department, on a Perkin Elmer spectrophotometer, Model 21, using a sodium chloride crystal. , f ) The nuclear magnetic resonance (n. m. r.) analyses were done by Mrs. E . Brion of this Department on a Varian Associates' A60 instrument. Tetramethylsilane (TMS) was used as an internal standard. g) Microanalyses were performed by Dr. A. Bernhardt, Mikroanalytisches Laboratorium, ±m Max-Planck Institut fur Kohlenforschung, Mulheim (Ruhr), Germany and by Mrs. A. Aldridge of this Department. - 6 6 -B. Carbonylation of Benzophenone Semicarbazone at 2U0° To a mixture of 1 0 . 0 g (0.01*2 mole) of benzophenone semicarbazone i n 1*5 ml of dry, purified benzene, was added 3*0 g ( 0 . 0 1 mole) of preformed dicobalt octacarbonyl and 2100 p . s . i . of carbon monoxide. The mixture was heated at 235-21*5° for 150 minutes. The bomb was then cooled overnight (pressure drop at room temperature was 1*0 p . s . i . , equal to 0.02 mole of carbon monoxide) and vented. The vented gas contained no basic material (shown by bubbling a portion (700 p.s.i.) of the vented gases through ethanolic hydrogen chloride). The reaction product consisted of 7*1* g of a blue solid (A) and a brown liquid (essentially free of catalyst), which on evaporation under reduced pressure, yielded I*.6 g of a brown solid (B)., The latter material was shown to contain five substances by thin layer chromatography (113) on s i l i c a gel using chloroform as a developer and concentrated sulfuric-n i t r i c acid (95s5) as a detector. C. Chromatographic Separation of the Products from B A. 2.17 g portion of material B, dissolved i n a minimum of warm benzene, was chromatographed on an alumina column (133 x 51* ram diam.)., The results are shown i n Table I. D. Characterization of the Products from B 1. Diphenylmethane (XXXII) Compound XXXII, a liq u i d at room temperature, was purified by vapor phase chromatography using a silicone column at 2 7 0 ° . Scratching of the -67-Table 1 Chromatographic Separation of Material B from the Carbonylation of Benzophenone Semicarbazone at 2U0° Developer a Volume (ml) Weight Yield 1 Compound (Symbol) Benzene:petroleum ether (b.p. 39-60°) (50:50) Benzene Benzene:Ethanol (99:1) (98:2) (85:15) 600 300 Uoo 600 800 1200 5oo 300 Uoo 0.2:83 clear liquid 0*050 white solid trace 0.328 white-solid 9 2 0.595 yellow solid 15 O.312 brown syrup Diphenylmethane (XXXII) 1,1,2,2-Tetraphenyl ethane (XXXIIl) ' 3-Phe nyl-2-(N-benz-hydrylcarboxamido) -phthalimidine (XXXIV) N,W'-dibenz-hydrylurea (XXXV) N-benzhydryl-urea (XXXVI) a . Developers were added consecutively b. Yields are calculated in mole percent -68-effluent l i q u i d induced crystallization, m.p.. 25 j mixed m.p* with an authentic sample of diphenylmethane was 2l*-25°. n.m.r* signals (given in h unitsj spectrum obtained i n carbon tetrachloride): 3«80 (R^C-Phg, area - 2: H), 7.01 (aromatic H, area = 10 H). Infrared spectrum (film): 3060 (w), 3030 (w), 2900 (w), 1720 (w), 1596 (w), ll*93 (m), H*5l (m), 107U (w), 1028 (w), 735 (s), 695 (s). Comparison of this spectrum with that of authentic diphenylmethane showed them to be identical. 2. 1,1,2,2-Tetraphenylethane (XXXIII) Compound XXXIII was recrystallized from l i g r o i n , m.p. 210-212°. Elemental analysis showed this compound to be a hydrocarbon while the n.m..r. spectrum showed only aromatic and benzylic protons. Infrared spectrum (KBr): 3060 (w), 3020 (w), 2880 (w), 1593 (w), 1577 (w), U493 (m), H*50 (m), 1206 (W), 1180 (w), 1157 (w), 1070 (m), 1029 (m), 7l*l* (s), 695 (s). n.m.r. signals (given i n ^  units; spectrum obtained i n carbon tetrachloride): 1**65 (HC-Phg, area = 2 H), 6.99 (C^H^-, area = 20 H). Anal. Found: C, 93-69j H> 6.1*0. Mol. wt. (Rast) 306. Calc. for C 26H 2 2: C, 93.50; H, 6.61** Mol. wt. 33U* Comparison of Compound XXXIII with an authentic sample of tetraphenylethane (infrared and mixed melting point) showed them to be identical. 3. Reduction of Tetraphenylethylene i n Sodium and Liquid Ammonia (95) To a 150 ml cylindrical vessel equipped with a gas i n l e t tube and containing 3*12 g (0*01 mole) of tetraphenylethylene (Aldrich Chem. Co.), and 0*50 g (0.2:7 mole) of clean, finely cut sodium metal, was added -69-1+0 ml of freshly d i s t i l l e d ammonia at -70°. The blue solution was magnetically stirred, without further cooling, for thirty minutes. The original volume of li q u i d ammonia was then replenished and an excess of ammonium chloride added directly u n t i l the blue color had disappeared. The ammonia was allowed to evaporate at room temperature and the remaining white residue extracted with 3 x 25 ml of benzene. The combined benzene extracts were f i l t e r e d and the f i l t r a t e evaporated to dryness (in vacuo). The product (3.0 g - 9&% yield) was recrystallized from carbon tetrachloride, m. p. 210-212°. 1*. 3-Phenyl-2-(N-benzhydrylcarboxamido)phthalimidine (XXXIV) Compound XXXIV was recrystallized from benzene-petroleum ether (b.p. 30-60°) to give white f l u f f y crystals, m.p.. 200-201°.. Mixed melting point of compound XXXIV with an authentic sample of 3-phenyl-2-(N-benzhydrylcarboxamido)phthalimidine, 200-201°. Infrared spectrum (KBr)s 3260 (w), 3050 (w), 3020 (w), 2930 (w), 1700 (s), 1681* (s), 1607 (w), 1593 (w), 1582 (w), 1528 (s), 11*93 (m), li|65 (w), 11*53 My 1359 (m), 13U0 (m), 132l* (m), 1295 W, 1236 (w), 1201 (w), 1185 (m), 1158 (w), 1137 (m), 1090 (w), IO83 (m), 102i* (w), 89U (w), 81*9 (w), 770 (m), 762 (m), 750 (s), 738 (s), 727 (s), 697 (s). n.m.r. signals (given i n 6 units; spectrum obtained in deuterio-chloroform): 6.09 (HC-Phg, area » IH), 6..2:0 (H>Ph, area = 1 H), 7.20 (aromatic H, area = 15 H), 7.1+8 (phenylphthalimidine aromatic H, area about 1; H), 9.1*5 (N-H, doublet, area = 1 H). Anal. Found: C, 80.80; H, 5.29; N, 6.58. C a l c for CggHggNgO^ C, 80.35; H, 5.30; N, 6.70. -70-5. Exchange Reaction of 3-F^eryl-2-(N-benzhydrylcarboxamido)phthalimid with Deuterium Oxide A few milligrams of 3-phenyl-2-(N-benzhydrylcarboxamido)phthalijiiidine were refluxed for 17 hours i n 10 ml of DgO containing a pinch of K^ GO^ . The deuterated product was obtained by extraction with warm benzene. Mixed melting point of the white crystalline product with the starting material, 198-200°. The infrared spectrum showed a strong N-D band at 2U30 cm""1 (10U) and a lowering of the exocyclic carbonyl band to 1695 cm"1. 6. -Synthesis of 3-P^enyl-2-(N-benzhydrylcarboxamido)phthalimidine a) Diphenylacetylchloride (97) Diphenylacetic acid (20.O g) was dissolved i n 50 ml of dry, freshly d i s t i l l e d carbon tetrachloride containing 30.0 g of thionyl chloride (BDH reagent grade) and the mixture refluxed gently during 2: hours while a stream of nitrogen was passed through the reaction mixture. The cooled solution was suction f i l t e r e d and the f i l t r a t e evaporated under reduced pressure yielding a yellow solid mass. The latter was taken up i n dry ethyl ether (25 ml) and cooled i n a dry ice - acetone bath giving a white crystalline solid from which the yellow supernatant was decanted* The product (18.2 g - Qk% yield) was washed with 10 ml of cold dry ethyl ether, m.p. 56-58°. Literature m.p. 57° ( l l i i ) * b) Benzhydrylisocyanate (115) Sodium azide (2.9 g, O.OI4 mole), dissolved i n 10 ml of water was added to a 100 ml flask equipped with a dropping funnel containing - 7 1 -diphenylacetylchloride (5»0 g, 0.02: mole) in 35 ml of acetone. The latter was added to the well stirred azide solution at such a rate that the temperature remained between 1 0 - 1 5 ° (20 minutes). Stirring was continued for a further 75 minutesj then 20 ml of cold aqueous sodium bicarbonate solution (10%) was added. The reaction mixture was transferred to a separatory funnel containing 50 ml of ice-cold water and extracted with 3 x 1*0 ml portions of cold ethyl ether. The combined ethereal extract was washed with 20 ml of cold aqueous sodium bicarbonated (10%) then with 2 x 20 ml of cold water and f i l t e r e d on anhydrous magnesium sulfate. The dried ethereal extract was f i l t e r e d into 100 ml of sodium-dried benzene and warmed to 65° for 90 minutes • with simultaneous d i s t i l l a t i o n of the ether. Removal of the benzene (in vacuo) yielded 3»32 g (13% yield) of the crude isocyanate which was subsequently d i s t i l l e d yielding 2 . 0 g (1*5$ of theoretical, based on diphenylacetylchloride), b.p. 1 1 0 - 1 1 3 ° , 0.08 mm Hg, n§ 6 1 .5765. The infrared spectrum (film) showed the characteristic strong absorption band at 22:70 cm - 1 (116) and a medium absorption band at 2130 cm - 1. c) Condensation of Benzhydrylisocyanate with 3-Phenylphthalimidine  (67, 96) —3 Benzhydrylisocyanate (0.1*8 g, 2 .3 x 10 mole) and 3-phenyI-phthalimidine (0.1*8 g, 2 .3 x 10"^ mole), i n 30 ml of anhydrous toluene was refluxed for 21* hours. Upon cooling, a white so l i d ( 0 . 8 9 g, 93$ yield) was removed by f i l t r a t i o n and dried, m.p. 1 9 7 - 1 9 9 ° •• Mixed melting point with compound XXXIV, 1 9 7 . 5 — 1 9 9 . 5 ° . The infrared spectra of the condensation product and 3-phenyl-2-(N-benzhydrylcarboxamido)-- 7 2 -phthalimidine (XXXIV), were identical.. Anal- Found: C, 80-37j H, 5 - l i l . Calc. for CggHggNgOg: c> 80 .35j H, 5-30. 7- N.N'-dibenzhydryltirea (XXXV) Compound XXXV was rechromatographed on alumina using benzene: chloroform ( l * : l ) . The f i r s t fraction was decolorized with Norite and recrystallized from ethyl acetate, m.p. 289-290° (needles).-Infrared spectrum (KBr) of purified XXXV: 3290 (m), 3050 (w), 3020 (w), 2890 (w), 1623 ( s ) , 1583 (sh-S), 1568-1560 (broad-s), 11*90 (m), U*5l U ) , 13U0 (w), 1305 (w), 1270) (m), 123h (w), 1188 (w), 1082 (w), 1057 (w), 1026 (w), 982 (w), 920 (w), 910 (w), 880 (w), 8U0 (w), 767 (m), 71*3 (m), 727 (w), 702 (3), 693 (s). The strong absorption at 1623 cm"^ " was indicative of the sym-disubstituted ureas ( 5 2 ) . 8. Synthesis of N,N'-dibenzhydrylurea (117) An authentic sample of XXXV was prepared by allowing the benzhydryl-isocyanate to react with the moisture i n the a i r . The product, after recrystallization from acetone, had a melting point of 291-291.5° (needles)j mixed melting point with XXXV, 290-291°. The literature melting point for this compound i s 269-270° ( 9 2 ) . Anal. Found: C , 82.81 j H, 6.1*7; N, 6 . 9 5 -Calc. for C g ^ ^ O : C, 82.62j; H, 6J.63 N, 7.M*. 9- N-benzhydrylurea (XXXVI) Compound XXXVI was recrystallized from benzene then from hot water,; m. p. ll*8-ll*9° (long needles). The infrared spectrum was similar to that -73-of monobenzylurea formed under similar,conditions using benzaldehyde oxime (118). Anal. Found: C, 73.89; H, 6.1*5; N, 12.33 Calc. for C^H-^NgO: C, 71**30; H, 6*23; N, 12.38. 10. Synthesis of N-benzhydrylurea Concentrated ammonia (3 drops) was added to 3 drops of benzhydrylisocyanate dissolved i n 2 ml of dry benzene. Dry acetone was added to effect a single phase and the mixture refluxed for one hour; then a further 3 drops of concentrated ammonia was added and refluxing continued for another hour* The solvent was then removed under reduced pressure and the resulting white solid recrystallized from hot water, m.p. H*7»-5-ll*9.5° (needles)* Mixed melting point with XXXVI, ll*7*5-lli9°» Literature melting point of N-benzhydrylurea, H*3° (98)* E* 3-Phenylphthalimidine (XXXVII) The blue solid (A) was extracted with ethanol for 2l* hours i n a Soxhlet apparatus yielding 1**3 g of crystalline material* Chromatography of 0.105 g of the latter material on alumina using benzene:chloroform (5:1) as developer, yielded 0.019 g (10%) of N,N'-dibenzhydrylurea (XXXV). Further elution with chloroform afforded 0.051* g (25$) of a-,.white solid which, on recrystallization from ethanol, had a melting point of 222-22l*°. The mixed melting point of the latter substance and authentic 3-phenylphthalimidine (93) was 222-22i*°* The infrared spectra of the two compounds were identical. -7lt-F* Blue Cobalt Complex The blue solid (3»1 g) remaining after the ethanol extraction i n E, did not melt below 360° and evolved ammonia (litmus reaction) when heated with concentrated sodium hydroxide. Attempts to dissolve the complex in a variety of organic solvents, including carbon disulfide, dimethylsulfoxide and N,N-dimethylformamide, were unsuccessful. Treatment with 2N HCl afforded COg (precipitate with Ba(OH) 2). The latter acid solution was basified with NaOH and extracted with ethyl ether but yielded nothing* Anal* Found: C,' 2h»3$5 H, 3*86; N, 19.88* G* Carbonylation of Benzophenone Semicarbazone at 200-22:0° Benzophenone semicarbazone (8*0 g) was carbonylated at 200-220° under conditions similar to those used under section B. The reaction product consisted of 1,*10 g of a blue solid (C) and a brown liq u i d , which on evaporation under reduced pressure, yielded 7.16 g of a brown solid (D). A 2.2galiquot of the latter was chromatographed on alumina, the results of which are shown in Table I I * The blue solid (C) was extracted i n a Soxhlet apparatus with acetone for 3 hours yielding 0.20? g of a yellow crystalline solid (XXXVIII), m*p* 90-91°* The remaining blue complex was insoluble i n a l l the common organic solvents. Analysis of the blue complex* Found: C, 22.k5; H, 3.3O3 N, 31...61* Table II Chromatographic Separation of Material B from the Carbonylation of Benzophenone Semicarbazone at 200-220° Developer 3 1 Volume (ml) Weight .(g) Yield b Compound (Symbol) Benzene 50 -50 0.07 clear liquid k D iphenylme thane ( m n ) 75 0.28 yellow solid 10 Benzophenone azir (XXXVIII) 2300 -Benzene:chloroform (75:25) 1200 0.U5 white solid 11 Benzophenone k-benzhydrylsemi-carbazone (XXXIX) (50:50) 300 700 200 0.10 brown ) solid ] ) 0.75 yellow ) syrup ) 35 Benzophenone semicarbazone (XXXI) Chloroform 200 300 0.10 brown solid Benzene:ethanol (98:2) 1000 -(90:10) Uoo 0.09 brown solid h N-benzhydryl-urea (XXXVI) (50:50) 600 -a. Developers were added consecutively b. Yields are calculated i n mole percent based on moles of substrate consumed. - 7 6 -H. Characterization of the Products from G 1. Benzophenone Azine (XXXVIII) Compound XXXVIII was recrystallized from benzene-petroleum ether (b*p* 30 -60° ) , m.p* 159-160°. Infrared spectrum (KBr): 3050 (w), 3020 (w), 1581* (m), 1560 (m), 11*86 (m), ll*l*l* (m), 1319 (s)., 1291* (w), 1270 (w), 1175 (w), 1157 (w), 1075 (w), 1025 (w), 999 (w), 983 (w)» 973 (w), 956 (s), ..917(w), 909 (w), 771* (s), 761* (s), 721* (w), 690 (s), 666 (w), 655 Cs). Anal. Found: C, 87.13j H, 5.69; - N, 7-30; mol. wt.. (Rast) 36O* Calc. for C-26H2o%: C, 86.635. H, 5 .60; N, 7*78; mol. wt. 36O. 2• Synthesis of Benzophenone Azine (91) Benzophenone semicarbazone (1*.65 g) was heated at 2i*0° and atmospheric pressure for 90 minutes. The yellow melt was extracted with boiling ethyl ether u n t i l the ether was colorless. Concentration of the combined ethereal extracts afforded light yellow prisms (3*32: g, 95$ yield), m. p* 163-165°. Mixed melting point with XXXVIII, 163-165°* 3* Benzophenone i*-benzhydrylsemicarbazone (XXXDC) Compound XXXIX was recrystallized from benzene-petroleum ether (b.p* 30-60°), m..p. 179-181°. Infrared spectrum (KBr): 3U10 (m), 3150 (w), 3060 (w), 1668 (s), 1580 (m), 11*95 (s), 11*1*5 (m), 1365 (w), 1325 (w), 1230 (w), 1180 (m), 1105 (s), 1065 (m), 1025 (m), 91*5 (w), 910 (w), 862 (w), 835 («:), 782 (m), 753 (s), 735 U), 695 (s). n.m*r. signals (given i n ^ units; spectrum obtained i n deuterio-chloroform): 6*25 (HCPh2, doublet, area • 1 H), 6.95 (NH, area • 1 H), -77-7-32 (aromatic H, area = 20 H), 7«72 (NH, area = I H). Anal- Found: C, 79*60; H, 5 . 6 7 ; N, 1 0 . 5 8 ; 0 , U . l l ; mol. wt. (East) 3 ° 9 . Gale, for C27H23N3O: C, 79.97; H, 5.72; N, 1 0 . 1 3 ; 0 , 3 - 9 5 ; mol. wt* 1*05. <-• Hydrolysis of XXXIX with dilute sulfuric acid yielded benzophenone (isolated as benzophenone 2,t|.-dinitrophenylhydrazone). h* Synthesis of Benzophenone l*-benzhydrylsemicarbazone a) Benzhydrylamine (92) Benzophenone oxime ( 2 . 5 0 g, 0*013 mole)} prepared i n the usual manner (117), i n J4O ml of absolute ethanol was poured down a reflux condenser on1 a freshly cut piece of sodium metal (U*30 g, 0.187 mole). The oxime dissolved and sufficient heat was generated to dissolve the sodium* After 50 minutes (time required to completely dissolve the sodium), the excess ethanol was removed under reduced pressure and water (50 ml) was added to the remaining residue* After partial neutralization with dilute sulfuric acid, .the solution was extracted with 2 x 100 ml portions of ethyl ether and the combined ethereal extracts dried over potassium hydroxide pellets and f i l t e r e d . Gaseous hydrogen chloride precipitated the benzhydrylamine as the hydrochloride which was subsequently removed by f i l t r a t i o n and dried to yield 2*70 g (97$ of theoretical) of product* b) Condensation of Benzhydrylamine with Benzophenone Semicarbazone Benzhydrylamine (0.1+7 g} 2 .5 m moles), was added to powdered benzophenone semicarbazone (0*38 g, 1*6 m moles) and heated at 120° for - 7 8 -U hours. The reaction was followed by the evolution of ammonia. A white precipitate formed after about 2 hours. The white solid was taken up in boiling ethanol (25 ml) which, upon cooling, afforded o 0 . U7 g (7k% yield) of white crystals, m.p. 1 7 9 . 5 - 1 8 0 . 5 * Mixed melting point with benzopheone U-benzhydrylsemicarbazone (XXXIX),, 1 7 9 - 1 8 0 ° • 1 . Carbonylation of Benzophenone Semicarbazone at 175-180° A mixture of 15»3 g ( 0 . 0 6 mole) of benzophenone semicarbazone, lt . 6 g ( 0 * 0 1 mole) of preformed dicobalt octacarbonyl i n 6 0 ml of purified chlorobenzene was placed i n the glass liner of the bomb. To the a i r freed bomb was added 3280 p . s - i . (1.1; moles) of carbon monoxide at 20°. . In one hour the temperature had reached 175 (5100 p.s.i*).. Rocking was continued at 1 7 5 ° for a further one and one-half hours. The venting pressure was 3010 p.s.i.* at 1 5 ° , which corresponds to 0 . 0 9 mole of carbon monoxide used* The catalyst was decomposed at 8 0 ° under an atmosphere of nitrogen. The solution was suction f i l t e r e d and the blue residue ( 3 - 0 g) that remained was washed with acetone. The f i l t r a t e and washings were then evaporated to dryness under reduced pressure yielding 13 g of solid material. J* Chromatographic Separation of the Products from I The mixture was analyzed by chromatography using the gradient elution technique (119) on an alumina column (330 mm x 5 0 mm diam.) which had been washed with 300 ml petroleum ether (b.p* 3 0 - 6 0 ° ) . An amount of 3-6I4. g was dissolved i n boiling chloroform ( 5 0 ml) and applied to part of the so l i d phase (alumina) contained i n a beaker. The chloroform -79-was evaporated by passing warm a i r over the contents and the alumina was then added to the top of the column* 'The results are shown in Table III. K* Carbonylation of Benzophenone Azine at 2I4.O0 Benzophenone azine (l.3>0 g) was carbonylated at 235>-2ltS>° under conditions similar to those used i n the f i r s t experiment (see Section B). Removal of the solvent under reduced pressure yielded 2-0 g of crude reaction product. A O.83O g sample of the latter was extracted with petroleum ether (b.p. 30-60°) in a Soxhlet apparatus yielding 0.17 g of"solid. Further extraction using benzene afforded O.63 g of solid leaving 0*03 g of insoluble residue. The petroleum ether-soluble fraction was redissolved i n a minimum of refluxing petroleum ether (b. p. 30-60°) and stored at 0° overnight to y i e l d 0.06 g of 3-phenylphthalimidine (XXXVIl), identified by comparison (mixed melting point and infrared) with authentic 3-phenylphthalimidine (93)* The supernatant was evaporated to dryness yielding 0.118 g of solid. A 0.06 g sample of the latter was chromatographed on alumina, as previously described, yielding 0.03 g of l i g h t yellow solid, m. p. 168-170°, which was shown to be benzophenone azine (XXXVIIl) by comparison (mixed melting point and infrared) with the starting material. A portion of the benzene-soluble fraction (0.110 g) was chromatographed on alumina yielding 0*011 g of benzophenone azine (XXXVIIl) using benzene as a developer* Further elution with benzene:chloroform (1:1) afforded 0.076 g of 3£phenylphthalimdine (XXXVIIl), m. p* 221+-2260. -80-Table III Chromatographic Separation of the Products from the Carbonylation of  Benzophenone Semicarbazone at 175-180° Developer Volume (ml) Weight (g) Yield a (*) Compound (Symbol) Petroleum ether (b.p. 30-60°) 500 mm Petroleum ether (b.p. 30-60°):benzene (75:25) 300 mm 200 0.106 clear liquid 6 D iphenylmethane (XXXII) 100 -(50:50) 150 -200 0.050 white solid 1 1,1,2,2-Tetraphen ethane (XXXIII) (25:75) 600 -Benzene 200 U50 0.01U brown s :yrup 750 0..970 yellow solid 2U Benzophenone azine (XXXVIIl] 200 -Benzene:chloroform (75:25) 5oo -(50:50) 600 -(25:75) Uoo -Chloroform 1200 -Uoo 0.7U0 yellow solid 16 Benzophenone U-benzhydrylsemi-carbazone | (XXXIX) contd. -81-1100 1.1*00 yellow solid 35 Benzophenone semicarbazone (XXXI) 300 -Benzene:ethanol (98:2.) 200 -(95:5) 800 -(90:10) 500 -(75:25) 700 0..080 green o i l Ethanol (100$) 300 — a. Yields are calculated i n mole percent. -82-L. Carbonylation of Benzophenone U-benzhydrylsemicarbazone at 21*0° Benzophenone U-benzhydrylsemicarbazone (0.U7 g, 1.16 m moles) and preformed dicobalt octacarbonyl (0.8 g, 0.23 m mole) in 10 ml of anhydrous, thiophene-free benzene was carbonylated at 2UO-2U5° for 150 minutes. The reaction mixture was then refluxed to decompose the catalyst, f i l t e r e d hot and the solvent removed under reduced pressure yielding O.3U1 g of solid. The latter was taken up i n a minimum of warm benzene and chromatographed on an alumina column (12U x 35 mm diam.). The results are shown in Table IV. Identities of each component were confirmed by mixed melting points and comparison of the infrared spectra with those compounds previously identified with the exception of benzophenone (XL), which was identified as i t s 2?,U-dinitrophenylhydrazone, again by comparison (infrared and mixed melting point) with an authentic sample of benzophenone 2,U-dinitrophenylhydrazone. M. Carbonylation of Benzaldehyde Semicarbazone at 215-220° To a solution of 10.0 g (0.06 mole) of benzaldehyde semicarbazone i n 50 ml of anhydrous thiophene-free benzene, was added 3*0 g (0..01 mole) of preformed dicobalt octacarbonyl and 2050 p . s . i . of carbon monoxide. The mixture was heated with rocking, for three hours at 215-220°. The reaction product consisted of 5-U7 g of blue solid (E) and a brown liquid which, on evaporation under reduced pressure, afforded U*32: g of a solid green-colored material ( F ) . Table IV Chromatographic Separation of the Products from the Carbonylation of i o Benzophenone u-benzhydrylsemicarbazone at 21*0 Developer a Volume (ml) Weight (g) Yield ° (*) Compound (Symbol) Benzene 100 0.01*1* liquid 23 Diphenylmethane (XXXII) 100 0.015 o i l 7 •-Benzophenone (XL) 100 0.029 white solid 6 3-Phenyl-2-(N-benz hydrylcar-boxamido)phthal-imidine (XXXIV) 100 -900 0.01*0 white solid 21 N, N'-dibenzhydryl urea (XXXV) 300 -Benzene:chloroform (67:33) 600 -(50:50) 200 -1300 0.170 white solid 70.0 3-Phenylphthalimi dine (XXXVII) 100 -Benzene:ethanol (90:10) 800 -(50:50) 1+00 -Ethanol :tL>0 (50:5or 100 200 Trace 0.011 white solid -a. Developers were added consecutively b. Yields are calculated i n mole percent -81*-N* Chromatographic Separation of the Products from M The blue solid (E) was washed exhaustively with warm, absolute ethanol which yielded, on evaporation under reduced pressure, 1.66 g of crystalline solid. A 1*20 g portion of the latter, dissolved in a minimum of warm benzene, was chromatographed on an alumina column (133 x 51* mm diam.). The results are shown i n Table V. The blue solid, having been exhaustively extracted, remained insoluble i n the common organic solvents. Anal. Found; C, I9.38; H, 3«09j N, 2:8.1*3. Infrared spectrum (KBr disc): 35*00-32:00 (s-broad), 162$ (s-broad), 11*50 (w), 11*00 (w), 82.0 (w).. A 0.81 g sample of the green solid (F) dissolved i n a minimum of benzene, was chromatographed on an alumina column (96 x 35 mm diam..). The results are shown i n Table VI. A portion of Material F was extracted with 2 x 2.0 ml portions of petroleum ether (b.p.. 30-60°) to remove benzaldehyde azine. A O..86 g sample of the petroleum ether - insoluble portion was dissolved i n 10 ml of benzene and chromatographed on an alumina column (112: x 51* mm diam.). The results are shown i n Table VII. -85-Table V Chromatographic Separation of Material E from the Carbonylation of  Benzaldehyde Semicarbazone at 215-220° Developer a Volume (ml) Weight (g) Yield (*) Compound (Symbol) Petroleum ether (b.p., 30-60°) 100 0*011 clear liquid i b Bibenzyl (XLI) 800 0.628 yellow solid i i * b Benzaldehyde azin (XLII) Benzene 600 0*179 clear syrup 3 c Benzene:ethanol (98:2) 100 -(96:U) 150 O.I38 syrup 2 c (50:50) 0*08U white solid 1 c Ethanol (100$) 100 -a. Developers were added consecutively b. Yields calculated i n mole percent c. Yields calculated i n weight percent -86-Table VI Chromatographic Separation of Material F from the Carbonylation of o Benzaldehyde Semicarbazone at 215-220 Developer a Volume (ml) Weight (g) Yield OO Compound (Symbol) Petroleum ether (b.p. 30-60°) 200 — Benzene tPetroleum ether (b.p. 30-60°)(50:50) 175 0.061 white solid 6 b Bibenzyl (XLI) 225 0.1*60 yellow solid U o b Benzaldehyde azin (XIII) 100 -Benzene 100 -Benzene:EthanoI (99:1) U25 -100 0.098 orange syrup 5 c 75 -(85:15) 150 150 trace syrup trace brown o i l (50:50) 100 trace syrup Ethanol 2.00 -a. Developers were added consecutively b. Yields calculated i n mole percent c. Yield calculated i n weight percent Table VII Chromatographic Separation of Material F after Extraction with Petroleum Ether (b> p. 30 - 60°) Developer Volume (ml) Weight (g) Compound Petroleum ether (b.p. 65-110°) Petroleum ether (b.p. 65-110°):benzene (75:25) (50:50) Benzene:chloroform (80:20) (50:50) (25:75) Chloroform Benzene:ethanol (99:1) (96:10 (90:10) 250 250 250 250 250 250 5oo 5oo 5oo 1+00 300 200 5oo 200 200 1+00 1200 0..006 clear l i q u i d 0.78 yellow solid 0.051+ green o i l trace yellow o i l 0.031 yellow o i l 0.075 grey solid Bibenzyl (XLI) Benzaldehyde azine (XLII) XLIII .contd -88-250 _ (80:20) 250 -(50:50) 5oo -Ethanol 250 -Ethanol:water (75:25) Uoo trace red o i l (25:75) 200 O.O36 yellow-white solid a. Developers were added consecutively. -89-0. Carbonylation of Benzaldehyde Semicarbazone at 2U0° To 5*90 g (O.O36 mole) of benzaldehyde semicarbazone in h$ ml anhydrous, thiophene-free benzene, was added 1.8 g (5»3 m mole) preformed dicobalt octacarbonyl and 2000 p . s . i . of carbon monoxide. The mixture was heated for 150 minutes at 235-21*5° • The reaction product consisted of 2.76 g of blue solid (G) and a brown liq u i d , which on evaporation under reduced pressure afforded 3*50 g of a brown solid material (H). The blue solid (G) was placed i n a Soxhlet apparatus and extracted for U8 hours with 150 ml of ethyl ether. The latter, on evaporation, yielded 0.19 g of yellow solid. Further extraction with chloroform for 2k hours yielded only a trace of yellow solid and the remaining blue solid was insoluble i n the common organic solvents. The 0.19 g of yellow solid was extracted with petroleum ether (b.p. 65-110°) to yield 0.06 g of yellow needles (m.p. 90-92°), the infrared spectrum of which, was identical to that of benzaldehyde azine obtained previously. P. Chromatographic Separation of the Products from 0 A O.87 g sample of material H was dissolved in a minimum of benzene and chromatographed on an alumina column (125 x 35 mm diam.). The results are shown in Table VIII. -90-Table VIII Chromatographic Separation of Material H from the Carbonylation of  Benzaldehyde Semicarbazone at 21+0° Developer a Volume (ml) Weight (g) Yield (*) Compound (Symbol) Benzene 50 0.019 white solid 2° Bibenzyl (XLI) 100 0.569 yellow solid 61 D Benzaldehyde azin (XLII) 200 trace yellow solid 1650 * -Benzene:chloroform (50:50) 500 100 1+00 0.01+5 brown solid Chloroform 200 -Benzene:Ethanol (98:2) 250 - ! i (50:50) 200 50 O.Ol+O white solid 3 c XLIV Ethanol (100$) 250 -a. Developers were added consecutively b. Yields are calculated i n mole percent c. Yield of XLIV calculated i n weight percent -91-Q. Characterization of the Products from M and 0 1 . Bibenzyl (XLI) This fraction was suspected as being bibenzyl by analogy with the previous experiments with the ketone semicarbazones and comparison of the infrared spectrum (film) of compound XLI with that of an authentic sample of bibenzyl (Eastman Kodak Chem. Co.) showed the two to be identical. 2 . Benzaldehyde izjne (XLII) Compound XLII was recrystallized from absolute ethanol to give yellow needles, m.p. 92-93°• Infrared spectrum (KBr): 3000 (w), 2920 (w), 1619 (m), 1570 (w), 11*92 (w), 11*1*6 (m), 1320 (w), 1305 (w), 1288 (w), 1210 (m), 1170 (w), 1070 (w), 1020 (w), 999 (w), 955 (m), 912 (w), 857 (m), 751 (s), 691 (s), 675 ( m ) . Anal. Found: N, 13 .20. Calc. for C^H-j^N^: N, 13.1*5. VJhen XLII was warmed in 15$ sulfuric acid, the odor of benzaldehyde was detected almost immediately. The addition of 2,i*-dinitrophenylhydrazine reagent resulted i n an immediate orange precipitate, m.p. 2 5 0 - 2 5 1 ° . The infrared spectrum of the 2,l*-dinitrophenylhydrazone of hydrolyzed XLII was identical to. the infrared spectrum of authentic benzaldehyde 2,1*-dinitrophenylhydrazone. Mixed melting point, 2 5 0 - 2 5 1 ° . Literature m.p. 250° (117). 3 . Synthesis of Benzaldehyde Azine (103) To 9 .1 g (0 .07 mole) of hydrazine sulfate dissolved in 150 ml of water, was added 1**7 ml of concentrated ammonia. This was followed by - 9 2 -the slow addition of 1 5 . 0 g (0.11+ mole) of benzaldehyde under rapid s t i r r i n g . The s t i r r i n g was continued for thirty minutes after the addition was completed, whereupon the yellow crystalline solid was removed by f i l t r a t i o n , washed with water and recrystallized from hot ethanol yielding 2 2 . 5 g (78$ of theoretical) of yellow needles, m. p. 93 .5-9U°. Literature value, 92° ( 1 0 3 ) . The infrared spectrum of the authentic benzaldehyde azine was identical to the infrared spectrum of XLII and an admixture showed no depression on melting. h* Compound XLIII This fraction was treated with Norite which removed the slight discoloration then recrystallized, f i r s t from carbon tetrachloride containing trace amounts of ethanol, then from benzene-petroleum ether yielding a white solid of m.p. 2 5 0 . 5 - 2 5 1 . 5 ° . Infrared spectrum (KBr): 3380 (s), 3170 (s), 3060 (w), 1652 (s), 1620 (s), 1575 (s), 1U50 (m), 11+00 (s), 1295 (w), 1270 (w), 1179 (w), 111+0 (m), 1118 (m), 1068 (w), 1019 (m), 916 (w), 8^5 (w), 807 (m), 787 (m), 768 (m), 700 (s), 681 (s). n.m.r. signals (given i n b units; spectrum obtained i n deuterio-chloroform), 7.5 + 0 .5 (area = 5 H), 6 .2 + 0 . 2 (area about 1 H). 5» Compound XLIV This fraction was recrystallized from hot benzene to yield a white solid, m. p. 2U+-215.5 0 . Infrared spectrum (KBr): 3U6O (m), 3380 (m), 3180 (m), 3070 (m), 3000 (m), 2980 (m), 2920 (m), 1685 (s), 161+5 (s), 1595 (s), 1517 (w), 11+89 (w) 11+52: (m), 11+30 (m), 1353 (m), 1325 (w), 1311 (w), 1291+ (w), 1230 (w), - 9 3 -11U0 (m), 1087 (m), 1069 (w), 1025 (w), 986 (w), 962 (w), 9U2 (m), 855 (w), 759 (s), 690 (s), 665 ( « ) • Rv Carbonylation of Benzaldehyde Azine at 2lt0° To 8 . 2 0 g (0.0l|. mole) of benzaldehyde azine in 50 ml of anhydrous, thiophene-free benzene, was added 3 . 0 g ( 0 . 0 1 mole) of preformed dicobalt octacarbonyl and 1900 p . s . i . of carbon monoxide. The mixture was heated for 2 .5 hours at 21*0°. The pressure drop was 110 p . s . i . at 1 8 ° . The reaction vessel contained 2 .28 g of a black solid (J) and a dark green solution which upon evaporation under reduced pressure, afforded 7«15 g of greenish black solid (K). S. Chromatographic Separation of the Products from R The black solid J was extracted using methanol i n a Soxhlet apparatus for 2h hours yielding O.83 g of a green solid after removal of the methanol under reduced pressure. A 0.22 g sample of the latter green solid was dissolved i n U ml of hot benzene and chromatographed on an alumina column (125 x 28 mm diam.). The results are shown i n Table IX. A 2.28 g sample of the greenish-black solid (K) was chromatographed on an alumina column (130 x 60 mm diam.). The results are shown in Table X. The f i r s t fraction from the chromatography of the greenish-black solid K (see Table X) was dried i n vacuo, dissolved in hot benzene and petroleum ether (b.p. 30-60°) added to turbidity. The resulting white solid (0 .130 g) was removed by f i l t r a t i o n and dried (Compound XLVII). The f i l t r a t e was evaporated to dryness under reduced pressure, redissolved in a minimum of benzene and rechromatographed on alumina. The results are shown in Table XI. -9U-Table EC Chromatographic Separation of the Material Extracted from the Black Solid  (j) from the Carbonylation of Benzaldehyde Azine at 2l|Q° Developer Volume (ml) Weight (g) Yield Compound Symbol Benzene Benzene:chloroform (75:25) (50:50) Chloroform Benzene :Ethanol (98:2) Ethanol:H20 (50:50) 300 100 100 300 350 1200 900 100 200 200 800 600 Uoo Uoo 200 600 5oo 5oo 5oo trace l i q u i d trace solid 0.006 white solid trace solid trace o i l 8.113 white solid trace blue solid 0.021 blue solid black solid LI A. Developers were added consecutively b. Yield of LI calculated in weight percent -95-Table X Chromatographic Separation of the Greenish-black Solid (K) from the  Carbonylation of Benzaldehyde Azine at 2J+0° Developer a Volume (ml) Weight (g) Yield (%) Compound (Symbol) Benzene 75 -1100 0.372 oily solid (See Table XI) 1300 trace o i l 300 0.kh9 white solid 16 b 2-Benzylphthal-imidine (XLVIII) Benzene:chloroform (75:25) 800 800 0.077 brown solid 0.057 white; solid 550 0 .187 green solid 6 c XUX 350 -(50:50) 600 50 0.091+ white solid 125 0.028 red sol Ld 5oo -Chloroform 100 -150 green solid < 0.021+ green solid 250 Benzene:ethanol (8:2:) 600 750 0.211 white solid 0.21+3 white solid > ) h ) 13 d ) 1 Phthalimidine ( L ) contd. -96-50 -250 green o i l -Ethanol (100$) 5oo -Ethanol:water (50:50) 2000 0.369 grey 12 c s o l i d a. Developers were added consecutively b. Yields calculated i n mole percent c. Yield of XLEC calculated i n weight percent -97-Table XI Rechromatography of the F i r s t Fraction from the Chromatography of Material K (See Table X) Developer Volume (ml) Weight (g) Yield Compound (Symbol) Petroleum ether (b.p. 30-60°) Benzene:petroleum ether (b.p. 30-60°) (50:50) Benzene Benzene:chloroform (75:25) Chloroform 100 100 100 100 200 300 600 1+00 100 100 200 0.023 clear li q u i d 0.033 white solid green solid green solid 0.01+3 grey } solid ) ) ) 0.127 white ) solid ]' trace yellow solid Bibenzyl (XLI) XLV 2-(N-benzylcar-boxamido )pht halimi' dine (XLVI) a. b. c. •Developers were added consecutively. Yields calculated i n mole percent. Yield of XLV calculated i n weight percent. - 9 8 -T. Characterization of the Products from R 1. Bibenzyl (XLI) This compound was readily identified by comparison with the bibenzyl previously isolated. 2. Compound XL? Compound XL? was twice recrystallized from ethyl ether-petroleum ether (b.p. 30-60°) to yield colorless needles, m.p. 21+2-21*2.5°. Infrared spectrum (KBr): 31+00 (broad-w), 1585 (w), 1520 (s), 11*1*1+ (w), 1366 (s), 1296 (w), 1171 (w), 1061+ (w), 1025 (w), 81+0 (w), 71+3 (m), 682 (m), 61*5 (w). 3. 2-(N^benzylcarbaxamido)phthalimidine (XL?I) Compound XL?I was recrystallized from benzene-petroleum ether (b.p. 3 0 - 6 0 ° ) , decolorized with charcoal, and recrystallized from ethyl ether-petroleum ether (b.p. 30-60°) to yield colorless needles, m.p. 1 2 7 - 1 2 8 ° . Infrared spectrum (KBr): 3290 (m), 3030 (w), 291+0-2920 (w), 1710 (s), 1675 (m), 1613 M, 1590 (w), 1533 (s), H*9l* (w), 11*70 (w), 11+1*2 (m), 11*35 (sh), 1369 (s), 131+3 (w), 1321* (m), 1302 (m), 1258 (m), 1237 (w), 1216 (w), 1193 (w), 1162 (sh), 1155 (m), 1101+ (w), 1078 (w), 751* (m), 737 ( B ) , 693 (s), 682 (m), 650 (m). 1*. Synthesis of 2-(N-benzylcarboxamido)phthalimidine a.) Preparation and Characterisation of Benzylisocyanate (101*) To 15*0 g of freshly d i s t i l l e d benzyl chloride (B & A reagent) was added 21.6 g of silver cyanate (Eastman Kodak) contained in a 100 ml flask equipped with a reflux condenser. The flask was warmed -99-with a bunsen flame to i n i t i a t e the reaction after which the reaction proceeded on i t s own and appeared complete i n about ten minutes. The apparatus was arranged directly for downward d i s t i l l a t i o n and 6*1+ g (1+0$ of the theoretical) of a lig h t yellow liq u i d was d i s t i l l e d over at the water aspirator. A few drops of concentrated ammonia was added to a few drops of the yellow l i q u i d product above and set aside. Long white needles were subsequently f i l t e r e d off, m. p. 150-152°. Literature melting point for monobenzyl urea, H+7-Hi9u (52). b. Condensation of Benzylisocyanate with Phthalimidine (55, 67, 96) To 70 mg of phthalimidine (0.52 m:>mole) dissolved i n dry toluene, was added 70 mg (0.52 m mole) of the freshly d i s t i l l e d benzylisocyanate. The mixture was refluxed gently over 12 hours and the toluene subsequently removed i n vacuo, to afford a white sol i d . The latter was chromatographed on alumina using! benzene as developer to give 95 mg (68$ of theoretical) of a white solid which, after recrystallization ifrom carbon tetrachloride-petroleum ether (b.p. 30-60°), gave white needles, m.p. 126-127°. Mixed melting point with compound XLVI, 126*5-127.5°. The infrared spectra were identical. Anal. Found: C, 72.28; H, 5.13; N, 10.17. Calc. for Ci6H ]jN 20 2..C, 72.l6j H, 5.30; N, 10.52. 5. Compound XLVII Compound XLVH was recrystallized from hot benzene to yield colorless needles, m.p. 288-288.5°* Infrared spectrum (KBr): 3020 (m), 1593 (m), 1581 (m), 1500 (m), 11+85 (m), 11+80 (sh), 1U59 (s), 11+1+5 (w), li+1+1 (w), 11+07 (w), 1395 (w), 1320 (w), -100-1200 (w), 1173 (w), 1155 (w), 1125 (m), 1068 (m), 1025 (w), 1000 (w), 980 (w), 965 (m), 915 (m), 851 (w), 837 (w), 775 (m), 765 ( s ) , 73U ( s ) , 712 ( s ) , 705 ( s ) , 696 ( s ) , 689 ( s ) , 6&9 (m). Anal. Found: C, 81+.90; H, 6 . 6 6 ; N, 8 .17. Calc* for C2^ H23N2: C, 81+.92; H, 6.87; N, 8 .26* 6 . 2-Benzylphthalimidine (XLVIII) Compound XLVIII was rechromatographed on alumina using benzene as developer, then r e c r y s t a l l i z e d from b o i l i n g petroleum ether (b.p. 30 -60°) , y i e l d i n g white f l u f f y needles, m.p. 90-91°. Literature melting point of 2-benzylphthalimidine 91° ( 5 9 ) . The infrared spectrum of compound XLVIII, and that of an authentic sample of 2-benzylphthalimidine (57)., prepared by the method of Murahashi and co-workers ( 5 9 ) , were i d e n t i c a l * Infrared spectrum(KB^: 3020 (w), 2900 (w), 1667 ( s ) , 11+92 (w), 11+66 (m), 11+50 (m), U+36 (w), l l + l l (m), 135U (m), 1321+ (w), 1315 ( w ) , 1298 (w), 1281+ (w), 1261+ (m), 1219 (w), 1203 (m), 1180 (w), lll+O (w), 1086 (w), 1070 (w), 968 (w), 926 (w), 900 (w), 855 (w), 809 (w), 792: (w), 761+ (w), 71+7 (sh-s), 735 ( s ) , 697 (m), 680 (w). n.m.r. signals (given i n i> u n i t s ; spectrum obtained i n deuterio-chloroform), 7 .5 + 0*5 (area • 9 H), 1+.7? (area = 2 H), It.2.0 (area * 2 H). Anal. Found: C, 80*61 j H, 5«97; N, 6 . 2 5 * Calc. f o r C^H^NO: C, 80 .67; H, 5 . 8 7 ; N, 6 . 2 7 . 7. Compound XLIX Compound XLIX was rechromatographed on alumina using benzene: chloroform ( 9 s l ) as developer y i e l d i n g 0.119 g' of white s o l i d . -101-The latter was recrystallized from hot benzene, m.p. 295-297° . Infrared spectrum (KBr): 31*00 (broad-s), 301+0 (w), 2900 (w), 1715 (s), 1680 (s), 1655 (sh), 1615 (m), 11+66 (m), 11+39 (m), 1370 (m), 130l+.(m), 1297 (m), 1210 (m), 1195 (sh), 1159 (m), 1150 (w), 1100 (m), 1070 (w), 10U+ (w), 995 (w), 950-957 (broad-w), 81+6 (w), 795 (w), 790 (sh), 762 (w), 71+5 (m), 758 (s), 708 (m), 679 (m). 8. Phthalimidine (L) Compound L was dissolved in a benzene-ethanol mixture, treated with, charcoal, f i l t e r e d and the f i l t r a t e evaporated to dryness under reduced pressure and recrystallized from benzene-petroleum ether (b. p. 30-60°) yielding colorless needles, m. p. 151+-15U.50. Literature melting point for phthalimidine ( 1 2 0 ) , 11+9° (needles). Comparison of compound L (infrared and mixed melting point) to an authentic sample of phthalimidine ( 118) , prepared by the method of Graebe (121) showed them to be identical. Infrared spectrum (KBr): 3190 (m), 3060 (w), 2900 (w), 1670 (s), 1616 (w), 1585 (w), 11+69 (m), 11+1+8 (m), 1350 (m), 1316 (w), 1300 (w), 1210 (w), 1181+ (w), 1136 (w), 1051 (w), 1011 (w), 939 (w), 81+1 (w), 796 (w), 771 (w), 726 (s), 710 (m), 680 (w). 9 . Compound LI Compound LI was recrystallized from hot benzene, m.p. 255-256 d. Purified LI was only slightly soluble i n benzene, carbon tetrachloride, chloroform, dioxane and ethanol but dissolved readily i n dimethylsulfoxide, trifluoroacetic acid and trifluoroacetic anhydride. Infrared spectrum (KBr): 3380 (s), 3220 (m), 3030 (w), 2900 (w), 1715 (s), 1661+ (s), 1597 (sh-s), 1580 (s), 1555 (sh-m), 11+70 (m), li+55 (m), 1391 (m), -102-1363 (s), 1320 (m), 1300 (m), 1219 (m), 1183 (w), l i f t U ) , l l i ; 5 (m), 1082 (w), 922 (w), 820 (w), 800 (w), 761 (m), 730 (m), 677 (w), 668 (w), 6$1 (w), 6U3 (w). n.m.r. signals (given i n 3 units): l ) spectrum obtained in trifluoroacetic anhydride, ii.96 (area = 2 H), 7.$5, 7.60, 7*79 (area = k H), 7.90, 8.01 (area = 2 H); 2) spectrum obtained i n dimethyl-sulfoxide, 1+.80 (area = 2 H), 1.12 + 0.30 (area «= 6 H). When compound LI was heated i n concentrated sulfuric acid, carbon dioxide was evolved (precipitate with Ba(0H) 2); when heated i n concentrated sodium hydroxide, a basic (to litmus) gas was evolved. Anal. Found: C, 61.65; -H, it.82; N, 15.78; 0, I8.I3.. Mol. wt. (Rast) 58?. Calc. for C 9H 8N 20 2: C, 61.35; H, i+.58; N, 15.91J 0, 18.16. Mol. wt. 176. - 1 -103-Bibliography 1* F* Codignola and M. Piacenza. 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