5% \IWIHHHUIITHHHWWIHIIHIIIIIIIIHIWHHIIHIHII IIIIIILIIIQIIIIWill III I mm LIBRARY THESIS This is to certify that the thesis entitled SYNTHESIS, PHOTOLYSIS AND THERMOLYSIS 0F SUBSTITUTED I, I'DIOXO-h-THIAZOLIDINONES: A CONVENIENT SYNTHESIS OF B-LACTAMS‘ presented by MICHAEL JOSEPH FAZIO has been accepted towards fulfillment of the requirements for M.S. Chemistry degree in @% Major professor Date W 0-7639 OVERDUE FINES ARE 25¢ PER DAY . PER 112M Return to book d this checkout from 1 rep to remove your record. SYNTHESIS, PHOTOLYSIS AND THERMOLYSIS OF SUBSTITUTED l,l-DIOXO-4-THIAZOLIDINONES: A CONVENIENT SYNTHESIS OF B-LACTAMS BY Michael Joseph Fazio A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1979 ABSTRACT SYNTHESIS, PHOTOLYSIS AND THERMOLYSIS OF SUBSTITUTED l,1-DIOXO-4-THIAZOLIDINONES: A CONVENIENT SYNTHESIS OF B-LACTAMS BY MICHAEL JOSEPH FAZIO The B-lactam ring is a key feature in penicillin and cephalosporin antibiotics. Despite many years of synthetic work, there are relatively few useful syntheses of the B—lactam ring system with the desired gig geometry often needed for biological activity. The synthetic approach explored in this thesis was the ring contraction of substituted, 1,1-dioxo-4— thiazolidinones by the extrusion of sulfur dioxide. The extrusion can be carried out thermally to yield the thermodynamically favored product, the trans s—lactam, from the gi§_or trans sulfone. Photolysis, however, is at least partially stereospecific. The gig sulfone yields the gi§_B-lactam as the major product, while the trans B-lactam is formed from the trans sulfone. The reaction is fairly general; and phenyl, methoxyphenyl, chlorOphenyl, thienyl and furyl substituted 1,1-dioxo-3,5-dimethyl-4- thiazolidinones yield B-lactams. Thienyl and furyl l,l-dioxo—4-thiazolidinones gave B'lactams in the highest yields and with functionality amiable to further elaboration. Photolysis of the gig 3,5-dimethyl-l,l-dioxo-Z-furyl-4-thiazolidinone in t-butyl alcohol/acetonitrile gave the gig l,3-dimethyl-4-furyl-2-azetidinone in 54% yield. C) (3 .——->. I CH. 3 / \ J / I H 02 H 0 CH3 0 The reaction will also tolerate some substituent changes in the five position of the 4-thiazolidinone. S-Acetamido-l,l-dioxo-3-methyl-2—phenyl-4—thiazolidinone was synthesized and photolyzed to yield a S-lactam with amido functionality in the three position analogous to penicillin and cephalosporin. () V H ---€’r QJQCPHI .8 ‘x R 01 ’ - CH (N H TABLE OF CONTENTS LIST OF TABLES . . . . . . . . . . . . . . . . . . LIST OF FIGURES. . . . . . . . . . . . . . . . . . INTRODUCTION AND BACKGROUND. . . . . . . . . . . . RESULTS AND DISCUSSION Synthesis of Substituted l,l-Dioxo- 4-Thiazolidinones . . . . . . . . . . . . . . Photolysis of Substituted l,l-Dioxo- 4-Thiazolidinones . . . . . . . . . . . . . . Thermolysis of Substituted l,l-Dioxo- 4-Thiazolidinone. . . . . . . . . . . . . . . Mechanistic DiscusSion of 2-Aryl-3,5-Dimethy1- l,l—Dioxo-4-Thiazolidinones Photolysis and Thermolysis . . . . . . . . . . . . . . . . . Synthesis and Photolysis of l,l-Dioxo- 2-Phenyl-3-Methyl-4-Thiazolidinones with Different Substituents in the 5-Position. . . EXPERIMENTAL . . . . . . . . . . . . . . . . . . . LIST OF REFERENCES 0 O O O O O O O O O O O O O O 0 ii iii 11 19 24 26 34 43 66 LIST OF TABLES 13C Chemical Shifts for Substituted 4-Thiazolidinones and l,l—Dioxo-4- Thiazolidinones , , , , , , , , , , Thermolysis of Substituted l,l-Dioxo-4- Thiazolidinones . . . . . . . . . . . . . . . . 25 LIST OF FIGURES Substituted l,l-Dioxo-4-Thiazolidinones Synthesized and Photolyzed . . . . . . . . . PMR Spectrum of cis-1,3-Dimethyl-4- Thienyl-Z-Azetidinone. . . . . . . . . . . . PMR Spectrum of trans-1,3-Dimethyl-4— Thienyl-Z-Azetidinone. . . . . . . . . . . . Mechanistic Scheme for the Thermolysis of Substituted l,l-Dioxo-4-Thiazolidinones . Mechanistic Scheme for the Photolysis of Substituted l,l-Dioxo-4-Thiazolidinones. . . Synthetic Schemes for 5-Acetamido-l,l- Dioxo-3-Methyl-2-Phenyl-4-Thiazolidinone . . PMR Spectrum of cis and trans-S-Acetamido- 1,l-Dioxo-B—Methyl-2-Phenyl-4-Thiazolidinone 12 21 22 28 33 37 41 INTRODUCTION AND BACKGROUND There has been great interest in B-lactams Since the discovery thirty-five years ago that the B-lactam ring is a key feature of the penicillin (1) molecule. d H s R‘CNH\5 3 / L} 0 £0an 1 Numerous publications on the chemistry of B-lactams and their physiological properties have been written. However, despite many years of synthetic work, there are relatively few useful syntheses of the B-lactam ring system with the desired cis geometry often needed for biological activity. The synthesis of the chemically sensitive and strained B—lactam ring system has been approached in numerous ways. In principle the 2-azetidinone ring can be constructed by cyclization at each of the four bonds. Three of the four possibilities have been demonstrated; cyclization by formation of the C2-C3 bond has not. C) 1 1 Rr—N/ .4 Cyclization through the formation of the C2-N bond can be done with 3-aminOprOpionic acids. The direct cyclization of 3—aminopropionic acids by thermal dehydra- tion, however, is not readily achieved. Cyclizing agents must be utilized to facilitate the formation of the B-lactam ring, i.e. acetic anhydride,2 acetyl chloride,3 phosphorous trichloride,“ thionyl chloride5 and carbo- diimides.6 The approach is versatile for alkyl and aryl substituents with yields of 50-90%. The principle disadvantages are the limitation on reactive functional groups (e.g. hydroxyl and carbonyl groups) which may be present, and the lack of stereochemical control. The N-Cu bond can be formed by the intramolecular displacement on a halide by the amide nitrogen.7 3-Ha10pr0pionamide can by cyclized if the amide is first converted to the conjugate base. Strong bases employed to generate the conjugate base include lithium carbonate, sodium amide, sodium hydride and hydroxide, and amines. Br Br? Base l, . I o v R a / 0 R’ 0 Bond formation between the 3 and 4 carbons can be accomplished if an appropriate leaving group and carban- ionic center are present. The haloacetanilidomalonate (2), for example, was cyclized to a B-lactam in high yield at room temperature in the presence of a base.9 The functionality necessary to carry out this reaction, however, limits its generality. C6281 _ c N C\CQ£( B355 git CH- 1/ 0// 4 X . 0 Several useful syntheses of 2-azetidinones have been developed which involve the formation of two bonds in a single step. The reactions of a ketene with an imine or an acid chloride with an imine in the presence of a base (which may generate the ketene in situ) are approaches which have been widely studied.10 Recently, Doyle}1 re- porting on the synthesis of some cephem derivatives, prepared B-lactam (3). The imine (4) was treated with azidoacetyl chloride followed by triethylamine to yield €93“!th the gig B-lactam in 83% yield. In general, however, the stereochemistry and yield depend on substituents and on how the reaction is carried out, ie., the order in which reagents are mixed and the origin of the ketene. Bose12 prepared the phenam ring (5) system from a thiazoli— dine (6) and azidoacetyl chloride; the stereochemistry was trans and the yield only 5-8%. "2 3 Na‘fH. s H 5 /C\ + (“If ! U 0/ cs 0/, MI Cam. 6 5 col C”: B—Lactams can also be synthesized by the cycloaddition of an isocyanate with an olefin.13 The cycloaddition is regiospecific and stereospecific. Chlorosulfonyl isocy- anate is the most active and preferred isocyanate, but others have been used. The synthesis is general and a variety of substituents can be tolerated. The olefin can be a vinyl ether,1“ vinyl ester}5 enamine16 or allene.r7 R¢N=c=o \ .r \=\ \r—N R Numerous miscellaneous syntheses of B-lactams have been reported but few are of general utility for pre- paring substituted 2-azetidinones. B-Lactams have been synthesized by ring expansions of substituted aziridines,18 1 20 cyclopropenones, 9and cyclopropanones; as well as by 21 ring contraction of pyrazolidones. A number of B-lactams have also been synthesized using an extension , of the Passerini reaction?“2 Several photochemical syntheses of B-lactam systems have been reported.23 Irradiation of a-diazo acid amides (7), for example, was developed for the synthesis of penicillin analoguesf” In general, the selectivity of these photochemical syntheses to yield the desired gig isomer is poor. 8v “\C/0 HGHzC/z r—I’S J 346m AF." Pa \ cozcma Johnson and Sousainshowever, have recently found a largely stereospecific photochemical synthesis. Irradia- tion of 3,S-dimethyl-l,l—dioxo-2-phenyl—4-thiazolidinone (8) yielded the corresponding B-lactam by the extrusion of sulfur dioxide. The reaction proceeds with high retention of configuration; the gig thiazolidinone yields the gig B—lactam as the major isomer. Although the thermal and photochemical expulsion of sulfur dioxide from sulfones is known,25there is little precedent for the stereospecificity of this ring closure. The synthesis of several 4-thiazolidinones (and their subsequent oxidation) was required for the further study of this s-lactam forming reaction. So a brief review of 4-thiazolidinone synthesis is appropriate. 4-Thiazolidinones (9) are derivatives of thiazolidine with a carbonyl group in the 4 position. Numerous references to the preparation of 4-thiazolidinones, with various substitutents in the 2,3 and 5 positions are found in the literature. The majOrity of the work pertains to the preparation of 4-thiazolidinones sub- stituted.with a heteroatom in the 2 position, i.e. 2,4- thiazolidindione (10), 2-thioxo—4-thiazolidinone (11), (D Ckb Pf, /:?:‘4V” f:2:—-hr’ S 0 N R 10 11 12 and 2-imino-4-thiazolidinones (12). 4-Thiazolidinones substituted with alkyl or aryl groups in the 2 position are not as common. The synthesis of a 2-alkyl or aryl 4-thiazolidinone is readily carried out by condensation of an a-mercapto alkanoic acid and an imine.27 The reaction proceeds by addition of the mercapto alkanoic acid to the carbon of the imino group, with cyclization occurring in a subsequent § OH N’ o a" / O / D NH N SH ./\_ ‘5‘,kr 5 step. The intermediate addition product (13) has been 27b in the reaction of thioglycolic isolated by Surrey acid and benzylidiene-Z—carboxyaniline. Removal of the water formed during the reaction facilitates the conden- sation, and yields of 50-70% have been reported. CQJ‘ ‘(::l\ ’H 4’2;::7 f" S-cuacozn 13 Variations in the preparation of 4-thiazolidinones involve the use of a—mercapto alkanoic esters instead of acid.28 The reaction proceeds readily in good yields when benzylidene alkylamines are used. However, the situation changes when benzylidene aniline derivatives are employed, and starting material is recovered even after extended heating. 2-Aryl-4-thiazolidinones unsubstituted in the 3 position can be synthesized by heating a mixture of the apprOpriate aldehyde or ketone with a mercapto alkanoic acid and ammonia or an ammonium salt. Surrey and Cutler29 prepared a series of 2-halophenyl derivatives by this procedure using ammonium carbonate as the ammonia source and benzene as the solvent. Mercaptoacetamide has been used to prepare 4-thiazolidinones instead of the mercapto alkanoic acid or ester. The amide is condensed with an aldehyde or ketone in a hydrocarbon solvent and acid catalyst. Pennington, et al,30 prepared the antibiotic, 2-(5-carboxypentyl)-4-thiazolidinone (14) with the methyl ester pimelaldehydic acid and thioglycolamide. 10 The degree of stereospecificity of the 802 ex- trusion reaction and the relative ease of synthesis of l,l-dioxo-4—thiazolidinone with a wide variety of sub- stituents, makesthis a noteworthy and potentially very useful approach to synthesizing cis B-lactams. RESULTS AND DISCUSSION Synthesis of Substituted l,l-Dioxo-4-Thiazolidinones. The synthesis of a number of 4-thiazolidinones and their oxidation to sulfone derivatives was required for the study of the photochemical s-lactam synthesis. The 4-chlorophenyl (15) and 4-methoxyphenyl (16) substituted 0 O F,“ o N’R §r___N/K R" S’L' —, R" :5; n’ —_’ RJ—‘L O 0 H R, 1,l-dioxo-4-thiazolidinones were synthesized to evaluate the effect of radical stability on B-lactam formation and stereochemistry. Thienyl (17) and furyl (l8) derivatives were prepared because of the usefulness of these groups as synthons, thus offering an Opportunity for further elaboration after the formation of the B-lactam ring. Penicillin molecules contain amido functionality in the 3 position; the 5-acetamido-l,l-dioxo-4-thiazolidinone (19) was therefore synthesized and photolyzed.i The scope of the reaction was further tested with the 5-acetyl (20) and 5-dibromo (21) 1,1-dioxo-4-thiazolidinones. 11 12 Figure l Substituted l,l-Dioxo-4-Thiazolidinones Synthesized and Photolyzed O C ”3 /S\I\Qu agi/flJ‘QO O O o 0 CH‘, 15 16 O :2“ ’0'“ 2"” /\ 5 3 / O 0 <3 >3 17 18 o\ H o O I‘N/CJ O \ N’CHJ H "W" “O “to \ /\ o O o 19 20 ° "/01, ”'72 *c S B' / \ o O 13 The general procedure used in this work for the synthesis of the 2-aryl-3-methyl-4-thiazolidinones con- sists of heating a mixture of the apprOpriate imine with thioglycolic or thiolactic acid. Benzene or toluene was used as a solvent and water was removed as it formed. After the theoretical amount of water was collected, the ION NICHJ o N/CH3 + " -> + H O R 5H H/KF‘II' R s/kfir a mixture was cooled, poured into water and worked up. The product was generally isolated and purified by crystallization. In general, no attempt was made to recover all of the product formed or to Optimize yields. The stereochemical assignments of the 2-aryl- 3,5-dimethyl-4-thiazolidinones were made based on PMR spectral data and X-ray crystallography. PMR spectra of the isomers of 2—aryl-3,5-dimethyl-4-thiazolidinone reveals different signals for the benzylic hydrogens. The benzylic hydrogen signal is a Singlet from isomer A and a doublet (J=2Hz) for isomer B. The coupling of the 14 benzylic hydrogen signal disappears when the 4-thiazol- idinone is stererospecifically oxidized to the sulfoxide or sulfone. X-ray analysis of the sulfoxide and sulfone prepared by oxidation of isomer A of 3,5-dimethyl-2-phenyl- 4-thiazolidinone led to the assignment of the gig_con- formation to isomer A. Stereochemical assignments for the 2-aryl-3,5-dimethyl-4-thiazolidinones prepared in this work were made by analogy to the 3,5—dimethyl- 2-pheny1-4-thiazolidinone. 2-(4-Chloropheny1)-3,5-dimethyl-4-thiazolidinone and 3,5-dimethyl-2-(4-methoxyphenyl)-4-thiazolidinone were prepared in 48 and 50% yields, respectively. They were synthesized from the crude methyl imine of the corresponding aldehydes, and thiolactic acid. One con- figurational isomer was isolated and was assigned the gig configuration based on the absence of coupling of the benzylic hydrogen signals in the PMR spectrum (see above). 15 3,Sanimethyl—2n(2—fury1)r4athiazolidinone was pre« pared in 72% yield, from thiolactic acid and furfurylia diene methylamine. The sensitivity of the furfural ring to acid necessitates that the addition of thiolactic acid to the furfural imine be carried out at <10°C. Carrying out the addition at room temperature or extended heating of the mixture resulted in the formation of a viscous black tar. The epimeric mixture of 3,5-dimethyl-2- (2-furyl)-4-thiazolidinones is 80% cis and 20% trans. The condensation of thiolactic acid and furfuryli- diene methylamine can also be carried out using a dehy- drating agent such as dicyclohexylcarbodiimide (DCC). Thiolactic acid was added to a cold solution of imine in dichloromethane, followed by the addition of a solution of DCC. The mixture was allowed to warm to room temper- ature and stirred for three hours to yield 56% of a 1:1 mixture of gig and EEEEE 3,5-dimethyl-2-(2-furyl)- 4-thiazolidinone. 2-Thienylidiene methylamine reacted with thiolactic acid to form the gig 3,S-dimethyl—Z—(2-thienyl)—4- thiazolidinone in 60% yield. The crystalline product, however, is not stable. After one month, the crystalline product had turned into a yellow oil. 16 The oxidatiOn of 4-thiazolidinones to the 1,1- dioxides can be carried out using a peracid32 or potassium permanganate§3The oxidations were carried out using potassium permanganate in acetic acid, at <10°C. Hrj‘m NHCH xmo, ”’01 Hone : § g5; H H New An aqueous solution of permanganate was added dropwise to a stirred solution of 4-thiazolidinone in acetic acid. After the addition the mixture was decolorized with bisulfite and extracted with dichloromethane. The products were isolated and purified by crystallization. In general only one crop of crystals was isolated, and no attempt was made to maximize yields. Yields for the oxidation of 2-aryl-3,5-dimethyl-4-thiazolidinone were 12, 26, 42 and 32% for the 2-fury1, 2-thienyl, p-chloro- phenyl and p-methoxyphenyl substituted 4-thiazolidinones, respectively. 17 The oxidation is stereospecific and the configur- ation of the 4-thiazolidinone is retained in the l,l—dioxo-4-thiazolidinone. Epimerization of the l,l—dioxo-4-thiazolidinone can be carried out in metHanol with a base to generate a mixture of gig and giggg isomers. The benzylic hydrogens in the PMR spectrum of the gig and EEEEE l,l—dioxo-4—thiazolidinones are singlets; unlike the observation made for the 4- thiazolidinones where the methine hydrogen in one isomer appeared as a doublet. Oxidation of 3,5-dimethyl-2-(2-thienyl)-4- thiazolidinone could conceivably proceed at either sulfur. One product, however, was isolated: 3,5—dimethyl- l,l-dioxo-Z-thienyl-4-thiazolidinone. The assignment of this structure was based on C13 NMR spectral data. Comparison of the chemical shift differences from the same carbon of the corresponding sulfide and sulfone were made for 2-(2-thienyl).and 2-(4-chlor0phenyl)-4- thiazolidinones. The shifts were comparable in Sign and magnitude (Table 1). These chemical shift differences are also in good agreement with those reported from thiolane and thiolane l,l-dioxide?“ the a-carbon shift difference is +402 Hz and that of the B-carbon is -l68 Hz. Carbons l and 4 in 2-(2-thienyl)-4-thiazolidinone shift +208 Hz and +375 Hz, while carbons 6 and 3 (which are analogous to the B-carbon of thiolane) shift -297 Hz 18 mmHI mHNI mom Nval HHI bmm om Emu no DMD“ any mm o~m~ Nemm mm mmmm OSmm AN ommm Hmmm comm mamm 5mm- asmm Hpmm mad Hos mom- mma mam soda «Sm mew mafia hmm Hmmm msvm AMA- mamm msvm Nam mom N omm mam mama emma mum mama mead mqomasm mcfimasm. q maomHsm USAOHSm NBmmm 2H mBmHmm A¢UH2mmU ”:0 . N . mmzozHquoNnpmaou Ame m.m.h conncu 19 and -l3l Hz. Assignments for the carbons of the 2-thienyl- 4-thiazolidinone were based on off-resonance decoupling experiments. Photolysis of‘Substituted'l,l-Dioxo—4-Thiazolidinones. Photolysis of 2-aryl-3,5-dimethyl-1,1-dioxo-4-thia- zolidinones was done in acetonitrile/t-butanol at 15 to 20°C. The solutions were irradiated through a Vycor filter (cut off 230 nm) with a Hanovia 450 watt medium pressure lamp. Solutions were purged with argon prior to and during the photolysis, to remove oxygen and to facilitate the removal of sulfur dioxide. The photolysate was recovered by removingthe solvent under reduced pres- sure. The crude product was either filtered through C) z’CTE (D 2““ 1w... " IR ~$ 1Hr 4_— /\ cu_,c~ /¢ 1;, on R Hr OO florisil or taken up in dichloromethane and washed with water. Analysis was done by proton magnetic resonance, and yields and conversions were determined by an internal standard technique. 20 The products were identified by PMR spectroscopy and .by characterization of the isolated products. PMR spectra of B-lactams with the same substitutions pre— pared in this work were not available in the literature. The stereochemical assignments were made by analogy to l,3-dimethyl-4-phenyl-2-azetidinone, which had previously been reported. Magnetic non-equivalence of the benzylic protons is induced by the methyl group in the 3 position. The proton gig to the methyl is shifted upfield (SOH£BI¢IH>£DOEHQIM.Hnmwo mo Ednuoomm mzm m musmflm mZB 22 mcocwcauOlem Iamcmflnelvlaanumfiflaum.Hlmcouu mo Esuuoomm mam m onsmflm 23 B-lactam as the major product. The sulfone recovered after photolysis of the 1:1 mixture was 80% gig and 20% EEEEE! suggesting that the giggg_isomer reacts faster than the gig and/or that the giggg epimer isomerizes to the gig epimer during the photolysis. Johnson and Sousa36 photolyzed gig_and EEEEE 3,5-dimethyl-l,1-dioxo-2- phenyl-4-thiazolidinone individually to yield gig_and giggg,B-lactam as the major product respectively. Photo- isomerization of the EEEEE sulfone to the gig sulfone was observed but the reverse reaction, i.e. gig to trans, was not. Photolysis of the gig 3,5-dimethy1-l,l-dioxo-2- (2—thieny)-4-thiazolidinone afforded the 2-azetidinone in 40% yield. The major isomer (80%) was the desired gig epimer. Irradiation of a 1:1 mixture of gig and Egggg sulfones yielded a mixture which was 65% gig and 35% trans B-lactam. The recovered sulfone was 75% cis. Photolysis of 100 mg of a mixture of 90% gig_and 10% giggg.3,5-dimethyl-l,l-dioxo-2-(2-fury1)-4-thiazolidinone for 20 minutes produced gig 1,3-dimethyl-4-(2-furyl)-2— azetidinone in 31% yield, and 9% of the giggg_isomer. Irradiation of 200 mg of sulfone for 30 minutes, however, produced gig and EEEEE 2-azetidinone in 54% and 14% yields, respectively. The average rate of disappearance 24 for sulfone is one mmole/hour in both experiments, but the average rate of generation of B—lactam is disparate. In the first experiment B-lactam was generated at 0.4 mmole/ hour, while in the second photolysis B-lactam was pro- duced at 0.7 mmole/hour. This data along with the fact that conversion of sulfone was greater in the first case, i.e. 77% versus 67%, suggests photolysis of B-lactam is a competing reaction. Johnson36 has shown that irradiation of 1,3-dimethyl—4-phenyl-2-azetidinone results in decomposition. A small amount of isomerization was observed when the gig B-lactam photolyzed, no isomeri- zation of the giggg B-lactam was found. The photolysis of l,4-dipheny1-2-azetidinone is reported to yield a mixture of imine, ketene, olefin and isocyanate. Thermolygis of Substituted l,l-Dioxo-4—Thiazolidinone. The desulfonylation of l,l-dioxo-4-thiazolidinones can be done thermally as well as photochemically. Thermolysis of several gig l,l-dioxo-4-thiazolidinones was carried out at 200°C for five minutes (Table 2). In all cases, giggg_B-lactam was the only product observed, except for 1,l-dioxo-3-methyl-2-phenyl—4-thiazolidinone, which did not yield B-lactam. Yields were generally high, 70-90%. The conversion of sulfone was complete for the 2-furyl and 2-thienyl-3,5-dimethyl-l,l-dioxo—4-thiazol- idinones and 1,l-dioxo-B-methyl-2-phenyl-4-thiazolidinones. 25 TABLE 2 THERMOLYSISa OF SUBSTITUTED 1,l-DIOXO-4-THIAZOLIDINONES )( 1 C) O) I": ~< d: 130217 5 y % Conversion % Yield of B-Lactamb CH3 2-thienyl 100 76 CH3 2-furyl 100 92 CH3 p-chlorophenyl 65 85 CH3 p-methoxyphenyl 61 89 CH3 phenyl 69 73 H phenyl 100 0 (a) 5 minutes at 200°C; (b) yield based on recovered starting material 26 For the pheny1,4-methoxyphenyl and 4-chlor0phenyl thiazolidinone dioxides conversion was 60-70%, with recovered sulfone a mixture of cis and trans epimers. Mechanistic Discussion of 2-Aryl-3,5-Dimethyl-l,l-Dioxo- 4-Thiazolidinones Photolysis and Thermolysis. Mechanistically the results of the photolysis and thermolysis of the l,l-dioxo-4-thiazolidinones are very interesting. The evidence for the thermal desulfonylation suggests that decomposition occurs by homolytic cleavage of the RC-SOZCR bond into RC- and RCSOz-. The radical fragments are tied together in the l,l-dioxo-4- thiazolidinones and can recombine resulting in the epimerization of the starting material. The sulfonyl radical can also lose sulfur dioxide to form a new diradical which can subsequently recombine to produce a B-lactam. Which carbon sulfur bond cleaves first is uncertain. The relative stability of the two possible radical inter- mediates, (22) and(23) cannot readily be estimated. A benzylic radical is m20 kcal more stable than an ethyl radical, based on dissociation energies. The effect of the “iii—«111‘1 and n-‘c'own- groups on radical stabilities is uncertain. Both groups are known to stabilize radical centers on adjacent carbons by electron pair n' donation. 27 In the thermolysis, which diradical forms is irrelevant. Either radical (22) or (23) can be used to rationalize the products (Figure 4). C) \ N/CHa °\\ N/cua (3% ° F%1 (Jg~;¢ . I; H '98 H u 50; H r 22 23 The mechanism for the photochemical expulsion of SO from 2-aryl-3,S-dimethyl-l,1-dioxo-4-thiazolidinones 2 is more complex. Mixtures of gig_and Egggg_ 8-1actam are formed, and the predominance of one isomer over the other is dependent on the aryl substituent and the stereochemistry of the sulfone. Irradiation of the gig 4-chlorophenyl and 4-methoxypheny1-4-thiazolidinone dioxides yields the corresponding giggg’s-lactams as the major products. However, the gig B-lactams are the major products from the photolysis of the ging-furyl and ging-thienyl- 4-thiazolidinone dioxides. Photolysis of the gig and Eggggf 3,5-dimethyl-2-phenyl-l,1-dioxo-4-thiazolidinone separately yielded the gig and Egggg B-lactam as the major product, respectively.36 These results suggest that the photochem- ical expulsion of sulfur dioxide from 4-thiazolidinone 28 I it ~ IO\Z my W $u m I I... a \\\\ n=u\ O Jl/f e 9qule . ..:u\zINo.|.=u I .8": q N. z 4 I Lm'm/ . 0.» 3.5 II” Huh/Ar. «Om/NO \5 “in”. .OM, azunlv. élm1\% M. £0 th\ Z / fd\2ull.v/ 2% mmcocHOHHonfinalv 10x0flolata mo mflm>HOEHOSB How mammom Ofiumflconooz e whomwm 29 dioxides is partially stereospecific. Along with the stereospecificity, any proposed mechanism would have to rationalize isomerization of the 4-thiazolidinone dioxides and the trapping of diradical type intermediates. Isomerization of the 4-thiazolidinone dioxides could be rationalized through the formation of a diradical inter- mediate, which recombines to form an epimerized mixture. Such a mechanism would, however, make rationalization of the stereospecificity of the reaction difficult if B-lactam is formed through the same diradical intermediate. An alternative mechanism for the epimerization of the 4-thiazolidinone dioxides wOuld be by hydrogen abstraction of the hydrogen a to the carbonyl. I O 0 ,CH3 0 CH /CH N .——’- N, 3 -—)- \ N 3 '21 *— .2 J\ I‘ C": H /S\ H HI- CH 5 9" H ' S/l‘fir O O 3 O/\O The existence of a diradical intermediate is implied by products isolated in trapping experiments. When the photolysis is carried out in a solvent with an abstractable 30 hydrogen, such as isopropanol, acyclic amides (24) and sulfonic esters (25) were isolated.36 The formation of B-lactam was completely surpressed when 3,5-dimethyl- l,l-dioxo-Z-(4-methoxyphenyl)-4-thiazolidinone was photolyzed in isopropanol, and acyclic amide (24) was formed. Photolysis of the 3,5-dimethyl-l,l-dioxo-2- phenyl-4-thiazolidinone in isopropanol, however, yields a mixture of acyclic amide and B—lactam. o \\ CH ~ / x .. .. (H.301, \ang Quiz $02 c\H CH3 24 25 One possible mechanistic scheme involves a diradical intermediate analogous to that prOposed for the thermolysis. Initial C-S bond cleavage to form a diradical (22 or 23) which then expels sulfur dioxide to generate a new di- radical. The stereochemistry of the products would depend on the stability of the diradicals. 31 The methoxyphenyl and chlorophenyl-4-thiazolidinone dioxides form stabilized diradicals relative to the phenyl-4-thiazolidinone dioxide. Based on the dissoc— iation constants of hexaphenylethanes,38 methoxyphenyl and chlorophenyl substituted radicals should be four to five times more stable than the unsubstituted derivative. The stability of the thienyl and furyl type radicals relative to the benzyl radical is not readily available in the literature. The effect of a group containing a heteroatom B to the radical should be very much the same as the isoconjugate carbon group, based on pertabation molecular orbital theory.39 Experimentally this is observed in radical-catalyzed vinyl polymerizations which involve the formation of a radical (26) in the propagation R-CH=CHZ + 7 -——> R-éHCsz 26 steps. Studies of the polymerization of styrene and vinyl pyridine have shown that the rates of propagation are similar.“0 Assuming that the oxygen and sulfur of the furyl and thienyl groups do not effect the radical, 32 and that electron delocalization in the ring is equated to aromaticity, the furyl and thienyl radicals should be less stable than the benzyl derivative, since furan and thiophene are less aromatic than benzene. The methoxyphenyl and chlorophenyl 4-thiazolidinone dioxides should form the most stable radical intermed- iates of the 2-aryl-4-thiazolidinone dioxides photolyzed. The stability, and therefore life-time, of these radicals is such that s—lactams are produced under thermodynamic control. The most stable isomer, the trans, is the major product from photolysis of the gig sulfone or an epimerized mixture. The stability of the radical intermediate may also explain the poor selectivity, i.e. low yields of B-lactam. The longer lived intermediates react by other routes than ring closure to form azetidinones. Phenyl, furyl and thienyl-4-thiazolidinone dioxides form diradical intermediates with higher energy and, therefore, shorter life-time than the substituted phenyl derivatives. Products are formed under kinetic control and are stereospecific. The coupling of the diradical must be as fast or faster than the rate of equilibration of the diradical. The inability to completely interrupt the formation of B-lactam when photolyzing 3,5-dimethyl- l,l-dioxo-2-phenyl-4-thiazolidinone in isopropanol is testimony to the short life of the radical intermediate. 33 m o _ z r L m a n N \ 9 i 3 . m. an.» n. z . . m r 9“ I. O I £ "0 .MIU U f'fl/O CM ”:0 ..3\z 1?! n All azuleIAI. .28 #0 m. $.90 3.8 r g 1 ~ 2 w. I 0 M I III A? O M N 0 II .5. . .m z t {I}. x 2 Ir é nlNleu % éVW on... flu ”WU‘z-IIIA JPV‘L _ A 9!U\2 o ”20‘ o o o gmluY\m.m I ;m w .W a a JH'NI‘ 2U «=9\ l. N n=u\z monocflcwHoNMHnalvloxowala.H pwusuflquSm mo mamwaouosm on» How wemnom owumflcmsomfi m munmwm 34 A plausible mechanism for the photolysis of 3,5- dimethyl-l,l-dioxo-2-aryl-4-thiazolidinone is illustrated in Figure 5. The stereochemical consequences of the extrusion are as discussed above dependent upon the aryl group, i.e. radical stabilities, which influence the relative rates of the steps in this reaction scheme. Synthesis and Photolysis of l,l-Dioxo-Z-Phenyl-3-Methyl-4- Thiazolidinones with Different Substituents in the S-Position. The scope of the photochemical extrusion of sulfur dioxide from 4-thiazolidinone dioxides to yield B-lactams was investigated with additional functional groups present. 5-Acetyl, S-acetamido, and 5,5-dibromo-4-thia- zolidinone dioxides were synthesized and photolyzed. The protons at the 5 carbon of the 4-thiazolidinone dioxides are a to a carbonyl and a sulfonyl group, and therefore relatively acidic. Weak bases such as methoxide and even florisil were strong enough bases to epimerize gig 3,5-dimethyl l,l-dioxo-2-phenyl-4-thiazolidinone. The facile formation of the 4-thiazolidinone dioxide anion provides a convenient route to the 5-acetyl derivative. The sodium salt of l,l-dioxo-3-methyl—2-phenyl-4- thiazolidinone was prepared in tetrahydrofuran with sodium hydride and acylated with acetyl chloride. The 35 5-acetyl-l,l-dioxo-3-methyl-4-thiazolidinone (20) was isolated in 30% yield by column chromatography. The presence of a singlet downfield at 6= 12.7 in the PMR spectrum, suggests that the 5-acetyl-4-thiazolidinone dioxide exists mostly in the enol form (28). 0 <3 \ ‘Va’Cflg )e' V> (V’MCFG .__a_. <3 6 V'— \ / / \ /‘S\ C) () C) C) 20 28 Photolysis of the 5-acetyl-l,l-dioxo-B-methyl- 2-pheny1-4-thiazolidinone under conditions identical to those used for the 5-methyl derivative was unsuccessful. Irradiation for thirty minutes yielded only starting material. Bromination of 3-methyl-l,l-dioxo-Z-phenyl-4- thiazolidinone (29) in refluxing chloroform yielded a mixture of mono and dibrominated 4-thiazolidinone. At 75% conversion of the starting material the ratio of mono 36 to dibrominated product was 2:1. The products were isolated by column chromatography and recrystallized to yield 8% 5-bromo-1,l-dioxo-3-methyl-2-phenyl-4-thiazolidinone (30) and 15% 5,5-dibromo-l,l-dioxo-3-methyl-2-phenyl- 4-thiazolidinone (21). Irradiation of the dibromo 4-thiazolidinone dioxide in t-butyl alcohol/acetonitrile for 20 minutes yielded a mixture of monobrominated 4-thiazolidinone, l,l- dioxo-3-methyl-2-phenyl-4-thiazolidinone and starting material. No B-lactam formation was observed; photolytic cleavage of a halogen atom“1 was the predominate reaction. /\ Ph (D C) c! Eb ((15 21 30 29 ‘Two approaches were taken to synthesize the 5-acetamido- l,l-dioxo-3-methyl-2-phenyl-4-thiazolidinone (19) (Figure 6). The displacement of bromine from the 5-bromo-l,l-dioxo-3-methyl-2-phenyl-4-thiazolidinone was carried out in tetrahydrofuran with sodium acetamide. 37 .a l.\ :2 WE £J\~% anIUQ .3\ Au/fi .o E . (w 3n?» , &J\mN\.m é £u\z wnonflofiHonHssueuascmsmum namnuozlmloxowola.Hlowaamumofilm on monomoummm oaumnucmm m musmflm 38 This route failed to produce the desired 5-acetamido derivative, yielding only the unsubstituted l,l-dioxo- 3-methy1—2-phenyl-4-thiazolidinone. An alternate approach was to react an electrophilic nitrogen derivative, which could later be converted to the desired acetamido derivative, with the 4—thiazolidinone dioxide. Patnaik and Rout“2 coupled 2-arylimino-4- thiazolidinones with diazotized aniline under alkaline conditions to yield the 5-phenylazo-2-ary1imino-4- thiazolidinones (45-65%). Bhargavo and Chaurasia“3 carried out a similar reaction in 45-75% yield under acidic conditions, using glacial acetic acid as the solvent. Under acidic conditions, the l,l-dioxo-3-methy1- 2—phenyl-4-thiazolidinone failed to react with diazotized aniline. The 1,l-dioxo-3-methyl-5-phenylazo-2-pheny1- 4-thiazolidinone (31) was obtained, however, under basic conditions in 52% yield. The presence of a broad singlet downfield («5= 10.6 ppm) in the PMR spectrum indicates the product exists mostly as the tautomer, (32). Infrared and mass spectral data were consistent with the proposed structure. 39 Ph’"=" o. P». 31 32 Following the procedure of Pfister and Tishler“” the reductive acylation of the 5-phenylazo-4-thiazolidinone dioxide was carried out. The 5-phenylazo-4-thiazolidinone dioxide was reduced with zinc dust in acetic acid and acetic anhydride to yield the 5-acetamido-l,l-dioxo- 3-methyl-2-phenyl-4-thiazolidinone. A mixture of the gig and EEEEE isomers was isolated by preparative thin layer silica gel chromatography. The PMR spectrum of the gig and EEEEE 5-acetamido- l,l-dioxo-3-methyl-2-phenyl-4-thiazolidinone is illustrated in Figure 7. Absorptions at 2.07 and 2.12 ppm were assigned to the acetyl methyl protons. The N-methyl protons assignments were 2.78 and 2.88 ppm. The singlets at 5.52 and 5.65 ppm were assigned to the benzylic protons. The methine protons appear as doublets at 5.10 and 5.78 ppm. The addition of D20 to the sample results in the collapse 40 of the doublets to singlets, and the area of the aromatic protons (‘5= 7.3 ppm) decreases from 6 to 5 as a new signal appears at 4.52 ppm. The stereochemistry was assigned by analogy of the chemical shifts for the benzylic protons and N-methyl protons to those of the 3,5-dimethy-l,l-dioxo-2-aryl-4-thiazolidinones. The benzylic proton in the gig configuration is downfield relative to the EEEEE configuration, and the N-methyl protons of the gig isomer are upfield relative to the EEEEE isomer. PMR signals at 6: 2.07, 2.88, 5.10 and 5.52 were assigned to the giggg acetamido-4-thiazolidinone dioxide, and signals at 6: 2.12, 2.78, 5.65 and 5.78 were assigned to the gig isomer. The ratio of E£22§.t° gig_ in the mixture is 2:1. The mixture of 5-acetamido-l,l-dioxo-3-methyl-2- phenyl-4-thiazolidinone was irradiated for ten minutes in t-butyl alcohol/acetonitrile through a Vycor filter. The starting material was completely consumed yielding a 1:1 mixture of gig and giggg|B-lactam (33), 28%, after preparative silica gel chromatography. Infrared spectra Pb C) C (3 ‘3‘ 2"“ "3 by N’CH3 ewe-NW 5A ‘—"*' a ‘1 mac-N.” Ph 33 41 a; 2mm N I 0 gm.“ I“ IZWmT-U nzu\;‘ o O msochHHoNMHSBIVIawcmnm . I . . -muas m . oxofla H.HI0@HEmumo«Imlmswnu can mHo mMuEMHmommm mam h mnsmwm o.m 42 of the isolated product reveals two carbonyl absorptions 1 at 1760 cm-' and 1685 cm-} PMR and mass spectral data were consistent with the proposed product. EXPERIMENTAL General NMR spectra were recorded on a Varian T—60 spectro- meter. Chemical shifts are given in ppm (6) relative to tetramethylsilane. Melting points were determined in a Thomas-Hoover capillary melting point apparatus and are uncorrected. Infrared spectra were recorded on a Perkin-Elmer 237B grating spectrophotometer. Mass spectra were taken on a Hitachi Perkin-Elmer RMV-60 spectrometer. Microanalysis were performed by Instranal Laboratory, Rensselaer, New York. Preparation of 3,5-Dimethyl-2-(2-Furyl)-4-Thiazolidinone. Thiolactic acid (2.6 g. 25 mmol) was added to a solution of 2.7 g (25 mmol) furfurylidiene methylamine (prepared from furfural and methylamine in toluene and isolated by distillation, bp 65-67°C) in 50 mL of dichloromethane. The addition was made over fifteen minutes and the temperature was held at 0-5°C. A solution of 5.3 g (26 mmol) dicyclohexylcarbodiimide in dichloro- methane was added to the mixture and stirred for three hours at room temperature. The mixture was filtered, acidified with acetic acid, washed with water and dilute ammonium carbonate solution. The organic solution was 43 44 dried with M980“, and solvent removed under reduced pressure. The solid residue was recrystallized from ether-pentane to yield 2.7 g (56%) of a 1:1 mixture of gig andtgigggf3,5— dimethyl-Z—(2-furyl)-4-thiazolidinones: mp 55-69°C; 1H NMR (CDC13) 51.6 (6H, t), 2.8 (6H, d), 3.9 (2H, m), 5.3 (1H, d) 5.4 (1H, s), 6.2 (4H, m), 7.2 (2H, m); IR (CDC13) 1675 cm"1 (vs). The EEEEE isomer was isolated by silica gel (Davidson Chemical) chromatography, eluting with a 1:1 ether pentane mixture: 1H NMR (CDC13) 1.5 (3H, d, J=7Hz), 2.8 (3H, s) 4.0 (1H, m, J=7Hz), 5.4 (1H, d, J=2Hz), (2H, m), 7.3 (1H, m); mass spectrum m£g_(relative intensity) 198 (12), 197 (100), 113 (12), 111 (13), 110 (56), 109 (54), 108 (64), 81 (28). Anal. Calcd. for C9H11NOZS: C, 54.79; H, 5.63; N, 7.10. Found: C, 54.41; H, 5.58; N, 6.91. Alternatively, 3,5-dimethy1-2-(2—furyl)—4—thiazoli- dinone was prepared by the direct condensation of thiolactic acid and furfurylidiene methylamine. Thiolactic acid (8.3 g, 78 mmol) was added to a cold (below 10°C) solution of 8.5 g (78 mmol) of imine in 125 mL of benzene. The mixture was refluxed for thirty minutes. Water was removed with a Dean Stark trap (1.4 mL). The mixture was cooled, washed with dilute ammonium carbonate solution, dried and solvent removed under reduced pressure. The 45 brown oil crystallized on standing and was recrystallized from ether-pentane to yield 11.2 g (72%) of a mixture of 80% cis and 20% trans-3,5-dimethyl-2—(2-fury1)- 4-thiazolidinone. Synthesis of 2-(4-Chloropheny1)-3,5-Dimethyl- 4-Thiazolidinone. At room temperature, 5.3 g (50 mmol) of thiolactic acid was added to a solution of 8.6 g (56 mmol) of 4-chlorobenzy1idiene methylamine in 90 mL of toluene and refluxed for four hours, collecting 0.8 mL of water in a Dean Stark trap. (The chlorobenzylidiene methylamine was prepared by adding chlorobenzaldehyde to a cold solution of methylamine in toluene. After three hours at room temperature water was salted out of the reaction mixture, the organic layer separated, dried with M9804 and the solvent removed under reduced pressure. The crude product was used without further purification). The solution was cooled and poured into water. The organic layer was separated, dried, and the solvent removed under reduced pressure. The residue was recrystallized from ether-pentane to yield 5.9 g (48%) of ging-(4-chloro- phenyl)-3,5-dimethyl-4-thiazolidinone: mp 61-63°C; 1H NMR (CDC13) 51.6 (3H, d, J=7Hz), 2.6 (3H, s), 3.9 (1H, m, J=7Hz), 5.3 (1H, s), 7.2 (4H, s); IR (CHC13) 1670 cm-1 (vs); mass spectrum m/e (relative intensity) 46 243 (25), 242 (14), 241 (64), 240 (15), 197 (17), 184 (19), 156 (21), 155 (21), 154 (77), 153 (34), 152 (100), 149 (32), 130 (72), 125 (17), 111 (17), 98 (11), 89 (15). Anal. Calcd for C11H12C1NSO: c, 54.65; H, 5.01; N, 5.80. Found: C, 54.42; H, 4.98; N, 5.60. Preparation of 3,5-Dimethy1-2-(2-Thienyl)-4- Thiazolidinone. Thioactic acid (10.8 g, 102 mmol) was added to a cold solution of 12.5 g (100 mmol) of thienylidiene methyl- amine (prepared from thiophene carboxaldehyde and methylamine by the procedure used to prepare the chlorobenzylidiene methylamine) in 150 mL of benzene. The mixture was refluxed and 1.7 mL of water was col- lected. The solution was cooled, poured into water, and the organic layer separated, washed with dilute ammonium carbonate solution and dried. Benzene was removed under reduced pressure. The product crystallized from ether- pentane to yield 8.8 g (41%) of gig73,5-dimethy1-2- (2-thienyl)-4-thiazolidinone: mp 50-54°C. The mother liquor was concentrated and cooled to yield 4.09 (19%) of additional product, mp 48-53°C. Recrystallized from ether: mp 53—56°C; 1H NMR (CDC13) 61.6 (3H, d, J=7Hz), 2.7 (3H, s), 3.8 (1H, m, J=7Hz), 5.6 (1H, s), 6.7-7.3 (3H, m); IR (CDC13) 1675 cm"1 (vs); mass spectrum 47 mZgi(relative intensity) 215 (11), 214 (14), 213 (100), 212 (16), 157 (13), 125 (51). 124 (99), 97 (31). Anal. Calcd for C9H11N0S2: C, 50.67; H, 5.21; N, 6.57. Found: C, 50.42; H, 5.15; N, 6.38. Synthesis of 3,5-Dimethyl-2-(4-Methoxypheny1)-4— Thiazolidinone. Thiolactic acid (7.0 g, 66 mmol) was added to 10.1 g (67 mmol) of 4-methoxybenzylidiene methylamine (prepared from anisaldehyde and methylamine by the procedure used to prepare the chlorobenzylidiene methylamine) in 100 mL of benzene. The solution was refluxed for 1.5 hours and 1.1 mL of water was collected. The mixture was cooled, washed with dilute ammonium carbonate solution, dried, and the solvent removed under reduced pressure. Product crystallized from ether to yield 7.8 g (50%) of gigf3,5- dimethyl-Z-(4-methoxyphenyl)—4-thiazolidinone: mp 92—94°C; 1H NMR (CDC13)6 1.6 (3H, d, J=6.5 Hz), 2.6 (3H, s), 3.8—4.0 (4H, m), 5.4 (1H, s) 6.9 (4H, m); mass spectrum gig (relative intensity) 237 (56), 235 (15), 189 (11), 152 (14), 150 (29), 149 (42), 148 (100), 147 (11), 133 (11), 130 (18), 121 (20), 76 (12). Anal. Calcd for CIZHISNOZS: C, 60.73; H, 6.38; N, 5.90. Found: C, 60.58; H, 6.53; N, 5.91. 48 Preparation of 3,5-Dimethyl—1,l-Diox0h2-(4—Methoxyphenyl)- ‘4-Thiazolidinone. A solution of 4.1 g (26 mmol) of potassium perman- ganate in 95 mL of water was added dropwise over 30 minutes to a cold solution of 3.1 g (13 mmol) ofgigf 3,5-dimethyl-2-(4-methoxyphenyl)-4-thiazolidinone in 20 mL of acetic acid. The mixture was then treated with sodium bisulfite to discharge the color, and extracted with dichloromethane. The organic layer was washed with water, dried, and the solvent removed. Product crystallized from dichloromethane-hexane to yield 1.1 g (32%) of gig: 3,5-dimethy1-l,1-dioxo-2-(4-methoxyphenyl)-4-thiazolidinone: mp 123-127°C (recrystallization from ether gave material with mp 124.5-126°C); 1H NMR (CDC13) 61.6 (3H, d, J=7Hz), 2.8 (3H, s), 3.4-3.8 (4H, m), 5.4 (1H, s), 7.0 (4H, m); mass spectrum gig (relative intensity) 205 (11), 174 (11), 149 (51), 148 (100), 133 (11), 64 (21). Anal Calcd for C12H15N0.S= c, 53.51; H, 5.63; N, 5.20. Found: C, 52.85; H, 5.59; N, 5.11. 49 Preparation‘of'3,5-Dimethyl-l,l-Dioxo-Z-(Z-Thienyl)- 4-Thiazolidinone. To a cold solution of 2.0 g (9 mmol) of‘gig73,5- dimethyl-Z-(2-thienyl)-4-thiazolidinone in 30 mL acetic acid was added dropwise 3.2 g (20 mmol) of potassium permanganate in water over a period of 30 minutes. The mixture was then decolorized with sodium bisulfite and extracted with dichloromethane. The organic extract was washed with water, dried, and the solvent removed under reduced pressure. Product was crystallized from ether- pentane to yield 0.6 g (26%) of gig-3,5-dimethyl—l,l- dioxo-2-(2-thienyl)-4-thiazolidinone: mp 120-124°C (mp after recrystallization from ether-pentane, 121.5-123°C): 1H NMR (00013) 51.6 (3H, d, J=7Hz), 2.9 (3H, s), 3.7 (1H, m, J=7Hz), 5.8 (1H, s), 7.2 (3H, m); IR (CDCl3) 1700 (vs), 1335 (s), 1140 cm"1 (s); mass spectrum gig (relative intensity) 181 (27), 126 (27), 125 (56), 124 (100) 97 (62). Anal. Calcd for C9H11NO3 S: C, 44.06; H, 4.53; N, 5.71. Found: C, 44.07; H, 4.52; N, 5.67. Preparation of‘3,5-Dimethyl-1,l-Dioxo-Z-(2-Furyl)-4- Thiazolidinone. To a cold solution of 2.9 g (14 mmol) of 3,5- dimethyl-Z-(2-furyl)-4-thiazolidinone in 40 mL of acetic acid was added dropwise over 20 minutes a solution of 50 3.3 g (21 mmol) of potassium permanganate in 60 mL of water. After the addition, the color of the solution was discharged with sodium bisulfite, and the solution was extracted with dichloromethane. The organic layer was washed with water, dried, and the solvent removed under reduced pressure. Product crystallized from chloroform-hexane to yield 0.4 g (12%) 3,5-dimethy1- l,l-dioxo-Z-(2-fury1)-4-thiazolidinone: (90% gig, 10% giggg) mp, 122-128°C; 1H NMR (coc13) 51.6 (3H, d, J=7Hz), 2.9 (3H, s), 3.6 (1H, m), 5.2 (1H, s), 6.5 (2H, m), 7.4 (13, m); IR (c0013) 1700 (vs), 1330 (s), 1130 cm"1(s); mass spectrum gig (relative intensity) 165 (18), 137 (15), 110 (38), 109 (69), 108 (100), 81 (95), 79 (21), 76 (13), 69 (18), 64 (97), 56 (90), 55 (51), 54 (74), 52 (51), 51 (26), 50 (18). Anal. Calcd for CnglNOuS: C, 47.15; H, 4.85; N, 6.11. Found: C, 47.02; H, 4.32; N, 5.95. Preparation of 3-Methyl-2-Phenyl-4-Thiazolidinone. Mercaptoacetic acid (20.0 g, 218 mmol) was added to a solution of 25.9 g (217 mmol) of benzylidiene methylamine in 300 mL of benzene at room temperature. The mixture was refluxed for 40 minutes. Four mL of 51 water was collected in a Dean Stark trap. The cooled mixture was washed with dilute ammonium carbonate solution, dried, and the solvent removed under reduced pressure. The light yellow oil, 34.0 g, was not purified; 1H NMR (c0013) 52.6 (3H, s), 3.6 (2H, s), 5.2 (1H, s), 7.2 (5H, 5). Preparation of 1,l-Dioxo-3-Methy1-2-Phenyl- 4-Thiazolidinone. A solution of 15.9 g (101 mmol) of potassium permanganate in 270 mL of water was added dropwise over a period of two hours to a cold solution of 9.6 g (50 mmol) of 3-methyl-2-phenyl-4-thiazolidinone in 100 mL of acetic acid. The color of the solution was discharged with sodium bisulfite and extracted with dichloromethane. The organic layer was washed three times with water, dried, and the solvent removed under reduced pressure. The crude oil crystallized on standing and was recrys- tallized from chloroform-hexane to yield 6.5 g (58%), 1,l-dioxo-3-methyl-2-phenyl-4-thiazolidinone: mp 120-123°C. The mother liquor was concentrated and cooled to yield a second (0.9 9; mp 122-123°C) and third (0.3 g, mp 121.5-123°C) crop of crystalline product: 1H NMR (CDC13) 52.9 (3H, s), 3.8 (2H, s), 5.4 (1H, s), 7.3 (5H, m). 52 Bromination‘of'l,1-Dioxo-3-Methy1-2-Phenyl-4- Thiazolidinone. Bromine (1 mL) in chloroform was added to a solution of 2.9 g (13 mmol) of l,l-dioxo-B-methyl- 2-phenyl-4-thiazolidinone in chloroform containing 1-2 drops of acetic acid. The mixture was gently refluxed for eight hours, cooled and washed with dilute ammonium carbonate solution and water. The organic layer was dried, and the solvent removed under reduced pressure. The crude product, analyzed by 1H NMR, was a mixture of 50% monobromo sulfone, 25% dibromo sulfone and 25% starting material. The products were isolated by Silica Gel (Davison Chemical) chromatography, eluting with 0.5% methanol in dichloromethane. Early chromatographic fractions gave 0.8 g (15%) of 5,5-dibromo-l,l-dioxo- 3-methyl-2-phenyl-4-thiazolidinone: mp l60.5-161.5°C (recrystallized from chloroform-hexane); 1H NMR (CDC13) 62.9 (3H, s), 5.4 (1H, s), 7.4 (5H, 5); IR (CDC13) 1725 (s), 1365 (s), 1165 cm"1 (3); mass spectrum gig. (relative intensity) 119(38), 118 (100), 106 (11), 105 (12), 91 (17), 82 (20), 80 (21), 78 (17), 77 (35), 64 (31), 51 (21). 53 Later chromatographic fractions gave 5-bromo-l,l- dioxo-3-methy1-2-pheny1-4-thiazolidinone, which after recrystallization from chloroform-hexane gave 0.4 g (8%): mp 122.5-123°C; 1H NMR (CDC13) 62.9 (3H, s), 5.1 (1H, s), 5.6 (1H, s), 7.4 (5H, m); IR (CDC13) 1710 (s), 1350 (s), 1250 (s), 1205 (s), 1160 cm"1 (s); mass spectrum gig (relative intensity) 160 (26), 132 (11), 120 (10), 119 (26), 118 (100), 91 (14), 78 (12), 77 (20), 64 (12). Anal. Calcd for CIOHIOBrNOBS: C, 39.48; H, 3.32; N, 4.61. Found: C, 39.37; H, 3.29; N, 4.39. Preparation of 1,l-Dioxo-3-Methy1-2-Pheny1-5-Phenylazo- 4-Thiazolidinone. A diazonium salt solution of 0.86 g (9.0 mmol) of aniline was prepared following an Organic Synthesis preparation}+5 The diazotized aniline was added over 15 minutes to a cold alkaline solution (pH 10) of 2.0 g (9 mmol) of l,l-dioxo-3-methy1-2-phenyl-4-thiazolidinone. The_mixture was stirred at 0-5°C for five hours and at room temperature for two hours. The reaction mixture was acidified with acetic acid, filtered and the precipitate washed with water. The crude product was then recrystal- lized from ethanol to yield 1.5 g (52%) of l,l-dioxo- 3-methyl-2-pheny1-5-phenylazo-4-thiazolidinone: mp 188-189.5°C; In NMR (c0c13) 52.9 (3H, s), 5.4 (1H, s), 54 7.3 (10H, m), 12.6 (1H, br, 5); IR (CDC13) 1665 (s), 1545 (vs) 1325 (s), 1130 cm"1 (s); mass spectrum gig (relative intensity) 329 (17), 265 (19), 264 (21), 174 (14), 173 (100), 149 (12), 120 (12), 119 (30); 118 (83), 116 (10), 105 (21), 93 (17), 92 (18), 91 (41), 82 (12), 80 (11), 78 (21), 77 (68), 67 (48), 65 (37); 64 (19), 63 (12); 51 (28). Preparation of S-Acetamido-l,l-Dioxo-3-Methyl-2-Phenyl- 4-Thiazolidinone. In a modified literature procedure,“*a solution of 0.9 g (3 mmol) of 1,1-dioxo-3-methyl-2-phenyl-5- phenylazo-4-thiazolidinone in 2 mL of acetic acid was added to a mixture of 2.2 g of zinc (dust), 3 mL acetic acid and 1.5 mL acetic anhydride at 5°C. After the addition (30 minutes), the mixture was stirred for eight hours as it warmed to room temperature. The slurry was filtered and the zinc washed with acetic acid. The filtrate was then concentrated under reduced pressure, and the residue dissolved in dichloromethane. The organic layer was washed with water, dried, and solvent removed under reduced pressure. The crude product was chromato- graphed through Silica Gel (Davison Chemical) eluting with 0.5% methanol-dichloromethane, to separate the product from acetyl aniline, a by-product of the 55 reaction. The final product was isolated by thin layer chromatography on silica gel, eluting with ethyl acetate (Rf = 0.13), to yield 67 mg (9%) of a mixture of gig and giggg 5-acetamido—1,l-dioxo-3-methyl-2—phenyl-4-thiazoli- dinone: 1H NMR (CDC13) 62.07 and 2.12 (3H, 23), 2.8 (1H, s), 2.9 (2H, s),.5.1 (0.6H, d, J=7.8Hz), 5.5 (0.6H, s), 5.2 (0.4H, s), 5.8 (0.4H, d, J=7.8 Hz), 7.33 (6H, m); IR (CDC13) 1700 (s), 1645 cm'4(s); mass spectrum gig (relative intensity) 161 (17), 159 (33), 121 (11), 120 (100), 119 (60), 118 (33), 91 (15), 77 (12), 64 (65), 57 (15). Preparation of 5—Acety1-1,l-Dioxo-3-Methyl-2-Pheny1- 4-Thiazolidinone. Acetyl chloride (0.3 g, 4 mmol) was added to a solu- tion of 1.0 g (4 mmol) of l,l-dioxo-B-methyl-2-phenyl- 4-thiazolidinone and 43 mg of sodium hydride in 200 ml of tetrahydrofuran. The addition was carried out at room temperature over 15 minutes, and the mixture stirred for three hours. The mixture was acidified with acetic acid and the THF removed under reduced pressure. The residue was taken up in dichloromethane, washed with water, dried, and the solvent removed. The oil was chromatographed on a Silica Gel (Davison Chemical) column, eluting with 2% methanol-dichloromethane, to yield 380 mg (36%) of 5-acetyl-l,l-dioxo-3-methy1-2-pheny1-4-thiazoli- dinone: 1H NMR (CDC13) 52.3 (3H, s), 2.8 (3H, s), 5.3 (1H, s), 56 7.3 (5H, m), 12.7 (1H, br, 3); IR (CDC13) 1635 (vs), 1310 (s), 1140 cm.1 (5); mass spectrum m/e (relative intensity) 120 (12), 119 (54), 118 (100), 91 (18), 84 (17), 78 (15), 77 (26), 69 (19): 64 (30): 51 (17). 57 General Procedure for the Photolysis of l,l-Dioxo- 4-Thiazolidinones. A solution of 100 mg of l,l-dioxo-4—thiazolidinone in 30 ml of acetonitrile and 150 mL of t-butyl alcohol was purged with argon and irradiated through a Vycor filter with a Hanovia 450-w medium pressure lamp. Sol- vent was removed under reduced pressure and the crude product filtered through florisil (Fisher Scientific) with 3% methanol-dichloromethane. Yields were de- termined by PMR analysis using an internal standard technique. Photolysis of 3,5-Dimethy1-l,l-Dioxo-2-(4-Methoxyphenyl)- 4-Thiazolidinone. The gig isomer (120 mg) was photolyzed for 20 minutes to yield 20 mg (24%) of EEEEE 1,3-dimethyl-4- (4-methoxyphenyl)-2-azetidinone, 4 mg (5%) of the gig azetidinone, and 18 mg (17%) of starting material. Acetone was used as an internal standard for the PMR determina- tion of yields. The structures of the products were determined by analysis after isolation. A mixture of 58 gig and EEEEE azetidinone was isolated by prep gas- liquid chromatography (Varian Aerograph 920, 6' x 1/4" stainless steel column, liquid phase 5% 0V-101, 100°C (4 min) to 200°C). The retention time for the azeti- dinones was 7.3 minutes relative to air. The gig azetidinone spectral data were: 1H NMR (CDC13) 60.8 (3H, d, J=7Hz), 2.77 (3H, s), 2.8 (1H, m), 3.8 (3H, s), 4.6 (1H, d, J=5.5Hz), 7.0 (4H, m). The spectral data of the compound identified as the giggg azetidinone were: In NMR (c0013) 51.4 (3H, d, J=7Hz), 2.7 (3H, s), 2.8 (1H, m), 3.8 (3H, s), 3.9 (1H, d, Jéznz), 7.0 (4H, m); IR (CDC13) 1740 cm‘1(vs); mass spectrum gig (relative intensity) 205 (917), 174 (17), 149 (36), 148 (100), 147 (16), 135 (13), 133 (13), 119 (25), 77 (15). An epimerized mixture (68 mg) of 50% gig and 50% gigggfl,l-dioxo-4-thiazolidinone was photolyzed for 10 minutes to yield 1 mg (2%) of gig azetidinone, 3 mg (6%) of EEEEE azetidinone, 16 mg (24%) of gigfl,l-dioxo- 4-thiazolidinone and 3 mg (5%) of'gigggfl,l-dioxo-4-thiazol- idinone. The internal standard was trichloroethylene. 59 Photolysis of 2—(4-Chlorophenyl)h3,5-Dimethy1-l,1-Dioxo- 4-Thiazolidinone. Irradiation of 87 mg of the gig isomer for 20 minutes yielded 3 mg (4%) of‘gigggf4-(4-chloropheny1)- l,3-dimethy1-2-azetidinone, 1 mg (2%) of the gig azetidinone, and 8 mg (9%) starting material. Trichloro- ethylene was used as an internal standard for the PMR determination of yields. IR (CDC13) carbonyl absorptions were present at 1735 and 1700 cm'd. PMR spectral data for the photolysis products were: 51.4 (3H, d, J=7Hz), 2.6 (3H, s), 3.4 (1H, m), 4.0 (1H, d, J=2Hz), 7.0 (4H, m), for the giggg B-lactam, and 0.8 (3H, d, J=7Hz), 2.55 (3H, s), 3.4 (1H, m), 4.4 (1H, d), 7.0 (4H, m) for the cis s—lactam. Photolysis of 3,5—Dimethyl-1,1-Dioxo-2-(2-Thieny1)-4- Thiazolidinone. The gig isomer (114 mg) was photolyzed for 20 minutes to yield 21 mg (23%) of gigfl,3-dimethy1-4- (2-thienylye-azetidinone, 5 mg (6%) of the giggg azetidinone, and 35 mg (29%) of starting material; IR carbonyl absorptions were at 1740 and 1710 cm'd. The internal PMR standard used was acetone. These gig and giggg azetidinones were isolated by silica gel preparative thin layer chromatography, with development by diethyl ether. 'Cis azetidinone (Rf =0.3) was identified from 60 the following spectral data; _1H.NMR (CDC13)60.9 (3H, d, J=7.5 Hz), 218 (3H, s), 3.5 (1H, m), 4.6 (1H, d, J=7.5Hz), 7.0 (31:, m). ' 25.922 azetidinone (Rf = 0.5) was identified by this spectral data: 1H NMR (CDC13)61.40 (3H, d, J=7.5Hz), 2.7 (3H, 8), 3.7 (1H, m), 4.3 (1H, d, J=2 Hz), 7.0 (3H, m): IR (CDC13) 1740 cm"1 (vs); mass spectrum.gig (relative intensity) 181 (33), 126 (20), 125 (31), 124 (100), 123 (31), 97 (41). gigf3,5-dimethyl-l,l-dioxo-2-(2-thienyl)-4- thiazolidinone (196 mg) was epimerized in methanol with florisil, isolated and photolyzed for 20 minutes. After photolysis trichloroethylene was added as an internal PMR standard, and the spectrum showed 16 mg (11%) of gigfl,3-dimethyl-4—(2-thienyl)-2-azetidinone, 9 mg (6%) of the giggg_azetidinone, 30 mg (15%) of gig—1,l-dioxo- 4-thiazolidinone and 6 mg (3%) of gigggfl,l-dioxo- 4-thiazolidinone. Photolysis of 3,5-Dimethy1-IL1-Dioxo-2-(2-Fury1)—4— Thiazolidinone. The cis isomer (183 mg) was photolyzed for 30 minutes, and the crude product was isolated by removing the solvent under reduced pressure. The product was then taken up in 50 mL of dichloromethane, washed with 61 50 mL of water and dried. The solvent was removed to yield 49 mg (37%) of gigfl,3-dimethyl-4-(2-furyl)- 2-azetidinone, 13 mg (10%) of the corresponding EEEEE azetidinone and 57 mg (32%) of starting material. Dichloromethane was used as the internal PMR standard for this yield determination. IR carbonyl absorptions of the product were at 1740 and 1715 cm'l. PMR spectral data for the photolysis products were: 60.9 (3H, d), 2.67 (3H, s), 3.4 (1H, m), 4.5 (1H, d), 6.3 (2H, m), 7.3 (1H, m) for the gig azetidinone and 61.4 (3H, d), 2.7 (3H, d), 3.4 (1H, m), 4.0 (1H, d), 6.3 (2H, m), 7.3 (1H, m) for the trans azetidinone. Photolysis of 5-Acetamido-l,l-Dioxo-3-Methyl-2-Phenyl— 4-Thiazolidinone. A mixture of isomers (53 mg) was photolyzed for ten minutes. The solvent was removed and the crude product analyzed by PMR; no starting material was present. The products were isolated by preparative thin layer chromatography on silica gel, eluting with ethyl acetate. The band eluting with an Rf = 0.2 contained the B-lactam product; 12 mg (28%) of gig_and giggng-acetamido- 1-methy1-4~phenyl-2—azetidinone judging from the spectral data: 1H NMR (CDC13) 51.6 (3H, s), 1.8 (3H, s), 2.7 (2H, s), (2H, s), 2.8 (3H, s), 4.4 (2H, m), 4.8(1H, d, J=5Hz), 5.2 (1H, m), 6.0 (1H, m), 6.7 (1H, br, m), 62 7.2 (12 H, M); IR (CDC13) 1755 and 1685 cm"1 (s); mass speCtrum m/e_(relative.intensity) 161 (16) 159 (38),_ 121 (13), 120 (100), 119 (52), 118 (23) 91 (16), 77 (13), 57 (20). Photolysis of 5,5-Dibromo-1,l-Dioxo-3-Methyl-2-Phenyl— 4-Thiazolidinone. Irradiation of 87 mg of 5,5-dibromo-l,l—dioxo- 3-methy1-2-pheny1-4-thiazolidinone for ten minutes yielded 10 mg (15%) 5-bromo-l,1-dioxo-3-methy1-2-pheny1 4-thiazolidinone, 1H NMR (coc13) 62.9 (3H, s), 5.1 (3H, s), 5.6 (1H, s), 7.4 (5H, m); 6 mg (12%) l,l—dioxo- 3-methyl-2-phenyl-4-thiazolidinone, 1H NMR (CDC13) 62.9 (3H, s), 3.8 (2H, s), 5.4 (1H, s), 7.3 (5H, m); and 4 mg (4%) starting material. Trichloroethylene was used as an internal standard for the PMR analysis. Photolysis of 5-Acetyl-l,1-Dioxo-3-Methyl-2-Phenyl—4- Thiazolidinone. Irradiation of 222 mg of 5-acetyl-1,l-dioxo-B-methyl- 2-phenyl-4-thiazolidinone for 30 minutes yielded only starting material; 1H NMR (CDC13) 62.2 (3H, s), 2.7 (3H, s), 5.2 (1H, s), 7.7 (5H, m), 12.7 (1H, br, 5); IR (CDC13) 1635 (vs), 1310 (s), 1140 cm'1 (s). 63 General Procedure'for the Thermolysis of Substituted 1,1-Dioxo-4eThiazolidinones. The 1,1-dioxo-4-thiazolidinone was weighed into a 5 mm NMR tube purged with nitrogen, and placed in an oil bath at 200°C for five minutes. After cooling to room temperature the samples were analyzed by PMR using an internal standard technique. ThermolysiS'of'3,5—Dimethy1-1,1-Dioxo-2-(2-Thieny1)- 4-Thiazolidinone. Thermolysis of the gig isomer (33 mg) yielded 19 mg (70%) of gigggfl,3-dimethyl-4-(2-thieny1)-2—azetidinone. Dichloromethane was used as an internal PMR standard. Spectral data are: 1H NMR (CDC13) 51.4 (3H, d, J=7Hz), 2.7 (3H, s), 5.1 (1H, m), 4.3 (1H, d, J=2Hz), 7.0 (3H, m). Thermolysis of 3,5-Dimethyl-l,l-Dioxo-2-(2-Fury1)-4- Thiazolidinone. The cis isomer (22 mg) thermolyzed to yield 15 mg (92%) trans-1,3-dimethy1—4-(2-furyl)-2-azetidinone. The internal PMR standard was dichloromethane. In a large scale preparation 101 mg of 3,5— dimethy1-1,l-dioxo-2-(2-fury1)-4-thiazolidinone was thermolyzed at.200°C in a test tube for five minutes. The product (50 mg) was isolated by florisil column 64 chromatography, eluting with 2% methanol in dichloromethane and proved to be‘giggg-l,3-dimethyl-4-(2-furyl)-2- azetidinone. Spectral data are: 1H NMR (CDC13) 61.4 (3H, d, J=7Hz), 2.7 (3H, s), 3.3 (1H, m); 4.0 (1H, d, J=2Hz), 6.1 (2H, m), 7.3 (1H, m); IR (CDC13) 1740 cm'q(vs); mass spectrumgig (relative intensity) 165 (21), 110 (14), 109 (69), 108 (100), 107 (15), 81 (27), 79 (47); 77 (l4). Thermoiysis of 2-(4-Chlorophenyl)-3,5-Dimethy1-1,1-Dioxo- 4-Thiazolidinone. Thermolysis of the gig isomer (24 mg) yielded 10 mg (55%) of gigggfl,3-dimethy1-4-(4-chlorophenyl)-2- azetidinone (1H NMR (CDC13) 61.4 (3H, d, J=7Hz), 2.7 (2H, s), 4.0 (1H, d, J=7Hz), 7.2 (4H, m)) and 8 mg (35%) of a 1:1 mixture of gig_and EEEBE starting material. The internal PMR standard was trichloroethylene. Thermolysis of 3,5-Dimethyl-l,l-Dioxo-Z-Pheny1-4- Thiazolidinone. The cis isomer (36 mg) thermolyzed to yield 13 mg (50%) trans-1,3-dimethyl-4-phenyl-2-azetidinone and 11 mg (31%) of‘cis and trans starting material. Spectral 65 data for the B-lactam product are: 1H NMR (CDC13) 61.3 (3H, d, J=8HZ), 2.7 (3H, S), 3.5 (1H, m), 4.0 (1H, d, J=2Hz), 7.2 (5H, m). Trichloroethylene was used in the internal PMR standard. Thermolysis of 1,l-Dioxo-B-Methyl-Z-Phenyl-4- Thiazolidinone. Thermolysis of 44 mg l,l-dioxo-3-methyl-2-phenyl- 4-thiazolidinone yielded no identifiable product, and starting material was completely consumed. Thermolysis of 3,5-Dimethyl -l,1-Dioxo-2-(4-Methoxyphenyl)- 4-Thiazolidinone. The gig isomer (160 mg) thermolyzed to yield 67 mg (55%) of gigggfl,3-dimethyl-4-(4-methoxypheny1)-2- azetidinone (In NMR (c0c13) 51.4 (3H, d, J=6Hz), 2.7 (3H, s), 2.9 (1H, m), 3.7 (3H, s), 3.9 (1H, d, J=2Hz), 6.9 (4H, q)) and 62 mg (39%) gig_and giggg starting material. Nitromethane was the internal PMR standard used for this yield determination. LIST OF REFERENCES A. K. Mukerjie and A. K. Singh, Synthesis 547 (1975); (b) H. T. Clarke, J. R. Johnson and R. Robinson, "The Chemistry of Penicillins", Princeton Univ. Press, 1949; (c) E. H. Flynn, Ed., "Cephalosporins and Penicillins: Chemistry and Biology", Academic Press, New York, 1972; (d) M. S. Manhas and A. K. Bose, "Synthesis of Penicillin, Cephalosporin C and Analogs", Marcel Dekker Inc., New York, 1969; (e) P. A. Lemke, D. R. Brannon and E. H. Flynn, "Cephalosporins and Penicillins", Academic Press, New York, 1972; and (f) M. S. Manhas and A. K. Bose, "B-Lactams, Natural and Synthetic", Wiley-Interscience, New York, 1971. (a) A. Dobrev and C. Ivanov, Chem. Ber., 1&3, 981 (1971); and (b) C. Ivanov and A. Dobrev, Montsh. Chem., 36, 1946 (1965). H. Staudinger, H. W. Klevea and P. Kober, Liebigs Ann. Chem., 314, 1 (1910). E. Testa and L. Fontanella, Brit. Patent 829,663 (1957). (a) J. C. Sheehan, K. R. Henery-Logan and D. A. Johnson, J. Amer. Chem. Soc., 15, 3292 (1953); (b) F. F. Blicke and W. A. Goul, J. Org:JChem., 29, 1102 (1958); and (c) K. D. Dampe, Ger. Patent 1,807,496 (1968). (a) J. C. Sheehan and K. R. Henery-Logan, J. Amer. Chem. Soc., 8 , 5838 (1959); (b) J. C. Sheehan and J. . Schneider, J. Org. Chem., 31, 1635 (1966); and (c) S. D. Levine, _—J. Org.“‘8hem., 55, 1064 (1970). '66 10. 11. 12. 13. 67 (a) M. S. Manhas and S J. Jeng, J. 056. Chem., 32, 1246 (1967); (b) E. Testa, L. Fontanella and L. Rosterkeine, Zhur Org. Khim., 10, 436 (1974); (c) J. H. Baldwin, A. An, M. Christe, Sm’B. Haber and D. Hesson, J. Amer. Chem. Soc., 97, 5957 (1975); and (d) S. Nakatomka, H. Tamino and Y. KiEfli, ibid., 5008 (1975). (a) A. K. Bose, B. N. Shosh-Mazumdar and B. G. Chatterjei, J. Amer. Chem. Soc., 82, 2382 (1960); (b) B. G. Chatterjei and V. V. Rav, Tetrahedron, 23, 487 (1967); and (c) T. A. Martin, W. T. gComer, C? M. Combs and J. R. Corrigan, J. Org. Chem., 35, 3814 (1970). (a) H. Staudinger, Liebigs Ann. Chem., 6, 51 (1907); (b) H. Staudinger and H. Schnei er, Helv. Chim. Acta., 6, 304 (1923); (c) R. Pfleger and A. Jager, Chem.“"13er., g0, 2460 (1957); (d) J. C. Sheehan and E. J. Corey, "Organic Reactions", Volume 9, p. 388 (1957); and (e) A. K. Bose, B. Anjanegula, S. K. Bhattacharya and M. S. Manhas, Tetrahedron, 29, 4763 (1967). (a) W. T. Brady and E. F. Hoff, J. gger. Chem. Soc., 90, 6256 (1908); (b) D. A. Nelson, Tetrahedron Letters, 2543 (1971); (c) F. Duran and L. Ghosez, Tetrahedron Letters, 245 (1970); (d) R. Hull, J. Chem. Soc. (c), 1154 (1967); (e) W. T. Brady, E. D. Dorsey and F. H. Parry, J. Org. Chem., ,ig, 2846 (1969); (f) M. S. Manhas, S. Jeng and A. K. Bose, Tetrahedron, 4, 1237 (1968); and (g) P. G. Bird and W. J. rwin, J. Chem. Soc. Perkins Trans. I, 2664 (1973). T. W. Doyle, B. Luh and A. Martel, Can. J. Chem., 55, 2700 (1977). A. K. Bose, G. Spiegelman and M. S. Manhas, J. Amer. Chem. Soc., 99, 4506 (1968). (a) H. Bestian, H. Biener, K. Clauss and H. Hey, Annalen, 71 , 94 (1968); (b) R. Graf, Annalen, 661, Ill 63); and (c) T. Haug, F. Lohse, (KibMetzger and H. Batzer, Helv.‘Chim. Acta., 51, 2069 (1968). 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 68 (a) J. C..Martin, J. L. Chitwood and P. G. Gott, ‘J. Org. Chem., 36,_2228 (1971); and (b) F. Effenberg and R. G1etter,”Ehem. Ber., 33, 1576 (1964). H. Bestian and D. Grimm, Gen. Offen., 1,906,401 (1970). G. Opitz and J. Koch, Angew. Chem., L5, 167 (1963). E. I. Moriconi and J. F. Kelly, J. Amer. Chem. Soc., , 3657 (1966) and J. Org. CHEm., 33, 3036 (1 68). J. A. Deyrup and S. C. Clough, J. Amer. Chem. Soc., ,gi, 4590 (1969). F. Toda, T. Mitote and K. Akagi, Bull. Chem. Soc. Japan, 43, 1777 (1969). H. H. Wasserman, R. E. Cochag and M. S. Baird, J. Amer. Chem. Soc., 9%, 2376 (1969). S. N. Ege, Chem. Commun., 759 (1968). J. 091, Angew. Chem., 74, 9 (1962). (a) R. R. Rando, J. Amer. Chegi, Soc., 32, 6706 (1970); (b) G. Lowe and J. Parker, J. Chem. Soc., Chem. Commun., 577 (1971); (c) B. T. Golding and D. R. Hall, giChem. Soc.i_Pgrkin Trans. I, 1517 (1975): (d) G. Lowe and D. D. Ridley, ibid., 2907 (1973); (e) G. Lowe and H. W. Young, ibid., 2907 (1973); (f) O. L. Chapman and W. R. Adams, J. Amer. Chem. Soc., 90, 2333 (1968); and (g) D. S. C. Black and A. B. Boscacci, J. Chem. Soc., Chem. Commun., 129 (1974). E. J. Corey and A. M. Felix, J. Amer. Chem. Soc., 8], 2518 (1965). E. Block, Quart. Rep. on Sulfur Chem., 4, 236 (1969). F. C. Brown, Chem. Rev.,lgk, 463 (1961). 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 69 (a) A. R. Surrey, J Amer. Chem. Soc., 63, 2911 (1947); (b) ibid., 7 , 4262 (1948);. and (c) ibid., 164 3450 (195 ). (a) H. D. Troutman and L. M. Long, J. Amer. Chem. SOC., Z9, 3436 (1948); and (b) A. R. Surrey, ibid., $1, 3105 (1949). A. R. Surrey and R. A. Cutler, J. Amer. Chem. Soc., IJR' 578 (1954). F. C. Pennington, W. D. Celmer, W. M. McLamore, V. V. Bogent and I. A. Solomons, J. Amer. Chem. Soc., Z5, 109 (1953). D. L. Ward, L. R. Sousa and M. R. Johnson, unpublished results. (a) H. D. Troutman and L. M. Long, J. Amer. Chem. Soc., 70, 3436 (194w); (b) A. R. Surrey, U. s. pa%ent 3, 377, 355 (1968); and (c) A. R. Surrey, French Patent M1906 (1963). (a) J. C. Wilson, R. N. Downer and H. E. Sheffer, ’J. Heterocyclic Chem., 7, 955 (1970); (b) A. S. Gomes and M. M. Jbullie, ibid., 6, 729 (1969); (c) A. R. Surrey, U. S. Patent 2, 520, 179 (1950) and 2,647, 905 (1953); (d) A. R. Surrey, J. Amer. Chem. Soc., 0, 4262 (1948); and (e) A. R. Surrey and R. A. utler, J. Amer. Chem. Soc., 76, 578 (1954). G. Barbarella, P. Dembeck, A. Garlesi and A. Fava, Org. Mag. Res., 8, 108 (1976). K. D. Barrow and T. M. Spotswood, Tetrahedron Letters, 3325 (1965). M. R. Johnson and L. R. Sousa, unpublished results. M. Fischer, Chem. Ber., 101, 2669 (1968). A. L. Buchuchinko, "Stable Radicals", Consultant Bureau, New York, 1965, p. 40. 39. 40. 41. 42. 43. 44. 45. 70 M. J. S. Dewar, "The Molecular Orbital Theory of Organic Chemistry", McGraw-Hill Book Company, New York, 1969. C. H. Bamford, W. G. Barb, A. D. Jenkins and P. F. Onyon, "Kinetics of Vinyl Polymerization by Radical Mechanisms", Butterworth Scientific Publications, London, 1958. R. P. Vayne, "Photochemistry", Butterworth Scientific Publications, London, 1958, p. 66. B. K. Patnaik and M. K. Rout, J. Ind. Chem. Soc., 3%, 563 (1955). P. N. Bhargava and M. B. Chawiasia, J. Pharm. Sci., 38, 896 (1969). K. Pfister and M. Tishler, U.S. Patent 2,489,927 (1949). "Organic Syntheses Collective VOlume 4", John Wiley and Sons, Inc., New York, 1963, p. 633. N TRT HICHIGR S llHlWlllHll! 3129 UN V. L Iumfml fimum Il‘ui 31006339 RARIES WWI 551