Eastern Illinois University The Keep Masters Theses Student Theses & Publications 1995 The yS nthesis of N-Chlorosulfonyl β-Lactams and Their Rearrangements Lihua Zhang Eastern Illinois University This research is a product of the graduate program in Chemistry at Eastern Illinois University. Find out more about the program. Recommended Citation Zhang, Lihua, "The yS nthesis of N-Chlorosulfonyl β-Lactams and Their Rearrangements" (1995). Masters Theses. 1967. https://thekeep.eiu.edu/theses/1967 This is brought to you for free and open access by the Student Theses & Publications at The Keep. It has been accepted for inclusion in Masters Theses by an authorized administrator of The Keep. For more information, please contact [email protected]. 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Date I respectfully request Booth Library of Eastern Illinois University not allow my thesis to be reproduced because: Author Date The Synthesis of N-Chlorosulfonyl ~-Lactams and Their Rearrangements (TITLE) BY Lihua Zhang THESIS . - SUBMITIED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN CHEMISTRY IN THE GRADUATE SCHOOL, EASTERN ILLINOIS UNIVERSITY CHARLESTON, ILLINOIS 1995 YEAR I HEREBY RECOMMEND THIS THESIS BE ACCEPTED AS FULFILLING THIS PART OF THE GRADUATE DEGREE CITED ABOVE I r - f DAT~ V( I """"'"' • v DATE DEPARTMENT HEAD THE SYNTHESIS OF N-CHLOROSULFONYL p-LACTAMS AND THEIR REARRANGEMENTS THESIS APPROVED BY ' {)ate Dr. T. Howard Black, fhesis Advisor Dr. Ellen A. Keiter, Department Head uate Dr. Daniel J. Sheeran Date D(/ Jonathan fl. Blitz L_ The Syntheses of N-Chlorosulfonyl-g-Lactams and Their Rearrangements L To: Xiaoping, Tina and my parents TABLE OF CONTENTS ABSTRACT -------------------------------------------------- i ACKNOWLEDGEMENT ------------------------------------------ ii LIST OF TABLES------------------------------------------ iii LIST OF FIGURES------------------------------------------ iv INTRODUCTION ---------------------------------------------- 1 RESULTS AND DISCUSSION ----------------------------------- 16 CONCLUSION ----------------------------------------------- 47 EXPERIMENTALSECTION-------------------------------------49 REFERENCES ----------------------------------------------- 58 FIGURES -------------------------------------------------- 64 ABSTRACT The synthesis of several N-chlorosulfonyl-g-lactams and their rearrangements have been carried out via CSI (chlorosulfonylisocyanate) reaction. The mechanism of g_ lactam synthesis as well as its rearrangements were also studied. The characterization of g-lactams was performed with IR, 1H and 13C NMR, and HRMS. g-lactams 2-chlorosulfonyl-l­ methyl-2-azabicyclo[4.2.0]octan-3-one (71), l-chlorosulfonyl- 4-methyl-4- (phenylmethyl)azetidin-2-one (74) and l­ chlorosulfonyl-4,4-(diphenylmethyl)azetidin-2-one (75) were synthesized for the first time. g-lactam 4-chlorosulfonyl- 3, 9, 9-trimethyl-4-azatricyclo [6. 1. O. 03 ' 6 ] nonan-5-one ( 73) was obtained as crystalline solid instead of liquid. Different effects, such as temperature, sol vents and catalysts, on the rearrangement of the g-lactam 74 have been studied. There was no expected rearrangement to r-lactam observed, and usually the unsaturated amide resulted. The rearrangement products of a g-lactam can be r-lactam, a,g- or g,r-unsaturated amide, and alkene, depending on the conformation of the g-lactam and reaction conditions. -i- I_ ACKNOWLEDGEMENT I am very grateful to my advisor, Dr. T. Howard Black, for his continuous guidance and academic help during this study. I also thank those in our research group for their assistance and cooperation, especially Mr. J. T. Olson and Mr. D. C. Abt for their previous studies. I appreciate the opportunity the Chemistry Department provided to me for studying here with financial aid, and the help from all faculty and staff, especially Dr. Ellen. A. Keiter for her help in the NMR spectra analysis. -ii- L LIST OF TABLES Table 1: Synthesis of alkenes from ketones Table 2: Synthesis of :IS-Lactams by CSI with alkenes Table 3 : High-Resolution MS Data of :IS-Lac tam 73 Table 4: High-Resolution MS Data of :IS-Lactam 74 Table 5: High-Resolution MS Data of :IS-Lac tam 75 Table 6: High-Resolution MS Data of :IS-Lactam 71 Table 7: High-Resolution MS Data of Alkene 63 Table 8: High-Resolution MS Data of Alkene 65 Table 9: High-Resolution MS Data of Alkene 67 -iii- L LIST OF FIGURES Figure 1: 1 H NMR Spectrum of B-Lactam 73 Figure 2: COSY Spectrum of B-Lactam 73 Figure 3: 13C NMR Spectrum of B-Lactam 73 Figure 4: DEPT Spectrum of B-Lactam 73 Figure 5: HETCOR Spectrum of B-Lactam 73 Figure 6: MS Spectrum of B-Lactam 73 Figure 7: IR Spectrum of B-Lactam 73 Figure 8: 1 H NMR Spectrum of B-Lactam 71 Figure 9: 13C & DEPT NMR Spectrum of B-Lactam 71 Figure 10: IR Spectrum of B-Lactam 71 Figure 11: 1 H NMR Spectrum of Unsaturated Amide 83 Figure 12: COSY Spectrum of Unsaturated Amide 83 Figure 13: 13C & DEPT NMR Spectrum of Unsaturated Amide 83 Figure 14: HETCOR Spectrum of Unsaturated Amide 83 Figure 15: 1 H NMR Spectrum of r-Lactam 49 Figure 16: 13 C & DEPT NMR Spectrum of r-Lactam 49 Figure 17: IR Spectrum of r-Lactam 49 Figure 18: 1 H NMR Spectrum of Alkene 61 Figure 19: 13C NMR Spectrum of Alkene 61 Figure 20: MS Spectrum of Alkene 61 -iv- Figure 21: IR Spectrum of Alkene 61 Figure 22: 1 H NMR Spectrum of B-Lactam 74 Figure 23: 13c NMR & DEPT Spectrum of B-Lactam 74 Figure 24: MS Spectrum of B-Lactam 74 Figure 25: IR Spectrum of B-Lactam 74 Figure 26: 1 H NMR Spectrum of Alkene 97 Figure 27: i3c & DEPT NMR Spectrum of Alkene 97 Figure 28: IR Spectrum of Alkene 97 Figure 29: 1 H NMR Spectrum of Alkene 63 Figure 30: 13c NMR Spectrum of Alkene 63 Figure 31: IR Spectrum of Alkene 63 Figure 32: 1 H NMR Spectrum of B-Lactam 75 Figure 33: 13c & DEPT NMR Spectrum of B-Lactam 75 Figure 34: MS Spectrum of B-Lactam 75 Figure 35: IR Spectrum of B-Lactam 75 Figure 36: 1 H NMR Spectrum of Alkene 65 Figure 37: 13c NMR Spectrum of Alkene 65 Figure 38: IR Spectrum of alkene 65 Figure 39: 1 H NMR Spectrum of alkene 67 Figure 40: 13c NMR Spectrum of Alkene 67 Figure 41: IR Spectrum of alkene 67 -v- L INTRODUCTION Dr. T. Howard Black's research group has been engaged for a long time in the chemistry of B-lactones. These useful synthetic intermediates can be converted into butyrolactones, 1 B, r-unsaturated carboxylic acids2 and a-halo3 or alkyl 4 butenolides. The ring expansion of B-lactones to r-lactones was the main focus in the early studies and was very successful, 5 as shown in Scheme I. Some analogous chemistry of B-lactams is also under active study, which includes the rearrangement of B-lactams to r-lactams by ring expansion. Previous students have shown6 that some B-lactams readily undergo thermal rearrangements to r-lactams through ring expansion, as shown in Scheme II, and we herein report the results of our further studies. B-Lactams and their syntheses are always one of the most interesting areas in the studies of antibiotics. 7 Staudinger et al. 8 synthesized the first B-lactam, N, 3, 3, 4, 4-penta­ phenylazetidinone (23) by the cycloaddition of diphenylketene with benzophenone anil. After Fleming's unexpected discovery of penicillin9 (24) and the antibiotic activity of the B­ lactam moiety was recognized, 10 many methods11 were developed -1- Scheme I R=HorMe ;/ R 4 rroH MgBr2 ~··~<o H R 6 MgBr2 or R3 TiCI 4 R1 R2 8 fo AgN03 R2 R1 10 -2- Scheme II H a, b )lo c • ct>=o - . Me ' S02CI 11 12 13 0 a,b c • Ph~O )lo --j'-N(S0 CI Ph~ 2 14 16 15 0 )\ ,,,so2c1 a,b - N Ph IH\/ 17 19 18 0 c Et~ a, b )lo Ph~ )lo PhANJ=O 'so2c1 20 21 22 -3- Ph Ph "'-N Ph ~.I.____,___ Ph 0 Ph 23 24 Scheme III Cl02S Cl02S I I R~(R2 N- RI cw + c R3 R4 II ~<~r:: 0 0 R 26 3 25 27 2 2 CI0 S "'- - 4 R CI0 s,~N-4 R2 1Nit + 2 I I > 3 > ~2 R4 /2 3 R4 0 R3 R3 28 29 -4- for synthesizing B-lactams, which is the center ring of the penicillins and other antibiotics. Other applications of B­ lactams are also found, for example, in making fibers by the polymerizations of some B-lactams. 12 Our approach to B-lactams is by way of the cycloaddition of chlorosulfonylisocyanate (CSI) to alkenes, which was discovered by Graf in 1956, 13 ' 14 as shown in Scheme III. The mechanism of the [2+2] cycloaddition is not completely understood, but the general explanation15 ' 16' 17' 18 , 19 is as follows (Scheme III): First the C=C double bond of alkene (26) attacks the carbon of CSI (25) to form a n-complex18 (27) , an allyl-type stabilized carbonium ion. Then-complex 27 then rearranges to the 1,4-dipole (28) which finally forms the B-lactam (29). It is noted14c that the formation of the carbocation in 28 follows the Markovnikov rule, i.e., the carbocation in 28 should be the more stable one.