Recently we reported chlorinolysis of the carbon-sulfur bond in penicillins1.
Depending on the amount of halogen used, two kinds of products are
.isolated. With 1 mole of chlorine, the reaction gives azetidinone sulfenyl
chlorides III and with 2 moles of chlorine, olefinic azetidinone derivatives IV are formed

S. Kukolja

S. R. Lammert

English

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CROATICA CHEMICA ACTA 44 (1972) 423 CCA-727 615.779.07 Preliminary Communication Reactions of Penicillin Esters and Related Compounds with 1-Chlorobenzotriazole * S. Kukolja and S. R. Lammert The Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46206, U.S.A. Received April 4, 1972 Recently we reported chlorinolysis of the carbon-sulfur bond in penicil-lins1. Depending on the amount of halogen used, two kinds of products are .isolated. With 1 mole of chlorine, the reaction gives azetidinone sulfenyl chlorides III and with 2 moles of chlorine, olefinic azetidinone derivatives IV are formed. . As an extension of our studies of the reactions of penicillin esters with electrophiles, the use of 1-chlorobenzotriazole (CTBA) as an electrophile source was investigated. 1-Chlorobenzotriazole is an easily available, inexpensive and effective source of positive chlorine, and in addition reactions with this reagent are simple, clean and high-yielding under mild conditions.2- 5 The results reported in this paper fully corroborate all these advantages and also describe the utility of CBTA in preparing monocyclic azetidinone compounds from penicillins. The reactions of p-nitrobenzyl 6-phthalimidopenicillanate (I) with 1 equiv of CBTA in methylene chloride at room temperature for 90 min yields the benzotriazol-1-yl sulfenamide II in 81!0/o yield; ir (CHC13) 1801 (azetidinone C=O), 1787 and 1735 (phthalimido C=O) and 1750 cm-1 (ester C=O). The structure of II is revealed by elemental analysis and NMR data (see Table I). TABLE I NMR Chemical Shift Values (CDCl3) Compound" I C(CH3l2 I CHCOOR lcoocH2-I Azetidinone H I Arom H I 89; 111 287 322 338 (d, J = 4.5) 342 (d, J = 4.5) 472 II 93; 95 288 328 334 (d, J = 2) 385 (d, J = 2) 470 III 103.5 281 328 334 (d, J = 2) 367 (d, J = 2) 474 IV 128; 142 - 323 333 (d, J = 2) 370 (d, J = 2) 474 I • Satisfactory elemental analyses were obtained for a ll compounds. Chemical shift and J values are in Hz. • Azetidinone Antibiotics. IV. 424 S. KUKOLJA AND S. R. LAMMERT COOR COOR o~ h:rc~ N CH3 1 CBTA HµS CH3 H a CH3 .. ~ 5-BTA Ft Ft H II c,\.'). 2 BTA I! HCl ) 2. 3 Cl2 or o' 3 CBTA <o"-... '\ (, COOR COOR ~CH Ot1~CH3 Ou 3 CBTA H Cl . CH or Cl2 H N Ci CH3 s ~ 3 ;; '- SCl Ft H Ft H IV Ill BTA = benzotriazole; Ft= phthalimido; R = p-nitrobenzyl. Evidence that the benzotriazolyl group is attached to the sulfur, and not to the C-2 of the azetidinone ring, is furnished unambigously by conversion of II with 1 equiv of Cl2 or CBTA to the olefinic compound IV, and by synthesis of II from the corresponding sulfenyl chloride III and benzotriazole. When 2 S-chloro-1-(1' -S-p-nitrobenzyloxy-carbonyl-2' -chlorothio-2'methylpropyl) -3 R--phthalimidoazetidin-4-one (III) is treated with 2 equiv .of benzotriazole in methylene chloride at room temperature for 1 hr, colorless benzotriazole hy-drochloride is precipitated. After filtration of the salt, an amorphous product is isolated in 670/o yield and is shown by spectral properties to be identical with compound II. An additional evidence in support of structure II is obtained by hydrolysis of the sulfenamide II to the sulfenyl chloride III with hydro-chloric acid.6 The benzotriazol-1-yl sulfenamide II is dissolved in methylene chloride and treated with dry hydrogen chloride at mom temperature for 7 min. During this time the hydrochloride salt of benzotriazole is precipitated and subsequently removed by filtration. From the filtrate, sulfenyl chloride III is obtained in almost quantitative yield; ir (CHCl,,) 1800 (azetidinone C=O), 1785 and 17 30 (phthalimido C = 0) and 1750 cm-1 (ester C = 0). Compound III is also prepared by chlorinolysis of penicillin ester I according to the method reported previously.1 Characterization of III is made from spectral data (Table I) and analysis. The successful application of 1-chlorobenzotriazole as a source of positive chlorine in preparation of II prompted us to extend its use to the olefin--forming reaction described previously.1 When I is reacted with 3 equiv of 1·-chlorobenzotriazole in methylene chloride at room temperature for 90 min, benzotriazole hydrochloride is obtained as a colorless precipitate. After filtration of the hydrochloride salt, 2 S-chloro-1-(1 ' -p-nitrobenzyloxycarbonyl--2' -methylprop-1'-enyl)-3 R-phthalimido azetidin-4-one IV is isolated in nearly quantitative yield; ir (CHC13) 1798 (azetidinone C=O), 1785 and 1733 (phtha-limido C=O) and 1740 cm-1 (ester C=O). Compound IV also can be made from I, II, and III by the reaction with the appropriate amount of chlorine. AZETIDINONE ANTIBIOTICS. IV 425 The mechanism of heterolysis of the sulfur-carbon bond in penicillin with CBTA is not clear. There is a question whether the reaction is an ionic or free-radical process, and in addition the role of the ambident benzotriazolyl anion also is not established. Since details of the reaction mechanism have not been investigated these questions cannot be answered on the basis of presently available data. Apparently, the previously postulated mechanism for the c:hlorinolysis of penicillins cannot explain adequately the formation of II. REFERENCES l. (a) S. Kuk o 1 j a, J. Am. Chem. Soc. 93 (1971) 6267, Part I; (b) S. Kuk o 1 j a and S. R. Lammert, Croat. Chem. A.eta 44 (1972) 299, Part III. 2. C. W. Rees and R. C. S torr, Chem. Commun. (1968) 1305. 3. C. W. Rees and R. C. Storr, J. Chem. Soc. C (1969) 1474 and 1478. 4. W. D. Kingsbury and C. R. John son, Chem. Commun. (1969) 365. 5. P. M. B ow ye r, D. H. I 1 es, and A. Ledwith, J . Chem. Soc. C (1971) 2775. 6. L. Z er v as, D. B or ova s, and E. Ga z is, J. Am. Chem. Soc. 85 (1963) 3660. IZVOD Reakcija penicilinskih estera i srodnih spojeva s 1-klorbenzotriazolom S. Kukolja i S. R. Lammert Opisana je reakcija p-nitrobenzil-6-ftalimidopenicilinata (I) s 1, 2 i 3 m ola 1- klorbenzotriazola (CBTA). Izolirani su kao produkti cijepanja S 1-C5 veza spo-jevi II, III i IV; njihova struktura potvrdena je na osnovu spektralnih svojstava (IR, NMR) kao i medusobnom interkonverzijom. Tako je II preveden u IV u pri-sustvu jednog mola klora ili CBTA, a III je dao u reakciji s benzotriazolom spoj II. Hidrolizom sulfenamidne gru pe u spoju II s klorovodikom u metilenkloridu dobiven je sulfenil klorid III. ELI LILLY AND COMPANY I NDIANAP8 LIS, INDIANA 46206 U.S.A. Primlje n o 4. t ravnja 1972. 

Reactions of Penicillin Esters and Related Compounds with 1-Chlorobenzotriazole

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