1976 1615Syntheses based on I ,Z-Secopenicillins. Part 111.l Hydration of 4-(3-Substituted Prop-2-yny1thio)azetidin-Zones and a New CephalosporinSynthesisBy John H. C. Nayler," Neal F. Osborne, Michael J. Pearson, ar;d Robert Southgate, Beecham Pharma-ceuticals, Research Division, Brockham Park, Betchworth, Surrey RH3 7AJAddition of secondary amines to the triple bond of 4-(3-substituted prop-Z-ynyIthio)azetidin-2-ones or the derivedsulphoxides. followed by very ready hydrolysis of the resulting enamines. provides a convenient route to the corre-sponding P-oxo-sulphides and -sulphoxides. Generation of the carbonyl group in this way, followed by anintramolecular Wittig reaction to close the dihydrothiazine ring, leads to a new synthesis of cephalosporins, illus-trated by the preparation of an antibacterially active isostere of cephaloridine.A PROJECTED synthesis of cephalosporins (1) required asintermediates ketones of type (2).We describe here thepreparation of such ketones by hydration of the triplebond of the acetylenic precursors (3) reported in thepreceding paper.l Utilisation of the hydration step ina synthesis of a representative cephalosporin is alsode~cribed.~The most usual method of adding the elements ofwater to the acetylenic bond is treatment with aqueousacid in the presence of mercury(I1) ions. Complicationswere anticipated in applying such conditions to com-pounds containing the acid-labile tritylamino-group, sothe readily available model compound (4) was treatedwith toluene-j5-sulphonic acid to give the primary amine( 5 ) , which with phenoxyacetyl chloride afforded the acid-stable amide (6).Treatment of the latter with mercury-(11) sulphate and dilute sulphuric acid in boiling methanolfor 1 h gave a 70% yield of the desired ketone (7), butthis procedure failed with compounds (3) in which theacetylene function was non-terminal.The search for a potentially more versatile procedurefor hydrating the triple bond led us to try treatmentwith mercury(@ chloride in piperidine, previously used 4to prepare steroidal ketones. These non-acidic condi-tions had the attraction of being directly applicable toPart 11, M. A. Harris, I. McMillan, J. H. C. Nayler, N. F.Osborne, M. J. Pearson, and R. Southgate, preceding paper.Preliminary report, J.H. C. Nayler, M. J. Pearson, and R.Southgate, J.C.S. Chem. Comm., 1973, 57.tritylamino-compounds, and treatment of the acetylene(4) with mercury(I1) chloride in piperidine for 1 h. atroom temperature gave the ketone (9a) in 90% yield.This conversion proceeded smoothly even when allmoisture was excluded from the original reaction mixture,suggesting that the primary reactant was piperidine andthat the resulting enamine underwent very ready hydro-lysis to the ketone (9a) during work-up (which did notrequire the recommended use of hydrogen sulphide) .This reasoning led us in turn to question the role of themercury(r1) sa experiments showed that it could infact be omitted, although the mixture then needed to berefluxed.Alternatively, if the isomeric allene (8) wasused in place of the acetylene (4), reaction with piperidineoccurred during 22 h at room temperature with or with-out mercury(I1) chloride. In all these experimentspyrrolidine or morpholine could be used instead ofpiperidine.Ketone formation by way of secondary amine additionalso proved to be applicable to a number of non-terminalacetylenes. Thus the phenylacetylene (lob), refluxedfor 2 h in piperidine, gave a high yield of the ketone (9b),and in this case inclusion of mercury(i1) chloride did notpermit the use of any milder conditions. Hence in theremaining experiments described here use of mercuryPreliminary report, J. H. C. Nayler, M. J. Pearson, and R.Southgate, J.C.S. Chem.Comm., 1973, 58.H. B. Kagan, A. Marquet, and J. Jacques, Buli. SOC. cliim.France, 1960, 10791616compounds was discontinued. When the acetylene (lob)was heated in pyrrolidine and the mixture was then0 J- N\R,(2).H H.PhO.CH2CO.NH 1 SCHiCOMe0 D+COi C H2 Ph(7)COi CH2 P hXNH - S*CHjC i CHC 02*C H 2 Ph(4) X = Ph,C( 5 ) x = H(6) X = PhO*CHiCOCOi CH2Ph(8)a; R = H b; R = Ph c; R = 3-pyridyl d; R = C6HLC02Me-pe; R = CcHdNOj-p f ; R = Me g; R = CH2Phevaporated, the residue showed strong i.r. absorption at1 560 cm-l indicative of an enamine, but chromatographyon silica gel sufficed to cause conversion into the ketoneAmine addition was facilitated when the terminalsubstituent (R) on the propynyl group had electron-withdrawing properties.Thus only 1 h in refluxingpiperidine, followed by the usual work-up, was requiredto convert the 3-pyridyl compound (1Oc) into the ketone(9c). Reaction was even easier with the 9-methoxy-carbonyl- and p-nitro-phenyl compounds (10d and e) ,occurring in piperidine at room temperature during 3 and1 h, respectively. On the other hand, electron-releasingR groups markedly reduced reactivity, so that the but-2-ynyl and 4-phenylbut-2-ynyl sulphides (10f and g) didnot react with piperidine even under forcing conditions.The problem of achieving addition to the triple bondeven when the R group had a deactivating effect was(9b) *J.C.S. Perkin Iovercome by first oxidising the sulphides to the corres-ponding sulphoxides with m-chloroperbenzoic acid.Addition of piperidine to these acetylenic sulphoxidesoccurred readily at room temperature, and reduction ofthe appropriate p-0x0-sulphoxide to the desired sulphide(9f) was effected with triphenylphosphine and acetylchloride.Further information on the nature of the amineaddition was gained by studying the behaviour of theacetylenic sulphoxide (11) with various amines.Theketone (12) was formed most readily by using eithercyclic or acyclic saturated secondary aliphatic amines orunhindered primary aliphatic amines, and more slowlywith diallylamine or t-butylamine. Aniline was notsatisfactory. In the case of volatile amines, work-up bysimple evaporation afforded the enamine intermediates.The relative slowness of the addition with t-butyl-amine permitted the identification of a further inter-mediate between the acetylene (11) and the enamine (14).The main product after a short reaction period was thedlene (13), also obtained by treating the acetylene with0PhO-CH2.C0.NHH 7 &0 q A COiCH2Ph(11) R = CHiCiCH(12) R = CHiCOMe(14) R = CH:CMe.NH.CMe3(131 R = CH:C:CH,(15) R =(16) R =(17) R =(18) R =HHCH(OH).CO~Ct4e3CHCI COfCMe,C(: PPh,).COiCMe,0 u3cH2ph COiCMe,(20) X = Ph3C(21) x = H(22) X = 2- thienylacetyl& - - ~ J ~ c H , R ~0 R(23) R' = Ph, R2 = C02H(24) R' = OAC, R2= C02H(25) R'= pyridinio, R = CO; 2triethylamine ; longer reaction with t-butylamine gavethe enamine (14).The general reaction sequence for the conversion o1976 1617prop-2-ynyl sulphoxides into p-oxo-sulphoxides by treat-ment with primary or secondary amines thereforeappears to be (i) base-promoted isomerisation to theallene, (ii) nucleophilic addition of amine to the centralcarbon atom of the allene system, and (iii) hydrolysis ofthe resulting enamine during work-up.Whether thesame sequence holds for the reactive prop-2-ynyl sul-phides is less certain, since we were unable to demonstrateisomerisation of such compounds to dlenes by use oftriethylamine. Nevertheless, simple prop-2-ynyl sul-phides are converted into allenes by strong bases,5 andparticipation of an allene intermediate would explainwhy, in both the sulphide and sulphoxide series, thecarbonyl groups in our end-products were invariably pto sulphur.With a simple method established for preparingketones of type (2) from acetylenes (3), it remained toincorporate this key step into a new conversion ofpenicillins into cephalosporins. We here illustrate theprocedure devised by describing the formation of a novelcephalosporin, 3-benzyl-7p-(2-thienylacetamido)ceph-3-em-4-carboxylic acid (23).In the event it provedadvantageous to leave the acetylenic function intactuntil a late stage in the synthesis.was accordingly subjected to asequence of reactions used by Scartazzini and his co-workers6" in a different approach to cephems lackingany 3-substituent. Thus condensation with an excess oft-butyl glyoxylate in refluxing benzene gave the a-hydroxy-ester (16), which with thionyl chloride affordedthe a-chloro-ester (17), both products being mixtures ofisomers.Treatment with triphenylphosphine and 2,6-lutidine then gave the stable phosphorane (lS), at whichpoint it was convenient to introduce the carbonylfunction. The acetylene (18) was accordingly refluxedwith piperidine to yield the readily isolable ketone (19)which, unlike a related aldehyde,' showed no tendencyto cyclise spontaneously. Indeed the desired intra-molecular Wit tig condensation required refluxing indioxan for 25 h, but then gave the cephem (20) in excel-lent yield. The latter was readily detritylated withtoluene-9-sulphonic acid, and acylation of the resultingprimary amine (21) then gave the amide (22). Finally,brief treatment with trifluoroacetic acid removed the t-butyl group and gave the new cephalosporin (23).Theoptical activity of this compound, and the characteristiclH n.m.r. pattern for cis-coupled P-lactam protons 8shown by it and all its precursors, confirmed that thestereochemistry about the P-lactam ring had been main-tained throughout the entire synthesis from 6-amino-penicillanic acid.Antibacterial tests by Mr. R. Sutherland and hiscolleagues showed that against most Gram-positiveThe azetidinone (15)C. J . M. Stirling, J. Chem. SOC., 1964, 5856.R. Scartazzini, H. Peter, H. Bickel, K. Heusler, and R. B.Woodward, Helv. Chim. Acta, 1972, 55, 408.R. Scartazzini and H. Bickel, Helv. Chim. Acta, 1972,55, 423.K. D. Barrow and T. M. Spotswood, Tetrahedron Letters,1965, 3325; G.I;. H. Green, J. E. Page, and S. E. Staniforth, J.Chem. SOC., 1965, 1595.bacteria the new product (23) possessed activity similarto those of typical marketed cephalosporins such ascephalothin (24) and cephaloridine (25). It was, how-ever, slightly less effective than cephalothin against p-lactamase-producing staphylococci, in which respect itresembles cephaloridine, with which it is isosteric. Thebenzyl compound (23) was distinctly less active thanboth cephalothin and cephaloridine against Gram-negative bacteria.The synthesis described here is of considerable general-ity and has been used to prepare cephalosporins (1)containing a variety of groups R and R'. Details ofsome of these are in a patent.gEXPERIMENTALGeneral experimental procedures were as outlined inPart 1.10(3R, 4 R ) -3-A mino- 1- ( l-benzyloxycarbonyZ-2-methyl~rop- 1 -enyl)-4- (prop-2-ynylthio) azetidin-2-one (5) Toluene-p-sulphon-ate Salt.-A solution of the 3-(triphenylmethylamino) -azetidinone (4) (8.52 g) in acetone (20 ml) was cooled to-20 "C and toluene-p-sulphonic acid (3.03 g) in acetone(10 ml) was added during 5 min.The mixture was kept at0" overnight and fine needles of the toluene-p-sulphonate saltwere collected (6.48 g), m.p. 175-179' (from acetone-ether), vmx. (Nujol) 1 780, 1 685, and 1 625 cm-l,6 [(CD,),SO]1.98 ( 3 H, s), 2.21 ( 3 H, s), 2.3 ( 3 H, s), 3.16 (1 H, t , J 2.5Hz), 3.5 ( 2 H, d, J 2.5 Hz), 4.95 (1 H, d, J 5 Hz), 5.25 ( 2 H,s), 5.43 ( 1 H, d, J 5 Hz), and 7.0-7.7 (9 H, m) (Found: C ,57.7; H, 5.7; N, 5.3; S , 12.6.C2,H,,N,0,S, requires C,57.9; H, 5.8; N, 5.4; S, 12.4%).(3R,4R)-l-( l-Benzyloxycarbonyl-2-methyZpvop- l-enyl-3-phenoxyacetamido-4- (prop-2-ynylthio) azetidin-2-one ( 6 ) .-The toluene-P-sulphonate salt of (5) (2.58 g) was stirred indry methylene chloride with cooling while triethylamine(2.2 g) was added, then phenoxyacetyl chloride (950 mg)in methylene chloride (10 ml) was added at - 20 "C. After5 min the mixture was washed with water, dried, andevaporated. Chromatography of the residue gave thephenoxyacetamide (6) (1.85 g), amorphous, vmarr. 3 375, 3 260,1 768, 1720, 1690, and 1630 cm-l; 6 2.07 ( 3 H, s), 2.11(1 H, t, J 5 Hz), 2.30 ( 3 H, s), 3.08 ( 2 H, d, J 2.5 Hz), 4.58( 2 H, s), 5.09 and 5.33 ( 2 H, ABq, J 12 Hz), 5.43 ( 2 H , m),and6.8-7.5 ( 1 1 H, m) (Found: M+, 478.1571.C,,H,,N,O,Srequires M , 478.1562).(3R,4R) -4-A cetonylthio- 1- ( 1-benzyloxycarbonyl-Z-methyl-~ro~-1-enyE)-3-(~Izenoxyacetanzido)azetidin-2-one ( 7 ) .-Theacetylene ( 6 ) (638 mg) was dissolved in methanol (10 ml)and water (1 ml) was added. A saturated solution ofmercury(I1) sulphate in dilute sulphuric acid (0.4 ml) wasadded and the mixture refluxed with stirring for 1 h,cooled, and poured into ethyl acetate. The solution waswashed with water until the washings were no longer acidic,then dried and evaporated to a gum. Chromatographygave the amorphous ketone ( 7 ) (449 mg), vmx. 3 360, 1 770,1 720, 1 705, 1 690, and 1 630 cm-l; 6 2.07 ( 3 H, s ) , 2.10( 3 H, s ) , 2.28 ( 3 H, s) 3.12 ( 2 H, s ) , 4.58 (2 H, s), 5.1 and5.35 (2 H, ABq, J 12 Hz), 5.1-5.43 ( 2 H, m), and 6.8-7.5( 1 1 H, m) (Found: M+, 496.1686.C,,H,,N20,S requiresM , 496.1668).J. H. C. Nayler, M. J. Pearson, and R. Southgate, B.P.1,405,758/1975.lo E. G. Brain, A. J. Eglington, J. H. C . Nayler, M. J. Pearson,and R. Southgate, J.C.S. Perkin I, 1976, 4471618 J.C.S. Perkin I(3R, 4R) -4-A cetonylthio- 1- ( l-benzyloxycarbonyl-2-methyl-prop- l-enyl)-3- (tri~henylnzethylarnino)azetidin-2-one (9a). -(a) The acetylene (4) (586 mg) and mercury(I1) chloride (544mg) were stirred in piperidine (4.5 ml) at room temperaturefor 1 h. The mixture was washed through kieselguhr withethyl acetate and water.The organic layer was separated,washed with 0.h-hydrochloric acid and brine, dried, andevaporated. Chromatography gave the amorphous ketone(9a) (534 mg), vmax. 1 760, 1 710, and 1 620 cm-l; 6 1.98 (3 H,s), 2.02 (3 H, s), 2.22 (3 H, s), 2.53 and 2.86 (2 H, ABq, J15 Hz), 2.94br (1 H, s, exch.), 4.53 (1 H, m, collapsing to d,J 5 Hz, on D20 exch.), 4.65 (1 H, d, J 5 Hz), 5.0 and 5.25(2 H, ABq, J 12 Hz), and 7.1-7.6 (20 H, m) (Found: C,73.5; H, 6.1; N, 4.4; S, 5.1. C3,H,,N2O4S requires C,73.5; H, 6.0; N, 4.6; S, 5.3%).(b) The acetylene (4) (287 mg) in piperidine ( 5 ml) wasrefluxed for 2 h ; work-up as in (a) gave the ketone (9a)(192 mg).(288 mg) was stirred at room tempera-ture in piperidine (2 ml) for 22 h ; work-up as in (a) gavestarting material (8) (26 mg) and the ketone (9a) (195 mg).Reaction of (3R,4R) - 1-( 1-Benzyloxycarbonyl-2-methylprop-1-enyl) -4- (3-substituted prop-2-ynylthio) -3- (triphenylmethyl-amino)azetidin-2-ones (10) with Piperidine.-(a) The phenyl-acetylene (lob) (50 mg), refluxed in piperidine (2 ml) for2 h, with work-up as before, gave the amorphous (3R,4R)-1- ( 1-benzyloxycarbonyl-2-methylprop- 1-enyl) -4-(2-oxo-3-pJzen-ylpropylthio)-3-(triphenylmethylamino)azetidin-2-one (9b) (40mg), vmX.1 765, 1 720, and 1 630 cm-l; 6 1.97 (3 H , s), 2.2(3 H, s), 2.56 and 3.03 ( 2 H, ABq, J 15 Hz), 2.84br (1 H, s,exch.), 3.62 (2 H, s), 4.45 (1 H, m, collapsing to d, J 5 Hz, onD20 exch.), 4.65 (1 H, d, J 5 Hz), 5.02 and 5.22 (2 H, ABq,J 12 Hz), and 6.9-7.6 (25 H, m) (Found: C, 76.0; H, 6.0;N, 4.2; S, 4.9. C4,H4,N20,S requires C, 75.8; H, 5.9; hT,4.1; S, 4.7%).(b) The pyridylacetylene (lOc),l refluxed in piperidine for1 h, similarly gave (3R,4R)- 1-( 1-benzyloxycarbonyl-2-methyl-prop- l-enyl) -4- [2-oxo-3- (3-pyridyl)propylthio]-3- (triphenyl-methylamino)azetidin-2-one (9c) (48y0), vmax.1 760 and 1 715cm-l; 6 2.00 (3 H, s), 2.23 (3 H, s), 2.53 and 2.94 (2 H, ABq,J 15 Hz), 3.02 (1 H, d, J 8 Hz, exch.), 3.67 (2 H, s), 4.40-4.74 (2 H, m), 5.02 and 5.25 (2 H, ABq, J 12 Hz), 7.2-7.7(22 H, m), and 8.25-8.75 (2 H, m) (Found: C, 73.7; H,6.2; N, 6.5; S, 4.9. C,,H,,N,O,S requires C, 74.0; H,5.7; N, 6.2; S, 4.7%).(c) The p-methoxycarbonylphenylacetylene (1Od) (0.3 g)was left in piperidine at room temperature for 3 h ; work-upas before gave (3R,4R)- 1-( l-benzyloxycarbonyl-2-nzethylprop-l-enyl)-4- (3-p-methoxycarbonylphenyl-2-oxo~ropylthio) -3- (tri-phenylmethylamino)azetidin-2-one (0.3 g), vmax.1 770, 1 720,and 1 630 cm-l; 6 1.98 (3 H, s), 2.20 (3 H, s), 2.57 and 2.93(2H, ABq, J 15Hz), 2.98 ( 1 H, d, J 7Hz, exch.), 3.68 (2H,s), 3.90 (3 H, s ) , 4.41 (1 H, dd, J 5 and 7 Hz, collapsingto d, J 5 Hz, on D20 exch.), 4.70 (1 H, d, J 5 Hz), 4.98and 5.23 (2 H, ABq, J 13 Hz), 7.1-7.7 (22 H, m), and 8.0(2 H, d, J 8 Hz) (Found: C, 73.3; H, 5.9; N, 3.5; S, 3.8.C4,H,,N20,S requires C, 73.8; H, 5.7; N, 3.8; S, 4.3%).(d) The p-nitrophenylacetylene (10e) (300 mg) was left inpiperidine at room temperature for 1 h ; work-up as beforegave (3R,4R)- 1- ( l-benzyloxycarbonyl-2-nzethylpro~- l-enyl)-4-(3-p-nitro~henyl-2-oxo~ro~ylthio)-3-(tri~henyl~ethylamino)-azetidin-2-one (9e) (116 mg), v,,,.1 765, 1 720br, 1 630,1520, and 1350 cm-l; 6 2.06 (3 H, s), 2.27 (3 H, s), 2.63and 3.04 (2 H, ABq, J 15 Hz, covering exchangeable NHsignal), 3.82 (2 H, s ) , 4.64br (1 H, s, collapsing t o d, J 5 Hz,( c ) The allene (8)on D20 exch.), 4.79 (1 H, d, J 5 Hz), 5.09 and 5.32 (2 H,ABq, J 13Hz), 7.2-7.7 (22H, m), and 8.27 (2 H, d, J 9 Hz)(Found: C , 71.3; H, 5.4; N, 5.5; S, 4.4. C4,H,,N,0,Srequires C, 71.2; H, 5.4; N, 5.8; S, 4.4%).(3R, 4R)- 1- ( l-Benzyloxycarbonyl- 2-y~ethylprop- 1 -enyl) -4-(but-2-ynylsulphiny l) - 3- (triphenylnzetJiylanzilzo) azetidin-2-one.-The sulphide (1Of) (1.5 g) in chloroform (25 ml) wascooled (ice-bath) and treated with nz-chloroperbenzoic acid(0.45 g) in chloroform (10 ml), added dropwise over 20 min.After a further 20 min the solution was washed with sodiumhydrogen carbonate solution and then with water.Thedried solution was evaporated and the residue crystallisedfrom ether-light petroleum to give a single isomer (n.m.r.)of the sulphoxide (0.94 g), m.p. 133-135", vmx. 1 770, 1 715,and 1 620 cm-l; 6 1.71 (3 H, t, J 2.5 Hz), 2.22 (3 H, s ) , 2.23(2 H, s), 3.26 (2 H, q, J 2.5 Hz), 3.4br ( 1 H, s, exch.), 4 . 4 64.85 (2 H, m, collapsing to d, 6 4.48, J 5 Hz, and d, 6 4.51,J 5 Hz on D20 exch.), 4.98 and 5.20 (2 H, ABq, J 12 Hz),7.0-7.6 (20 H, m) (Found: C, 73.5; H, 6.0; N, 4.4; S,5.3. C,,H,,N204S requires C, 74.0; H, 5.9; N, 4.5; S,5.2%).(3R, 4R) - 1- ( l-Benzyloxycarbonyl-2-nzetJ~ylprop- l-enyl) -4- (2-oxobutylthio)-3-(triPhei~ylnzethylamino)azetidin-2-one (9f) .-The above butynyl sulplioxide (0.6 g) in piperidine (10 ml)was left at room temperature for 4 h ; work-up in the usualway gave (3R,4R) - 1- ( l-benzyloxycarbonyl-2-methylprop-l-enyl)-4- (2-oxobutylsulphinyl) -3-(triphenylmethylamino) -azetidin-2-one (0.436 g), vmax.1 770, 1 710 (ester and ketone),and 1620 cm-l; 6 0.97 (3 H, t, J 7 Hz), 2.1-2.4 (8 H, 2Me, covering CH,-CH2 signal), 3.33br ( 1 H, s, exch.), 3.23and 3.62 (2 H, ABq, J 14 Hz), 4.46br (1 H, collapsing to d,J 5 Hz, on D20 esch.), 4.97 and 5.25 ( 2 H, ABq, J 12 Hz),and 7.0-7.5 (20 H, ni). This sulphoxide (0.3 g) in dimethyl-fornianiide (3 nil) was cooled to 0 "C and treated with tri-phenylphosphine (0.246 g) and acetyl chloride ( l l 1 mg) .After 5 h in the refrigerator, the solution was poured intoethyl acetate and washed with sodium hydrogen carbonatesolution followed by water.The dried organic layer wasevaporated; chromatography of the residue gave the oxo-sulphide (9f) (0.22 g), vmax. 1 760, 1710br, and 1 625 cm-l;8 0.95 (3 H, t , J 7.5 Hz), 1.98 (3 H, s), 2.21 (3 H, s), 2.31(2 H, q, J 7.5 Hz), 2.50 and 2.85 (2 H, ABq, J 14 Hz),2.96br (1 H, s, exch.), 4.46br (1 H, collapsing to d, J 5 Hz,on D20 exch.), 4.65 (1 H, d, J 5 Hz), 5.00 and 5.25 (2 H,ABq, J 12 Hz), 7.1-7.6 (20 H, m) (Found: C, 73.2; H,6.2; N, 4.3. C,,H,,N,O,S requires C, 73.7; H, 6.2; K,4.5%).More (335 mg) of the same compound was obtainedby similar treatment of the non-crystalline isomeric mixtureof the acetylenic sulphoxide recovered from the crystallis-ation mother liquor.(3R, 4R)- 1-( 1 -BenzyZoxycarbonyl- 2-methylprop- l-enyl) -4- (4-phenylbut-2-ynylsulpl~inyl) -3- (triphenylnzethy lamino) azetidin-2-one.-The 4-phenylbut-2-ynyl sulphide (10 g ) (676 mg)was oxidised with m-chloroperbenzoic acid (190 mg) asdescribed for the but-2-ynyl analogue to give the amorphoussulphoxide (480 mg), vmax. 1 775 and 1 720 cm-l; 8 2.21 (3 H,s ) , 2.23 (3 H, s), 3.2-3.6 ( 5 H, m, 1 H exch. with D,O),4.5-4.8 (2 H, m), 4.96br (2 H, s), and 7.0-7.6 (m, ArH).(3R, 4R) - 1 - ( 1-Benzyloxycarbonyl- 2-methylprop- l-eny I ) -4- (2-oxo-4-phenylbutylsulphinyl)-3- (triphenyZmethy1amino)azetidin-2-one.-The above acetylene (150 mg) in piperidine (4 ml)was stirred at room temperature for 4 h; work-up in theusual way gave the amorphous ketone (99 mg), vmax.1 775and 1 715 cm-l; 6 2.22 (6 H, s), 2.5-2.9 (4 H, m), 3.0-3.7(3 H, m, collapsing to 3.17 and 3.55, 2 H, ABq, J 14 Hz1976 1619on D20 exch.), 4.4-4.75 ( 2 H, m), 4.94 and 5.22 (2 H,ABq, J 12 Hz), and 7.0-7.5 (m, ArH).( 3 R ,411) - 1 - ( 1 - B enzy loxy curb ony 1- 2 -met hy lpr op- 1 -eny 1) - 3-(phenoxyacetamido) -4- (prop-2-ynylsulphinyl) azetidin-2-one(ll).--The sulphide (6) (3.2 g) in chloroform (70 ml) at 0 "Cwas treated during 5 min with m-chloroperbenzoic acid(1.26 g). Usual work-up followed by careful chromato-graphy on silica gel H (150 g) gave the two pure isomericsulphoxides as amorphous solids.The faster-running isomer(1.12 g ) had vmx. 3 320, 3 250, 1 788, 1 725 sh, 1 625, and1 065 cm-l; 8 2.12 (1 H, t, J 3 Hz), 2.32 (6 H, s), 3.58 (2 H,t, J3Hz),4.62(2H,s),5.18and5.43(2H,ABq,J14Hz),5.5 (1 H, d, J 4 Hz), 6.05 (1 H, dd, J 4 and 10 Hz),6.87-7.67 (10 H, m), and 7.95 (1 H, d, J 10 Hz) (Found:The slower-running isomer (1.57 g) had vmx. 3 260, 1795,1 724, 1 695, 1 627, and 1 062 cm-1; 13 2.25 (1 H, s, J 3 Hz),2.2 (3 H, s ) , 2.35 (3 H, s), 3.47 (2 H, t, J 3 Hz), 4.63 (2 H,s), 5.1 and 5.23 (2 H, ABq, J 12 Hz), 5.18 (1 H, d, J 5 Hz),6.12 (1 H, dd, J 5 and 10 Hz), 6.87-7.6 (10 H, m), and8.75 (1 H, d, J 10 Hz) (Found: C, 62.5; H, 5.5; N, 5.3;S, 6.7. C,,H,,N20,S requires C, 63.1; H, 5.3; N, 5.7; S,6.5%).(3K,4R) -4-Acetonylsulphinyl- 1- ( l-benzyloxycarbonyl-2-methylprop- 1-enyl) -3-(phenoxyacetamido)azetidin-2-one ( 12).--Method 1.The acetylene (11; mixed isomers) (10 mg)was dissolved in the minimum volume of a secondary orprimary amine (ca. 0.2 ml). Work-up by addition of ethylacetate and washing with dilute hydrochloric acid ( x 2)and brine gave the Ketolze (12; mixed isomers) essentiallyquantitatively, vmx 3 350, 1 780, 1 720sh, 1 690, and 1 625cm-l (Found: C, 60.6; H, 5.4; N, 5.3; S, 6.5. C2,H28N20,Srequires C, 60.9; H, 5.1; N, 5.5; S , 6.3%).With the following amines the reaction was worked upafter 2-3 min: dimethylamine (33% in EtOH), ethylamine(33% in EtOH) , n-butylamine, benzylamine, cyclohexyl-amine, diethylamine.pyrrolidine, piperidine , and morphol-ine. Diallylamine and t-butylamine each required ca. 5-10min .Use of the individual acetylenic sulphoxide isomers gavethe separate isomers of the (3-0x0-sulphoxide (12) as amor-phous solids. The product from the faster-running isomerof the acetylene (11) had 6 2.12 (3 H, s), 2.27 (6 H, s), 3.52and 3.85 (2 H, ABq, J 15 Hz), 4.6 (2 H, s), 5.25 (1 H, d, J5 Hz), 5.28 (2 H, s), 5.92 (1 H, dd, J 5 and 10 Hz), 6.82-7.6(10 H, m), and 7.88 (1 H, d, J 10 Hz). That from theslower-running isomer of the acetylene (1 1) had 8 2.17 (6 H,s), 2.33 (3 H, s), 3.65 (2 H, s), 4.67 (2 H, s), 5.0 (1 H, d, J5 Hz), 5.17 and 5.4 (2 H, ABq, J 12 Hz), 6.1 (1 H, dd, J 5and 10 Hz), 6.7-7.7 (10 H, m), and 8.58 (1 H, d, J 10Hz).The acetylene (11) (25 mg) was dissolved inbenzene (0.2 ml) and treated with a secondary or primaryamine (5 equiv.) at room temperature.Work-up as inmethod 1 gave the ketone (12) quantitatively. The morereactive amines previously mentioned required ca. 10 min,diallylamine 1 h, and t-butylamine 6 h.In the case of volatile amines, alternative work-up byevaporation gave enamines. That from diethylamine hadvmx. 3 260, 1775, 1710, 1685, 1620, and 1550 cm-l(enamine). That from n-butylamine had v,, 3 360, 3 270,1 775, 1 718, 1 685, 1 620, and 1 588 cm-1 (enamine).(3R,4R) - 1- ( 1-Benzyloxycarbonyl-Z-methylprop- 1-enyl) -3-(phenoxyacetamido) -4- (2-t-butylaminoprop- 1-enylsulplzinyl) -azetidin-2-one (14) .-(a) The faster-running isomer of theN, 5.4; s, 6.7. C2,H2,N,O,jS requires N, 5.7; s, 6.5%).Method 2.acetylene (11) (43 mg) in dry benzene (0.5 ml) was treatedwith t-butylamine (30 mg) for 6 h, then the mixture wasevaporated and the product dried under high vacuum toleave a single isomer of the enamine (14) (48 mg), v,, 3 350,3 280, 1 775, 1 715, 1 685, 1 620, 1 590 (enamine), and 1 060cm-1; 6 1.2 (9 H, s), 1.97 (3 H, s), 2.30 (3 H, s), 2.40 (3 H,s), 4.17br (1 H, s, exch.), 4.60 (2 H, s), 4.95 (1 H, d, J 5 Hz),5.03 (1 H, s), 5.10 and 5.34 (2 H, ABq, J 12 Hz), 5.87 (1 H,dd, J 5 and 10 Hz), 6.9-7.7 (10 H, m), and 8.42 (1 H, d, J10 Hz).(b) The slower-running isomer of the acetylene (11) (95mg) was dissolved in t-butylamine (1 ml).After 5 min theamine was evaporated off, the residue dissolved in toluene,and the mixture re-evaporated.Drying under high vacuumthen gave an amorphous solid consisting of a mixture (ca.1 : 1) of two further (E- and 2-) isomers of the enamine (14) ;vmai 3 360, 3 260, 1775, 1715, 1 685, 1 620sh, 1590, and1060 cm-l; 6 1.15 and 1.2 (9 H, two s, lower field signalslightly more intense), 2.07 (3 H, s), 2.28 (3 H, s), 2.35 (3 H,s), 4.37br ( 1 H, s, exch.), 4.59 and 4.60 (2 H, two s, lowerfield signal slightly more intense), 4.80 (1 H, d, J 5 Hz),5.10 and 5.49 (2 H, ABq, J 12 Hz), 5.24 and 5.30 (1 H, twos, olefinic CH), 6.10 (1 H, dd, J 5 and 10 Hz, collapsingto d, J 5 Hz, on D,O exch.), 6.8-7.6 (10 H, m), and 9.27(1 H, d, J 10 Hz, exch.).(3R,4R)- 1- (1-Benzyloxycarbonyl-2-methylprop 1-enyl) -3-(phenoxy acetamido) -4- (propa- 1 , 2-dieny lsulphiny l) azetidin- 2-one (13) .-(o) The acetylene (1 1 ; mixed isomers) (342 mg)was dissolved in dry benzene (2.5 ml) and treated with t-butylamine (0.37 ml) for 15 min; then the mixture wasevaporated. Chromatography of the residue gave the allene(13; mixed isomers), an amorphous solid, vmx 3 360,1950w and 1 930w (allene), 1 780, 1 720, 1690, 1620, and1 068 cm-l (Found : N, 5.4; S, 6.8.C,,H,,N,O,S requiresN, 5.7; S, 6.5%).(b) Each isomer of the acetylene (11) (95 mg) in benzene(3 ml) was treated with triethylamine (0.5 ml) for 30 min;then the mixture was evaporated to give the allene (13) (95mg). The isomer from the faster-running acetylene (11)had 8 2.33 (6 H, s), 4.6 (2 H, s), 5.0-5.4 (5 H, m), 5.48-5.8(1 H, ni), 5.95 (1 H, dd, J 5 and 10 Hz), 6.8-7.6 (10 H, m),and 7.95 (1 H, d, J 10 Hz).The isomer from the slower-running acetylene (11) had 8 2.22 (3 H, s), 2.35 (3 H, s),4.62 (2 H, s), 4.88 (1 H, d, J 5 Hz), 4.95-5.45 (5 H, m),5.87 (1 H, m), 6.12 (1 H, dd, J 5 and 10 Hz), 6.8-7.58(10 H, m), and 8.65 (1 H, d, J 10 Hz).(3R,4R)-l-( 1-t-Butoxycarbonyl- l-hydroxynzethyl)-4-(3-p,henylProp-Z-ynylthio) - 3- (tripheny lmethylanzino) azetidin-2-one (16).-The azetidinone (15) (966 mg) and t-butylglyoxylate monohydrate ( 1.5 g) were refluxed in benzene(25 ml) with provision for removal of water. After 75 minthe solution was cooled, washed with water ( x 5), dried,and evaporated.Chromatography gave the amorphous a-hydroxy-ester (16) (940 mg) as a mixture of isomers, v,,,3 450, 1770, and 1735 cm-l; 8 1.78 and 1.80 (9 H, two s),3.17 and 3.35 (2 H, two s), 3-3.8vbr (2 H, exch.), 4.43-4.88 (2 H, m), 5.08 and 5.22 (1 H, two s), and 7.1-7.7(20 H, m).(3R,4R)- 1 - ( 1-Chloro- 1-t-butoxycarbonylmethyl) -4- (3-phelzyl-~ro~-2-ynyZthio)-3-(tri~henyZmethylamino)azetidin-2-one (1 7).-A solution of the a-hydroxy-ester (16) (606 mg) in drytetrahydrofuran (25 ml) was cooled to -15 "C and treatedwith dry 2,6-lutidine (315 mg), followed during 1-2 minby thionyl chloride (357 mg) in tetrahydrofuran (5 ml).After 15 rnin a precipitate was removed and the filtrat1620 J.C.S. Perkin Ievaporated to leave the cc-chloro-ester (17) as an amorphoussolid (629 mg), vmx.1 780 and 1 745 cm-1.(3R,4R)-4-( 3-PhenyZprop-2-ynylthio)- 1-( l-t-butoxycarbonyl-l-tri~henylphos~horanylidenemethyl) -3-(triphenylmethylami-no)azetidin-2-one (18). The cc-chloro-ester (17) (626 mg) wasdissolved in freshly distilled dioxan (15 ml) and treatedunder nitrogen with triphenylphosphine (525 mg) and 2,6-lutidine (210 mg), and the mixture was heated at 55-60 "Cfor 15 h, cooled, and filtered. The filtrate was evaporatedand the residue taken up in ethyl acetate and washed suc-cessively with very dilute hydrochloric acid, brine, aqueoussodium hydrogen carbonate, and brine again. The organiclayer was separated, dried, and evaporated, and the residuepurified by chromatography to give the phosphorane (18)as a white solid (827 mg), vmax.1 755 and 1 640 cm-1.( 3RJ4R)-4- (2-Oxo-3-~henylpropylthio) - 1- (l-t-butoxycarbon-yl- l-triphenyl~hosphoranylidenemethyl) -3- (triphenylmethyl-amino)azetidin-2-one ( 1 9) .-The acetylenic phosphorane (18)(445 mg) in piperidine (13 ml) was refluxed under nitrogenfor 54 h; the mixture was cooled and poured into ethylacetate, and the solution was washed with dilute hydro-chloric acid ( x 2) and brine ( x 2), dried, and evaporated.Chromatography gave the ketone (19) (331 mg), vmaX 1 755,1 720, and 1 635 cm-l.t-Butyl3-Benzyl-7~-triPhenylmethylarninoceph-3-em-4-carb-oxylate (20).-A solution of the ketone (19) (331 mg) indry dioxan (15 ml) was refluxed under nitrogen for 25 h,cooled, and evaporated. Chromatography of the residuegave the cephem (20) (141 mg), m.p.161-162' (fromacetone), [OiJ,, +lo (c 1 in CHCl,), vmx. 3 480, 1 775, 1 710,and1630cm-l; 6 1 . 5 0 ( 9 H , s ) , 2 . 9 2 ( l H , d , JlOHz,exch.),2.85 and 3.20 (2 H, ABq, J 18 Hz), 3.48 and 3.97 ( 2 H,ABq, J 15 H z ) , 4.25 ( 1 H , d, J 5 H z ) , 4.70 ( 1 H , dd, J 5 and10 H z , collapsing to d, J 5 Hz, on D20 exch.), and 7.1-7.7(20 H, m) (Found: C, 75.3; H , 6.2; N , 4.8; S , 5.4.C3,H36N203S requires C, 75.5; H, 6.2; N , 4.8; S , 5.5%).Toluene-p-sulphonic Acid Salt of t-Butyl 7P-Amino-3-benzylceph-3-euvl-4-carboxylate ( 2 1) .-A solution of the tri-tylaminocephem (20) (929 mg) in acetone (2 ml) was cooledto -20 "C and treated dropwise during 3 min with toluene-p-sulphonic acid (330 mg) in acetone ( 2 ml).The mixturewas left at 0 "C for 18 h, then the crystalline amine toluene-p-sulphonate salt (493 mg) was collected, washed with a littlecold acetone, and dried; 1n.p. 181-182', V,,~. (Nujol)1778, 1720, and 1640 cm-l (Found: C, 57.6; H, 5.8; N ,5.6; S , 12.3. C,,H2,N,06S2 requires C, 57.9; H , 5.8; N ,5.4; S , 12.4%).t-Butyl 3-Benzyl-7P-( 2-thienylacetamido)ceph-3-em-4-carb-oxylate (22) .-The amine toluene-9-sulphonate salt (258 mg)was suspended in dry methylene chloride (15 ml) a t - 20 'Cand treated with dry triethylamine (200 mg), followed drop-wise by 2-thienylacetyl chloride (90 mg) in dry methylenechloride ( 1 ml). After 10 min, the mixture was washed withwater, dried, and evaporated. Chromatography affordedthe amide (22) (129 mg), m.p. 153' (from ethyl acetate-lightpetroleum), -80" (c 1.1 in CHCl,); Am=. (EtOH) 237(c 13 900) and 266 nm (9 000); vmx (Nujol) 3 250, 1 780,1 718, 1 665, and 1 640 cm-l; 6 1.54 (9 H, s ) , 3.04 and 3.43( 2 H, ABq, J 19 H z ) , 3.77 and 4.05 ( 2 H, ABq, J 13 Hz),3.85 ( 2 H, s), 4.98 ( 1 H, d, J 5 H z ) , 5.83 (I H, dd, J 5 and10 Hz), 6.38 ( 1 H , d, J 10 Hz), and 6.98-7.3 ( 8 H, m)(Found: C, 61.0; H, 5.5; N , 5.8; S , 13.7. C2,H2,N20,S,requires C, 60.9; H, 5.6; N , 6.0; S , 13.6%).3-Benzyl-7 (3- (2-thienylacetnunido) cePh-3-em-4-carboxylicAcid (23).-The t-butyl ester (22) (97 mg) was dissolved inanhydrous trifluoroacetic acid ( 2 ml). After 5 min thesolution was evaporated, the residue treated with toluene,and the mixture re-evaporated ( x 3). The residue was dis-solved in ethyl acetate and extracted ( x 2) with saturatedsodium hydrogen carbonate solution. The combinedextracts and aqueous washings were covered with ethylacetate, cooled to 0 "C, and treated with 20% hydrochloricacid (to pH 2.8), and the layers were separated. Thesolvent layer was washed with brine, dried, and evaporatedto leave the amorphous cephalosporin (23) (64 mg),-63' ( c 0.97 in CHCl,); A,,, (EtOH) 237 (E 11 600) and265.5 nm (6 900); vmax. 2 500-3 400br, 1 780, 1 720sh,1680, and 1 630sh cm-1; 6 3.02 and 3.40 ( 2 H, ABq, J 20Hz), 3.57 and 4.13 ( 2 H, ABq, J 15 Hz), 3.81 ( 2 H, s ) , 4.97( 1 H, d, J 5 Hz), 5.75 ( 1 H, m, collapses to d, J 5 Hz, onD20 exch.), 6.75 ( 1 H, d , J 9 Hz, exch.), 6.86-7.4 (8 H ,m), and 7.73br (1 H, s, exch.).[6/343 Received, 18th February, 1976
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