β-Lactam  reacts with hetero nucleophiles under ring cleavage to give 2,2-dimethyl-3-oximinobutanoic esters 6 and 7 . N-hydroxyazetidine 5 , the precursor of β-lactam 1, is prepared by a new method

Elburg, P.A. van

Harkema, S.

Hummel, G.J. van

Reinhoudt, D.N.

English

β-Lactam reacts with hetero nucleophiles under ring cleavage to give 2,2-dimethyl-3-oximinobutanoic esters 6 and 7 . N-hydroxyazetidine 5 , the precursor of β-lactam 1, is prepared by a new method

van Elburg, P.A.

Reinhoudt, David

Harkema, Sybolt

van Hummel, G.J.

University of Twente Research Information

Tetrahedron Letters,Vo1.26,No.23,pp 2809-2812,1985 0040-4039/85 $3.00 + .OO Printed in Great Britain 01985 Pergamon Press Ltd. 1,4-DIACETOXY-@-JACTAMS. REACTIONS WITH NUCLEOPHILES P.A. van Elburg,a D.N. Reinhoudt, a* S. Harkemab and G.J. van Hummel b Laboratories of Organic Chemistrya and Chemical Physics, b Twente University of Technology, Enschede, The Netherlands Abstract. S-Lactam 1 reacts with hetero nucleophiles under ring cleavage to give 2,2-dimethyl-3- oximinobutanoic esters 6 and 7. N-hydroxyazetidine 2, - -- the precursor of 8-lactam 1, is prepared by a new method. As part of our work on four-membered cyclic nitrones we have recently reported that l-hydroxy- asetidine 5 can be oxidized with lead tetraacetate to 1,4-diacetoxy-3,3,4-trimethyl-2-azetidinone ($ - 4-Acetoxy-2-azetidinones have been widely used in S-lactam chemistry2 and 1-hydroxy-2- azetidinones have recently received much attention after the discovery of the biologically active monocyclic S-lactams. 3 Previously we have shown that the ester function in N,N-diethyl-1-(acetoxy)-4-methyl-3-phenyl- -- 2-asetidinone-4-carboxamide4 can be saponified with sodium methoxide in diethyl ether without ring opening of the &lactam. Therefore we have investigated reactions of &lactam 1 with two - equivalents of nucleophile as a possible route to 4-substituted l-hydroxy-2-asetidinones. 1-Hydroxyazetidines can be synthesized by reductive cyclization of c-benzyl-B_tosyloxy ox- imes. 1 The disadvantage of this method is the possibility of S-elimination of the leaving group and therefore we have developed an alternative method. Recently Sammes and Smith reported the synthesis of N-substituted asetidines by cyclisation of y-hydroxyamines. 5 We found that the same - type of reaction can be used for the cyclization of hydroxylamine derivatives (Scheme I). Reac- tion of 3,3-dimethyl-4-hydroxy-2-butanone' with 0-benzylhydroxylamine afforded the oxime 2 in a yield of 79% [bp 86-88 'C/O.1 mm Hg; ni2 1.5148; -13 - C-NMR (CDC13) 6 163.1 (s, C=N), 70.1 (t, CH20H); MS: (M - OH>+ 204.138 (CIBHIsNO)]. Reduction of oxime 2 with NaCNBHB in acetic acid af- - forded the hydroxylamine 2 in a yield of 79% [bp 98-100 'C/O.07 mm Hg; G2 1.5022; 'H-NMR (CDC13) 6 4.48 (bs, 2H, NH and OH), 3.38 (s, 2H, CH20H); 13C-NMR (CDC13) 6 72.6 (t, CH20H); MS: M+ 223.156 (C13H21N02)]. Th e cyclization of compound 3 to 1-benzyloxyazetidine 4 was achieved in a - - yield of 75% by the addition of carbon tetrabromide and triethylamine to a solution of triphenyl- phosphine and hydroxylamine 3 in acetonitrile, - followed by further reaction at room temperature for 4h. Catalytic debensylation of the azetidine 4 and subsequent oxidation of the resulting l- hydroxyasetidine 5 to the 1,4-diacetoxy-2-asetidinone 1 were carried out as described previous- - ly.1 2809 2810 PPh3 ,OCHzPh CBr4, Et3N Me CH3CN Me 4 Me A Me Me Me 5 ?. Scheme I (Fig. I). From this figure it can be concluded data: C7HlBNOB; monoclinic; space group P21/c, S = 94.47 (l)O, Z = 8. Structure determination ite monochromator) with intensity greater than The structure was solved by direct methods and Reaction of 1,4-diacetoxy-S-lactam 1 with two equivalents of sodium methoxide, at 0 'C in - diethyl ether, afforded 3-hydroximino-2,2-dimethylbutanoic acid methyl ester (6a)7 (Scheme II) - [yield 47%; mp 59-60 "C (petroleum ether bp 40-60 "C); lH-NMR (CDClB) 6 8.70 (bs, lH, OH), 3.70 (8, 3H, OCH3); 13C-NMR (CDClB) 6 175.3 (s, C=O), 159.3 (8, C=N); IR (KBr) 1740 (C=O), 1670 (C=N) cm -l; MS: M+ 159.090 (C7Hl$iOB)]. The structure and stereochemistry were proven by X-ray analysis that compound 6a has the E-configuration. Crystal - - a = 7.521 (l), b = 20.122 (Z), c = 11.529 (1) A, based on 2631 reflections (MO Ka radiation, graph- the standard deviation from counting statistics. refined with full matrix least squares to a final R-factor of 4.5X." Parameters refined: scale factor, extinction parameter, positional and ther- ma1 (isotropic for hydrogen atoms, anisotropic for others) parameters. 8b All hydrogen atoms have been found from a difference Fourier synthesis. Me 1) 2 Re 2) AcCI/Et3N c Me - Me 0 7 1 2 Re Me Me Me 0 s 9. R:MeO Q. R-Et0 E. R=EtS Me /N-OH ;(r 3. R=PhO z: b. R= 4-NO2 -PhO R c. R= 4- t&r-PhO 0 g. R= PhS ? Me,+d-OR’ Me Me OMe 0 8 a. R’ = AC Q. R’ I: CH2COOEt E. R’= SQCH3 9. R’ = SO$%(nBu)4 Scheme II 2811 Similar reactions with two equivalents of sodium ethoxide and sodium thioethoxide gave the oximes 6b and 6c in yields of 47% and 52%, respectively.6 Reaction of &lactam 1 with sodium phenoxides -- - and sodium thiophenoxides in aqueous acetone (1:l) resulted in a mixture of the acylated oximes 7 and the oximes z These compounds could not be separated but acylation of the crude product af- forded the oximes 7a-d (Scheme II). Compound 7c yield 34%; mp 104-105 'C (petroleum ether bp -- -7 [ 40-60 "C); 'II-NMR (CDC13) 6 2.21 (6, 3H, 0CH3); 13C-NMR (CDC13) 6 172.9 (6, C=O>, 168.9 (8, COCH3), 165.8 (s, C=N); IR (KBr) 1775 (OAc), 1754 (GO), 1640 (C=N) cm-'; MS: M+ 319.175 (C16H25N04)]; compound 7d [yield 48%; oil; - 'H-NMR (CDC13) 6 2.23 (s, 3H, COCH3); 13C-NMR (CDC13) 6 184.1 (s, c=o), 169.0 (s, COCH3), 165.6 (6, GN); IR (NaCl) 1775 (OAc), 1700 (C=O), 1632 (C-N) cm -1; MS: M+ 279.091 (C1,+H17N03S)]. Woulfe and Miller have reported that IJ-hydroxy-O-substituted 8-lactams - are usually more susceptible to nucleophilic attack at the 8-lactam carbonyl moiety than the corresponding N-alkyl 8-lactams. 3b This in- - creased reactivity was also found in the activity of monobactams, 3c sulfactams3a and oxamaains.3b The enhanced susceptibility of 1,4-diace- toxy-2-azetidinone 1 to ring opening is illustrated by the difference in the reactivity of 8-lactam 1 and 1-acetoxy-8-lactams with sodium carbo- - nate in aqueous methanol. Reaction of &lactam 1 resulted in the forma- - tion of oxime &, while the 1-acetoxy-2-azetidinones could be saponified Fig.1 View of 6a to give the 1-hydroxy-&lactams. 3b A similar ring opening of 8-lactams - as shown in Scheme II has been reported by Page and Proctor in the reac- tion of cephalosporines with nucleophiles. 9 The oximes 6 can be acylated with acetyl chloride and triethylamine. Acylation of oxime 6a - - afforded compound 8a as an oil in quantitative yield (Scheme II) [lH-NMR (CDC13) 6 2.19 (8, 3H, - COCH3), 1.93 (6, 3H, CH3-C=N); 13C-NMR (CDC13) 6 174.7 (6, C=O), 169.1 (8, COCH3), 166.1 (6, C=N); IR (NaCl) 1795 (OAc), 1760 (GO), 1660 (C-N) cm-l; MS: M+ 170.082 (CSH15N0,,>]. Catalytic deacylation of oximes 7a-d and 8a with Pd/C (5%) in ethanol afforded the oximes 9a-d and &, res- -- - -- pectively, in high yields; oxime &: [ mp 123-125 "C (diisopropyl ether); 'H-NMR (CDC13) 6 8.20 (bs, lH, OH), 2.26 (8, 3H, CH3-C=N); 13C-NMR (CDC13) 6 173.7 (8, C=O), 158.9 (s, C=N), 11.6 (q, CH3-C=N); MS: M+ 277.167 (C16H23N03)]. Besides acylation, oxime 6a could be alkylated and reacted - with methanesulfonyl chloride and pyridine*S03. Oxime 6a was alkylated by ethyl bromoacetate in - diethyl ether to give compound 8b (Scheme II) [yield 58%; oil; - 'H-NMR (CDC13) 6 4.60 and 4.58 (6, 2H, OCH$O), 3.69 (s, 3H, OCH3); MS: M' 245.127 (C11H19N05)]. Reaction of 6a with methanesulfonyl - chloride afforded compound 8c [yield 88%; oil; lH-NMR (CDC13) 6 3.72 (6, 3H, 0CH3), 3.12 (s, 3H, - SOzCH3); IR (NaCl) 1750 (C=O), 1380 and 1200 (OSO2CH3) cm-'] (Scheme II). Oxime 6a was reacted - with pyridine*S03 in pyridine followed by treatment with tetrabutylammonium hydrogen sulfate to afford compound 8d as a thick colourless oil (Scheme II) [yield 65%; 'H-NMR (CDC13) 6 3.66 (s, - 3H, 0CH3), 3.28 (t, J = 7.1 Hz, 8H, NCH$; "C-NMR (CDC13) 6 175.7 (s, C=O), 161.3 (6, C-N), 58.8 (t, NCH2); IR (NaCl) 1782 (C-O) cm-']. The above results show that 1,4-diacetoxy-3,3,4-trimethyl-2-azetidinone (i) is much more susceptible to ring opening by nucleophiles than 4-acetoxy-2-asetidinones or 1-acetoxy-2-azet- idinones. 2812 Acknowledgement. This investigation was supported by the Netherlands Foundation for Chemical Research (SON) with financial aid from the Netherlands Organization for Advancement of Pure Research (ZWO). References and notes 1. M.L.M. Pennings and D.N. Reinhoudt, J. Org. Chem. 5, 4043 (1983). 2. K. Clauss, D. Grimm and G. Prossel, Liebigs Ann. Chem. 539 (1974); M.M. Campbell and B.P. Connarty, Heterocycles 19, 1853 (1982); T. Kobayashi, N. Ishido and T. Hiraoka, J. Chem. Sot., Chem. Commun. 736 (1980); M.D. Bachi and A. Gross, J. Chem. Sot., Perkin Trans. 1.1157 (1983); M. Ihara, A. Nakayama and K. Fukumoto, Tetrahedron 38, 2489 (1982); K. Clauss, H.J. Friedrich and H. Jensen, Liebigs Ann. Chem. 561 (1974); K. Hirai, Y. Iwano and K. Fujimoto, Tetrahedron Lett. 23, 4025 (1982); M. Aratani, K. Sawada and M. Hashimoto, Tetrahedron Lett. 23, 3921 -- (1982). 3. 8) M.J. Miller, A. Biswas and M.A. Krook, Tetrahedron 2, 2571 (1983); b) S.R. Woulfe and M.J. - Miller, Tetrahedron Lett. 5, 3293 (1984); 2) C.M. Cimarusti, D.P. Bonner, H. Breuer, H.W. Chang, A.W. Fritz, D.M. Floyd, T.P. Kissick, W.H. Koster, D. Kronenthal, F. Massa, R.H. Mueller, J. Pluscec, W.A. Slusarchyk, R.B. Sykes, M. Taylor and E.R. Weaver, Tetrahedron 2, 2577 (1983); d_) E.M. Gordon, M.A. Ondetti, J. Pluscec, C.M. Cimarusti, D.P. Bonner and R.B. Sykes, J. Am. Chem. Sot. 2, 6053 (1982); e) D.M. Floyd, A.W. Fritz, J. Pluscec, E.R. Weaver - and C.M. Cimarusti, J. Org. Chem. 47, 5160 (1982); f) F.R. Atherton and R.W. Lambert, Tetrahedron 2, 1039 (1984). 4. M.L.M. Pennings and D.N. Reinhoudt J. Org. Chem. 48, 486 (1983). 5. P.G. Sammes and S. Smith, J. Chem. Sot., Perkin Trans. 1241 (1984). 6. Compound 6b: yield 47%; oil; - 'H-NMR (CDClB) 6 9.15 (bs, lH, OH), 4.17 (q, J = 7.1 Hz, 2H, OCH2); 13C-NMR (CDClB) 6 174.8 (8, C=O), 159.3 (8, C-N); IR (KBr) 1740 (C=O) cm-'; MS: M+ 173.105 (CSHISNOB); compound 6c7: yield 52%; mp 35-36 'C (petroleum ether bp 40-60 "C); 'H-NMR - (CDClS) 6 9.22 (bs, lH, OH), 2.87 (q, I = 7.3 Hz, 2H, SCH2); '+NMR (CDClB) 6 202.8 (8, C-O), 158.9 (s, C=N); IR (KBr) 1660 (C=O and C=N) cm-l; MS: M' 189.082 (CsHISN02S); compound 2: yield 33%; oil; 'H-NMR (CDClB) 6 2.21 (8, 3H, COCHS); 13C-NMR (CDClB) 6 172.9 (s, C=O), 169.0 (s, COCHS), 166.0 (s, C=N); IR (NaCl) 1780 (OAc), 1765 (C=O), 1660 (C-N) cm-'; MS: M+ 263.116 (C14H17N04); compound E . 7* yield 29%; mp 59-60 'C (petroleum ether bp 40-60 "C); 'H-NMR (CDClS) 6 2.20 (8, 3H, COCHS); 13C-NMR (CDC13) 6 172.0 (8, C=O), 168.2 (s, COCH3), 165.9 (8, C=N); IR (KBr) 1780-1760 (OAc and C-O), 1640 (C=N) cm-'; MS: (M - 4-N02-PhO)+ 170.082 (CSHI2NOR). 7. Satisfactory elemental analyses were obtained for all new crystalline compounds (C, H, N + 0.3%). 8. a) The atomic co-ordinates for this work are available on request from the Director of the - Cambridge Crystallographic Data Centre, University Chemical Laboratory, Lensfield Road, Cambridge CB2 IEW, UK. Any request should be accompanied by the full literature citation for this communication. b) Supplementary data available: a list of observed and calculated structure factors. See Announcement to Authors, Tetrahedron Lett. 4, 5154 (1983). 9. M.I. Page and P. Proctor, J. Am. Chem. Sot. 106, 3820 (1984). (Received in UK 4 March 1985) 

1,4-diacetoxy-β-lactams. Reactions with nucleophiles

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