An electrochemical alternative strategy to the synthesis of β-lactams

Electrochimica Acta 51 (2006) 5540–5547

An electrochemical alternative strategy to the synthesis of ␤-lactams Part 2 [1]. C3 C4 bond formation M. Feroci a,∗ , M. Orsini a , L. Rossi b , G. Sotgiu c , A. Inesi a,∗ a

Dip. Ingegneria Chimica, Materiali, Materie Prime e Metallurgia, Universit`a “La Sapienza”, via Castro Laurenziano 7, I-00161 Roma, Italy b Dip. Chimica, Ingegneria Chimica e Materiali, Universit` a degli Studi, I-67040 Monteluco di Roio, L’Aquila, Italy c Dip. Elettronica Applicata, Universit` a di Roma Tre, via Vasca Navale 84, I-00146 Roma, Italy Received 17 January 2006; received in revised form 20 February 2006; accepted 21 February 2006 Available online 11 April 2006

Abstract Electrochemically induced synthesis of ␤-lactams, by cyclization (via C3 C4 bond formation) of haloamides XCHR1 CONR2 CHR3 R4 (X: Br, Cl), has been achieved in suitable solvent-supporting electrolyte solutions previously electrolyzed under galvanostatic control. The yields and the stereochemistry of the process are affected by the nature of substituents R1 –R4 and of solvent-supporting electrolyte solutions and by the electrolysis conditions. © 2006 Elsevier Ltd. All rights reserved. Keywords: ␤-Lactams; Cyclization; Bromoamides; Stereoselectivity; Organic electrosynthesis

1. Introduction The azetidin-2-one ring (␤-lactam), a four-membered cyclic amide, is the key structural unit of the most important classes of antibiotic agents such as penicillins, cephalosporins, monobactams, etc. [2]. Recently, new biologically active substrates, based on the azetidin-2-one core, have been reported: prostate specific antigen [3], thrombin [4], human cytomegalovirus protein [5], cysteine protease [6], human leukocyte elastase [7] and cholesterol absorption inhibitors [8]. Furthermore, the considerable variety of transformations related to the selective bond cleavage (enhanced by the ring strain) of the azetidin-2-one core has suggested a systematic use of the ␤-lactam skeleton as a synthon in organic synthesis [9]. Consequently, a great deal of work has been promoted for developing new and more efficient strategies for the synthesis of the azetidin-2-one ring [9c,10]. In addition to the most frequently employed methodology (the [2 + 2] ketene–imine cycloaddition, i.e. the Staudinger reaction [11]), the synthesis of the ␤-lactam ring via base

∗

Corresponding authors. Tel.: +39 06 49766563; fax: +39 06 49766749. E-mail addresses: [email protected] (M. Feroci), [email protected] (A. Inesi). 0013-4686/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.electacta.2006.02.026

promoted cyclization of suitable substrates has been reported [12]. Recently, we have synthesized the azetidin-2-one ring by N–C4 cyclization of haloamides induced by pre-electrolyzed solvent-supporting electrolyte solutions [1]. Constant current electrolyses of these solutions yield basic intermediates that can deprotonate suitable substrates, i.e. linear amides containing an acidic N H function and a leaving group. In this way, these electrogenerated bases can induce the cyclization of haloamides to ␤-lactam via N C4 bond formation. At present, we are engaged to study a possible extension of such electrochemical methodology to a C3 C4 cyclization, using these pre-electrolyzed solutions to deprotonate C H acidic haloamides, thus inducing an intramolecular nucleophilic substitution to yield ␤-lactams. Keeping in mind that the nature of the substituents at the C3 and C4 atoms and their relationship (trans or cis) are both essential for the biological activity, and that the stereochemistry of the ␤-lactam can be controlled by the structure of the precursor (substrate control) and/or by proper choice of the reagents (reagent control), we have planned to investigate (as concern the yield and the cis/trans ratio of the isolated ␤-lactams) the reactivity of several haloamides 1a–p in different pre-electrolyzed solvent-supporting electrolyte solutions (Scheme 1).

M. Feroci et al. / Electrochimica Acta 51 (2006) 5540–5547

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Scheme 1.

2. Experimental 2.1. Starting material Purifications of solvents and supporting electrolytes have been described elsewhere [1]. Compounds 1a–p were synthesized following the described procedure [13]; the spectral data of known compounds were in accordance with those reported: 1a–f [13] and 1l [14]. 2.1.1. Ethyl 2-(N-benzyl-2-chloro-2-phenylacetamido) acetate 1g, mixture of two rotamers 1 H NMR (CDCl ), δ: 1.12–1.29 (m, 3H), 3.82–4.21 (m, 3 4.3H), 4.53–4.60 (m, 1.4H), 4.79 (d, 0.3H, J = 15.0 Hz), 5.58 (s, 0.3H), 5.71 (s, 0.7H), 7.07–7.50 (m, 10H). 13 C NMR (CDCl3 ), δ: 14.1, 48.1 (major rotamer, M), 48.5 (minor rotamer, m), 50.8 (m), 52.4 (M), 57.8 (m), 58.1 (M), 61.2 (M), 61.7 (m), 126.9, 127.8, 128.1, 128.5, 128.9, 129.1, 135.3, 135.8, 168.0 (m), 168.3, 168.6 (M). 2.1.2. N-Benzyl-N-cyanomethyl-2-bromo-2-propanamide 1h, mixture of two rotamers 1 H NMR (CDCl ), δ: 1.84 (d, 3H, J = 6.5 Hz), 3.97 (d, 0.3H, 3 J = 18.6 Hz), 4.22 (s, 2H), 4.33–4.86 (m, 2.4H), 5.05 (d, 0.3H,

J = 14.9 Hz), 7.24–7.40 (m, 5H). 13 C NMR (CDCl3 ), δ: 21.5, 33.8 (M), 35.1 (m), 37.1 (M), 37.7 (m), 49.5 (m), 51.8 (M), 114.8, 127.0, 128.3 (m), 128.7 (M), 129.4, 134.0 (M), 134.4 (m), 168.7 (m), 169.8 (M). MS m/e (relative intensity): 201 (M•+ —Br, 18), 174 (10), 145 (3), 91 (100). 2.1.3. Ethyl 2-(2-bromo-N-(4-methoxyphenyl) propanamido)acetate 1i 1 H NMR (CDCl ), δ: 1.23 (t, 3H, J = 7.1 Hz), 1.70 (d, 3 3H, J = 6.7 Hz), 3.78 (s, 3H), 4.10–4.23 (m, 3H), 4.28 (q, 1H, J = 6.7 Hz), 4.44 (d, 1H, J = 17.1 Hz), 6.86–6.90 (m, 2H), 7.24–7.35 (m, 2H). 13 C NMR (CDCl3 ), δ: 14.0, 21.5, 38.2, 51.9, 55.4, 61.2, 114.8, 128.9, 134.3, 159.6, 168.5, 170.2. MS m/e (relative intensity): 345 (M•+ , 9), 343 (M•+ , 9), 209 (35), 136 (100), 120 (33). 2.1.4. Ethyl 2-(2-bromo-N-(4-nitrophenyl) propanamido)acetate 1j 1 H NMR (CDCl ), δ: 1.26 (t, 3H, J = 7.2 Hz), 1.75 (d, 3H, 3 J = 6.6 Hz), 4.20 (q, 3H, J = 7.2 Hz), 4.52 (d, 1H, J = 17.2 Hz), 7.65 (d, 2H, J = 8.7 Hz), 8.30 (d, 2H, J = 8.7 Hz). 13 C NMR (CDCl3 ), δ: 14.1, 21.5, 37.9, 51.7, 61.8, 125.2, 129.1, 147.2, 147.5, 168.2, 169.3. MS m/e (relative intensity): 360 (M•+ , 1), 358 (M•+ , 1), 224 (62), 151 (100).

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2.1.5. Diethyl 2-(2-bromo-N-(4-methoxyphenyl) propanamido)malonate 1k 1 H NMR (CDCl ), δ: 1.21 (app. t, 6H, J = 7.1 Hz), 1.71 (d, 3 3H, J = 6.6 Hz), 3.80 (s, 3H), 4.04–4.27 (m, 4H), 4.52 (q, 1H, J = 6.6 Hz), 5.32 (s, 1H), 6.88 (d, 2H, J = 9.0 Hz), 7.41 (d, 2H, J = 9.0 Hz). 13 C NMR (CDCl3 ), δ: 13.8, 13.9, 21.5, 26.4, 38.2, 55.5, 61.9, 62.2, 114.6, 130.5, 131.7, 160.1, 165.3, 165.4, 167.2. MS m/e (relative intensity): 336 (M•+ —Br, 8), 335 (M•+ —HBr, 42), 149 (81), 134 (100). 2.1.6. 2-Bromo-N-(4-methoxyphenyl)N-(2-phenyl-2-oxoethyl)-propanamide 1m 1 H NMR (CDCl ), δ: 1.76 (d, 3H, J = 6.6 Hz), 3.80 (s, 3H), 3 4.41 (q, 1H, J = 6.6 Hz), 4.80 (d, 1h, J = 17.3 Hz), 5.29 (d, 1H, J = 17.3 Hz), 6.87–6.92 (m, 2H), 7.37–7.46 (m, 5H), 7.89–7.93 (m, 2H). 13 C NMR (CDCl3 ), δ: 21.8, 38.5, 55.5, 56.9, 114.9, 127.9, 128.7, 129.3, 133.6, 134.6, 135.2, 159.6, 170.3, 193.1. MS m/e (relative intensity): 377 (M•+ , 4), 375 (M•+ , 3), 296 (9), 136 (100). 2.1.7. N-Benzyl-2-bromo-N-(2-phenyl-2-oxoethyl) propanamide 1n, mixture of two rotamers 1 H NMR (CDCl ), δ: 1.86 (d, 3H, J = 6.5 Hz), 3.95 (d, 0.4H, 3 J = 15.2 Hz), 4.20 (q, 0.4H, J = 6.5 Hz), 4.55–5.01 (m, 3.8H), 5.37 (d, 0.4H, J = 15.2 Hz), 7.24–7.65 (m, 8H), 7.85–7.90 (m, 2H). 13 C NMR (CDCl3 ), δ: 21.5 (m), 21.8 (M), 37.8 (M), 39.0 (m), 50.4 (m), 52.0 (M), 52.5, 53.1 (m), 126.9, 127.4, 127.6, 127.9, 128.0 (m), 128.1 (M), 128.6 (m), 129.0 (M), 133.5 (M), 134.2 (m), 135.8 (M), 136.5 (m), 170.3 (M), 170.4 (m). MS m/e (relative intensity): 279 (M•+ —HBr, 38), 280 (M•+ —Br, 8), 224 (20), 105 (39), 91 (100). 2.1.8. 2-Bromo-N,N-dibenzylpropanamide 1o 1 H NMR (CDCl ), δ: 1.84 (d, 3H, J = 6.5 Hz), 3.98 (d, 1H, 3 J = 14.9 Hz), 4.31 (d, 1H, J = 17.5 Hz), 4.50 (d, 1H, J = 6.5 Hz), 4.77 (d, 1H, J = 17.5 Hz), 5.29 (d, 1H, J = 14.9 Hz), 7.10–7.40 (m, 10H). 13 C NMR (CDCl3 ), δ: 21.7, 38.5, 48.9, 50.2, 127.5, 127.8, 128.0, 128.4, 128.7, 129.1, 136.2, 136.7, 170.2. MS m/e (relative intensity): 252 (M•+ —Br, 49), 106 (38), 91 (100). 2.1.9. N-Benzyl-N-methyl-2-bromopropanamide 1p, mixture of two rotamers 1 H NMR (CDCl ), δ: 1.78 (d, 0.9H, J = 6.5 Hz), 1.84 3 (d, 2.1H, J = 6.6 Hz), 2.95 (s, 0.9H), 2.97 (s, 2.1H), 4.40 (d, 1H, J = 15.3 Hz), 4.49 (q, 0.3H, J = 6.5 Hz), 4.60 (q, 0.7H, J = 6.6 Hz), 4.76 (d, 0.7H, J = 14.6 Hz), 4.80 (d, 0.3H, J = 16.7 Hz), 7.12–7.34 (m, 5H). 13 C NMR (CDCl3 ), δ: 21.6 (M), 21.7 (m), 34.6 (m), 34.8 (M), 38.1 (m), 38.4 (M), 53.3 (M), 53.4 (m), 126.1, 127.4 (m), 127.8 (M), 128.5 (M), 128.9 (m), 136.1 (m), 136.6 (M), 169.2 (M), 169.6 (m). MS m/e (relative intensity): 176 (M•+ —Br, 51), 120 (5), 91 (100). 2.2. Instrumentation GC–MS measurements were carried out on a SE 54 capillary column using a Fisons 8000 gas chromatograph coupled with a Fisons MD 800 quadrupole mass selective detector. 1 H

and 13 C NMR spectra were recorded using a Bruker AC 200 spectrometer using CDCl3 as internal standard. Electrolyses under galvanostatic or potentiostatic control were carried out with an Amel 552 potentiostat equipped with an Amel 721 integrator. A two-compartment cell was used; the cathode was a Pt spiral (apparent area 4.5 cm2 ) and the counter electrode was a cylindrical platinum gauze (apparent area 1.3 cm2 ). The reference electrode was a modified saturated calomel electrode. Its potential was −0.07 V versus SCE. The anodic solution (MeCN-0.1 mol dm−3 Et4 NClO4 ) was separated from the cathodic compartment through a porous plug filled with methylcellulose in DMF-TEAP. 2.3. General procedure Constant current electrolyses were carried out (using Pt electrodes and solvent-supporting electrolyte system described in the tables) in solvent-0.1 mol dm−3 supporting electrolyte solutions (30 ml) with continuous nitrogen bubbling. At the end of the electrolyses, compounds 1a–p (0.5 mmol) were added to the catholyte and the solution was allowed to stand under stirring for 3 h. Potentiostatic electrolyses were carried out in solvent0.1 mol dm−3 supporting electrolyte solutions (30 ml) containing probase A (tetraethyl ethenetetracarboxylate, 0.5 mmol). At the end of the electrolyses, bromoamide 1a (0.5 mmol) was added to the catholyte and the solution was allowed to stand under stirring for 3 h. The solvent was evaporated under reduced pressure, the residue poured into water and extracted with diethyl ether (3 × 30 ml). The extracts were analyzed by thin layer chromatography, GC–MS and 1 H NMR; all products were purified by flash chromatography, using n-hexane–ethyl acetate 8:2 as eluent. All known compounds were identified by comparison of their spectral data with data reported in literature: 2a–f [13], 2i [15], 2l [14]. 2.3.1. Ethyl 1-benzyl-4-oxo-3-phenylazetidine2-carboxylate 2g, mixture of trans and cis isomers 1 H NMR (CDCl ), δ: 0.75 (cis, t, 3H, J = 7.1 Hz), 1.26 3 (trans, t, 3H, J = 7.2 Hz), 3.73 (cis, dq, 1H, J = 7.2 and 1.8 Hz), 3.90 (trans, d, 1H, i = 2.6 Hz), 4.23 (trans, d, 1H, J = 14.9 Hz), 4.25 (cis, d, 1H, J = 14.8 Hz), 4.19 (q, 2H, J = 7.2 Hz), 4.39 (trans, d, 1H, J = 2.2 Hz), 4.69 (cis, d, 1H, J = 6.1 Hz), 4.90 (trans, d, 1H, J = 14.9 Hz), 4.99 (cis, d, 1H, J = 14.8 Hz), 7.20–7.37 (m, 10H). 13 C NMR (CDCl3 ), δ, cis: 13.5, 45.3, 57.1, 59.2, 61.0, 127.3, 127.9, 128.4, 128.7, 128.9, 131.7, 134.8, 166.7, 168.5; trans: 14.1, 45.5, 58.4, 59.7, 61.6, 127.3, 128.0, 128.2, 128.5, 128.9, 133.9, 134.9, 166.8, 169.9. MS m/e (relative intensity): 309 (M•+ , 1), 265 (3), 236 (2), 176 (78), 131 (100), 91 (77). 2.3.2. 1-Benzyl-4-cyano-3-methyl-2-oxoazetidine 2h, mixture of trans and cis isomers 1 H NMR (CDCl ), δ, cis: 1.45 (d, 3H, J = 7.3 Hz), 3.44–3.57 3 (m, 1H), 4.11 (d, 1H, J = 5.3 Hz), 4.12 (d, 1H, J = 15.0 Hz), 4.71 (d, 1H, J = 15.0 Hz), 7.23–7.41 (m, 5H); trans: 1.35 (d,

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3H, J = 7.2 Hz), 3.60–3.56 (m, 2H), 4.10 (d, 1H, J = 15.1 Hz), 4.76 (d, 1H, J = 15.1 Hz), 7.24–7.43 (m, 5H). MS m/e (relative intensity): 200 (M•+ , 2), 163 (8), 133 (54), 105 (57), 91 (100). 2.3.3. cis-Ethyl 3-methyl-1-(4-nitrophenyl)2-oxoazetidine-4-carboxylate 2j 1 H NMR (CDCl ), δ: 1.28 (t, 3H, J = 7.2 Hz), 1.31 (d, 3H, 3 J = 7.4 Hz), 3.78 (dq, 1H, J = 7.4 and 6.4 Hz), 4.23–4.35 (m, 2H), 4.69 (d, 1H, J = 6.4 Hz), 7.38 (d, 2H, J = 9.0 Hz), 8.20 (d, 2H, J = 9.0 Hz). 13 C NMR (CDCl3 ), δ: 9.6, 14.3, 48.6, 56.0, 62.2, 116.5, 125.3, 142.4, 143.7, 166.7, 167.8. MS m/e (relative intensity): 278 (M•+ , 13), 250 (8), 205 (12), 177 (20), 164 (64), 149 (100), 102 (86). 2.3.4. trans-Ethyl 3-methyl-1-(4-nitrophenyl)2-oxoazetidine-4-carboxylate 2j 1 H NMR (CDCl ), δ: 1.27 (t, 3H, J = 7.2 Hz), 1.52 (d, 3H, 3 J = 7.4 Hz), 2.78 (dq, 1H, J = 7.4 and 2.8 Hz), 4.20 (d, 1H, J = 2.8 Hz), 4.27 (q, 2H, J = 7.2 Hz), 7.35 (d, 2H, J = 9.0 Hz), 8.21 (d, 2H, J = 9.0 Hz). 13 C NMR (CDCl3 ), δ: 13.2, 14.1, 51.1, 58.7, 62.3, 116.4, 125.3, 142.5, 143.7, 166.9, 167.9. MS m/e (relative intensity): 278 (M•+ , 13), 250 (5), 205 (15), 177 (24), 164 (100), 149 (100), 122 (7). 2.3.5. Diethyl 1-(4-methoxyphenyl)-3-methyl-2oxoazetidine-4,4-dicarboxylate 2k 1 H NMR (CDCl ), δ: 1.16–1.43 (m, 9H), 3.76 (s, 3H), 3.95 3 (q, 1H, J = 7.5 Hz), 4.23 (q, 2H, J = 7.2 Hz), 4.32 (q, 2H, J = 7.1), 6.80 (d, 2H, J = 9.0 Hz), 7.41 (d, 2H, J = 9.0 Hz). 13 C NMR (CDCl3 ), δ: 10.2, 13.8, 14.1, 53.4, 55.4, 62.3, 62.6, 69.4, 113.9, 120.6, 130.1, 156.8, 166.4, 166.7, 166.8. MS m/e (relative intensity): 335 (M•+ , 33), 307 (5), 234 (92), 162 (22), 149 (75), 134 (100). 2.3.6. 4-(4-Methoxyphenyl)-2-methyl-6phenyl-2H-1,4-oxazin-3(4H)-one 3m 1 H NMR (CDCl ), δ: 1.65 (d, 3H, J = 6.7 Hz), 3.82 (s, 3 3H), 4.75 (q, 1H, J = 6.7 Hz), 6.41 (s, 1H), 6.90–6.98 (m, 2H), 7.23–7.39 (m, 5H), 7.47–7.53 (m, 2H). 13 C NMR (CDCl3 ), δ: 15.5, 55.5, 74.3, 108.6, 114.5, 123.8, 126.9, 128.1, 128.5, 132.3, 132.5, 139.4, 158.7, 164.7. MS m/e (relative intensity): 295 (M•+ , 31), 252 (4), 239 (11), 134 (100). 2.3.7. 4-Benzyl-2-methyl-6-phenyl2H-1,4-oxazin-3(4H)-one 3n 1 H NMR (CDCl ), δ: 1.61 (d, 3H, J = 6.7 Hz), 4.67 (q, 1H, 3 J = 6.7 Hz), 4.77 (s, 3H), 6.14 (s, 1H), 7.23–7.45 (m, 10H). 13 C NMR (CDCl3 ), δ: 15.6, 48.6, 73.6, 106.3, 123.6, 127.6, 127.7, 127.9, 128.3, 128.7, 132.4, 136.2, 139.2, 165.1. MS m/e (relative intensity): 279 (M•+ , 56), 224 (26), 160 (5), 105 (44), 91 (100). 2.3.8. N-Benzyl-2-(cyanomethyl)-N-methylpropanamide 5p, mixture of two rotamers 1 H NMR (CDCl ), δ: 1.26 (d, 1.8H, J = 10.9 Hz), 1.30 (d, 3 1.2H, J = 10.5 Hz), 2.48–2.78 (m, 2H), 2.92 (s, 1.2H), 2.95 (s, 1.8H), 3.00–3.17 (m, 1H), 4.40–4.53 (m, 0.8H), 4.46 (d, 0.6H, AB, JAB = 14.6 Hz, ν = 23.8 Hz), 4.70 (d, 0.6H, AB,

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JAB = 14.6 Hz, ν = 23.8 Hz), 7.12–7.37 (m, 5H). 13 C NMR (CDCl3 ), δ, major rotamer: 17.2, 21.5, 33.6, 34.6, 51.2, 118.7, 126.1, 127.9, 128.7, 136.7, 172.9; minor rotamer: 17.9, 21.7, 33.8, 34.5, 51.5, 118.5, 126.5, 127.6, 129.0, 136.4, 173.4. MS m/e (relative intensity): 216 (M•+ , 17), 201 (3), 148 (2), 120 (10), 91 (100). 2.3.9. 2-(1-Cyanoprop-1-en-2-ylamino)N,N-dibenzylpropanamide 6o, (E + Z) 1 H NMR (CDCl ), δ: 1.35 (d, 2,1H, J = 6.6 Hz), 1.46 (d, 3 0.9H, J = 6.5 Hz), 2.04 (s, 0.9H), 2.08 (s, 2.1H), 3.43–3.66 (m, 1H), 4.09–4.80 (m, 3H), 4.91 (d, 0.7H, J = 14.7 Hz), 5.09 (d, 0.3H, J = 14.7 Hz), 5.45 (bd, 0.3H), 5.58 (bd, 0.7H). 13 C NMR (CDCl3 ), δ, major isomer: 17.6, 20.4, 48.6, 49.7, 61.1, 121.1, 126.4, 128.0, 129.1, 136.3, 158.0, 172.4; minor isomer: 14.6, 21.7, 48.6, 49.7, 61.1, 123.2, 126.6, 127.7, 128.7, 135.2, 156.2, 174.3. MS m/e (relative intensity): 333 (M•+ , 2), 242 (10), 224 (8), 196 (2), 109 (100), 91 (50). 2.3.10. 2-(1-Cyanoprop-1-en-2-ylamino)N-benzyl-N-methylpropanamide 6p, (E + Z) 1 H NMR (CDCl ), δ: 1.31 (d, 0.9H, J = 6.6 Hz), 1.34 (d, 2.1H, 3 J = 6.7 Hz), 2.09 (s, 0.9H), 2.13 (s, 2.1H), 2.93 (s, 2.1H), 2.95 (s, 0.9H), 3.57 (s, 0.3H), 3.70 (s, 0.7H), 4.15 (q, 0.7H, J = 6.7Hz), 4.18 (q, 0.3H, J = 6.6 Hz), 4.47–4.67 (m, 2H), 5.50–5.51 (m, 0.3H9, 5.59 (d, 0.7H, J = 5.6 Hz), 7.10–7.38 (m, 5H). 13 C NMR (CDCl3 ), δ, major isomer: 16.8, 20.5, 34.4, 48.4, 51.4, 60.8, 121.4, 126.3, 127.9, 128.8, 136.2, 158.1, 171.7; minor isomer: 17.7, 20.5, 34.4, 48.4, 52.9, 60.8, 121.4, 126.7, 128.2, 129.2, 125.3, 158.1, 172.1. MS m/e (relative intensity): 257 (M•+ , 3), 148 (3), 120 (5), 91 (100). 3. Results and discussion Bromoamide 1a, taken as model compound, was added to MeCN solutions, containing a suitable supporting electrolyte, previously electrolyzed under galvanostatic conditions. From these solutions, ␤-lactam 2a was isolated after the usual work up (see Section 2); this result is consistent with a deprotonation of the C4–H group of bromoamide 1a (caused by the electrogenerated base) and subsequent cyclization via an intramolecular SN reaction. The yields (η) and the stereochemistry (i.e. the cis/trans ratio (ρ) of the isolated 2a) of the process are strongly affected by the electrolysis conditions: the number of Faradays per mole of 1a supplied to the electrodes (Q), the nature of the supporting electrolyte and the temperature of the cathodic solution (Table 1). A good result (η = 75%, ρ = 87/13) has been obtained using Et4 NPF6 as supporting electrolyte (Q = 2.0 F mol−1 , rt, Table 1, entry 2 versus entries 4–6). Further, it is worth noting that a decrease of the temperature of the cathodic solution gives rise to a moderate increase of the cis/trans ratio (according to an increase of the more abundant cis isomer) as well as a notable decrease of the yields (Table 1, entries 2, 4–6). Some preliminary results of this work can be found in ref. [13].

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Table 1 Electrochemically induced cyclization of bromoamide 1a to ␤-lactam 2a via constant current electrolyses of MeCN-0.1 mol dm−3 supporting electrolyte solutions, with subsequent addition of 1a Entry 1 2 3 4 5 6 7 8 9 10

Supporting electrolyte

Temperature

Qa

2a, yield (%)b

cis/trans ratioc

Recovered 1a (%)

Et4 NPF6 Et4 NPF6 Et4 NPF6 Et4 NPF6 Et4 NPF6 Et4 NPF6 Bu4 NBF4 Et4 NOTs Et4 NCl Ph3 PCH2 PhCl

rt rt rt −20 ◦ C 0 ◦C 50 ◦ C rt rt rt rt

1.0 2.0 3.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0

33 75 76 57 72 63 46 41 28 22

75/25 87/13 85/15 96/04 85/15 75/25 77/23 76/24 80/20 72/28

61 – – – – 29 – 30 39 77

Divided cell, Pt cathode and anode; I = 75 mA cm−2 . a Number of Faradays per mol of 1a supplied to the electrodes. b Isolated yields, based on starting 1a. c Determined by 1 H NMR of the crude product.

To extend our investigation to solvents different from acetonitrile, substrate 1a was added to EtCN, DMF, DMSO-Et4 NPF6 solutions, previously electrolyzed under galvanostatic conditions. ␤-Lactam 2a, after the usual work up, was isolated from the EtCN-Et4 NPF6 solution in moderate yield (Table 2, entry 2), but was not detected at all from DMF-Et4 NPF6 and DMSOEt4 NPF6 solutions (Table 2, entries 3 and 4). This electrochemical methodology is able to generate basic intermediates directly from MeCN-Et4 NPF6 and EtCN-Et4 NPF6 as well as from DMFEt4 NPF6 and DMSO-Et4 NPF6 solutions. These basic intermediates are potentially strong enough to deprotonate the C–H group of the bromoamide 1a, i.e. to promote the first step of the overall process 1a–2a (the pKa value of MeCN in MeCN and that of DMSO in DMSO is about 32–33, and that one of DMF in DMF is in the range 25–31 [16]). Nevertheless, it should be borne in mind that these intermediates may undergo competing reactions with respect to the proton exchange reaction; e.g.: (a) the denticity (O-, S- and Cnucleophilic reactivity) of dimethylsulfinyl carbanion [17]; (b) the decomposition of Me2 N-CO− to Me2 N− and CO [18]; (c) the reaction of − CH2 CN versus the parent molecule yielding 3-

aminocrotonitrile anion [1]. Therefore, the yield of 2a is affected by the comprehensive reactivity of the intermediates and consequently 2a either can, or cannot, be isolated from solvents having the same pKa value. Afterwards, to understand if there is (apart from the basic intermediate) a further influence of the solvents in this deprotonation–cyclization process, MeCN-Et4 NPF6 , EtCNEt4 NPF6 , DMF-Et4 NPF6 and DMSO-Et4 NPF6 solutions, charged with a probase (tetraethyl ethenetetracarboxylate, A) were electrolyzed under potentiostatic control, i.e. at a cathodic potential negative enough for the selective reduction of the probase. After the consumption of 2.0 Faradays per mol of probase, the current was switched off and bromoamide 1a was added to the cathodic solutions (1.0 mole of 1a per mole of probase). ␤-Lactam 2a was isolated, after the usual work up, from all the electrolyzed solutions (Table 2, entries 5–8). Consequently, the deprotonation of the C4–H group can be carried out by electrogenerated tetraethyl ethenetetracarboxylate dianion in all the examined solutions. Nevertheless, the yields (strongly) and the cis/trans ratio (slightly) of isolated ␤-lactam 2a are affected by the nature of the solvents (Table 2, entries 5–8).

Table 2 Electrolyses of solvent-0.1 mol dm−3 Et4 NPF6 solutions with subsequent addition of bromoamide 1a (entries 1–4) and electrolyses of solvent-0.1 mol dm−3 Et4 NPF6 solutions containing probase tetraethyl ethenetetracarboxylate (A) and bromoamide 1a (entries 5–8); distribution and yields of the products Entry

Solvent

Probase

I/E

Qa

2a, yield (%)b

cis/trans ratioc

Recovered 1a (%)

1 2 3 4 5 6 7 8

MeCN EtCN DMF DMSO MeCN EtCN DMF DMSO

– – – – A A A A

75 mA cm−2 75 mA cm−2 75 mA cm−2 75 mA cm−2 −1.4 V −1.4 V −1.4 V −1.4 V

2.0 2.0 2.0 2.0 1.6 1.8 1.6 2.1

75 14 – – 64 9 34 19

87/13 78/22 – – 88/12 81/19 77/22 88/12

– 55 81 78 34 50 35 44

Electrolyses carried under galvanostatic (entries 1–4) or potentiostatic (entries 5–9) conditions; divided cell, Pt cathode and anode. a Number of Faradays per mol of 1a supplied to the electrodes. b Isolated yields, based on starting 1a. c Determined by 1 H NMR of the crude product.

M. Feroci et al. / Electrochimica Acta 51 (2006) 5540–5547

Moreover, the most efficient system is again the acetonitrile one, with a yield that is lower than the one in entry 1, thus rendering the use of an external probase not advantageous from a synthetic point of view. Considering the high yield and stereoselectivity (cis/trans ratio) of the electrochemical synthesis of 2a from 1a in MeCNEt4 NPF6 , we were spurred to check the efficiency and generality of this electrochemical methodology. Consequently, the investigation was extended to haloamides 1b–p containing different substituents (R1 –R4 ) at C3, C4 and N atoms (see Scheme 1). As already seen, the synthesis of the ␤-lactam ring from these substrates is consistent with a reaction pathway involving a preliminary deprotonation of the C4–H group in the ␣-position with respect to the N atom, followed by intramolecular halogen displacement of the resulting carbanion (C3 C4 bond formation). Therefore, every substrate containing an acidic C4–H group and a suitable leaving group at C3 atom should be able to allow this reaction pathway (deprotonation–cyclization); nevertheless, the acidity of the C4–H group and the stereochemistry of the cyclization (and consequently, the yield and the cis/trans ratio of the resulting ␤-lactam) can be strongly affected by the nature of substituents R1 –R4 . The reactivity of haloamides 1a–p, containing different R1 –R4 substituents, has been investigated under the optimized conditions, i.e. in MeCN-Et4 NPF6 solutions (Q = 2.0 F mol−1 , rt). The results may be summarized as follows: 3.1. Influence of the nature of substituent R1 at C3 atom 3.1.1. Bromoamides 1a–f (Table 3, entries 1–6) Irrespective of the nature of substituent R1 , the synthesis of ␤-lactams 2a–f is a diasteroselective process: in every case a large excess of the cis isomer has been pointed out, the cis/trans ratio varying from 87/13 to 93/07. ␤-Lactams 2a–d (R1 : linear aliphatic groups) and ␤-lactams 2e–f (R1 : cyclic aliphatic groups) have been isolated in excellent (75–90%) and good (57–63%) yields, respectively (Table 3, entries 1–6). 3.1.2. Bromoamide 1g (Table 3, entries 7–9) The presence of a phenyl group and of a chlorine atom at the C4 atom causes a strongly decrease in the yields of ␤-lactam 2g and an inversion of the stereochemistry of the process. In fact, a large excess of the trans isomer was found: the cis/trans ratio is 29/71 at rt. Moreover, a decrease of the temperature give rise to a decrease of the yields and an increase of the cis/trans ratio. 3.2. Influence of the nature of substituent R2 at N atom 3.2.1. Bromoamides 1b, i, j When N-substituent R2 is an aryl group, the yields of isolated ␤-lactams are lower than in the case of bromoamide 1b (R2 : −CH2 Ph) (Table 3, entries 11 and 12 versus entry 2) irrespective to the nature of the substituents on the aromatic ring (i.e. an electron-donating group (p-CH3 O-Ph: 1i) or an electronwithdrawing group (p-NO2 -Ph: 1j) in the para position).

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Table 3 Electrochemically induced synthesis of ␤-lactams 2a–l via constant current electrolyses of MeCN-0.1 mol dm−3 Et4 NF6 P with subsequent addition of haloamides 1a–l Entry

Bromoamide

Temperature

␤-Lactam

2, yield (%)a

cis/trans ratiob

1 2 3 4 5 6 7 8 9 10 11 12 13 14

1a 1b 1c 1d 1e 1f 1g 1g 1g 1h 1i 1j 1k 1l

rt rt rt rt rt rt rt 0 ◦C 50 ◦ C rt rt rt rt rt

2a 2b 2c 2d 2e 2f 2g 2g 2g 2h 2i 2j 2k 2l

75 84 90 85 57 63 46 8 70 57 33 55 44 64

87/13 91/09 90/10 93/07 90/10 91/09 29/71 9/91 31/69 58/42 97/03 74/26 – –

Divided cell, Pt cathode and anode; Q = 2.0 (number of Faradays per mol of haloamides 1 supplied to the electrodes); I = 75 mA cm−2 . a Isolated yields, based on starting 1a–l. b Determined by 1 H NMR of the crude product.

3.3. Influence of the nature of substituents R3 and R4 at C4 atom 3.3.1. Bromoamides 1b, h, i, k, l The yields of isolated ␤-lactams depend, inter alia, on the nature of the substituents at the carbon atom adjacent to the nitrogen. In fact, comparing amides 1b (R2 = PhCH2 , R3 = H, R4 = CO2 Et) and 1h (R2 = PhCH2 , R3 = H, R4 = CN), the influence of the R4 group seems substantial, especially as regards the cis/trans ratio: 2b and 2h were isolated in 84 and 58% yields, with 91/09 and 58/42 ratios, respectively (Table 3, entries 2 and 10). The great difference in this ratio is probably due to the smaller steric hinderance of the cyano group with respect to the ethoxycarbonyl one. When the nitrogen substituent R2 is aromatic one (R2 = p-CH3 O-Ph), the yields in ␤-lactam are lower (2i: 33%; Table 3, entry 11), also if the acidity of the C–H group is enhanced (2k: R3 = R4 = CO2 Et: 44%; Table 3, entry 13) and the steric hinderance at the carbon atom bearing the leaving group is reduced (2l: R1 = H, R3 = R4 = CO2 Et: 64%; Table 3, entry 14). 3.4. Formation of a six-membered ring 3.4.1. Bromoamides 1m–n Six-membered rings may be produced, instead of fourmembered ones (␤-lactam rings), from bromoamides containing a benzoyl group in the ␤-position with respect to the N-atom. Compounds 3m–n (47 and 58%, respectively) have been isolated by addition of bromoamides 1m–n to electrolyzed MeCNEt4 NPF6 solutions and after the usual work up (Scheme 2). The six-membered ring may be related to an electrochemically induced intramolecular O-alkylation of structures 4m–n, due to an enhanced stability of the oxygen anion in these intermediates [19].

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M. Feroci et al. / Electrochimica Acta 51 (2006) 5540–5547

As previously reported [1], constant current electrolyses of MeCN-Et4 NPF6 solutions yield cyanomethyl anion 7 and 3amino-crotonitrile anion 8. In MeCN solutions containing Et4 N+ salts, these anions may show a remarkable reactivity as bases as well as nucleophiles, therefore structures 5p and 6o–p may be related to an intramolecular SN reaction between anions 7 and 8, respectively, and bromoamides 1o–p (i.e. bromoamides containing a suitable leaving group in the absence of a sufficiently acidic C4–H group). 4. Conclusions

Scheme 2.

3.5. Coupling reaction bromoamide-solvent 3.5.1. Bromoamides 1o–p Structures 5p and 6o–p (Scheme 3) have been isolated (23, 51 and 18% yields, respectively) after addition of bromoamides 1o–p (in which no acidic C–H group is present: R3 = CH2 Ph, R4 = H).

The cyclization of haloamides XCHR1 CONR2 CHR3 R4 (X: Br, Cl) 1a–n to ␤-lactams 2a–n (via C4–H deprotonation) has been carried out, under very mild conditions, without any addition of bases, in suitable solvent-supporting electrolyte solutions previously electrolyzed under galvanostatic control. The yields and the stereochemistry of the process are affected by the nature of substituents R1 –R4 and of the solvent-supporting electrolyte solutions and by the electrolysis conditions. The diastereoselective synthesis of cis-3-alkyl-1-benzyl-4ethoxycarbonyl-␤-lactams 2a–f (cis/trans ratio varying from 87/13 to 93/07) has been achieved in high yields by additions of bromoamides 1a–f to pre-electrolyzed MeCN-Et4 NPF6 solutions. Bromoamide-solvent coupling products (5p and 6o–p) and six-membered ring structures (3m–n) have been produced by reaction of haloamides 1o–p and 1m–n, respectively, in preelectrolyzed MeCN-Et4 NPF6 solutions. References

Scheme 3.

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