Electrogenerated cyanomethyl anion in organic synthesis: A simple diastereoselective synthesis of cis-3-alkyl-1-benzyl-4-ethoxycarbonyl-β- lactams

Article abstract of DOI:10.1016/j.tetlet.2005.10.008

A ready diastereoselective synthesis of cis-3-alkyl-1-benzyl-4- ethoxycarbonyl-β-lactams has been developed by galvanostatic electrolysis of MeCN-Et₄NPF₆ solutions and subsequent addition of a N-(ethoxycarbonyl)methyl-N-benzyl-2-bromoalkylcarboxamide. The yields in β-lactams are very high and the cis isomers have been obtained in a large excess, the cis/trans ratios varying from 87/13 to 93/07.

Full text of DOI:10.1016/j.tetlet.2005.10.008

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8517–8519
Electrogenerated cyanomethyl anion in organic synthesis:
a simple diastereoselective synthesis of
cis-3-alkyl-1-benzyl-4-ethoxycarbonyl-b-lactams
Marta Feroci,a,* Jean Lessard,b Monica Orsinia and Achille Inesic,*
a
`
Dip. Ingegneria Chimica, Materiali, Materie Prime e Metallurgia, Universita ꢀLa Sapienzaꢁ, via Castro Laurenziano,
7, I-00161 Roma, Italy
bLaboratoire de Chimie et Electrochimie Organiques, De´p. de Chimie, Universite´ de Sherbrooke, Sherbrooke, Que´bec,
Canada VIK 2R1
c
`
Dip. Chimica, Ingegneria Chimica e Materiali, Universita degli Studi, I-67040, Monteluco di Roio, LꢁAquila, Italy
Received 6 July 2005; revised 3October 2005; accepted 5 October 2005
Available online 21 October 2005
Abstract—A ready diastereoselective synthesis of cis-3-alkyl-1-benzyl-4-ethoxycarbonyl-b-lactams has been developed by galvano-
static electrolysis of MeCN–Et4NPF6 solutions and subsequent addition of a N-(ethoxycarbonyl)methyl-N-benzyl-2-bromoalkyl-
carboxamide. The yields in b-lactams are very high and the cis isomers have been obtained in a large excess, the cis/trans ratios
varying from 87/13to 93/07.
ꢀ 2005 Elsevier Ltd. All rights reserved.
b-Lactams are known to be of high clinical importance.1
For this reason, many methods of synthesis of b-lactams
have been developed.2 Among them, electrochemical
approaches are of interest because of mild reaction con-
ditions and elimination of the use of toxic and harmful
chemicals. Thus b-lactams have been synthesized by
electrochemical cyclization involving intramolecular dis-
placement of a halide by a nitrogen anion (N–C4 bond
formation) or by a carbanion (C3–C4 bond formation).
The cyclization of bromoamides (N–C4 cyclization)
involved electrogenerated bases,3 whereas C3–C4 cycli-
zation was accomplished either by the reduction of a
1,4-dibromoamide4 or by electrochemically induced
deprotonation of a N-aryl-N-(diethoxycarbonyl)methyl-
2-haloalkylcarboxamide.4,5
In our laboratory, we have developed new methodolo-
gies of electroorganic synthesis based on EGBs to obtain
electrogenerated bases by simple galvanostatic reduction
of solvent-supporting electrolyte.6 In continuation of
our studies, we report the use of electrogenerated
cyanomethyl anion for a highly diastereoselective syn-
thesis of 3,4-disubstituted b-lactams 2 from N-(ethoxy-
carbonyl)methyl-N-benzyl-2-bromoalkylcarboxamides
O
Br
O
-
Et4N+ CH2CN
N
N
R
EtO2C
EtO2C
R
1
2
R = CH3 (1, 2a), CH2CH3 (1, 2b), CH(CH3)2 (1, 2c), (CH2)3CH3 (1, 2d), c-C5H9 (1, 2e), c-C6H11 (1, 2f)
Scheme 1.
Keywords: b-Lactams; Electrogenerated cyanomethyl anion; Electrosynthesis; Cathodic reduction.
*
Corresponding authors. Tel.: +39 0649766563; fax: +39 0649766749 (M.F.); e-mail addresses: marta.feroci@uniroma1.it; inesi@ing.univaq.it
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.008

8518
M. Feroci et al. / Tetrahedron Letters 46 (2005) 8517–8519
Table 1. Cyclization of N-(ethoxycarbonyl)methyl-N-benzyl-2-bromoalkyl-carboxamides 1 by electrogenerated cyanomethyl aniona
Entry
Rb
F/molc
b-Lactam 2, yield (%)d
cis/trans ratioe
1
2
(CH3)2CH
(CH3)2CH
3)2CH
1
2
376
2
2
2
2
2
33f
75
75/25
87/13
3(CH
85/15
4
5
6
7
8
CH3
84
90
85
57
91/09
90/10
93/07
90/10
CH3CH2
CH3(CH2)3
c-C5H9
c-C6H11
6391/09
a Reaction conditions: MeCN–Et4NPF6 as solvent-supporting electrolyte, Pt anode and cathode, two-compartment cell, I = 75 mA cmÀ2, rt, N2
bubbling. At the end of the electrolysis, 0.5 mmol of amide was added to the cathodic solution and the mixture was stirred at rt for 16 h under N2.
b See Scheme 1.
c Number of Faradays per mol of amide supplied to the electrodes.
d Isolated yields based on the starting amide.
e The cis/trans ratio was determined by 1H NMR of the crude product.
f 61% of recovered starting material.
1 (Scheme 1). The advantage of this approach comes
from the high reactivity of the naked cyanomethyl
anion, the counter ion being a tetraalkylammonium cation.
strongly associated with a metallic cation. Indeed, Kawa-
bata, Minami and Hiyama9 have reported a highly
diastereoselective synthesis of cis-3,4-disubstituted b-
lactams by treating the dianion of N-[(tert-butoxy-
carbonyl)methyl]-N-(4-methoxyphenyl)butanamide with
N-iodosuccinimide (NIS). To explain the high cis diaste-
reoselectivity, they propose that the conformation of the
dianion is fixed by intramolecular association of the two
oxygen atoms of the dianion with a lithium cation. The
conformation would be retained in the 2-iododerivative
resulting from the reaction of the dianion with NIS for
the SN2 displacement of the iodide. Since, in our case,
no such strong coordination can be invoked, other fac-
tors must be responsible for the cis diastereoselectivity.
This aspect is the subject of a separate study. When the
electrolysis was carried out using a sacrificial anode
(Mg), in a one compartment cell, only the starting amide
was recovered (in quantitative yield); this unfavourable
result may be related to the presence of electrogenerated
Mg2+ cations, that strongly coordinate the cyanomethyl
anion, thus inhibiting its reactivity.
The cyanomethyl anion was generated by galvanostatic
electrochemical reduction of a solution of acetonitrile
containing a tetraalkylammonium salt, Et4NPF6, as
supporting electrolyte at room temperature and under
a nitrogen atmosphere. The electrolysis was carried
out at constant current in a two-compartment cell with
a sintered glass/agar gel separator, and a platinum
cathode and anode, and was stopped after the desired
quantity of electricity was reached. The N-(ethoxycar-
bonyl)methyl-N-benzyl-2-bromoalkylcarboxamide 1 was
then added and the mixture stirred at room temperature
under nitrogen overnight.7 The results are reported in
Table 1.
In entries 1–3, the effect of the charge passed is
illustrated with the N-(ethoxycarbonyl)methyl-N-benz-
yl-2-bromoalkylcarboxamide 1c (R = (CH3)2CH) as
substrate. Complete conversion of the substrate required
two moles of electrons per mole of substrate (2 F/mol)
(entry 2). An equimolar amount of electrogenerated
base (1 F/mol) was not sufficient to ensure complete
conversion of substrate (entry 1), whereas the use of a
larger excess of electrogenerated base (3F/mol) had no
noticeable effect (entry 3).8 So the reactions in entries
4–8 were carried out with two equivalents of electricity
(2 F/mol) to ascertain the efficiency and generality of
this method.
In conclusion, we have described a novel and simple
method of cyclization of N-(ethoxycarbonyl)methyl-N-
benzyl-2-bromoalkylcarboxamides under mild condi-
tions using electrogenerated cyanomethyl anion. The
method is easy to apply (constant current electrolysis,
facile work-up) and allow to avoid the manipulation
of strong bases. Unexpectedly, a high cis/trans ratio
was obtained with all the substrates.
The two mean features of Table 1 are (i) the high yields of
b-lactams 2a–d (R = linear alkyl group, 75–90%) and the
good yields of b-lactams 2e–f (R = cyclic alkyl group,
57–63%), obtained under very mild and convenient con-
ditions (electrolysis under constant current at room tem-
perature, no manipulation of strong bases, easy work-up
procedure); and (ii) the high cis/trans ratios (87/13to 93/
07), irrespective of the nature of the R group. Such high
cis/trans ratios were quite unexpected considering (i) the
most probable mechanism of cyclization (intramolecular
SN2 displacement of the bromide by the ester enolate
generated by proton abstraction at C-2 of carboxamide
1) and (ii) the fact that the ester enolate is naked or not
Acknowledgements
The authors wish to thank Mr. M. Di Pilato for his con-
tribution to the experimental part of this work. This
work was supported by research grants from MURST
(Prin 2004) and CNR, Roma, Italy.
Supplementary data
In this file, the syntheses of starting amides and of b-
lactams are reported, along with their spectral data.
Supplementary data associated with this article can be

M. Feroci et al. / Tetrahedron Letters 46 (2005) 8517–8519
8519
Rossi, L.; Inesi, A. Electrochim. Acta 2005, 50, 2029, and
references cited therein.
found, in the online version, at doi:10.1016/j.tetlet.
2005.10.008.
7. Typical experimental procedure: The constant current
electrolyses were carried out (using Pt electrodes, I =
75 mA cmÀ2) in MeCN–0.1 mol dmÀ3 Et4NPF6 solutions
(25 ml), at room temperature and with continuous nitrogen
bubbling. At the end of the electrolyses, bromoamides
(0.5 mmol) were added to the catholyte and the solution
was allowed to stand under stirring for 16 h. The solvent
was then evaporated under reduced pressure and the
residue extracted with diethyl ether (3 · 30 ml). The extracts
were analyzed by thin layer chromatography, GC–MS and
1H NMR; all products were purified by flash chromato-
graphy, using n-hexane–ethyl acetate 95:5 to 8:2 as eluent.
cis-1-Benzyl-4-ethoxycarbonyl-3-isopropyl-2-azetidinone. 1H
NMR (CDCl3) d: 7.33–7.16 (5H, m), 4.82 (1H, d, J =
14.9 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.02 (1H, d, J =
14.9 Hz), 3.96 (1H, d, J = 5.6 Hz), 3.14 (1H, dd, J = 9.9,
5.6 Hz), 2.07–1.89 (1H, m), 1.24 (3H, t, J = 7.2 Hz), 1.11
(3H, d, J = 6.6 Hz), 0.87 (3H, d, J = 6.5 Hz). 13C NMR
(CDCl3) d: 169.78, 168.28, 135.02, 128.76, 128.46, 127.78,
61.41, 61.26, 54.81, 44.92, 26.17, 21.56, 20.18, 14.04. EIMS,
m/z (%): (M+Æ absent), 247 (M+Æ-CO, 5), 202 (M+Æ-CO2Et,
6), 143 (32), 115 (30), 91 (100). Anal. Calcd for C16H21NO3:
C, 69.79; H, 7.69, N, 5.09. Found: C, 69.15; H, 8.09; N,
4.80.
References and notes
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