A facile synthesis of 7-amino-3-desacetoxycephalosporanic acid derivatives by indium-mediated reduction of 3-iodomethylcephems in aqueous media

Article abstract of DOI:10.1016/S0040-4039(00)00512-8

An efficient reductive conversion of 3-iodomethylcephalosporin and 3- acetoxymethylcephalosporin derivatives mediated by indium into the corresponding 3-methylcephems and 3-methylenecephams in moderate to good yields has been developed in an aqueous system. 3-Methylenecephams are converted into the corresponding 3-methylcephems under previously reported basic conditions quantitatively. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00512-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3899–3901
A facile synthesis of 7-amino-3-desacetoxycephalosporanic acid
derivatives by indium-mediated reduction of
3-iodomethylcephems in aqueous media
Hyungsun Chae, Sangwon Cho, Gyochang Keum, Soon Bang Kang, Ae Nim Pae and
Youseung Kim ∗
Biochemicals Research Center, Korea Institute of Science and Technology, Cheongryang P.O. Box 131, Seoul 130-650,
South Korea
Received 31 January 2000; revised 6 March 2000; accepted 24 March 2000
Abstract
An efficient reductive conversion of 3-iodomethylcephalosporin and 3-acetoxymethylcephalosporin derivatives
mediated by indium into the corresponding 3-methylcephems and 3-methylenecephams in moderate to good
yields has been developed in an aqueous system. 3-Methylenecephams are converted into the corresponding 3-
methylcephems under previously reported basic conditions quantitatively. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: cephalosporin; halogens and compounds; indium and compounds; dehalogenation; water, reactions in.
3-Methylcephem (2) is a key intermediate for the preparation of novel oral cephem antibiotics such as
cephalexin,1 cephradine,2 cephadroxil,3 cefetamet pivoxil,4 etc. Several methods have been known for the
synthesis of these compounds: isomerization of 3-methylenecephams under basic conditions,5 hydroge-
nolysis of 7-ACA derivatives,6 electrochemical reduction of cephalosporanic acids7 and ring expansion
of penicillin sulfoxides.8–10 Herein we wish to report a new and convenient synthesis of 7-amino-3-
desacetoxycephem derivatives by the reduction of 3-iodomethylcephem with indium in aqueous media
(Scheme 1). Although many indium mediated organic transformation reactions have been reported,11–14
there have been relatively few reports15 on the use of indium metal in dehalogenation reactions.
Thus treatment of iodomethylcephems 1 (entries a–c, Table 1), prepared from commercially available
3-chloromethylcephems 1 (X=Cl) by the known method,16,17 with 2 equimolar amounts of indium
powder in a 1:1 mixture of H2O and THF at room temperature for 2 h gave a 1:1.2 mixture of 2
and 3 in 60–74% yields. With 3-acetoxymethylcephems (entries d–h) synthesized from 7-ACA,17 the
compounds were reacted with 200 M% of KI18 then dehalogenated with 2 equimolar amounts of indium
in situ in a 1:1 mixture of H2O and THF at 40–60°C to produce a mixture of 2 and 3 in 71–79% yields.
∗
Corresponding author. Tel: +82 2 958 5138; fax: +82 2 958 5189; e-mail: yosekim@kist.re.kr (Y. Kim)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00512-8
tetl 16791

3900
Scheme 1.
The crude mixture products were treated without purification with 120 M% of trimethylsilyl chloride
in the presence of pyridine for 24 h at room temperature19 to yield the compound 2 as a sole product
as shown in Table 1. This reaction is particularly attractive since 7-ACA (1h) can be transformed into
7-ADCA (2h) without protection of the amine and carboxylic acid functional groups of 7-ACA. The
compound 3h is transformed into 2h quantitatively using N-trimethylsilylacetamide and triethylamine.20
Although a variety of reaction conditions using other metals such as zinc or tin were explored, no
dehalogenation of cephems was observed except zinc/ammonium chloride conditions21 which gave 3-
exomethylenecephams 3a exclusively in poor yield (15%). A typical procedure is as follows. To a
solution of 7-amino-3-acetoxymethyl carboxylic acid (100 mg, 0.367 mmol) in 3 ml of THF:H2O (1:1),
200 M% of indium powder (–100 mesh, 0.085 g) and KI (0.060 g, 200 M%) were added succesively.
The reaction mixture was heated at 60°C for 4 h, cooled to room temperature, and then 1 ml of 1N
HCl and 2 ml of CH3CN were added and filtered off the indium residue. The filtrate was neutralized by
dilute aqueous NaHCO3 solution and the precipitate was dried under vacuum. The crude mixture was
dissolved in 5 ml of CH3CN and reacted with N-trimethylsilylacetamide (144 mg, 1.10 mmol) for 0.5 h.
Triethylamine (0.3 ml, 0.004 mmol) was added to the clear solution and the reaction mixture was stirred
for 3 h followed by addition of 3 ml of MeOH. The solution was acidified with 0.1N HCl to pH 3.6 to
precipitate 62 mg (78%) of 2h.
Table 1
In conclusion we could demonstrate that indium can dehalogenate 3-iodomethylcephems in aqueous
media and extend the scope of indium utility in organic synthesis. Further studies on the use of indium
in aqueous media are in progress.

3901
Acknowledgements
This work was fully supported by the Korea Institute of Science & Technology and the Ministry of
Science & Technology.
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