Electroreductive intramolecular coupling of aromatic δ- and ε-keto esters

Article abstract of DOI:10.1016/S0040-4039(03)01526-0

Electroreduction of aromatic δ- and ε-keto esters in the presence of chlorotrimethylsilane and triethylamine gave five- and six-membered cyclized products. The products were transformed to the corresponding α-hydroxy ketones.

Full text of DOI:10.1016/S0040-4039(03)01526-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6281–6284
Electroreductive intramolecular coupling of aromatic d- and
o-keto esters
Naoki Kise,* Kie Arimoto and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Received 24 May 2003; revised 17 June 2003; accepted 19 June 2003
Abstract—Electroreduction of aromatic d- and o-keto esters in the presence of chlorotrimethylsilane and triethylamine gave five-
and six-membered cyclized products. The products were transformed to the corresponding a-hydroxy ketones.
© 2003 Elsevier Ltd. All rights reserved.
Reductive intramolecular coupling of keto esters is a
useful method for the synthesis of cyclic ketones and
has been effectively realized by McMurry and Miller
with low-valent titanium as a reducing agent.1 Recently,
it has been reported that the reductive coupling of
aromatic d-keto esters with SmI2 produced cyclic 2-
hydroxycyclopentanones and 2-cyclopentenones.2 On
the other hand, electroreduction is an effective tool for
reductive cross-coupling of ketones with a variety of
functional groups. For instance, we have reported the
electroreductive intra- and intermolecular couplings of
ketones with nitriles,3 O-methyl oximes,4 and aromatic
rings.5 We wish to report herein that the electroreduc-
tion of aromatic d- and o-keto esters in the presence of
chlorotrimethylsilane (CTMS) gave five- and six-mem-
bered intramolecularly coupled products, respectively
(Scheme 1). This reaction provides a new method for
the synthesis of a-hydroxy cyclopentanones and a-
hydroxy cyclohexanones.
Conditions for the constant current electroreduction of
keto esters were surveyed with methyl 5-keto-5-
phenylpentanoate 1a using a divided cell, and the
results are summarized in Table 1. The cyclized prod-
ucts were obtained as a-trimethylsiloxy ketal 2a (about
2:1 mixture of two diastereomers) and a-trimethylsiloxy
ketone 3a together with ketone 4a. In the absence of
CTMS, complex mixtures were formed (run 1). The
presence of CTMS was crucial for the reductive
intramolecular coupling of 1a (run 2). Furthermore, the
addition of triethylamine significantly improved the
yields of the cyclized products (run 3).6 From the
results of runs 3–5, THF was the solvent of choice. As
a supporting electrolyte, tetrabutylammonium salts
were suitable (runs 3, 6–9). Among them, Bu4NClO4,
Bu4NBr, Bu4NPF6, and Bu4NCl gave almost the same
combined yields of 2a and 3a. The use of LiClO4,
however, brought about a considerably poor result (run
10). Although Pb seemed to be the best cathode mate-
Scheme 1.
Keywords: electroreduction; reductive coupling; d-keto esters; o-keto esters; a-hydroxy ketones.
* Corresponding author. Fax: +81-857-31-5636; e-mail: kise@bio.tottori-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01526-0

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N. Kise et al. / Tetrahedron Letters 44 (2003) 6281–6284
Table 1. Electroreduction of 1a
Run
Solvent of catholytea
Additiveb
Cathode material
Yield (%)c
2a
3a
4a
1
2
3
4
5
6
7
8
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/DMF
Bu4NClO4/CH3CN
Bu4NBr/THF
Bu4NPF6/THF
Bu4NCl/THF
Bu4NBF4/THF
LiClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
Bu4NClO4/THF
None
CTMS
Pb
Pb
Pb
Pb
Pb
Pb
Pb
Pb
Pb
Pb
Pt
Ag
Zn
Sn
Cu
Al
0
12
32
25
3
39
32
29
29
1
33
34
29
25
20
17
0
20
30
16
13
23
31
38
23
8
25
17
21
23
22
8
0
16
17
0
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
CTMS/TEA
0
20
12
4
9
9
10
11
12
13
14
15
16
10
10
11
8
16
0
1
a 0.3 M Electrolyte in solvent.
b 5 mol amount.
c Isolated yields.
The electroreductions of other d-keto esters (1b and 1c)
and o-keto esters (5a and 5b) were carried out under the
same conditions as run 6 in Table 1, and the results are
exhibited in Scheme 2. The reduction of 1b, a para-
methoxylated analog of 1a, gave the corresponding
cyclized products 2–4b in yields higher than those
obtained with 1a. Cyclic d-keto ester 1c derived from
1-tetralone afforded tricyclic products 2–4c. 5-Keto-5-
rial (run 3), other cathode materials (Pt, Au, Ag, Zn,
Sn, and Cu) except for Al cathode also afforded the
cyclized products in moderate to good yields (runs
11–16). The reaction profile of the electroreduction of
1a (1 mmol scale) under the conditions of run 3 is
illustrated in Figure 1. This result showed that 1a was
almost completely consumed at 300C (3.11 F/mol) and
product 4a was formed from 3a by further reduction.
Indeed, the electroreduction of 3a under the same con-
ditions gave 4a in a separate experiment.
A typical procedure is as follows (run 6 in Table 1). A
0.3 M solution of Bu4NBr in THF (15 mL) was placed
in the cathodic chamber of a divided cell (40 mL
beaker) equipped with a lead cathode (5×5 cm2), a
platinum anode (2×1 cm2), and a ceramic cylindrical
diaphragm. A 0.3 M solution of Bu4NClO4 in DMF (4
mL) was placed in the anodic chamber. Keto ester (1a)
(206 mg, 1 mmol), CTMS (0.64 mL, 5 mmol), and
triethylamine (0.70 mL, 5 mmol) were added to the
cathodic chamber. After 300C of electricity was passed
at a constant current of 50 mA at room temperature,
the catholyte was evaporated in vacuo. To the residue
was added Et2O (30 mL) and insoluble Bu4NBr was
filtered off. After removal of the solvent, the crude
mixture was purified by column chromatography on
silica gel (hexane:ethyl acetate, 50:1) to 2–4a. Although
the products 2a and 3a were isolated as a mixture, these
compounds could be separated by preparative TLC
(hexane:ethyl acetate, 20:1).7
Figure 1. Reaction profile of electroreduction of 1a under the
conditions of run 3 in Table 1.

N. Kise et al. / Tetrahedron Letters 44 (2003) 6281–6284
6283
Scheme 2.
Scheme 3.
phenylpentanoate 5a and its para-methoxylated analog
5b produced six-membered a-trimethylsiloxy ketals 6
(almost single diastereomers) and a-trimethylsiloxy
ketones 7. In these cases, no a-desiloxylated ketone 8
corresponding to 4 was detected and small amounts of
simply reduced trimethylsiloxyethers 9 were formed.
two-electron transfer and subsequent O-silylation. The
anion attacks the ester carbonyl group intramolecu-
larly to give 13. While O-silylation of 13 yields ketal
2a, elimination of the methoxy anion leads to ketone
3a. Further reduction of 3a results in a-desiloxylated
ketone 4a through the formation of silyl enol ether
14.
The obtained mixtures of a-trimethylsiloxy ketals 2 (6)
and a-trimethylsiloxy ketones 3 (7) could be easily
desilylated by treatment with Bu4NF/THF to give the
corresponding a-hydroxy ketones 10 (11) in high yields
(Scheme 3).
In summary, the reductive intramolecular couplings of
aromatic d- and o-keto esters were effectively achieved
by electroreduction in the presence of chlorotrimethyl-
silane and triethylamine to give five- and six-mem-
bered cyclized products. Desilylation of the
a-siloxylated products afforded a-hydroxy cyclopen-
tanones and a-hydroxy cyclohexanones.
The reaction mechanism can be speculated to be as
shown in Scheme 4. Anion 12 is formed from 1a by

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N. Kise et al. / Tetrahedron Letters 44 (2003) 6281–6284
Scheme 4.
References
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7. 2a (2:1 mixture of two diastereomers): Rf 0.81 and 0.73
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1
(hexane:ethyl acetate, 5:1); H NMR (CDCl3) l −0.20 (s, 6
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