Electroreductive acylation of aromatic ketones with acylimidazoles

Article abstract of DOI:10.1021/jo051498w

The intermolecular reductive coupling of aromatic ketones with acylimidazoles was effected by electroreduction in the presence of chlorotrimethylsilane and gave α-trimethylsiloxy ketones and esters. The best result was obtained using Bu₄NPF₆ as a supporting electrolyte and a Pb cathode in THF. The α-trimethylsiloxy-containing products were transformed to the corresponding α-hydroxy ketones and esters by treatment with TBAF in THF. This method was also effective for the intramolecular reductive coupling of δ- and ε-keto acylimidazoles.

Full text of DOI:10.1021/jo051498w

Electroreductive Acylation of Aromatic Ketones with
Acylimidazoles
Naoki Kise,* Syun Agui, Shinji Morimoto, and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori University,
Koyama, Tottori 680-8552, Japan
kise@bio.tottori-u.ac.jp
Received July 19, 2005
The intermolecular reductive coupling of aromatic ketones with acylimidazoles was effected by
electroreduction in the presence of chlorotrimethylsilane and gave R-trimethylsiloxy ketones and
esters. The best result was obtained using Bu4NPF6 as a supporting electrolyte and a Pb cathode
in THF. The R-trimethylsiloxy-containing products were transformed to the corresponding R-hydroxy
ketones and esters by treatment with TBAF in THF. This method was also effective for the
intramolecular reductive coupling of δ- and ꢀ-keto acylimidazoles.
SCHEME 1
Introduction
Reductive cross-coupling of ketones with carboxylic
acid derivatives provides a useful method for the syn-
thesis of R-hydroxy ketones. This type of intra- and
intermolecular cross-coupling has been achieved between
ketones and nitriles with Zn-chlorotrimethylsilane
(CTMS),1 Yb,2 electroreduction,3 Li-naphthalene,4 SmI2,5
or low-valent titanium.6 Reductive intramolecular coupl-
ing of keto esters has also been realized with low-valent
titanium7 or SmI2.8 In addition, reductive intermolecular
cross-coupling of aromatic aldehydes and ketones with
aliphatic acid chlorides has been achieved with Mg as a
reducing agent.9 We have recently reported that the
electroreduction in the presence of CTMS is a useful
method for the reductive intramolecular coupling of
aromatic δ- and ꢀ-keto esters.10 However, this reaction
was limited to intramolecular coupling to give five- and
six-membered cyclized products. Therefore, we attempted
intermolecular coupling of aromatic ketones with car-
boxylic acid derivatives more reactive than esters. In this
context, we wish to report that the electroreduction of
aromatic ketones with acylimidazoles in the presence of
chlorotrimethylsilane (CTMS) and triethylamine (TEA)
effected inter- and intramolecular reductive acylation of
aromatic ketones (Scheme 1). This electroreduction pro-
vides a useful method for the synthesis of aryl R-hydroxy
ketones and esters.
Results and Discussion
Intermolecular Electroreductive Acylation of Aro-
matic Ketones with Acylimidazoles. Conditions for
the electroreductive acetylation of aromatic ketones were
surveyed with acetophenone (1a) as an aromatic ketone
and N-acetylimidazole (5 equiv) as an acetylating agent
using a divided cell (Table 1). The acetylated product was
isolated as R-trimethylsiloxy ketone 2a′. In the absence
of CTMS, the acetylated product was not obtained, and
simply reduced alcohol, 1-phenylethanol, was formed as
the only product (run 1). The presence of CTMS was
crucial for the reductive acetylation of 1a (run 2). The
addition of 5 equiv of CTMS to 1a was the optimal
condition (1 equiv of CTMS, 32% yield of 2a′; 3 equiv,
56%; 7 equiv, 63%). The addition of triethylamine (5
(1) Corey, E. J.; Stephen, G. P. Tetrahedron Lett. 1983, 24, 2821.
(2) Hou, Z.; Takamine, K.; Aoki, O.; Shiraishi, H.; Fujiwara, Y.;
Taniguchi, H. J. Org. Chem. 1988, 53, 6077.
(3) Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita, H. J.
Org. Chem. 1992, 57, 7175.
(4) Guijarro, D.; Manchen˜o, B.; Yus, M. Tetrahedron 1993, 49, 1327.
(5) (a) Molander, G. A.; Wolfe, C. N. J. Org. Chem. 1998. 63, 9031.
(b) Zhou, L.; Zhang, Y.; Shi, D. Tetrahedron Lett. 1998, 39, 8491.
(6) Yamamoto, Y.; Matsumi, D.; Itoh, K. Chem. Commun. 1998, 875.
(7) McMurry, J. E.; Miller, D. D. J. Am. Chem. Soc. 1983, 105, 1660-
1661.
(8) Liu, Y.; Zhang, Y. Tetrahedron Lett. 2001, 42, 5745-5748.
(9) Nishiguchi, I.; Sakai, M.; Maekawa, H.; Ohno, T.; Yamamoto,
Y.; Ishino, Y. Tetrahedron Lett. 2002, 43, 635.
(10) Kise, N. Arimoto, K. Ueda, N. Tetrahedron Lett. 2003, 44, 6281.
10.1021/jo051498w CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/11/2005
J. Org. Chem. 2005, 70, 9407-9410
9407

Kise et al.
TABLE 1. Electroreduction of Acetophenone with
Acetylimidazole
TABLE 2. Electroreduction of Acetophenone and
Benzophenone with Acylating Agents
cathode yieldc (%)
run solvent of catholytea
additiveb
none
CTMS
material
of 2a′
run
R1
R2COXa
yieldb (%) of 2 and 3
1
2
3
4
5
6
7
8
9
Bu4NPF6/THF
Bu4NPF6/THF
Bu4NPF6/THF
Bu4NBr/THF
Bu4NClO4/THF
Bu4NPF6/THF
Bu4NPF6/THF
Bu4NPF6/THF
Bu4NPF6/THF
Pb
Pb
0
65
76
67
70
72
68
69
65
67
60
1
2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
CH3COlm
2a, 72
2a, 58
2b, 76
2b, 65
2c, 74
2d, 83
2e, 86
3a, 68
3a, 70
3b, 86
3b, 67
3c, 92
3d, 87
3e, 82
(CH3CO)2O
C2H5COlm
(C2H5CO)2O
n-C3H7COlm
i-C3H7COlm
n-C7H15COlm
CH3COlm
CTMS/TEA Pb
CTMS/TEA Pb
CTMS/TEA Pb
CTMS/TEA Pt
CTMS/TEA Au
CTMS/TEA Ag
CTMS/TEA Zn
CTMS/TEA Sn
CTMS/TEA Cu
3
4
5
6
7
8
9
Ph
(CH3CO)2O
C2H5COlm
(C2H5CO)2O
n-C3H7COlm
i-C3H7COlm
n-C7H15COlm
10 Bu4NPF6/THF
11 Bu4NPF6/THF
10
11
12
13
14
Ph
Ph
a 0.3 M electrolyte in solvent. b 5 equiv. c Isolated yields.
Ph
Ph
Ph
equiv) to the catholyte improved the yield of 2a′ to some
extent (run 3), although it was not essential.11 As a
supporting electrolyte, tetrabutylammonium salts were
suitable. Among them, Bu4NPF6 gave better yield of 2a′
than Bu4NBr and Bu4NClO4 (runs 3-5). Although this
reductive acetylation seemed to proceed irrespective of
the cathode material, Pb brought about slightly better
results than the other cathode materials such as Pt, Au,
Ag, Zn, Sn, and Cu (runs 3, 6-11). Consequently, the
best yield of 2a′ was obtained using Bu4NPF6 as a
supporting electrolyte and a Pb cathode (run 3). One of
us previously reported that the electroreduction of acylim-
idazoles in the presence of CTMS formed acylsilanes.12
In the present reactions, it was difficult to detect the
formation of acetylsilane, since it is volatile. In the case
of octanoylimidazole as described later (Table 2, run 7),
a small amount of octanoylsilane was obtained as a
byproduct (>5% yield). The product R-trimethylsiloxy
ketone 2a′ could be easily desilylated by treatment with
Bu4NF in THF to give the corresponding R-hydroxy
ketone 2a in 95% yield (Scheme 2).
a 5 equiv. b Isolated yields.
TABLE 3. Electroreduction of Aromatic Ketones with
Acetylimidazole
The electroreduction of acetophenone and benzophe-
none (1b) with a number of acylating agents was carried
out under the same conditions as run 3 in Table 1. The
resulting R-trimethylsiloxy ketones were successively
desilylated to the corresponding R-hydroxy ketones with
Bu4NF in THF. The results exhibited in Table 2 show
that acylimidazoles are better acylating agents than acid
anhydrides and afford the corresponding R-hydroxy
ketones 2a-e and 3a-e in good to excellent yields. Next,
a variety of aromatic ketones were subjected to the
reductive acetylation with acetylimidazole (Table 3). In
the case of isobutyrophenone, the yield of R-hydroxy
ketone 2h decreased, presumably due to steric hindrance
(run 3). Aromatic substitution of either the electron-
donating or electron-withdrawing group lowered the
yields of R-hydroxy ketones (2i-m) (runs 4-8). In addi-
a Isolated yields.
SCHEME 2
tion, when the electroreduction of aromatic ketones was
carried out with methoxycarbonylimidazole as an acy-
lating agent, the corresponding R-hydroxy esters 4 were
formed in moderate to good yields (Table 4).
Under the present conditions, intermolecular coupling
of aromatic ketones with esters did not proceed com-
(11) When TEA was added to the THF solution of acetophenone and
CTMS, the solution became clouded. The silyl enol ether of acetophe-
none did not form, even if the solution was stirred at room temperature
for 1 h prior to adding current.
(12) Kise, N.; Kaneko, H.; Uemoto, N.; Yoshida, J. Tetrahedron Lett.
1995, 36, 8839.
9408 J. Org. Chem., Vol. 70, No. 23, 2005

Acylation of Aromatic Ketones with Acylimidazoles
TABLE 4. Electroreduction of Aromatic Ketones with
Methoxycarbonylimidazole
SCHEME 4
SCHEME 5
a Isolated yields.
attempted the electroreduction of several keto acylimi-
dazoles 7-10 under the same conditions as described
above (Scheme 5). The reactions of δ- and ꢀ-keto acylimi-
dazoles 8 and 9 gave the five- and six-membered cyclized
products 12 (74%) and 13 (61%), respectively. The yields
of these products were slightly better than those obtained
from the corresponding δ- and ꢀ-keto esters (63% and
53%, respectively). On the other hand, the electroreduc-
tion of γ- and ú-keto acylimidazoles 7 and 10 afforded
the four- and seven-membered cyclized products 11 (17%)
and 14 (21%), although the yields of these products were
low. The electroreduction of the corresponding γ- and
ú-keto esters did not give any cyclized product; the
alcohols resulting from a simple reduction were formed
as the main products from these esters.
SCHEME 3
pletely. For example, the electroreduction of acetophe-
none with methyl acetate (5 equiv) in the presence of
CTMS-TEA gave no cross-coupling product. Accordingly,
it would be expected that the reaction of aromatic ketones
with acylimidazoles possessing an ester group gave the
products reacted only with the acylimidazole moiety
chemoselectively. In fact, the electroreduction of 1a,b
with acylimidazoles derived from succinic acid and glu-
taric acid monomethyl esters afforded the chemoselec-
tively coupled products 2r, 2s, 3f, and 3g as shown in
Scheme 3.
One of the authors reported that the addition of CTMS
shifted the reduction potential of octanoylimidazole from
-2.34 to -1.38 V vs SCE.12 In the same manner, we
observed that the addition of CTMS also shifted the
reduction potential of acetophenone from -2.00 to -1.04
V vs SCE. These results suggest that acetophenone is
more reducible than acylimidazoles. Therefore, the reac-
tion mechanism of the electroreductive acylation of
aromatic ketones with acylimidazoles can be speculated
to be as shown in Scheme 4. Anion 5 is formed from
acetophenone by a two-electron transfer and subsequent
O-silylation. The anion 5 attacks the carbonyl group of
acetyl imidazole to give 6. Elimination of the imidazole
anion from 6 leads to R-trimethylsiloxy ketone 2a′.
Intramolecular Electroreductive Acylation of
Aromatic Ketones with Acylimidazoles. We have
already reported the electroreductive intramolecular
coupling of aromatic δ- and ꢀ-keto esters.10 We also
Conclusion
This paper describes the electroreductive intermolecu-
lar coupling of aromatic ketones with acylimidazoles in
the presence of CTMS and TEA followed by desilylation
with TBAF in THF to produce R-hydroxy ketones and
esters. The presence of CTMS in the catholyte is essential
to promote the electroreductive coupling. This method is
also effective for the intramolecular reductive coupling
of δ- and ꢀ-keto acylimidazoles to form five- and six-
membered cyclized products. Four- and seven-membered
cyclized products were obtained from the electroreduction
of γ- and ú-keto acylimidazoles, although the yields were
low.
Experimental Section
General Methods. Column chromatography was per-
formed on silica gel 60. THF was distilled from sodium
benzophenone ketyl. CTMS and TEA were distilled from CaH2.
Acetylimidazole and the aromatic ketones employed are com-
mercially available. The other acylimidazoles, shown in Table
2 and Scheme 3, and methoxycarbonylimidazole were prepared
from the corresponding acid chlorides and imidazole (2 equiv)
by stirring in THF. Keto acylimidazoles 7-10 were prepared
from the corresponding keto acids by treatment with 1,1′-
carbonyldiimidazole in THF, and the THF solutions were
subjected to electroreduction directly.
Typical Procedure for Electroreduction (Table 1, Run
3). A 0.3 M solution of Bu4NPF6 in THF (15 mL) was placed
J. Org. Chem, Vol. 70, No. 23, 2005 9409

Kise et al.
in the cathodic chamber of a divided cell (40-mL beaker, 3-cm
diameter, 6-cm height) equipped with a lead cathode (5 × 5
cm2), a platinum anode (2 × 1 cm2), and a ceramic cylindrical
diaphragm (1.5-cm diameter). A 0.3 M solution of Bu4NClO4
in DMF (4 mL) was placed in the anodic chamber (inside the
diaphragm). Acetophenone (1a) (120 mg, 1 mmol), acetylimi-
dazole (550 mg, 5 mmol), CTMS (0.64 mL, 5 mmol), and
triethylamine (0.70 mL, 5 mmol) were added to the cathodic
chamber. After 300 C of electricity was passed at a constant
current of 100 mA at room temperature, the catholyte was
evaporated in vacuo. The residue was diluted with Et2O (30
mL), and insoluble Bu4NPF6 was filtered off. The filtrate was
evaporated in vacuo. The crude mixture was purified by
column chromatography on silica gel (hexanes-ethyl acetate,
50:1) to give 2a′ in 76% yield.
Typical Procedure of Successive Electrolysis and
Desilylation (Table 2, Run 1). After the electroreduction was
carried out as described above, the catholyte was evaporated
in vacuo. The residue was diluted with Et2O (30 mL), and
insoluble Bu4NPF6 was filtered off. The filtrate was evaporated
in vacuo. The residue was diluted with THF (10 mL). To the
solution was added 1 M TBAF in THF (1 mL, 1 mmol) in an
ice bath, and then the mixture was stirred at this temperature
for 30 min. After addition of acetic acid (60 mg, 1 mmol), the
solvent was removed in vacuo. The crude mixture was purified
by column chromatography on silica gel (hexanes-ethyl
acetate, 10:1) to give 2a in 72% yield. All the known com-
pounds, 2a,13 2b,13 2c,14 2f,13 2g,15 2q,16 3a,2 3d,2 4a,17 4b,18
12,19 and 13,19 gave the spectral data in accordance with those
reported in the literature. The other products were identified
by spectroscopic and elemental analyses (Supporting Informa-
tion).
Supporting Information Available: A drawing of the
electrolysis cell and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051498W
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