Novel one-pot vicinal double C-acylation of styrenes and methacrylates by electroreduction

Article abstract of DOI:10.1021/ol035020v

Electroreduction of styrenes or alkyl methacrylates in the presence of aliphatic acid anhydrides or N-acylimidazoles with an undivided cell equipped with zinc electrodes as the anode and the cathode brought about novel one-pot vicinal double C-acylation to afford the corresponding 1,4-diketones in satisfactory yields.

Full text of DOI:10.1021/ol035020v

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ORGANIC
LETTERS
2003
Vol. 5, No. 15
2755-2758
Novel One-Pot Vicinal Double
C-Acylation of Styrenes and
Methacrylates by Electroreduction
Yoshimasa Yamamoto, Hirofumi Maekawa, Satoshi Goda, and Ikuzo Nishiguchi*
Department of Chemistry, Nagaoka UniVersity of Technology,
1603-1, Kamitomioka-cho, Nagaoka, Niigata 940-2188, Japan
nishiiku@Vos.nagaokaut.ac.jp
Received June 6, 2003
ABSTRACT
Electroreduction of styrenes or alkyl methacrylates in the presence of aliphatic acid anhydrides or N-acylimidazoles with an undivided cell
equipped with zinc electrodes as the anode and the cathode brought about novel one-pot vicinal double C-acylation to afford the corresponding
1,4-diketones in satisfactory yields.
Many studies have concentrated upon the synthesis of 1,4-
dicarbonyl compounds, particularly 1,4-diketones. These
substances are important as synthetic intermediates of many
biologically active substrates and useful heterocyclic com-
pounds such as pharmaceutical drugs, insecticides, and
perfume materials containing the ring systems of cyclopen-
tenones,1 furans,2 pyrroles,3 and thiophenes.4
We have already reported electrochemical or Mg-promoted
regioselective C-acylation5 of R,â-unsaturated carbonyl com-
pounds to give the corresponding C-acylated 1,4-dicarbonyl
compounds which may be obtained by electrophilic attack
of acylating agents to the â-carbons of the anion radicals
generated by electron transfer from cathode or Mg metal, as
shown in Scheme 1. The R-carbanions generated by the
subsequent second electron transfer are subjected to proto-
nation. These products formally possess the same structures
as the ones which would be obtained by the Michael-type
of nucleophilic attack of difficult-to-generate acyl anion to
the electron-deficient olefinic bonds.
(1) (a) Wenkert, E. Acc. Chem. Res. 1980, 13, 27. (b) McMurry, J. E.;
Melton, J. J. Am. Chem. Soc. 1971, 93, 5309. (c) Miyashita, M.; Yanami,
T.; Yoshikoshi, A. J. Am. Chem. Soc. 1976, 98, 4679. (d) Mukaiyama, T.;
Narasaka, K.; Furusato, M. J. Am. Chem. Soc. 1972, 94, 8641. (e) Herrmann,
J. L.; Richman, J. E.; Schlessinger, R. H. Tetrahedron Lett. 1973, 14, 3275.
(2) (a) Nienhouse, E. J.; Irwin, R. M.; Finni, G. R. J. Am. Chem. Soc.
1967, 89, 4557. (b) Adams, R.; Gold, M. H. J. Am. Chem. Soc. 1940, 62,
56. (c) Lauer, W.; Spielman, M. A. J. Am. Chem. Soc. 1933, 55, 4923. (d)
Nowlin, G. J. Am. Chem. Soc. 1950, 72, 5754. (e) Lutz, R. E.; Wilder, F.
N. J. Am. Chem. Soc. 1934, 56, 1987. (f) Gaertner, R.; Tonkyn, R. G. J.
Am. Chem. Soc. 1951, 73, 5872. (g) Jones, R. G. J. Am. Chem. Soc. 1955,
77, 4069.
In this study, we report novel one-pot vicinal double
C-acylation of styrene derivatives and methacrylates by
electroreduction using an undivided cell to afford the
corresponding 1,4-diketones in good yields (Scheme 2).
(3) (a) Jones, R. G. J. Am. Chem. Soc. 1955, 77, 4069. (b) Young, D.
M.; Allen, C. F. H. Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. II, p 219.
(4) (a) Gaertner, R.; Tonkyn, R. G. J. Am. Chem. Soc. 1951, 73, 5872.
(b) Jones, R. G. J. Am. Chem. Soc. 1955, 77, 4069. (c) Wolf, D. E.; Folkers,
K. Org. React. 1951, 6, 410. (d) Youtz, M. A.; Perkins, P. P. J. Am. Chem.
Soc. 1929, 51, 3511.
(5) (a) Shono, T.; Nishiguchi, I.; Ohmizu, H. J. Am. Chem. Soc. 1977,
99, 7396. (b) Ohno, T.; Aramaki, H.; Nakahiro, H.; Nishiguchi, I.
Tetrahedron 1996, 52, 1943. (c) Ohno, T.; Sakai, M.; Ishino, Y.; Shibata,
T.; Maekawa, H.; Nishiguchi, I. Org. Lett. 2001, 3, 3439. (d) Nishiguchi,
I.; Yamamoto, Y.; Sakai, M.; Ohno, T.; Ishino, Y.; Maekawa, H. Synlett
2002, 759.
10.1021/ol035020v CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/02/2003

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Scheme 1. Mono C-Acylation of Activated Olefins by
Table 1. Electroreductive Vicinal Double C-Acylation of
Styrenea
Electron Transfer
entry
R1 in 1
X in 1
R2 in 2, 3
yield of 4 (%)b
1
2
3
4
5
6d
7
8
9e
10e
H
H
H
H
H
H
H
H
H
H
H (1a )
H (1a )
H (1a )
H (1a )
H (1a )
H (1a )
H (1a )
H (1a )
H (1a )
H (1a )
Me (2a )
Me (2a )
Et (2b)
n-Pr (2c)
iso-Pr (2d )
Me (3a )
Et (3b)
n-Pr (3c)
MeO (3e)
EtO (3f)
82 (4a )
73 (4a )
81 (4b)
85 (4c)
73 (4d )
73 (4a )
63 (4b)
75 (4c)
82 (4e)
72 (4f)
a Reaction conditions: substrate (10 mmol), acylating agent (10 equiv
per mol), n-Bu4NBr (1.66 equiv per mol), current density (7 mA/cm2),
supplied electricity (6 F/mol), DMF (60 mL), -5 to 5 °C, under N2
atmosphere b GC yield. c The presence of 1.0 equiv per mol of H2O gave
4-phenyl-2-butanone as the byproduct in 9% yield. d 4-Phenyl-2-butanone
was obtained as the byproduct in 17% yield. e n-Bu4NBr (3 equiv per mol)
Scheme 2. Electroreductive Vicinal Double C-Acylation of
Activated Olefins
nal R- and â-carbon atoms of 1a to give corresponding
phenylsuccinic acid esters (4e,f) as the main products in good
yields (entries 9 and 10).
Introduction of a variety of substituents to the benzene
ring or to the R-carbon of styrenes (1b-i)9 in this reaction
with acetic anhydride (2a) also brought about similar vicinal
double C-acylation, and the results are summarized in Table
2. It may be a general tendency that the presence of electron-
Table 2. Electroreductive Vicinal Double C-Acylation of
Styrene Derivativesa
entry
X in 1
R1 in 1
R2 in 2
conv (%) yield of 4 (%)b
Although electrochemical vicinal double C-carboxylation6
and C-formylation7 of styrene derivatives in the presence of
carbon dioxide and N,N-dimethylformamide (DMF), respec-
tively, has been reported, vicinal double C-acylation has not
been known as yet to our best knowledge.
1
2
3
4
5
6
7
8
9
H
m-F
H (1a )
H (1b)
H (1c)
Me (2a )
Me (2a )
Me (2a )
Me (2a )
Me (2a )
Me (2a )
100
100
100
100
84
82 (4a )
72 (4g)
54 (4h )c
77 (4i)
40 (4j)
d
m-Cl
m-MeO H (1d )
p-Me
p-MeO
H
H
H
H (1e)
H (1f)
Me (1g) Me (2a )
Et (1h ) Me (2a )
0
The corresponding 1,4-diketones (4a-f) were obtained in
satisfactory yields, as shown in Table 1. It is interesting that
the addition of 1.0 equiv per mol of H2O to the medium in
the reaction of styrene (1a) with acetic anhydride (2a)
brought about the formation of a small amount of the
â-monoacylated product (entry 2), which was also obtained
from the reaction of 1a with a less electrophilic acylating
agent, N-acetylimidazole (3a),8 as the byproduct (entry 6),
indicating that the first C-acylation took place at the â-carbon
atom of 1a.
80
67
100
56 (4k )
33 (4l)
46 (4m )
Ph (1i)
Me (2a )
a Reaction conditions: substrate (10 mmol), acetic anhydride (10 equiv
per mol), n-Bu4NBr (1.66 equiv per mol), current density (7 mA/cm2),
supplied electricity (6 F/mol), DMF (60 mL), -5 to 5 °C, under N2
atmosphere. b GC yield. c Dehalogenated product, 3-phenyl-2,5-hexanedi-
one, was obtained in 14% yield. d Not detected.
withdrawing groups on the phenyl ring of styrene gave
the 1,4-diketones 4g-i in satisfactory yield (Table 2, en-
tries 2-4), whereas that of electron-donating groups on
the phenyl ring resulted in much decrease in product yield
(entry 5) or quantitative recovery of the starting material
(entry 6).
Use of N-carboalkoxyimidazoles (3e,f) also led to suc-
cessful introduction of two carboalkoxy groups to the vici-
(6) Senboku, H.; Komatsu, H.; Fujimura, Y.; Tokuda, M. Synlett 2001,
418.
(7) In the electroreductive vicinal double C-formylation of styrene, the
double C-formylated products were not isolated, but were characterized as
the corresponding O-methyloxime derivatives. See: Engels, Y.; Scha¨fer,
H. J. Angew. Chem., Int. Ed. Engl. 1978, 17, 460.
(9) The styrenes, 1d-f,h, were prepared by Wittig reaction, and 1b and
1c were prepared by the reported method. See: Ishino, Y.; Mihara, M.;
Nishihama, S.; Nishiguchi, I. Bull. Chem. Soc. Jpn. 1998, 71, 2669.
(8) Staab, H. A. Angew. Chem., Int. Ed. Engl. 1962, 1, 351.
2756
Org. Lett., Vol. 5, No. 15, 2003

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It is also noteworthy that the presence of alkyl or phenyl
groups at the R-carbon of styrene led to only some decrease
in the yield of the diacylated products possibly by steric and/
or electronic effects (entries 7-9) while that at the â-carbon
resulted in quantitative recovery of the starting compounds
or formation of a complex mixture (Scheme 3).
Table 4. Reduction Potentials of Activated Olefinsa
reduction potential
entry R1
Y
(V vs Ag/AgCl)
Scheme 3. Electroreduction of Substituted Styrenes in the
1
2
3
4
5
6
7
H
H
H
H
Ph (1a )
Ph (1g)
COOBn (5a )
COOEt (5c)
-2.81
-2.88
-2.38
-2.50
-1.88
-2.68
-2.96
diacylation
diacylation
diacylation
diacylation
monoacylation
monoacylation
no reaction
Presence of Acetic Anhydride
Ph COOEt (5e)
Me COOEt (5f)
Me Ph (1j)
a Counter electrode, Pt; working electrode, Pt; reference electrode, Ag/
AgCl; solvent, DMF; supporting electrolyte, n-Bu4NClO4; scan rate 200
mV/s
From these experimental results, the following reaction
scheme may be proposed although the detailed mechanistic
studies have not been conducted as yet. Thus, the first elec-
tron transfer from the cathode to styrene derivatives (1) gen-
erates anion radicals (8) which may be subjected to the first
electrophilic attack by the acylating agent at the â-carbon
of 1 followed by the fast second electron transfer, giving
more stable benzylic anions (9) preferentially rather than less
stable methylene anions (10). Subsequently the second elec-
trophilic acylation and protonation take place toward ben-
zylic anions (9) to give vicinal double C-acylation prod-
ucts (4) and monoacylation products (11), respectively
(Scheme 4).
Furthermore, electroreduction of alkyl methacrylates
5a-c and methacrylonitrile (5d) in the presence of acetic
anhydride (2a) under similar conditions provided the cor-
responding vicinal double acylated products 6a-d in good
to moderate yields. In contrast, only â-monoacylated products
7e,f were obtained from the reaction of ethyl cinnamate (7e)
and crotonate (7f) under the same conditions, as shown in
Table 3.10
Table 3. Electroreductive C-Acylation of Activated Olefinsa
Scheme 4. Proposed Reaction Mechanism for C-Acylation of
Styrenes
yield (%)b
entry
R1 in 5
R2 in 5
Y in 5
6
7
1
2
3
4
5
6
H
H
H
H
Ph
Me
Me
Me
Me
Me
H
COOBn (5a )
COOMe (5b)
COOEt (5c)
CN (5d )
COOEt (5e)
COOEt (5f)
72 (6a )
61 (6b)
59 (6c)
45 (6d )
c
11 (7a )
c
c
c
68 (7e)
50 (7f)
H
c
a Reaction conditions: substrate (10 mmol), acetic anhydride (15 equiv
per mol), n-Bu4NBr (1.66 equiv per mol), current density (7 mA/cm2),
supplied electricity (6 F/mol), DMF (60 mL), 15-25 °C, under N2
atmosphere. b GC yield. c Not detected.
In the case of alkyl methacrylates (5a-c), methacryloni-
trile (5d), ethyl cinnamate (5e), and crotonate (5f), anion
radicals (12) generated by the first electron transfer undergo
â-acylation followed by a second fast electron transfer giving
enolate anions (13). The tertiary enolate anions (13) derived
from 5a-d (R1 ) H, R2 ) Me) are presumably less stable
but more reactive to the second acylation than the secondary
enolates derived from 5e (R1 ) Ph, R2 ) H) and 5f (R1 )
Me, R2 ) H), which are preferentially subjected to proto-
On the other hand, reduction potentials measured by cyclic
voltammetry as shown in Table 4 indicate that acetic
anhydride (2a: no reduction peak up to -3.0V vs Ag/AgCl)
and â-methylstyrene (1j: Ep ) -2.96 V) are quite difficult
to reduce electrochemically while styrene (1a), R-methyl-
styrene (1g), alkyl methacrylates (5a-c), ethyl cinnamate
(5e), and crotonate (5f) (Ep ) -1.88 to -2.88 V) are
accessible to electrochemical reduction.
Org. Lett., Vol. 5, No. 15, 2003
2757

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Acknowledgment. This work was financially sup-
ported by the 21st Century COE program and a Grant-in-
Aid for Scientific Research (No. 13029038) from The
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
Scheme 5. Proposed Reaction Mechanism for C-Acylation of
Alkyl Methacrylate, Ethyl Cinnamate, and Crotonate
Supporting Information Available: Spectral (1H NMR,
13C NMR, IR, and mass) data for all the products 4a-m,
6a-d, 7a, 7e, and 7f. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL035020V
(10) In a 100-mL beaker-type undivided cell equipped with Zn plates
(40 × 70 × 0.5 mm3, nacalai tesque, 99%) as the cathode and the anode
were introduced 60 mL of anhydrous DMF as a solvent, n-Bu4NBr (16.6
mmol) as a supporting electrolyte, acid anhydrides or N-acylimidazoles (100
mmol) and styrenes or alkyl methacrylates (10 mmol). The electrolysis was
carried out under constant current conditions (current density: 7mA/cm2)
at -5 to 5 °C with magnetic stirring until 6 F/mol of electricity was passed.
After the electrolysis, the reaction mixture was poured into saturated
NaHCO3 solution when acid anhydrides were used as the acylating agents.
When N-acylimidazoles were used, the reaction mixture was poured into
1% HCl solution after the electrolysis. Organic materials were extracted
with three 100-mL portions of ether. The combined ethereal solution was
washed with saturated NaCl solution and dried over anhydrous MgSO4.
After removal of MgSO4 by filtration and evaporation of the solvent, the
isolation by column chromatography gave diacylated compounds in
satisfactory yields.
(11) This hypothesis is consistent with the phenomenon obtained in Mg-
promoted silylation of aromatic active olefins. Simply hydrogenated products
are easier to form than the corresponding silylated products in the reaction
of the starting substrates possessing less negative reduction potentials, giving
more stable anion species through electron transfer from Mg-metal. See:
Kyoda, M.; Yokoyama, T.; Kuwahara, T.; Maekawa, H.; Nishiguchi, I.
Chem. Lett. 2002, 228.
nation. Thereby this hypothesis may account for the sharp
contrast between one-pot vicinal R,â-diacylation for 5a-d
11
and â-monoacylation for 5e and 5f (Scheme 5).
In conclusion, novel one-pot vicinal double C-acylation
of styrene derivatives and alkyl methacrylate was successfully
accomplished to give useful 1,4-diketones or their precursors.
The reaction is characterized by a simple procedure, mild
conditions, high selectivity, and a unique reaction pattern.
In addition, the products are useful, the starting materials
are readily available, and the yields are good.
2758
Org. Lett., Vol. 5, No. 15, 2003