Unusual head-to-tail coupling of alkyl benzoates by electroreduction

Article abstract of DOI:10.1021/jo0013599

The electroreduction of alkyl benzoates in an alcoholic solvent gave unusual head-to-tail coupled products. Usual head-to-head coupled products derived from acyloin condensation could not be detected. The best result (73% yield) was obtained from methyl benzoate using an undivided cell with an Sn cathode in i-PrOH containing tetraalkylammonium salt as a supporting electrolyte. Using an undivided cell, the products cross-coupled with a solvent molecule were obtained as byproducts. The substitution at the para position of methyl benzoate considerably decreased the yields of the head-to-tail coupled products and increased those of the cross-coupled products. The possible mechanism of the head-to-tail coupling is the attack of anion radical, generated from methyl benzoate by one-electron transfer, to another methyl benzoate. The cross-coupled products were formed by the reaction with carbonyl compound anodically produced from a solvent molecule. The cross-coupling between methyl benzoate and aromatic aldehydes was also effected by the mixed electroreduction under the same conditions.

Full text of DOI:10.1021/jo0013599

862
J . Org. Chem. 2001, 66, 862-867
Un u su a l Hea d -to-Ta il Cou p lin g of Alk yl Ben zoa tes by
Electr or ed u ction
Naoki Kise,* Yoshihiko Hirata, and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori University, Tottori 680-8552, J apan
kise@bio.tottori-u.ac.jp
Received September 13, 2000
The electroreduction of alkyl benzoates in an alcoholic solvent gave unusual head-to-tail coupled
products. Usual head-to-head coupled products derived from acyloin condensation could not be
detected. The best result (73% yield) was obtained from methyl benzoate using an undivided cell
with an Sn cathode in i-PrOH containing tetraalkylammonium salt as a supporting electrolyte.
Using an undivided cell, the products cross-coupled with a solvent molecule were obtained as
byproducts. The substitution at the para position of methyl benzoate considerably decreased the
yields of the head-to-tail coupled products and increased those of the cross-coupled products. The
possible mechanism of the head-to-tail coupling is the attack of anion radical, generated from methyl
benzoate by one-electron transfer, to another methyl benzoate. The cross-coupled products were
formed by the reaction with carbonyl compound anodically produced from a solvent molecule. The
cross-coupling between methyl benzoate and aromatic aldehydes was also effected by the mixed
electroreduction under the same conditions.
In tr od u ction
benzaldehyde with SmI2-HMPA8 or Li(Hg)-U(IV)9 has
also been reported to give the similar head-to-tail coupled
products. In this paper, we report the results of the
unusual head-to-tail coupling of alkyl benzoates in
detail.10 We propose the reaction mechanism of the head-
to-tail coupling promoted by electroreduction.
We have already reported the electroreductive cross-
coupling of ketones with aromatic rings,1 nitriles,2 and
O-methyl oximes3 using an Sn cathode in i-PrOH con-
taining tetraalkylammonium salt as a supporting elec-
trolyte. Next, we have planed to realize the electro-
reductive cross-coupling of ketones with esters. In the
course of the study, we found the unusual head-to-tail
homo-coupling of alkyl benzoates under these conditions.
The reductive homo-coupling of esters with alkali metals
has been well-known as acyloin condensation.4 The
electroreduction of aromatic esters using a consumable
Mg anode in the presence5 or absence6 of SmCl3 has been
found to yield 1,2-diketones. The head-to-tail coupling of
aromatic esters is hitherto unknown, although it has been
reported that the electroreduction of acetophenone in the
presence of â-cyclodextrin promoted the head-to-tail
coupling.7 Recently, the reaction of aromatic ketones and
Resu lts a n d Discu ssion
At first, the electroreduction of methyl benzoate in 0.3
M Et4NOTs/i-PrOH using an undivided cell and an Sn
cathode was carried out at a constant current of 0.2 A.
As shown in Scheme 1, head-to-tail coupled product 1a
was obtained in 73% yield with a small amount of benzyl
alcohol (12%) and the product cross-coupled with i-PrOH
(2a ′, 7%). The same reaction using a divided cell gave
the head-to-tail coupled product as an isopropyl ester 1b
in 29% yield with benzyl alcohol (15%), whereas no cross-
coupled product was formed. The homo-coupled products,
1a and 1b, were formed as mixtures of two diastereo-
mers. Under these conditions, bezoin and its related
products such as benzil and 1,2-diphenylethane-1,2-diol
could not be detected.
The results of the electroreduction of methyl benzoate
under the different conditions using an undivided cell are
summarized in Table 1. The other cathode materials Zn,
Pb, Ag, and Cd gave 1a (runs 2-5), although the yields
decreased to some extent. However, methyl benzoate was
recovered completely with Pt cathode due to exclusive
hydrogen evolution (run 6). As a supporting electrolyte,
tetraalkylammonium salts were crucial to promote the
(1) (a) Shono, T.; Kise, N.; Suzumoto, T.; Morimoto, T. J . Am. Chem.
Soc. 1986, 108, 4676. (b) Kise, N.; Suzumoto, T.; Shono, T. J . Org.
Chem. 1994, 59, 1407.
(2) (a) Shono, T.; Kise, N. Tetrahedron Lett. 1990, 31, 1303. (b)
Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita, H. J . Org.
Chem. 1992, 57, 7175.
(3) (a) Shono, T.; Kise, N.; Fujimoto, T. Tetrahedron Lett. 1991, 32,
525. (b) Shono, T.; Kise, N.; Fujimoto, T.; Yamanami, A.; Nomura, R.
J . Org. Chem. 1994, 59, 1730.
(4) Bloomfield, J . J .; Owsley, D. C.; Nelke, J . M. Organic Reactions;
Dauben, W. G., Ed.; Robert E. Krieger Publishing Company: Malabar,
1976; Vol. 23, Chapter 2.
(5) He´bri, H.; Dun˜ach, E.; Heintz, M.; Troupel, M.; Pe´richon, J .
Synlett 1991, 901.
(6) (a) Kashimura, S.; Murai, Y.; Ishifune, M.; Masuda, H.; Murase,
H.; Shono, T. Tetrahedron Lett. 1995, 36, 4805. (b) Kashimura, S.;
Murai, Y.; Washika, C.; Yoshihara, D.; Kataoka, Y.; Murase, H.; Shono,
T. Tetrahedron Lett. 1997, 38, 6717.
(8) Shiue, J .-S.; Lin, M.-H.; Fang, J .-M. J . Org. Chem. 1997, 62,
4643.
(7) (a) Smith, C. Z.; Utley, J . H. P. J . Chem. Soc., Chem. Commun.
1981, 492. (b) Farnia, G.; Sandona´, G.; Fornasier, R.; Marcuzzi, F.
Electrochim. Acta 1990, 35, 1149. (c) Martre, A. M.; Mousset, G.;
Pouillen, P.; Prime, R. Electrochim. Acta 1991, 36, 1911.
(9) Maury, O.; Villiers, C.; Ephritikhine, M. Tetrahedron Lett. 1997,
38, 6591.
(10) Preliminary report: Shono, T.; Kise, N.; Inakoshi, N. Denki
Kagaku 1993, 61, 870.
10.1021/jo0013599 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/18/2001

Head-to-Tail Coupling of Alkyl Benzoates
J . Org. Chem., Vol. 66, No. 3, 2001 863
Sch em e 1
Sch em e 2
Ta ble 1. Electr or ed u ction of Meth yl Ben zoa te Usin g a n
Un d ivid ed Cella
Sch em e 3
% yieldb
of 1
% yieldb
of BnOH
run
cathode
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Sn
Pb
Zn
Ag
Cd
Pt
Sn
Sn
Sn
Sn
Sn
Sn
Sn
Sn
Sn
Sn
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOHc
i-PrOHd
i-PrOHe
t-BuOH
EtOH
73
52
68
53
47
0
70
0
0
52
35f
40f
0
13
20
0
12
8
16
5
9
0
10
0
4
4
13
8
product was detected (Scheme 2). Since hydrogen evolu-
tion occurred exclusively in MeOH, methyl benzoate was
unchanged (run 13). Aprotic solvents such as DMF,
acetonitrile, and THF brought about poor results (runs
14-16).
n-PrOH
MeOH
DMF
0
3
2
0
CH3CN
The mixtures of saturated and unsaturated products
1a ′, 2a ′, 3′, and 4′ were transformed to diastereomeric
mixtures of saturated products 1a , 2a , 3, and 4, respec-
tively, by hydrogenation (Scheme 4). The structures of
the saturated products were determined by spectroscopic
analysis and also supported by the conversion of 1a ′, 2a ′,
3′, and 4′ to the corresponding methyl 4-alkylbenzoates
and comparison with authentic samples (Scheme 4). At
the stage of methyl alkylbenzoates, the formation of the
regioisomers such as 2- or 3-alkylbenzoates could not be
detected by 1H NMR and GLC analyses. The other
products were confirmed by their spectroscopic data or
comparison with authentic samples.
Next, we investigated the substituent effect in the
electroreductive coupling of alkyl benzoates. First, ethyl
and isopropyl benzoates also gave the corresponding
head-to-tail coupled products 1c (50%) and 1b′ (20%),
though the yields of 1 were lower than that obtained from
methyl benzoate (Scheme 5). This result shows that large
alkoxy groups in alkyl benzoates hindered the head-to-
tail coupling. The decrease of the yield of 1 under the
conditions using a divided cell (Schemes 1 and 2) can be
explained by transesterification of the starting methyl
benzoate to ethyl or isopropyl one.
THFc
a
The electroreduction was carried out at 0.2 A with Et4NOTs
as an electrolyte. Isolated yields. c With Bu4NClO4 as an electro-
b
lyte. With LiClO4 as an electrolyte. e With NaClO4 as an electro-
d
lyte. f See text.
head-to-tail coupling. Use of Bu4NClO4 leaded the result
similar to that in run 1 (run 7). On the other hand, use
of LiClO4 caused deposition of Li metal on the cathode
surface and resulted in complete recovery of methyl
benzoate (run 8). Almost all of methyl benzoate was
recovered with a small amount of benzyl alcohol using
NaClO4 (run 9). The other alcoholic solvents t-BuOH,
n-PrOH, and EtOH also promoted the head-to-tail cou-
pling (runs 10-12). The electroreductions in EtOH and
n-PrOH gave the homo-coupled product (1a ′) and con-
siderable amounts of the products reacted with a solvent
molecule at the para position (3′ and 4′) as depicted in
Schemes 2 and 3. These products (X′) were obtained as
mixtures of saturated and unsaturated products. In the
case of EtOH solvent, the products coupled with EtOH
at the carbonyl carbon, 1-phenyl-1,2-propanediol (7%) and
1-phenyl-1-propanol (8%), were also formed (Scheme 2).
Using a divided cell in EtOH, the head-to-tail coupled
product was obtained as an ethyl ester 1c in 58% yield
together with benzyl alcohol (10%), and no cross-coupled
Second, the effect of para substituents on the aromatic
ring was examined. The electroreduction of methyl 4-

864 J . Org. Chem., Vol. 66, No. 3, 2001
Kise et al.
Sch em e 4
Sch em e 6
Sch em e 7
Sch em e 5
Sch em e 8
methylbenzoate gave the head-to-tail coupled product 5
in a low yield (13%) (Scheme 6). In this case, considerable
amounts of the products formed from reaction with
i-PrOH at the carbonyl carbon, diol 7 and alcohol 8, were
produced along with the product cross-coupled with
i-PrOH at the para position (6). In the electroreductions
of methyl 4-tert-butylbenzoate and methyl 4-methoxy-
benzoate, the coupled product at the para position was
no longer detectable and only the cross-coupled products
at the carbonyl carbon, 9-12, were obtained (Scheme 7).
It should be emphasized that the formation of the both
head-to-head (acyloin type) and tail-to-tail homo-coupled
products could not be detected throughout all the experi-
ments described above.
As shown in Scheme 8, benzaldehyde and acetophenone
afforded the simply reduced alcohols as main products
together with pinacols under the same conditions as
above. The reduction of N,N-dimethylbenzamide yielded
only benzyl alcohol. These results imply that the elec-
The electroreduction of the other aromatic carbonyl
compounds other than alkyl benzoates was also explored.

Head-to-Tail Coupling of Alkyl Benzoates
J . Org. Chem., Vol. 66, No. 3, 2001 865
Ta ble 2. DF T (UB3LYP /6-311++G**) Ca lcu la tion s of Aa
Mulliken chargesb,c
gas phase
PCM (EtOH)f
1.189 0.640
natural chargesb,d
gas phase
PCM (EtOH)f
-0.241 -0.274
MKS chargesb,e
gas phase
PCM (EtOH)f gas phase PCM (EtOH)f
-0.012
Mulliken spin densitiesc
C1
-0.130
0.098
0.199
0.019
0.254
C2 -0.695 (-0.562) -0.540 (-0.389) -0.224 (-0.022) -0.276 (-0.077) -0.178 (-0.117) -0.226 (-0.163)
C3 -0.017 (0.091) -0.191 (0.010) -0.239 (-0.065) -0.228 (0.020) -0.097 (-0.037) -0.093 (0.018)
C4 -0.573 (-0.492) -0.571 (-0.351) -0.347 (-0.172) -0.310 (-0.085) -0.318 (-0.239) -0.287 (-0.141)
0.023 (0.132) -0.091 (0.113) -0.239 (-0.066) -0.227 (0.054) -0.072 (-0.013) -0.053 (0.054)
C6 -0.712 (-0.569) -0.598 (-0.402) -0.233 (-0.035) -0.259 (-0.017) -0.229 (-0.179) -0.254 (-0.174)
-0.048
0.347
-0.093
0.338
C5
-0.062
0.210
-0.097
0.251
C7 -0.358
O8 -0.416
O9 -0.172
-0.094
-0.528
-0.256
0.674
-0.740
-0.614
0.628
-0.799
-0.626
0.473
-0.641
-0.344
0.446
-0.721
-0.381
0.132
0.148
0.018
-0.003
0.201
0.143
0.025
-0.003
C10 -0.229 (0.156) -0.235 (0.258) -0.197 (0.281) -0.214 (0.317)
0.030 (0.110) -0.026 (0.191)
a
b
Structure of A was optimized by UB3LYP/6-311++G** and confirmed by vibration analysis. The values in parentheses were the
atomic charges with hydrogens summed into heavy atoms. c Calculated by the Mulliken population analysis. Calculated by the natural
d
population analysis. Reference 14. e Calculated by the Melz-Kollman-Singh method. f Single point calculation with the Tomasi solvent
model in EtOH (ꢀ ) 24.55).
Sch em e 9
troreductive head-to-tail coupling is limited to alkyl
benzoates.
Rea ction Mech a n ism . It has generally been accepted
that the key step of usual acyloin condensation involves
homolytic coupling of anion radicals induced by one-
electron transfer to esters. In the unusual head-to-tail
coupling, it is likely that the active intermediate is an
anion radical species. Actually, when the electroreduction
of a 1:1 mixture of methyl benzoate and a methyl
alkanoate such as methyl formate, acetate, and pivalate
was carried out under the same condition as run 1 in
Table 1, no cross-coupled product was formed and 1a was
obtained in 65-70% yield with complete recovery of the
methyl alkanoate. This result suggests that the key
step of the head-to-tail coupling is not the nucleophilic
attack of an anionic species, but it is the reaction of anion
radical species. In the first step of the electroreduction,
it is undoubted that the anion radical species A is
generated by one-electron transfer to methyl benzoate,
and the countercation of A is a tetraalkylammonium salt
in contrast to usual acyloin condensation, in which the
countercation is a alkali metal cation. It is reasonable
that A is present as a naked anion, since the interaction
between A and the countercation is much less than in
the case of usual acyloin condensation. The DFT calcula-
tions (UB3LYP/6-311++G**) of atomic charges in the
naked anion radical A (Table 2) show that para (C4)
carbon is negatively charged. Even if carbonyl (C7)
carbon is positively charged, this carbon atom is sur-
rounded by highly negative oxygen atoms (O8 and O9).
These results suggest that the homolytic coupling of
negatively charged A is strongly inhibited by the elec-
tronic repulsion between them. Therefore, the head-to-
tail coupling proceeds via attack of A to another methyl
benzoate. The calculations of atomic spin densities in A
reveal that high spin density exists at the ortho (C2
and C6), para (C4), and carbonyl (C7) carbons (Table 2).
There are two possible mechanisms for the head-to-
tail coupling, that is, attack of A at the carbonyl carbon
(C7) to the para position of methyl benzoate (path a)
and attack of A at the para position (C4) to the
carbonyl carbon of methyl benzoate (path b). It seems
that path b is more favorable than path a from the result
of the cross-coupling reaction of methyl benzoate with
acetone described below. In addition, path b is consistent
with the calculated results that C4 carbon has the highest
spin density in A. Consequently, the overall reaction
mechanism can be illustrated as Scheme 9. The head-
to-tail coupled product B is formed through path b and
then converted to unsaturated ketoester C. The carbonyl
group and conjugated olefins of C were electrochemically
reduced to saturated hydroxy ester 1a .
The products coupled with a solvent molecule were
formed only when the electroreduction was carried out
using an undivided cell. This fact suggests that the anodic
oxidation of a solvent alcohol to the corresponding
carbonyl compound plays an important role in the cross-
coupling. In fact, the addition of acetone to the reaction
mixture increased the yield of cross-coupled product
2a ′ as shown in Scheme 10. This result shows that
methyl benzoate is more susceptible to reduction than
acetone. The reported half-wave polarographic potentials
of methyl benzoate (-2.14 V VS SCE) and acetone
(-2.46 V VS SCE) in 0.05 M Et4NI/75% dioxane also

866 J . Org. Chem., Vol. 66, No. 3, 2001
Kise et al.
Sch em e 10
Sch em e 12
Sch em e 11
scribed above imply the possibility of cross-coupling
between aromatic esters and other carbonyl compounds.
For example, the mixed electroreduction of methyl
benzoate and aromatic aldehydes gave cross-coupled
products 13′ and 14′, although the major products were
pinacols (Scheme 12). In these reactions, the anion
radical generated by one-electron transfer to aromatic
aldehyde attacks the para position of methyl benzoate
(like path a) to give the cross-coupled product.
Con clu sion
The electroreduction of alkyl benzoates in an alcoholic
solvent containing a tetraalkylammonium salt gave
unusual head-to-tail homo-coupled products. Head-to-
head coupled products such as benzoin and its related
compounds were not formed at all under the conditions.
This result is attributed to the nature of the anion radical
generated from alkyl benzoate electrochemically. Since
the countercation of the anion radical is a tetraalkyl-
ammonium salt, the anion radical cannot couple each
other due to the electronic repulsion and attack the
carbonyl carbon of another alkyl benzoate. Using an
undivided cell, cross-coupled products of alkyl benzoates
with a solvent molecule were also obtained. The cross-
coupled products were brought about by the reaction with
the carbonyl compound anodically produced from a
solvent alcohol. The electroreduction of a mixture of
methyl benzoate and an aromatic aldehyde afforded the
similar cross-coupled product.
support it.11,12 Therefore, a possible mechanism is pro-
posed in Scheme 11. Carbonyl compound is anodically
produced from a solvent. Similarly to the homo-coupling,
the anion radical A attacks the carbonyl compound at
the carbonyl carbon (path c) or the para position (path
d) to produce D or F , respectively. The cross-coupled
product F is further reduced to saturated hydroxy ester
such as 2, while D is transformed to hydroxy ketone E
which is subsequently reduced to 1,2-diol. The 1,2-diol
undergoes dehydration to aromatic ketone followed by
reduction to alcohol.
Exp er im en ta l Section
Typ ica l P r oced u r e for Electr or ed u ction . A solution of
methyl benzoate (0.41 g, 3.0 mmol) and Et4NOTs (3.6 g, 12
mmol) in i-PrOH (40 mL) was put into an undivided cell (50
mL beaker) equipped with an Sn cathode (5 × 10 cm2) and a
Pt anode (2 × 2 cm2). The electricity was passed with a
constant current of 0.2 A until almost all of the esters were
consumed (1740 C). The electrolyte was poured into water and
extracted with Et2O. The products were isolated by column
chromatography on silica gel (hexane-AcOEt).
Cr oss-Cou p lin g w ith Ar om a tic Ald eh yd es. The
results of cross-coupling with a solvent molecule de-
Typ ica l P r oced u r e for Ar om a tiza tion of Un sa tu r a ted
P r od u cts. A solution of 1a ′ (0.1 g) and p-TsOH‚H2O (10 mg)
in benzene (10 mL) was refluxed for 2 h with continuous
removal of water using a Dean-Stark apparatus. After the
(11) von Stackelberg, M.; Stracke, W. Z. Electrochem. 1949, 53, 118.
(12) The cyclic voltammogram of methyl benzoate in 0.05-0.3 M
Et4NOTs/i-PrOH at an Sn cathode showed no reproducible reduction
peak.

Head-to-Tail Coupling of Alkyl Benzoates
J . Org. Chem., Vol. 66, No. 3, 2001 867
usual workup, the crude product (94 mg) and DDQ (0.23 g)
were dissolved in benzene (5 mL) and the mixture was refluxed
for 12 h. After the usual workup, methyl 4-benzylbenzoate (31
mg) was isolated by column chromatography on silica gel. By
the same method, 2a ′, 3′ and 4′ were transformed to methyl
4-isopropyl benzoate, methyl 4-ethylbenzoate, and methyl
4-propylbenzoate, respectively. The products were confirmed
by their comparison with authentic samples.
DF T Ca lcu la t ion s. The DFT calculations were carried
out using the Gaussian 98W13 program at the unrestricted
B3LYP/6-311++G** level.
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Typ ica l P r oced u r e for Hyd r ogen a tion of Un sa tu r a ted
P r od u cts. A solution of 1a ′ (0.2 g) and 10% Pd/C (0.1 g) in
MeOH (5 mL) was stirred under H2 (1 atm) at room temper-
ature for 12 h. After the usual workup, the product 1a was
obtained quantitatively by column chromatography on silica
gel. By the same method, 2a -c′, 3′, 4′, 13′ and 14′, were
transformed to the corresponding saturated products 2a -c,
3, 4, 13, and 14.
Syn th esis of Au th en tic Sa m p les. Methyl 4-benzylben-
zoate was prepared from commercially available 4-benzoyl-
benzoic acid by its hydrogenolysis and subsequent esteri-
fication. Methyl 4-alkylbenzoates were accessible from the
corresponding 4-alkylbenzoic acids. 1-Phenyl-1,2-propane-
diol was derived from commercially available 1-phenyl-1,2-
propanedione by treatment with NaBH4. Alcohols 8, 10, and
12 were prepared by usual reaction of i-PrMgBr with the
corresponding aromatic aldehydes.
J O0013599
(13) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Baboul, A. G.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J . Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen,
W.; Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J . A. Gaussian 98W, Revision A.9; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(14) Gleindening, E. D.; Reed, A. E.; Carpenter, J . E.; Weinhold, F.
NBO Version 3.1.