Alkaloid induced asymmetric electrocarboxylation of 4-methylpropiophenone

Article abstract of DOI:10.1016/j.tetlet.2011.03.076

The alkaloid-induced electrocarboxylation of 4-methylpropiophenone is examined in mild conditions. Comparative studies with several inductors indicate that the efficient enantiodiscrimination of the electrocarboxylation depends on the nucleophilic quinucl

Full text of DOI:10.1016/j.tetlet.2011.03.076

Tetrahedron Letters 52 (2011) 2702–2705
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Alkaloid induced asymmetric electrocarboxylation of 4-methylpropiophenone
⇑
Shu-Feng Zhao, Mei-Xia Zhu, Kai Zhang, Huan Wang , Jia-Xing Lu
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The alkaloid-induced electrocarboxylation of 4-methylpropiophenone is examined in mild conditions.
Comparative studies with several inductors indicate that the efficient enantiodiscrimination of the elec-
trocarboxylation depends on the nucleophilic quinuclidine nitrogen atom and the OH group of the
inductors.
Received 19 November 2010
Revised 25 February 2011
Accepted 17 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cinchonine
Induction
Electrocarboxylation
Enantiomeric excess
Carbon dioxide
1. Introduction
Pursuant to our efforts toward the asymmetric electrocarboxy-
lation of acetophenone under mild conditions, and to understand
The electrochemical activation of aromatic ketones is one of the
most important reactions in organic electrochemistry. In recent
decades, an electrochemical methodology based on the use of an
undivided cell equipped with a sacrificial anode (Mg, Al) has been
a very convenient and cheap way to generate carboxylic acids via
the coupling of CO2 and aromatic ketones.1–7 These acids are an
important class of compounds, used to cure certain skin diseases,
or used as pharmaceutical/fine chemical intermediates in the pro-
duction of certain anti-inflammatory drugs.8 One of the most ac-
tive current areas of chemical research focuses on how to
synthesize chiral compounds, because different enantiomers of a
biomolecule can display dramatically different biological activities.
Drawing inspiration from generic electrocarboxylation, there is a
great need to synthesize chiral carboxylic acids in organic
electrochemistry.
the mechanism of asymmetric electrocarboxylation of aromatic
ketones, we are interested in studying the role of chiral inductors
on enantiodifferentiation. To our knowledge, the specific role of
inductors in asymmetric electrocarboxylation has not been re-
ported. Herein, we describe a convenient route to optically active
a-ethyl-a-hydroxy-4-methylbenzeneacetic acid (2) through the
coupling reaction of CO2 and 4-methylpropiophenone (1) using
simple and easily accessible inductors. The electrocarboxylation
of 1 was involved in several competitive reactions that lead to
the formation of the target carboxylic acid 2, and the correspond-
ing alcohol and pinacol. In this Letter, we focus on the preliminary
exploration of efficient inductors in the enantiodifferentiation of
carboxylic acids.
2. Result and discussion
However, only a few electrocarboxylic reactions have been re-
ported for the synthesis of chiral carboxylic acids. To the best of
our knowledge, most of the preparations of optically active carbox-
ylic acids are based on the electrocarboxylation of chiral substrates
in an aprotic solvent.9–11 Indeed, the exploration of an efficient
route for the asymmetric electrocarboxylation reaction between
CO2 and prochiral substrates remains a challenge due to the diffi-
culty in the selective fixation of the small molecule carbon dioxide.
Our recent study found two alkaloids, cinchonidine (CD) and cin-
chonine (CN), to be efficient inductors for the asymmetric electro-
carboxylation of acetophenone.12
Electrolysis were carried out at 0 °C in N,N-dimethylformamide
(DMF), under constant current conditions, in an undivided glass
cell tank of cylindrical geometry fitted with sacrificial Mg rod an-
odes and a stainless steel cathode. The results are summarized in
Scheme 1 and Table 1. No reaction occurred in the absence of cur-
rent (Table 1, entry 1). No chiral induction occurred in the absence
of alkaloids and n-butanol (Table 1, entry 2). Recently, our re-
search12 found that n-butanol as the co-catalyst is essential for
the enantiodifferentiation of carboxylic acids. Without the n-buta-
nol, only a racemic carboxylated product is obtained in the asym-
metric electrocarboxylation of prochiral acetophenone. The
remarkable similarities of the effect of CN in the asymmetric elec-
trocarboxylation of acetophenone and 1 indicate that the sub-
⇑
Corresponding author. Tel.: +86 21 6223 7606; fax: +86 21 6223 3491.
E-mail address: hwang@chem.ecnu.edu.cn (H. Wang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.076

S.-F. Zhao et al. / Tetrahedron Letters 52 (2011) 2702–2705
2703
O
COOH
COOH
Mg
stainless steel
inductor/n-butanol
+
+ CO2
OH
OH
S
R
1
2
Inductors
Cl
OH
S
R
N
N
H
OH
S
R
N
N-9-anthracenylmethylcinchoninium chloride (3)
N
H
Cinchonine(CN)
Br
O
S
R
N
N
H
O(9)-benzyl-N-9-anthracenylmethylcinchoninium bromide (4)
Scheme 1. Asymmetric electrocarboxylation of 4-methylpropiophenone.
Table 1
With replacement of CN with the same concentration of 3, a low
ee value was obtained (Table 1, entry 8). With 4 as the inductor,
only a 1.3% ee value and 29.7% yield were obtained (Table 1, entry
9).
Asymmetric electrocarboxylation of 4-methylpropiophenonea
Entry
Inductor
Inductor (mM)
Yieldb (%)
eec (%)
1
2d
3
4
5
6
7
8
9
CN
—
2.50
0
0
—
—
40.0
26.9
31.4
31.6
37.4
34.6
28.8
29.7
CN consists of three basic functional groups, a quinoline aro-
matic ring, a quinuclidine ring (a tertiary amine) containing the vi-
nyl group, and a methylenic alcohol group linking the two.
Multiple studies13,14 have indicated that the catalytic activity of
cinchona alkaloids is due to the nucleophilicity of the nitrogen of
the quinuclidine ring. Therefore, the very low ee value when 3
was used as an inductor in the asymmetric electrocarboxylation
of 1 is a strong indication that the key structural feature for CN
is the nucleophilic quinuclidine nitrogen atom. Arx et al.15 also
showed that methylation of the quinuclidine nitrogen of CD leads
to a complete loss of enantioselectivity in the heterogeneous enan-
tioselective hydrogenation of trifluoromethyl ketones. Similarly,
with 4 as inductor, the OH group of the modifiers was involved
in the process of enantiodiscrimination. Most reports16,17 on cin-
chona-promoted chiral catalysis have referred to this combination
of the tertiary amine and the OH group to contribute to the enanti-
oselectivity. The synergistic effect between the OH group of induc-
tors and the enantioselectivity may provide valuable information
on the reaction mechanism, and is currently being studied.
From a mechanistic point of view (Scheme 2), the inductor
could obtain a proton from the co-catalyst of n-butanol. Studies
have shown that the alkaloids could be adsorbed at the cathode
surface as a chiral proton-donating species after the protonation
of the quinuclidine nitrogen by the co-catalyst of n-butanol. Com-
pound 1 accepts an electron at the cathode to form an anion radical
intermediate (1a). As noted by Amatore et al.18 the cyclodextrins
act mostly as weak proton donors to the electronegative acetophe-
none anion radical in DMF. Similarly, the protonated inductor (CN–
H) is implied to act as a weak proton donor to the electronegative
CN
CN
CN
CN
CN
3
1.25
2.50
3.75
5.00
6.75
2.50
2.50
S-19.7
S-28.4
S-30.4
S-32.8
S-29.8
S-2.9
S-1.3
4
a
Experimental conditions: 0 °C, stainless steel cathode, 4-methylpropiophenone
0.1 M, tetrabutylammonium iodide (TBAI) 0.1 M, n-butanol 25 mM, DMF 10 mL,
current density 1.1 mA cmꢀ2, charge 193 C and CO2 pressure 1 atm.
b
The yield based on starting substrate.
The enantiopurity of 2 was determined by HPLC.
Run in the absence of n-butanol.
c
d
strates were transformed to the corresponding optically active car-
boxylic acids via the same reaction pathway. Therefore, CN should
be adsorbed on the surface of the cathode to act as a chiral inductor
in DMF. The n-butanol could act as co-catalyst by facilitating cin-
chona protonation. In the induction of CN, the S enantiomer of 2
was more abundant than the R enantiomer. The effect of CN con-
centration on the enantiomeric excess (ee) value has been studied
in the asymmetric electrocarboxylation of 1 (Table 1, entries 3–7).
The solubility of the cinchona alkaloids was clearly restricted in
DMF. The dependence of the ee value (28.4%) on the CN concentra-
tion was approximately 2.50 mM (Table 1, entry 4). However, with
higher concentration of CN, the ee value of 2 slightly increased
(Table 1, entries 5 and 6). Moreover, when the concentration of
CN was 6.75 mM (Table 1, entry 7), the asymmetric electrocarb-
oxylation of 1 resulted in an ee value of 29.8% and a 34.6% yield.

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S.-F. Zhao et al. / Tetrahedron Letters 52 (2011) 2702–2705
OH
OH
S
N
S
R
N
n-butanol
R
N
H
N
H
H
CN-H
CN
O-
OH
O
*
e
1b
1
1a
e
CO2
H+
COOH
OH
COOH
+
OH
S
R
2
Scheme 2. Mechanism in the asymmetric electrocarboxylation of 4-methylpropiophenone.
1a to fix the oxygen atom (1b) to one side, and to precede the
reaction with CO2 from the other side to give the enantioselective
carboxylated anion. After acidification of the enantioselective car-
boxylated anion, the optically active carboxylic acid (2) is pro-
duced. Further optimization of such inductor systems and
exploration of the details of the mechanism are now ongoing in
our laboratory.
6890 gas chromatograph (Aglient, USA). The following data were
obtained. GC–MS (m/z,%): 194 (M+, 1), 57 (100), 150 (67), 55
(39), 92 (36), 120 (30), 65 (24), 51 (14), 89 (10), 147 (10), 78
(10). 1H NMR (500 MHz, CDCl3): d 7.50 (2H, d, J = 8.0 Hz), 7.19
(2H, d, J = 8.0 Hz), 2.38 (3H, s), 2.36–2.24 (1H, m), 2.09–2.05 (1H,
m), 0.97 (3H, t, J = 7.3 Hz). The yield and the enantiomeric excess
were determined by HPLC (Alltech 426 HPLC Pump) analysis with
chiralpak AD-H column (hexane/2-propanol/trifluoroacetic
acid = 90:10:1, 0.5 ml/min, UV (Linear UVIS 200) detection at
254 nm, the S enantiomer (2): 23.2 min, the R enantiomer (2):
27.0 min). The enantioselectivity was expressed as enantiomeric
excess (ee), calculated as
3. Conclusions
A convenient route to the optically active a-ethyl-a-hydroxy-4-
methylbenzeneacetic acid has been established using simple
inductor systems under mild conditions. Comparative studies with
several inductors indicate that the quinuclidine (a tertiary amine)
nitrogen atom is crucial to enantiodifferentiation in asymmetric
electrocarboxylation. The hydroxyl group of the inductors is also
involved in the enantiodiscrimination.
½ðRÞ ꢀ 2ꢁ ꢀ ½ðSÞ ꢀ 2ꢁ
eeð%Þ ¼
ꢂ 100
½ðRÞ ꢀ 2ꢁ þ ½ðSÞ ꢀ 2ꢁ
As reported by Corey et al.,19 N-9-anthracenylmethylcinchoni-
nium chloride (3) was prepared in one step from cinchonine and
9-(chloromethyl)-anthracene in toluene. Compound 3 was crystal-
lized from a CH2Cl2/Et2O solvent mixture. The desired product is a
light yellow solid. With 50% aqueous KOH, O(9)-benzyl-N-9-anth-
racenylmethylcinchoninium bromide (4) was prepared from 3
and benzyl bromide in CH2Cl2. Compound 4 was crystallized from
a MeOH/Et2O solvent mixture. The desired product is a yellow
solid.
4. Experimental
4.1. General electrolysis procedure
The galvanostatic electrolysis was carried out using a dc regu-
lated power supply HY3002D (HYelecÒ, China) in an undivided
glass cell tank of cylindrical geometry, equipped with a gas inlet
and outlet, a sacrificial magnesium rod anode and a reticulate
stainless steel cathode ring at 0 °C. The volume of the electrolyte
solution was 10 mL. DMF (10 mL), TBAI (1 mmol), the inductor,
n-butanol (25 mM) and 1 (1 mmol) were introduced into the cell.
During electrolysis the electrolyte solution was continuously stir-
red and the same current density (1.1 mA cmꢀ2) was applied until
a charge of 193 C was consumed. The crude mixture was hydro-
lyzed with 2 M HCl solution and extracted with Et2O. Subse-
quently, the organic layers were washed with saturated NaHCO3
solution repeatedly. A second acidification and extraction followed
by washing with saturated sodium chloride solution and drying
over anhydrous MgSO4 gave nearly pure 2. 1H NMR spectra were
recorded on an AVANCE 500 (500 MHz, Bruker, Germany) spec-
trometer in CDCl3 with Me4Si as an internal standard. Mass spectra
were obtained on a 5973 N spectrometer connected with a HP
Acknowledgments
This work was financially supported by the Project for the Na-
tional Natural Science Foundation of China (20973065), Basic Re-
search in Natural Science Issued by Shanghai Municipal
Committee of Science, China (08dj1400100), ‘Chen Guang’ project
supported by Shanghai Municipal Education Commission and
Shanghai Education Development Foundation, China (10CG26),
the Fundamental Research Funds for the Central Universities,
China and Shanghai Leading Academic Discipline Project, China
(B409).
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