Benzylation of carboxylic acids by oxidation-reduction condensation using quinones and benzyloxydiphenylphosphine

Article abstract of DOI:10.1246/cl.2002.1126

Various carboxylic benzyl esters were obtained in high yields by way of oxidation-reduction condensation in which benzyloxydiphenylphosphine (BDPP), having been prepared easily from chlorodiphenylphosphine and benzyl alcohol, was treated with various carboxylic acids in the presence of 2,6-dimethyl-1,4-benzoquinone(DMBQ) under mild conditions.

Full text of DOI:10.1246/cl.2002.1126

1126
Chemistry Letters 2002
Benzylation of Carboxylic Acids by Oxidation-Reduction Condensation
Using Quinones and Benzyloxydiphenylphosphine
Teruaki Mukaiyama,ꢀ Taichi Shintou, and Wataru Kikuchi
The Kitasato Institute, Center for Basic Research, TCI, 6-15-5, Toshima, Kita-ku, Tokyo 114-0003
(Received August 7, 2002; CL-020663)
Various carboxylic benzyl esters were obtained in high yields
by way of oxidation-reduction condensation in which benzyloxy-
diphenylphosphine (BDPP), having been prepared easily from
chlorodiphenylphosphine and benzyl alcohol, was treated with
various carboxylic acids in the presence of 2,6-dimethyl-1,4-
benzoquinone(DMBQ) under mild conditions.
Table 1. Screening of quinone derivatives on benzylation of
benzoic acid
Ph2POBn (1.0 equiv.)
Quinone (1.0 equiv.)
PhCOOH
PhCOOBn
Quinone
CH2Cl2, rt, 3 h
Yield /%
Entry
Quinone
Entry
9
Yield /%
66
1
none
Ph
N.R.
O
O
O
The fundamental concept of oxidation-reduction condensa-
tion is to perform dehydration condensation with removal of H2O
as 2[H] and [O] by using a combination of weak reductant and
oxidant. For example, several acylating reactions were carried out
by using combinations of diphenylmercury and tri-n-
O
2
3
4
5
55
10
11
12
13
12
O
O
buthylphosphine,1
trans-dibenzoylethylene
and
tri-n-
Ph
N
butylphosphine,2 and 2,20-dipyridyl disulfide and phosphine.3
Preparation of phosphoric esters was also carried out by using
(EtO3)P and diethyl azodicarboxylate in the presence of
alcohols.4 Mitsunobu developed this concept into the efficient
alkylation methods by using a combination of triphenylphosphine
and diethyl azodicarboxylate (DEAD) and achieved condensa-
tion reaction between alcohols and various nucleophiles, which is
a method widely known as Mitsunobu reaction.5 Recently,
Tsunoda et al. reported alkylating reaction which took place
OEt
N
OMe
O
O
73
45
70
19
77
O
O
O
O
O
O
OMe
OEt
Cl
Cl
Ph
N.R.
N.R.
N.R.
O
O
O
O
CN CN
Ph
Cl
Cl
tBu
likewise
by
using
alcohols
and
cyanomethylene-
tributylphosphorane.6 Here, we would like to describe high-
yielding preparation of carboxylic benzyl esters by way of new
type oxidation-reduction condensation using benzyloxydiphe-
nylphosphine, carboxylic acids and 2,6-dimethyl-1, 4-benzoqui-
none under mild conditions.
O
O
O
Cl
Cl
Cl
tBu
tBu
6
7
8
14
15
16
O
In the first place, benzylation of benzoic acid with 1.0 equiv
of BDPP7 was tried by using 1.0 equivalent of trans-dibenzoyl-
ethylene in dichloromethane, and the desired product was
obtained in 55% yield within 3 h (Table 1, entries 1,2). When
DEAD was used under the above conditions, carboxylic benzyl
ester was then obtained in 73% yield (entry 3). On the other hand,
the carboxylic esters were not obtained even when powerful
oxidizing agents as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ), tetrachloro-1,4-benzoquinone ( p-chloranil) and 2,6-
dichloro-1,4-benzoquinone were used (entries 4–6). On the
contrary, the desired product was obtained in 75% yield when a
milder oxidant such as 1,4-benzoquinone was used under the
above conditions (entry 7). After screening several oxidants, the
benzyl carboxylic ester was found to be obtained in 90% yield
under milder conditions when DMBQ was used (entries 8–16).
While benzyloxydialkylphosphines, e.g. benzyloxydiisopro-
pylphosphine or benzyloxydicyclohexylphosphine, afforded the
desired ester in 60% and 57% yields, respectively, BDPP afforded
the ester effectively in 90% yield (Table 2, entries 1–3). The
reaction proceeded rapidly (0.5 h) and the ester was still more
obtained in 98% yield when 1.1 equivalent of BDPP was used
Cl
tBu
OH
O
O
O
O
O
O
O
75
90
19
32
OH
O
(entries 3–7).
The benzylation of several carboxylic acids using BDPP and
DMBQ was then tried (Table 3). As a result, esterification of
various carboxylic acids smoothly proceeded to afford the
corresponding carboxylic esters in high yields under mild
conditions. In the case of N-tert-butoxycarbonyl-L-valine, the
corresponding benzyl ester was obtained exclusively and no
epimerization was observed.8
A proposed reaction mechanism is shown in Scheme 1:
BDPP initially reacted with DMBQ to form adduct 1, which was
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
1127
Table 2. Effect of substituents of phospine on benzylation of
benzoic acid
corresponding carboxylic acid ester along with diphenylphos-
phiric acid 4-hydroxy-3,5-dimethylphenyl ester 3. The key
intermediate of this new oxidation-reduction condensation is
different from that of Mitsunobu reaction that involves alkoxy-
phosphonium carboxylate.9
Typical experimental procedure is as follows: to a mixture of
carboxylic acid (0.60 mmol) and 2,6-dimethyl-1,4-benzoquinone
(0.60 mmol) under argon atmosphere was added a solution of
benzyloxydiphenylphosphine (0.66 mmol) in dichloromethane
(0.50 ml) at room temperature. The reaction mixture was stirred
for 0.5 h at room temperature. On completion of the reaction
(detected by TLC), it was quenched with water and the mixture
was extracted with dichloromethane. The organic layers were
dried over anhydrous sodium sulfate, filtered and concentrated.
The crude product was purified by preparative TLC to afford the
corresponding benzyl esters in high yields.
Thus, a new and efficient method for the benzylation of
carboxylic acid was established by way of oxidation-reduction
condensation on treating benzyloxydiphenylphosphine and
milder oxidizing agent such as DMBQ, followed by the reaction
with carboxylic acid. Thus, the corresponding carboxylic esters
were obtained in excellent yields under mild conditions. Further
study on this type of condensation reaction is now in progress.
R2POBn
DMBQ(1.0 equiv.)
PhCOOH
Entry
PhCOOBn
CH2Cl2, Time, rt
R2POBn /equiv
Time /h
Yield /%
R
1
2
3
iPr
cyclohexyl
Ph
1.0
1.0
1.0
3
3
3
60
57
90
4
Ph
1.1
3
97
5
6
7
Ph
Ph
Ph
1.3
1.1
1.1
3
0.5
1
97
98
97
Table 3. Benzylation of carboxylic acids with BDPP and
DMBQ
Ph2POBn(1.1 equiv.)
DMBQ(1.0 equiv.)
RCOOH
Entry
RCOOBn
Yield /%
CH2Cl2, rt, 0.5 h
Carboxylic Acid
1
2
3
98
98
95
COOH
COOH
This work was supported by a Grant-in-aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
MeO
O2N
COOH
References and Notes
1
2
3
4
5
T. Mukaiyama, I. Kuwajima, and Z. Suzuki, J. Org. Chem.,
28, 2024 (1963).
I. Kuwajima and T. Mukaiyama, J. Org. Chem., 29, 1385
(1964).
T. Mukaiyama, R. Matsueda, and M. Suzuki, Tetrahedron
Lett., 22, 1901 (1970).
O. Mitsunobu, M. Yamada, and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 40, 935 (1967).
4
5
95
93
COOH
COOH
Ph
COOH
tBuCOOH
COOH
6
7
89
89
8
9
86
O
NHBoc
a) O. Mitsunobu and M. Yamada, Bull. Chem. Soc. Jpn., 40,
2380 (1967). b) O. Mitsunobu and M. Eguchi, Bull. Chem.
Soc. Jpn., 44, 3427 (1971). c) O. Mitsunobu, Synthesis, 1981,
1. d) D. L. Hughs, in ‘‘Organic Reactions,’’ ed. by P. Beak, et
al., John Wiley & Sons, New York (1992), Vol. 42, p 335.
a) T. Tsunoda, F. Ozaki, and S. Ito, Tetrahedron Lett., 35,
5081 (1994). b) S. Ito, Yakugaku Zasshi, 121, 567 (2001).
The equimolar amounts of chlorodiphenylphosphine and
benzyl alcohol were mixed with the equimolar amounts of
pyridine in diethyl ether at room temperature under argon
atmosphere. Distillation gave colorless oil, Yield 55% (bp.
155–157 ꢁC/0.2 mmHg). See: B. A. Arbouzov and N. P.
Grechkin, Zh. Obshch. Khim., 20, 107 (1950).
90a
COOH
a Determined by HPLC using Daicel CHIRALPAK AF.8
Ph
6
7
O
Ph
Ph2POBn
P
Ph
O
O
H OOCPh
O
O
1
Ph
OOCPh
OH
O
O
Ph
Ph
O
8
9
HPLC (Daicel Chiralpak AF, hexane/iPrOH = 19/1, flow rate
Ph
P
PhCOOBn
+
P
OH
t
t
Ph
O
= 1.0 ml/min): R = 7.8 min (L-valine derivative), R =
9.6 min (D-valine derivative). N-tert-butoxycarbonyl-D-va-
line afforded the corresponding benzyl ester in 89% yield and
no epimerization took place.
3
2
Scheme 1.
The reaction of benzoic acid with 1.1 equivalent of benzyl
alcohol and triphenylphosphine was tried by using 1.0
equivalent of BDMQ in dichloromethane at room tempera-
ture, but the desired product was not obtained.
in turn transformed to the phosphonium carboxylate 2 by the
interaction with carboxylic acid. Intramolecular attack of the
carboxylate anion to the benzylic carbon of the salt 2 afforded the