Convenient method for the preparation of carboxylic esters using (chloromethylene)dimethylammonium chloride

Article abstract of DOI:10.1080/00397910802109299

(Chloromethylene)dimethylammonium chloride (Vilsmeier reagent) works as an efficient condensation reagent in the formation of carboxylic esters from carboxylic acids and alcohols under mild conditions in a one-pot procedure. Secondary alcohols are convert

Full text of DOI:10.1080/00397910802109299

Synthetic Communications1, 38: 3208–3214, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802109299
Convenient Method for the Preparation of
Carboxylic Esters Using
(Chloromethylene)dimethylammonium Chloride
Hitoshi Nagao, Makoto Michida, and Teruaki Mukaiyama
Center for Basic Research, Kitasato Institute, Tokyo, Japan
Abstract: (Chloromethylene)dimethylammonium chloride (Vilsmeier reagent)
works as an efficient condensation reagent in the formation of carboxylic esters
from carboxylic acids and alcohols under mild conditions in a one-pot procedure.
Secondary alcohols are converted successively into the corresponding esters in
moderate to high yields with inversion of configurations.
Keywords: Condensation, inversion, mild conditions, one-pot, Vilsmeier reagent
Preparation of carboxylic esters is one of the most fundamental and
frequently used important reactions in organic chemistry. For instance,
conversion of secondary alcohols into the corresponding esters with car-
boxylic acids by oxidation–reduction condensation using a phosphorus
reagent system such as Ph3P-DEAD-RCO2H (Mitsunobu reaction[1–3]
)
is considered quite useful in the construction of chiral centers via the
inversion of configuration by Sn2 displacement. However, this conven-
tional method has some disadvantages in the process. That is, first,
isolation of the desired product from the coproduct such as triphenylpho-
sphine oxide or diethyl hydrazinedicarboxylate is often difficult. Second,
azodicarboxylate, such as diethyl azodicarboxylate, is a poisonous com-
pound. Therefore, to develop a reaction more efficient and convenient for
the preparation of various esters under absolute stereochemical control is
still an important topic.
Received February 6, 2008.
Address correspondence to Teruaki Mukaiyama, Center for Basic Research,
Kitasato Institute, 6–15–5 (TCI), Toshima, Kita-ku, Tokyo 114–0003, Japan.
E-mail: mukaiyam@abeam.ocn.ne.jp
3208

Preparation of Carboxylic Esters
3209
(Chloromethylene)dimethylammonium chloride (Vilsmeier reagent),
which is easily derived from N,N-dimethylformamide and a chlorinating
reagent, is frequently used not only as a formylating reagent[4,5] but also
as an activating reagent for carboxylic acids to form esters[6] and
amides.[7] Although the Vilsmeier reagent has a powerful ability to
dehydrate carboxylic acids, only a few examples have been reported
on the dehydration from an alcoholic moiety.[8–10] Of the few methods,
Barrett et al. reported that secondary alcohols were converted into the
corresponding esters in an inverted fashion when the Vilsmeier reagent
and potassium benzoate were used in combination.[8] This method
requires tough reaction conditions (e.g., reflux for 3 days in THF),
and the esterification of chiral 1-phenylethyl alcohol proceeded with
partial inversion (ee ¼ 51%). Recently, our laboratory reported that
(chloromethylene)dimethylammonium chloride was a useful reagent
for the preparation of inverted alkyl aryl sulfides from various chiral
alcohols.[11]
In this communication, we report a convenient method for the prep-
aration of esters from various primary and secondary alcohols via (alkoxy-
methylene) dimethylammonium chloride under mild conditions (Scheme 1).
In the first place, we tried esterification of (S)-(–)-1-phenylethyl alco-
hol with 1.5 equivalents of Vilsmeier reagent using 3.0 equivalents of
triethylamine in THF at room temperature (Table 1). When benzoic acid
was used, the desired ester was obtained in 66% yield with 90% ee
(entry 1). The yield and enantiomeric excess further increased when
benzoic acids with electron-withdrawing groups were used (entries 3–6).
The best result of all was obtained when 2,4-dinitrobenzoic acid was used
(entry 6), and the yield was 96% with almost complete inversion of
stereochemistry (95% ee). It is noteworthy that the reaction proceeded
with clean inversion of configuration even when the easily epimerizable
substrate was used.
Next, the effect of solvents was examined (Table 2). When the
solvents such as dichloromethane, acetonitrile, or acetone were used,
the yield of the desired ester was obtained in low (entries 1–3). On the
other hand, the esterification of (S)-(–)-1-phenylethyl alcohol gave the
ester in low enantiomeric purities when solvents such as diethylether or
Scheme 1. Preparation of carboxylic esters from alcohol.

3210
H. Nagao, M. Michida, and T. Mukaiyama
Table 1. Esterfication of (S)-(–)-1-phenylethyl alcohol using various carboxylic acids
Entry
1
ArCO2H
Product
Yield (%)a
Ee (%)b
3a
66
90
2
3
3b
3c
55
80
72
85
4
5
6
7
8
3d
3e
3f
82
85
96
44
80
93
93
95
96
90
3g
3h
aIsolated yield.
bDetermined by HPLC analysis using a chiral column (DAICEL Chiralpak
ADꢀH or ASꢀH) with hexane=2-propanol as an eluent.
1,4-dioxane were used (entries 7 and 8). Low enantioselectivities and
yields are because the present reaction proceeded by either a mixed
Sn2=Sn1 pathway or partially via the corresponding benzylic chloride.

Preparation of Carboxylic Esters
3211
Table 2. Effect of solvents
Entry
Solvent
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
CH2Cl2
CH3CN
Acetone
Toluene
AcOEt
THF
28
39
54
81
79
96
91
46
92
95
96
86
98
95
25
6
Et2O
1,4-dioxane
aIsolated yield.
bDetermined by HPLC analysis using a chiral column (DAICEL Chiralpak
ADꢀH or ASꢀH) with hexane=2-propanol as an eluent.
As a result, tetrahydrofuran was found to be the most effective solvent of
the present reaction (entry 6).
Then, esterification of various alcohols was tried with 2,4-dinitroben-
zoic acid in THF at room temperature for 16 h (Table 3). The reactions of
primary and secondary alcohols proceeded smoothly to provide the cor-
responding esters in moderate to good yields (entries 1–9). The desired
2,4-dinitrobenzoates were obtained in good yields with almost complete
inversion of the stereochemistry when chiral secondary alcohols were
used (entries 5–9). However, when a tertiary alcohol having an ester
group at the quaternary center was tried, the corresponding ester was
obtained in only 9% yield (entry 12).
In conclusion, it is noted that a convenient and efficient method for
the preparation of inverted alkyl carboxylates from various chiral sec-
ondary alcohols was established using the readily available Vilsmeier
reagent under mild conditions.
TYPICAL EXPERIMENTAL PROCEDURE
Experimental procedure is exemplified in the following (Table 1, entry
6): To a stirred solution of DMF (117 mL, 1.37 mmol) in dry CH2Cl2
(3.0 mL), oxalyl chloride (108 mL, 1.24 mmol) was added dropwise at

3212
H. Nagao, M. Michida, and T. Mukaiyama
Table 3. Esterification of various alcohols
Entry
1
RR0OH
Product
Yield (%)a
Ee (%)b
3i
76
—
2
3
3j
65
87
—
—
3k
4
5
3l
74
92
—
95
3m
6
7
3n
3o
94
86
96
99
8
3p
76
96
9
3q
3r
65
9
95
—
10
aIsolated yield.
bDetermined by HPLC analysis using a chiral column (DAICEL Chiralcel
OD-H, Chiralpak AD-H or AS-H) with hexane=2-propanol as an eluent.

Preparation of Carboxylic Esters
3213
0 ꢁC under an argon atmosphere. The mixture was stirred for 5 min at
the same temperature, and solvent was evaporated. The obtained white
solid was cooled down to 0 ꢁC and suspended in dry THF (3.0 mL).
(S)-(–)-1-Phenylethyl alcohol (151.2 mg, 1.24 mmol), triethylamine
(346.7 mL, 2.49 mmol), and 2,4-dinitorobenzoic acid (176.1 mg,
0.83 mmol) were added sequentially. After the reaction mixture was stir-
red for 16 h at room temperature, it was quenched with water. The mix-
ture was extracted with AcOEt. The organic layer was washed with
brine, dried over anhydrous Na2SO4, filter, and concentrated. The
crude
product
was
purified
by
column
chromatography
(hexane=EtOAc ¼ 3=1) to afford the desired product 3f (250.8 mg,
96%, 95% ee) as a coloress solid. 1H NMR (270 MHz, CDCl3) d
8.77 (d, J ¼ 2.1 Hz, 1H), 8.50 (dd, J ¼ 8.4 Hz, 2.1 Hz, 1H), 7.90 (d,
J ¼ 8.4 Hz, 1H), 7.41–7.29 (m, 5H), 6.16 (q, J ¼ 6.6 Hz, 1H), 1.69 (d,
J ¼ 6.6 Hz, 1H). The enantiomeric purity was determined by HPLC
analysis using DAICEL Chiralpak AD-H, hexane=2-propanol ¼ 20=1,
k ¼ 254 nm, flow rate ¼ 1.0 mL=min, retention times ¼ 19.1 min (R)
and 24.6 min (S).
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