Microwave-assisted, facile, rapid and solvent-free one pot two-component synthesis of some special acylals

Article abstract of DOI:10.1016/j.cclet.2014.11.001

A facile, rapid and solvent-free method for the conversion of acids and dihalomethane to the corresponding methylene diesters (acylals) using microwave as activators or assistor, is reported. This method is particularly powerful for the diesterification o

Full text of DOI:10.1016/j.cclet.2014.11.001

Chinese Chemical Letters 26 (2015) 81–84
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Microwave-assisted, facile, rapid and solvent-free one pot two-
component synthesis of some special acylals
a
b
c
a
a
a,
Yu-Heng Ma , Gang Wu , Nan Jiang , Shu-Wang Ge , Qian Zhou , Bai-Wang Sun *
a
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210096, China
b
Nanjing SimnovTecPharmaceuticals, Nanjing 210096, China
c
School of Pharmacy, Nanjing Medical University, Nanjing 210096, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A facile, rapid and solvent-free method for the conversion of acids and dihalomethane to the
corresponding methylene diesters (acylals) using microwave as activators or assistor, is reported. This
method is particularly powerful for the diesterification of carboxylic acids, which afford methylene
diesters in good to excellent yields (up to >99%). When the intermediate is trapped, a ‘‘double successive
Received 28 June 2014
Received in revised form 8 October 2014
Accepted 22 October 2014
Available online 10 November 2014
N
S 2 reactions’’ mechanism is proved.
ß 2014 Bai-Wang Sun. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of
Keywords:
Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
Double successive S
Acylal
N
2 reactions
Anilines
Methylene diester
1
. Introduction
Acylals have the general structure R
harmful solvents, the use of sensitive and costly catalysts and the
requirement of special apparatus.
1 2 2
–CH(OOCR ) , which were
Recently, we developed a novel method for the conversion of
acids and dihalomethane to the corresponding methylene diesters
(acylals). Our method overcomes the abovementioned disadvan-
tages that make this method attractive for large-scale synthesis.
Surprisingly, dichloromethane, which is a relatively inert com-
pound, seldom acts as a strong enough electrophile to react with
carboxylic acids [8]. The formation of methylene diester (1a), as
shown in Scheme 1, was unexpected.
introduced by Hurd and Cantor [1]. They are important starting
materials in organic synthesis, particularly for the synthesis of
dienes and chiral allylic esters. They also act as cross-linking
reagents for cellulose in cotton [2]. In spite of the fact that the first
acylal was synthesized more than 150 years ago and a number of
methods have been developed since then for this purpose, two
synthetic routes predominate [3]. The most widely used route is
thereactionofaldehydeswithcarboxylicanhydridesinthepresence
of an acid catalyst such as protic or Lewis acid, iodine, and N-
bromosuccinimide [4]. Several inorganic heterogeneous reagents
have also been developed such as sulfated zirconia, montmorillonite
clay, expansive graphite, and zeolite HSZ-360 [5]. Wicke and
Engelhardt developed the second major route by the reaction of
silver carboxylates with 1,1-dihaloalkanes. When cations other than
silver ions were used as the carboxylate counterion, the reaction
conditions were slightly modified [6].
2. Experimental
Unless otherwise noted, all materials were obtained from
1
13
commercial suppliers. H NMR and C NMR spectra were acquired
on 300 or 500 MHz Bruker Avance spectrometer [9] with CDCl as
the solvent and tetramethylsilane (TMS) as the internal standard.
The chemicalshiftswerereportedin (ppm). Massspectra(MS)data
3
d
were obtained using an Esquire 6000 Mass Spectrometer. The single
crystal X-ray diffraction data was collected at 293 K with graphite
Thus, although acylals are readily available, the existing
methodologies suffer from one or more of the following
disadvantages [7]: longer reaction time, low yields, the use of
monochromated Mo-K
a
radiation (
l
= 0.071073 nm), and a Rigaku
SCX mini diffractometer with the
v-scan technique was used. The
lattice parameters were integrated using vector analysis and refined
from the diffraction matrix, and the absorption correction was
carried out by using Bruker SADABS program with the multi-scan
method [10]. CCDC reference numbers 978475 contains the
*
Corresponding author.
E-mail address: chmsunbw@seu.edu.cn (B.-W. Sun).
http://dx.doi.org/10.1016/j.cclet.2014.11.001
001-8417/ß 2014 Bai-Wang Sun. Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. All rights reserved.
1

8
2
Y.-H. Ma et al. / Chinese Chemical Letters 26 (2015) 81–84
Scheme 1. Discovery of methylene diester.
supplementary crystallographic data in CIF format reported in this
paper. Thesedatacan beobtained freeofchargefromThe Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif. Column chromatography was performed with silica gel
or s-collidine improved the isolated yield to >90% in oil bath, and
the reaction time significantly decreased. But it did not happen in
the other reactions using the bases as N,N-diisopropylethylamine
(DIPEA), 4-methylmorpholine, triethylamine. Surprisingly, in the
condition of microwave, the reactions using the organic bases were
improved which afford methylene diesters in good to excellent
yields (up to >99%).
(200–300 mesh, Qingdao Haiyang Chemical Co., Ltd., China).
3
. Results and discussion
To demonstrate the general applicability of this method, various
para-substituted benzoic acids were reacted under the optimized
An impurity generated during the synthesis of Vinpocetine
reaction conditions, e.g., –Me, –OMe, –F, and –NO . The results are
2
(API) aroused our attention. It is very interesting that the results of
summarized in Table 2. The electronic effects and the nature of the
the reaction stirring in oil bath and microwave oven are very
different. When the reaction was stirred in oil bath, the HPLC
analyses showed that the content of impurity increased with
increasing time. The reaction was continued for 7 days to obtain
this impurity, and the yield of the impurity increased from 0.1% to
substituents on the aromatic ring strongly affected the yields under
the optimized reaction conditions. p-Nitrobenzoic acid was proved
to be inert at low temperature. Several attempts to improve the
outcome of this reaction by adding different catalysts (CuCl, CuBr,
CuI, AgNO , Pd(C H O ) )wereunsuccessful. Whenthe temperature
3
2 3 2 2
1
0%. But in the condition of microwave, it needs only 45 min to
of the reaction was raised to 120 8C, the yield of the reaction
improved. Assuming that C–Br bondwould be more reactive thanC–
Cl bond in this reaciton, CH Br was reacted instead of CH Cl ;
however, the reaction was not successful. When the temperature
of the reaction was raised up to 120 8C, the yield of the reaction
improved. Intrigued by this result, we tried to synthesize
methylidyne triesters by reacting benzoic acid (10 mmol) in CHCl3
(5 mL) and N-methyl-2-pyrrolidon (NMP) (10 mL) at 200 8C in a
microwave reactor; a new spot was detected by TLC. However, it
was difficult to isolate the product to confirm its structure.
reach this result. Then, the impurity was purified by column
chromatography and the structure was established by the MS, H
NMR, and C NMR spectral analyses. The main difference in the H
NMR spectrum of the impurity than that of Vinpocetine was the
1
2
2
2
2
13
1
disappearance of the H-20 (
d
4.40, 2H) and H-21 (
d
d
1.37, 3H)
6.25 in the H NMR spectrum
80.86 in the C NMR and DEPT (135) spectra of the
impurity to confirmed the presence of a methylene (–CH –) group.
The ESI-MS analysis showed the mass of the impurity at m/z
1
signals. New signals appeared at
13
and at
d
2
+
6
57 [M+H] . Thus, the structure of the impurity was established as
Based on the above-mentioned results, various heterocyclic
carboxylic acids were investigated. They afforded the corresponding
products in excellent yields. The results are summarized in Table 3.
the methylene diester (1a), as shown in Scheme 1.
Although the abovementioned diesterification between the
2 2
acid and CH Cl seemed to be an unexpected result for the
synthesis of methylene diesters. To prove our conjecture, benzoic
acid was chosen to test and verify the reaction. Methylene
dibenzoate (2a) was isolated by column chromatography, and the
molecular structure was unambiguously confirmed by the X-ray
crystallographic analysis (Fig. 1).
Table 1
Optimization studies.
Various conditions were evaluated for optimizing the reaction
conditions, and the results are shown in Table 1. Inorganic bases
such as K
2 3 2 3
CO , Cs CO , and NaOH slightly affected the reaction in
a
b
oil bath and microwave, because they could not be dissolved in
Entry
Lewis base
Conditions
Yield (%)
CH
2
Cl
2
. To our delight, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
1
2
3
4
5
6
7
8
9
K
K
2
CO
CO
3
3
5 Â 24 h/40 8C
<5
12
<5
13
<5
15
10
92
18
94
15
93
92
99
93
99
2
Microwave/1 h/40 8C
5 Â 24 h/40 8C
Cs
Cs
2
CO
CO
3
3
2
Microwave/1 h/40 8C
5 Â 24 h/40 8C
NaOH
NaOH
DIPEA
DIPEA
Microwave/1 h/40 8C
40 h/40 8C
Microwave/45 min/80 8C
40 h/40 8C
Microwave/45 min/80 8C
40 h/40 8C
Microwave/45 min/80 8C
8 h/40 8C
Microwave/45 min/80 8C
8 h/40 8C
4-Methylmorpholine
4-Methylmorpholine
Triethylamine
Triethylamine
DBU
10
11
12
13
14
15
16
DBU
s-Collidine
s-Collidine
Microwave/45 min/80 8C
a
All the reactions were carried out under the following conditions: benzoic acid
Cl , 30 mL; base 30 mmol.
Yields of the isolated products.
1
0 mmol; CH
b
2
2
Fig. 1. Molecular structure of methylene dibenzoate.

Y.-H. Ma et al. / Chinese Chemical Letters 26 (2015) 81–84
83
Table 2
Effect of different functional groups.
a
b
Entry
R
Conditions
Yield (%)
2
3
4
5
6
H
45 min/80 8C
45 min/80 8C
45 min/80 8C
45 min/80 8C
45 min/80 8C
CuCl/80 8C/1 h
93
95
97
91
CH
3
OCH
F
3
Scheme 2. Possible mechanism for the synthesis of methylene diesters [11].
NO
2
<1
<1
<1
<1
22
c
d
CuBr/80 8C/1 h
e
CuI/80 8C/1 h
f
DBU/DMF: CH
2 2
Cl = 5:1/1208C/1.5 h
g
2
CH Br2/80 8C/1 h
<1
a
Unless otherwise noted, the reaction was carried out on a para-substituted
Cl 30 mL, base 30 mmol.
Yield of the isolated products.
benzoic acid 10 mmol, CH
b
2
2
Scheme 3. Selective reaction between acid and C–I bond.
c
d
e
f
1
0 mmol CuCl.
0 mmol CuBr.
0 mmol CuI.
DMF 50 mL, CH
1
1
2
Cl
2
10 mL.
2
Br is 96 8C.
g
The boiling point of CH
2
From the abovementioned results (Table 2, entries 2–6; Table 3,
entries 7–11), methylene diesters were observed unambiguously;
other intermediates were not detected by the HPLC analyses
except for the reaction between p-nitrobenzoic acid and
2 2
CH Cl . When p-nitrobenzoic acid was used as the starting
1
material, an intermediate was trapped. The H-NMR spectrum
of this intermediate confirmed the structure as chloromethyl-4-
nitrobenzoate (6b). This was the only case when substantial
amounts of a chloromethyl ester was observed and ruled out the
possibility of path 2 in Scheme 2. Thus, we propose that this direct
esterification most probably proceed via a double successive
Scheme 4. Competitive reaction between furan-2-carboxylic acid and benzoic acid.
N
S 2 processes.
To prove our proposed mechanism, the first was to explain
that the chloromethyl esters did not form in other reactions.
Therefore, we designed two reactions: the first reaction is
Table 3
Direct synthesis of methylene diesters .
a
b
using p-nitrobenzoic acid and CH
Scheme 3. As expected, both p-nitrobenzoic and chloromethyl-
2
ICl, and the result is shown in
Entry
7
Compound
Yield (%)
80
4
-nitrobenzoate did not have sufficient activity to continue.
The second reaction is using furan-2-carboxylic acid (20 mmol),
OH
N
O
2 2
benzoic acid (10 mmol) and CH Cl (50 mL) as the starting
materials. The result is shown in Scheme 4. Methylene dibenzoate
was not detected by the HPLC analysis. Because furan-2-carboxylic
8
9
76
85
acid is more reactive than benzoic acid, it first reacted with CH
Because the C–Cl bond in the intermediate was more activated
than that in CH Cl , it reacted with both the types of carboxylic
acids without selectivity. This result verified the proposed double
successive S 2 processes.
2
Cl2.
2
2
N
1
0
1
97
99
4. Conclusions
In summary, we established a facile, rapid and solvent-free
method for preparing methylene diesters in good to excellent
yields. Our studies show that CH Cl is not an excellent solvent
1
2
2
under mild reaction conditions. It is very important for the
process development of active pharmaceutical ingredients. In
a
All the reactions were carried out under the following conditions: microwave
this work, a ‘‘double successive S
also proved.
N
2 reactions’’ mechanism is
8
0 8C; heterocyclic carboxylic acid 10 mmol; CH
Yields of the isolated products.
2
Cl
2
, 30 mL; DBU, 30 mmol.
b

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Y.-H. Ma et al. / Chinese Chemical Letters 26 (2015) 81–84
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