Dichloromethane as a methylene synthon for regioselective linkage of diverse carboxylic acids: Direct access to methylene diesters under metal-free conditions

Article abstract of DOI:10.1016/j.cclet.2019.04.053

A metal-free cross coupling between common CH₂Cl₂ and carboxylic acids has been achieved with K₂CO₃ as the sole additive. This simple protocol is a convenient and cost-effective route to synthesize methylene die

Full text of DOI:10.1016/j.cclet.2019.04.053

Accepted Manuscript
Title: Dichloromethane as a methylene synthon for
regioselective linkage of diverse carboxylic acids: direct
access to methylene diesters under metal-free conditions
Authors: Shuiliang Wang, Zhengjiang Fu, Zhicong Huang,
Yongqing Jiang, Shengmei Guo, Hu Cai
PII:
DOI:
Reference:
S1001-8417(19)30222-0
https://doi.org/10.1016/j.cclet.2019.04.053
CCLET 4946
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
31 December 2018
16 April 2019
18 April 2019
Please cite this article as: Wang S, Fu Z, Huang Z, Jiang Y, Guo S, Cai H,
Dichloromethane as a methylene synthon for regioselective linkage of diverse
carboxylic acids: direct access to methylene diesters under metal-free conditions,
Chinese Chemical Letters (2019), https://doi.org/10.1016/j.cclet.2019.04.053
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Communication
Dichloromethane as a methylene synthon for regioselective linkage of diverse
carboxylic acids: direct access to methylene diesters under metal-free conditions
Shuiliang Wang a, Zhengjiang Fu a,b, , Zhicong Huang a, Yongqing Jiang a, Shengmei Guo a, Hu Cai a,

a College of Chemistry, Nanchang University, Nanchang 330031, China
b State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, CAS, Fuzhou 350002, China
 Corresponding authors.
E-mail addresses: fuzhengjiang@ncu.edu.cn (Z. Fu); caihu@ncu.edu.cn (H. Cai).
ARTICLE INFO
Article history:
Received 1 January 2019
Received in revised form 16 April 2019
Accepted 17 April 2019
Available online
Graphical Abstract
This simple protocol is a convenient and cost-effective route to synthesize methylene diesters from a wide scope of carboxylic
acids substrates with good functional group tolerance. Several gram-scale reactions have been performed to evaluate the
effectiveness and practicality of this protocol.
ABSTRACT
A metal-free cross coupling between common CH2Cl2 and carboxylic acids has been achieved with K2CO3 as the sole additive. This simple protocol
is a convenient and cost-effective route to synthesize methylene diesters from a wide scope of carboxylic acids substrates with good functional group
tolerance. Several gram-scale reactions have been performed to evaluate the effectiveness and practicality of this protocol.
Keywords:
Carboxylic acids
Dichloromethane
Methylene synthon
Methylene diesters
Metal-free conditions
Carboxylic acids are widely found in nature, which are a kind of nontoxic and inexpensive compounds. As a result, one of the
current research interests is the transition-metal catalyzed carboxylate-directed C-H transformation or decarboxylative conversion to
form new C-C and C-Hetero bonds [1]. Along this line, we have gained extensive knowledge in the realm of Pd-mediated
decarboxylative ortho-halogenation of aromatic carboxylic acids using carboxyl as traceless directing group and Cu-promoted
decarboxylative ipso-functionalization of aryl carboxylic acids [2], including decarboxylative methylthiolation [3a], arylation [3b],
protonation [2c], cyanation and halogenation [2d-f]. In addition, carboxylic acids can also be employed to synthesize esters, it is worth
to note ester scaffolds serve as value intermediates in organic synthesis and key structural units in a variety of natural products,
pharmaceuticals and polymers [3]. As a consequence, the development of efficient methods for facile construction of organic esters
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molecules has attracted considerable attention in the past several decades. The traditional method toward the condensation of
carboxylic acids or their derivatives with alcohols represents one of the most conventional methods to synthesize corresponding esters,
although the drawbacks associated with incomplete transformation and/or generation of a large amounts of unwanted by-products [3].
Moreover, great progress has been made to prepare esters via catalytic coupling of carboxylic acids with various partners including aryl
organometallic reagents [4], aldehydes [5], and arenes [6]. More recently, significant attention has been paid to esterification
conversion via cross coupling of carboxylic acids with aryl halides C-Halo bond activation, in this regard, McCusker and MacMillan
firstly reported the coupling of carboxylic acids with aryl bromides to provide aryl esters under excited-state organometallic catalysis
via direct photoexcitation [7a], whereas Itami described carboxylic acids and aryl iodides underwent a transition-metal Pd-catalyzed
coupling reaction to furnish the desired aryl esters [7b].
Compared to aryl halides, dichloromethane (DCM) is one of the simplest and cheapest halogenated hydrocarbon molecules that
widely used as solvent in laboratory, in addition, methylene chloride can also be employed as reagent to build new C-C bond and C-
Hetero bond. On this point, with double C-Cl activation of dichloromethane, Kozak [8a] and Zhang [8b] disclosed the insertion of
methylene fragment of DCM into two equivalents of Grignard reagents or oxazolidin-2-ones partner using iron or NaH as promoter
respectively. To the best of our knowledge, it is seldom used DCM as C1 synthon in the synthesis of methylene-bridged acylals [9],
which are important starting material for the preparation of dienes and chiral allylic esters in organic synthesis [10]. As one part of our
continuous efforts to develop efficient functionalization transformation of cheap and abundant carboxylic acids [3], herein we reveal a
simple, effective, metal-free and scalable approach for the synthesis of methylene diesters via cross coupling of dichloromethane with
various carboxylic acids using K2CO3 as the sole additive.
Unless otherwise noted, the reagents used for experiments were commercially available and were used as received. All reactions
were performed in dried glass reaction tube equipped with a magnetic stir bar under air atmosphere. Column chromatography was
performed on silica gel 300-400 mesh. The yields reported are the isolated yields and the average of two runs. 1H, 13C and 19F NMR
spectra of compounds were recorded at 400, 100 and 377 MHz with CDCl3 as solvent respectively. All coupling constants (J values)
were reported in Hertz (Hz). HRMS were performed by Center of Analysis and Testing, Nanchang University.
The research was commenced by performing the coupling of 1-adamantanecarboxylic acid 1 (1-AdCOOH) with CH2Cl2 as the
model reaction for the optimization studies, in which CH2Cl2 was used as a solvent and stoichiometric methylene source. Table 1
presented some selected results from the optimization studies, which illustrated the effects of the additive, temperature, reaction time
and other reaction parameters on the transformation outcome. As our recently developed decarboxylative ipso-functionalization
reactions have been performed at 140 °C [2a-d], initially, in the presence of 1 equivalent of Li2CO3 as additive, the model reaction
between CH2Cl2 and 1-AdCOOH 1 was performed at 130 °C without metal mediator under an air atmosphere to provide desired
methylene diadamantanecarboxylate 1p in 28% yield (Table 1, entry 1). To improve conversion of the reaction, a careful examination
of different alkali carbonates was next performed, which revealed that K2CO3 gave superior yield than that of Li2CO3 and Na2CO3
under otherwise identical conditions (entries 1-3), furthermore, upon evaluating the effect of the counterion of potassium salt
compound on the transformation, it’s found K2CO3 was a much better choice than either K3PO4 or KOtBu (entries 3-5). Nevertheless,
lower yields were obtained when employing organic base instead of K2CO3 as additive for the model reaction (entry 6). It’s noteworthy
that doubling of K2CO3 inputs resulted into enhanced reaction efficiency in synthetically useful levels (88%) (entry 7). To our delight,
reaction temperature was an important factor to affect the conversion efficiency, since lowering temperature to 100 °C exerted a
detrimental effect on the reaction and delivered the corresponding product 1p in 75% yield (entry 8). It is gratifying to obtain as high as
93% yield of the desired product 1p when the reaction time was reduced to 5 h (entry 9), unfortunately, both switching mixed solvent
CH2Cl2/DMSO to CH2Cl2/NMP and CH2Cl2/DMF and changing reaction atmosphere to aerobic conditions led to inferior reaction
conversion under the same reaction time (5 h, entries 10 and 11).
Table 1
Optimization of the reaction conditions.a
Entry
1
2
3
4
5
6
7
8
Base (equiv.)
Li2CO3 (1)
Na2CO3 (1)
K2CO3 (1)
K3PO4 (1)
KOtBu (1)
Et3N (1)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (0)
Temp. (oC)
130
130
130
130
130
130
130
100
130
130
130
130
Yield (%)b
28
37
77
22
39
25
88
75
93
84
89
0
9
10
11
12

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a Conditions: 1 (0.2 mmol), CH2Cl2 (1 mL), DMSO (1 mL), air, 20 h.
b Yield of the isolated product. c 5 h. d NMP instead of DMSO. e DMF instead of DMSO.
Finally, controlled experiment showed that none of target product 1p could be detected in the absence of K2CO3, suggesting that the
base is essential for this conversion (entry 12). Weighing the pros and cons, the coupling of dichloromethane with carboxylic acids
using 2 equivalent of K2CO3 as the sole additive at 130 °C for 5 hours under an air atmosphere was employed as standard conditions to
synthesize methylene diesters.
Subsequently, the obtained optimality conditions (entry 9, Table 1) to achieve methylene diadamantanecarboxylate 1p encouraged
us to evaluate the scope of this metal-free coupling of methylene chloride with respect to carboxylic acids, as illustrated in Table 2, the
transformation was shown to be an effective strategy for a diverse array of alkyl carboxylic acids 1-7, α,β-unsaturated carboxylic acids
8-10, heteroaryl carboxylic acids 11-22 and α-oxobenzeneacetic acid 23. Besides tertiary aliphatic carboxylic acids 1 and 2 provided
the desired products in good to excellent yields in this protocol, cyclohexanecarboxylic acid 3 also proceeded straightforward with
DCM to give product 3p in nearly quantitative yield. Remarkablely, primary carboxylic acids including aminoacetic and oxyacetic acid
6-7 as well as the substrates 4-5 tolerated carbon-carbon double bond and aryl functional groups, which were well carried out with
CH2Cl2 under the standard conditions. For the substrates α,β-unsaturated carboxylic acids, crotonic acid 8 and cinnamic acid 9
successfully furnished desired products in nearly quantitative yield, cinnamalacetic acid 10 comprised a conjugated diene unit also
generated the end product, albeit with mild conversion. Gratifyingly, O-, S- and N-containing heteroaryl carboxylic acids 11-22 were
proved to be suitable starting materials to afford hoped-for products. Significantly, it is no matter whether carboxyl group at the
position ortho or meta to the sulfur, thiophenic acids 12-13 were also quantitatively transformed to corresponding products. Even
though a methyl substituent presented on the position ortho to the carboxyl, the substrates 16-19 and 21 gave expected products in
good to excellent yields without being affected by the steric effect. Finally, α-oxobenzeneacetic acid 23 delivered the desired product
in moderate yield, and it’s failed to improve conversion efficiency through increasing reaction temperature or enhancing the amount of
K2CO3 additive.
Table 2
Scope of carboxylic acids in the transformation.a
1, 93%
2, 79%
3, 99%
4, 80%
5, 99%
6, 55%
7, 72%
8, 97%
9, 99%
10, 38%
15, 90%
11, 93%
12, 99%
14, 84%
13, 99%
16, 86%
20, 61%
17, 84%
18, 84%
22, 99%
19, 99%
23, 42%
21, 96%
a Reaction conditions: acid (0.2 mmol), K2CO3 (2 equiv.), CH2Cl2 (1 mL), DMSO (1 mL), air, 130 °C, 5 h.
The feasibility of coupling of dichloromethane with alkyl and heteroaryl carboxylic acids inspired us to further explore the
generality of other aromatic carboxylic acids with different substituents. As illustrated in Table 3, a wealth of benzoic acids 24-40 were
favorably carried out with CH2Cl2 under the standard conditions. It’s observed that benzoic acid 32 was a viable substrate to afford

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desired methylene dibenzoate 32p with CH2Cl2 in quantitative yield, which was the divide between electron-withdrawing (fluoro,
chloro, cyano, nitro and sulfonyl) 24-31 and electron-donating (methyl, methoxy and morpholinyl) substituents 33-40 on the benzoic
acid substrate, thus, the substituent groups were found to be broad and well-tolerated in this protocol. Apart from the substrates 24, 26,
28 and 29, the conversion efficiency of benzoic acids bearing electron-donating groups was superior to that of benzoic acids with
electron-withdrawing groups in this protocol, which could be explained as a result of enhanced electron density of aryl carboxylate
through electron-donating substituent on the aromatic ring in the presence of K2CO3. Moreover, steric hindrance did not significantly
affect the efficiency of the reaction, compared with their isomers, benzoic acids (27, 29, 31, 34-35, 37 and 39) with ortho group gave
target products in good to excellent yields. No matter where the nitro or methoxy substituent was in the carboxyl group, nitrobenzoic
acids 28-30 and methoxybenzoic acids 36-38 were effective substrates to conveniently provided corresponding products in good yields.
Notably, the substituent of halo-moiety in substrate 25 survived well in the reaction, which offered the possibility for late-stage
functionalization via the activation of carbon-halogen bond.
Table 3
Scope of benzoic acids in the transformation.a
24, 99%
25, 86%
30, 94%
26, 98%b
27, 74%
28, 99%
29, 98%
31, 87%b
32, 99%
33, 98%
34, 96%
38, 97%
35, 99%
39, 99%
36, 94%
40, 93%
37, 95%
a Reaction conditions: acid (0.2 mmol), K2CO3 (2 equiv.), CH2Cl2 (1 mL), DMSO (1 mL), air, 130 °C, 5 h. b 140 °C, 8 h.
To prove the effectiveness and practicality of this method, a 40-fold scale-up of the metal-free synthesis was performed under the
optimized conditions. As shown in Scheme 1, employing 8 mmol of carboxylic acid as starting material with K2CO3 (2 equiv.) in
DMSO under an air atmosphere, as a result, no matter what type of carboxylic acid successfully reached nearly the same efficiency as
the reaction conducted on a 0.2 mmol scale, which declared a great potential of the method on large-scale synthesis.
Scheme 1. Gram-scale synthesis of products 1p, 9p, 11p and 32p.
Basing on the above results, though the proposal of a detailed mechanism should be awaited further investigation, a plausible
mechanism for this transformation was hypothesized in Scheme 2. Initially, the carboxylic acid substrate was easily transformed to
potassium carboxylate salt in the presence of stoichiometric amounts of K2CO3, subsequently, the carboxylate anion's negatively
charged oxygen nucleophilic attacked the considerably electrophilic methylene chloride's carbon. As a result, the final methylene

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diester was generated with the liberation of KCl product. Due in part to the decreased electron density of carboxylate by induced effect
of heteroatom, the transformation yields with using benzoic acids were generally better than that employing heteroaryl carboxylic
acids. Since K2CO3 was unable to regenerate during the process, that is why stoichiometric amounts of additive were needed in the
reaction.
Scheme 2. Proposed mechanism for the transformation.
In summary, we have established a simple and practical method for the metal-free coupling reaction between easily available CH2Cl2
and carboxylic acids with K2CO3 as the sole additive. The transformation demonstrated an efficient protocol to synthesize methylene
diesters in fair to excellent results with several distinguishing features: extensive substrate scope including readily available carboxylic
acids with good functional group tolerance; a simple reaction system to efficiently offer corresponding esters products with cheap
K2CO3 as the sole additive under metal-free conditions. Further synthetic application of the protocol is currently in progress.
Acknowledgment
Financial support from the National Natural Science Foundation of China (NSFC, Nos. 21761021 and 21571094), Natural Science
Foundation of Jiangxi Province (No. 20171BAB203002), Sci & Tech Project of Education Department of Jiangxi Province (No.
60007) is gratefully acknowledged.

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