One-step Conversion of Amides and Esters to Acid Chlorides with PCl3

Article abstract of DOI:10.1002/ejoc.202100630

A general and efficient iodine-promoted chlorination of amides and esters with phosphorus trichloride is described. For the first time. Various inactivated amides including secondary and tertiary amides were directly converted to the corresponding acid chlorides in one-step. The substrate scope of methyl esters including aromatic and aliphatic esters was also explored under this system. This method is simple, scalable and wide in scope, which provides an approach to preparation of these acid chlorides.

Full text of DOI:10.1002/ejoc.202100630

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: One-step conversion of amides and esters to acid chlorides with
PCl3
Authors: Fangshao Li, Xiaofang Wu, Fengzhe Guo, Zi-Long Tang, and
Jing Xiao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100630
Link to VoR: https://doi.org/10.1002/ejoc.202100630
01/2020

10.1002/ejoc.202100630
European Journal of Organic Chemistry
COMMUNICATION
One-step conversion of amides and esters to acid chlorides with
PCl3
Fangshao Li, § Xiaofang Wu, § Fengzhe Guo, Zi-Long Tang and Jing Xiao*
Abstract: A general and efficient idine-promoted chlorination of
amides and esters with phosphorus trichloride is described. For the
first time, various inactivated amides including secondary and
tertiary amides were directly converted to the corresponding acid
chlorides in one-step. The substrate scope of methyl esters including
aromatic and aliphatic esters was also explored under this system.
This method is simple, scalable and wide in scope, which provides
an approach to preparation of these acid chlorides.
Introduction
Acid chlorides are highly important intermediates in organic
synthesis.[1, 2] They are generally synthesized by the reaction of
carboxylic acids with chlorinating reagents such as thionyl
chloride,[3] oxalyl chloride,[4] phosphorus oxychloride,[5]
2]
phosphorus pentachloride,[6] phosgene[7] and others.[1, Apart
from the chlorination of carboxylic acids, there are only few
literatures reported for the direct conversion of other functional
groups to aid chlorides. Early reports by the groups of Molander,
Middleton and Wissner have shown that lactones,[8] ethyl
Scheme 1. Direct conversion of esters and amides to acid chlorides.
chlorofluoroacetate[9] and tert-butyldimethylsilyl esters[10] could
undergo this chlorination to afford acid chlorides (Scheme 1a).
Results and Discussion
Recently, Sammakia group successfully demonstrated the
chlorination of tert-butyl esters (Scheme 1b).[11] However, methyl
esters are unreactive under the above systems. To the best of
our knowledge, there is also no report on the direct conversion
of amides to acid chlorides in one step. Thus, the development
of a new, simple and practical approach for broadening the
substrate scope of noncarboxylic acids is highly desirable.
Recently, we focused on the utilization of P-containing small
molecules in the organic synthesis.[12] As part of our ongoing
work, we are attracted by the conversion of noncarboxylic acid
compounds to the acid chlorides with PCl3 due to the potential of
high chloride atom utilization in PCl3. Herein, we report the direct
conversion of various amides and esters to the corresponding
acid chlorides with PCl3 in one-step (Scheme 1c). This reaction
is practical, easily scale-up and has a broad substrate scope,
which provides an alternative method to synthesis of acid
chlorides from noncarboxylic acid compounds.
We initiated our research on the direct chlorination of N, N-
dimethylbenzamide. As demonstrated in Table 1, a mixture of N,
N-dimethylbenzamide 1a (0.3 mmol), PCl3 (0.36 mmol) and DMF
o
(0.6 mmol) was stirred in DCE (0.6 mL) at 100 C for 22 h under
air to afford benzoyl chloride in 57% yield (entry 1). Interestingly,
when 10 mmol% molecular I2 was added in the reaction, the
product was generated in 98% yield (entry 2). Further reducing
the amount of PCl3 or I2 did not improve the reaction efficiency
(entries 3-5). A screening of solvents failed to show any
improvement in the yield of 2a (entries 6-9). We observed 93%
yield of the product was generated when the reaction time was
reduced to 12 hours (entry 10). Lowering the reaction
temperature led to decrease the yield of 2a (entry 11). It is
known that DMF could react with PCl3 to form the
Vilsmeier−Haack reagent, which serves as the active
chlorinating agent.[13a, 13b] However, it should be noted that the
reaction also occurred in the absence of DMF, albeit with low
yield (entry 12). A control experiment showed that, in the
absence of I2 and DMF, only trace of the product 2a was formed
(entry 13). These results indicated that molecular I2 also plays
an important role this reaction. We suspected that another active
chlorinating agent adduct PCl3I2 was probably generated by the
reaction of PCl3 with I2.[13c] Interestingly, control experiments
showed that the proper amount of water is beneficial to the
reaction (entries 14 and 15).
M.Sc. Fangshao Li, M. Eng. Xiaofang Wu, M. Eng. Fengzhe Guo,
Prof. Dr. Zi-Long Tang, Dr.Jing Xiao
Key Laboratory of Theoretical Organic Chemistry and Functional
Molecule of Ministry of Education, School of Chemistry and
Chemical Engineering, Hunan University of Science and
Technology, Xiangtan 411201, China
E-mail: XiaoJing@hnust.edu.cn
Homepage: http://chem.hnust.edu.cn/szdw/jybzdsys/111770.htm
§F. L. and X. W. contributed equally.
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10.1002/ejoc.202100630
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope of chlorination of amides.[a]
PCl3
Solvent
entry
I2 (equiv.)
Yield[b]
(equiv.)
(mL)
1
2
1.2
1.2
1.0
2/3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0
0.1
0.1
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0
DCE
DCE
57%
98%
3
DCE
95%
4
DCE
51%
5
DCE
81%
6
CH3CN
toluene
hexane
PhCl
65%
7
71%
8
47%
9
82%
10
11
12
13
14
15
DCE
DCE
93%[c]
77%[d]
23%[e]
Trace[e]
69%[f]
83%[f,g]
DCE
[a] Reaction conditions: A mixture of 1 (1.3 mmol), PCl3 (1.3 mmol), I2 (0.13
mmol), DMF (2.6 mmol) in DCE (2.0 mL) was stirred at 100 oC for 12 hours
under air; Isolated yields were based on three parallel reactions. [b]DMF (1.3
DCE
0.1
0.1
DCE
[
mmol), 160 oC for 36 h. c]I2 (0.26 mmol) was used. [d]No DMF was used and
DCE
PCl3 (1.0 mmol) were used.
[a] Reaction conditions: A mixture of 1a (0.3 mmol), PCl3, DMF (0.6 mmol) in
solvent (0.6 mL) was stirred in a sealed tube with air at 100 oC for 22 hours;
[b]GC yield based on 1a using n-dodecane as an internal standard. [c]12 hours.
bromine and formyl chloride groups were chlorinated smoothly
to give the desired products in good yields (2b, 2d-2h and 2q-
2s). Delightfully, when dimethyl terephthalate was subjected to
the reaction, monochlorination could be achieved selectively
under the slightly modified conditions (2k). Moreover, methyl 2-
naphthoate was also well tolerated in this system (2n). Notably,
[g]
[d]80 oC. [e]No DMF was used. [f]Dried DCE and DMF were used under N2.
H2O (0.3 mmol) was added.
With the established procedure in hand, the scope of amides
was investigated. As shown in Table 2, various amides bearing
whether electron-rich groups or electron-deficient groups such
as methyl, methoxy, halogen, CF3 and CN groups proceeded
efficiently with PCl3 in one-step to give the corresponding
products in good to excellent yields (2a-2i). To our delight,
substrate bearing a strong electron-withdrawing group NO2 was
also well chlorinated (2j). Notably, when methyl 4-
(dimethylcarbamoyl)benzoate was subjected to the reaction, the
ester group remained intact, affording the corresponding product
in 65% yield (2k). This result indicated that amides are more
easily chlorinated than esters by PCl3 under this system.
Table 3. Substrate scope of chlorination of methyl esters.[a]
Moreover,
dimethylcyclohexanecarboxamide
alkyl
amides
such
and
as
N,
N-
N-
N,
dimethylhexanamide were also formed the corresponding
products in 96% and 33% yield, respectively (2l and 2m). N, N-
dimethyl-2-naphthamide proceeded readily to afford acid
chloride in 94% yield (2n). It should be noted that heterocyclic
amides such as N, N-dimethylfuran-2-carboxamide and N, N-
dimethylthiophene-2-carboxamide exhibited good reactivity,
furnishing the products in 76% and 92%, respectively (2o and
2p).
Encouraged by the above results, we explored the possibility
of chlorination of methyl esters. As demonstrated in Table 3, the
use of methyl benzoate afforded the corresponding acid chloride
in 85% yield (2a). Various methyl esters bearing whether
electron-donating or electron-withdrawing substituents such as
methyl, tert-butyl, methoxy, fluorine, chlorine, trifluoromethyl,
[a] Reaction conditions: A mixture of 3 (1.3 mmol), PCl3 (1.3 mmol) and I2
(0.26 mmol) was stirred in a sealed tube at 160 oC for 48 hours. [b]PhCl (0.6
mL). [c]I2 (0.52 mmol) were used. [d]PCl3 (2.6 mmol) were used.
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10.1002/ejoc.202100630
European Journal of Organic Chemistry
COMMUNICATION
thiophene-derived ester could also be introduced, albeit in lower
yield (2p). Employing different alkyl esters such as methyl
cyclohexanecarboxylate, methyl hexanoate and methyl 2-
phenylacetate in the reaction all gave modest yields (2l, 2m and
2t). With respect to the low yields of these aliphatic clusters, we
attributed to the remaining starting materials (14%-50%) in the
reaction and the decomposition in high temperature due to the
less table of aliphatic acid chlorides.
Table 5. Reactions of different amides with PCl3.[a]
To examine the generality of this reaction, we subjected
different amides and esters to this system. As shown in Table 4,
secondary or tertiary amides could be directly converted to the
corresponding acid chlorides in good to excellent yields (entries
1-4). However, only trace of product was generated when N, N-
diphenylbenzamide was used (entry 5). On the other hand, in
addition to methyl esters, phenyl, benzyl, n-hexyl, cinnamyl, n-
hexyl and cyclohexyl esters all provided the desired product 2a
in good to excellent yields under the similar conditions (entries
6-10). These results indicated that this method could be a useful
approach for the conversion of amides and esters to the
corresponding acid chlorides.
[a] Reaction conditions: A mixture of 1 (0.3 mmol), PCl3 (0.3 mmol), I2 (0.03
mmol), DMF (0.6 mmol) in DCE (0.6 mL) was stirred at 100 oC for 12 hours
under air.
Table 4. Substrate scope with different amides and esters.[a]
[a] Reaction conditions: A mixture of 1 (1.3 mmol), PCl3 (1.3 mmol), I2 (0.13
mmol), DMF (2.6 mmol) in DCE (2.0 mL) was stirred at 100 oC for 12 hours
under air. [b]A mixture of 3 (1.3 mmol), PCl3 (1.3 mmol) and I2 (0.26 mmol) was
stirred at 160 oC for 48 hours under air. [c]130 oC.
Scheme 2. Scale-up reactions.
methyl benzoate 3a underwent smoothly to afford the product in
68% yield (equation 2).
To further explore the difference in reactivity between amides
and esters, four different amides bearing methyl ester group
were examined under this system. As shown in Table 5, good
For further understanding of this reaction, we established
two Hammett equations by using different amides and esters.
Pleasingly, two linear relationships between different electron-
rich and electron-deficient groups were found independently in
the chlorination of p-substituted N, N-dimethylbenzamide
(Scheme 3a) and methyl benzoate derivatives (Scheme 3b).
Both Hammett equations are linear with negative slope, which
suggested that the electron-rich groups accelerated the process.
The reason for this phenomenon may be attributed to the high
reactivity of forming the corresponding carboxylic acid from
electron-rich amides and esters.
yields
of
2k
were
obtained
(1u)
when
and
methyl
methyl
4-
4-
(phenylcarbamoyl)benzoate
(methyl(phenyl)carbamoyl)benzoate (1v) were used in this
system. However, more sterically hindered methyl 4-
(dibutylcarbamoyl)benzoate
(1w)
and
methyl
4-
(diphenylcarbamoyl)benzoate (1x) gave the corresponding
products in 20% and 18% yields, respectively. Interestingly, a
large number of starting materials were recovered, and the
methyl ester group remained intact in these reactions. Therefore,
it is reasonable to conclude that amides are more reactive than
esters under this system. It appears that the steric effect of
amides affects this chlorination reaction.
To probe the scaling possibilities, we conducted two gram-
scale reactions. As shown in Scheme 2, a mixture of N, N-
dimethylbenzamide 1a (10.0 mmol), PCl3 (10.0 mmol), I2 (1.0
mmol) and DMF (20.0 mmol) was stirred in CH3CN (20 mL) at
o
100 C for 12 hours under air in a 100 mL sealed Schlenk tube.
As anticipated, 72% (1.01 g) yield of product 2a was generated
(3a)
（3b）
(equation 1). Under the solvent-free condition, the chlorination of
Scheme 3. Hammett equations.
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10.1002/ejoc.202100630
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Conclusions
Han, J. Chem. Res. 2019, 43, 205–210. (e) X. Wu, L. Zhou, R. Yang, F.
Guo, Z.-L. Tang, J. Xiao, J. Chem. Res. 2020, 44, 301–304.
In conclusion, we have successfully developed an iodine-
promoted direct conversion of inactivated amides and esters to
valuable acid chlorides in one-step. By using PCl3/I2 system, a
variety of substrates including aliphatic and aromatic amides and
esters could react with PCl3 to afford the corresponding products
in good yields. This protocol features of practical, simple and
easily scaled-up, providing not only a direct way for the
preparation of acid chlorides, but also insights for transformation
of amides and esters under metal-free conditions.
Experimental Section
Typical procedure for the chlorination of amides: Under air, a mixture of
amides 1 (1.3 mmol), PCl3, I2 and DMF in DCE (2.0 mL) was stirred in a
25 mL closed sealed tube in oil bath at indicated temperature for
indicated time. After the mixture was cooled down to the room
temperature, the solvent was evaporated under vacuum and distillation of
the residue under reduced pressure gave analytically pure acid chlorides
2.
Typical procedure for the chlorination of esters: Under air, a mixture of
esters 3 (1.3 mmol), PCl3 and I2 was stirred in a 25 mL closed sealed
tube in oil bath at indicated temperature for indicated time. After the
mixture was cooled down to the room temperature, the solvent was
evaporated under vacuum and distillation of the residue under reduced
pressure gave analytically pure acid chlorides 2.
Acknowledgments ((optional))
JX thanks financial support from National Natural Science
Foundation of China (21703061).
Keywords: phosphorus trichloride • chlorination• acid chlorides •
esters • amides
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Key Topic*
Fangshao Li, § Xiaofang Wu, § Fengzhe
Guo, Zi-Long Tang and Jing Xiao*
Page No. – Page No.
One-step conversion of amides and
esters to acid chlorides with PCl3
A general and efficient iodine-promoted chlorination of amides and esters with phosphorus trichloride is described. For the first time,
various inactivated amides including secondary and tertiary amides were directly converted to the corresponding acid chlorides in
one-step. The substrate scope of methyl esters including aromatic and aliphatic esters was also explored under this system. This
method is simple, scalable and wide in scope, which provides an approach to preparation of these acid chlorides.
This article is protected by copyright. All rights reserved.