Decarboxylative thioamidation of arylacetic and cinnamic acids: A new approach to thioamides

Article abstract of DOI:10.1021/ol501482g

A new decarboxylative strategy has been developed for the synthesis of thioamides via a three-component reaction involving arylacetic or cinnamic acids, amines and elemental sulfur powder, without the need of a transition metal and an external oxidant.

Full text of DOI:10.1021/ol501482g

Letter
pubs.acs.org/OrgLett
Decarboxylative Thioamidation of Arylacetic and Cinnamic Acids: A
New Approach to Thioamides
Tirumaleswararao Guntreddi, Rajeshwer Vanjari, and Krishna Nand Singh*
Department of Chemistry (Centre of Advanced Study), Faculty of Science, Banaras Hindu University, Varanasi 221005, India
S
* Supporting Information
ABSTRACT: A new decarboxylative strategy has been developed for the
synthesis of thioamides via a three-component reaction involving arylacetic or
cinnamic acids, amines and elemental sulfur powder, without the need of a
transition metal and an external oxidant.
ecarboxylative reactions have recently come out as a
Dpowerful advance to form carbon−carbon or carbon−
heteroatom bonds in organic synthesis. The starting carboxylic
acids are easily available at low cost in great structural diversity
and are stable, nontoxic, and easy to store and handle.1
However, most of the decarboxylative coupling reactions
described so far necessitate transition-metal catalysts including
palladium,2 copper,3,4 and other metals.5 Therefore, the direct
oxidative decarboxylation routes under metal-free conditions to
form new C−C or C−heteroatom bonds is of overriding value
and challenging.
of arylacetic acid or substituted cinnamic acid, amines, and
elemental sulfur without the need of any transition metal and
oxidant (Scheme 1).
Scheme 1. Thioamide Synthesis
Thioamides are vital structural motifs widely used as key
intermediates6 and versatile building blocks for the construction
of biologically important sulfur-containing heterocycles.7 The
functionality is extremely crucial in the field of medical science
and organic chemistry, and the advancement of creative
strategies to achieve thioamides is a continuing synthetic
venture owing to its huge synthetic utility.8 Compared to the
amide analogue, the synthetic methods for the formation of
thioamides are somewhat limited. The most commonly used
conventional methods are thionation9 of amides and Will-
gerodt−Kindler10 reaction involving aryl alkyl ketones,
elemental sulfur, and amine. However, these methods have
limited applications because of the harsh reaction conditions,
long reaction time, and low yields. Recently, some three-
component reactions have nicely exploited the use of
benzylamine,11 alkyne,12 and aldehydes13 in combination with
elemental sulfur and amine for the synthesis of thioamides,
albeit the use of benzylamine requires rather high temperature
and prolonged reaction time. Therefore, the development of
fresh strategies for the synthesis of thioamides employing new,
readily available, inexpensive, and environmentally benign
starting materials is highly desirable. In light of the above
facts and as a part of our recent endeavors in C−H activation14
and for development of other protocols,15 we describe herein
for the first time an efficient, one-pot, metal-free decarbox-
ylation reaction for the synthesis of thioamides by the reaction
Our initial efforts were focused on the optimization of the
reaction conditions employing phenylacetic acid, 2-phenethyl-
amine, and elemental sulfur powder as model reactants by
varying different parameters (Table 1). The product was
finished in 90% yield in the absence of a catalyst and solvent at
100 °C in 10 h (entry 1). Increasing the reaction temperature
to 110 °C did not enhance the yield of the product (entry 2),
but decreasing the temperature to 80 °C decreased the yield
Received: April 2, 2014
© XXXX American Chemical Society
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a
a
Table 1. Reaction Optimization
Scheme 2. Reaction Scope Using Arylacetic Acids
b
entry
solvent (1 mL)
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
100
110
80
90
90
58
23
83
35
86
88
15
19
73
89
toluene
100
100
100
100
100
100
100
100
100
DMSO
chlorobenzene
DMF
pyridine
water
1,4-dioxane
c
11
d
12
a
Conditions: phenylacetic acid (1 mmol), amine (2 mmol), sulfur (4
b
c
d
mmol, 128 mg) for 10 h. Isolated yield. Amine (1 mmol). Under
nitrogen atmosphere.
considerably (entry 3). In regard to the effect of different
solvents (entries 4−10), the use of DMSO, DMF, and pyridine
encouraged the reaction to a high extent (entries 5, 7, and 8),
but toluene, chlorobenzene, water, and dioxane performed
poorly (entries 4, 6, 9, and 10). However, none of them could
match the yield obtained under solvent-free conditions. The
best molar ratio of the reactants phenylacetic acid, amine, and
elemental sulfur was found to be 1:2:4.
With the optimized conditions in hand, the scope and
versatility of the decarboxylative thioamidation was then
thoroughly examined, and the outcome is given in Scheme 2.
A variety of aryl(hetaryl)acetic acids and amines were subjected
to the reaction which effectively offered the desired products in
high yields. Phenylacetic acids containing both the electron-rich
and electron-deficient substituents on the aromatic ring could
smoothly afford the thioamidated products. The location of the
substituents on the aromatic rings was noticed to have some
effect on the product yield; ortho-substitution provided inferior
yield as compared to the meta- and para-substitution, which
may be attributed to the steric effect. The nitro group was
notably reduced to NH2 group during the course of reaction,
which remained intact in the reaction (3q). Heteroaromatic
acids like 2- and 3-thiopheneacetic acid also underwent the
transformation adequately to provide the corresponding
thioamides 3i and 3j. 3-Methoxyphenylacetic acid was also
made to react with 1-benzhydrylpiperazine to give the
corresponding product 3s in 61% yield. Functionalized amines
like glycine and ethanolamine, however, could not undergo the
desired conversion. Aromatic amines when tried under standard
conditions were also unsuccessful, but the reaction using 2-
aminopyridine could give the product 3h in good yield.
As the aromatic amines did not work under the established
conditions, it was imperative to explore some other suitable
conditions to effect the reaction, and therefore, the use of a base
like K2CO3 was realized to make the amine more nucleophilic
for a model reaction involving phenylacetic acid, 4-methylani-
line, and elemental sulfur.
a
Reaction conditions: arylacetic acid (1 mmol), amine (2 mmol),
sulfur (4 mmol). Dimethylamine 40% aq solution (0.5 mL). Yields
refer to isolated products.
respectively. Hence, the use of K2CO3/DMSO was adopted to
bring about the reaction of different aromatic amines like
aniline, 4-methoxyaniline, and 4-chloroaniline with some
arylacetic acids to give the corresponding products 5a−c in
good yields (Scheme 3). It is interesting to note that the use of
ortho-substituted anilines, viz. o-phenylenediamine, o-amino-
phenol, and o-aminothiophenol, under the present conditions
eventually led to cyclization to afford the substituted imidazole
5d, oxazole 5e, and thiazoles 5f and 5g, respectively. To our
delight, o-nitroaniline also worked well to give the substituted
imidazole 5d under the present conditions.
Encouraged by the above findings, it was thought worthwhile
to apply the optimized set of reaction conditions (100 °C,
solvent-free) to cinnamic acids as well. Interestingly, the trial
combination of cinnamic acid, 2-phenethylamine, and ele-
mental sulfur, under the established conditions, gave rise to N-
phenethyl-2-phenylethanethioamide in 87% isolated yield. In
this case, a decrease in the reaction temperature to 80 °C
distinctly provided similar yields, but further decrease in the
temperature lowered the yield. Therefore, the same parameters
with a lowered temperature (80 °C) were adopted to test the
versatility and functional group tolerance of the reaction in
As a result, the solvent-free conditions could not provide the
desired product, but the use of DMF, DMSO, and pyridine
gave rise to the product 5a in 60, 75, and 66% yields,
B
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a
reduced to a NH2 group during the course of reaction and
remained intact under established conditions (7n). Aromatic
amines such as aniline as well as functionalized amines such as
glycine, however, failed to undergo the reaction even under
K2CO3/DMSO combination.
Scheme 3. Reaction Scope Using Aromatic Amines
The structures of two representative products 3c and 7j, one
each from both the categories, have been conclusively proved
by the single-crystal XRD (Figure 1).16
a
Reaction conditions: phenylacetic acid (1.0 mmol), aromatic amine
b
(1 mmol), sulfur (4 mmol), K2CO3 (2 mmol), DMSO (1 mL). Using
Figure 1. X-ray crystal structures of 3c (3ac in CIF, Supporting
Information) and 7j (4ca in CIF, Supporting Information).
o-nitroaniline. Yields refer to isolated products.
On the basis of the existing literature12,17 and isolation of
products, a plausible mechanism is briefly outlined in Figure 2
(cf. Supporting Information for details).
subsequent studies. Different cinnamic acids having substitu-
ents such as p-Br, p-CH3, p-NO2, p-OCH3, o-Cl, 3,4,5-
trimethoxy, and 2,4-dichloro; bicyclic acid like 3-(naphthalen-
2-yl)acrylic acid; and heterocyclic acids like 2-thiopheneacrylic
acid and 3-(3-pyridyl)acrylic acid were reacted with numerous
amines namely dimethylamine, piperidine, pyrrolidine, n-
butylamine, n-hexylamine, cyclohexylamine, diethylamine,
dibutylamine, 1-phenylpiperazine and morpholine to afford
the corresponding 2-arylethanethioamidated products in practi-
cally high yields (Scheme 4). The nitro group was again
a
Scheme 4. Reaction Scope Using Cinnamic Acids
Figure 2. Proposed mechanism.
In conclusion, the present report describes a practical and
easy approach to thioamides and benzazoles adopting a novel
decarboxylative approach. The methodology employs a new
class of readily available and inexpensive reactant, offers many
advantages, and is free from the use of metals and external
oxidants.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: knsingh@bhu.ac.in, knsinghbhu@yahoo.co.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful to the Department of Science and Technology,
Government of India, New Delhi, for providing financial
assistance (Grant No. SR/S1/OC-78/2012). T.G. and R.V. are
thankful to the CSIR for research fellowships.
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■
a
Reaction conditions: cinnamic acid (1 mmol), amine (2 mmol),
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C
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