Functionalization of activated methylene C-H bonds with nitroarenes and sulfur for the synthesis of thioamides

Article abstract of DOI:10.1039/c9ob01751h

We report a method to obtain arylthioamides by the functionalization of sp³ C-H bonds in phenylacetic acids and benzyl alcohols. Reactions proceeded without the use of any solvents and were compatible with many functionalities and heterocycles. These conditions allow for a rapid synthesis of thioamides from simple, commercial substrates.

Full text of DOI:10.1039/c9ob01751h

Organic &
Biomolecular Chemistry
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Functionalization of activated methylene C–H
bonds with nitroarenes and sulfur for the synthesis
of thioamides†
Cite this: Org. Biomol. Chem., 2019,
17, 8987
Received 8th August 2019,
Accepted 27th September 2019
Nhan T. Do,‡ Khoa M. Tran,‡ Hao T. Phan, Tuong A. To,
Nam T. S. Phan
Tung T. Nguyen * and
DOI: 10.1039/c9ob01751h
*
rsc.li/obc
We report a method to obtain arylthioamides by the functionali-
Until now, the known methods for the synthesis of
zation of sp3 C–H bonds in phenylacetic acids and benzyl alcohols. N-arylthioamides commonly start with anilines. It has been
Reactions proceeded without the use of any solvents and were shown that primary aromatic amines are prone to oxidation.6
compatible with many functionalities and heterocycles. These Yet, anilines often require prior hydrogenation of nitroarenes.
conditions allow for a rapid synthesis of thioamides from simple, It will be beneficial if nitroarenes could be used for the syn-
commercial substrates.
thesis of thioamides, thus shortening the synthetic schemes.
Examples showing the uses of nitroarenes in C–N bond for-
mation have been recently disclosed. In 2015, a pioneering
study by Baran described an iron-catalyzed hydroamination of
olefins with nitrobenzenes, nitropyrroles, and nitroindoles.7a
Nickel-promoted relay amination has also been reported.7b
Later, Driver,7c Niggemann,7d Radosevich,7e and Hu7f reported
the methods for reductive coupling of aryl/alkyl halides or aryl-
boronic acids with nitroarenes to afford arylamines. Despite
these successes, the transformations are still limited due to
the need for strong, hygroscopic reductants such as zinc or
hydrosilanes.
Thioamides are prevalent structures found in biologically
active compounds, pharmaceutical molecules, agricultural
chemicals, and sensor systems.1 Yet, their functionalities
could be used as valuable intermediates for the synthesis
of heterocycles or complex structures.2 Thionation of CvO
bonds in amides using Lawesson’s reagent or isosteric phos-
phorus–sulfur complexes is perhaps the most common
method to obtain thioamides.3 Benzothioamides could be
obtained from the Friedel–Crafts substitution of arenes with
isothiocyanates or the Willgerodt–Kindler reaction.4 However,
the transformations suffer from the limitation of substrate
scope, as aliphatic amines or amides are commonly used
(eqn (1), Scheme 1). Only a few studies have described the
preparation of N-arylthioamides from readily available
reagents.5 Singh and co-workers reported one example of
N-arylthioamides obtained from sulfur-mediated thioamida-
tion of 2-aminopyridine.5a Sodium sulfide-catalyzed conden-
sation of anilines and aromatic aldehydes in the presence of
elemental sulfur has been reported.5b Chen and Wu have pre-
sented a rare method for the coupling of anilines, styrenes,
and elemental sulfur, affording thiobenzanilides (eqn (2),
Scheme 1).5c Notably, the conditions used in the last two
examples were not compatible with electron-poor or hetero-
cyclic substrates.
Metal-free, sulfur-mediated synthesis of benzothiazoles and
sultams using ortho-halo or ortho-alkenyl nitroarenes has been
Faculty of Chemical Engineering, HCMC University of Technology, VNU-HCM, 268 Ly
Thuong Kiet, District 10, Ho Chi Minh City, Vietnam. E-mail: tungtn@hcmut.edu.vn,
ptsnam@hcmut.edu.vn
†Electronic supplementary information (ESI) available: Details of optimization,
experimental procedures, and characterization of unknown compounds. See
DOI: 10.1039/c9ob01751h
‡These authors equally contributed to this work.
Scheme 1 Elemental sulfur-mediated synthesis of thioamides.
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reported.8 The reactions presumably proceeded through a
nucleophilic substitution of a sulfide anion, followed by a
nitro reduction and an electrophile trapping. We speculated
that if a thiobenzaldehyde is formed, quenching of the inter-
mediate with a nucleophilic nitrogen source would afford
N-arylthioamide. Formation of thiobenzaldehyde intermedi-
ates was possible when phenylacetic acids were condensed
with elemental sulfur in the presence of a tertiary amine.8d We
report here a method for the synthesis of thioamides from
simple nitroarenes, elemental sulfur, and arylacetic acids or
benzyl alcohols (eqn (3), Scheme 1). Reactions occurred in the
presence of the DABCO base. The combination of abundant
and stable nitroarenes with environmentally benign and non-
toxic elemental sulfur without additional organic solvents is
the important advantage of the protocol.
We commenced our investigation by exploring the synthesis
of N-phenylbenzothioamide (3aa) from the coupling of nitro-
benzene (1a), phenylacetic acid (2a), and elemental sulfur. The
reaction optimization was carried out with respect to the base,
amount of the base, amount of sulfur, and reaction tempera-
ture (Table 1). Sodium acetate (entry 1) and potassium carbon-
ate (entry 2) were inferior bases to aliphatic amines and
N-heterocycles. Complexation with amines presumably
increases the nucleophilicity of elemental sulfur.8 Among an
array of amine bases (entries 3–8), DABCO gave the best yield
Scheme 2 Reaction scope with respect to nitroarenes. Reagents and
conditions: Nitroarenes (0.5 mmol), phenylacetic acid (0.75 mmol),
sulfur (1 mmol, 32 g mol−1), DABCO (0.5 mmol), under Ar, 120 °C, 16 h.
Yields are isolated yields. Please see the ESI for more details. a 1.5 mmol
scale.
of 3aa. Lowering the amount of DABCO decreased the product the reaction at temperatures lower or higher than 120 °C plum-
yield (entries 9 and 10). Using less than 2 equivalents of sulfur meted the yield of 3aa (entries 13–15).
afforded sluggish mixtures (entries 11 and 12). Lastly, running
The scope of nitroarenes is studied next and presented in
Scheme 2. Either electron-rich (3ab and 3ac) or electron-poor
(3ad) substrates afforded thioamides in good yields. A low
yield of thioamide 3ae was obtained when phenylacetic
acid was coupled with a sterically hindered 2-nitrobiphenyl.
The transformation could offer a rare method for the rapid
synthesis of thioamide-containing heterocycles. Products
derived from 3-nitropyridine (3af) and 6-nitrobenzothiazole
(3ag) were obtained in moderate yields. If 3-nitro-N,N′-dialkyl-
anilines were used, the major products were 2-phenylbenzo-
thiazole derivatives (3ah and 3ai, Scheme 3), possibly
obtained through electrophilic cyclization of electron-rich
thioamide.9
Table 1 Studies of the reaction conditionsa
Sulfur
amount, Temperature Yield of
Studies on phenylacetic acids were also performed. The
scope of the substrates is illustrated in Scheme 4. Successful
thioamidation of arylacetic acids was achieved regardless of
Entry Base
(equiv.)
(°C)
3aa (%)
1
2
3
4
5
6
7
8
NaOAc
K2CO3
1-Methylimidazole
N-Methylpiperidine
N,N′-Dimethylpiperazine
EtiPr2N
DBU
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
2
2
2
2
2
2
2
2
2
2
1.5
1
2
2
120
120
120
120
120
120
120
120
120
120
120
120
100
80
Trace
12
24
50
52
16
36
94
89
59
89
60
70
23
41
9b
10c
11
12
13
14
15
DABCO
2
140
a Nitrobenzene (0.5 mmol), base (1 mmol), under argon for 16 h.
Yields are GC yields using a diphenyl ether internal standard. b DABCO
(0.75 mmol). c DABCO (0.5 mmol).
Scheme 3 Synthesis of 2-phenylbenzothiazoles.
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Table 2 Synthesis of arythioamides from benzyl alcoholsa
Entry
1
R
Product
Compound, yield (%)
H
3aa, 60
2
4Me
3ca, 42
Scheme 4 Reaction scope with respect to arylacetic acids. Reagents
and conditions: Nitrobenzene (0.5 mmol), arylacetic acid (0.75 mmol),
sulfur (1 mmol, 32 g mol−1), DABCO (0.5 mmol), under Ar, 120 °C, 16 h.
Yields are isolated yields. Please see the ESI for more details. a 3-
Nitropyridine (0.5 mmol).
3
4
3Me
3ia, 47
3ba, 52
4MeO
the electronic properties of aryl moieties. Most of the para-
and meta-substituted phenylacetic acids were competent sub-
strates, while ortho-methyl phenylacetic acid failed to give the
product. Functionalities such as methoxy (3ba and 3da),
methyl (3ca), chloro (3ea), and trifluoromethoxy (3fa and 3ff)
were tolerant to the reaction conditions. Thiophenylacetic
acids successfully coupled with nitrobenzene to afford thioa-
mides (3ga and 3ha), showing the compatibility of heteroaryl
acetic acids. Scaling up of the reactions was also attempted
and is presented in Scheme 5. Products were isolated without
a dramatic decrease in the yields.
5b
3Me
3ig, trace
a Benzyl alcohols (0.5 mmol), nitrobenzene (1 mmol), sulfur
(1.5 mmol, 32 g mol−1), DABCO (1 mmol), under Ar, 120 °C, 16 h.
Yields are isolated yields. b 6-Nitrobenzothiazole (1 mmol).
reductant such as hydrochlorosilanes be used.10a Such a sulfur
transfer did not occur under our conditions, since no trace of
carboxamides was found with or without sulfur. Thus, our
initial thought on the reaction mechanism (Scheme 6) was
that thioaldehyde was possibly formed by the reaction of phe-
nylacetic acid and elemental sulfur,8d followed by amine-type
nucleophilic addition (2aa → 4 → 3aa). Alternatively, nitro-
benzene coupled with phenylacetic acid to give the nitroalkane
radical intermediate (2aa → 6 → 7) which was then trapped by
the DABCO–sulfur complex 8.10b Some control experiments
were carried out to differentiate the possibilities. Trapping
benzothialdehyde with nitrosobenzene furnished thioamide in
40% yield.11 It should be noted that, unlike the example
shown by McLaughlin,12 aniline was not obtained from a
simple reduction of nitrobenzene.13 Meanwhile, N-phenyl-1-(o-
tolyl)methanimine 5, detected by GC-MS, was the major
product from the reaction using an ortho-methyl phenylacetic
acid substrate. Nguyen and co-workers described that ortho-
substituted phenylacetic acids failed to react with elemental
sulfur,8d presumably because the nucleophilic addition of the
amine–sulfur adduct to hindered electrophiles was hampered.
We also attempted some experiments to detect the possible
radical intermediates.13 Reactions in the presence of radical
Functionalization of methylene sp3 C–H bonds in benzyl
alcohols was also viable and is presented in Table 2. These
reactions required excess amounts of nitroarenes and afforded
arylthioamides in moderate yields (entries 1–4). Notably, the
use of heterocyclic nitroarenes failed to give the product
(entry 5). Studies on the reaction conditions to expand the
scope of benzyl alcohols are ongoing.
Shibahara and Murai reported that thionation of carboxa-
mides with elemental sulfur was possible should a strong
Scheme 5 Large-scale synthesis of thioamides.
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Acknowledgements
Vietnam National University – Ho Chi Minh City (VNU-HCM) is
acknowledged for financial support via project no. NCM2019-20-
01. We also thank Tuan H. Ho (HCMC University of Technology,
VNU-HCM) for the preliminary results of benzyl alcohols.
Notes and references
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Scheme 6 Mechanistic considerations.
quenchers such as TEMPO or diphenylethylene afforded
thioamide in lower yields. More importantly, a product derived
from the addition of the benzyl thiol radical to diphenylethylene
was observed, somewhat confirming the relevance of the benzyl
radical 6 in the reaction. At this moment, the transformation
likely proceeded through a nitroalkane radical intermediate,
although a mechanism that involves benzothialdehyde followed
by the quenching of nitrogen-based nucleophiles cannot be
excluded.
Conclusions
In conclusion, we have developed a method for the three-
component coupling of nitroarenes, elemental sulfur, and
methylene C–H bonds in phenylacetic acids or benzyl alcohols.
The reactions proceed in the presence of the DABCO base and
are tolerant to many functional groups such as halogens,
alkoxy, amine, trifluoromethyl and heterocycles. The use of
simple, cheap elemental sulfur in combination with stable,
commercial nitroarenes is the prominent benefit of our
method compared to the available examples. Studies on the
expansion of the reaction scope and on the reaction mecha-
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Conflicts of interest
There are no conflicts to declare.
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13 Please see the ESI† for more details.
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