Transition-Metal-Free, General Construction of Thioamides from Chlorohydrocarbon, Amide and Elemental Sulfur

Article abstract of DOI:10.1002/ejoc.202100588

A general method for one-pot synthesis of thioamides is developed through a three-component reaction involving chlorohydrocarbon, amide and elemental sulfur. Such a strategy does not only avoid residual transition metal in the product but also prevent the generation of C?N coupling by-product. The latter is prone to be generated when alkane halide and amine are present. With the protocol proposed in this work, both alkyl and aryl thioamides can be obtained in moderate to excellent yields with a high tolerance of various functional groups. External oxidants are not required in the reaction. In addition, the reaction mechanisms are addressed using a combination of controlling experiments and quantum chemical calculations.

Full text of DOI:10.1002/ejoc.202100588

Communications
doi.org/10.1002/ejoc.202100588
Transition-Metal-Free, General Construction of Thioamides
from Chlorohydrocarbon, Amide and Elemental Sulfur
Hao Jin,[a, b] Xinzhi Chen,[a, b] Chao Qian,[a, b] Xin Ge,*[c] and Shaodong Zhou*[a, b]
conditions, long reaction times, unsatisfactory yields, unfriendly
environment, and high toxicity. Recently, several green ap-
proaches existed that use aldehyde, ketones, amines, arylacetic
acids, alkyne and aryl enoic acid as starting materials via the
Willgerodt-Kindler reaction (Scheme 1, eq 1).[13] Besides, Zhou
and co-workers have presented Cu-catalyzed reactions of
dimethylformamide with arylacetonitriles and S8 (Scheme 1,
eq 2).[14] Liu et al. reported an efficient three-component syn-
thesis of aromatic thioamides from aromatic alkynes, S8, and
amides (Scheme 1, eq 3).[15] Further, quaternary ammonium salts
can react with N-formamides and sodium sulfide to produce
aryl thioamides, during which N-formamides dissociate to
amine to serve as the nitrogen source.[16] Very recently, Jiang
demonstrated an aqueous protocol to access thioamides
through the reaction of aldehydes, N-substituted formamides
and sodium sulfide in the presence of oxidant.[17] However,
protocols that employ inexpensive, more abundant substrates
and afford more general thioamide products are still demand-
ing.
As an abundant sulfur source, elemental sulfur is becoming
more and more popular in constructing sulfur-containing
organic compounds[18] However, the presence of elemental
sulfur may be poisonous to metallic catalysts.[19] Thus, for the
CÀ S coupling upon CÀ H bond activation,[20] when elemental
sulfur is employed anti-poisoning reaction protocol is required.
In 1989, Bhattacharyaet al reported the synthesis of thiobenza-
mides from benzyl chlorides and secondary amines in the
presence of pyridine.[21] However, this method was applied only
A general method for one-pot synthesis of thioamides is
developed through three-component reaction involving
a
chlorohydrocarbon, amide and elemental sulfur. Such a strategy
does not only avoid residual transition metal in the product but
also prevent the generation of CÀ N coupling by-product. The
latter is prone to be generated when alkane halide and amine
are present. With the protocol proposed in this work, both alkyl
and aryl thioamides can be obtained in moderate to excellent
yields with a high tolerance of various functional groups.
External oxidants are not required in the reaction. In addition,
the reaction mechanisms are addressed using a combination of
controlling experiments and quantum chemical calculations.
Introduction
The synthesis of sulfur-containing organic compounds contin-
ues to attract considerable attention in recent years due to their
various functions in biology, chemistry, and materials science.[1]
As an important class of organosulfur species, thioamides
constitute the functional motifs of numerous biological and
pharmaceutical
hydroxymethyl
molecules,
thiolactam
such
as
closthioamide,[2]
N-
cyclothialidine,[3]
cyclohexylethylÀ ETAsV[4] and so on. In addition, they are widely
employed to construct kinds of important sulfur-containing
heterocycles, such as thiazolins,[5] thiazolinones,[6] thiazoles,[7]
tetrazoles,[8] diones,[9] etc.. As a result, quite a few approaches
have been developed for the synthesis of thioamides. The
conventional methods for preparation of thioamides employ
Lawesson’s reagent[10] or sulfurÀ phosphorus-type reagents.[11]
Besides, isothiocyanates are also used to prepare thioamides
through Friedel-Crafts conditions.[12] However, these methods
are associated with several limitations such as harsh reaction
[a] H. Jin, Prof. Dr. X. Chen, Prof. Dr. C. Qian, Prof. Dr. S. Zhou
College of Chemical and Biological Engineering
Zhejiang Provincial Key Laboratory of Advanced Chemical Engineering
Manufacture Technology,
Zhejiang University
Zheda Rd. 38, 310027 Hangzhou, P. R. China
E-mail: szhou@zju.edu.cn
https://person.zju.edu.cn/en/0016108
[b] H. Jin, Prof. Dr. X. Chen, Prof. Dr. C. Qian, Prof. Dr. S. Zhou
Institute of Zhejiang University – Quzhou, Zhejiang University
Jiuhua Boulevard North 78, 324000 Quzhou, P. R. China
[c] Prof. Dr. X. Ge
School of Chemical and Material Engineering
Jiangnan University
Lihu Avenue 1800, 214122 Wuxi, P. R. China
E-mail: gexin@jiangnan.edu.cn
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100588
Scheme 1. Approaches for the synthesis of thioamides.
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for benzyl chlorides as the substrate; meanwhile, the coupling
Once the optimized conditions were established, the
conversion of various chlorohydrocarbons to corresponding
thioamides were investigated. As shown in Table 2, a wide array
of alkyl chlorohydrocarbons, such as linear alkyl (2a, 2 g),
branched alkyl (2b, 2 h) and cycloalkyl (2i), react with N,N-
dimethylformamide to generate the corresponding thioamides
in good yields. In addition, different formamides including N-
methylformamide (2c), N-formylmorpholine (2d–e, 2n), and N-
formylpiperidine (2 m), are also highly reactive concerning the
CÀ S coupling process. Further, such a protocol to prepare
thioamide is also suitable for chlorohydrocarbons containing β-
and γ- phenyl group (2k–n).
Further, the generality of the reaction regarding various aryl
chlorides was examined; moderate to good yields were
obtained (Table 3). In general, benzyl chlorides with electron-
rich, -neutral, and -deficient groups can be transformed
smoothly to corresponding thioamides (3b–j), while unsubsti-
tuted benzyl chloride outperformed the others(3a). The results
indicated that many popular functional groups were well
tolerated. Notably, nitro- and cyano- substituted benzyl chloride
gave relatively lower yields. This is because À NO2 was reduced
to À NH2, while À CN to À MeNH2 under the reaction conditions.
Additionally, dithiobenzamide (3k and 3 l) could also be
obtained through double thioamidation in this transformation
in 63% and 56% yields, respectively. Moreover, this method
could also be applied to heterocycles, such as benzothiophene
(3 m), benzofuran (3n), thiophene (3o), furan (3p), pyridine (3q)
naphthalene (3r). They all could react smoothly and give the
of amine and chloride is inevitable and thus low yields resulted.
Herein, we report a novel, general synthesis of thioamides
by three-component reaction from chlorohydrocarbon, elemen-
tal sulfur and amide (Scheme 1, eq 4). With the protocol
proposed in this work, both alkyl and aryl thioamides can be
obtained in moderate to excellent yields with a high tolerance
of various functional groups. In addition, the reaction mecha-
nisms are revealed by quantum chemical calculations.
The reaction of benzyl chloride, elemental sulfur and N,N-
dimethylformamide
(DMF)
to
produce
N,N-dimeth-
ylthiobenzamide was selected as a model for the optimization
of reaction conditions, and the detailed results are summarized
in Table 1. In general, the existence of base is crucial (Table 1,
entry 8) and all bases tested could mediate the generation of
the target product (Table 1, entries 1–7); NaOH (Table 1, entry 4)
was found to be the best choice giving 88% yield. Further, we
found the amount of sublimed sulfur, temperature or the
introduction of other solvent also affect much on the reaction.
For instance, increasing the amount of elemental sulfur
benefited the formation of dibenzyl polysulfide (Table 1,
entries 4, 9–12); and the yield dropped obviously with a
decrease in the temperature due to the formation of dibenzyl
disulfide and dibenzyl trisulfide (Table 1, entries 4, 13–15). In
addition, we have also tried using less amount of DMF, and
there was little influence on the yield (Table 1, entries 4, 18–19).
On the basis of the results, the optimized conditions turned out
to be benzyl chloride (2.0 mmol), NaOH (3.0 mmol), and
elemental sulfur (3.0 mmol) in N,N-dimethylformamide (2 mL) at
°
100 C.
Table 2. Scope of alkyl thioamides.a
Table 1. Optimization of reaction conditions.a
°
Entry
S8 [equiv.]
Base
Temp [ C]
Yieldb
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.5
2.5
3.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
NaOAc
Na2CO3
NaOMe
NaOH
Cs2CO3
KOH
100
100
100
100
100
100
100
100
100
100
100
100
60
69%
41%
10%
88%
14%
67%
37%
0
83%
92%
70%
50%
45%
75%
89%
71%
46%
90%
87%
K2CO3
no
9
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
10
11
12
13
14
15
16c
17d
18e
19f
80
120
100
100
100
100
[a] Typical conditions: benzyl chloride (2.0 mmol), base (3.0 mmol), DMF
°
(2 mL). [b] Determined by HPLC (Hypersil ODS C18, 35 C, λ=254 nm,
[a] Reagents and conditions: chlorohydrocarbon (2.0 mmol), elemental
sulfur (0.10 g, 3.0 mmol), and NaOH (3.0 mmol) in N-formamide (2 mL) for
8 h. [b] Elemental sulfur (0.20 g, 6.0 mmol), NaOH (6.0 mmol), DMF (4 mL).
[c] Isolated yield.
MeOH, 1 mL/min) analysis: Benzyl chloride (3.207 min), N,N-dimeth-
ylthiobenzamide (2.834 min). [c] DMF/H2O (1:1, 2 mL). [d] DMF/Dioxane
(1:1, 2 mL). [e] DMF (1 mL). [f] DMF (0.5 mL).
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Table 3. Scope of aryl thioamides.a
Scheme 2. Control experiments. Reagents: benzyl chloride/N,N-dimeth-
ylbenzylamine (2.0 mmol), elemental sulfur (0.10 g, 3.0 mmol), NaOH (0.12 g,
3.0 mmol), N-formylmorpholine/morpholine (2 mL). Isolated yields.
[a] Reagents and conditions: arylmethyl chlorides (2.0 mmol), elemental
sulfur (0.10 g, 3.0 mmol), and NaOH (3.0 mmol) in N-formamide (2 mL) for
8 h, Isolated yield. [b] Elemental sulfur (0.20 g, 6.0 mmol), NaOH (6.0 mmol),
DMF (4 mL). [c] Isolated yield based on twice the amount of 4-
hydroxybenzyl chloride.
corresponding products in good yields. Further, various for-
mamides could be assembled with benzyl chloride to afford the
desired products in moderate to excellent yields (3 s–x).
In order to gain mechanistic insight into this protocol, some
control experiments were carried out (Scheme 2). The following
findings were addressed: 1) amide as reagent[22] outperforms
amine on serving as the nitrogen source, as the latter reacts
efficiently with chlorohydrocarbon upon elimination of HCl; 2)
the combination of either benzyl chloride & S8 or S8 & amide
does not give any product, while benzyl chloride reacts with
amide slowly to generate N,N-dimethylbenzylamine;[23] 3) N,N-
dimethylbenzylamine couldn’t react with S8, amide or amine,
indicating that N,N-dimethylbenzylamine wasn’t the intermedi-
ate in affording thioamide.
Figure 1. Simplified PES and selected structural information for the synthesis
of N,N-dimethylthiobenzamide from benzyl chloride. Bond lengths are given
in Å.
form the intermediate IM3. From IM3, by eliminating ClÀ the
CÀ N coupling process achieves thus producing IM4. Further, a
second CÀ H bond activation occurs by transferring a hydrogen
to the terminal sulfur atom, generating IM5. Subsequent
elimination of anionic S6H group affords IM6. Finally, the
interaction of IM6 with hydroxyl anion spontaneously generates
the C6H5CSN(CH3)2À COÀ H2O complex, which dissociates to
produce the product N,N-dimethylthiobenzamide. In the de-
scribed route, the S7 cluster serves as the sulfur source. In fact,
we have compared computationally the participation of other
sulfur clusters in the reaction. However, they are less preferred
by relatively larger barrier concerning SÀ H bond formation (see
Table 4). The transition state TS4/5 has the highest barrier for
the whole reaction and thus rate limiting. In addition to the
Further, in order to obtain an even further understanding of
the above experimental findings, quantum chemical calculation
was performed. Two possible reaction paths were found, and
the potential energy surfaces (PES) for the energetically most
favorable pathway are shown in Figure 1. As shown in Figure 1,
the reaction is initiated from the C6H5CHÀ H bond activation by
a hydroxyl anion, i.e. IM1!IM2; the latter further releases an
intact water molecule to form chlorophenylmethane
([C6H5CHCl]À ). Next, upon
a S7 cluster approaching the
[C6H5CHCl]À ion the CÀ S coupling takes place spontaneously to
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[1] a) T. S. Jagodzinski, Chem. Rev. 2003, 103, 197–227; b) A. Degl’Innocenti,
Table 4. Barriers between IM4 and TS4/5 with various sulfur clusters.
A. Capperucci, Eur. J. Org. Chem. 2000, 2000, 2171–2186; c) C. Shen, P.
Zhang, Q. Sun, S. Bai, T. S. A. Hor, X. Liu, Chem. Soc. Rev. 2015, 44, 291–
314; d) M. Jirasek, K. Strakova, T. Nevesely, E. Svobodova, Z. Rottnerova,
R. Cibulka, Eur. J. Org. Chem. 2017, 2017, 2139–2146.
Sulfur cluster
Barrier [kJ·molÀ 1
]
S1
S2
S3
S4
S5
S6
S7
S8
87
35
13
41
16
10
9
[2] T. Lincke, S. Behnken, K. Ishida, M. Roth, Angew. Chem. Int. Ed. 2010, 49,
2011–2013; Angew. Chem. 2010, 122, 2055–2057.
[3] P. Angehrn, E. Goetschi, H. Gmuender, P. Hebeisen, M. Hennig, B. Kuhn,
T. Luebbers, P. Reindl, F. Ricklin, A. Schmitt-Hoffmann, J. Med. Chem.
2011, 54, 2207–2224.
[4] A. Bach, J. N. N. Eildal, N. Stuhr-Hansen, R. Deeskamp, M. Gottschalk,
S. W. Pedersen, A. S. Kristensen, K. Stromgaard, J. Med. Chem. 2011, 54,
1333–1346.
17
[5] Y. Suzuki, M. Iwata, R. Yazaki, N. Kumagai, M. Shibasaki, J. Org. Chem.
2012, 77, 4496–4500.
[6] E. A. Jaseer, D. J. C. Prasad, A. Dandapat, G. Sekar, Tetrahedron Lett.
2010, 51, 5009–5012.
[7] T. Murai, F. Hori, T. Maruyama, Org. Lett. 2011, 13, 1718–1721.
[8] P. Gopinath, T. Watanabe, M. Shibasaki, J. Org. Chem. 2012, 77, 9260–
9267.
[9] I. Shibuya, K. Honda, Y. Gama, M. Shimizu, Heterocycles 2000, 53, 929–
933.
[10] a) T. J. Curphey, J. Org. Chem. 2002, 67, 6461–6473; b) M. Gholinejad,
Eur. J. Org. Chem. 2015, 2015, 4162–4167; c) T. Ozturk, E. Ertas, O. Mert,
Chem. Rev. 2007, 107, 5210–5278; d) M. Szostak, J. Aube, Chem.
Commun. 2009, 7122–7124.
[11] a) V. Polshettiwar, Synlett 2004, 2245–2246; b) A. Manaka, M. Sato,
Synth. Commun. 2005, 35, 761–764.
Scheme 3. Proposed Mechanism.
[12] a) T. Jagodzinski, E. Jagodzinska, Z. Jablonski, Tetrahedron 1986, 42,
3683–3688; b) B. V. Varun, A. Sood, K. R. Prabhu, RSC Adv. 2014, 4,
60798–60807.
[13] a) Z. Q. Weng, L. Y. Goh, Acc. Chem. Res. 2004, 37, 187–199; b) F.
Shibahara, R. Sugiura, T. Murai, Org. Lett. 2009, 11, 3064–3067; c) J.
Bergman, B. Pettersson, V. Hasimbegovic, P. H. Svensson, J. Org. Chem.
2011, 76, 1546–1553; d) D. L. Priebbenow, C. Bolm, Chem. Soc. Rev.
2013, 42, 7870–7880; e) T. Guntreddi, R. Vanjari, K. N. Singh, Org. Lett.
2014, 16, 3624–3627; f) N. Thanh Binh, T. Minh Quan, L. Ermolenko, A.
Al-Mourabit, Org. Lett. 2014, 16, 310–313.
pathway presented in Figure 1, an alternative one was also
found, while it is energetically less favorable (see Figure S1,
Supporting Information).
Based on these controlling experiments and quantum
chemical calculations, an intact reaction route is thus summar-
ized in Scheme 3.
In summary, we have developed a general method for the
one-pot synthesis of thioamides through a three-component
reaction involving chlorohydrocarbon, elemental sulfur and
amides. Both alkyl and aryl thioamides could be obtained in
moderate to excellent yields through this protocol. A high
tolerance regarding various substituents on chlorohydrocarbon
or amide was justified. Notably, no transition metal or external
oxidants were required for this protocol, making it appealing
for utilization in biochemical processes. In addition, the reaction
mechanisms have been interrogated with a combination of
controlling experiments and quantum chemical calculations.
[14] Y. Qu, Z. Li, H. Xiang, X. Zhou, Adv. Synth. Catal. 2013, 355, 3141–3146.
[15] W. Liu, C. Chen, H. Liu, Beilstein J. Org. Chem. 2015, 11, 1721–1726.
[16] Z. Zhou, J. T. Yu, Y. N. Zhou, Y. Jiang, J. Cheng, Org. Chem. Front. 2017,
4, 413–416.
[17] J. Wei, Y. Li, X. Jiang, Org. Lett. 2016, 18, 340–343.
[18] a) J. Lim, J. Pyun, K. Char, Angew. Chem. Int. Ed. 2015, 54, 3249–3258;
Angew. Chem. 2015, 127, 3298–3308; b) F. Zamberlan, A. Fantinati, C.
Trapella, Eur. J. Org. Chem. 2018, 2018, 3248–3264; c) M. J. H. Worthing-
ton, R. L. Kucera, J. M. Chalker, Green Chem. 2017, 19, 2748–2761; d) N.
Thanh Binh, P. Retailleau, J. Org. Chem. 2019, 84, 5907–5912.
[19] a) J. A. Rodriguez, J. Hrbek, Acc. Chem. Res. 1999, 32, 719–728; b) L. S.
Carvalho, C. L. Pieck, M. D. Rangel, N. S. Figoli, J. M. Parera, Ind. Eng.
Chem. Res. 2004, 43, 1222–1226; c) S. Cimino, L. Lisi, Ind. Eng. Chem. Res.
2012, 51, 7459–7466; d) X. Chen, J. Jiang, F. Yan, K. Li, S. Tian, Y. Gao, H.
Zhou, ACS Sustainable Chem. Eng. 2017, 5, 10248–10257.
[20] a) D. G. Musaev, T. M. Figg, A. L. Kaledin, Chem. Soc. Rev. 2014, 43, 5009–
5031; b) C. Yan, Y. Yu, B. Peng, X. Huang, Eur. J. Org. Chem. 2020, 2020,
723–727; c) D.-S. Kim, W.-J. Park, C.-H. Jun, Chem. Rev. 2017, 117, 8977–
9015; d) C. Shan, L. Zhu, L.-B. Qu, R. Bai, Y. Lan, Chem. Soc. Rev. 2018, 47,
7552–7576; e) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem. Rev. 2010,
110, 624–655; f) P. B. Arockiam, C. Bruneau, P. H. Dixneuf, Chem. Rev.
2012, 112, 5879–5918.
Acknowledgements
We gratefully acknowledge the financial support from the Na-
tional Natural Science Foundation of China (Nos. 21878265,
22078130).
[21] P. K. Bhattacharya, S. Bandyopadhyay, S. C. Pakrashi, Indian J. Chem. B
1989, 28, 673–674.
[22] X. F. Wu, Solvents as Reagents in Organic Synthesis: Reactions and
Applications. Wiley-VCH, 2018.
[23] a) B. Basu, S. Paul, A. K. Nanda, Green Chem. 2009, 11, 1115–1120; b) S.
Borukhova, T. Noël, V. Hessel, ChemSusChem 2016, 9, 67–74.
Conflict of Interest
The authors declare no conflict of interest.
Manuscript received: May 14, 2021
Revised manuscript received: May 31, 2021
Accepted manuscript online: June 1, 2021
Keywords: Amide
Haloalkane · Thioamides
·
CÀ S coupling
· Elemental sulfur ·
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