Mixed bases mediated synthesis of thioamides in water

Article abstract of DOI:10.1080/17415993.2020.1722818

A mixed bases mediated protocol is developed to synthesize thioamides from N-aryl or N-alkylamide, aldehyde and elemental sulfur in water. This reaction requires no addition of external oxidant and avoids large excess of amides. Various functional groups

Full text of DOI:10.1080/17415993.2020.1722818

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
Mixed bases mediated synthesis of thioamides in
water
Jiao Li, Xuanhe Ren, Ganzhong Li, Helong Liang, Yajie Zhao, Zhiwu Wang,
Heng Li & Bingxin Yuan
To cite this article: Jiao Li, Xuanhe Ren, Ganzhong Li, Helong Liang, Yajie Zhao, Zhiwu Wang,
Heng Li & Bingxin Yuan (2020): Mixed bases mediated synthesis of thioamides in water, Journal of
Sulfur Chemistry, DOI: 10.1080/17415993.2020.1722818
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2020.1722818
SHORT COMMUNICATION
Mixed bases mediated synthesis of thioamides in water
Jiao Li, Xuanhe Ren, Ganzhong Li, Helong Liang, Yajie Zhao, Zhiwu Wang, Heng Li
and Bingxin Yuan
Green Catalysis Center, College of Chemistry, Zhengzhou University, Zhengzhou, Henan, Republic of China
ABSTRACT
ARTICLE HISTORY
Received 10 December 2019
Accepted 14 January 2020
A mixed bases mediated protocol is developed to synthesize
thioamides from N-aryl or N-alkylamide, aldehyde and elemental sul-
fur in water. This reaction requires no addition of external oxidant
and avoids large excess of amides. Various functional groups and
pharmaceutically interesting heteroaromatic rings could be intro-
duced via this efficient procedure.
KEYWORDS
Transition-metal-free; mixed
bases mediated; thioamides;
water as solvent; elemental
sulfur
1. Introduction
Thioamides, as an important class of sulfur-containing compounds, are known as signif-
icant building blocks to furnish heterocyclic compounds in synthetic chemistry [1–7].
Thioamide motifs are also widely present in a large variety of biologically active com-
pounds for pharmaceutical and agrochemical use [8,9]. For instance, ethionamide (ETH)
and prothionamide (PTH) are generally used as second-line drugs in tuberculosis treat-
ment [10]. Elesclomol has been proved to show anticancer activity by elevating oxidative
stress and reactive oxygen species [11]. Extensive researches have been made to apply
thioamides as ligands in organic chemistry and fluorescence quenching probes in material
science [3,12–18].
CONTACT Zhiwu Wang
wangzhiwu@zzu.edu.cn; Heng Li
hengli@zzu.edu.cn; Bingxin Yuan
bxyuan@zzu.edu.cn
Green Catalysis Center, College of Chemistry, Zhengzhou University, 450001 Zhengzhou,
Henan, Republic of China
This article makes reference to supplementary material available on the publisher’s website at
https://doi.org/10.1080/17415993.2020.1722818.
© 2020 Informa UK Limited, trading as Taylor & Francis Group

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J. LI ET AL.
Figure 1. Synthetic strategies for thioamides.
Traditional methods toward the synthesis of thioamides used sulfur reagents, mostly
Lawesson’s reagent and P2S5 [19,20]. Both Lawesson’s reagent and P2S5 have obvious
drawbacks since they are sensitive to moisture. The Willgerodt–Kindler-type reaction of
aldehydes (or ketones), amines and elemental sulfur is an alternative strategy [21–26].
Despite those classic methods, multicomponent coupling reactions have been proved to
be step-economic and experimentally simple approaches to afford thioamide derivatives
[27–36]. By using amides as nitrogen sources, Liu and co-workers reported a reaction of
aldehyde or ketones with DMF (also as solvent) in the presence of elemental sulfur and
DBU (Figure 1, Reaction 1) [37]. Later, Jiang et al. developed an aqueous procedure for
the synthesis of alkyl and aryl thioamides (Figure 1, Reaction 2) [38]. This reaction of
aldehydes, N-substituted formamides and sodium sulfide require the assistance of K2S2O8
or benzoyl peroxide (BPO) as the oxidant. Bian’s group reported that K2S2O8 promoted
aryl thioamides synthesis from aryl aldehydes with thiourea as the sulfur source in DMF
(Figure 1, Reaction 3) [39]. Other methods to achieve thioamides with formamides as
nitrogen source have been developed by altering various types of coupling partners.
Recently, Cheng et al described a three-component reaction between quaternary ammo-
nium salts and N-substituted formamides in aqueous solution of Na2S2 [40]. Liu’s group
accomplished thioamidation between alkynes and S8 with amide as the solvent [41].
Despite their great advances, those methods are predominantly conducted with large
excess of amides and require certain oxidants. Moreover, only N-alkylformamides (mostly
DMF, DMAc or N-formylmorpholine) could be converted to the desired thioamide com-
pounds. Hence, our research aimed at the development of a more versatile strategy using
the green solvent while avoiding the usage of an external oxidant. In this article, we disclose
a mixed bases mediated synthesis of thioamides from N-alkyl or N-arylamides, elemental
sulfur and arylaldehydes in water.

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3
Table 1. Optimal reaction screeninga.
Entry
Base
Yieldb (%)
1
NaOH (3 eq.)
61
2
Na2CO3 (3 eq.)
70
3
K3PO4 (3 eq.)
59
4
DBU (3 eq.)
63
5
TEA (3 eq.)
62
6
TMDEA (3 eq.)
63
7
8
9
10
11
12
13
NaOH (1.5 eq.) + TEA (1.5 eq.)
Na2CO3 (1.5 eq.) + TEA (1.5 eq.)
Na2CO3 (0.5 eq.) + TEA (0.5 eq.)
Na2CO3 (1 eq.) + TEA (1 eq.)
Na2CO3 (2 eq.) + TEA (2 eq.)
Na2CO3 (2 eq.) + TEA (1 eq.)
Na2CO3 (1 eq.) + TEA (2 eq.)
72
90 (64c, n.p.d)
10
83
91
70
81
aReactionconditions:1a(0.2 mmol), S8 (0.2 mmol), 2a(5eq.), base, H2O(1 mL), 120°C, sealedtube, N2, 12 h. bIsolatedyields.
cSealed tube, air. dNo base.
Table 2. Reaction parameters screening for the synthesis of thioamidesa.
Entry
2a (eq.)
T(°C)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
1
2
3
4
6
80
100
130
120
120
70
H2O (1 mL)
H2O (1 mL)
H2O (1 mL)
H2O (0.5 mL)
H2O (2 mL)
THF (1 mL)
EtOH (1 mL)
Toluene (1 mL)
H2O (1 mL)
H2O (1 mL)
H2O (1 mL)
H2O (1 mL)
H2O (1 mL)
51
88
90
90
52
trace
n.p.
n.p.
20
32
57
70
120
120
120
120
120
120
9
10
11
12
13
81
91
aReaction conditions: 1a (0.2 mmol), S8 (0.2 mmol), 2a (x eq. of 1a), Na2CO3 (1.5 eq.), TEA(1.5 eq.), solvent, 120°C, sealed
tube, N2, 12 h. bIsolated yields.
2. Results and discussion
Our efforts to develop this reaction start with a model reaction between
p-methylphenylaldehyde 1a and N-phenylformamide 2a with elemental sulfur as the sulfur
source in water. Initially, various inorganic bases and organic bases were tested, as shown

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J. LI ET AL.
Table 3. Reaction of formamides with 4-methylbenzaldehydea.
aReactionconditions:1a(0.2 mmol), S8 (0.2 mmol), 2(1 mmol), Na2CO3 (0.3 mmol), TEA(0.3 mmol), H2O(1 mL), sealedtube,
N2, 120°C, 12 h. bNa2CO3 (0.3 mmol), TEA (0.6 mmol). c1a (0.4 mmol), S8 (0.4 mmol), 2 (2 mmol), Na2CO3 (0.6 mmol), TEA
(0.6 mmol).
in Table 1. While other bases exhibited not much difference in the desired transformation
(Table 1, Entries 1, 3–6), Na2CO3 led to higher product yield (Table 1, Entry 2). Compared
to the result of NaOH as the sole base (Table 1, Entry 1), we found that the combina-
tion of NaOH and triethylamine (TEA) could increase the product yield to 72% (Table
1, Entry 7). By keeping the total amount of mixed bases as 3 equivalents while the ratio
of Na2CO3 to TEA as 1:1, the combination of Na2CO3 and TEA furnished the desired
thioamide 3a in 90% yield (Table 1, Entry 8). Variations from either the above-mentioned
total amount or ratio led to similar or lower yields (Table 1, Entries 9–13). Control exper-
iment performed under air atmosphere gave thioamide 3a in 64% yield (Table 1, Entry 8).
Moreover, no product was formed in the absence of base, indicating the necessity of base
in the transition-metal-free thioamidation (Table 1, Entry 8). Other parameters, including
ratio of 2a against 1a, base amount, solvent volume and reaction temperature, were evalu-
ated as well (Table 2). The use of organic solvents (THF, EtOH and toluene) gave only trace
amount or no product (Table 2, Entries 6–8).

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5
Table 4. Reaction of aryl aldehydes with amidesa.
aReaction conditions: 1 (0.2 mmol), S8 (0.2 mmol), 2 m (1 mmol), Na2CO3 (0.3 mmol), TEA (0.3 mmol), H2O (1 mL), sealed
tube, N2, 120°C, 12 h. bS8 (0.4 mmol), 2 m (2 mmol), Na2CO3 (0.6 mmol), TEA (0.6 mmol), H2O (2 mL).
With the optimal reaction condition in hand, the scope of formamides was explored
with 4-methylbenzaldehyde 1a as a model substrate. A wide range of N-alkyl and
N-arylamides could be smoothly converted to thioamides (Table 3). N-phenylformamides
bearing electron-donating groups on the phenyl ring, such as methyl and hydroxyl or
electron-withdrawing groups, such as halides, furnished thioamides 3a–g in 90–95%
yields. To be noticed, halide groups (Cl, Br) were well tolerated under this reaction
condition, providing potential synthetic applications via conventional coupling reaction.
N-(pyridin-3-yl)formamide could lead to thioamide 3h in 91% yield while higher equiv-
alent of TEA was needed. This transition-metal-free protocol is also compatible with
primary and secondary N-alkylamides as substrates (3i–n). Piperazine-1,4-dicarbaldehyde
containing two formamide motifs furnished the corresponding thioamide 3n in good

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J. LI ET AL.
Scheme 1. Proposed reaction mechanism.
yield, demonstrating the high efficiency of this aqueous compatible transition-metal-free
method.
As part of an effort to expand the synthetic utility of this base-mediated thioami-
dation protocol, we investigated the substrate scope of arylaldehydes to react with
N-formylmorpholine (Table 4). Aryl aldehydes bearing electron-donating groups, such
as methyl (para- or meta-), isopropyl, hydroxyl, methoxy, and N,N-dimethylamino, or
electron-withdrawing group, such as chloro, result in excellent yields (4a–h). Arylalde-
hyde with extended π-framework afford product 4i in 93% yield. Noteworthy examples
include the introduction of pharmaceutically interesting heteroaromatic rings such as thio-
phene, pyridine, pyrrole and imidazole to thioamides 4j–n. Terephthalaldehyde and 4,4’-
diformylbiphenyl could react with N-formylmorpholine to give product 4o and 4p in mod-
est yields, respectively. The replacement of N-formylmorpholine with N-acetylmorpholine
as the reaction partner in these examples did not affect the reaction outcome much in most
cases, except for 4k–m. In general, the product yields afforded by N-acetylmorpholine
would be a little bit lower than they were in the situation of N-formylmorpholine. How-
ever, reactions of N-acetylmorpholine with aldehydes containing pyridine or pyrrole rings
gave much lower yields (4k, l) or no product (4m) at all.
Based on previous reports [27,38,39], and our experimental results, the plausible reac-
tion mechanism is proposed in Scheme 1. Initially, amine is formed by decarbonylation of
formamide and undergoes nucleophilic attack to an aryl aldehyde, generating the iminium
intermediate A. In the meantime, elemental sulfur undergoes nucleophilic attack by amine
to form polysulfide B. Then, the iminium A react with polysulfide B to afford intermediate
C. In the final step, elemental-sulfur-promoted oxidation of intermediate C releases the
target product.
3. Conclusions
In conclusion, we have reported a mixed bases mediated thioamidation of aldehyde, amides
and elemental sulfur in water. In contrast to other thioamidation strategies between aldehy-
des and N-alkylamides, there is no need for transition metal, external oxidant, large excess

JOURNAL OF SULFUR CHEMISTRY
7
of amides or organic solvent. This transition-metal-free protocol uses water as the solvent
and is compatible with a wide range of N-aryl and N-alkylamides, while various functional
groups (including Cl, Br) on the aromatic ring could be well tolerated. Noticeably, a series
of pharmaceutically interesting heteroaromatic rings could be introduced in high efficiency
via this aqueous compatible procedure.
4. Experimental
4.1. Typical procedure for the thioamides
A 25 mL Schlenk tube was charged with S8 (51.2 mg, 0.2 mmol), TEA (30.4 mg, 0.3 mmol),
Na2CO3 (31.8 mg, 0.3 mmol), 2 (121.1 mg, 1 mmol), 1 (24.1 mg, 0.2 mmol), H2O (1 mL),
and N2, and then the resulting mixture was stirred at 120°C. After 12 h, the reaction mix-
ture was extracted with dichloromethane (3 × 50 mL), and then dried over anhydrous
sodium sulfate and filtered. After evaporation of the solvent under vacuum, the residue was
subjected to flash column chromatography on silica gel to afford products 3a–3n, 4a–4p.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The authors thank the National Natural Science Foundation of China (No. 21801229) for funding
support.
ORCID
Bingxin Yuan http://orcid.org/0000-0003-4580-366X
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