Microwave-Assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines: A rapid and efficient protocol for thioamides

Article abstract of DOI:10.1039/c9ra05939c

An efficient protocol for synthesis of thioamides was developed via the microwave-Assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines. This process is scalable and tolerates a wide spectrum of amines to deliver the corresponding products in moderate to excellent yields in 10 minutes, providing a cheap and rapid approach to thioamides.

Full text of DOI:10.1039/c9ra05939c

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Microwave-assisted iodine-catalyzed oxidative
coupling of dibenzyl(difurfuryl)disulfides with
amines: a rapid and efficient protocol for
thioamides†
Cite this: RSC Adv., 2019, 9, 28576
a
Lan Mei, Jialing Liu, Chuntao Zhong, Binfang Yuan *a
a
a
a
Jinyang Chen,
and Qiang Li
b
Received 31st July 2019
Accepted 3rd September 2019
An efficient protocol for synthesis of thioamides was developed via the microwave-assisted iodine-
catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines. This process is scalable and
tolerates a wide spectrum of amines to deliver the corresponding products in moderate to excellent
yields in 10 minutes, providing a cheap and rapid approach to thioamides.
DOI: 10.1039/c9ra05939c
rsc.li/rsc-advances
Thioamides have become an attractive synthetic goal in organic of amines. Thiols can also be used as sulfur reagent for
1
13b,c
chemistry, because thioamide skeletons are widely present in construction of thioamides,
but its pungent smell makes
2
3
drugs and natural products, such as cycasthioamide, 6-thio- this reaction difficult to carry out (Scheme 2b). Recently,
yuanine, 2-thiocytidine and closthioamide (Scheme 1), and Nguyen's group described a novel process to thioamides by
their application as useful precursors and versatile building using sulfur as catalyst. This method was suitable for a large
blocks for construction of a range of heterocyclic compounds has range of amines for giving the corresponding products in good
also been studied. In addition, thioamides also can be used as to excellent yields at 80 C for a long time of 16 h.
4
5
2a
14
1a,6
ꢀ
7
15
a synthetic isostere for amides in peptide backbones, and their
application as directing groups has also been reported.
Other methods for thioamides were also reported, but
challenges still exist in developing more convenient and effi-
8,1c
Furthermore, the application of thioamides in developing novel cient ways to these important scaffolds. In our previous work,
a uorophore/quencher pair for monitoring the unfolding of thioamides were synthesized via the iodine-promoted thio-
9
16
a small protein was also explored.
amidation of several of amines. However, this reaction must
ꢀ
Because of their wide application, efforts are devoted toward be performed under high temperature, for a long time (100 C,
their generation. The Willgerodt–Kindler reaction is a well- 8.0 h), and 0.5 equiv. of I must to be used to promote the thi-
10
2
known method for construction of thioamides by using alde- oamidation effectively (Scheme 2c).
11
hydes and secondary amines as starting materials. However,
As one of the efficient and clean procedures in modern
this thioamidation always suffers from the problems of low synthetic organic chemistry, microwave-assisted organic synthesis
conversions and harsh conditions. Though, modied variations (MAOS) has aroused wide interest among scientists, which are
1
a,12
in Willgerodt–Kindler reaction were also reported,
the use of suited to the increased demands in industry with the advantages of
17
excessive amounts of elemental sulphur makes it a less short reaction times and expanded reaction range. Herein, we
economical method. Lawesson's reagent was also used as reported an efficient method for synthesis of thioamides via the
13
common sulfur reagent for synthesis of thioamides, however,
this reaction was also occur under harsh conditions. Another
thioamidation, where elemental sulfur was used as sulfur
reagent, was also reported by Savateev's groups via a photo-
11a
initiated reaction (Scheme 2a). However, this transformation
was only suitable for special thioamides with the same structure
a
College of Chemistry and Chemical Engineering, Yangtze Normal University, Fuling,
Chongqing, 408000, P. R. China. E-mail: 6781022@163.com
b
Institution of Functional Organic Molecules and Materials, School of Chemistry and
Chemical Engineering, Liaocheng University, No. 1, Hunan Street, Liaocheng,
Shandong, 252059, P. R. China
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9ra05939c
1
Scheme 1 Structures of natural products bearing thiocarbonyl group.
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reaction obviously, and highest yield was obtained when the
ꢀ
temperature was increased to 130 C for 10 minutes (Table 1,
entry 4). But no increase in yield was observed when the
ꢀ
temperature was increased to 140 C (Table 1, entry 5) and the
reaction time to 15 minutes (Table 1, entry 8). Next, a series of
solvents (such as DMSO, DMF, 1,4-dioxane, THF, CH CN,
3
HOAc, chlorobenzene and toluene, or solvent-free) were also
examined to promote the reaction (Table 1, entries 7–14), and
results showed that DMSO is the best solvent, affording the
desired product (3a) in the yield of 88% in 10 minutes (Table 1,
entry 4). Then we explored the inuence of the catalyst on the
thioamidation, and results showed that the amount of
5
(
.0 mol% of I
88%, Table 1, entry 15). The yield of desired product decreased
to 73% and 78% respectively, even extending the reaction time
to 15 minutes, when 3.0 mol% of I was used. In addition, no
increase in yield was observed, when the ratio of reactants (2a/
a) was increased to 3.0 (Table 1, entry 18). Only 18% of desired
2
was enough to promote the reaction effectively
2
1
product was obtained, when the reaction was performed in the
ꢀ
Scheme 2 General methods for synthesis of thioamides.
presence of 5.0 mol% of I in DMSO at 130 C for 10 minutes
2
without microwave irradiation (Table 1, entry 18). Aer exten-
sive screening, we were glad to nd that the reaction of diben-
zyldisulde (1a) with N-methylpiperazine (2a) in DMSO
catalyzed by 5.0 mol% of I and assisted by microwave radiation
2
provided the desired product (3a) with an excellent yield of 88%
within 10 min (Table 1, entry 15).
With the optimal conditions in hand, the scope of the
amines and disuldes were investigated, and results were
summarized in Table 2. As shown in Table 2, we can see that
microwave-assisted iodine-catalyzed oxidative coupling of
dibenzyl(furan-2-ylmethyl) disuldes with amines (Scheme 2d).
We initiated our studies with the reaction of dibenzyldi-
sulde (1a) with N-methylpiperazine (2a) catalyzed by 10 mol%
ꢀ
of I
2
in DMSO under microwave radiation (100 C) for 10
minutes, and the desired product (3a) was obtained in the yield
of 36% (Table 1, entry 1). The reaction temperature affected the
a
Table 1 Optimization of the reaction conditions
ꢀ
b
Entry
I
2
(mol%)
Solvent
Temp. ( C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(10 mol%)
(5 mol%)
(3 mol%)
(3 mol%)
(5 mol%)
(5 mol%)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
1,4-Dioxane
THF
3
CH CN
100
110
120
130
140
130
130
130
130
130
130
130
130
130
130
130
130
130
130
10
10
10
10
10
15
10
10
10
10
10
10
10
10
10
10
15
10
10
36%
48%
65%
88%
88%
88%
74%
67%
65%
70%
62%
74%
63%
21%
88% (86%)
73%
78%
88%
18%
0
1
2
3
4
5
6
7
8
9
HOAc
Chlorobenzene
Toluene
Solvent-free
DMSO
DMSO
DMSO
c
d
e
DMSO
DMSO
a
b
2
Reaction conditions: dibenzyldisulde 1a (0.2 mmol), N-methylpiperazine 2a (0.4 mmol), I , solvent (2.0 mL). GC yields based on
e
c
d
dibenzyldisulde 1a. Isolated yields based on dibenzyldisulde 1a. 0.6 mmol of N-methylpiperazine 2a was used. Without microwave radiation.
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Table 2 Microwave-assisted iodine-catalyzed oxidative coupling of Table 3 Microwave-assisted iodine-catalyzed oxidative coupling of
a,b
a,b
dibenzyl disulfide with amines
difurfuryl disulfide with amines
a
Reaction conditions: difurfuryldisulde (1b) (0.5 mmol), amines 2 (1.0
ꢀ
b
mmol), I (0.025 mmol), DMSO (2.0 mL), 130 C, 10 min. Isolated
2
yields based on difurfuryldisulde (1b).
equiv. of TEMPO or BHT as radical scavengers (Scheme 3b), and
desired product 3a was obtained in the yields of 86% and 80%
respectively, suggesting that no single-electron transfer process
was involved through the whole reaction. In addition, thio-
amides have been used as important intermediates for the
construction of heterocycles and other compounds containing
a
Reaction conditions: dibenzyldisulde 1a (0.5 mmol), amines 2 (1.0
ꢀ
b
mmol), I (0.025 mmol), DMSO (2.0 mL), 130 C, 10 min. Isolated
yields based on dibenzyldisulde 1a.
2
both aliphatic amines and aralkyl amines could efficiently
undergo oxidative coupling effectively, affording corresponding
products in good to excellent yields. The length and the steric
hindrance of the alkyl affected the reactions slightly, and gave
corresponding products with an excellent yield of 85–92% (3a–
18
both nitrogen and sulfur in their backbones (Scheme 3c).
On the basis of the above experimental results and previous
16,19
works,
a possible mechanism has been depicted in Scheme 4.
The rst step of the thioamidation is the generation of the
intermediate A by the reaction of dibenzyldisulde (1a) with I
2
,
3
h). The optimal conditions were also suitable for other N-
À
with concomitant loss of HI and BnS . Then intermediate A react
with N-methylpiperazine (2a) to yield intermediate B, which was
containing heterocyclic amines (such as pyrrolidine, morpho-
line, 1-methylpiperazine and 1-ethylpiperazine), and corre-
sponding products were obtained in the yield of 85–89% (3i–3l).
Good yield was also obtained, when dibenzyldisulde (1a) was
treated with benzylamine (2-phenylethan-1-amine or 3-
phenylpropan-1-amine) under the optimal conditions (3m–3p,
À
converted to species C via coupling with BnS in the presence of
88–92%), and the strong electron-withdrawing group (CF3)
presenting at the ring of the benzyl amine affected the thio-
amidation slightly, giving the desired product 3p in the yield of
88%.
In subsequent studies, we examined the reaction of various
amines with difurfuryl disulde under the optimal conditions,
and the results were summarized in Table 3. Analyzing Table 3,
we can see that the thioamidation of difurfuryldisulde with
both alkylamines and heterocyclic amines gave desired prod-
ucts in moderate to good yields (3q–3w, 75–88%). And the steric
hindrance (n-hexyl or cyclopentyl) of the aliphatic group affects
the reaction slightly (3t and 3u, 80% and 83%). To our delight,
phenethyl amine was also prone to this thioamidation, for
giving the desired product (3w) in the yield of 87%.
The thioamidation can also be carried out on a larger scale
reaction, and the desired product (3a) were obtained in the
yields of 87%, when 5 mmol of dibenzyldisulde (1a) was
treated with 10 mmol of N-methylpiperazine (2a) under the
standard conditions (Scheme 3a). To shed light on the mecha-
nism of the reaction, dibenzyldisulde (1a) was treated with N-
methylpiperazine (2a) under standard conditions by using 2.0
Scheme 3 (a) Larger-scale synthesis of 3a. (b) Control experimental
for mechanism study. (c) Selected transformation of thioamides.
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In summary, we have developed a rapid and efficient protocol
for the synthesis of thioamides via the microwave-assisted
iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)
ꢀ
disuldes with amines at 130 C for 10 minutes. A broad range
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obtained in good to excellent yields. Comparing with the
previous methods, the present strategy has the advantages of
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Conflicts of interest
There are no conicts to declare.
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We gratefully acknowledge the National Natural Science Foun-
dation of China (21902014) and the Basic and Frontier Research
Project of Chongqing (Cstc2018jcyjAX0051) for the funding
support.
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