A multipathway coupled domino strategy: I2-mediated oxidative thionation for direct synthesis of thiobenzamides from miscellaneous substrates

Article abstract of DOI:10.1016/j.tetlet.2015.08.060

An efficient iodine-mediated multipathway coupled domino reaction has been developed for the synthesis of thiobenzamides from benzylamines, benzylamines/aldehydes, and N-alkyl benzylamines under the same reaction conditions. This approach combines two consecutive domino processes in one pot using iodine as the oxidant.

Full text of DOI:10.1016/j.tetlet.2015.08.060

Tetrahedron Letters 56 (2015) 5843–5846
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A multipathway coupled domino strategy: I -mediated oxidative
2
thionation for direct synthesis of thiobenzamides from
miscellaneous substrates
Hong-Zheng Li , Wei-Jian Xue , Guo-Dong Yin , An-Xin Wu a,b,
a,b
b
a,
⇑
⇑
a
Hubei Collaborative Innovation Center for Rare Metal Chemistry, Hubei Key Laboratory of Pollutant Analysis and Reuse Technology, Hubei Normal University, Huangshi 435002,
PR China
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient iodine-mediated multipathway coupled domino reaction has been developed for the synthe-
sis of thiobenzamides from benzylamines, benzylamines/aldehydes, and N-alkyl benzylamines under the
same reaction conditions. This approach combines two consecutive domino processes in one pot using
iodine as the oxidant.
Received 28 June 2015
Revised 18 August 2015
Accepted 22 August 2015
Available online 22 August 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Multipathway coupled domino reactions
Imines
Iodine
Thiobenzamides
Introduction
we attempted to conveniently obtain thioamides under the same
conditions of employing
I
2
as the oxidant and sodium
Thioamides are a class of vital structural scaffolds, which widely
exist in biologically active molecules1 and frequently used as key
building blocks to construct versatile sulfur-containing com-
pounds and natural products.3 In addition, they have played
hydrosulfide as the sulfur source through the MPCD strategy
(Scheme 1). Compared with the traditional methods, this kind of
reaction will not only reduce the dosage of sulfur and amines but
also allow for changes in substrates and provide flexibility in
synthetic plans.
2
4
important roles in many fields, such as organocatalysis, peptide
chemistry, and medical chemistry.6 The most conventional
5
7
methods for thioamides are using of Lawesson reagents and
Results and discussion
Willgerodt–Kindler reactions.8 They have successfully provided
feasible solutions. More recently, some excellent three-component
reactions have been reported to synthesize thioamides and they
could not avoid utilizing excess elemental sulfur to ensure the
completion of reactions.9 Therefore, it is significant to develop a
new synthetic strategy to access thioamides. In our previous work,
we have put forward a multipathway coupled domino reaction
To initiate our study, the reaction of benzylamine (1a, 1.0 mmol),
and sodium hydrosulfide (2a, 1.0 mmol) with iodine at 120 °C was
selected as the model reaction for optimization of the reaction con-
ditions. First, the dosage of iodine was screened, it was found that
the target product 3a was not obtained without iodine (Table 1,
entry 1), which implied that iodine played a crucial role. More
experiments indicated that 2.0 equiv of iodine is the best choice
(
MPCD) strategy, which successfully utilized the multiplicative
effect of coupled domino reactions from various substrates. By
virtue of this strategy, we have realized the formation of hydan-
(
entries 2–5). Next, sodium hydrosulfide was replaced by several
other sulfur sources, including sulfur sublimed, sulfur powder,
and sodium sulfide, but no desired results were obtained (entries
toins,1 2-acylbenzothiazoles,
0a
10b
and 2-acyloxazoles.
10c
Herein,
6
–8). However, the reaction did not work under lower temperature
(
(
entries 9 and 10), and 100 °C promoted the reaction with 92% yield
entries 11 and 12). Different solvents were also examined, and
⇑
Corresponding authors. Tel./fax: +86 027 6786 7773 (A.-X.W.), +86 714
515602 (G.-D.Y.).
E-mail addresses: gdyin_hbnu@163.com (G.-D. Yin), chwuax@mail.ccnu.edu.cn
A.-X. Wu).
6
DMSO was found to be the best one (entries 13–16). Finally as con-
cluded above, the suitable reaction conditions were determined as
(
http://dx.doi.org/10.1016/j.tetlet.2015.08.060
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

5
844
H.-Z. Li et al. / Tetrahedron Letters 56 (2015) 5843–5846
Previous work:
Ar CHO
Table 1
a
S
Optimization of the reaction conditions
R1
R2
R1
+
+
S8
S8
+
+
H N
Ar
N
R2
S
NH2
conditions
N
H
S
+ NaSH·nH2O
Ar
NH2
NH2
H2N
R
3a
Ar
N
R
1a
2a
H
Our approach:
Entry
Solvent
I
2
(equiv)
S source (equiv)
T (°C)
Yieldb (%)
Pathway 1
Pathway 2
—c
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
0
NaSHÁnH
NaSHÁnH
NaSHÁnH
NaSHÁnH
NaSHÁnH
S
2
2
2
2
2
O
O
O
O
O
120
120
120
120
120
120
120
120
60
Ar
0.5
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
70
73
80
90
Ar CHO
+
S
R
I2
—
—
c
Ar
N
R
Ar
N
H
S8
c
NaSH
Ar
NH2
Na
2
SÁ9H
2
O
O
O
10
c
NaSHÁnH
2
2
—
c
10
NaSHÁnH
80
—
R
Pathway 3
Domino I
11
NaSHÁnH
2
O
O
O
O
O
O
100
140
100
100
100
100
92
90
20
Ar
N
H
Coupled in one pot
12
NaSHÁnH
NaSHÁnH
NaSHÁnH
NaSHÁnH
NaSHÁnH
2
Domino II
13
14
15
16
2
2
2
2
c
EtOH
—
2
Scheme 1. I -mediated MPCD strategy for the synthesis of thiobenzamides.
CH
3
CN
Dioxane
<5
40
a
b
c
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol) in 3 mL solvent for 1 h.
Isolated yields.
No desired product was obtained.
benzylamine (1a, 1.0 mmol), NaSHÁnH
2.0 mmol) at 100 °C in DMSO.
With the optimal conditions in hand, a wide range of substi-
2
O (2a, 1.0 mmol) and iodine
(
tuted benzylamines (1) were investigated to synthesize the sym-
metrical thiobenzamides. As shown in Table 2, the reactions
proceeded smoothly when electron-donating substituents
attached to the phenyl rings, such as para-Me and para-OMe
the neutral or electron-donating substituents (H, para-Me, and
para-OMe) attached to the phenyl rings; the reactions gave the
expected product 3a, 7a, and 7b in good yields. When the elec-
tron-withdrawing groups (F, Cl, and Br) were located on the
para-position of the phenyl rings, the yields of 7c–e had a slight
decrease. It was satisfying to find that thiophene-2-carbaldehyde
and 3-methylbutanal could be tolerated, resulting in 7f and 7g in
81% and 90% yields, respectively. We finally investigated the scope
of benzylamines under the standard conditions. Much to our satis-
faction, when the aromatic rings were attached with electron
donating groups such as para-Me and para-OMe, 7h–i were
obtained in good yields. Moreover, the electron with-drawing
(3b–c). The yields of desired products 3d–f showed a slightly
decrease while electron-withdrawing groups (F, Cl, and CF ) were
3
situated at the para-position of the phenyl rings. To our delight,
furan-2-ylmethanamine could also provide 3g in 71% yield.
Subsequently, various N-alkyl benzylamines (4) were examined
under the standard conditions (Table 3). It was found that N-alkyl
(
–Me, –Et, and –Bn) benzylamines could afford the target products
in moderate to good yields (5a, 5b, and 3a). Furthermore, 1,2,3,4-
tetrahydroisoquinoline could effectively finish this reaction with
8
0% yield of 5d.
3
groups including para-Cl and para-CF , could also furnish the reac-
To make the reaction system compatible with more different
types of substrates, the aldehydes (6), and various benzylamines
1) were employed. As can be seen from Table 4, the reactions of
aldehydes with benzylamines produced the asymmetrical prod-
ucts 3a and 7a–l in moderate to good yields. It should be noted that
tions with good yield (7j–k). When furan-2-ylmethanamine was
used as the substrate, 7l was obtained in 94% yield.
In order to verify the utility of the MPCD strategy, a mixing
experiment was performed. As shown in Scheme 2, benzaldehyde
(6a), benzylamine (1a), and dibenzylamine (4c) were all conducted
(
Table 2
Reaction scope of benzylaminesa
S
NH2
R
I2
N
+
NaSH·nH O
2
R
R
o
H
3
DMSO, 100 C
1
2a
S
S
S
N
H
N
H
N
H
O
O
3a
92%
3b 81%
3c 85%
S
S
S
N
H
N
H
N
H
F
F
Cl
Cl F3C
CF3
3d
80%
3e 78%
3f 70%
S
O
O
N
H
3g
71%
a
2
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), and I (2.0 mmol) in 3 mL DMSO for 1 h.

H.-Z. Li et al. / Tetrahedron Letters 56 (2015) 5843–5846
5845
Table 3
a
Reaction scope of N-alkyl benzylamines
S
R1
R1
N
H
I2
DMSO, 100 C
N
H
+
NaSH·nH2O
o
4
2a
3a/5
S
S
S
S
N
H
N
H
N
H
NH
5a
70%
5b 62%
3a 91%
5d 80%
a
Reaction conditions: 4 (1.0 mmol), 2a (1.0 mmol), and I
2
(2.0 mmol) in DMSO (3 mL) at 100 °C for 1 h.
Table 4
a
Reaction scope of aldehydes and benzylamines
S
7
I2
R1 CHO
+
H2N
+
NaSH·nH2O
R2
o
R1
N
H
DMSO, 100 C
R2
6
1
2a
S
S
S
N
H
N
N
H
H
O
3
a
85%
7a 84%
7b 85%
S
S
S
N
H
N
H
N
H
F
Cl
Br
7
c
75%
7d 76%
7e 75%
S
S
S
N
H
N
H
7
f
81%
7g 90%
S
S
S
N
H
N
H
N
H
O
Cl
7
h 90%
7i 87%
7j 87%
S
S
O
N
H
N
H
CF3
7
k
83%
7l 94%
a
Reaction conditions: 6 (1.0 mmol), 1 (1.0 mmol), 2a (1.0 mmol), and I
2
(2.0 mmol) in 3 mL DMSO for 1 h.
CHO
H2N
S
I2
+
+
NH
+
NaSH·nH O
N
H
2
o
DMSO, 100 C
2a (4 mmol)
3a
6a (1 mmol)
1a (3 mmol)
n=2.6 mmol
Conversion= 260%
4c (1 mmol)
Scheme 2. The one-pot mixing experiment.
under the standard conditions. To our delight, it was found that 3a
could be obtained with 2.6 equiv of substrate. The results strongly
proved that different types of substrates could be integrated in
one-pot from multiple pathways under appropriate reaction
conditions.
was carried out under the standard conditions. As depicted in
Scheme 3, it was found that all of the starting materials were
recovered and no desired product was obtained. This result effec-
tively demonstrates the importance of hydrogen atom located on
the nitrogen. Therefore, we considered that the formation of imine
by the reaction of iodine and hydrogen atom might be the pivotal
step in this approach.
To gain some insights into the mechanism of the reaction pro-
cess, the reaction of tribenzylamine (8a) with sodium hydrosulfide

5
846
H.-Z. Li et al. / Tetrahedron Letters 56 (2015) 5843–5846
Commission of Hubei Province (D20142051). We also thank Dr.
Chuanqi Zhou, Hebei University, for analytical support.
S
I2
DMSO, 100 C
N
+
NaSH·nH2O
N
o
Supplementary data
2
a
8
a
Supplementary data (the general experimental methods and
1
13
the characterizing data including H NMR, C NMR, IR and HRMS
for products) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2015.08.060. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
Scheme 3. Controlled experiments to prove the mechanism.
I2
-HI
Ph
Ph
Ph
N
H
Ph
Ph
N
Ph
I
4
c
13
References and notes
H2N
Ph
I
-HI
O
1a
Ph
NH
N
H
N
11
Ph
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10
-NH3
9
1) SH-
(
+
Ph
(2) H
I2
6
a
S
SH
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Ph
NH2
Ph
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H
Ph
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1a
3a
12
Scheme 4. The proposed mechanism.
3
4
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2
9,
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3
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À
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2
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2
In conclusion, an efficient I -mediated MPCD strategy has been
developed for the direct synthesis of thiobenzamides from
multiform substrates benzylamines, benzylamines/aldehydes, and
N-alkyl benzylamines. This protocol presented three distinct reac-
tions and one self-sequential assembly reaction in single vessel
under the same conditions, which should be of extensive utility
in combinatorial and synthetic chemistry.
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We thank the National Natural Science Foundation of China
(
Grant Nos. 21032001 and 21272085) and the Educational