An Aluminum(III)-Catalyzed Thioamide-Aldehyde-Styrene Condensation: Direct Synthesis of Allylic Thioamide Derivatives

Article abstract of DOI:10.1055/s-0035-1562507

An aluminum(III) triflate catalyzed three-component synthesis of allylic thioamide derivatives by condensation of a thioamide, paraformaldehyde and a styrene is reported.

Full text of DOI:10.1055/s-0035-1562507

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
B. Xu et al.
Letter
Synlett
An Aluminum(III)-Catalyzed Thioamide–Aldehyde–Styrene Con-
densation: Direct Synthesis of Allylic Thioamide Derivatives
Bin Xua,b
S
R
S
R
Xue Zhonga,b
Xi-Cun Wang*a,b
Zheng-Jun Quan*a,b
Al(OTf)3
NH
Ar
N
Ar
+ (CH2O)n
+
xylene, 110 °C
1. cyclic and acyclic thioamides
2. transition-metal-free
3. direct allylation of thioamides
19 examples
up to 86% yield
a Key Laboratory of Eco-Environment-Related Polymer Materials,
Ministry of Education of China, Gansu 730070, P. R. of China
b Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Gansu
730070, P. R. of China
wangxicun@nwnu.edu.cn
quanzhengjun@hotmail.com
Received: 05.05.2016
Accepted after revision: 31.05.2016
Published online: 27.06.2016
tives as substrates. Here, we present a useful method for the
preparation of allylic thioamides by direct allylation of thio-
amides (Scheme 1, c).
DOI: 10.1055/s-0035-1562507; Art ID: st-2016-w0321-l
Abstract An aluminum(III) triflate catalyzed three-component synthe-
sis of allylic thioamide derivatives by condensation of a thioamide, para-
formaldehyde and a styrene is reported.
Previous work: two-step protocols
R
S
S
N
a)
b)
H2N
C
H
N
Friedel–Crafts
reaction
Key words thioamides, paraformaldehyde, styrenes, allyl thioamides,
multicomponent reactions, condensation
R
O
S
P2S5
or LR
H2N
R1
R
N
R1
Allylamines form a significant class of biologically active
nitrogen compounds, and the allylamine skeleton is found
in various natural products and drugs.1–6 Moreover, allyl-
amines are fundamental building blocks in organic chemis-
try and have been used as starting materials for the synthe-
sis of numerous compounds, such as amino acids, alkaloids,
and carbohydrate derivatives.7–10 Consequently, the synthe-
sis of allylamine derivatives has attracted considerable in-
terest among researchers.11–21
R
N
R1
H
thionation
H
Present work: one-pot direct allylation of thioamides
S
S
R
R
c)
Al(OTf)3
NH
N
Ar
+ (CH2O)n
+
Ar
xylene, 110 °C
Scheme 1 Methods for the synthesis of allylic thioamides
The thioamides and their derivatives are also an import-
ant class of biologically and pharmaceutically active com-
pounds.22 Allylic thioamides are particularly important,23,24
especially in regio- and stereoselective preparations of 4,5-
dihydro-1,3-thiazoles.25 Therefore, the development of
methods for synthesizing allylic thioamide derivatives is es-
sential in organic chemistry.
N-Allylbenzothioamides can be prepared by the reac-
tion of aromatic compounds, under Friedel–Crafts reaction
conditions, with 3-isothiocyanatoprop-1-ene, prepared
from allylamine (Scheme 1, a).26 However, few methods
have been developed for the synthesis of N-(3-substitut-
ed)allyl thioamides; the most widely used method is thion-
ation of an allylic amide with phosphorus pentasulfide or
Lawesson’s reagent (LR; Scheme 1, b).27 To the best of our
knowledge, there are no reports in the literature on the di-
rect synthesis of allylic thioamides from thioamide deriva-
Our group’s recent research has been devoted to the de-
velopment of simple and efficient methods for preparing
allylamine derivatives, and we have developed a general
protocol for the direct N-allylation of electron-deficient
amides by Lewis acid catalyzed amide–aldehyde–alkene
condensation reactions.28–31 On the basis of our previous
work, we developed an efficient strategy for the synthesis
of allylic thioamide derivatives by an Al(OTf)3-catalyzed
thioamide–aldehyde–alkene reaction. In this reaction, we
successfully constructed C–N and C–C bonds in one pot
without any additives. Furthermore, the use of an alumi-
num(III) salt as a cheap and abundant catalyst increases the
attractiveness of this method.
Initially, we examined the three-component reaction of
azepane-2-thione (1a), paraformaldehyde (2a) and styrene
(3a) as a model reaction (Table 1). When we used our previ-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
B. Xu et al.
Letter
Synlett
ous reaction conditions29,31 with I2 or Bi(OTf)3 as the cata-
lyst, no reaction occurred (Table 1, entries 1 and 2). When
the iron catalysts Fe(OTf)3, Fe(acac)3, and FeCl3 were tested,
FeCl3 promoted the three-component reaction to give
the desired product 4a in 10% yield (entries 3–5). In con-
trast, combinations of I2 with Fe catalysts [I2/Fe(OTf)3 and
I2/FeCl3/TBAB] promoted the conversion into 4a in 21% and
51% yield, respectively (entries 6 and 7). Interestingly, I2
combined with TfOH successfully promoted the reaction to
deliver an 82% yield of 4a (entry 8), whereas the reaction
catalyzed by Al(OTf)3 gave 4a in 86% yield (entry 9). When
the loading of Al(OTf)3 was decreased to 10 mol%, a consid-
erably lower yield was obtained (entry 10). Finally, we ex-
amined the effect of the solvent on this reaction and found
that xylene gave better results than MeNO2 or 1,4-dioxane
(entries 11 and 12). The reaction is therefore best conduct-
ed with Al(OTf)3 (20 mol%) as the catalyst and xylene as the
solvent at 110 °C for 24 hours.
taining electron-withdrawing groups (Cl, Br, or OAc). Note
that both ortho- and para-substituted styrenes as sub-
strates gave the desired products 4d and 4e in good yields,
indicating that the steric effects of the methyl and tert-bu-
tyl group are negligible. α-Methylstyrene as a substrate also
reacted smoothly to give the corresponding allylic thioam-
ide derivative 4f in 72% yield. Furthermore, electron-defi-
cient 2-vinylnaphthalene also reacted successfully to give
the corresponding product 4j in 70% yield.
S
S
R
R
NH
N
Ar
Al(OTf)3, xylene
110 °C, 24 h
(CH2O)n +
+
Ar
1a
2a
3
4
S
Ph
S
S
N
N
N
OMe
Me
4c, 75%
4b, 78%
4a, 86%
Table 1 Optimization of Conditions for the Three-Component Reac-
S
S
S
Me
tiona
N
N
Ph
N
S
S
tBu
Me
Ph
catalyst, solvent
110 °C, 24 h
NH
N
4f, 72%
4d, 73%
4e, 76%
Ph
+
+
(CH2O)n
S
S
1a
2a
3a
4a
N
N
Entry
Catalyst (mol%)
2 (200)
Solvent
Yieldb (%)
Br
Cl
4g, 67%
4h, 69%
4j, 70%
1
2
I
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
MeNO2
0
0
S
S
Bi(OTf)3 (20)
Fe(OTf)3 (20)
Fe(acac)3 (20)
FeCl3 (20)
N
N
O
3
0
O
Me
4
0
4i, 65%
5
10
21
52
82
86
76
57
68
Scheme 2 Three-component reactions of azepane-2-thione (1a),
paraformaldehyde (2a), and various styrenes
6
I2 (30)/Fe(OTf)3 (5)
I2 (20)/FeCl3 (20)/TBAB (20)
I2 (20)/TfOH (10)
Al(OTf)3 (20)
7
8
To further expand the range of thioamide products, we
explored the three-component reactions of acyclic thioam-
ides 1b–e, paraformaldehyde (2a), and styrenes 3 (Scheme
3).33 The reactions proceeded smoothly to give the corre-
sponding products in good yields. Acyclic thioamides bear-
ing N-benzyl, N-butyl, or N-methyl substituents gave the
corresponding allylic thioamide derivatives 5a–i in good
yields. The existence of thioamide 5h as a mixture of iso-
mers due to restricted rotation around the thioamide bond
was confirmed by 1H NMR and 13C NMR spectroscopy; how-
ever, the two isomers could not be separated by simple col-
umn chromatography.
We also examined the reactions of ethyl oxoacetate, as
well as those of other aryl aldehydes such as 4-nitro-, 4-fluo-
ro-, 4-bromo-, and 4-methylbenzaldehydes; however, no
reactions were observed, and further optimization of the
conditions might be needed.
9
10
11
12
Al(OTf)3 (10)
Al(OTf)3 (20)
Al(OTf)3 (20)
1,4-dioxane
a Reaction conditions: 1a (1 mmol), 2a (4 mmol), 3a (1.2 mmol), solvent (3
mL), 110 °C, 24 h.
b Isolated yield after column chromatography.
Next, we applied the optimized protocol to the allyla-
tion of the cyclic thioamide 1a with paraformaldehyde (2a)
and various styrenes 3 (Scheme 2).32 The reaction proved to
be relatively broad in scope, tolerating a variety of steric
and electronic changes in the styrene reaction partner to
give products 4a–j in good yields. Reactions of styrenes
bearing electron-donating groups (Me, OMe, or t-Bu) on the
phenyl ring gave the corresponding products 4b–e in high-
er yields than those of products 4g–i from styrenes con-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
B. Xu et al.
Letter
Synlett
In summary, we have developed an Al(OTf)3-catalyzed
three-component reaction of thioamides with paraformal-
dehyde and styrenes to give a series of allylic thioamide de-
rivatives. Both cyclic and acyclic thioamides participate in
the reaction, and we successfully achieved the construction
of a C–N and a C–C bond in one pot by using a simple cata-
lyst system without any additives. Furthermore, the reac-
tion tolerates a wide range of thioamides and styrenes as
reaction partners and it gives good to excellent yields. The
present method should prove to be a useful tool in the syn-
thetic chemistry of allylic thioamides.
S
R
S
R
R2
Al(OTf)3, xylene
R1
N
R2
R1
N
H
Ar
(CH2O)n
+
Ar
+
110 °C, 24 h
1b–e
2a
3
5
S
S
Me
N
Me
S
N
Ph
Ph
Me
Ph
5a, 72%
5b, 74%
S
S
Me
Me
N
Me
Me
N
Ph
Ph
Ph
5c, 65%
tBu
Ph
5d, 63%
Acknowledgment
S
Me
Me
N
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (Nos. 21362032, 21362031, and 21562036).
N
nBu
Ph
5e, 67%
5f, 68%
Me
N
Supporting Information
S
S
Ph
Supporting information for this article is available online at
N
nBu
http://dx.doi.org/10.1055/s-0035-1562507.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
5g, 72%
5h, 58%
S
References and Notes
O
N
Ph
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Scheme 3 Three-component reactions of acyclic thioamides, paraform-
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S
S
Al(OTf)3
NH
OTf
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(CH O)
+
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n
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AlIII
S
– H
4
II
Scheme 4 Proposed mechanism for the Al-catalyzed direct allylation
through thioamide–aldehyde–alkene condensation
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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the mixture was stirred at 110 °C for 24 h while the reaction
was monitored by TLC. The mixture was cooled to r.t., and the
reaction was quenched with sat. aq NH4Cl (3 mL). The mixture
was extracted with EtOAc (3 × 15 mL) and the organic layers
were combined, washed with brine, and dried (MgSO4). The
crude product was purified by column chromatography [silica
gel, PE–EtOAc (1:6)] to give a yellow oil; yield: 211 mg (0.86
mmol, 86%). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.23 (m, 5 H),
6.49 (d, J = 15.6 Hz, 1 H), 6.18–6.11 (m, 1 H), 4.16 (d, J = 5.2 Hz, 2
H), 3.34 (s, 2 H), 2.57 (d, J = 5.2 Hz, 2 H), 1.66 (d, J = 38.4 Hz, 6 H).
13C NMR (100 MHz, CDCl3): δ = 175.6, 136.6, 132.5, 128.5, 127.5,
126.3, 125.1, 49.8, 48.6, 37.1, 29.9, 28.4, 23.4. HRMS (ESI+): m/z
[M + H]+ calcd for C15H20NS: 246.1311; found: 246.1316.
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An oven-dried tube was charged with a mixture of acyclic thio-
amide 1b (1 mmol, 0.165 g), paraformaldehyde (2a; 4 mmol,
0.120 g), styrene (3a; 1.2 mmol, 0.125 g), and Al(OTf)3 (20 mol%,
0.191 g). Anhydrous xylene (3 mL) was added from a straw, and
the mixture was stirred at 110 °C for 24 h while the reaction
was monitored by TLC. The mixture was cooled to r.t., and the
reaction was quenched with sat. aq NH4Cl (3 mL). The mixture
was extracted with EtOAc (3 × 15 mL) and the organic layers
were combined, washed with brine, and dried (MgSO4). The
crude product was purified by column chromatography [silica
gel, PE–EtOAc (1:6)] to give a yellow oil; yield: 202 mg (0.72
mmol, 72%). 1H NMR (600 MHz, CDCl3): δ = 7.36–7.22 (m, 10 H),
6.43 (t, J = 16.2 Hz, 1 H), 6.19–6.05 (m, 1 H), 4.65 (s, 1 H), 4.54 (s,
1 H), 4.16 (d, J = 6.6 Hz, 1 H), 3.99 (d, J = 5.4 Hz, 1 H), 2.20 (d, J =
27.0 Hz, 3 H). 13C NMR (150 MHz, CDCl3): δ = 170.9, 133.1,
131.9, 128.9, 128.7, 128.6, 128.5, 128.2, 127.9, 127.7, 127.6,
127.4, 126.4, 124.5, 123.8, 50.9, 49.5, 48.1, 47.3, 21.7, 21.6.
HRMS (ESI+): m/z [M + H]+ calcd for C18H20NS: 282.1311; found:
282.1314.
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(32) 1-[(2E)-3-Phenylprop-2-en-1-yl]azepane-2-thione
(4a);
Typical Procedure
An oven-dried tube was charged with a mixture of cyclic thio-
amide 1a (1 mmol, 0.129 g), paraformaldehyde (2a; 4 mmol,
0.120 g), styrene (3a; 1.2 mmol, 0.125 g), and Al(OTf)3 (20 mol%,
0.191 g). Anhydrous xylene (3 mL) was added from a straw, and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D