Efficient synthesis of N-sulfonylacetamidines from propiolic acid by copper-catalyzed three-component coupling reactions

Article abstract of DOI:10.1055/s-0030-1258587

Using propiolic acid as one of the reacting components, a copper-catalyzed three-component reaction of sulfonyl azide and amines affords N-sulfonylacetamidines via a decarboxylation process in high yields under mild conditions. This one-pot method is efficient, general, and versatile. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258587

LETTER
2664
Efficient Synthesis of N-Sulfonylacetamidines from Propiolic Acid by
Copper-Catalyzed Three-Component Coupling Reactions
Synthesis of
N-
Sulfony
e
lacetamidin
i
es via
a
DecaX
rboxylationProceuss ,a Chunxiang Kuang,*a Zhuo Wang,a Qing Yang*b
a
Department of Chemistry, Tongji University, Siping Road 1239, Shanghai 200092, P. R. of China
Fax +86(21)65983191; E-mail: kuangcx@tongji.edu.cn
b
Department of Biochemistry, School of Life Sciences, Fudan University, Handan Road 220, Shanghai 200433, P. R. of China
Received 1 August 2010
R
CuI, DBU
THF, r.t.
Ar1SO2N
Abstract: Using propiolic acid as one of the reacting components,
a copper-catalyzed three-component reaction of sulfonyl azide and
amines affords N-sulfonylacetamidines via a decarboxylation pro-
cess in high yields under mild conditions. This one-pot method is
efficient, general, and versatile.
Ar1SO2N3
H
+
N
CO2H
+
Ar2
N
R
Ar2
1
2
3
Scheme 1 Synthesis of N-sulfonylacetamidines 3
Key words: amidine, azides, copper, catalysis, propiolic acid
amine. The reaction proceeds in THF with CuI as a
catalyst in the presence of DBU to yield N-ethyl-N-phe-
nyl-N′-tosylacetamidine 3a in 90% yield (Table 1, entry
1). Among the various solvents it was found that DMF
and CH2Cl2 were less satisfactory than THF. Coupled
product was not generated in the absence of additional
amine bases. Moreover, the use of triethylamine resulted
in a lower yield of desired product than DBU.
Amidines are found in numerous bioactive natural
products1 and are widely applied in medicinal and syn-
thetic chemistry due to their prominent structural motifs.2
Furthermore, substituted amidines serve as important
pharmacophores, synthetic intermediates, and efficient
metal complexes.3 The transition-metal-catalyzed multi-
component reactions (MCRs) have frequently offered a
rapid and efficient route to generate complex molecular
frameworks from simple and readily available substrates
because they have excellent catalytic efficiency in most
cases.4,5 Recently, a highly efficient copper-catalyzed
MCR6 was reported concerning sulfonyl azides or phos-
phoryl azides,7 alkynes, and the third components such as
amines,8 water,9 alcohols,10 pyrroles,11 iminophospho-
ranes,12 or ammonium salts13 under mild conditions. Syn-
With the suitable reaction conditions in hand, we next
tested the feasibility of the protocol using various amine,
sulfonyl azides, and propiolic acid (Table 1). As shown in
Table 1, the one-pot three-component reaction afforded
the N-sulfonylacetamidines 3 in moderate to excellent
yields (55–92%). Generally, electronic effects and the po-
sitions of substitutents did not appear to exert much appre-
ciable influence on the efficiency. Substrates with several
functional groups such as methoxy or chloro on the para
or meta positions of the aromatic ring could afford the cor-
responding N-sulfonylacetamidines in high yields (entries
1–5). However, the yield was decreased when the aryl-
amine was substituted with ortho substituents (entry 6).
Using 4-methyl-N-(4-methylbenzyl)benzenamine as the
amine having large steric hindrance at nitrogen atom low-
er the yield of the product even after a much longer reac-
tion time (entry 7). Furthermore, the desired products
were not observed in the reactions of diphenylamine or
10H-phenothiazine under the standard reaction condi-
tions. Thus steric hindrance effects play an important role
in this reaction. In comparison to phenylsulfonyl azide, no
obvious electronic effect was observed compared with
TsN3 (entries 8–10). Several kinds of amines including
primary, aliphatic, or aromatic were also efficient sub-
strates (entries 11 and 12).
thetically
interesting
applications
including
intermolecular or intramolecular reactions have been also
achieved on the basis of the same approach.14,15 On the
other hand no example of utilizing propiolic acid as a
source of terminal alkyne in the catalytic three-component
coupling reactions has been shown to afford amidine de-
rivatives. To our surprise, an unexpected decarboxylation
product of N-ethyl-N-phenyl-N′-tosylacetamidine was ob-
served while synthesizing N-ethyl-N-phenyl-N′-tosyl-2-
amidinoacetic acid through three-component coupling re-
action using p-toluenesulfonyl azide, propiolic acid, and
N-ethylbenzenamine catalyzed by CuI in the presence of
Et3N. Herein we report a new, mild, and efficient method
for the preparation of N-sulfonylacetamidines 3, in which
propiolic acid was reacted with sulfonyl azide 1 and
amine 2 via copper-catalyzed three-component reactions
in the presence of DBU (Scheme 1).
According to the literature,17 a proposed reaction mecha-
nism is shown in Scheme 2. In the initial stage, deproto-
nation of propiolic acid by DBU and reaction with
sulfonyl azide 1 produces a five-membered cyclic trizole
intermediate B, in which the Cu metal is coordinated to
the oxygen atom from carbonate ion and to one carbon
We started from the study of the reaction of p-toluene-
sulfonyl azide with propiolic acid and N-ethylbenzen-
SYNLETT 2010, No. 17, pp 2664–2666
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258587; Art ID: W12410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of N-Sulfonylacetamidines via a Decarboxylation Process
2665
atom of the triazole. Extrusion of molecular nitrogen and In conclusion, we have developed a mild and efficient
carbon dioxide from B followed by the hetero-Wolff rear- method for synthesis of a variety of N-sulfonylaceta-
rangement provides the key ketenimine intermediate C. midines derivatives using propiolic acid as a new type of
Then an addition of amines 2 to C leads to the desired N- reacting partner in the copper-catalyzed three-component
sulfonylacetamidines 3.
Table 1 Synthesis of N-Sulfonylacetamidines 3a
R
CuI, DBU
Ar1SO2N
THF, r.t.
Ar1SO2N3
H
N
+
CO2H
+
Ar2
N
R
Ar2
1
2
3
Entry
Ar1
Amine 2
3
Yield of 3 (%)b
4-MeC6H4SO2N
4-MeC6H4SO2N
1
2
4-MeC6H4
3a
90
HN
N
N
4-MeC6H4
4-MeC6H4
4-MeC6H4
3b
3c
3d
87
85
84
HN
Me
Me
Me
Me
Me
4-MeC6H4SO2N
4-MeC6H4SO2N
4-MeC6H4SO2N
3
4
HN
Me
N
N
N
HN
Me
OMe
OMe
5
4-MeC6H4
3e
86
HN
Me
Cl
Cl
4-MeC6H4SO2N
4-MeC6H4SO2N
6
7
4-MeC6H4
4-MeC6H4
3f
64
55
N
N
HN
Me
Me
HN
3g
C6H5SO2N
8
9
Ph
Ph
Ph
3h
3i
3j
92
87
84
HN
N
C6H5SO2N
C6H5SO2N
HN
Me
N
Me
Me
10
HN
Me
N
4-MeC6H4SO2N
4-MeC6H4SO2N
11
12
4-MeC6H4
4-MeC6H4
3k
3l
85
80
H2N
H2N
HN
HN
a Reaction conditions: sulfonyl azide (0.3 mmol), propiolic acid (0.45 mmol), amine (0.12 mmol), CuI (0.06 mmol), and DBU (0.15 mmol) in
2 mL of THF were stirred in a flask at r.t. under N2 for 10 h.16
b Isolated yield.
Synlett 2010, No. 17, 2664–2666 © Thieme Stuttgart · New York

2666
M. Xu et al.
LETTER
(10) (a) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org.
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reaction of with sulfonyl azides and amine in the present
of DBU via a decarboxylation process.
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(12) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2008, 10, 1267.
(13) Kim, J.; Lee, S. Y.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem.
2008, 73, 9454.
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Han, S. K. J. Am. Chem. Soc. 2006, 128, 12366. (b) Kim, J.
Y.; Kim, S. H.; Chang, S. Tetrahedron Lett. 2008, 49, 1745.
(c) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163.
(d) Mandal, S.; Gauniyal, H. M.; Pramanik, K.;
HO2C
H
N
DBU
CO2
– CO2
– N2
+ H+
N
O
Ar1SO2
N
[Cu]
– H+
–
Ar1SO2N3
+
O
Cu
1
A
B
R
H
N
Ar2
Mukhopadhyay, B. J. Org. Chem. 2007, 72, 9753. (e) Xu,
X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9,
1585. (f) Whiting, M.; Fokin, V. V. Angew. Chem. Int. Ed.
2006, 45, 3157.
Cu
Ar1SO2N
Ar2
2
Ar1SO2N
N
R
H
3
C
(15) (a) Cui, S. L.; Lin, X. F.; Wang, Y. G. Org. Lett. 2006, 8,
4517. (b) Cui, S. L.; Wang, J.; Wang, Y. G. Org. Lett. 2007,
9, 5023. (c) Cui, S. L.; Wang, J.; Wang, Y. G. Tetrahedron
2008, 64, 487. (d) Lu, W.; Song, W.; Hong, D.; Lu, P.;
Wang, Y. Adv. Synth. Catal. 2009, 351, 1768.
Scheme 2 A proposed mechanism of the reaction
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(16) General Procedure for the Synthesis of 3
A solution of sulfonyl azide (1.2 mmol), amine (1.2 mmol),
propiolic acid (1.0 mmol), DBU (1.5 mmol), and CuI (0.1
mmol) in THF (2 mL) was stirred at r.t. under N2 for 10 h.
After the reaction was completed, which was monitored with
TLC, the reaction solution was diluted with CH2Cl2 (2 mL)
and then with aq NH4Cl solution (3 mL). The mixture was
stirred for an additional 30 min at r.t., and the two layers
were separated. The aqueous layer was extracted with
CH2Cl2 (3 × 3 mL), and the combined organic layers were
dried over Na2SO4 and concentrated in vacuo. The crude
residue was purified by flash column chromatography with
EtOAc–PE to give N-sulfonylacetamidines 3a–l.
Acknowledgment
The work was supported by Natural Science Foundation of China
(No. 30873153), the Key Projects of Shanghai in Boimedical
(No.08431902700), and the Scientific Research Foundation of State
Education Ministry for the Returned Overseas Chinese Scholars.
We would like to thank the Center for Instrumental Analysis, Tongji
University, P. R. of China.
Selected Data
N-Ethyl-N-phenyl-N¢-tosylacetamidine (3a)
References and Notes
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Light yellow solid, mp 130.0–131.0 °C. IR (KBr): 3458,
2929, 1547, 1495, 1267, 1139, 1089, 685 cm–1. 1H NMR
(500 MHz, CDCl3): d = 7.88 (2 H, d, J = 8.2 Hz), 7.45 (2 H,
t, J = 7.8 Hz), 7.39 (1 H, t, J = 7.5 Hz), 7.29 (2 H, d, J = 8.0
Hz), 7.12 (2 H, d, J = 7.5 Hz), 3.83 (2 H, q, J = 14.2 Hz,),
2.42 (3 H, s), 2.24 (3 H, s), 1.12 (3 H, t, J = 7.1 Hz). 13
C
NMR (125 MHz, CDCl3): d = 165.4, 141.9, 141.6, 140.3,
130.0, 129.1, 128.6, 127.7, 126.3, 47.2, 21.4, 19.8, 11.9.
ESI-MS: m/z (%) = 316 [M+]. HRMS: m/z calcd for
C17H21N2O2S: 317.1324 [M + H]+; found: 317.1321.
N-p-Tolyl-N¢-tosylacetamidine (3k)
Light yellow solid (a mixture of two isomers with a ratio 1:3,
which is tentatively assigned as Z/E of the generated imino
C=N double bond), mp 109.6–127.9 °C. IR (KBr): 3750,
3308, 1535, 1457, 1275, 1143, 1089, 730 cm–1. 1H NMR
(500 MHz, CDCl3): d = 9.7 (0.7 H, br, Z/E), 7.87 (1.9 H, d,
J = 8.2 Hz, E), 7.82 (0.6 H, d, J = 8.0 Hz, Z), 7.36 (0.6 H, d,
J = 8.5 Hz, Z), 7.31 (2 H, d, J = 8.1 Hz, E), 7.26 (0.6 H, d,
J = 8.0 Hz, Z), 7.20 (2 H,d, J = 8.0 Hz, E), 7.08 (0.6 H, d,
J = 8.5 Hz, Z), 7.02 (2 H, d, J = 8.2 Hz, E), 2.61 (0.9 H, s, Z),
2.43 (3 H, s, E), 2.41 (1.0 H, s, Z), 2.37 (3 H, s, E), 2.30 (1.0
H, s, Z), 2.01 (2.9 H, s, E). 13C NMR (125 MHz, CDCl3):
d = 165.6, 162.9, 143.0, 142.2, 140.4, 139.3, 138.2, 135.2,
134.8, 134.0, 130.2, 129.4, 129.3, 129.2, 126.4, 126.3,
126.1, 121.7, 22.0, 21.7, 21.5, 21.4, 20.9, 20.8. ESI-MS:
m/z (%) = 302 [M+]. HRMS: m/z calcd for C16H19N2O2S:
303.1167 [M + H]+; found: 303.1170.
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Soc. 2005, 127, 16046. (b) Cho, S. H.; Chang, S. Angew.
Chem. Int. Ed. 2007, 46, 1897.
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V. V.; Chang, S. J. Org. Chem. 2008, 73, 5520.
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