Synthesis of 1,3,4-Trisubstituted Pyrazoles from α-(1,3-Dithian-2-yl) Enamine Ketones via [4+1] Cyclization

Article abstract of DOI:10.1055/s-0034-1378858

A novel method for the synthesis of 1,3,4-trisubstituted pyrazoles from α-(1,3-dithian-2-yl) enamine ketones and primary amines, involving copper(II)-catalyzed oxidative N-N coupling, has been developed. This unprecedented [4+1] approach is versatile in the synthesis of N-aryl, N-benzyl and N-alkyl pyrazoles, and provides an alternative to the conventional [3+2] methods.

Full text of DOI:10.1055/s-0034-1378858

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1895–1899
letter
1895
S. Wang et al.
Letter
Synlett
Synthesis of 1,3,4-Trisubstituted Pyrazoles from α-(1,3-Dithian-
2-yl) Enamine Ketones via [4+1] Cyclization
Shugang Wanga,b
Yongguang Lib
Xihe Bia
R1
R2
O
S
O
S
S
NH4OAc
R1
R2
S
O
EtOH, 70 °C
Qun Liu*a
NH2
a Department of Chemistry, Northeast Normal University,
5268 Renmin Street, Changchun 130024, P. R. of China
liuqun@nenu.edu.cn
b College of Chemistry, Jilin University, 2519 Jiefang Road,
Changchun 130023, P. R. of China
R3
O
R3-NH2
N
N
R1
CuBr2, Et3N
MeCN, 60 °C
R2
Received: 19.04.2015
Accepted after revision: 02.06.2015
Published online: 20.07.2015
tion (Scheme 1).10 The method has a broad substrate scope,
and provides the products regiospecifically, but not escape
from the conventional [3+2] cyclization.
DOI: 10.1055/s-0034-1378858; Art ID: st-2015-w0286-l
R4
Abstract A novel method for the synthesis of 1,3,4-trisubstituted pyr-
azoles from α-(1,3-dithian-2-yl) enamine ketones and primary amines,
involving copper(II)-catalyzed oxidative N–N coupling, has been devel-
oped. This unprecedented [4+1] approach is versatile in the synthesis of
N-aryl, N-benzyl and N-alkyl pyrazoles, and provides an alternative to
the conventional [3+2] methods.
R4
R1
N
N
N
Cu(OAc)2
110 °C
R1
R3
+
N
H
R2
R3
R2
Scheme 1 Copper(II)-catalyzed oxidative N–N bond formation
Key words enamine ketones, primary amines, copper(II), catalysis,
N–N coupling, [4+1] cyclization
Inspired by Glorius’s work, synthesis of triazoles via
[4+1] cyclization involving N–N coupling reactions were re-
ported by Tam, Berkel and their co-workers (Scheme 2), re-
spectively.11,12 However, a similar breakthrough has still not
been made in the synthesis of pyrazoles. Herein, we report
an unprecedented N–N coupling strategy for the synthesis
of 1,3,4-trisubstituted pyrazoles via [4+1] cyclization from
α-(1,3-dithian-2-yl) enamine ketones and primary amines
(Scheme 3).
Substituted pyrazoles have shown a broad spectrum of
pharmacological and biological activities.1 For instance,
1,3,4-trisubstituted pyrazole derivatives can be utilized as
antitumor and antiangiogenic agents;2 1,3,5-trisubsttuted
pyrazole motif is adopted in inhibitors of mycobacteria tu-
berculosis and estrogen receptors;3 Celebrex, Viagra and
Acomplia, which have been successfully commercialized,
are not exempt from pyrazole-containing compounds.4
The most commonly used approaches to the synthesis
of pyrazoles, which involve the classical condensation of hy-
drazines with 1,3-dicarbonyl compounds and their equiva-
lents,5 the 1,3-dipolar [3+2] cycloadditions and the transi-
tion-metal-catalyzed C–N or C–C cross coupling on pre-
formed pyrazoles6–8 have been extensively studied.
However, regioselective synthesis of the pyrazole ring re-
mains a significant challenge.9 Recently, Glorius and co-
workers constructed a new method for the preparation of
tetrasubstituted pyrazoles from enamines and nitriles in-
volving a copper(II)-catalyzed oxidative N–N bond forma-
NH2
N
NOTs
HC(OEt)3
Ar
N
Ar
N
EtSO3H
NH2
THF, 50–60 °C
Ts
R2
NH
N
R2-NH2
N
N
N
Cl
DIPEA
MeCN–EtOH
r.t.
R1
R1
Cl
Scheme 2 Synthesis of triazoles via [4+1] cyclization involving N–N
coupling reactions
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1895–1899

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S. Wang et al.
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Table 1 Optimization of Reaction Conditions
R1
R2
S
R3
O
N
N
R3-NH2
S
Entry Catalyst
Base
Solvent
Temp Time Yield
O
(°C)
(h)
(%)a
R1
catalyst, base
NH2
R2
1
2
Cu(OAc)2·H2O
–
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
EtOH
CHCl3
MeCN
DMF
DMF
DMF
60
12
19
55b
72c
78
32
–
Scheme 3 Synthesis of 1,3,4-trisubstituted pyrazoles via [4+1] cycliza-
tion involving N–N coupling reactions
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuSO4·5H2O
CuBr2
K2CO3
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
80
100
12
20
20
24
12
6
3
Et3N
4
Et3N
A model study was initiated with α-(1,3-dithian-2-yl)
enamine ketone 1aa and 4-methylaniline as substrates to
investigate competent substrates and catalysts. Encourag-
ingly, a 19% yield of the desired pyrazole 4ba was achieved
after stirring for 12 hours at 60 °C in the presence of
Cu(OAc)2·H2O as the catalyst (Table 1). However, attempts to
use other catalysts, such as FeCl3, Ce(NH4)2(NO3)6 and Et3N,
were not as successful as Cu(OAc)2·H2O. Alternative sub-
strates, such as 2-(1,3-dithian-2-yl)-3-oxo-N-phenylbutan-
amide (2aa) and 3-acetyl-4-(phenylamino)but-3-en-2-one
(3aa), could not react with 4-methylaniline or failed to as-
semble pyrazole derivatives under attempted conditions
(Scheme 4).
5
Et3N
6
K2CO3
Et3N
7
CuBr2
90
90d
64
86e
–
8
CuBr2
Et3N
6
9
CuBr2
Et3N
24
12
24
24
6
10
11
12
13
14
15
16
17
18
19
20
21
CuCl2
Et3N
CuO
Et3N
CuI
Et3N
44
89
67
–
CuBr2
piperidine
Et2N
CuBr2
12
12
12
12
6
CuBr2
pyridine
Et3N
CuBr2
–
S
O
CuBr2
Et3N
–
catalyst A (or B/C/D)
THF
N
N
CuBr2
Et3N
Et3N
91
62
56
62
O
S
+
CuBr2
12
12
12
NH2
NH2
catalyst A = FeCl3
B = Cu(OAc)2⋅H2O
4ba
CuBr2
Et3N
1aa
yield = 0%
CuBr2
Et3N
19%
0%
a Reaction conditions: 1aa (1.0 mmol), 4-methylaniline (1.0 mmol), base
(1.5 mmol), catalyst (0.5 mmol), solvent (10 mL), 60 °C.
b Amount of K2CO3 used was 1.0 mmol.
C = Ce(NH4)2(NO3)6
D = Et3N
0%
O
O
S
c Amount of Et3N used was 1.0 mmol.
Ph
d Amount of CuBr2 used was 1 mmol.
N
e Amount of CuBr2 used was 0.1 mmol.
catalyst A (or B/C/D)
H
no pyrazole
+
THF
S
NH2
tions in entry 18 were deemed the best, and they were cho-
sen for further investigation.
2aa
O
O
Having identified these optimal conditions, we then ex-
tended the substrate scope of this reaction. As illustrated in
Table 2, a variety of anilines, regardless of the electron-do-
nating or electron-withdrawing group on the aromatic ring,
were broadly tolerated, giving the products in moderate-to-
good yields (4ba–4bm). Valuable functional groups, such as
methyl (4ba), methoxy (4bc), chloro (4bm), bromo (4bd),
iodo (4bk) and nitro (4be), were also present in the corre-
sponding products. Generally, electron-rich anilines
showed higher reactivity to afford the 1,3,4-trisubstituted
pyrazoles than those with electron-withdrawing groups at
the same substitution position. It is easy to understand that
the higher electron density at the nitrogen atom of anilines
was beneficial to the initial nucleophilic substitution. More-
over, steric hindrance of both 1a (4bd, 4bh, 4bj) and prima-
ry amines (4ba, 4bi, 4bl) had remarkable effect on this
catalyst A (or B/C/D)
THF
+
no pyrazole
NH
Ph
NH2
3aa
Scheme 4 Model study of catalysts and substrates
Further investigation showed that this transformation
was highly solvent dependent. Higher yields were achieved
in MeCN and THF (Table 1, entries 7 and 18), while other
solvents, such as EtOH, CHCl3 and DMF (entries 16, 17 and
19), led to no reaction or lower yield. It seems that the solu-
bility of substrates was the key factor. When the reaction
was conducted in DMF, it was observed that higher tem-
peratures could not speed up the reactions and improve the
yields apparently (entries 19–21). Consequently, the condi-
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S. Wang et al.
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transformation. It was verified that substituent R3 could be
alkyl and aryl, including heterocyclic groups like thienyl
(4bj).
To confirm the mechanism of this N–N coupling, the cy-
clization was conducted under N2 atmosphere. An 11% yield
of pyrazole was obtained by the use of a 0.5 equivalent
amount of CuBr2 (Scheme 5,A). In contrast, reactions con-
ducted under the same conditions without N2 (Scheme 5,B)
afforded the optimal reaction rate and conversion ratio
(91% yield). Even a 0.1 equivalent amount of CuBr2 could
lead to a 64% yield under air atmosphere (Scheme 5,D).
However, insufficient catalyst paralyzed the reaction com-
pletely when N2 was filled (Scheme 5,C). Suitable oxidant
was also indispensable to this N–N bond formation, and O2
in the air was the only candidate.
In addition, N-benzylpyrazole (4bn) could be obtained
successfully through the method. Especially noteworthy
was the regioselective synthesis of N-propylpyrazole (4bo),
since N-alkylpyrazoles were difficult to synthesize by clas-
sical methods due to the limited availability and high cost
of alkylhydrazine.13 Points discussed above indicated a
wide scope of the method unanimously.
To our surprise, neither excess catalysts10a,14 nor suit-
able oxidants,10b,15 which were essential conditions to an
oxidative N–N bond formation, were loaded in this method.
Table 2 Synthesis of 1,3,4-Trisubstituted Pyzolesa
R1
R2
S
R3
O
N
N
CuBr2, Et3N
+ R3-NH2
O
S
R1
MeCN, 60 °C
R2
NH2
1a
4b
MeO
O
O
O
N
N
N
N
N
N
4ba 91%
4bb 88%
4bc 96%
Br
O
O
O
N
N
O2N
N
N
N
N
4be 71%
4bd 64%
4bf 49%
MeO
Br
O
O
O
N
N
N
N
N
N
4bi 68%
4bh 47%
4bg 56%
Br
I
O
S
O
O
O
N
N
N
N
N
N
4bl 81%
4bo 42%
4bk 73%
4bj 58%
O
O
N
N
N
N
Cl
N
N
4bn 59%
4bm 77%
a Reaction conditions: 1a (1.0 mmol), R3NH2 (1.0 mmol), Et3N (1.5 mmol), CuBr2 (0.5 mmol), MeCN (10 mL), 60 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1895–1899

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In summary, we have reported a novel copper-catalyzed
S
approach for the synthesis of 1,3,4-trisubstituted pyrazoles
from α-(1,3-dithian-2-yl) enamine ketones and primary
amines, involving a copper(II)-catalyzed oxidative N–N cou-
pling and a non-oxidative C–N bond formation.17 Regiose-
lective synthesis of N-arylpyrazoles, N-benzylpyrazoles and
N-alkylpyrazoles using the same method was achieved. Fur-
thermore, this unprecedented and highly practical [4+1] cy-
clization provides an alternative to the conventional [3+2]
methods of pyrazole synthesis5,6 with a broad substrate
scope, high atom efficiency, without the need of carcino-
genic hydrazines and with less formation of toxic by-prod-
ucts. Notably, air, the most environment friendly oxidant,
was employed under mild reaction conditions. Studies are
ongoing in our laboratory to investigate further synthetic
applications.
conditions A (or B/C/D)
O
O
S
N
N
Et3N (1.5equiv)
MeCN, 60 °C
+
NH2
NH2
1aa
4ba
A: CuBr2 (0.5 equiv), N2, 24 h, 11% yield
B: CuBr2 (0.5 equiv), air, 6 h, 91% yield (Table 1, entry 18)
C: CuBr2 (0.1 equiv), N2, 24 h, 0% yield
D: CuBr2 (0.1 equiv), air, 24 h, 64% yield (Table 1, entry 9)
Scheme 5 Study of oxidants
On the basis of the above results and completed
work,10,16 a possible mechanism is proposed in Scheme 6.
The CuII first coordinates to the nitrogen and sulfur atoms
in α-(1,3-dithian-2-yl) enamine ketone 1a, forming the in-
termediate I. Subsequently, one C–S bond is cleaved to give
the intermediate II. After that, the amine attacking at the
carbon atom of II leads to the desulfurization which results
in the formation of 1,3-bisimine IV. Then, CuII coordinates
to the nitrogen atom of amine to generate CuII-(1,3-imine-
enamine) chelate V. With reductive elimination, the desired
N–N bond is formed to generate the corresponding 1,3,4-
trisubstituted pyrazoles. Reduced copper catalyst follows, is
oxidized to CuII by oxygen molecules in the air and reenters
the catalytic cycle.
References and Notes
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O
R2
O
R2
R1
S
R1
NH
CuII
R1
NH
CuII
– Br–
Br
CuBr2
– HBr
O
S
S
S
S
S
R3NH2
R2 NH2
1a
I
II
O
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NH
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NR3
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Scheme 6 Proposed reaction mechanism
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(17) General Procedure for the Synthesis of α-(1,3-Dithian-2-
yl)enamine Ketones (1a): To a 25.0-mL round-bottomed flask,
dithiane (10.0 mmol), NH4OAC (3.85 g, 50.0 mmol) and EtOH
(5.0 mL) were added successively. The mixture was stirred at 70
°C. Solid in the flask dissolved into liquid gradually, and a clear
solution was obtained. Continuous heating made the solution
muddy, and finally solid was precipitated from the solution. The
solvent was removed and the residue was cooled. The residue
(crude product) was washed with cool EtOH to obtain pure
product 1a.
Selected Spectral Data of 4-Amino-3-(1,3-dithian-2-yl)pent-
3-en-2-one (1aa): yield: 92%; white solid; mp 163–164 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.70–1.83 (m, 2 H), 2.39 (s, 3 H),
2.49 (s, 3 H), 2.81–2.86 (m, 2 H), 2.94–3.01 (m, 2 H), 5.22 (s, 1
H). 13C NMR (100 MHz, CDCl3): δ = 22.40, 25.25, 28.74, 33.86,
48.14, 104.64, 167.15, 195.09.
General Procedure for the Synthesis of 1,3,4-Trisubstituted
Pyrazoles (4b): To a solution of α-(1,3-dithian-2-yl) enamine
ketones 1a (1.0 mmol) and primary amine (1.0 mmol) in MeCN
(10.0 mL), CuBr2 (0.1116 g, 0.5 mmol) and Et3N (0.1518 g, 1.5
mmol) were added. The reaction mixture was warmed to 60 °C
and stirred until the staring material was consumed (monitored
by TLC). Upon cooling to r.t., the reaction mixture was filtrated
and washed with CH2Cl2. The filtrate was concentrated in vacuo
and purified by column chromatography over silica gel to give
product 4b.
Selected Data:
1-[3-Methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]ethanone
(4ba): 91% yield; white solid; mp 101–103 °C. 1H NMR (300
MHz, CDCl3): δ = 2.40 (s, 3 H), 2.47 (s, 3 H), 2.57 (s, 3 H), 7.25–
7.28 (d, J = 8.4 Hz, 2 H), 7.54–7.57 (d, J = 8.4 Hz, 2 H), 8.25 (s, 1
H). 13C NMR (75 MHz, CDCl3): δ = 14.26, 20.98, 28.65, 119.38,
122.37, 130.08, 130.84, 136.99, 137.25, 151.71, 192.49. HRMS
(ESI, TOF): m/z [M + H]+ calcd for C13H15N2O: 215.1186; found:
215.1179.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1895–1899