Practical synthesis of pyrazoles via a copper-catalyzed relay oxidation strategy

Article abstract of DOI:10.1039/c4cc06747a

Various 1,3- and 1,3,4-substituted pyrazoles are smoothly formed via copper-catalyzed cascade reactions of oxime acetates, amines and aldehydes. This relay oxidative process involves copper-promoted N-O bond cleavage and C-C/C-N/N-N bond formations to furnish pyrazolines, and sequential Cu-O₂ system-involved oxidative dehydrogenation of pyrazolines to afford pyrazoles. This transformation provides a novel and versatile approach for the synthesis of pyrazoles, with an inexpensive copper catalyst and green oxidants. It is atom- and step-economical, and possesses a good functional group tolerance, as well as operational simplicity. This journal is

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Practical Synthesis of Pyrazoles via Copper-Catalyzed Relay Oxidation
Strategy
Xiaodong Tang, Liangbin Huang, Jidan Yang, Yanli Xu, Wanqing Wu, and Huanfeng Jiang*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
oxime acetates, anilines and paraformaldehyde (Figure 1c). It is
noteworthy that many oxidative CꢀC and Cꢀhetero bond
50 formations can be achieved using various of transition metal
catalysts.1 However, there is scarce examples about the oxidative
NꢀN bond formation.14 One seminal work was reported by
Glorius et al., who had developed a novel strategy for pyrazoles
from enamines and excess nitriles via oxidative NꢀN bond
55 formation under the treatment of copper catalyst.14a,b Our process
involves copperꢀcatalyzed NꢀO bond cleavage, CꢀC/CꢀN/NꢀN
bond formation and oxidative dehydrogenation process which is a
relay oxidation process and the oxidants are oxime acetates and
O2.
Various 1,3- and 1,3,4-substituted pyrazoles are smoothly
formed via copper-catalyzed cascade reactions of oxime
acetates, amines and aldehydes. This relay oxidative process
involves copper-promoted N-O bond cleavage and C-C/C-
10 N/N-N bond formations to furnish pyrazolines, and sequential
Cu/O2 system-involved oxidative dehydrogenation of
pyrazolines to afford pyrazoles. This transformation provides
a novel and versatile approach for the synthesis of pyrazoles,
with inexpensive copper catalyst and green oxidants. It is of
15 atom- and step-economy, good functional group tolerance, as
well as operational simplicity.
60
Oxidation reactions are an important component of organic
chemistry to construct CꢀC and Cꢀhetero bonds.1 There is no
doubt that molecular oxygen (O2), comparing with other
20 commonly used oxidants such as BQ, hypervalent iodonium salts
and heavy metal salts, is an ideal oxidant which is inexpensive,
atom economical and environmentally friendly.2 However, O2 is a
relatively weak oxidant which is often used in oxidative
dehydrogenation process. Thus, using O2 as the sole oxidant to
25 realize oxidative formation of several chemical bonds is
challenging. Recently, the NꢀO bond containing compounds were
frequently used as the internal oxidant and substrates for
transitionꢀmetal catalyzed CꢀH activation and cross couplings.3, 4
We proposed that a relay oxidation process combining O2 with
30 the green internal oxidant might be able to construct several
bonds in one pot.
Figure 1 Our previous work and this work
R2
Our Previous work
HN
R2
R2
cat. [Cu]
R2
(a)
R
OAc
N
R1
R1
R3
R
R3
N
N
N
cat. [Cu]
R
R1
(b)
O
OAc
(1) Cu
SO2R3
N
R3SO2Na
+
R1
R
(2) hydrolysis
R1
R
This work
R2
N
O2
Cu
N-O
OAc
N
N
Pyrazole is an important motif which is widely used in
agricultural and pharmaceutical area and also as classical
ligands.5 Selected pharmaceutical examples include Zometapine,
35 Tebufenpyrad, Celebrex and Viagra.6 Owing to their good
synthetic utility, numerous approaches have been developed in
past decades, such as the reactions of hydrazine with 1,3ꢀ
diketones or their analogues,7 dipolar [3 + 2] cycloadditions,8 and
hydrohydrazination of alkynes.9 However, the most methods for
40 the synthesis of pyrazoles limit to construct 5ꢀsubsituted
pyrazoles and need to the employment of NꢀN bond containing
substrates, that is hydrazines. In the past several years, oxime
esters have become a powerful synthon for Nꢀheterocycles such
as pyridines,10 pyrroles,11 and imidazo[1,2ꢀ a]pyridines12 in the
45 presence of copper catalyst. Based on our continuous interest in
oxime esters (Figure 1a, 1b),11a,12,13 herein, we present a copperꢀ
catalyzed synthesis of 1,3ꢀ and 1,3,4ꢀsubstituted pyrazoles from
(c)
Cu
R2NH2 (CH O)
R1
+
+
2
n
R
R
oxidation relay
R1
In our initial studies, we took acetophenone oxime acetate (1a),
65 aniline (2a) and paraformaldehyde (3a) as our model reaction to
investigate different copper salts, bases and solvents under air
atmosphere (Table 1). Fortunately, the expected transformation
occurred when we used CuCl (10 mol %) as catalyst and Cs2CO3
(20 mol %) as base in DMSO. The desired product 4aaa was
70 formed in 57% GC yield (entry 1). The screening of other copper
salts indicated that copper(I) salts were better than copper(II)
salts for this conversion. More satisfying isolated yield (83%)
was obtained by utilizing 10 mol % copper bromide as the
catalyst and 20 mol % of Cs2CO3 as the base (entries 2ꢀ5).
75 However, when 50 mol % or 100 mol % Cs2CO3 was used, the
yields of product were trace and acetophenone oxime acetate was
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decomposed into acetophenone oxime and acetophenone (entries
6ꢀ7). The examination of different bases such as K2CO3, Li2CO3,
Na2SO3, NaHSO3, DBU, and NEt3 revealed that the base was
crucial to this reaction (entries 8ꢀ13). Cs2CO3 was proved to be
the best choice and only trace amount of desired product was
obtained without base (entry 14). No product was obtained in the
absence of copper salt (entry 15). Different solvents such as
xylene and DMF were also investigated, and DMSO was found to
be the optimal solvent (entries 16ꢀ17). A gram scale preparation
strategy was also available for the construction of 1,3,4ꢀ
substituted pyrazole derivatives in good yields (4qaa-4raa).
40 Table 2 Substrate scope of various oxime acetates.a
5
10 was performed and the isolated yield was 71% (entry 18).
Table 1. Screening for optimal reaction conditions.a
Entry
[Cu]
Base
Solvent
Yield (%)
1
2
CuCl
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Li2CO3
Na2SO3
NaHSO3
DBU
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
xylene
DMF
57
79
3
CuBr
CuBr2
CuCl2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
ꢀꢀꢀ
87 (83)
41
4
5
15
6b
7c
8
trace
trace
65
9
71
a
10
11
12
13
14
15
16
17
18d
22
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol),
Cs2CO3 (20 mol %), CuBr (10 mol %), DMSO (3.0 mL), under air, 120
24
oC for 12 h. Isolated yields.
68
NEt3
37
45
The reaction scope with respect to the anilines was next
examined (Table 3). A variety of monosubstituted anilines
reacted smoothly to generate the corresponding pyrazoles in good
to excellent yields (4aba-4aka). Generally, electronꢀwithdrawing
groups on the anilines slightly increased the yield of product. We
ꢀꢀꢀ
trace
n.r.
45
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuBr
CuBr
CuBr
74
DMSO
75 (71)
50 were excited that polysubstitutd anilines were also suitable
starting materials and the desired products were formed in 80%
and 82% yields, respectively (4ala and 4ama). Unfortunately,
aliphatic amines such as nꢀpropylamine and benzylamine were
not able to give the pyrazole products. Except paraformaldehyde,
55 other aldehydes such as benzaldehyde and nꢀbutylaldehyde were
failed to transfer into the corresponding products. The reason may
be their electrophilicity was lower than that of paraformaldehyde.
a
Reaction conditions: unless otherwise noted, all reactions were
performed with 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), [Cu] (10
15 mol %), base (20 mol %) and DMSO (3.0 mL) at 120 oC under air for 12
h. GC yield. Number in parentheses is isolated yield. b 50 mol % Cs2CO3
c
d
was used. 100 mol % Cs2CO3 was used. A gram scale preparation
were performed with 1a (7 mmol), 2a (7 mmol), 3a (7 mmol), CuBr (10
mol %), Cs2CO3 (20 mol %) and DMSO (15 mL) at 120 oC under air for
20 12 h.
Table 3 Substrate scope of various anilines.a
Based on the optimization study, we studied the scope of
oxime acetates and the results are summarized in Table 2.
Different substituents on the aromatic ring of acetophenone
oxime acetate such as methyl, methoxyl, fluoro, chloro, bromo
25 were well tolerated and the corresponding products could be
formed in good to excellent yields (4aaa-4jaa). Interestingly,
electronꢀdonating groups exhibited positive effect on this
transformation. 3,4ꢀMethylenedioxyacetophenone oxime acetate
could also be transformed into the corresponding pyrazole in 87%
30 yield (4kaa). Moreover, oxime acetates derived from other
aromatic ketones such as αꢀaetonaphthone, βꢀaetonaphthone
could be accessed through this route to generate the annulation
products (4laa-4maa) in good yields. To our delight, the
heteroarene containing oxime acetates were compatible in this
35 transformation (4naa-4oaa). It is worth noting that aliphatic
ketone was also applicable under these reaction conditions and
afforded product 4paa in 65% yield. More importantly, the
2
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a
Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), 3a (0.5 mmol),
In summary, various 1,3ꢀ and 1,3,4ꢀsubstituted pyrazoles
were efficiently synthesized via copperꢀcatalyzed assembly of
40 oxime acetates, aniline and paraformaldehyde. This process
involved copperꢀcatalyzed NꢀO bond cleavage, CꢀC/CꢀN/NꢀN
bond formations and oxidative dehydrogenation. In addition, this
protocol utilized the oxime acetate as the internal oxidant to
initiate the reaction and the green oxygen to end up the
45 transformation. Detailed mechanistic studies showed that this
transformation went through two processes, which included the
formation of pyrazoline ring and oxidative dehydrogenation
under the Cu/O2 system. The oxidant of the first process was
oxime acetate and the following was O2, which could be called
50 oxidation relay. Further study on this topic is currently
undergoing in our laboratory.
Cs2CO3 (20 mol %), CuBr (10 mol %), DMSO (3.0 mL), under air, 120
oC for 12 h. Isolated yields.
5
To gain more insight into the mechanism of the process, we
conducted several control experiments. When we coupled
compound 9 with paraformaldehyde 3a in the standard conditions,
we could not obtain product 8 [Eq. (1)]. This result revealed that
9 was not an intermediate in the transformation.15 Moreover,
10 when we took our standard reaction under N2, 7 was formed in
70% GC yield,16 and the yield of 8 was low [Eq. (2)]. When
increasing the amount of Cs2CO3, the yield of product 8 was
trace.17 However, when we made the standard reaction continue
under air after 1 h, pyrazoline 7 was completely transformed into
15 product 8, which indicated that 8 should come from 7 by
oxydehydrogenation under the Cu/O2 system.18
The authors thank the National Natural Science Foundation of
China (21172076 and 21202046), the National Basic Research
55 Program of China (973 Program) (2011CB808600), and the
Guangdong Natural Science Foundation (10351064101000000)
and the Fundamental Research Funds for the Central Universities
(2014ZP0004 and 2014ZZ0046) for financial support.
Notes and references
60 School of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou 510640, China. Fax: +86 20-87112906; Tel:
+86 20-87112906; E-mail: jianghf@scut.edu.cn
† Electronic Supplementary Information (ESI) available: Experimental
section, characterization of all compounds, copies of 1H and 13C NMR
65 spectra for selected compounds. See DOI: 10.1039/b000000x/
20
On the basis of these experiments and previous reports,10ꢀ14
a
plausible mechanism is illustrated in Scheme 1. Firstly,
acetophenone oxime acetate 1 was smoothly transferred to copper
enamide intermediate 2 with copper catalyst and produced
another CuII species.10ꢀ13 Subsequently, imine intermediate 3 was
1 (a) C. Li, Acc. Chem. Res. 2009, 42, 355. (b) A. S. Girard, T. Knauber,
C. Li, Angew. Chem. Int. Ed. 2014, 53, 74. (c) C. S. Yeung, V. M.
Dong, Chem. Rev. 2011, 111, 1215. (d) S. Zhang, F. Zhang, Y. Tu,
25 formed via nucleophilic addition of 2 to paraformaldehyde.10b
Imine intermediate 3 was coupled with aniline, followed by the
coordination with copper catalyst to give intermediate 4. Then,
intermediate 5 was formed by losing one molecule of H2O.14a,b
With the release of H+, intermediate 5 was converted to
30 intermediate 6,14a,b which underwent reductive elimination to
afford pyrazoline 7 and copper(0).14 Finally, copper(0) was
oxidized by copper(II) to form copper(I) and product 8 was
obtained by oxidative dehydrogenation process under the Cu/O2
system.18
70
75
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80
35
OAc
N
Ph
1
CuII
Cu0
2 CuI
85
CuII
HN
Ph
[O]
N
CuII
N
N
NPh
Ph
Ph
8
7
Ph
2
3
CuII
(CH2O)n
90
N
NPh
Ph
6
NH OCuII
H+
Ph
CuII
95
3
NH NPh
CuIIOH
NHPh
Ph
PhNH2
5
NH
4
H2O
Ph
100
4
Scheme 1 Possible reaction mechanism.
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16 Pyrazoline 7 and product 8 are difficult to separate. When we made
the reaction continue in the air after 1 h, pyrazoline 7 completely
transformed into product 8.
60 17 When we increased the amount of the Cs2CO3 to 50 mol % or 120
mol % under N2, the yields of 7 and 8 were trace and acetophenone
oxime acetate was decomposed into acetophenone oxime and
acetophenone.
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An efficient Cu-catalyzed cascade reaction involving N-O bond cleavage and C-C/C-N/N-N bond
formations is developed to afford various 1,3- and 1,3,4-substituted pyrazoles.