Copper-mediated pyrazole synthesis from 2,3-allenoates or 2-alkynoates, amines and nitriles

Article abstract of DOI:10.1039/c4cc02856b

An efficient copper-mediated three-component reaction of 2,3-allenoates or 2-alkynoates, amines, and nitriles affording fully substituted pyrazoles with a very nice diversity has been developed. A tandem conjugate addition, 1,2-addition, and N-N bond formation mechanism has been proposed for this diverse synthesis of pyrazoles based on mechanistic studies.

Full text of DOI:10.1039/c4cc02856b

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Copper-mediated pyrazole synthesis from
2,3-allenoates or 2-alkynoates, amines and
nitriles†
Bo Chen,‡a Can Zhu,‡a Yang Tanga and Shengming Ma*ab
Cite this: Chem. Commun., 2014,
50, 7677
Received 24th April 2014,
Accepted 21st May 2014
DOI: 10.1039/c4cc02856b
www.rsc.org/chemcomm
An efficient copper-mediated three-component reaction of 2,3- compounds with unsaturated compounds,6 the reaction of aryl
allenoates or 2-alkynoates, amines, and nitriles affording fully substi- amines with 1,3-dicarbonyl compounds forming b-amino-a,b-
tuted pyrazoles with a very nice diversity has been developed. A tandem enoates or enones, which would react further with nitriles,7 and
conjugate addition, 1,2-addition, and N–N bond formation mechanism catalyzed azacyclization of propargylic hydrazines or N-propargylic
has been proposed for this diverse synthesis of pyrazoles based on sulfonylhydrazones.8 Most of these reported approaches are based on
mechanistic studies.
starting materials, which are either with a limited scope or not readily
available and should be obtained via multi-step synthesis or even
Pyrazoles are some of the most important heteroaromatic with danger. On the other hand, functionalized allenes, especially
compounds considering their wide existence in natural products 2,3-allenoates, have been proven to be useful building blocks due to the
as well as in pharmacologically active substances.1 Many pyrazole- reactivity and substituent-loading capability of the allene unit. Based
containing compounds such as rimonabant, celebrex, viagra, and on our studies on the reactivities of 2,3-allenoates, we envisioned
fipronil have been successfully commercialized as medicines or that the reaction of 2,3-allenoates, amines, and nitriles may offer an
pesticides (Scheme 1).2 Additionally, pyrazoles are used in poly- efficient and convenient three-component approach to pyrazole
mer and supramolecular chemistry, and as cosmetic colorings skeletons via a conjugated addition of amines to 2,3-allenoates,9
and UV stabilizers.3 Poly-substituted pyrazoles have also been subsequent 1,2-addition to nitriles, and copper-involved N–N bond
utilized as ligands for some transition metal-catalyzed reactions.4 formation process (Scheme 2). We wish to disclose the realization of
such a three-component reaction with diversity due to the substituent
loading ability of the three readily available starting materials.
Scheme 1 Some commercialized bioactive pyrazole compounds.
Scheme 2 Concept of the diverse synthesis of pyrazoles via 2,3-allenaotes.
Typical approaches towards the synthesis of poly-substituted
At first, we treated the parent 2,3-allenoate 1a with BnNH2
pyrazoles1 are based on the reaction of hydrazines with 1,3-dicarbonyl
(1.1 equiv) in PhCN using Cu(OAc)2 as the oxidant at 120 1C for
compounds or unsaturated hydrocarbons,5 the reaction of diazo
12 h (Table 1, entry 1). The desired product 3a was formed in 56%
yield based on NMR analysis. The yield was improved to 85% by
increasing the loading of BnNH2 from 1.1 to 1.5 equiv. (entries 1–3).
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
Further study on the effect of temperature led to the observation
that the reaction at 120 1C afforded the best result (entries 5 and 6).
Reducing the amount of Cu(OAc)2 or switch to other oxidants such
as dioxygen or PhI(OAc)2 did not afford better results (entries 8–10).
Thus, we defined the reaction of 2,3-allenoate 1a with 1.5 equiv.
BnNH2 and 2 equiv. Cu(OAc)2 in PhCN at 120 1C for 6 h as the
standard conditions (entry 4, Table 1).
P. R. China
b Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department
of Chemistry, East China Normal University, 3663 North Zhongshan Road,
Shanghai 200062, P. R. China. E-mail: masm@sioc.ac.cn; Fax: +86-21-6260-9305
† Electronic supplementary information (ESI) available: The experimental proce-
dures, characterization data, and copies of 1H and 13C NMR spectra of all
products. See DOI: 10.1039/c4cc02856b
‡ These two authors contributed equally to this work.
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Table 1 Optimization of reaction conditions: reaction of 2,3-allenoate 1a
with BnNH2 in PhCNa
benzylic amine and PhCN, producing the pyrazoles 3l–3o in
decent yields, showing the diversity (Table 3).10
Table 3 Substrate scope: reaction of allenoates with amines in PhCNa
Entry
n
X
T (1C)
Time (h)
Yield of 3ab (%)
1
2
3
4
5
6
7
8
9
10
1.1
1.3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
2
2
2
2
2
2
0.1
0.1
1.5
120
120
120
120
100
130
120
120
120
120
12
12
12
6
6
6
56
81
85
85
43
77
68
Entry
R1
R2
R4
Isolated yields of 3 (%)
1
2
3
4
n-C9H19
n-Bu
Me
Et
Et
Bn
Me
Bn
51 (3l)
p-FBn
p-FBn
p-FBn
51 (3m)
59 (3n)
61 (3o)
3
10c
Traced
71
Cy
12
12
12
a
The reaction was conducted with 0.2 mmol of 2,3-allentoates,
0.3 mmol of amines, 0.4 mmol of Cu(OAc)2 in 2 mL of PhCN at 120 1C.
a
The reaction was conducted with 0.2 mmol of 2,3-allentoate and
b
0.3 mmol of BnNH2 which were pre-stirred for 0.5 h. Determined by
NMR using mesitylene as the internal standard. Dioxygen balloon was
used as the oxidant. 2 equiv. of PhI(OAc)2 were used as the oxidant.
The reaction may also be extended to 2-alkynoates and
amines in different nitriles (Table 4).10
c
d
Table 4 Synthesis of pyrazoles from 2-alkynoatesa
The scope of this transformation was then investigated
under the standard conditions (Table 2). The reaction of
2,3-allenoate 1a with different alkylic and benzylic amines in
PhCN afforded the corresponding pyrazoles in moderate to
good yields: substituents on the aromatic ring of benzylic
amine may be halide, methyl and methoxy groups (entries 2–9,
Table 2); either n-alkyl or cyclohexyl amines may react with
2,3-allenoate 1a affording the corresponding pyrazoles in
moderate yields (entries 6–9, Table 2). It is worth noting that
alkyl nitriles may also be applied, although a longer reaction
time is required (entries 10 and 11, Table 2).
Entry
R2
R3
R4
Isolated yields of 3 (%)
1
2
3
4
5
Me
Ph
Ph
Ph
Ph
Bn
Bn
p-FBn
n-C8H17
n-C8H17
50b (3p) + 14 (6)10
44 (3q)c
p-O2NBn
p-O2NBn
p-O2NBn
p-O2NBn
44 (3r)d
52 (3s)
33 (3t)
m-MeC6H4
a
The reaction was conducted with 0.2 mmol of 4, 0.3 mmol of amines,
b
0.4 mmol of Cu(OAc)2 in 0.5 mL of nitrile at 120 1C. For details see the
c
ESI. Purity = 97% based on the 1H NMR analysis with CH3NO2 as the
Table 2 Substrate scope: reaction of allenoate 1a with amines in different
nitrilesa
d
internal standard. Purity = 93% based on the 1H NMR analysis with
CH3NO2 as the internal standard.
A possible mechanism has been proposed (Scheme 3). In
terms of pyrazole formations, the Michael addition of 2,3-
allenoate with amine may give the intermediate Int 1, which
would react with the Cu(II)-activated nitrile followed by CQC
bond migration allowing the formation of bisimine Int 2. This
intermediate would react with Cu(OAc)2 to produce metallacyclic
intermediate Int 3 by releasing two molecules of HOAc. Subse-
quent reductive elimination furnishes the pyrazole products 3.
Entry
R3
R4
Isolated yields of 3 (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-Bu
Me
Bn
75 (3a)
80 (3b)
65 (3c)
61 (3d)
71 (3e)
67 (3f)
56 (3g)
60 (3h)
52 (3i)
p-FBn
p-ClBn
p-MeOBn
p-MeBn
n-Bu
n-C6H13
n-C8H17
Cy
9
10
11
Bn
Bn
49 (3j)b,c
60 (3k)d
a
The reaction was conducted with 0.2 mmol of 1a, 0.3 mmol of amines,
b
0.4 mmol of Cu(OAc)2 in 2 mL of nitrile at 120 1C. The reaction was
conducted for 48 h. 4 Å MS was used. The reaction was conducted in
a sealed tube for 24 h.
c
d
Further studies on the substrate scope were carried out
using 1,3-disubstitued allenoates: allenoates with a normal
linear substituent such as n-C9H19, n-C4H9, or Me and a
secondary alkyl group, such as cyclohexyl, could also react with Scheme 3 Possible mechanism for the diverse synthesis of pyrazoles.
7678 | Chem. Commun., 2014, 50, 7677--7679
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In order to confirm this mechanism, especially the possibi-
lity of forming the N–N bond under the current reaction
conditions, the Int 2-type of compound 5 was prepared.11 It
indeed underwent the Cu(OAc)2-mediated N–N formation reac-
tion to afford pyrazole 3u in 79% isolated yield (eqn (1)). This
evidence supports the mechanism presented in Scheme 3.
Communication
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In conclusion, we have developed three-component reactions
affording fully substituted pyrazoles from 2,3-allenoates or
2-alkynoates, alkyl amines, and nitriles with diversity. Because
of the easy availability of starting materials,12 the easy transfor-
mation nature of the carboxylic acid ester functionality and
potential of the products,1 this chemistry will be of high interest
of organic and medicinal chemists. Further studies involving
pyrazole chemistry are currently underway in our laboratory.
Financial support from the National Natural Science Foun-
dation of China (21232006) and the National Basic Research
Program of China (2011CB808700) is greatly appreciated. We
thank Miss Xue Can in this group for reproducing the results
presented in entry 2 of Table 2 and entry 1 of Table 3.
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