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Table 1: (Continued)
Entry
Pyrazole
Yield [%][a]
65[c]
Entry
32
Pyrazole
Yield [%][a]
70[d]
15
2o
2af
16
17
2p
2q
75[c]
88[c]
33
2ag
73[d]
[a] Yield of analytically pure, isolated pyrazole product 2. [b] Reaction conditions A: enamine 1 (1.0 mmol), Cu(OAc)2 (1.5 equiv), RCN (1.5 mL),
1108C, 24 h. [c] Reaction conditions B: enamine 1 (1.0 mmol), Cu(OAc)2 (3.0 equiv), RCN (3.0 mL), 1208C, 14–24 h. [d] Reaction conditions C:
enamine 1 (1.0 mmol), Cu(OAc)2 (6.0 equiv), R2CN (6.0 mL), 110–1208C, 16–24 h.
concentration 0.33m), in the presence of 3.0 equivalents of
Cu(OAc)2 under an atmosphere of air at 1208C. Alterna-
tively, using half the amount of Cu(OAc)2 (1.5 equiv) and
nitrile (0.66m) generally provided the desired products in only
slightly reduced yields.
With the optimized reaction conditions in hand, we
explored the substrate scope of this reaction (Table 1).
Using (Z)-methyl-3-(phenylamino)but-2-enoate (1a) and its
para-fluoro derivative, several different nitriles were success-
fully coupled in good yields (Table 1, entries 1–10). Aliphatic
(Table 1, entries 1–6) as well as aromatic nitriles worked well
(Table 1, entries 7–10). Competition experiments clearly
show that the aromatic benzonitrile reacts faster than
aliphatic propionitrile and that electron-withdrawing groups
on the aromatic nitrile render the substrate even more
reactive (Table 2). For example, employing equimolar
Moreover, it is important to note that unsymmetrical
pyrazoles (R2 ¼ R4) were formed with complete regioselec-
tivity (Table 1, entries 4–33), for example providing 3-ethyl-5-
methyl-pyrazoles (Table 1, entries 4, 5, 11—15, 17, 19, 22–25,
32, 33). By using deuterated acetonitrile the origin of the 3-
methyl group could be clearly proven and the advantage of
regiospecificity emphasized (Table 1, entry 3).
To investigate the substrate scope regarding the substitu-
ents R1, R3, and R4, several differently substituted enamines
were reacted with representative nitrile reaction partners:
First of all, the scope of the N substituents was found to be
impressively broad. The ortho-, meta- and para-substituted
aryl groups, as well as the electron-rich and electron-poor aryl
groups were well tolerated, including functional groups such
as nitro or ester moieties (Table 1, entries 11–21). Especially
noteworthy is the synthesis of N-mesityl pyrazoles (Table 1,
entries 19 and 20), since their construction by classical
methods involves the expensive and rather sensitive mesityl
hydrazine. The possibility of employing exceedingly sterically
demanding aromatic systems as nitrogen substituents of the
Table 2: Competition experiments.[a]
ꢀ
ꢀ
pyrazole, represents a special feature of this C C/N N bond-
forming cascade. This culminates in the creation of the first
2,6-diisopropylphenyl-substituted pyrazole 2u (Table 1,
entry 21). In addition, since alkylhydrazines are generally
not readily available, the use of non-aromatic substituents on
the nitrogen is especially valuable (Table 1, entry 22).[14]
A certain level of variation is possible at the 4-position of
the pyrazole ring. For example, the ester group can be
changed from methyl to tert-butyl or benzyl esters (73% and
84% respectively; Table 1, entries 23 and 24), allowing the
mild ester cleavage and decarboxylation of the pyrazole
products. Interestingly, enaminoketones also provide the
corresponding pyrazoles, albeit 2y is formed in lower yield
(Table 1, entry 25). Concerning the 5-position of the pyra-
zoles, aliphatic (Table 1, entries 1–26) and aromatic (Table 1,
entries 27–30) substituents can be placed equally successfully.
Furthermore, the 5-unsubstituted system can be formed,
although only in lower yield (Table 1, entry 31). Finally, two
bispyrazoles, which might represent a new class of easily
obtainable, highly modular ligands, were efficiently prepared
in good yields (Table 1, entries 32 and 33).
Entry
R1
R2
Ratio of pyrazole products[b]
1[c]
2[d]
3[e]
Et
Et
Ph
Me
Ph
m-CF3C6H4
2d/2a=63:37
2d/2g=22:78
2g/2i=9:91
[a] Reaction conditions: Enamine 1a (1.0 mmol), Cu(OAc)2 (3.0 equiv),
R1CN, R2CN, 1108C, 24 h. [b] Determined by 1H NMR analysis of the
crude reaction mixture. [c] R1CN (28.5 equiv), R2CN (28.5 equiv);
[d] R1CN (21.0 equiv), R2CN (21.0 equiv); [e] R1CN (14.7 equiv), R2CN
(14.7 equiv).
amounts of benzonitrile and meta-trifluoromethylbenzoni-
trile, and using the enaminone substrate 1a as the limiting
component resulted in a 9:91 ratio of the corresponding
products (Table 2, entry 3). Interestingly, the more electron-
rich propionitrile proved to be more reactive than acetonitrile
(Table 2, entry 1).[13]
7792
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7790 –7794