An efficient copper-catalyzed formation of highly substituted pyrazoles using molecular oxygen as the oxidant

Article abstract of DOI:10.1039/c2gc35476d

An efficient Cu-catalyzed formation of tetra-substituted pyrazoles is reported. In this atom economic process, readily available enamines and nitriles are reacted by C-C and N-N bond formation. Oxygen has been successfully used as the oxidant, which has i

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An Efficient Copper-Catalyzed Formation of Highly Substituted
Pyrazoles Using Molecular Oxygen as the Oxidant
Mamta Suri, Thierry Jousseaume, Julia J. Neumann and Frank Glorius*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
An efficient Cu-catalyzed formation of tetra-substituted
pyrazoles is reported. In this atom economic process, readily
available enamines and nitriles are reacted by C-C and N-N
bond formation. Oxygen has been successfully used as the
10 oxidant, which has important economic and environmental
advantages. A broad scope of enamines and nitriles can be
utilized in this process.
Table 1 Optimization of the amount of the nitrile with other reaction
parametersa
Entry
1c
2
3
4
5
6
7
8
9d
10e
11f
12
13
Eq. PhCN
10
10
Solvent
2,4-DCT
2,4-DCT
1,2-DCB
DCE
Yield%b
74
82
78
80
97 (90)
88
95
64 (61)
54
53
Pyrazoles are an intriguing class of important heterocycles:
although rarely found in nature, many man-made biologically
15 active compounds possessing agricultural1 and pharmaceutical
activities2 contain pyrazole moieties. Surprisingly, the efficient
and selective synthesis of highly substituted pyrazoles still
10
10
10
10
DMF
1,4-Dioxane
DMSO
DMF
represents
a major challenge. The most commonly used
10
1.5
1.5
1.5
1.5
3.0
5.0
approaches to the synthesis of tetrasubstituted pyrazoles involve
20 either the classical condensation of hydrazines with 1,3-
dicarbonyl compounds (or their equivalents), the 1,3-dipolar
[3+2] cycloadditions or the transition metal catalyzed C-N and/or
C-C cross coupling on the preformed pyrazoles.3,4
DMF
DMF
DMF
DMF
DMF
46
(72)
(79)
a Reaction conditions: 1a (0.25 mmol), Cu(OAc)2 (1.5 eq.), PhCN, solvent
50 (0.26 mL), air (closed tube), 110 °C, 24 h; b determined by GC analysis
with mesitylene as an internal standard; isolated yield of 3aa (1 mmol
Recently, we have published a novel method for the synthesis
25 of tetrasubstituted pyrazoles involving the coupling of enamines5
with nitriles by oxidative C-C/N-N bond formation.6,7 This
approach leads to a highly efficient regioselective synthesis of a
variety of tetrasubstituted 1H-pyrazoles. It provides an alternative
to the use of carcinogenic hydrazines, with a broad substrate
30 scope and a convenient practical synthesis. However, it required
the use of a stoichiometric amount of Cu(OAc)2 as Lewis acid
and oxidant. In addition, an excess amount of nitrile without any
additional solvent was employed which lower the atom-economy
and also it limited the use of a wide range of nitriles.
scale reaction) is given in parentheses; c with Cu(OAc)2 (1.0 eq.); d time
e
48h; at 140 °C.
f DMF (0.13 mL); 2,4-DCT = 2,4-dichlorotoluene,
1,2-DCB = 1,2-dichlorobenzene, DCE = 1,2-dichloroethane, DMF = N,N-
55 dimethylformamide, DMSO = dimethyl sulfoxide.
We commenced our study by first optimizing the amount of
nitrile while keeping the stoichiometric amount of Cu(OAc)2.
Choosing (Z)-methyl 3-(phenylamino)but-2-enoate (1a) and
60 benzonitrile as the standard substrates, we started screening
different solvents (Table 1). It can be seen that both the polar
solvents as well as the non-polar solvents furnish the product
(3aa) in good yields. Lewis acids were also tested as additives for
the activation of the nitrile.9 However, they do not provide any
65 promising results.10 Among the different solvents screened, DMF
was found to be the best solvent. Interestingly, either increasing
the time or the temperature of the reaction, the yield of the
product (3aa) did not improve (Table 1, entries 9 and 10).
However, it has been observed that the yield of the product (3aa)
70 could be improved by increasing the equivalents of benzonitrile
with respect to the enamine (1a), (Table 1, entries 8, 12, 13 and
5).
35
With the growing concern over the production of
environmentally hazardous chemical wastes, the development of
more efficient, catalytic oxidative processes would be highly
desirable. The use of molecular oxygen as the terminal oxidant
coupled with the catalytic metal system provides a challenging
40 but attractive greener approach to it owing to its high abundance,
low cost and reduction of toxic by-product formation.8
Herein, we report a novel synthetic approach to tetrasubstituted
pyrazoles using equivalent amounts of nitriles with an efficient
metal catalyst system employing molecular oxygen as the sole
45 stoichiometric oxidant.
With the first goal - optimizing the amount of the nitrile with
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respect to the enamine achieved, the second goal to develop the
reaction catalytic with molecular oxygen as the stoichiometric
oxidant was set up. Under the atmosphere of molecular oxygen (1
bar), choosing again (Z)-methyl 3-(phenylamino)but-2-enoate
(1a) and benzonitrile as the standard substrates, different solvents
were screened. Among them DCE was found to be the best
solvent (Table 2, entries 1-8). Combining different terminal metal
oxidants as well as benzoquinone (Table 2, entries 9-15), the
yield of the product was found deteriorated. Also, using Cu(I)
5
10 sources instead of Cu(OAc)2 yielded no product.10 Carrying out
the reaction at higher pressure of molecular oxygen, the yield
dropped drastically (Table 2, entry 16). Among the different
additives screened10 it was found that 2-picolinic acid (5 mol%)
not only improved the yield but also allowed lowering of the
15 catalyst loading (Table 2, entry 19).
Fig. 1 Kinetic study of the effect of 2-picolinic acid on the the formation
35 of 3aa; data points with (•) and without ( ) the additive; (R = Standard
deviation).
▲
Me
Me
Cu(OAc)2
additive
N
Ph
N
Ph
CO2Me
+
N
H
tolylamino)but-2-enoate (1d) and 4-fluorobenzonitrile as the
coupling partners, inhibited the formation of desired product
(3db).11 It seems that under the reaction condition the nitrile and
40 the pyrazole compete with each other to chelate with copper
solvent, O2
110 °C, 24 h
N
Ph
CO2Me
Ph
1a
2a
3aa
Table 2 Screening the catalytic conditions with different reaction
parametersa
hence,
the
pyrazole
in
higher
amount
slows
down/quenches/poisons the reaction.
Entry
Additive (eq.)
Solvent
Yield%b
With the optimized conditions in hand (Table 1, entry 12 and
Table 2, entry 19), we explored the substrate scope of this
45 reaction (Table 3). Using (Z)-methyl 3-(phenylamino)but-2-
enoate (1a) as the coupling partner, different nitriles were
successfully coupled to give the respective products in good
yields (Table 3, entries 3aa-3an). Both aromatic and
heteroaromatic (Table 3, entries 3aa-3aj) as well as aliphatic
50 (Table 3, entries 3ak-3am) nitriles furnished good results.
Among the aromatic nitriles, different ortho-, meta- and para-
substituted groups, both electron-withdrawing and electron-
donating were well tolerated. Also, the styryl group at 3-position
can be introduced into the pyrazole which can be further modified
55 by a plenty of known coupling reactions (Table 3, entry 3an). In
addition to different nitriles - solid and liquid, the gaseous nitrile
trifluoroacetonitrile has been coupled for the first time with the
enamine (1a) in good yield (Table 3, 3am).
To investigate the scope of R1, R4 and R5 groups, differently
60 substituted enamines were reacted with 4-fluorobenzonitrile as
the coupling partner (Table 3, entries 3bb-3rb). Both electron-
donating (Table 3, entries 3bb-3db) and electron-withdrawing
groups (Table 3, entries 3ib-3kb) at o-, m- and p-positions on the
aryl group at R1 gave good yields. Also, different functional
65 groups were well tolerated (Table 3, entries 3eb-3hb). Sterically
demanding groups at R1 position (Table 3, entries 3lb-3mb) do
not affect the reactivity of the enamines with the nitrile and gives
the products in good to moderate yields, which were difficult to
obtain by the classical methods of pyrazole formation owing to
1
2
3
4
5
--
--
--
--
--
Toluene (1 M)
DMF (1 M)
7
< 5
31
14
21
Dioxane (1 M)
DMSO (1 M)
t-amyl alcohol
(1 M)
6
7
--
--
DCE (1 M)
DCE (0.5 M)
DCE (0.25 M)
DCE (0.5 M)
DCE (0.5 M)
DCE (0.5 M)
DCE (0.5 M)
DCE (0.5 M)
DCE (0.5 M)
DCE (0.5 M)
DCE (0.5 M)
DCE (0.5 M)
39
58
50
0
8
--
9
FeCl3 (0.25)
Fe(acac)3 (0.25)
Fe(NO3)3.H2O (0.25)
FeF3 (0.25)
CuBr (0.25)
10
11
12
13
14
15
16c
17d
19
0
39
59
0
FeBr2 (0.25)
Benzoquinone (0.25)
--
26
8
N-methoxy pivalamide
(0.05)
N-acetamido benzoic acid
(0.05)
2-picolinic acid (0.05)
69 (65)
18d
DCE (0.5 M)
69 (64)
19d
DCE (0.5 M)
84 (68)
a Reaction conditions: 1a (0.25 mmol), Cu(OAc)2 (25 mol%), PhCN (3.0
20 eq.), additive, solvent, 110 °C, 24 h, under an atmosphere of O2 (1 bar,
closed tube); b determined by GC analysis with mesitylene as an internal
standard; isolated yield of analytically pure product is given in
parentheses; c under O2 (2 bar), closed tube; d Cu(OAc)2 (10 mol%).
25
The exact role of 2-picolinic acid as an additive in the catalytic
reaction condition is not clearly understood. However, it has been 70 the expensive and difficult formation of their respective
hydrazines. In addition, N-alkyl pyrazoles have also been
obtained in good yields (Table 3, entries 3nb-3pb), which were
also difficult to obtain by classical methods due to the limited
availability of their respective hydrazines.12 R4 can also be varied
75 from OMe, OEt to Ph, giving pyrazole ester to pyrazole ketone
(Table 3, entry 3rb). Hence, the scope of the reaction yielding
differently substituted products was found to be quite broad.
The following mechanism can be proposed for the catalytic
found that the rate of the reaction is higher than the reaction
without the additive (Figure 1).10 It can be assumed that it acts as
a catalytic H+ source and helps in the redox cycle in regenerating
30 Cu(II) from Cu(I); it may also act as a better coordinating anion
than acetate and helps in stabilizing various intermediates.
Interestingly, it was observed that addition of an equivalent
amount of the pyrazole (3aa) to the reaction of (Z)-methyl 3-(p-
2
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Table 3 Substrate scope under the optimized reaction conditions.
R = H, 3aa, 72%a, 68%b
R = 2-methyl, 3bb, 70%a, 67%b
3-methyl, 3cb, 65%a, 62%b
Me
CO2Me
Me
CO2Me
4-fluoro, 3ab, 75%a, 70%b
4-acetyl, 3ac, 84%a, 80%b
3-trifluoromethyl, 3ad, 83%a, 78%b
2-fluoro, 3ae, 48%a, 20%b
3-methyl, 3af, 67%a, 40%b
4-dimethylamino, 3ag, 50%a, 20%b
4-ethoxy, 3ah, 63%a, 35%b
4-methyl, 3db, 74%a, 69%b
N
N
Ph
N
N
4-ethoxy, 3eb, 80%a, 74%b
4-dimethylamino, 3fb, 28%a, 15%b
4-fluoro, 3gb, 65%a, 59%b
4-ethoxycarbonyl, 3hb, 68%a, 62%b
2-trifluoromethyl, 3ib, 60%a, 49%b
3-trifluoromethyl, 3jb, 68%a, 60%b
4-trifluoromethyl, 3kb, 63%a, 57%b
F
R
R
Me
CO2Me
N
Me
CO2Me
O
Me
CO2Et
Ar = mesityl, 3lb, 79%a, 72%b
N
Ph
N
N
Ph
N
2,6-diisopropylphenyl, 3mb, 44%a, 25%b
N
Ar
N
F
3ai, 77%a, 66%b
3aj, 65%a
Me
CO2Me
Me
CO2Me
Alkyl
Alkyl = Me, 3ak, 55%a, 30%b
Et, 3al, 52%a, 32%b
Alkyl = Me, 3nb, 74%d, 42%b
n-butyl, 3ob, 70%d, 35%b
iso-propyl, 3pb, 35%d
N
Alkyl
N
trifluoromethyl, 3am, 65%c
N
Ph
N
N
F
O
Ph
CO2Et
Me
CO2Me
Me
Ph
N
Ph
Ph
N
N
N
Ph
Ph
N
F
F
3an, 19%a
3qb, 73%a, 67%b
3rb, 30%a, 18%b
Isolated yield of analytically pure product is given. Reaction conditions a A: 1 (1.0 mmol), 2 (3.0 eq.), Cu(OAc)2 (1.5 eq.), DMF (1 M), 110 °C, 24 h, air
(closed tube); b B: 1 (0.25 mmol), 2 (3.0 eq.), Cu(OAc)2 (10 mol%), 2-picolinic acid (5 mol%), DCE (0.5 M), 110 °C, 24 h, under an atmosphere of O2 (1
bar, closed tube). c Reaction condition A, after adding the substrate 1a, the reagents and the solvent to a Schlenk tube (10 mL, 0.5 mmol scale), the tube
was evacuated (in an ice bath) and filled with trifluoroacetonitrile gas. d Reaction condition A, nitrile (7.0 eq.), N,N-dimethylacetamide (1 M).
5
R5
R5
R1
R1
N
H
R5
N
H2O
O
R4
R1
HOPic
HX
O
CuII
O
R4
N
CuX2
CuII
O
-HX
O
R4
N
2 HX + 1/2 O2
Cu0 / 2 Cu+
X
II
I
CuII
N
R5
O
R5
R1
N
R4
CuII
N
R1
R5
O
R3
N
N
R5
R3
R1
- H+
- [CuOPic]+
CuII
O
R4
N
R4
R1
O
N
R3
CuII
O
N
N
R3
O
R4
V
IV
III
Fig. 2 Proposed mechanism of the catalytic reaction (X = OAc or OPic, where HOPic = 2-picolinic acid)
10 reaction (Figure 2). CuX2 coordinates with the (Z)-enamine via
removal of HX to give CuII-chelate I, which undergoes anion
The nitrile coordinates with the Cu-complexes present in the
reaction mixture. The coordinated enamine attacks the activated
exchange with HOPic (if X = OAc) to generate CuII-chelate II. 15 nitrile in either intramolecular or intermolecular fashion to give
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J. Conn, J. Med. Chem., 2006, 49, 3332; (e) A. A. Bekhit and T.
Abdel-Aziem, Bioorg. Med. Chem., 2004, 12, 1935; (f) A. Tanitame,
Y. Oyamada, K. Ofuji, M. Fujimoto, K. Suzuki, T. Ueda, H.
Terauchi, M. Kawasaki, K. Nagai, M. Wachi and J.-I. Yamagishi,
Bioorg.Med. Chem., 2004, 12, 5515; (g) J. Elguero, P. Goya, N.
Jagerovic and A. M. S. Silva, In Targets in Heterocyclic Chemistry-
Chemistry and Properties, (Eds.: O. A. Attanasi and D. Spinelli),
Italian Society of Chemistry, Rome, 2002, 6, 52 and the references
cited therein.
complex IV. Complex IV undergoes a σ-bond rotation followed
by the loss of one equivalent HOPic to generate CuII-(1,3-imine-
enamine) chelate V. With reductive elimination, complex V gives
the desired product and Cu0 or two equivalents of CuI, which are
oxidized by HX and molecular oxygen to CuX2 that enters again
into the catalytic cycle.
5
Conclusions
3
4
For up to date review see: S. Fustero, M. S.-Rosello, P. Barrio and A.
S.-Fuentes, Chem. Rev., 2011, 111, 6984.
In conclusion, we have reported an efficient, atom economic and
greener method for the regioselective synthesis of tetrasubstituted
For some recent interesting synthesis of substituted pyrazoles see: (a)
Jiantao Hu, Yongfeng Cheng, Yiqing Yang and Yu Rao, Chem.
Commun., 2011, 47, 10133; (b) G. Shan, P. Liu and Y. Rao, Org.
Lett., 2011, 13, 1746; (c) R. Goikhman, T. L. Jacques and D. Sames,
J. Am.Chem. Soc., 2009, 131, 3042; (d) B. S. Gerstenberger, M. R.
Rauckhorst and J. T. Starr, Org. Lett., 2009, 11, 2097; (e) S.
Majumder, K. R. Gipson, R. J. Stapls and A. L. Odom Adv. Synth.
Catal., 2009, 351, 2013; (f) Y. S. Chun, K. K. Lee, Y. O. Ko, H. Shin
and S. Lee, Chem. Commun., 2008, 5098.
10 pyrazoles as opposed to our previously reported method. This
represents the first preparation of tetrasubstituted pyrazoles
catalytic in copper and with molecular oxygen as the sole
oxidant. This provides a new set of products, which could not be
synthesized by the earlier methods. This highly practical and
15 modular synthesis represents an alternative to the known methods
of pyrazole synthesis with a broad substrate scope, high atom
efficiency, without the need of carcinogenic hydrazines and less
formation of toxic by-products.
5
For interesting transition metal catalyzed coupling of enamines see:
(a) S. Rakshit, F. W. Patureau and F. Glorius, J. Am. Chem. Soc.
2010, 132, 9585; (b) R. Bernini, G. Fabrizi, A. Sferrazza and Sandro
Cacchi, Angew. Chem. Int. Ed., 2009, 48, 8078; (c) Z. Shi, C. Zhang,
S. Li, D. Pan, S. Ding, Y. Cui and Ning Jiao, Angew. Chem. Int. Ed.,
2009, 48, 4572; (d) S. Würtz, S. Rakshit, J. J. Neumann, T. Dröge
and F. Glorius, Angew. Chem. Int. Ed., 2008, 47, 7230; (e) H. Ge, M.
J. Niphakis and G. I. Georg, J. Am. Chem. Soc., 2008, 130,
3708.
Acknowledgements
20 This work was supported by the European Research Council
under the European Community's Seventh Framework Program
(FP7 2007-2013)/ERC Grant agreement no 25936. Generous
financial support by the International NRW Graduate School of
Chemistry (M.S.) is gratefully acknowledged. The research of
25 F.G. has been supported by the Alfried Krupp Prize for Young
University Teachers of the Alfried Krupp von Bohlen und
Halbach Foundation. We also thank Dr. S. Rakshit and T. Dröge
for the preparation of some enamines.
6
For a few copper-promoted N-N bond formation see: (a) C. Zhang
and N. Jiao, Angew. Chem. Int. Ed., 2010, 49, 6174; (b) S. Ueda and
H. Nagasawa, J. Am. Chem. Soc., 2009, 131,15080; (c) H. Mori, K.
Sakamoto, S. Mashito, Y. Matsuoka,M. Matsubayashi and K. Sakai,
Chem. Pharm. Bull., 1993, 41, 1944; (d) B. E. Love and L. Tsai,
Synth. Commun., 1992, 22, 165; (e) T. Kauffmann, J. Albrecht, D.
Berger and J. Legler, Angew. Chem. Int. Ed., 1967, 6, 633; (f) T.
Kauffmann and W. Sahm, Angew. Chem. Int. Ed., 1967, 6, 85.
(a) J. J. Neumann, M. Suri and F. Glorius, Angew. Chem. Int. Ed.,
2010, 49, 7790; (b) Patent application filed: PCT/EP2011/054484.
For reviews see: (a) A. E. Wendlandt, A. M. Suess and S. S. Stahl,
Angew. Chem. Int. Ed., 2011, 50, 11062; (b) K. M. Gligorich and M.
S. Sigman, Chem. Commun., 2009, 3854; (c) T. Punniyamurthy, S.
Velusamy and J. Iqwal, Chem. Rev., 2005, 105, 2329.
7
8
Notes and references
30 *M. Suri, Prof. Dr. F. Glorius,Westfälische Wilhelms-Universität
Münster, NRW Graduate School of Chemistry, Organisch-Chemisches
Institut Corrensstrasse 40, 48149 Münster, Germany. Fax: (+49) 251-
833-3202; E-mail: glorius@uni-muenster.de; Homepage:
9
For activation of nitrile by transition metals see: (a) J. Lindh, P. J. R.
Sjöberg and M. Larhed, Angew. Chem. Int. Ed., 2010, 49, 7733; (b)
see ref. 6(b); (c) R. S. Ramón, N. Marion and S. P. Nolan, Chem.
Eur. J., 2009, 15, 8695; (d) C. Zhou and R. C. Larock, J. Am. Chem.
Soc., 2004, 126, 2302; (e) V. Y. Kukushkin and A. J. L. Pombeiro,
Chem. Rev., 2002, 102, 1771.
http://www.uni-muenster.de/Chemie.oc/glorius/index.html
35 † Electronic Supplementary Information (ESI) available: [screening data,
experimental procedures and full spectroscopic data for all new
compounds]. See DOI: 10.1039/b000000x/
1
(a) G. P. Lahm, D. Cordova and J. D. Barry, Bioorg. Med. Chem.,
2009, 17, 4127; (b) S. Fustero, R. Roman, J. F. Sanz-Cervera, A.
Simon-Fuentes, J. Bueno and S. J. Villanova, J. Org. Chem., 2008,
73, 8545; (c) C. Lamberth, Heterocycles, 2007, 71, 1467; (d) C. B.
Vicentini, C. Romagnoli, E. Andreotti and D. J. Mares, Agric. Food
Chem., 2007, 55, 10331; (e) Y. Li, H.-Q. Zhang, J. Liu, X.-P. Yang
and Z.-J. Liu, J. Agric. Food Chem., 2006, 54, 3636; (f) G.
Theodoridis, In Modern Crop Protection Compounds; (Eds.: W.
Krämer and U. Schirmer), Wiley-VCH: Weinheim, Germany, 2007,
1, 153-186; (g) Y. Shiga, I. Okada, Y. Ikeda, E. Takizawa and T.
Fukuchi, J. Pesticide Sci., 2003, 28, 313.
10 See the Supporting Information for further details.
11 To the reaction mixture 1d (0.25 mmol), 4-fluorobenzonitrile (3.0
eq.), Cu(OAc)2 (10 mol%), 2-picolinic acid (5 mol%), DCE (0.5 M)
was added the pyrazole product 3aa (1 eq.) and the reaction was
stirred at110 °C for 24 h under O2 (1 bar). After the completion of the
reaction, the sample was analyzed by GCMS and no desired product
3q was observed.
12 (a) A. Armstrong, L. H. Jones, J. D. Knight and R. D. Kelsey, Org.
Lett. 2005, 7, 713; (b) U. Ragnarsson, Chem. Soc. Rev. 2001, 30, 205.
2
(a) C. E. Mowbray, C. Burt, R. Corbau, S. Gayton, M. Hawes, M.
Perros, I. Tran, D. A. Price, F. J. Quinton, M. D. Selby, P. A. Stupple,
R. Webster and A. Wood, Bioorg. Med. Chem. Lett., 2009, 19, 5857;
(b) P. G. Wyatt, A. J. Woodhead, V. Berdini, J. A. Boulstridge, M. G.
Carr, D. M. Cross, D. J. Davis, L. A. Devine, T. R. Early, R. E.
Feltell, E. J. Lewis, R. L. MsMenamin, E. F. Navarro, M. A. O’Brien,
M. O’Reilly, M. Reule, G. Saxty, L. A. Seavers, D.-M. Smith, M.
Squires, G. Trewartha, M. T. Walker and A. J.-A. Woolford, J. Med.
Chem., 2008, 51, 4986; (c) A.-R. Farghaly and H. El-Kashef,
Arkivoc, 2006, xi, 76; (d) T. de Paulis, K. Hemstapat, Y. Chen, Y.
Zhang, S. Saleh, D. Alagille, R. M. Baldwin, G. D. Tamagnan and P.
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Green Chemistry
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This Cu-catalyzed C-C/C-N-bond formation cascade allows the efficient synthesis of pyrazoles from
solid, liquid or gaseous nitriles and enamines.