Nickel-catalyzed oxidative cyclotrimerization of α-amino ketones: Selective synthesis of pyrazoles

Article abstract of DOI:10.1055/s-0033-1340014

A new strategy for the synthesis of 3-methylene-2,3-dihydro-1H-pyrazoles is presented by Ni-catalyzed oxidative cyclotrimerization of α-amino ketones. This unprecedented method allows three α-amino ketones to undergo sequential multiple deprotonations and deamination through two C-C bonds and one N-N bond formation cascade. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340014

64▌
LETTER
lNettierckel-Catalyzed Oxidative Cyclotrimerization of α-Amino Ketones: Selective
Synthesis of Pyrazoles
Selective Synthesis of Pyrazoles
Ri-Yuan Tang,a,b Xiao-Kang Guo,b Ming Hu,a Zhi-Qiang Wang,a Jian-Nan Xiang,*a Jin-Heng Li*a
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. of China
Fax +86(731)88713642; E-mail: jhli@hnu.edu.cn; E-mail: jnxiang@hnu.edu.cn
b
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Received: 18.07.2013; Accepted after revision: 22.09.2013
ring (often onto the nitrogen atom).7 However, these
Abstract: A new strategy for the synthesis of 3-methylene-2,3-di-
methods suffer from the poor reactivity, somewhat limited
hydro-1H-pyrazoles is presented by Ni-catalyzed oxidative cy-
substrate scope, and the potential hazardousness and det-
onation of the substrates; moreover, regio- and chemose-
clotrimerization of α-amino ketones. This unprecedented method
allows three α-amino ketones to undergo sequential multiple depro-
tonations and deamination through two C–C bonds and one N–N lectivity are usually unsatisfactory in many cases.
bond formation cascade.
Therefore, the development of new strategies for the syn-
thesis of functionalized pyrazoles is highly desirable.
Herein we report a novel route to prepare pyrazoles by Ni-
catalyzed oxidative cyclotrimerization of α-amino arylke-
tones wherein sequential multiple C–H bonds cleavage,
deamination and carbonyl isomerization take place to si-
multaneously form three C–C bonds and one N–N bond
(Scheme 1).8,9
Key words: nickel, oxidation, cyclotrimerization, α-amino
ketones, pyrazoles
The functionalization of α-amino carbonyl compounds is
one of the most important tasks for biochemists or syn-
thetic chemists because the α-amino carbonyl motif is a
ubiquitous structural component of multitudinous natural
products and biomolecules.1,2 Despite the impressive
progress in the field, the functionalization of α-amino car-
bonyl compounds remains challenging due to the pres-
ence of some highly reactive functional groups in them,
such as an active α-C–H bond, a free N–H bond and a car-
bonyl group, often resulting in some competing reactions.
To our knowledge, however, a method using the three
functional groups for constructing new chemical bonds in
one reaction has not been established.
Our investigation began with the reaction of 1-phenyl-
2-(phenylamino)ethanone (1a) to optimize the reaction
conditions (Table 1). Gratifyingly, substrate 1a could un-
dergo cyclotrimerization with NiCl2 in CH2ClCH2Cl at
80 °C, providing the desired product 2a in 28% yield (en-
try 1). Encouraged by the results a number of other Ni cat-
alysts were examined (entries 2–6). Extensive screening
revealed that (C5H5)Ni(II)Cl(PPh3) displayed the highest
catalytic reactivity (entry 5). It is noteworthy that
Ni(PPh3)4, a zerovalent Ni catalyst, also effected the reac-
tion (entry 6). Interestingly, benzoic acid was found to fa-
vor the reaction: The yield of 2a was enhanced to 75%
when one equivalent PhCO2H was added (entry 7). In
light of the results, a series of other organic acids were
subsequently evaluated (entries 8–11). While 4-cyano-
benzoic acid could improve the reaction, the other acids,
4-methoxybenzoic acid, AcOH and PivOH, lowered the
yield slightly. Gratifyingly, good yield was still achieved
under O2 atmosphere (entry 12). However, substrate 1a
was found to be inert under argon atmosphere (entries 13
and 14) as well as in the absence of Ni catalysts (entry 15).
Pyrazoles are important structural units found in numer-
ous pharmaceuticals, agricultural chemicals and function-
al materials as well as valuable synthetic intermediates in
organic synthesis.3 Many elegant methods have been de-
veloped for their synthesis,4–8 including, (i) the cyclocon-
densation of hydrazines with 1,3-dielectrophiles (1,3-
dicarbonyl compounds or α,β-unsaturated aldehydes and
ketones),5 (ii) the intermolecular 1,3-dipolar cycloaddi-
tion of diazoalkanes and nitrilimines with unsaturated
compounds (such as alkenes or alkynes),6 and (iii) the in-
troduction of substituents onto a pre-existing aromatic
R1
R1
R1HN
O
R1HN
O
R1HN
O
N
N
(C5H5)Ni(II)Cl(PPh3)
air, PhCO2H
H
H
H
R2
O
+
H
+
H
H
R2
DCE, 80 °C, 12 h
R2
R2
R2
R2
O
1
1
1
2
Scheme 1 Synthesis of pyrazoles
SYNLETT 2014, 25, 0064–0068
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340014; Art ID: ST-2013-W0674-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective Synthesis of Pyrazoles
65
Table 1 Screening Optimal Conditionsa
such as Ph, 4-MeOC6H4, 4-ClC6H4 or 2,3-dihydro-1H-in-
den-5-yl group, on the amino moiety successfully under-
went the cyclotrimerization in the presence of
(C5H5)Ni(II)Cl(PPh3), PhCO2H and air (products 2h–k).
Ph
O
Ph
Ph
[Ni], additive
PhHN
Ph
O
O
N
N
1a
R2
O
Ph
Ph
R2
R2
2a
(C5H5)Ni(II)Cl(PPh3)
R1HN
R2
O
air, PhCO2H
DCE, 80 °C, 12 h
Entry [Ni]
Additive
Isolated
yield (%)
O
N
N
1
R1
R1
2
1
NiCl2
NiBr2
NiCl2(dppe)2
–
28
40
29
28
59
40
75
51
64
51
43
74
trace
0
Ph
O
Ph
2
3
4
5
6
7
8
9
–
O
–
Ph
O
N
N
NiCl2(PCy3)2
–
R1
R1
O
2b R1 = 4-MeC6H4, 64%
2c R1 = 3-MeC6H4, 52%
2d R1 = 2-MeC6H4, 33%
2e R1 = 4-MeOC6H4, 50%
2f R1 = 4-ClC6H4, 68%
2g R1 = 4-FC6H4, 56%
N
N
R1
R1
(C5H5)Ni(II)Cl(PPh3)
Ni(PPh3)4
–
2h R1 = C6H5, 59%
2i R1 = 4-MeOC6H4, 50%
2j R1 = 4-ClC6H4, 59%
–
(C5H5)Ni(II)Cl(PPh3)
(C5H5)Ni(II)Cl(PPh3)
(C5H5)Ni(II)Cl(PPh3)
(C5H5)Ni(II)Cl(PPh3)
(C5H5)Ni(II)Cl(PPh3)
(C5H5)Ni(II)Cl(PPh3)
(C5H5)Ni(II)Cl(PPh3)
Ni(PPh3)4
PhCO2H
p-MeOC6H4CO2H
p-CNC6H4CO2H
AcOH
R2
O
R2
O
R2
O
10
N
N
O
Ph
Ph
11
PivOH
N N
2l R2 = 4-MeOC6H4, 71%
2m R2 = 4-ClC6H4, 40%
2n R2 = 4-NCC6H4, 8%a
2o R2 = 4-F3COC6H4, 24%b
2p R2 = naphthalen-1-yl, 65%
12b
13c
14c
15
PhCO2H
PhCO2H
PhCO2H
2k, 49%
R2
O
–
PhCO2H
0
R2
O
S
a Reaction conditions: 1a (0.3 mmol), [Ni] (5 mol%), additive (1
equiv) and 1,2-dichloroethane (2 mL) at 80 °C for 12 h under air at-
mosphere. (C5H5)Ni(II)Cl(PPh3) = [chloro(cyclopentadienyl)(triphe-
nylphosphine)nickel(II)]. Aniline (3a) was observed by GC–MS
analysis.
S
R2
O
N
N
S
O
N
N
Ph
2q, 62%c
Ph
b The reaction was carried out under O2 atmosphere.
c The reaction was carried out under argon atmosphere.
2r R2 = 3,4-Cl2C6H3, 30%
2s R2 = 4-FC6H4, 41%
Scheme 2 (C5H5)Ni(II)Cl(PPh3)-Catalyzed cyclotrimerization of α-
amino ketones (1) in the presence of PhCOOH. Reagents and condi-
tions: 1 (0.3 mmol), (C5H5)Ni(II)Cl(PPh3) (5 mol%), PhCOOH (1
The structure of 2a was unambiguously confirmed by the
single-crystal X-ray diffraction analysis.
equiv) and DCE (2 mL) at 80 °C for 12 h under air atmosphere. a
A
As shown in Scheme 2, the above cyclotrimerization pro-
tocol was found to be applicable to a diverse range of
dimerization/deamination product, (E)-2-(phenylamino)-1,4-bis(4-
cyanophenyl)but-2-ene-1,4-dione (4n), was obtained in 55% yield. b
A dimerization/deamination product, (E)-2-(phenylamino)-1,4-bis[4-
(trifluoromethyl)phenyl]but-2-ene-1,4-dione (4o), was obtained in
49% yield. c A dimerization/deamination product, (E)-2-(phenylami-
no)-1,4-di(thiophen-2-yl)but-2-ene-1,4-dione (4q), was obtained in
24% yield.
α-amino arylketones
1
in the presence of
(C5H5)Ni(II)Cl(PPh3), PhCO2H and air.10 Initially, a vari-
ety of 2-(substituted arylamino)-1-phenylethanone were
investigated under the optimal conditions (products 2b–
g): several substituents, such as Me, MeO, Cl and F, on the
aryl ring of the arylamino moiety were tolerated well.
Methyl-substituted substrates 1b–d, for instance, were
successfully cyclotrimerized in moderate yields, and the
reactive order was found to be para >meta >ortho (prod-
ucts 2b–d). Importantly, functional groups F and Cl were
compatible with the optimal conditions, thereby facilitat-
ing additional modifications at the halogenated positions
(products 2f, 2g, 2j, 2m, 2r and 2s). It is noteworthy that
2-amino-1-p-tolylethanones 1h–k with an aryl group,
We next set out to examine the effect of substituents on
the aryl group of the 1-arylethanone moiety under the op-
timal conditions (products 2l–s). The results disclosed that
a number of substituents, including MeO, Cl, CN, and
CF3, displayed reactivity for the reaction, but the electron-
donating groups were superior to the electron-withdraw-
ing groups (products 2l–o). Using substrates with the elec-
tron-withdrawing groups, however, the selectivity was
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 64–68

66
R.-Y. Tang et al.
LETTER
shifted toward dimerization as the major reaction. For ex- tetrahydro-1H-furo[3,4-c]pyrazole (5a) was prepared in
ample, treatment of substrate 1n with a CN group with 59% yield, which is a structural unit found in some bioac-
(C5H5)Ni(II)Cl(PPh3), PhCO2H and air provided the cor- tive molecules.11
responding dimerization product 4n in 55% yield. We are
pleased to disclose that naphthalen-1-ylketone (1p) un-
derwent the cyclotrimerization smoothly to offer the de-
During the reaction of substrate 1a, imine 6a as a side-
product was observed by in situ GC–MS analysis.12 In-
deed, imine 6a could be cyclotrimerized leading to prod-
sired product 2p in 65% yield. Notably, heterocycle-
uct 2a in the presence of Ni catalyst, such as
containing substrate, 2-(phenylamino)-1-(thiophen-2-
(C5H5)Ni(II)Cl(PPh3), Ni(cod)2 or Ni(Ph3)4, albeit with
yl)ethanone (1q), was also suitable for the reaction, there-
lower activity of the latter two Ni catalysts (equation 2 in
by making this methodology more useful for the prepara-
Scheme 3), suggesting that this present cyclotrimerization
tion of pharmaceuticals and natural products. The reaction
reaction may proceed via the first generation of an imine
of diCl-substituted substrate 1r also proceeded smoothly,
intermediate 6a.
albeit in 30% yield (product 2r). In the presence of
Notably, the results in Table 1 also disclosed that without
either air or Ni catalysts the cyclotrimerization reaction of
(C5H6)Ni(II)Cl(PPh), PhCOOH and air, substrate 1s with
a Me group and a F group in different aryl rings furnished
substrate 1a could not take place even in the presence of
the desired product 2s in moderate yield. However, ethyl
PhCO2H (entries 13 and 14 in Table 1). These suggest that
Ni complex is the real catalyst, and PhCO2H is only used
to promote the reaction.
2-(phenylamino)acetate (1t), 2-aminophenylethanone
(1u) and 1-(phenylamino)propan-2-one (1v) resulted in
no detectable cyclotrimerization products.
Consequently, two possible mechanisms outlined in
Scheme 4 are proposed on the basis of the results de-
The obtained pyrazole 2a was employed to synthesize di-
heterocycle 5a (equation 1 in Scheme 3). In the presence
scribed above and by the in situ HRMS analysis data
of KBH4, (Z)-3-benzylidene-1,2,4,6-tetraphenyl-2,3,4,6-
(Schemes S1 and S2, and Figures S1 and S2 in Supporting
Information).12 Initially, substrate 1a may proceed via two
pathways, one is directly transferred into intermediate A
Ph
Ph
O
with the aid of the NiII/[O] system, and the other includes
the formation of imine 6a in the presence of NiII and air,
followed by reaction of imine 6a with NiII and [O] to af-
ford the intermediate A.11 Dimerization of the intermedi-
ate A with a molecule of imine 6a offers intermediate B,
followed by a hydride shift which furnishes the intermedi-
ate C. Intermediate D is achieved by insertion of Ni into
the C–N bond in intermediate C. The third molecule of
imine 6a is used to react with intermediate D with the aid
of acid,13 providing intermediate E. Isomerization of in-
termediate E affords intermediate F. Finally, reductive
elimination and dehydroxylation reaction of intermediate
F produces the desired product 2a.9 To rule out a radical
process for the current reaction, a control experiment us-
ing a radical scavenger (TEMPO) was carried out: a stoi-
O
O
KBH4 (10 equiv)
(1)
Ph
Ph
Ph EtOH, 100 °C, 3h Ph
N
N
N N
Ph
Ph
Ph
Ph
2a
5a (59%)
Ph
O
Ph
NiII (5 mol%)
air, PhCO2H (1 equiv)
Ph
(2)
Ph
O
PhN
N
N
DCE, 80 °C, 12 h
O
Ph
Ph
6a
2a
(C5H5)NiCl(PPh3): 70%
Ni(cod)2: 35%
Ni(PPh3)4: 38%
Scheme 3
Ni(II)/[O]
Ph
PhN
NiII
PhHN
PhN
O
NiII
PhN
O
O
6a
PhN
NiII
[O]
Ph
Ph
O
O
Ph
6a
Ph
1a
Ph
PhN
A
O
O
B
2a + H2O + NiII
H+ + [O]
OH
Ph
PhN
H
Ph
+ acid
Ph
O
NiII
O
O
Ph
Ph
N
Ph
NiII
PhN
N
Ph
O
6a
PhHN
Ph
Ph
Ph
Ph
NiII
NiII
N
O
PhN
PhN
PhHN
O
Ph
H+
PhNH2
O
O
Ph
Ph
O
D
C
F
E
Scheme 4 Possible mechanism
Synlett 2014, 25, 64–68
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective Synthesis of Pyrazoles
67
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chiometric amount of TEMPO (1 equiv) had no effect on
the reaction.
In summary, we have described a new route to polysubsti-
tuted 3-methylene-2,3-dihydro-1H-pyrazoles via Ni-cata-
lyzed oxidative cyclotrimerization of α-amino carbonyl
compounds, which utilizes three highly reactive function-
al groups, the active α-C–H bond, the free N–H bond and
the carbonyl group, in α-amino carbonyl compounds to
construct three new chemical bonds: two C–C bonds and
one N–N bond. Importantly, this method employs acces-
sible α-amino carbonyl compounds as the starting materi-
als, which facilitates introduction of the α-amino carbonyl
units into pyrazoles and makes the obtained pyrazole
compounds more useful with some special complex bio-
activities. Applications of this new Ni-catalyzed transfor-
mation in organic synthesis are currently underway in our
laboratory.
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Acknowledgment
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We thank the Specialized Research Fund for the Doctoral Program
of Higher Education (No. 20120161110041), Hunan Provincial Na-
tural Science Foundation of China (No. 13JJ2018), and the Natural
Science Foundation of China (No. 21172060) for financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578.
(c) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
© Georg Thieme Verlag Stuttgart · New York
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LETTER
Eur. J. Org. Chem. 2004, 695. (d) Mukherjee, A.; Sarkar, A.
Tetrahedron Lett. 2004, 45, 9525. (e) Zhu, L.; Guo, P.; Li,
G.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 8535.
(f) Xi, Z.; Liu, F.; Zhou, Y.; Chen, W. Tetrahedron 2008, 64,
4254. (g) McLaughlin, M.; Marcantonio, K.; Chen, C. Y.;
Davies, I. W. J. Org. Chem. 2008, 73, 4309.
(h) Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett.
2009, 11, 3326. (i) Goikhman, R.; Jacques, T. L.; Sames, D.
J. Am. Chem. Soc. 2009, 131, 3042. (j) Deng, X.; Roessler,
A.; Brdar, I.; Faessler, R.; Wu, J.; Sales, Z. S.; Mani, N. S.
J. Org. Chem. 2011, 76, 8262.
Schlenk tube were added α-amino arylketones 1 (0.3 mmol),
(C5H5)Ni(II)Cl(PPh3) (5 mol%), PhCOOH (1 equiv) and
DCE (CH2ClCH2Cl, 2 mL). Then the tube was sealed under
air and stirred at 80 °C (the temperature of the heating bath)
for the indicated time until complete consumption of the
starting material as monitored by TLC and GC–MS analysis.
After the reaction was finished, the reaction mixture was
diluted with Et2O, filtered by a short crude silica gel column
and concentrated in vacuum, and the resulting residue was
purified by silica gel column chromatography (hexane–
EtOAc) to afford the desired product 2.
(8) To our knowledge, only one paper has been reported on the
synthesis of tetrasubstituted pyrazoles from the Cu-mediated
reaction of enaminones with nitriles using the oxidative
strategy, in which 1.5–6 equiv of Cu(OAc)2 were used as
both a Lewis acid activator and as an oxidizing agent, and
two new bonds, a C–C bond and a C–N bond, were formed;
see: Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem. Int.
Ed. 2010, 49, 7790.
(9) Although few papers on the N–N single bond oxidative
formations have been reported, Ni-catalyzed oxidative
formation of the N–N single bond remains an unexploited
area. LDA/O2: (a) Barbieri, A.; Montevecchi, P. C.; Nanni,
D.; Navacchia, M. L. Tetrahedron 1996, 52, 13255. Cu/air:
(b) Kauffmann, T.; Sahm, W. Angew. Chem. Int. Ed. 1967,
6, 85. (c) Kauffmann, T.; Albrecht, J.; Berger, D.; Legler, J.
Angew. Chem. Int. Ed. 1967, 6, 633. (d) Ueda, S.; Nagasawa,
H. J. Am. Chem. Soc. 2009, 131, 15080. PbO2 or KMnO4:
(e) Wieland, H.; Gambarjan, S. Ber. 1906, 39, 1499.
(f) Windaus, A. Ann. Chem. 1957, 604, 251.
(Z)-(5-Benzylidene-1,2-diphenyl-2,5-dihydro-1H-
pyrazole-3,4-diyl)bis(phenylmethanone) (2a): Yellow
solid: 38.9 mg, 75% yield; mp 190.2–191.5 °C
(uncorrected). 1H NMR (500 MHz, CDCl3): δ = 8.11 (d, J =
7.4 Hz, 1 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.21–7.32 (m, 13 H),
7.09 (td, J = 7.3, 4.0 Hz, 7 H), 6.92–6.95 (m, 2 H), 6.59–6.62
(d, J = 8.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): δ = 191.9,
186.3, 144.0, 139.1, 138.7, 136.8, 132.6, 132.5, 131.4,
131.2, 130.9, 129.2, 128.7, 128.1, 127.9, 127.7, 127.5,
127.4, 127.0, 126.9, 126.8, 126.6, 125.3, 122.8, 120.0,
114.2. IR (neat): 1715, 1593, 1448, 1363, 1223, 958, 804,
736, 690 cm–1. LRMS (EI, 70 eV): m/z (%) = 518 [M+] (100),
295 (94). HRMS (ESI): m/z [M + H]+ calcd for C36H26N2O2:
519.2067; found: 519.2089.
(11) (a) Fanshawe, W. J.; Bauer, V. J.; Safir, S. R. J. Med. Chem.
1972, 15, 980. (b) Ernst, G. E.; Frietze, W. E.; Simpson, T.
R. PCT Int. Appl WO2006068591, 2006; Chem. Abstr.,
2006, 145, 103669
(12) See the data in detail in Supporting Information (Figures S1
and S2 and Schemes S1 and S2).
(13) For paper on the effect of a hydrogen donor (such as benzoic
acid), see: (a) Ren, H.; Wulff, W. D. J. Am. Chem. Soc. 2011,
133, 5656. (b) Ren, H.; Wulff, W. D. Org. Lett. 2013, 15,
242. (c) Azap, C.; Rueping, M. Angew. Chem. Int. Ed. 2006,
45, 7832. (d) Zheng, L.-S.; Li, L.; Yang, K.-F.; Zheng, Z.-J.;
Xiao, X.-Q.; Xu, L.-W. Tetrahedron 2013, 69, 8777.
PhI(III)(CF3CO2)2: (g) Correa, A.; Tellitu, I.; Domínguez,
E.; SanMartin, R. J. Org. Chem. 2006, 71, 3501. Iron(IV)-
Oxo complex: (h) Nehru, K.; Jang, Y. K.; Seo, M. S.; Nam,
W.; Kim, J. Bull. Korean Chem. Soc. 2007, 28, 843. NO2:
(i) Naimi-Jamal, M. R.; Hamzeali, H.; Mokhtari, J.; Boy, J.;
Kaupp, G. ChemSusChem 2009, 2, 83.
(10) Typical Experimental Procedure for the Ni-Catalyzed
Cyclotrimerization of α-Amino Arylketones: To a
Synlett 2014, 25, 64–68
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