Assembly of N, N -disubstituted hydrazines and 1-aryl-1 H-indazoles via copper-catalyzed coupling reactions

Article abstract of DOI:10.1021/ol300847v

CuI-catalyzed coupling of N-acyl-N′-substituted hydrazines with aryl iodides takes place at 60-90 °C to afford N-acyl-N′,N′- disubstituted hydrazines regioselectively and thereby gives a facile method for assembling N,N-diaryl hydrazines. N-Acyl-N′-substituted hydrazines can also react with 2-bromoarylcarbonylic compounds at 60-125 °C under the catalysis of CuI/4-hydroxy-l-proline to provide 1-aryl-1H-indazoles.

Full text of DOI:10.1021/ol300847v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Assembly of N,N-Disubstituted
Hydrazines and 1-Aryl-1H-indazoles via
Copper-Catalyzed Coupling Reactions
Xiaodong Xiong,† Yongwen Jiang,‡ and Dawei Ma*,‡
Department of Chemistry, Fudan University, Shanghai 200433, China, and State Key
Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032,
China
Madw@mail.sioc.ac.cn
Received April 3, 2012
ABSTRACT
CuI-catalyzed coupling of N-acyl-N0-substituted hydrazines with aryl iodides takes place at 60ꢀ90 °C to afford N-acyl-N0,N0-disubstituted
hydrazines regioselectively and thereby gives a facile method for assembling N,N-diaryl hydrazines. N-Acyl-N0-substituted hydrazines can also
react with 2-bromoarylcarbonylic compounds at 60ꢀ125 °C under the catalysis of CuI/4-hydroxy-L-proline to provide 1-aryl-1H-indazoles.
In the past decades, a considerable number of bioactive
N,N-disubstituted hydrazines have been discovered, which
include sensory neuron inhibitors,1 cell harm inhibitors,2
R-adrenoceptorantagonists,3 potentialagentsforthetreat-
ment of thrombolic disease,4 PGI2 agonists,5 papilloma
virus inhibitors,6 and D1 dopamine receptor antagonists.7
Additionally, N,N-disubstituted hydrazines are versatile
intermediates for assembling azo heterocycles, such as
indazoles,8 indoles,9 and 1,2,4-benzotriazines.10
Conventional methods for preparing N,N-diaryl hydra-
zines involve oxidation of diaryl amines and subsequent
reduction of the resulting aryl diazoniums.11 This ap-
proach normally suffers from multistep synthesis, harsh
reaction conditions, and low yields. This drawback has
stimulated some investigations on assembly of N,N-diaryl
hydrazines via metal-catalyzed or metal-mediated reac-
tions. Successful examples include Cu-catalyzed diaryla-
tionofN-acyl hydrazines,12 Pd-catalyzedcross-coupling of
benzophenone hydrazine with aryl halides,13 Cu-catalyzed
(1) Hamlyn, R.; Huckstep, M.; Lynch, R.; Stokes, S.; Tickle, D.;
Patient, L. Azacyclic Compounds As Inhibitors of Sensory Neurone
Specific Channels. WO 2005005392, January 20, 2005.
(2) Kuratani, K.; Nakahama, K.; Morita, I.; Murota, S. Phenylhy-
drazine derivative and cytotoxic preventive. JP 09110815, April 28, 1997.
(3) Hong, S.; Bavadekar, S.; Lee, S.; Patil, P.; Lalchandani, S.; Feller,
D.; Miller, D. Bioorg. Med. Chem. Lett. 2005, 15, 4691.
(4) Werner, M.; Dieter, D.; Chistos, T.; Christopher, B.; Bertram, C.;
Johannes, G. Semicarbazide Derivatives for Combating Thromboem-
bolic Diseases. US 20050171102, April 7, 2003.
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S.; Hamada, S.; Kato, H.; Tokumoto, H.; Kondo, K. Bioorg. Med.
Chem. Lett. 1995, 5, 1087.
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ing to Fabric Treatment Compositions. WO 2009065893, September 21,
2011.
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121, 10251. Okiko, M.; Norihiko, T.; Yasuo, K.; Yoshiji, T.; Norimitsu,
T.; Mikiji, M.; Takeaki, N. Tetrahedron 2006, 62, 3629. (b) Thorsten, G.;
Julio L, F.; Solveig A, S.; Hubert, W.; Lutz H, G. Angew. Chem., Int. Ed.
2011, 50, 5757.
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1998, 120, 6621. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2090.
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r
10.1021/ol300847v
XXXX American Chemical Society

Table 1. CuI-Catalyzed Coupling of 4-Iodoanisole with N-Acyl-
N0-substituted Hydrazinesa
Table 2. CuI-Catalyzed Coupling of Aryl Iodides with N-Phenyl
Hydrazidesa
entry
R
R0
product
yield (%)b
1
2
Ph
Ph
Ph
Ph
3a
3a
3b
3c
3d
3e
3f
94c
98
95
70
98
76
85
94
97
96
15
53
32
3
Me
Ph
4
Bn
Ph
5
2-furanyl
t-BuO
CF3
Ph
Ph
6d
7d
8
Ph
Ph
4-MeOC6H4
4-NO2C6H4
3-ClC6H4
2-MeC6H4
n-Pr
3g
3h
3i
9
Ph
10
11e
12d
13d
Ph
Ph
3j
Ph
3k
3l
Ph
Bn
a Reaction conditions: 1a (0.4 mmol), 2 (0.6 mmol), CuI (0.04 mmol),
K2CO3 (0.8 mmol), DMSO (1 mL), 60 °C, 20ꢀ30 h. b Isolated yield.
c The reaction was carried out at 30 °C in the presence of 4-hydroxy-L-
proline (0.08 mmol). d Stirred at 90 °C. e Stirred at 130 °C.
N-arylation of hydrazines with bismuthanes,14 and addi-
tion of organometallic nucleophiles to symmetrical and
unsymmetrical azo compounds.15 During the studies on
exploring the scope of Cu-catalyzed arylation by using
unusual nucleophiles,16,17 we revealed that N-acyl-N0-
substituted hydrazines were excellent coupling partners,
which could regioselectively react with aryl iodides and
2-bromoarylcarbonylic compounds under mild conditions.
This advantage offers a facile method for synthesizing
N,N-disubstituted hydrazines and 1-aryl-1H-indazoles.
Herein, we wish to disclose our results.
As indicated in Table 1, we initially attempted the
coupling of N0-phenylbenzohydrazide with 4-iodoanisole.
This reaction worked well under the catalysis of 10 mol %
CuI and 20 mol % 4-hydroxy-L-proline in DMSO at 30 °C
to afford 3a in 94% yield (entry 1). Further attempts
revealed that ligand was not necessary if the reaction was
carried out at 60 °C (entry 2). Under these conditions a
(14) (a) Loog, O.; Maeorg, U.; Ragnarsson, U. Synthesis 2000, 1591.
(b) Yutaka, A.; Yuko, S.; Takeshi, S.; Yasuo, K. Synth. Commun. 2000,
ꢀ
€
30, 131. (c) Starkov, P.; Zemskov, I.; Sillard, R.; Tsubrik, O.; Maeorg, U.
Tetrahedron Lett. 2007, 48, 1155.
ꢀ
€
€
(15) (a) Kisseljova, K; Tsubrik, O.; Sillard, R.; Maeorg, S.; Maeorg,
U. Org. Lett. 2006, 8, 43. (b) Tsubrik, O.; Sillard, R.; Maeorg, U.
Synthesis 2006, 15, 843.
a Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), CuI (0.04 mmol),
K2CO3 (0.8 mmol), DMSO (1 mL), 60 °C, 20ꢀ30 h. b Isolated yield.
c Stirred at 90 °C.
(16) (a) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y.
Angew. Chem., Int. Ed. 2009, 48, 4222. (b) Jiang, Y.; Qin, Y.; Xie, S.;
Zhang, X.; Ma, D. Org. Lett. 2009, 11, 5250. (c) Jiang, L.; Lu, X.; Zhang,
H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 4542. (d) Ma, D.; Lu, X.;
Shi, L.; Zhang, H.; Jiang, Y.; Liu, X. Angew. Chem., Int. Ed. 2011, 50,
1118.
(17) For related studies from other groups, see: (a) Wolter, M.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. (b) Liu, X.; Fu, H.;
Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 348. (c) Cortes, M.;
Nguyen, B.; Cuevas, J.; Pennypacker, K.; Antilla, J. C. Org. Lett. 2010,
12, 1316. (d) Racine, E.; Monnier, F.; Vors, J.; Taillefer, M. Org. Lett.
2011, 13, 2818.
series of N-acyl-N0-substituted hydrazines were examined.
We were pleased that other N-acyl-N0-phenylhydrazines
gavethe corresponding coupling products withgood yields
(entries 3ꢀ7) and thereby allowing assembly of N,N-diaryl
hydrazines with different protecting groups. The N-aryl
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. One-pot Reaction Process for Assembly of 1-Aryl-1H-
indazolesa
Scheme 1
Scheme 2
hydrazides with electron-donating as well as electron-
withdrawing substituents at the meta- or para-positions
also proceeded well (entries 8ꢀ10). However, a low yield
was obtained when an ortho-substituted N-aryl hydrazide
was used (entry 11), indicating that the steric hindrance of
aryl hydrazides plays a key role in the coupling reaction.
Additionally, preparation of N-aryl-N-alkyl hydrazides
was proven possible from N-alkyl hydrazides (entries 12
and 13). In these cases the yields were not satisfactory due
to incomplete conversion, which illustrated that subtle
change in electronic nature of substituted hydrazides could
alter the reaction process.
In another set of experiments, we explored the reaction
scope via coupling N-phenyl hydrazides with various aryl
iodides, and the results were summarized in Table 2. To
our delight, both electron-rich and electron-deficient aryl
iodides were compatible with these conditions, providing
the corresponding N,N-diaryl hydrazides in 80ꢀ98%
yields (entries 1ꢀ12). Interestingly, six ortho-substi-
tuted aryl iodides worked well (entries 8ꢀ13), indicat-
ing that steric hindrance of aryl iodides has little
influence on coupling reaction. This phenomenon is in con-
trast with that observed with sterically hindered hydrazides.
a Reaction conditions: 6 (0.5 mmol), ArNHNHCOPh (0.6 mmol),
CuI (0.05 mmol), 4-hydroxy-L-proline (0.1 mmol), K2CO3 (1.0 mmol),
dioxane (1 mL), 60 °C, 30 h; then HOAc (2 mL), 60 °C. b Isolated yield.
c The coupling reaction was carried out at 125 °C. d Methyl 2-bromo-
benzoate was used as the starting material.
Two heterocycle-embodied N,N-diaryl hydrazides 4m and
4n (entries 14 and 15) were successively obtained from
2-iodopyridine and 2-iodothiophene, respectively. Another
notable feature is that a wide range of functional groups,
including hydroxy, amino, ketone, ester, amide, nitro, and
Org. Lett., Vol. XX, No. XX, XXXX
C

bromo, were well tolerated to these conditions. These char-
acters would allow diversity synthesis of N,N-diaryl hydra-
zides. Indeed, by employing some functionalized N-phenyl
hydrazides, neurokinin receptor antagonist 4p (entry 17),1
cell harm inhibitor 4q (entry 18),2 and compound 4r (entry
19), that is useful for the treatment of thrombolic disease,4
were effectively prepared.
1-substituted 3-methylindazoles (entries 1ꢀ7). The yields
are generally excellent except for a nitro-substituted pro-
duct, which might probably result from the poor nucleo-
phility of the corresponding N-aryl hydrazide. The similar
problem was observed when a pyridine-embodied sub-
strate was utilized (entry 8). It seemed that electronic
nature of aryl bromides has little influence to this process,
as evident from the 11j and 11k that were obtained in
similar yields (entries 9 and 10). Further investigations
indicated that the method was amenable to 1-(2-bromo-
pyridin-3-yl)ethanone (entry 11) and 2-bromophenyl-
acetone with different R-substituents (entries 12ꢀ16),
although in some cases the yields were not so satisfactory.
In conclusion, we have discovered a convenient method
for assembling N,N-disubstituted hydrazines, which relies
on a CuI-catalyzed coupling of aryl iodides with N-acyl-
N0-substituted hydrazines. We also revealed that CuI/4-
hydroxy-L-proline catalyzed coupling of aryl hydrazides
with 2-bromoarylcarbonylic compounds worked under
mild conditions, thereby providing a facile method for
preparing 1-aryl-1H-indazoles. Various functional groups
were found to tolerate these reaction conditions, and
therefore these methods may find applications in organic
synthesis.
When 4-bromoanisole was utilized as coupling partner,
poor conversion was observed even at 140 °C (Scheme 1).
Using 4-hydroxy-L-proline as a promoter could help the
coupling, but the reaction yield was still poor. However,
CuI/4-hydroxy-L-proline catalyzed coupling of 2-bromo-
phenyl-acetone 6a with 2a could complete at 60 °C to
afford N-aryl hydrazide 7 with a good yield in either DMSO
or dioxane. This result implied that there is an ortho-
substituent effect18 directed by an acyl group in this case.
This hypothesis was further supported by poor conversion of
4-bromophenylacetone 8 to 4c even at 130 °C and exclusive
formation of N-aryl hydrazide 9 from dibromide 6b.
The easy coupling of 2-bromoarylcarbonylic compounds
caused by their ortho-acyl groups prompted us to design a
one-pot reaction process for preparing 1-aryl-1H-inda-
zoles, a class of biologically important heterocycles.19,20
As outlined in Scheme 2, we believed that the coupling
products could undergo deprotection and subsequent
intramolecular condensation to afford 1-aryl-1H-inda-
zoles. After some attempts, we found that formation of
3-methyl-1-phenyl-1H-indazole 11a from 6a could be
achieved by adding HOAc after coupling reaction was
completed.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foun-
dation of China (grants 20921091 and 20572119) and
Ministry of Science and Technology (grant 2009CB940900)
for their financial support.
This one-pot reaction process was then checked by
varying aryl bromides and N-aryl hydrazides. As summar-
ized in Table 3, a number of N-aryl hydrazides bear-
ing either electron-donating or electron-withdrawing
groups could be used for obtaining the corresponding
Supporting Information Available. Experimental proce-
dures and copies of 1H NMR and 13C NMR spectra for
all new products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
D
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