A Synthesis of 1H-Indazoles via a Cu(OAc)2-Catalyzed N-N Bond Formation

Article abstract of DOI:10.1021/acs.orglett.6b00611

A facile synthesis of 1H-indazoles featuring a Cu(OAc)₂-catalyzed N-N bond formation using oxygen as the terminal oxidant is described. The reaction of readily available 2-aminobenzonitriles with various organometallic reagents led to o-aminoar

Full text of DOI:10.1021/acs.orglett.6b00611

Letter
pubs.acs.org/OrgLett
A Synthesis of 1H‑Indazoles via a Cu(OAc)2‑Catalyzed N−N Bond
Formation
Cheng-yi Chen,*,† Guangrong Tang,‡ Fengxian He,‡ Zhaobin Wang,‡ Hailin Jing,‡ and Roger Faessler†
†Janssen R&D, Pharmaceutical Development and Manufacturing Sciences, Small Molecule API Switzerland, Cilag AG, Hochstrasse
201, 8205 Schaffhausen, Switzerland
‡Porton (Shanghai) R&D Center, 1299 Ziyue Road, Zizhu Science Park, Minhang District, Shanghai 200241, China
S
* Supporting Information
ABSTRACT: A facile synthesis of 1H-indazoles featuring a Cu(OAc)2-catalyzed N−N bond formation using oxygen as the
terminal oxidant is described. The reaction of readily available 2-aminobenzonitriles with various organometallic reagents led to
o-aminoaryl N−H ketimine species. The subsequent Cu(OAc)2-catalyzed N−N bond formation in DMSO under oxygen
afforded a wide variety of 1H-indazoles in good to excellent yields.
1H-Indazoles are ubiquitous in the realms of pharmacologically
active agents even though their occurrence in nature is scarce
(Figure 1).1 A number of important drugs containing 1H-
employing condensation of highly toxic hydrazine or organo-
hydrazines with o-haloaryl aldehyde or aryl ketone derivatives
under fairly harsh conditions.4 Other methods employing
organoazide reagents and utilizing precious transition metals as
catalysts are less attractive.5 Herein, we report a facile synthesis
of 1H-indazoles via a Cu(OAc)2-catalyzed N−N bond
formation employing oxygen as the terminal oxidant.6,7 We
envisioned that addition of Grignard or organolithium reagents
to readily available o-aminobenzonitriles would form o-
aminoaryl N−H ketimines. The subsequent intramolecular
N−N bond formation using copper catalysts under aerobic
oxidation conditions would then lead to the formation of 1H-
indazoles. To the best of our knowledge, this approach to make
1H-indazoles has not been reported.5a,8
Two metal-free syntheses of a variety of 1H-indazoles
featuring an intramolecular N−N bond formation have been
reported.9 As shown in Scheme 1, these syntheses rely on the
selective activation of the oxime in the presence of the amino
group followed by an intramolecular displacement reaction to
form the indazole ring. In this approach, the oximes were
derived from o-aminoaryl ketones 4, which, in turn, were
prepared from o-aminobenzonitriles 1 and organometallic
reagents through the hydrolysis of the ketimine intermediates
2.10,11 Taking into account atom and step economy, we
envisioned that a direct N−N bond formation from the
ketimine species 2 should be a viable and attractive approach to
this important class of compounds. We further anticipated that
such transformations could be facilitated via a metal-catalyzed
Figure 1. 1H-Indazoles as medicinal agents and natural products.
indazole pharmacores such as granisetron, gamendazole, and
benzydamine have been developed.2 In addition, a few
structurally interesting tricyclic indazoles have been isolated
from Nigella glandulifera and display diverse biological
activities.3 The importance of this class of heterocycles as
medicinal agents has continued to inspire the pursuit of their
general and efficient syntheses. Many existing approaches to
1H-indazoles rely on the formation of a C7a−N1 bond
Received: March 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00611
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prepared from addition of various organometallic reagents to
nitrile 6. As shown in Scheme 2, all the N−N bond formations
Scheme 1. Synthetic Strategy for 1H-Indazoles via Direct N−
N Bond Formation
Scheme 2. Synthesis of 1H-Indazoles from 2-
a
Methylaminobenzonitriles
N−N bond formation using oxygen as the terminal oxidant.
Our strategy, therefore, relies on generation of o-aminoaryl
ketimine species and its subsequent usage in the N−N bond
formation to 1H-indazoles.
We started our work by preparing ketimine 712 from nitrile 6
and phenylmagnesium bromide and explored its metal-
catalyzed N−N bond formation to form the indazole ring.
We were delighted to find that this conceptually simple
approach worked very well when prepared 2-methylaminoaryl
N−H ketimine 7 was treated with a catalytic amount of
Cu(OAc)2 (20 mol %) in DMSO under oxygen to afford 1H-
indazole 8 in 77.8% yield (Table 1, entry 1). Continued catalyst
Table 1. Catalyst Screening for the N−N Bond Formation
a
All reactions were run under oxygen in DMSO (20 g/g substrate) at
85 °C for 3−6 h, and products were isolated in gram quantities after
b
SiO2 column chromatography. 5 mol % of the catalyst was used on a
5 g scale.
occurred smoothly to afford a wide variety of 3-substitued 1H-
indazoles (10a−j) under mild conditions. The N−N bond
formation is independent of the arylmagnesium as several 3-aryl
1H-indazoles (10a−f) were obtained in good to excellent
yields. The reaction also tolerated chloride moiety such that
10b was obtained in excellent yield through this two-step
sequence. The reaction also tolerated a pyridinyl group to
afford 1H-indazole 10g in 65.9% yield. Furthermore, alkyl
groups and cyclopropyl group can be incorporated in the
indazole framework to give 1H-indazole 10h−j in 72.4−84.5%
yields. All of these reactions were carried out in gram quantities
in good yields, demonstrating the efficiency and practicality of
this methodology. The catalyst loading of Cu(OAc)2 can be
reduced to 5 mol % as illustrated in the preparation of 1H-
indozole (10a, 79.4%) on a 5 g scale without compromising the
efficiency of the N−N bond formation.
Having successfully prepared a range of 3-substituted N-Me
indazoles (10) from o-methylaminoaryl N−H ketimines (2)
employing Cu(OAc)2-catalyzed N−N bond formation, we
decided to extend this protocol to N-aryl-substituted ketimines
for the preparation of N-aryl-substituted indazoles.13 Delight-
fully, this extension was rather straightforward, and a wide array
of 3-substituted N-arylindazoles (11a−h) were obtained from
the corresponding o-aminoaryl ketimines as summarized in
Scheme 3. While most reactions were carried out under oxygen,
the N−N bond formation was also feasible under air with 1H-
indazole 11a obtained in 70.4% yield. In addition to the
installation of the aromatic groups at the 3-position of 1H-
indazoles, both propenyl and cyclopropyl groups can be
a
b
entry
catalyst
Cu(OAc)2
yield (%)
c
1
2
77.8
Cu(OTf)2
CuBr2
42.5
53.3
69.4
58.6
68.7
30.7
1.0
3
4
CuCl
5
CuI
6
CuBr
7
CuO
8
Pd(OAc)2
Ni(dppe)Cl2
Pd(dppf)Cl2/PPh3
9
0.10
0.10
10
a
All screening experiments were carried out on 0.5 g scale under
oxygen in DMSO (10 g) at 85 °C for 3 h. All the yields except entry 1
were based on HPLC assay against the standard sample of 8. Isolated
b
c
yield.
screening indicated that Cu(OAc)2 is superior to other catalysts
in facilitating the N−N bond formation (Table 1, entries 2−7).
Neither Pd nor Ni catalysts are effective in the catalysis with
only a trace amount of 1H-indazole 8 formed. This preliminary
yet exciting lead prompted us to develop a versatile method for
the direct access to various 1H-indazoles from o-aminoaryl
ketimines.
Next, we explored the generality of the defined conditions in
the synthesis of indazoles from ketimines 9 which were readily
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Scheme 3. Synthesis of 1H-Indazoles from 2-Aryl- or tert-
Butylaminobenzonitriles
Scheme 4. Synthesis of 1H-Indazoles from 2-
Aminobenzonitrile
a
a
a
All reactions were run under oxygen in DMSO (20 g/g substrate) at
85 °C for 3−6 h and compounds were isolated in gram quantity after
SiO2 column chromatography.
Scheme 5. Preparation of Chiral 1H-Indazole
a
All reactions were run under oxygen in DMSO (20 g/g of the
substrate) at 85 °C for 3−6 h, and products were isolated in gram
b
quantities after SiO2 column chromatography. Reaction was carried
out under air.
introduced (11e and 11f) to these molecules. Compound 11g
was prepared in a much more straightforward manner than with
the literature protocol.9 We noticed that the reaction gave a
higher yield of 1H-indazoles with the bulky substituted group
attached to the amino moiety (11h and 11i). This observation
warrants further examination to gain more understanding of the
steric effect on the efficiency of the N−N bond formation.
Furthermore, the methodology can be extended to the
preparation of 3-substituted 1H-indazoles from 2-amino-
benzonitrile (13). Three 2-aminobenzonitrile-derived 1H-
indazoles (15a−c) were prepared in 76.3−84.3% yields
(Scheme 4). Moreover, the N,N-dimethylamino nitrile 16 was
subjected to the reaction sequence to afford N-methylindazole
8 in 51% yield. Interestingly, demethylation occurs during the
N−N bond formation.
A highlight of this N−N bond formation protocol is shown
in Scheme 5, where a chiral amino moiety can be readily
incorporated into the indazole ring. Addition of cyclo-
propylmagnesium bromide to nitrile 19 followed by N−N
bond formation of ketiminium species 20 afforded 1H-indazole
21 in 73.8% yield. We believe this is a unique example of
preparation of a 1H-indazole-bearing chiral moiety in the
molecule. This example also proved the tolerance of bromide
moiety of this protocol. This shows that molecular complexity
can be readily built through this versatile methodology.
On the basis of literature reports,5a,6a,b we speculate that the
reaction proceeds with the coordination of Cu(OAc)2 with o-
aminoketimine 14 to form species 22, which could also be
oxidized further to species 23. Reductive elimination leads to
N−N formation to afford the desired 1H-indazole and reduced
copper species, CuOAc. The copper(I) acetate, in turn, is
oxidized by oxygen to regenerate the Cu(OAc)2 catalyst.
Oxygen plays a critical role in the catalytic cycle to reoxidize
presumably the CuOAc species (Scheme 6). For example, the
N−N bond formation reaction was performed using 20 mol %
of Cu(OAc)2 but under argon stalled at 23% conversion to the
desired 1H-indazole. However, removal of argon and
reintroduction of oxygen allowed the reaction proceed to
completion.
In conclusion, we have developed a new and efficient
synthetic method for the construction of 1H-indazoles based on
C
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Scheme 6. Mechanistic Hypothesis for the N−N Bond
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Cu(OAc)2-catalyzed N−N bond formation using oxygen as the
terminal oxidant. This protocol takes advantage of the readily
accessible ketimine precursors prepared from o-aminobenzoni-
triles and organometallic reagents. The simplicity and high
efficiency of this protocol renders it attractive when compared
to the others reported in the literature. Importantly, both
nitrogen atoms in the starting material were conserved. The
method demonstrated here allows easy access to structurally
diverse 1H-indazoles and could serve as a versatile tool for the
modular synthesis of 1H-indazole containing medicinal agents.
We hope this work will prompt others to explore application of
the N−N bond formation methodology using o-amino
ketimines in the arena of heterocycle syntheses.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00611.
Experimental details, characterization data, and NMR
spectra (PDF)
(9) (a) Wray, B. C.; Stambuli, J. P. Org. Lett. 2010, 12, 4576.
(b) Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P.
Org. Lett. 2008, 10, 1021.
(10) Addition of organometallics to o-aminoaryl nitrile followed by
hydrolysis of the imine species serves as an effective protocol to
prepare o-aminoacetophenones. For examples, see: (a) the Supporting
Information in ref 6. (b) Cook, J. M.; Zhang, W.; Liu, R. Heterocycles
1993, 36, 2229. (c) Huang, J.; Mao, T.; Zhu, Q. Eur. J. Org. Chem.
2014, 2014, 2878. (d) Ellis, D.; Kuhen, K. L.; Anaclerio, B.; Wu, B.;
Wolff, K.; Yin, H.; Bursulaya, B.; Caldwell, J.; Karanewsky, D.; He, Y.
Bioorg. Med. Chem. Lett. 2006, 16, 4246.
(11) Only a few o-aminoaryl imine species have been isolated and
characterized, and their synthetic utilization remains scarce. For
examples, see: (a) Ozeryanskii, V. A.; Pozharskii, A. F.; Antonov, A. S.;
Filarowski, A. Org. Biomol. Chem. 2014, 12, 2360. (b) Adachi, M.;
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(c) Dubrovskiy, A.; Larock, R. C. J. Org. Chem. 2012, 77, 11232.
(12) Preparation and isolation of ketamine 7 is straightforward, and
the crude intermediate was directly used in the N−N bond formation
without further purification: For details, see the Supporting
Information.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cchen117@its.jnj.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge Mrs. Yiping Zhang and Mrs. Jingjing Shi at
Porton (Shanghai) R&D Center for analytical support. We also
acknowledge Mr. Peter J. Yao of Janssen R&D at Cilag AG for
helpful discussions during the preparation of this manuscript.
REFERENCES
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D
DOI: 10.1021/acs.orglett.6b00611
Org. Lett. XXXX, XXX, XXX−XXX