Synthesis of indazoles and azaindazoles by intramolecular aerobic oxidative C-N coupling under transition-metal-free conditions

Article abstract of DOI:10.1002/chem.201304923

A transition-metal-free oxidative C-N coupling method has been developed for the synthesis of 1H-azaindazoles and 1H-indazoles from easily accessible hydrazones. The procedure uses TEMPO, a basic additive, and dioxygen gas as the terminal oxidant. This reaction demonstrates better reactivity, functional group tolerance, and broader scope than comparable metal catalyzed reactions. A transition-metal-free oxidative C-N coupling method has been developed for the synthesis of 1H-azaindazoles and 1H-indazoles from easily accessible hydrazones (see scheme). The procedure uses TEMPO, a basic additive, and dioxygen gas as the terminal oxidant. This reaction demonstrates better reactivity, functional group tolerance, and broader scope than comparable metal catalyzed reactions. TEMPO=2,2,6,6-tetramethyl-1-piperidinyloxy.

Full text of DOI:10.1002/chem.201304923

DOI: 10.1002/chem.201304923
Communication
&
Heterocycles
Synthesis of Indazoles and Azaindazoles by Intramolecular
Aerobic Oxidative CÀN Coupling under Transition-Metal-Free
Conditions
Jiantao Hu,[a] Huacheng Xu,[a] Pengju Nie,[a] Xiaobo Xie,[b] Zongxiu Nie,*[b] and Yu Rao*[a]
Abstract: A transition-metal-free oxidative CÀN coupling
method has been developed for the synthesis of 1H-aza-
indazoles and 1H-indazoles from easily accessible hydra-
zones. The procedure uses TEMPO, a basic additive, and
dioxygen gas as the terminal oxidant. This reaction dem-
onstrates better reactivity, functional group tolerance, and
broader scope than comparable metal catalyzed reactions.
Azaindazole and indazole derivatives play an increasingly im-
portant role in today’s pharmaceutical industry.[1,2] Compounds
containing these types of scaffolds are being developed for
the treatment of oncological, HIV, CNS, and inflammatory dis-
eases, etc.[3] (Figure 1) Despite the importance of azaindazole
and indazole in pharmaceutical development, only a limited
number of approaches are available for the synthesis of aza-
indazoles and indazoles.[4–7] Especially in the case of azainda-
zole, the major method is employing traditional cycloaddition
Figure 1. Important azaindoles and indozoles.
chemistry, which usually suffers low efficiencies in terms of
practicality and overall yields.
Over the last decade, considerable progress has been made
towards the development of CÀH bond functionalization
methods that can be applied to the synthesis of biologically
important aromatic and heteroaromatic compounds.[8] As an
atom-economic and efficient strategy, constructing a CÀN
bond through direct CÀH functionalization[9] becomes highly
attractive in recent years. Nevertheless, these approaches
always require the addition of catalytic or stoichiometric
amounts of transition metals, most of which are expensive and
non-environmentally benign. Moreover, especially for the phar-
maceutical industry, the removal of harmful transition-metal
contamination is often costly and difficult.[10] In recent years,
there has been growing demand for new environmentally
benign methods suitable for large-scale synthesis[11] and the
use of molecular oxygen[12] as terminal oxidant has received
great attention for both environmental and economic pros-
pects. We are particularly interested in the development of an
alternative transition-metal-free oxidative CÀN bond formation
with molecular oxygen as an interesting and practical addition
to the transition metal involved protocols. To the best of our
knowledge, the development of C(sp2)ÀH functionalization for
preparing azaindazole and indazole molecules under transi-
tion-metal-free conditions remains unexplored. Inspired by the
effectiveness of TEMPO-based reagents and cocatalysts in the
aerobic alcohol oxidation,[13] we proposed that a proper combi-
nation of TEMPO/O2 with suitable bases might provide an effi-
cient catalytic system for intramolecular oxidative CÀN cou-
pling to furnish azaindazoles and indazoles (Scheme 1) through
a potential radical process (TEMPO=2,2,6,6-tetramethyl-1-pi-
peridinyloxy).[14] Here, we report the first example of the syn-
thesis of azaindazoles and indazoles through aerobic oxidative
CÀN bond formation without using transition metals.
[a] J. Hu,+ H. Xu,+ P. Nie, Prof. Dr. Y. Rao
MOE Key Laboratory of Protein Sciences
Department of Pharmacology and Pharmaceutical Sciences
School of Medicine and School of Life Sciences, Tsinghua University
Beijing 100084 (China)
E-mail: yrao@mail.tsinghua.edu.cn
[b] X. Xie, Prof. Dr. Z. Nie
Key Laboratory of Analytical Chemistry for Living Biosystems
Institute of Chemistry Chinese Academy of Sciences
Beijing 100190 (China)
E-mail: znie@iccas.ac.cn
[+] These authors contributed equally to this work.
At the beginning, a model study was initiated with hydra-
zone 1 in the presence of TEMPO in DMSO under one atmos-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304923.
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such as Ru, Rh, Pd, Cu, Ni, and Fe were not as efficient as our
catalytic system (either serious decomposition of starting ma-
terials or only low yields of 2 was observed). Interestingly,
a 33% yield of product 2 was also achieved by using air as the
oxidant (entry 14). It is noteworthy that this protocol was con-
ducted without the need for moisture-proof conditions
(entry 15). Typically the reaction will proceed to completion in
DMSO within 6 h, in a clean manner, under one atmosphere of
O2.
Scheme 1. A new strategy towards azaindazole and indazole through CÀH
functionalization without using transition metal.
Having identified these optimal conditions, we set out to ex-
plore the scope for this new reaction. A variety of aromatic hy-
drazines, and aromatic ketones were surveyed to prepare dif-
ferent 3-alkyl azaindazoles and indazoles. As displayed in
Table 2, the scope of the ring substituents was found to be
very broad. Diverse azaindazole and indazole derivatives were
prepared readily from corresponding aromatic hydrazones. A
variety of ortho-, meta-, and para-substituted aryl groups, as
well as the electron-rich and electron-deficient aryl groups
were well tolerated. For instance, modest to good yields were
observed with substrates which contain strong electron-with-
drawing groups, such as NO2 and CF3 (3i and n). Various 3-
alkyl groups including adamantyl, tert-butyl, isopropyl, cyclo-
hexyl, trifluoromethyl, diphenylmethyl, and 3-pentyl are com-
patible with the conditions to afford correponding 3-alkylind-
azoles (3a–j). Pleasingly, 4-azaindazole products (3l–q) were
prepared with satisfactory yields with 2-acyl pyridine deriva-
tives. Interestingly, when 3-acyl pyridine was employed, only
regioisomeric 7-azaindazole product (3k) was formed and no
corresponding 5-azaindazole counterpart was observed. For
some substrates, such as 3g, i, and l, steric hindrance, strong
electron-withdrawing groups and the low reactivity of pyridine
may account for the relative low yields.
Table 1. Optimization of the reaction conditions.
Entry Additives
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
TEMPO (0.3 equiv)/NaHCO3 (1.0 equiv)
80
110
130
140
140
140
140
140
140
140
140
140
140
140
140
0
24
48
55
72
73
63
75
65
57
76
85
83
33
59
TEMPO (0.3 equiv)/NaHCO3 (1.0 equiv)
TEMPO (0.3 equiv)/NaHCO3 (1.0 equiv)
TEMPO (0.1 equiv)/NaHCO3 (1.0 equiv)
TEMPO (0.5 equiv)/NaHCO3 (1.0 equiv)
TEMPO (0.3 equiv)/NaOAc (1.0 equiv)
TEMPO (0.3 equiv)/K2CO3 (1.0 equiv)
TEMPO (0.3 equiv)/DMAP (1.0 equiv)
TEMPO (0.3 equiv)/DABCO (1.0 equiv)
TEMPO (0.3 equiv)/NEt3 (1.0 equiv)
TEMPO (0.3 equiv)/NaHCO3 (0.5 equiv)
TEMPO (0.3 equiv)/NaHCO3 (1.0 equiv)
TEMPO (0.3 equiv)/NaHCO3 (2.0 equiv)
14[b] TEMPO (0.3 equiv)/NaHCO3 (1.0 equiv)
15[c] TEMPO (0.3 equiv)/NaHCO3 (1.0 equiv)
16
With metals such as Ru, Rh, Pd, Cu, Ni or Fe Low yields (<30%)
[a] Isolated yield; [b] under 1 atmosphere air (54% of starting material re-
mained); [c] 2.0 equivalents of H2O was added
Gratifyingly, the scope of this intramolecular cyclization reac-
tion was further successfully expanded to the synthesis of 3-
aryl substituted azaindazole and indazole derivatives as well
(Table 3). Varied aryl hydrazines were employed to smoothly
provide desired products (4a–p). Impressively, a broad func-
tional group compatibility was observed with this reaction, in-
cluding 2,4,6-trichlorophenyl group (4k) which is strongly elec-
tron-withdrawing and sterically demanding. It is noteworthy
that those functional groups (CN, CO2Et, halides, NO2 etc.) can
readily undergo further chemical manipulations to give very di-
verse compounds. For unsymmetric diaryl ketone substrates,
two regioisomers of indazoles were obtained (4q–t and 5). In
most cases, the more electron-rich parts would react preferen-
tially. If phenyl(pyridinyl)methanones were used, both ind-
azoles and azaindazoles would be formed (4u–y). Interestingly,
in the case of phenyl(pyridin-3-yl)methanone substrate, only
two regioisomers of azaindazoles (4v and v‘) were observed
and no corresponding indazole product can be found.
phere of O2 to test our hypothesis (Table 1). Although no reac-
tion occurred in the initial temperature range (80–1008C), we
were pleased to observe the desired azaindazole 2 in 24%
yield after stirring for 10 h (entry 2) at elevated temperature
(1108C). Encouraged by this preliminary result, we started to
optimize the reaction conditions. After
a comprehensive
screening, we found that DMSO was superior over other sol-
vents, such as DMF, DMA, alcohols, and 1,4-dioxane, etc. It was
observed that higher temperatures (such as 1408C) could
speed up the reactions and improve the yields. Moreover, we
found that the yields notably increased and reactions went to
completion in a shorter time with the addition of a base such
as NaHCO3 or DMAP (entries 8 and 12; DMAP=4-dimethylami-
nopyridine). It was believed that the base would serve as
a proton shuttle and assist the transformation. There is only
slight differences with higher TEMPO/base loadings in terms of
reaction rates and conversion ratios (entry 13). In the absence
of base and TEMPO, the yield will suffer a significant drop.
Generally, 0.1–0.3 equivalents amount of TEMPO and 1.0 equiv-
alent of base was enough to effectively promote the reaction.
Control experiments using various metal catalysts (entry 16),
To prove both practicality and effectiveness of this method
in the large-scale synthesis, we prepared 3-alkyl and 3-arylind-
azole products 3b, 4p and 5 on a gram-scale (Scheme 2). It
was found the large-scale reactions can be smoothly promoted
under the optimized conditions in excellent yields. Remarkably,
we were very pleased to notice that the yields of large-scale
reactions are generally better than their small-scale counter-
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Table 2. Scope 1: synthesis of 3-alkyl azaindazole and indazole.
Entry
1
Product
Yield [%][a]
Entry
6
Product
Yield [%][a]
63 (3a)
67 (3b)
79 (3c)
40 (3i)
2
74 (3d)
67 (3e)
7
91 (3j)
44 (3k)
3
4
8
9
55 (3 f)
22 (3g)
34 (3l)
59 (3m)
80 (3n)[b]
72 (3o)[b]
53 (3p)
5
75 (3h)
10
54 (3q)[b]
[a] Isolated yields; [b] 24h.
To verify the synthetic utility of this new reaction, both 1-ar-
ylazaindazole (3n) and 1-arylindazole (4a) were readily con-
verted into 1-H azaindazole 7 and indazole 6 through a cleav-
age of the 4-nitrophenyl group. As illustrated in Scheme 3,
a two-step procedure including deprotection and alkylation/
benzylation can smoothly transform 3n and 4a into the corre-
sponding 1-alkyl substituted products 8 and 9, respectively,
with high efficiency. In addition, as shown in Scheme 4, the ap-
plicability and effectiveness of this reaction was further dem-
onstrated in a sequential one-pot CÀN formation/deprotection
procedure which can directly transform aryl hydrazone into un-
protected 1H-indazole 6 in a satisfactory yield.
Next, investigations were performed to gain some insight of
the reaction mechanism. As shown in Scheme 5, both an intra-
molecular and intermolecular isotope effect studies were con-
ducted and a small KIE values (1.09 and 1.16) were consistently
obtained (KIE=kinetics isotope effects). These results indicate
that CÀH bond cleavage did not involve in the rate-limiting
step of this transformation.
Scheme 2. Gram-scale synthesis of 1H-indazoles.
To further probe the reaction mechanism, the reaction was
monitored by electron paramagnetic resonance (EPR) spectros-
copy with PBN (Z-N-benzylidene-2-methylpropan-2-amine
oxide) as the radical trap (Figure 2). A group of six peaks were
labeled a. The calculated hyperfine splittings are g0 (2.0021)
parts. In comparison with conventional approaches, the cur-
rent method is advantageous for rapid access to these types
of molecules because of its operational simplicity, broad availa-
bility of starting materials, and transition-metal free conditions.
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Table 3. Scope 2: synthesis of 3-aryl azaindazole and indazole.
Entry
Product
Yield [%][a]
Entry
Product
Yield [%][a]
89 (4a)[c]
68 (4b)[c]
65 (4c)[c]
61 (4d)
79 (4e)
62 (4 f)
85 (4g)
81 (4h)[c]
58 (4i)
52
1
8
(41% 4v+11 % 4v’)
73 (4j)
59 (4k)[c]
78 (4l)
62 (4m)
67 (4n)
65 (4o)
82 (4p)
84
2
3
4
5
9
(56% 4w+28% 4w’)
77
77
10
11
12
(35% 4q+42% 4q’)
(23% 4x+54% 4x’)
71
69
(40% 4r+31% 4r’)
(31% 4y+38% 4y’)
71
53 (4z)[c]
(26% 4s+45% 4s’)
79
92
6
13
(27% 4t+52% 4t’)
(80% 5+12% 5’)
74
7
(13% 4u+61% 4u’)
[a] Isolated yields; [b] reactions were conducted at 1508C.
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1.489 mT,
aH1 =0.275 mT, aN2 =
0.149 mT, which indicates the
presence of nitrogen radicals[15]
during the transformation (for
more details see the Supporting
Information). Additionally, the re-
action mixtures were monitored
by Mass Spectra during the reac-
tion course. As shown in
Figure 3, the MS data of the po-
tential nitrenium radical inter-
mediate B could be observed
with 253.17 for the correspond-
ing substrate A (for more details
see the Supporting Information).
Although details about the
Scheme 3. Synthesis of N-free 1H-azaindazole and indazole and further transformations. a) NaOEt (3.0 equiv),
DMSO, Ar, 120 8C, 2h; b) NaH (3.0 equiv), DMF/DMSO, 0 8C, 10min, Ar, Br(CH2)4Br (4.0 equiv), 0 8C–RT, 12h; c) NaH
(3.0 equiv), DMF/DMSO, 0 8C, 10min, Ar, BnBr (2.0 equiv), 0 8C–RT, 12h.
mechanism remain to be ascertained, on the basis of these ob-
servations, a possible overall mechanism of this new and tran-
sition-metal-free oxidation can be delineated as followings.
Step (i) involves TEMPO/O2-promoted NÀH oxidation of the
substrate which will afford a nitrenium radical intermediate. In
the following steps (ii) and (iii), an intramolecular CÀN bond
formation and base-directed deprotonation could afford the
desired product. Molecular oxygen serves as the terminal oxi-
dant to transform TEMPOH back into TEMPO. (Scheme 6)
In summary, an unprecedented transitional-metal-free, aero-
bic oxidative CÀN coupling method has been developed for
heterocycle synthesis. Dioxygen gas (1 atm) is employed as the
oxidant in this transformation. This method has been found to
be generally useful for the preparation of a variety of multi-
substituted azaindazole and indazole derivatives from easily
accessible starting materials. Most azaindazole products are
difficult to make by conventional approaches. Mecha-
nistic studies suggest a potential TEMPO/O2 promot-
ed radical pathway for this reaction. Compared with
metal-catalyzed reactions, this reaction demonstrates
better reactivity, functional group tolerance, and
broader scope. Further studies into the mechanism
and synthetic applications of this method are cur-
rently underway in our laboratory.
Scheme 4. One-pot-synthesis of N-free 1H-indazole.
and aN1 =1.489 mT, aH1 =0.275 mT, which indicates the pres-
ence of carbon radicals during the transformation. Another
group of peaks were labeled b. The corresponding calculated
hyperfine splittings are aN1 =1.489 mT, aH1 =0.350 mT, which
potentially indicates the presence of superoxide anion radicals
during the transformation. Three groups of small peaks were
labeled c. The calculated hyperfine splittings are aN1
=
Experimental Section
General procedure
To a solution of hydrazone (0.2 mmol, 1.0 equiv) in
DMSO (1.0–1.5 mL) was added TEMPO (0.1–0.3 equiv)
and NaHCO3 or DMAP (0.5–1.0 equiv). The reaction mix-
ture was then stirred at 1408C under 1 atmosphere of O2
for 4–24 h, which was monitored by TLC. The resulting
mixture was quenched with water and extracted with
CH2Cl2 (2ꢁ10.0 mL). The combined organic layers were
washed with brine and dried over Na2SO4. After filtration
and concentration, the crude product was purified by
flash column chromatography with petroleum ether/Et2O
or petroleum ether/DCM or petroleum ether/ethyl ace-
Scheme 5. KIE studies. a) TEMPO (0.3 equiv), NaHCO3 (1.0 equiv), DMSO (1.5 mL), O2, 1h.
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tate or DCM/acetone to afford product.
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Acknowledgements
This work was supported by 973 grant (grant 2011CB965300),
NSFC (grant 21302106), Tsinghua University 985 Phase II funds
and the Tsinghua University Initiative Scientific Research Pro-
gram.
Keywords: aerobic oxidative CÀN coupling · azoindazole ·
heterocycles · indazole · metal-free condition
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Communication
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Received: December 17, 2013
Revised: January 8, 2014
Published online on March 3, 2014
Chem. Eur. J. 2014, 20, 3932 – 3938
www.chemeurj.org
3938
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