Synthesis of 1H-indazoles from N-tosylhydrazones and nitroaromatic compounds

Article abstract of DOI:10.1039/c4cc00962b

A new method for the synthesis of 1H-indazoles from readily available N-tosylhydrazones and nitroaromatic compounds has been developed. This transformation occurs under transition-metal-free conditions and shows a wide substrate scope. The method has been

Full text of DOI:10.1039/c4cc00962b

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Synthesis of 1H-indazoles from N-tosylhydrazones
and nitroaromatic compounds†
Cite this:DOI: 10.1039/c4cc00962b
Zhenxing Liu, Long Wang, Haocheng Tan, Shiyi Zhou, Tianren Fu, Ying Xia,
Yan Zhang and Jianbo Wang*
Received 5th February 2014,
Accepted 26th March 2014
DOI: 10.1039/c4cc00962b
www.rsc.org/chemcomm
A new method for the synthesis of 1H-indazoles from readily available
N-tosylhydrazones and nitroaromatic compounds has been developed.
This transformation occurs under transition-metal-free conditions and
shows a wide substrate scope. The method has been successfully
applied to the formal synthesis of a bioactive compound, WAY-169916.
Owing to their diverse pharmacological activities, 1H-indazoles
are frequently found in drugs and drug candidates as demon-
Fig. 1 Some drugs and drug candidates containing the 1H-indazole
strated by the examples shown in Fig. 1.1 Besides, 1H-indazoles structure.
also find applications in other areas, such as being ligands in
metal complexes.2 Due to the importance of these types of
compounds, many efficient methods have been developed to
access 1H-indazoles. Among them, diazotization or nitrosation
of ortho-alkyl-substituted anilines (Jacobson modification,
Scheme 1a),3 condensation of ortho-substituted arylaldehydes
or ketones with hydrazines (Scheme 1b),4 and [3+2] cyclization
of diazomethanes with benzynes (Scheme 1c)5 are the three
most commonly explored strategies. Recently, the rapid develop-
ment of transition-metal catalysis has opened alternative ways
to access these structures. 1H-Indazoles are synthesized by
transition-metal-catalyzed intramolecular amination of o-halo
arylhydrazones or direct C–H amination of arylhydrazones
Scheme 1 The reported strategies for the synthesis of 1H-indazoles.
(Scheme 1d).6 Despite the success of these synthetic methods,
some drawbacks still remain, such as the use of toxic hydrazines,
low regioselectivity of the reactions, and the need of pre- aromatic C–H bond functionalization with N-tosylhydrazones.8
functionalization of starting materials. Therefore, further develop- As a continuation, we have conceived to extend this type of
ment of efficient methods is highly demanded.
reaction with electron-deficient arenes such as 1,3-dinitrobenzene
On the other hand, N-tosylhydrazones have emerged as in Cu(I)-catalyzed direct C–H bond functionalization. In the control
useful reagents in transition-metal-catalyzed cross-coupling experiments, we found with surprise that in the absence of the Cu(I)
reactions.7 In this context, we have recently reported the direct catalyst, 1,3-dinitrobenzene reacts directly with N-tosylhydrazone
to give 6-nitro-3-phenyl-1H-indazole 1a under basic conditions
(Scheme 2). Changing the solvent from MeCN to DMF signifi-
cantly improved the yield of 1a.
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China.
E-mail: wangjb@pku.edu.cn; Fax: +86 10 6275-1708
This unusual reaction raises an intriguing question concerning
its reaction mechanism. As shown in Scheme 3, there are several
possible mechanisms for this reaction. Path a is based on [3+2]
cycloaddition between diazo compounds and benzynes. It is known
that diazo compounds are formed in situ from N-tosylhydrazones
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, and 1H and 13C NMR spectra for products. CCDC 985185. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc00962b
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Scheme 2 Reaction of 1,3-dinitrobenzene with N-tosylhydrazone under
transition-metal-free conditions.
Scheme 3 Possible reaction mechanisms.
under basic conditions (Bamford–Stevens reaction),9 while benzyne
A may be generated via nitro-elimination under basic conditions.10
However, careful analysis of the crude reaction mixture reveals that
only one isomer could be identified.11 This is not in agreement with
the result of normal benzyne-involved [3+2] cycloaddition reactions,
where the mixture of two regioisomers is usually produced.12
Path b starts with the deprotonation of N-tosylhydrazone.
Then the deprotonated tosylhydrazone B (in resonance with C)
undergoes nucleophilic addition to the less hindered ortho
position of the nitro group of 1,3-dinitrobenzene to afford
the intermediate D. Through intramolecular cyclization, nitro-
elimination and [1,3]-H-migration, the final product 1a is formed.13
Path c, which is similar to path b, involves the direct nucleophilic
attack of the nitro-attached carbon of the 1,3-dinitrobenzene sub-
Scheme 4 Reaction scope of transition-metal-free synthesis of 1H-indazoles.
Reaction conditions (A) nitroarene (0.3 mmol), N-tosylhydrazone (0.36 mmol)
and Cs2CO3 (1.08 mmol) in DMF (2.0 mL) at 80 1C for 2 h; reaction conditions
(B) nitroarene (0.3 mmol), N-tosylhydrazone (0.36 mmol) and NaH (1.08 mmol)
in DMF (2.0 mL) at 60 1C for 4 h. All the yields refer to isolated yields. a 110 1C;
b additive: tetrabutylammonium bromide (TBAB) (0.3 mmol).
strate, giving intermediate G. While this step is thermodynamically were suitable substrates, affording the corresponding products 1b–d
disfavoured, the fast cyclization from G to D should drive the in moderate yields. For para- or ortho-substituted nitrobenzenes,
reaction forward. Paths b and c cannot be distinguished with strong base NaH is needed instead of Cs2CO3.14 For para-
currently available experimental evidence.
substituted nitrobenzenes, in addition to 1,4-dinitrobenzene,
Since this highly efficient reaction can serve as a new structures containing weak electron-withdrawing substituents
methodology for the synthesis of 1H-indazoles, we then proceeded (Cl, Br and I) could also be employed as the right substrates to
to study the scope of the reaction (Scheme 4). For the nitrobenzenes, give the corresponding products 1e–h in moderate to excellent
it turned out that m-CF3-, m-EtO2C-, and m-NC-substituted ones yields. As for ortho-substituted nitrobenzene, the corresponding
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Scheme 5 Application to the formal synthesis of WAY-169916. a Reaction
conditions: 1-nitro-2-(trifluoromethyl)benzene (0.3 mmol), N-tosylhydrazone
(0.45 mmol), NaH (1.35 mmol), TBAB (0.3 mmol), DMF (2.0 mL), 110 1C.
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attributed to the ortho effect.15
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from aldehydes with weak electron-donating or -withdrawing groups
worked smoothly (1k–l). However, those derived from the aldehydes
bearing strong electron-withdrawing or bulky substituents gave only
diminished yields of the corresponding products (1m–n). For the
reactions with 1-chloro-4-nitrobenzene, the results were somewhat
similar (1o–s). N-Tosylhydrazones derived from heteroaromatic
aldehydes also worked well to give the corresponding products in
moderate yields (1t–u). Besides, the N-tosylhydrazones derived from
alkyl aldehydes and alkenyl aldehydes could also be used to afford
3-alkyl or alkenyl-substituted indazoles in good yields (1v–y).
Finally, the reaction with 1-nitro-2-(trifluoromethyl)benzene
afforded moderate yield of the product (1z). For one of the
products 1k, the structure is unambiguously confirmed by X-ray
diffraction analysis.16
WAY-169916 is the first example of an ER ligand that has
broad anti-inflammatory activity in vivo with the potential use
in the treatment of rheumatoid arthritis but lacks the classical
proliferative effects associated with estrogens.17 The access to
this molecule from previous reports calls for multi-step synthesis.
Herein, the current methodology has been employed to prepare
the key intermediate 3 in one step from the readily available
starting materials (Scheme 5). The intermediate 3 could be easily
transformed to WAY-169916 according to the literature.17c
In conclusion, we have developed a straightforward method
for the synthesis of 1H-indazoles from N-tosylhydrazones and
nitroaromatic compounds. The reaction is efficient and shows
a wide substrate scope. Compared with the existing methods,
ready availability of the starting materials, easy operation, and
no need for transition-metal catalysts are its attractive features.
With these merits, we expect that this methodology would find
applications in the synthesis of 1H-indazoles.
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