Metal-free regioselective mono- and poly-halogenation of 2-substituted indazoles

An unprecedented metal-free regioselective halogenation of 2H-indazoles has been revealed, which not only realized the highly selective synthesis of mono-halogenated products, but also completed poly-halogenations by fine tuning the reaction conditions. Various mono-/poly-/hetero-halogenated indazoles were obtained in moderate to excellent yields. Notably, this approach features environmentally friendly solvents, mild reaction conditions, simple execution and short reaction time.

Halogens can signicantly alter the biological properties of molecules, rendering the use of these compounds as drugs, agrochemicals, biocides, etc. 1 In addition, organic halides are one of the most widely used precursors or intermediates for numerous organic transformations. 2 For example, heteroaromatic bromides and iodides play an important role in Grignard reactions 3 and cross-coupling. 4 Therefore, the construction of halogenated hetero-aromatic compounds through direct C-H halogenation is highly desirable.
Recognizing the importance of these molecules, chemists have developed various methods to synthesize indazole halides. However, C-H direct bromination of indazoles without metal catalysts has been rarely reported. Clarisse declared the bromination of 2-phenyl-2H-indazole employing Br 2 as brominating reagent. 12 Although 3-bromo-2H-indazole was formed in high yield, a mixture of 3,5-dibromo-and 3,7-dibromo-2Hindazole was obtained with poor selectivity and low yield. At the same time, the use of Br 2 was environmentally unfriendly and troublesome. Herein, an efficient C-H direct halogenation of 2H-indazoles employing NXS (X = Br, Cl) was reported, which achieved the selective synthesis of mono-, poly-and heterohalogenated products in high yields by adjusting reaction conditions.
In our initial study, 2-phenyl-2H-indazole (1a) and NBS (1.0 equiv.) were selected as model substrates to react at 25°C. It was delighted that 88% mono-brominated product 2a was obtained aer 2.0 h (  [8][9][10]. It was worth to mention that no byproduct 3,5-dibromo-2H-indazole was detected. This reaction was then carried out at 80°C by increasing the equiv. of NBS, suggesting that trisubstitution was best performed at 4.0 equiv. of NBS in MeCN and the yield of tribrominated product 4a could be increased to 71% (Table 1, entry 13).
With the mentioned optimized reaction protocol in hand, rst of all, the scopes of the mono-bromination were examined ( Table 2). The effects of different substituents on the N-phenyl ring of 2H-indazoles were investigated, and the desired products could be obtained in the yield of 80-98% for both electrondonating and electron-withdrawing groups (2a-2l). Steric hindrance had effect on the yield, m-substituents on the phenyl ring resulting in lower yields compared to p-substituents (2b and 2g), and 3,4-disubstituents on the phenyl ring furnishing the desired products in moderate yields (2m and 2n). However, the situation changed when the substituents was on the indazole skeleton. It was found that electron-withing groups such as F or Cl were compatible with the optimized reaction conditions and afforded the corresponding desired products in good to excellent yields (2p vs. 2q). While the substituent was methoxy, the raw material could not be completely converted giving product in 31% yield (2o). Furthermore, this method could be extended to the mono-bromination of N-pyridyl indazole with 81% yield (2r). In addition, applicability of aliphatic substituted substrates was also explored. The yield decreased sharply to 36% when the substituent was tert-butyl (2s), while none product was detected with n-butyl substituted indazole (2r).
To identify the structures, we took product 3c and 3j as examples to measure DEPT135, 1 H-1 H COSY, 1 H-13 C HSQC and 1 H-13 C HMBC spectra (Fig. 2), the details are listed in the ESI. † For purpose of demonstrating the suitability of this halogenation method on a large scale, a gram-scale reaction was investigated. The results showed that 6.0 mmol of 1a (1.164 g) could be cleanly converted to 2a with either EtOH or H 2 O as solvent (Scheme 1).
We considered that a radical pathway mechanism could be involved on the grounds of experimental results and previous reports. 13 At rst, NBS was pyrolyzed under heating conditions to generate bromine radical and radical A. Then substrate 1a reacted with bromine radical to generate intermediate I, which would further oxidize by radical A to produce cationic intermediate II and succinimide anionic B. The proton transfer occurred between the above two ions, and nally succinimide C and mono-brominated product 2a were generated. Similarly, dibrominated product 3a could be obtained from 2a via the above pathway (Scheme 3).

Conclusions
In summary, we have successfully developed a simple and universal metal-free method for the synthesis of mono-and poly-halogenated 2H-indazoles. The mono-halogenation could be carried out in water giving products with good yields. Furthermore, hetero-halogenated 2H-indazole compounds were also achieved via a one-pot reaction. In addition, the gram-scale reaction also produced excellent yields. This new transformation exhibits high selectivity, good functional group tolerance, easy handing and eco-friendliness, rendering the "green" methodology as potential applications in agrochemical and pharmaceutical industries.

Conflicts of interest
There are no conicts to declare.