One-Pot Synthesis of Novel 2,3-Dihydro-1H-indazoles

A copper(I)-mediated one-pot synthesis of 2,3-dihydro-1H-indazole heterocycles has been developed. This synthetic route provides the desired indazoles in moderate to good yields (55%–72%) which are substantially better than those achievable with an alternative two-step reaction sequence. The reaction is tolerant of functionality on the aromatic ring.

Additionally, there have been a few studies in which formation of derivatives of indazole 5 have been observed as a result of trapping experiments on reactive intermediates [9][10][11]. However, other than Zenchoff's limited work, we are unaware of the development of any general routes for the synthesis of this class of heterocycles.
In addition to being interesting compounds in their own right, 2,3-dihydro-1H-indazoles 5 have also served as synthetic intermediates for their more thoroughly-studied counterparts, the 1H-indazoles 4 [8]. Thus, development of synthetic routes towards the synthesis of indazoles 5 similarly creates novel routes for the synthesis of indazoles 4.
The sparse number of investigations into the synthesis of this class of heterocycles is, therefore, quite surprising given that 2,3-dihydro-1H-indazoles have such strong potential for biological activity and as convenient synthetic intermediates. Detailed investigations of their properties, however, demand robust synthetic methods for their preparation. Herein, we describe our initial investigations towards the synthesis of this understudied class of heterocyclic compounds.

Results and Discussion
Ullman-type copper(I)-mediated coupling of bis-BOC protected hydrazine 8 to aryl and vinyl halides in DMF using CuI, 1,10-phenanthroline and Cs 2 CO 3 is a well-established synthetic procedure (see Scheme 2) [14,15]. We initially envisioned the synthesis of bis-BOC protected 2,3-dihydro-1Hindazoles 10 via intramolecular coupling of the free N-H bond of hydrazines 9 at the iodo-substituted carbon atom to form the five-membered indazole nucleus (Scheme 3). Indeed, this proved to be an excellent method for the synthesis of substituted indazoles, providing high yields of 10 (Scheme 3).

Scheme 2.
Ullman-type coupling of hydrazine 8 to halogenated aromatics. Unfortunately, however, synthesis of the required trisubstituted hydrazine starting materials 9 proved to be problematic (Scheme 4). Although we utilized reaction conditions optimized by Rasmussen for selective monoalkylation of 8 [16], only poor yields of monoalkylated product were obtained (i.e., compounds 10a-c were obtained in 25%, 27% and 16% yields, respectively). Surprisingly, bisalkylation of hydrazine 8 was the preferred reaction route. We attempted to increase the yield of monoalkylated product by increasing the amount of starting 8 relative to starting benzyl bromides 11, but this led to difficulties in separation of the product from excess 8. Additionally, other than 11a, which was commercially available, the required substituted ortho-iodobenzyl bromides (compounds 11b-f) needed to be synthesized from the corresponding benzylic alcohols via a two step process of iodination of the aromatic ring (silver CF 3 CO 2 Ag/I 2 ) followed by bromination at the benzylic alcohol position (PBr 3 ). Thus, although the intramolecular coupling reactions afforded high yields (Scheme 3), the effective yields from the synthetically expensive ortho-iodobenzyl bromides were unsatisfactorily low.

Scheme 4. Synthesis of monoalkylated bis-BOC protected hydrazines 9.
To bypass the problem of dialkylation, we considered the possibility of developing a one-pot procedure in which copper-mediated coupling of the initially formed monoalkylated hydrazines 9 to form indazoles 10 might be able to compete with the complicating dialkylation process. A mixture of 8 and ortho-iodobenzyl bromide 11a was added slowly, via syringe pump (over a period of 7 h), to a pre-heated stirring mixture of CuI, 1,10-phenanthroline and Cs 2 CO 3 . After 24 h, we were gratified to note that the only major product detected by TLC analysis of the crude reaction mixture was the desired indazole 10a. Reaction workup, followed by column chromatography afforded 10a in 60% yield, a substantial increase from the effective 22% yield obtained via the two-step process (i.e., 11a→9a→10a) starting from the ortho-iodobenzyl bromide 11a. In addition, this procedure avoided the need for purification of the intermediate hydrazine 9a. Similarly, indazoles 9b and 9c were formed in 60% yields utilizing the one-pot procedure rather than the effective 25% and 15% yields, respectively, from the corresponding two-step procedures.
Given the success of this one-pot procedure, we subjected a number of substituted ortho-iodobenzyl bromides to the same reaction conditions. The yields were consistent at ~60% (Table 1), and the products were obtained in pure form following column chromatography. The reaction was tolerant of electron-donating (i.e., OCH 3 ) and electron-withdrawing (i.e., CO 2 CH 3 ) groups.

General
All chemicals and solvents were used as received (Aldrich, St Louis, MO, USA) Anhydrous DMF was kept under nitrogen and sealed with a septum. Column chromatography was performed using 230-400 mesh silica gel 60. NMR spectra were recorded on a Varian 60 MHz instrument in CDCl 3 as solvent, unless otherwise indicated, and referenced relative to TMS (0.0 PPM). Combustion analysis was performed by Micro Analysis Inc. (Wilmington, DE, USA). Other than unsubstituted 2-iodobenzyl bromide 11a, which was commercially available (Aldrich), benzyl bromides 11b-f were synthesized via standard aromatic iodination (I 2 , CF 3 CO 2 Ag) followed by bromination of the benzylic alcohol (PBr 3 ) following procedures described in the literature [17].

Conclusions
In summary, a convenient synthesis of substituted 2,3-dihydro-1H-indazoles has been developed. This one-pot procedure provides indazoles at considerably higher yields than the corresponding twostep process. This constitutes one of the first general synthetic methods for this class of heterocyclic compounds.