The Suzuki Reaction Applied to the Synthesis of Novel Pyrrolyl and Thiophenyl Indazoles

The paper describes the Suzuki cross-coupling of a variety of N and C-3 substituted 5-bromoindazoles with N-Boc-2-pyrrole and 2-thiopheneboronic acids. The reactions, performed in the presence of K2CO3, dimethoxyethane and Pd(dppf)Cl2 as catalyst, gave the corresponding adducts in good yields. The methodology allows the facile production of indazole-based heteroaryl compounds, a unique architectural motif that is ubiquitous in biologically active molecules.

Due to the broad variety of their biological activities, the synthesis of indazole derivatives as well as the functionalization of the indazole ring system have recently been reviewed [4][5][6][7][8][9][10][11][12], especially in the context of drug development. During the last years, indazole derivatives bearing aryl groups on the 5 or 6 position have been prepared and identified as potent, selective glucocorticoid receptor agonists and antagonists [13] or inhibitors of protein kinase c-zeta [14]. Conversely, to the best of our knowledge, the functionalization of the indazole ring with aromatic heterocycles like pyrrole and thiophene has been less explored. Among the very few reported examples, some recent patents have described 3-substituted-5-thienyl-1H-indazole as ligands for nicotinic acetylcholine receptors [15] or inhibitors of kinase activity [16,17]. Likewise, only 6-pyrrolyl-indazoles have recently been disclosed for their inhibitory activity of glycogen synthase kinase-3, and their synthesis was performed starting from pyrrolylbenzonitriles [18]. As part of the effort to discover novel indazole derivatives as valuable building blocks in medicinal chemistry [19], we were looking for an efficient and effective synthetic protocol of wide applicability towards 5-(pyrrol-2-yl)-and 5-(thiophen-2-yl)-1H-indazoles. The Suzuki reaction provides a very reliable method for the preparation of biaryl derivatives [20]. However, although simple aryl halides and aryl boronic acids are widespread employed coupling partners, the corresponding reactions involving their heteroaryl analogues are noticeably fewer [21][22][23][24][25][26][27][28]. Herein, we report our initial investigations on the Suzuki cross-coupling between differently N-substituted 5-bromo-indazoles and pyrrole-or thiopheneboronic acids.

Results and Discussion
In order to determine the optimal reaction conditions we began by studying the cross-coupling of 5-bromo-1-ethyl-1H-indazole (3a) with N-Boc-2-pyrroleboronic acid (4) [29] as a pilot reaction (Scheme 1). Indazole 3a was prepared by the alkylation of the 5-bromo-1H-indazole with ethyl bromide [30]. In the presence of cesium carbonate (Cs 2 CO 3 ), a 1.2:1 ratio of 3a and the N-2 isomer 3g was obtained. The two regioisomers were purified and identified by comparison of their spectral data with that reported for similar N-alkylated indazoles [31]. The Suzuki reaction was carried out by employing K 2 CO 3 as base, dimethoxyethane as solvent and heating the reaction mixture at 80 °C. As shown in Table 1, we examined four palladium catalysts and found that [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride [Pd(dppf)Cl 2 ] [32] was the best choice, affording the coupling product in high yield after only two hours. Interestingly, bis(tricyclohexylphosphine)palladium [Pd(PCy 3 ) 2 ] yielded the product in modest yield, although generally the electron richness and the sterical hindrance of the phosphinic ligands make it an efficient palladium source for cross-coupling reaction [33,34]. The commonly used tetrakis(triphenylphosphine)palladium [Pd(PPh 3 ) 4 ] and bis(triphenylphosphine)palladium(II) dichloride [Pd(PPh 3 ) 2 Cl 2 ] were less effective than [Pd(dppf)Cl 2 ] for this transformation, affording the final product after longer reaction times and in lower yields. Having identified Pd(dppf)Cl 2 as the most suitable catalyst, in order to explore the versatility of this type of Suzuki coupling, a series of 5-bromoindazoles bearing alkyl or acyl groups on the N-1 or N-2 positions were prepared [30,[35][36][37][38] and tested with Boc-protected-2-pyrroleboronic acid 4 (Scheme 2). Scheme 2. Synthesis of 5-(pyrrol-2-yl)-1H-indazoles by the Suzuki cross-coupling. In all cases the expected coupling products were obtained in very modest to quite good yields and fully characterized ( Table 2). The lower yields registered for the N-acyl-indazoles 3e and 3f may be a consequence of the facile deacylation of these substrates under basic conditions [39]. This is confirmed by the isolation of 5c (30% yield) as an additional product in their reaction mixtures. The reaction was also performed on the unsubstituted 5-bromoindazole 3c and afforded the corresponding product 5c in 50% yield, due to the likely formation of side-products, not further investigated. Moreover, it is worthy to note that the N-Boc-indazole 3d resulted to be a very good substrate for the cross-coupling. The easy removal of the Boc group would make the coupling product 5d a valuable building block in the synthesis of new interesting indazole-based molecules.
On the basis of these positive results, we extended the scope of the Suzuki cross-coupling to the synthesis of 5-(thiophen-2-yl)-1H-indazoles. Thiophene, like pyrrole, is found in a variety of natural products and pharmaceutically interesting compounds [40]. In addition, polythiophenes, which are often prepared via Suzuki-Miyaura processes, are highly conducting polymers that possess good processing qualities [41].

Products 5 Yield 5 [a] Products 7 Yield 7 [a]
a N N N Boc On the bases of the described successful results and in view of the interest in C-3 substituted indazole derivatives reported in the literature [5], a preliminary study for the extension of the above reaction to C-3 substituted indazoles has been also initiated. To this purpose, 5-bromo-1H-indazole-3carboxylic acid methyl ester (8, Scheme 4) was prepared by a known esterification of 5-bromo-1Hindazole-3-carboxylic acid, reported to afford 8 as the unique product [42]. However, in our hands, the protocol gave a 1:1 mixture of two products identified as 8 and the corresponding unprecedented 1-methyl derivative 9, respectively. Therefore, both substrates 8 and 9 were reacted with the Boc-protected-2-pyrroleboronic acid 4 (Scheme 4) and gave the corresponding 3-substituted-(5-pyrrol-2-yl)-indazoles 10 and 11, thus indicating that the C-3 substituent doesn't invalidate the success of the Suzuki reaction. The extension of this methodology to variously C-3 functionalized indazole derivatives by using pyrrole and thiophene boronic acids is currently under investigation.

General Experimental Methods
Solvents and common reagents were purchased from a commercial source and used without further purification. N-Boc-2-pyrroleboronic acid 4 was prepared according to the literature procedure [29].

Conclusions
In summary, this work establishes that indazoles bearing alkyl or acyl groups at either the N-1 or N-2 positions are suitable substrates for Suzuki cross-coupling reactions with pyrrole-and thiopheneboronic acids. We found that in the presence of Pd(dppf)Cl 2 as palladium catalyst, the Suzuki reactions proceed in relatively short times (2 h) and in good yields. The best results were obtained when N-alkyl and N-Boc indazoles were employed as starting materials. Moreover, it was demonstrated that even bromoindazoles bearing a carbomethoxy group on C-3 are good coupling partners in these reactions. To the best of our knowledge, this is the first systematic study of Suzuki reactions between various 5-bromoindazoles and 2-pyrrole-or 2-thiopheneboronic acids. This could provide a promising access to new heterobiaryl compounds, valuable building blocks for use in medicinal chemistry.