An expedient general synthesis of pyrrolo[3,2-e ]indazoles: domino Sonogashira/Cacchi coupling-heteroannulation reactions

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Introduction
The indole ring constitutes the structural core of a host of bioactive compounds of natural and synthetic origins. 1,2More than 10,000 bioactive indoles are known, of which over 200 are either used as drugs or are in clinical trials. 3Substituted indazoles too are of considerable pharmaceutical importance because of their therapeutic potential and use, 4 amongst which benzydamine is a notable anti-inflammatory agent. 5,6In continuation of our ongoing interest in the development of general synthetic routes to potentially bioactive condensed nitrogen heterocycles, [7][8][9][10][11][12][13][14] we recently focused our attention on a relatively less studied class of heterocycles which incorporate both the indole and the indazole nuclei, viz.pyrazoloindoles which may also be regarded as pyrroloindazoles.A report on the study of indazole-containing polycyclic compounds in search of antitumor agents 15 strengthened our motivation.
The reported bioactivity, hence the bioactive potential of pyrrolo[3,2-e]indazoles and particularly the absence of a general synthetic route to this particular isomeric class called for the development of a general synthesis of pyrrolo [3,2-e]indazoles, which we have now accomplished and is reported herein.
Several classical routes to the synthesis of indoles are known. 34,35Indazoles too have been the subject of synthetic efforts during the past decades. 36Our plan was to utilize one of the recently developed palladium-catalyzed synthetic routes to indoles 37,38 because of the mild reaction conditions involved, tolerance of a wide variety of functional groups (thereby avoiding the use of protecting groups), high regioselectivities and high yields.
The aminopalladation/reductive elimination domino reaction of alkynes containing a proximate nitrogen nucleophile, first observed by Yamanaka and subsequently by Cacchi, 39 has proved to be very useful for the formation of a pyrrole ring incorporated into an indole nucleus.To be precise, Cacchi's novel approach to 2,3-disubstituted indoles through a palladiumcatalyzed cyclisation of ortho-alkynyl-trifluoroacetanilides with aryl, heteroaryl and alkenyl halides, specially iodides, or triflates 40,41 was of interest to us.Later, Flynn modified conditions to develop a one-pot, two-step synthesis of only one 2,3-disubstituted indole using bis(triphenylphosphine)palladium(II) dichloride as the catalyst. 42
Accordingly, the desired starting amine 8 was prepared from commercially available indazole 6 by successive N(1)-phenylsulfonylation (PTC-mediated) and reduction (hydrazine hydrate and palladized charcoal) of the resulting protected nitroindazole 7. It was then iodinated exclusively at C-4 by N-iodosuccinimide (NIS) to efficiently furnish 9.The site of iodination received support from the appearance of 1 H NMR signals at δ 7.09 and ca.7.84 ppm (1H, d each J 9 Hz) in the 1 H NMR spectrum of 9, which corresponded to H-6 and H-7.The aminoiodoindazole 9 was trifluoroacetylated to furnish the Sonogashira/Cacchi substrate, ortho-iodotrifluoroacetamidoindazole 10 in very good yield (Scheme 2).Scheme 2. Preparation of the key precursor 10.
The reaction of the Sonogashira/Cacchi substrate 10 was first tried with TMSA 11a since TMSAs can be hydrodesilylated using a fluoride source, mostly TBAF, or an inorganic base, usually aq.KOH-MeOH.We used bis(triphenylphosphine)palladium(II) dichloride [Pd(Ph 3 P) 2 Cl 2 ] (10 mol %) as the catalyst in our experiments.Thus, 10 was treated with 11a (1.4 equiv) and Pd(Ph 3 P) 2 Cl 2 (10 mol %) in DMF in the presence cuprous iodide (10 mol %) as the co-catalyst and Et 3 N (10 equiv) as the base and stirred at 100-110 ºC in an argon atmosphere (to avoid Hay-Glaser homocoupling of terminal acetylenes 47 ) until the substrate was consumed.The optimal concentrations of the catalyst, the co-catalyst and the base were determined by trial experiments which have not been described in the Experimental Section.A usual work-up of the reaction mixture, followed by purification of the crude product by column chromatography over silica gel, furnished a single product.Though expected to be the corresponding 7-TMSpyrroloindazole, the sole product was indeed identified as 7-unsubstituted 3-phenylsulfonyl-3,6dihydropyrrolo[3,2-e]indazole 12a by combined spectroscopic (IR, 1 H and 13 C NMR, MS) and elemental analyses.The presence of two 1 H NMR signals at δ 7.71 and 7.87 ppm (1H, each d, J 9 Hz), corresponding to H-4 and H-5 of the pyrrolo[3,2-e]indazole nucleus, lent support to its type of isomer.It thus transpired that the tandem Sonogashira/Cacchi coupling-heteroannulation as well as hydrodesilylation had occurred in one pot.
The observed cleavage of the TMS group occurring under the tandem Sonogashira-Hagihara/Cacchi cross-coupling-heteroannulation reactions requires explanation since we did not use any hydrodesilylating agent in our experiment.We believe, direct palladium-coppercatalyzed coupling of 10 with 11a in a so-called "sila"-Sonogashira reaction 48 led to the elimination of trimethylsilyl iodide with the formation of ortho-ethynyl-trifluoroacetamidoindazole.It was immediately followed by 5-endo-dig cyclisation to form 12a. The occurrence of two reactions in tandem and the high yield of the product encouraged us to check the generality of the reaction.Hence, 10 was separately treated with seven other terminal acetylenes 11b-h under the aforesaid conditions.Gratifyingly, the respective 7-substituted 3phenylsulfonyl-3,6-dihydropyrrolo[3,2-e]indazoles 12b-h were isolated as the sole products in 82-94% yields in 5-8 h (Table 1).In the 1 H NMR spectra of all these products, the signals for H-4 and H-5 appeared as 1H, doublet each in the range δ 7.59-8.0ppm showing, as expected, an ortho-coupling (J 8.5-9.5 Hz).The formation of [3,2-e]-type of pyrroloindazoles was thus confirmed.Pertinently, H-1 appeared at δ 8.6-8.9 ppm (s) in 12a-h, whereas H-8 appeared at ca. δ 6.5 ppm (s) in the 7-alkyl derivatives 12b-e and at δ 7.2-7.3ppm (s) in the 7-aryl derivatives 12f-h.For N(3)-deprotection, each of 12a-h was refluxed with aqueous methanolic potassium carbonate for 2 h, which generated the parent 7H/substituted 3,6-dihydropyrrolo[3,2-e]indazoles (13a-h) in 85-91% yields (Table 2).As expected, H-1 showed an upfield shift (to δ 8.1-8.3 ppm, s) in 13a-h, whereas there was not much effect on the chemical shifts of H-8.

Conclusions
An efficient, general synthesis of 7-H/substituted 3,6-dihydropyrrolo[3,2-e]indazoles has been developed by the reaction of 4-iodo-1-phenylsulphonyl-5-trifluoroacetamidoindazole with terminal alkynes using Sonogashira/Cacchi coupling-heteroannulation reactions, followed by N(3)-deprotection.To the best of our knowledge, this is the first general synthesis of this class of compounds, that too involving domino reactions.The overall procedure is simple, the yields are consistently high and both the indolic and the indazolic nitrogens are amenable to derivatization, thereby rendering our method even more useful.Furthermore, our work opens up the study of the reactions of 10 with internal alkynes, which is likely to unveil interesting results on 7,8disubstituted pyrroloindazoles.Pertinently, after the completion of our work, a report was published only a few months ago on a convenient synthesis of pyrrolo [3,4-g]indazoles by the annelation of the pyrazole ring on the isoindole moiety, and four members of the synthesized pyrroloindazoles showed modest antitumor activity against a host of human tumor cell lines. 49

Experimental Section
General.All melting points (in Celsius) were recorded on a Toshniwal apparatus.The IR spectra were recorded on KBr pellets using a Perkin-Elmer-782 spectrophotometer, the 1 H (500 MHz) and 13