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Home > Synthesis and Applications of 9H-Pyrrolo[1,2-a]indole and 9H-Pyrrolo[1,2-a]indol-9-one Derivatives
Synthesis and Applications of 9H-Pyrrolo[1,2-a]indole and 9H-Pyrrolo[1,2-a]indol-9-one Derivatives
Charlotte Lorton[a] and Arnaud Voituriez
1. Introduction
Tricyclic indole backbone is often encountered in natural products and pharmaceuticals. This class of heterocycles, and especially the pyrrolo[1,2-a]indole scaffolds, has attracted much attention due to their potent biological activities (Scheme 1a). As representative examples, mitomycin A and C (compounds 1 and 2) are two effective antitumor agents;[1a] the antiparasitic isoborreverine 3[1b–1c] and the antimalarial alkaloid flinderole C (4) [1d–1e] show interesting biological properties and compound 5 acts as sphingosine-1 phosphate (S1P1) antagonist.[1f–1g]
Moreover, compound 6 is a protein kinase C inhibitor selective for isozyme [1h–1i] and isatisine A (7) acts as an anti-HIV agent.[1j] Since the ‘60s, many synthetic pathways have been developed worldwide for the synthesis of the pyrrolo[1,2-a]-indoles, often driven by the interest of the organic chemistry community for the mitomycinoid alkaloids. These strategies have been reviewed in 2016,[2] but in view
of the renewed interest of the scientific community for this structure, it seemed to us interesting to make this update. In the context of this mini-review, among the three isomeric structures of the pyrrolo[1,2-a]indoles, our attention will be focused towards the 9H-isomer 8 and its oxidized form, the 9H-pyrrolo[1,2-a]indol-9-one 9, with respect to the 3H- and 1H-isomers (respectively products 10 and 11, Scheme 1b). The articles evoking the syntheses of 9H-pyrrolo[1,2-a]indoles will not be fully detailed in this review.[3] On the other hand, the synthetic methodologies (organometallic or non-metallic) for the synthesis of these three-membered nitrogen-containing rings will be detailed. First, the synthesis of 9H-pyrrolo[1,2-a]indoles will be resumed, and then, in the second part, the preparation of 9Hpyrrolo[1,2-a]indol-9-one derivatives. Before the conclusion, various applications in medicinal chemistry and materials chemistry of these molecules of interest will be summarized.
2. Synthesis of 9H-Pyrrolo[1,2-a]indoles
In this part, the synthetic pathways used for the isolation of 9H-pyrrolo[1,2-a]indole derivatives will be developed. First, the reactions promoted by non-metallic reagents will be presented. Both phosphonium and ammonium salts were used, but also acid-promotors, radical precursors, amine-catalyzed and thermal processes. Then will follow metal-catalyzed and metal-promoted reactions, classified according to the type of metal used (copper, palladium, silver, and others).
2.1. Non-Metal Promoted Reactions
In 1966, Schweizer and Light developed the synthesis of unsubstituted 9H-pyrrolo[1,2-a]indole 8 from indole-2-carboxaldehyde 12 and vinyltriphenylphosphonium bromide, in presence of sodium hydride (Scheme 2a).[4] The product was isolated in 58 % yield. It was noticed in this paper that the structure of this product was first incorrectly assigned to the 3H-pyrrolo-[1,2-a]indole 10. [5] As subsequently demonstrated in numerous examples, it turned out that the initially 3H-isomer formed after the intramolecular Wittig reaction isomerizes in situ to the most stable 9H-isomer.[6] This work is the logical extension of the methodologies used by the same team for the synthesis of 3Hpyrrolizine[5,7] and 2H-chromene derivatives.[8] The same strategy was later successfully applied to the synthesis of polysubstituted 9H-pyrrolo[1,2-a]indole 14, [9] with methoxy- and benzyloxy-substituents in position 7 and 8 (Scheme 2b) or with substituents in positions 6 and 7 (compound 16, Scheme 2c).[10]
With substituted-indole-2-carboxaldehydes 17 as starting materials, in presence of methylvinylketone and a benzyltrimethylammonium hydroxide solution, Matsui et al. synthesized five 9Hpyrrolo[1,2-a]indoles 18 in moderate yields (Scheme 3a).[11] Inoue described an original reaction of tris(isopropylthio)cyclopropenylium perchlorate 20 with two different indoles 19, in presence of sodium hydride.[12] Two pyrroloindoles 21 were isolated in 51–84 % yield (Scheme 3b).
Starting from 1-keto-1H-pyrrolo[1,2-a]indoles 22, Remers described a new rearrangement, giving direct access to the 9Hpyrrolo[1,2-a]indole structures 23, substituted with a chlorine atom and a methyl 2-oxoacetate group. The two-steps procedure first involves the reaction with oxalyl chloride and then the addition of methanol (Scheme 4).[13]
In 2009, Su et al. described the synthesis of twelve (9Hpyrrolo[1,2-a]indole-1,2-diyl)dimethanol analogs 26, using a three-steps methodology (Scheme 5).[14] Reaction of indoline-2-carboxylic acids 24 with different alkoyl- or aroyl chlorides furnished the corresponding protected indolines 25. They were reacted then at 120 °C with dimethyl acetylenedicarboxylate (DMAD) in acetic anhydride. The corresponding pyrroloindoles 26 were isolated in 71–89 % yield, after recrystallization. Some post-functionalizations, included reduction of the diester functions to alcohols and reaction with methyl isocyanate, delivered
the desired molecules 27. These products were specifically designed for biological evaluation as antitumor drugs. They are expected to act as DNA bifunctional alkylating agents. They exhibited cytotoxicity against human leukemia and tumor remission in nude mice bearing human breast carcinoma MX–1 xenograft. This work and the preliminary interesting biological results highlighted the interest to develop new methodologies for the synthesis of the 9H-pyrrolo[1,2-a]indole backbone (see part 4 for further applications).
Yavari and Esmaeili independently reported a halide and base-free phosphine-promoted Michael addition/intramolecular Wittig reaction (Scheme 6a).[15] Using a stoichiometric quantity of triphenylphosphine, the reaction pathway started with the addition of the phosphine to the dialkylacetylenedicarboxylate 28 (DAAD), to form the zwitterionic species A. This intermediate deprotonates the indole-2-carboxaldehyde 29, which consequently performs a Michael addition on the corresponding vinylphosphonium salt B, to in situ form a phosphorus ylide C. After the intramolecular Wittig reaction, the 3Hpyrrolo[1,2-a]indole derivatives 30 were isolated. In this process, the use of mild reaction conditions (room temperature for 15 minutes) allows isolating the 3H-pyrrolo[1,2-a]indole isomer. In fact, when the 9-chloro-3H-pyrrolo[1,2-a]indole-2,3-dicarboxylate product was refluxed 24 h in toluene, the authors described the isomerization into the 9H-pyrrolo[1,2-a]indole. As a potential derivatization of these compounds, we can notice that the hydrolysis of 9-chloro-9H-pyrrolo[1,2-a]indole product occurred in a mixture CHCl3/H2O, 24 h at reflux. Even if this synthetic protocol proves to be very efficient in term of conversion rate Mainly to facilitate the purification issue, we proposed recently to use in this reaction a sub-stoichiometric quantity of trivalent phosphine (Scheme 6b). The in situ chemoselective
reduction of the phosphine oxide could be achieved efficiently using 1.0 equiv. of a reducing agent, such as phenylsilane.[16]
Even if this catalytic protocol was previously used in different venerable reactions (Wittig, Mitsunobu, Staudinger), that was to the best of our knowledge, the first example of a tandem Michael addition/Wittig reaction, catalytic in phosphine. Using this protocol, it was possible to realize a wide range of Michael addition/intramolecular Wittig reactions, using electron-rich (such as 5-methyl, 5-methoxy and 5-benzyloxy-indoles) and electron-poor substrates (such as 5-fluoro, 5-nitro, and 5-triflateindole-2-carbaldehydes).[17] Using these reaction conditions (60 °C in toluene for 16 h), the most stable 9H-pyrrolo[1,2-a]-indole isomer 31 was directly isolated. In our hand, the use of microwave heating allowed to shorten the reaction time to 2 h, while maintaining excellent yield (93 % yield for the synthesis of the diethyl 7-bromo-9H-pyrrolo[1,2-a]indole-2,3-dicarboxylate product). The structural assignment of this molecule was ascertained by single-crystal X-ray analysis, which verified the formation of the 9H-pyrroloindole isomer.
In our hand, with the 3-chloro-1H-indole-2-carbaldehyde substrate 29, the hydrolysis of the chlorinated intermediate was directly observed (Scheme 7). Subsequent oxidation into the 9H-pyrrolo[1,2-a]indol-9-one derivative 33 was accomplished in 90 % yield, using pyridinium chlorochromate (PCC). The procedure (cyclization/isomerization/hydrolysis/oxidation) could be achieved sequentially in one pot, with 90 % overall yield. In the following, we fully expanded the scope of this catalytic one-pot Michael addition/intramolecular Wittig reaction to the synthesis of numerous nitrogen-containing heterocycles. Notably, pyrrolizine, pyrroloquinoline, dihydroquinoline, and benzothienopyridine backbones were easily obtained using this catalytic protocol.
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