Synthesis of Structurally Diverse 2,3-Fused Indoles via Microwave-Assisted AgSbF₆-Catalysed Intramolecular Difunctionalization of o-Alkynylanilines

Abstract

2,3-Fused indoles are found in numerous natural products and drug molecules. Although several elegant methods for the synthesis of this structural motif have been reported, long reaction times and harsh conditions are sometimes required and the yields tend to be low. Herein, we report a microwave method for straightforward access to various types of 2,3-fused indoles via AgSbF₆-catalysed intramolecular difunctionalization of o-alkynylanilines. AgSbF₆ played a role in both the hydroamination step and the imine-formation step. This method, which exhibited excellent chemoselectivity (no ring-fused 1,2-dihydroquinolines were formed), was used for formal syntheses of the natural products conolidine and ervaticine and the antihistamine drug latrepirdine.

Introduction

Ring-fused indoles in general and 2,3-fused indoles in particular, are found in numerous natural products and drug molecules (Fig. 1)^{1,2,3,4,5,6,7,8}. Hexahydro-1H-azocino[4,3-b]indole is the core motif of numerous natural products, such as (+)-condylocarpine⁹, (+)-uleine¹⁰, conolidine and ervaticine¹¹, (−)-actinophyllic acid¹² and (−)-strychnine¹³. In addition, the clinical antihistamine drug latrepirdine contains a tetrahydro-1H-pyrido[4,3-b]indole skeleton (also known as γ-carboline)¹⁴. 2,3-Fused indoles have synthetically challenging structures and interesting biological activities and much attention has been paid to the development of new approaches to the synthesis of this structural motif^{15,16,17,18,19}. However, a practical method for the efficient synthesis of 2,3-fused indoles in a single operation is lacking.

Figure 1

Representative compounds with 2,3-fused indole motifs.

Intramolecular difunctionalization of o-alkynylanilines is widely used to construct ring-fused indoles^20,21,22, but this method and other conventional synthetic methods, suffer from long reaction times, harsh conditions and low yields. Microwave-assisted organic synthesis, which was first reported by Gedye et al. and Giguere et al. in 1986^23,24, can be used to increase product yields and dramatically reduce reaction times compared to those of conventional synthetic methods^25,26. Therefore, we wondered whether microwave-assisted intramolecular difunctionalization could be used to construct 2,3-fused indoles efficiently.

Results

To evaluate this possibility, we initially carried out the reaction of o-alkynylaniline 1a and benzaldehyde (2 equiv) with 10 mol% Sc(OTf)₃ as a catalyst in 1,2-dichloroethane for 1.5 h at 80 °C at a microwave power of 100 W. These reaction conditions yielded indole 3aa′ as the sole product in 10% yield (Table 1, entry 1) and bicyclization product 3aa was still not obtained when In(OTf)₃ or Cu(OAc)₂ was used instead of Sc(OTf)₃ (entries 2 and 3). However, 3aa was obtained in 94% yield when AgSbF₆ was used as the catalyst (entry 4). The nature of the solvent greatly influenced the outcome of the reaction. No 3aa formed when the solvent was 1,4-dioxane or acetonitrile and the yield was only 54% in toluene (entries 5–7, respectively). Neither lowering the reaction temperature (entry 8) nor shortening the reaction time (entry 9) provided any benefit. Other silver(I) catalysts gave no better results than AgSbF₆ (entries 10–12) and in the absence of microwaves, more than 30 h was required to give 3aa in 86% yield (entry 13). These preliminary results indicated that the optimal reaction conditions were as follows: 10 mol% AgSbF₆ in 1,2-dichloroethane at 80 °C (entry 4). This reaction exhibited excellent chemoselectivity: no ring-fused 1,2-dihydroquinoline 3aa′′ was obtained²⁷.

Table 1 Optimization of reaction conditions^a.

We then used the optimal conditions to investigate the substrate scope of the reaction (Fig. 2). First, we carried out reactions of 1a with various substituted benzaldehydes (2a–2i). The corresponding difunctionalization products (3aa–3ai) were obtained in more than 80% yield, indicating that neither the position nor the electronic properties of the substituents had a marked effect on the reaction outcome. We evaluated the electronic effects of substituents (R) on the benzene ring of 1 by carrying out reactions of 1a–1k with 2j. Substrates with no substituents, a weakly electron-withdrawing substituent (1a–1e), or an electron-donating substituent (1f–1g) afforded desired compounds 3aj–3gj in more than 80% yield. Substrates with a strongly electron-withdrawing group, such as a cyano, trifluoromethyl, nitro, or methoxycarbonyl group, could also be converted to the desired products (3hj–3kj), albeit in slightly lower yields. Difunctionalization products 3ak–3ao were obtained in moderate to good yields when 1a was allowed to react with aliphatic aldehydes 2k–2o and the structures of 3aa and 3ak were confirmed by X-ray diffraction analysis²⁸. Substrate 1a reacted with aromatic aldehydes 2-naphthaldehyde (3ap, 81%), thiophene-2-carbaldehyde (3aq, 64%), furan-2-carbaldehyde (3ar, 36%) and piperonyl aldehyde (3as, 87%).

Figure 2

Synthesis of tetrahydro-1H-pyrido[4,3-b]indole and tetrahydropyrano[4,3-b]indole by intramolecular difunctionalization^[a].

^[a]The yields given are isolated yields. DCE = 1,2-dichloroethane, Ts = 4-methylphenylsulfonyl, Ms = methanesulfonyl, MW = microwave. ^[b]The reaction was conducted with 1a (1 equiv) in the presence of AgSbF₆ (10 mol%) in DCE at a MW power of 100 W for 1 h at 80 °C. Then 2k (2 equiv) and CF₃COOH (1.5 equiv) were added and the mixture was reacted under the same conditions for 3 h.

We also evaluated various nucleophilic moieties. The reaction worked well when the methylphenylsulfonyl group (XH = NHTs) was changed to a methanesulfonyl group (3lj, 72%) and tetrahydropyrano[4,3-b]indole (3mj) was obtained in 64% when XH was OH rather than NHTs. However, when YH was OH, intramolecular difunctionalization product 3nj was not obtained, owing to the poor nucleophilicity of the phenolic hydroxyl group; instead, 5-endo-trig product 3nj′ resulting from a reaction in which water acted as a nucleophile was the sole product.

We also investigated ring-closure reactions to form ring systems of various sizes (Fig. 3). Substrate 1o (n = 1) reacted both with aromatic aldehydes (2a, 2d, 2e and 2q) and with aliphatic aldehydes (2j, 2l and 2n) to afford the corresponding hexahydro-1H-azocino[4,3-b]indoles. We investigated both a one-pot method (Method A) and a stepwise method (Method B) and found that the latter gave higher yields. When CF₃COOH was added to the reaction mixture (Method C), indoles fused to seven- to nine-membered-rings (3ok, 3pk and 3qk) were obtained; 3pk (hexahydro-1H-azocino[4,3-b]indole) is the core skeleton of many natural products (Fig. 1). The structures of 3pk and 3oq were confirmed by X-ray diffraction analysis²⁸.

Figure 3

Synthesis of indoles fused to saturated medium-sized N-containing rings by means of intramolecular difunctionalization^[a].

^[a]The yields given are isolated yields. DCE = 1,2-dichloroethane, MW = microwave. ^[b]Method A: The reaction was conducted with 1 (1 equiv) and 2 (2 equiv) in the presence of AgSbF₆ (10 mol%) at a MW power of 100 W in DCE for 6 h at 80 °C. ^[c]Method B: The reaction was conducted with 1 (1 equiv) in the presence of AgSbF₆ (10 mol%) at a MW power of 100 W in DCE for 3 h at 80 °C. Then 2 (2 equiv) was added and the mixture was allowed to react under the same conditions for another 3 h. ^[d]Method C: Similar to method B, except that CF₃COOH (1.5 equiv) was added along with 2 (2 equiv) in the second step.

Plausible pathways for the difunctionalization reactions between n-butanal and 1a (YH = NHTs) and 1n (YH = OH) are depicted in Fig. 4a. Pathway 1 involves initial closure of the B ring to form 3aa′ via an AgSbF₆-catalysed hydroamination reaction. Subsequently, AgSbF₆ promotes the formation of imine A²⁹, which is further transformed to target compound 3aj via a 6-endo-trig cyclization. In this pathway, AgSbF₆ catalyses both the hydroamination step and the formation of imine A. In pathway 2, an initial AgSbF₆-catalysed imination reaction results in the formation of imine B, which can undergo two possible cyclizations: (1) 6-endo-trig cyclization leading to intermediate C, which can then be transformed to 3aj or (2) 5-endo-trig cyclization (when YH = OH) leading to intermediate D, which can afford pyrrolidine 3nj′ by means of the addition of water. A third reaction pathway, leading to ring-fused 1,2-dihydroquinoline 3aa′′ via 5-endo-dig cyclization, is also possible; however, no 3aa′′ was obtained from the reaction.

Figure 4

(a) Plausible reaction pathways and (b) time course of ¹H NMR spectra measured during synthesis of 3aj.

To determine which of these pathways occurred under our reaction conditions, we monitored the formation of 3aj over time by means of ¹H NMR spectroscopy (Fig. 4b). The ¹H NMR spectrum of 1a exhibited a triplet at δ = 2.61 ppm and a quartet at δ = 3.17 ppm. After 10 min of reaction under the optimal conditions (Table 1, entry 4), a new singlet (δ = 6.38 ppm), attributable to the hydrogen at the 3-position of indole 3aa′ (Fig. 2a), was observed, along with a new triplet (δ = 3.22 ppm) and a new quartet (δ = 3.38 ppm), which are attributable to the two CH₂ protons of 3aa′. Note also that at this stage, the triplet and quartet attributable to 1a shifted from 2.61 and 3.17 ppm to 2.80 and 3.10 ppm, respectively, owing to the formation of a complex between 1a and AgSbF₆. At 30 min, all of the complex had been transformed to 3aa′. As the reaction progressed, the signals for 3aa′ disappeared gradually and signals due to 3aj appeared and increased in intensity. The reaction was almost complete after 60 min. These ¹H NMR spectroscopy results suggest that the intramolecular difunctionalization reaction of 1a occurred via pathway 1 in Fig. 4a.

Because our intramolecular difunctionalization method efficiently gave hexahydro-1H-azocino[4,3-b]indole 3pk, we used the method for the rapid formal synthesis of the natural products ervaticine and conolidine as follows (Fig. 5a). Reaction of 2-iodoaniline with Ts-protected hex-5-yn-1-amine gave the corresponding coupled product, which reacted with 4-methylbenzene-1-sulfonyl chloride to give 1p in 72% yield for the two steps²⁷. Exposure of 1p to the optimal difunctionalization reaction conditions afforded 3pk in 73% yield. Removal of the N-tosyl group with sodium and naphthalene³⁰ followed by protection with Boc₂O provided 5pk in 81% over two steps and subsequent oxidation with SeO₂ afforded 6pk (56% yield)³¹, which has been converted to ervaticine and conolidine as described previously³².

Figure 5

Formal syntheses of (a) ervaticine and conolidine and (b) latrepirdine.

We also used our method for a formal synthesis of latrepirdine as follows (Fig. 5b). Compound 1f was obtained by Sonogashira coupling and subsequent protection of the primary amine with 4-methylbenzene-1-sulfonyl chloride in 67% yield for the two steps. Reaction between 1f and formaldehyde by means of the method described for the synthesis of 3ak (Fig. 2) gave 3fk in 95% yield. Removal of the N-tosyl group³⁰ and subsequent reductive amination³³ afforded 5fk (81% yield over two steps), which could be converted to latrepirdine as reported in the literature³⁴.

In summary, we developed a straightforward method for accessing various 2,3-fused indoles via microwave-assisted AgSbF₆-catalysed intramolecular difunctionalization of o-alkynylanilines. The reaction exhibited excellent chemoselectivity: no ring-fused 1,2-dihydroquinolines were formed. In addition to indoles fused to six-membered rings, indoles fused to saturated medium-sized N-containing rings could also be constructed. We used the method for efficient formal syntheses of the indole alkaloids ervaticine and conolidine and the antihistamine drug latrepirdine.

Methods

One-pot synthesis of 3aa

A microwave vessel was charged with o-alkynylaniline 1a (98.5 mg, 0.21 mmol, 1 equiv), AgSbF₆ (7.1 mg, 0.021 mmol, 0.1 equiv), aldehyde 2a (26.7 mg, 0.25 mmol, 1.2 equiv) and DCE (5.0 mL); and the mixture was heated at a microwave power of 100 W at 80 °C for 1.5 h. After the reaction mixture cooled to room temperature, CH₂Cl₂ (10 mL) and H₂O (10 mL) were added. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography with 10:1 (v/v) petroleum ether/ethyl acetate as the eluent to afford 3oa (110.0 mg, 94%) as a white solid (see Supplementary Information).

Stepwise synthesis of 3pk

A microwave vessel was charged with 1p (100.0 mg, 0.20 mmol, 1 equiv), AgSbF₆ (6.8 mg, 0.02 mmol, 0.1 equiv) and DCE (5.0 mL) in that order; and the mixture was heated at a microwave power of 100 W at 80 °C for 3 h. Then 2k (40% formaldehyde, 30.0 mg, 0.40 mmol, 2.0 equiv) and CF₃COOH (34.2 mg, 0.30 mmol, 1.5 equiv) were added and the mixture was allowed to react under the same conditions for another 1 h. CH₂Cl₂ (10 mL) and H₂O (10 mL) were added to the resulting mixture. The organic layer was separated, dried over anhydrous Na₂SO₄ and filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography with 10:1 (v/v) petroleum ether/ethyl acetate as the eluent to afford 3pk (74.2 mg, 73%) as a white solid.