Copper-catalyzed Tandem Annulation/Arylation for the Synthesis of Diindolylmethanes from Propargylic Alcohols

Abstract

Various highly substituted 2,3′-diindolylmethane heterocycles were prepared from propargylic alcohols and indole nucleophiles via a transition metal-catalyzed tandem indole annulation/arylation reaction for the first time. Among the metal catalysts we examined, the most economical copper(I) catalyst provided the highest efficiency. The indole nucleophiles could also be replaced by other electron-rich arenes or alcohols.

As one of the most abundant heterocycles in natural products and pharmaceutical agents, indole continuously attracts significant attention of the synthetic community and many efficient indole annulation methods have been developed to date.¹ To increase the synthetic efficiency of indole derivatives, it is ideal to combine the indole annulation with other transformations in a cascade process. We have recently coupled indole annulation with [4+3] cycloaddition for the synthesis of cyclohepta[b]indoles² and arylation for the synthesis of 2,3′-diindolylmethanes using platinum or rhodium catalysts.³ 2,3′-Diindolylmethanes are not only present in bioactive compounds⁴ but also important precursors for other heterocycles.⁵ We recently evaluated various 2,3′-diindolylmethanes as selective agonists of arylhydrocarbon receptor,⁶ which are potential therapeutics for benign prostate hyperplasia,⁷ inflammation disorders,⁸ and cancers.⁹

Our previously developed Pt- or Rh-catalyzed indole annulation/arylation cascade is shown in Figure 1a. Metal carbene intermediate 4 was generated from annulation of propargylic ether 1 via intermediate 3.¹⁰ An indole nucleophile could then react with this carbene to afford 2,3′-diindolylmethane 2.³ Substituent on the 2′-position can be introduced by starting with the corresponding substituted indoles. However, substituent on the 3-position of 2 cannot be introduced by this method. Being able to access these heterocycles with diverse substituents under mild conditions would help us to further study their biological activities.⁶ Inspired by Chan’s pioneering work on preparing indole derivatives from propargylic alcohol 5,¹¹ we proposed the synthesis of 2,3′-diindolylmethane 6 from the same type of propargylic alcohol to overcome the limitation of our previous method (Figure 1b). In addition to expensive platinum, gold, and palladium catalysts, we found that the much cheaper copper catalysts were also very effective for the synthesis of heterocycle 6 with an additional R²-substituent from alcohol 5. Preliminary mechanistic investigations suggest that the mechanism for the formation of 6 involves an allyl cation intermediate instead of a metal carbene intermediate in the synthesis of product 2 from ether 1. The starting material, mechanism and products of the new method described here are thus all different from our previous approach. The current method has the advantages of being able to access more substituted indoles and use cheaper copper catalyst.

Figure 1.

Two Complementary Approaches for 2,3′-Diindolylmethanes via Tandem Indole Annulation and Arylation

Propargylic alcohol 7 was prepared according to literature procedures¹² and treated with various catalysts in the presence of N-methylindole 8a (equation 1, Table 1). A 71% yield of product 9a was obtained when previously used PtCl₂ catalyst³ was employed (entry 1). Lower yields were observed for most other catalysts (entries 2–8). Cationic copper (I) catalysts afforded the highest yield of 9a (entries 9 and 10). We also examined other solvents including toluene, acetonitrile, THF, dioxane, methylene chloride, methanol, and DMF. No desired product was observed in DMF. The yields ranged from 27% to 60% in other solvents. Conditions in entry 10 using economically affordable copper catalyst was then selected for further studies.

Table 1.

Screening conditions^a

entry	conditions	yield (%)
1	PtCl2 (10 mol %)	71
2	Pd(OAc)2 (10 mol %)	55
3	Au(PPh3)Cl (10 mol %)	0
4	Au(PPh3)Cl (10 mol %), AgOTf (10 mol%)	50
5	AgO2CCF3 (10 mol%)	48
6	CuI	0
7	CuCl2 (10 mol%)	58
8	CuBr2 (10 mol%)	trace
9	CuOTf (10 mol%)	72
10	Cu(CH3CN)4PF6 (10 mol%)	75

^aThe yield of 9a was determined by ¹H NMR of crude product.

Under the conditions in entry 10 of Table 1, we also tried to replace the tosyl group in 7 by Boc or hydrogen (free aniline). No desired product was observed.

(1)

We next examined the scope of indole nucleophiles using propargylic alcohol 7 as the electrophile (equation 2, Table 2). A similar yield was obtained for the parent indole 8b without the N-methyl group. The structure of 9b was unambiguously established by X-ray analysis (CCDC 1016687). We also tried cationic gold catalyst (entry 4 in Table 1) for the reaction between propargylic alcohol 7 and indole 8b. No desired product was observed in this case.

Table 2.

Scope of Indoles 8^a

Entry	Substrate	Product	Yield (%)b
1	8a	9a	73
2	8b	9b	75
3	8c	9c	77
4	8d, R = OMe	9d	95
5	8e, R = Me	9e	68
6	8f, R = Cl	9f	63
7	8g, R = F	9g	70
8	8h, R = Me	9h	70
9	8i, R = F	9i	70
10	8j, R = Me	9j	67
11	8k, R = Cl	9k	65
12	8l, R = F	9l	81
13	8m	9m	71
14	8n	10	78
15	8o	no reaction
16	8p	no reaction
17	8q	no reaction

^aConditions: 7 (1 equiv), indole 8 (2 equiv), Cu(CH₃CN)₄PF₆ (10 mol %), 60 °C, ClCH₂CH₂Cl.

^bIsolated yield.

We next examined different substituents on the benzene part of indole (C4–C7 positions). Most indoles could participate in the tandem reaction. The reaction was not very sensitive to steric hindrance since 4-methyl substituted indoles 8c worked fine. The highest yield was obtained with electron-rich indole 8d. Other substituents such as methyl, chloro, and fluoro groups could be tolerated on 5-, 6-, and 7-positions of indoles 8e to 8l. A phenyl group could be tolerated on the 2-position of indole 8m. For 3-substituted indole 8n, the alkylation occurred on the 2-position to yield 2,2′-diindolylmethane 10. Surprisingly, complex mixtures were observed for 2-, or 3-methyl substituted indoles 8o and 8p. No desired product was obtained for indole 8q, which may be due to the combination of unfavorable steric and electronic factors.

The scope of the propargylic alcohols was also examined by varying R¹ and R² substituents in structure 11 (equation 3, Table 3).^{11, 13} The R¹ of 11 could be various alkyl groups (11a and 11b) or aryl groups (11c and 11d), though the yields were lower for the latter. Surprisingly, product 13 was observed when R² was a phenyl group in substrate 11e. The structure of compound 13 was unambiguously determined by X-ray analysis (CCDC 1016688). No reaction occurred when both R¹ and R² were methyl group. When both R¹ and R² were hydrogen, no desired product was observed, suggesting that the two methods outined in Figure 1 are completely complementary to each other.

Table 3.

Scope of Propargylic Alcohols 9^a

Entry	Substrate	Product	Yield (%)b
1	11a, R = nBu	12a	72
2	11b, R = iPr	12b	83
3	11c, R = Ph	12c	42
4	11d	12d	60
5	11e	13	63c

^aConditions: 9 (1 equiv), indole 8a (2 equiv), Cu(CH₃CN)₄PF₆ (10 mol %), 60 °C, ClCH₂CH₂Cl.

^bIsolated yield.

^cIndole 8b was employed.

(2)

We also examined nucleophiles besides indoles. We were pleased to find that 1,3-dimethoxybenzene also participated in the tandem indole annulation/arylation cascade reaction (Figure 2). Alcohols could also serve as the nucleophile to yield adducts 15 and 16. Product 16 has been previously prepared from substrate 11e using cationic gold catalyst.¹¹ We demonstrated that a much more economically affordable copper catalyst was also effective for this transformation.

Figure 2.

Coupling with other nucleophiles

(3)

Chan’s group reported that 7 could undergo intramolecular hydroamination to yield product 17 in the presence of a silver catalyst (Figure 3).¹⁴ This intermediate can undergo further cycloisomerization and addition reactions to afford various indole derivatives in the presence of gold catalyst.^{11–12, 14–15} When we treated compound 17 derived from silver-catalyzed hydroamination with indole 8a under our standard conditions, product 9a was obtained. No reaction occurred between 17 and 8a in the absence of any catalyst. Brønsted acid could promote the arylation of 17 but not the cyclization of 7.

Figure 3.

Preliminary investigation of the mechanism

The mechanism for the copper-catalyzed indole annulation/arylation is proposed in Figure 4. Copper-catalyzed intramolecular hydroamination will afford intermediate 17, which can be trapped by indole nucleophile 8a. The alkylation of indole 8a occurs at the 3′-position only. In the presence of acid, an allyl cation intermediate 19 may be formed. Indole nucleophile 8a attacks the 2α-position of the allyl cation to afford the final product 9a.

Figure 4.

Proposed mechanism

In summary, we have developed an efficient method for the synthesis of diverse substituted 2,3′-diindolylmethanes from propargylic alcohols and indoles. The indole nucleophiles can be replaced by other carbon or oxygen nucleophiles. Being able to use economical copper catalyst to promote the hydroamination and arylation cascade reaction makes this method and the syntheses of related indole derivatives ideal for both medicinal and process chemistry.