Palladium-Catalyzed Enantioselective C-3 Allylation of 3-Substituted-1H-indoles Using Trialkylboranes

The asymmetric construction of a quaternary center at C-3 of the indole core represents a great synthetic challenge as well as a powerful entry into the structurally diverse family of indole alkaloids.¹ While many reports describe the asymmetric synthesis of 3,3-disubstituted oxindoles,² there is only one example of an enantioselective process that takes advantage of the nucleophilicity of the C-3 of indoles to build a quaternary center directly from 3-substituted indoles.^3,4 Recently, Tamaru and co-workers reported a C-3 selective palladium-catalyzed allylation of 1H -indoles promoted by triethylborane using allyl alcohols.⁵ Of particular interest to us was the reaction of 3-methylindole which provided the corresponding 3-methyl-3-allyl-indolenine. Since this reaction seems to proceed via a π-allylpalladium intermediate, we envisioned that our chiral ligands⁶ could be used to develop an enantioselective version. Here we report our progress in this area, which, to the best of our knowledge, is the first example of an enantioselective allylic alkylation using allyl alcohol as electrophile and reveals some insight into the mechanism of this interesting transformation.

Preliminary experiments indicated that the anthracene derived ligand A gave the best enantioselectivities and that 1 eq of Et₃B and 3 eq of allyl alcohol were necessary for the reaction to proceed in good yield. Solvent studies (Table 1) revealed that non-coordinating solvents provided higher selectivities with CH₂Cl₂ giving the best result. We then envisioned that since the high selectivity for C-3- versus N-allylation might result from the borane being tightly bound to the indole nitrogen during the allylation step,⁷ the nature of the borane should greatly influence the enantioselectivity. Indeed, we were pleased to observe an increase of the ee to 83% using the more bulky borane derived from the hydroboration of 1-hexene with 9-BBN (Table 1, entry 6). Further increasing the steric bulk of the borane using the dicyclohexylborane derivative was detrimental to the yield and ee, while using disiamylborane-C₆H_{1 3} completely inhibited the reaction. Finally, optimal conditions (entry 9) were achieved with 1.05 eq of borane at 4°C, providing the indolenine in 92 % yield and 85 % ee. The product is then liberated from the borane by basic hydrolysis or treatment with ethanolamine in THF.⁸

Table 1.

Selected optimization studies for C-3 allylation

Entry	Borane	T (°C)	Solvent	Yielda (%)	eeb (%)
1	Et3B	25	DME	82	43
2	Et3B	25	dioxane	85	33
3	Et3B	25	THF	89	53
4	Et3B	25	toluene	85	61
5	Et3B	25	CH2Cl2	88	66
6	9-BBN-C6H1 3	25	CH2Cl 2	88	83
7	(Chx)2B-C6H1 3	25	CH2Cl 2	70	70
8	Sia2B-C6H1 3	25	CH2Cl 2	-	-
9	9-BBN-C6H1 3	4	CH2Cl 2	92	85

^aAll reactions were performed using 2.5 mol % of Pd₂(dba)₃CHCl₃, 7.5 % of (S,S)-A, 1 (entry 1-6) or 1.05 eq (entry 7-9) of borane. and 3 eq of allyl alcohol.

^bEnantiomeric excess was determined by chiral HPLC after reduction of the imine using NaBH₃CN.

We then examined the effect of substitution of the indole on the outcome of the reaction (Table 2). Surprisingly, the electronic character of the indole seems to influence the selectivity while the reactivity seems hardly affected (except for 3a which failed to react). The electron deficient indole 3 b reacts with moderate selectivity and the ee increases in correlation with the electron donating character of the C-5 substituent. Electron donating substituents in the 4- and 6-position also give high selectivities, while the 7-substituted indole failed to react most likely because it prevents binding of the boron to the indole nitrogen. This electronic effect could be ascribed to the stronger boron-nitrogen interaction in electron rich indoles.

Table 2.

Effect of the substitution of the indole benzene ring

Entry	R	Product	Yielda (%)	ee (%)
1	5-NO2	4a	-	-
2	5-Br	4b	89	60
3	H	4c	92	74
4	5-MeO	4d	95	84
5	5-BnO	4e	87	83
6	5-HO	4f	88	86
7	5-Bn2N	4g	94	90
8	4-MeO	4h	92	83
9	6-MeO	4i	89	78
10	7-MeO	4j	-	-

^aAll reactions were performed on a 0.2 mmol scale for 20h at 4 °C using 2.5 mol % of Pd₂(dba)₃CHCl₃, 7.5 % of (S,S)-A, 1.05 eq of 9-BBN-(C₆H₁₃) and 3 eq of allyl alcohol.

With these results in hand we examined the scope of this reaction using mainly readily available and synthetically relevant 5-methoxy-3-substituted indoles (Table 3). In all cases, high yield were achieved using the previously optimized conditions, with enantiomeric excess from 72% to 90%. Of particular interest are the substrates with a pendant nucleophile which cyclizes onto the imine under the reaction conditions (entry 3-11). In these cases, the corresponding indoline is obtained with a cis-5,5- or 5,6-fused ring system⁹ found in numerous natural products.¹ These results also exemplify the very high chemoselectivity of this reaction since alcohol, phenol, carbamate¹⁰ and malonate functional groups are tolerated.¹¹

Table 3.

Scope of the reaction

Entry	Substrate	Product	Yielda (%)	ee (%)
1			85	84
2			89	85
3			87	72
4			91	82
5			90	81
6			91	86
7			84	90
8			93	88
9			89b	84
10			85b	81
11			91	85

^aAll reactions were performed on a 0.2 mmol scale for 20h using 2.5 mol % of Pd₂(dba)₃CHCl₃, 7.5 % of (S,S)-A, 1.1 eq of 9-BBN-(C₆H₁₃) and 3 eq of allyl alcohol.

^bCyclization to the indoline occurred after addition of ethanolamine to the indolenine in THF (5 min stirring for 18 and 24h stirring for 20).

We were also interested in the oxidation of indolenines which could allow an easy access to the oxindole family of natural products. After examining various oxidative conditions, we found that treatement of 2 with tetrabutylammonium oxone®¹² and acetic acid gave oxindole 23 in good yield (scheme 1). Recrystallization of 23 provided enantiopure material. Furthermore, after methylation and oxidative cleavage, aldehyde 24 was converted to (-)-esermethol by reductive amination-cyclization following Overman’s procedure.¹³ This intermediate has been previously used to synthesize (-)-phenserine,^2b which is a drug candidate for treatment of Alzheimer’s disease.

Scheme 1.

Synthesis of (-)-esermethole.

In summary, we have developed a new enantioselective C-3 allylation of 3-substituted indoles to give the corresponding 3,3-disubstituted indolenines and indolines. High enantioselectivities could be achieved using 9-BBN-C₆H_{1 3} as the promoter of the reaction and electron rich indoles give higher selectivities. The dependence of the selectivity on the nature of the borane suggests that, in addition to promoting the ionization of allyl alcohol,¹⁴ the boron is directly involved in the enantiodiscriminating step. Studies to elucidate the mechanism of this reaction are underway and will be reported shortly.