Efficient Iridium-catalyzed C-H Functionalization/Silylation of Heteroarenes

As a consequence of their unique chemical, physical and biological properties, silyl-substituted arenes have attracted wide interest from the synthetic,^[1] material science,^[2] and pharmaceutical sectors.^[3] Traditionally, silyl substituents have been introduced via addition of aryl lithium or magnesium reagents to silicon electrophiles, although this often necessitates the use of protecting groups.^[4] Consequently, transition metal catalyzed cross couplings of aryl halides with disilanes or hydrosilanes have grown in popularity, especially if base-or nucleophile-sensitive functionality are present.^[5] More recently, direct C-H functionalization^[6] has emerged as a conceptually and economically attractive alternative for the direct silylation of arenes. It is evident, however, that challenges remain and the general utility of this strategy is restricted in many instances by, inter alia, (1) poor regioselectivity, (2) stringent structural requirements, (3) noncommercial/expensive reagents, (4) harsh reaction conditions (typically 120°–200°C), and/or (5) impractical ratios of arene to silicon reagent (10:1 to 60:1).^[7–9] Herein, we report an efficient, regioselective protocol for the bipyridine-ligated, iridium-catalyzed^[9] C-H functionalization/silyation of a wide variety of heteroarenes under comparatively mild conditions. Importantly, the reaction does not require protection of N-H groups and uses only a small excess (3 equiv) of inexpensive triethylsilane (eq 1).

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Indole 1 was selected as the model heteroarene for initial studies due to its prominence in many natural products and pharmaceuticals.^[10] While several laboratories have cogently demonstrated arylation^[11] and borylation^[12] of indoles via transition metal catalyzed C-H functionalization, corresponding silylations are much less efficient (Figure 1). In an instructive example, Ishiyama et al. reported^[13] unprotected 1 gave only complex product mixtures using the catalytic system [Ir(OMe)(COD)]₂/4,4-di-tert-butyl-2, 2-bipyridine (dtbpy) in octane; silylated adducts could only be obtained using N-substituted indoles at elevated temperatures (120°C) and if a large excess of substrate was utilized. It was, thus, not surprising that 1 was unreactive to triethylsilane under comparable reaction conditions and could be recovered unchanged despite prolonged heating (Table 1, Entry 1). However, switching to THF as solvent and lowering the temperature to 80°C rewarded us with 2-(triethylsilyl)-1H-indole 2,^[14] albeit in just 4% yield (Entry 2). This was then boosted to 15% upon addition of cyclopentene as a co-reactant (Entry 3). Optimization ultimately led to the more hindered olefin 2-norbornene^[15] and a dramatically improved yield of 2 (Entry 4).^[16,17] Notably, no 3-(triethylsilyl)-1H-indole was detected in the crude reaction mixture by ¹H/¹³C NMR. Other solvents including octane (Entry 5), DME (Entry 6), and dioxane (Entry 7) were less satisfactory. Reducing the equivalents of Et₃SiH and 2-norbornene from 5 equiv to 3 equiv had no effect on the yield or reaction rate (Entry 8), but further reductions in either reagent were detrimental to the yield (Entries 9–11).

Figure 1.

Comparison of silyl indole syntheses.

Table 1.

Reaction parameters for C-H functionalization of indole 1 to 2.^[a]

Entry	Et3SiH (equiv)	Co-Reactant (equiv)	Solvent	Yield [%]
1	5	none	Octane	0[b]
2	5	none	THF	4
3	5	Cyclopentene (5)	THF	15
4	5	2-norbornene (5)	THF	85
5	5	2-norbornene (5)	Octane	22
6	5	2-norbornene (5)	DME	49
7	5	2-norbornene (5)	dioxane	59
8	3	2-norbornene (3)	THF	87
9	1.5	2-norbornene (1.5)	THF	15
10	3	2-norbornene (0.5)	THF	7
11	1.5	2-norbornene (3)	THF	43

^[a]Reaction conditions: 5 mol% [Ir(OMe)(COD)]₂ and 10 mol% 4,4-di-tert- butyl-2,2-bipyridine (dtbpy) at 80°C for 24 h.

^[b]At 120°C for 24 h.

Having established suitable reaction conditions, it was of interest to explore the scope and generality of the methodology starting with substituted indoles (Table 2). Generally, silylations of indoles bearing electron-donating substituents proceeded well, e.g., 5-methoxy (3→4, Entry 1), 4-tert-butyldimethylsilyloxy (5→6, Entry 2), and 6-methyl (7→8, Entry 3). 3-Methylindole (9→10, Entry 4), on the other hand, reacted sluggishly, which we attribute to steric congestion, but continued the strict C(2)-regioselectivity found with the others of the series. Electron-withdrawing substituents were tolerated including 5-fluoro (11→12, Entry 5) and 7-chloro (13→14, Entry 6). More modest yields of silylated adducts were obtained with 5-bromo (15→16, Entry 7) and 4-cyano (17→18, Entry 8) which were accompanied by lesser amounts of unidentified byproducts; ca. 20% of the starting material was recovered.

Table 2.

C-H functionalization/triethylsilylation of substituted indoles.^[a]

Entry	Indole	Adduct	Yield [%]
1	3	4	90
2	5	6	82
3	7	8	86
4	9	10	55[b]
5	11	12	76
6	13	14	64
7	15	16	52[b]
8	17	18	41[b]
9	19	20	49
10	21	22	70

^[a]Reaction conditions: 5 mol% [Ir(OMe)(COD)]₂, 10 mol% 4,4-di-tert- butyl-2,2-bipyridine (dtbpy), Et₃SiH (3 equiv), and norbornene (3 equiv) in THF at 80°C for 24 h.

^[b]Same as [a], except 10 mol% [Ir(OMe)(COD)]₂ and 20 mol% dtbpy for 36–48 h.

While the mechanistic details have yet to be elucidated, the observed regioselectivity is most consistent with a chelation-assisted reaction, i.e., coordination between the iridium catalyst and indole nitrogen followed by insertion into the adjacent C-H.^[12a] As anticipated, N-methylindole (19→20, Entry 9) behaved similarly, although the increased steric hinderance around the nitrogen suppressed the yield somewhat (cf., Entry 4). Notably, tosylation of the ring nitrogen redirected the regioselectivity towards C(3)-silylation (21→22, Entry 10), suggesting a change in mechanism or metal migration from C(2) to C(3) as proposed for palladium-mediated indole C-H functionalizations.^[6b]

It was gratifying to find S- and O-heteroarenes were also suitable substrates (Table 3). Thiophene (23) was smoothly functionalized to the 2,5-disilyl derivative (24) in excellent yield (Entry 1) when 4 equivalents each of triethylsilane and norbornene were used.^[18] Not surprisingly, a 2-substituted thiophene underwent C(5)-mono-silylation in very good yield (25→26, Entry 2) whereas a 3-substituted thiophene gave rise to a 2:1 mixture of 5-triethylsilyl (67%) and 2,5-bis-silylated (33%) adducts (27→28, Entry 3). Benzofuran (31) and furan (33) gave analogous results (Entries 5 and 6, respectively).

Table 3.

C-H functionalization/triethylsilylation of S- and Oheteroarenes.^[a]

Entry	Heteroarene	Adduct	Yield [%]
1	23	24	98[b]
2	25	26	91
3	27	28	67[c]
4	29	30	99
5	31	32	83
6	33	34	93

^[a]Reaction conditions described in Table 2, footnote [a].

^[b]Used triethylsilane (4 equiv) and norbornene (4 equiv).

^[c]2,5-bis-TES adduct obtained in 33% yield.

In summary, this report describes an efficient Ir-catalyzed C-H functionalization/silylation of N-/S-/O-heteroarenes including N-unsubstituted indoles under mild conditions and only a modest excess (3 equiv) of Et₃SiH. The silylation is strongly promoted by 2- norbornene and features a high level of regioselectivity. Initial results indicate the general procedure described herein is also applicable to other triorganosilyl groups including those suitable for further transformations, e.g., 29 →35 (eq 2).^[19]

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Experimental section

General procedure

A flamed-dried Schlenk tube was charged with heteroarene (0.2 mmol), [Ir(OMe)(COD)]₂ (6.6 mg, 0.01 mmol) and dtbpy (5.4 mg, 0.02 mmol), then evacuated and flushed with argon three times. Under a positive flow of argon, 2-norbornene (56 mg, 0.6 mmol) and dry THF (1 mL) were added. After stirring for 5 min, triethylsilane (98 μL, 0.6 mmol) was added dropwise and the reaction mixture was heated at 80°C for 24 h or indicated time. The solvent was concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel to give 2-(triethylsilyl)heteroarene.

For 1-tosyl-indole, the 3-silylation product was obtained using the above general procedure.

For furan (0.2 mmol) and thiophene (0.2 mmol), 2-norbornene (75 mg, 0.8 mmol) and triethylsilane (130 μL, 0.8 mmol) were employed.