Direct and site-selective Pd(II)-catalyzed C-7 arylation of indolines with arylsilanes

Abstract

The palladium-catalyzed oxidative arylation of indolines with arylsilanes at the C-7 position via C–H bond activation has been reported. This transformation has been applied to a wide range of substrates. It represents a facile access to C-7 arylated indolines, which can be conveniently transformed into C-7 arylated indoles.

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The indole and indoline scaffolds are important nitrogen-containing heterocycles which can be widely found in natural alkaloids, commercial drugs and other functional molecules.^1,2 With the development of C–H bond functionalization,³ it has become the most straight forward protocol leading to C-7 substituted indoles and indolines. Recently, a great deal of effort have been devoted to the formation of C-2 and C-3 functionalized indoles.⁴ Nevertheless, the C–H bond functionalization of indoles at the C-7 position remains relatively unexplored.⁵ As far as we know, many examples of transition-metal-catalyzed C-7 C–H bond functionalizations of indolines with various coupling partners have been disclosed such as olefination,⁶ alkynylation,⁷ alkylation,⁸ and carbonylation.⁹ Equally importantly, arylation in the C-7 position of indoline was first be reported by Sanford group with the hypervalent iodine compound and assisted by acetyl group.¹⁰ In 2007, Shi group developed the palladium catalyzed C–H functionalizations of the Suzuki–Miyaura reaction.¹¹ In the same year, Lipshutz group developed a mild condition cross coupling reaction directed by urea group.¹² In addition, the Oestreich group developed a dehydrogenative C–H/C–H arylation of indolines in a mild condition.¹³ However, the methods for the synthesis of C-7 arylated indolindes and C-7 arylated indoles are very limited.

On the other hand, the Hiyama cross-coupling reaction is one of the most useful and reliable approaches for the formation of C–C bonds.^14,15 Compared with many other organometallic coupling-partners, organosilicon reagents have many unique advantages, including nontoxicity, high stability, environmental benignity and ease of introduction into substrates. Up to now, there are still very few examples on C–H bond direct arylation using organosilanes as the coupling reagents.^16,17 To the best of our knowledge, the C-7 arylation of indoline with arylsilanes has not been reported. Herein, we reported palladium-catalyzed oxidative arylation of indolines with arylsilanes at the C-7 position via C–H bond activation. The reaction proceeds smoothly under very mild conditions and it shows a much wider substrate scope (Scheme 1).

Scheme 1 Methods for direct C7 C–H arylation of the indoline.

At the outset of the investigation, we first examined the direct C-7 C–H arylation of N-acetylindoline 1a coupling with phenyltrimethoxysilane 2a in the presence of 10 mol% of Pd(OAc)₂ in dioxane at 80 °C, and 2.0 equiv. AgF was used as the fluorine source. After preliminary screening of different copper salts as the oxidants, Cu(OTf)₂ turned out to be the suitable additive for the reaction (Table 1, entries 1–4). One of the key points of the Hiyama coupling reaction is to find an appropriate fluorine source to break the C–Si bond. Then, different fluorine sources such as AgF, TBAF, KF, and CsF were examined (Table 1, entries 4–7). All the fluorine sources except TBAF were found to be effective, affording the desired product 3aa. Among these salts, AgF is the best choice for the reaction; affording the desired product in a yield of 79% (Table 1, entries 4). The effect of solvent was also investigated (Table 1, entries 8–11), dioxane and THF were both found to be suitable for the reaction. However, trace amounts of or no desired product could be detected by using DMF, DMSO and toluene as solvents. Furthermore, in order to gain a more mild reaction condition, the reaction temperature was tried to reduce. To our delight, the reaction could proceed smoothly when temperature was reduced to 40 °C or 60 °C, which can afford the better yield in 91% (Table 1, entries 13). It was noted that only 32% yield could be observed when the reaction was performed at room temperature (Table 1, entries 14).

Table 1 Optimization of reaction conditions for the direct Pd-catalyzed C-7 C–H arylation of N-acetylindoline 1a with phenyltrimethoxysilane 2a^a

Entry	Oxidant	F source	Solvent	Yield^b (%)
a Unless otherwise noted, the reaction conditions are as follows: 1a (0.2 mmol), 2a (0.4 mmol), solvent (4 mL).b Isolated yield after purification by flash column chromatography on silica gel.c Reaction time was 48 h.d T = 60 °C or 40 °C.e Room temperature.
1	CuCl2	AgF	Dioxane	0
2	CuBr2	AgF	Dioxane	0
3	Cu(OAc)2	AgF	Dioxane	0
4	Cu(OTf)2	AgF	Dioxane	79
5	Cu(OTf)2	TBAF	Dioxane	0
6	Cu(OTf)2	KF	Dioxane	35
7	Cu(OTf)2	CsF	Dioxane	41
8	Cu(OTf)2	AgF	DMF	0
9	Cu(OTf)2	AgF	DMSO	0
10	Cu(OTf)2	AgF	Toluene	<5%
11	Cu(OTf)2	AgF	THF	85
12^c	Cu(OTf)2	AgF	THF	91
13^d	Cu(OTf)2	AgF	THF	91
14^e	Cu(OTf)2	AgF	THF	32

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With the optimized reaction condition, we then proceeded to explore the scope of the direct C-7 C–H arylation with various substituted indolines with phenyltrimethoxysilane. The results are summarized in Table 2. Firstly, various indolines bearing carbonyl kind direct groups (3aa–3ad) were investigated, most of them led to moderate to excellent yield. Especially, the indolines with pivaloyl group gave the best yield in 92% (3ab). For the direct group replaced as urea unit, the reaction gave a little diminished yield of the product 3ac in 55%. While the substrate bearing a pyrimidine direct group (3ae) was tested, only trace product was detected by ¹H NMR spectra. Using the pivaloyl group as the direct group, various indoline derivatives was used to react with phenyltrimethoxysilane. In general, the indolines bearing electron-donating groups on the aromatic ring such as 4-methyl and 5-methoxyl group react smoothly to afford the corresponding arylated products in very excellent yields (3af–3ag). In addition, the reactions with the indolines bearing electron-drawing group on the aromatic ring also afford moderate to good yield (3ah–3aj). Notably, the substrates with C-2 or C-3 methyl substituted group also show excellent compatibility with the reaction condition (3aj–3ak). But indolines with two substituent groups on both C-2 and C-3 positions were used to carry out the reaction, the diminished yield will obtained in 50% and 31% yield, respectively (3al–3am).

Table 2 Pd-catalyzed the direct C-7 C–H arylation of various indoline 1 with phenyltrimethoxysilane 2a^a,b

a Unless otherwise noted, the reaction conditions are as follows: 1 (0.2 mmol), 2a (0.4 mmol), THF (4 mL).b All the yields refer to isolated yields.

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To further evaluate the substrate scope, a series of arylsilanes were used to test the reaction with the N-pivaloylindoline 1b under the optimized reaction conditions. The results are summarized in Table 3. At first, phenyltriethoxysilane was used to test the reaction and it shows a good compatibility in our reaction. For this reaction, all substituted arylsilanes were prepared by following the reported method from the corresponding Grignard reagents.¹⁸ To investigate the steric effect, the phenyltriethoxysilanes bearing methyl group on different positions were employed as the substrates. The results indicate that the phenyltriethoxysilane with ortho-methyl substituent was found to afford the desired product for a little diminished yield in 61% (3bd). Essentially no steric effect was observed as shown in the reactions by using the other two meta- and para-methyl phenyltriethoxysilanes as the substrates; affording the same yield in 87% (3bb–bc). The direct C–H arylation of the indolines has shown excellent tolerance to both electron-withdrawing and electron-donating groups of aromatic substituents, including methyl (3bb–bd), methoxy (3be), fluoro (3bf) and chloro groups (3bg). In addition, the heterocyclic triethoxy(thiophen-2-yl)silane was also used to explore the possibility of the C–H arylation, the reaction also afforded the corresponding product, but only low yield (21%) was obtained (3bh).

Table 3 Pd-catalyzed the direct C-7 C–H arylation of N-pivindoline 1b with phenyltriethoxysilane 2^a,b

a Unless otherwise noted, the reaction conditions are as follows: 1b (0.2 mmol), 2 (0.4 mmol), THF (4 mL).b All the yields refer to isolated yields.c Phenyltrimethoxysilane was used.d Reaction temperature was 80 °C.

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Scheme 2 Palladium-catalyzed direct C–H arylation of the N-pivindole 3a.

Next, we tried to explore direct C-7 C–H arylation with N-pivindole 3a and phenyltrimethoxysilane 2a under the standard condition. But it was very disappointing that the reaction was totally messy, which was observed by TLC plate (Scheme 2). It means that the reaction cannot afford a single arylated product by using N-pivindole as the substrate under the standard conditions. Then, the transformation of C-7 arylated indoline into C-7 arylated indole was considered to be crucial for this method. As shown in Scheme 3, the transformation was begun with the oxidation of C-7 arylated N-pivindoline by the addition of DDQ (2,3-dicyano-5,6-dichlorobenzoquinone), followed by removing the directing group with the hydrolysis of the amide strategy. Finally, 84% yield of the arylated indole product was successfully obtained.

Scheme 3 Transformation of C7-arylated indoline to the corresponding indole.

Conclusions

In summary, we have demonstrated a direct Pd-catalyzed C-7 arylation of indolines with arylsilanes via C–H activation. In this reaction, carbonyl based directing group is needed on the indoline nitrogen atom. These transformations have been applied to a wide range of substrates. It represents a facile access to 7-arylated indolines, which can be conveniently transformed into 7-arylated indoles. Since this reaction exhibits excellent reactivity and broad substrate scope in very mild conditions, it may be found useful applications in organic synthesis.

Acknowledgements

The project is supported by Natural Science Foundation of China (No. 21562003), the Natural Science Foundation of Jiangxi Province (No. 20151BAB203009) and Natural Science Foundation of Jiangxi Provincial Education Department (No. KJLD14080 and 13081).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra06915k

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