B(C6F5)3-Catalyzed (Convergent) Disproportionation Reaction of

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B(C6F5)3‑Catalyzed (Convergent) Disproportionation Reaction of Indoles Yuxi Han, Sutao Zhang, Jianghua He, and Yuetao Zhang* State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, Jilin 130012, China S Supporting Information *

ABSTRACT: A metal-free B(C6F5)3-catalyzed approach is developed for the disproportionation reaction of a series of indoles with various hydrosilanes, without any additives such as base and production of any small molecule such as dihydrogen. This boron catalyst system also exhibits excellent catalytic performance for practical application, such as catalyst loading as low as 0.01 mol % under solvent-free conditions, and a long-life catalytic performance highlighted by a constant catalytic activity being maintained and excellent yields being achieved for the desired products over 10 sequential additions of starting materials. On the basis of characterization of key intermediates through a series of in situ NMR reactions and detailed experimental data, we proposed a reaction mechanism which illustrated pathways for the formation of different products, including both major products and byproducts. Additional control experiments were conducted to support our proposed mechanism. Understanding the mechanism enables us to successfully suppress side reactions by choosing appropriate substrates and hydrosilanes. More importantly, the use of an elevated reaction temperature for continuous oxidation of the resulting indoline to indole makes the convergent disproportionation reaction an ideal atom-economical process. Nearquantitative conversions and up to 99% yields of C3-silylated indoles were achieved for various indoles with trisubstituted silanes, Ph3SiH (2b) or Ph2MeSiH (2d).

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INTRODUCTION As an important family of bioactive natural products, indole and its derivatives have attracted considerable attention in the fields of synthetic chemistry,1 material science,2 and medicinal chemistry.3 Owing to the very useful physicochemical properties of silylated indoles, various synthetic strategies have been developed to synthesize regioselective silylated indoles in the past few decades,4 including stoichiometric silylation reactions between heteroaryl organometallic species and silicon electrophiles5 or direct, transition-metal-catalyzed intermolecular C−H silylation using rhodium or iridium complexes,6 and the transition-metal-free C−H silylation as well.7 In general, metalbased catalyst is required for C−H silylation or excessive hydrogen acceptors or additives are necessary for achieving enhanced catalyst turnover,6b,c which restricts these synthetic methods from their practical applications. Therefore, it remains a challenging task to develop a general synthetic method to overcome such limitations for preparation of silylated indoles. The potent boron Lewis acid tris(pentafluorophenyl)borane, B(C6F5)3, and related electron-deficient boron catalysts have often served as powerful metal-free tools for activation of dihydrogen and related transformations,8 see the seminal work reported by Stephan and Erker.9 More recently, great advancements have also been achieved in the boron-catalyzed hydrosilylation and hydrogenation.10 In 2014, Ingleson and co-workers achieved silylated indole and indoline in 30% and 21% yield in © 2017 American Chemical Society

the same reaction, but the equimolar B(C6F5)3 catalyst was required. They also proposed that there exist competing reaction pathways between dehydrogenative coupling and hydrosilylation and hydrogenation in the C−H silylation of heteroarenes with hydrosilanes. By adding a steric bulky base, 2,6-dichloropyridine, they were able to suppress these side reactions to a certain extent and achieved the C3-silylated indole and indoline in 59% and 19% yield, respectively.11 In 2016, Hou and co-workers reported the effective C−H silylation of a broad range of anilines by B(C6F5)3 at 120 °C, which indicated that a high temperature promotes the C−H silylation and releases molecular hydrogen. For 1-methylindole, C5-silylated indole is isolated in 34% yield plus a small amount of C3,C5-disilylated indole.12 Later, Grimme and Paradies discovered that, at 120 °C, B(C6F5)3 could catalyze the dehydrogenative oxidation of a series of N-protected indolines into indoles, with concomitant liberation of molecular hydrogen.13 It is noted that indoline is always observed as a byproduct in the C−H silylation of indoles as reported by Oestreich and co-workers in the Brønsted acid [H(OEt)2]+[BArF4]−-catalyzed C−H silylation of heteroarenes.14 Interestingly, with B(C6F5)3/diphenylhydrosilane (Ph2SiH2), Zhang and co-workers successfully achieved indoline in 75% yield from the reduction of indole at 75 °C.15 As shown by the above overview, Received: April 10, 2017 Published: May 8, 2017 7399

DOI: 10.1021/jacs.7b03534 J. Am. Chem. Soc. 2017, 139, 7399−7407

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Journal of the American Chemical Society

summarized in Table 1. With a fixed 2:1 indole:2a ratio, we observed that 93% of 1a was converted into 4aa in 43% yield and

there are still several unadressed key issues in the C−H silylation of indoles by B(C6F5)3. First, an atom-economical process without additives is needed. Second, a green and practical synthetic method is desirable. Third, detailed mechanistic studies of B(C6F5)3-catalyzed silylation or reduction of indoles are lacking. To this end, this study revealed the disproportionation nature of the B(C6F5)3-catalyzed C−H silylation (oxidation reaction) and transfer hydrogenation (reduction reaction) of indoles at room temperature (Scheme 1a), which produces C3-

Table 1. Disproportionation Reaction of Indoles with Diphenylsilanea

Scheme 1. B(C6F5)3-Catalyzed (Convergent) Disproportionation Reaction of Indoles

silylated indoles (oxidation products) and indolines (reduction products), respectively. This catalyst system exhibited green chemistry features, such as a low catalyst loading of 0.01 mol %, solvent-free conditions, and most notably a long-life catalytic performance over 10 sequential additions of starting materials. On the basis of the characterization of key reaction intermediates through a series of in situ NMR reactions and detailed experimental data, we proposed a mechanism for the disproportionation reaction of indoles to describe the pathway for the formation of silylated indoles and indolines, including both major products and byproducts. Additional control experiments were conducted to support our proposed mechanism. With the understanding of the mechanism, we could successfully suppress side reactions by choosing appropriate substrates and hydrosilanes. More importantly, with increased reaction temperature, we successfully realized the B(C6F5)3-catalyzed convergent disproportionation reaction with ideal atom economy such that indolines are continuously converted back to indole starting materials, which proceed with disproportionation reaction to afford C3-silylated indoles and indolines for the next catalytic cycle, and thus, up to 99% yield of C3-selective silylation products is achieved (Scheme 1b).

entry

1

conversionb (%)

4, yieldb (%)

5, yieldb (%)

6, yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

1a, R = H 1b, R = 4-Me 1c, R = 5-Me 1d, R = 6-Me 1e, R = 7-Me 1f, R = 5-F 1g, R = 6-F 1h, R = 5-Cl 1i, R = 6-Cl 1j, R = 5-Br 1k, R = 6-Br 1l, R = 5-Ph 1a, R = H 1b, R = 4-Me 1c, R = 5-Me 1d, R = 6-Me 1e, R = 7-Me 1f, R = 5-F 1g, R = 6-F 1h, R = 5-Cl 1i, R = 6-Cl 1j, R = 5-Br 1k, R = 6-Br 1l, R = 5-Ph

93 85 97 97 91 92 95 94 94 94 96 96 99 98 99 99 99 99 98 99 99 99 99 99

4aa, 43 4ba, 43 4ca, 49 4da, 49 4ea, 46 4fa, 45 4ga, 41 4ha, 46 4ia, 47 4ja, 45 4ka, 48 4la, 45 4aa, 41 4ba, 46 4ca, 49 4da, 49 4ea, 46 4fa, 49 4ga, 20 4ha, 49 4ia, 41 4ja, 49 4ka, 44 4la, 49

5a, 45 5b, 41 5c, 48 5d, 47 5e, 43 5f, 45 5g, 42 5h, 46 5i, 46 5j, 46 5k, 47 5l, 47 5a, 41 5b, 45 5c, 49 5d, 47 5e, 43 5f, 49 5g, 26 5h, 49 5i, 44 5j, 49 5k, 46 5l, 49

6aa, 2 6ba, 1 6ca, 0 6da, 0 6ea, 2 6fa, 0 6ga, 12 6ha, 0 6ia, 1 6ja, 0 6ka, 1 6la, 0 6aa, 18 6ba, 7 6ca, 0 6da, 3 6ea, 10 6fa, 0 6ga, 52 6ha, 0 6ia, 15 6ja, 0 6ka, 9 6la, 0

a

Entries 1−12, 1:2a = 2:1, entries 13−24, 1:2a = 1:2. bConversion and yield determined by 1H NMR analysis.

5a in 45% yield (Table 1, entry1). Indoles bearing electrondonating methyl group at the C4−C7 positions furnished 4ba4ea in 43−49% yield and corresponding transfer hydrogenated products 5b−5e in 41−48% yield (Table 1, entries 2−5), respectively, while indoles bearing electron-withdrawing substituents such as halogen-containing motifs (F, Cl, and Br) at the C5 or C6 position all steered the reaction toward the highly selective production of 4fa−4ja in 41−48% yield and 5f−5j in 42−47% yield without dehalogenation (Table 1, entries 6−11). These reactive halogen substituents have the further derivation potential to form diverse silylated products. With a phenyl substituent at the C5 position, 1-methyl-5-phenyl-indole (1l) afforded a 45% yield of 4la and a 47% yield of 5l (Table 1, entry 12). It is noted that the conversions of these indoles remained unchanged even with a prolonged reaction time to 24 h. These results suggested such disproportionation of indole is a reversible reaction and reached equilibrium under these conditions. Therefore, adding more starting material 2a is expected to shift the equilibrium toward the right direction. To our delight, nearquantitative conversions are achieved for all indoles with a 1:2 indole:2a ratio. However, in addition to silylated indoles and substituted indolines, the presence of an excess amount of reducing agent 2a also led to the formation of C5-silylated indolines. It is noted that the corresponding C5-silylated indoline

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RESULTS AND DISCUSSION We initiated our studies with the reaction of 1-methylindole (1a) with Ph2SiH2 (2a) by various electron-deficient boron catalysts and found that B(C6F5)3 is the only highly effective catalyst for the reaction (Table S1, Supporting Information). Combined with the screening results of the other parameters (solvent, temperature, reaction time, catalyst loading, and substrate ratio), the reaction was carried out with a 1 mol % catalyst loading of B(C6F5)3 to expand the scope of indoles in deuterated benzene at room temperature for about 10 min, affording C3-silylated indoles and indolines. Some representative results are 7400


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Journal of the American Chemical Society yield for C6-substituted indoles follows the increasing order of electron-withdrawing power of the C6 substituent: Me (1d, 3% yield of 6da) < Br (1k, 9% yield of 6ka) < Cl (1i, 15% yield of 6ia) < F (1g, 52% yield of 6ga). The molecular structure of 6ga is confirmed by single-crystal X-ray diffraction analysis (Figure 1).

Figure 2. Long-life catalytic performance of the B(C6F5)3-catalyzed disproportionation reaction of 1f.

Table 2. Screening of Hydrosilane Scopes in the Disproportionation Reaction of Indolesa

Figure 1. X-ray crystal structure of 6ga. Hydrogen atoms are omitted for clarity, and ellipsoids are drawn at the 50% probability level.

Interestingly, if the C5 position is occupied, this side reaction could be completely suppressed, and thus near-quantitative conversion of such indoles and near 50% yield for both silylated indole and indoline are successfully achieved (Table 1, entries 15, 18, 20, 22, and 24). For example, 99% conversion is achieved for 5-Me-substituted indole (1c), and 4ca and 5c are produced in 49% and 49% yield, respectively. Similar results are also achieved for 5-F (1f), 5-Cl (1h), 5-Br (1j), and 5-Ph (1l) with 99% conversion and 49% yield for both C3-silylated indole and indoline. The preparative scale (13 g) and environmentally friendly feature of this new method have been demonstrated by performing this disproportionation reaction under solvent-free conditions. With a 0.01 mol % catalyst loading and 2:1 1a:2a ratio, we were greatly gratified to observe that 97% of 1a was converted into 4aa in 46% yield and 5a in 45% yield. It is also noteworthy that the separation of 4aa and 5a is very convenient (check the Supporting Information for details). More significantly, the practicability of this new method was also verified by the reuse experiments of this borane catalyst. To shift the equilibrium but avoid the formation of 6fa, we used a 2:1.2 1f:2a ratio instead of 2:1 to repeat the reaction 10 times at room temperature, it is striking to see that such a borane catalyst has a long-life catalytic performance and maintains a constant catalytic activity. The conversion remained unchanged around 96%, and an excellent yield of more than 47% was achieved for both 4fa and 5f (Figure 2). Next, using 1a as a model substrate, we examined the scope of hydrosilanes for the reaction with a 2:1 1a:silane ratio in deuterated benzene at room temperature (Table 2). It turned out that a much wider range of hydrosilanes could be employed, and no specific substituent at the silicon atom of hydrosilanes is required. Good to high conversions are achieved for hydrosilanes with either alkyl or phenyl substituents. More remarkably, chlorohydrosilanes containing a highly reactive Si−Cl bond, such as Me2SiHCl (2h; Table 2, entry 4) and Ph2SiHCl (2i; Table 2, entry 5), could also selectively undergo the silylation and transfer hydrogenation of indoles, leaving the reactive chloride intact. The excellent Si−Cl compatibility of the present borane catalyst should enable the synthesis of further functionalized silylated

entry

hydrosilane

time (h)

conversionb (%)

4, yieldb (%)

5a yieldb (%)

1 2 3 4 5 6 7

MePh2SiH Me2PhSiH Et2SiH2 Me2SiHCl Ph2SiHCl Ph3SiH PhSiH3

3 3 3 72 12 14 3

96 94 93 85 98 91 88

4ad, 49 4ae, 45 4af, 42 4ah, 28 4ai, 43 4ab, 48 7ac, 29 4ac, 11

46 43 39 42 46 42 40

a b

Reaction conditions: 1a:hydrosilane = 2:1, 1−5 mol % B(C6F5)3. Conversion and yield determined by 1H NMR analysis.

organic compounds. It is also notable that sterically encumbered Ph3SiH (2b; Table 2, entry 6) achieved 91% conversion and high yields of 4ab of 48% and 5a of 42%, as 2b is typically either ineffective or inactive for the silylation of indoles.6c,16 The molecular structure of 4ab was further confirmed by singlecrystal X-ray diffraction analysis (Figure 3). On the basis of these

Figure 3. X-ray crystal structure of 4ab. Hydrogen atoms are omitted for clarity, and ellipsoids are drawn at the 50% probability level. 7401


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Figure 4. Various bis(indol-3-yl)-substituted products.

consisted of a group of unknown peaks (Figure 5a), while the 19F NMR spectrum clearly exhibited a four-coordinated borohydride analogue (Figure 5a),17 which might be ascribed to the reaction intermediate. To determine its structure, at first, we conducted a series of in situ NMR reactions with two compounds from the group of 1a, 2a, 3a, and 5a and found there is no obvious interaction observed in the different combinations of two species (Figures S2 and S3, Figures S2 and S3), except for the reaction of 3a and 5a.13 It is clear that the intermediate does not result from such combinations, while the reaction of 3a, 5a, and 2a with a 1:1:1 ratio afforded complex 3e as the major product (Figure 5b) and the reaction of 3a, 5a, and 4aa with a 1:1:1 ratio yielded complex 3f as the major product (Figure 5c). 19F NMR spectra indicated that both products are ion pairs composed of silylindolinium ion and a borohydride (Figure 6). Oestreich discovered unexpected intermediates of free amine and Nsilylated enamine in an equimolar ratio instead of an ion pair in the borane-catalyzed Si−N hydrosilylation of imine,18 while a borohydride species was proposed for the Si−N hydrosilylation of indoles.19 However, there is no characterization of such an ion pair intermediate to date. Adding 1 equiv of 4aa to complex 3e shifted the equilibrium toward the partial conversion of 3e into 3f (Figure 5d vs Figure 5b). In addition, according to the characterization of 3f, those small unknown peaks observed in the reaction of 1a, 2a, and 3a with a 10:5:1 ratio could be assigned to complex 3f (Figure 5c vs Figure 5a). Notably, the 19F NMR spectra of these above-mentioned reactions all contained the

results, we investigated the disproportionation reaction of 2b with a series of indoles; there was no observation of the formation of C5-silylated indoline (Table S3, Supporting Information). It took 2b more than 14 h to reach around 90% conversion for most reactions with a 2:1 indole:2b ratio, which indicated 2b is less effective than 2a, probably due to its steric hindrance. With a 1:2 indole:2b ratio, near-quantitative conversion was achieved for most reactions at room temperature for 18 h, except for 1,4-dimethylindole (1b; 23% conversion; Table S3, entry 40) and 1,7-dimethylindole (1e; 55% conversion; Table S3, entry 47). The corresponding yield (Table S3) for C3silylated products and transfer hydrogenated products is 47− 49% and 45−48%, respectively, while with the less sterically crowded phenylsilane PhSiH3 (2c; Table 2, entry 7) and a 2:1 1a:2c ratio, the major product is achieved as bis(indol-3-yl)substituted product 7ac in 29% yield instead of 4ac as expected (11% yield), along with 5a in 40% yield. To improve the yield of 7ac, we employed a 4:1 1a:2c ratio to achieve an enhanced yield of 7ac of 44% along with 5a in 45% yield and a trace amount of 4ac. It is noted that 2c is effective for various indoles, and a series of bis(indol-3-yl)-substituted products, 7bc−7lc, were achieved in high yields (Figure 4). Understanding the mechanism will enable us to make advancements in the catalyst development. We initially examined the above-mentioned disproportionation reaction of 1a, 2a, and 3a with a 10:5:1 ratio. In addition to the corresponding disproportionation products 4aa and 5a, the 1H NMR spectrum 7402


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Figure 5. Overlay of the 1H NMR spectra for (a) the reaction with a 1:10:5 3a:1a:2a ratio, (b) complex 3e as the major product obtained in the reaction with a 1:1:1 2a:3a:5a ratio, (c) complex 3f as the major product obtained in the reaction with a 1:1:1 3a:4aa:5a ratio, and (d) addition of 1 equiv of 4aa to the reaction with a 1:1:1 2a:3a:5a ratio (CD2Cl2, 500 MHz).

Figure 6. Overlay of 19F NMR spectra for reaction with (a) a 1:10:5 3a:1a:2a ratio, (b) a 1:1:1 2a:3a:5a ratio, and (c) a 1:1:1 3a:4aa:5a ratio and for (d) addition of 1 equiv of 4aa to the in situ NMR reaction with a 1:1:1 2a:3a:5a ratio (CD2Cl2, 471 MHz).

same species (borohydride). These results strongly suggested that complexes 3e and 3f are very important key intermediates for the disproportionation reaction. The equilibrium between complexes 3e and 3f could be disturbed by changing the reactants, and thus yielded different products and byproducts. With successful characterization of key intermediates and detailed experimental data, we proposed the reaction mechanism

given in Scheme 2 in which 3a activates 2a through a B···H interaction to form the weak adduct 3b, which undergoes nucleophilic attack by the electron-rich indole 1a to yield highly Brønsted-acidic Wheland complex 3c along with a borohydride. 3c undergoes subsequent nucleophilic attack by another unreacted molecule of 1a to form the desired C3-silylated product 4aa and the Wheland complex 3d. The hydride is 7403


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Journal of the American Chemical Society Scheme 2. Possible Mechanism for the B(C6F5)3-Catalyzed Disproportionation Reaction of Indoles

transferred onto 3d to form indoline 5a and regenerate the catalyst 3a. In the presence of hydrosilane 2a, the equilibrium reaction between 3a and 5a is shifted to produce 3e as the major borohydride intermediate, which undergoes nucleophilic attack by 1a to yield 5a and re-form the Wheland complex 3c, which reenters the next catalytic cycle (cycle 1, black), while the attack of complex 3e by 5a produces another molecule of 5a and Wheland complex 3h, which is subsequently attacked by 1a to form byproduct 6aa and regenerate Wheland complex 3d, which reenters the next catalytic cycle (cycle 2, red). With C5-substituted indoles, the C−H silylation occurring at the C5 position is inhibited, and thus, no C5-silylated indoline is formed, which also confirms cycle 2 of the proposed mechanism. We also verified cycle 2 by conducting the following control reaction of 1, 3dimethylindole (1m), 1-methyl-6-fluoroindoline (5g), and 2a with a 1:1:2 ratio at room temperature: similar to cycle 2, 5g undergoes C5-silylation to afford 5-(diphenylsilyl)-6-fluoro-1methylindoline (6ga) in 32% yield, while 1m is completely consumed, but only a 38% yield of 1, 3-dimethylindoline (5m) and a 16% yield of 5-(diphenylsilyl)-1,3-dimethylindoline (6ma) are observed, which implies that 5m partially consumes 1m for C5-silylation, and thus results in around 14% of 5g remaining unreacted (Figure S11, Supporting Information). In the late stage of the reaction, with increased amounts of 4aa, the equilibrium reaction between 3a and 5a is shifted to form complex 3f, which is attacked by another molecule of 1a to produce reduced product 5a and Wheland complex 3g, followed by attack of another molecule of 1a to yield bis(indol-3-yl)substituted byproduct 7aa and regenerate complex 3d (cycle 3, blue). We also ran a control experiment to test cycle 3: as expected, 4aa serving as the silane to react with 1a in a 1:2 ratio at room temperature afforded both 7aa and 5a in 41% yield (Figure S12, Supporting Information). Furthermore, we have successfully isolated and characterized 7aa from the above-described reaction. The molecular structure of 7aa was also confirmed by single-crystal X−ray diffraction analysis (Figure 7), which

Figure 7. X-ray crystal structure of 7aa. Hydrogen atoms are omitted for clarity, and ellipsoids are drawn at the 50% probability level.

provided additional evidence to support cycle 3 of the proposed mechanism. Therefore, by choosing the appropriate reactants, we could verify the reaction pathways as shown in cycle 2 and cycle 3 of the proposed mechanism. After thorough investigation of the disproportionation reaction, we turned our attention to improving the atom economy of the reaction, which is not very good for disproportionation reactions in general because the reaction simultaneously produces an oxidation product and a reduction product, and thus, the ideal yield for each product is only 50%. However, a convergent disproportionation reaction usually exhibits higher atom economy as it will initially convert one of the resulting products back to starting materials, which subsequently undergo the disproportionation reaction to give the desired products.20 As reported by Grimme and Paradies, borane served as a highly effective catalyst to oxidize indoline to indole in excellent yield at 120 °C.13 Therefore, we envisioned that, with increased temperature of the above-mentioned 7404


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Journal of the American Chemical Society Table 3. Convergent Disproportionation Reaction of Indolesa

entry

substrate

hydrosilane

time (h)

conversionb (%)

4, yieldb (%)

other yieldb (%)

1c 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

1c, R = 5-Me 1c, R = 5-Me 1c, R = 5-Me 1f, R = 5-F 1h, R = 5-Cl 1j, R = 5-Br 1l, R = 5-Ph 1f, R = 5-F 1h, R = 5-Cl 1j, R = 5-Br 1l, R = 5-Ph 1a, R = H 1b, R = 4-Me 1d, R = 6-Me 1e, R = 7-Me 1g, R = 6-F 1i, R = 6-Cl 1k, R = 6-Br 1a, R = H 1b, R = 4-Me 1d, R = 6-Me 1e, R = 7-Me 1g, R = 6-F 1i, R = 6-Cl 1k, R = 6-Br

Ph2SiH2 Ph3SiH Ph2MeSiH Ph3SiH Ph3SiH Ph3SiH Ph3SiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph2MeSiH Ph3SiH Ph3SiH Ph3SiH Ph3SiH Ph3SiH Ph3SiH Ph3SiH

48 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 14 2.5 2.5 2.5 2.5 2.5 9 14 2.5 2.5 2.5 2.5 2.5

100 100 100 96 96 97 100 100 100 100 100 100 88 100 100 100 99 100 96 76 100 100 99 98 98

4ca, 69 4cb, 93 4 cd, 95 4fb, 92 4hb, 91 4jb, 83 4 lb, 99 4fd, 99 4hd, 99 4jd, 95 4ld, 99 4ad, 86 4bd, 79 4dd, 93 4ed, 90 4gd, 79 4id, 95 4kd, 98 4ab, 94 4bb, 75 4db, 93 4eb, 98 4gb, 94 4ib, 94 4kb, 94

9 7 5 4 5 14 1 1 1 5 1 14d 9d 7d 10d 21d 4d 2d 2 1 7 2 5 4 4

a

Reaction condition: [1]/[hydrosilane] = 1:2. bConversion and yield determined by 1H NMR analysis. cThe yield of 7ca is 22%. dC3,C5-disilylated products.

great delight, 2b afforded near-quantitative conversion and a more than 91% yield of C3-silylated indole for almost all C5substituted indoles (1f, 92%; 1h, 91%; 1l, 99%), except for 1j (83%), while 2d achieved 100% conversion and an excellent yield of C3-silylated indole in the range of 95−99% (1f, 99%; 1h, 99%; 1j, 95%; 1l, 99%). As shown in the disproportionation reaction of indoles (Table S3, Supporting Information), 2b exhibited excellent C3-silylation selectivity without formation of C5silylated indolines for all indoles, probably due to its large steric hindrance. Therefore, we also examined the convergent disproportionation reaction of 2b or 2d with non-C5-substituted indoles. For 2d with smaller steric hindrance (Table 3, entries 12−18), quantitative conversion of indoles and high yield of C3silylated products are achieved for most indoles (such as 1d (93%), 1e (90%), 1i (95%), and 1k (98%)), except for 1a (86%), 1b (79%), and 1g (79%). However, C3,C5-disilylated byproduct is always observed for all non-C5-substituted indoles (up to 21% yield). Such a byproduct probably results from the C5-silylation of indolines, followed by dehydrogenation to form C5-silylated indole and then C3-silylation to afford the C3,C5-disilylated products. It is worth noting that more sterically hindered 2b, which is typically either ineffective or inactive for the C3silylation of indoles,6c,16 exhibited high selectivity for C3silylation in the convergent disproportionation reaction of indoles without formation of C5-silylated products and C3,C5disilylated products. Near-quantitative conversion and an excellent yield of C3-silylated indole in the range of 93−98% were achieved for most non-C5-substituted indoles (1a, 94%; 1d,

disproportionation reaction, the resulting indolines could be continuously converted back to indoles, which proceed with the disproportionation reaction to reproduce C3-silylated indole and indoline again, and thus, the enhanced yield of the C3-selective silylation will be achieved (Scheme 1b). Obviously, such a goal could not be accomplished by the reaction of 1a with 2a, as we have demonstrated that at room temperature 6aa and 7aa always exist as byproducts (vide supra) while elevated temperature facilitates dehydrogenative oxidation of indolines and thus yields 7aa and C3,C5-disilylated product, which makes the silylation of indole more complicated. A similar result was observed by Hou.12 According to the mechanism, we should be able to prevent or suppress these side reactions by choosing the appropriate reactants. 1,5-Dimethylindole (1c) was employed as the substrate to react with different silanes to prevent formation of C5-silylated indoline. A disubstituted silane, 2a, furnished C3-silylated indole product 4ca in 69% yield and bis(indol-3-yl)-substituted byproduct 7ca in 22% yield without formation of indolines (Table 3, entry 1). This result indicated that we are heading in the right direction. As 7ca is clearly produced from the side reaction as shown in cycle 3 (Scheme 2), to prevent the formation of such byproducts, we chose trisubstituted silanes 2b (Ph3SiH) and 2d (Ph2MeSiH) as silicon sources for the reaction. Highly C3-selective silylation products were achieved in excellent yield for 2b (4cb, 93%) and 2d (4cd, 95%) (Table 3, entries 2 and 3). These results encouraged us to further examine the reaction of trisubstituted silane with the other C5-substituted indoles (Table 3, entries 4−11). To our 7405


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residual solvent. Air-sensitive NMR reactions were conducted in Teflonvalve-sealed J. Young-type NMR tubes. Ph2SiH2 and 5-phenyl-1H-indole were purchased from J&K. Cyclohexane, Et3N(TEA), methyl tert-butyl ether (TBME), PhSiH3, PhMe2SiH, and BF3.Et2O were purchased from Titan. Tribromoborane, boron trichloride (1.0 M solution in hexanes), 4-methyl-1H-indole, 5methyl-1H-indole, 6-methyl-1H-indole, 7-methyl-1H-indole, 5-fluoro1H-indole, 6-fluoro-1H-indole, 5-chloro-1H-indole, 6-chloro-1H-indole, 5-bromo-1H-indole, and 6-bromo-1H-indole were purchased from Energy Chemical. Fluorodimesitylborane, Ph3SiH, Ph2MeSiH, and B(C6H5)3 were purchased from TCI. Et2SiH2, Me2SiHCl, Ph2SiHCl, and 1-methylindole were purchased from Alfa Aesar. All chemicals were used as received unless otherwise specified as follows. Tris(pentafluorophenyl)borane, B(C6F5)3, was prepared according to literature procedures.21 Methylindole was prepared according to literature procedures.13 Typical Procedure for Disproportionation Reaction of Indoles. Method A. In a glovebox, indole (0.25 mmol) was added to a 0.5 mL C6D6 solution of B(C6F5)3 (3a) (1 or 5 mol %) in a 2 mL NMR tube. Then the hydrosilane (62.5 μmol, 0.125 mmol, or 0.5 mmol) was added. After completion of the reaction and measurement of NMR, the reaction mixture was quenched with Et3N (0.5 mL). The mixture was further purified by flash column chromatography on silica gel using the solvents cyclohexane/Et3N/TBME (100/10/1) as the eluent. Method B. In a glovebox, indole (0.25 mmol) was added to a 0.5 mL C6D6 solution of 3a (1 or 5 mol %) in a 2 mL NMR tube. Then the hydrosilane (62.5 μmol, 0.125 mmol, or 0.5 mmol) was added. After completion of the reaction and measurement of NMR, the reaction mixture was concentrated under vacuum to give a white precipitate. The solid was collected by filtration, then washed with hexane, and dried in vacuo to afford the C3-silylated indole. The filtrate was concentrated in vacuo, and the residue was further purified by flash column chromatography on silica gel using cyclohexane/TBME (100/1) as the eluent to give the indoline. Typical Procedure for Convergent Disproportionation Reaction of Indoles. Method C. In a glovebox, indole (0.25 mmol) was added to a 0.5 mL C6D6 solution of 3a (5.0 mol %) in a J. Young-type NMR tube. Then the hydrosilane (0.5 mmol) was added to the resulting mixture. The NMR tube was taken out of the glovebox, and the reaction mixture was heated to 120 °C. After completion of the reaction and measurement of NMR, the reaction mixture was concentrated under vacuum to give a white precipitate. The solid was collected by filtration, then washed with hexane, and dried in vacuo to afford the C3-silylated indole.

93%; 1e, 98%; 1g, 94%; 1i, 94%; 1k, 94%). The yield of C3silylation product for 1b (74%) and 1e (98%) obtained in convergent disproportionation is also significantly enhanced, while it is only 19% for 1b and 38% for 1e obtained in the disproportionation reaction. Similar to the disproportionation reaction, the convergent disproportionation reaction of 2d with 1c also exhibited a long-life performance and maintained a constant catalytic activity. The conversion remained unchanged, and an excellent yield of more than 93% was achieved for 4cd (Figure S13, Supporting Information).

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CONCLUSIONS In summary, we have reported here an efficient, metal-free B(C6F5)3-catalyzed method for rapid access to C3-silylated indoles and transfer hydrogenated product indolines in the disproportionation reaction, with a catalyst loading as low as 0.01 mol %. In addition to its features of green chemistry and long-life catalytic performance, this method could also be applied to a series of indoles with a variety of hydrosilanes under mild conditions, without any additives and production of any small molecules. Characterization of key reaction intermediates through a series of in situ NMR reactions and detailed experimental data led to the proposed reaction mechanism, which illustrated the pathways for the formation of different silylated indoles and indolines, including both major products and byproducts. Additional control experiments were conducted to support our proposed mechanism. Understanding the mechanism of the disproportionation reaction enabled us to successfully suppress side reactions by choosing the appropriate substrates and hydrosilanes. More importantly, the use of an elevated reaction temperature for continuous oxidation of the resulting indoline to indole makes the convergent disproportionation reaction an ideal atom-economical process in which B(C6F5)3 could continuously catalyze the oxidation of the resulting indoline to indole, which then proceeds with the disproportionation reaction to reproduce C3-silylated indole and indoline, which re-enters the next catalytic cycle, thus achieving C3-silylated indoles in up to 99% yield. To this end, with 12 indoles as substrates, we have successfully isolated 38 C3silylated indoles, 14 bis(indol-3-yl)-substituted indoles, 12 indolines, 1 C5-silylated indoline, and 1 C3,C5-disilylated indole in total. These findings also enable us to synthesize various regioselective silylated products through such a green and highly efficient methodology on the expanding the substrates and hydrosilanes. Relevant research work is in progress.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b03534. Experimental details, NMR spectra, crystal data, bond lengths and angles, and further tabular data (PDF) Crystallographic data for 4ab (C27H23NSi) (CIF) Crystallographic data for 6ga (C21H20FNSi) (CIF) Crystallographic data for 7aa (C30H26N2Si) (CIF)

EXPERIMENTAL SECTION

General Information. All syntheses and manipulations of air- and moisture-sensitive materials were carried out in flamed Schlenk-type glassware on a dual-manifold Schlenk line, on a high-vacuum line, or in an argon-filled glovebox. Toluene, benzene, and THF were refluxed over sodium/potassium alloy, followed by distillation under nitrogen atmosphere; hexane, dichloromethane, acetonitrile and dimethylacetamide were refluxed over CaH2, followed by distillation under nitrogen atmosphere. Then all solvents were stored over molecular sieves 4 Å. C6D6, C7D8, CDCl3, and CD2Cl2 were dried over molecular sieves 4 Å. NMR spectra were recorded on a Varian Inova 300 (300 MHz, 1H; 75 MHz, 13C; 282 MHz, 19F) or Bruker Avance II 500 (500 MHz, 1H; 126 MHz, 13C; 471 MHz, 19F) instrument at room temperature. Chemical shifts for 1H and 13C spectra were referenced to internal solvent resonances and are reported as parts per million relative to SiMe4, whereas 19F NMR spectra were referenced to external CFCl3. 1H and 13 C NMR chemical shifts are reported in parts per million relative to the

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Yuetao Zhang: 0000-0002-6406-1959 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (Grant Nos. 21374040 and 21422401), 7406


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1000 Young Talent Plan of China funds, and startup funds from Jilin University.

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B(C6F5)3-Catalyzed (Convergent) Disproportionation Reaction of

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