DOI: 10.1002/chem.201405077
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& Catalysis
Rhodium(III)- and Iridium(III)-Catalyzed C7 Alkylation of Indolines with Diazo Compounds Wen Ai ,[a, b] Xueyan Yang,[b] Yunxiang Wu,[a] Xuan Wang,[a] Yuanchao Li,[a] Yaxi Yang,*[a] and Bing Zhou*[a] Abstract: A RhIII-catalyzed procedure for the C7-selective C H alkylation of various indolines with a-diazo compounds at room temperature is reported. The advantages of this process are: 1) simple, mild, and pH-neutral reaction conditions, 2) broad substrate scope, 3) complete regioselectivity, 4) no need for an external oxidant, and 5) N2 as the sole byprod-
uct. Furthermore, alkylation and bis-alkylation of carbazoles at the C1 and C8 positions have also been developed. More significantly, for the first time, a successful IrIII-catalyzed intermolecular insertion of arene C H bonds into a-diazo compounds is reported.
Introduction The indole skeleton is very important due to its ubiquity in numerous natural bioactive products, pharmaceutically important compounds, marketed drugs, and other functional molecules.[1] Therefore, there is a continued interest in the development of synthetic methods to access functionalized indole derivatives. Among them, direct C H bond functionalization of indoles is one of the most straightforward and effective methods.[2] In stark contrast to the vast majority of examples of C H functionalization of indoles at the C2 and C3 positions,[3] regioselective C7 C H functionalization of indoles has very limited reports, thus is a formidable challenge.[4] In 2002, Chatani and co-workers developed the first example of Ru3(CO)12-catalyzed carbonylation of the C7 C H bond of indolines (Scheme 1 a).[4a] Later, a palladium-catalyzed C7 arylation of indolines was developed by several groups (Scheme 1 b).[4b–e] Recently, an oxidative transition-metal-catalyzed C7 alkenylation of indolines was reported by several groups (Scheme 1 c)[4f–i] and Shibata and Sanford reported the transition-metal-catalyzed C7 alkylation of indolines (Scheme 1 d).[4j–k] Given the prevalence of 7-substituted indoles in numerous natural products, pharmaceutically important compounds, and marketed drugs (Figure 1),[5] the development of efficient [a] W. Ai , Y. Wu, X. Wang, Prof. Y. Li, Dr. Y. Yang, Dr. B. Zhou Department of Medicinal Chemistry Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zu Chong Zhi Road, Shanghai 201203 (P. R. China) Fax: (+ 86) 21-50807288 E-mail: [email protected] [email protected] [b] W. Ai , X. Yang Key Lab for Advanced Materials and Institute of Fine Chemicals East China University of Science and Technology 130 Meilong Road, Shanghai 200237 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405077. Chem. Eur. J. 2014, 20, 17653 – 17657
Scheme 1. C7-selective C H functionalization of indolines. BINAP = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, EWG = electron-withdrawing group.
methods that will enable high-yielding and selective formation of valuable C7 substituted indoles (especially under mild and pH-neutral reaction conditions) is highly desirable. Recently, rhodium(III)-catalyzed insertion of aromatic C H bonds into a-diazocarbonyl compounds become a promising strategy for C–C coupling,[6, 7] pioneered by Yu’s group.[6f] Inspired by these results,[3s, 6f–g] we were intrigued by the possibility of developing a C7 alkylation of indolines with a-diazocarbonyl compounds. Along with our continuous efforts on regioselective C H functionalization of indoles[3l, o] and RhIII-catalyzed C H functionalization,[8] we disclose here a broadly applicable, C7-selective C H alkylation of indolines with a-diazocarbonyl 17653
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Figure 1. Bioactive compounds based on C7-substituted indoles.
compounds under an air atmosphere at room temperature by RhIII-catalyzed C H activation (Scheme 1 e). This reaction tolerates various synthetically important functional groups, requires no external oxidants, and releases benign N2 as the only byproduct, thus provides various 7-acetate-substituted indoles in excellent yields under very mild and pH-neutral reaction conditions. Furthermore, an IrIII-catalyzed intermolecular insertion of indole C7 C H bonds into a diazo derivative of Meldrum’s acid was also successfully developed.
Results and Discussion
Scheme 2. Substrate scope for indolines. Reaction conditions: 1 d– l (0.2 mmol), 2 a (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %), EtOH (2 mL), rt, 24 h. Yield of isolated product.
presence of a lower catalyst loading (1 mol %; Table S1, entry 11). With this efficient catalytic system in hand, the substrate scope of indolines was subsequently explored (Scheme 2). To our delight, indolines that bear both electron-donating (3 e–i, 3 l) and electron-withdrawing (3 j and 3 k) groups at the C2, C3, C4, C5, and even C6 positions of the indoline ring were all well tolerated in this coupling and the corresponding products were afforded in excellent yields (84–95 %). Notably, the tolerance of a bromo substituent (3 j) offers the opportunity for further transformations. The scope of the reaction with respect to the diazo substrate was also explored (Scheme 3). Various diazomalonates smoothly coupled with 1 d to give 3 d and 3 o–q in yields ranging from 90 to 95 %. In addition to these diazomalonates, excellent yield was also obtained when one of the ester groups
In an initial attempt, the reaction of various N-substituted indolines (1 a–d) with ethyl diazomalonate (2 a) was conducted in the presence of [Cp*RhCl2]2 (2.5 mol %; Cp* = pentamethylcyclopentadiene) and AgSbF6 (10 mol %) in EtOH at 70 8C for 5 h under an air atmosphere (Table S1 in the Supporting Information). N-acetylindoline 1 a and carbamoylated indoline 1 b did not give the desired product (Table S1, entries 1 and 2). To our delight, changing the acetyl protecting group to pyridinyl or pyrimidyl groups gave a dramatic increase of the reaction yield (Table S1, entries 3 and 4), with the pyrimidyl group being optimal. Reactions performed in 1,2dichloroethane (DCE) gave the same yield (Table S1, entry 5), whereas other organic solvents decreased the yield (Table S1, entries 6–8). Notably, this reaction could be performed at room temperature without any decrease in yield (Table S1, entry 9) and could also be carried out on a 5.0 mmol scale without a decrease in yield (Table S1, entry 10). In addition, Scheme 3. Scope for diazo substrates. Reaction conditions: 1 d (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), this reaction can be performed AgSbF6 (10 mol %), EtOH (2 mL), rt, 24 h. Yield of isolated product. [a] The reaction was carried out in MeOH with excellent efficiency in the (2 mL). [b] The reaction was carried out in DCE (2 mL). Bn = benzyl. Chem. Eur. J. 2014, 20, 17653 – 17657
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Full Paper was replaced by another electron-withdrawing group, such as a sulfonyl, phosphonate, or amide (3 r–t, respectively). However, in contrast to the efficient coupling with these diazo compounds, no desired product was observed when the diazo derivative of Meldrum’s acid (4 a) was used (Table S2 in the Supporting Information, entry 1). Interestingly, the reaction proceeded smoothly, followed by a tandem ethanolysis of the acetal functionality and subsequent decarboxylation, to provide product 5 a in good yield when an iridium(III) catalyst was employed (Table S2, entry 3). Next, various alkyl alcohols were examined with the iridium catalyst system (Scheme 4). The reaction proceeded smoothly to give 5 b in 77 % yield when isopropanol was used as the solvent. Notably, tert-butyl alcohol was also tolerated as a solvent
Scheme 5. RhIII- and IrIII-catalyzed reactions of carbazole.
Scheme 4. IrIII-catalyzed C7 alkylation of indolines with the diazo derivative of Meldrum’s acid. Reaction conditions: 1 d (0.2 mmol), 4 a (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %), EtOH (2 mL), 100 8C, 6 h. Yield of isolated product. [a] The reaction was carried out in iPrOH (2 mL). [b] The reaction was carried out in tBuOH (2 mL).
and gave tert-butyl ester 5 c in good yield. Both electron-rich and electron-poor indoline substrates participated well in the reaction to provide the corresponding products (5 d and 5 e) in good yields. Carbamoylated indoline was also tolerated to give 5 f in moderate yield. Notably, this is the first example of an IrIII-catalyzed intermolecular insertion of a-diazocarbonyl compounds into arene C H bonds. In addition to indolines, we were also intrigued to develop the alkylation of carbazoles due to the unique structural features and biological activities of carbazole derivatives, including anticancer, anti-HIV, and antibacterial activities.[9] Moreover, methods for the catalytic direct C H functionalization of the carbazole core are quite rare[4f, 10] and eight possible competing C H positions make it a formidable challenge in terms of regioselectivity of the C H activation. To our delight, carbazole was also found to be a favorable substrate for this reaction; 6 a was obtained in 65 % yield (Scheme 5 a). Furthermore, the bis-alkylation (C1 and C8) product 6 b was also readily obtained in satisfactory yields and with complete regiocontrol when an excess of diethyl diazomalonate (2 a) was introduced (Scheme 5 b). In addition to RhIII-catalyzed reactions, carbazole could also undergo an IrIII-catalyzed alkylation to give product 6 c in a synthetically useful yield (Scheme 5 c). Chem. Eur. J. 2014, 20, 17653 – 17657
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Scheme 6. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TIPS = triisopropylsilyl.
The utility of this method was further demonstrated by successful oxidation of indolines to indoles in good yields (Scheme 6 a and b). Notably, the resulting indoles could directly undergo a second C H functionalization at the C2 position. For example, RhIII-catalyzed C H alkynylation of indole 6 d proceeded exclusively at the C2 position to give 7 d in excellent yield under very mild reaction conditions (Scheme 6 c).[11] Finally, the pyrimidyl group was successfully removed by treatment with NaOEt in DMSO at 100 8C for 3 h to give 8 c in 78 % yield (Scheme 6 d). To gain insight into the reaction mechanism, the following experiments were carried out. Significant H–D scrambling was observed at the C7 position of indoline 1 d when DCE and D2O were employed as a mixed solvent system (Scheme 7 a). When the reaction was performed in the presence of 2 a, deuterium incorporation was also observed in recovered 1 d (Scheme 7 b). Together these studies revealed a reversible H–D exchange re-
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Full Paper gives the diazonium intermediate B, which could undergo intramolecular 1,2-migratory insertion of the aryl group to afford seven-membered intermediate C with extrusion of N2. Alternatively, formation of a Rh–carbene intermediate followed by migratory insertion could also produce intermediate C. Finally, protonolysis of C generates the desired product 3 d and regenerates the active Rh catalyst.
Conclusion
Scheme 7. Mechanistic studies.
Scheme 8. Synthesis of stable rhodium complex 9.
action. Furthermore, a kinetic isotope effect (KIE) of 1.45 was observed in an intermolecular competition experiment, which indicated that C H bond cleavage might not be involved in the rate-limiting step (Scheme 7 c).[12] In addition, equimolar amounts of 1 i, 1 k, and 2 a were allowed to react under the standard conditions. A mixture of 3 k and 3 i in a 1:1.5 ratio was obtained, which suggested that the more electron-rich indoline is kinetically favored (Scheme 7 d). More importantly, treatment of 1 d with [RhCp*Cl2]2 and NaOAc gave a stable cyclometalated RhIII complex 9, which was further characterized by X-ray crystallography (Scheme 8).[13] Furthermore, complex 9 successfully catalyzed the coupling of 1 d with 2 a (Scheme 9), which indicated that the cationic metalacycle is an active species during the course of the catalysis. Based on literature precedent,[6] a plausible mechanistic pathway is proposed (Scheme 10). First, a RhIII-catalyzed C7 C H bond cleavage occurs to form six-membered rhodacyclic intermediate A. Coordination of the diazo compound with A Chem. Eur. J. 2014, 20, 17653 – 17657
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We have developed a general method for RhIII-catalyzed C7-selective C H alkylation of indolines with a-diazo compounds under very mild and pH-neutral reaction conditions. The reaction is compatible with air, exhibits high functional-group tolerance and regioselectivity, and releases N2 as the sole byproduct, thus offers an environmentally benign method to synthesize C7-substituted indoles that can be readily scaled up. Furthermore, the alkylation and bis-alkylation of carbazoles at the C1 and C8 positions are also described. More importantly, for the first time, an IrIII-catalyzed intermolecular insertion of arene C H bonds into a-diazocarbonyl compounds was also successfully developed. We believe that this method greatly widens the C7 derivatization of indoles, thereby further expands the utility of indoles in medicinal and materials chemistry, as well as in total synthesis.
Experimental Section Synthesis of 3 d [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), indoline 1 d (0.2 mmol), diazomalonate 2 a (0.3 mmol, 1.5 equiv), and EtOH (2 mL, 0.1 m) were added to a test tube under air. The tube was sealed with a rubber stopper. The reaction mixture was stirred at rt for 24 h.
Scheme 9. Catalysis by rhodium complex 9.
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[5]
Scheme 10. Proposed mechanism.
The crude mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography to give 3 d.
[6]
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Received: September 1, 2014 Published online on October 30, 2014
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& Catalysis
Rhodium(III)- and Iridium(III)-Catalyzed C7 Alkylation of Indolines with Diazo Compounds Wen Ai ,[a, b] Xueyan Yang,[b] Yunxiang Wu,[a] Xuan Wang,[a] Yuanchao Li,[a] Yaxi Yang,*[a] and Bing Zhou*[a] Abstract: A RhIII-catalyzed procedure for the C7-selective C H alkylation of various indolines with a-diazo compounds at room temperature is reported. The advantages of this process are: 1) simple, mild, and pH-neutral reaction conditions, 2) broad substrate scope, 3) complete regioselectivity, 4) no need for an external oxidant, and 5) N2 as the sole byprod-
uct. Furthermore, alkylation and bis-alkylation of carbazoles at the C1 and C8 positions have also been developed. More significantly, for the first time, a successful IrIII-catalyzed intermolecular insertion of arene C H bonds into a-diazo compounds is reported.
Introduction The indole skeleton is very important due to its ubiquity in numerous natural bioactive products, pharmaceutically important compounds, marketed drugs, and other functional molecules.[1] Therefore, there is a continued interest in the development of synthetic methods to access functionalized indole derivatives. Among them, direct C H bond functionalization of indoles is one of the most straightforward and effective methods.[2] In stark contrast to the vast majority of examples of C H functionalization of indoles at the C2 and C3 positions,[3] regioselective C7 C H functionalization of indoles has very limited reports, thus is a formidable challenge.[4] In 2002, Chatani and co-workers developed the first example of Ru3(CO)12-catalyzed carbonylation of the C7 C H bond of indolines (Scheme 1 a).[4a] Later, a palladium-catalyzed C7 arylation of indolines was developed by several groups (Scheme 1 b).[4b–e] Recently, an oxidative transition-metal-catalyzed C7 alkenylation of indolines was reported by several groups (Scheme 1 c)[4f–i] and Shibata and Sanford reported the transition-metal-catalyzed C7 alkylation of indolines (Scheme 1 d).[4j–k] Given the prevalence of 7-substituted indoles in numerous natural products, pharmaceutically important compounds, and marketed drugs (Figure 1),[5] the development of efficient [a] W. Ai , Y. Wu, X. Wang, Prof. Y. Li, Dr. Y. Yang, Dr. B. Zhou Department of Medicinal Chemistry Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zu Chong Zhi Road, Shanghai 201203 (P. R. China) Fax: (+ 86) 21-50807288 E-mail: [email protected] [email protected] [b] W. Ai , X. Yang Key Lab for Advanced Materials and Institute of Fine Chemicals East China University of Science and Technology 130 Meilong Road, Shanghai 200237 (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405077. Chem. Eur. J. 2014, 20, 17653 – 17657
Scheme 1. C7-selective C H functionalization of indolines. BINAP = 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, EWG = electron-withdrawing group.
methods that will enable high-yielding and selective formation of valuable C7 substituted indoles (especially under mild and pH-neutral reaction conditions) is highly desirable. Recently, rhodium(III)-catalyzed insertion of aromatic C H bonds into a-diazocarbonyl compounds become a promising strategy for C–C coupling,[6, 7] pioneered by Yu’s group.[6f] Inspired by these results,[3s, 6f–g] we were intrigued by the possibility of developing a C7 alkylation of indolines with a-diazocarbonyl compounds. Along with our continuous efforts on regioselective C H functionalization of indoles[3l, o] and RhIII-catalyzed C H functionalization,[8] we disclose here a broadly applicable, C7-selective C H alkylation of indolines with a-diazocarbonyl 17653
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Figure 1. Bioactive compounds based on C7-substituted indoles.
compounds under an air atmosphere at room temperature by RhIII-catalyzed C H activation (Scheme 1 e). This reaction tolerates various synthetically important functional groups, requires no external oxidants, and releases benign N2 as the only byproduct, thus provides various 7-acetate-substituted indoles in excellent yields under very mild and pH-neutral reaction conditions. Furthermore, an IrIII-catalyzed intermolecular insertion of indole C7 C H bonds into a diazo derivative of Meldrum’s acid was also successfully developed.
Results and Discussion
Scheme 2. Substrate scope for indolines. Reaction conditions: 1 d– l (0.2 mmol), 2 a (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %), EtOH (2 mL), rt, 24 h. Yield of isolated product.
presence of a lower catalyst loading (1 mol %; Table S1, entry 11). With this efficient catalytic system in hand, the substrate scope of indolines was subsequently explored (Scheme 2). To our delight, indolines that bear both electron-donating (3 e–i, 3 l) and electron-withdrawing (3 j and 3 k) groups at the C2, C3, C4, C5, and even C6 positions of the indoline ring were all well tolerated in this coupling and the corresponding products were afforded in excellent yields (84–95 %). Notably, the tolerance of a bromo substituent (3 j) offers the opportunity for further transformations. The scope of the reaction with respect to the diazo substrate was also explored (Scheme 3). Various diazomalonates smoothly coupled with 1 d to give 3 d and 3 o–q in yields ranging from 90 to 95 %. In addition to these diazomalonates, excellent yield was also obtained when one of the ester groups
In an initial attempt, the reaction of various N-substituted indolines (1 a–d) with ethyl diazomalonate (2 a) was conducted in the presence of [Cp*RhCl2]2 (2.5 mol %; Cp* = pentamethylcyclopentadiene) and AgSbF6 (10 mol %) in EtOH at 70 8C for 5 h under an air atmosphere (Table S1 in the Supporting Information). N-acetylindoline 1 a and carbamoylated indoline 1 b did not give the desired product (Table S1, entries 1 and 2). To our delight, changing the acetyl protecting group to pyridinyl or pyrimidyl groups gave a dramatic increase of the reaction yield (Table S1, entries 3 and 4), with the pyrimidyl group being optimal. Reactions performed in 1,2dichloroethane (DCE) gave the same yield (Table S1, entry 5), whereas other organic solvents decreased the yield (Table S1, entries 6–8). Notably, this reaction could be performed at room temperature without any decrease in yield (Table S1, entry 9) and could also be carried out on a 5.0 mmol scale without a decrease in yield (Table S1, entry 10). In addition, Scheme 3. Scope for diazo substrates. Reaction conditions: 1 d (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), this reaction can be performed AgSbF6 (10 mol %), EtOH (2 mL), rt, 24 h. Yield of isolated product. [a] The reaction was carried out in MeOH with excellent efficiency in the (2 mL). [b] The reaction was carried out in DCE (2 mL). Bn = benzyl. Chem. Eur. J. 2014, 20, 17653 – 17657
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Full Paper was replaced by another electron-withdrawing group, such as a sulfonyl, phosphonate, or amide (3 r–t, respectively). However, in contrast to the efficient coupling with these diazo compounds, no desired product was observed when the diazo derivative of Meldrum’s acid (4 a) was used (Table S2 in the Supporting Information, entry 1). Interestingly, the reaction proceeded smoothly, followed by a tandem ethanolysis of the acetal functionality and subsequent decarboxylation, to provide product 5 a in good yield when an iridium(III) catalyst was employed (Table S2, entry 3). Next, various alkyl alcohols were examined with the iridium catalyst system (Scheme 4). The reaction proceeded smoothly to give 5 b in 77 % yield when isopropanol was used as the solvent. Notably, tert-butyl alcohol was also tolerated as a solvent
Scheme 5. RhIII- and IrIII-catalyzed reactions of carbazole.
Scheme 4. IrIII-catalyzed C7 alkylation of indolines with the diazo derivative of Meldrum’s acid. Reaction conditions: 1 d (0.2 mmol), 4 a (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %), EtOH (2 mL), 100 8C, 6 h. Yield of isolated product. [a] The reaction was carried out in iPrOH (2 mL). [b] The reaction was carried out in tBuOH (2 mL).
and gave tert-butyl ester 5 c in good yield. Both electron-rich and electron-poor indoline substrates participated well in the reaction to provide the corresponding products (5 d and 5 e) in good yields. Carbamoylated indoline was also tolerated to give 5 f in moderate yield. Notably, this is the first example of an IrIII-catalyzed intermolecular insertion of a-diazocarbonyl compounds into arene C H bonds. In addition to indolines, we were also intrigued to develop the alkylation of carbazoles due to the unique structural features and biological activities of carbazole derivatives, including anticancer, anti-HIV, and antibacterial activities.[9] Moreover, methods for the catalytic direct C H functionalization of the carbazole core are quite rare[4f, 10] and eight possible competing C H positions make it a formidable challenge in terms of regioselectivity of the C H activation. To our delight, carbazole was also found to be a favorable substrate for this reaction; 6 a was obtained in 65 % yield (Scheme 5 a). Furthermore, the bis-alkylation (C1 and C8) product 6 b was also readily obtained in satisfactory yields and with complete regiocontrol when an excess of diethyl diazomalonate (2 a) was introduced (Scheme 5 b). In addition to RhIII-catalyzed reactions, carbazole could also undergo an IrIII-catalyzed alkylation to give product 6 c in a synthetically useful yield (Scheme 5 c). Chem. Eur. J. 2014, 20, 17653 – 17657
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Scheme 6. DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, TIPS = triisopropylsilyl.
The utility of this method was further demonstrated by successful oxidation of indolines to indoles in good yields (Scheme 6 a and b). Notably, the resulting indoles could directly undergo a second C H functionalization at the C2 position. For example, RhIII-catalyzed C H alkynylation of indole 6 d proceeded exclusively at the C2 position to give 7 d in excellent yield under very mild reaction conditions (Scheme 6 c).[11] Finally, the pyrimidyl group was successfully removed by treatment with NaOEt in DMSO at 100 8C for 3 h to give 8 c in 78 % yield (Scheme 6 d). To gain insight into the reaction mechanism, the following experiments were carried out. Significant H–D scrambling was observed at the C7 position of indoline 1 d when DCE and D2O were employed as a mixed solvent system (Scheme 7 a). When the reaction was performed in the presence of 2 a, deuterium incorporation was also observed in recovered 1 d (Scheme 7 b). Together these studies revealed a reversible H–D exchange re-
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Full Paper gives the diazonium intermediate B, which could undergo intramolecular 1,2-migratory insertion of the aryl group to afford seven-membered intermediate C with extrusion of N2. Alternatively, formation of a Rh–carbene intermediate followed by migratory insertion could also produce intermediate C. Finally, protonolysis of C generates the desired product 3 d and regenerates the active Rh catalyst.
Conclusion
Scheme 7. Mechanistic studies.
Scheme 8. Synthesis of stable rhodium complex 9.
action. Furthermore, a kinetic isotope effect (KIE) of 1.45 was observed in an intermolecular competition experiment, which indicated that C H bond cleavage might not be involved in the rate-limiting step (Scheme 7 c).[12] In addition, equimolar amounts of 1 i, 1 k, and 2 a were allowed to react under the standard conditions. A mixture of 3 k and 3 i in a 1:1.5 ratio was obtained, which suggested that the more electron-rich indoline is kinetically favored (Scheme 7 d). More importantly, treatment of 1 d with [RhCp*Cl2]2 and NaOAc gave a stable cyclometalated RhIII complex 9, which was further characterized by X-ray crystallography (Scheme 8).[13] Furthermore, complex 9 successfully catalyzed the coupling of 1 d with 2 a (Scheme 9), which indicated that the cationic metalacycle is an active species during the course of the catalysis. Based on literature precedent,[6] a plausible mechanistic pathway is proposed (Scheme 10). First, a RhIII-catalyzed C7 C H bond cleavage occurs to form six-membered rhodacyclic intermediate A. Coordination of the diazo compound with A Chem. Eur. J. 2014, 20, 17653 – 17657
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We have developed a general method for RhIII-catalyzed C7-selective C H alkylation of indolines with a-diazo compounds under very mild and pH-neutral reaction conditions. The reaction is compatible with air, exhibits high functional-group tolerance and regioselectivity, and releases N2 as the sole byproduct, thus offers an environmentally benign method to synthesize C7-substituted indoles that can be readily scaled up. Furthermore, the alkylation and bis-alkylation of carbazoles at the C1 and C8 positions are also described. More importantly, for the first time, an IrIII-catalyzed intermolecular insertion of arene C H bonds into a-diazocarbonyl compounds was also successfully developed. We believe that this method greatly widens the C7 derivatization of indoles, thereby further expands the utility of indoles in medicinal and materials chemistry, as well as in total synthesis.
Experimental Section Synthesis of 3 d [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), indoline 1 d (0.2 mmol), diazomalonate 2 a (0.3 mmol, 1.5 equiv), and EtOH (2 mL, 0.1 m) were added to a test tube under air. The tube was sealed with a rubber stopper. The reaction mixture was stirred at rt for 24 h.
Scheme 9. Catalysis by rhodium complex 9.
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[5]
Scheme 10. Proposed mechanism.
The crude mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography to give 3 d.
[6]
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Received: September 1, 2014 Published online on October 30, 2014
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