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Palladium[II] catalysed C(sp3)–H oxidation of dimethyl carbamoyl tetrahydrocarbazoles† Yuji Nakano and David W. Lupton*
Received 8th November 2013, Accepted 4th December 2013 DOI: 10.1039/c3cc48545e www.rsc.org/chemcomm
Dimethyl carbamoyl tetrahydrocarbazoles undergo directed oxidation using standard conditions to exclusively provide products from C(sp3)–H oxidation. This result is in contrast to recent studies on the directed C–H olefination of hydrocarbazoles, which result in selective aromatic functionalisation.
The discovery of methods for directed C–H functionalisation has enriched approaches to the synthesis of complex organic targets.1,2 While a range of directing groups have been developed, pyridyl functionality has seen extensive application due to its robust coordination chemistry, and ubiquity.3 In contrast, C–H functionalisation using other N-heterocycles common in medicinal and natural product chemistry has received less attention.4,5 As part of studies on the chemistry of hydrocarbazoles6 we recently commenced studies on the C(sp3)–H oxidation of tetrahydrocarbazoles using Pd[II] catalysis. It was envisaged that C(sp3)–H functionalisation should occur in favour of the more common C(sp2)–H as a consequence of benzylic activation.7,8 If this proved to be the case then access to C1 oxidised hydrocarbazoles, motifs found in natural products such as kopsiyunnanine H (1), and NPY-1 antagonist 2 and antiviral 3, should be possible (Fig. 1).9 After commencing studies on this topic examples of the undesired C(sp2)–H functionalisation of tetrahydrocarbazole 4 (eqn (1))12c and hexahydrocarbazole 5 (eqn (2))12b have been communicated.10–12 While the latter involves non-benzylic substrates, the former reports the C(sp2)–H olefination of sulfonyl tetrahydrocarbazole 4, a substrate bearing benzylic C(sp3)–H. Remarkably, our studies demonstrate that in contrast to the C–H olefination reaction (eqn (1)), C(sp3)–H oxidation proceeds with exclusive selectivity for the C1 centre (eqn (3)) (Fig. 2).13 Studies commenced with N-protection of commercially available tetrahydrocarbazole with diethyl carbamoyl chloride to afford urea containing 6a.14,15 When subjected to conditions developed by Sanford in which 5 mol% Pd(OAc)2 is used in association with School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. E-mail: [email protected]; Fax: +61 3 9905 4597; Tel: +61 3 9902 0327 † Electronic supplementary information (ESI) available: Experimental details, 1 H and 13C NMR spectra of all new compounds. See DOI: 10.1039/c3cc48545e
This journal is © The Royal Society of Chemistry 2014
Fig. 1
Naturally occurring and medicinal C8 oxidized carbazoles.
Fig. 2
Proposed selective C(sp3)–H oxidation.
hypervalent iodonium reagents as the terminal oxidant we were pleased to isolate carbazole 7a in 25% yield (Table 1, entry 1), with no aromatic oxidation observed. Changing from phenyliodonium bistrifluoroacetate (PIFA) to phenyliodonium diacetate (PIDA) increased the yield to 49% (Table 1, entry 2), while performing the reaction at room temperature, or with either K2S2O8 or Oxones as the stoichiometric oxidant, gave an unsatisfactory outcome (Table 1, entries 3–5). Increasing the catalyst loading to 10 mol% increased the yield (Table 1, entry 6); however at higher catalyst loadings palladium
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Table 1
Selected reaction optimisation
Entry
mol% Pd
Oxidant (equiv.)
Temp. (1C)
Yielda (%)
1 2 3 4 5 6 7 8
5 5 5 5 5 10 20 0
PhI(OCOCF3)2 (1.1) PhI(OAc)2 (1.1) PhI(OAc)2 (1.1) K2S2O8 (2.0) Oxone (2.0) PhI(OAc)2 (1.1) PhI(OAc)2 (1.1) PhI(OAc)2 (1.1)
100 100 rt 100 100 100 100 100
25 49 8 — — 65 50 —
a
Table 2
C(sp3)–H oxidation of various tetrahydrocarbazoles 6db–dja
Isolated yield following column chromatograph.
deposition was observed and the isolated yield was decreased (Table 1, entry 7). In the absence of the palladium[II] catalyst the reaction failed to occur (Table 1, entry 8). Modification of the directing group was examined with a variety of urea (6b–d), carbamate (6e), and amide (6f–h) functionalities (eqn (5)). Although there was little difference in the outcome when the urea N-substituent was varied, dimethyl carbamoyl 6d gave the highest yield of the product (i.e. 7d). The yield of hydrocarbazole 7d could be further improved to 86% using 2 equivalents of PIDA. Unfortunately, Boc-protected tetrahydrocarbazole 6e, which could potentially serve as a useful protecting and directing group, failed to afford the expected product 7e. In contrast pivaloyl-protected substrate 6h gave the oxidized material 7h in a similar yield to that observed with ureas 6a–d. a
With suitable conditions identified for the C(sp3)–H oxidation the generality of the reaction was investigated by examining the nature of the alcohol. Exchanging methanol for ethanol or benzyl alcohol gave the expected ethers 8d and 9d in good yields, while allyl alcohol gave a modest yield of ether 10d (eqn (6)). This latter result may occur as a consequence of decomposition pathways involving the readily oxidized allyl functionality. The success of benzyl alcohol was pleasing since product 9d could be readily deprotected under hydrogenolytic conditions. Next the sensitivity of the reaction to modifications about the aromatic ring was investigated (Table 2). Substituents were introduced to perturb the electronic environment of tetrahydrocarbazole. In all cases selective C(sp3)–H oxidized products were identified in yields ranging from 51 to 86%. Specifically, introduction of electron
Chem. Commun.
Isolated yield following column chromatography.
releasing or withdrawing functionality in the 6-position had little effect on the reaction outcome with products 7db–dg formed in good yields. In addition the reaction conditions are compatible with aryl halides with 6dd, de, dh and di providing the expected products without loss of the halogen. Finally, substitution in the C5 position, as in 6dh, and in the C7 position (6di and dj) provided the expected product in good yield. C(sp3)–H oxidation of dimethyl carbamoyl 6d was investigated on a multigram scale and found to provide the expected product 7d in comparable yield (80%, 2.17 g cf. 86%, 118 mg). In addition deprotection using reported conditions was viable, affording carbazole 11 in a 58% isolated yield (Scheme 1).15
Scheme 1 Multi-gram synthesis of carbazole 7d and deprotection to provide indole 11.
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The use of carbamoyl protected tetrahydrocarbazoles in the directed C(sp3)–H oxidation has been examined. In contrast to alternate examinations of the functionalisations of hydrocarbazoles these studies gave materials arising solely from aliphatic C–H oxidation. The generality of this reaction is broad with respect to tetrahydrocarbazoles; however the reaction is not suited to alternate ring sizes and non-cyclic structures. Financial support from the Australian Research Council through the Discovery and Future Fellowship programs is acknowledged. Fig. 3
Substrates poorly suited to the C–H oxidation.
Surprisingly, variation of the tetrahydrocarbazole ring system to nonannulated substrates (12), or substrates bearing alternate ring sizes (13 and 14), failed to provide the expected products with unreacted starting materials isolated in all cases (Fig. 3). Presumably this sensitivity can be attributed to subtle conformational changes within substrates 12–14 that limit the viability of the C–H insertion (eqn (8) and (9)). ´s’ pyridine sulfonyl C–H oxidation using Carretero and Arraya directing group was investigated with tetrahydrocarbazole 4.12c Using the conditions developed in this study (Table 2), the reaction failed to afford any oxidised product; however increasing the stoichiometry of the oxidant provided a complex mixture of oxidised materials that were inseparable. Subsequent removal of the directing group allowed the C(sp3)–H oxidised product 15 to be isolated in 21% yield16 with a trace of the C(sp3)–H oxidised product 16. Mechanistically both oxidation and olefination commence with Pd(II) C–H insertion which is presumed to be turnover limiting.3i,17 The difference in outcomes indicates that with these substrates this may not be the case, and implicates a reversible C–H insertion. Further investigations are required to allow this difference in outcome to be fully appreciated.
To examine the possibility that acetate 17 is an intermediate in the C(sp3)–H etherification, 17 was prepared13a and subjected to the reaction conditions, or methanol at 100 1C. In both cases this led to rapid conversion to ether 7d (eqn (11)). In addition when the conversion of carbazole 6d - 7d (eqn (6)) was monitored by TLC analysis rapid formation of acetate 17 was observed, which subsequently provided 7d.
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Notes and references 1 For general reviews on catalytic directed C(sp3)–H functionalisation see: R. Jazzar, J. Hilce, A. Renaudat, J. Sofack-Kreutzer and O. Baudoin, Chem.–Eur. J., 2010, 16, 2654. 2 For a reviews on C–H activation in total synthesis see: (a) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (b) D. Y. K. Chen and S. W. Youn, Chem.–Eur. J., 2012, 18, 9452. 3 For general reviews on palladium catalyzed directed C–H functionalisation see: (a) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788; (b) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (c) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (d) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (e) A. J. Hickman and M. S. Sanford, Nat. Rev., 2012, 484, 178; ( f ) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; ( g) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624; (h) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (i) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147. 4 For selected examples of directed functionalisation using alternate heterocycles see: (a) J.-J. Li, R. Giri and J.-Q. Yu, Tetrahedron, 2008, 64, 6979; (b) X. Wang, L. Truesdale and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 3648; (c) A. V. Gulevich, F. S. Melkonyan, D. Sarkar and V. Gevorgyan, J. Am. Chem. Soc., 2012, 134, 5528; (d) P. Sadhu, S. K. Alla and T. Punniyamurthy, J. Org. Chem., 2013, 78, 6104. 5 For a review on sp3 bond activation using various heterocycles, with a discussion of directed C–H functionlisation see: K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069. 6 For other studies from our group on the derivatisation of carbazoles see: (a) C. J. Gartshore and D. W. Lupton, Angew. Chem., Int. Ed., 2013, 52, 4207; (b) C. J. Gartshore and D. W. Lupton, Aust. J. Chem., 2013, 66, 882. 7 W. D. Jones, Inorg. Chem., 2005, 44, 4475. 8 For examples of selective sp3 functionalisation with Pd(II) when the C–H is allylic see: M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14058. 9 For examples see: (a) R. DiFabio, R. Giovannini, B. Bertani, M. Borriello, A. Bozzoli, D. Donati, A. Falchi, D. Ghirlanda, C. P. Leslie, A. Pecunioso, G. Rumboldt and S. Spada, Bioorg. Med. Chem. Lett., 2006, 16, 1749; (b) K. S. Gudmundsson, P. R. Sebahar, L. D. Richardson, J. G. Catalano, S. D. Boggs, A. Spaltenstein, P. B. Sethna, K. W. Brown, R. Harvey and K. R. Romines, Bioorg. Med. Chem. Lett., 2009, 19, 3489; (c) L. Li, C. Beaulieu, M.-C. Carriere, D. Denis, G. Greig, D. Guay, G. O’Neill, R. Zamboni and Z. Wang, Bioorg. Med. Chem. Lett., 2010, 20, 7462. 10 For selected examples of ortho-lithiation with protected carbazoles and indoles see: (a) A. R. Katrizky, G. W. Rewcastle and L. M. Vazquez de Miguel, J. Org. Chem., 1988, 53, 794; (b) C. G. Hartung, A. Fecher, B. Chapell and V. Snieckus, Org. Lett., 2003, 5, 1899. 11 For arylation of carbazoles see: J.-H. Chu, C.-C. Wu, D.-H. Chang, Y.-M. Lee and M.-J. Wu, Organometallics, 2013, 32, 272. 12 For olefination of carbazole and indole see: (a) L.-Q. Zhang, S. Yang, X. Huang, J. You and F. Song, Chem. Commun., 2013, 49, 8830. For olefination of carbazoles which are selective for C(sp2)–H centres with hexahydrocarbazoles see: (b) L.-Y. Jiao and M. Oestreich, Org. Lett., 2013, 15, 5374. For olefination of carbazoles which are selective for C(sp2)–H centres with tetrahydrocarbazoles see: (c) B. Urones, ´s and J. C. Carretero, Org. Lett., 2013, 15, 1120. For directed R. G. Arraya methylation of indolines see: (d) S. R. Neufeldt, C. K. Seigerman and M. S. Sanford, Org. Lett., 2013, 15, 2302.
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Angew. Chem., Int. Ed., 2009, 48, 1830. For Suzuki–Miyaura with this directing group see: (c) T. Nishikata, A. R. Abela, S. Huang and B. H. Lipshutz, J. Am. Chem. Soc., 2010, 132, 4978. 15 For the C2 Rh[III] catalyzed C2 alkenylation of protected indoles see: D. J. Schipper, M. Hutchinson and K. Fagnou, J. Am. Chem. Soc., 2010, 132, 6910. 16 R. J. Owellen, J. Org. Chem., 1974, 39, 69. 17 K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 9651.
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13 For alternate synthesis of oxidised tetrahydrocarbazoles see: (a) H. Zaimoku, T. Hatta, T. Taniguchi and H. Ishibashi, Org. Lett., 2012, 14, 6088; (b) K. Higuchi, M. Tayu and T. Kawasaki, Chem. Commun., 2011, 47, 6728. ´, G. C. Lloyd 14 (a) C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagne Jones and K. I. Booker-Milburn, J. Am. Chem. Soc., 2008, 130, 10066; (b) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. ´, G. C. Lloyd-Jones and K. I. Booker-Milburn, Tyler, M. R. Gagne
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Palladium[II] catalysed C(sp3)–H oxidation of dimethyl carbamoyl tetrahydrocarbazoles† Yuji Nakano and David W. Lupton*
Received 8th November 2013, Accepted 4th December 2013 DOI: 10.1039/c3cc48545e www.rsc.org/chemcomm
Dimethyl carbamoyl tetrahydrocarbazoles undergo directed oxidation using standard conditions to exclusively provide products from C(sp3)–H oxidation. This result is in contrast to recent studies on the directed C–H olefination of hydrocarbazoles, which result in selective aromatic functionalisation.
The discovery of methods for directed C–H functionalisation has enriched approaches to the synthesis of complex organic targets.1,2 While a range of directing groups have been developed, pyridyl functionality has seen extensive application due to its robust coordination chemistry, and ubiquity.3 In contrast, C–H functionalisation using other N-heterocycles common in medicinal and natural product chemistry has received less attention.4,5 As part of studies on the chemistry of hydrocarbazoles6 we recently commenced studies on the C(sp3)–H oxidation of tetrahydrocarbazoles using Pd[II] catalysis. It was envisaged that C(sp3)–H functionalisation should occur in favour of the more common C(sp2)–H as a consequence of benzylic activation.7,8 If this proved to be the case then access to C1 oxidised hydrocarbazoles, motifs found in natural products such as kopsiyunnanine H (1), and NPY-1 antagonist 2 and antiviral 3, should be possible (Fig. 1).9 After commencing studies on this topic examples of the undesired C(sp2)–H functionalisation of tetrahydrocarbazole 4 (eqn (1))12c and hexahydrocarbazole 5 (eqn (2))12b have been communicated.10–12 While the latter involves non-benzylic substrates, the former reports the C(sp2)–H olefination of sulfonyl tetrahydrocarbazole 4, a substrate bearing benzylic C(sp3)–H. Remarkably, our studies demonstrate that in contrast to the C–H olefination reaction (eqn (1)), C(sp3)–H oxidation proceeds with exclusive selectivity for the C1 centre (eqn (3)) (Fig. 2).13 Studies commenced with N-protection of commercially available tetrahydrocarbazole with diethyl carbamoyl chloride to afford urea containing 6a.14,15 When subjected to conditions developed by Sanford in which 5 mol% Pd(OAc)2 is used in association with School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. E-mail: [email protected]; Fax: +61 3 9905 4597; Tel: +61 3 9902 0327 † Electronic supplementary information (ESI) available: Experimental details, 1 H and 13C NMR spectra of all new compounds. See DOI: 10.1039/c3cc48545e
This journal is © The Royal Society of Chemistry 2014
Fig. 1
Naturally occurring and medicinal C8 oxidized carbazoles.
Fig. 2
Proposed selective C(sp3)–H oxidation.
hypervalent iodonium reagents as the terminal oxidant we were pleased to isolate carbazole 7a in 25% yield (Table 1, entry 1), with no aromatic oxidation observed. Changing from phenyliodonium bistrifluoroacetate (PIFA) to phenyliodonium diacetate (PIDA) increased the yield to 49% (Table 1, entry 2), while performing the reaction at room temperature, or with either K2S2O8 or Oxones as the stoichiometric oxidant, gave an unsatisfactory outcome (Table 1, entries 3–5). Increasing the catalyst loading to 10 mol% increased the yield (Table 1, entry 6); however at higher catalyst loadings palladium
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Table 1
Selected reaction optimisation
Entry
mol% Pd
Oxidant (equiv.)
Temp. (1C)
Yielda (%)
1 2 3 4 5 6 7 8
5 5 5 5 5 10 20 0
PhI(OCOCF3)2 (1.1) PhI(OAc)2 (1.1) PhI(OAc)2 (1.1) K2S2O8 (2.0) Oxone (2.0) PhI(OAc)2 (1.1) PhI(OAc)2 (1.1) PhI(OAc)2 (1.1)
100 100 rt 100 100 100 100 100
25 49 8 — — 65 50 —
a
Table 2
C(sp3)–H oxidation of various tetrahydrocarbazoles 6db–dja
Isolated yield following column chromatograph.
deposition was observed and the isolated yield was decreased (Table 1, entry 7). In the absence of the palladium[II] catalyst the reaction failed to occur (Table 1, entry 8). Modification of the directing group was examined with a variety of urea (6b–d), carbamate (6e), and amide (6f–h) functionalities (eqn (5)). Although there was little difference in the outcome when the urea N-substituent was varied, dimethyl carbamoyl 6d gave the highest yield of the product (i.e. 7d). The yield of hydrocarbazole 7d could be further improved to 86% using 2 equivalents of PIDA. Unfortunately, Boc-protected tetrahydrocarbazole 6e, which could potentially serve as a useful protecting and directing group, failed to afford the expected product 7e. In contrast pivaloyl-protected substrate 6h gave the oxidized material 7h in a similar yield to that observed with ureas 6a–d. a
With suitable conditions identified for the C(sp3)–H oxidation the generality of the reaction was investigated by examining the nature of the alcohol. Exchanging methanol for ethanol or benzyl alcohol gave the expected ethers 8d and 9d in good yields, while allyl alcohol gave a modest yield of ether 10d (eqn (6)). This latter result may occur as a consequence of decomposition pathways involving the readily oxidized allyl functionality. The success of benzyl alcohol was pleasing since product 9d could be readily deprotected under hydrogenolytic conditions. Next the sensitivity of the reaction to modifications about the aromatic ring was investigated (Table 2). Substituents were introduced to perturb the electronic environment of tetrahydrocarbazole. In all cases selective C(sp3)–H oxidized products were identified in yields ranging from 51 to 86%. Specifically, introduction of electron
Chem. Commun.
Isolated yield following column chromatography.
releasing or withdrawing functionality in the 6-position had little effect on the reaction outcome with products 7db–dg formed in good yields. In addition the reaction conditions are compatible with aryl halides with 6dd, de, dh and di providing the expected products without loss of the halogen. Finally, substitution in the C5 position, as in 6dh, and in the C7 position (6di and dj) provided the expected product in good yield. C(sp3)–H oxidation of dimethyl carbamoyl 6d was investigated on a multigram scale and found to provide the expected product 7d in comparable yield (80%, 2.17 g cf. 86%, 118 mg). In addition deprotection using reported conditions was viable, affording carbazole 11 in a 58% isolated yield (Scheme 1).15
Scheme 1 Multi-gram synthesis of carbazole 7d and deprotection to provide indole 11.
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The use of carbamoyl protected tetrahydrocarbazoles in the directed C(sp3)–H oxidation has been examined. In contrast to alternate examinations of the functionalisations of hydrocarbazoles these studies gave materials arising solely from aliphatic C–H oxidation. The generality of this reaction is broad with respect to tetrahydrocarbazoles; however the reaction is not suited to alternate ring sizes and non-cyclic structures. Financial support from the Australian Research Council through the Discovery and Future Fellowship programs is acknowledged. Fig. 3
Substrates poorly suited to the C–H oxidation.
Surprisingly, variation of the tetrahydrocarbazole ring system to nonannulated substrates (12), or substrates bearing alternate ring sizes (13 and 14), failed to provide the expected products with unreacted starting materials isolated in all cases (Fig. 3). Presumably this sensitivity can be attributed to subtle conformational changes within substrates 12–14 that limit the viability of the C–H insertion (eqn (8) and (9)). ´s’ pyridine sulfonyl C–H oxidation using Carretero and Arraya directing group was investigated with tetrahydrocarbazole 4.12c Using the conditions developed in this study (Table 2), the reaction failed to afford any oxidised product; however increasing the stoichiometry of the oxidant provided a complex mixture of oxidised materials that were inseparable. Subsequent removal of the directing group allowed the C(sp3)–H oxidised product 15 to be isolated in 21% yield16 with a trace of the C(sp3)–H oxidised product 16. Mechanistically both oxidation and olefination commence with Pd(II) C–H insertion which is presumed to be turnover limiting.3i,17 The difference in outcomes indicates that with these substrates this may not be the case, and implicates a reversible C–H insertion. Further investigations are required to allow this difference in outcome to be fully appreciated.
To examine the possibility that acetate 17 is an intermediate in the C(sp3)–H etherification, 17 was prepared13a and subjected to the reaction conditions, or methanol at 100 1C. In both cases this led to rapid conversion to ether 7d (eqn (11)). In addition when the conversion of carbazole 6d - 7d (eqn (6)) was monitored by TLC analysis rapid formation of acetate 17 was observed, which subsequently provided 7d.
This journal is © The Royal Society of Chemistry 2014
Notes and references 1 For general reviews on catalytic directed C(sp3)–H functionalisation see: R. Jazzar, J. Hilce, A. Renaudat, J. Sofack-Kreutzer and O. Baudoin, Chem.–Eur. J., 2010, 16, 2654. 2 For a reviews on C–H activation in total synthesis see: (a) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (b) D. Y. K. Chen and S. W. Youn, Chem.–Eur. J., 2012, 18, 9452. 3 For general reviews on palladium catalyzed directed C–H functionalisation see: (a) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788; (b) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (c) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (d) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (e) A. J. Hickman and M. S. Sanford, Nat. Rev., 2012, 484, 178; ( f ) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; ( g) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624; (h) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (i) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147. 4 For selected examples of directed functionalisation using alternate heterocycles see: (a) J.-J. Li, R. Giri and J.-Q. Yu, Tetrahedron, 2008, 64, 6979; (b) X. Wang, L. Truesdale and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 3648; (c) A. V. Gulevich, F. S. Melkonyan, D. Sarkar and V. Gevorgyan, J. Am. Chem. Soc., 2012, 134, 5528; (d) P. Sadhu, S. K. Alla and T. Punniyamurthy, J. Org. Chem., 2013, 78, 6104. 5 For a review on sp3 bond activation using various heterocycles, with a discussion of directed C–H functionlisation see: K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069. 6 For other studies from our group on the derivatisation of carbazoles see: (a) C. J. Gartshore and D. W. Lupton, Angew. Chem., Int. Ed., 2013, 52, 4207; (b) C. J. Gartshore and D. W. Lupton, Aust. J. Chem., 2013, 66, 882. 7 W. D. Jones, Inorg. Chem., 2005, 44, 4475. 8 For examples of selective sp3 functionalisation with Pd(II) when the C–H is allylic see: M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14058. 9 For examples see: (a) R. DiFabio, R. Giovannini, B. Bertani, M. Borriello, A. Bozzoli, D. Donati, A. Falchi, D. Ghirlanda, C. P. Leslie, A. Pecunioso, G. Rumboldt and S. Spada, Bioorg. Med. Chem. Lett., 2006, 16, 1749; (b) K. S. Gudmundsson, P. R. Sebahar, L. D. Richardson, J. G. Catalano, S. D. Boggs, A. Spaltenstein, P. B. Sethna, K. W. Brown, R. Harvey and K. R. Romines, Bioorg. Med. Chem. Lett., 2009, 19, 3489; (c) L. Li, C. Beaulieu, M.-C. Carriere, D. Denis, G. Greig, D. Guay, G. O’Neill, R. Zamboni and Z. Wang, Bioorg. Med. Chem. Lett., 2010, 20, 7462. 10 For selected examples of ortho-lithiation with protected carbazoles and indoles see: (a) A. R. Katrizky, G. W. Rewcastle and L. M. Vazquez de Miguel, J. Org. Chem., 1988, 53, 794; (b) C. G. Hartung, A. Fecher, B. Chapell and V. Snieckus, Org. Lett., 2003, 5, 1899. 11 For arylation of carbazoles see: J.-H. Chu, C.-C. Wu, D.-H. Chang, Y.-M. Lee and M.-J. Wu, Organometallics, 2013, 32, 272. 12 For olefination of carbazole and indole see: (a) L.-Q. Zhang, S. Yang, X. Huang, J. You and F. Song, Chem. Commun., 2013, 49, 8830. For olefination of carbazoles which are selective for C(sp2)–H centres with hexahydrocarbazoles see: (b) L.-Y. Jiao and M. Oestreich, Org. Lett., 2013, 15, 5374. For olefination of carbazoles which are selective for C(sp2)–H centres with tetrahydrocarbazoles see: (c) B. Urones, ´s and J. C. Carretero, Org. Lett., 2013, 15, 1120. For directed R. G. Arraya methylation of indolines see: (d) S. R. Neufeldt, C. K. Seigerman and M. S. Sanford, Org. Lett., 2013, 15, 2302.
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Angew. Chem., Int. Ed., 2009, 48, 1830. For Suzuki–Miyaura with this directing group see: (c) T. Nishikata, A. R. Abela, S. Huang and B. H. Lipshutz, J. Am. Chem. Soc., 2010, 132, 4978. 15 For the C2 Rh[III] catalyzed C2 alkenylation of protected indoles see: D. J. Schipper, M. Hutchinson and K. Fagnou, J. Am. Chem. Soc., 2010, 132, 6910. 16 R. J. Owellen, J. Org. Chem., 1974, 39, 69. 17 K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 9651.
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13 For alternate synthesis of oxidised tetrahydrocarbazoles see: (a) H. Zaimoku, T. Hatta, T. Taniguchi and H. Ishibashi, Org. Lett., 2012, 14, 6088; (b) K. Higuchi, M. Tayu and T. Kawasaki, Chem. Commun., 2011, 47, 6728. ´, G. C. Lloyd 14 (a) C. E. Houlden, C. D. Bailey, J. G. Ford, M. R. Gagne Jones and K. I. Booker-Milburn, J. Am. Chem. Soc., 2008, 130, 10066; (b) C. E. Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. ´, G. C. Lloyd-Jones and K. I. Booker-Milburn, Tyler, M. R. Gagne
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