Unsymmetrical Difunctionalization of Two Different C–H Bonds in One Pot Under Transition-Metal Catalysis

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

Recent advancements in unsymmetrical difunctionalization based on the substitution of two different C–H bonds in one-pot are described. Due to the difficulty of controlling reactivity and selectivity, multi-functionalization via substitution of several C–H bonds to install different functional groups has been limited until recently, in comparison with well-studied functionalization via sequential addition to unsaturated π-bonds. This difunctionalization protocol provides an efficient and rapid approach to a library of structurally complicated target molecules through the formation of multiple C–X bonds with high atom- and step-economy.

1 Introduction

2 ortho-Selective Functionalization of Two Different C–H Bonds Relative to the Directing Group

2.1 Unsymmetrical Difunctionalization with the Introduction of Similar Functional Groups

2.2 Unsymmetrical Difunctionalization with the Introduction of Different Functional Groups

2.3 ortho-Selective Unsymmetrical Difunctionalization Promoted by Two Different Directing Groups Appearing During the Progress of the Reaction

3 ortho/meta-Selective C–H Bond Difunctionalization Relative to the Directing Group

4 Sequential Difunctionalization of Fused Aromatic Compounds and Heterocycles

5 Summary and Outlook

Key words

difunctionalization - C–H activation - regioselectivity

• References

• 1a Tietze LF, Brasche G, Gericke KM. Domino Reactions in Organic Synthesis . Wiley-VCH; Weinheim: 2006. 1st Ed.
• 1b D’Souza DM, Müller TJ. J. Chem. Soc. Rev. 2007; 36: 1095
• 1c Kirsch SF. Synthesis 2008; 3183
• 1d Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
• 1e Pellissier H. Chem. Rev. 2013; 113: 442
• 1f Muzart J. Tetrahedron 2013; 69: 6735
• 1g Zeng X. Chem. Rev. 2013; 113: 6864
• 1h Sebren LJ, Devery JJ. III, Stephenson CR. J. ACS Catal. 2014; 4: 703
• 1i Düfert A, Werz DB. Chem. Eur. J. 2016; 22: 16718
• 1j Levi L, Müller TJ. J. Chem. Soc. Rev. 2016; 45: 2825
• 2a Colby DA, Bergman RG, Ellman JA. Chem. Rev. 2010; 110: 624
• 2b Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
• 2c Ackermann L. Chem. Rev. 2011; 111: 1315
• 2d Wencel-Delord J, Dröge T, Liu F, Glorius F. Chem. Soc. Rev. 2011; 40: 4740
• 2e Cho SH, Kim JY, Kwak J, Chang S. Chem. Soc. Rev. 2011; 40: 5068
• 2f Engle KM, Mei T.-S, Wasa M, Yu J.-Q. Acc. Chem. Res. 2012; 45: 788
• 2g Li B.-J, Shi Z.-J. Chem. Soc. Rev. 2012; 41: 5588
• 2h Arockiam PB, Bruneau C, Dixneuf PH. Chem. Rev. 2012; 112: 5879
• 2i Yamaguchi J, Yamaguchi AD, Itami K. Angew. Chem. Int. Ed. 2012; 51: 8960
• 2j Kuhl N, Hopkinson MN, Wencel-Delord J, Glorius F. Angew. Chem. Int. Ed. 2012; 51: 10236
• 2k Rouquet G, Chatani N. Angew. Chem. Int. Ed. 2013; 52: 11726
• 2l Yang L, Huang H. Chem. Rev. 2015; 115: 3468
• 2m Liu C, Yuan J, Gao M, Tang S, Li W, Shi R, Lei A. Chem. Rev. 2015; 115: 12138
• 2n Gensch T, Hopkinson MN, Glorius F, Wencel-Delord J. Chem. Soc. Rev. 2016; 45: 2900
• 2o Sun H, Guimond N, Huang Y. Org. Biomol. Chem. 2016; 14: 8389
• 2p Wang C.-S, Dixneuf PH, Soulé J.-F. Chem. Rev. 2018; 118: 7532
• 2q Gandeepan P, Ackermann L. Chem 2018; 4: 199
• 2r Sambiagio C, Schönbauer D, Blieck R, Dao-Huy T, Pototschnig G, Schaaf P, Wiesinger T, Zia MF, Wencel-Delord J, Besset T, Maes BU. W, Schnürch M. Chem. Soc. Rev. 2018; 47: 6603

For typical examples, see:
• 3a Sonoda M, Kakiuchi F, Chatani N, Murai S. Bull. Chem. Soc. Jpn. 1997; 70: 3117
• 3b Ackermann L, Althammer A, Born R. Angew. Chem. Int. Ed. 2006; 45: 2619
• 3c Umeda N, Tsurugi H, Satoh T, Miura M. Angew. Chem. Int. Ed. 2008; 47: 4019
• 3d Nakano M, Tsurugi H, Satoh T, Miura M. Org. Lett. 2008; 10: 1851
• 3e Hiroshima S, Matsumura D, Kochi T, Kakiuchi F. Org. Lett. 2010; 12: 5318
• 3f Li B, Bheeter CB, Darcel C, Dixneuf PH. ACS Catal. 2011; 1: 1221
• 3g Truong T, Klimovica K, Daugulis O. J. Am. Chem. Soc. 2013; 135: 9342
• 3h Yadav MR, Rit RK, Shankar M, Sahoo AK. J. Org. Chem. 2014; 79: 6123

For selected representative examples, see:
• 4a Yanagisawa S, Ueda K, Sekizawa H, Itami K. J. Am. Chem. Soc. 2009; 131: 14622
• 4b Engle KM, Wang D.-H, Yu J.-Q. Angew. Chem. Int. Ed. 2010; 49: 6169
• 4c Gulevich AV, Melkonyan FS, Sarkar D, Gevorgyan V. J. Am. Chem. Soc. 2012; 134: 5528
• 4d Sarkar D, Melkonyan FS, Gulevich AV, Gevorgyan V. Angew. Chem. Int. Ed. 2013; 52: 10800
• 4e Kim HJ, Ajitha MJ, Lee Y, Ryu J, Kim J, Lee Y, Jung Y, Chang S. J. Am. Chem. Soc. 2014; 136: 1132
• 4f Deb A, Bag S, Kancherla R, Maiti D. J. Am. Chem. Soc. 2014; 136: 13602
• 4g Rit RK, Yadav MR, Ghosh K, Shankar M, Sahoo AK. Org. Lett. 2014; 16: 5258
• 4h Zong Y, Rao Y. Org. Lett. 2014; 16: 5278
• 4i Sarkar D, Gulevich AV, Melkonyan FS, Gevorgyan V. ACS Catal. 2015; 5: 6792
• 4j Bera M, Maji A, Sahoo SK, Maiti D. Angew. Chem. Int. Ed. 2015; 54: 8515
• 4k Yadav MR, Shankar M, Ramesh E, Ghosh K, Sahoo AK. Org. Lett. 2015; 17: 1886
• 4l Mboyi CD, Testa C, Reeb S, Genc S, Cattey H, Fleurat-Lessard P, Roger J, Hierso J.-C. ACS Catal. 2017; 7: 8493
• 4m Shankar M, Ghosh K, Mukherjee K, Rit RK, Sahoo AK. Org. Lett. 2018; 20: 5144
• 4n Sen M, Rajesh N, Emayavaramban B, Premkumar JR, Sundararaju B. Chem. Eur. J. 2018; 24: 342

For reviews, see:
• 5a Grzybowski M, Skonieczny K, Butenschön H, Gryko DT. Angew. Chem. Int. Ed. 2013; 52: 9900
• 5b Ye J, Lautens M. Nat. Chem. 2015; 7: 863
• 5c Della Ca’ N, Fontana M, Motti E, Catellani M. Acc. Chem. Res. 2016; 49: 1389
• 5d Li S.-S, Qin L, Dong L. Org. Biomol. Chem. 2016; 14: 4554
• 5e Yang Y, Lan J, You J. Chem. Rev. 2017; 117: 8787
• 5f Minami Y, Hiyama T. Tetrahedron Lett. 2018; 59: 781

Annulation via a two-component coupling reaction was ignored because it results in the introduction of the same functional group into the two different C–H bonds (i.e., not unsymmetrical difunctionalization). For selected examples, see:
• 5g Wang H, Chen C, Huang Z, Yao L, Li B, Peng J. Synthesis 2015; 47: 2457
• 5h Zheng Q, Luo P, Lin Y, Chen W, Liu X, Zhang Y, Ding Q. Org. Biomol. Chem. 2015; 13: 4657
• 5i Li S.-S, Lin H, Liu C.-F, Xia Y.-Q, Zhang X.-M, Dong L. Adv. Synth. Catal. 2016; 358: 1595
• 6 Umeda N, Hirano K, Satoh T, Miura M. J. Org. Chem. 2009; 74: 7094
• 7 Cong X, You J, Gao G, Lan J. Chem. Commun. 2013; 49: 662

For reviews on removable and modifiable directing groups, see:
• 8a Rousseau G, Breit B. Angew. Chem. Int. Ed. 2011; 50: 2450
• 8b Zhang F, Spring DR. Chem. Soc. Rev. 2014; 43: 6906
• 8c Yadav MR, Rit RK, Shankar M, Sahoo AK. Asian J. Org. Chem. 2015; 4: 846
• 8d Ma W, Gandeepan P, Li J, Ackermann L. Org. Chem. Front. 2017; 4: 1435
• 9a Wang D.-H, Engle KM, Shi B.-F, Yu J.-Q. Science 2010; 327: 315
• 9b Engle KM, Wang D.-H, Yu J.-Q. J. Am. Chem. Soc. 2010; 132: 14137

For pioneering studies on the use of a pyridylsilyl group as a removable directing group for C–H functionalization, see:
• 10a Itami K, Mitsudo K, Kamei T, Koike T, Nokami T, Yoshida J.-i. J. Am. Chem. Soc. 2000; 122: 12013
• 10b For a review, see: Itami K, Yoshida J.-i. Synlett 2006; 157
• 11 Zhang B, Li B, Zhang X, Fan X. Org. Lett. 2017; 19: 2294
• 12a Ghosh K, Rit RK, Ramesh E, Sahoo AK. Angew. Chem. Int. Ed. 2016; 55: 7821
• 12b Ghosh K, Shankar M, Rit RK, Dubey G, Bharatam PV, Sahoo AK. J. Org. Chem. 2018; 83: 9667
• 13 Rit RK, Yadav MR, Ghosh K, Sahoo AK. Tetrahedron 2015; 71: 4450
• 14 Wu Y, Chen Z, Yang Y, Zhu W, Zhou B. J. Am. Chem. Soc. 2018; 140: 42

For oxidizing directing groups, see:
• 15a Patureau FW, Glorius F. Angew. Chem. Int. Ed. 2011; 50: 1977
• 15b Mo J, Wang L, Liu Y, Cui X. Synthesis 2015; 47: 439
• 16 Li W, Zhao Y, Mai S, Song Q. Org. Lett. 2018; 20: 1162
• 17 Huang J.-R, Song Q, Zhu Y.-Q, Qin L, Qian Z.-Y, Dong L. Chem. Eur. J. 2014; 20: 16882
• 18 Mukherjee K, Shankar M, Ghosh K, Sahoo AK. Org. Lett. 2018; 20: 1914
• 19 Samanta R, Antonchick AP. Angew. Chem. Int. Ed. 2011; 50: 5217
• 20 Li G, Zhu B, Ma X, Jia C, Lv X, Wang J, Zhao F, Lv Y, Yang S. Org. Lett. 2017; 19: 5166

For reviews on meta-C–H functionalization of aromatic compounds, see:
• 21a Yang J. Org. Biomol. Chem. 2015; 13: 1930
• 21b Dey A, Agasti S, Maiti D. Org. Biomol. Chem. 2016; 14: 5440
• 21c Leitch JA, Frost CG. Chem. Soc. Rev. 2017; 46: 7145

A radical mechanism is proposed for the addition step of p-tosyl chloride onto an aromatic ring, see:
• 22a Saidi O, Marafie J, Ledger AE. W, Liu PM, Mahon MF, Kociok-Köhn G, Whittlesey MK, Frost CG. J. Am. Chem. Soc. 2011; 133: 19298
• 22b Marcé P, Paterson AJ, Mahon MF, Frost CG. Catal. Sci. Technol. 2016; 6: 7068
• 23 Korvorapun K, Kaplaneris N, Rogge T, Warratz S, Stückl AC, Ackermann L. ACS Catal. 2018; 8: 886
• 24a Paterson AJ, St John-Campbell S, Mahon MF, Press NJ, Frost CG. Chem. Commun. 2015; 51: 12807
• 24b Li J, Warratz S, Zell D, De Sarkar S, Ishikawa EE, Ackermann L. J. Am. Chem. Soc. 2015; 137: 13894
• 25a Liu X.-Y, Gao P, Shen Y.-W, Liang Y.-M. Org. Lett. 2011; 13: 4196
• 25b Liu X, Tong K, Zhang AH, Tan RX, Yu S. Org. Chem. Front. 2017; 4: 1354
• 25c John A, Nicholas KM. Organometallics 2012; 31: 7914
• 25d Tu D, Luo J, Jiang C. Chem. Commun. 2018; 54: 2514

For reviews on C–H functionalization of indoles, see:
• 26a Sandtorv AH. Adv. Synth. Catal. 2015; 357: 2403
• 26b Leitch JA, Bhonoah Y, Frost CG. ACS Catal. 2017; 7: 5618
• 27 These external bromide sources appeared to generate Cu(II) species, which were reported to promote the bromination of indoles, see: Yang L, Lu Z, Stahl SS. Chem. Commun. 2009; 6460
• 28 Pierre C, Baudoin O. Org. Lett. 2011; 13: 1816
• 29a Murai M, Takami K, Takai K. Chem. Eur. J. 2015; 21: 4566
• 29b Murai M, Takami K, Takeshima H, Takai K. Org. Lett. 2015; 17: 1798

For our other contributions on the direct silylation of C–H bonds, see:
• 29c Ureshino T, Yoshida T, Kuninobu Y, Takai K. J. Am. Chem. Soc. 2010; 132: 14324
• 29d Murai M, Takeshima H, Morita H, Kuninobu Y, Takai K. J. Org. Chem. 2015; 80: 5407
• 29e Murai M, Matsumoto K, Takeuchi Y, Takai K. Org. Lett. 2015; 17: 3102
• 29f Murai M, Takeuchi Y, Yamauchi K, Kuninobu Y, Takai K. Chem. Eur. J. 2016; 22: 6048
• 29g Murai M, Okada R, Nishiyama A, Takai K. Org. Lett. 2016; 18: 4380
• 29h Murai M, Takeuchi Y, Takai K. Chem. Lett. 2017; 46: 1044
• 29i Murai M, Okada R, Asako S, Takai K. Chem. Eur. J. 2017; 23: 10861
• 30 Murai M, Nishinaka N, Takai K. Angew. Chem. Int. Ed. 2018; 57: 5843

Direct functionalization at the C-8 position of quinolines without conversion into quinoline N-oxides is rare, see:
• 31a Iwai T, Sawamura M. ACS Catal. 2015; 5: 5031
• 31b Stephens DE, Larionov OV. Tetrahedron 2015; 71: 8683
• 32 Murai M, Yanagawa M, Nakamura M, Takai K. Asian J. Org. Chem. 2016; 629
• 33 For a review on direct functionalization of azulene with C–H bond activation, see: Shi X, Sasmal A, Soulé J.-F, Doucet H. Chem. Asian J. 2018; 13: 143
• 34 For a review on photoredox-catalyzed C–C bond-formation reactions, see: Xie J, Jin H, Hashmi AS. K. Chem. Soc. Rev. 2017; 46: 5193
• 35 Su B, Cao Z.-C, Shi Z.-J. Acc. Chem. Res. 2015; 48: 886
• 36a Galloway WR, Isidro-Llobet A, Spring DR. Nat. Commun. 2010; 1: 80
• 36b Duncton MA. J. Med. Chem. Commun. 2011; 2: 1135
• 36c Caro-Diaz EJ. E, Urbano M, Buzard DJ, Jones RM. Bioorg. Med. Chem. Lett. 2016; 26: 5378
• 36d Taylor AP, Robinson RP, Fobian YM, Blakemore DC, Jones LH, Fadeyi O. Org. Biomol. Chem. 2016; 14: 6611
• 36e Sengupta S, Mehta G. Tetrahedron Lett. 2017; 58: 1357