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Synthesis
DOI: 10.1055/s-0043-1775377
DOI: 10.1055/s-0043-1775377
short review
Recent Advances in Saturated N-Heterocycle C–H Bond Functionalization for Alkylated N-Heterocycle Synthesis
The authors thank the University of British Columbia (UBC), Natural Sciences and Engineering Research Council of Canada (NSERC), and the Canada Research Chairs program for funding. CHMZ thanks UBC and NSERC for graduate scholarships.
Abstract
The prominence of saturated N-heterocycle motifs in pharmaceuticals is undeniable. Challenges associated with the alkylation of saturated N-heterocycle scaffolds to efficiently access new drug analogues are hampered by synthetically laborious routes. Stereocontrolled alkyl-substitutions onto saturated N-heterocycles are particularly difficult to access in high yields by traditional synthetic methods. Alternatively, C–H bond functionalization provides a new and powerful synthetic avenue by directly and selectively functionalizing/alkylating/ arylating the abundantly available C–H bonds of saturated N-heterocycles. This review highlights complementary methods for directly activating and functionalizing C–H bonds of saturated N-heterocycles chemo-, regio-, and or stereoselectively to access alkylated products. This synthetic challenge has required catalyst development to access useful N-heterocyclic building blocks or for late-stage functionalization. Early transition metal, late transition metal, photoredox, and electrochemical methods are discussed. The selective functionalization of α, β, and γ C–H bonds to form new C–C, C–N, C–O, and C–B bonds is presented.
1 Introduction
2 Early Transition Metal Catalyzed α-Alkylation
3 Late Transition Metal Catalyzed α-Functionalization
4 Photoredox-Catalyzed α-Functionalization
5 Electrochemical α-Functionalization
6 C–H Functionalization of β and γ C–H Bonds
7 Conclusions/Outlook
Key words
amines - catalysis - electrocatalysis - photoredox catalysis - transition-metal catalysis - N-heterocycles - late-stage functionalizationPublication History
Received: 24 April 2024
Accepted after revision: 29 May 2024
Article published online:
01 August 2024
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References
- 1 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
- 2 Brown DG, Boström J. J. Med. Chem. 2016; 59: 4443
- 3 Busacca CA, Fandrick DR, Song JJ, Senanayake CH. Transition Metal Catalysis in the Pharmaceutical Industry. In Applications of Transition Metal Catalysis in Drug Discovery and Development. Crawley MC, Trost BM. John Wiley & Sons; Hoboken: 2012: 1-24
- 4 Roughley SD, Jordan AM. J. Med. Chem. 2011; 54: 3451
- 5 Li JJ, Johnson DS, Sliskovic DR, Roth BD. Contemporary Drug Synthesis . John Wiley & Sons; Hoboken: 2004
- 6 Hartwig JF. J. Am. Chem. Soc. 2016; 138: 2
- 7 Holmberg-Douglas N, Nicewicz DA. Chem. Rev. 2022; 122: 1925
- 8 Noisier AF. M, Brimble MA. Chem. Rev. 2014; 114: 8775
- 9 Sinha SK, Guin S, Maiti S, Biswas JP, Porey S, Maiti D. Chem. Rev. 2022; 122: 5682
- 10 Lu MZ, Goh J, Maraswami M, Jia Z, Tian JS, Loh TP. Chem. Rev. 2022; 122: 17479
- 11 Qin Y, Zhu L, Luo S. Chem. Rev. 2017; 117: 9433
- 12 Liu B, Romine AM, Rubel CZ, Engle KM, Shi BF. Chem. Rev. 2021; 121: 14957
- 13 Altus KM, Love JA. Commun. Chem. 2021; 4: 173
- 14 Crabtree RH, Lei A. Chem. Rev. 2017; 117: 8481
- 15 Wencel-Delord J, Dröge T, Liu F, Glorius F. Chem. Soc. Rev. 2011; 40: 4740
- 16 Cernak T, Dykstra KD, Tyagarajan S, Vachal P, Krska SW. Chem. Soc. Rev. 2016; 45: 546
- 17 Williamson JB, Lewis SE, Johnson RR, Manning IM, Leibfarth FA. Angew. Chem. Int. Ed. 2019; 58: 8654
- 18 Bura T, Blaskovits JT, Leclerc M. J. Am. Chem. Soc. 2016; 138: 10056
- 19 Abrams DJ, Provencher PA, Sorensen EJ. Chem. Soc. Rev. 2018; 47: 8925
- 20 Glorius F, Spielkamp N, Holle S, Goddard R, Lehmann CW. Angew. Chem. Int. Ed. 2004; 43: 2850
- 21 Maity S, Bera A, Bhattacharjya A, Maity P. Org. Biomol. Chem. 2023; 21: 5671
- 22 Vo C.-VT, Bode JW. J. Org. Chem. 2014; 79: 2809
- 23 Campos KR. Chem. Soc. Rev. 2007; 36: 1069
- 24 Dutta S, Li B, Rickertsen DR. L, Valles DA, Seidel D. SynOpen 2021; 5: 173
- 25 DiPucchio RC, Rosca S.-C, Schafer LL. J. Am. Chem. Soc. 2022; 144: 11459
- 26 Hunt AJ, Matharu AS, King AH, Clark JH. Green Chem. 2015; 17: 1949
- 27 Jin T, Berlin M. In Handbook on the Toxicology of Metals, 4th ed., Vol. 1. Nordberg GF, Fowler BA, Nordberg M. Academic; London: 2015: 1287-1296
- 28 Egorova KS, Ananikov VP. Organometallics 2017; 36: 4071
- 29 Manßen M, Deng D, Zheng CH. M, DiPucchio RC, Chen D, Schafer LL. ACS Catal. 2021; 11: 4550
- 30 Anastas P, Eghbali N. Chem. Soc. Rev. 2010; 39: 301
- 31 Zheng CH. M, Balatsky DA, Dipucchio RC, Schafer LL. Org. Lett. 2022; 24: 6571
- 32 Edwards PM, Schafer LL. Chem. Commun. 2018; 54: 12543
- 33 Hannedouche J, Schulz E. Organometallics 2018; 37: 4313
- 34 Herzon SB, Hartwig JF. J. Am. Chem. Soc. 2007; 129: 6690
- 35 Herzon SB, Hartwig JF. J. Am. Chem. Soc. 2008; 130: 14940
- 36 Kubiak R, Prochnow I, Doye S. Angew. Chem. Int. Ed. 2009; 48: 1153
- 37 Eisenberger P, Ayinla RO, Lauzon JM. P, Schafer LL. Angew. Chem. Int. Ed. 2009; 48: 8361
- 38 Reznichenko AL, Hultzsch KC. J. Am. Chem. Soc. 2012; 134: 3300
- 39 Nuñez Bahena E, Sirohey SA, Schafer LL. Organometallics 2023; 42: 1291
- 40 Bahena EN, Griffin SE, Schafer LL. J. Am. Chem. Soc. 2020; 142: 20566
- 41 Manßen M, Scott SS, Deng D, Zheng CH. M, Schafer LL. Green Chem. 2023; 25: 2629
- 42 Payne PR, Garcia P, Eisenberger P, Yim JC. H, Schafer LL. Org. Lett. 2013; 15: 2182
- 43 DiPucchio RC, Lenzen KE, Daneshmand P, Ezhova MB, Schafer LL. J. Am. Chem. Soc. 2021; 143: 11243
- 44 Dörfler J, Doye S. Angew. Chem. Int. Ed. 2013; 52: 1806
- 45 Dörfler J, Doye S. Eur. J. Org. Chem. 2014; 2014: 2790
- 46 Dörfler J, Preuß T, Schischko A, Schmidtmann M, Doye S. Angew. Chem. Int. Ed. 2014; 53: 7918
- 47 Rosien M, Töben I, Schmidtmann M, Beckhaus R, Doye S. Chem. Eur. J. 2020; 26: 2138
- 48 Manßen M, Schafer LL. Trends Chem. 2021; 3: 428
- 49 DiPucchio RC, Roşca S.-C, Schafer LL. Angew. Chem. Int. Ed. 2018; 57: 3469
- 50 DiPucchio RC, Rosca S, Athavan G, Schafer LL. ChemCatChem 2019; 11: 3871
- 51 Daneshmand P, Roşca SC, Dalhoff R, Yin K, Dipucchio RC, Ivanovich RA, Polat DE, Beauchemin AM, Schafer LL. J. Am. Chem. Soc. 2020; 142: 15740
- 52 Scott SS, Kaur B, Zheng CH. M, Brant P, Gilmour DJ, Schafer LL. J. Am. Chem. Soc. 2023; 145: 22871
- 53 Scott SS, Roşca SC, Gilmour DJ, Brant P, Schafer LL. ACS Macro Lett. 2021; 10: 1266
- 54 Andersen K, Liljefors T, Hyttel J, Perregaard J. J. Med. Chem. 1996; 39: 3723
- 55 Hafner Ĉesen M, Repnik U, Turk V, Turk B. Cell Death Dis. 2013; 4: e818
- 56 Nako AE, Oyamada J, Nishiura M, Hou Z. Chem. Sci. 2016; 7: 6429
- 57 Geik D, Rosien M, Bielefeld J, Schmidtmann M, Doye S. Angew. Chem. Int. Ed. 2021; 60: 9936
- 58 Labinger JA. Chem. Rev. 2017; 117: 8483
- 59 Davies HM. L, Beckwith RE. J. Chem. Rev. 2003; 103: 2861
- 60 Zhao Q, Meng G, Nolan SP, Szostak M. Chem. Rev. 2020; 120: 1981
- 61 Gandeepan P, Müller T, Zell D, Cera G, Warratz S, Ackermann L. Chem. Rev. 2019; 119: 2192
- 62 Trowbridge A, Walton SM, Gaunt MJ. Chem. Rev. 2020; 120: 2613
- 63 Lahm G, Opatz T. Org. Lett. 2014; 16: 4201
- 64 Schinkel M, Wang L, Bielefeld K, Ackermann L. Org. Lett. 2014; 16: 1876
- 65 Kulago AA, Van Steijvoort BF, Mitchell EA, Meerpoel L, Maes BU. W. Adv. Synth. Catal. 2014; 356: 1610
- 66 Smout V, Peschiulli A, Verbeeck S, Mitchell EA, Herrebout W, Bultinck P, Vande Velde CM. L, Berthelot D, Meerpoel L, Maes BU. W. J. Org. Chem. 2013; 78: 9803
- 67 Bergman SD, Storr TE, Prokopcová H, Aelvoet K, Diels G, Meerpoel L, Maes BU. W. Chem. Eur. J. 2012; 18: 10393
- 68 Chatani N, Asaumi T, Yorimitsu S, Ikeda T, Kakiuchi F, Murai S. J. Am. Chem. Soc. 2001; 123: 10935
- 69 Verma P, Richter JM, Chekshin N, Qiao JX, Yu JQ. J. Am. Chem. Soc. 2020; 142: 5117
- 70 Braga FC, Ramos TO, Brocksom TJ, De Oliveira KT. Org. Lett. 2022; 24: 8331
- 71 Tran AT, Yu JQ. Angew. Chem. Int. Ed. 2017; 56: 10530
- 72 Phapale VB, Cárdenas DJ. Chem. Soc. Rev. 2009; 38: 1598
- 73 Johansson Seechurn CC. C, Kitching MO, Colacot TJ, Snieckus V. Angew. Chem. Int. Ed. 2012; 51: 5062
- 74 Palani V, Perea MA, Sarpong R. Chem. Rev. 2022; 122: 10126
- 75 Cordier CJ, Lundgren RJ, Fu GC. J. Am. Chem. Soc. 2013; 135: 10946
- 76 Mu X, Shibata Y, Makida Y, Fu GC. Angew. Chem. Int. Ed. 2017; 56: 5821
- 77 Schönherr H, Cernak T. Angew. Chem. Int. Ed. 2013; 52: 12256
- 78 White MC, Zhao J. J. Am. Chem. Soc. 2018; 140: 13988
- 79 Feng K, Quevedo RE, Kohrt JT, Oderinde MS, Reilly U, White MC. Nature 2020; 580: 621
- 80 Chang Z, Huang J, Wang S, Chen G, Zhao H, Wang R, Zhao D. Nat. Commun. 2021; 12: 1
- 81 Valles DA, Dutta S, Paul A, Abboud KA, Ghiviriga I, Seidel D. Org. Lett. 2021; 23: 6367
- 82 Yu F, Valles DA, Chen W, Daniel SD, Ghiviriga I, Seidel D. Org. Lett. 2022; 24: 6364
- 83 Chen W, Paul A, Abboud KA, Seidel D. Nat. Chem. 2020; 12: 545
- 84 Paul A, Kim JH, Daniel SD, Seidel D. Angew. Chem. Int. Ed. 2021; 60: 1625
- 85 Paul A, Seidel D. J. Am. Chem. Soc. 2019; 141: 8778
- 86 Chan AY, Perry IB, Bissonnette NB, Buksh BF, Edwards GA, Frye LI, Garry OL, Lavagnino MN, Li BX, Liang Y, Mao E, Millet A, Oakley JV, Reed NL, Sakai HA, Seath CP, MacMillan DW. C. Chem. Rev. 2022; 122: 1485
- 87 Romero NA, Nicewicz DA. Chem. Rev. 2016; 116: 10075
- 88 McNally A, Prier CK, MacMillan DW. C. Science 2011; 334: 1114
- 89 Prier CK, MacMillan DW. C. Chem. Sci. 2014; 5: 4173
- 90 Shaw MH, Shurtleff VW, Terrett JA, Cuthbertson JD, MacMillan DW. C. Science 2016; 352: 1304
- 91 Noble A, MacMillan DW. C. J. Am. Chem. Soc. 2014; 136: 11602
- 92 Le C, Liang Y, Evans RW, Li X, MacMillan DW. C. Nature 2017; 547: 79
- 93 Vasilopoulos A, Krska SW, Stahl SS. Science 2021; 372: 398
- 94 Mao E, MacMillan DW. C. J. Am. Chem. Soc. 2023; 145: 2787
- 95 Ham JS, Park B, Son M, Roque JB, Jurczyk J, Yeung CS, Baik MH, Sarpong R. J. Am. Chem. Soc. 2020; 142: 13041
- 96 Olden K, Breton P, Grzegorzewski K, Yasuda Y, Gause BL, Oredipe OA, Newton SA, White SL. Pharmacol. Ther. 1991; 50: 285
- 97 Daly JW, Garraffo HM, Spande TF. Alkaloids 1993; 43: 228
- 98 Thullen SM, Rovis T. J. Am. Chem. Soc. 2017; 139: 15504
- 99 McManus JB, Onuska NP. R, Nicewicz DA. J. Am. Chem. Soc. 2018; 140: 9056
- 100 McManus JB, Onuska NP. R, Jeffreys MS, Goodwin NC, Nicewicz DA. Org. Lett. 2020; 22: 679
- 101 Pan Y, Wang S, Kee CW, Dubuisson E, Yang Y, Loh KP, Tan CH. Green Chem. 2011; 13: 3341
- 102 Orejarena Pacheco JC, Lipp A, Nauth AM, Acke F, Dietz JP, Opatz T. Chem. Eur. J. 2016; 22: 5409
- 103 Kolbe H. Justus Liebigs Ann. Chem. 1848; 64: 339
- 104 Pollok D, Waldvogel SR. Chem. Sci. 2020; 11: 12386
- 105 Yoshida JI, Kataoka K, Horcajada R, Nagaki A. Chem. Rev. 2008; 108: 2265
- 106 Sbei N, Hardwick T, Ahmed N. ACS Sustainable Chem. Eng. 2021; 9: 6148
- 107 Shono T, Hamaguchi H, Matsumura Y. J. Am. Chem. Soc. 1975; 97: 4264
- 108 Shono T, Matsumura Y, Tsubata K, Uchida K, Kanazawa T, Tsuda K. J. Org. Chem. 1984; 49: 3711
- 109 Shono T, Matsumura Y, Tsubata K. J. Am. Chem. Soc. 1981; 103: 1172
- 110 Jones AM, Banks CE. Beilstein J. Org. Chem. 2014; 10: 3056
- 111 Yamamoto K, Kuriyama M, Onomura O. Chem. Rec. 2021; 21: 2239
- 112 Novaes LF. T, Ho JS. K, Mao K, Liu K, Tanwar M, Neurock M, Villemure E, Terrett JA, Lin S. J. Am. Chem. Soc. 2022; 144: 1187
- 113 Rein J, Lin S, Kalyani D, Lehnherr D. High-Throughput Experimentation for Electrochemistry. In The Power of High-Throughput Experimentation: General Topics and Enabling Technologies for Synthesis and Catalysis, Vol. 1. Emmert MH, Jouffroy M, Leitch DC. ACS Symposium Series 1419; American Chemical Society; Washington DC: 2022: 167-187
- 114 Wang F, Rafiee M, Stahl SS. Angew. Chem. Int. Ed. 2018; 57: 6686
- 115 Hilt G. ChemElectroChem 2020; 7: 395
- 116 Xiao KJ, Wang Y, Huang YH, Wang XG, Huang PQ. J. Org. Chem. 2013; 78: 8305
- 117 Lennox AJ. J, Goes SL, Webster MP, Koolman HF, Djuric SW, Stahl SS. J. Am. Chem. Soc. 2018; 140: 11227
- 118 Bernardi L, Bonini BF, Capitò E, Dessole G, Fochi M, Comes-Franchini M, Ricci A. Synlett 2003; 2003: 1778
- 119 Lee M, Sanford MS. Org. Lett. 2017; 19: 572
- 120 Lee M, Sanford MS. J. Am. Chem. Soc. 2015; 137: 12796
- 121 Gould CA, Pace AL, MacMillan DW. C. J. Am. Chem. Soc. 2023; 145: 16330
- 122 Talele TT. J. Med. Chem. 2020; 63: 13291
- 123 Schultz DM, Lévesque F, DiRocco DA, Reibarkh M, Ji Y, Joyce LA, Dropinski JF, Sheng H, Sherry BD, Davies IW. Angew. Chem. Int. Ed. 2017; 56: 15274
- 124 Sarver PJ, Bacauanu V, Schultz DM, DiRocco DA, Lam Y.-h, Sherer EC, MacMillan DW. C. Nat. Chem. 2020; 12: 459
- 125 Wichur T, Więckowska A, Więckowski K, Godyń J, Jończyk J, Valdivieso ÁD. R, Panek D, Pasieka A, Sabaté R, Knez D, Gobec S, Malawska B. Eur. J. Med. Chem. 2020; 187: 111916
- 126 Hagmann WK. J. Med. Chem. 2008; 51: 4359
- 127 Mkhalid IA. I, Barnard JH, Marder TB, Murphy JM, Hartwig JF. Chem. Rev. 2010; 110: 890
- 128 Liskey CW, Hartwig JF. J. Am. Chem. Soc. 2012; 134: 12422
- 129 Li Q, Liskey CW, Hartwig JF. J. Am. Chem. Soc. 2014; 136: 8755
- 130 Shilov AE, Shteinman AA. Coord. Chem. Rev. 1977; 24: 97
- 131 Oeschger R, Su B, Yu I, Ehinger C, Romero E, He S, Hartwig J. Science 2020; 368: 736
- 132 Kuroda Y, Park K, Shimazaki Y, Zhong RL, Sakaki S, Nakao Y. Angew. Chem. Int. Ed. 2023; 62: e202300704
- 133 Ishiyama T, Takagi J, Ishida K, Miyaura N, Anastasi NR, Hartwig JF. J. Am. Chem. Soc. 2002; 124: 390
- 134 Topczewski JJ, Cabrera PJ, Saper NI, Sanford MS. Nature 2016; 531: 220
- 135 Liu W, Babl T, Röther A, Reiser O, Davies HM. L. Chem. Eur. J. 2020; 26: 4236
- 136 Merchant RR, Lopez JA. Org. Lett. 2020; 22: 2271
- 137 Liang H, Morken JP. J. Am. Chem. Soc. 2023; 145: 20755
- 138 Ye S, Yang W, Coon T, Fanning D, Neubert T, Stamos D, Yu JQ. Chem. Eur. J. 2016; 22: 4748
- 139 Griffiths RJ, Kong WC, Richards SA, Burley GA, Willis MC, Talbot EP. A. Chem. Sci. 2018; 9: 2295
- 140 Beltran F, Miesch L. Synthesis 2020; 52: 2497
- 141 Dudognon Y, Rodriguez J, Constantieux T, Bugaut X. Eur. J. Org. Chem. 2018; 2018: 2432
- 142 Holmberg-Douglas N, Choi Y, Aquila B, Huynh H, Nicewicz DA. ACS Catal. 2021; 11: 3153
- 143 Trindade AF, Faulkner EL, Leach AG, Nelson A, Marsden SP. Chem. Commun. 2020; 56: 8802