Non-Directed β- or γ-C(sp³)–H Functionalization of Saturated Nitrogen-Containing Heterocycles

Abstract

Reactions that take place via C–H functionalization are valuable tools in organic synthesis because they can be used for the synthesis of target compounds and for the late-stage functionalization of bioactive compounds. Among these, non-directed C(sp³)–H functionalization reactions of saturated nitrogen-containing heterocycles have been developed in recent years. However, most of these lead to functionalization at the α-position relative to the heteroatom, and reactions at the β- or γ-positions are limited since these bonds are stronger and less electron-rich. Hence, in this review, we will discuss non-directed β- or γ-C(sp³)–H functionalization reactions of saturated nitrogen-containing heterocycles, which are of recent interest to medicinal chemists. These methods are attractive in order to avoid the pre-functionalization of substrates, and to reduce the number of synthetic steps and the formation of byproducts. Such non-directed β- and γ-C(sp³)–H functionalization reactions can be divided into enamine-intermediate-mediated processes and other reaction types described in this review.

1 Introduction

2 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles via an Enamine Intermediate

2.1 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Acidic, Basic or Thermal Conditions

2.2 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Oxidative Conditions

2.3 Non-Directed β-C(sp³)–H Functionalization of Saturated Nitrogen­-Containing Heterocycles under Redox-Neutral Conditions

3 Strategies for Non-Directed β- or γ-C(sp³)–H Functionalization of Saturated Heterocycles Excluding Examples Proceeding via an Enamine Intermediate

4 Summary

Key words

directing-group-free - C(sp³)–H functionalization - nitrogen-containing heterocycles - enamine intermediate - borrowing hydrogen - late-stage functionalization

Publication History

Received: 05 March 2021

Accepted after revision: 15 April 2021

Accepted Manuscript online:
15 April 2021

Article published online:
19 May 2021

• References


Reviews:
• 1a Li Y, Pan GA, Luo MJ, Li JH. Chem. Commun. 2020; 56: 6907
• 1b Baccalini A, Faita G, Zanoni G, Maiti D. Chem. Eur. J. 2020; 26: 9749
• 1c Ohno S, Arisawa M. J. Org. Chem. 2020; 85: 6831
• 1d Zhu Y, Huang Y. Synthesis 2020; 52: 1181
• 1e Zhao F, Masci D, Tomarelli E, Castagnolo D. Synthesis 2020; 52: 2948

Reviews:
• 2a Zhan BB, Jiang MX, Shi BF. Chem. Commum. 2020; 56: 13950
• 2b Lim Y.-J, Kuang Y, Wu J, Yao SQ. Chem. Eur. J. 2020; 26: 1
• 2c Börgel J, Ritter T. Chem 2020; 6: 1877

Reviews:
• 3a Joule JA, Mills K. Heterocyclic Chemistry, 5th ed. John Wiley & Sons; Chichester: 2010
• 3b Katritzky AR, Ramsden CA, Joule JA, Zhdankin VV. Handbook of Heterocyclic Chemistry, 3rd ed. Elsevier; Oxford: 2010
• 4a Murai S, Kakiuchi F, Sekine S, Tanaka Y, Kamatani A, Sonoda M. Nature 1993; 366: 529
• 4b Shrikant MK, Chatani N. Chem 2020; 6: 1056
• 5 Nagib DA, Macmillan DW. C. Nature 2011; 480: 224

Reviews:
• 6a Aziz J, Piguel S. Synthesis 2017; 49: 4562
• 6b Leitch JA, Bhonoah Y, Frost CG. ACS Catal. 2017; 7: 5618
• 6c Murakami K, Yamada S, Kaneda T, Itami K. Chem. Rev. 2017; 117: 9302
• 6d Patel OP. S, Nandwana NK, Legoabe LJ, Das BC, Kumar A. Adv. Synth. Catal. 2020; 362: 4226
• 6e Bagdi AK, Hajra A. Org. Biomol. Chem. 2020; 18: 2611
• 6f Jagtap RA, Punji B. Asian J. Org. Chem. 2020; 9: 326

Reviews:
• 7a Ye Z, Gettys KE, Dai M. Beilstein J. Org. Chem. 2016; 12: 702
• 7b Antermite D, Bull JA. Synthesis 2019; 51: 3171
• 7c Kapoor M, Singh A, Sharma K, Hsu MH. Adv. Synth. Catal. 2020; 362: 4513

Reviews:
• 8a Yi H, Zhang G, Wang H, Huang Z, Wang J, Singh AK, Lei A. Chem. Rev. 2017; 117: 9016
• 8b Matsui JK, Lang SB, Heitz DR, Molander GA. ACS Catal. 2017; 7: 2563
• 8c Revathi L, Ravindar L, Fang WY, Rakesh KP, Qin HL. Adv. Synth. Catal. 2018; 360: 4652
• 8d Trowbridge A, Walton SM, Gaunt MJ. Chem. Rev. 2020; 120: 2613

For examples of α,β-difunctionalization, see:
• 9a Chen W, Kang Y, Wilde RG, Seidel D. Angew. Chem. Int. Ed. 2014; 53: 5179
• 9b Ma L, Paul A, Breugst M, Seidel D. Chem. Eur. J. 2016; 22: 18179
• 9c Chamorro-Arenas D, Nolasco-Hernández AA, Fuentes L, Quintero L, Sartillo-Piscil F. Chem. Eur. J. 2020; 26: 4671

For examples of β,β-difunctionalizations, see:
• 10a Rugheimer L. Chem. Ber. 1891; 24: 2186
• 10b Rugheimer L. Chem. Ber. 1892; 25: 24
• 10c Poirier RH, Morin RD, Bearse AE, McKim AM. J. Org. Chem. 1961; 26: 4275
• 10d Kameswari U. React. Kinet. Catal. Lett. 1996; 59: 135

For examples of β-C(sp³)–H functionalization via α-C(sp³)–H activation using directing groups, see:
• 11a Seel S, Thaler T, Takatsu K, Zhang C, Zipse H, Straub BF, Mayer P, Knochel P. J. Am. Chem. Soc. 2011; 133: 4774
• 11b Millet A, Larini P, Clot E, Baudoin O. Chem. Sci. 2013; 4: 2241
• 11c Trindade AF, Faulkner EL, Leach AG, Nelson A, Marsden SP. Chem. Commun. 2020; 56: 8802
• 12a Wittig G, Hesse A. Liebigs Ann. Chem. 1971; 746: 149
• 12b Wittig G, Hesse A. Liebigs Ann. Chem. 1971; 746: 174
• 13a Whitesell JK, Whitesell MA. Synthesis 1983; 517
• 13b Mangelinckx S, Giubellina N, De Kimpe N. Chem. Rev. 2004; 104: 2353
• 14a Pal K, Behnke ML, Tong L. Tetrahedron Lett. 1993; 34: 6205
• 14b Nenajdenko VG, Pronin SV, Balenkova ES. Russ. Chem. Bull. 2007; 56: 336
• 15 Oda M, Fukuchi Y, Ito S, Thanh NC, Kuroda S. Tetrahedron Lett. 2007; 48: 9159
• 16 Polackova V, Veverkova E, Toma S, Bogdal D. Synth. Commun. 2009; 39: 1871
• 17 Mandal S, Mahato S, Jana CK. Org. Lett. 2015; 17: 3762
• 18 Zhou L, An X.-D, Yang S, Li XJ, Shao CL, Liu Q, Xiao J. Org. Lett. 2020; 22: 776
• 19 Chen W, Paul A, Abboud KA, Seidel D. Nat. Chem. 2020; 12: 545
• 20 Xia XF, Shu XZ, Ji KG, Yang YF, Shaukat A, Liu XY, Liang YM. J. Org. Chem. 2010; 75: 2893
• 21 He Y, Wang F, Zhang X, Fan X. Chem. Commun. 2017; 53: 4002
• 22 Takasu N, Oisaki K, Kanai M. Org. Lett. 2013; 15: 1918
• 23 Rachmilovich-Calis S, Masarwa A, Meyerstein N, Meyerstein D, Van Eldik R. Chem. Eur. J. 2009; 15: 8303
• 24 He Y, Yang J, Liu Q, Zhang X, Fan X. J. Org. Chem. 2020; 85: 15600
• 25 Zhou MJ, Zhu SF, Zhou QL. Chem. Commun. 2017; 53: 8770
• 26 Shi X, Chen X, Wang M, Zhang X, Fan X. J. Org. Chem. 2018; 83: 6524
• 27 Wang F, Zhang X, He Y, Fan X. J. Org. Chem. 2020; 85: 2220
• 28 Griffiths RJ, Kong WC, Richards SA, Burley GA, Willis MC, Talbot EP. A. Chem. Sci. 2018; 9: 2295
• 29 Rong X, Guo J, Hu Z, Huang L, Gu Y, Cai Y, Liang G, Xia Q. Eur. J. Org. Chem. 2021; 701
• 30 Muralirajan K, Kancherla R, Rueping M. Angew. Chem. Int. Ed. 2018; 57: 14787
• 31 He Y, Zheng Z, Liu Y, Qiao J, Zhang X, Fan X. Chem. Commun. 2019; 55: 12372
• 32a Corma A, Navas J, Sabater MJ. Chem. Rev. 2018; 118: 1410
• 32b Irrgang T, Kempe R. Chem. Rev. 2019; 119: 2524
• 33a Sundararaju B, Achard M, Sharma GV. M, Bruneau C. J. Am. Chem. Soc. 2011; 133: 10340
• 33b Sundararaju B, Tang Z, Achard M, Sharma GV. M, Toupet L, Bruneau C. Adv. Synth. Catal. 2010; 352: 3141
• 34a Murugesh V, Bruneau C, Achard M, Sahoo AR, Sharma GV. M, Suresh S. Chem. Commun. 2017; 53: 10448
• 34b Murugesh V, Sahoo AR, Achard M, Sharma GV. M, Bruneau C, Suresh S. Adv. Synth. Catal. 2021; 363: 453
• 35 Zhang J, Park S, Chang S. J. Am. Chem. Soc. 2018; 140: 13209
• 36 Chen Y, Wan HL, Huang Y, Liu S, Wang F, Lu C, Nie J, Chen Z, Yang G, Ma C. Org. Lett. 2020; 22: 7797
• 37 Chang Y, Yesilcimen A, Cao M, Zhang Y, Zhang B, Chan JZ, Wasa M. J. Am. Chem. Soc. 2019; 141: 14570
• 38 Chang Y, Cao M, Chan JZ, Zhao C, Wang Y, Yang R, Wasa M. J. Am. Chem. Soc. 2021; 143: 2441
• 39 Zhou L, Shen Y.-B, An X.-D, Li X.-J, Li S.-S, Liu Q, Xiao J. Org. Lett. 2019; 21: 8543
• 40 Wang H, Li Y, Lu Q, Yu M, Bai X, Wang S, Cong H, Zhang H, Lei A. ACS Catal. 2019; 9: 1888
• 41 Oeschger R, Su B, Yu I, Ehinger C, Romero E, He S, Hartwig JF. Science 2020; 368: 736
• 42 Liu W, Babl T, Röther A, Reiser O, Davies HM. L. Chem. Eur. J. 2020; 26: 4236
• 43a Liao K, Negretti S, Musaev DG, Bacsa J, Davies HM. L. Nature 2016; 533: 230
• 43b Liao K, Pickel TC, Boyarskikh V, Bacsa J, Musaev DG, Davies HM. L. Nature 2017; 551: 609
• 44 Davies HM. L, Manning JR. Nature 2008; 451: 417
• 45 Lee M, Sanford MS. Org. Lett. 2017; 19: 572
• 46 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
• 47 Tzirakis MD, Lykakis IN, Orfanopoulos M. Chem. Soc. Rev. 2009; 38: 2609
• 48 Sarver PJ, Bacauanu V, Schultz DM, DiRocco DA, Lam Y.-h, Sherer EC, MacMillan DW. C. Nat. Chem. 2020; 12: 459