Synthesis 2023; 55(15): 2343-2352
DOI: 10.1055/a-2022-1511
paper
Special Issue dedicated to Prof. David A. Evans

Synthesis of Polycyclic Imidazoles via α-C–H/N–H Annulation of Alicyclic Amines

Subhradeep Dutta
,
Kamal Bhatt
,
Fabian Cuffel
,
Daniel Seidel
Financial support from the National Institutes of Health–National Institute of General Medical Sciences (NIH–NIGMS, grant no. R01GM101389) is gratefully acknowledged. Mass spectrometry instrumentation was supported by a grant from the NIH (S10 OD021758-01A1).


Abstract

Secondary alicyclic amines are converted into their corresponding ring-fused imidazoles in a simple procedure consisting of oxidative imine formation followed by a van Leusen reaction. Amines with an existing α-substituent undergo regioselective ring-fusion at the α′-position. This method was utilized in a synthesis of fadrozole.

Supporting Information



Publication History

Received: 18 November 2022

Accepted after revision: 30 January 2023

Accepted Manuscript online:
30 January 2023

Article published online:
13 April 2023

© 2023. Thieme. All rights reserved

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  • References


    • Selected reviews on the relevance of azacycles in medicine:
    • 1a Taylor RD, MacCoss M, Lawson AD. G. J. Med. Chem. 2014; 57: 5845
    • 1b Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257

      Recent examples of mechanistically diverse methods for amine C–H bond functionalization:
    • 3a Ohmatsu K, Suzuki R, Furukawa Y, Sato M, Ooi T. ACS Catal. 2020; 10: 2627
    • 3b Verma P, Richter JM, Chekshin N, Qiao JX, Yu J.-Q. J. Am. Chem. Soc. 2020; 142: 5117
    • 3c Walker MM, Koronkiewicz B, Chen S, Houk KN, Mayer JM, Ellman JA. J. Am. Chem. Soc. 2020; 142: 8194
    • 3d Chen L, Yang Y, Liu L, Gao Q, Xu S. J. Am. Chem. Soc. 2020; 142: 12062
    • 3e Xu L.-P, Roque JB, Sarpong R, Musaev DG. J. Am. Chem. Soc. 2020; 142: 21140
    • 3f Feng K, Quevedo RE, Kohrt JT, Oderinde MS, Reilly U, White MC. Nature 2020; 580: 621
    • 3g Sarver PJ, Bacauanu V, Schultz DM, DiRocco DA, Lam Y.-h, Sherer EC, MacMillan DW. C. Nat. Chem. 2020; 12: 459
    • 3h Oeschger R, Su B, Yu I, Ehinger C, Romero E, He S, Hartwig J. Science 2020; 368: 736
    • 3i Short MA, Blackburn JM, Roizen JL. Synlett 2020; 31: 102
    • 3j Trindade AF, Faulkner EL, Leach AG, Nelson A, Marsden SP. Chem. Commun. 2020; 56: 8802
    • 3k Holmberg-Douglas N, Choi Y, Aquila B, Huynh H, Nicewicz DA. ACS Catal. 2021; 11: 3153
    • 3l Yi M.-J, Zhang H.-X, Xiao T.-F, Zhang J.-H, Feng Z.-T, Wei L.-P, Xu G.-Q, Xu P.-F. ACS Catal. 2021; 11: 3466
    • 3m Aguilera EY, Sanford MS. Angew. Chem. Int. Ed. 2021; 60: 11227
    • 3n Chang Y, Cao M, Chan JZ, Zhao C, Wang Y, Yang R, Wasa M. J. Am. Chem. Soc. 2021; 143: 2441
    • 3o Yue W.-J, Day CS, Martin R. J. Am. Chem. Soc. 2021; 143: 6395
    • 3p Koperniku A, Schafer LL. Chem. Eur. J. 2021; 27: 6334
    • 3q 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
    • 3r Rodrigalvarez J, Reeve LA, Miró J, Gaunt MJ. J. Am. Chem. Soc. 2022; 144: 3939
    • 3s Shu X, Zhong D, Lin Y, Qin X, Huo H. J. Am. Chem. Soc. 2022; 144: 8797
    • 3t Feng T, Wang S, Liu Y, Liu S, Qiu Y. Angew. Chem. Int. Ed. 2022; 61: e202115178
    • 3u Gong Y, Su L, Zhu Z, Ye Y, Gong H. Angew. Chem. Int. Ed. 2022; 61: e202201662
    • 3v Lee W, Kim D, Seo S, Chang S. Angew. Chem. Int. Ed. 2022; 61: e202202971
    • 3w Guo R, Xiao H, Li S, Luo Y, Bai J, Zhang M, Guo Y, Qi X, Zhang G. Angew. Chem. Int. Ed. 2022; 61: e202208232
    • 4a Chen W, Ma L, Paul A, Seidel D. Nat. Chem. 2018; 10: 165
    • 4b Paul A, Seidel D. J. Am. Chem. Soc. 2019; 141: 8778
    • 4c Chen W, Paul A, Abboud KA, Seidel D. Nat. Chem. 2020; 12: 545
    • 4d Paul A, Kim JH, Daniel SD, Seidel D. Angew. Chem. Int. Ed. 2021; 60: 1625
    • 4e Kim JH, Paul A, Ghiviriga I, Seidel D. Org. Lett. 2021; 23: 797
    • 4f Chen W, Seidel D. Org. Lett. 2021; 23: 3729
    • 4g Valles DA, Dutta S, Paul A, Abboud KA, Ghiviriga I, Seidel D. Org. Lett. 2021; 23: 6367
    • 4h Paul A, Vasseur C, Daniel SD, Seidel D. Org. Lett. 2022; 24: 1224
    • 4i Yu F, Valles DA, Chen W, Daniel SD, Ghiviriga I, Seidel D. Org. Lett. 2022; 24: 6364

      For an early review, see:
    • 5a Majewski M, Gleave DM. J. Organomet. Chem. 1994; 470: 1

    • Selected key contributions:
    • 5b Wittig G, Schmidt HJ, Renner H. Chem. Ber. 1962; 95: 2377
    • 5c Wittig G, Hesse A. Justus Liebigs Ann. Chem. 1971; 746: 149
    • 5d Wittig G, Hesse A. Justus Liebigs Ann. Chem. 1971; 746: 174
    • 5e Wittig G, Häusler G. Justus Liebigs Ann. Chem. 1971; 746: 185
  • 6 For an excellent recent review on organic oxidants serving as hydride acceptors, see: Miller JL, Lawrence J.-MI. A, Rodriguez del Rey FO, Floreancig PE. Chem. Soc. Rev. 2022; 51: 5660
  • 7 van Leusen AM, Wildeman J, Oldenziel OH. J. Org. Chem. 1977; 42: 1153

    • Selected reviews on the van Leusen imidazole synthesis and its use in medicinal chemistry:
    • 8a Slobbe P, Ruijter E, Orru RV. A. MedChemComm 2012; 3: 1189
    • 8b Akritopoulou-Zanze I. In Isocyanide Chemistry . Nenajdenko VG. Wiley-VCH; Weinheim: 2012: 451
    • 8c Hulme C, Ayaz M, Martinez-Ariza G, Medda F, Shaw A. In Small Molecule Medicinal Chemistry . Czechtizky W, Hamley P. Wiley; Weinheim: 2015: 145
    • 8d Zheng X, Ma Z, Zhang D. Pharmaceuticals 2020; 13: 37

      Examples of van Leusen imidazole syntheses with cyclic imines:
    • 9a Sasaki T, Eguchi S, Toi N. J. Org. Chem. 1979; 44: 3711
    • 9b Sisko J, Kassick AJ, Mellinger M, Filan JJ, Allen A, Olsen MA. J. Org. Chem. 2000; 65: 1516
    • 9c Murugesh V, Harish B, Adiseshu M, Babu Nanubolu J, Suresh S. Adv. Synth. Catal. 2016; 358: 1309
    • 9d Satyam K, Murugesh V, Suresh S. Org. Biomol. Chem. 2019; 17: 5234
    • 9e Rudy H.-KA, Mayer P, Wanner KT. Eur. J. Org. Chem. 2020; 3599
  • 10 For a photochemical approach to the synthesis of ring-fused imidazoles from tertiary amines, see: Li J, Zhang P, Jiang M, Yang H, Zhao Y, Fu H. Org. Lett. 2017; 19: 1994

    • Examples of mechanistically unrelated amine N–H/C–H annulations leading to the installation of a fused pyrrole ring:
    • 11a Grigg R, Nimal Gunaratne HQ, Henderson D, Sridharan V. Tetrahedron 1990; 46: 1599
    • 11b Deb I, Seidel D. Tetrahedron Lett. 2010; 51: 2945
    • 11c Yang Z, Lu N, Wei Z, Cao J, Liang D, Duan H, Lin Y. J. Org. Chem. 2016; 81: 11950
    • 11d Zheng K.-L, Shu W.-M, Ma J.-R, Wu Y.-D, Wu A.-X. Org. Lett. 2016; 18: 3526
    • 11e Zheng K.-L, You M.-Q, Shu W.-M, Wu Y.-D, Wu A.-X. Org. Lett. 2017; 19: 2262
  • 12 Allentoff AJ, Markus B, Duelfer T, Wu A, Jones L, Ciszewska G, Ray T. J. Labelled Compd. Radiopharm. 2000; 43: 1075
  • 13 Schlepphorst C, Wiesenfeldt MP, Glorius F. Chem. Eur. J. 2018; 24: 356
  • 14 The propensity of alicyclic imines such as 1-pyrroline and 1-piperideine to undergo the formation of more stable and typically unreactive trimers is well documented. For a leading study, see: Fandrick DR, Hart CA, Okafor IS, Mercadante MA, Sanyal S, Masters JT, Sarvestani M, Fandrick KR, Stockdill JL, Grinberg N, Gonnella N, Lee H, Senanayake CH. Org. Lett. 2016; 18: 6192
  • 15 Claxton GP, Allen L, Grisar JM. Org. Synth. 1977; 56: 118
  • 16 Yujiro N, Keiichiro O, Yoshito T, Shuji T. Chem. Lett. 1977; 693
  • 17 Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A. J. Med. Chem. 1991; 34: 725
    • 18a Maligres PE, Waters MS, Fleitz F, Askin D. Tetrahedron Lett. 1999; 40: 8193
    • 18b Li X, Li J, Huang Y, Gong Q, Fu Y, Xu Y, Huang J, You H, Zhang D, Zhang D, Mao F, Zhu J, Wang H, Zhang H, Li J. Eur. J. Med. Chem. 2022; 229: 114045
  • 19 Suffert J. J. Org. Chem. 1989; 54: 509
    • 20a Sisko J, Mellinger M, Sheldrake PW, Baine NH. Org. Synth. 2000; 77: 198
    • 20b Wang L, Studer A. Org. Lett. 2017; 19: 5701
  • 21 Liu Z.-Y, Wen Z.-H, Wang X.-C. Angew. Chem. Int. Ed. 2017; 56: 5817