Iron-Catalyzed Synthesis of Pyrrolo[2,1-a]isoquinolines via 1,3-Dipolar Cycloaddition/Elimination/Aromatization Cascade and Modifications

Abstract

We have developed an iron-catalyzed synthesis of pyrrolo[2,1-a]isoquinoline derivatives with tetrahydroisoquinolines, arylacyl bromides, and nitroolefins. Highly functionalized pyrrolo[2,1-a]isoquinolines can be obtained in moderate to good yields through a three-component N-alkylation/oxidative 1,3-dipolar cycloaddition/elimination/aromatization cascade. The obtained products in this study can be easily modified by easy chemical transformations to structurally complex molecules bearing privileged framework.

Key words

iron catalysis - pyrrolo[2,1-a]isoquinoline - tetrahydroisoquinoline - nitroolefin - dipolar cycloaddition

Publication History

Received: 13 June 2022

Accepted after revision: 11 July 2022

Accepted Manuscript online:
11 July 2022

Article published online:
19 August 2022

• References and Notes

• 1a Fan H, Peng J, Hamann MT, Hu JF. Chem. Rev. 2008; 108: 264
• 1b Banwell M, Lan P. In Targets in Heterocyclic Systems – Chemistry and Properties, Vol. 24. Attanasi OA, Gabriele B, Merino P, Spinelli D. Società Chimica Italiana; Roma: 2020: 208-226
• 1c Fukuda T, Ishibashi F, Iwao M. Heterocycle 2011; 83: 491
• 1d Mohan C, Krishna RB, Sivanandan ST, Ibnusaud I. Eur. J. Org. Chem. 2021; 4911
• 2a Bailly C. Mar. Drugs 2015; 13: 1105
• 2b Reyes-Gutiérrez PE, Camacho JR, Ramírez-Apan MT, Osornio YM, Martínez R. Org. Biomol. Chem. 2010; 8: 4374
• 2c Chávez-Santos RM, Reyes-Gutiérrez PE, Torres-Ochoa RO, Ramírez-Apan MT, Martínez R. Chem. Pharm. Bull. 2017; 65: 973
• 3a Matveeva MD, Purgatorio R, Voskressensky LG, Altomare CD. Future Med. Chem. 2019; 11: 2735
• 3b Pässler U, Knölker H.-J. The Pyrrolo[2,1-a]isoquinoline Alkaloids. In The Alkaloids: Chemistry and Biology, Vol. 70 . Knölker H.-J. Academic Press; London: 2011: 79-151
• 3c Cui H.-L. Org. Biomol. Chem. 2022; 20: 2779
• 4a Guan Z.-H, Li L, Ren Z.-H, Li J, Zhao M.-N. Green. Chem. 2011; 13: 1664
• 4b Ghabraie E, Balalaie S, Bararjanian M, Bijanzadeh HR, Rominger F. Tetrahedron 2011; 67: 5415
• 4c Cai Q, Li D.-K, Zhou R.-R, Shu W.-M, Wu Y.-D, Wu A.-X. Org. Lett. 2016; 18: 1342
• 4d Mangalaraj S, Ramanathan CR. RSC Adv. 2012; 2: 12665
• 4e Meshram HM, Babu BM, Kumar S, Thakur PB, Bangade VM. Tetrahedron Lett. 2013; 54: 2296
• 4f Maiti S, Biswas S, Jana U. J. Org. Chem. 2010; 75: 1674
• 5a Ploypradith P, Mahidol C, Sahakitpichan P, Wongbundit S, Ruchirawat S. Angew. Chem. Int. Ed. 2004; 43: 866
• 5b Korotaev VY, Sosnovskikh VY, Barkov AY, Slepukhin PA, Ezhikova MA, Kodess MI, Shklyaev YV. Tetrahedron 2011; 67: 8685
• 5c Boonya-udtayan S, Yotapan N, Woo C, Bruns CJ, Ruchirawat S, Thasana N. Chem. Asian J. 2010; 5: 2113
• 5d Ploypradith P, Petchmanee T, Sahakitpichan P, Litvinas ND, Ruchirawat S. J. Org. Chem. 2006; 71: 9440
• 6 Nevskaya AA, Matveeva MD, Borisova TN, Niso M, Colabufo NA, Boccarelli A, Purgatorio R, de Candia M, Cellamare S, Voskressensky LG, Altomare CD. ChemMedChem 2018; 13: 1588
• 7a Zou Y.-Q, Lu L.-Q, Fu L, Chang N.-J, Rong J, Chen J.-R, Xiao W.-J. Angew. Chem. Int. Ed. 2011; 50: 7171
• 7b Koohgard M, Hosseinpour Z, Hosseini-Sarvari M. Tetrahedron 2021; 89: 132166
• 7c Firoozi S, Hosseini-Sarvari M, Koohgard M. Green Chem. 2018; 20: 5540
• 7d Wang H.-T, Lu C.-D. Tetrahedron Lett. 2013; 54: 3015
• 8a Feng C, Su J.-H, Yan Y, Guo F, Wang Z. Org. Biomol. Chem. 2013; 11: 6691
• 8b Xie ZY, Li F, Niu L, Li HB, Zheng JC, Han RJ, Ju Z, Li SS, Li D. Org. Biomol. Chem. 2020; 18: 6889
• 8c Xu Y.-W, Wang J, Wang G, Zhen L. J. Org. Chem. 2021; 86: 91
• 9a Tóth J, Váradi L, Dancsó A, Blaskó G, Tőke L, Nyerges M. Synlett 2007; 1259
• 9b Tóth J, Váradi L, Dancsó A, Blaskó G, Tőke L, Nyerges M. Synthesis 2009; 4149
• 10a Zheng K, Zhuang S, Shu W, Wu Y, Yang C, Wu A. Chem. Commun. 2018; 54: 11897
• 10b Zheng K.-L, Zhuang S, You M.-Q, Shu W.-M, Wu A.-X, Wu Y.-D. ChemistrySelect 2017; 2: 10762
• 10c Shang Z.-H, Zhang X.-J, Li Y.-M, Wu R.-X, Zhang H.-R, Qin L.-Y, Ni X, Yan Y, Wu A.-X, Zhu Y.-P. J. Org. Chem. 2021; 86: 15733
• 10d Zhu Z, Chandak HS, Seidel D. Org. Lett. 2018; 20: 4090
• 10e Zhu Z, Lv X, Anesini J, Seidel D. Org. Lett. 2017; 19: 6424
• 10f Mantelingu K, Lin Y, Seidel D. Org. Lett. 2014; 16: 5910
• 11 Zheng K.-L, You M.-Q, Shu W.-M, Wu Y.-D, Wu A.-X. Org. Lett. 2017; 19: 2262
• 12a Hazra A, Mondal S, Maity A, Naskar S, Saha P, Paira R, Sahu KB, Paira P, Ghosh S, Sinha C, Samanta A, Banerjee S, Mondal NB. Eur. J. Med. Chem. 2011; 46: 2132
• 12b An J, Yang Q.-Q, Wang Q, Xiao W.-J. Tetrahedron Lett. 2013; 54: 3834
• 12c Krishnan J, Vedhanarayanan B, Sasidhar BS, Varughese S, Nair V. Chem. Asian J. 2017; 12: 623
• 12d Liu Y, Sun J.-W. J. Org. Chem. 2012; 77: 1191
• 12e Dumitrascu F, Georgescu E, Georgescu F, Popa MM, Dumitrescu D. Molecules 2013; 18: 2653
• 12f Yang Y, Gao M, Zhang D.-X, Wu L.-M, Shu W.-M, Wu A.-X. Tetrahedron 2012; 68: 7338
• 12g Zhou W, Liu H, Guo Y, Gu Y, Han J, Chen J, Deng H, Shao M, Zhang H, Cao W. J. Fluorine Chem. 2019; 222-223: 51
• 12h Wang W, Han J, Sun J, Liu Y. J. Org. Chem. 2017; 82: 2835
• 12i Liu Y, Hu H, Zhou J, Wang W, He Y, Wang C. Org. Biomol. Chem. 2017; 15: 5016
• 13a Muthusaravanan S, Perumal S, Yogeeswari P, Sriram D. Tetrahedron Lett. 2010; 51: 6439
• 13b Manjappa KB, Jhang J.-W, Lakshmi KC. S, Yang D.-Y. Asian J. Org. Chem. 2022; 11: e202100659
• 13c Manjappa KB, Lin J.-M, Yang D.-Y. J. Org. Chem. 2017; 82: 7648
• 13d Manjappa KB, Syu J.-R, Yang D.-Y. Org. Lett. 2016; 18: 332
• 14a Cui H.-L, Liu S.-W, Xiao X. J. Org. Chem. 2020; 85: 15382
• 14b Xiao X, Chen X.-H, Wang X.-X, Li W.-Z, Cui H.-L. Synthesis 2022; 54: 2019

For our efforts on the synthesis of pyrrolo[2,1-a]isoquinolines, see:
• 15a Cui H.-L, Jiang L, Tan H, Liu S. Adv. Synth. Catal. 2019; 361: 4772
• 15b Liu S.-W, Ma D.-D, Zhu X.-X, Luo C.-D, Tan H.-L, Ju X.-L, Tan X, Tang X.-H, Huang J, Wang J, Wang X.-X, Cui H.-L. Asian J. Org. Chem. 2020; 9: 1617
• 15c Tang X, Gao Y.-J, Deng H.-Q, Lei J.-J, Liu S.-W, Zhou L, Shi Y, Liang H, Qiao J, Guo L, Han B, Cui H.-L. Org. Biomol. Chem. 2018; 16: 3362
• 15d Tang X, Yang M.-C, Ye C, Liu L, Zhou H.-L, Jiang X.-J, You X.-L, Han B, Cui H.-L. Org. Chem. Front. 2017; 4: 2128
• 15e Liu S.-W, Gao Y.-J, Shi Y, Zhou L, Tang X, Cui H.-L. J. Org. Chem. 2018; 83: 13754
• 16 Yang M.-C, Tang X, Liu S.-W, Deng H.-Q, Lei J.-J, Gao Y.-J, Han B, Cui H.-L. Tetrahedron Lett. 2018; 59: 138

For selected reviews on iron catalysis, see:
• 17a Sarhan AA. O, Bolm C. Chem. Soc. Rev. 2009; 38: 2730
• 17b Bolm C, Legros J, Paih LL, Zani L. Chem. Rev. 2004; 104: 6217
• 17c Sun C.-L, Li B.-J, Shi Z.-J. Chem. Rev. 2011; 111: 1293
• 17d Shang R, Ilies L, Nakamura E. Chem. Rev. 2017; 117: 9086
• 17e Cornil J, Gonnard L, Bensoussan C, Serra-Muns A, Gnamm C, Commandeur C, Commandeur M, Reymomd S, Guérinot A, Cossy J. Acc. Chem. Res. 2015; 48: 761
• 17f Kyne SH, Lefèvre G, Ollivier C, Petit M, Cladera V.-AR, Fensterbank L. Chem. Soc. Rev. 2020; 49: 8501
• 17g Gopalaiah K. Chem. Rev. 2013; 113: 3248
• 17h Bauer I, Knölker H.-J. Chem. Rev. 2015; 115: 3170

For selected examples on the synthesis of pyrrolo[2,1-a]isoquinolines through oxidative 1,3-dipolar cycloaddition, see:
• 18a Yu C, Zhang Y, Zhang S, Li H, Wang W. Chem. Commun. 2011; 47: 1036
• 18b Huang H.-M, Li Y.-J, Ye Q, Yu W.-B, Han L, Jia J.-H, Gao J.-R. J. Org. Chem. 2014; 79: 1084
• 18c Nekkanti S, Kumar NP, Sharma P, Kamal A, Nachtigall FM, Forero-Doria O, Santos LS, Shankaraiah N. RSC Adv. 2016; 6: 2671
• 18d Fujiya A, Tanaka M, Yamaguchi E, Tada N, Itoh A. J. Org. Chem. 2016; 81: 7262
• 18e Vila C, Lau J, Rueping M. Beilstein J. Org. Chem. 2014; 10: 1233
• 18f Huang L, Zhao J. Chem. Commun. 2013; 49: 3751
• 18g Quan Y, Li Q.-Y, Zhang Q, Zhang W.-Q, Lu H, Yu J.-H, Chen J, Zhao X, Wang X.-J. RSC Adv. 2016; 6: 23995

For selected examples on the synthesis of pyrrolo[2,1-a]isoquinolines through multicomponent reaction, see:
• 19a Tao L, Xu Z, Han J, Deng H, Shao M, Chen J, Zhang H, Cao W. Synthesis 2016; 48: 4228
• 19b Chen R, Zhao Y, Sun H, Shao Y, Xu Y, Ma M, Ma L, Wan X. J. Org. Chem. 2017; 82: 9291
• 19c Yang Z, Lu N, Wei Z, Cao J, Liang D, Duan H, Lin Y. J. Org. Chem. 2016; 81: 11950
• 19d Aminkhani A, Sharifi S. Lett. Org. Chem. 2022; 19: 244
• 19e Verma AK, Jha RR, Chaudhary R, Tiwari RK, Reddy KS. K, Danodia A. J. Org. Chem. 2012; 77: 8194
• 20 CCDC 2122680 (3a) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 21a Li J.-Q, Chen X.-H, Cui H.-L. J. Org. Chem. 2022; 87: 2421
• 21b Li J.-Q, Tan H.-L, Ma D.-D, Zhu X.-X, Cui H.-L. J. Org. Chem. 2021; 86: 10118
• 22 Costa M, Noro Jr, Brito A, Proença F. Synlett 2013; 24: 2255
• 23 CCDC 2117618 (8) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 24 General Procedure for the Synthesis of Compounds 3 A suspension of tetrahydroisoquinoline hydrochloride 4 (0.3 mmol), arylacyl bromide 5 (0.3 mmol), nitroolefin 2 (0.2 mmol), FeCl₃·6H₂O (10 mol%), and K₂CO₃ (0.4 mmol) in PhCl (2 mL) was stirred at 120 °C for the indicated reaction time shown in the text under air atmosphere. Then the reaction mixture was cooled to rt and purified directly by a silica gel flash chromatography (hexane/EtOAc) to afford compound 3. Analytical Data for Typical Compounds
  Compound 3a Yellow solid, 40.2 mg, 49% yield; purified by a silica gel flash chromatography (hexane/EtOAc = 9/1). ¹H NMR (400 MHz, CDCl₃): δ = 7.57 (d, J = 7.3 Hz, 2 H), 7.21 (t, J = 7.4 Hz, 1 H), 7.12 (s, 1 H), 7.10–6.97 (m, 7 H), 6.78 (s, 1 H), 6.58 (s, 1 H), 4.55 (t, J = 6.8 Hz, 2 H), 3.94 (s, 3 H), 3.94 (s, 3 H), 3.10 (t, J = 6.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.6, 149.1, 148.3, 139.1, 135.9, 135.6, 135.5, 131.4, 129.9, 129.4, 127.5, 127.4, 127.3, 126.1, 125.3, 120.5, 111.1, 107.1, 105.3, 56.1, 56.0, 42.9, 28.7. ESI-HRMS: m/z calcd for C₂₇H₂₄NO₃ ⁺ [M + H]⁺: 410.1751; found: 410.1758. Compound 3f Yellow solid, 49.5 mg, 60% yield; purified by a silica gel flash chromatography (hexane/EtOAc = 9/1). ¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 2 H), 7.11 (s, 1 H), 7.02 (d, J = 5.0 Hz, 1 H), 6.77 (s, 1 H), 6.67–6.62 (m, 1 H), 6.59 (s, 1 H), 6.54 (d, J = 3.3 Hz, 1 H), 4.45 (t, J = 6.7 Hz, 2 H), 3.95 (s, 3 H), 3.93 (s, 3 H), 3.07 (t, J = 6.7 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.5, 149.1, 148.4, 139.2, 137.4, 135.5, 131.8, 129.7, 127.7, 127.6, 127.2, 126.9, 125.2, 124.8, 120.3, 111.0, 107.0, 105.8, 56.1, 56.0, 43.1, 28.7. ESI-HRMS: m/z calcd for C₂₅H₂₂NO₃S⁺ [M + H]⁺: 416.1315; found: 416.1320. Compound 3i Yellow solid, 66.5 mg, 75% yield; purified by a silica gel flash chromatography (hexane/EtOAc = 9/1). ¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.46 (m, 2 H), 7.12 (s, 1 H), 7.05 (s, 5 H), 7.03–6.99 (m, 2 H), 6.78 (s, 1 H), 6.58 (s, 1 H), 4.55 (t, J = 6.8 Hz, 2 H), 3.94 (s, 3 H), 3.94 (s, 3 H), 3.10 (t, J = 6.7 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 186.1, 149.2, 148.4, 137.7, 137.6, 136.0, 135.9, 135.7, 131.3, 129.5, 127.74, 127.68, 127.0, 126.5, 125.5, 120.4, 111.1, 107.1, 105.5, 56.2, 56.1, 43.0, 28.7. ESI-HRMS: m/z calcd for C₂₇H₂₃ClNO₃ ⁺ [M + H]⁺: 444.1361; found: 444.1369.