Ni(0)-Catalyzed Synthesis of Polycyclic α,β-Unsaturated γ-Lactams via Intramolecular Carbonylative Cycloaddition of Yne-imines with CO

Abstract

A Ni(0)-catalyzed intramolecular carbonylative cycloaddition between 1,5-yne-imines and carbon monoxide (CO) is disclosed. When Ni(CO)₃PCy₃ was employed as a pre-catalyst, a variety of polycyclic α,β-unsaturated γ-lactams were prepared in up to 78% yield with 100% atom efficiency. Aza-nickelacycles, generated by the oxidative cyclization of yne-imines on the Ni(0) center, were experimentally confirmed as key intermediates. Moreover, diastereoselective transformations of the obtained products to afford highly substituted polycyclic γ-lactams with three contiguous carbon stereocenters are reported.

Key words

nickel-catalysis - carbonylative cycloaddition - α,β-unsaturated γ-lactams - aza-nickelacycle - yne-imines

Publication History

Received: 06 August 2020

Accepted after revision: 03 September 2020

Article published online:
08 October 2020

• References and Notes

• 1a Khand IU, Knox GR, Pauson PL, Watts WE, Foreman MI. J. Chem. Soc., Perkin Trans. 1 1973; 977
• 1b Exon C, Magnus P. J. Am. Chem. Soc. 1983; 105: 2477
• 1c Shibata T. Adv. Synth. Catal. 2006; 348: 2328
• 1d The Pauson–Khand Reaction: Scope, Variations and Applications. Torres RR. Wiley-VCH; Weinheim: 2012

For selected examples of the application of the Pauson–Khand reaction in the total synthesis of complex natural products, see:
• 2a Castro J, Sörensen H, Riera A, Morin C, Moyano A, Pericàs MA, Greene AE. J. Am. Chem. Soc. 1990; 112: 9388
• 2b Jamison TF, Shambayati S, Crowe WE, Schreiber SL. J. Am. Chem. Soc. 1994; 116: 5505
• 2c Jamison TF, Shambayati S, Crowe WE, Schreiber SL. J. Am. Chem. Soc. 1997; 119: 4353
• 2d Brummond KM, Lu J. J. Am. Chem. Soc. 1999; 121: 5087
• 2e Cassayre J, Zard SZ. J. Am. Chem. Soc. 1999; 121: 6072
• 2f Madu CE, Lovely CJ. Org. Lett. 2007; 9: 4697
• 2g Pallerla MK, Fox JM. Org. Lett. 2007; 9: 5625
• 2h Hirose T, Miyakoshi N, Mukai C. J. Org. Chem. 2008; 73: 1061
• 2i Nakayama A, Kogure N, Kitajima M, Takayama H. Angew. Chem. Int. Ed. 2011; 50: 8025
• 2j Jøgensen L, McKerrall SJ, Kuttruff CA, Ungeheuer F, Felding J, Baran PS. Science 2013; 341: 878
• 2k Chuang KV, Xu C, Reisman SE. Science 2016; 353: 912
• 2l Liang X.-T, Chen J.-H, Yang Z. J. Am. Chem. Soc. 2020; 142: 8116

For selected examples of biologically active compounds including α,β-unsaturated γ-lactam cores, see:
• 3a Koehn FE, McConnell OJ, Longley RE, Sennett SH, Reed JK. J. Med. Chem. 1994; 37: 3181
• 3b Shiraki R, Sumino A, Tadano K, Ogawa S. J. Org. Chem. 1996; 61: 2845
• 3c Mandal AK, Hines J, Kuramochi K, Crews CM. Bioorg. Med. Chem. Lett. 2005; 15: 4043
• 3d Micheli F, Pasquarello A, Tedesco G, Hamprecht D, Bonanomi G, Checchia A, Jaxa-Chamiec A, Damiani F, Davalli S, Donati D, Gallotti C, Petrone M, Rinaldi M, Riley G, Terreni S, Wood M. Bioorg. Med. Chem. Lett. 2006; 16: 3906
• 3e Feng Z, Chu F, Guo Z, Sun P. Bioorg. Med. Chem. Lett. 2009; 19: 2270
• 3f Zhu G.-Y, Chen G, Liu L, Bai L.-P, Jiang Z.-H. J. Nat. Prod. 2014; 77: 983
• 3g Yang X.-R, Tanaka N, Tsuji D, Lu F.-L, Yan X.-J, Itoh K, Li D.-P, Kashiwada Y. Tetrahedron 2019; 75: 130779

For examples of the synthesis of polycyclic α,β-unsaturated γ-lactams via transition-metal-catalyzed intramolecular carbonylative cycloaddition reactions, see:
• 4a Chatani N, Morimoto T, Kamitani A, Fukumoto Y, Murai S. J. Organomet. Chem. 1999; 579: 177
• 4b Mukai C, Yoshida T, Sorimachi M, Odani A. Org. Lett. 2006; 8: 83
• 5a Chatani N, Tobisu M, Asaumi T, Murai S. Synthesis 2000; 925
• 5b Göbel A, Imhof W. Chem. Commun. 2001; 593
• 5c Kang S.-K, Kim K.-J, Hong Y.-T. Angew. Chem. Int. Ed. 2002; 41: 1584
• 5d McLaughlin M, Takahashi M, Micalizio GC. Angew. Chem. Int. Ed. 2007; 46: 3912
• 5e Iwata T, Inagaki F, Mukai C. Angew. Chem. Int. Ed. 2013; 52: 11138
• 5f Fukuyama T, Okada T, Nakashima N, Ryu I. Helv. Chim. Acta 2019; 102: e1900186

For reviews on nickel-catalyzed reactions via (hetero)nickelacycle intermediates, see:
• 6a Montgomery J. Angew. Chem. Int. Ed. 2004; 43: 3890
• 6b Moslin RM, Miller-Moslin K, Jamison TF. Chem. Commun. 2007; 4441
• 6c Ng S.-S, Ho C.-Y, Schleicher KD, Jamison TF. Pure Appl. Chem. 2008; 80: 929
• 6d Tanaka K, Tajima Y. Eur. J. Org. Chem. 2012; 3715
• 6e Montgomery J. Organonickel Chemistry . In Organometallics in Synthesis: Fourth Manual . Lipshutz BH. Wiley; Hoboken: 2013: 319-428
• 6f Tasker SZ, Standley EA, Jamison TF. Nature 2014; 509: 299
• 6g Ogoshi S, Hoshimoto Y, Ohashi M, Kumar R. Reactions via Nickelacycles . In Nickel Catalysis in Organic Synthesis: Methods and Reactions . Ogoshi S. Wiley-VCH; Weinheim, 2020; 3–67;

For selected studies on aza-nickelacycles derived from imines and unsaturated compounds, see:
• 7a Ogoshi S, Ikeda H, Kurosawa H. Angew. Chem. Int. Ed. 2007; 46: 4930
• 7b Ogoshi S, Ikeda H, Kurosawa H. Pure Appl. Chem. 2008; 80: 1115
• 7c Ohashi M, Kishizaki O, Ikeda H, Ogoshi S. J. Am. Chem. Soc. 2009; 131: 9160
• 7d Hoshimoto Y, Ohata T, Ohashi M, Ogoshi S. Chem. Eur. J. 2014; 20: 4105
• 7e Ohashi M, Hoshimoto Y, Ogoshi S. Dalton Trans. 2015; 12060
• 7f Shirataki H, Ono T, Ohashi M, Ogoshi S. Org. Lett. 2019; 21: 851
• 8 Hoshimoto Y, Ohata T, Sasaoka Y, Ohashi M, Ogoshi S. J. Am. Chem. Soc. 2014; 136: 15877
• 9 Hoshimoto Y, Ashida K, Sasaoka Y, Kumar R, Kamikawa K, Verdaguer X, Riera A, Ohashi M, Ogoshi S. Angew. Chem. Int. Ed. 2017; 56: 8206
• 10 Ashida K, Hoshimoto Y, Tohnai N, Scott DE, Ohashi M, Imaizumi H, Tsuchiya Y, Ogoshi S. J. Am. Chem. Soc. 2020; 142: 1594
• 11 Hoshimoto Y, Nishimura C, Sasaoka Y, Kumar R, Ogoshi S. Bull. Chem. Soc. Jpn. 2020; 93: 182

For studies on Ni(0)-mediated or -catalyzed cycloaddition reactions of ene-ynes with isocyanides, see:
• 12a Tamao K, Kobayashi K, Ito Y. J. Am. Chem. Soc. 1988; 110: 1286
• 12b Zhang M, Buchwald SL. J. Org. Chem. 1996; 61: 4498
• 13 All manipulations were conducted under a nitrogen atmosphere using standard Schlenk or dry-box techniques. ¹H, ¹³C, ¹⁹F, and ³¹P NMR spectra were recorded with Bruker AVANCE III 400 spectrometers at 25 °C. The chemical shifts in the ¹H NMR spectra were recorded relative to residual protonated solvent (C₆D₅H (δ = 7.16 ppm) or CHCl₃ (δ = 7.26 ppm)). The chemical shifts in the ¹³C NMR spectra were recorded relative to deuterated solvent (CDCl₃ (δ = 77.16 ppm)). Assignment of the resonances in the ¹H and ¹³C NMR spectra was based on ¹H-¹H COSY, HMQC, and HMBC experiments. Medium-pressure column chromatography was carried out with a Biotage Flash Purification System Isolera, equipped with a 254 nm UV detector. High-resolution mass spectrometry (HRMS) and elemental analyses were performed at the Instrumental Analysis Centre, Faculty of Engineering, Osaka University. Melting points were determined with a Stanford Research Systems MPA100 OptiMelt Automated Melting-Point System. X-ray crystal data were collected with Rigaku XtaLAB Synergy equipped with the HyPix-6000HE detector. Catalytic reactions were carried out by using multiple autoclave reactors (3.7 mL × 18 reactors, EYELA, HIP-7518). Caution: Carbon monoxide is toxic and may react with Ni(0) to afford Ni(CO)₄. All experiments in this manuscript must be carried out under well-ventilated conditions. Ni(0)-Catalyzed [2+2+1] Carbonylative Cycloadditions of 1 with CO; General Procedure A multiple reactor (3.7 mL × 18 reactors, EYELA, HIP-7518) was used. To a solution of Ni(CO)₃PCy₃ (4.2 mg, 0.010 mmol) in CPME (1.0 mL) was added 1 (0.100 mmol) at r.t. The mixture was transferred into a 2 mL vial, followed by pressurization with CO (0.5 atm, < 7.0 equiv). After heating at 80 °C for 6 h without stirring, the resulting mixture was quenched with MeOH. After filtration through silica gel (eluted with MeOH), all volatiles were removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, 10% then 20–60% EtOAc/hexane) and subsequent recrystallization (CHCl₃/pentane, –20 °C) or recycling HPLC, to afford α,β-unsaturated γ-lactams 2. 3-Methyl-1-tosyl-4,8b-dihydroindeno[1,2-b]pyrrol-2(1H)-one (2a): Obtained by following the general procedure using 1a (31.4 mg, 0.100 mmol). The residue was purified by silica gel column chromatography (10% then 40% EtOAc/hexane) and recrystallization from CHCl₃/pentane at –20 °C to afford 2a as a white solid in 75% yield (25.6 mg, 0.0754 mmol); mp 144–148 °C. ¹H NMR (CDCl₃, 400 MHz): δ = 8.07 (d, J = 7.2 Hz, 1 H, Ar-H), 8.01 (d, J = 8.4 Hz, 2 H, Ar-H), 7.37–7.26 (m, 5 H, Ar-H, overlapped with solvent peak), 5.87 (s, 1 H, CHNTs), 3.75 (d, J = 18.0 Hz, 1 H, CCH ₂C), 3.66 (d, J = 18.0 Hz, 1 H, CCH ₂C), 2.43 (s, 3 H, Ts-CH ₃), 1.79 (s, 3 H, C(O)CCH ₃). ¹³C{¹H} NMR (CDCl₃, 100 MHz): δ = 171.8, 161.8, 145.1, 142.8, 137.9, 135.6, 129.8, 129.1, 128.7, 128.2, 126.5, 126.2, 125.2, 67.7, 31.2, 21.8, 9.2. HRMS (CI): m/z [M + H]⁺ calcd for C₁₉H₁₈NO₃S: 340.1007; found: 340.1013. Preparation of 3h: To a solution of Ni(cod)₂ (27.5 mg, 0.100 mmol) and PCy₃ (28.0 mg, 0.100 mmol) in THF (3.0 mL) was added 1h (37.4 mg, 0.100 mmol) at r.t. The reaction solution was stirred vigorously for 1 h to confirm the precipitation of reddish purple solids. After removal of all volatiles, the resulting solids were washed with cold THF/hexane to afford aza-nickelacycle 3h as a reddish-purple solid in 80% yield (57.2 mg, 0.0803 mmol). A single crystal of 3h suitable for X-ray diffraction analysis was obtained by slow diffusion of pentane into a THF solution of 3h. Complex 3h was almost insoluble in the common solvents. While two distinctive resonances, which can be derived from the existence of diastereomeric isomers such as (S _C,R _S)- and (S _C,S _S)-3h as well as (R _C,R _S)- and (R _C,S _S)-3h (see Figure S21), were observed when 3h was dispersed in THF-d ₈, the observed resonances could not be fully assigned due to its complexity. ¹H NMR (400 MHz, THF-d ₈): δ = 9.05 (brs, 2 H, Ar-H, minor), 7.89 (brs, 2 H, Ar-H, major), 7.57 (brs, 2 H, Ar-H, minor), 7.31–6.82 (m, major + minor), 6.52 (brs, 1 H, Ar-H, major), 6.10 (s, 1 H, CHNTs, major), 4.78 (s, 1 H, CHNTs, minor), 3.19 (d, J = 17.6 Hz, 1 H, CCH ₂C, major), 2.86 (d, J = 17.6 Hz, 1 H, CCH ₂C, minor), 2.75 (d, J = 17.6 Hz, 1 H, CCH ₂C, major), 2.63 (d, J = 17.6 Hz, 1 H, CCH ₂C, minor), 2.49–2.16 (m, major + minor), 1.73–1.62 (m, major + minor + THF), 1.26–0.87 (m, major + minor). ¹³C{¹H} NMR (100 MHz, THF-d ₈): δ = 144.0, 128.9, 128.0, 127.4, 126.3, 124.2, 123.4, 31.4, 29.9, 29.5, 27.4, 26.9, 26.2, 25.9, 25.4, 20.4. Several peaks were not observed due to the low concentration. ³¹P{¹H} NMR (162 MHz, THF-d ₈): δ = 30.2 (minor), 26.8 (major). Anal. Calcd for C₄₁H₅₂NNiO₂PS: C, 69.11; H, 7.36; N, 1.97. Found: C, 68.15; H, 7.41; N, 2.25. Accurate elemental analyses of 3h was precluded by extreme air or thermal sensitivity and/or systematic problems.