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Synlett 2021; 32(15): 1537-1541
DOI: 10.1055/s-0040-1707308
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Modern Nickel-Catalyzed Reactions

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

Keita Ashida
,
Yoichi Hoshimoto
,
Sensuke Ogoshi∗

This work was supported by Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number; 15H05803 (S.O.) and 18K14219 (Y.H.)). K.A. expresses his special thanks for a Grant-in-Aid for JSPS Fellows.
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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.


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Key words

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

The transition-metal-catalyzed [2+2+1] carbonylative cycloaddition of ene-ynes with carbon monoxide (CO), also known as the intramolecular Pauson–Khand reaction,[1] is a straightforward method for the construction of polycyclic carbon frameworks.[2] Carbonylative cycloaddition between yne-imines and CO are also of interest, as this reaction enables the rapid construction of α,β-unsaturated γ-lactam cores, which are frequently found in biologically active compounds.[3] Nevertheless, this type of carbonylative cy­cloaddition using C=N π-components has been much less studied due to the difficulties associated with the repeated generation of the key aza-metalacycle intermediates under a CO atmosphere.[4] [5]

Our research group has contributed to the development of Ni(0)-catalyzed carbonylative cycloaddition reactions based on the characteristic reactivity of Ni(0) to engage in facile oxidative cyclization between two π-components.[6] [7] For example, we have reported a Ni(0)-catalyzed intermolecular carbonylative cycloaddition between imines and alkynes, in which CO was generated in situ by treatment of phenyl formate with NEt3.[8] We have also disclosed a method for the direct use of CO gas for a Ni(0)-catalyzed intramolecular carbonylative cycloaddition of 1,5- or 1,6-ene-imines to prepare polycyclic γ-lactams with 100% atom efficiency (Scheme [1]A).[9] Moreover, this Ni(0)-catalyzed intramolecular system was expanded to the corresponding enantioselective variant.[10] As part of these studies, we describe herein a Ni(0)-catalyzed intramolecular carbonylative cycloaddition of 1,5-yne-imines under a CO atmosphere for the synthesis of polycyclic α,β-unsaturated γ-lactams (Scheme [1]B). Furthermore, we derivatized the olefinic moieties in the produced α,β-unsaturated γ-lactams, which demonstrates the synthetic utility of the present method for the synthesis of N-heterocyclic compounds that bear multiple contiguous carbon stereocenters. The results of mechanistic studies that clarify the role of nickelacycles are also reported. It should be noted here that we have already explored the corresponding carbonylative cy­cloaddition in the presence of phenyl formate and NEt3, which predominantly yielded isoquinoline derivatives via the NEt3-catalyzed 6-exo-cyclization of the 1,5-yne-imines.[11]

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Scheme 1 Ni(0)-catalyzed intramolecular carbonylative cycloadditions with (A) ene-imines or (B) yne-imines

Initially, the optimal reaction conditions were explored using 1,5-yne-imine 1a, which contains an N-tosyl (Ts) group, and 0.5 atm of CO (Scheme [2]). To avoid rapid saturation of the reaction medium with CO, the experiments were conducted without stirring.[9] [10] The reaction was examined in THF at 80 °C using 10 mol% Ni(cod)2 and PCy3, which resulted in the formation of tricyclic α,β-unsaturated γ-lac­tam 2a in 58% yield (entry 1), whereas P n Bu3, PPh3, and P t Bu3 furnished 2a in lower yield (entries 2–4). The use of Ni(CO)3PCy3 as the catalyst precursor furnished 2a in higher yield (68%) than using Ni(cod)2/PCy3 (entry 5). Thus, we employed Ni(CO)3PCy3 in the subsequent catalytic reactions. Next, further optimizations of the reaction conditions with respect to the solvent and reaction temperature were carried out. Among the various solvents that we examined, cyclopentyl methyl ether (CPME) afforded the best result (93% yield; entry 6). The reaction in toluene afforded 2a in good yield (83%; entry 7), while the targeted reaction did not proceed catalytically when DMF was used (entry 8). Decreasing the reaction temperature to 40 °C resulted in a lower reaction efficiency (63% yield; entry 9). We also confirmed that the catalytic reaction was hampered by stirring the reaction solution (in parentheses of entry 6). Based on these results, we concluded that the optimal conditions are those shown in entry 6.

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Scheme 2 Optimization of the reaction conditions for the Ni(0)-catalyzed carbonylative cycloaddition between 1a and CO. All reactions were carried out in a multiple autoclave reactor (V: 3.7 mL × 18 reactors). 1a (0.10 mmol), Ni(cod)2/PR3 (cod = 1,5-cyclooctadiene; R = Cy, nBu, Ph, tBu) or Ni(CO)3PCy3 (0.010 mmol), and solvent (1 mL) were mixed in each reactor, followed by pressurization with CO (0.5 atm) at r.t. and heating. Yield was determined by 1H NMR spectroscopy using 2-methoxynaphthalene as the internal standard. a The reaction was carried out with stirring at 1350 rpm.

We then explored the substrate scope of this catalytic reaction using 1a–k under the optimal reaction conditions (Scheme [3]). The reaction between 1a and CO afforded 2a in 75% isolated yield. Substrates with meta-fluorine (1b) and para-methoxy (1c) groups relative to the propargyl groups afforded 2b and 2c in 67% and 78% yield, respectively. The molecular structure of 2c was determined by single-crystal X-ray diffraction (XRD) analysis. The reactions of 1d, which contains a para-chlorine substituent, and 1e, which contains a naphthyl skeleton, afforded 2d and 2e in 48% and 58% yield, respectively. In order to obtain 2f from 1f in 68% yield, the reaction had to be carried out at 100 °C for 24 h. The use of 1g, which bears an n-pentyl group at the alkyne terminal, afforded 2g in 75% yield. In the case of 1h, which contains a phenyl group at the alkyne terminal, γ-lactam 2h was obtained in 72% yield when the reaction was carried out at 100 °C for 24 h. However, when 1i and 1j were employed, a significant amount of the starting material remained unreacted even after 24 h at 100 °C, and the formation of the corresponding γ-lactams (2i and 2j) was not confirmed. These results suggest that the η2 coordination of the alkyne moieties to the Ni(0) center was prevented due to steric hindrance, and thus the progress of oxidative cyclization on Ni(0) was hampered, which was experimentally confirmed (Figures S7–11). When the N-Ts group was replaced with an N-diphenyl phosphinoyl group, a mixture of unidentified products devoid of the target 2k was obtained. The details of this reaction remain unclear.

Zoom Image
Scheme 3 Ni(0)-catalyzed carbonylative cycloaddition of 1,5-yne-imines. Compound 1a–k (0.10 mmol), Ni(CO)3PCy3 (0.010 mmol), and CPME (1 mL) were mixed, followed by pressurization with CO (0.5 atm) at r.t. and heating. Isolated yields are shown. NMR yield is given in parentheses. a The reaction was performed at 100 °C for 24 h.

To gain insight into the reaction mechanism, a stoichiometric reaction of 1h with Ni(cod)2/PCy3 was conducted in THF at room temperature, which furnished aza-nickelacycle 3h in 80% isolated yield (Scheme [4]A). The molecular structure of 3h was determined by single-crystal XRD analysis, which revealed a set of enantiomers, i.e., (S C,R S)- and (R C,S S)-3h, in the asymmetric unit of the single crystals; the molecular structure of (S C,R S)-3h is shown in Figure [1]A. The chiral sulfur centers are generated from the desymmetrization of the achiral environment around the sulfur center via the intramolecular coordination of the S=O moiety to the Ni center (Ni–O1: 2.082(1) Å). We also confirmed that the coordinated S=O group can be easily exchanged with another one at room temperature in THF-d 8, as two resonances are observed at 30.2 and 26.8 ppm in the 31P NMR spectrum of 3h, probably showing the existence of diastereomers that are generated via the coordination exchange between two S=O ligands. These results are supported by the DFT calculations, i.e., the relative Gibbs free energy of (S C,S S)-3h with respect to (S C,R S)-3h is estimated as –0.4 kcal mol–1 and the activation energy barrier for the generation of (S C,S S)-3h from (S C,R S)-3h is +13.7 kcal mol–1 (Figure S21). The reaction between 3h and CO (3.0 atm) in THF-d 8 quantitatively afforded 2h and Ni(CO)3PCy3 (Scheme [4]B). These results suggest the formation of an intermediary aza-nickelacycle in the reaction of 1h under the applied reaction conditions. To gain further information regarding the reaction between 3h and CO, we monitored the reaction of 3h with CNCy, which is isoelectronic with CO.[12] Treatment of 3h with an equimolar amount of CNCy resulted in the generation of 4h, in which the tricyclic α,β-unsaturated amidine coordinates to Ni(0) (Scheme [4]C). After the addition of another equivalent of CNCy and recrystallization, 4h was isolated in 82% yield. The molecular structure of 4h was determined by single-crystal XRD analysis (Figure [1]B).

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Scheme 4 Isolation and reactivity of 3h. Isolated yield of the products is given. a The yield was confirmed by NMR analyses.
Zoom Image
Figure 1 Molecular structures of (S C,R S)-3h and 4h with thermal ellipsoids at 30% probability; only selected H atoms are shown and cyclohexyl groups are omitted for clarity. Selected bond lengths [Å] of (S C,R S)-3h: Ni–O1, 2.082(1); Ni–N1, 1.893(2); Ni–C1, 1.931(2); S1–O2, 1.490(1); S1–O2, 1.434(2); 4h: Ni–C1, 1.978(2); Ni–C2, 1.926(2); Ni–C5, 1.819(3); C1–C2, 1.451(3); C5–N3, 1.163(4); C4–N1, 1.439(3); C4–N2, 1.268(3).

Based on the aforementioned results, this Ni(0)-catalyzed carbonylative [2+2+1] cycloaddition can be expected to proceed via the mechanism shown in Scheme [5]. Replacement of the CO ligands in Ni(CO)3PCy3 with yne-imine 1 generates (η2:η2-1)Ni(PCy3), which is then subject to an oxidative cyclization to give aza-nickelacycle 3. The reaction of CO with 3 and the subsequent reductive elimination afford (η2-2)Ni(CO)(PCy3) (4′). Finally, ligand substitution between 4′ and 1 occurs to furnish 2 under concomitant regeneration of (η2:η2-1)Ni(PCy3).

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Scheme 5 A plausible mechanism for the Ni(0)-catalyzed [2+2+1] carbonylative cycloaddition of 1 with CO

To show the synthetic utility of the present Ni-catalyzed reaction, diastereoselective transformations of 2a via the derivatization of its olefinic moiety were examined (Scheme [6]). Hydrogenation of 2a in the presence of 3 mol% Pd/C afforded 5a, which bears three contiguous carbon stereogenic centers, in 94% yield (Scheme [6]A). The conjugate addition of [ n Bu2Cu]Li to 2a proceeded to furnish a diastereomeric mixture of 6a (86% yield; d.r. 80:20), which bears quaternary carbon centers at the C4 positions (Scheme [6]B). A Diels–Alder reaction with Danishefsky’s diene successfully expanded the fused-ring system of 2a to 7a (46% yield), and two contiguous quaternary carbon centers were constructed (Scheme [6]C). The molecular structure of 7a was determined by a single-crystal XRD analysis (Figure S20).

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Scheme 6 Diastereoselective transformations of 2a. Relative stereochemistry is shown for 5a–7a. Yield of the isolated products is shown.

In conclusion, we have developed a Ni(0)-catalyzed [2+2+1] carbonylative cycloaddition of yne-imines with CO to afford polycyclic α,β-unsaturated γ-lactam derivatives with 100% atom efficiency.[13] The isolation of an aza-nickelacycle and investigation of its reactivity revealed that the present Ni(0)-catalyzed reaction proceeds via aza-nickelacycle intermediates. The obtained products can be diastereo­selectively transformed into compounds with consecutive quaternary carbon centers, which demonstrates the synthetic utility of the present method.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707308.
  • Supporting Information
  • CIF File

  • References and Notes


      • 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
      CrossrefSearch in Google Scholar
    • 4b Mukai C, Yoshida T, Sorimachi M, Odani A. Org. Lett. 2006; 8: 83
      CrossrefPubMedSearch in Google Scholar

      For reviews on nickel-catalyzed reactions via (hetero)nickelacycle intermediates, see:
    • 6a Montgomery J. Angew. Chem. Int. Ed. 2004; 43: 3890
      CrossrefPubMedSearch in Google Scholar
    • 6b Moslin RM, Miller-Moslin K, Jamison TF. Chem. Commun. 2007; 4441
      PubMed
    • 6c Ng S.-S, Ho C.-Y, Schleicher KD, Jamison TF. Pure Appl. Chem. 2008; 80: 929
      CrossrefPubMedSearch in Google Scholar
    • 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
      CrossrefSearch in Google Scholar
    • 6f Tasker SZ, Standley EA, Jamison TF. Nature 2014; 509: 299
      CrossrefPubMedSearch in Google Scholar
    • 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;
  • 8 Hoshimoto Y, Ohata T, Sasaoka Y, Ohashi M, Ogoshi S. J. Am. Chem. Soc. 2014; 136: 15877
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 10 Ashida K, Hoshimoto Y, Tohnai N, Scott DE, Ohashi M, Imaizumi H, Tsuchiya Y, Ogoshi S. J. Am. Chem. Soc. 2020; 142: 1594
    CrossrefPubMedSearch in Google Scholar
  • 11 Hoshimoto Y, Nishimura C, Sasaoka Y, Kumar R, Ogoshi S. Bull. Chem. Soc. Jpn. 2020; 93: 182
    CrossrefSearch in Google Scholar
  • 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.

Corresponding Author

Sensuke Ogoshi
Department of Applied Chemistry, Faculty of Engineering, Osaka University
Suita, Osaka 565-0871
Japan   

Publication History

Received: 06 August 2020

Accepted after revision: 03 September 2020

Article published online:
08 October 2020

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  • References and Notes


      • 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
      CrossrefSearch in Google Scholar
    • 4b Mukai C, Yoshida T, Sorimachi M, Odani A. Org. Lett. 2006; 8: 83
      CrossrefPubMedSearch in Google Scholar

      For reviews on nickel-catalyzed reactions via (hetero)nickelacycle intermediates, see:
    • 6a Montgomery J. Angew. Chem. Int. Ed. 2004; 43: 3890
      CrossrefPubMedSearch in Google Scholar
    • 6b Moslin RM, Miller-Moslin K, Jamison TF. Chem. Commun. 2007; 4441
      PubMed
    • 6c Ng S.-S, Ho C.-Y, Schleicher KD, Jamison TF. Pure Appl. Chem. 2008; 80: 929
      CrossrefPubMedSearch in Google Scholar
    • 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
      CrossrefSearch in Google Scholar
    • 6f Tasker SZ, Standley EA, Jamison TF. Nature 2014; 509: 299
      CrossrefPubMedSearch in Google Scholar
    • 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;
  • 8 Hoshimoto Y, Ohata T, Sasaoka Y, Ohashi M, Ogoshi S. J. Am. Chem. Soc. 2014; 136: 15877
    CrossrefPubMedSearch in Google Scholar
  • 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
    CrossrefPubMedSearch in Google Scholar
  • 10 Ashida K, Hoshimoto Y, Tohnai N, Scott DE, Ohashi M, Imaizumi H, Tsuchiya Y, Ogoshi S. J. Am. Chem. Soc. 2020; 142: 1594
    CrossrefPubMedSearch in Google Scholar
  • 11 Hoshimoto Y, Nishimura C, Sasaoka Y, Kumar R, Ogoshi S. Bull. Chem. Soc. Jpn. 2020; 93: 182
    CrossrefSearch in Google Scholar
  • 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.

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Scheme 1 Ni(0)-catalyzed intramolecular carbonylative cycloadditions with (A) ene-imines or (B) yne-imines
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Scheme 2 Optimization of the reaction conditions for the Ni(0)-catalyzed carbonylative cycloaddition between 1a and CO. All reactions were carried out in a multiple autoclave reactor (V: 3.7 mL × 18 reactors). 1a (0.10 mmol), Ni(cod)2/PR3 (cod = 1,5-cyclooctadiene; R = Cy, nBu, Ph, tBu) or Ni(CO)3PCy3 (0.010 mmol), and solvent (1 mL) were mixed in each reactor, followed by pressurization with CO (0.5 atm) at r.t. and heating. Yield was determined by 1H NMR spectroscopy using 2-methoxynaphthalene as the internal standard. a The reaction was carried out with stirring at 1350 rpm.
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Scheme 3 Ni(0)-catalyzed carbonylative cycloaddition of 1,5-yne-imines. Compound 1a–k (0.10 mmol), Ni(CO)3PCy3 (0.010 mmol), and CPME (1 mL) were mixed, followed by pressurization with CO (0.5 atm) at r.t. and heating. Isolated yields are shown. NMR yield is given in parentheses. a The reaction was performed at 100 °C for 24 h.
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Scheme 4 Isolation and reactivity of 3h. Isolated yield of the products is given. a The yield was confirmed by NMR analyses.
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Figure 1 Molecular structures of (S C,R S)-3h and 4h with thermal ellipsoids at 30% probability; only selected H atoms are shown and cyclohexyl groups are omitted for clarity. Selected bond lengths [Å] of (S C,R S)-3h: Ni–O1, 2.082(1); Ni–N1, 1.893(2); Ni–C1, 1.931(2); S1–O2, 1.490(1); S1–O2, 1.434(2); 4h: Ni–C1, 1.978(2); Ni–C2, 1.926(2); Ni–C5, 1.819(3); C1–C2, 1.451(3); C5–N3, 1.163(4); C4–N1, 1.439(3); C4–N2, 1.268(3).
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Scheme 5 A plausible mechanism for the Ni(0)-catalyzed [2+2+1] carbonylative cycloaddition of 1 with CO
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Scheme 6 Diastereoselective transformations of 2a. Relative stereochemistry is shown for 5a–7a. Yield of the isolated products is shown.