Synlett 2017; 28(14): 1816-1820
DOI: 10.1055/s-0036-1588424
letter
© Georg Thieme Verlag Stuttgart · New York

Nucleophilic Addition of Alkanenitriles to Aldehydes via N-Silyl Ketene Imines Generated In Situ

Fumihiko Yoshimura*
a   Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan   Email: fumi@sci.hokudai.ac.jp   Email: ktanino@sci.hokudai.ac.jp
,
Hiroki Saito
b   Department of Chemistry, School of Science, Hokkaido University, Sapporo 060-0810, Japan
,
Taiki Abe
c   Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan
,
Keiji Tanino*
a   Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan   Email: fumi@sci.hokudai.ac.jp   Email: ktanino@sci.hokudai.ac.jp
› Author Affiliations
This work was supported by a Grant for Basic Science Research Projects from The Sumitomo Foundation (to F.Y.) and JSPS KAKENHI Grant Numbers JP15K01795 (to F.Y.), JP15H03806 (to K.T.), and JP15H05842 in Middle Molecular Strategy (to K.T.).
Further Information

Publication History

Received: 14 March 2017

Accepted after revision: 24 April 2017

Publication Date:
17 May 2017 (online)


Abstract

Upon treatment with triisopropylsilyl trifluoromethanesulfonate and 2,2,6,6-tetramethylpiperidine, alkanenitriles undergo direct addition to aldehydes under mild non-basic neutral conditions to provide triisopropylsilyl ethers of β-hydroxy nitriles in good yield. The reaction proceeds through generation of an N-silyl ketene imine intermediate in situ from the alkanenitrile followed by nucleophilic addition of the intermediate to the aldehyde.

Supporting Information

 
  • References and Notes


    • For reviews of nitrile-containing natural products and pharmaceuticals, see:
    • 1a Fleming FF. Nat. Prod. Rep. 1999; 16: 597
    • 1b Fleming FF. Yao L. Ravikumar PC. Funk L. Shook BC. J. Med. Chem. 2010; 53: 7902

      For utilization in the synthesis of biologically active substrates, see:
    • 2a Kamal A. Khanna GB. G. Ramu R. Tetrahedron: Asymmetry 2002; 13: 2039
    • 2b Ankati H. Zhu D. Yang Y. Biehl ER. Hua L. J. Org. Chem. 2009; 74: 1658
    • 3a For a review, see: Arseniyadis S. Kyler KS. Watt DS. Org. React. 1984; 31: 1
    • 3b For a non-basic nucleophilic addition, see: Hamana H. Sugasawa T. Chem. Lett. 1982; 1401
  • 4 Bordwell FG. Acc. Chem. Res. 1988; 21: 456
    • 5a Suto Y. Kumagai N. Matsunaga S. Kanai M. Shibasaki M. Org. Lett. 2003; 5: 3147
    • 5b Kumagai N. Matsunaga S. Shibasaki M. J. Am. Chem. Soc. 2004; 126: 13632
    • 5c Fan L. Ozerov OV. Chem. Commun. 2005; 4450
    • 5d Goto A. Endo K. Ukai Y. Irle S. Saito S. Chem. Commun. 2008; 2212
    • 5e Chakraborty S. Patel YJ. Krause JA. Guan H. Angew. Chem. Int. Ed. 2013; 52: 7523
    • 5f Sureshkumar D. Ganesh V. Kumagai N. Shibasaki M. Chem. Eur. J. 2014; 20: 15723

      For a review of N-silyl ketene imines, see:
    • 6a Denmark SE. Wilson TW. Angew. Chem. Int. Ed. 2012; 51: 9980

    • For recent examples, see:
    • 6b Nishimoto Y. Nishimura T. Yasuda M. Chem. Eur. J. 2015; 21: 18301
    • 6c Sasaki M. Ando M. Kawahata M. Yamaguchi K. Takeda K. Org. Lett. 2016; 18: 1598
  • 8 Emde H. Simchen G. Synthesis 1977; 636
  • 9 It has been reported that N-(trimethylsilyl)diphenylketene imine undergoes nucleophilic addition to several benzaldehyde derivatives under solvent-free conditions, see: Cazeau P. Llonch J.-P. Simonin-Dabescat F. Frainnet E. J. Organomet. Chem. 1976; 105: 145
  • 10 For, Lewis base catalyzed nucleophilic addition of N-silyl ketene imines to aldehydes, see: Denmark SE. Wilson TW. Burk MT. Heemstra JR. J. Am. Chem. Soc. 2007; 129: 14864

    • For related hydrosilylation reactions mediated by a silyl triflate and a tertiary alkylamine, see:
    • 11a Downey CD. Fleisher AS. Rague JT. Safran CL. Venable ME. Pike RD. Tetrahedron Lett. 2011; 52: 4756
    • 11b Ho C. Chan C. He L. Angew. Chem. Int. Ed. 2015; 54: 4512
  • 12 The combination of TIPSOTf and PMP smoothly promoted hydrosilylation of benzaldehyde (6) to afford TIPS ether 13 in 82% yield (Scheme 6).
  • 13 A deuterium-labeling experiment proved that PMP acts as the hydride source (Scheme 7).
  • 14 The reason for the superior reactivity of TMP is not yet clear. Very low solubility of 2,2,6,6-tetramethylpiperidinium triflate (TfOH·TMP) in DCE might cause the equilibrium to shift slightly toward the N-silyl ketene imine.
  • 15 When DCE was used as the solvent, a significant amount of inseparable double aldol type addition product accompanied 15f. Solvent screening revealed that toluene could suppress such side reactions, although it required heating of the reaction mixture to 100 °C.
  • 16 General Procedure (Table [1], Entry 5): To a mixture of benzaldehyde (6; 40.8 μL, 0.400 mmol), 2-methoxy-2-phenylacetonitrile (11; 55.5 μL, 0.400 mmol), and 2,2,6,6-tetramethylpiperidine (136 μL, 0.800 mmol) in DCE (2.0 mL) was added TIPSOTf (215 μL, 0.800 mmol), and the mixture was stirred at room temperature for 22 h, at which point the consumption of starting materials 6 and 11 was complete (as determined by TLC analysis, hexane/EtOAc = 4:1). After cooling to 0 °C, the reaction was quenched by slow addition of saturated aqueous NaHCO3 (1 mL), and the resulting mixture was filtered through a cotton plug to remove the precipitate (rinsed with CH2Cl2). The filtrate was extracted with CH2Cl2 (3 × 1 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2; hexane/EtOAc = 50:1) to give nitrile 12 (139.6 mg, 0.341 mmol, 85% yield) as an inseparable 55:45 mixture of diastereomers. Compound 12: Colorless oil. 1H NMR (500 MHz, CDCl3): δ = 7.53–7.51 (m, 1 H), 7.40–7.36 (m, 3 H), 7.31–7.27 (m, 2 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.13–7.04 (m, 2 H), 6.92 (m, 1 H), 4.98 (s, 0.55 H), 4.97 (s, 0.45 H), 3.34 (s, 0.45 × 3 H), 3.18 (s, 0.55 × 3 H), 1.15–1.09 (m, 0.45 × 3 H), 1.06 (d, J = 6.9 Hz, 0.45 × 9 H), 1.00 (d, J = 7.5 Hz, 0.45 × 9 H), 0.81–0.74 (m, 0.55 × 21 H). 13C NMR (125 MHz, CDCl3): δ = 139.08, 137.95, 134.79, 133.93, 129.21, 128.99, 128.51, 128.45, 128.18, 128.09, 127.96, 127.86, 127.76, 127.41, 127.20, 127.07, 117.15, 116.89, 88.12, 86.64, 81.44, 81.06, 54.03, 53.97, 17.87, 17.82, 17.70, 17.63, 12.44, 12.40. IR (ATR): 2943, 2867, 2365, 1122, 1069 cm–1. HRMS (FD): m/z [M+H]+ calcd for C25H36NO2Si: 410.2515; found: 410.2484.
  • 17 Attempts to detect N-silyl ketene imine intermediates by 1H or 13C NMR spectroscopic analysis were unsuccessful, suggesting that these reactive species in equilibrium with the corresponding nitriles exist only in low concentration. The reaction of 6 with 11 did not proceed in the absence of either TIPSOTf or TMP. The alkanenitrile underwent isomerization at the α-position of the cyano group upon treatment with TIPSOTf/TMP (i.e., nitrile 28 in Scheme S2). These results support the conclusion that the nucleophilic addition proceeds via the N-silyl ketene imine intermediate. For details, see Scheme S2 in the Supporting Information.