E
F. Yoshimura et al.
Letter
Synlett
(3) (a) For a review, see: Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org.
React. 1984, 31, 1. (b) For a non-basic nucleophilic addition, see:
Hamana, H.; Sugasawa, T. Chem. Lett. 1982, 1401.
CD3
N
D
Me
Me
Me
Me
TIPSOTf (2.0 equiv)
+
PhCHO
Ph
OTIPS
DCE (0.2 M)
80 °C, 9 h
6
25
>99%D
(4) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
24
(5) (a) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki, M.
Org. Lett. 2003, 5, 3147. (b) Kumagai, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 13632. (c) Fan, L.;
Ozerov, O. V. Chem. Commun. 2005, 4450. (d) Goto, A.; Endo, K.;
Ukai, Y.; Irle, S.; Saito, S. Chem. Commun. 2008, 2212.
(e) Chakraborty, S.; Patel, Y. J.; Krause, J. A.; Guan, H. Angew.
Chem. Int. Ed. 2013, 52, 7523. (f) Sureshkumar, D.; Ganesh, V.;
Kumagai, N.; Shibasaki, M. Chem. Eur. J. 2014, 20, 15723.
(6) For a review of N-silyl ketene imines, see: (a) Denmark, S. E.;
Wilson, T. W. Angew. Chem. Int. Ed. 2012, 51, 9980. For recent
examples, see: (b) Nishimoto, Y.; Nishimura, T.; Yasuda, M.
Chem. Eur. J. 2015, 21, 18301. (c) Sasaki, M.; Ando, M.;
Kawahata, M.; Yamaguchi, K.; Takeda, K. Org. Lett. 2016, 18,
1598.
(7) (a) Yoshimura, F.; Torizuka, M.; Mori, G.; Tanino, K. Synlett 2012,
251. (b) Yoshimura, F.; Abe, T.; Tanino, K. Synlett 2014, 25, 1863.
(c) Yoshimura, F.; Abe, T.; Tanino, K. Org. Lett. 2016, 18, 1630.
(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.
(2.0 equiv)
87%
Me Me
Si(i-Pr)3
D
D
O
D
N
Ph
H
Me Me
Scheme 7
(16) General Procedure (Table 1, Entry 5): To a mixture of benzal-
dehyde (6; 40.8 μL, 0.400 mmol), 2-methoxy-2-phenylacetoni-
trile (11; 55.5 μL, 0.400 mmol), and 2,2,6,6-tetramethylpiperi-
dine (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 tem-
perature for 22 h, at which point the consumption of starting
materials 6 and 11 was complete (as determined by TLC analy-
sis, 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.
(10) For, Lewis base catalyzed nucleophilic addition of N-silyl ketene
imines to aldehydes, see: Denmark, S. E.; Wilson, T. W.; Burk, M.
T.; Heemstra, J. R. J. Am. Chem. Soc. 2007, 129, 14864.
(11) For related hydrosilylation reactions mediated by a silyl triflate
and a tertiary alkylamine, see: (a) Downey, C. D.; Fleisher, A. S.;
Rague, J. T.; Safran, C. L.; Venable, M. E.; Pike, R. D. Tetrahedron
Lett. 2011, 52, 4756. (b) Ho, C.; Chan, C.; He, L. Angew. Chem. Int.
Ed. 2015, 54, 4512.
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.
(12) The combination of TIPSOTf and PMP smoothly promoted
hydrosilylation of benzaldehyde (6) to afford TIPS ether 13 in
82% yield (Scheme 6).
Me
Me
Me
N
Me
Me
TIPSOTf (2.0 equiv)
+
PhCHO
Ph
OTIPS
DCE (0.2 M)
80 °C, 4 h
13
6
PMP
(2.0 equiv)
82%
1
(17) Attempts to detect N-silyl ketene imine intermediates by H or
Scheme 6
13C NMR spectroscopic analysis were unsuccessful, suggesting
that these reactive species in equilibrium with the correspond-
ing 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-posi-
tion 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 Support-
ing Information.
(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.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E