LETTER
Regio- and Stereoselective Radical Additions of Thiols to Ynamides
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(7) For the first example of a radical reaction involving
ynamides, see: Marion, F.; Courillon, C.; Malacria, M. Org.
Lett. 2003, 5, 5095.
(8) Our group has reported the hydrothiolation of ynamides with
dithiophosphinic acid via cationic intermediates: Kanemura,
S.; Kondoh, A.; Yasui, H.; Yorimitsu, H.; Oshima, K. Bull.
Chem. Soc. Jpn. 2008, 81, 506.
(9) For examples of the synthesis of (Z)-1-amino-2-thio-1-
alkene derivatives, see: (a) Apparao, S.; Schmidt, R. R.
Synthesis 1987, 896. (b) Kondo, T.; Baba, A.; Nishi, Y.;
Mitsudo, T. Tetrahedron Lett. 2004, 45, 1469.
(10) For hydrothiolations under transition-metal catalysis, see:
(a) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem.
Soc. 1999, 121, 5108. (b) Cao, C.; Fraser, L. R.; Love, J. A.
J. Am. Chem. Soc. 2005, 127, 17614. (c) Ananikov, V. P.;
Malyshev, D. A.; Beletskaya, I. P.; Aleksandorov, G. G.;
Eremenko, I. L. Adv. Synth. Catal. 2005, 347, 1993; and
references cited therein.
(15) The diastereoselectivity can be explained by steric effect. In
reference 4b, Montevecci and Spagnolo insisted that primary
alkyl groups are bulkier than a phenylthio group. We thus
assume that vinyl radical 5 would exist almost as a Z-form to
prevent the steric repulsion between the bulky amide moiety
and the alkyl group. The Z-form abstracts hydrogen from
benzenethiol selectively. On the other hand, Montevecci et
al. also insisted that a methyl group is smaller than a phenyl-
thio group. Indeed, the reaction of N-methyl-N-(1-
propenyl)-p-toluenesulfonamide with benzenethiol resulted
in favorable formation of the corresponding Z-adduct (E/Z =
2:3).
(16) The addition reaction of phenyl-substituted ynamide
PhC≡CNTs(Bn) led to a mixture of stereo- and regioisomers.
(17) Alkenes and ketones can be reduced under these conditions.
See: Kursaniov, D. N.; Parnes, Z. N.; Bassova, G. L.; Loim,
N. M.; Zdanovich, V. I. Tetrahedron 1967, 23, 2235.
(18) Typical Experimental Procedure for Hydrogenations of
the Double Bonds of Enamides: Under an argon
atmosphere, Et3SiH (0.048 mL, 0.30 mmol) was added to a
solution of 3aa (0.096 g, 0.20 mmol) in TFA (1.0 mL, 13.5
mmol) at 0 °C. The solution was stirred for 11 h at the same
temperature. Then the reaction was quenched with a sat.
NaHCO3 solution and extracted with EtOAc (2 × 10 mL).
The organic extracts were dried over Na2SO4 and
concentrated in vacuo. Silica gel column chromatography
(hexane–EtOAc, 20:1) afforded N-benzyl-N-[2-(phenylthio)-
octyl]-p-toluenesulfonamide (6aa) as a colorless oil in 87%
yield (0.084 g, 0.17 mmol).
(11) (a) Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc.
1987, 109, 2547. (b) Nozaki, K.; Oshima, K.; Utimoto, K.
Bull. Chem. Soc. Jpn. 1987, 60, 3465.
(12) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.;
Vera, E. L. Org. Lett. 2004, 6, 1151.
(13) Typical Experimental Procedure for Radical
Hydrothiolation of Ynamides: Under air, Et3B (1.0 M
hexane solution, 0.050 mL, 0.050 mmol) was added to a
solution of N-benzyl-N-(1-octynyl)-p-toluenesulfonamide
(1a, 0.18 g, 0.50 mmol) and benzenethiol (2a, 0.062 mL,
0.60 mmol) in CH2Cl2 (2.0 mL) at –30 °C. The solution was
stirred for 30 min at the same temperature and concentrated
in vacuo. 1H NMR analysis of the crude mixture showed a
94% yield of the adduct (Z/E >99:1). Silica gel column
chromatography (hexane–EtOAc = 10:1 → 5:1) afforded
N-benzyl-N-[(Z)-2-phenylthio-1-octenyl]-p-toluenesulfon-
amide (3aa) as a white solid in 89% yield (0.21 g, 0.45
mmol).
6aa: IR (neat): 2926, 2855, 1599, 1456, 1439, 1342, 1162,
1092, 737, 654 cm–1. 1H NMR (CDCl3): d = 0.88 (t, J = 7.5
Hz, 3 H), 1.02–1.31 (m, 8 H), 1.34–1.46 (m, 1 H), 1.65–1.75
(m, 1 H), 2.42 (s, 3 H), 2.95–3.05 (m, 2 H), 3.26–3.34 (m, 1
H), 4.05 (d, J = 14.5 Hz, 1 H), 4.31 (d, J = 14.5 Hz, 1 H),
7.17–7.32 (m, 12 H), 7.57–7.61 (m, 2 H). 13C NMR (CDCl3):
d = 14.07, 21.49, 22.58, 26.62, 28.94, 30.82, 31.64, 47.40,
53.96, 54.26, 126.75, 127.30, 127.96, 128.58, 128.62,
128.83, 129.69, 131.62, 134.66, 135.82, 136.21, 143.37.
Anal. Calcd for C28H35NO2S2: C, 69.81; H, 7.32. Found: C,
70.03; H, 7.38.
3aa: IR (Nujol): 2925, 1456, 1351, 1339, 1161, 1089, 1024,
741, 661 cm–1. 1H NMR (CDCl3): d = 0.83 (t, J = 7.5 Hz, 3
H), 1.02–1.15 (m, 4 H), 1.16–1.35 (m, 4 H), 1.89 (t, J = 7.0
Hz, 2 H), 2.45 (s, 3 H), 4.46 (s, 2 H), 5.64 (s, 1 H), 6.90–6.94
(m, 2 H), 7.13–7.21 (m, 3 H), 7.26–7.35 (m, 5 H), 7.36–7.41
(m, 2 H), 7.76–7.80 (m, 2 H). 13C NMR (CDCl3): d = 14.04,
21.57, 22.50, 28.09, 28.25, 31.40, 33.36, 54.15, 124.26,
127.14, 127.62, 127.67, 128.32, 128.58, 128.77, 129.60,
132.31, 133.10, 135.63, 135.83, 142.86, 143.59. Anal. Calcd
for C28H33NO2S2: C, 70.11; H, 6.93. Found: C, 70.00; H,
6.94.
(19) Markgren, P.-O.; Schaal, W.; Hämäläinen, M.; Karlén, A.;
Hallberg, A.; Samuelsson, B.; Danielson, U. H. J. Med.
Chem. 2002, 45, 5430.
(20) Chiral vic-aminothio compounds serve as ligands in
enantioselective reactions. See: (a) Vargas, F.; Sehnem,
J. A.; Galetto, F. Z.; Braga, A. L. Tetrahedron 2008, 64, 392;
and references cited therein. (b) Jin, M.-J.; Sarkar, S. M.;
Lee, D.-H.; Qiu, H. Org. Lett. 2008, 10, 1235; and references
cited therein.
(14) It was reported that arylthiyl radicals behave as electron-
deficient radicals: Ito, O.; Fleming, M. D. C. M. J. Chem.
Soc., Perkin Trans. 2 1989, 689.
Synlett 2009, No. 1, 28–31 © Thieme Stuttgart · New York