Thieme Chemistry Journal Awardees - Where are They Now? Regio- and Stereoselective Radical Additions of Thiols to Ynamides

Abstract

Regioselective and stereoselective radical additions of arenethiols to various ynamides have been developed. Mixing yn­amides and arenethiols in the presence of a catalytic amount of triethylborane affords the corresponding adducts, (Z)-1-amino-2-thio-1-alkenes, in excellent yields with high selectivities. The products can be reduced by means of trifluoroacetic acid and triethylsilane to yield 1-amino-2-thioalkanes.

Key words

radical - hydrothiolation - ynamide - hydrogenation

References and Notes

• 1a Page P. Organosulfur Chemistry   Academic Press; London: 1995. 
• 1b Kondo T. Mitsudo T. Chem. Rev.  2000,  100:  3205 
• 1c Arisawa M. Yamaguchi M. Pure Appl. Chem.  2008,  80:  993 
• 2a Renaud P. Sibi MP. Radicals in Organic Synthesis   Vol. 2:  Wiley-VCH; Weinheim: 2001.  Chapter 5.5.3.
• 2b Griesbaum K. Angew. Chem., Int. Ed. Engl.  1970,  9:  273 
• 2c Ichinose Y. Wakamatsu K. Nozaki K. Birbaum J.-L. Oshima K. Utimoto K. Chem. Lett.  1987,  16:  1647 
• 2d Benati L. Capella L. Montevecchi PC. Spagnolo P. J. Chem. Soc., Perkin Trans. 1  1995,  1035 
• 2e Chatgilialoglu C. Ferreri C. Acc. Chem. Res.  2005,  38:  441 
• For recent studies including radical hydrothiolations of alkynes, see:
• 3a Yorimitsu H. Wakabayashi K. Shinokubo H. Oshima K. Bull. Chem. Soc. Jpn.  2001,  74:  1963 
• 3b Miyata O. Nakajima E. Naito T. Chem. Pharm. Bull.  2001,  49:  213 
• 3c Friestad GK. Jiang T. Fioromi GM. Tetrahedron: Asymmetry  2003,  14:  2853 
• 3d Beaufils F. Dénès F. Renaud P. Org. Lett.  2004,  6:  2563 
• 3e Benati L. Leardini R. Minozzi M. Nanni D. Scialpi R. Spagnolo P. Zanardi G. Synlett  2004,  987 
• 3f Beaufils F. Dénès F. Becattini B. Renaud P. Schenk K. Adv. Synth. Catal.  2005,  347:  1587 
• 3g Yasuda H. Uenoyama Y. Nobuta O. Kobayashi S. Ryu I. Tetrahedron Lett.  2008,  49:  367 
• 3h Bencivenni G. Lanza T. Leardini R. Minozzi M. Nanni D. Spagnolo P. Zanardi G. Org. Lett.  2008,  10:  1127 
• 4a Wadsworth DH. Detty MR. J. Org. Chem.  1980,  45:  4611 
• 4b Benati L. Montevecchi PC. Spagnolo P. J. Chem. Soc., Perkin Trans. 1  1991,  2103 
• 4c Montevecchi PC. Navacchia ML. Spagnolo P. Eur. J. Org. Chem.  1998,  1219 ; and references cited therein
• 4d Montevecchi PC. Navacchia ML. Spagnolo P. Tetrahedron  1998,  54:  8207 
• 4e Fernández-Gonzáles M. Alonso R. J. Org. Chem.  2006,  71:  6767 
• For boron-substituted alkynes, see:
• 5a Matteson DS. Peacock K. J. Org. Chem.  1963,  28:  369 
• 5b Lhermitte F. Carboni B. Synlett  1996,  377 
• 5c For sulfur-substituted alkynes, see: Melandri D. Montevecchi PC. Navacchia ML. Tetrahedron  1999,  55:  12227 
• 6a Zificsak CA. Mulder JA. Hsung RP. Rameshkumar C. Wei L.-L. Tetrahedron  2001,  57:  7575 
• 6b Mulder JA. Kurtz KCM. Hsung RP. Synlett  2003,  1379 
• 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 
• For examples of the synthesis of (Z)-1-amino-2-thio-1-alkene derivatives, see:
• 9a Apparao S. Schmidt RR. Synthesis  1987,  896 
• 9b Kondo T. Baba A. Nishi Y. Mitsudo T. Tetrahedron Lett.  2004,  45:  1469 
• For hydrothiolations under transition-metal catalysis, see:
• 10a Ogawa A. Ikeda T. Kimura K. Hirao T. J. Am. Chem. Soc.  1999,  121:  5108 
• 10b Cao C. Fraser LR. Love JA. J. Am. Chem. Soc.  2005,  127:  17614 
• 10c Ananikov VP. Malyshev DA. Beletskaya IP. Aleksandorov GG. Eremenko IL. Adv. Synth. Catal.  2005,  347:  1993 ; and references cited therein
• 11a Nozaki K. Oshima K. Utimoto K. J. Am. Chem. Soc.  1987,  109:  2547 
• 11b Nozaki K. Oshima K. Utimoto K. Bull. Chem. Soc. Jpn.  1987,  60:  3465 
• 12 Zhang Y. Hsung RP. Tracey MR. Kurtz KCM. Vera EL. Org. Lett.  2004,  6:  1151 
• 14 It was reported that arylthiyl radicals behave as electron-deficient radicals: Ito O. Fleming MDCM. J. Chem. Soc., Perkin Trans. 2  1989,  689 
• 17 Alkenes and ketones can be reduced under these conditions. See: Kursaniov DN. Parnes ZN. Bassova GL. Loim NM. Zdanovich VI. Tetrahedron  1967,  23:  2235 
• 19 Markgren P.-O. Schaal W. Hämäläinen M. Karlén A. Hallberg A. Samuelsson B. Danielson UH. J. Med. Chem.  2002,  45:  5430 
• Chiral vic-aminothio compounds serve as ligands in enantioselective reactions. See:
• 20a Vargas F. Sehnem JA. Galetto FZ. Braga AL. Tetrahedron  2008,  64:  392 ; and references cited therein
• 20b Jin M.-J. Sarkar SM. Lee D.-H. Qiu H. Org. Lett.  2008,  10:  1235 ; and references cited therein

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).
3aa: IR (Nujol): 2925, 1456, 1351, 1339, 1161, 1089, 1024, 741, 661 cm^-¹. ^¹H NMR (CDCl₃): δ = 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): δ = 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.

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.

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).
6aa: IR (neat): 2926, 2855, 1599, 1456, 1439, 1342, 1162, 1092, 737, 654 cm^-¹. ^¹H NMR (CDCl₃): δ = 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): δ = 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.