M. K. Denk, X. Ye / Tetrahedron Letters 46 (2005) 7597–7599
7599
to the use of alkyl iodides and an easy access to the
Acknowledgments
S-tert-butyl isothiourea.
We thank the Natural Sciences and Engineering Re-
search Council of Canada ( NSERC) for support of this
work through an operating grant and the Government
of Ontario for a PremierÕs Research Excellence Award
(MKD). The comments of Professor Gordon Lange
during the writing of the manuscript are gratefully
acknowledged.
5. Synthesis of S-alkyl-isothioureas from ethylenethiourea
and alcohols
Ethylenethiourea (20 mmol), the alcohol (60 mmol), and
the respective acid (30 mmol) are heated under constant
stirring (compare Table 1). The cold reaction mixture is
brought to pH 11 with 40% aqueous NaOH and
extracted with 3 · 20 mL of diethyl ether. After drying
of the combined organic phases over NaOH pellets
(24 h) and CaH2 (24 h), the anhydrous 2-(alkylthio)-
4,5-dihydro-1H-imidazoles 5 are isolated as colorless,
crystalline solids.
References and notes
1. (a) Luzio, F. A. Synth. Commun. 1984, 14, 209–214; (b)
Szargan, R.; Scheibe, R.; Beyer, L.; Salyn, Ya. V.;
Nefedov, V. I. Tetrahedron 1979, 35, 59–62; (c) Kessler,
H.; Kalinowski, H.-O. Angew. Chem., Int. Ed. Engl. 1970,
9, 641–642; (d) Boyd, R. N.; Meadow, M. J. Chem. Ed.
1960, 32, 551–554.
5.1. 5a. 2-(Methylthio)-4,5-dihydro-1H-imidazole
CAS [20112-79-2]. Colorless crystals, mp 106–107 ꢂC,
lit.1d 101–102 ꢂC. 1H NMR (CDCl3): 2.49 [s, 3H,
2. (a) Zepik, H. H.; Benner, S. A. J. Org. Chem. 1999, 64,
8080–8083; (b) Bogartsky, A. V.; Lukyanenko, N. G.;
Kirichenko, T. I. Synthesis 1982, 464–465; (c) Assef, G.;
Kister, J.; Metzger, J. Bull. Soc. Chim. Fr. 1979, 165–176;
(d) Bandelin, F. J.; Tuschhoff, J. V. J. Am. Chem. Soc.
1952, 74, 4271–4273.
3. (a) Gers, T.; Kunce, D.; Markowski, P.; Izdebski, J.
Synthesis 2004, 37–42; (b) Liu, F.; Lu, G.-Y.; He, W.-J.;
Hu, J.; Mei, Y.-H.; Zhu, L.-G. Synthesis 2001, 607–611;
(c) Ibatullin, F. M.; Selivanov, S. I.; Shavva, A. G.
Synthesis 2001, 419–422; (d) Radics, U.; Liebscher, J.;
Pa¨tzel, M. Synthesis 1992, 673–677; (e) Grosso, J. A.;
Nichols, D. E.; Kohli, J. D.; Glock, D. J. Med.
Chem. 1982, 25, 703–708; (f) Khym, J. X.; Doherty, D.
G.; Shapira, R. J. Am. Chem. Soc. 1958, 80, 3342–
3349.
3
SCH3], 3.48 [t, 2H, J(H,H) = 9 Hz, HNCH2], 3.85 [t,
2H, 3J(H,H) = 9 Hz, NCH2], 4.37 [broad, 1H, NH].
13C (CDCl3): 13.8 [SCH3], 46.1 [HNCH2], 55.4 [NCH2],
165.1 [HNC(N)S]. GC–MS: tR 7.23 min, m/z (rel int.%)
116(100), 100(20), 87(25), 72(75), 59(10), 45(30).
5.2. 5b. 2-(Ethylthio)-4,5-dihydro-1H-imidazole
CAS [7320-60-7]. Colorless crystals, mp 62–65 ꢂC, lit.1d
58–60 ꢂC. 1H (CDCl3): 1.36 [t, 3H, 3J(H,H) = 7 Hz,
SCH2CH3], 3.06 [q, 2H, 3J(H,H) = 7 Hz, SCH2CH3],
3.47 [t, 2H, 3J(H,H) = 9 Hz, HNCH2], 3.83 [t, 2H,
3J(H,H) = 9 Hz, NCH2], 4.45 [broad, 1H, NH]. 13C
(CDCl3): 14.9 [SCH2CH3], 25.6 [SCH2CH3], 45.9
[HNCH2], 55.6 [NCH2], 164.1 [HNC(N)S]. GC–MS:
tR = 7.85 min, m/z (rel int.%) = 131(10) [MH]+, 115(7),
102(100), 97(25), 72(38), 45(17).
4. (a) Di Giacomo, C.; Sorrenti, V.; Salerno, L.; Cardile, V.;
Guerrera, F.; Siracusa, M. A.; Avitabile, M.; Vanella, A.
Exp. Biol. Med. 2003, 228, 486–490; (b) Garvey, E. P.;
Oplinger, J. A.; Tanoury, G. J.; Sherman, P. A.; Fowler,
M.; Marshall, S.; Harmon, M. F.; Paith, J. E.; Furfine, E.
S. J. Biol. Chem. 1994, 269, 26669–26676.
5.3. 5c. 2-(Isopropylthio)-4,5-dihydro-1H-imidazole
5. (a) Yokoyama, H.; Onodera, K.; Maeyama, K.; Sakurai,
E.; Iinuma, K.; Leurs, R.; Timmerman, H.; Watanabe, T.
Eur. J. Pharmacol. 1994, 260, 23–28; (b) Van der Goot, H.;
Schepers, M. J. P.; Sterk, G. J.; Timmerman, H. Eur. J.
Med. Chem. 1992, 27, 511–517.
6. (a) Farzin, D.; Attarzadeh, M. Eur. J. Pharmacol. 2000,
404, 169–174; (b) Sterk, G. J.; van der Goot, H.;
Timmerman, H. Agents Actions 1986, 18, 137–140.
7. (a) Uetani, T.; Matsubara, T.; Nomura, H.; Murohara, T.;
Nakayama, S. J. Biol. Chem. 2003, 278, 47491–47497; (b)
Watano, T.; Kimura, J.; Morita, T.; Nakanishi, H. Br. J.
Pharmacol. 1996, 119, 555–563.
CAS [99115-66-9]. Colorless crystals, mp 113–115 ꢂC,
1
3
lit.1d 106–108 ꢂC. H (CDCl3): 1.39 [d, 6H, J(H,H) =
7 Hz, SCH(CH3)2], 3.43 [t, 2H, 3J(H,H) = 9 Hz,
3
HNCH2], 3.87 [t, 2H, J(H,H) = 9 Hz, C@NCH2], 3.79
[sept, 1H, 3J(H,H) = 7 Hz, SCH(CH3)2], 4.28 [broad,
1H, NH]. 13C (CDCl3): 23.6 [SCH(CH3)2], 36.9 [SCH-
(CH3)2], 45.2 [HNCH2], 55.6 [NCH2], 164.0 [NCS]. GC–
MS: tR = 8.18 min, m/z (rel int.%) = 145(6) [MH]+,
129(8), 111(32), 102(100), 86(2), 74(30), 59(10), 45(15).
8. (a) Mandrugin, A. A.; Rodyunin, A. A.; Fedoseev, V. M.;
Konstantinova, M. M.; Dontsova, G. V.; Rakhmanina, O.
N. Khim.-Fharm. Zh. 1989, 23, 832–834; (b) Bauer, L.;
Suresh, K. S. J. Org. Chem. 1963, 28, 1604–1608.
9. Stevens, H. P. J. Chem. Soc. Trans. 1902, 79–81.
10. (a) Wagner, B. J.; Doi, J. T.; Musker, W. K. J. Org. Chem.
1990, 55, 4156–4162; (b) Frank, R. L.; Smith, P. V. J. Am.
Chem. Soc. 1946, 68, 2103–2104; (c) Sprague, J. M.;
Johnson, T. B. J. Am. Chem. Soc. 1937, 59, 1837–
1840.
5.4. 5d. 2-(tert-Butylthio)-4,5-dihydro-1H-imidazole
Colorless crystals, mp 82–84 ꢂC. 1H (CDCl3): 1.54 [s, 9H,
3
SC(CH3)3], 3.35 [t, 2H, J(H,H) = 9 Hz, HNCH2], 3.90
3
[t, 2H, J(H,H) = 9 Hz, NCH2], 4.28 [broad, 1H, NH].
13C (CDCl3): 30.8 [SC(CH3)3], 44.2 [HNCH2] 47.6
[SC(CH3)3], 56.2 [C@NCH2], 162.7 [HNC(N)S]. GC–
MS: tR = 8.38 min, m/z (rel int.%) = 159(100), 148(5),
102(50), 74(7), 57(6) 45(4). HR-MS: 158.0881 (exp.),
158.0878 (calcd for C7H14N2S), deviation 2.2 ppm.
11. In the case of 5d, prolonged heating in 56% HI led to the
formation of ethylenethiourea and isobutene.