LETTER
Synthesis of Condensed Sulfur-Oxygen Heterocycle
1477
Scheme 4
(7) (a) Kamila, S.; Mukherjee, C.; De, A. Tetrahedron Lett.
2001, 42, 5955. (b) Kamila, S.; Mukherjee, C.; Mondal, S.
S.; De, A. Tetrahedron 2003, 1339.
22.1, 42.5, 56.5, 110.6, 118.6, 133.1, 135.7, 136.4, 152.1,
153.7. Anal. Calcd for C14H21O3NS: C, 59.36; H, 7.42; N,
4.94. Found: C, 59.18; H, 6.99; N, 5.0.
(8) Zhang, P.; Gawley, R. E. J. Org. Chem. 1993, 58, 3223.
(9) Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424.
(10) Kalinin, A. V.; Jalil Miah, M. A.; Chattopadhay, S.;
Tsukazaki, M.; Wicki, M.; Nguyen, T.; Coelho, A. L.; Kerr,
M.; Snieckus, V. Synlett 1997, 839.
(13) Mukherjee, C.; De, A. Synlett 2002, 325.
(14) Representative Example of Preparation of N,N-Diethyl-
2-hydroxy Aryl Thioacetamide.
To a stirred solution of TMEDA (0.54 mL, 2.5 equiv), sec-
BuLi (2.01 mL of 1.8 M solution, 2.5 equiv). in anhyd THF
(7 mL) kept at –78 °C in argon atmosphere, a solution of
N,N-diethyl-1-carbamyloxy-2-methylsulfanyl-4-methyl-6-
methoxybenzene 2e (14.5 mmol), in dry THF (3 mL) was
added via syringe. Stirring was continued for 1 h at that
temperature, then the reaction mixture was allowed to attain
r.t. and kept for 8 h. Ammonium chloride work up afforded
crude material which was purified by crystallisation
(EtOAc–petroleum ether) to obtain N,N-diethyl-2-hydroxy-
3-methoxy-5-methylphenylthioacetamide 3d, 85% yield. IR
(KBr): 3120 (-OH), 1624 (C=O) cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.09 (t, 6 H, -CH2CH3), 2.21 (s, 3 H, -CH3), 3.30
(q, 4 H, -CH2CH3), 3.61 (s, 2 H, -SCH2-), 3.82 (s, 3 H, -
OMe), 6.65 (d, 1 H, J = 1.6 Hz, Ar-4H), 6.87 (d, 1 H, J = 1.6
Hz, Ar-6H). 13C (75 MHz, CDCl3): d = 13.2, 14.58, 21.2,
39.3, 41.6, 42.7, 56.5, 114.5, 119.3, 128.2, 129.3, 146.6,
148.4, 169.3. Anal. Calcd for C14H21O3NS: C, 59.36; H, 7.4;
N, 4.9. Found: C, 59.4; H, 7.5; N, 5.1.
(11) Representative Example of Synthesis of O-Aryl N,N-
Diethyl Carbamates.
To a well stirred suspension of NaH (3 equiv), in anhyd THF
(10 mL), a solution of 2-methoxy-4-methylphenol (28
mmol) in anhyd THF (10 mL) was added through a pressure
equalising dropping funnel at r.t. After stirring the reaction
mixture for 2 h, N,N-diethylcarbamylchloride (7.3 mL, 2
equiv) in THF (10 mL) was added to the reaction mixture.
Stirring was continued for another 8 h. THF was removed in
vacuo and usual aqueous work up afforded the crude product
N,N-diethyl-1-carbamyloxy-2-methoxy-4-methylbenzene
1e which was purified by crystallisation (EtOAc:petroleum
ether). Colourless needles, 95% yield; mp 51–53 °C. IR
(neat): 1720 (C=O) cm–1. 1H NMR (300 MHZ, CDCl3): d =
1.23 (t, 6 H, -CH2CH3), 2.34 (s, 3 H, -CH3), 3.41 (q, 4 H, -
CH2CH3), 3.8 (s, 3 H, -OMe), 6.74 (dd, 1 H, J = 3.0, 8.0 Hz,
Ar-5H), 6.76 (d, 1 H, J = 3.0 Hz, Ar-3H), 6.96 (d, 1 H,
J = 8.0 Hz, Ar-6H). 13C (75 MHZ, CDCl3): d = 13.2, 13.8,
14.4, 21.8, 42.4, 42.5, 56.3, 113.7, 121.4, 123.2, 136.3,
138.7, 151.6, 154.7. Anal. Calcd for C13H19O3N: C, 65.82;
H, 8.01; N, 5.90. Found: C, 65.68; H, 7.87; N, 6.0.
(12) Representative Example of Introduction of Methyl
Sulfanyl Function by Directed Metalation.
(15) Synthesis of N,N-Diethyl-2-hydroxy-3-methyl Sulfanyl
Benzamide.
To a stirred solution of TMEDA (1.34 mL, 3 equiv) was
added sec-BuLi (4.0 mL of 1.9 M solution in cyclohexane,
2.5 equiv) in anhyd THF (7 mL) kept at –78 °C in argon
atmosphere, a solution of N,N-diethyl-1-carbamyloxy-2-
methylsulfanylbenzene 2a (3.0 mmol) in dry THF (3 mL)
was added via syringe. Stirring was continued for 1 h at that
temperature, then the mixture was allowed to attain r.t. and
kept for 8 h. Ammonium chloride work up afforded crude
N,N-diethyl-2-hydroxy-3-methyl sulfanyl benzamide 3a
which was purified by crystallisation (EtOAc–petroleum
ether). Yellowish needles, 89% yield; mp 56–58 °C. IR
(KBr): 3057 (-OH), 1604 (C=O) cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.16 (t, 6 H, -CH2CH3), 2.34 (s, 3 H, -SMe),
3.37–3.45 (q, 4 H, -CH2CH3), 6.80 (dd, 1 H, J = 7.7, 7.7 Hz,
Ar-4H), 7.07 (dd, 1 H, J = 1.3, 7.7 Hz, Ar-3H), 7.26 (dd, 1
H, J = 1.3, 7.7 Hz, Ar-5H). 13C (75 MHz, CDCl3): d = 13.8,
16.9, 42.3, 119.7, 125.9, 126.04, 127.6, 131.6, 155.2, 170.7.
Anal. Calcd for C12H17O2NS: C, 62.88; H, 7.4; N, 6.1.
Found: C, 63; H, 7.5; N, 6.2.
To a well stirred solution of TMEDA (5.5 mL, 2.5 equiv),
anhyd THF (10 mL), sec-BuLi [26 mL of 1.4 M solution in
cyclohexane, 2.5 equiv] kept at –78 °C under argon
atmosphere, a solution of N,N-diethyl-1-carbamyloxy-2-
methoxy-4-methylbenzene 1e (14.5 mmol), in THF (5 mL)
was added via syringe. After stirring for 30 min at that
temperature, dimethyl disulfide (3.3 mL, 2.5 equiv) was
added and stirring continued for further 45 min at the same
temperature. The reaction mixture was then allowed to warm
to r.t. and stirred for 10 h. Usual ammonium chloride work
up afforded the crude N,N-diethyl-1-carbamyloxy-2-
methylsulfanylbenzene. Purification by crystallisation
(EtOAc–petroleum ether) afforded N,N-diethyl-1-
carbamyloxy-2-methylsulfanyl-4-methyl-6-
methoxybenzene 2e. Yellowish needles, 96% yield; mp 31–
33 °C. IR (neat): 1724 (C=O) cm–1. 1H NMR (300 MHz,
CDCl3): d = 1.18–1.25 (t, 6 H, -CH2CH3), 2.25 (s, 3 H, -Me),
2.33 (s, 3 H, -SMe), 3.35–3.37 (q, 4 H, -CH2CH3), 3.72 (s, 3
H, -OMe), 6.49 (d, 1 H, J = 1.6 Hz, Ar-5H), 6.53 (d, 1 H,
J = 1.6 Hz, Ar-3H). 13C (75 MHz, CDCl3): d = 14.0, 15.5,
(16) Representative Example of Preperation of
Benz[1,4]oxathiin-2-ones:
Hydroxy compound 3d (0.88 mmol) was refluxed with
glacial acetic acid (7 mL) for 18 h under magnetic stirring.
After cooling, the reaction mixture was extracted with
Synlett 2003, No. 10, 1474–1478 © Thieme Stuttgart · New York