Synlett 2003(10): 1474-1478
DOI: 10.1055/s-2003-40822
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Application of Directed Metalation in Synthesis. Part 5: [1] [2] Synthesis of Condensed Sulfur-Oxygen Heterocycle via Novel Anionic Rearrangement-Cyclisation

Chandrani Mukherjee, Sukanta Kamila, Asish De*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata-700032, W.B, India
Fax: +91(33)24732805; e-Mail: ocad@mahendra.iacs.res.in;
Further Information

Publication History

Received 23 April 2003
Publication Date:
24 July 2003 (online)

Abstract

Introduction of the methyl sulfanyl function in the ortho-position to O-carbamate functionality under standard directed metalation condition was followed by side-chain deprotonation with sec-butyl lithium at -78 °C. Upon warming to room temperature, the deprotonated species underwent intramolecular anionic rearrangement to afford N,N-diethyl-2-hydroxyarylthioacetamides. The rearranged products were cyclised with hot glacial acetic acid to afford condensed oxathiin-2-ones in excellent yields.

2

Abstracted in part from the Ph.D. thesis submitted by C. M. to Jadavpur University, 2003.

    References

  • 1 Part 4, see: Mukherjee C. Kamila S. De A. Tetrahedron  2003,  59:  4767 
  • 3 Snieckus V. Chem. Rev.  1990,  90:  879 
  • 4 Sibi MP. Snieckus V. J. Org. Chem.  1983,  48:  1935 
  • 5 Seebach D. Bauer VW. Helv. Chim. Acta  1984,  67:  1972 
  • 6 Sibi MP. Chattopadhay S. Dankwardt JW. Snieckus V. J. Am. Chem. Soc.  1985,  107:  6312 
  • 7a Kamila S. Mukherjee C. De A. Tetrahedron Lett.  2001,  42:  5955 
  • 7b Kamila S. Mukherjee C. Mondal SS. De A. Tetrahedron  2003,  1339 
  • 8 Zhang P. Gawley RE. J. Org. Chem.  1993,  58:  3223 
  • 9 Wang W. Snieckus V. J. Org. Chem.  1992,  57:  424 
  • 10 Kalinin AV. Jalil Miah MA. Chattopadhay S. Tsukazaki M. Wicki M. Nguyen T. Coelho AL. Kerr M. Snieckus V. Synlett  1997,  839 
  • 13 Mukherjee C. De A. Synlett  2002,  325 
  • 17 Marks IE. In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon; Oxford: 1992.  p.913 
  • 18 Marshall JA. In Comprehensive Organic Synthesis   Vol 3:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.913 
  • 19 Clarke RD. Jahargir A. Org. React.  1995,  47:  1 
  • 20 Greenwood D. Stevenson HA. J. Chem. Soc.  1953,  1514 
  • 21 Horner L. Sturm K. Liebigs Ann. Chem.  1955,  597:  1 
2

Abstracted in part from the Ph.D. thesis submitted by C. M. to Jadavpur University, 2003.

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): δ = 1.23 (t, 6 H, -CH2CH 3), 2.34 (s, 3 H, -CH3), 3.41 (q, 4 H, -CH 2CH3), 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): δ = 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.

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Representative Example of Introduction of Methyl Sulfanyl Function by Directed Metalation. 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): δ = 1.18-1.25 (t, 6 H, -CH2CH 3), 2.25 (s, 3 H, -Me), 2.33 (s, 3 H, -SMe), 3.35-3.37 (q, 4 H, -CH 2CH3), 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): δ = 14.0, 15.5, 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.

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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): δ = 1.09 (t, 6 H, -CH2CH 3), 2.21 (s, 3 H, -CH3), 3.30 (q, 4 H, -CH 2CH3), 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): δ = 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.

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): δ = 1.16 (t, 6 H, -CH2CH 3), 2.34 (s, 3 H, -SMe), 3.37-3.45 (q, 4 H, -CH 2CH3), 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): δ = 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.

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 CH2Cl2 (2 × 100 mL). The organic layer was washed with H2O and dried (Na2SO4). Removal of solvent afforded crude 6-methyl-8-methoxy-benz[1,4]oxathiin-2-one 5d which was purified by crystallisation (EtOAc-light petroleum), 83% yield; mp 117-121 °C. IR (KBr): 1759 (C=O) cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.3 (s, 3 H, -CH3), 3.41 (s, 2 H, -SCH2-), 3.85 (s, 3 H, -OMe), 6.63 (s, 1 H, Ar-5H), 6.69 (s, 1 H, Ar-7H). 13C NMR (75 MHz, CDCl3): δ = 21.6, 29.1, 56.5, 112.1, 119.9, 120.7, 135.2, 138.6, 148.8, 163.1. Anal. Calcd for C10H10O3S: C, 57.14; H, 4.76. Found: C, 57.2; H, 4.62.