Application of Directed Metallation in Synthesis, Part 2 [1] : An Expedient Synthesis of Methoxybenzo[b]thiophenes

Abstract

A short, simple and expedient synthesis of substituted benzo[b]thiophenes involving directed ortho lithiation-side-chain deprotonation-cyclisation-reduction is described. This method is a valuable improvement over earlier syntheses of the same class of compounds, both with respect to the number of steps and overall yields.

benzo[b]thiophene - thioindoxyl - directed metallation

References

<A NAME="RD24301ST-1">1</A> Kamila S. Mukherjee C. De A. Tetrahedron Lett  2001,  42:  5955 

<A NAME="RD24301ST-2A">2a</A> Iddon B. Scrowston RM. In Advances in Heterocyclic Chemistry   Vol. 11:  Katritzky AR. Boulton AJ. Academic Press; New York: 1970.  p.178 

<A NAME="RD24301ST-2B">2b</A> Scrowston RM. In Advances in Heterocyclic Chemistry   Vol. 29:  Katritzky AR. Boulton AJ. Academic Press; New York: 1980.  p.172 

<A NAME="RD24301ST-3A">3a</A> Campaigne E. Knapp DR. Neiss ES. Bosin TR. Adv. in Drug Res.  1970,  5:  1 

<A NAME="RD24301ST-3B">3b</A> Bosin TR. Campaigne E. Adv in Drug Res.  1977,  12:  191 

<A NAME="RD24301ST-4">4</A> Chapmann NB. Clarke K. Iddon B. J Med Chem.  1966,  9:  1899 

<A NAME="RD24301ST-5A">5a</A> Jones CD. Suarez T. Ger. Offen  1977,  647:  864 ; Chem Abs. 1977, 87, 102155

<A NAME="RD24301ST-5B">5b</A> Akaita T. Araki F. Kurono H. Harada T. Japan Kokai  1976,  118:  835 ; Chem. Abs. 1977, 86, 66846

<A NAME="RD24301ST-6A">6a</A> Connor DT. Cetenko WA. Mullicans MD. Sorenson RJ. Unangst PC. Weibert RJ. Adolphson RL. Kennedy JA. Thueson DO. Wright CW. Conroy MC. J. Med. Chem.  1992,  35:  958 

<A NAME="RD24301ST-6B">6b</A> Hrib NJ. Jurcak JG. Bregna DE. Dunn RW. Geyer HM. J. Med. Chem  1992,  35:  2712 

<A NAME="RD24301ST-6C">6c</A> Boschelli DH. Kramer JB. Khatana SS. Sorenson RJ. Connor DT. Ferin MA. Wright CD. Lesch ME. Imre K. J. Med. Chem.  1995,  38:  4597 

<A NAME="RD24301ST-6D">6d</A> Francesco G. Loredana S. Lamartina L. Spinelli D. J. Chem. Soc, Perkin Trans. 1  1995,  1243 

<A NAME="RD24301ST-7">7</A> Malamas MS. Sredy J. Moxham C. Katz A. Xu W. McDevitt R. Adebayo F. Sawtcki DR. Seestaller L. Sullivan D. Taylor JR. J. Med. Chem.  2000,  43:  1293 

<A NAME="RD24301ST-8A">8a</A> Levacher V. Bonsad N. Dupas G. Bourguignon J. Queginer G. Tetrahedron. Lett.  1992,  48:  831 

<A NAME="RD24301ST-8B">8b</A> Dutta S. De A. J. Chem. Soc., Perkin Trans 1  1989,  603 

<A NAME="RD24301ST-8C">8c</A> Mukherjee S. Jash SS. De A. J. Chem. Res. (S)  1993,  192 

<A NAME="RD24301ST-8D">8d</A> Bhattacharya S. De A. Ewing DF. J. Chem. Soc., Perkin Trans 1  1994,  689 

<A NAME="RD24301ST-8E">8e</A> Samanta SS. Ghosh SC. De A. J. Chem. Soc., Perkin 1  1997,  3673 

<A NAME="RD24301ST-9">9</A>

Kamila, S.; Mondal, S. S.; De, A. unpublished work.

<A NAME="RD24301ST-10">10</A>

All the compounds reported in this paper showed correct elemental analysis and the structures were corroborated by characteristic spectroscopic data.

<A NAME="RD24301ST-11">11</A>

Representative Procedure for Synthesis of Compound 2: Compound 1 (R₁ = OMe, R₂ = H, R₃ = OMe, R₄ = H) was added to a stirred mixture of sec- BuLi (1.1 equiv) and TMEDA (1.1 equiv) in THF at -78 °C. After 40 minutes the ortho lithiated species was quenched with dimethyldisulfide (2 equiv) at -78 °C. The reaction mixture was allowed to attain room temperature and was kept at that temperature for 10 hours. Usual aqueous work up afforded compound 2d. Yield: 84%; mp 80 °C (Ether-Petroleum ether); IR (KBr) = 1637.5 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.4 (d, 1 H, J = 2 Hz), 6.27 (d, 1 H, J = 2 Hz), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.24 (q, 4 H), 2.42 (s, 3 H), 1.13 (t, 6 H); ¹³C NMR (300MHz, CDCl₃) δ_c: (167.15, 161.18, 157.13, 137.76, 119.75, 104.39, 96.09, 56.04, 55.83, 43.03, 39.14, 16.75, 14.22, 13.01.

<A NAME="RD24301ST-12">12</A>

Representative Procedure for Synthesis of Compound 3: Compound 2d was treated with LDA (2 equiv) in THF at -78 °C for 50 min and the reaction mixture was stirred for 12 h at room temperature. Usual work up of the reaction mixture afforded compound 3d. IR (KBr) = 1679.9 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ_H: 6.37 (d, 1 H, J = 1.8 Hz), 6.07 (d, 1 H, J = 1.8 Hz), 3.83 (s, 3 H), 3.79 (s, 3 H), 3.68 (s, 2 H); ¹³C NMR (300 MHz, CDCl₃) δ_c: 196.47, 167.47, 161.85, 160.05, 113.91, 100.2, 96.05, 56.27, 40.12.

<A NAME="RD24301ST-13">13</A>

Representative Procedure for the Synthesis of Compound 4: To a solution of compound 3d in methanol and 10% NaOH (6:1), NaBH₄ (2 equiv) in methanol and 10% NaOH solution (10:3) were added. This mixture was refluxed for 1 h on steam bath and then allowed to stand just under boiling condition for 12 h. Methanol was removed and the reaction mixture was acidified with 10% H₂SO₄ and extracted with ether. Usual aqueous work up and removal of solvent afforded compound 4d. ¹H NMR (300 MHz, CDCl₃) δ_H: 7.28 (d, 1 H, J = 5.49 Hz), 7.05 (d, 5.49), 6.82 (d, 1 H, J = 1.8 Hz), 6.31 (d, 1 H, J = 1.8), 3.81 (s, 3 H), 3.75 (s, 3 H); ¹³C NMR (300 MHz, CDCl₃) δ_c: 159.23, 155.78, 142.5, 125.41, 122.25, 120.61, 96.62, 96.21, 56.06, 55.83.

<A NAME="RD24301ST-14">14</A> Snieckus V. Chem. Rev.  1990,  90:  879 

<A NAME="RD24301ST-15">15</A> Mills RJ. Taylor NJ. Snieckus V. J. Org. Chem  1989,  54:  4372 

<A NAME="RD24301ST-16">16</A> We observed exclusive deprotonation in the 2-position of N,N-diethyl-3-methoxy benzamide under standard directed metallation condition although there is a literature report on expected deprotonation in the 2-position along with the formation of 6-lithio derivative as a minor product: Beak P. Brown RA. J. Org. Chem.   1982.  47:  p.32 

<A NAME="RD24301ST-17">17</A> Court JJ. Hlasta DJ. Tetrahedron Lett.  1996,  37:  1335 

<A NAME="RD24301ST-18">18</A> Katritzky AR. Serdyuk L. Xie L. J. Chem. Soc., Perkin Trans. 1  1998,  1059 

<A NAME="RD24301ST-19">19</A> Desvoye ML. Demerseman P. Lechartier JP. Pene C. Cheutin A. Royer R. Bull. Soc. Chim. France  1965,  1473 

<A NAME="RD24301ST-20">20</A> Rahman LKA. Scrowston RM. J. Chem. Soc., Perkin Trans. 1  1983,  2973 

<A NAME="RD24301ST-21">21</A> Truce WE. Bannister WW. Knospe RH. J. Org. Chem.  1962,  27:  2821