Regioselective Synthesis of Functionalized Resorcins by Cyclization of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with 3,3-Dimethoxypentanoyl Chloride

Abstract

Functionalized resorcins are regioselectively prepared by cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3,3-dimethoxypentanoyl chloride. The regioselectivity is controlled by the type of Lewis acid employed.

arenes - cyclizations - regioselectivity - silyl enol ethers

References and Notes

1a Staunton J. Weissman KJ. Nat. Prod. Rep.  2001,  18:  380 

1b Koskinen AMP. Karisalmi K. Chem. Soc. Rev.  2005,  34:  677 

1c Römpp-Lexikon Naturstoffe   Fugmann B. Thieme; Stuttgart / New York: 1997. 

For a review, see:

2a Harris TM. Harris CM. Tetrahedron  1977,  33:  2159 

See also:

2b Murray TP. Harris TM. J. Am. Chem. Soc.  1972,  94:  8253 

2c Harris CM. Roberson JS. Harris TM. J. Am. Chem. Soc.  1976,  98:  5380 

2d Harris TM. Hay JV. J. Am. Chem. Soc.  1977,  99:  1631 

2e Hubbard JS. Harris TM. Tetrahedron Lett.  1978,  47:  4601 

2f Sandifer RM. Bhattacharya AK. Harris TM. J. Org. Chem.  1981,  46:  2260 

2g Gilbreath SG. Harris CM. Harris TM. J. Am. Chem. Soc.  1988,  110:  6172 

3 For a review of 1,3-bis(silyl enol ethers), see: Langer P. Synthesis  2002,  441 

4 For a review of formal [3+3] cyclizations of 1,3-bis(silyl enol ethers), see: Feist H. Langer P. Synthesis  2007,  327 

5 Chan T.-H. Brownbridge P. J. Chem. Soc., Chem. Commun.  1979,  578 

6a Chan T.-H. Stössel D. J. Org. Chem.  1988,  53:  4901 

6b Chan T.-H. Stössel D. J. Org. Chem.  1986,  51:  2423 

7 Langer P. Krummel T. Chem. Eur. J.  2001,  7:  1720 

8 Rahn T. Nguyen VTH. Dang THT. Ahmed Z. Lalk M. Fischer C. Spannenberg A. Langer P. J. Org. Chem.  2007,  72:  1957 

9 For a review of cyclizations of silyl enol ethers with oxalyl chloride, see: Langer P. Synlett  2006,  3369 

10 Albrecht U. Nguyen VTH. Langer P. Synthesis  2006,  1111 

11 Reim S. Nguyen VTH. Albrecht U. Langer P. Tetrahedron Lett.  2005,  46:  8423 

12a

Some years ago, an isolated example of the cyclization of a protected β-keto ester was reported, see ref. 12b. In the case of 2, this reaction failed to give the desired product (formation of a complex mixture). An isolated reaction of a 1,3-dioxolan-protected β-keto acid chloride was also reported by Chan and Chaly. However, in our hands, the use of the dioxolan group proved to be disadvantageous in order to isolate the desired product in pure form.

12b Chan TH. Chaly T. Tetrahedron Lett.  1982,  23:  2935 

13

Typical Procedure for the Synthesis of 6a-l
To a CH₂Cl₂ solution (8 mL) of 1,3-bis(trimethylsilyloxy)-1-methoxy-1,3-butadiene (5a, 860 mg, 3.32 mmol) and of 4 (660 mg, 3.65 mmol) was dropwise added TMSOTf (0.3 mL, 1.66 mmol, 0.5 equiv) at -78 °C. The reaction mixture was allowed to warm to 20 °C during 6-12 h. After stirring for additional 2-6 h at 20 °C, HCl (10%, 25 mL) was added. The organic and the aqueous layers were separated and the latter was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried (NaSO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptanes-EtOAc) to give 6a as yellow solid (280 mg, 43%). ¹H NMR (300 MHz, CDCl₃): δ = 1.13 (t, 3 H, J = 7.6 Hz, CH₃), 2.48 (q, 2 H, J = 7.5 Hz, CH₂), 3.99 (s, 3 H, OCH₃), 6.28 (s, 2 H, CH_Ar), 9.54 (s, 2 H, OH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.4 (CH₃), 29.2 (CH₂), 52.7 (OCH₃), 97.7 (C), 107.8 (CH), 154.6,164.5, 169.8 (C). IR (KBr): 3427 (s), 2960 (s), 1670 (s), 1571 (s), 1377 (m), 1257 (s), 1103 (s), 1040 (m), 949 (m), 846 (s)799 (s), 738 (s), 613 (s), 531 (m) cm^-1. GC-MS (EI, 70 eV): m/z (%) = 196.0(35) [M⁺], 164.0(100), 136.0(21), 121.0(27). Anal. Calcd for C₁₀H₁₂O₄ (196.07): C, 61.22; H, 6.16. Found: C, 61.32; H, 6.11.

14

Typical Procedure for the Synthesis of 7a-i To a CH₂Cl₂ solution (5 mL) of 1,3-bis(trimethylsilyloxy)-1-methoxy-1,3-butadiene (500 mg, 1.91 mmol) and of 4 (385 mg, 2.11 mmol) was added dropwise TiCl₄ (0.21 mL, 1.91 mmol) at -78 °C. The reaction mixture was allowed to warm to 20 °C during 6-12 h. After stirring for additional 2-6 h at 20 °C, a sat. aq solution of NaHCO₃ (20 mL) was added. The organic and the aqueous layers were separated and the latter was extracted with Et₂O (3 × 25 mL). The combined organic layers were dried (NaSO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO₂, heptane-EtOAc) to give 7a as a yellow solid (230 mg, 61%). ¹H NMR (300 MHz, CDCl₃): δ = 1.30 (t, 3 H, J = 7.5 Hz, CH₃), 3.28 (q, 2 H, J = 7.5 Hz, CH₂), 4.01 (s, 3 H, OCH₃), 6.08 (s, 1 H, CH_Ar), 6.78 (s, 1 H, CH_Ar), 12.06 (s, 1 H, OH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.8 (CH₃), 28.8 (CH₂), 52.7 (OCH₃), 110.5, 116.0, 155.0, 166.0, 167.6, 170.5, 179.9. IR (KBr): 3427 (s), 2960 (s), 1670 (s), 1571 (s), 1377 (m), 1257 (s), 1103 (s), 1040 (m), 949 (m), 846 (s), 799 (s), 738 (s), 613 (s), 531 (m)
cm^-1. GC-MS (EI, 70 eV): m/z (%) = 196.0(37) [M⁺], 164.0(100), 136.0(26), 121.0(27). HRMS (EI): m/z calcd for C₁₀H₁₂O₄ [M]⁺: 196.072572; found: 196.07301.

15 Murata S. Suzuki M. Noyori R. J. Am. Chem. Soc.  1980,  102:  3248