First Synthesis of Functionalized Benzonitriles by Formal [3+3] Cyclocondensations of 1,3-Bis(silyloxy)buta-1,3-dienes

Abstract

A variety of functionalized benzonitriles were regioselectively prepared by formal [3+3] cyclocondensation of 1,3-bis(silyloxy)buta-1,3-dienes with 3-ethoxy- and 3-silyloxy-2-cyano-2-en-1-ones.

Key Words

arenas - benzonitriles - cyclizations - regioselectivity - silyl enol ethers

References and Notes

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17

Typical Experimental Procedure for the Synthesis of 4a-l To a stirred solution of CH₂Cl₂ (3 mL per 1.0 mmol of 2a-e) of 2a-e was added 3a-h (1.1 mmol) and, subsequently, TiCl₄ (1.1 mmol) at -78 ˚C under argon atmosphere. The temperature of the reaction mixture was allowed to rise to 20 ˚C over 14 h with stirring. To the solution was added HCl (10%, 20 mL) and the organic and the aqueous layer were separated. The latter was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, heptanes-EtOAc) to give 4a-l. Starting with 2a (0.209 g, 1.5 mmol) and 3a (0.446 g, 1.65 mmol), 4a was isolated as a colorless solid (101 mg, 33%), mp 86-87 ˚C. ^¹H NMR (250 MHz, CDCl₃): δ = 1.39 (t, ^³ J = 7.1 Hz, 3 H, OCH₂CH ₃), 2.72 (s, 3 H, CH₃), 4.42 (q, ^³ J = 7.1 Hz, 2 H, OCH ₂CH₃), 6.84 (d, ^³ J = 8.8 Hz, 1 H, Ar), 7.53 (d, ^³ J = 8.8 Hz, 1 H, Ar), 11.78 (s, 1 H, OH). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.1 (CH₃), 20.8 (OCH₂ CH₃), 61.7 (OCH₂), 104.8 (CCN), 112.6 (CCO₂Et), 116.0 (CH), 117.4 (CN), 136.7 (CH), 145.5 (CCH₃), 164.8 (COH), 169.6 (C=O). IR (neat): ν = 3072 (w), 2991 (w), 2923 (w), 2851 (w), 2777 (w), 2692 (w), 2589 (w), 2224 (w), 1660 (s), 1588 (m), 1570 (w), 1476 (m), 1450 (w), 1398 (m), 1375 (s), 1348 (m), 1318 (m), 1302 (m), 1231 (s), 1182 (w), 1146 (m), 1108 (w), 1057 (w), 1021 (m), 996 (w), 909 (w), 856 (m), 831 (m), 723 (w), 632 (w), 609 (w), 558 (w) cm^-¹. MS (GC-MS, 70 eV): m/z (%) = 205 (26) [M⁺], 159 (100), 130 (22), 103 (8), 77 (12), 51 (6). HRMS (EI): m/z calcd for C₁₁H₁₁NO₃: 205.07334; found: 205.073572.

18

CCDC-703181 contains all crystallographic details of this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallo-graphic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: [phone]; or [e-mail].

20

Typical Experimental Procedure for the Synthesis of 6a-f To a CH₂Cl₂ solution of 5 was added TiCl₄ at -78 ˚C in the presence of MS (4 Å). The appropriate bis(silyl enol ether) 3 was subsequently added. The reaction mixture was allowed to warm to 20 ˚C during 20 h and was stirred for further 4 h. To the solution was added CH₂Cl₂, the MS were removed, and a sat. aq soln of NaHCO₃ was added. The organic layer was separated, and the aqueous layer was repeatedly extracted with CH₂Cl₂. All organic extracts were combined, dried (Na₂SO₄), and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂) to give salicylates 6. Starting with 5 (188 mg, 0.95 mmol), CH₂Cl₂ (3.0 mL), MS (4 Å, 0.4 g), TiCl₄ (0.11 mL, 1.0 mmol), and 3i (356 mg, 1.4 mmol), compound 6a was isolated by column chromatography (SiO₂; n-heptane-EtOAc, 10:1) as a colorless solid (67 mg, 34%), mp 109-110 ˚C; R _f  = 0.21 (n-heptane-EtOAc, 10:1); reaction time 21 h. ^¹H NMR (250 MHz, CDCl₃): δ = 2.48 (d, ⁴ J = 0.9 Hz, 3 H, ArCH₃), 2.75 (s, 3 H, ArCH₃), 3.98 (s, 3 H, OCH₃), 6.76 (s, 1 H, CH_Ar), 11.72 (s, 1 H, OH). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.4, 21.8 (ArCH₃), 52.7 (OCH₃), 107.0, 111.0, 117.3 (2 × C_Ar, CN), 117.4 (CH_Ar), 146.6, 148.4 (C_Ar), 165.1, 171.0 (C_ArOH, CO). IR (KBr): ν = 3431 (br, m), 2957 (m), 2217 (s), 1668 (s), 1601 (s), 1581 (s), 1442 (s), 1368 (s), 1358 (s), 1319 (s), 1241 (s), 810 (s) cm^-¹. MS (EI, 70 eV): m/z (%) = 205 (83) [M⁺], 174 (76), 173 (100), 145 (66), 144 (37), 116 (20), 91 (14). Anal. Calcd for C₁₁H₁₁NO₃ (205.21): C, 64.38; H, 5.40; N, 6.83. Found: C, 64.64; H, 5.52; N, 6.65.