Synthesis of Chiral 3-Substituted Phthalides via Rhodium(I)-catalyzed Crossed Alkyne Cyclotrimerisation

Abstract

3-Substituted phthalides were synthesized for the first time by crossed alkyne cyclotrimerisations with Wilkinson’s catalyst. Esterification of propiolic acids with chiral propargylic alcohols by either the DCC/DMAP or the Mitsunobu method allows the synthesis of either enantiomeric form of diyne esters, that are used in crossed alkyne cyclotrimerisations with acetylene to provide 3-substituted phthalides in both enantiomeric forms.

phthalides - alkyne cyclotrimerisation - Wilkinson’s catalyst - propargylic alcohols - (S)-3-n-butylphthalide

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17

Selected data for diyne esters 3:
3a: Mp: 101-103 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.99-7.94 (m, 1 H), 7.79-7.74 (m, 3 H), 7.64-7.59 (m, 1 H), 7.40-7.20 (m, 4 H), 5.06 (s, 2 H), 2.97 (s, 1 H), 2.33 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 151.9, 145.4, 134.7, 134.0, 130.5, 130.0, 129.9, 126.9, 125.5, 123.8, 120.4, 113.5, 103.7, 85.9, 78.9, 75.9, 73.9, 54.4, 21.5. MS (EI):
m/z (%) = 377 (100) [M⁺]. Anal. Calcd for C₂₁H₁₅NO₄S: C, 66.83; H, 4.01; N, 3.71. Found: C, 66.99; H, 3.99; N, 3.60.
(S)-3g: ¹H NMR (400 MHz, CDCl₃): δ = 5.40 (dt, J = 6.7 Hz, J = 2.2 Hz, 1 H), 2.93 (s, 1 H), 2.52 (d, J = 2.2 Hz, 1 H), 1.87-1.81 (m, 2 H), 1.49-1.26 (m, 4 H), 0.93 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ = 151.6, 80.0, 75.4, 74.6, 74.3, 65.9, 34.1, 26.9, 22.1, 13.8. MS (EI): m/z (%) = 164 (8) [M⁺].
(S)-3i: Mp: 59-61 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.61-7.58 (m, 2 H), 7.48-7.43 (m, 1 H), 7.40-7. 35 (m, 2 H), 5.56 (dq, J = 6.6, J = 2.2 Hz, 1 H), 2.53 (d, J = 2.2 Hz, 1 H), 1.60 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 152.8, 133.0, 130.8, 128.6, 119.4, 87.1, 81.2, 80.2, 73.8, 61.7, 21.1. MS (EI): m/z (%) = 198(7) [M⁺]. Anal. Calcd for C₁₃H₁₀O₂: C, 78.77; H, 5.09. Found: C, 78.82; H, 4.98.

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19

The enantiopurity of the esters 3g-i was analyzed after their conversion to the phthalides 4f-h, that proceeded without any detectable racemisation.

20

Selected data for phthalides 4:
(S)-4f: Oil; [α]_D ²² = -42 (c 0.45, CHCl₃); 88% ee as determined by chiral capillary GLC analysis with Supleco Beta-Dex^{Τ Μ} 325; {lit. [6l] [α]_D ²² -62 (c 0.42, CHCl₃)}. ¹H NMR (400 MHz, CDCl₃): δ = 7.89 (d, J = 7.6 Hz, 1 H), 7.67 (dt, J = 7.6 Hz, J = 3.3 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 5.49 (dd, J = 7.9 Hz, J = 4.1 Hz, 1 H), 2.10-2.01 (m, 1 H), 1.81-1.71 (m, 1 H), 1.53-1.33 (m, 4 H), 0.88 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.5, 150.0, 133.8, 128.9, 126.0, 125.5, 121.7, 81.3, 34.3, 26.7, 22.3, 13.7. MS (EI): m/z (%) = 190(5) [M⁺].
(S)-4g: oil; [α]_D ²² = -22.1 (c 0.83, MeOH); 94% ee as determined by chiral capillary GLC analysis with Supleco Beta-Dex^{Τ Μ} 325. (R)-4g: [α]_D ²² = +21.4 (c 0.81, MeOH); 94% ee as determined by chiral capillary GLC analysis with Supleco Beta-Dex^{Τ Μ} 325.
(S)-4h: [α]_D ²² = -15.6 (c 0.94, CHCl₃). (R)-4h: [α]_D ²² = +14.9 (c 0.98, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.71 (t, J = 7.6 Hz, 1 H), 7.58-7. 55 (m, 2 H), 7.50-7.41 (m, 5 H), 5.56 (q, J = 6.6 Hz, 1 H), 1.69 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.1, 152.5, 142.7, 136.4, 133.8, 130.8, 129.5, 128.3, 127.9, 121.8, 120.3, 76.1, 20.6. MS (EI): m/z (%) = 224(100) [M⁺].