Trialkylamine versus Trialkylphosphine: Catalytic Conjugate Addition of Alcohols to Alkyl Propiolates

Abstract

The conjugate addition of activated propargylic alcohols to alkyl propiolates is shown to be catalyst-dependent. Whereas trialkylamines catalyze the expected 1,4-adition of the alcohol on the alkynoate to give the β-alkoxyacrylate derivative, the trialkylphosphine-catalyzed reaction affords densely functionalized bicyclic hexahydrofuro[2,3-b]furan derivatives. A mechanistic proposal for the phosphine-catalyzed addition of alcohols to alkyl propiolates according with these observations is presented.

catalysis - amines - phosphorus - bicyclic compounds - alkynes

References and Notes

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11

We have shown that under different reaction conditions
1,3-dioxolane derivatives can be obtained regardless of the catalyst used, see reference 9a.

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13

The Et₃N in CH₂Cl₂ proved to be the best catalytic system.

14

Six different isomers were isolated with relative intensities of 0.81:0.72:0.94:1.00:0.07:0.01 and identified on the basis of their NMR spectra and the X-ray crystal structure analysis of one of the isomers.

15 For a review of formal [3+2] cycloaddition of propargylic substrates, see: Yamazaki S. Chem. Eur. J.  2008,  14:  6026 

16 This is true as long as the R^¹ substituent shown in Scheme 1 is an aliphatic group. It has been shown that activated propargylic alcohols bearing aromatic substituents isomerize to the corresponding alkenoates in the presence of tertiary amines: Sonye JP. Koide K. Org. Lett.  2006,  8:  199 ; and references cited therein

17

Unactivated propargylic alcohols behave as expected affording the corresponding product 1 (see ref. 1).

18

Experimental Details for the Et ₃ N-Catalyzed Addition of Activated Propargylic Alcohols to Methyl Propiolate: Product 2a was synthesized from 4a as described in Scheme  [³] . A cooled (0 ˚C) solution of propargylic alcohol and methyl propiolate (1.0 mmol of each) in CH₂Cl₂ (5 mL) was stirred with Et₃N (0.2 mmol) until a TLC showed complete starting material disappearance. Solvent and excess reagents were removed under reduced pressure and the product was isolated by flash column chromatography (silica gel, n-hexane-EtOAc). ^¹H NMR (400 MHz, CDCl₃): δ = 1.30 (t, J = 7.2 Hz, 3 H), 3.69 (s, 3 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.62 (s, 2 H), 5.31 (d, J = 12.5 Hz, 1 H), 7.52 (d, J = 12.5 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.9, 51.3, 57.5, 62.4, 79.3, 79.7, 98.6, 152.5, 160.2, 167.3. IR (CHCl₃): 3021.7, 2248.3, 1710.2, 1629.6, 1259.6, 1137.4 cm^-¹. Anal. Calcd for C₁₀H₁₂O₅: C, 56.60; H, 5.70. Found: C, 56.61; H, 5.65. MS: m/z (%) = 212 (21) [M⁺], 181 (86), 156 (95), 139 (70), 125 (50), 67 (95), 66 (100), 55 (69).
Experimental Details for the Bu ₃ P-Catalyzed Addition of Activated Propargylic Alcohols to Methyl Propiolate: Product 5a was synthesized from 4a as described in Scheme  [4] . A cooled (-78 ˚C) solution of propargylic alcohol and methyl propiolate (1.0 mmol of each) in CH₂Cl₂ (5 mL) was stirred with Bu₃P (0.8 mmol) for a few minutes at
-78 ˚C and allowed to react without further cooling for 1 h (lower amounts of Bu₃P slow down the reaction while higher temperatures have a negative impact on the overall yield). After the reaction was completed, solvent and excess reagents were removed under reduced pressure. Product was isolated by flash column chromatography as a mixture of two isomers (silica gel, n-hexane-EtOAc), i.e. a mixture of 2Z,2′Z (minor) and 2Z,2′E (major) isomers. Data for major isomer: ^¹H NMR (500 MHz, CDCl₃): δ = 1.25 (t, J = 6.9 Hz, 3 H), 1.27 (t, J = 6.9 Hz, 3 H), 3.75 (s, 3 H), 4.14-4.21 (m, 4 H), 4.59 (dd, J = 2.0, 15.0 Hz, 1 H), 4.67 (dd, J = 2.1, 15.0 Hz, 1 H), 5.09 (dd, J = 2.8, 16.8 Hz, 1 H), 5.18 (dd, J = 2.7, 16.8 Hz, 1 H), 5.80 (s, 1 H), 5.90 (t, J = 2.0 Hz, 1 H), 6.27 (t, J = 2.7 Hz, 1 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 14.06, 14.07, 52.9, 60.5, 61.0, 67.5, 71.6, 73.1, 113.1, 114.2, 117.5, 155.9, 156.0, 165.2, 165.8, 168.1. IR (CHCl₃): 3017.2, 1734.8, 1711.6, 1667.7, 1374.1, 1266.1, 1228.5, 1155.9
cm^-¹. Anal. Calcd for C₁₆H₂₀O₈: C, 56.47; H, 5.92. Found: C, 56.43; H, 6.03. MS: m/z (%) = 340 (6.0) [M⁺], 295 (61), 294 (100), 166 (69), 163 (55), 77 (49), 59 (38), 51 (35).