The Highly trans-Selective Darzens Reaction via Ammonium Ylides

Abstract

The Darzens reaction using electron deficient p-substituted benzyltriethylammonium chlorides with aromatic aldehydes afforded 2,3-diaryl epoxides with trans selectivity (> 99%) while the corresponding reaction with electron releasing p-substituted benzyltriethylammonium salts gave the epoxides as diastereomeric mixtures. Epoxide formation of p-trifluoromethylbenzylammonium salt, prepared from p-trifluoromethylbenzyl chloride and DABCO, afforded the corresponding 2,3-diaryl epoxide in high yield (>98%).

Key word

Darzens reaction - ammonium ylides - 2,3-diaryl epoxides

References

• 1a Arai S. Shioiri T. Tetrahedron Lett.  1998,  39:  2145 
• 1b Arai S. Shioiri T. Tetrahedron  2002,  58:  1407 ; and references cited therein
• 2a Li A.-H. Dai L.-X. Aggarwal VK. Chem. Rev.  1997,  97:  2341 
• 2b Aggarwal VK. Calamai S. Ford JG. J. Chem. Soc., Perkin Trans. 1  1997,  593 
• 2c Aggarwal VK. Ford JG. Fonquerna S. Adams H. Jones RVH. Fieldhouse R. J. Am. Chem. Soc.  1998,  120:  8328 
• 2d Julienne K. Metzner P. Henryon V. J. Chem. Soc., Perkin Trans. 1  1999,  731 
• 2e Aggarwal VK. Winn CL. Acc. Chem. Res.  2004,  37:  611 
• 3 Jonczyk A. Konarska A. Synlett  1999,  1085 
• 5 Quaternary ammonium salts containing methyl groups are known to promote 2,3-Stevens-type rearrangement reaction under strong basic condition. See: Marko IE. In Comprehensive Organic Synthesis   Vol. 3:  Trost B. Pergamon Press; Oxford England: 1991.  p.913 
• 8 When carbonyl compounds such as aliphatic aldehydes and ketones, other than aryl aldehydes were used under the reaction condition, no epoxides were formed and carbonyl compounds were recovered.
• 10a Dilling WL. Hickner RA. Farber HA. J. Org. Chem.  1967,  32:  3489 
• 10b Taranko LB. Perry RH. J. Org. Chem.  1969,  34:  226 

4

Typical Procedure for the Preparation of p -Substituted Benzyltriethylammonium Chlorides(1d).
A mixture of 4-chloromethyl-N,N-diethylbenzamide (2.25 g, 10 mmol) and Et₃N (5.5 mL, 40 mmol) in acetone (5 mL) was heated under reflux for 16 h. Acetone was removed in vacuo and EtOAc was added. The formed colorless solid was filtered off to afford 4-diethylcarbamyl-benzyltriethylammonium chloride (1d, 2.27 g, 6.95 mmol) in 70% yield as white solid; mp 125-127 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.11 (m, 3 H), 1.26 (m, 3 H), 1.48 (t, 9 H, J = 7.3 Hz), 3.44 (m, 2 H), 3.47 (q, 8 H, J = 7.3 Hz), 5.03 (s, 2 H), 7.45 (d, 2 H, J = 8.4 Hz), 7.7 (d, 2 H, J = 8.1 Hz). ¹³C NMR (126 MHz, CDCl₃): δ = 8.5, 12.9, 14.3, 39.4, 43.4, 53.2, 61.1, 127.3, 128.4, 133.0, 139.6, 170.0. IR (CHCl₃): ν_max = 2900, 1615, 1565, 1510 cm^-1. HRMS (FAB⁺): m/z calcd for [C₁₈H₃₁N₂O]⁺: 291.2436; found: 291.2434. Anal. Calcd for C₁₈H₃₁N₂OCl·H₂O: C, 62.7; H, 9.65; N, 8.12. Found: C, 62.55; H, 9.99; N, 8.12.

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Typical Procedure.
To an ice cooled stirred solution of 4-diethylcarbamyl benzyltriethylammonium chloride (1d, 326.8 mg, 1 mmol) and benzaldehyde (0.1 mL, 1 mmol) in THF (4 mL) was slowly added t-BuOK (224.4 mg, 2 mmol). Yellow colored suspension was stirred for 1 h at r.t. The mixture was diluted with CHCl₃ and sat. aq NH₄Cl. The mixture was separated and the aqueous layer was washed with H₂O, brine, and then dried over MgSO₄. Removal of the solvent and purification by flash chromatography (hexane-EtOAc = 1:1) afforded N,N-diethyl-4-(3-phenyloxiranyl)benzamide (2d, 264 mg, 89%) as a colorless solid; mp 83-85 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.20 (m, 6 H), 3.30 (m, 2 H), 3.54 (m, 2 H), 3.86 (d, 1 H, J = 1.83 Hz), 3.88 (d, 1 H, J = 1.83 Hz), 7.32-7.41 (m, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 13.0, 14.2, 39.3, 43.3, 62.4, 62.9, 125.6, 126.7, 128.5, 128.6, 136.9, 137.4, 138.2, 170.9. IR (CHCl₃): ν_max = 3000, 1612, 1565, 1510 cm^-1. HRMS (EI⁺): m/z calcd for C₁₉H₂₁NO₂: 295.1572; found: 295.1572. Anal. Calcd for C₁₉H₂₁NO₂: C, 77.25; H, 7.17; N, 4.74. Found: C, 77.13; H, 7.28; N, 4.71. DABCO dissolved in the aqueous layer as an ammonium ion was recovered when the aqueous layer was basified by KOH and extracted with CH₂Cl₂.

7

Quinuclidine (the second N of DABCO is replaced by CH) was also tried as an amine candidate. The ammonium salt was formed but it was too moisture sensitive to be isolated. When one-pot and successive preparation of trans-2,3-diaryl epoxide was carried out using quinuclidine, 2h was obtained in 89%. Thus, the role of the second N of DABCO is not clear to date.

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According to the literature method,¹⁰ we have tried the reaction using benzylic chloride [e.g. (p-chloromethyl)benzonitrile, p-nitrobenzyl chloride] and benzaldehyde in the presence of phase-transfer catalyst. Corresponding epoxides were obtained in 88% and 70%, respectively, as diastereomeric mixtures.