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Synlett 2015; 26(05): 656-660
DOI: 10.1055/s-0034-1379969
letter
© Georg Thieme Verlag Stuttgart · New York

Aqueous Enantioselective Aldol Reaction of Methyl- and Phenylglyoxal Organocatalyzed by N-Tosyl-(S a)-binam-l-prolinamide

Fernando J. N. Moles
Dpto. Química Orgánica and Instituto de Síntesis Orgánica, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain   Email: gabriela.guillena@ua.es   Email: cnajera@ua.es
,
Gabriela Guillena*
Dpto. Química Orgánica and Instituto de Síntesis Orgánica, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain   Email: gabriela.guillena@ua.es   Email: cnajera@ua.es
,
Carmen Nájera*
Dpto. Química Orgánica and Instituto de Síntesis Orgánica, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain   Email: gabriela.guillena@ua.es   Email: cnajera@ua.es
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Further Information

Publication History

Received: 10 November 2014

Accepted after revision: 12 December 2014

Publication Date:
20 January 2015 (online)

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Abstract

The direct aldol reaction between methylglyoxal (40% aqueous solution) or phenylglyoxal monohydrate and ketones or aldehydes is catalyzed by N-tosyl-(S a)-binam-l-prolinamide to afford the corresponding chiral γ-oxo-β-hydroxy carbonyl compounds, mainly as anti isomers with enantioselectivities up to 97%.

Key words

methylglyoxal - organocatalysis - aldol - prolinamide - aqueous conditions

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1379969.
  • Supporting Information
 

  • References and Notes

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    • 12a Moles FJ. N, Guillena G, Nájera C. RSC Adv. 2014; 4: 9963
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    • 12b Moles FJ. N, Guillena G, Nájera C, Gómez-Bengoa E. Synthesis 2014;
  • 13 Moles FJ. N, Bañón-Caballero A, Guillena G, Nájera C. Tetrahedron: Asymmetry 2014; 25: 1323
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  • 16 Stereochemistry was assigned by comparison of the optical rotation values given in the literature, in reference 5a.
  • 17 To a mixture of the methylglyoxal (40% aqueous solution, 0.25 mmol, 0.038 mL) and catalyst (10 mol%) at the indicated temperature was added the corresponding ketone (1.25 mmol). The reaction was stirred until the methylglyoxal was consumed (monitored by TLC). The resulting residue was purified by chromatography (hexanes–EtOAc) to yield the pure aldol product. During purification aldols 7d–f underwent a slight epimerization. Analytical data of compound 7b are given as a representative compound (see the Supporting Information for the rest of the compound data): (2S,1′R)-isomer; yellow oil (yield: 0.034 g, 80%); [α]26 D –29 (c = 0.5, CHCl3); Rf 0.43 (hexane–EtOAc, 7:3; revealed with KMnO4). IR: 3460.6 (OH), 1733.69 (C=O), 1703.8 (C=O), 1421.3 (MeC=O) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.87 (dd, J = 7.9, 3.0 Hz, 1 H, CHOH), 3.56 (d, J = 7.9 Hz, 1 H, OH), 3.03–3.15 (m, 1 H, Hcyclo), 2.32–2.51 (m, 2 H, Hcyclo), 2.30 (s, 3 H, Me), 2.06–2.20 (m, 2 H, Hcyclo), 1.65–2.06 (m, 4 H, Hcyclo). 13C NMR (75 MHz, CDCl3): δ = 212.3 (C), 210.0 (C), 77.9 (CH), 53.7 (CH), 42.0 (CH2), 30.3 (CH2), 26.9 (CH2), 25.7 (Me), 24.8 (CH2). HRMS: m/z [M+ + H] calcd for C9H14O3: 171.1021; found: 171.1020. To a mixture of methylglyoxal (40% aqueous solution, 0.25 mmol, 0.038 mL) and catalyst (10 mol%) at the indicated temperature was added the corresponding aldehyde (0.5 mmol). The reaction was stirred until the methylglyoxal was consumed (monitored by TLC). Ph3PCHCO2Et (0.178 g, 0.5 mmol) was added and the reaction mixture was stirred for 2 h. Upon completion, the reaction was quenched by passing the reaction mixture through a silica gel pad, and concentrated in vacuo. The resulting residue was purified by chromatography (hexanes–EtOAc) to yield the α,β-unsaturated ester. Analytical data of compound 10e are given as a representative compound (see the Supporting Information for the rest of the compound data): obtained as a diastereoisomer mixture (61:39, anti:syn); colorless oil (yield: 0.035 g, 53%); [α]26 D –12 (c = 1.2; CHCl3); Rf 0.30 (hexane–EtOAc, 70:30; revealed with KMnO4). IR: 3439.4 (OH), 1708.6 (C=O), 11692.2 (C=O), 1269.9 (MeC=O) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.88–7.98 (m, 2 H, ArH), 7.50–7.73 (m, 3 H, ArH), 7.15 (dd, J = 15.7, 7.4 Hz, 1 H, CH=CH), 5.94 (dd, J = 15.7, 1.4 Hz, 1 H, CH=CH), 5.20 (dd, J = 6.4, 2.4 Hz, 1 H, CHOH), 4.22 (q, J = 7.1 Hz, 2 H, OCH 2CH3), 3.78 (d, J = 6.4 Hz, 1 H, OH), 2.78–2.91 (m, 1 H), 1.32 (t, J = 7.1 Hz, 3 H, OCH2CH 3), 0.87 (d, J = 6.8 Hz, 3 H, CHMe).13C NMR (75 MHz, CDCl3): δ = 200.6 (C), 166.3 (C), 149.8 (CH), 134.3 (CH), 133.5 (C), 129.1 (2 × CH), 128.5 (2 × CH), 121.7 (CH), 75.0 (CH), 60.4 (CH2), 40.7 (CH), 14.3 (Me), 11.5 (Me). HRMS: m/z [M+ + Na] calcd for C15H18O4: 285.1103; found: 285.1111.
  • 18 Arylglyoxals are important reagents for the synthesis of heterocyclic compounds. See, for instance: Eftekhari-Sis B, Zirak M, Akbari A. Chem. Rev. 2013; 113: 2953
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  • 19 To a mixture of the phenylglyoxal monohydrate (0.25 mmol, 0.028 g) and catalyst (10 mol%) at the indicated temperature was added the corresponding aldehyde (0.5 mmol). The reaction was stirred until the phenylglyoxal was consumed (monitored by TLC). Ph3PCHCO2Et (0.178 g, 0.5 mmol) was added and the reaction mixture was stirred for 2 h. Upon completion, the reaction was quenched by passing the reaction mixture through a silica gel pad, and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography (hexanes–EtOAc) to yield the α,β-unsaturated ester.