Synlett 2007(13): 2041-2044  
DOI: 10.1055/s-2007-984891
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Regioselective Opening of Epoxides by Nucleophiles in Water under Simultaneous Ultrasound/Microwave Irradiation

Giovanni Palmisanoa, Silvia Tagliapietrab, Alessandro Bargeb, Arianna Binellob, Luisa Boffab, Giancarlo Cravotto*b
a Dipartimento di Scienze Chimiche e Ambientali, Università degli Studi dell’Insubria, Via Valleggio 11, 22100 Como, Italy
b Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Giuria 9, 10235 Torino, Italy
Fax: +39(011)6707687; e-Mail: giancarlo.cravotto@unito.it;
Further Information

Publication History

Received 14 May 2007
Publication Date:
12 July 2007 (online)

Abstract

Epoxide cleavage by nucleophiles in aqueous media may suffer from competition by water itself, yielding the diol as byproduct. However, when the reaction was carried out under high-intensity ultrasound or microwaves, attack by the nucleophile was strongly promoted and water no longer reacted. Best results were achieved under simultaneous ultrasound/microwave irradiation: a series of mono-, di- and trisubstituted oxiranes reacted rapidly with sodium azide or 1-(3-chlorophenyl)piperazine, usually leading to the corresponding more substituted alcohols in acceptable to high yields. This catalyst-free, greener protocol achieves a much faster cleavage of epoxides with a high regioselectivity.

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General Procedure
In a 50 mL two-necked round-bottomed flask (equipped with an optical-fiber thermometer for reactions under MW or combined US/MW) the epoxide (2.5 mmol), the amine (or NaN3, 2.5 mmol), and H2O (15 mL) were mixed and subjected to procedures 1-4.

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2-[4-(3-Chlorophenyl)piperazin-1-yl]-2-phenylethanol (1Aα): pale yellow oil; R f = 0.56 (CHCl3-MeOH, 19:1). IR (film): 3584, 1595, 1452, 1238, 1028, 954, 765 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.37-7.22 (m, 5 H, H-2′, -3′, -4′, -5′, -6′), 7.14 (t, J = 8.1 Hz, 1 H, H-5′′′), 6.83-6.72 (m, 3 H, H-2′′′, -4′′′, -6′′′), 4.03 (m, 1 H, H-2), 3.74 (m, 2 H, H-2, -3), 3.20 (m, 4 H, H-3′′a,b, H-5′′a,b), 2.74-2.54 (m, 4 H, H-2′′a,b, H-6′′a,b). MS (CI, isobutane): m/z = 317 [MH]+.

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2-[4-(3-Chlorophenyl)piperazin-1-yl]-1-phenylethanol (1Aβ): pale yellow oil; R f = 0.43 (CHCl3-MeOH, 19:1). IR (film): 3400, 1595, 1566, 1481, 1244, 1057, 947, 777 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.46-7.38 (m, 5 H, H-2′, -3′, -4′, -5′, -6′), 7.22 (t, J = 8.1 Hz, 1 H, H-5′′′), 6.94-6.83 (m, 2 H, H-2′′′, -4′′′, -6′′′), 4.86 (m, 1 H, H-1), 3.31 (m, 4 H, H-3′′a,b, H-5′′a,b), 2.95-2.92 (m, 2 H, H-2′′a,b), 2.70-2.56 (m, 4 H, H-2, -3, H-6′′a,b). MS (CI, isobutane): m/z = 317 [MH]+.

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2-{3-[4-(3-Chlorophenyl)piperazin-1-yl]-2-hydroxypropyl} isoindoline-1,3-dione (2Aβ): pale yellow oil; R f = 0.39 (CHCl3-MeOH, 19:1). IR (film): 3327, 1626, 1576, 1437, 1244, 893 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.87-7.81 (m, 4 H, H-3, -4, -5, -6,), 7.17 (m, 1 H, H-5′′′), 6.80-6.65 (m, 3 H, H-2′′′, -4′′′, -6′′′), 4.21 (m, 1 H, H-2′), 3.50 (m, 2 H, H-1′a,b), 2.57 (m, 2 H, H-3′a,b), 2.90-2.40 (m, 8 H, H-2′′a,b, H-3′′a,b, H-5′′a,b, H-6′′a,b). MS (CI, isobutane): m/z = 400 [MH]+.

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1-[4-(3-Chlorophenyl)piperazin-1-yl]octan-2-ol (3Aβ): pale yellow oil; R f = 0.40 (hexane-EtOAc, 7:3). IR (film): 3460, 1595, 1487, 1234, 1153, 987, 837, 769 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.10 (t, J = 8.1 Hz, 1 H, H-2′′), 6.85-6.50 (m, 3 H, H-4′′, -5′′, -6′′), 3.70 (m, 1 H, H-2), 3.10 (m, 4 H, H-3′a,b, H-5′a,b), 2.75 (m, 2 H, H-2′a,b), 2.50 (m, 2 H, H-6′a,b), 2.30 (m, 2 H, H-1a,b), 1.50-1.00 (m, 10 H, H-3a,b, H-4a,b, H-5a,b, H-6a,b, H-7a,b), 0.95 (br s, 3 H, CH3). MS (CI, isobutane): m/z = 325 [MH]+.

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trans-2-[4-(3-Chlorophenyl)piperazin-1-yl]cyclohexanol (4A): pale yellow oil; R f = 0.13 (PE-EtOAc, 8:2). IR (film): 3462, 1597, 1495, 1263, 1105, 1014, 954, 771, 681 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.02-6.77 (m, 4 H, H-2′′, -4′′, -5′′, -6′′), 4.16 (m, 1 H, H-1), 3.43 (m, 1 H, H-2), 3.23-3.19 (m, 4 H, H-3′a,b, H-5′a,b), 2.88 (m, 2 H, H-2′a,b), 2.58 (m, 2 H, H-5′a,b), 2.40-1.15 (m, 8 H, H-3,a,b, H-4a,b, H-5a,b, H-6a,b). MS (CI, isobutane): m/z = 295 [MH]+.

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(1R,2R)-2-[4-(3-Chlorophenyl)piperazin-1-yl]-1-methyl-4-(prop-1-en-2-yl)cyclohexanol (5Aβ): pale yellow oil; R f = 0.62 (hexane-EtOAc, 7:3). IR (film): 3462, 2361, 1595, 1450, 1238, 1126, 987, 767 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.17 (t, J = 8.1 Hz, 1 H, H-2′′′), 6.87 (m, 3 H, H-4, -5, -6), 4.96 (m, 1 H, H-9a), 4.87 (m, 1 H, H-9b), 3.47 (m, 1 H, H-2), 3.22 (m, 4 H, H-3′′a,b, H-5′′a,b), 2.90 (m, 2 H, H-2′′a,b), 2.68 (m, 2 H, H6′′a,b), 2.5 (br s, 1 H, OH). MS (CI, isobutane): m/z = 349 [MH]+.

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(1R,2R,4R)-2-Azido-1-methyl-4-(prop-1-en-2-yl)cyclo-hexanol (5Bβ): colorless oil; R f = 0.24 (CHCl3-MeOH, 19:1). IR (film): 3450, 2094, 1645, 1454, 1261, 1032, 891 cm-1. 1H NMR (300 MHz, CDCl3): δ = 4.8 (m, 2 H, H-9a,b), 3.55 (br s, 1 H, H-2), 2.20 (m, 1 H, H-4), 2.00 (m, 1 H, H-3a), 1.85 (m, 1 H, H-3b), 1.73 (m, 3 H, H-10, CH3), 1.45 (br s, 1 H, OH), 1.40 (m, 3 H, H-7, CH3). MS (CI, isobutane): m/z = 196 [MH]+.