One-pot two-step synthesis of 2,5-dihydro-2-oxofuran-3-carboxamides

Gayane Tokmajyan 1  and Lusine Karapetyan 1
  • 1 Yerevan State University, Alex Manoogian 1, 0025, Yerevan, Armenia
Gayane Tokmajyan and Lusine Karapetyan

Abstract

2,5-Dihydro-2-oxofuran-3-carboxamides were synthesized by a one-pot two-step reaction catalyzed by sodium methoxide. Readily available tertiary α-hydroxyketones were condensed with substituted cyanoacetamides to give 2-imino-2,5-dihydrofuran-3-carboxamides that, without isolation, were hydrolized to the title products.

Introduction

2,5-Dihydro-2-oxofuran derivatives are a large family of heterocycles that include synthetically useful compounds, several natural products [1–14], and a number of drugs with diverse biological activities such as antifungal, antibacterial, and anti-inflammatory properties [15–19]. There has been a continuous interest in the development of efficient and convenient methods for the preparation of these heterocycles [10–14, 20–22]. In an extension of our synthetic studies on 2,5-dihydro-2-oxofurans, here we report a convenient and efficient synthesis of the title compounds starting from readily available tertiary α-hydroxyketones 1a,b (Scheme 1).

Scheme 1
Scheme 1

Citation: Heterocyclic Communications 20, 2; 10.1515/hc-2014-0023

The condensation of α-hydroxyketones 1a,b with cyanoacetamides 2a–d in the presence of a catalytic amount of sodium methoxide afforded 2-imino-2,5-dihydrofuran-3-carboxamides 3a–f that, without isolation, were hydrolized to 2,5-dihydro-2-oxofuran-3-carboxamides 4a–f in good yields. The products 4a–f are unsubstituted or substituted at the carboxamide nitrogen atom.

Several syntheses of 2,5-dihydro-2-oxofuran-3-carboxamides have been reported in the literature [23–30]. These authors have previously synthesized compounds 4a–f by related reactions [24–29]. The key step in the current synthesis is the preparation of 2,5-dihydro-2-oxofuran-3-carboxamides 4a–f by Knoevenagel condensation of compounds 1a,b with 2a–d. After hydrolysis of the resultant product 3a–f, without isolation, the overall yield of this one-pot two-step synthesis is 74–79%. This method is simpler and more convenient than the methods described earlier.

Experimental

General procedure for 4a–f

A mixture of an α-hydroxyketone 1a,b (10 mmol), a cyanoacetamide 2a–d (10 mmol), and sodium methoxide (1 mmol) in absolute methanol (15 mL) was heated at 35–40°C for 5 h. After concentration, the residue was acidified with (1:1) aqueous HCl to pH 1–2 and kept at room temperature for 24 h. The solution was extracted with ethyl ether (3 × 20 mL), and the combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated. The product 4a–f was crystallized as indicated below.

4,5,5-Trimethyl-2,5-dihydro-2-oxofuran-3-carboxamide (4a)

Yield 77%; mp 125–126°C (from petroleum ether), Refs. [23, 24] mp 125–126°C.

N-Methyl-(4,5,5-trimethyl-2,5-dihydro-2-oxofuran)-3-carboxamide (4b)

Yield 79%; mp 65–66°C (from petroleum ether), Refs. [23, 24] mp 65–66°C.

N-Benzyl-(4,5,5-trimethyl-2,5-dihydro-2-oxofuran)-3-carboxamide (4c)

Yield 76%; mp 84–85.5°C (from petroleum ether), Ref. [23] mp 86–88°C (from petroleum ether), Ref. [24] mp 84–85°C, Ref. [30] mp 83–84°C.

N-Phenyl-(4,5,5-trimethyl-2,5-dihydro-2-oxofuran)-3-carboxamide (4d)

Yield 75%; mp 97–98°C (from petroleum ether), Ref. [23] mp 96.5–98°C.

4-Methyl-5,5-pentamethylene-2,5-dihydro-2-oxofuran-3-carboxamide (4e)

Yield 79%; mp 161–163°C (from octane), Ref. [23] mp 161–162.5°C.

N-Methyl-(4-methyl-5,5-pentamethylene-2,5-dihydro-2-oxofuran)-3-carboxamide (4f)

Yield 79%; mp 108–109°C (from octane), Ref. [23] mp 108–109°C.

References

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    • Crossref
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    Bellina, F.; Rossi, R. Mucochloric and mucobromic acids: inexpensive, highly functionalized starting materials for the selective synthesis of variously substituted 2(5H)-furanone derivatives, sulfur- or nitrogen-containing heterocycles and stereodefined acyclic unsaturated dihalogenated compounds. Curr. Org. Chem. 2004, 8, 1089–1103.

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    Avetissyan, A. A.; Karapetyan, L. V. The synthesis of new 2-iminoderivatives of 2,5-dihydrofurans and their chemical transformations. Synth. Commun.2009, 39, 7–19.

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    Avetisyan, A. A.; Karapetyan, L. V.; Tadevosyan, M. D. Synthesis of 2-imino-4-vinyl-2,5-dihydrofuran-3-carboxamides and some their chemical transformations. Russ. J. Org. Chem.2009, 45, 1031–1035.

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    Avetisyan, A. A.; Karapetyan, L. V. Synthesis and chemical transformations of N-cyclohexyl-2-imino-4-methyl-5,5-pentamethylene-2,5-dihydrofuran-3-carboxamide. Russ. J. Org. Chem.2009, 45, 1578–1580.

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    Avetisyan, A. A.; Karapetyan, L. V. Synthesis of new heterocyclic derivatives of 2-imino-2,5-dihydrofurans and some of their chemical transformations. Chem. Heterocycl. Compd.2010, 46, 15–19.

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    Avetisyan, A. A.; Karapetyan, L. V.; Tadevosyan, M. D. Synthesis and chemical transformations of novel functionalized 2-imino-2,5-dihydrofurans. Russ. Chem. Bull. 2010, 59, 974–976.

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    Avetisyan, A. A.; Karapetyan, L. V. Synthesis and chemical transformations of bis-2-imino-2,5-dihydrofurans. Chem. Heterocycl. Compd.2013, 48, 1613–1620.

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    Cheikh, N.; Bar, N.; Choukchou-Braham, N.; Mostefa-Kara, B.; Lohier, J. F.; Sopkova, J.; Villemin, D. Efficient synthesis of new butenolides by subsequent reactions: application for the synthesis of original iminolactones, bis-iminolactones and bis-lactones. Tetrahedron2011, 67, 1540–1551.

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  • [1]

    Ortega, J. J.; Zubia, E.; Ocana, J. M.; Naranjo, S.; Salva, J. New rubrolides from the Ascidian Synoicum blochmanni. Tetrahedron2000, 56, 3963–3967.

  • [2]

    Surivet, J. P.; Vatele, J. M. Concise total synthesis of (+)-goniofufurone and goniobutenolides A and B. Tetrahedron Lett. 1996, 37, 4373–4376.

  • [3]

    Jung, J. H.; Pummangura, S.; Chaichantipyuth, S.; Patarapanich, C.; Fanwick, P. E.; Chang, C. J.; McLaughlin, J. L. New bioactive heptenes from Melodorum fruticosum (Annonaceae). Tetrahedron1990, 46, 5043–5054.

  • [4]

    Dawidson, B. S.; Ireland, C. M. Lissoclinolide, the first non-nitrogenous metabolite from a Lissoclinum tunicate. J. Nat. Prod.1990, 53, 1036–1038.

  • [5]

    Miao, S.; Andersen, R. J.; Rubrolides, A.-H. Metabolites of the colonial tunicate Ritterellarubra. J. Org. Chem.1991, 56, 6275–6280.

  • [6]

    Bohlmann, F.; Brindopke, G.; Rastogi, R. Hirsutinolides and other sesquiterpene lactones from Vernonia species. Phytochemistry1982, 21, 695–699.

  • [7]

    Avetisyan, A. A.; Dangyan, M. T. Chemistry of α,β-butenolides. Usp. Khim.1977, 46, 1250–1278.

  • [8]

    Avetisyan, A. A.; Tokmadzhyan, G. G. Chemistry of Δβ,γ - butenolides. Khim. Geterotsikl. Soedin.1987, 6, 723–739.

  • [9]

    Avetisyan, A. A.; Tokmajyan, G. G. Biologically active derivatives of 2-buten- and 3-buten-4-olides. Chem. J. Arm.1993, 46, 219–236.

  • [10]

    Marshallin, P. G. In Chemistry of Carbon Compounds; Rodd, E. H., Ed. Elsevier: New York, 1970; Vol. IID, chapter 17.

  • [11]

    Siddall, J. B. US Patent 1972, 3700694. Chem. Abstr.1973, 78, 43254.

  • [12]

    Payne, G. B. US Patent 1965, 3177227. Chem. Abstr.1965, 63, 6866e.

    • Crossref
  • [13]

    Laduwahetty, T. Saturated and unsaturated lactones. Contemp. Org. Synth. 1995, 2, 133–149.

  • [14]

    Collins, I. Saturated and unsaturated lactones. Contemp. Org. Synth. 1996, 3, 295–321.

  • [15]

    Larock, R. C.; Reifling, B. Mercury in organic chemistry. 12. Synthesis of.beta.-chloro-DELTA..alpha.,.beta.-butenolides via mercuration-carbonylation of propargylic alcohols. J. Org. Chem.1978, 43, 131–137 (and references therein).

  • [16]

    Caine, D.; Stephen, F.; Uckachukawa, V. C. Synthesis of (.+-.)-umbelactone. J. Org. Chem.1983, 48, 740–741.

  • [17]

    Desmond, R.; Dolling, U.; Marcune, B.; Tillyer, R.; Tschaen, D. World Patent 1996, WO96/08482. Chem. Abstr.1996, 25, P86474.

  • [18]

    Rao, Y. S. Chemistry of butenolides. Chem. Rev. 1964, 64, 353–388.

  • [19]

    Rao, Y. S. Recent advances in the chemistry of unsaturated lactones. Chem. Rev. 1976, 76, 625–694.

  • [20]

    Garzelli, R.; Samaritani, S.; Malanga, C. 2,5-Dimethoxy-2,5-dihydrofuran chemistry: a new approach to 2(5H)-furanone derivatives. Tetrahedron2008, 64, 4183–4186 (and references therein).

    • Crossref
  • [21]

    De Souza, M. V. N. The furan-2(5H)-ones: recent synthetic methodologies and its application in total synthesis of natural products. Mini-Rev. Org. Chem. 2005, 2, 139–145 (and references therein).

    • Crossref
  • [22]

    Bellina, F.; Rossi, R. Mucochloric and mucobromic acids: inexpensive, highly functionalized starting materials for the selective synthesis of variously substituted 2(5H)-furanone derivatives, sulfur- or nitrogen-containing heterocycles and stereodefined acyclic unsaturated dihalogenated compounds. Curr. Org. Chem. 2004, 8, 1089–1103.

  • [23]

    Avetisyan, A. A.; Tatevosyan, G. E.; Dangyan, M. T. Investigations in the field of unsaturated lactones. The reaction of 3-carbethoxy-4-methyl-5,5-dialkyl-Δ3-butenolides with amines. Arm. Chem. J.1971, 24, 688–693.

  • [24]

    Avetissyan, A. A.; Karapetyan, L. V. The synthesis of new 2-iminoderivatives of 2,5-dihydrofurans and their chemical transformations. Synth. Commun.2009, 39, 7–19.

  • [25]

    Avetisyan, A. A.; Karapetyan, L. V.; Tadevosyan, M. D. Synthesis of 2-imino-4-vinyl-2,5-dihydrofuran-3-carboxamides and some their chemical transformations. Russ. J. Org. Chem.2009, 45, 1031–1035.

  • [26]

    Avetisyan, A. A.; Karapetyan, L. V. Synthesis and chemical transformations of N-cyclohexyl-2-imino-4-methyl-5,5-pentamethylene-2,5-dihydrofuran-3-carboxamide. Russ. J. Org. Chem.2009, 45, 1578–1580.

  • [27]

    Avetisyan, A. A.; Karapetyan, L. V. Synthesis of new heterocyclic derivatives of 2-imino-2,5-dihydrofurans and some of their chemical transformations. Chem. Heterocycl. Compd.2010, 46, 15–19.

  • [28]

    Avetisyan, A. A.; Karapetyan, L. V.; Tadevosyan, M. D. Synthesis and chemical transformations of novel functionalized 2-imino-2,5-dihydrofurans. Russ. Chem. Bull. 2010, 59, 974–976.

  • [29]

    Avetisyan, A. A.; Karapetyan, L. V. Synthesis and chemical transformations of bis-2-imino-2,5-dihydrofurans. Chem. Heterocycl. Compd.2013, 48, 1613–1620.

  • [30]

    Cheikh, N.; Bar, N.; Choukchou-Braham, N.; Mostefa-Kara, B.; Lohier, J. F.; Sopkova, J.; Villemin, D. Efficient synthesis of new butenolides by subsequent reactions: application for the synthesis of original iminolactones, bis-iminolactones and bis-lactones. Tetrahedron2011, 67, 1540–1551.

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