A Two-Step Synthesis of Selected 1,2,3,4-Tetrahydroquinoxaline Derivatives from N-Aryl-2-nitrosoanilines and Arylidenecyanoacetic Esters

Magdalena Królikiewicz; Kacper Błaziak; Witold Danikiewicz; Zbigniew Wróbel

doi:10.1055/s-0033-1339467

Synlett, Table of Contents

Synlett 2013; 24(15): 1945-1948
DOI: 10.1055/s-0033-1339467

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A Two-Step Synthesis of Selected 1,2,3,4-Tetrahydroquinoxaline Derivatives from N-Aryl-2-nitrosoanilines and Arylidenecyanoacetic Esters

Magdalena Królikiewicz

^aThe Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland

,

Kacper Błaziak

^bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw 42, Poland Fax: +48(22)6326681 Email: zbigniew.wrobel@icho.edu.pl

,

Witold Danikiewicz

^bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw 42, Poland Fax: +48(22)6326681 Email: zbigniew.wrobel@icho.edu.pl

,

Zbigniew Wróbel*

^bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw 42, Poland Fax: +48(22)6326681 Email: zbigniew.wrobel@icho.edu.pl

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Abstract

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Abstract

Reaction of N-aryl-2-nitrosoanilines with alkyl arylidenecyanoacetates in the presence of Et₃N in MeCN leads to substituted 1,2,3,4-tetrahydroquinoxaline derivatives in reasonable yields. The reaction comprises nucleophilic addition of the nitrosoaniline to the Michael acceptor followed by cyclization involving the nitroso group. Since the reactive nitrogen groups in N-aryl-2-nitrosoanilines are of opposite character the reaction is regioselective and additionally it was found to be diastereoselective.

Key words

Michael addition - ring closure - condensation - heterocycles - reduction

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References

References and Notes

1a For a review of recent advances in the synthesis of quinoxalines and medicinal compounds containing a quinoxaline moiety, see: Mamedov VA, Zhukova NA. Prog. Heterocycl. Chem. 2012; 24: 55
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4 Kwast A, Stachowska K, Trawczyński A, Wróbel Z. Tetrahedron Lett. 2011; 6484
5 Wróbel Z, Stachowska K, Grudzień K, Kwast A. Synlett 2011; 1439
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7 Wróbel Z, Królikiewicz M. J. Heterocycl. Chem. 2013; 50: in press
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9 Instability of similar hydroxylamines was reported: López-Cantarero J, Cid MB, Poulsen TB, Bella M, Ruano JL. G, Jørgensen KA. J. Org Chem. 2007; 72: 7062
10 General Procedure for the Synthesis of Compound 4 To a solution of N-aryl-2-nitrosoaniline 1 (1 mmol) and arylidenecyanoacetic ester 2 (1.2 mmol) in dry MeCN (10 mL) was added Et₃N (0.73 mL, 5 mmol). The mixture was stirred until the reaction was complete (TLC control, times shown in Table 1). The mixture was then evaporated to dryness, treated with AcOH (10 mL), then Zn dust (650 mg, 10 mmol) was added. The mixture was stirred for 30 min at r.t. and evaporated to dryness in vacuo. The residue was treated with EtOAc (30 mL) and aq NaHCO₃, filtered through a Celite pad, and extracted with EtOAc (3 × 20 mL). The extract was dried (Na₂SO₄), the solvent was evaporated, and the product was isolated by column chromatography (SiO₂, hexane–EtOAc).
11 Analytical Data for Representative Products Compound 3a: grey crystals; mp 132–134 °C (Et₂O–hexane). ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.95 (t, J = 7.0 Hz, 3 H), 2.20 (s, 3 H), 4.00–4.06 (m, 2 H), 5.60 (s, 1 H), 6.10 (s, 1 H), 6.84 (dd, J = 8.5, 1.1 Hz, 1 H), 7.10 (s, 5 H), 7.45 (d, J = 8.5 Hz, 1 H), 7.22–7.28 (m, 3 H), 7.33–7.40 (m, 2 H), 10.52 (s, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 13.4, 20.5, 63.0, 66.2, 70.9, 113.2, 114.2, 117.6, 118.5, 126.6, 128.1, 128.8, 129.1, 129.2, 130.2, 132.9, 133.9, 136.4, 137.4, 139.6, 162.8. Anal. Calcd for C₂₅H₂₂ClN₃O₃: C, 67.04; H, 4.95; N, 9.38. Found: C, 67.08; H, 5.03; N, 9.28. Compound 4a: white crystals; mp 185–187 °C (EtOH). ¹H NMR (500 MHz, DMSO-d ₆): δ = 1.01 (t, J = 7.0 Hz, 3 H), 2.24 (s, 3 H), 4.06–4.17 (m, 2 H), 5.25 (s, 1 H), 6.27 (d, J = 2.3 Hz, 1 H), 6.74 (dd, J = 8.5, 2.3 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 1 H), 6.89–6.92 (m, 2 H), 7.11–7.15 (m, 2 H), 7.32 (s, 5 H), 7.76 (s, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.1, 20.9, 60.2, 63.7, 64.8, 114.2, 116.2, 116.4, 119.5, 123.1, 126.3, 128.7, 128.9, 129.2, 130.6, 130.8, 133.6, 135.8, 136.9, 142.1, 165.4. MS (EI): m/z = 433 (36), 432 (29), 431 (100), 406 (13), 405 (10), 404 (35), 360 (28), 359 (23), 358 (81), 333 (21), 332 (18), 331 (58), 330 (13), 329 (30), 328 (12), 327 (54). Anal. Calcd for C₂₅H₂₂ClN₃O₂: C, 69.52; H, 5.13; N, 9.73. Found: C, 69.60; H, 5.19; N, 9.79.
12 Comesse S, Sanselme M, Daich A. J. Org. Chem. 2007; 73: 5566

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