Expedient Entry into 1,4-Dihydroquinoxalines and Quinoxalines via a Novel Variant of Isocyanide-Based MCR

Abstract

A novel multicomponent reaction of o-phenylenediamines with aldehydes and isonitriles yields 1,4-dihydroquinoxalines. These intermediates are unstable under reaction conditions. They undergo oxidation with DDQ to furnish 33-54% isolated yields of the respective quinoxalines. This reaction is general for aromatic 1,2-diamines. Monoalkylated aryl 1,2-diamines lead to stable 1,4-dihydroquinoxalines.

combinatorial chemistry - dehydrogenations - multicomponent reactions - isocyanides - quinoxalines

References and Notes

<A NAME="RD28507ST-1">1</A>

New address: M. Krasavin, Department of Chemistry, McGill University, Montreal, Quebec H3A 2K6, Canada.

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<A NAME="RD28507ST-10A">10a</A> One example of an aliphatic diamine participating in the intramolecular Ugi-type MCR has been reported in: Keung W. Bakir F. Patron AP. Rogers D. Priest CD. Darmohusodo V. Tetrahedron Lett.  2004,  45:  733 

<A NAME="RD28507ST-10B">10b</A> An account of the use of ethylene diamines appeared in print when the present manuscript was in preparation: Kysil V. Tkachenko S. Khvat A. Williams C. Tsirulnikov S. Churakova M. Ivachtchenko A. Tetrahedron Lett.  2007,  48:  6239 

<A NAME="RD28507ST-11A">11a</A>

One of the redundant byproducts was identified as 2-(R¹)-substituted benzimidazole, presumably formed from the oxidative cyclization of the intermediate aldimine. This observation is in accordance with our previous results, see ref. 11b. The unwanted benzimidazole formation could be minimized by thorough exclusion of air from the reaction medium.

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<A NAME="RD28507ST-12">12</A>

Analytical Data for Selected CompoundsCompound 5b: pale yellow solid, mp 156-157ºC. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.50-7.59 (m, 7 H), 7.21-7.31 (m, 5 H), 6.34 (s, 1 H, NH), 3.64 (unresolved dd, 2 H, NHCH₂), 2.93 (unresolved t, 2 H, NHCH₂CH₂), 2.37 (s, 3 H), 2.33 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 150.0, 145.7, 140.3, 140.1, 139.6, 137.3, 135.5, 133.5, 129.6, 129.2 (two signals overlapped), 128.9, 128.8, 128.2, 126.4, 125.7, 42.9, 34.7, 20.2, 19.7. LCMS: m/z = 354 [M + 1]. HRMS (EI): m/z calcd for C₂₄H₂₃N₃: 353.4710; found: 353.4711.Compound 5g: grey solid, mp 203 °C (decomp.). ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.95 (br s, 1 H, COOH), 8.33 (d, J = 1.5 Hz, 1 H), 8.04 (dd, J = 8.6, 1.8 Hz, 1 H), 7.74 (m, 2 H), 7.64 (d, J = 8.6 Hz, 1 H), 7.55 (m, 3 H), 6.61 (d, J = 6.6 Hz, 1 H, NH), 4.46 (m, 1 H, NHCH), 2.00 (m, 2 H), 1.65 (m, 2 H), 1.54 (m, 4 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 167.5 (COOH), 150.9, 148.2, 144.3, 136.7, 135.6, 130.8, 130.1, 129.8, 129.3, 128.9, 126.1, 125.8, 52.9, 32.2, 24.0. LCMS: m/z = 334 [M + 1]. HRMS (EI): m/z calcd for C₂₀H₁₉N₃O₂: 333.3933; found: 333.3932.Compound 5h: yellow sticky solid, mp 68-69 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.86 (dd, J = 3.8, 0.9 Hz, 1 H), 7.83 (dd, J = 5.1, 0.9 Hz, 1 H), 7.78 (dd, J = 8.2, 1.1 Hz, 1 H), 7.62 (dd, J = 8.4, 1.1 Hz, 1 H), 7.55 (ddd, J = 8.4, 6.8, 1.1 Hz, 1 H), 7.37 (ddd, J = 8.2, 6.8, 1.3 Hz, 1 H), 7.27 (dd, J = 5.1, 3.8 Hz, 1 H), 6.87 (t, J = 5.3 Hz, NHCH₂), 3.70 (dt, J _d = 5.3, J _t = 5.1 Hz, 2 H, NHCH₂), 3.62 (t, J = 5.1 Hz, 2 H, MeOCH₂), 3.31 (s, 3 H, OCH₃). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 149.4, 140.9, 140.8, 140.0, 136.4, 130.3, 130.0, 128.7, 128.4, 128.2, 125.9, 124.8, 70.3, 58.4, 40.7. LCMS: m/z = 286 [M + 1]. HRMS (EI): m/z calcd for C₁₅H₁₅N₃OS: 285.3703; found: 285.3703.

<A NAME="RD28507ST-13">13</A>

Crystallographic data (excluding structure factors) for the structure 5b have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 671798. Copies of the data can be obtained free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

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<A NAME="RD28507ST-16">16</A>

Characterization Data for 8Brown oil. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.79 (dd, J = 5.1, 1.8 Hz, 1 H), 8.50 (d, J = 7.3 Hz, 1 H), 7.73 (br s, 1 H, NH), 7.64 (m, 2 H), 7.53-7.59 (m, 4 H), 7.28-7.35 (m, 4 H), 7.22 (m, 1 H), 3.72 (dd, J = 14.2, 7.2 Hz, 2 H, NHCH₂CH₂), 2.98 (t, J = 7.2 Hz, 2 H, NHCH₂CH₂). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 158.4, 151.6, 147.0, 142.1, 136.7, 135.0, 134.9, 133.6, 130.1, 129.6, 128.5, 127.9, 127.2, 126.4, 125.8, 43.6, 35.2. LCMS: m/z = 327 [M + 1]. HRMS (EI): m/z calcd for C₂₁H₁₈N₄: 326.4044; found: 326.4047.

<A NAME="RD28507ST-17">17</A>

Characterization Data for 10Off-white solid, mp 110-112 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.24 (m, 3 H), 7.15 (m, 2 H), 6.86 (m, 1 H), 6.83 (m, 1 H), 6.72 (ddd, J = 7.6, 7.5, 1.6 Hz, 1 H), 6.53 (dd, J = 7.5, 1.6 Hz, 1 H), 5.47 (s, 1 H, dihydroquinaxoline-NH), 4.24 (br s, 1 H, NH-cycloC ₇H₁₃), 3.52 (s, 3 H, NCH₃), 3.48 (m, 1 H, NHCH), 1.72-1.82 (m, 2 H), 1.44-1.67 (m, 8 H), 1.18-1.35 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 149.8, 140.5, 132.1, 132.0, 128.8, 127.7, 126.4, 120.3, 119.9, 114.5, 113.0, 58.7, 53.4, 37.2, 36.6, 30.6, 28.3, 28.1, 24.7, 24.5. LCMS: m/z = 334 [M + 1]. HRMS (EI): m/z calcd for C₂₂H₂₇N₃: 333.4806; found: 333.4803.

<A NAME="RD28507ST-18">18</A>

Characterization Data for 12Brown viscous oil. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.33 (dd, J = 4.9, 1.3 Hz, 1 H), 7.89 (dd, J = 7.6, 1.3 Hz, 1 H), 7.56 (m, 2 H), 7.51 (m, 3 H), 7.07 (dd, J = 4.9, 7.6 Hz, 1 H), 4.55 (t, J = 6.3 Hz, 2 H, MeOCH₂), 3.65 (t, J = 6.3 Hz, 2 H, NHCH₂), 3.30 (s, 3 H, OCH₃), 3.24 (m, 1 H, NHCH), 1.44 (m, 2 H), 1.30-1.40 (m, 6 H), 1.21 (m, 2 H), 0.95 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 154.2, 149.0, 146.1, 139.8, 139.5, 136.1, 130.0, 129.0, 127.4, 117.1, 114.2, 68.3, 58.4, 58.0 (one signal obscured by DMSO sept). LCMS: m/z = 379 [M + 1]. HRMS (EI): m/z calcd for C₂₃H₃₀N₄O: 378.5218; found: 378.5221.

<A NAME="RD28507ST-19">19</A> Kajiki T. Moriya H. Hoshino K. Kuroi T. Kondo S. Nabeshima T. Yano Y. J. Org. Chem.  1999,  61:  9679 

<A NAME="RD28507ST-20">20</A> Linden AA. Johansson M. Hermanns N. Bäckvall J.-E. J. Org. Chem.  2006,  71:  3849