A Chemoselective Microwave-Assisted One-Pot Cross-Stille Reaction of Benzylic Halides with 2(1H)-Pyrazinones Using Simultaneous Cooling

Prasad Appukkuttan; Mofazzal Husain; Rajinder K. Gupta; Virinder S. Parmar; Erik Van der Eycken

doi:10.1055/s-2006-941607

LETTER

A Chemoselective Microwave-Assisted One-Pot Cross-Stille Reaction of Benzylic Halides with 2(1H)-Pyrazinones Using Simultaneous Cooling

Prasad Appukkuttan^a, Mofazzal Husain^a,b,c, Rajinder K. Gupta^c, Virinder S. Parmar^b, Erik Van der Eycken*^a
^a Department of Chemistry, University of Leuven, Celestijnenlaan 200 F, 3001 Leuven, Belgium
Fax: +32(16)327990; e-Mail: erik.vandereycken@chem.kuleuven.be;
^b Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 100 007, India
^c School of Biotechnology, GGSIP University, Delhi 100 006, India

Abstract

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Abstract

This manuscript reports the chemoselective one-pot cross-Stille coupling of benzylic halides with 3,5-dichloro-2(1H)-pyrazinones, which avoids the purification and handling of toxic stannylated intermediates. Significant improvements in yields were established when microwave irradiation was performed with simultaneous cooling.

Key words

microwave - 2(1H)-pyrazinone - Stille - cross-coupling - simultaneous cooling

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References and Notes

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Representative Experimental Procedure Using a Dedicated Multimode Microwave Apparatus - Synthesis of 1,3-Dibenzyl-5-chloro-6-methylpyrazin-2 (1 H )-one ( 3e).
Pyrazinone 1e (0.324 g, 1.0 mmol), bromide 2a (0.205 g, 1.2 mmol, 1.2 equiv), hexabutyldistannane (0.649 g, 1.1 mmol, 1.1 equiv) and Pd(Ph₃P)₄ (0.058 g, 5 mol%) were suspended in DMF (12 mL) in a 50 mL glass vial equipped with a small magnetic stirring bar. The mixture was irradiated in the cavity of a Milestone-MYCROSYNTH multimode oven at a preselected maximum temperature of 170 °C for 10 min, using a maximum irradiation power of 120 W. The mixture was then cooled to r.t., poured into crushed ice, diluted with Et₂O and the contents were stirred at r.t. for 2 h. It was then extracted with Et₂O and dried over MgSO₄. The solvent was removed under reduced pressure and the crude residue was subjected to column chromatography (silica gel, PE-EtOAc, 3:1) as eluent to afford analytically pure product 3e (0.224 g, 69%) as a viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.17-7.35 (m, 10 H), 5.38 (s, 2 H), 4.12 (s, 2 H), 2.49 (s, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 158.2, 153.3, 136.1, 134.1, 133.9, 129.2, 129.0, 128.5, 127.2, 127.0, 126.4, 123.2, 50.2, 39.1, 16.9 ppm. MS (CI): m/z (%) = 325 (100) [MH⁺]. HRMS (EI): m/z calcd for C₁₉H₁₇N₂ClO: 324.1029; found: 324.1034.

3-Benzyl-5-chloro-1-(4-methoxybenzyl)-2(1 H )-pyrazinone ( 3a).
Mp 102-103 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.8 (s, 3 H), 4.12 (s, 2 H), 4.93 (s, 2 H), 6.9 (d, 2 H, J = 8.7 Hz), 7.01 (s, 1 H), 7.30-7.35 (m, 5 H), 7.44 (d, 2 H, J = 7.0 Hz) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 39.8, 51.8, 55.2, 114.4, 124.3, 125.7, 125.8, 126.5, 128.3, 129.3, 130.2, 136.3, 154.4, 158.8, 159.8 ppm. MS (CI): m/z (%) = 341 [MH⁺], 121 (100). HRMS (EI): m/z calcd for C₁₉H₁₇N₂ClO₂: 340.0978; found: 340.0972.
3-Benzyl-5-chloro-(3-phenylpropyl)-2(1 H )-pyrazinone ( 3b).
Mp 98-100 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.03-2.19 (m, 2 H), 2.68 (t, J = 7.35 Hz, 2 H), 3.84 (t, J = 7.35 Hz, 2 H), 4.12 (s, 2 H), 6.92 (s, 1 H, C-6H), 7.15-7.44 (m, 10 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 29.6, 32.7, 39.9, 49.8, 125.3, 125.6, 126.3, 126.7, 128.2, 128.3, 128.4, 128.6, 136.0, 139.0, 154.5, 158.9 ppm. MS (CI): m/z (%) = 339 (100) [MH⁺]. HRMS (EI): m/z calcd for C₂₀H₁₉N₂ClO: 338.1185; found: 338.1194.
3-Benzyl-5-chloro-1-cyclohexylmethyl-2(1 H )-pyrazinone ( 3c). Mp 107-108 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.13-1.90 (m, 11 H), 3.78 (d, J = 7.41 Hz, 2 H), 4.10 (s, 2 H), 7.21 (s, 1 H), 7.12-7.18 (m, 3 H), 7.32 (d, J = 7.32 Hz, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 25.5, 26.1, 30.6, 36.8, 40.2, 57.4, 122.4, 126.2, 126.7, 128.4, 129.3, 136.5, 154.1, 158.7 ppm. MS (CI): m/z (%) = 317 (100) [MH⁺]. HRMS (EI): m/z calcd for C₁₈H₂₁N₂ClO: 316.1342; found: 316.1344.
3-Benzyl-5-chloro-1-cyclohexyl-2(1 H )-pyrazinone ( 3d).
Mp 139-140 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.37-1.91 (m, 10 H), 4.10 (s, 2 H), 4.68-4.76 (m, 1 H), 7.12 (s, 1 H), 7.18-7.30 (m, 3 H), 7.41 (d, J = 7.32 Hz, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 25.2, 25.6, 30.0, 40.3, 55.5, 121.8, 126.2, 126.7, 128.5, 129.6, 136.7, 154.2, 158.6 ppm. MS (CI): m/z 303 (100) [MH⁺]. HRMS (EI): m/z calcd for C₁₇H₁₉N₂ClO: 302.1185; found: 302.1184.
3-Benzyl-5-chloro-1,6-diphenyl-2(1 H )-pyrazinone ( 3f).
Mp 180-181 °C. ¹H NMR (300 MHz, CDCl₃): δ = 4.12 (s, 2 H), 6.96-7.84 (m, 15 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 40.2, 125.6, 126.87, 128.2, 128.2, 28.6, 128.7, 129.0, 129.1, 129.8, 130.0, 130.7, 131.2, 136.7, 137.2, 155.5, 158.3 ppm. MS (CI): m/z (%) = 373 (100) [MH⁺]. HRMS (EI): m/z calcd for C₂₃H₁₇N₂ClO: 372.1029; found: 372.1020.
5-Chloro-3-(4-methoxybenzyl)-1,6-diphenyl-2(1 H )-pyrazinone ( 3g).
Mp 194-195° °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.80 (s, 3 H), 4.16 (s, 2 H,), 6.89 (d, 2 H, J = 8.47 Hz), 6.96-7.29 (m, 10 H), 7.49 (d, 2 H, J = 8.29 Hz) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 39.8, 55.3, 114.0, 125.6, 128.2, 128.7, 129.0, 129.2, 130.0, 130.8, 131.3, 136.4, 137.2, 155.1, 158.3, 159.5 ppm. MS (CI): m/z (%) = 403 (100) [MH⁺]. HRMS (EI): m/z calcd for C₂₄H₁₉N₂ClO₂: 402.1135; found: 402.1142.
5-Chloro-3-(4-methoxybenzyl)-1-(3-phenylpropyl)-2(1 H )-pyrazinone ( 3h).
Mp 113-114 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.03-2.08 (m, 2 H), 2.66 (t, J = 7.32 Hz, 2 H), 3.75 (s, 3 H), 3.82 (t, J = 7.32 Hz, 2 H), 4.03 (s, 2 H), 6.83 (d, J = 8.22 Hz, 2 H), 6.99 (s, 1 H), 7.14 (d, J = 6.39 Hz, 2 H), 7.19-7.28 (m, 5 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 29.7, 32.7, 39.1, 49.8, 55.2, 113.9, 125.2, 125.7, 126.7, 128.2, 128.5, 128.6, 130.5, 140.0, 154.6, 158.5, 159.2 ppm. MS (CI): m/z = 369 (100) [MH⁺]. HRMS (EI): m/z calcd for C₂₁H₂₁N₂ClO₂: 368.1291; found: 368.1287.
5-Chloro-1-(3-phenylpropyl)-3-(3,4,5-trimethoxy-benzyl)-2(1 H )-pyrazinone ( 3i).
Mp 104-105 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.05-2.10 (m, 2 H), 2.67 (t, J = 7.44 Hz, 2 H), 3.80-3.88 (m, 11 H), 4.03 (s, 2 H), 6.67 (s, 2 H), 7.02 (s, 1 H), 7.15-7.30 (m, 5 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 29.8, 32.8, 40.1, 50.0, 56.2, 56.3, 55.4, 106.5, 125.5, 125.7, 126.5, 128.3, 128.7, 132.3, 136.8, 140.0, 153.2, 153.3, 154.7, 158.7 ppm. MS (CI): m/z (%) = 429 (100) [MH⁺]. HRMS (EI): m/z calcd for C₂₃H₂₅N₂ClO₄: 428.1502; found: 428.1499.
5-Chloro-3-(2-fluorobenzyl)-1-(3-phenylpropyl)-2(1 H )-pyrazinone ( 3j).
Mp 97-98 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.03-2.13 (m, 2 H), 2.67 (t, J = 7.40 Hz, 2 H), 3.85 (t, J = 7.47 Hz, 2 H), 4.15 (s, 2 H), 7.01 (s, 1 H), 7.02-7.31 (m, 9 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 29.8, 32.8, 33.2, 49.9, 115.6, 124.0, 125.5, 125.8, 126.5, 128.3, 128.5, 128.7, 131.5, 131.6, 140.1, 154.5, 158.7, 162.9 ppm. MS (CI): m/z (%) = 357 (100) [MH⁺]. HRMS (EI): m/z calcd for C₂₀H₁₈N₂FClO: 356.1092; found: 356.1098.
3-Allyl-5-chloro-1-(3-phenylpropyl)-2(1 H )-pyrazinone ( 3m).
Viscous oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.05-2.13 (m, 2 H), 2.22 (dd, J = 1.83, 5.49 Hz, 2 H), 2.71 (t, J = 7.34 Hz, 2 H), 3.89 (t, J = 7.30 Hz, 2 H), 6.83 (dd, J = 1.88, 14.16 Hz, 2 H), 6.99 (s, 1 H), 7.17-7.33 (m, 6 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 30.1, 31.9, 33.1, 50.2, 124.6, 124.5, 125.8, 126.8, 128.6, 129.1, 139.3, 140.5, 152.3, 154.7 ppm. MS (CI): m/z (%) = 289 (100) [MH⁺]. HRMS (EI): m/z calcd for C₁₆H₁₇N₂ClO: 288.1029; found: 288.1034. Anal. Calcd for C₁₆H₁₇N₂ClO: C, 66.55; H, 5.93; N, 9.70. Found: C, 66.60; H, 5.97; N, 9.68.