Download PDF
Synlett 2006(10): 1491-1496  
DOI: 10.1055/s-2006-941607
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Prasad Appukkuttana, Mofazzal Husaina,b,c, Rajinder K. Guptac, Virinder S. Parmarb, 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
Further Information

Publication History

Received 23 February 2006
Publication Date:
12 June 2006 (online)

    Permissions and Reprints All articles of this category

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

    References and Notes

  • 1a Hoornaert G. Bull. Soc. Chim. Belg.  1994,  103:  583 
    CrossrefGoogle Scholar
  • 1b Kaval N. Van der Eycken J. Caroen J. Dehaen W. Strohmeier GA. Kappe CO. Van der Eycken E. J. Comb. Chem.  2003,  5:  560 
    CrossrefGoogle Scholar
  • 1c Kaval N. Dehaen W. Van der Eycken E. J. Comb. Chem.  2005,  7:  90 ; and references cited therein
    CrossrefGoogle Scholar
  • 1d Jiang B. Yang C.-G. Wang J. J. Org. Chem.  2001,  66:  4865 
    CrossrefGoogle Scholar
  • 1e Heeres J. de Jonge MR. Koymans LMH. Daeyaert FFD. Vinkers M. Van Aken KJA. Arnold E. Das K. Kilonda A. Hoornaert GJ. Compernolle F. Cegla M. Azzam RA. Andries K. de Bethune M.-P. Azijn H. Pauwels R. Lewi PJ. Janssen PAJ. J. Med. Chem.  2005,  48:  1910 
    CrossrefGoogle Scholar
  • 1f Parlow JJ. Case BL. Dice TA. Fenton RL. Hayes MJ. Jones DE. Neumann WL. Wood RS. Lachance RM. Girard TJ. Nicholson NS. Clare M. Stegeman RA. Stevens AM. Stallings WC. Kurumbail RG. South MS. J. Med. Chem.  2003,  46:  4050 
    CrossrefGoogle Scholar
  • 2a Kaval N. Ermolat’ev D. Appukkuttan P. Dehaen W. Kappe CO. Van der Eycken E. J. Comb. Chem.  2005,  7:  490 
    CrossrefGoogle Scholar
  • 2b Kaval N. Dehaen W. Kappe CO. Van der Eycken E. Org. Biomol. Chem.  2004,  2:  154 
    CrossrefGoogle Scholar
  • 2c Van der Eycken E. Appukkuttan P. De Borggraeve W. Deahen W. Dallinger D. Kappe CO. J. Org. Chem.  2002,  67:  7904 
    CrossrefGoogle Scholar
  • 3 De Borggraeve WM. Rombouts FJR. Van der Eycken EV. Toppet SM. Hoornaert GJ. Tetrahedron Lett.  2001,  42:  5693 
    CrossrefGoogle Scholar
  • 4 Pawar VG. De Borggraeve WM. Maes V. Tourwe DA. Compernolle F. Hoornaert GJ. Tetrahedron Lett.  2005,  46:  1707 
    CrossrefGoogle Scholar
  • 5 De Borggraeve WM. Verbist BMP. Rombouts FJR. Pawar VG. Smets WJ. Kamoune L. Alen J. Van der Eycken EV. Compernolle F. Hoornaert GJ. Tetrahedron  2004,  60:  11597 
    CrossrefGoogle Scholar
  • 6a Stille JK. Angew. Chem.  1986,  98:  504 
    Google Scholar
  • 6b Stille JK. Simpson JH. J. Am. Chem. Soc.  1987,  109:  2138 
    Google Scholar
  • 6c Farina V. Pure Appl. Chem.  1996,  68:  73 
    Google Scholar
  • 6d Bedford RB. Hazelwood SL. Limmert ME. Albisson DA. Draper SM. Scully PN. Coles SJ. Hursthouse MB. Chem. Eur. J.  2003,  9:  3216 ; and references cited therein
    Google Scholar
  • 7 Kaval N. Bisztray K. Dehaen W. Kappe CO. Van der Eycken E. Mol. Diversity  2003,  7:  125 
    CrossrefGoogle Scholar
  • 8a Iyoda M. Miura M. Sasaki S. Kabir SMH. Kuwatani Y. Yoshida M. Tetrahedron Lett.  1997,  38:  4581 
    CrossrefGoogle Scholar
  • 8b Corsico BM. Rossi RA. Synlett  2000,  230 
    CrossrefGoogle Scholar
  • 8c Broutin P.-E. Čerňa I. Companiello M. Leroux F. Colbert F. Org. Lett.  2004,  6:  4419 
    CrossrefGoogle Scholar
  • 8d Cahiez G. Chaboche C. Mahuteau-Betzer F. Ahr M. Org. Lett.  2005,  7:  1943 
    CrossrefGoogle Scholar
  • 8e Micozzia A. Ottaviania M. Giardinaa G. Riccia A. Pizzoferratob R. Zillerb T. Compagnone D. Lo Sterzoc C. Adv. Synth. Catal.  2005,  347:  143 
    CrossrefGoogle Scholar
  • 9 Arvela RK. Leadbeater NE. Org. Lett.  2005,  7:  2101 
    CrossrefPubMedGoogle Scholar
  • 10a Chen JJ. Deshpande SV. Tetrahedron Lett.  2003,  44:  8873 
    Google Scholar
  • 10b Humphrey CE. Easson MAM. Tierney JP. Turner NJ. Org. Lett.  2003,  5:  849 
    Google Scholar
  • 10c Katritzky AR. Zhang Y. Singh SK. Steel PJ. Arkivoc  2003,  (xv):  47 
    Google Scholar
11

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.

12

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.