Palladium-catalyzed cross-coupling of benzylzinc reagents with methylthio N-heterocycles: A new coupling reaction with unusual selectivity

Synlett

Volumn , Issue 6, 2000, Pages 905-907

  Angiolelli, Mary E ^a   Casalnuovo, Albert L ^a   Selby, Thomas P ^a  

^a DUPONT COMPANY   (United States)

Author keywords

Benzylzinc reagents; Cross coupling; Heterocycles; Regioselectivity; Thioethers

Indexed keywords

HETEROCYCLIC COMPOUND; PALLADIUM; REAGENT; ZINC DERIVATIVE;

ARTICLE; CATALYSIS; CATALYST; CHEMICAL REACTION KINETICS; METAL BINDING; ORGANIC CHEMISTRY; STEREOCHEMISTRY; STRUCTURE ANALYSIS;

EID: 0034042632     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (20)

1. Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
2. Koether, G. M.; Selby, T. P.; Stevenson, T. M. PCT Int. Patent Appl. WO 99 28,301; Chem. Abstr. 1999, 131, 31951p.
3. a) Sandosham, J.; Undheim, K. Heterocycles 1994, 37(1), 501;
4. b) Gaare, K.; Repstad, T.; Benneche, T.; Undheim, K. Acta Chem. Scand. 1993, 47, 57.
5. 1H NOE experiments. 4-Benzyl-5-methyl-2-(methylthio)pyrimidines show a measurable NOE between the benzyl and 5-methyl resonances, whereas no NOE was observed between the methylthio and 5-methyl resonance in 3.
6. a) Stanforth, S. P. Tetrahedron 1998, 54, 263-303 and ref. therein;
7. b) Pridgen, L. N.; Killmer, L. B.; Webb, R. L. J. Org. Chem. 1982, 47, 1985.
8. Sulfonium salts and thioesters have been used in cross-coupling reactions with organozinc reagents. See a) Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Amer. Chem. Soc. 1997, 119, 12376;
9. b) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett. 1998, 39, 3189.
10. The zinc reagents were prepared from the benzyl bromides with activated zinc dust. The concentration of the zinc reagent was determined by quenching a sample of the reagent in 1 N HCl, and then quantifying the resulting toluene derivative by a calibrated GC procedure. See Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390.
11. -), and elemental analyses (C, H, N). Further supporting information and experimental details can be obtained by contacting the author.
12. f = 0.35). Yield 2.206 g of an orange oil (89%).
13. 2) coupling reactions with 2-(methylthio)benzothiazole were successful. The substrate scope of the nickel-catalyzed system may differ from the palladium-catalyzed system.
14. White precipitates, presumably zinc-heterocycle complexes, formed within minutes after adding the benzylzinc reagent to these substrates.
15. Nucleophilic substitution usually occurs at the 4 position in these pyrimidine type systems. For examples of both 2 and 4 substitution see a) Lee, Y. S.; Kim, Y. H. Synth. Commun. 1999, 29(9), 1503;
16. b) Gundersen, L.; Langli, G.; Rise, F. Tetrahedron Lett. 1995, 36(11), 1945;
17. c) Acevedo, O. L.; Andrews, R. S.; Dunkel, M.; Cook, P. D. J. Heterocycl. Chem. 1994, 31, 989.
18. Nucleophilic displacement of methylthio groups in pyrimidines has been observed before. See a) Robins, R. K. J. Amer. Chem. Soc. 1957, 79, 6407; and
19. b) Shadbolt, R. S.; Ulbricht, T. L. V. J. Chem. Soc. (C) 1967, 1172.
20. For example, our preliminary work suggests that aryl-and alkyzinc halides will undergo a palladium-catalyzed coupling reaction with these methythio substrates.