1114
M. Zhao et al. / Tetrahedron 62 (2006) 1110–1115
3.1.7. 4-Benzyl-piperazine-1-carboxylic acid methyl-
amide (23). Phenyl chloroformate (2.59 kg) was added to
a mixture of aqueous K2CO3 (4.56 kg in 6.0 L water),
acetonitrile (12 L) and methylamine (40 wt% in water,
1.40 kg) as rapidly as possible while maintaining the
exothermic reaction at 0–15 8C. After stirring for 15 min,
1-benzyl-piperazine (2.65 kg) was added and the mixture
was heated to 70 8C and stirred for 1 h. The reaction mixture
was concentrated under vacuum to remove the MeCN.
NaOH (5 N, 7.5 L) was added and the mixture was seeded
and then cooled to rt to crystallize the product. It was filtered
and washed with cold 0.5 N aqueous NaOH, ice-cold water
and dried to give 3.59 kg of the dihydrate of 23, 87% yield.
Mp 99–100 8C; 1H NMR (DMSO-d6) d 7.32–7.24 (m, 5H),
6.37 (q, JZ4.4 Hz, 1H), 3.45 (s, 2H), 3.25 (t, JZ4.9 Hz,
4H), 2.55 (d, JZ4.4 Hz, 3H), 2.82 (t, JZ4.9 Hz, 4H); 13C
NMR (DMSO-d6) d 158.4, 138.4, 129.3, 128.6, 127.4, 62.5,
52.9, 43.8, 27.5. Anal. Calcd for C13H19N3O: C, 66.92; H,
8.21; N, 18.01. Found: C, 66.93; H, 8.14; N, 18.17.
Acknowledgements
We thank Robert Reamer for NMR assistance.
References and notes
1. (a) Bilodeau, M. T.; Fraley, M. E.; Hartman, G. D. Expert Opin.
Investig. Drugs 2002, 11, 737–745. (b) Sepp-Lorenzino, L.;
Thomas, K. A. Expert Opin. Investig. Drugs 2002, 11,
1447–1465.
2. Bilodeau, M. T.; Balitza, A. E.; Koester, T. J.; Manley, P. J.;
Rodman, L. D.; Buser-Doepner, C.; Coll, K. E.; Fernandes, C.;
Gibbs, J. B.; Heimbrook, D. C.; Huckle, W. R.; Kohl, N.;
Lynch, J. J.; Mao, X.; McFall, R. C.; McLoughlin, D.;
Miller-Stein, C. M.; Rickert, K. W.; Sepp-Lorenzino, L.;
Shipman, J. M.; Subramanian, R.; Thomas, K. A.;
Wong, B. K.; Yu, S.; Hartman, G. D. J. Med. Chem. 2004, 47,
6363–6372.
3. (a) Plazzi, P. V.; Bordi, F.; Silva, C.; Morini, G.; Catellani, P. L.;
Vaona, G.; Impicciatore, M. Farmaco 1989, 44, 1011–1030. (b)
Borthwick, A. D.; Foxton, M. W.; Gray, B. V.; Gregory, G. I.;
Seala, P. W.; Warburton, W. K. J. Chem. Soc., Perkin Trans. 1
1973, 2769–2772. (c) Francisco, G. D.; Li, Z.; Albright, J. D.;
Eudy, N. H.; Katz, A. H.; Petersen, P. J.; Labthavikul, P.;
Singh, G.; Yang, Y.; Rasmussen, B. A.; Lin, Y.-I.;Mansour, T. S.
Bioorg. Med. Chem. Lett. 2004, 14, 235–238.
3.1.8. Piperazine-1-carboxylic acid methylamide hydro-
chloride (9$HCl). HCl (12 N, 74 mL) was added to MeOH
(7 L) and then N-benzylpiperizine 23 dihydrate (2.69 kg,
10.0 mol) was added. The mixture was hydrogenated using
5% Pd/C (180 g) under 40 psi of hydrogen pressure at 40 8C
for 18 h. The mixture was filtered and concentrated. i-PrOH
(5 L) was added followed by HCl (12 N aqueous, 0.77 L)
until the pH of the solution reached w3. The mixture was
then concentrated under vacuum and flushed with more
i-PrOH until the water content was !1%. After stirring at
15 8C for 5 h, the crystallized product was filtered, washed
with i-PrOH and dried to give 1.53 kg of 9$HCl in 95%
yield. Mp 185.5–187.0 8C; 1H NMR (DMSO-d6) d 9.51 (br
s, 2H), 6.79 (q, JZ4.3 Hz, 1H), 3.53 (t, JZ5.2 Hz, 4H),
2.98 (t, JZ5.2 Hz, 4H), 2.55 (d, JZ4.3 Hz, 3H); 13C NMR
(DMSO-d6) d 157.6, 42.4, 40.4, 27.1. Anal. Calcd for
C6H14ClN3O: C, 40.11; H, 7.85; N, 23.39; Cl, 19.73. Found:
C, 39.99; H, 7.73; N, 23.22; Cl, 19.91.
4. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046. (c) Hartwig, J. F. Acc. Chem.
Res. 1998, 31, 852. (d) Yang, B. H.; Buchwald, S. L.
J. Organomet. Chem. 1999, 576, 125. (e) Muci, A. R.;
Buchwald, S. L. In Miyaura, N., Ed.; Topics in Current
Chemistry; Springer: Berlin, 2002; Vol. 219, p 133.
5. (a) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240.
(b) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin
Trans. 1 1999, 1505. (c) Khan, M. M.; Ali, H.; van Lier, J. E.
Tetrahedron Lett. 2001, 42, 1615. (d) Yang, J.-S.; Lin, Y.-H.;
Yang, C.-S. Org. Lett. 2002, 4, 777. (e) Ogawa, K.; Radke, K. R.;
Rothstein, S. D.; Rasmussen, S. C. J. Org. Chem. 2001, 66, 9067.
For an example of Ni- or Cu-catalyzed couplings between a
protected 5-iodouracil and heteroarylamines, see: (f) Arterburn,
J. B.; Pannala, M.; Gonzalez, A. M. Tetrahedron Lett. 2001, 42,
1475.
3.1.9.
4-[2-(2-Cyano-thiazol-5-ylamino)-pyridin-4-
ylmethyl]-piperazine-1-carboxylic acid methylamide
(1). NaBH(OAc)3 (2.54 kg, 12.0 mol) was added in six
portions (0.5 h/portion) to a mixture of pyridine aldehyde 10
(2.44 kg, 94.5 wt%, 10.0 mol), piperazine urea 9$HCl salt
(1.99 kg, 11.0 mol), DMAc (15 L), Et3N (1.53 L, 11.0 mol)
and acetic acid (2.29 L, 40.0 mol) with slight cooling
(15 8C). After stirring for 1 h, water (7.5 L) was slowly
added to complete the crystallization. The product was
filtered, washed sequentially with 2:1 DMAc/water, 1:1
acetone/water, and acetone, dried at 100 8C to give 3.07 kg
of 1 in 85% yield. Mp 248–249.5 8C; 1H NMR (DMSO-d6) d
12.16 (s, 1H), 8.30 (d, JZ5.3 Hz, 1H), 8.24 (s, 1H), 7.12 (s,
1H), 7.01 (dd, JZ5.3, 0.9 Hz, 1H), 6.40 (q, JZ4.4 Hz, 1H),
3.50 (s, 2H), 3.28 (t, JZ4.7 Hz, 4H), 2.55 (d, JZ4.3 Hz,
3H), 2.33 (t, JZ4.7 Hz, 4H); 13C NMR (DMSO-d6) d 163.1,
157.9, 150.4, 150.2, 145.9, 117.7, 114.2, 110.6, 94.6, 60.6,
52.5, 43.3, 27.1; IR (KBr, cmK1): 2209, 1622, 1552, 1446,
1265, 1147, 1007, 882, 786. Anal. Calcd for C16H19N7OS:
C, 53.76; H, 5.36; N, 27.43; S, 8.97. Found: C, 53.63; H,
5.27; N, 27.41; S, 8.79.
`
6. (a) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.;
ˇ
Dommisse, R. Tetrahedron 2001, 57, 7027. (b) Kosmrlj, J.;
`
Maes, B. U. W.; Lemiere, G. L. F.; Haemers, A. Synlett 2000,
1581.
7. Kim, K. S.;Kimball, D.;Cai, Z. -w.;Rawlins,D. B.;Misra, R. N.;
Poss, M. A.;Webster, K. R.;Hunt, J. T.;Ham, W.-C., U.S. Patent
6,262,096, 2001.
8. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.
J. Org. Chem. 2000, 65, 1158.
9. XantphosZ4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
The reason for the success of Xantphos is not clear, but it may
be related to its trans-chelation configuration to the Pd. See
Ref. 9g. For other examples where the use of Xantphos
provides the best results, see Ref. 9e–j. (a) Kranenburg, M.;
van der Burgt, Y. E. M.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081.
For previous examples using Xantphos in Pd-catalyzed C–N