I. Akritopoulou-Zanze et al. / Tetrahedron Letters 50 (2009) 5773–5776
5775
Table 2
Two-step sequential Ugi/Inverse electron demand Diels–Alder reactions
Aldehyde
Amine
Isocyanide
N+ C-
Acid
Ugi Yielda (%) Diels–Alder product
Diels–Alder yieldb (%)
O
O
NH2
N
N
N
H
OH
25c
1
50
N
H
N
N
O
O
O
O
N
N+
C-
NH2
N
O
OH
H
2
32
43
N
N
H
N
N
N
O
N
O
O
N
N+
C-
NH2
O
N
OH
H
3
76
46
N
H
N
N
N
N
O
N
a
b
c
Isolated yield of the Ugi step carried out in MeOH, rt, 4–24 h.
Isolated yield of the Diels–Alder step carried out in chlorobenzene, 220 °C, MW, 3 h.
Chlorobenzene, 130 °C, 48 h.
Lett. 2004, 45, 8439; (d) Gracias, V.; Gasiecki, A. F.; Moore, J. D.; Akritopoulou-
Zanze, I.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8977; (e) Akritopoulou-Zanze, I.;
Whitehead, A.; Waters, J. E.; Henry, R. F.; Djuric, S. W. Org. Lett. 2007, 9, 1299; (f)
Akritopoulou-Zanze, I.; Whitehead, A.; Waters, J. E.; Henry, R. F.; Djuric, S. W.
Tetrahedron Lett. 2007, 48, 3549; (g) Ribelin, T. P.; Judd, A. S.; Akritopoulou-Zanze,
I.; Henry, R. F.; Cross, J. L.; Whittern, D. N.; Djuric, S. W. Org. Lett. 2007, 9, 5119.
the corresponding pyrazines and pyrimidines. Lower temperatures
and shorter periods of time resulted only in partial conversions.
2. Conclusions
4. (a) Broughton, H. B.; Watson, I. A. J. Mol. Graphics Modell. 2005, 23, 51; (b) Ertl,
P.; Jelfs, S.; Mühlbacher, J.; Schuffenhauer, A.; Selzer, P. J. Med. Chem. 2006, 49,
4568.
5. (a) Boger, D. L. Tetrahedron 1983, 39, 2869; (b) Boger, D. L. Chem. Rev. 1986, 86,
781; (c) Boger, D. L. J. Heterocycl. Chem. 1998, 35, 1003; (d) Lahue, B. R.; Lo,
S. -M.; Wan, Z.-K.; Woo, G. H. C.; Snyder, J. K. J. Org. Chem. 2004, 69, 7171. and
references therein.
In conclusion, we have developed a multicomponent / inverse
electron demand Diels–Alder reaction sequence,12 that provided
access to fused pyrrolidino-pyridines, pyrrolidino-pyrazines, pyrr-
olidino-pyrimidines and azepinone pyridines. In the case of pyrr-
olidino-pyridines the transformation afforded
a convenient
6. Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851.
approach to access all four regioisomers in a one-pot procedure.
7. (a) Lee, D.; Sello, J. K.; Schreiber, S. L. Org. Lett. 2000, 2, 709; (b) Wright, D. L.;
Robotham, C. V.; Aboud, K. Tetrahedron Lett. 2002, 43, 943; (c) Sello, J. K.;
Andreana, P. R.; Lee, D.; Schreiber, S. L. Org. Lett. 2003, 5, 4125; (d) Paulvannan,
K. J. Org. Chem. 2004, 69, 1207; (e) Oikawa, M.; Ikoma, M.; Sasaki, M.
Tetrahedron Lett. 2005, 46, 415; (f) Oikawa, M.; Ikoma, M.; Sasaki, M.
Tetrahedron Lett. 2005, 46, 5863; (g) Lu, K.; Luo, T.; Xiang, Z.; You, Z.; Fathi,
R.; Chen, J.; Yang, Z. J. Comb. Chem. 2005, 7, 958; (h) Ilyin, A.; Kysil, V.; Krasavin,
M.; Kusashvili, I.; Ivachtchenko, A. V. J. Org. Chem. 2006, 71, 9544; (i) Fayol, A.;
González-Zamora, E.; Bois-Choussy, M.; Zhu, J. Heterocycles 2007, 73, 729; (j)
Ikoma, M.; Oikawa, M.; Sasaki, M. Eur. J. Org. Chem. 2009, 72.
Acknowledgements
The authors thank Dr. Zhenmin He and co-workers at WuXi
AppTec Co., Ltd for support with triazine building block synthesis,
and the High Throughput Purification and Structural Chemistry
groups at Abbott for support with compound purification and
structural analysis, respectively.
8. Triazine carboxylic acids were isolated as the potassium salts from the
corresponding esters (Schemes 1 and 2) upon treatment with KOH in MeOH.
Prior to the Ugi reactions the salts were dissolved in MeOH, acidified with
1 equiv of 4 N HCl in dioxane and used as methanolic solutions for the Ugi step.
References and notes
EtO
O
O
1. (a) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Dömling, A.
Curr. Opin. Chem. Biol. 2002, 6, 306; (c) Zhu, J. Eur. J. Org. Chem. 2003, 1133; (d)
Hulme, C.; Nixey, T. Curr. Opin. Drug Disc. Devel. 2003, 6, 921; (e) Hulme, C.;
Gore, V. Curr. Med. Chem. 2003, 10, 51; (f) Dömling, A. Chem. Rev. 2006, 106, 17;
(g) Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324; (h) El Kaim, L.;
Grimaud, L. Tetrahedron 2009, 65, 2153.
CO2Et
CO2Et
NH2
N
HO
O
N
N
N
N
CN
H2N
EtO
a, b
d,e
N
N
2. (a) Tempest, P. A. Curr. Opin. Drug Disc. Devel. 2005, 8, 776; (b) Marcaccini, S.;
Torroba, T.. In Multicomponent Reactions: Post-condensation modifications of the
Passerini and Ugi reactions; Zhu, J., Bienaymé, H., Eds.; Wiley-VCH: Weinheim,
2005; Vol. 33, pp 33–75; (c) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles
2007, 73, 125.
3. (a) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45, 417; (b)
Akritopoulou-Zanze, I.; Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett.
2004, 45, 3421; (c) Akritopoulou-Zanze, I.; Gracias, V.; Djuric, S. W. Tetrahedron
c
Scheme 1. Reagents and conditions: (a) HCl (gas), MeOH, À78 °C to rt, 24 h; (b)
N2H4ÁH2O, EtOH, 0 °C 48 h, 74% in two steps; (c) EtOH, 0 °C to rt, 16 h, reflux 6 h,
40%; (d) PCl5, toluene, reflux, 1 h, 70%; (e) H2, Pd/C, Et3N, rt, 11/2 h, 22%.