A. Chilin et al. / Tetrahedron Letters 48 (2007) 3229–3231
3231
Table 3. Comparison between conventional synthesis and MAOS
R1
R2
NHCO2Et
N
R
N
i
R3
Entry
Starting product
R2
Product
Yield
Number of cycles
R1
R3
(a)
(b)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
CH3
H
H
H
H
H
H
CH3
OCH3
OH
NHCO2Et
H
H
H
CH3
OCH3
Cl
6-Methylquinazoline
6-Methoxyquinazoline
6-Hydroxyquinazoline
6-Aminoquinazoline
7-Methoxyquinazoline
7-Aminoquinazoline
7-Amino-8-methylquinazoline
7-Amino-6-methylquinazoline
7-Amino-6-methoxyquinazoline
6-Chloroquinazoline
49
19
24
54
22
45
38
44
43
15
95
92
86
90
79
91
83
80
84
55a
4
3
3
3
3
3
4
3
3
4
OCH3
NHCO2Et
NHCO2Et
NHCO2Et
NHCO2Et
H
10
H
Reagents and conditions: (i) (1). HMTA, TFA, MW, 110 ꢁC, 10 min. (2). KOH aq EtOH, K3Fe(CN)6, 100 ꢁC, three or four cycles of 10 min each.
(a) Yield of conventional synthesis. (b) Yield of microwave-assisted reaction.
a See text for details.
6. (a) Niementowski, S. J. Prakt. Chem 1895, 51, 564–571;
(b) Bischler, A. Chem. Ber. 1891, 24, 506; (c) Riedel, A.
Ger. Pat. 1905, 174941.
quinazoline from simple and easy available starting
materials.
7. Marzaro, G.; Chilin, A.; Pastorini, G.; Guiotto, A. Org.
Lett. 2006, 8, 255–256.
Acknowledgment
8. (a) Kappe, C. O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005; (b)
Microwave-Assisted Organic Synthesis; Tierney, J. P.,
Lidstro¨m, P., Eds.; Blackwell: Oxford, 2005; (c) Kappe,
C. O.; Dallinger, D. Nat. Rev. Drug Discovery 2006, 5, 51–
63; (d) Mavandadi, F.; Pilotti, A. Drug Discovery Today
2006, 11, 165–174.
The present work has been carried out with financial
support of the Italian Ministry for University and
Research (MIUR), Rome, Italy.
References and notes
9. Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9,
69–72.
1. (a) Dayam, R.; Grande, F.; Al-Mawsawi, L. Q.; Neamati,
N. Expert Opin. Ther. Patents 2007, 17, 83–102, and
references cited therein; (b) Klutchko, S. R.; Zhou, H.;
Winters, R. T.; Tran, T. P.; Bridges, A. J.; Althaus, I. W.;
Amato, D. M.; Elliott, W. L.; Ellis, P. A.; Meade, M. A.;
Roberts, B. J.; Fry, D. W.; Gonzales, A. J.; Harvey, P. J.;
Nelson, J. M.; Sherwood, V.; Han, H.-K.; Pace, G.;
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Chem. 2006, 49, 1475–1485, and references cited therein;
(c) Mazitschek, R.; Giannis, A. Curr. Opin. Chem. Biol
2004, 8, 432–441.
2. (a) Ellsworth, E. L.; Tran, T. P.; Showalter, H. D.;
Sanchez, J. P.; Watson, B. M.; Stier, M. A.; Domagala, J.
M.; Gracheck, S. J.; Joannides, E. T.; Shapiro, M. A.;
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W.; Bronstein, J. C.; Liu, J. Y.; Nguyen, D. Q.; Singh, R.
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4. Biological activities of quinazoline scaffold were well
described and reviewed in: Vogtle, M. M.; Marzinzik, A.
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10. The monomode reactor (CEM Discoverꢂ) is equipped
with PowerMaxꢂ technology that allows simultaneous
cooling of a reaction with compressed gas, while irradi-
ating it with microwave energy (enhanced microwave
synthesis). Thus, energy can be continuously applied while
keeping bulk temperature at a set level: this feature
prevents unwanted side reactions and allows for cleaner
11. Bacsa, B.; Desai, B.; Dibo, G.; Kappe, C. O. J. Pept. Sci.
2006, 12, 633–638.
12. General MW experimental procedure (performed in a CEM
Discoverꢂ monomode reactor with the temperature mon-
itored by a built-in infrared sensor). A mixture of
carbamate (1 mmol) and HMTA (1 mmol) in TFA
(3 mL) was microwave irradiated at 110 ꢁC (power set
point 80 W; ramp time 1 min; hold time 10 min). After
cooling, the mixture was diluted with aqueous ethanolic
(water/EtOH: 1:1) 10% KOH (50 mL) and the solution
was microwave irradiated at 100 ꢁC for several cycles
(power set point 110 W; ramp time 4 min; hold time
10 min for each cycle) (see Table 3 for the number of
cycles), adding K3Fe(CN)6 (1 mmol) for each irradiation
cycle. After cooling, the mixture was diluted with water
(50 mL), extracted with EtOAc or toluene (5 · 20 mL),
and the organic phase was evaporated under reduced
pressure to give the final quinazoline. Yields are reported
in the text (Table 3). The analytical data were in agreement
with the literature values.5
5. Chilin, A.; Marzaro, G.; Zanatta, S.; Barbieri, V.; Pasto-
rini, G.; Manzini, P.; Guiotto, A. Tetrahedron 2006, 62,
12351–12356.