C. Guo / Tetrahedron Letters 51 (2010) 548–549
549
Table 2
Compounds 6 prepared
Compound
R1
R2
R3
Yield of 3a
Yield of 6b
Referencec
6a
6b
6c
6d
6e
n-Bu
Ph
Me
Me
Me
Ph
Me
4-NO2-benzyl
Propargyl
Allyl
Me
Ph
70
72
68
59
63
77
81
78
75
54
21
22
23
24
25
2-Thiophenyl
2-Cl-phenyl
n-Pr
a
Isolated yield based on 1 (2 not purified) after purification by column chromatography or preparative thin layer chromatography.
Isolated yield based on 3 (5 not purified) after purification by column chromatography or preparative thin layer chromatography.
All products are known (prepared by different methods) and their analytical data are consistent with those reported.
b
c
11. Compound 4g was isolated in 84% by heating 3g with ammonium acetate in
acetic acid at 120 °C for 1 h.
12. Zhang, Z.; Zhang, Q.; Yan, Z.; Liu, Q. Journal Org. Chem. 2007, 72, 9808–9810.
13. Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625–628.
14. Zanatta, N.; Fantinel, L.; Lourega, R. V.; Bonacorso, H. G.; Martins, M. A. P.
Synthesis 2007, 358–362.
15. Font, D.; Heras, M.; Villalgordo, J. M. Synthesis 2002, 1833–1842.
16. Reddy, J. T.; Reddy, V. V.; Sridevi, B. S.; Kumar, P. R.; Reddy, G. O. Indian Pat.
Appl., 2007, IN2003MA00010.
17. Papet, A. L.; Marsura, A. Synthesis 1993, 478–481.
18. Breeze, A. L.; Green, O. M.; Hull, K. G.; Ni, H.; Hauck, S. I.; Mullen, G. B.; Hales, N.
J.; Timms, D. PCT Int. Appl., 2005, WO2005026149.
Scheme 2. Reagents and conditions: (a) 29method A: R3X (R3 = alkyl, X = Cl, Br or I),
K2CO3, acetone, reflux, 2–4 h; method B: R3X (R3 = aryl, X = I), CuI, Cs2CO3,
L-proline,
DMSO, microwave irradiation, 100 °C, 30 min; (b) 28NH4OAc, HOAc, microwave
irradiation, 120 °C, 15 min.
19. Miller, G. W.; Rose, F. L. J. Chem. Soc. 1963, 5642–5659.
20. Ho, K.-K.; Auld, D. S.; Bohnstedt, A. C.; Conti, P.; Dokter, W.; Erickson, S.; Feng,
D.; Inglese, J.; Kingsbury, C.; Kultgen, S. G.; Liu, R.-Q.; Masterson, C. M.;
Ohlmeyer, M.; Rong, Y.; Rooseboom, M.; Roughton, A.; Samama, P.; Smit, M.-J.;
Son, E.; Van der Louw, J.; Vogel, G.; Webb, M.; Wijkmans, J.; You, M. Bioorg.
Med. Chem. Lett. 2006, 16, 2724–2728.
21. Bru-Magniez, N.; Teulon, J. M.; Nicolai, E. Eur. Pat. Appl., 1992, EP465323.
22. Tice, C. M. Eur. Pat. Appl., 1994, EP579425.
23. Naganuma, K.; Yokoi, H. PCT Int. Appl., 2006, WO2006123639.
24. Pierce, A.; Come, J.; Court, J.; Gao, H.; Henkel, G.; Liu, M.; Neuberger, T. PCT Int.
Appl., 2008, WO2008112651.
application of microwave technology to key steps led to short
reaction times and clean products.26 We believe that the current
methodology will serve as a valuable complement to the existing
ones.
Acknowledgments
25. Kuroita, T.; Sakamoto, H.; Igawa, H.; Sasaki, M.; Asano, K.; Maekawa, T. PCT Int.
Appl., 2008, WO2008062905.
26. Both N-acyl b-ketoamides and pyrimidin-4-ones can be obtained under
thermal conditions in comparable or slightly lower yields albeit longer
reaction times.9,11
27. General procedure for preparation of N-acyl b-ketoamides (3): A mixture of 2
(1 mmol) and amide (1 mmol) in 3:1 toluene/chloroform (3 mL) was irradiated
with microwave at 80 °C on a BiotageÒ Initiator reactor for 15–20 min. The
reaction mixture was cooled to room temperature, concentrated under
reduced pressure, and purified by either flash column chromatography or
preparative thin layer chromatography to provide 3.
The author thanks Dr. Peter R. Guzzo, Dr. David D. Manning, and
Dr. Mark A. Wolf for their helpful discussions throughout this work
and during the preparation of this manuscript.
References and notes
1. (a) Uehara, F.; Aritomo, K.; Shoda, A.; Hiki, S.; Okuyama, M.; Usui, Y.; Ooizumi,
M.; Watanabe, K. PCT Int. Appl., 2003, WO2003027080.; (b) Watanabe, K.;
Ando, R.; Saito, K.-I; Kawamoto, R.; Shoda, A. PCT Int. Appl., 2000,
WO2000018758.
2. Madhavan, G. R.; Venkateswarlu, A.; Rajagopalan, R.; Chakrabarti, R.; Misra, P.;
Lohray, Braj, B.; Lohray, V. B.; Rao, P. B. Indian Pat. Appl., 2005,
IN2001MA00568.
3. Herold, P.; Buehlmayer, P. Eur. Pat. Appl., 1991, EP407342.
4. Ku, T. W. F.; Lin, H.; Luengo, J. I.; Marquis, R. W., Jr.; Ramanjulu, J. M.; Trout, R.;
Yamashita, D. S. PCT Int. Appl., 2007, WO2007062370.
28. General procedure for preparation of pyrimidin-4-ones (4 or 6): A mixture of 3 or
5 (0.5 mmol) and ammonium acetate (5 mmol) in acetic acid (2 mL) was
irradiated with microwave at 120 °C on a BiotageÒ Initiator reactor for 15 min.
The reaction mixture was cooled to room temperature, diluted with water,
neutralized with sodium bicarbonate, and extracted with dichloromethane
(3Â). The combined extracts were dried over sodium sulfate, filtered, and
concentrated to give crude
recrystallization.
4 or 6, which was purified by trituration or
5. For a recent example of this approach, see: Orjales, A.; Mosquera, R.; Lopez, B.;
Olivera, R.; Labeaga, L.; Nunez, M. T. Bioorg. Med. Chem. 2008, 16, 2183–2199.
6. An N-acyl b-ketoamide was indirectly converted to a pyrimidin-4-one via a 4H-
1,3-thiazin-4-one intermediate: (a) Yamamoto, Y.; Ohnishi, S.; Azuma, Y. Chem.
29. General procedure for preparation of intermediate 5. Method A: A mixture of N-
acyl b-ketoamides 3 (1 equiv), alkyl halide (1 equiv), and potassium carbonate
(4 equiv) was heated at reflux in acetone (0.25 M) or stirred at room temperature
in N,N-dimethylformamide (0.25 M) for 2–4 h, quenched with water, and
extracted with ethyl acetate (3Â). The combined extracts were dried over
sodium sulfate, filtered, and concentrated to give crude 5, which was used in the
Pharm. Bull. 1983, 31, 1929–1935; (b) In
a related methodology, 1-
(hydroxyphenyl)-2,6-dimethyl-5-phenyl-pyrimidin-4-ones were prepared by
the reaction of N-acetyl-3-oxo-2-phenylbutanamide with an aminophenol in
acetic acid under reflux: Zhdanov, Y. A.; Vedernokova, I. V.; Simkina, Y. N.;
Ryabukhin, Y. I.; Khaitin, M. I.; Koro’chenko, G. A.; Il’chenko, I. A.; Sadekova, E. I.
Khim.-Farm. Zh. 1989, 23, 557–561; Chem. Abstr. 1989, 111, 126459.
following step without further purification. Method B:
A
mixture of
3
(1.0 mmol), aryl iodide (0.5 mmol), copper(I) iodide (0.05 mmol),
L-proline
(0.1 mmol), and cesium carbonate (2 mmol) in dimethylsulfoxide (2 mL) was
degassed and irradiated with microwave at 90 °C on a BiotageÒ Initiator reactor
for 20 min. The reaction mixture was cooled to room temperature, diluted with
water, and extracted with ethyl acetate (3Â). The combined extracts were dried
over sodium sulfate, filtered, and concentrated to give crude 5, which was used in
the following step without further purification.
7. Grayson, D. H.; Tuite, M. R. J. J. Chem. Soc., Perkin Trans. 1 1986, 2137–2142.
8. Yamamoto, Y.; Ohnishi, S.; Azuma, Y. Chem. Pharm. Bull. 1982, 30, 3505–3512.
9. In our hands, 3g was isolated in 62% (over two steps from 1) by heating crude 2
with benzamide at 80 °C in 3:1 toluene–CHCl3 for 2 h.
10. Herrero, M. A.; Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 36–47.