Efficient and Convenient Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 3
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synthesis of N-alkyl-4-(trihalomethyl)-1H-pyrimidin-2-ones. Eur.
J. Org. Chem., 2008, 5832, doi:10.1002/ejoc.200800822.
Wang, X.-C.; Quan, Z.-J.; Zhang, Z. Michael additions of
dihydropyrimidines and 2-amino-1,3,4-thiadiazoles to ꢀ, ꢁ-
REFERENCES AND NOTES
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General procedure for compounds 4a. To a suspension of 3,4-
dihydropyrimidinone 1a (1.0 mmol), paraformaldehyde (5.0
mmol), and CH2Cl2 (5 mL), TMSCl (2.5 mmol) were added and the
reaction mixture was stirred at 40 oC for 24 h. After reaction
completion, the solution was concentrated and purified by silicagel
column chromatography affording ethyl 1-(chloromethyl)-1,2,3,6-
tetrahydro-4-methyl-2-oxo-6-phenylpyrimidine-5-carboxylate 4a.
1H NMR (400 MHz, CDCl3): ꢀ = 9.72 (br, 1H, NH), 7.38-7.26 (m,
5H, HAr), 5.60 (d, J = 10.4 Hz, 1H, NCHH), 5.43 (s, 1H, 4-CH),
5.15 (d, J = 10.4 Hz, 1H, NCHH), 4.14-3.98 (q, J = 7.2 Hz, 2H,
OCH2CH3), 2.34 (s, 3H, CH3), 1.15 (t, J = 7.2 Hz, 3H, OCH2CH3).
13C NMR (100 MHz, CDCl3) ꢀ = 165.7, 153.5, 146.7, 141.0, 128.6,
Kolosov, M. A.; Orlov, V. D.; Beloborodov, D. A.; Dotsenko,
V. V. A chemical placebo: NaCl as an effective, cheapest, non-
acidic and greener catalyst for Biginelli-type 3,4-dihydropyrimidin-
2(1H)-ones (-thiones) synthesis. Mol. Diversity, 2009, 13, 5.
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the synthesis of Biginelli 3,4-dihydropyrimidin-2(1H)-one
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Singh, K.; Arora, D.; Poremsky, E.; Lowery, J.; Moreland, R. S.
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[8]
[9]
128.1, 127.6, 100.5, 66.8, 59.9, 18.3, 14.1. MS:m/z = 308 (M+),
310 (M+2)+.
[10]
[11]
[28]
General procedure for compounds 3a-j. To a suspension of 3,4-
dihydropyrimidinone (1.0 mmol), paraformaldehyde (5.0 mmol),
and CH2Cl2 (5 mL), TMSCl (2.5 mmol) were added and the
reaction mixture was stirred at 40 oC for 24 h. Acid (1 mmol),
potassium iodide (0.3 mmol), and Et3N (0.5 mmol) were then
added and the reaction mixture was stirred for an additional 6 h
until the reaction was complete (monitored by TLC). After reaction
completion, the solid was filtered and the filtrate was quenched
with saturated aqueous NaHCO3 solution (10 mL). The aqueous
phase was extracted with CH2Cl2 (15 mL) and the combined
organic phase was washed with brine (15 mL), dried over Na2SO4,
and concentrated. Purification by recrystallization from aq. EtOH
(EtOH: H2O = 4:1) or silicagel column chromatography afforded
N3-substituted 3,4-dihydropyrimidinone (3a-k). 3a: White solid,
yield 80%, mp = 166-168 oC. 1H NMR (400 MHz, CDCl3): ꢀ =
8.37 (br, 1H, NH), 7.38-7.22 (m, 5H, HAr), 5.63 (d, J = 10.4 Hz,
1H, NCHH), 5.50 (s, 1H, 4-CH), 5.21 (d, J = 10.4 Hz, 1H, NCHH),
4.10 (q, J = 7.2 Hz, 2H, OCH2CH3), 2.36 (s, 3H, CH3), 1.89 (s, 3H,
CH3), 1.21 (t, J = 7.2 Hz, 3H, OCH2CH3). 13C NMR (100 MHz,
CDCl3): ꢀ = 170.8, 165.2, 153.1, 145.6, 141.8, 128.6, 128.1, 127.3,
102.7, 69.5, 60.5, 60.0, 20.7, 18.5, 14.1. Anal. Calcd for
C17H20N2O5: C, 61.44; H, 6.07; N, 8.43. Found: C, 61.70; H, 6.02;
N, 8.28. MS: m/z = 332 (M+). 3b: White solid, yield 85%, mp =
Singh, K.; Arora, D.; Singh, K.; Singh, S. Genesis of
Dihydropyrimidinone calcium channel blockers: Recent progress in
structure-activity relationships and other effects. Mini Rev. Med.
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[12]
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Gambacorta, A.; Tofani, D.; Loreto, M. A.; Gasperi, T.; Bernini, R.
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Kappe, C. O.; Roschger, P. Synthesis and reactions of “Biginelli-
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chemistry: Access to various heterocycles from ꢀ,ꢁ-unsaturated
ketones on the solid phase. J. Org. Chem., 1998, 63, 723.
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direct solid-phase split-pool Biginelli synthesis of 3,4-
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[16]
[17]
[18]
o
1
166-168 C. H NMR (400 MHz, CDCl3): ꢀ = 8.36 (br, 1H, NH),
7.32 (d, J= 8.0 Hz, 2H, HAr), 7.16 (d, J = 8.0 Hz, 2H, HAr), 5.61 (d,
J = 10.4 Hz, 1H, NCHH), 5.58 (s, 1H, 4-CH), 5.22 (d, J = 10.4 Hz,
1H, NCHH), 4.13 (q, J = 7.2 Hz, 2H, OCH2CH3), 2.40 (s, 3H,
CH3), 2.32 (s, 3H, CH3), 1.91 (s, 3H, CH3), 1.22 (t, J = 7.2 Hz, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3): ꢀ = 170.5, 165.0, 153.8,
146.3, 137.9, 129.2, 127.2, 101.6, 69.4, 60.5, 59.8, 21.1, 20.6, 18.5,
14.2. Anal. Calcd for C18H22N2O5: C, 62.42; H, 6.40; N, 8.09.
Found: C, 62.21; H, 6.50; N, 8.21. MS: m/z = 346 (M+). 3c: White
solid, yield 80%, mp = 150-152 oC. 1H NMR (400 MHz, CDCl3): ꢀ
= 8.86 (br, 1H, NH), 8.21-8.18 (m, 4H, HAr), 5.66 (s, 1H, 4-CH),
5.60 (d, J = 10.4 Hz, 1H, NCHH), 5.24 (d, J = 10.4 Hz, 1H,
NCHH), 4.13 (q, J = 7.2 Hz, 2H, OCH2CH3), 2.40 (s, 3H, CH3),
1.92 (s, 3H, CH3), 1.25 (t, J = 7.2 Hz, 3H, OCH2CH3). 13C NMR
(100 MHz, CDCl3): ꢀ = 170.7, 164.8, 152.9, 147.6, 146.6, 144.8,
128.2, 123.9, 101.9, 69.4, 60.5, 59.8, 20.6, 18.6, 14.2. Anal. Calcd
for C17H19N3O7: C, 54.11; H, 5.08; N, 11.14. Found: C, 53.93; H,
5.16; N, 11.03. MS: m/z = 377 (M+). 3d: White solid, yield 90%,
[19]
[20]
[21]
Singh, K.; Singh, S.; Mahajan, A. Metalation of Biginelli
compounds. A general unprecedented route to C-6 functionalized
4-aryl-3,4-dihydropyrimidinones. J. Org. Chem., 2005, 70, 6114.
Singh, K.; Singh, S.
A mild and practical method for the
regioselective synthesis of N-acylated 3,4-dihydropyrimidin-2-ones.
New acyl transfer reagents. Tetrahedron Lett., 2006, 47, 8143.
Schnell, B.; Strauss, U. T.; Verdino, P.; Faber, K.; Kappe, C. O.
Synthesis of enantiomerically pure 4-aryl-3,4-dihydropyrimidin-
2(1H)-ones via enzymatic resolution: preparation of the
antihypertensive agent (R)-SQ 32926. Tetrahedron: Asymmetry,
2000, 11, 1449.
[22]
[23]
Schnell, B.; Krenn, W.; Faber, K.; Kappe, C. O. Synthesis and
reactions of Biginelli-compounds. Part 23. Chemoenzymatic
syntheses of enantiomerically pure 4-aryl-3,4-dihydropyrimidin-
2(1H)-ones. J. Chem. Soc., Perkin Trans. 1., 2000, 4382,
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Zanatta, N.; Faoro, D.; Fernandes, L. da S.; Brondani, P. B.; Flores,
D. C.; Flores, A. F. C.; Bonacorso, H. G.; Martins, M. A. P.
Comparative study of the chemoselectivity and yields of the
o
1
mp = 178-180 C. H NMR (400 MHz, CDCl3): ꢀ = 7.92 (br, 1H,
NH), 7.83-7.21 (m, 10H, HAr), 5.73 (d, J = 10.4 Hz, 1H, NCHH),
5.61 (d, J = 10.4 Hz, 1H, NCHH), 5.62 (s, 1H, 4-CH), 4.12 (q, J =
7.2 Hz, 2H, OCH2CH3), 2.36 (s, 3H, CH3), 1.20 (t, J = 7.2 Hz, 3H,
OCH2CH3). 13C NMR (100 MHz, CDCl3) ꢀ = 166.1, 165.2, 152.9,
145.5, 142.0, 133.1, 129.7, 129.3, 128.6, 128.1, 128.0, 127.2,
102.8, 70.5, 60.7, 60.1, 18.5, 14.1. Anal. Calcd for C22H22N2O5: C,
66.99; H, 5.62; N, 7.10. Found: C, 67.17; H, 5.56; N, 7.22. MS: