A Convenient Synthesis of N1-Substituted 3,4-Dihydropyrimidin-2(1H)-ones by Cyclocondensation of α-Chlorobenzyl Isocyanates with Ethyl N-alkyl(aryl)-β-aminocrotonates

Abstract

A new convenient approach to the synthesis of N1-substituted 3,4-dihydropyrimidin-2(1H)-ones was developed using the regioselective cyclocondensation of α-chlorobenzyl isocyanates with ethyl N-alkyl(aryl)-β-aminocrotonates. A number of N1-aryl and N1-alkyl substituted Biginelli compounds difficult to obtain by other methods were prepared with high yields.

cyclocondensation - regioselectivity - α-chloroalkyl isocyanates - dihydropyrimidones - β-aminocrotonic esters

References and Notes

For reviews see:

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17

Improved Protocol for Preparation of α-Chlorobenzyl Isocyanates 1.
The mixture of aromatic aldehyde (1 mol, 1 equiv) and ethylcarbamate (2.2 mol, 2.2 equiv) was heated to 140-160 °C and then few drops of concd H₂SO₄ was added. The reaction mixture was heated at this temperature for 15 min and then cooled. A solidified mass was quenched by H₂O, product(benzylidenebiscarbamate) was collected by filtration, washed with H₂O, dried and used without further purification. The suspension of obtained benzylidenebis-carbamate (0.5 mol, 0.5 equiv) and PCl₅ (1.1 mol, 2.2 equiv) in 500 mL of dry benzene was refluxed until no gas evolution observed (usually 3-4 h). The homogeneous solution was cooled, solvent and volatile substances were distilled off and the residue fractioned at reduced pressure.

18 Abdel-Fattah AAA. Synthesis  2003,  2358 

19 Gao Y. Zhang Q. Xu J. Synth. Commun.  2004,  34:  909 

20

General Procedure for Preparation of 3,4-Dihydro-pyrimidin-2(1 H )-ones 3.
To the solution of appropriate ethyl β-aminocrotonate 2 (5 mmol, 1 equiv) in 20 mL of CH₂Cl₂ the solution of isocyanate 1 (5.5 mmol, 1.1 equiv) in 10 mL of CH₂Cl₂ was added dropwise. The reaction mixture was refluxed for 2 h, cooled and the solvent was evaporated. The crude product was treated with hot 70-80% aq EtOH, allowed to stand overnight at 9 °C and then collected by filtration, washed with small amount of EtOH and dried in air.

21

Selected Data.
1-(4′-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1 H )-one (3b).
IR (KBr pellets): 3250, 3130, 1710, 1700, 1650 cm^-1. ¹H NMR [300 MHz, (CD₃)₂SO-CCl₄, 2:1]: δ = 1.14 (t, J = 6.5 Hz, 3 H), 2.04 (s, 3 H), 4.06 (q, J = 6.5 Hz, 2 H), 5.27 (d, J = 1.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.35 (m, 5 H), 7.45 (d, J = 8.0 Hz, 2 H), 8.14 (d, J = 1.0 Hz, 1 H). ¹³C NMR [75.5 MHz, (CD₃)₂SO]: δ = 14.50, 18.54, 53.65, 60.28, 104.48, 126.78, 128.03, 129.13, 129.37, 132.23, 133.13, 137.10, 144.35, 148.91, 152.36, 165.86.
1-Benzyl-4-(4′-chlorophenyl)-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1 H )-one (3h).
IR (KBr pellets): 3260, 3120, 1730, 1700, 1640 cm^-1. ¹H NMR [300 MHz, (CD₃)₂SO-CCl₄, 2:1]: δ = 1.14 (t, J = 6.6 Hz, 3 H), 2.40 (s, 3 H), 4.03 (q, J = Hz, 2 H), 4.85 (d, J = 18.9 Hz, 1 H), 5.09 (d, J = 18.9 Hz, 1 H), 5.22 (d, J = 3.3 Hz, 1 H), 7.07 (d, J = 6.3 Hz, 2 H), 7.26 (m, 7 H), 8.15 (d, J = 3.3 Hz, 1 H). ¹³C NMR [75.5 MHz, (CD₃)₂SO]: δ = 14.47, 16.50, 45.43, 52.44, 60.22, 103.65, 126.62, 127.35, 128.62, 128.85, 128.95, 132.47, 139.06, 143.38, 150.30, 153.34, 165.91.

22 Puebla PHZ. Medarde MML. Caballero EFA. Tetrahedron  1999,  55:  7915 

23 For examples of this heterocyclic system see: Chorvat R. Radak SE. Desai BN. J. Org. Chem.  1987,  52:  1366 

24

Prepared from 5 according to the general procedure for preparation of 3.
Selected Data.
4-Ethoxycarbonyl-3-phenyl-2,3-dihydropyrimido[6,1- c ][1,4]benzothiazin-1(1 H )-one (6a).
IR (KBr pellets): 3240, 3140, 1710, 1650 cm^-1. ¹H NMR [300 MHz, (CD₃)₂SO-CCl₄, 2:1]: δ = 1.17 (t, J = 6.8 Hz, 3 H), 3.54 (d, J = 16.5 Hz, 1 H), 4.11 (q, J = 6.8 Hz, 2 H), 5.17 (d, J = 16.5 Hz, 1 H), 5.37 (d, J = 4.2 Hz, 1 H), 7.29 (m, 2 H), 7.36 (m, 7 H), 8.62 (d, J = 4.2 Hz, 1 H). ¹³C NMR [75.5 MHz, (CD₃)₂SO]: δ = 14.46, 30.59, 53.06, 53.07, 60.97, 103.73, 126.03, 126.53, 126.70, 128.00, 128.20, 129.13, 129.25, 130.63, 135.20, 143.15, 149.59, 152.08, 165.36.
3-(3′-Bromophenyl)-4-ethoxycarbonyl-2,3-dihydro-pyrimido[6,1- c ][1,4]benzothiazin-1(1 H )-one (6c).
IR (KBr pellets): 3250, 3130, 1710, 1650 cm^-1. ¹H NMR [300 MHz, (CD₃)₂SO-CCl₄, 2:1]: δ = 1.21 (t, J = 6.8 Hz, 3 H), 3.52 (d, J = 16.5 Hz, 1 H), 4.15 (m, 2 H), 5.19 (d, J = 16.5 Hz, 1 H), 5.35 (d, J = 5.1 Hz, 1 H), 7.33 (m, 8 H), 8.61 (d, J = 5.1 Hz, 1 H). ¹³C NMR [75.5 MHz, (CD₃)₂SO]: δ = 14.45, 30.46, 52.62, 61.05, 102.91, 122.35, 125.51, 126.14, 126.73, 127.92, 129.17, 129.63, 130.68, 131.11, 131.60, 135.04, 145.78, 150.24, 151.86, 165.17.