New Reactivity of Nitropyrimidinone: Ring Transformation and N-C Transfer Reactions

Abstract

Nitropyrimidinone 1 revealed new reactivity upon treatment with active methylene compounds 2 under basic conditions. The N1-C2-C3-C4 moiety of 1 combined with two carbon units of 2 affording polyfunctionalized pyridones 4, which was hitherto unknown ring transformation. On the other hand, the N1-C2 moiety of 1 was transferred to the methylene group of 2 giving functionalized enamines 3. It was also possible to modify the amino group in 3a by reactions with primary amines. Enamines 3 reacted with hydrazines, and leading to functionalized pyrazoles 7 quantitatively. The ratios of regioisomeric pyrazoles 7/8 were moderately controlled by use of sterically hindered enamines 3h, 3k and 3l. Furthermore, enamine 3a was readily converted to 1,4-diazepines 9 having a functional group at the 6-position.

diazepine - functionalized enamine - nitropyrimidinone - pyrazole - pyridone

References

1

Pyrimidinone 1 is readily prepared from 2-thiouracil by reduction, methylation and nitration [2b] in 43% overall yield.

2a Nishiwaki N. Adachi T. Matsuo K. Wang H.-P. Matsunaga T. Tohda Y. Ariga M. J. Chem. Soc., Perkin Trans. 1  2000,  27 

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7

Typical Procedure: To a solution of pyrimidinone 1 (155 mg, 1 mmol), in EtOH (20 mL), were added 2a (253 µL, 2.0 mmol) and piperidine (198 µL, 2.0 mmol), and the mixture was heated under reflux for 1 d. After removal of the solvent, the residue was extracted with benzene (20 mL × 3), and the extract was concentrated. The residual red oil was treated with column chromatography on silica gel to afford 4a [5] (eluted with chloroform/EtOAc = 7:1, 162 mg, 0.67 mmol, 67%).

8

Pyridone 4f: Colorless needles (recrystallized from EtOH); mp 253-255 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.32 (t, J = 7.1 Hz, 3 H), 3.37 (s, 3 H), 4.29 (q, J = 7.1 Hz, 2 H), 8.72 (brs, 1 H), 8.84 (s, 1 H), 9.28 (brs, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.0 (q), 28.9 (q), 60.8 (t), 89.3 (s), 123.4 (s), 140.0 (d), 153.7 (s), 156.9 (s), 165.2 (s). Anal. Calcd for C₉H₁₁N₂O₅: C, 44.82; H, 4.60; N, 17.42. Found: C, 44.70; H, 4.50; N, 17.41.

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11 Menozzi G. Mosti L. Schenone P. J. Heterocycl. Chem.  1987,  24:  1669 

Pyrazoles having an ethoxycarbonyl group are widely used for synthetic intermediates of agrochemicals such as insecticides, fungicides, herbicides and so on, see:

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12d

The NOESY spectrum of 7o showed correlation between the phenyl group and the methyl one that was derived from the acetyl group of 3a.

13 Kopp M. Lancelot J.-C. Dallemagne P. Rault S.
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14

Enamine 3q: Isolated yield 91%. Brown oil. ¹H NMR (400 MHz, CDCl₃): E-isomer δ = 1.11 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.80-2.30 (br, 1 H), 2.49 (s, 3 H), 2.60-2.80 (m, 2 H), 2.84 (t, J = 5.6 Hz, 2 H), 3.46 (q, J = 7.2 Hz, 2 H), 4.19 (q, J = 7.2 Hz, 2 H), 8.03 (d, J = 13.6 Hz, 1 H), 10.90-11.20 (br, 1 H); Z-isomer δ = 1.11 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.80-2.30 (br, 1 H), 2.42 (s, 3 H), 2.60-2.80 (m, 2 H), 2.84 (t, J = 5.6 Hz, 2 H), 3.46 (q, J = 7.2 Hz, 2 H), 4.37 (q, J = 7.2 Hz, 2 H), 8.17 (d, J = 14.8 Hz, 1 H), 9.20-9.40 (br, 1 H), 8.90-9.10 (br, 1 H); E/Z = 9/1. ¹³C NMR (100 MHz, CDCl₃): E-isomer δ = 14.1 (q), 15.3 (q), 30.9 (q), 43.8 (t), 49.2 (t), 52.0 (t), 59.7 (t), 100.4 (s), 160.3 (d), 167.4 (s), 199.4 (s); Z-isomer δ = 14.1 (q), 15.3 (q), 30.9 (q), 41.4 (t), 49.2 (t), 52.0 (t), 59.7 (t), 100.3 (s), 160.2 (d), 169.2 (s), 195.7 (s).

15

Diazepine 9q: Isolated yield 30%. Dark brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.23 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.2 Hz, 3 H), 2.31 (s, 3 H), 3.31 (q, J = 7.2 Hz, 2 H), 3.44 (t, J = 4.0 Hz, 2 H), 3.80-4.00 (br, 2 H), 4.19 (q, J = 7.2 Hz, 2 H), 7.64 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (q), 14.5 (q), 27.7 (q), 51.2 (t), 53.1 (t), 55.0 (t), 60.0 (t), 97.0 (s), 150.0 (d), 168.6 (s), 169.7 (s).

16

Enamine 3r: Isolated yield 82%. Colorless needles; mp 203-204 °C. ¹H NMR (400 MHz, DMSO-d ₆): isomer A δ = 1.25 (t, J = 7.1 Hz, 6 H), 2.24 (s, 6 H), 3.55 (brs, 4 H), 4.16 (q, J = 7.1 Hz, 4 H), 7.94 (d, J = 14.1 Hz, 2 H), 9.12 (brd, J = 14.1 Hz, 2 H); isomer B δ = 1.19 (t, J = 7.1 Hz, 6 H), 2.30 (s, 6 H), 3.55 (brs, 4 H), 4.05 (q, J = 7.1 Hz, 4 H), 7.88 (d, J = 13.2 Hz, 2 H), 10.72 (brd, J = 13.2 Hz, 2 H); A/B = 1/7. Since NMR spectra suggested both isomers A and B had symmetrical structures, they were thought to be EE and ZZ isomers. ¹³C NMR (100 MHz, DMSO-d ₆): isomer A δ = 13.6 (q), 29.7 (q), 48.9 (t), 58.1 (t), 98.6 (s), 159.5 (d), 165.7 (s), 196.2 (s); isomer B δ = 13.6 (q), 29.9 (q), 48.9 (t), 58.0 (t), 98.6 (s), 159.5 (d), 165.7 (s), 196.2 (s). IR (nujol): 1648, 1699 cm^-1. MS (FAB): m/z (%) = 341 (100) [M⁺ + 1]. Anal. Calcd for C₇H₁₁NO₃: C, 56.46; H, 7.11; N, 8.23. Found: C, 56.19; H, 7.17; N, 8.23.