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Synlett 2008(19): 3036-3040  
DOI: 10.1055/s-0028-1087346
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

4-(Isoxazol-3-yl)pyrimidines from Pyrimidinyl Nitrile Oxides

Wonken Chounga, Beth A. Lorsbachb, Thomas C. Sparksb, James M. Ruizb, Mark J. Kurth*a
a Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
Fax: +1(530)7528995; e-Mail: mjkurth@ucdavis.edu;
b Dow AgroSciences, Discovery Research, Indianapolis, IN 46268, USA
Further Information

Publication History

Received 26 February 2008
Publication Date:
12 November 2008 (online)

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Abstract

The 1,3-dipolar cycloaddition reaction of pyrimidinyl aldoxime derived nitrile oxides and alkynes delivers 4-(isoxazol-3-yl)pyrimidines. The procedures reported accommodate three points of diversification around this bisheterocyclic scaffold and the resulting library of compounds has been added to the National Institutes of Health repository (ca. 10 mg of each with >90% purity) for pilot-scale biomedical studies with bioassay data available at the National Center for Biotechnology Information PubChem database.

Key words

nitrile oxide - 2-aminopyrimidine - isoxazoles - isoxazolines - ipso substitution - cycloaddition

    References and Notes

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15

Demeter, D., log Kow model developed at Dow AgroSciences, unpublished work

17

Representative Examples of 5
4-Methyl-6-(5-phenylisoxazol-3-yl)- N -propylpyrimidin-2-amine
¹H NMR (300 MHz, CDCl3): δ = 7.80 (m, 2 H), 7.42 (m,
3 H), 7.10 (s, 1 H), 7.00 (s, 1 H), 3.42 (m, 2 H), 2.31 (s, 3 H), 2.18 (s, 1 H), 1.62 (m, 2 H), 0.93 (m, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 170.9, 162.9, 162.7, 156.3, 130.6, 129.3, 127.5, 126.1, 106.8, 105.8, 98.7, 43.5, 23.3, 23.1, 11.8.
N -(Cyclopropylmethyl)-4-isopropyl-6-(5-phenylisoxazol-3-yl)pyrimidin-2-amine
¹H NMR (300 MHz, CDCl3): δ = 7.60 (m, 2 H), 7.24 (m,
3 H), 6.91 (s, 1 H), 6.84 (s, 1 H), 5.22 (br s, 1 H), 3.11 (m,
2 H), 2.64 (m, 1 H), 1.27 (d, J = 7.0 Hz, 6 H), 0.82 (m, 1 H), 0.30 (m, 2 H), 0.05 (m, 2 H). ¹³C NMR (75 MHz, CDCl3):
δ = 178.2, 170.9, 163.6, 162.8, 156.2, 130.6, 129.3, 127.5, 126.1, 104.4, 98.7, 46.8, 36.3, 21.9, 11.9, 3.7.
4-Isopropyl-6-(5-phenylisoxazol-3-yl)- N -propyl-pyrimidin-2-amine
¹H NMR (300 MHz, CDCl3): δ = 7.87 (m, 2 H), 7.50 (m,
3 H), 7.19 (s, 1 H), 7.11 (s, 1 H), 3.50 (m, 2 H), 2.91 (m, 1 H), 1.70 (m, 2 H), 1.30 (d, J = 7.2 Hz, 6 H), 1.02 (t, J = 6.2 Hz, 3 H); note: NH proton not detected. ¹³C NMR (75 MHz, CDCl3): δ = 170.9, 163.8, 162.6, 156.4, 130.6, 130.2, 129.3, 127.5, 126.1, 104.1, 98.7, 43.6, 36.1, 23.1, 21.9, 11.9.
4-[5-(4-Chlorophenyl)isoxazol-3-yl]-6-isopropyl- N -propyl-pyrimidin-2-amine
¹H NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 8.7 Hz, 2 H), 7.48 (d, J = 8.7 Hz, 2 H), 7.16 (s, 1 H), 7.09 (s, 1 H), 5.90 (br s, 1 H), 3.48 (br s, 2 H), 2.90 (m, 1 H), 1.70 (m, 2 H), 1.32 (d, J = 7.2 Hz, 6 H), 1.03 (t, J = 7.5 Hz, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 178.2, 170.9, 163.6, 162.8, 156.2, 130.6, 129.3, 127.5, 126.1, 104.4, 98.7, 46.8, 36.3, 21.9, 11.9, 3.7.

18

Representative Examples of 8
N -Cyclopentyl-3-[2-(2-methoxyethylamino)-6-methyl-pyrimidin-4-yl]isoxazole-5-carboxamide
¹H NMR (300 MHz, CDCl3): d = 7.42 (s, 1 H), 7.10 (s, 1 H), 6.55 (br s, 1 H), 5.53 (br s, 1 H), 4.41 (m, 1 H), 3.69-3.55 (m, 4 H), 3.38 (s, 3 H), 2.39 (s, 3 H), 2.13-2.04 (m, 2 H), 1.85-1.52 (m, 6 H). ¹³C NMR (75 MHz, CDCl3): d = 169.7, 164.3, 163.9, 162.8, 155.5, 154.9, 107.1, 106.2, 71.5, 59.0, 51.9, 41.4, 33.3, 24.4, 24.0.
N -Benzyl-3-[2-(cyclopentylamino)-6-methylpyrimidin-4-yl]isoxazole-5-carboxamide
¹H NMR (300 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.35 (m, 5 H), 7.06 (br s, 2 H), 5.22 (d, J = 6.9 Hz, 1 H), 4.64 (d, J = 6.9 Hz, 2 H), 4.33 (m, 1 H), 2.37 (s, 3 H), 2.04 (m, 2 H), 1.72-1.24 (m, 6 H). ¹³C NMR (75 MHz, CDCl3): δ = 169.5, 163.9, 162.6, 162.4, 155.9, 154.8, 137.2, 129.1, 129.0, 128.2, 106.7, 106.5, 53.2, 43.8, 33.5, 24.5, 23.9.
N -(4-Methoxybenzyl)-3-[2-(2-methoxyethylamino)-6-methyl-pyrimidin-4-yl]isoxazole-5-carboxamide
¹H NMR (300 MHz, CDCl3): δ = 8.46 (br s, 1 H), 7.46 (s,
1 H), 7.30 (d, J = 8.7 Hz, 2 H), 7.09 (s, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 5.59 (br s, 1 H), 4.59 (d, J = 5.4 Hz, 2 H), 3.80 (s, 3 H), 3.69-3.56 (m, 4 H), 3.38 (s, 3 H), 2.39 (s, 3 H). ¹³C NMR (75 MHz, CDCl3): δ = 169.6, 164.0, 163.8, 162.7, 159.6, 155.7, 154.9, 129.7, 129.2, 114.5, 107.1, 106.5, 70.4, 59.0, 55.6, 43.4, 41.4, 24.4.
3-[2-(Cyclopentylamino)-6-isopropylpyrimidin-4-yl]- N -(4-methoxybenzyl)isoxazole-5-carboxamide
¹H NMR (300 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.29 (d, J = 7.5 Hz, 2 H), 7.08 (s, 1 H), 6.97 (br s, 1 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.23 (br s, 1 H), 4.58 (d, J = 5.1 Hz, 2 H), 4.30 (m, 1 H), 3.79 (s, 3 H), 2.84 (m, 1 H), 2.06 (m, 2 H), 1.73-1.61 (m, 4 H), 1.45 (m, 2 H), 1.25 (d, J = 5.1 Hz, 6 H). ¹³C NMR (75 MHz, CDCl3): δ = 178.2, 164.1, 163.9, 162.5, 159.6, 155.8, 155.0, 129.7, 129.3, 114.5, 106.6, 104.2, 55.6, 53.3, 43.4, 36.3, 33.5, 24.0, 21.8.