Synthesis of 2-Hydroxyimino-1,2,3,4-tetrahydropyrimidines

Full text of DOI:10.1007/s10593-013-1203-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
SYNTHESIS OF 2-HYDROXYIMINO-
1,2,3,4-TETRAHYDROPYRIMIDINES
I. V. Vozny1, D. P. Stepanov1, A. F. Mishnev1, and R. Žalubovskis1*
Keywords: hydroxyimino derivatives, tetrahydropyrimidines, inhibitors, Zn-containing enzymes.
Interest in 2-imino-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid esters is mainly because they are
structural subunits of a series of marine alkaloids (batzelladine B) showing a broad spectrum of biological
activity [1]. Compounds of this type with a hydroxy group on an exocyclic nitrogen atom have not been
reported to this time. Meanwhile, several hydroxyimino compounds of other classes are known as inhibitors of
zinc-containing enzymes. Hence amidoximes are known inhibitors of histone deacetylases [2], and hydroxamic
acids and their heterocyclic analogs are inhibitors of matrix metalloproteinases [3].
We propose a rather simple and convenient synthetic scheme for obtaining the 2-hydroxyimino-1,2,3,4-
tetra-hydropyrimidine-5-carboxylic acid esters 2a,b in reasonable yields.
R
R
MeO
O
O
H3PMo12O40
AcOH
MeI
+
S
O
MeO
Me
NH
THF
O
Me
N
H
1a,b
S
H2N
NH2
R
R
1) H2NOH·HCl
Et3N, DMF
2) HCl (gas.)
O
O
NH+
SMe
·HCl
I
MeO
Me
MeO
NH
OH
N
H
Me
N
N
H
2a,b
a R = H, b R = OMe
_______
*To whom correspondence should be addressed, e-mail: raivis@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1846-1848, November, 2012.
Original article submitted July 9, 2012.
0009-3122/13/4811-1731©2013 Springer Science+Business Media New York
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1
The structures of the obtained compounds 2a,b were determined from H and 13C NMR and from IR
spectroscopic data, from elemental analysis, and by X-ray structural analysis of compound 2b (Fig. 1).
IR spectra were recorded on a Shimadzu FTIR IR Prestige-21 spectrometer for KBr pellets. The 1H and
13C NMR spectra were recorded on a Varian 400 spectrometer (400 and 100 MHz, respectively) using
DMSO-d6 and referenced to the solvent signals at 2.50 ppm (1H nuclei) and 39.5 ppm (13C nuclei). Elemental
analysis was carried out on a Carlo Erba Elemental Analyzer EA 1108, and melting points were determined on
an SRS OptiMelt instrument. Column chromatography was performed with silica gel (0.035-0.070 mm) from
Acros.
Fig. 1. Structure of the compound 2b molecule with the atoms represented by thermal vibration ellipsoids of
50% probability.
Compounds 1a,b were prepared by a three-component Biginelli condensation using phosphomolybdic
acid as catalyst [4]. The physicochemical characteristics and spectroscopic data of these compounds agreed with
the literature [4, 5].
(2E)-N-Hydroxy-5-methoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-iminium
Chloride (2a). A solution of compound 1a (1.99 g, 7.58 mmol) and methyl iodide (1.62 g, 11.39 mmol) in
absolute THF (25 ml) was stirred at room temperature for 1 day and then evaporated to dryness at reduced
pressure. The residue was dissolved in anhydrous DMF (8 ml), H2NOH·HCl (2.63 g, 37.9 mmol) and Et3N
(5.36 g, 53.06 mmol) were added, and the mixture was stirred for 1 day at room temperature. The reaction
mixture was poured into water (250 ml) and extracted with EtOAc (350 ml). The extract was dried over
Na2SO4 and concentrated under reduced pressure. The product was isolated by column chromatography on
silica gel (using CH2Cl2–MeOH eluent (15:1)) as the free base and immediately converted to the hydrochloride
by passage of gaseous HCl through the eluate for several minutes. Evaporation of the solvent gave the product,
which was recrystallized from MeOH. Yield 1.13 g (50%). Colorless prisms; mp 220-222°C (decomp.). IR
spectrum, , cm-1: 950 (N–O), 1690 (C=N), 1730 (C=O), 3450 (O–H). 1H NMR spectrum, , ppm (J, Hz): 2.40
(3H, s, 6-CH3); 3.59 (3H, s, COOCH3); 5.42 (1H, d, J = 2.8, 4-СН); 7.25-7.44 (5H, m, H Ph); 9.92 (1H, br. s,
NH); 10.55 (1H, br. s, NH); 10.96 (1H, br. s, NH); 11.41 (1H, br. s, OH). 13C NMR spectrum, , ppm: 17.5
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(6-CH3); 51.5 (COOCH3); 51.7 (C-4); 102.9 (C-5); 126.5; 128.2; 128.8; 141.7; 144.7 (C-2); 151.2 (C-6); 164.9
(C=O). Found, %: C 52.46; H 5.37; N 13.98. C13H16ClN3O3. Calculated, %: C 52.44; H 5.42; N 14.11.
(2E)-N-Hydroxy-5-methoxycarbonyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-imi-
nium Chloride (2b). Prepared from compound 1b (0.59 g, 2 mmol) similarly to compound 2a. Yield 0.29 g
(44%). Colorless prisms; mp 194-196°C (decomp.). IR spectrum, , cm-1: 950 (N–O), 1690 (C=N), 1730 (C=O),
1
3450 (O–H). H NMR spectrum, , ppm (J, Hz): 2.39 (3H, s, 6-CH3); 3.58 (3H, s, COOCH3); 3.73 (3H, s,
ArOCH3); 5.36 (1H, d, J = 2.3, 4-СН); 6.79-7.01 (2H, m, H Ar); 7.09-7.32 (2H, m, H Ar); 9.85 (1H, br. s, NH);
10.51 (1H, br. s, NH); 10.91 (1H, br. s, NH); 11.35 (1H, br. s, OH). 13C NMR spectrum, , ppm: 17.5 (6-CH3);
51.2 (C-4); 51.5 (COOCH3); 55.2 (C ArOCH3); 103.0 (C-5); 114.1; 127.9; 133.7 (C Ar); 144.4 (C-2); 151.2
(C-6); 159.1 (C Ar); 164.8 (C=O). Found, %: C 51.22; H 5.39; N 12.69. C14H18ClN3O4. Calculated, %: C 51.30;
H 5.54; N 12.82.
X-ray Structural Study of Compound 2b. Single crystals of compound 2b (C14H18ClN3O4, M 327.77)
were prepared by crystallization from aqueous methanol solution. The parameters for the unit cell and
intensities of 3632 independent reflections with I > 2(I) were measured at a temperature of 190 K on a Bruker-
Nonius Kappa CCD automatic X-ray diffractomer (MoK radiation,  0.71073 Å). Crystals of compound 2b
were rhombic: a 8.6118(2), b 14.3429(4), c 25.133(1) Å; V 3104.4(2) Å3; Z 8, dcalc 1.403 g/cm3; space group
Pbc21. The structure was solved by the direct method [6] and refined in full-matrix least-squares analysis using
the SHELX program [7, 8]. The final difference factor values were R 0.064 and wR(F2) 0.160. The
crystallographic parameters, atomic coordinates and their thermal parameters, bond lengths, and valence angle
values in compound 2b have been deposited at the Cambridge Crystallographic Data Center (deposit CCDC
890695).
This work was carried out with the financial support of the European Social Fund (No.
2009/0203/1DP/1.1.1.2.0/09/APIA/VIAA/023).
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