Methyl 4-(4-hydr­oxy-3-methoxy­phen­yl)-6-methyl-2-thioxo-1,2,3,4-tetra­hydro­pyrimidine-5-carboxyl­ate

The title compound, C₁₄H₁₆N₂O₄S, was synthesized by the reaction of 4-hydr­oxy-3-methoxy­benzaldehyde, thio­urea and methyl 3-oxobutanoate in ethanol under reflux. The crystal structure is stabilized mainly through inter­molecular N—H...S and O—H...O hydrogen bonds. The tetrahydropyrimidin-2-one ring is twisted.

Key indicators

• Single-crystal X-ray study
• T = 294 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.043
• wR factor = 0.115
• Data-to-parameter ratio = 12.5

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT066_ALERT_1_C Predicted and Reported Transmissions Identical .          ?

Alert level G
PLAT793_ALERT_1_G Check the Absolute Configuration of C4     = ...          S
PLAT860_ALERT_3_G Note: Number of Least-Squares Restraints .......          2

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   1 ALERT level C = Check and explain
   2 ALERT level G = General alerts; check

   2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   0 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

---

S1. Comment

Dihydropyrimidinones (DHPMs) and their derivatives exhibit a wide range of biological activities such as antibacterial, antiviral, antitumor and anti-inflamatory actions (Kappe, 1993). These compounds also exhibit pharmacological activities as calcium channel blockers, antihypertensive agents, and neuropeptide Y(NPY) antagonists (Atwal et al., 1989, 1991; Rovnyak et al., 1992; Kappe & Fabian, 1997). The structure of the title compound (Fig. 1.) was synthesized by the reaction of 4-hydroxy-3-methoxybenzaldehyde, thiourea and methyl 3-oxobutanoate in ethanol under reflux. The tetrahydropyrimidin-2-one ring is twisted [C3—N2—C4—C5= 35.0 (3) °]; the phenyl ring is almost perpendicular to the tetrahydropyrimidin-2-one ring [C3—N2—C4—C8=-90.7 (3)° and C8—C4—C5—C2=98.9 (3)°]. The crystal structure is stabilized mainly through intermolecular N—H···S and O—H···O hydrogen bonds.

Related literature

For related literature, see: Atwal et al. (1989, 1991); Kappe (1993); Kappe & Fabian (1997); Rovnyak et al. (1992).

S2. Experimental

A solution of methyl 3-oxobutanoate (1.74 g, 15 mmol), 4-hydroxy-3-methoxybenzaldehyde (1.52 g, 10.0 mmol) and thiourea (0.76 g, 10 mmol) in ethanol (10 ml) was heated under reflux in the presence of a catalytic amount of HCl for 5 h. The reaction mixture was cooled and filtered. the product was recrystallized from ethanol to afford the pure product. The title product was dissolved in 100 ml absolute ethanol and crystals suitable for X-ray analysis were grown by slow evaporation of the absolute ethanol solution at room temperature over a period of 15 d.

S3. Refinement

Carbon-bound H atoms were positioned geometrically, with C—H =0.93–0.96 Å, and refined in a riding model, with U_iso(H)= 1.2Ueq(carrier). The positional parameters of the nitrogen-bound H atoms were refined freely, with U_iso(H)=1.2Ueq(N).

Computing details

Data collection: SMART (Bruker, 1997); cell refinement: SAINT (Bruker, 1997); data reduction: SAINT (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1997); software used to prepare material for publication: SHELXTL (Bruker, 1997).

Figures

	Fig. 1. The molecular structure of (I), drawn with 30% probability ellipsoids.
	Fig. 2. The formation of the title compound.

Methyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate

Crystal data

C14H16N2O4S	Z = 2
Mr = 308.35	F(000) = 324
Triclinic, P1	Dx = 1.425 Mg m^−3
Hall symbol: -P 1	Melting point = 235–236 K
a = 7.267 (3) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.863 (3) Å	Cell parameters from 1119 reflections
c = 12.002 (5) Å	θ = 2.9–25.9°
α = 103.234 (7)°	µ = 0.24 mm^−1
β = 90.318 (7)°	T = 294 K
γ = 106.710 (6)°	Prism, colourless
V = 718.6 (5) Å^3	0.24 × 0.20 × 0.18 mm

Data collection

Bruker SMART CCD area-detector diffractometer	2531 independent reflections
Radiation source: fine-focus sealed tube	1753 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.025
φ and ω scans	θmax = 25.0°, θmin = 1.8°
Absorption correction: multi-scan (SADABS; Bruker, 1997)	h = −8→8
Tmin = 0.944, Tmax = 0.958	k = −10→10
3781 measured reflections	l = −14→7

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.043	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.115	H atoms treated by a mixture of independent and constrained refinement
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0524P)^2 + 0.1382P] where P = (Fo^2 + 2Fc^2)/3
2531 reflections	(Δ/σ)max = 0.001
202 parameters	Δρmax = 0.21 e Å^−3
2 restraints	Δρmin = −0.25 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	0.31510 (9)	0.62332 (8)	0.54227 (6)	0.0388 (2)
O1	−0.2713 (3)	1.0669 (2)	0.66422 (19)	0.0483 (6)
O2	−0.0006 (2)	1.26508 (18)	0.72514 (16)	0.0363 (5)
O3	−0.2544 (3)	0.6472 (3)	1.06798 (17)	0.0574 (6)
H3	−0.1590	0.6879	1.1137	0.086*
O4	0.0976 (2)	0.8131 (2)	1.04330 (16)	0.0443 (5)
N1	0.2938 (3)	0.9175 (2)	0.63172 (19)	0.0328 (5)
N2	0.0090 (3)	0.7232 (2)	0.58519 (18)	0.0297 (5)
C1	0.3447 (4)	1.2034 (3)	0.6602 (3)	0.0434 (7)
H1A	0.2761	1.2743	0.6432	0.065*
H1B	0.4397	1.1945	0.6058	0.065*
H1C	0.4071	1.2469	0.7363	0.065*
C2	0.2072 (3)	1.0404 (3)	0.6530 (2)	0.0294 (6)
C3	0.1972 (3)	0.7589 (3)	0.5887 (2)	0.0296 (6)
C4	−0.0958 (3)	0.8260 (3)	0.6518 (2)	0.0275 (6)
H4	−0.2191	0.8051	0.6087	0.033*
C5	0.0173 (3)	1.0000 (3)	0.6617 (2)	0.0264 (6)
C6	−0.0997 (4)	1.1106 (3)	0.6815 (2)	0.0305 (6)
C7	−0.1091 (4)	1.3800 (3)	0.7458 (3)	0.0521 (8)
H7A	−0.1830	1.3699	0.6765	0.078*
H7B	−0.0224	1.4880	0.7697	0.078*
H7C	−0.1944	1.3587	0.8048	0.078*
C8	−0.1382 (3)	0.7839 (3)	0.7652 (2)	0.0261 (6)
C9	−0.3190 (4)	0.6940 (3)	0.7815 (2)	0.0346 (6)
H9	−0.4169	0.6633	0.7233	0.042*
C10	−0.3575 (4)	0.6485 (3)	0.8831 (2)	0.0405 (7)
H10	−0.4811	0.5878	0.8935	0.049*
C11	−0.2150 (4)	0.6924 (3)	0.9683 (2)	0.0354 (6)
C12	−0.0310 (3)	0.7810 (3)	0.9522 (2)	0.0304 (6)
C13	0.0065 (3)	0.8277 (3)	0.8523 (2)	0.0290 (6)
H13	0.1298	0.8892	0.8425	0.035*
C14	0.2913 (4)	0.8916 (4)	1.0324 (3)	0.0513 (8)
H14A	0.3376	0.8273	0.9697	0.077*
H14B	0.3663	0.9054	1.1021	0.077*
H14C	0.3026	0.9959	1.0179	0.077*
H1	0.4218 (15)	0.947 (3)	0.632 (2)	0.037 (7)*
H2	−0.066 (3)	0.6219 (16)	0.556 (2)	0.044 (8)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0328 (4)	0.0352 (4)	0.0451 (5)	0.0123 (3)	0.0001 (3)	0.0002 (3)
O1	0.0286 (11)	0.0344 (10)	0.0798 (16)	0.0103 (8)	−0.0030 (10)	0.0086 (10)
O2	0.0356 (10)	0.0243 (9)	0.0473 (12)	0.0085 (8)	−0.0015 (9)	0.0056 (8)
O3	0.0382 (12)	0.0775 (15)	0.0423 (13)	−0.0137 (11)	0.0001 (10)	0.0260 (12)
O4	0.0270 (10)	0.0600 (12)	0.0381 (12)	−0.0040 (9)	−0.0035 (9)	0.0181 (10)
N1	0.0205 (11)	0.0300 (11)	0.0424 (14)	0.0033 (9)	0.0021 (10)	0.0036 (10)
N2	0.0245 (11)	0.0242 (11)	0.0342 (13)	0.0036 (9)	0.0008 (9)	−0.0007 (9)
C1	0.0324 (15)	0.0310 (14)	0.062 (2)	0.0009 (12)	0.0139 (14)	0.0130 (14)
C2	0.0298 (14)	0.0250 (13)	0.0304 (15)	0.0045 (11)	0.0035 (11)	0.0056 (11)
C3	0.0257 (13)	0.0318 (14)	0.0278 (15)	0.0056 (11)	0.0000 (11)	0.0041 (11)
C4	0.0220 (12)	0.0249 (12)	0.0321 (15)	0.0042 (10)	−0.0023 (11)	0.0040 (11)
C5	0.0261 (13)	0.0226 (12)	0.0286 (14)	0.0044 (10)	0.0005 (11)	0.0063 (10)
C6	0.0308 (15)	0.0283 (13)	0.0318 (15)	0.0061 (11)	0.0012 (12)	0.0094 (11)
C7	0.065 (2)	0.0315 (15)	0.062 (2)	0.0245 (15)	−0.0072 (17)	0.0028 (15)
C8	0.0214 (12)	0.0202 (12)	0.0342 (15)	0.0043 (10)	0.0033 (11)	0.0036 (11)
C9	0.0252 (13)	0.0346 (14)	0.0378 (16)	0.0017 (11)	−0.0037 (12)	0.0057 (12)
C10	0.0237 (14)	0.0418 (15)	0.0469 (18)	−0.0062 (12)	0.0062 (13)	0.0127 (13)
C11	0.0301 (14)	0.0355 (14)	0.0340 (16)	−0.0026 (12)	0.0047 (13)	0.0111 (12)
C12	0.0247 (13)	0.0269 (13)	0.0352 (16)	0.0021 (10)	0.0004 (12)	0.0064 (11)
C13	0.0210 (12)	0.0254 (13)	0.0370 (16)	0.0007 (10)	0.0050 (11)	0.0084 (11)
C14	0.0249 (15)	0.070 (2)	0.052 (2)	0.0020 (14)	−0.0022 (14)	0.0169 (17)

Geometric parameters (Å, º)

S1—C3	1.667 (3)	C4—C5	1.501 (3)
O1—C6	1.196 (3)	C4—C8	1.503 (4)
O2—C6	1.329 (3)	C4—H4	0.9800
O2—C7	1.438 (3)	C5—C6	1.454 (3)
O3—C11	1.353 (3)	C7—H7A	0.9600
O3—H3	0.8200	C7—H7B	0.9600
O4—C12	1.358 (3)	C7—H7C	0.9600
O4—C14	1.401 (3)	C8—C9	1.368 (3)
N1—C3	1.353 (3)	C8—C13	1.384 (3)
N1—C2	1.384 (3)	C9—C10	1.376 (4)
N1—H1	0.891 (10)	C9—H9	0.9300
N2—C3	1.310 (3)	C10—C11	1.359 (4)
N2—C4	1.457 (3)	C10—H10	0.9300
N2—H2	0.894 (10)	C11—C12	1.382 (3)
C1—C2	1.485 (3)	C12—C13	1.359 (4)
C1—H1A	0.9600	C13—H13	0.9300
C1—H1B	0.9600	C14—H14A	0.9600
C1—H1C	0.9600	C14—H14B	0.9600
C2—C5	1.334 (3)	C14—H14C	0.9600
C6—O2—C7	116.6 (2)	O2—C6—C5	114.3 (2)
C11—O3—H3	109.5	O2—C7—H7A	109.5
C12—O4—C14	118.0 (2)	O2—C7—H7B	109.5
C3—N1—C2	123.9 (2)	H7A—C7—H7B	109.5
C3—N1—H1	117.5 (16)	O2—C7—H7C	109.5
C2—N1—H1	117.1 (16)	H7A—C7—H7C	109.5
C3—N2—C4	124.5 (2)	H7B—C7—H7C	109.5
C3—N2—H2	121.0 (17)	C9—C8—C13	119.0 (2)
C4—N2—H2	112.6 (18)	C9—C8—C4	120.1 (2)
C2—C1—H1A	109.5	C13—C8—C4	120.8 (2)
C2—C1—H1B	109.5	C8—C9—C10	120.7 (2)
H1A—C1—H1B	109.5	C8—C9—H9	119.7
C2—C1—H1C	109.5	C10—C9—H9	119.6
H1A—C1—H1C	109.5	C11—C10—C9	119.9 (2)
H1B—C1—H1C	109.5	C11—C10—H10	120.0
C5—C2—N1	118.1 (2)	C9—C10—H10	120.0
C5—C2—C1	128.7 (2)	O3—C11—C10	119.5 (2)
N1—C2—C1	113.2 (2)	O3—C11—C12	120.7 (2)
N2—C3—N1	115.2 (2)	C10—C11—C12	119.9 (3)
N2—C3—S1	123.90 (19)	O4—C12—C13	126.3 (2)
N1—C3—S1	120.90 (18)	O4—C12—C11	113.5 (2)
N2—C4—C5	108.29 (19)	C13—C12—C11	120.2 (2)
N2—C4—C8	110.69 (19)	C12—C13—C8	120.3 (2)
C5—C4—C8	113.99 (19)	C12—C13—H13	119.8
N2—C4—H4	107.9	C8—C13—H13	119.8
C5—C4—H4	107.9	O4—C14—H14A	109.5
C8—C4—H4	107.9	O4—C14—H14B	109.5
C2—C5—C6	126.2 (2)	H14A—C14—H14B	109.5
C2—C5—C4	120.1 (2)	O4—C14—H14C	109.5
C6—C5—C4	113.7 (2)	H14A—C14—H14C	109.5
O1—C6—O2	122.3 (2)	H14B—C14—H14C	109.5
O1—C6—C5	123.3 (2)
C3—N1—C2—C5	18.8 (4)	C4—C5—C6—O2	160.2 (2)
C3—N1—C2—C1	−159.8 (2)	N2—C4—C8—C9	−102.9 (2)
C4—N2—C3—N1	−18.7 (4)	C5—C4—C8—C9	134.8 (2)
C4—N2—C3—S1	162.42 (19)	N2—C4—C8—C13	73.6 (3)
C2—N1—C3—N2	−10.7 (4)	C5—C4—C8—C13	−48.7 (3)
C2—N1—C3—S1	168.2 (2)	C13—C8—C9—C10	0.5 (4)
C3—N2—C4—C5	35.0 (3)	C4—C8—C9—C10	177.1 (2)
C3—N2—C4—C8	−90.7 (3)	C8—C9—C10—C11	−0.3 (4)
N1—C2—C5—C6	−178.8 (2)	C9—C10—C11—O3	179.9 (2)
C1—C2—C5—C6	−0.4 (5)	C9—C10—C11—C12	−0.7 (4)
N1—C2—C5—C4	1.7 (4)	C14—O4—C12—C13	−4.9 (4)
C1—C2—C5—C4	−180.0 (3)	C14—O4—C12—C11	175.3 (2)
N2—C4—C5—C2	−24.8 (3)	O3—C11—C12—O4	0.7 (4)
C8—C4—C5—C2	98.9 (3)	C10—C11—C12—O4	−178.6 (2)
N2—C4—C5—C6	155.6 (2)	O3—C11—C12—C13	−179.1 (2)
C8—C4—C5—C6	−80.8 (3)	C10—C11—C12—C13	1.6 (4)
C7—O2—C6—O1	−3.0 (4)	O4—C12—C13—C8	178.8 (2)
C7—O2—C6—C5	179.6 (2)	C11—C12—C13—C8	−1.3 (4)
C2—C5—C6—O1	163.2 (3)	C9—C8—C13—C12	0.3 (3)
C4—C5—C6—O1	−17.2 (4)	C4—C8—C13—C12	−176.2 (2)
C2—C5—C6—O2	−19.4 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O2^i	0.82	2.14	2.905 (3)	155
O3—H3···O4	0.82	2.16	2.614 (3)	115
N1—H1···O1^ii	0.89 (1)	2.17 (1)	3.039 (3)	166 (2)
N2—H2···S1^iii	0.89 (1)	2.44 (1)	3.312 (2)	167 (2)

Symmetry codes: (i) −x, −y+2, −z+2; (ii) x+1, y, z; (iii) −x, −y+1, −z+1.