Crystal structure of (E)-2-amino-4-methyl­sulfanyl-6-oxo-1-{[(thiophen-2-yl)­methyl­idene]­amino}-1,6-di­hydro­pyrimidine-5-carbo­nitrile

Elgemeie, G.H.; Salah, A.M.; Mohamed, R.A.; Jones, P.G.

doi:10.1107/S205698901501885X

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ISSN: 2056-9890

Volume 71| Part 11| November 2015| Pages 1319-1321

https://doi.org/10.1107/S205698901501885X

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Crystal structure of (E)-2-amino-4-methylsulfanyl-6-oxo-1-{[(thiophen-2-yl)methylidene]amino}-1,6-dihydropyrimidine-5-carbonitrile

Galal H. Elgemeie,^a Ali M. Salah,^a Reham A. Mohamed ^a and Peter G. Jones ^b ^*

^aChemistry Department, Faculty of Science, Helwan University, Cairo, Egypt, and ^bInstitut für Anorganische und Analytische Chemie, Technische Universität Braunschweig, Postfach 3329, D-38023 Braunschweig, Germany
^*Correspondence e-mail: p.jones@tu-bs.de

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 17 September 2015; accepted 7 October 2015; online 14 October 2015)

The title compound, C₁₁H₉N₅OS₂, a 1-thiophen-2-ylmethyleneaminopyrimidine derivative, displays an essentially planar C—NH₂ group. The conformation across the N=C bond linking the pyrimidine and thienyl groups is E. The pyrimidine and thienyl ring systems subtend an inter-planar angle of 42.72 (5)°. In the crystal, molecules are linked by N–H⋯N_nitrile and N–H⋯O=C hydrogen bonds, forming chains parallel to the b axis.

Keywords: crystal structure; pyrimidine; thienyl; N—H⋯N and N—H⋯O hydrogen bonds..

CCDC reference: 1430030

1. Chemical context

Pyrimidines are well known for their biological activities as antimetabolic agents and have attracted much attention from the standpoint of pharmaceutical chemistry. Many drugs, such as 5-fluorouracil, containing a pyrimidine moiety have been developed and used as anticancer agents. It is difficult to find a general method for the introduction of specific substituents into the pyrimidine nucleus directly, and thus many synthetic methods have been developed for the construction of pyrimidine rings bearing potential functional groups (Elgemeie & Sood, 2001 ). As part of our program directed toward the preparation of potential antimetabolites (Elgemeie & Hussain, 1994 ), we have recently reported various successful approaches for the syntheses of purine and pyrimidine analogues (Elgemeie, 2003 ; Elgemeie et al., 2009 ). Derivatives of these ring systems are interesting as antimetabolic agents in biochemical reactions (Scala et al., 1997 ).

We report herein on the synthesis and crystal structure of a new 1-thiophen-2-ylmethyleneaminopyrimidine derivative, obtained by reaction of dimethyl N-cyanodithioiminocarbonate with 1-cyanoacetyl-4-thiophenemethylidene semicarbazide in dioxane containing KOH at room temperature. To the best of our knowledge, this is the first example of this approach to be reported for N-substituted aminopyrimidine derivatives. The X-ray structure determination was undertaken to establish the nature of the product unambiguously.

2. Structural commentary

The molecular structure of the title compound is shown in Fig. 1. The E conformation across the double bond N2=C10 is confirmed, with a bond length of 1.2879 (14) Å. Both ring systems are, as expected, planar (r.m.s. deviations are 0.017 Å for the pyrimidine and 0.001 Å for the thienyl ring). Atom N2 lies 0.189 (2) Å out of the pyrimidine plane; all other immediate substituent atoms lie effectively in the ring plane. Carbon atom C7 of the thiomethyl group is rotated slightly out of the ring plane, with torsion angle N3—C4—S1—C7 being −6.30 (10)°. The inter-planar angle between the rings is 42.72 (5)°; the relative orientation is influenced by the torsion angles C6—N1—N2—C10 = −51.78 (13), N1—N2—C10—C11 = 174.68 (9) and N2—C10—C11—S12 = 5.22 (15)°. The NH₂ group is planar; the nitrogen atom lies only 0.048 (9) Å out of the plane of its substituents. The intramolecular contact H041⋯N2 = 2.22 (2) Å may be construed as a hydrogen bond, although the angle at the H atom is necessarily narrow at 108.4 (14) ° (Table 1).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N4—H041⋯N2	0.827 (18)	2.224 (17)	2.6062 (13)	108.4 (14)
N4—H041⋯N5ⁱ	0.827 (18)	2.513 (17)	3.0555 (14)	124.2 (15)
N4—H042⋯O1ⁱ	0.823 (17)	2.144 (17)	2.9414 (12)	163.1 (15)
C13—H13⋯N5ⁱⁱ	0.95	2.49	3.2722 (15)	139
C10—H10⋯O1ⁱⁱⁱ	0.95	2.35	3.2124 (13)	150
Symmetry codes: (i) $[-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (ii) $[x+1, -y+{\script{3\over 2}}, z-{\script{1\over 2}}]$ ; (iii) $[x, -y+{\script{3\over 2}}, z-{\script{1\over 2}}]$ .

Figure 1
The molecule structure of the title compound, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular hydrogen bond, H042⋯N1, is not shown.

3. Supramolecular features

In the crystal, molecules are connected into chains parallel to the b axis by the two classical hydrogen bonds, H041⋯N5 2.51 (2) Å and H042⋯O1 2.14 (2) Å (Table 1 and Fig. 2), both involving the 2₁ screw operator −x + 1, y − $[{1\over 2}]$ , −z + $[{3\over 2}]$ . The longer of these two contacts forms part of a three-center system with the intramolecular contact H041⋯N2 (Table 1). The `weak' hydrogen bond H13⋯N5 of 2.49 Å, formed via the c glide operator x + 1, −y + $[{3\over 2}]$ , z − $[{1\over 2}]$ , connects the chains to form layers parallel to (102) (Table 1 and Fig. 2).

Figure 2
Crystal packing diagram of the title compound, viewed perpendicular to (102). Classical hydrogen bonds are drawn as thick dashed lines and `weak' hydrogen bonds as thin dashed lines (see Table 1

4. Database survey

A search of the Cambridge Structural Database (Version 5.36, 2014; Groom & Allen, 2014 ) revealed 42 hits for pyrimidines with the amino and C=O functions located as for the title compound.

5. Synthesis and crystallization

Dimethyl N-cyanodithioiminocarbonate (0.01 mol) was added to a stirred solution of 1-cyanoacetyl-4-thiophenemethylidenesemicarbazide (0.01 mol) in dry dioxane (50 ml), containing potassium hydroxide (0.01 mol), at room temperature. The solution was stirred overnight at room temperature, after which a colourless solid product was collected by filtration and crystallized from ethanol (m.p. 541–542 K), giving colourless block-like crystals.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. The NH hydrogen atoms were located in a difference Fourier map and freely refined. The C-bound H atoms were included in calculated positions and treated as riding atoms: C—H = 0.95–0.98 Å with U_iso(H) = 1.5U_eq(C) for methyl H atoms and 1.2U_eq(C) for other H atoms. The methyl group was refined as an idealized rigid group, allowed to rotate but not to tip.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₁H₉N₅OS₂
M_r	291.35
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	100
a, b, c (Å)	11.4650 (4), 14.7715 (4), 7.5924 (3)
β (°)	96.397 (3)
V (Å³)	1277.81 (8)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.42
Crystal size (mm)	0.40 × 0.40 × 0.12

Data collection
Diffractometer	Oxford Diffraction Xcalibur, Eos
Absorption correction	Multi-scan (CrysAlis PRO; Agilent, 2013 )
T_min, T_max	0.949, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	40035, 3838, 3400
R_int	0.035
(sin θ/λ)_max (Å⁻¹)	0.719

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.030, 0.078, 1.05
No. of reflections	3838
No. of parameters	181
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.45, −0.28
Computer programs: CrysAlis PRO (Agilent, 2013), SHELXS97, SHELXL97 and XP in SHELXTL (Sheldrick, 2008 ).

Supporting information

CCDC reference: 1430030

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S205698901501885X/su5217sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S205698901501885X/su5217Isup2.hkl

checkCIF report

Computing details top

Data collection: CrysAlis PRO (Agilent, 2013); cell refinement: CrysAlis PRO (Agilent, 2013); data reduction: CrysAlis PRO (Agilent, 2013); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

(E)-2-Amino-4-methylsulfanyl-6-oxo-1-{[(thiophen-2-yl)methylidene]amino}-1,6-dihydropyrimidine-5-carbonitrile top

Crystal data top

C₁₁H₉N₅OS₂	F(000) = 600
M_r = 291.35	D_x = 1.514 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yc	Cell parameters from 11992 reflections
a = 11.4650 (4) Å	θ = 2.8–30.7°
b = 14.7715 (4) Å	µ = 0.42 mm⁻¹
c = 7.5924 (3) Å	T = 100 K
β = 96.397 (3)°	Block, colourless
V = 1277.81 (8) Å³	0.40 × 0.40 × 0.12 mm
Z = 4

Data collection top

Oxford Diffraction Xcalibur, Eos diffractometer	3838 independent reflections
Radiation source: Enhance (Mo) X-ray Source	3400 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.035
Detector resolution: 16.1419 pixels mm^-1	θ_max = 30.7°, θ_min = 2.3°
ω–scan	h = −16→16
Absorption correction: multi-scan (CrysAlis Pro; Agilent, 2013)	k = −21→20
T_min = 0.949, T_max = 1.000	l = −10→10
40035 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.030	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.078	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ²(F_o²) + (0.0353P)² + 0.5986P] where P = (F_o² + 2F_c²)/3
3838 reflections	(Δ/σ)_max = 0.001
181 parameters	Δρ_max = 0.45 e Å⁻³
0 restraints	Δρ_min = −0.28 e Å⁻³

Special details top

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.

NH H atoms were refined freely. The methyl was refined as an idealized rigid group allowed to rotate but not tip (AFIX 137). Other H atoms were included using a riding model starting from calculated positions.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
S1	0.18882 (2)	0.570453 (19)	0.93852 (4)	0.01607 (8)
N1	0.53629 (8)	0.58971 (6)	0.73366 (12)	0.01132 (17)
C2	0.48455 (9)	0.50790 (7)	0.76239 (14)	0.01123 (19)
N3	0.37941 (8)	0.50061 (6)	0.82064 (12)	0.01267 (18)
C4	0.32601 (9)	0.57730 (7)	0.86044 (14)	0.01173 (19)
C5	0.37518 (9)	0.66299 (7)	0.84526 (14)	0.0122 (2)
C6	0.48602 (9)	0.67272 (7)	0.77860 (14)	0.01108 (19)
C7	0.15734 (11)	0.45152 (8)	0.91405 (16)	0.0186 (2)
H7A	0.1624	0.4334	0.7910	0.028*
H7B	0.0781	0.4395	0.9450	0.028*
H7C	0.2144	0.4169	0.9929	0.028*
C8	0.31807 (10)	0.74448 (7)	0.88764 (15)	0.0147 (2)
O1	0.53764 (7)	0.74475 (5)	0.75918 (11)	0.01462 (16)
N2	0.65393 (8)	0.58528 (6)	0.69401 (13)	0.01224 (18)
N4	0.54197 (9)	0.43358 (6)	0.72510 (14)	0.01410 (18)
H041	0.6097 (16)	0.4387 (12)	0.699 (2)	0.027 (4)*
H042	0.5115 (14)	0.3849 (11)	0.746 (2)	0.020 (4)*
N5	0.27567 (9)	0.81204 (7)	0.92072 (15)	0.0213 (2)
C10	0.67911 (9)	0.64245 (7)	0.57588 (14)	0.0123 (2)
H10	0.6191	0.6792	0.5165	0.015*
C11	0.79798 (9)	0.65073 (7)	0.53371 (14)	0.0124 (2)
S12	0.91097 (2)	0.58149 (2)	0.62072 (4)	0.01827 (8)
C13	1.01057 (10)	0.64133 (9)	0.51488 (16)	0.0190 (2)
H13	1.0919	0.6273	0.5232	0.023*
C14	0.96003 (11)	0.71124 (8)	0.41744 (16)	0.0189 (2)
H14	1.0022	0.7516	0.3505	0.023*
C15	0.83751 (10)	0.71713 (8)	0.42687 (15)	0.0157 (2)
H15	0.7883	0.7616	0.3666	0.019*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.01141 (13)	0.01430 (13)	0.02338 (15)	−0.00065 (9)	0.00585 (10)	−0.00028 (10)
N1	0.0097 (4)	0.0088 (4)	0.0158 (4)	0.0005 (3)	0.0028 (3)	−0.0004 (3)
C2	0.0122 (5)	0.0093 (4)	0.0120 (5)	−0.0008 (4)	0.0002 (4)	−0.0001 (3)
N3	0.0116 (4)	0.0110 (4)	0.0154 (4)	−0.0006 (3)	0.0014 (3)	−0.0001 (3)
C4	0.0099 (4)	0.0130 (5)	0.0121 (5)	−0.0001 (4)	0.0001 (4)	0.0006 (4)
C5	0.0110 (5)	0.0105 (4)	0.0153 (5)	0.0007 (4)	0.0024 (4)	−0.0004 (4)
C6	0.0107 (5)	0.0094 (4)	0.0130 (5)	0.0010 (3)	0.0007 (4)	−0.0008 (4)
C7	0.0168 (5)	0.0164 (5)	0.0235 (6)	−0.0054 (4)	0.0058 (4)	−0.0012 (4)
C8	0.0127 (5)	0.0136 (5)	0.0185 (5)	−0.0014 (4)	0.0045 (4)	0.0010 (4)
O1	0.0142 (4)	0.0086 (3)	0.0217 (4)	−0.0011 (3)	0.0044 (3)	−0.0012 (3)
N2	0.0090 (4)	0.0109 (4)	0.0173 (4)	0.0003 (3)	0.0035 (3)	−0.0014 (3)
N4	0.0134 (4)	0.0079 (4)	0.0214 (5)	−0.0002 (3)	0.0036 (4)	−0.0005 (3)
N5	0.0189 (5)	0.0158 (5)	0.0308 (6)	0.0014 (4)	0.0104 (4)	−0.0002 (4)
C10	0.0123 (5)	0.0115 (4)	0.0130 (5)	0.0009 (4)	0.0008 (4)	−0.0022 (4)
C11	0.0124 (5)	0.0111 (4)	0.0139 (5)	0.0009 (4)	0.0023 (4)	−0.0014 (4)
S12	0.01309 (14)	0.01868 (14)	0.02389 (16)	0.00414 (10)	0.00586 (11)	0.00657 (11)
C13	0.0128 (5)	0.0241 (6)	0.0210 (6)	−0.0025 (4)	0.0058 (4)	−0.0022 (5)
C14	0.0202 (6)	0.0181 (5)	0.0199 (5)	−0.0053 (4)	0.0084 (4)	−0.0004 (4)
C15	0.0181 (5)	0.0140 (5)	0.0158 (5)	0.0001 (4)	0.0048 (4)	0.0000 (4)

Geometric parameters (Å, º) top

S1—C4	1.7446 (11)	C11—C15	1.3811 (15)
S1—C7	1.7990 (12)	C11—S12	1.7234 (11)
N1—C2	1.3744 (13)	S12—C13	1.7133 (12)
N1—C6	1.4127 (13)	C13—C14	1.3617 (18)
N1—N2	1.4158 (12)	C14—C15	1.4172 (16)
C2—N4	1.3268 (13)	C7—H7A	0.9800
C2—N3	1.3337 (14)	C7—H7B	0.9800
N3—C4	1.3382 (13)	C7—H7C	0.9800
C4—C5	1.3956 (14)	N4—H041	0.827 (18)
C5—C8	1.4242 (15)	N4—H042	0.823 (17)
C5—C6	1.4265 (14)	C10—H10	0.9500
C6—O1	1.2343 (13)	C13—H13	0.9500
C8—N5	1.1500 (15)	C14—H14	0.9500
N2—C10	1.2879 (14)	C15—H15	0.9500
C10—C11	1.4395 (14)

C4—S1—C7	101.52 (5)	C10—C11—S12	123.65 (8)
C2—N1—C6	122.00 (9)	C13—S12—C11	91.48 (6)
C2—N1—N2	115.55 (8)	C14—C13—S12	112.37 (9)
C6—N1—N2	121.03 (8)	C13—C14—C15	112.54 (10)
N4—C2—N3	119.49 (10)	C11—C15—C14	112.22 (10)
N4—C2—N1	117.42 (10)	S1—C7—H7A	109.5
N3—C2—N1	123.07 (9)	S1—C7—H7B	109.5
C2—N3—C4	117.37 (9)	H7A—C7—H7B	109.5
N3—C4—C5	123.36 (10)	S1—C7—H7C	109.5
N3—C4—S1	118.70 (8)	H7A—C7—H7C	109.5
C5—C4—S1	117.93 (8)	H7B—C7—H7C	109.5
C4—C5—C8	123.21 (10)	C2—N4—H041	118.5 (12)
C4—C5—C6	120.31 (9)	C2—N4—H042	116.8 (11)
C8—C5—C6	116.44 (9)	H041—N4—H042	123.9 (16)
O1—C6—N1	120.35 (9)	N2—C10—H10	119.9
O1—C6—C5	125.96 (10)	C11—C10—H10	119.9
N1—C6—C5	113.69 (9)	C14—C13—H13	123.8
N5—C8—C5	177.44 (12)	S12—C13—H13	123.8
C10—N2—N1	114.23 (9)	C13—C14—H14	123.7
N2—C10—C11	120.12 (10)	C15—C14—H14	123.7
C15—C11—C10	124.88 (10)	C11—C15—H15	123.9
C15—C11—S12	111.39 (8)	C14—C15—H15	123.9

C6—N1—C2—N4	−176.23 (10)	N2—N1—C6—C5	−169.29 (9)
N2—N1—C2—N4	−9.70 (14)	C4—C5—C6—O1	179.88 (11)
C6—N1—C2—N3	5.62 (16)	C8—C5—C6—O1	2.07 (17)
N2—N1—C2—N3	172.15 (10)	C4—C5—C6—N1	−0.23 (15)
N4—C2—N3—C4	178.49 (10)	C8—C5—C6—N1	−178.04 (9)
N1—C2—N3—C4	−3.40 (16)	C2—N1—N2—C10	141.55 (10)
C2—N3—C4—C5	−0.54 (16)	C6—N1—N2—C10	−51.78 (13)
C2—N3—C4—S1	−179.55 (8)	N1—N2—C10—C11	174.68 (9)
C7—S1—C4—N3	−6.30 (10)	N2—C10—C11—C15	−171.31 (11)
C7—S1—C4—C5	174.63 (9)	N2—C10—C11—S12	5.22 (15)
N3—C4—C5—C8	179.96 (11)	C15—C11—S12—C13	0.11 (9)
S1—C4—C5—C8	−1.01 (15)	C10—C11—S12—C13	−176.84 (10)
N3—C4—C5—C6	2.31 (17)	C11—S12—C13—C14	0.08 (10)
S1—C4—C5—C6	−178.67 (8)	S12—C13—C14—C15	−0.25 (14)
C2—N1—C6—O1	176.40 (10)	C10—C11—C15—C14	176.64 (10)
N2—N1—C6—O1	10.60 (15)	S12—C11—C15—C14	−0.26 (13)
C2—N1—C6—C5	−3.50 (15)	C13—C14—C15—C11	0.33 (15)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N4—H041···N2	0.827 (18)	2.224 (17)	2.6062 (13)	108.4 (14)
N4—H041···N5ⁱ	0.827 (18)	2.513 (17)	3.0555 (14)	124.2 (15)
N4—H042···O1ⁱ	0.823 (17)	2.144 (17)	2.9414 (12)	163.1 (15)
C13—H13···N5ⁱⁱ	0.95	2.49	3.2722 (15)	139
C10—H10···O1ⁱⁱⁱ	0.95	2.35	3.2124 (13)	150

Symmetry codes: (i) −x+1, y−1/2, −z+3/2; (ii) x+1, −y+3/2, z−1/2; (iii) x, −y+3/2, z−1/2.

References

Agilent (2013). CrysAlis PRO. Agilent Technologies Ltd, Yarnton, England. Google Scholar
Elgemeie, G. H. (2003). Curr. Pharm. Des. 9, 2627–2642. Web of Science CrossRef PubMed CAS Google Scholar
Elgemeie, G. H. & Hussain, B. A. (1994). Tetrahedron, 50, 199–204. CrossRef CAS Web of Science Google Scholar
Elgemeie, G. H. & Sood, S. A. (2001). J. Chem. Res. (S), pp. 439–441. CrossRef Google Scholar
Elgemeie, G. H., Zaghary, W. A., Amin, K. M. & Nasr, T. M. (2009). J. Carbohydr. Chem. 28, 161–178. Web of Science CrossRef CAS Google Scholar
Groom, C. R. & Allen, F. H. (2014). Angew. Chem. Int. Ed. 53, 662–671. Web of Science CSD CrossRef CAS Google Scholar
Scala, S., Akhmed, N., Rao, U. S., Paul, K., Lan, L., Dickstein, B., Lee, J., Elgemeie, G. H., Stein, W. D. & Bates, S. E. (1997). Mol. Pharm. 51, 1024–1033. CAS Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar

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