4-Amino-6-(piperidin-1-yl)pyrimidine-5-carbo­nitrile

In the crystal, mol­ecules of the title compound are linked into (100) sheets by N—H⋯N hydrogen bonds.

Abstract

In the title compound, C₁₀H₁₃N₅, the piperidine ring adopts a chair conformation with the exocyclic N—C bond in an axial orientation, and the dihedral angle between the mean planes of piperidine and pyrimidine rings is 49.57 (11)°. A short intra­molecular C—H⋯N contact generates an S(7) ring. In the crystal, N—H⋯N hydrogen bonds link the mol­ecules into (100) sheets and a weak aromatic π-π stacking inter­action is observed [centroid–centroid separation = 3.5559 (11) Å] between inversion-related pyrimidine rings.

Structure description

Pyrimidine derivatives exhibit a broad spectrum of biological activities such as GPR119 agonists (Fang et al., 2019 ▸), VEGFR-2 tyrosine kinase inhibitors (Sun et al., 2018 ▸) and anti­tumor activity (Hassan et al., 2017 ▸). As part of our studies in this area, we now describe the synthesis and structure of the title compound.

The title compound crystallizes with one mol­ecule in the asymmetric unit (Fig. 1 ▸). The piperidine ring adopts a chair conformation, with atoms N3 and C7 displaced from the mean plane of the other four atoms (C5/C6/C8/C9) by −0.2472 (2) and 0.2133 (3) Å, respectively. The exocyclic N3—C4 bond has an axial orientation and the dihedral angle between the piperidine ring mean plane (all atoms) and the pyrimidine ring is 49.57 (11)°. A short intra­molecular C9—H9B⋯N5 contact generates an S(7) ring.

Figure 1.

The mol­ecular structure of the title compound with displacement ellipsoids drawn at the 50% probability level. The short C—H⋯N contact is indicated by a double-dashed line.

In the crystal, N4—H4A⋯N1 hydrogen bonds (Table 1 ▸) link the mol­ecules into inversion dimers characterized by an (8) graph set motif (Fig. 2 ▸) and N4—H4B⋯N5 hydrogen bonds link the dimers into (100) sheets. The packing also features π–π stacking inter­actions between inversion-related pyrimidine rings at a centroid–centroid distance of 3.5559 (11) Å (Fig. 3 ▸).

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N4—H4A⋯N1i	0.86	2.12	2.983 (2)	173
N4—H4B⋯N5ii	0.86	2.44	3.115 (3)	135
C9—H9B⋯N5	0.97	2.61	3.484 (1)	148

Symmetry codes: (i) ; (ii) .

Figure 2.

Unit-cell packing of the title compound showing N—H⋯N inter­actions as dotted green and purple lines. H atoms not involved in hydrogen bonding have been excluded.

Figure 3.

A fragment of the packing depicting the π–π inter­action as a dashed line.

Synthesis and crystallization

A mixture of 4-amino-6-chloro-pyrimidine-5-carbo­nitrile 1.0 g (0.0065 mol) and piperidine (2.75 g, 0.0325 mol) was refluxed in 20 ml of ethanol for 6 h. The reaction mixture was then cooled and stirred for 2 h at room temperature. The solid obtained was filtered, washed with ethanol and dried giving 0.98 g of white solid (yield 74%), which was recrystallized from acetone solution to obtain colourless blocks of the title compound. IR (ν, cm⁻¹: 3426, 3308 (NH), 2190 (C=N), 1646 (C=N), 1223 (CN). ¹H NMR (400 MHz DMSO-d ₆): δ 8.01 (s, 1H, pyrimidine CH), 7.21 (br. s, 1 N, NH₂), 3.76 (t, 2H, CH₂), 1.73–1.48 (m, 6H, 3CH₂). ¹³C NMR (DMSO-d ₆): δ 168.5, 164.3, 159.9, 118.1, 58.9, 26.8, 24.9.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸.

Table 2. Experimental details.

Crystal data
Chemical formula	C10H13N5
M r	203.25
Crystal system, space group	Monoclinic, P21/c
Temperature (K)	446
a, b, c (Å)	10.7335 (9), 12.4005 (10), 7.9206 (6)
β (°)	93.654 (4)
V (Å3)	1052.09 (15)
Z	4
Radiation type	Mo Kα
μ (mm−1)	0.08
Crystal size (mm)	0.18 × 0.16 × 0.15
Data collection
Diffractometer	Bruker SMART APEX CCD
Absorption correction	Multi-scan (SADABS; Bruker, 1998 ▸)
No. of measured, independent and observed [I > 2σ(I)] reflections	12900, 1855, 1452
R int	0.034
(sin θ/λ)max (Å−1)	0.595
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.050, 0.180, 1.16
No. of reflections	1855
No. of parameters	136
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.21, −0.28

Computer programs: SMART and SAINT (Bruker, 1998 ▸), SHELXS97 (Sheldrick, 2008 ▸), SHELXL2018 (Sheldrick, 2015 ▸) and ORTEP-3 for Windows (Farrugia, 2012 ▸).

Supplementary Material

CCDC reference: 1988336

Additional supporting information: crystallographic information; 3D view; checkCIF report

full crystallographic data

Crystal data

C10H13N5	F(000) = 432
Mr = 203.25	Dx = 1.283 Mg m−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 10.7335 (9) Å	Cell parameters from 1855 reflections
b = 12.4005 (10) Å	θ = 1.9–25.0°
c = 7.9206 (6) Å	µ = 0.08 mm−1
β = 93.654 (4)°	T = 446 K
V = 1052.09 (15) Å3	Block, colourless
Z = 4	0.18 × 0.16 × 0.15 mm

Data collection

Bruker SMART APEX CCD diffractometer	1452 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.034
ω scans	θmax = 25.0°, θmin = 1.9°
Absorption correction: multi-scan (SADABS; Bruker, 1998)	h = −12→12
	k = −14→14
12900 measured reflections	l = −9→8
1855 independent reflections

Refinement

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)] = 0.050	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.180	H-atom parameters constrained
S = 1.16	w = 1/[σ2(Fo2) + (0.1087P)2 + 0.0972P] where P = (Fo2 + 2Fc2)/3
1855 reflections	(Δ/σ)max < 0.001
136 parameters	Δρmax = 0.21 e Å−3
0 restraints	Δρmin = −0.28 e Å−3

Special details

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

Refinement. H atoms were placed at calculated positions in the riding-model approximation, with N—H = 0.86 Å and C—H = 0.93 0.96 and 0.97 Å for aromatic, methyl and methine H atoms, respectively. The constraint Uiso(H) = 1.5Ueq(C) for methyl H atoms and 1.2Ueq(carrier) otherwise was applied.

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

	x	y	z	Uiso*/Ueq
C1	0.81607 (15)	0.03767 (13)	0.1080 (2)	0.0523 (5)
C2	0.88239 (16)	0.02327 (14)	0.2655 (2)	0.0549 (5)
C4	0.82310 (16)	−0.04487 (14)	−0.0150 (3)	0.0578 (5)
N1	0.95761 (14)	−0.06277 (12)	0.2958 (2)	0.0637 (5)
N3	0.75761 (15)	−0.04668 (14)	−0.1662 (2)	0.0722 (5)
C10	0.76188 (17)	0.14099 (15)	0.0789 (2)	0.0574 (5)
N4	0.87641 (16)	0.09400 (13)	0.3914 (2)	0.0702 (5)
H4A	0.919123	0.083441	0.485517	0.084*
H4B	0.829833	0.150200	0.378499	0.084*
N2	0.90227 (15)	−0.12859 (13)	0.0178 (3)	0.0691 (5)
N5	0.72548 (18)	0.22727 (14)	0.0646 (3)	0.0782 (6)
C3	0.96377 (18)	−0.12964 (16)	0.1669 (3)	0.0691 (6)
H3	1.020183	−0.186103	0.184080	0.083*
C8	0.5344 (2)	−0.0579 (2)	−0.2263 (3)	0.0902 (8)
H8A	0.460985	−0.016619	−0.263451	0.108*
H8B	0.520469	−0.087903	−0.115968	0.108*
C5	0.7794 (2)	−0.1314 (2)	−0.2914 (3)	0.0855 (7)
H5A	0.854903	−0.170765	−0.256953	0.103*
H5B	0.790807	−0.098612	−0.400522	0.103*
C6	0.6712 (2)	−0.2074 (2)	−0.3063 (3)	0.0802 (7)
H6A	0.665402	−0.245504	−0.200085	0.096*
H6B	0.684841	−0.260338	−0.393412	0.096*
C9	0.6452 (2)	0.01582 (19)	−0.2108 (3)	0.0776 (6)
H9A	0.653908	0.052850	−0.317313	0.093*
H9B	0.633297	0.069592	−0.124387	0.093*
C7	0.5513 (3)	−0.1489 (3)	−0.3494 (4)	0.1092 (10)
H7A	0.481912	−0.198846	−0.345855	0.131*
H7B	0.551740	−0.120234	−0.463297	0.131*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
C1	0.0429 (9)	0.0413 (9)	0.0733 (12)	−0.0013 (7)	0.0095 (8)	0.0058 (8)
C2	0.0461 (9)	0.0421 (9)	0.0771 (13)	−0.0017 (7)	0.0087 (8)	0.0062 (8)
C4	0.0398 (9)	0.0528 (10)	0.0819 (13)	−0.0079 (7)	0.0118 (8)	−0.0037 (9)
N1	0.0569 (10)	0.0484 (9)	0.0858 (12)	0.0083 (7)	0.0045 (8)	0.0039 (8)
N3	0.0522 (10)	0.0749 (12)	0.0894 (13)	−0.0009 (8)	0.0024 (8)	−0.0172 (9)
C10	0.0547 (10)	0.0478 (11)	0.0695 (12)	−0.0035 (8)	0.0036 (8)	0.0065 (8)
N4	0.0774 (11)	0.0569 (10)	0.0753 (12)	0.0180 (8)	−0.0036 (8)	−0.0008 (8)
N2	0.0502 (9)	0.0555 (10)	0.1022 (14)	0.0033 (7)	0.0089 (9)	−0.0119 (9)
N5	0.0879 (13)	0.0496 (10)	0.0955 (15)	0.0058 (9)	−0.0071 (10)	0.0081 (8)
C3	0.0503 (11)	0.0509 (11)	0.1066 (17)	0.0086 (8)	0.0076 (10)	−0.0009 (11)
C8	0.0557 (13)	0.118 (2)	0.0950 (17)	0.0059 (12)	−0.0105 (11)	−0.0233 (15)
C5	0.0727 (14)	0.1028 (19)	0.0825 (16)	0.0020 (13)	0.0154 (11)	−0.0248 (14)
C6	0.0959 (17)	0.0833 (15)	0.0607 (13)	−0.0066 (13)	0.0000 (11)	−0.0158 (10)
C9	0.0793 (15)	0.0737 (14)	0.0787 (15)	0.0076 (11)	−0.0039 (11)	0.0027 (11)
C7	0.0790 (17)	0.137 (3)	0.109 (2)	−0.0090 (16)	−0.0162 (14)	−0.0462 (19)

Geometric parameters (Å, º)

C1—C2	1.408 (3)	C8—C9	1.499 (3)
C1—C4	1.418 (3)	C8—C7	1.510 (4)
C1—C10	1.420 (3)	C8—H8A	0.9700
C2—N4	1.332 (2)	C8—H8B	0.9700
C2—N1	1.350 (2)	C5—C6	1.495 (3)
C4—N3	1.350 (3)	C5—H5A	0.9700
C4—N2	1.356 (3)	C5—H5B	0.9700
N1—C3	1.321 (3)	C6—C7	1.498 (4)
N3—C9	1.459 (3)	C6—H6A	0.9700
N3—C5	1.474 (3)	C6—H6B	0.9700
C10—N5	1.142 (2)	C9—H9A	0.9700
N4—H4A	0.8600	C9—H9B	0.9700
N4—H4B	0.8600	C7—H7A	0.9700
N2—C3	1.316 (3)	C7—H7B	0.9700
C3—H3	0.9300
C2—C1—C4	118.10 (16)	H8A—C8—H8B	107.8
C2—C1—C10	115.91 (16)	N3—C5—C6	110.29 (18)
C4—C1—C10	125.39 (18)	N3—C5—H5A	109.6
N4—C2—N1	116.35 (18)	C6—C5—H5A	109.6
N4—C2—C1	122.27 (16)	N3—C5—H5B	109.6
N1—C2—C1	121.37 (17)	C6—C5—H5B	109.6
N3—C4—N2	116.21 (18)	H5A—C5—H5B	108.1
N3—C4—C1	125.02 (18)	C5—C6—C7	111.4 (2)
N2—C4—C1	118.76 (19)	C5—C6—H6A	109.4
C3—N1—C2	114.68 (18)	C7—C6—H6A	109.4
C4—N3—C9	125.62 (18)	C5—C6—H6B	109.4
C4—N3—C5	120.85 (19)	C7—C6—H6B	109.4
C9—N3—C5	112.34 (18)	H6A—C6—H6B	108.0
N5—C10—C1	174.5 (2)	N3—C9—C8	109.6 (2)
C2—N4—H4A	120.0	N3—C9—H9A	109.8
C2—N4—H4B	120.0	C8—C9—H9A	109.8
H4A—N4—H4B	120.0	N3—C9—H9B	109.8
C3—N2—C4	116.86 (17)	C8—C9—H9B	109.8
N2—C3—N1	129.86 (18)	H9A—C9—H9B	108.2
N2—C3—H3	115.1	C6—C7—C8	110.6 (2)
N1—C3—H3	115.1	C6—C7—H7A	109.5
C9—C8—C7	112.4 (2)	C8—C7—H7A	109.5
C9—C8—H8A	109.1	C6—C7—H7B	109.5
C7—C8—H8A	109.1	C8—C7—H7B	109.5
C9—C8—H8B	109.1	H7A—C7—H7B	108.1
C7—C8—H8B	109.1
C4—C1—C2—N4	−176.67 (15)	C1—C4—N3—C5	174.72 (17)
C10—C1—C2—N4	11.7 (2)	N3—C4—N2—C3	−177.91 (17)
C4—C1—C2—N1	4.5 (3)	C1—C4—N2—C3	3.0 (3)
C10—C1—C2—N1	−167.09 (16)	C4—N2—C3—N1	2.8 (3)
C2—C1—C4—N3	174.67 (16)	C2—N1—C3—N2	−4.6 (3)
C10—C1—C4—N3	−14.6 (3)	C4—N3—C5—C6	108.9 (2)
C2—C1—C4—N2	−6.3 (3)	C9—N3—C5—C6	−59.3 (3)
C10—C1—C4—N2	164.43 (16)	N3—C5—C6—C7	55.9 (3)
N4—C2—N1—C3	−178.31 (16)	C4—N3—C9—C8	−109.3 (2)
C1—C2—N1—C3	0.6 (3)	C5—N3—C9—C8	58.3 (3)
N2—C4—N3—C9	162.23 (19)	C7—C8—C9—N3	−55.0 (3)
C1—C4—N3—C9	−18.7 (3)	C5—C6—C7—C8	−52.9 (3)
N2—C4—N3—C5	−4.3 (3)	C9—C8—C7—C6	52.8 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N4—H4A···N1i	0.86	2.12	2.983 (2)	173
N4—H4B···N5ii	0.86	2.44	3.115 (3)	135
C9—H9B···N5	0.97	2.61	3.484 (1)	148

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