4-(1-Adamantylamino)-2-amino-6-methoxy-5-nitrosopyrimidine

The title compound, C₁₅H₂₁N₅O₂, lies on a crystallographic mirror plane and is hydrogen bonded to neighbouring mol­ecules by infinite chains formed by combinations of strong N—H...N and soft C—H...O hydrogen bonds. The pyrimidine moiety shows extensive delocalization.

S1. Comment

Compounds containing the adamantanyl subunit have long been of interest to chemists due to its rigid structure and well defined substitution chemistry (Bingham et al., 1971). Furthermore, the discovery of the potent antiviral activity of amantadine (1-adamantanamine) and rimantidine (N-methyl-1-adamantylmethylamine) has stimulated interest in the synthesis of adamantane-containing compounds (Kirschbaum, 1983). Many articles highlight investigations of molecules in which various biological activities are enhanced by the presence of an adamantyl block (Hedayatullah et al., 1999). This is specifically due to the strong lipophilic character of the adamantyl group and the high resistance to metabolic degradation of the compounds containing this group (Sasaki et al., 1979; Galpin et al., 1979).

Compound (II) (Fig. 1) was prepared during the course of our investigations into the activation to nucleophilic substitution which a 5-nitroso group produces on methoxy groups linked to positions 2- and 4-(6) of a pyrimidine system. The 1-adamantyl moiety is a very bulky group whose steric requirements seriously hinder the participation of 1-adamantylamine as a nucleophile in substitution reactions. The resolution of the structure of (II) by X-ray diffraction analysis unambiguously confirms that this compound forms by aminolysis of (I), instead of the adamantylammonium salt that could be produced by base-catalysed hydrolysis of (I). The latter is a process which competes with aminolysis in aqueous media when strong steric hindrance exists, as was proven by the synthesis of piperidinium 6-amino-3-methyl-5-nitroso-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ide (Low et al., 1999). The formation of (II) proves that methoxy groups in nitroso derivatives are so activated towards nucleophilic substitution that even bulky amines such as adamantylamine are capable of effecting nucleophilic substitution at room temperature. \sch

The molecular dimensions of (II) show a similar delocalization to that found in the N-(6-amino-3,4-dihydro-3-methyl-5-nitroso-4-oxopyrimidinyl-2-yl) derivatives of glycine, valine, serine, threonine and methionine described by Low et al. (2000). The only significant difference in the bond lengths is the presence of the N3—C4 double bond in (II).

A feature of interest in the structure is the fact that the molecule lies on a crystallographic mirror plane at (0,1/4,0). This passes through the plane of the pyrimidine moiety and its substituents and two of the C atoms of the adamantanyl moiety. This is a consequence of the fact that the adamantanyl moiety is a substituent on N6, an amino group, which has a marked degree of sp² character, as evidenced by the C6—N6 bond length of 1.336 (5) Å. This is a common feature of 6-aminopyrimidines.

A strong N—H···N intermolecular hydrogen bond between N2 and N5ⁱ [symmetry code (i): x, y, 1 + z] links the molecules into a C₁¹(6) motif which forms, by translation, an infinite chain along [001]. Further, an intramolecular hydrogen bond between N6 and O5 helps to stabilize this planarity. A soft intermolecular C—H···O bond between C67 and O5ⁱ has the effect of pulling two of the adamantane C atoms into the plane of the pyrimidine moiety. These soft hydrogen bonds form a C₁¹(7) motif, generating an infinite chain along [001] by translation. The C₁¹(6) and C₁¹(7) motifs combine to produce an R₂²(13) ring structure (Fig. 2), which lies with the chain structures on the crystallographic mirror plane. The second amino-H atom attached to N2 is not involved in hydrogen bonding, this being prevented by the steric bulk of the adamantane. Examination of the structure with PLATON (Spek, 2000) showed that there were no solvent accessible voids in the crystal lattice.

Related literature

For related literature, see: Bingham et al. (1971); Galpin et al. (1979); Hedayatullah et al. (1999); Kirschbaum (1983); Low et al. (1999, 2000); Sasaki et al. (1979); Spek (2000).

S2. Experimental

1-Adamantanamine (0.46 g, 3 mmol, 1.5 eq.) was added to a solution of (I) (0.368 g, 2.00 mmol) in DMSO/H₂O (3:2 v/v, 25 ml). The mixture was stirred at room temperature and monitored by thin layer chromatography (eluent CH₂Cl₂/MeOH, 9:1 v/v) until a pink suspension was obtained after 36 h. The precipitate was filtered, washed with water and acetone, dried over blue silica and recrystallized from methanol/acetone to give crystals of (II) (yield 0.53 g, 87%; decomposes > 473 K). Analysis: IR (KBr, cm^-1): 3498, 3282, 3127, 3072 (NH₂/NH), 2901, 2852 (C—H), 1645 (NH₂), 1593 (C=N, C=C), 1519 (N=O), 1486, 1449 (a, C—H), 1385, 1349 (s, C—H), 1320 (C—N), 1214, 1188 (a, C—O—C), 1094 (s, C—O—C); ¹H NMR (DMSO-d₆, p.p.m.): 11.58 (s, 1H, NH), 7.94 (bs, 2H, NH₂), 4.02 (s, 3H, CH₃O), 2.51–2.01 (m, 6H+3H, CH₂/CH), 1.71–1.56 (m, 6H, CH₂); ¹³C NMR (DMSO-d₆, p.p.m.): 171.1, 162.2, 149.8, 138.4, 54.1, 52.1, 40.8, 35.7, 28.8; MS (EI), M+ 303 (100), m/z: 285 (22), 154 (6), 135 (71), 41 (65); UV/vis (MeOH): 327 (4.36), 536 (1.81); analysis calculated for C₁₅H₂₁N₅O₂: C 59.36, H 6.98, N 23.09%; found: C 59.34, H 7.01, N 22.85%.

S3. Refinement

Difference maps showed that the H atoms on methyl carbon C41 were disordered and this was allowed for by placing six H atoms with suitable occupancies around C41. H atoms were treated as riding atoms with C—H 0.98 to 1.00 Å, N—H 0.88 Å.

Computing details

Data collection: KappaCCD Server Software (Nonius, 1997); cell refinement: DENZO (Otwinowski & Minor, 1997); data reduction: DENZO; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2000); software used to prepare material for publication: SHELXL97 and PRPKAPPA (Ferguson, 1999).

Figures

	Fig. 1. A molecular view of (II) with the atomic numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii. The H atoms on methyl carbon C41 are disordered and for clarity only one set is shown.
	Fig. 2. A view of the crystal structure of (II) showing the hydrogen-bonding motifs formed by unit translations along [001].

4-(1-Adamantylamino)-2-amino-6-methoxy-5-nitrosopyrimidine

Crystal data

C15H21N5O2	F(000) = 648
Mr = 303.37	Dx = 1.401 Mg m^−3
Orthorhombic, Pnma	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2n	Cell parameters from 1463 reflections
a = 29.207 (2) Å	θ = 1.4–25.9°
b = 6.5860 (4) Å	µ = 0.10 mm^−1
c = 7.4782 (4) Å	T = 150 K
V = 1438.48 (16) Å^3	Block, pink
Z = 4	0.15 × 0.15 × 0.10 mm

Data collection

KappaCCD diffractometer	1463 independent reflections
Radiation source: fine-focus sealed X-ray tube	712 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.055
ϕ scans and ω scans with κ offsets	θmax = 25.9°, θmin = 1.4°
Absorption correction: multi-scan (SORTAV; Blessing, 1995)	h = −35→0
Tmin = 0.986, Tmax = 0.990	k = 0→8
8692 measured reflections	l = −9→0

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)] = 0.060	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.181	H-atom parameters constrained
S = 0.91	w = 1/[σ^2(Fo^2) + (0.106P)^2] where P = (Fo^2 + 2Fc^2)/3
1463 reflections	(Δ/σ)max < 0.001
124 parameters	Δρmax = 0.37 e Å^−3
0 restraints	Δρmin = −0.40 e Å^−3

Special details

Geometry. Mean-plane data from the final SHELXL97 refinement run:-

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
N1	0.53635 (12)	1/4	0.4280 (5)	0.0301 (9)
C2	0.49034 (16)	1/4	0.4468 (6)	0.0296 (11)
N2	0.47434 (12)	1/4	0.6120 (5)	0.0335 (10)
N3	0.45796 (11)	1/4	0.3152 (5)	0.0295 (10)
C4	0.47293 (15)	1/4	0.1520 (6)	0.0300 (11)
O4	0.44369 (10)	1/4	0.0155 (4)	0.0350 (9)
C41	0.39568 (15)	1/4	0.0603 (6)	0.0427 (13)
C5	0.52116 (14)	1/4	0.1070 (5)	0.0268 (11)
N5	0.53174 (13)	1/4	−0.0670 (5)	0.0342 (10)
O5	0.57434 (10)	1/4	−0.1102 (4)	0.0433 (9)
C6	0.55148 (16)	1/4	0.2594 (6)	0.0310 (11)
N6	0.59647 (12)	1/4	0.2251 (5)	0.0358 (10)
C61	0.63514 (13)	1/4	0.3512 (6)	0.0285 (11)
C62	0.67837 (13)	1/4	0.2342 (5)	0.0315 (12)
C63	0.72111 (14)	1/4	0.3505 (6)	0.0334 (12)
C64	0.72130 (10)	0.0613 (5)	0.4683 (4)	0.0391 (9)
C65	0.67843 (11)	0.0612 (5)	0.5853 (4)	0.0415 (10)
C66	0.63532 (10)	0.0603 (5)	0.4699 (4)	0.0344 (9)
C67	0.67846 (15)	1/4	0.7044 (6)	0.0494 (15)
H2A	0.4934	1/4	0.7031	0.040*
H2B	0.4446	1/4	0.6310	0.040*
H41A	0.3775	1/4	−0.0498	0.064*	0.50
H41B	0.3885	0.3715	0.1305	0.064*	0.25
H41C	0.3885	0.1285	0.1305	0.064*	0.25
H41D	0.3921	1/4	0.1906	0.064*	0.50
H41E	0.3811	0.1285	0.0103	0.064*	0.25
H41F	0.3811	0.3715	0.0103	0.064*	0.25
H6	0.6040	1/4	0.1112	0.043*
H62A	0.6784	0.1283	0.1565	0.038*	0.50
H62B	0.6784	0.3717	0.1565	0.038*	0.50
H63	0.7489	1/4	0.2726	0.040*
H64A	0.7490	0.0608	0.5446	0.047*
H64B	0.7218	−0.0620	0.3927	0.047*
H65	0.6786	−0.0628	0.6626	0.050*
H66A	0.6078	0.0594	0.5472	0.041*
H66B	0.6347	−0.0632	0.3945	0.041*
H67A	0.6510	1/4	0.7820	0.059*
H67B	0.7060	1/4	0.7818	0.059*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.021 (2)	0.034 (2)	0.035 (2)	0	0.0013 (18)	0
C2	0.040 (3)	0.023 (2)	0.026 (3)	0	0.002 (2)	0
N2	0.026 (2)	0.042 (2)	0.033 (2)	0	−0.0030 (18)	0
N3	0.029 (2)	0.035 (2)	0.025 (2)	0	−0.0007 (19)	0
C4	0.030 (3)	0.028 (3)	0.032 (3)	0	−0.001 (2)	0
O4	0.026 (2)	0.050 (2)	0.0290 (18)	0	−0.0051 (15)	0
C41	0.019 (3)	0.064 (3)	0.045 (3)	0	−0.003 (2)	0
C5	0.029 (3)	0.030 (3)	0.021 (3)	0	−0.005 (2)	0
N5	0.028 (3)	0.043 (2)	0.032 (2)	0	0.0018 (18)	0
O5	0.029 (2)	0.065 (2)	0.036 (2)	0	0.0032 (15)	0
C6	0.029 (3)	0.029 (3)	0.035 (3)	0	−0.001 (2)	0
N6	0.027 (2)	0.053 (3)	0.027 (2)	0	0.0032 (18)	0
C61	0.022 (3)	0.037 (3)	0.027 (3)	0	−0.001 (2)	0
C62	0.024 (3)	0.038 (3)	0.033 (3)	0	0.000 (2)	0
C63	0.023 (3)	0.041 (3)	0.036 (3)	0	0.007 (2)	0
C64	0.025 (2)	0.042 (2)	0.050 (2)	0.0046 (17)	−0.0031 (16)	0.0041 (17)
C65	0.032 (2)	0.042 (2)	0.051 (2)	0.0030 (17)	0.0007 (17)	0.0192 (19)
C66	0.029 (2)	0.029 (2)	0.046 (2)	0.0007 (15)	0.0018 (16)	−0.0010 (16)
C67	0.022 (3)	0.091 (4)	0.035 (3)	0	−0.004 (2)	0

Geometric parameters (Å, º)

N1—C6	1.336 (5)	N6—H6	0.8800
N1—C2	1.351 (5)	C61—C66^i	1.533 (4)
C2—N2	1.321 (5)	C61—C66	1.533 (4)
C2—N3	1.364 (5)	C61—C62	1.536 (5)
N2—H2A	0.8800	C62—C63	1.522 (5)
N2—H2B	0.8800	C62—H62A	0.9900
N3—C4	1.297 (5)	C62—H62B	0.9900
C4—O4	1.330 (5)	C63—C64^i	1.523 (4)
C4—C5	1.448 (6)	C63—C64	1.523 (4)
O4—C41	1.442 (5)	C63—H63	1.0000
C41—H41A	0.9800	C64—C65	1.528 (4)
C41—H41B	0.9800	C64—H64A	0.9900
C41—H41C	0.9800	C64—H64B	0.9900
C41—H41D	0.9800	C65—C66	1.526 (4)
C41—H41E	0.9800	C65—C67	1.530 (4)
C41—H41F	0.9800	C65—H65	1.0000
C5—N5	1.338 (5)	C66—H66A	0.9900
C5—C6	1.443 (6)	C66—H66B	0.9900
N5—O5	1.286 (4)	C67—C65^i	1.530 (4)
C6—N6	1.339 (5)	C67—H67A	0.9900
N6—C61	1.471 (5)	C67—H67B	0.9900
C6—N1—C2	115.3 (4)	N6—C61—C66^i	111.9 (2)
N2—C2—N1	116.7 (4)	N6—C61—C66	111.9 (2)
N2—C2—N3	115.4 (4)	C66^i—C61—C66	109.2 (4)
N1—C2—N3	127.9 (4)	N6—C61—C62	105.4 (3)
C2—N2—H2A	120.0	C66^i—C61—C62	109.1 (2)
C2—N2—H2B	120.0	C66—C61—C62	109.1 (2)
H2A—N2—H2B	120.0	C63—C62—C61	110.4 (3)
C4—N3—C2	116.4 (4)	C63—C62—H62A	109.6
N3—C4—O4	120.4 (4)	C61—C62—H62A	109.6
N3—C4—C5	123.1 (4)	C63—C62—H62B	109.6
O4—C4—C5	116.5 (4)	C61—C62—H62B	109.6
C4—O4—C41	116.5 (3)	H62A—C62—H62B	108.1
O4—C41—H41A	109.5	C62—C63—C64^i	109.5 (2)
O4—C41—H41B	109.5	C62—C63—C64	109.5 (2)
H41A—C41—H41B	109.5	C64^i—C63—C64	109.4 (4)
O4—C41—H41C	109.5	C62—C63—H63	109.5
H41A—C41—H41C	109.5	C64^i—C63—H63	109.5
H41B—C41—H41C	109.5	C64—C63—H63	109.5
O4—C41—H41D	109.5	C63—C64—C65	109.2 (3)
H41A—C41—H41D	141.1	C63—C64—H64A	109.8
H41B—C41—H41D	56.3	C65—C64—H64A	109.8
H41C—C41—H41D	56.3	C63—C64—H64B	109.8
O4—C41—H41E	109.5	C65—C64—H64B	109.8
H41A—C41—H41E	56.3	H64A—C64—H64B	108.3
H41B—C41—H41E	141.1	C66—C65—C64	110.6 (3)
H41C—C41—H41E	56.3	C66—C65—C67	109.4 (3)
H41D—C41—H41E	109.5	C64—C65—C67	109.4 (3)
O4—C41—H41F	109.5	C66—C65—H65	109.1
H41A—C41—H41F	56.3	C64—C65—H65	109.1
H41B—C41—H41F	56.3	C67—C65—H65	109.1
H41C—C41—H41F	141.1	C65—C66—C61	109.1 (3)
H41D—C41—H41F	109.5	C65—C66—H66A	109.9
H41E—C41—H41F	109.5	C61—C66—H66A	109.9
N5—C5—C6	128.8 (4)	C65—C66—H66B	109.9
N5—C5—C4	116.8 (4)	C61—C66—H66B	109.9
C6—C5—C4	114.4 (4)	H66A—C66—H66B	108.3
O5—N5—C5	117.9 (3)	C65^i—C67—C65	108.8 (4)
N1—C6—N6	120.4 (4)	C65^i—C67—H67A	109.9
N1—C6—C5	122.8 (4)	C65—C67—H67A	109.9
N6—C6—C5	116.8 (4)	C65^i—C67—H67B	109.9
C6—N6—C61	129.1 (4)	C65—C67—H67B	109.9
C6—N6—H6	115.5	H67A—C67—H67B	108.3
C61—N6—H6	115.5
C6—N1—C2—N2	180.0	C5—C6—N6—C61	180.0
C6—N1—C2—N3	0.0	C6—N6—C61—C66^i	−61.5 (2)
N2—C2—N3—C4	180.0	C6—N6—C61—C66	61.5 (2)
N1—C2—N3—C4	0.0	C6—N6—C61—C62	180.0
C2—N3—C4—O4	180.0	N6—C61—C62—C63	180.0
C2—N3—C4—C5	0.0	C66^i—C61—C62—C63	59.6 (2)
N3—C4—O4—C41	0.0	C66—C61—C62—C63	−59.6 (2)
C5—C4—O4—C41	180.0	C61—C62—C63—C64^i	−59.9 (2)
N3—C4—C5—N5	180.0	C61—C62—C63—C64	59.9 (2)
O4—C4—C5—N5	0.0	C62—C63—C64—C65	−59.3 (4)
N3—C4—C5—C6	0.0	C64^i—C63—C64—C65	60.7 (4)
O4—C4—C5—C6	180.0	C63—C64—C65—C66	60.0 (3)
C6—C5—N5—O5	0.0	C63—C64—C65—C67	−60.7 (4)
C4—C5—N5—O5	180.0	C64—C65—C66—C61	−59.8 (3)
C2—N1—C6—N6	180.0	C67—C65—C66—C61	60.8 (3)
C2—N1—C6—C5	0.0	N6—C61—C66—C65	175.1 (3)
N5—C5—C6—N1	180.0	C66^i—C61—C66—C65	−60.4 (4)
C4—C5—C6—N1	0.0	C62—C61—C66—C65	58.8 (4)
N5—C5—C6—N6	0.0	C66—C65—C67—C65^i	−60.9 (4)
C4—C5—C6—N6	180.0	C64—C65—C67—C65^i	60.4 (4)
N1—C6—N6—C61	0.0

Symmetry code: (i) x, −y+3/2, z.

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N6—H6···O5	0.88	1.87	2.589 (5)	138
N2—H2A···N5^ii	0.88	2.05	2.928 (5)	174
C67—H67A···O5^ii	0.99	2.38	3.342 (5)	164

Symmetry code: (ii) x, y, z+1.