2-tert-Butyl-5-methyl-7,8-dihydro-6H-cyclo­penta­[e]pyrazolo[1,5-a]pyrimi­dine: mol­ecular stacks built from C-H...[pi](pyrazole) hydrogen bonds and [pi]-[pi] stacking inter­actions

In the title compound, C₁₄H₁₉N₃, the bond distances within the heterocyclic portion of the mol­ecule indicate incomplete [pi] delocalization. The mol­ecules are linked into stacks by a combination of two C-H...[pi](pyrazole) hydrogen bonds and two independent [pi]-[pi] stacking inter­actions between inversion-related pyrimidine rings. The significance of this study lies in its observation of significant differences in both mol­ecular conformation and supra­molecular aggregation between the title compound, an example of a 2-alkyl­pyrazolo[1,5-a]pyrimidine, and some analogous 2-aryl­pyrazolo[1,5-a]pyrimidines.

S1. Comment

Pyrazolo[1,5-b]pyrimidines are purine analogues, and their pharmacological activity (Novinson et al., 1976; Senga et al., 1981) has prompted interest in the development of efficient, general procedures for their synthesis. One attractive route (Portilla et al., 2005) to such compounds involves the condensation of a substituted 5-amino-1H-pyrazole, (A) (see scheme), with a 2-acylcyclopentanone, (B), to give the 2,5-disubstituted product (C). We report here the molecular and supramolecular structure of the title compound, (I) (Fig. 1), which was prepared using a simple fusion-induced condensation reaction between 5-amino-3-tert-butyl-1H-pyrazole and 2-acetylcyclopentanone under solvent-free conditions. We compare the structure of (I) with those of the aryl-substituted analogues (II)–(V), which were all prepared using similar condensation reactions under solvent-free conditions but induced by microwave irradiation (Portilla et al., 2005).

By contrast with the conformations found for compounds (II)–(V), where the carbocyclic rings all adopt envelope conformations, the corresponding ring in (I) is effectively planar; the maximum deviations from the mean plane of the ring atoms in (I) is only 0.024 (3) Å, for atom C7. There is no obvious interpretation of this difference. While the tricyclic skeleton in (I) is effectively planar, the tert-butyl group is rotated by ca 10° from the conformation, which corresponds to an approximate mirror symmetry, as shown by the key torsion angles (Table 1). However, the pattern of the bond distances within the heterocyclic system in (I) (Table 1) shows a close similarity with those in (II)–(V) and, as before, this suggests a naphthalene-type arrangement of the ten π electrons in this system rather than full delocalization.

Despite the presence of two ring N atoms, N1 and N4, each carrying an in-plane lone pair of electrons potentially available for hydrogen-bond formation, there are, in fact, no C—H···N hydrogen bonds in the structure of (I). In this respect, (I) resembles compounds (II)–(IV), although a single C—H···N interaction is present in (V). The molecules of (I) are linked by a combination of C—H···π(pyrazone) hydrogen bonds (Table 2) and π–π stacking interactions. Atom C6 in the molecule at (x, y, z) acts as hydrogen-bond donor, via atoms H6A and H6B, respectively, to the pyrazole rings in the molecules at (-x + 1, -y + 1, -z + 1) and (-x + 2, -y + 1, -z + 1), respectively. Thus the pyrazole ring accepts a C—H bond onto each face, such that the angle H6A···Cg1ⁱ···H6Bⁱⁱⁱ [Cg1 represents the centroid of the pyrazole ring; symmetry codes: (i) -x + 1, -y + 1, -z + 1; (ii) x - 1, y, z] is 150°. In addition, the pyrimidine rings of the molecules at (x, y, z) and (-x + 1, -y + 1, z), which are strictly parallel because they are related by inversion, have an interplanar spacing of 3.422 (2) Å and a ring-centroid separation of 3.611 (2) Å, corresponding to a ring centroid offset of 1.152 (2) Å. Similarly, for the pyrimidine rings of the molecules at (x, y, z) and (-x + 2, -y + 1, -z + 1), the interplanar separation is 3.443 (2) Å and the ring-centroid separation is 3.674 (2) Å, corresponding in this case to a ring-centroid offset of 1.282 (2) Å. The combined and cooperative effect of the C—H···π hydrogen bonds and the π–π stacking interaction is to link the molecules into a stack running parallel to the [100] direction, in which alternate molecules are related by inversion (Fig. 2).

In the isostructural compounds (II)–(IV) (Portilla et al., 2005), the molecules are linked into chains by a single C—H···π(pyrazole) hydrogen bond, again involving atom C6 as the donor. In these hydrogen bonds, the H···A and D···A distances are all significantly greater than the corresponding distances in (I), while the organization of the molecules within the chains in (II)–(IV) effectively precludes the formation of a second C—H···π hydrogen bond, as found in (I). There is a single C—H···N hydrogen bond in (V), with one of the C—H bonds in the pendent aryl group providing the donor and the pyrimidine ring atom N4 as the acceptor. The resulting C(7) (Bernstein et al., 1995) chains are then linked into a sheet by means of a π–π stacking interaction between inversion-related heterocyclic rings. Compound (V) is thus the only member of this series so far observed to exhibit a C—H···N hydrogen bond, while (I) is the sole member in which the pyrazole ring acts as a double acceptor of hydrogen bonds.

Only in (V) does the substituent at taom C2 play any direct role in the hydrogen bonding. Nonetheless the pattern of supramolecular aggregation in (I) is different from that in the isomorphous series (II)–(IV); likewise the conformational difference between (I) and (II)–(V) involves the carbocyclic ring remote from the substituent at C2. Very subtle factors appear to connect the nature of the substituent at C2 with both the overall molecular conformation and the direction-specific intermolecular forces, making structure predictions extremely uncertain.

Related literature

For related literature, see: Bernstein et al. (1995); Novinson et al. (1976); Portilla et al. (2005); Senga et al. (1981); Spek (2003).

S2. Experimental

Equimolar quantities (2 mmol of each component) of 5-amino-3-tert-butyl-1H-pyrazole and 2-acetylcyclopentanone were thoroughly mixed at room temperature. The mixture was heated in an oil-bath at 393 K for 1.5 min. It was then stirred and allowed to cool to room temperature when it solidified. The solid material was extracted with ethanol; after removal of this solvent, the product (I) was recrystallized from dimethylformamide to give yellow crystals suitable for single-crystal X-ray diffraction (yield 93%, m.p. 459–461 K). MS (70 eV) m/z (%) 229 (64, M⁺), 214 (100), 187 (87), 106 (19), 53 (20), 41 (527), 39 (40).

S3. Refinement

Crystals of (I) are triclinic; the space group P1 was selected, and confirmed by the structure analysis. All H atoms were located in difference maps and then treated as riding atoms in geometrically idealized positions, with C—H distances of 0.95 Å (pyrazole), 0.98 Å (CH₃) or 0.99 Å (CH₂), and with U_iso(H) = kU_eq(C), where k = 1.5 for the methyl groups and 1.2 for all other H atoms. The ADDSYM routine in PLATON (Spek, 2003) suggested a possible revision of the space group to C2/m with Z' = 1/2, but in the revised unit-cell the angles α and γ deviated from 90° by more than 0.3° in each case; moreover, the orientation of the tert-butyl group relative to the adjacent ring, as indicated by the leading torsion angles (Table 1), suffices to rule out the possibility of any internal mirror symmetry for the molecule of (I).

Computing details

Data collection: COLLECT (Hooft, 1999); cell refinement: DIRAX/LSQ (Duisenberg et al., 2000); data reduction: EVALCCD (Duisenberg et al., 2003); program(s) used to solve structure: SIR2004 (Burla et al., 2005); program(s) used to refine structure: OSCAIL (McArdle, 2003) and SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and PRPKAPPA (Ferguson, 1999).

Figures

	Fig. 1. The molecular structure of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. A stereoview of part of the crystal structure of (I), showing the formation of a stack of molecules along [100] built from a combination of C—H···π(pyrazole) hydrogen bonds and π–π stacking interactions. For the sake of clarity, H atoms not involved in the motifs shown have been omitted.

2-tert-Butyl-5-methyl-7,8-dihydro-6H- cyclopenta[e]pyrazolo[1,5-a]pyrimidine

Crystal data

C14H19N3	Z = 2
Mr = 229.32	F(000) = 248
Triclinic, P1	Dx = 1.205 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 6.8665 (6) Å	Cell parameters from 2898 reflections
b = 9.4084 (14) Å	θ = 3.3–27.5°
c = 11.147 (2) Å	µ = 0.07 mm^−1
α = 91.611 (14)°	T = 120 K
β = 107.728 (14)°	Block, yellow
γ = 111.097 (12)°	0.38 × 0.37 × 0.25 mm
V = 632.22 (18) Å^3

Data collection

Bruker–Nonius KappaCCD diffractometer	2898 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	1804 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.049
Detector resolution: 9.091 pixels mm^-1	θmax = 27.5°, θmin = 3.3°
ϕ and ω scans	h = −8→8
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −12→12
Tmin = 0.966, Tmax = 0.982	l = −14→14
15695 measured reflections

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)] = 0.062	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.180	H-atom parameters constrained
S = 1.11	w = 1/[σ^2(Fo^2) + (0.0576P)^2 + 0.6693P] where P = (Fo^2 + 2Fc^2)/3
2898 reflections	(Δ/σ)max = 0.001
158 parameters	Δρmax = 0.29 e Å^−3
0 restraints	Δρmin = −0.29 e Å^−3

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

	x	y	z	Uiso*/Ueq
N1	0.8353 (3)	0.4136 (2)	0.75796 (18)	0.0259 (5)
N4	0.6022 (3)	0.2937 (2)	0.42163 (18)	0.0269 (5)
N9	0.7835 (3)	0.4343 (2)	0.63402 (17)	0.0226 (4)
C2	0.7503 (4)	0.2585 (3)	0.7516 (2)	0.0247 (5)
C3	0.6462 (4)	0.1820 (3)	0.6260 (2)	0.0256 (5)
C3A	0.6684 (4)	0.2966 (3)	0.5496 (2)	0.0242 (5)
C5	0.6507 (4)	0.4280 (3)	0.3787 (2)	0.0270 (5)
C5A	0.7658 (4)	0.5696 (3)	0.4619 (2)	0.0244 (5)
C6	0.8372 (4)	0.7323 (3)	0.4333 (2)	0.0296 (6)
C7	0.9487 (5)	0.8335 (3)	0.5664 (3)	0.0358 (6)
C8	0.9526 (4)	0.7262 (3)	0.6686 (2)	0.0301 (6)
C8A	0.8318 (4)	0.5711 (3)	0.5901 (2)	0.0237 (5)
C21	0.7785 (4)	0.1915 (3)	0.8733 (2)	0.0295 (6)
C22	0.6399 (6)	0.0200 (3)	0.8464 (3)	0.0541 (9)
C23	1.0238 (5)	0.2195 (4)	0.9372 (3)	0.0586 (10)
C24	0.7074 (6)	0.2702 (4)	0.9638 (3)	0.0500 (8)
C51	0.5778 (4)	0.4261 (3)	0.2373 (2)	0.0331 (6)
H3	0.5748	0.0738	0.5986	0.031*
H6A	0.7079	0.7535	0.3819	0.035*
H6B	0.9434	0.7510	0.3865	0.035*
H7A	1.1018	0.9040	0.5763	0.043*
H7B	0.8643	0.8965	0.5761	0.043*
H8A	1.1063	0.7414	0.7197	0.036*
H8B	0.8755	0.7430	0.7262	0.036*
H22A	0.4834	0.0022	0.8049	0.081*
H22B	0.6584	−0.0220	0.9267	0.081*
H22C	0.6881	−0.0314	0.7902	0.081*
H23A	1.0700	0.1654	0.8817	0.088*
H23B	1.0443	0.1807	1.0189	0.088*
H23C	1.1137	0.3303	0.9518	0.088*
H24A	0.7994	0.3808	0.9831	0.075*
H24B	0.7257	0.2256	1.0430	0.075*
H24C	0.5514	0.2546	0.9236	0.075*
H51A	0.5058	0.3192	0.1938	0.050*
H51B	0.7072	0.4808	0.2124	0.050*
H51C	0.4729	0.4772	0.2134	0.050*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0311 (11)	0.0238 (10)	0.0211 (10)	0.0088 (8)	0.0084 (8)	0.0069 (8)
N4	0.0298 (10)	0.0304 (11)	0.0225 (10)	0.0123 (9)	0.0106 (8)	0.0072 (8)
N9	0.0262 (10)	0.0206 (10)	0.0219 (10)	0.0087 (8)	0.0096 (8)	0.0057 (8)
C2	0.0259 (12)	0.0240 (12)	0.0258 (12)	0.0094 (10)	0.0114 (10)	0.0055 (9)
C3	0.0253 (12)	0.0234 (12)	0.0281 (13)	0.0083 (10)	0.0101 (10)	0.0046 (10)
C3A	0.0230 (11)	0.0258 (12)	0.0243 (12)	0.0093 (10)	0.0089 (9)	0.0024 (9)
C5	0.0270 (12)	0.0303 (13)	0.0273 (13)	0.0127 (10)	0.0118 (10)	0.0073 (10)
C5A	0.0216 (11)	0.0284 (12)	0.0282 (13)	0.0117 (10)	0.0122 (10)	0.0089 (10)
C6	0.0313 (13)	0.0307 (13)	0.0331 (14)	0.0143 (11)	0.0159 (11)	0.0145 (11)
C7	0.0411 (15)	0.0264 (13)	0.0370 (15)	0.0102 (11)	0.0125 (12)	0.0099 (11)
C8	0.0337 (13)	0.0229 (12)	0.0308 (13)	0.0081 (10)	0.0105 (11)	0.0047 (10)
C8A	0.0226 (11)	0.0217 (12)	0.0310 (13)	0.0099 (9)	0.0127 (10)	0.0079 (9)
C21	0.0359 (14)	0.0252 (12)	0.0234 (12)	0.0087 (10)	0.0080 (10)	0.0066 (10)
C22	0.083 (2)	0.0268 (15)	0.0356 (16)	0.0061 (15)	0.0152 (16)	0.0091 (12)
C23	0.0454 (18)	0.079 (2)	0.053 (2)	0.0264 (17)	0.0129 (15)	0.0390 (18)
C24	0.075 (2)	0.0549 (19)	0.0335 (16)	0.0312 (17)	0.0285 (15)	0.0193 (14)
C51	0.0389 (14)	0.0375 (14)	0.0255 (13)	0.0166 (12)	0.0120 (11)	0.0090 (11)

Geometric parameters (Å, º)

N1—C2	1.353 (3)	C51—H51A	0.9800
C2—C3	1.397 (3)	C51—H51B	0.9800
C3—C3A	1.387 (3)	C51—H51C	0.9800
C3A—N4	1.355 (3)	C21—C22	1.514 (4)
N4—C5	1.329 (3)	C21—C24	1.524 (4)
C5—C5A	1.409 (3)	C21—C23	1.534 (4)
C8A—N9	1.354 (3)	C6—H6A	0.9900
N9—N1	1.356 (3)	C6—H6B	0.9900
C3A—N9	1.389 (3)	C7—H7A	0.9900
C5A—C8A	1.360 (3)	C7—H7B	0.9900
C5A—C6	1.506 (3)	C24—H24A	0.9800
C6—C7	1.549 (4)	C24—H24B	0.9800
C7—C8	1.544 (3)	C24—H24C	0.9800
C8—C8A	1.482 (3)	C22—H22A	0.9800
C2—C21	1.501 (3)	C22—H22B	0.9800
C8—H8A	0.9900	C22—H22C	0.9800
C8—H8B	0.9900	C23—H23A	0.9800
C3—H3	0.9500	C23—H23B	0.9800
C5—C51	1.498 (3)	C23—H23C	0.9800
C8A—N9—N1	126.38 (19)	C2—C21—C24	109.9 (2)
C8A—N9—C3A	120.51 (19)	C22—C21—C24	109.3 (2)
N1—N9—C3A	113.11 (18)	C2—C21—C23	109.1 (2)
N4—C3A—C3	133.2 (2)	C22—C21—C23	109.6 (3)
N4—C3A—N9	121.8 (2)	C24—C21—C23	108.6 (3)
C3—C3A—N9	105.07 (19)	C5A—C6—C7	104.08 (19)
C2—N1—N9	103.65 (18)	C5A—C6—H6A	110.9
C5—N4—C3A	117.7 (2)	C7—C6—H6A	110.9
N1—C2—C3	112.3 (2)	C5A—C6—H6B	110.9
N1—C2—C21	118.8 (2)	C7—C6—H6B	110.9
C3—C2—C21	128.9 (2)	H6A—C6—H6B	109.0
N9—C8A—C5A	118.2 (2)	C8—C7—C6	108.3 (2)
N9—C8A—C8	126.4 (2)	C8—C7—H7A	110.0
C5A—C8A—C8	115.3 (2)	C6—C7—H7A	110.0
C8A—C8—C7	102.2 (2)	C8—C7—H7B	110.0
C8A—C8—H8A	111.3	C6—C7—H7B	110.0
C7—C8—H8A	111.3	H7A—C7—H7B	108.4
C8A—C8—H8B	111.3	C21—C24—H24A	109.5
C7—C8—H8B	111.3	C21—C24—H24B	109.5
H8A—C8—H8B	109.2	H24A—C24—H24B	109.5
C3A—C3—C2	105.9 (2)	C21—C24—H24C	109.5
C3A—C3—H3	127.1	H24A—C24—H24C	109.5
C2—C3—H3	127.1	H24B—C24—H24C	109.5
N4—C5—C5A	121.9 (2)	C21—C22—H22A	109.5
N4—C5—C51	118.1 (2)	C21—C22—H22B	109.5
C5A—C5—C51	120.0 (2)	H22A—C22—H22B	109.5
C8A—C5A—C5	119.9 (2)	C21—C22—H22C	109.5
C8A—C5A—C6	109.9 (2)	H22A—C22—H22C	109.5
C5—C5A—C6	130.2 (2)	H22B—C22—H22C	109.5
C5—C51—H51A	109.5	C21—C23—H23A	109.5
C5—C51—H51B	109.5	C21—C23—H23B	109.5
H51A—C51—H51B	109.5	H23A—C23—H23B	109.5
C5—C51—H51C	109.5	C21—C23—H23C	109.5
H51A—C51—H51C	109.5	H23A—C23—H23C	109.5
H51B—C51—H51C	109.5	H23B—C23—H23C	109.5
C2—C21—C22	110.4 (2)
C8A—N9—C3A—N4	0.5 (3)	C3A—N4—C5—C5A	−0.3 (3)
N1—N9—C3A—N4	−179.99 (19)	C3A—N4—C5—C51	−179.9 (2)
C8A—N9—C3A—C3	−179.3 (2)	N9—C8A—C5A—C5	−0.1 (3)
N1—N9—C3A—C3	0.2 (2)	C8—C8A—C5A—C5	179.7 (2)
C8A—N9—N1—C2	179.4 (2)	N9—C8A—C5A—C6	−179.47 (19)
C3A—N9—N1—C2	0.0 (2)	C8—C8A—C5A—C6	0.3 (3)
C3—C3A—N4—C5	179.6 (2)	N4—C5—C5A—C8A	0.4 (3)
N9—C3A—N4—C5	−0.2 (3)	C51—C5—C5A—C8A	−180.0 (2)
N9—N1—C2—C3	−0.1 (2)	N4—C5—C5A—C6	179.6 (2)
N9—N1—C2—C21	179.4 (2)	C51—C5—C5A—C6	−0.8 (4)
N1—N9—C8A—C5A	−179.8 (2)	N1—C2—C21—C22	170.4 (2)
C3A—N9—C8A—C5A	−0.3 (3)	N1—C2—C21—C23	−69.1 (3)
N1—N9—C8A—C8	0.5 (4)	N1—C2—C21—C24	49.8 (3)
C3A—N9—C8A—C8	179.9 (2)	C3—C2—C21—C22	−10.1 (4)
N9—C8A—C8—C7	−178.2 (2)	C3—C2—C21—C23	110.4 (3)
C5A—C8A—C8—C7	2.0 (3)	C3—C2—C21—C24	−130.7 (3)
N4—C3A—C3—C2	180.0 (2)	C8A—C5A—C6—C7	−2.5 (3)
N9—C3A—C3—C2	−0.2 (2)	C5—C5A—C6—C7	178.2 (2)
N1—C2—C3—C3A	0.2 (3)	C8A—C8—C7—C6	−3.5 (3)
C21—C2—C3—C3A	−179.3 (2)	C5A—C6—C7—C8	3.7 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C6—H6A···Cg1^i	0.99	2.76	3.602 (3)	144
C6—H6B···Cg1^ii	0.99	2.70	3.581 (3)	148

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