Unusual molecular conformation in dissymmetric propyl­ene-linker compounds containing pyrazolo­[3,4-d]­pyrimidine and phthalimide moieties

The crystal structure of 4,6-bis(methylsulfanyl)-1-phthalimidopropyl-1H-pyrazolo[3,4-d]pyrimidine, C₁₈H₁₇N₅O₂S₂, (VI), reveals an unusual folded conformation due to an apparent intramolecular C—H...π interaction between the 6-methyl­­sul­fanyl and phenyl groups. However, the closely related compound 6-methyl­sulfanyl-1-phthalimido­propyl-4-(pyrroli­din-1-yl)-1H-pyrazolo­[3,4-d]­pyrimidine, C₂₁H₂₂N₆O₂S, (VII), exhibits a fully extended structure, devoid of any intramol­ecular C—H...π or π–π interactions. The crystal packing of both mol­ecules involves intermolecular stacking interactions due to aromatic π–π interactions. In addition, (VI) exhibits intermolecular C—H...O hydrogen bonding and (VII) exhibits dimerization of the mol­ecules through intermolecular C—H...N hydrogen bonding.

S1. Comment

Interactions between aromatic units play significant roles in chemistry (Tsuzuki et al., 2002; Hunter et al., 2001), crystal engineering (Desiraju, 1995) and drug development (Meyer et al., 2003). The use of the `propylene linker' for the promotion of intramolecular stacking among nucleic acid bases was first introduced by Browne et al. (1968), and earlier literature has been reviewed (Leonard, 1979). We have reported previously the synthesis (Avasthi et al., 1995) and X-ray structure (Biswas et al., 1995) of compound (I), based on the pyrazolo [3,4-d]pyrimidine core, which is isomeric with the biologically important purine system. X-Ray crystallography of (I) not only confirmed the intramolecular stacking but also revealed the intermolecular stacking. Similar results were obtained for the ethyl analog, (II), via 1H NMR spectroscopy and X-ray crystallography (Avasthi et al., 2001). Subsequently, the syntheses of another three related compounds, (III)–(V), derived from (I), were reported by Avasthi et al. (1998); the results of 1H NMR spectroscopic data comparison indicated intramolecular stacking. X-ray structure determinations of (III)–(V) also showed inter- and intramolecular stacking (Maulik et al., 1998; Avasthi, Aswal & Maulik, 2001; Avasthi et al., 2002). In short, X-ray crystallography of all five symmetrical compounds (I)–(V) (Scheme 1) showed an unusual U motif, formed by intramolecular aromatic π–π interactions (APPI).

In this communication, we report X-ray structures of two more `propylene linker' dissymmetric compounds, (VI) and (VII) (Scheme 2), based on the same pyrazolo[3,4-d] pyrimidine core and phthalimido moiety. The phthalimido ring system was chosen to replace one of the pyrazolo[3,4-d]pyrimidinyl moieties of (I), and the effect of the substitution on the stacking interactions was examined by 1H NMR spectroscopy and X-ray crystallography. The phthalimido group was chosen because (a) it is known to stack intermolecularly with itself in parallel mode (Barrett et al., 1995), (b) it is a bicyclic system, like pyrazolo[3,4-d]pyrimidine, (c) it contains a phenyl ring, which is an important π-acceptor and (d) it contains an available N atom for linker connection.

The reaction of commercial 3-bromopropyl phthalimide with 4,6-dimethylthio-1H-pyrazolo[3,4-d]pyrimidine gave 4,6-dimethylthio-1- phthalimidopropyl-1H-pyrazolo[3,4-d]pyrimidine, (VI), in good yield. One of the two methylthio H atoms of (VI) appeared at a higher field in the 1H NMR spectrum; this behaviour is similar to that of (I), thus indicating the closeness of this H atom? to the phenyl portion of the phthalimido moiety. 6-Methylthio-1-phthalimidopropyl-4-pyrrolidino-1H-pyrazolo [3,4-d]pyrimidine, (VII), was similarly synthesized, and the methylthio H atoms were at a comparable higher field.

In order to determine the exact orientation for this unusual upfield shift of the methythio H atom [parallel mode like compounds (I)–(V) or other mode], crystallographic structural determination was necessary. The conformations of (VI) and (VII) as determined by X-ray crystallography are shown in Figs. 1 and 2, respectively. Surprisingly, (VI) showed an unusual folded conformation, in which two planar moieties are close to perpendicular and one methylthio group is brought close to the phenyl ring of the phthalimido unit, apparently as the result of an intramolecular C—H···π interaction. Atoms C12A and C13 of the phthalimido moiety are closest to atom C19 (3.58 and 3.61 Å, respectively), while the average distance between the cluster of the phenyl moiety and atom C19 is 3.85 Å. Although C—H···π interactions are now well established (Desiraju & Steiner et al., 1999; Jennings et al., 2001; & Nishio et al., 1998), to the best of our knowledge, the formation of a folded conformation in a `propylene linker' flexible compound that also involves a single methyl group not directly attached to an aromatic moiety is unprecedented.

Compound (VII) was synthesized only to investigate the robustness of the unusual conformation formed in (VI) a the result of the intramolecular C—H···π interaction. Interestingly, (VII) shows a fully extended open conformation, which permits efficient packing without any intramolecular C—H···π interaction.

Surprisingly, a pyrrolidino moiety remote from the involved methylthio group changes the conformation completely in the solid state. Compounds (VI) and (VII) are a unique and unprecedented pair of compounds, in which the remote substitution of a methylthio group by a pyrrolidino moiety changes the folded conformation to an unfolded one in the solid state. The similarity of the methylthio H atoms in the 1H NMR spectra of these compounds clearly indicates a folded conformation for both (VI) and (BVII); however, because of the very weak nature of the C—H···π interaction (Desiraju, 2002), the folded conformation is not observed in solid state for (VII), as the result of competing packing forces.

The crystal packing of (VI) reveals the presence of intermolecular stacking due to aromatic π–π interactions among the six-membered rings. The molecule of (VI) forms an interesting `fourfold' arrangement of phthalimide–pyrimidine–pyrimidine–phthalimide stacked rings (minimum C···C distance = 3.555 Å between phthalimide and pyrimidine rings, and 3.510 Å between two pyrimidine rings) with each phthalimide end `capped' by methylthio groups and a head-to-tail arrangement of the molecules in the case of phthalimide–pyrimidine stacking (Fig. 3). The crystal packing further shows that the molecules are connected by intermolecular C—H···O hydrogen bonds (Table 1). In (VII), on the other hand, the intermolecular stacking interactions appear to be entirely `segregated'. As seen in Fig. 4, phthalimide rings only stack with other phthalimide rings (minimum C···C distance = 3.462 Å) and pyrimdine rings only stack with other pyrimidine rings (minimum C···C distance = 3.725 Å). The molecules are further connected by C—H···N hydrogen bonding (Table 1), leading to the dimerization of the molecules. In conclusion, the new dissymmetrical compounds (VI) and (VII), formed by the replacement of one pyrazolo[3,4-d]pyrimidine moiety with a phthalimido group, do not show the U motif seen in the symmetrical compounds (I)–(V) in the solid state.

S2. Experimental

Compound (VII) was prepared by refluxing a solution of (VI) with pyrrolidine in benzene. Diffraction-quality crystals of (VII) were prepared from a mixture of chloroform and ethyl acetate solution by slow evaporation at room temperature.

Computing details

For both compounds, data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS (Siemens, 1996); data reduction: XSCANS (Siemens, 1996); program(s) used to solve structure: SHELXTL (Bruker, 1997); program(s) used to refine structure: SHELXTL (Bruker, 1997); molecular graphics: SHELXTL (Bruker, 1997); software used to prepare material for publication: SHELXTL (Bruker, 1997).

Figures

	Fig. 1. Displacement ellipsoid plot (30% probability), showing the molecular structure of (VI), with the atomic labelling scheme.
	Fig. 2. Displacement ellipsoid plot (30% probability), showing the molecular structure of (VII), with the atomic labelling scheme.
	Fig. 3. A view of the molecules of (VI), showing the intermolecular stacking of phthalimide–pyrimidin–pyrimidine–phthalimide rings.
	Fig. 4. A view of the molecules of (VII), showing intermolecular stacking between pyrimidine rings, and phthalimide and phthalimide rings, due to aromatic π-π interactions.

(VI) 4,6-Bis(methylsulfanyl)-1-phthalimidopropyl-1H-pyrazolo[3,4-d]pyrimidine

Crystal data

C18H17N5O2S2	Dx = 1.405 Mg m^−3
Mr = 399.49	Melting point: 393 K
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 10.471 (1) Å	Cell parameters from 40 reflections
b = 13.1323 (11) Å	θ = 4.8–14.8°
c = 14.0516 (12) Å	µ = 0.31 mm^−1
β = 102.19 (1)°	T = 293 K
V = 1888.7 (3) Å^3	Rectangular, colourless
Z = 4	0.38 × 0.31 × 0.26 mm
F(000) = 832

Data collection

Bruker P4 diffractometer	Rint = 0.026
Radiation source: fine-focus sealed tube	θmax = 25.0°, θmin = 2.2°
Graphite monochromator	h = −12→1
θ–2θ scans	k = −15→1
4279 measured reflections	l = −16→16
3327 independent reflections	3 standard reflections every 97 reflections
2566 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.037	H-atom parameters constrained
wR(F^2) = 0.092	w = 1/[σ^2(Fo^2) + (0.027P)^2 + 0.7345P] where P = (Fo^2 + 2Fc^2)/3
S = 1.02	(Δ/σ)max < 0.001
3327 reflections	Δρmax = 0.16 e Å^−3
247 parameters	Δρmin = −0.18 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0189 (10)

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
N1	0.64508 (15)	0.01666 (13)	0.21204 (12)	0.0475 (4)
S1	0.62861 (7)	−0.28497 (5)	0.00037 (5)	0.0711 (2)
N2	0.76754 (16)	−0.02536 (14)	0.22767 (13)	0.0556 (5)
S2	0.20255 (5)	−0.08510 (5)	0.01761 (4)	0.0634 (2)
C3	0.7583 (2)	−0.10443 (17)	0.16880 (16)	0.0556 (5)
H3	0.8279	−0.1465	0.1636	0.067*
C3A	0.62907 (19)	−0.11713 (15)	0.11455 (14)	0.0456 (5)
C4	0.5534 (2)	−0.18331 (16)	0.04637 (14)	0.0476 (5)
N5	0.42548 (16)	−0.16973 (13)	0.01854 (11)	0.0484 (4)
C6	0.37253 (19)	−0.08968 (16)	0.05734 (13)	0.0454 (5)
C7A	0.56024 (18)	−0.03774 (15)	0.14613 (13)	0.0421 (4)
N7	0.43077 (15)	−0.02041 (13)	0.11945 (11)	0.0461 (4)
C8	0.6131 (2)	0.09998 (16)	0.27028 (14)	0.0488 (5)
H8A	0.5399	0.1378	0.2329	0.059*
H8B	0.6872	0.1459	0.2861	0.059*
C9	0.5785 (2)	0.06207 (17)	0.36347 (15)	0.0538 (5)
H9A	0.5193	0.0048	0.3481	0.065*
H9B	0.6574	0.0376	0.4066	0.065*
C10	0.5158 (2)	0.14133 (19)	0.41665 (15)	0.0587 (6)
H10A	0.5123	0.1158	0.4808	0.070*
H10B	0.5694	0.2022	0.4250	0.070*
N11	0.38428 (17)	0.16750 (14)	0.36490 (12)	0.0523 (4)
C12	0.2741 (2)	0.11036 (17)	0.37005 (15)	0.0539 (5)
C12A	0.1627 (2)	0.16083 (15)	0.30514 (14)	0.0471 (5)
C13	0.0325 (2)	0.13398 (17)	0.28090 (15)	0.0549 (6)
H13	0.0010	0.0774	0.3084	0.066*
C14	−0.0491 (2)	0.19484 (18)	0.21397 (16)	0.0577 (6)
H14	−0.1373	0.1786	0.1959	0.069*
C15	−0.0023 (2)	0.27917 (18)	0.17343 (17)	0.0607 (6)
H15	−0.0597	0.3189	0.1291	0.073*
C16	0.1287 (2)	0.30561 (17)	0.19770 (17)	0.0573 (6)
H16	0.1605	0.3620	0.1700	0.069*
C16A	0.2098 (2)	0.24507 (16)	0.26442 (14)	0.0473 (5)
C17	0.3527 (2)	0.25082 (17)	0.30275 (16)	0.0523 (5)
C18	0.4938 (3)	−0.3551 (2)	−0.0682 (2)	0.0796 (8)
H18A	0.4389	−0.3779	−0.0256	0.119*
H18B	0.5258	−0.4129	−0.0979	0.119*
H18C	0.4442	−0.3121	−0.1178	0.119*
C19	0.1612 (3)	0.0196 (2)	0.0871 (2)	0.0982 (11)
H19A	0.2005	0.0098	0.1547	0.147*
H19B	0.0680	0.0232	0.0794	0.147*
H19C	0.1928	0.0818	0.0646	0.147*
O20	0.27551 (17)	0.03351 (14)	0.41856 (12)	0.0751 (5)
O21	0.43066 (15)	0.31204 (12)	0.28520 (12)	0.0673 (4)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0407 (9)	0.0491 (10)	0.0513 (9)	0.0006 (8)	0.0068 (8)	−0.0048 (8)
S1	0.0680 (4)	0.0650 (4)	0.0810 (4)	0.0111 (3)	0.0171 (3)	−0.0225 (3)
N2	0.0417 (10)	0.0602 (11)	0.0635 (11)	0.0018 (9)	0.0078 (8)	−0.0043 (10)
S2	0.0454 (3)	0.0777 (4)	0.0612 (4)	0.0026 (3)	−0.0023 (3)	−0.0156 (3)
C3	0.0453 (12)	0.0569 (13)	0.0650 (13)	0.0069 (10)	0.0126 (10)	−0.0056 (12)
C3A	0.0462 (11)	0.0464 (11)	0.0455 (11)	0.0047 (10)	0.0124 (9)	0.0013 (9)
C4	0.0549 (12)	0.0456 (12)	0.0439 (11)	0.0019 (10)	0.0140 (9)	0.0006 (9)
N5	0.0532 (11)	0.0495 (10)	0.0427 (9)	−0.0008 (8)	0.0102 (8)	−0.0022 (8)
C6	0.0477 (11)	0.0497 (12)	0.0379 (10)	0.0027 (10)	0.0068 (9)	0.0036 (9)
C7A	0.0421 (11)	0.0444 (11)	0.0389 (10)	−0.0028 (9)	0.0066 (8)	0.0025 (9)
N7	0.0438 (9)	0.0493 (10)	0.0438 (9)	0.0035 (8)	0.0064 (7)	−0.0013 (8)
C8	0.0484 (11)	0.0459 (11)	0.0525 (12)	−0.0050 (10)	0.0117 (9)	−0.0081 (10)
C9	0.0525 (12)	0.0569 (13)	0.0507 (12)	0.0016 (10)	0.0080 (10)	0.0019 (10)
C10	0.0559 (13)	0.0698 (15)	0.0493 (12)	−0.0022 (12)	0.0088 (10)	−0.0066 (11)
N11	0.0493 (10)	0.0533 (10)	0.0564 (10)	−0.0009 (9)	0.0162 (8)	−0.0005 (9)
C12	0.0607 (13)	0.0541 (13)	0.0504 (12)	−0.0066 (11)	0.0199 (10)	−0.0021 (11)
C12A	0.0511 (12)	0.0466 (11)	0.0472 (11)	−0.0067 (10)	0.0187 (9)	−0.0042 (9)
C13	0.0577 (13)	0.0561 (13)	0.0553 (12)	−0.0134 (11)	0.0218 (11)	−0.0036 (11)
C14	0.0495 (12)	0.0659 (15)	0.0603 (13)	−0.0088 (11)	0.0178 (11)	−0.0112 (12)
C15	0.0570 (14)	0.0621 (15)	0.0633 (14)	0.0053 (12)	0.0133 (11)	0.0027 (12)
C16	0.0569 (13)	0.0502 (13)	0.0683 (14)	−0.0030 (11)	0.0211 (11)	0.0045 (11)
C16A	0.0495 (11)	0.0454 (11)	0.0513 (11)	−0.0034 (10)	0.0201 (9)	−0.0052 (10)
C17	0.0530 (12)	0.0491 (12)	0.0597 (13)	−0.0036 (11)	0.0235 (10)	−0.0052 (11)
C18	0.098 (2)	0.0614 (16)	0.0829 (18)	−0.0078 (15)	0.0266 (16)	−0.0226 (14)
C19	0.0549 (15)	0.113 (2)	0.118 (2)	0.0204 (16)	−0.0004 (15)	−0.049 (2)
O20	0.0794 (12)	0.0721 (12)	0.0738 (11)	−0.0078 (9)	0.0165 (9)	0.0233 (10)
O21	0.0561 (9)	0.0634 (10)	0.0866 (11)	−0.0143 (8)	0.0245 (8)	0.0043 (9)

Geometric parameters (Å, º)

N1—C7A	1.346 (2)	C10—H10B	0.9700
N1—N2	1.371 (2)	N11—C12	1.391 (3)
N1—C8	1.447 (3)	N11—C17	1.396 (3)
S1—C4	1.742 (2)	C12—O20	1.216 (3)
S1—C18	1.788 (3)	C12—C12A	1.477 (3)
N2—C3	1.318 (3)	C12A—C13	1.379 (3)
S2—C6	1.751 (2)	C12A—C16A	1.383 (3)
S2—C19	1.792 (3)	C13—C14	1.384 (3)
C3—C3A	1.416 (3)	C13—H13	0.9300
C3—H3	0.9300	C14—C15	1.382 (3)
C3A—C7A	1.392 (3)	C14—H14	0.9300
C3A—C4	1.408 (3)	C15—C16	1.386 (3)
C4—N5	1.326 (3)	C15—H15	0.9300
N5—C6	1.355 (3)	C16—C16A	1.377 (3)
C6—N7	1.318 (3)	C16—H16	0.9300
C7A—N7	1.347 (2)	C16A—C17	1.481 (3)
C8—C9	1.515 (3)	C17—O21	1.208 (2)
C8—H8A	0.9700	C18—H18A	0.9600
C8—H8B	0.9700	C18—H18B	0.9600
C9—C10	1.510 (3)	C18—H18C	0.9600
C9—H9A	0.9700	C19—H19A	0.9600
C9—H9B	0.9700	C19—H19B	0.9600
C10—N11	1.457 (3)	C19—H19C	0.9600
C10—H10A	0.9700
C7A—N1—N2	110.87 (16)	H10A—C10—H10B	107.9
C7A—N1—C8	126.36 (16)	C12—N11—C17	111.45 (18)
N2—N1—C8	122.27 (16)	C12—N11—C10	123.66 (19)
C4—S1—C18	103.13 (12)	C17—N11—C10	124.87 (18)
C3—N2—N1	105.93 (17)	O20—C12—N11	124.3 (2)
C6—S2—C19	101.48 (11)	O20—C12—C12A	129.3 (2)
N2—C3—C3A	111.44 (18)	N11—C12—C12A	106.33 (18)
N2—C3—H3	124.3	C13—C12A—C16A	121.5 (2)
C3A—C3—H3	124.3	C13—C12A—C12	130.4 (2)
C7A—C3A—C4	115.10 (18)	C16A—C12A—C12	108.08 (18)
C7A—C3A—C3	103.92 (17)	C12A—C13—C14	117.2 (2)
C4—C3A—C3	140.91 (19)	C12A—C13—H13	121.4
N5—C4—C3A	120.43 (19)	C14—C13—H13	121.4
N5—C4—S1	120.10 (16)	C15—C14—C13	121.4 (2)
C3A—C4—S1	119.46 (16)	C15—C14—H14	119.3
C4—N5—C6	117.34 (17)	C13—C14—H14	119.3
N7—C6—N5	129.07 (18)	C14—C15—C16	121.2 (2)
N7—C6—S2	119.01 (15)	C14—C15—H15	119.4
N5—C6—S2	111.90 (15)	C16—C15—H15	119.4
N1—C7A—N7	125.54 (18)	C16A—C16—C15	117.3 (2)
N1—C7A—C3A	107.81 (17)	C16A—C16—H16	121.3
N7—C7A—C3A	126.58 (18)	C15—C16—H16	121.3
C6—N7—C7A	111.45 (17)	C16—C16A—C12A	121.4 (2)
N1—C8—C9	111.49 (17)	C16—C16A—C17	130.5 (2)
N1—C8—H8A	109.3	C12A—C16A—C17	108.14 (19)
C9—C8—H8A	109.3	O21—C17—N11	124.6 (2)
N1—C8—H8B	109.3	O21—C17—C16A	129.4 (2)
C9—C8—H8B	109.3	N11—C17—C16A	105.99 (18)
H8A—C8—H8B	108.0	S1—C18—H18A	109.5
C10—C9—C8	114.17 (18)	S1—C18—H18B	109.5
C10—C9—H9A	108.7	H18A—C18—H18B	109.5
C8—C9—H9A	108.7	S1—C18—H18C	109.5
C10—C9—H9B	108.7	H18A—C18—H18C	109.5
C8—C9—H9B	108.7	H18B—C18—H18C	109.5
H9A—C9—H9B	107.6	S2—C19—H19A	109.5
N11—C10—C9	112.30 (17)	S2—C19—H19B	109.5
N11—C10—H10A	109.1	H19A—C19—H19B	109.5
C9—C10—H10A	109.1	S2—C19—H19C	109.5
N11—C10—H10B	109.1	H19A—C19—H19C	109.5
C9—C10—H10B	109.1	H19B—C19—H19C	109.5
C7A—N1—N2—C3	1.8 (2)	N1—C8—C9—C10	−167.15 (17)
C8—N1—N2—C3	174.07 (18)	C8—C9—C10—N11	69.8 (2)
N1—N2—C3—C3A	−1.1 (2)	C9—C10—N11—C12	82.2 (2)
N2—C3—C3A—C7A	0.1 (2)	C9—C10—N11—C17	−96.4 (2)
N2—C3—C3A—C4	−176.5 (2)	C17—N11—C12—O20	179.4 (2)
C7A—C3A—C4—N5	−1.9 (3)	C10—N11—C12—O20	0.6 (3)
C3—C3A—C4—N5	174.5 (2)	C17—N11—C12—C12A	0.5 (2)
C7A—C3A—C4—S1	179.36 (14)	C10—N11—C12—C12A	−178.24 (18)
C3—C3A—C4—S1	−4.3 (4)	O20—C12—C12A—C13	−1.3 (4)
C18—S1—C4—N5	−6.4 (2)	N11—C12—C12A—C13	177.5 (2)
C18—S1—C4—C3A	172.43 (17)	O20—C12—C12A—C16A	−178.9 (2)
C3A—C4—N5—C6	0.8 (3)	N11—C12—C12A—C16A	−0.1 (2)
S1—C4—N5—C6	179.59 (14)	C16A—C12A—C13—C14	0.1 (3)
C4—N5—C6—N7	1.0 (3)	C12—C12A—C13—C14	−177.3 (2)
C4—N5—C6—S2	−177.46 (15)	C12A—C13—C14—C15	−0.3 (3)
C19—S2—C6—N7	−3.0 (2)	C13—C14—C15—C16	0.6 (3)
C19—S2—C6—N5	175.58 (17)	C14—C15—C16—C16A	−0.6 (3)
N2—N1—C7A—N7	175.48 (18)	C15—C16—C16A—C12A	0.4 (3)
C8—N1—C7A—N7	3.5 (3)	C15—C16—C16A—C17	177.9 (2)
N2—N1—C7A—C3A	−1.7 (2)	C13—C12A—C16A—C16	−0.2 (3)
C8—N1—C7A—C3A	−173.66 (18)	C12—C12A—C16A—C16	177.73 (19)
C4—C3A—C7A—N1	178.62 (17)	C13—C12A—C16A—C17	−178.16 (18)
C3—C3A—C7A—N1	1.0 (2)	C12—C12A—C16A—C17	−0.3 (2)
C4—C3A—C7A—N7	1.4 (3)	C12—N11—C17—O21	−179.6 (2)
C3—C3A—C7A—N7	−176.18 (19)	C10—N11—C17—O21	−0.9 (3)
N5—C6—N7—C7A	−1.4 (3)	C12—N11—C17—C16A	−0.7 (2)
S2—C6—N7—C7A	176.96 (14)	C10—N11—C17—C16A	178.06 (18)
N1—C7A—N7—C6	−176.62 (18)	C16—C16A—C17—O21	1.7 (4)
C3A—C7A—N7—C6	0.1 (3)	C12A—C16A—C17—O21	179.4 (2)
C7A—N1—C8—C9	86.9 (2)	C16—C16A—C17—N11	−177.2 (2)
N2—N1—C8—C9	−84.2 (2)	C12A—C16A—C17—N11	0.6 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C3—H3···O21^i	0.93	2.54	3.367 (3)	149

Symmetry code: (i) −x+3/2, y+1/2, −z+1/2.

(VII) 6-Methylsulfanyl-1-phthalimidopropyl-4-pyrrolidino-1H- pyrazolo[3,4-d]pyrimidine

Crystal data

C21H22N6O2S	F(000) = 444
Mr = 422.51	Dx = 1.362 Mg m^−3
Triclinic, P1	Melting point: 467 K
a = 7.5993 (6) Å	Mo Kα radiation, λ = 0.71073 Å
b = 9.3968 (7) Å	Cell parameters from 49 reflections
c = 15.376 (2) Å	θ = 5.1–12.5°
α = 80.684 (8)°	µ = 0.19 mm^−1
β = 82.48 (1)°	T = 293 K
γ = 72.685 (6)°	Block, colourless
V = 1030.54 (19) Å^3	0.28 × 0.20 × 0.16 mm
Z = 2

Data collection

Bruker P4 diffractometer	Rint = 0.063
Radiation source: fine-focus sealed tube	θmax = 25.0°, θmin = 2.3°
Graphite monochromator	h = −8→1
θ–2θ scans	k = −11→10
4402 measured reflections	l = −18→18
3580 independent reflections	3 standard reflections every 97 reflections
2420 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.057	H-atom parameters constrained
wR(F^2) = 0.171	w = 1/[σ^2(Fo^2) + (0.0734P)^2 + 0.6332P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max < 0.001
3580 reflections	Δρmax = 0.37 e Å^−3
273 parameters	Δρmin = −0.31 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.024 (4)

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
N1	0.2492 (3)	0.3246 (3)	0.34426 (16)	0.0464 (6)
S1	0.50532 (13)	−0.22207 (10)	0.32030 (6)	0.0598 (3)
N2	0.1435 (4)	0.4122 (3)	0.40541 (17)	0.0522 (7)
C3	0.1152 (4)	0.3178 (3)	0.4758 (2)	0.0495 (8)
H3	0.0465	0.3474	0.5278	0.059*
C3A	0.2019 (4)	0.1659 (3)	0.46264 (18)	0.0394 (7)
C4	0.2307 (4)	0.0171 (3)	0.50724 (18)	0.0399 (7)
N5	0.3250 (3)	−0.1001 (3)	0.46341 (16)	0.0437 (6)
C6	0.3923 (4)	−0.0695 (3)	0.38007 (19)	0.0440 (7)
C7A	0.2867 (4)	0.1767 (3)	0.37552 (18)	0.0400 (7)
N7	0.3843 (3)	0.0622 (3)	0.33112 (16)	0.0460 (6)
C8	0.3139 (4)	0.3909 (4)	0.2585 (2)	0.0519 (8)
H8A	0.4206	0.3174	0.2346	0.062*
H8B	0.3543	0.4760	0.2670	0.062*
C9	0.1714 (4)	0.4431 (3)	0.1917 (2)	0.0503 (8)
H9A	0.1237	0.3602	0.1865	0.060*
H9B	0.2311	0.4710	0.1345	0.060*
C10	0.0114 (5)	0.5752 (4)	0.2155 (2)	0.0622 (9)
H10A	−0.0629	0.5424	0.2667	0.075*
H10B	0.0593	0.6515	0.2315	0.075*
N11	−0.1056 (4)	0.6409 (3)	0.14279 (17)	0.0554 (7)
C12	−0.0694 (5)	0.7485 (4)	0.0751 (2)	0.0526 (8)
C12A	−0.2217 (4)	0.7849 (3)	0.0169 (2)	0.0487 (8)
C13	−0.2566 (5)	0.8877 (4)	−0.0577 (2)	0.0627 (10)
H13	−0.1772	0.9458	−0.0806	0.075*
C14	−0.4164 (6)	0.9008 (5)	−0.0974 (2)	0.0758 (12)
H14	−0.4444	0.9682	−0.1484	0.091*
C15	−0.5334 (6)	0.8148 (5)	−0.0619 (3)	0.0794 (12)
H15	−0.6399	0.8264	−0.0892	0.095*
C16	−0.4968 (5)	0.7125 (4)	0.0127 (3)	0.0694 (10)
H16	−0.5760	0.6545	0.0362	0.083*
C16A	−0.3389 (4)	0.6994 (4)	0.0511 (2)	0.0510 (8)
C17	−0.2646 (5)	0.6038 (4)	0.1320 (2)	0.0565 (9)
N18	0.1682 (3)	−0.0140 (3)	0.59133 (15)	0.0446 (6)
C19	0.0738 (5)	0.0986 (4)	0.64980 (19)	0.0512 (8)
H19A	−0.0526	0.1474	0.6355	0.061*
H19B	0.1386	0.1743	0.6463	0.061*
C20	0.0790 (9)	0.0072 (5)	0.7397 (3)	0.119 (2)
H20A	0.1677	0.0271	0.7726	0.143*
H20B	−0.0418	0.0351	0.7722	0.143*
C21	0.1289 (8)	−0.1437 (5)	0.7303 (3)	0.0941 (15)
H21A	0.0209	−0.1809	0.7437	0.113*
H21B	0.2188	−0.1995	0.7717	0.113*
C22	0.2100 (5)	−0.1676 (3)	0.6380 (2)	0.0495 (8)
H22A	0.3423	−0.2150	0.6361	0.059*
H22B	0.1520	−0.2289	0.6129	0.059*
C23	0.5128 (6)	−0.3815 (4)	0.4019 (3)	0.0680 (10)
H23A	0.5626	−0.3688	0.4534	0.102*
H23B	0.5900	−0.4705	0.3785	0.102*
H23C	0.3900	−0.3910	0.4176	0.102*
O24	0.0614 (4)	0.7986 (3)	0.06936 (19)	0.0785 (8)
O25	−0.3234 (4)	0.5116 (3)	0.18172 (19)	0.0795 (8)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N1	0.0495 (15)	0.0437 (14)	0.0417 (13)	−0.0100 (12)	−0.0039 (11)	0.0007 (11)
S1	0.0694 (6)	0.0484 (5)	0.0552 (5)	−0.0091 (4)	0.0067 (4)	−0.0126 (4)
N2	0.0627 (17)	0.0418 (14)	0.0470 (15)	−0.0087 (13)	−0.0030 (13)	−0.0041 (12)
C3	0.0587 (19)	0.0459 (17)	0.0401 (16)	−0.0108 (15)	−0.0014 (14)	−0.0050 (14)
C3A	0.0408 (16)	0.0370 (15)	0.0406 (15)	−0.0112 (12)	−0.0066 (12)	−0.0027 (12)
C4	0.0375 (15)	0.0441 (16)	0.0389 (15)	−0.0124 (13)	−0.0085 (12)	−0.0018 (12)
N5	0.0446 (14)	0.0420 (14)	0.0438 (14)	−0.0117 (11)	−0.0047 (11)	−0.0042 (11)
C6	0.0425 (17)	0.0447 (17)	0.0440 (16)	−0.0099 (13)	−0.0063 (13)	−0.0060 (13)
C7A	0.0367 (15)	0.0411 (16)	0.0420 (15)	−0.0119 (12)	−0.0068 (12)	−0.0003 (12)
N7	0.0461 (14)	0.0454 (14)	0.0428 (13)	−0.0100 (11)	−0.0004 (11)	−0.0032 (11)
C8	0.0509 (19)	0.0510 (18)	0.0485 (17)	−0.0139 (15)	−0.0004 (14)	0.0047 (14)
C9	0.0576 (19)	0.0446 (17)	0.0426 (16)	−0.0091 (15)	−0.0020 (14)	−0.0004 (13)
C10	0.067 (2)	0.061 (2)	0.0465 (18)	−0.0012 (17)	−0.0067 (16)	−0.0036 (16)
N11	0.0533 (16)	0.0570 (16)	0.0464 (15)	−0.0070 (13)	−0.0027 (12)	0.0027 (12)
C12	0.0504 (19)	0.0520 (19)	0.0509 (18)	−0.0124 (16)	0.0021 (15)	−0.0033 (15)
C12A	0.0514 (18)	0.0471 (17)	0.0409 (16)	−0.0072 (14)	0.0016 (14)	−0.0039 (13)
C13	0.073 (2)	0.060 (2)	0.0463 (18)	−0.0137 (18)	0.0086 (17)	−0.0034 (16)
C14	0.092 (3)	0.073 (3)	0.0408 (18)	0.014 (2)	−0.013 (2)	−0.0068 (18)
C15	0.068 (3)	0.096 (3)	0.068 (3)	−0.005 (2)	−0.018 (2)	−0.020 (2)
C16	0.058 (2)	0.068 (2)	0.080 (3)	−0.0117 (18)	−0.0041 (19)	−0.015 (2)
C16A	0.0469 (18)	0.0494 (18)	0.0498 (18)	−0.0059 (15)	−0.0005 (14)	−0.0044 (14)
C17	0.054 (2)	0.0461 (18)	0.058 (2)	−0.0065 (15)	0.0076 (16)	−0.0003 (16)
N18	0.0523 (15)	0.0428 (13)	0.0380 (13)	−0.0134 (11)	−0.0058 (11)	−0.0017 (10)
C19	0.062 (2)	0.0486 (18)	0.0433 (17)	−0.0185 (15)	−0.0011 (14)	−0.0046 (14)
C20	0.226 (7)	0.068 (3)	0.043 (2)	−0.031 (3)	0.029 (3)	−0.0031 (19)
C21	0.142 (4)	0.066 (3)	0.053 (2)	−0.013 (3)	0.014 (2)	0.0049 (19)
C22	0.0559 (19)	0.0428 (17)	0.0510 (18)	−0.0178 (15)	−0.0106 (15)	0.0031 (14)
C23	0.084 (3)	0.0457 (19)	0.072 (2)	−0.0140 (18)	−0.005 (2)	−0.0106 (17)
O24	0.0672 (17)	0.0806 (19)	0.091 (2)	−0.0303 (15)	−0.0092 (14)	−0.0004 (15)
O25	0.0779 (18)	0.0618 (16)	0.0859 (19)	−0.0207 (14)	0.0100 (15)	0.0158 (14)

Geometric parameters (Å, º)

N1—C7A	1.352 (4)	C12A—C16A	1.372 (5)
N1—N2	1.366 (3)	C12A—C13	1.374 (4)
N1—C8	1.454 (4)	C13—C14	1.395 (6)
S1—C6	1.768 (3)	C13—H13	0.9300
S1—C23	1.784 (4)	C14—C15	1.378 (6)
N2—C3	1.322 (4)	C14—H14	0.9300
C3—C3A	1.418 (4)	C15—C16	1.373 (6)
C3—H3	0.9300	C15—H15	0.9300
C3A—C7A	1.410 (4)	C16—C16A	1.370 (5)
C3A—C4	1.422 (4)	C16—H16	0.9300
C4—N18	1.335 (4)	C16A—C17	1.481 (5)
C4—N5	1.351 (4)	C17—O25	1.209 (4)
N5—C6	1.335 (4)	N18—C19	1.460 (4)
C6—N7	1.330 (4)	N18—C22	1.467 (4)
C7A—N7	1.343 (4)	C19—C20	1.503 (5)
C8—C9	1.510 (4)	C19—H19A	0.9700
C8—H8A	0.9700	C19—H19B	0.9700
C8—H8B	0.9700	C20—C21	1.381 (6)
C9—C10	1.512 (4)	C20—H20A	0.9700
C9—H9A	0.9700	C20—H20B	0.9700
C9—H9B	0.9700	C21—C22	1.496 (5)
C10—N11	1.460 (4)	C21—H21A	0.9700
C10—H10A	0.9700	C21—H21B	0.9700
C10—H10B	0.9700	C22—H22A	0.9700
N11—C17	1.390 (5)	C22—H22B	0.9700
N11—C12	1.390 (4)	C23—H23A	0.9600
C12—O24	1.208 (4)	C23—H23B	0.9600
C12—C12A	1.481 (5)	C23—H23C	0.9600
C7A—N1—N2	111.7 (2)	C12A—C13—H13	121.5
C7A—N1—C8	127.0 (3)	C14—C13—H13	121.5
N2—N1—C8	121.3 (2)	C15—C14—C13	120.7 (4)
C6—S1—C23	102.87 (16)	C15—C14—H14	119.7
C3—N2—N1	105.7 (2)	C13—C14—H14	119.7
N2—C3—C3A	112.0 (3)	C16—C15—C14	121.8 (4)
N2—C3—H3	124.0	C16—C15—H15	119.1
C3A—C3—H3	124.0	C14—C15—H15	119.1
C7A—C3A—C3	103.6 (2)	C16A—C16—C15	117.3 (4)
C7A—C3A—C4	115.0 (2)	C16A—C16—H16	121.3
C3—C3A—C4	141.4 (3)	C15—C16—H16	121.3
N18—C4—N5	117.5 (3)	C16—C16A—C12A	121.6 (3)
N18—C4—C3A	123.2 (3)	C16—C16A—C17	130.2 (3)
N5—C4—C3A	119.3 (2)	C12A—C16A—C17	108.1 (3)
C6—N5—C4	117.7 (2)	O25—C17—N11	124.1 (3)
N7—C6—N5	130.0 (3)	O25—C17—C16A	129.9 (4)
N7—C6—S1	112.0 (2)	N11—C17—C16A	106.0 (3)
N5—C6—S1	118.0 (2)	C4—N18—C19	124.7 (2)
N7—C7A—N1	126.1 (3)	C4—N18—C22	122.4 (3)
N7—C7A—C3A	126.8 (3)	C19—N18—C22	112.5 (2)
N1—C7A—C3A	107.1 (2)	N18—C19—C20	102.8 (3)
C6—N7—C7A	111.1 (2)	N18—C19—H19A	111.2
N1—C8—C9	114.5 (3)	C20—C19—H19A	111.2
N1—C8—H8A	108.6	N18—C19—H19B	111.2
C9—C8—H8A	108.6	C20—C19—H19B	111.2
N1—C8—H8B	108.6	H19A—C19—H19B	109.1
C9—C8—H8B	108.6	C21—C20—C19	109.4 (3)
H8A—C8—H8B	107.6	C21—C20—H20A	109.8
C8—C9—C10	113.4 (3)	C19—C20—H20A	109.8
C8—C9—H9A	108.9	C21—C20—H20B	109.8
C10—C9—H9A	108.9	C19—C20—H20B	109.8
C8—C9—H9B	108.9	H20A—C20—H20B	108.2
C10—C9—H9B	108.9	C20—C21—C22	110.4 (3)
H9A—C9—H9B	107.7	C20—C21—H21A	109.6
N11—C10—C9	112.2 (3)	C22—C21—H21A	109.6
N11—C10—H10A	109.2	C20—C21—H21B	109.6
C9—C10—H10A	109.2	C22—C21—H21B	109.6
N11—C10—H10B	109.2	H21A—C21—H21B	108.1
C9—C10—H10B	109.2	N18—C22—C21	102.6 (3)
H10A—C10—H10B	107.9	N18—C22—H22A	111.2
C17—N11—C12	111.7 (3)	C21—C22—H22A	111.2
C17—N11—C10	124.8 (3)	N18—C22—H22B	111.2
C12—N11—C10	123.5 (3)	C21—C22—H22B	111.2
O24—C12—N11	124.3 (3)	H22A—C22—H22B	109.2
O24—C12—C12A	129.9 (3)	S1—C23—H23A	109.5
N11—C12—C12A	105.8 (3)	S1—C23—H23B	109.5
C16A—C12A—C13	121.7 (3)	H23A—C23—H23B	109.5
C16A—C12A—C12	108.4 (3)	S1—C23—H23C	109.5
C13—C12A—C12	129.9 (3)	H23A—C23—H23C	109.5
C12A—C13—C14	116.9 (4)	H23B—C23—H23C	109.5
C7A—N1—N2—C3	0.2 (3)	C10—N11—C12—C12A	−179.3 (3)
C8—N1—N2—C3	−177.8 (3)	O24—C12—C12A—C16A	−179.5 (4)
N1—N2—C3—C3A	0.1 (4)	N11—C12—C12A—C16A	−0.3 (3)
N2—C3—C3A—C7A	−0.4 (4)	O24—C12—C12A—C13	−1.7 (6)
N2—C3—C3A—C4	178.2 (3)	N11—C12—C12A—C13	177.5 (3)
C7A—C3A—C4—N18	176.8 (3)	C16A—C12A—C13—C14	−0.2 (5)
C3—C3A—C4—N18	−1.7 (6)	C12—C12A—C13—C14	−177.8 (3)
C7A—C3A—C4—N5	−3.4 (4)	C12A—C13—C14—C15	0.7 (5)
C3—C3A—C4—N5	178.0 (4)	C13—C14—C15—C16	−0.8 (6)
N18—C4—N5—C6	−178.2 (2)	C14—C15—C16—C16A	0.3 (6)
C3A—C4—N5—C6	2.0 (4)	C15—C16—C16A—C12A	0.2 (5)
C4—N5—C6—N7	1.1 (5)	C15—C16—C16A—C17	178.2 (3)
C4—N5—C6—S1	−176.7 (2)	C13—C12A—C16A—C16	−0.2 (5)
C23—S1—C6—N7	175.8 (2)	C12—C12A—C16A—C16	177.8 (3)
C23—S1—C6—N5	−6.0 (3)	C13—C12A—C16A—C17	−178.6 (3)
N2—N1—C7A—N7	178.7 (3)	C12—C12A—C16A—C17	−0.6 (3)
C8—N1—C7A—N7	−3.4 (5)	C12—N11—C17—O25	179.1 (3)
N2—N1—C7A—C3A	−0.5 (3)	C10—N11—C17—O25	−0.5 (5)
C8—N1—C7A—C3A	177.4 (3)	C12—N11—C17—C16A	−1.5 (3)
C3—C3A—C7A—N7	−178.7 (3)	C10—N11—C17—C16A	179.0 (3)
C4—C3A—C7A—N7	2.2 (4)	C16—C16A—C17—O25	2.4 (6)
C3—C3A—C7A—N1	0.5 (3)	C12A—C16A—C17—O25	−179.3 (3)
C4—C3A—C7A—N1	−178.5 (2)	C16—C16A—C17—N11	−177.0 (3)
N5—C6—N7—C7A	−2.3 (5)	C12A—C16A—C17—N11	1.2 (3)
S1—C6—N7—C7A	175.6 (2)	N5—C4—N18—C19	176.1 (3)
N1—C7A—N7—C6	−178.6 (3)	C3A—C4—N18—C19	−4.1 (4)
C3A—C7A—N7—C6	0.5 (4)	N5—C4—N18—C22	4.5 (4)
C7A—N1—C8—C9	102.5 (3)	C3A—C4—N18—C22	−175.7 (3)
N2—N1—C8—C9	−79.8 (4)	C4—N18—C19—C20	−165.7 (4)
N1—C8—C9—C10	67.3 (4)	C22—N18—C19—C20	6.7 (4)
C8—C9—C10—N11	169.3 (3)	N18—C19—C20—C21	−13.5 (6)
C9—C10—N11—C17	94.2 (4)	C19—C20—C21—C22	15.5 (7)
C9—C10—N11—C12	−85.3 (4)	C4—N18—C22—C21	174.3 (3)
C17—N11—C12—O24	−179.6 (3)	C19—N18—C22—C21	1.8 (4)
C10—N11—C12—O24	0.0 (5)	C20—C21—C22—N18	−10.7 (6)
C17—N11—C12—C12A	1.1 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C3—H3···N2^i	0.93	2.58	3.351 (4)	140

Symmetry code: (i) −x, −y+1, −z+1.