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The title compound C29H28N8O4, 1,1′-(propane-1,3-diyl)bis(5-benzyl-7-methyl-1H-pyrazolo[3,4-d]••pyrimidine-4,6(5H,7H)-dione) is characterized by single crystal X-ray diffraction. It crystallizes in the centrosymmetric space group P $\bar 1$ , with two molecules in the unit cell. There is one formula unit in the asymmetric unit with a folded conformation due to arene interaction and an unusually large angle of 124° in the propylene linker. The crystal structure is stabilized due to the presence of π–π and C–H…O interactions.

We have designed and synthesized dissymmetrical diaryl 2-methylenepropylidenes based on pyrazolo[3,4-d]pyrimidine core for studying conformational control due to arene interactions in face-to-face (offset) mode. Dissymmetrical 2-methylenepropylidene linker models (N1-N1 isomers) show intramolecular π-π stacking (folded conformation) by 1H NMR in solution which carries over to solid state as revealed by single crystal X-ray crystallography. Corresponding, N1-N2 isomers do not show intramolecular π-π stacking at molecular level. In addition to arene interactions crystal structures are also stabilized by intermolecular C-H…O, C-H…S or C-H…N interactions.

Conformational analysis of nine designed flexible 1,2-diarylethanes with different substituents show syn conformation due to π–π interactions by 1H NMR in solution, this carries over to the solid state for three compounds while two show anti conformation in the solid state by X-ray crystallography and the remaining compounds do not give diffraction quality crystals.

A convenient synthesis of a new class of novel pyrazolo[3,4-d]pyrimidinophanes (four products, 41%), a new class of cyclophane, and X-ray structure of the first dissymmetrical [3.4]pyrazolo[3,4-d]pyrimidinophane (22%) are reported for the first time. The conformation of major syn product 6b is stabilized by weak pi-pi and O...Ar interactions.

Proton NMR analysis of three new symmetrical ‘trimethylene linker’ compounds 1,3-bis(4-chloro-6-methylsulfanyl-l H -pyrazolo[3,4- d ]pyrimidin-1-yl)propane ( 6 ), 1,3-bis(4-cyano-6-methylsulfanyl-l H -pyrazolo[3,4- d ]pyrimidin-1-yl)propane ( 7 ) and 1,3-bis(4,6-dimethylsulfanyl-l H -pyrazolo[3,4- d ]pyrimidin-1-yl)propane ( 8 ) show intramolecular stacking in solution like parent compound 1,3-bis(4,6-dimethylsulfanyl-l H -pyrazolo[3,4- d ]pyrimidin-1-yl)propane ( 1a ). Surprisingly, X-ray crystallographic analyses of the first two compounds having chloro- ( 6 ) or cyano- ( 7 ) groups do not show intramolecular stacking due to arene interaction present in parent compound ( 1a ). In contrast, X-ray crystallographic analysis of the third compound ( 8 ) having four electron donating methoxy groups in place of methylsulfanyl of parent compound ( 1a ) shows presence of intramolecular stacking like parent compound ( 1a ). Supramolecular structures of these three compounds ( 6 – 8 ), differing only in substituents, are stabilized by weak intermolecular π–π, Cl…π, S…π, S…Cl…N, C–H…Cl, C–H…N and C–H…S interactions.

X-ray crystallographic analysis of new symmetrical ‘Leonard/trimethylene linker’ isopropyl analog 1,3-bis(4-isopropoxy-6-methylsulfonyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane (1h) does not show chain motif formed due to intermolecular C H…O interactions between O atoms of sulfonyl groups and central methylene H atoms of linker along with C H…N interactions or plus (+) motif shown earlier by corresponding methyl- (1f) and ethyl- (1g) analogs. More importantly, the more or less superimposed U-motif conformation of 1h is very different from earlier related 10 symmetrical compounds (1a–1g & 2). In 1h intramolecular folding is in such a way that whole pyrazolo[3,4-d]pyrimidine core of one side stacks more or less face-to-face on opposite side of the same molecule while in earlier compounds (1a–1g & 2) there is no intramolecular stacking between pyrazolo portions and only pyrimidine portions partially stack with each other. Surprisingly, ethyl analog (1i) of 1h again shows U-motif conformation similar to earlier related ten symmetrical compounds (1a–1g & 2). Supramolecular structures of both compounds (1h & 1i) are stabilized by weak intermolecular C H…O, C H…N and π–π interactions.

Proton NMR analyses of several newly synthesized dissymmetrical ‘Leonard/trimethylene linker’ compounds 1/2/3-[(4,6-dimethylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl]-5,7-dimethyl/ethyl-sulfanyl-1H/2H/3H-triazolo[4,5-d]pyrimidines (6 and 8) show intramolecularly stacked conformation in solution. X-ray crystallography of one dissymmetrical ‘Leonard/trimethylene’ linker compound (6b) based on two different heterocycles namely pyrazolo[3,4-d]pyrimidine core and triazolo[4,5-d]pyrimidine, for the first time, shows unusual U-motif formed due to intramolecular π–π interactions, which is similar to earlier related pyrazolo[3,4-d]pyrimidine core based ten symmetrical (1 and 2) and one dissymmetrical compound (3). Supramolecular structures of the new compound (6b) show unusual chain motif due to weak intermolecular CH…N and CH…S interactions. More importantly, the new compound (6b) shows S…arene interaction not shown by any earlier compounds (1, 2 and 3).

X-ray crystallographic analysis of two new ‘Leonard/trimethylene linker’ compounds; 1,3-bis(4-methoxy-6-methylsulfonyl-lH-pyrazolo[3,4-d]pyrimidin-1-yl)propane (4a) and 1,3-bis(4-ethoxy-6-methylsulfonyl-lH-pyrazolo[3,4-d]pyrimidin-1-yl)propane (4b) not only confirm robustness of the unusual U-motif conformation seen in earlier related compounds (1 and 2) but in addition reveal novel chain motif formed due to intermolecular C H⋯O and C H⋯N interactions resulting in novel plus (+) motif.

Proton NMR analysis of two newly synthesized ‘Leonard/trimethylene linker’ dissymmetrical compounds 1-(4,6-dimethylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(5-methyl-6-methylsulfanyl-4-oxo-1,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)propane (8) and 1-(4-methoxy-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(6-methoxy-5-methyl-4-oxo-1,5-dihydropyrazolo[3,4-d]pyrimidin-1-yl)propane (10) show intramolecularly stacked conformation in solution. X-Ray crystallography of dissymmetrical ‘Leonard/trimethylene linker’ compound (8) based on pyrazolo[3,4-d]pyrimidine core, for the first time, shows unusual U-motif formed due to intramolecular π–π stacking interactions, which is similar to earlier related symmetrical compounds 1 & 2. Supramolecular structures of new compound (8) show additional CH…O, CH…N, CH…S and S…S interactions.

Proton NMR and X-ray crystallographic analysis of two newly synthesized ‘trimethylene linker,’ (Leonard linker) compounds 1,3-bis(4ethoxy-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidin-1-yl)propane (4c) and 1,3-bis(4-isopropoxy-6-methylsulfanyl-1H-pyrazolo[3,4d]pyrimidin-1-yl)propane (4d) show intramolecularly stacked conformations both in solution and solid state. Robustness of the unusual U-motif formed due to intramolecular stacking in earlier related compounds (1, nZ3 and 3, nZ3) is not only confirmed but additional fine tuning is also achieved in new compounds (4) formed by replacement of remote 4-alkylsulfanyl group in 1a by 4-alkoxy substituents. q 2005 Elsevier B.V. All rights reserved.

The butylidene-linker models 1-[2-(2,6-dimethylsulfanyl-9H-purin-9-yl)-2-methylidenepropyl]-4,6-bis(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine, C18H20N8S4, (XI), 7,7′-(2-methylidenepropane-1,3-diyl)bis[3-methyl-2-methylsulfanyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one], C20H22N6O2S2, (XIV), and 7-[2-(4,6-dimethylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-methylidenepropyl]-3-methyl-2-methylsulfanyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one, C19H21N7OS3, (XV), show folded conformations in solution, as shown by1H NMR analysis. This folding carries over to the crystalline state. Intramolecular π–π interactions are observed in all three compounds, but only (XIV) shows additional intramolecular C—H...π interactions in the solid state. As far as can be established, this is the first report incorporating the pyrrolo[2,3-d]pyrimidine nucleus for such a study. In addition to the π–π interactions, the crystal structures are also stabilized by other weak intermolecular C—H...S/N/O and/or S...N/S interactions.

The furanose ring in 4,6-bis(methylthio)-2-(2,3-anhydro-1-deoxy-β-D-allofuranosyl)-2H-pyrazolo[3,4-d]pyrimidine, C 13 H 16 N 4 O 4 S 2 , is almost planar with the epoxide ring in an exo orientation.

In 5-benzyl-1,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine-4,6-dione, C(14)H(14)N(4)O(2), which crystallizes in space group P 1 macro, weak intermolecular C[bond]H...O hydrogen bonds generate dimers. The isomeric compound 1-benzyl-5,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine-4,6-dione, C(14)H(14)N(4)O(2), crystallizes in space group P2(1)/n, and shows no such dimerization. Instead, it exhibits C[bond]H...pi interactions with the phenyl ring. In both structures, the molecules are linked by aromatic pi-pi-stacking interactions.

The synthesis of a series of 4-amino/hydroxy-6-substituted-12-(2′,2′-diethoxyethyl)-1H/2H-pyrazolo[3,4-d]pyrimidines by alkylation of substituted pyrazolo[3,4-d]pyrimidines has been described, and their antiallergic activity evaluated in mice. The 2 most active compounds 4b and 5b were also tested in the rat. The most active compound 4b showed non-significant antihistaminic or antiserotoninergic activity.

The structure of 1,3-bis(8-chloro­theophyl­lin-7-yl)­propane, C17H18Cl2N8O4, which has no acidic H atom for conventional hydrogen bonding, is described. The compound shows only intermolecular stacking, as found in many xanthines, and most importantly it does not show intramolecular stacking, unlike the closely related 1,3-bis­(theophyl­lin-8-yl)­propane which has an acidic NH group for conventional hydrogen bonding. The title compound, in addition, exhibits intermolecular Cl⋯O interactions.

Proton NMR analysis on newly synthesized 1,2-bis(4,6-diethylthio-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethane, 2c , and 1,2-bis(4,6-diethylthio-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane, 2d , showed intramolecular stacking in solution. X-Ray crystallography on 2c and 2d , however, confirmed the presence of such intramolecular stacking only in case of the ‘propylene linker’ compound, 2d , while the ‘ethylene linker’ compound, 2c , was devoid of it.

Steric control offered by the 3-substituents in D-xylofuranosyl- and D-glucofuranosyl sugars has been exploited for the regioselective N-2-glycosylation of 4,6-bis(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (1), to generate key intermediates suitable for later transformations to pyrazolo[3,4-d]pyrimidine nucleosides.

The furanose ring in 4,6-bis(methylthio)-2-(2,3-anhydro-1-deoxy-β-D-allofuranosyl)-2H-pyrazolo[3,4-d]pyrimidine, C 13 H 16 N 4 O 4 S 2 , is almost planar with the epoxide ring in an exo orientation.

In the crystal structures of 4,6-di­methyl­thio-1-[3-(4,6-di­methyl­thio-2H-pyra­zolo­[3,4-d]­py­rimi­din-2-yl)­propyl]-1H-py­ra­­zolo­[3,4-d]­py­rimi­dine, C17H20N8S4, and 1-[4-(4-meth­oxy-6-methyl­thio-1H-pyra­zolo­[3,4-d]py­rimi­din-1-yl)­butyl]-5-meth­yl-6-methyl­thio-4,5-di­hydro-1H-pyra­zolo­[3,4-d]py­rimi­din-4-one, C18H22N8O2S2, only intermolecular stacking due to aromatic π–π interactions between pyrazolo­[3,4-d]­pyrimidinerings is present.

Steric control offered by the 3-substituents in D-xylofuranosyl- and D-glucofuranosyl sugars has been exploited for the regioselective N-2-glycosylation of 4,6-bis(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (1), to generate key intermediates suitable for later transformations to pyrazolo[3,4-d]pyrimidine nucleosides.

Diastereoselective 1,4-addition of a vinyl cuprate to a γ-chiral α,β-unsaturated ketone intermediate provides an efficient asymmetric total synthesis of levuglandin E 2 . While resolution of a racemic precursor provided the second chiral center, preferential generation of the required configuration at the third center of this acyclic synthetic target involved a remarkably stereoselective epimerization

In the crystal structure of 1,3-bis[4,6-bis(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]propane, C l7 H 20 N 8 S 4 , the molecules exhibit a skewed mode of stacking of the two pyrazolo[3,4-d]pyrimidine rings due to an intramolecular π-π interaction between the heterocyclic rings.

The molecular structure of the title compound, C(17)H(20)N(4)OS(2), does not show any intramolecular aromatic pi-pi interactions, but the crystal packing reveals the presence of intermolecular C--H...O and C-H...pi interactions. The C--H...O interactions generate chains of molecules that are linked into sheets by C-H.pi interactions about inversion centres.

The crystal structure of 4,6-bis(methylsulfanyl)-1-phthalimidopropyl-1H-pyrazolo[3,4-d]pyrimidine, C 18 H 17 N 5 O 2 S 2 , (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, C 21 H 22 N 6 O 2 S, (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.

The crystal structures of 1-{5-[4,6-bis­(methyl­sulfanyl)-2H-py­razolo­[3,4-d]­pyrimidin-2-yl]­pentyl}-6-methyl­sulfanyl-4-(pyr­rolidin-1-yl)-1H-pyrazolo­[3,4-d]­pyrimidine, C22H29N9S3, and 6-methyl­sulfanyl-1-{5-[6-methyl­sulfanyl-4-(pyrrolidin-1-yl)-2H-pyrazolo­[3,4-d]­pyrimidin-2-yl]­pentyl}-4-(pyrrolidin-1-yl)-1H-pyrazolo­[3,4-d]­pyrimidine, C25H34N10S2, which differ in having either a pyrrolidine substituent or a methylsulfanyl group, show intermolecular stacking due to aromatic π–π interactions between the pyrazolo­[3,4-d]­pyrimidine rings.

The title compound, 6-methylsulfanyl-1-(3-phenylpropyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one, C(15)H(16)N(4)OS, crystallizes in space group Pbca, with two molecules of similar structure in the asymmetric unit. The molecular structure shows the absence of intramolecular stacking in the crystalline state, as indicated by earlier (1)H NMR analysis in solution. In addition, the crystal packing reveals the formation of a layered structure, due mainly to intermolecular N[bond]H...O[double bond]C hydrogen bonding and arene-arene interactions.

In the crystal structure of 1,3-bis(4,6-diisopropylsulfanyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propane, C(25)H(36)N(8)S(4), the pairs of pyrazolo[3,4-d]pyrimidine rings in the molecule stack as a result of intramolecular pi-pi interactions between the heterocyclic rings. The crystal packing also exhibits an intermolecular C--H...pi interaction between one methyl group of an isopropyl group and a pyrazolo[3,4-d]pyrimidine ring.

In the crystal structure of 1,1′-(butane-1,4-diyl)­bis(5-methyl-6-methyl­thio-4,5-di­hydro-1H-pyrazolo­[3,4-d]­pyrimidin-4-one),C18H22N8O2S2, (6), the pyrazolo­[3,4-d]­pyrimidine rings do not show any inter- or intramolecular stacking due to aromatic π–π interactions. There is a crystallographic inversion centre at the midpoint of the central C—C bond of the chain linking the two ring systems.

In the crystal structure of 1,1'-(1,3-propanediyl)bis(5-benzyl-6-methylsulfanyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one), C(29)H(28)N(8)O(2)S(2), the pairs of pyrazolo[3,4-d]pyrimidine rings stack as a result of intramolecular pi-pi interactions between the heterocyclic rings. The folded molecules are further stacked in pairs, due to intermolecular aromatic pi-pi interactions and C-H...O hydrogen bonds.

An alternative C-3 linker to ‘propylene/Leonard linker’ is proposed for studying arene interactions in face-to-face (offset) mode. The two new flexible symmetrical compounds with an electron deficient pyrazolo[3,4-d]pyrimidine core and biologically important isomeric purine systems and one dissymmetrical compound with a pyrazolo[3,4-d]pyrimidine core and electron-rich carbazole residue at the termini of the new linker show folding due to intramolecular π–π interactions by both 1H NMR in solution and X-ray crystallography in the solid state. Surprisingly, the replacement of the 4-methylsulfanyl group of the dissymmetrical compound by an electron donating methoxy group shows open conformation in the solid state by X-ray crystallography. The fifth symmetrical compound with an electron-rich carbazole residue at the termini of new linker, however, shows the normally expected open conformation.

In the crystal structure of 1,1'-(1,3-propanediyl)bis(5-ethyl-6-methylthio-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one), C(19)H(24)N(8)O(2)S(2), the pairs of pyrazolo[3,4-d]pyrimidine rings of the molecule stack between the heterocyclic rings, due to intramolecular pi-pi interactions. The substituted ethyl and methyl groups are comparable as far as intramolecular stacking is concerned.

Reaction of 4,6-bis(methylthio)-1H-pyrazolo[3,4-d]pyrimidine with alkyl halides in the presence of sodium hydride produces predominantly 2-alkyl-4,6-bis(methylthio)-2H-pyrazolo[3,4-d]pyrimidines in good yields

A study of the reactivity of 1,6-diazaphenalene (1) toward alkylating and acylating agents has been carried out in order to investigate the chemistry of this new heterocycle. Attempts to alkylate 1 were successfully completed by stirring the lithium stabilized anion of 1 with either methyl iodide or benzyl bromide to provide N-alkyldiazaphenalenes 4 and 5, respectively, whereas, experiments performed to alkylate 1 under conditions employed for alkylation of imidazole were unsuccessful. Studies directed toward acylation of 1 did not lead, in general, to isolable acyldiazaphenalenes; however, in one specific case successful acylation of 2-chloro-9-methoxy-1,6-diazaphenalene (10) did provide a characterisable amide (14). Where possible the chemistry of 1,6-diazaphenalene has been compared to that reported for imidazole.

The regiospecific (π2 + π4) cycloaddition reaction of N-carbonyl-1,2-dihydropyridines 2 with nitrosobenzene afford a mixture of 3-phenyl-2-oxa-3,6-diazabicyclo[2.2.2]oct-7-ene rotamers 3 and 4. Rotamers 3 and 4, which differ in configuration at the carbonyl to nitrogen (amide) bond, exhibit dual resonances for C(1)H, C(5)H, and the N(6) acetyl (methoxycarbonyl) substituents. An 1H nmr temperature study indicated that rotamers 3a and 4a coalesce at about 100 °C.

Reaction of 2(3,4)-pyridinecarboxaldehydes (5) with ethylidenetriphenylphosphorane afford a mixture of stereoisomers Z-(6) and E-1-[2(3,4)-pyridinyl]-1-propenes (7). m-Chloroperbenzoic acid oxidation of 6 and 7 yields a 60:40 mixture of Z-(8) and E-1-[1-oxido-2(3,4)-pyridinyl]-2-methyloxiranes (9). The regiospecific reaction of Z-isomers 8a-c with cyclic amines as piperidine give rise to threo-1-hydroxy-1-[1-oxido-2(3,4)-pyridinyl]-2-(1-piperidino)propanes (10) while the E-isomer 9a yields erythro-11. On tho other hand, the E-isomers 9b and 9c having 1-oxido-3(4)-pyridinyl substituents afford erythro-12 resulting from attack by piperidine at C-1 of the oxirane. Reductive deoxygenation using 10% palladium on charcoal and hydrogen gas effectively removed the N-oxide substituent from the threo-10 and erythro-11 β-aminoalcohols. Dilute solution ir spectroscopy indicated the existance of strong intramolecular hydrogen bonding in the β-aminoalcohols 10 and 11. The assignment of relative configuration of diastereoisomers 10 and 11 was based on the magnitude of the vicinal coupling constant J where J threo is greater than J erythro.

Reaction of pyridinecarboxaldehydes 1 with α-ethoxyvinyllithium 2 affords 2-ethoxy-1-(pyridinyl)-2-propen-1-ols 3 which on hydrolysis with aqueous formic acid give pyridinyl α-hydroxyketones 4. Selenium dioxide oxidation of 4a and 4b provides pyridinyl α-diketones 9 which on condensation with o-phenylenediamine afford 3-methyl-2-(pyridinyl) quinoxalines 11. Pyridinyl α-hydroxyketones 4a and 4b react with hydroxylamines to yield a mixture of E- and Z-oximes 5 and 6.

Reaction of 4,6-bis(methylthio)-1H-pyrazolo[3,4-d]pyrimidine with alkyl halides in the presence of sodium hydride produces predominantly 2-alkyl-4,6-bis(methylthio)-2H-pyrazolo[3,4-d]pyrimidines in good yields