An efficient and regiospecific strategy to N7-substituted purines and its application to a library of trisubstituted purines

A regiospecific strategy for the preparation of N(7)-substituted purines in an efficient manner was devised. This approach to 6,7,8-trisubstituted purines relies on the cyclization reactions of suitably substituted pyrimidines (1) with either a carboxylic acid or an aldehyde. The method development for the five-step synthetic strategy outlined here was completed using 5-amino-4,6-dichloropyrimidine (4) as the starting material. The utility of this methodology was demonstrated through the preparation of a 40-membered library of 6,7,8-trisubstituted purines (3) in good yields and high purity.     

6-(2-Alkylimidazol-1-yl)purines undergo regiospecific glycosylation at N9

[reaction: see text] Regioselective control of glycosylation of purines at N9 (versus N7) has been a continuing challenge. We now report Lewis acid catalyzed regiospecific glycosylations of 6-(2-alkylimidazol-1-yl)purines at N9. The 6-(2-alkyl)imidazole moiety also functions as a versatile leaving group that can be replaced by nucleophiles (S(N)Ar) and aryl groups (Suzuki cross-coupling).     

Chemoselective high-throughput purification mediated by solid-supported reagents: its application to the first 6, 9-disubstituted purine library synthesis

A new application of solid-supported reagents was developed to separate the alkylated N7/N9 regioisomers derived from commercially available 2-amino-6-chloropurine. Simple filtration through an alumina/H+ pad or scavenging by AG/Dowex-50W-X8 resin provides diverse N9 regioisomers selectively in moderate yields with high purities (>90%). This purification method can be conveniently used in a high-throughput format and facilitates the synthesis of a purine library without laborious regioisomer separation and aqueous work-up. The first library synthesis of 6,9-disubstituted purines is reported using the combination of this novel separation method in conjunction with polymer-supported reagents.     

Regioselective synthesis of novel N2- and N4-substituted 7-methylpyrazolo[4,5-e][1,2,4]thiadiazines

The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one1,1-dioxide (5) was synthesized and its novel mono N2- or N4-substituted derivatives 6 and 7 were prepared by regioselective N-alkylation of 5 with different molar ratios of NaH and alkyl halides. Based on the regioselective alkylation conditions found a facile one-pot synthesis of N2,N4-disubstituted pyrazolo[4,5-e][1,2,4] thiadiazines 8 was developed. The structures of the newly synthesized compounds were confirmed by IR,(1)H-NMR, (13)C-NMR and MS spectral analysis.     

Selective synthesis of 7-substituted purines via 7,8-dihydropurines

A simple and efficient protocol for the preparation of 7-substituted purines is described. 6- and 2,6-Dihalopurines were N(9)-tritylated and then transformed to 7,8-dihydropurines by DIBAL-H. Subsequent N(7)-alkylation followed by N(9)-trityl deprotection with trifluoroacetic acid was accompanied by spontaneous reoxidation, which led to the 7-substituted purines at 55-88% overall isolated yields.     

Reaction of substituted sulfenes with N,N-disubstituted α-amino-methyleneketones. I. Synthesis of N,N-disubstituted cis- and trans-4-amino-3,4,5,6,7,8-hexahydro-3-phenyl-1,2-benzoxathiin 2,2-dioxides

The polar 1, 4-cycloaddition of phenylsulfene (generated in situ from phenylmethanesulfony] chloride and triethylamine) to N, N-disubstituted (E)-2-aminomethylenecyclohexanones I gave in general a mixture of N, N-disubstituted cis- and trans-4-amino-3, 4, 5, 6, 7, 8-hexahydro-3-phenyl-1, 2-benzoxathiin 2, 2-dioxides III and IV, which were separated by column chromatography and whose structural and conformational features were determined from uv, ir and nmr spectral data. In the case of N, N-diisopropylamino enaminone 1c, the cyclo-addition took place with elimination of an alkyl group as propene to give the adduct III?.     

Reaction of dichloroketene and sulfene with N,N-disubstituted α-aminomethyleneketones. Synthesis of pyrano[2,3-e]indazole and 1,2-oxathiino[6,5-e]indazole derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-5-aminomethylene-1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones V, prepared from 1,5,6,7-tetrahydro-(1-methyl)(1-phenyl)-4H-indazol-4-ones via the 5-hydroxymethylene derivatives, gave in good yield N,N-disubstituted 4-amino-3,3-dichloro-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-(3H)ones VI, which are derivatives of the new heterocyclic system pyrano[2,3-e]indazole. Dehydrochlorination of VI with DBN afforded N,N-disubstituted 4-amino-3-chloro-6,7-dihydro(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(5H]-ones VII generally in satisfactory yield. Full aromatization with DDQ of VII was tried only in the case of dimethylamino derivatives, giving a moderate yield of 3-chloro-4-dimethylamino(7-methyl)(7-phenyl)pyrano[2,3-e]indazol-2(7H)-ones. Cycloaddition of sulfene to V occurred only in the case of aliphatic N-substitution to give in moderate yield 4-dialkylamino-4,5,6,7-tetrahydro-(7-methyl)(7-phenyl)-3H-1,2-oxathiino[6,5-e]indazole 2,2-dioxides, which are derivatives of the new heterocyclic system 1,2-oxathiino[6,5-e]indazole.     

Conversion of Primary Amines to N,N′-Disubstituted Ureas Using Montmorillonitebipyridinepalladium(II)-acetate and Di-Tert Butyl Peroxide

A simple and convenient methodology for the synthesis of N,N′-disubstituted ureas from primary amines by a heterogenized catalyst montmorillonitebipyridinepalladium (II)acetate for the first time at room temperature and atmospheric pressure is described.     

Use of 13C as an indirect tag in 15N specifically labeled nucleosides. Syntheses of [8-13C-1,7,NH2-15N3]adenosine, -guanosine, and their deoxy analogues

We have previously reported the use of a 13C tag at the C2 of 15N-multilabeled purine nucleosides to distinguish the adjacent-labeled 15N atoms from those in an untagged nucleoside. We now introduce the use of an indirect tag at the C8 of 15N7-labeled purine nucleosides. This tag allows unambiguous differentiation between a pair of 15N7-labeled purines in which only one is 13C8 labeled. Although the very small C8-N7 coupling (<1 Hz) precludes its direct detection in 1D 15N spectra, 2D 1H-15N NMR experiments display the large C8-H8 coupling (>200 Hz) because H8 is coupled to both N7 and C8. The 13C8 atom is introduced by means of a ring closure of the exocyclic amino groups of a pyrimidinone using [13C]sodium ethyl xanthate. Here, we present methods for the syntheses of [8-13C-1,7,NH2-15N3]adenosine, -guanosine, and their deoxy analogues.     

Structure and synthesis of 6-(substituted-imidazol-1-yl)purines: versatile substrates for regiospecific alkylation and glycosylation at N9

X-ray crystal structures of several 6-(azolyl)purine base and nucleoside derivatives show essentially coplanar conformations of the purine and appended 6-(azolyl) rings. However, the planes of the purine and imidazole rings are twisted approximately 57 degrees in a 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine nucleoside, and a twist angle of approximately 61 degrees was measured between the planes of the purine and pyrrole rings in the structure of a 6-(2,5-dimethylpyrrol-1-yl)purine nucleoside derivative. Shielding "above" N7 of the purine ring by a proximal C-H on the 6-azolyl moiety is apparent with the coplanar compounds, but this effect is diminished in those without coplanarity. Syntheses of 6-(azolyl)purines from both base and nucleoside starting materials are described. Treatment of 2,6-dichloropurine with imidazole gave 2-chloro-6-(imidazol-1-yl)purine. Modified Appel reactions at C6 of trityl-protected hypoxanthine and guanine derivatives followed by detritylation gave 6-(imidazol-1-yl)- and 2-amino-6-(imidazol-1-yl)purines. Imidazole was introduced at C6 of 2',3',5'-tri-O-acetylinosine by a modified Appel reaction, and solvolysis of the glycosyl linkage gave 6-(imidazol-1-yl)purine. Guanosine triacetate was transformed into the protected 2,6-dichloropurine nucleoside, which was subjected to S(N)Ar displacement with imidazoles at C6 followed by glycosyl solvolysis to provide 2-chloro-6-(substituted-imidazol-1-yl)purines. Potential applications of these purine derivatives are outlined.     

Structural and spectroscopic features of mono- and binuclear nickel(II) complexes with tetradentate N(amine)2S(thiolate)2 ligation

Three complexes containing Ni(II)N(amine)2S(thiolate)2 units have been prepared and characterized. Both (R,R)-N,N'-bis(1-carboxy-2-mercaptoethyl)-1,2-diaminoethane [(R,R)-1] and N,N'-bis(2-methyl-2-mercaptoprop-1-yl)-1,3-diamino-2,2-dimethylpropane (4) act as tetradentate S-N-N-S ligands to form complexes Ni((R,R)-1) and Ni4 with nearly planar cis-NiN2S2 units. The N-Ni-N and S-Ni-S angles differ significantly in the two complexes yet are very nearly supplementary. The 1,3-disubstituted cyclohexane species rac-N,N'-bis(2-mercapto-2-methylprop-1-yl)-1,3-cyclohexanediamine (6) behaves as a bis(bidentate-N,S) ligand to form an unexpectedly intense-blue dinickel complex (1S,3R,1'S,3'R)-7, which contains two trans-NiN2S2 units bridged by 1,3-disubstituted cyclohexane groups. The coordination geometry in (1S,3R,1'S,3'R)-7 is distorted 15 degrees toward tetrahedral, most likely as a result of steric crowding, suggested by several short contacts between the NiS2 units and both the cyclohexyl and gem-dimethyl groups of the N,S-chelate rings. The complexes exhibit rich UV-vis spectra, whose deconvoluted bands are now fully assigned, from low to high energy, as ligand field (LF), pi(S) --> Ni(II) ligand-to-metal charge transfer (LMCT), sigma(S) --> Ni(II) LMCT, sigma(N) --> Ni(II) LMCT, localized S, and S,N Rydberg transitions. The unusually intense LF absorptions shown by (1S,3R,1'S,3'R)-7 are thought to result from relaxation of the Laporte restriction arising from the 15 degrees tetrahedral twist.     

Experimental and GIAO 15N NMR study of substituent effects in 1H-tetrazoles

A series of 1-aryl/alkyl-1H-1,2,3,4-tetrazoles, 5-substituted 1H-tetrazoles, and 1,5- and 2,5-disubstituted 1H-tetrazoles were studied by a combination of experimental NMR (natural abundance (15)N, (15)N/(1)H HMBC, and (13)C) and computational GIAO-NMR techniques to explore substituent effects on (15)N (and (13)C) NMR chemical shifts in the tetrazole (TA) moiety. Computed (15)N chemical shifts via GIAO-B3LYP/6-311+G(2d,p) calculations gave satisfactory results in comparison with experimental data. Whereas N-alkylation leads to large (15)N chemical shift changes, changes in the N(1)-aryl derivatives bearing diverse substituent(s) are generally small except for polar ortho-substituents (COOH, NO(2)). Large Δδ(15)N values were computed in N(1)-aryl derivatives for p-COH(2)(+) and p-OMeH(+) as extreme examples of electron-withdrawing substituents on a TA moiety.     

Reaction of sulfene and dichloroketene with open-chain N,N-disubstituted α-aminomethyleneketones. Synthesis of N,N-disubstituted 4-amino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides and of 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones

Cycloaddition of sulfene to N,N-disubstituted 3-amino-2-methyl-1-phenyl-2-propen-1-ones (I) and 3-amino-1,2-diphenyl-2-propen-1-ones (II) occurred in good to moderate yield only in the case of aliphatic N-substitution to give 4-dialkylamino-3,4-dihydro-(5-methyl-6-phenyl)(5,6-diphenyl)-1,2-oxathiin 2,2-dioxides. Polar 1,4-cycloaddition of dichloroketene to I and II occurred only in the former case, giving in good to moderate yield N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-5-methyl-6-phenyl-2H-pyran-2-ones which were dehydrochlorinated with DBN to N,N-disubstituted 4-amino-3-chloro-5-methyl-6-phenyl-2H-pyran-2-ones. In the reaction of 2-methyl-1-phenyl-3-diphenylamino-2-propen-1-one with dichloroketene, a product was isolated which was proven by uv, ir, nmr and chemical evidence to be the dipolar ion VI, the supposed intermediate of the polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted enaminones.     

Synthesis of 1,3,4-thiadiazole, 1,3,4-thiadiazine, 1,3,6-thiadiazepane and quinoxaline derivatives from symmetrical dithiobiureas and thioureidoethylthiourea derivatives

Reactions of N,N;-disubstituted hydrazinecarbothioamides 8a-c and substituted thioureidoethylthioureas 9a-c with 2,3,5,6-tetrachloro-1,4-benzoquinone (chloranil, 10a) and 2,3,5,6-tetrabromo-1,4-benzoquinone (bromanil, 10b) to form N,N;-disubstituted [1,3,4]thiadiazole-2,5-diamines 11a-c, 6,7-dichloro-3-substituted amino-1H-benzo[1,3,4]- thiadiazine-5,8-diones 12a-c, 2,3,7,8-tetrahalothianthrene-1,4,6,9-tetraones 13a,b, 5,6,8- trihalo-7-oxo-3,7-dihydro-2H-quinoxaline-1-carbothioic acid substituted amides 14a-c, 15a-c and 7-substituted imino-[1,3,6]thiadiazepane-3-thiones 16a-c are reported. Rationales for the observed conversions are presented.     

A high-performance liquid chromatography method for determination 2-(n-(N,N,N-trimethyl)-n-alkyl)-5-alkylfuryl halides in dipalmitoylphosphatidilcholine liposome solutions

A high-performance liquid chromatography (HPLC) method for the determination of 2-(4-(N,N,N-trimethyl)-butyl)-5-dodecylfuryl bromide (DFTA) in dipalmitoylphophatidil-choline (DPPC) liposome solutions has been developed. Lipid-soluble furan derivatives, 2,5-disubstituted with different n-alkyl chains and a terminal trimethylammonium group are useful probes for studying singlet oxygen dynamics and equilibria in microcompartmentalized systems. The actual HPLC method uses a gradient elution and DAD detection. The chromatographic separation of these components is achieved using a C18 analytical column with a 10mM solution of 1-heptanesulfonic acid (PIC-7)-methanol (10:90, v/v) as initial mobile phase. Both DFTA peaks are well resolved and free of interference from matrix components and reaction products. The method has been found to be linear (r > 0.999) over a wide concentration range and reliable to perform kinetic experiments in which the time dependent consumption of a tetraalkylammonium surfactant in a microorganized systems composed by lipidic surfactants is followed.     

Reaction Products of Activated Aromatic and Heteroaromatic Chlorides with N,N-Disubstituted Formamides

Several N,N-disubstituted aromatic amines (3a–g) was obtained in very good yield by the reaction of adequate doubly activated aromatic or heteroaromatic halides (1a–e) with N,N-disubstituted formamides (2a–c). Analogously, starting from 4-chloro-3-pyridinesulfonamide, the appropriate 4-dialkylamino-1H ⁺-pyridinium-3-(N-formyl)sulfonamidates (5a,b) were obtained in 52–60% yield. Mechanisms of the reactions are discussed.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones VIII. Synthesis of N,N-disubstituted 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones

The dipolar 1,4-cycloaddition of dichloroketene to N,N-disubstituted 3-amino-1-phenyl-2-propene-1-onesled directly to N,N-disubstituted 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones only in the case of an usual aliphatic N,N-disubstitution. In the case of partial or full aromatic N-substitution, N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-6-phenyl-2H-pyran-2-ones were instead obtained, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones.     

Reaction of Pyrrolobenzoxazinetriones with N,N′-Disubstituted Ureas. Synthesis of Substituted Spiro[imidazole-2,2′-pyrroles]

Russian Journal of Organic Chemistry - 3-Aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with symmetrical N,N′-disubstituted ureas to give 1,3-disubstituted...     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. X. Synthesis of N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones and of 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted 1-amino-4-methyl-1-penten-3-ones and 1-amino-4,4-dimethyl-1-penten-3-ones occurred in moderate to fair yield only in the case of aromatic N-substitution to give N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution, cyclo-addition led directly to 6-alkyl-4-dialkylamino-3-chloro-2H-pyran-2-ones only for N,N-disubstituted 1-amino-4,4-dimethyl-1-penten-3-ones. The reaction between 1-dimethylamino-4-methyl-1-penten-3-one and dichloroketene gave 3-chloro-4-dimethylamino-3,6-dihydro-6-isopropylidene-2H-pyran-2-one in low yield.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XII. Synthesis of N,N-disubstituted 4-amino-3-chloro-6-(2-methyl-l-propenyl) (2-phenylethenyl)-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted (E)-amino-5-methyl-1,4-hexadien-3-ones IV and (E,E)-1-amino-5-phenyl-1,4-pentadien-3-ones V occurred in moderate to good yield only in the case of aromatic N-substitution to give N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-6-(2-methyl-l-propenyl) (2-phenylethenyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 4-amino-3-chloro-6-(2-methyl-propenyl)(2-phenylethenyl)-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution (dimethylamino group) of enaminones IV and V, the Cycloaddition led directly in low yield to 3-chloro-4-dimethylamino-6-(2-methyl-l-propenyl)(2-phenylethenyl)-2H-pyran-2-ones.