From Renewable Levulinic Acid to a Diversity of 3‐(Azol‐3‐yl)Propanoates

Efficient heterocyclization of methyl 7,7,7‐trifluoro‐4‐methoxy‐6‐oxo‐4‐heptenoate and methyl 7,7,7‐trichloro‐4‐methoxy‐6‐oxo‐4‐heptenoate into isoxazole and pyrazole derivatives that represent a new type of glutamate‐like 3‐(trihalomethylated‐1,2‐azol‐3‐yl)propanoate is reported. Preparation of the key methyl 7,7,7‐trihalo‐4‐methoxy‐6‐oxohept‐4‐enoate precursors from levulinic acid is also described. The synthetic potential of this synthetic protocol was indicated by the production of several methyl and ethyl 3‐(isoxazol‐3‐yl)propanoates and 3‐(1H‐pyrazol‐3‐yl)propanoates, and the respective acid derivatives, in good (70–95%) yields. The crystal structure for ethyl 5‐(3‐ethoxy‐3‐oxopropyl)‐1H‐pyrazole‐3‐carboxylate ( 10c ) has been determined by monocrystal X‐ray diffraction analysis. The N–H^…H intermolecular hydrogen bonds join the molecules into catamer.     

UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids,ADB‐FUBICA,AB‐FUBICA,AB‐BICA and ADB‐BICA,by human liver microsomes

Since 2012, several cannabimimetic indazole and indole derivatives with valine amino acid amide residue have emerged in the illicit drug market, and have gradually replaced the old generations of synthetic cannabinoids (SCs) with naphthyl or adamantine groups. Among them, ADB‐FUBICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐FUBICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐BICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] and ADB‐BICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] were detected in China recently, but unfortunately no information about their in vitro human metabolism is available. Therefore, biomonitoring studies to screen their consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated their phase I metabolism by incubating with human liver microsomes, and the metabolites were identified by ultra‐performance liquid chromatography–high resolution–tandem mass spectrometry. Metabolites generated by N‐dealkylation and hydroxylation on the 1‐amino‐alkyl moiety were found to be predominant for all these four substances, and others which underwent hydroxylation, amide hydrolysis and dehydrogenation were also observed in our investigation. Based on our research, we recommend that the N‐dealkylation and hydroxylation metabolites are suitable and appropriate analytical markers for monitoring their intake.     

Structure elucidation of a novel ring‐constrained biaryl pyrazole CB1 cannabinoid receptor antagonist

Upon irradiation with a 450 W high‐pressure mercury lamp, the CB₁ cannabinoid antagonist N‐(piperidinyl)‐5‐(4‐chlorophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide (SR14‐1716; 1 ) undergoes a photocyclization reaction to yield a single reaction product. This product, 2 , the structure of which is based on a pyrazolo[1,5‐f]phenanthridine ring system, was established by two‐dimensional NMR techniques (COSY, HSQC, HMBC and ROESY), and was later confirmed by single‐crystal x‐ray diffraction analysis. The crystal structure shows two independent molecules of 3 and a half molecule of the 1,2‐dichloroethane solvate. Compound 2 has reasonably high affinity for the CB₁ receptor (K_i = 48.0 ± 2.7 nM ). Copyright © 2003 John Wiley & Sons, Ltd.     

Two different products from the reaction of 1‐aryl‐5‐chloro‐3‐methyl‐1H‐pyrazole‐4‐carbaldehyde with cyclohexylamine when the aryl substituent is phenyl or pyridin‐2‐yl: hydrogen‐bonded sheets versus dimers

Cyclohexylamine reacts with 5‐chloro‐3‐methyl‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carbaldehyde to give 5‐cyclohexylamino‐3‐methyl‐1‐(pyridin‐2‐yl)‐1H‐pyrazole‐4‐carbaldehyde, C₁₆H₂₀N₄O, (I), formed by nucleophilic substitution, but with 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde the product is (Z)‐4‐[(cyclohexylamino)methylidene]‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one, C₁₇H₂₁N₃O, (II), formed by condensation followed by hydrolysis. Compound (II) crystallizes with Z′ = 2, and in one of the two independent molecular types the cyclohexylamine unit is disordered over two sets of atomic sites having occupancies of 0.65 (3) and 0.35 (3). The vinylogous amide portion in each compound shows evidence of electronic polarization, such that in each the O atom carries a partial negative charge and the N atom of the cyclohexylamine portion carries a partial positive charge. The molecules of (I) contain an intramolecular N—H...N hydrogen bond, and they are linked by C—H...O hydrogen bonds to form sheets. Each of the two independent molecules of (II) contains an intramolecular N—H...O hydrogen bond and each molecular type forms a centrosymmetric dimer containing one R₂²(4) ring and two inversion‐related S(6) rings.     

Spectral study of a new dihydroisocoumarin

A novel dihydroisocoumarin, 3,4‐dihydro‐6,8‐dihydroxy‐3‐(2′‐acetyl‐3′‐hydroxy‐5′‐methoxy)methyl‐1H‐[2]benzopyran‐1‐one, was isolated from the chloroform extract of the sap of the traditional herb Aloe vera. Its structure was determined by high‐resolution negative fast atom bombardment mass spectrometry (MS), 2D NMR spectroscopy and x‐ray crystallography. The molecular structure was elucidated by 2D NMR analysis. The complete assignment of the ¹H and ¹³C NMR spectra of this compound was performed by using ¹H detected one‐bond heteronuclear multiple quantum correlation (HMQC) and long‐range (two and three bonds) heteronuclear multiple quantum bond correlation (HMBC) experiments. Detailed analyses of the one‐ and two‐dimensional NMR techniques are presented in additional to the spectral properties (MS, IR and UV). Copyright © 2003 John Wiley & Sons, Ltd.     

New Chemical Constituents from Borreria verticillata (Rubiaceae)

A phytochemical study on Borreria verticillata has led to the isolation of two novel simple indole alkaloids, 6‐methoxy‐4‐(3‐methylbut‐2‐en‐1‐yl)‐1H‐indole, named verticillatine A ( 1 ), and 1‐(1H‐indol‐6‐yl)‐3‐methylbutan‐1‐one, named verticillatine B ( 2 ), one new iridoid, 6′‐O‐(2‐glyceryl)scandoside methyl ester ( 3 ), with the glycerol unit linked to a glucose unit, and two known ones, asperuloside ( 4 ) and scandoside methyl ester ( 5 ). The structures of these compounds were elucidated on the basis of spectroscopic‐data analyses, mainly ¹H‐ and ¹³C‐NMR, including 2D experiments (¹H,¹H‐COSY, NOESY, HMBC, and HMQC), and HR‐ESI‐MS.     

A concise and efficient synthesis of amino‐substituted (1H‐benzo[d]imidazol‐1‐yl)pyrimidine hybrids: synthetic sequence and the molecular and supramolecular structures of six examples

A concise and efficient synthesis of a series of amino‐substituted benzimidazole–pyrimidine hybrids has been developed, starting from the readily available N⁴‐(2‐aminophenyl)‐6‐methoxy‐5‐nitrosopyrimidine‐2,4‐diamine. In each of N⁵‐benzyl‐6‐methoxy‐4‐(2‐phenyl‐1H‐benzo[d]imidazol‐1‐yl)pyrimidine‐2,5‐diamine, C₂₅H₂₂N₆O, (I), 6‐methoxy‐N⁵‐(4‐methoxybenzyl)‐4‐[2‐(4‐methoxyphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, C₂₇H₂₆N₆O₃, (III), 6‐methoxy‐N⁵‐(4‐nitrobenzyl)‐4‐[2‐(4‐nitrophenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, C₂₅H₂₀N₈O₅, (IV), the molecules are linked into three‐dimensional framework structures, using different combinations of N—H…N, N—H…O, C—H…O, C—H…N and C—H…π hydrogen bonds in each case. Oxidative cleavage of 6‐methoxy‐N⁵‐(4‐methylbenzyl)‐4‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, (II), with diiodine gave 6‐methoxy‐4‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidine‐2,5‐diamine, which crystallized as a monohydrate, C₁₉H₁₈N₆O·H₂O, (V), and reaction of (V) with trifluoroacetic acid gave two isomeric products, namely N‐{5‐amino‐6‐methoxy‐6‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidin‐2‐yl}‐2,2,2‐trifluoroacetamide, which crystallized as an ethyl acetate monosolvate, C₂₁H₁₇F₃N₆O₂·C₄H₈O₂, (VI), and N‐{2‐amino‐6‐methoxy‐4‐[2‐(4‐methylphenyl)‐1H‐benzo[d]imidazol‐1‐yl]pyrimidin‐5‐yl}‐2,2,2‐trifluoroacetamide, which crystallized as a methanol monosolvate, C₂₁H₁₇F₃N₆O₂·CH₄O, (VIIa). For each of (V), (VI) and (VIIa), the supramolecular assembly is two‐dimensional, based on different combinations of O—H…N, N—H…O, N—H…N, C—H…O and C—H…π hydrogen bonds in each case. Comparisons are made with some related structures.     

A Convenient Synthesis of New Pyrazolo[4,3‐d]pyrimidines and Their Fused Heterocycles

A series of some fused heterocycles originated from pyrazolopyrimidines were synthesized using 4‐amino1‐methyl‐3‐propyl‐1H‐pyrazole‐5‐carboxamide as a starting material. The nucleophilic substitution reactions with different amino acids followed by cyclization and Suzuki–Miyaura cross‐coupling reactions with different aryl boronic acids of 7‐chloro‐5‐(4‐chlorophenyl)‐1‐methyl‐3‐propyl‐1H‐pyrazolo[4,3‐d]pyrimidine were performed. Also, the oxidative cyclization reactions of 1‐(5‐(4‐chlorophenyl)‐1‐methyl‐3‐propyl‐1H‐pyrazolo[4,3‐d]pyrimidin‐7‐yl)hydrazine with different aldehydes in the presence of diacetoxy iodobenzene are described. All the synthesized compounds were characterized by analytical and spectroscopic methods.     

1H and 13C NMR spectral assignments of novel chromenylchalcones

Several types of chalcones containing 2H‐chromen group were synthesized. Claisen–Schmidt condensation of 2H‐chromen‐3‐carbaldehydes (I) with methoxy substituted acetophenones afforded (E)‐3‐(2H‐chromen‐3‐yl)‐1‐(methoxyphenyl)prop‐2‐en‐1‐ones (chromenylchalcones, 1–7). Other types of chromenylchalcone, (E)‐1‐(6‐methoxy‐2H‐chromen‐3‐yl)‐3‐(methoxyphenyl)prop‐2‐en‐1‐ones (8–13) were also obtained between reaction of methoxy substituted benzaldehydes and 1‐(6‐methoxy‐2H‐chromen‐3‐yl)ethanone (II). Dichromenylchalcones (14–16) were also synthesized through the same reaction between aldehydes (I) and ketone (II). Their complete ¹H‐NMR and ¹³C‐NMR assignments are reported here and more polysubstituted chromenylchalcones synthesized or isolated from the natural sources in the future can be identified on the basis of the NMR data reported here. Copyright © 2012 John Wiley & Sons, Ltd.     

A New Glycine Derivative and a New Indole Alkaloid from the Fermentation Broth of the Plant Endophytic Fungus Pestalotiopsis podocarpi Isolated from the Chinese Podocarpaceae Plant Podocarpus macrophyllus

A new glycine derivative, podocarpiamide ( 1 ), a new indole alkaloid, 1‐methoxy‐1H‐indol‐3‐ethanol ( 2 ), together with two known compounds, 1‐methoxy‐1H‐indole‐3‐acetic acid ( 3 ) and methyl 1‐methoxy‐1H‐indole‐3‐acetate ( 4 ), were isolated from the fermentation broth of the plant endophytic fungus Pestalotiopsis podocarpi. Their structures were elucidated by extensive spectroscopic analysis including 1D‐ and 2D‐NMR (HSQC, HMBC, and COSY) and MS experiments. Compound 1 has an interesting unusual carbamic acid structure.     

1H and 13C chemical shifts for acridines: Part XVII. (1,3‐Benzothiazol‐2‐yl)amino‐9(10H)‐acridinone derivatives

The ¹H and ¹³C NMR resonances for 16 acridin‐9(10H)‐ones substituted with amino or (1,3‐benzothiazol‐2‐yl)amino groups were completely and unequivocally assigned by the concerted application of gs‐COSY, gs‐HMQC and gs‐HMBC experiments. Evidence for hydrogen bond and amino–imino tautomerism is presented for 1‐ and 4‐substituted acridin‐9(10H)‐ones. Copyright © 2002 John Wiley & Sons, Ltd.     

Four oxoindole‐linked α‐alkoxy‐β‐amino acid derivatives

Four structures of oxoindolyl α‐hydroxy‐β‐amino acid derivatives, namely, methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐methoxy‐2‐phenylacetate, C₂₄H₂₈N₂O₆, (I), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐ethoxy‐2‐phenylacetate, C₂₅H₃₀N₂O₆, (II), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐[(4‐methoxybenzyl)oxy]‐2‐phenylacetate, C₃₁H₃₄N₂O₇, (III), and methyl 2‐[(anthracen‐9‐yl)methoxy]‐2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐phenylacetate, C₃₈H₃₆N₂O₆, (IV), have been determined. The diastereoselectivity of the chemical reaction involving α‐diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N—H...O hydrogen bonds with the ester and ether O atoms in all four structures. The ether‐linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N—H...O hydrogen‐bond interactions. In contrast, the remaining three structures are sustained by C—H...O hydrogen‐bond interactions.     

Reduced 3,4′‐bipyrazoles from a simple pyrazole precursor: synthetic sequence,molecular structures and supramolecular assembly

The reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde and N‐benzylmethylamine under microwave irradiation gives 5‐[benzyl(methyl)amino]‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde, C₁₉H₁₉N₃O, (I). Subsequent reactions under basic conditions, between (I) and a range of acetophenones, yield the corresponding chalcones. These undergo cyclocondensation reactions with hydrazine to produce reduced bipyrazoles which can be N‐formylated with formic acid or N‐acetylated with acetic anhydride. The structures of (I) and of representative examples from this reaction sequence are reported, namely the chalcone (E )‐3‐{5‐[benzyl(methyl)amino]‐3‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl}‐1‐(4‐bromophenyl)prop‐2‐en‐1‐one, C₂₇H₂₄BrN₃O, (II), the N‐formyl derivative (3RS )‐5′‐[benzyl(methyl)amino]‐3′‐methyl‐1′,5‐diphenyl‐3,4‐dihydro‐1′H ,2H‐[3,4′‐bipyrazole]‐2‐carbaldehyde, C₂₈H₂₇N₅O, (III), and the N‐acetyl derivative (3RS )‐2‐acetyl‐5′‐[benzyl(methyl)amino]‐5‐(4‐methoxyphenyl)‐3′‐methyl‐1′‐phenyl‐3,4‐dihydro‐1′H ,2H‐[3,4′‐bipyrazole], which crystallizes as the ethanol 0.945‐solvate, C₃₀H₃₁N₅O₂·0.945C₂H₆O, (IV). There is significant delocalization of charge from the benzyl(methyl)amino substituent onto the carbonyl group in (I), but not in (II). In each of (III) and (IV), the reduced pyrazole ring is modestly puckered into an envelope conformation. The molecules of (I) are linked by a combination of C—H…N and C—H…π(arene) hydrogen bonds to form a simple chain of rings; those of (III) are linked by a combination of C—H…O and C—H…N hydrogen bonds to form sheets of R ²₂(8) and R ⁶₆(42) rings, and those of (IV) are linked by a combination of O—H…N and C—H…O hydrogen bonds to form a ribbon of edge‐fused R ²₄(16) and R ⁴₄(24) rings.     

Synthesis,Spectral Characterization and Antioxidant Activity of Novel Zafirlukast Sulfonyl Derivatives

A new series of cyclopentyl 3‐(2‐methoxy‐4‐(piperazine‐1‐carbonyl)benzyl)‐1‐methyl‐1H‐indol‐5‐ylcarbamate sulfonyl derivatives were synthesized by the reaclion of 4‐((5‐(cyclopentyloxycarbonylamino)‐1‐methyl‐1H‐indol‐3‐yl)methyl)‐3‐methoxybenzoic acid (ZAK drug intermediate) with Boc piperazine in the presence of EDC?HCl, HOBt, TEA in DMF followed by deboxylation by using 2N HCl or 35 % HCl in acetone to get an intermediate compound. Further, this compound was treated with various substituted benzene sulfonyl chlorides in the presence of TEA in THF to afford title compounds. All the title compounds were characterized by ¹HNMR, ¹³CNMR, IR and mass spectral data. The title compounds and starting material were evaluated for their antioxidant activity by using the DPPH, H₂O₂ and NO methods. The results revealed that some of the compounds have shown significant antioxidant activity.     

Synthesis and spectral study of a novel distamycin conjugate

The ¹H and ¹³C NMR resonances for a novel distamycin conjugate, 3‐[1‐methyl‐4‐[1‐methyl‐4‐[1‐methyl‐4‐[N¹‐[5‐methyl‐2,4(1H,3H)pyrimidinedione]acetylamino]pyrrole‐2‐carboxamido]pyrrole‐2‐carboxamido]pyrrole‐2‐carboxamido]propionamidine hydrochloride ( 1 ), were assigned, using the concerted application of one‐ and two‐dimensional NMR techniques including nuclear Overhauser effect difference, DEPT, HMQC and HMBC experiments. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of Hexahydro‐2‐pyrindine (=Hexahydrocyclopenta[c]pyridine) Derivatives as Conformationally Restricted Analogs of the Nicotinic Ligands Arecolone and Isoarecolone

Two hexahydropyrindine derivatives, 1,2,3,4,6,7‐hexahydro‐2‐methyl‐5H‐cyclopenta[c]pyridin‐5‐one ( 1 ) and 1,2,3,4,5,6‐hexahydro‐2‐methyl‐7H‐cyclopenta[c]pyridin‐7‐one ( 2 ), and their methiodides 14 and 26 , respectively, were synthesized. They can be considered rigid analogues of the known nicotinic agonists arecolone (=1‐(1,2,5,6‐tetrahydro‐1‐methylpyridin‐3‐yl)ethanone) and isoarecolone (=1‐(1,2,3,6‐tetrahydro‐1‐methylpyridin‐4‐yl)ethanone). The affinity for the central nicotinic receptor were measured on rat cerebral cortex. Although only the methiodide 14 , among the four conformationally restricted compounds, shows an appreciable affinity, the results obtained provide useful information on the molecular requirements at the interaction site of the central nicotinic receptors.     

Synthesis of novel pyrazolo[3,4‐d]pyridazine,pyrido[1,2‐a]benzimidazole,pyrimido[1,2‐a]benzimidazole and triazolo[4,3‐a]pyrimidine derivatives

4‐Acetyl‐5‐methyl‐1‐phenyl‐1H‐pyrazole reacts with dimethylformamide dimethylacetal (DMF‐DMA) to afford the corresponding (E)1‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐3‐(N,N‐dimethylamino)‐2‐propen‐1‐one. The latter product undergoes regioselective 1,3‐dipolar cycloaddition with nitrilimines and nitrile oxides to afford the novel 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)carbonyl‐1‐phenylpyrazole and 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)carbonyl isoxazole derivatives, respectively. It reacts also with 1H‐benzimidazole‐2‐acetonitrile, 2‐aminobenzimidazole and 3‐amino‐1,2,4‐triazole to afford the novel pyrido[1,2‐a]benzimidazole, pyrimido[1,2‐a]benzimidazole and the triazolo[4,3‐a]pyrimidine derivatives, respectively. The reaction of 3‐aroyl‐4‐(5‐methyl‐1‐phenyl‐1H‐pyrazol‐4‐yl) carbonyl‐1‐phenylpyrazole derivatives with hydrazine hydrate led to a new pyrazolo[3,4‐d]pyridazine derivatives.     

Structure of an unexpected trimer from the reaction of ageratochromene II with aluminum chloride

A new trimer from the reaction of ageratochromene [1] (6,7‐dimethoxy‐2,2‐dimethyl‐1‐benzopyran) with anhydrous aluminum chloride was shown to be 3,4‐dihydro‐6,7‐dimethoxy‐2,2‐dimethyl‐3‐(6′,7′‐dimethoxy‐2′,2′‐dimethyl‐2H‐1‐benzopyran‐4′‐yl)‐4‐(3′,4′‐dihydro‐6′, 7′‐dimethoxy‐2′,2′‐dimethyl‐2H‐1‐benzopyran‐3′‐yl)‐ 2H‐1‐benzopyran. Its structure was confirmed by NMR (¹H, ¹³C, DEPT‐135. COSY, HMBC, HSQC, TOCSY and NOESY), IR, mass spectra and elemental analysis. Copyright © 2002 John Wiley & Sons, Ltd.     

Cyanoacetamide in heterocyclic chemistry: Synthesis,antitumor and antioxidant activities of some new benzothiophenes

Cyanoacylation of 2‐amino‐tetrahydrobenzothiophene‐3‐carboxylate ethyl ester with 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile afforded cyanoacetamide 2 . The later was utilized as key intermediate for the synthesis of 3‐substituted 2‐iminocoumarins 3 , 4 , 5 , 6 and acrylamides 7a , b via Knoevenagel condensation with 2‐hydroxy‐1‐naphthaldehyde; 2‐hydroxybenzaldehyde; 1‐nitrosonaphthalen‐2‐ol; 7‐hydroxy‐5‐methoxy‐2‐methyl‐4‐oxo‐4H‐chromene‐6‐carbaldehyde; 4‐dimethylamino‐benzaldehyde; and 4‐piperidin‐1‐yl‐benzaldehyde in EtOH/piperidine. The derivatives 7a , b did not afford the pyrazoles 8a , b upon treating with phenyl hydrazine. Furthermore, coupling of 2 with 4‐amino‐1,5‐dimethyl‐2‐phenyl‐1H‐pyrazol‐3(2H)‐one and 4,6‐dimethyl‐1H‐pyrrolo[2,3‐b]pyridin‐3‐amine afforded the hydrazone derivatives 9 and 10 , respectively. The later derivative 10 was cyclized in acetic acid to afford the pyridopyrazolotriazine 11 . Finally, 2 was treated with dimethylformamide‐dimethylacetal (DMF‐DMA) to afford the dimethylaminoacrylamide 12 which underwent transamination with 4,6‐dimethyl‐1H‐pyrrolo[2,3‐b]pyridin‐3‐amine to afford the pyrazole 13 . Cyclization of compound 13 in acetic acid or pyridine was unsuccessful. The antitumor and antioxidant activities of the synthesized products were evaluated; several were found to exhibit promising antioxidant activities. J. Heterocyclic Chem., (2011).     

A New and Facile Synthesis of Novel Pyrazolothienopyrimidines and Imidazopyrazolothienopyrimidines

4‐Amino‐3‐methyl‐1‐phenyl‐1H‐thieno[2,3‐c]pyrazole‐5‐carboxamide ( 5 ), which was synthesized by an innovative method, was used as a versatile precursor for synthesizing pyrazolothienopyrimidines and imidazopyrazolothienopyrimidines compounds. Reaction of amino thienopyrazole carboxamide 5 with triethyl orthoformate afforded thienopyrazolopyrimidine 6 . Chlorination of the latter compound, using phosphorus oxychloride afforded the chloro pyrazolothienopyrimidine 7 , which underwent nucleophilic substitution reactions with various primary and secondary amines to give the alkyl (aryl) amino pyrimidine compounds 8a–d . On the other hand, the reaction of chloropyrimidine 7 with thiourea afforded the pyrimidine thione compound 9 , which was alkylated with α‐halogentaed compounds to afford the S‐alkylated derivatives 10a–c . Also, chloroacetylation of the amino carboxamide 5 using chloroacetyl chloride yielded the chloromethyl pyrazolothienopyrimidine 12 , which underwent nucleophilic substitu‐ tion reactions with various primary and secondary amines to afford the alkyl (aryl) aminomethyl compounds 13a–f . The latter Compounds underwent Mannich reaction to give imidazopyrimidothieno‐ pyrazoles 14a–c . The newly synthesized compounds and their derivatives were fully characterized by elemental and spectral analysis.