Unexpected Approach to the Synthesis of 2‐Phenylquinoxalines and Pyrido[2,3‐b]pyrazines via a Regioselective Reaction

An unexpected approach to the preparation of quinoxaline and pyrido[2,3‐b]pyrazine derivatives 5 is described. The reaction between 1H‐indole‐2,3‐diones 1 , 1‐phenyl‐2‐(triphenylphosphoranylidene)ethanone ( 2 ), and benzene‐1,2‐ or pyridine‐2,3‐diamines 3 proceeds in MeOH under reflux in good to excellent yields (Scheme 1 and Table). No co‐catalyst or activator is required for this multi‐component reaction (MCR), and the reaction is, from an experimental point of view, simple to perform. The structures of 5, 5′ , and 6 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and were confirmed by comparison with reference compounds. A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Synthesis of 2,3‐Diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ol Derivatives by the Reaction of Aryl(3‐isocyanopyridin‐4‐yl)methanones with Aryl Grignard Reagents

The reaction of aryl(3‐isocyanopyridin‐4‐yl)methanones 1 , easily prepared from commercially available pyridin‐3‐amine, with aryl Grignard reagents gave, after aqueous workup, 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐ols 2 . These rather unstable alcohols were O‐acylated with Ac₂O in pyridine in the presence of a catalytic amount of 4‐(dimethylamino)pyridine (DMAP) to afford the corresponding 2,3‐diaryl‐3H‐pyrrolo[2,3‐c]pyridin‐3‐yl acetates 3 in relatively good yields.     

Facile Synthesis of Naphtho[2,3‐d]thiazoles,Naphtho[2,3‐e][1,3,4]thiadiazines and Bis(naphtho[2,3‐d]thiazolyl)copper(II) Derivatives from Heteroylthiosemicarbazides

A one step synthesis protocol for the conversion of heteroylthiosemicarbazides and 2,3‐dichloro‐1,4‐naphthoquinone to naphtho[2,3‐d]thiazoles, naphtho[2,3‐e][1,3,4]thiadiazines as well as bis(naphtho[2,3‐d]thiazolyl)copper(II) derivatives is described. The products were conclusively confirmed by single crystal X‐ray analyses. A mechanism for the formation of the products is presented.     

Using Calcium Carbide as an Acetylene Source for Cascade Synthesis of Pyrrolo[2,3‐b]quinoxalines via Copper‐Free Sonogashira Coupling Reaction

A palladium‐catalyzed cascade protocol has been established for the synthesis of 4‐methyl‐1‐(1H‐pyrrolo[2,3‐b]‐quinoxalin‐2‐yl)cyclohexanols and 2‐phenyl‐1‐(1H‐pyrrolo[2,3‐b]quinoxalin‐2‐yl)propan‐1‐ols through the reaction of N‐alkyl(aryl)‐3‐chloroquinoxalin‐2‐amines with calcium carbide and cyclohexanones or 2‐phenylpropanal. This one‐pot process, carried out without any copper salt in the key step of the Sonogashira coupling reaction, provides an efficient method for the synthesis of 2,3‐disubstituted pyrrolo[2,3‐b]quinoxalines in the presence of catalytic amounts of Pd(PPh₃)₂Cl₂ in DMSO/H₂O with high yields. The benefit of this strategy is the use of a commercially available, inexpensive, and less hazardous primary chemical feedstock, calcium carbide, as an acetylene source in a wet solvent.     

A Facile One‐Pot Synthesis of Functionalized 1,5‐Dihydro‐2H‐[1]benzopyrano[2,3‐b]pyridin‐5‐ones

The highly reactive 1 : 1 intermediate generated in the reaction between dialkyl acetylenedicarboxylate (=but‐2‐ynedioic acid dialkyl ester) 4 and triphenylphosphine was trapped by 2‐amino‐4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehydes 5 to yield highly functionalized dialkyl‐1,5‐dihydro‐5‐oxo‐1‐phenyl‐2H‐[1]benzopyrano[2,3‐b]pyridine‐2,3‐dicarboxylates in high yield.     

Synthesis of Functionalized H‐[1]Benzopyrano[2,3‐b]pyridines by the Friedländer Approach: Antimycobacterial and Antimicrobial Profile

A series of functionalized H‐[1]benzopyrano[2,3‐b]pyridine derivatives were synthesized by the Friedländer reaction of 2‐amino‐4‐oxo‐4H‐chromene‐3‐carbonitriles 1 with malononitrile, ethyl cyanoacetate, or acetophenone (Scheme). The synthesized compounds 2 – 4 were screened for their in vitro activity against antitubercular, antibacterial, and antifungal species (Fig., Table). Among the synthesized compounds, 3c and 4f were the most active with 99% inhibition against Mycobacterium tuberculosis H₃₇Rv, while compounds 2f, 3f , and 4d exhibited 69%, 63%, and 61% inhibition, respectively. The 4‐amino‐7,9‐dibromo‐1,5‐dihydro‐2,5‐dioxo‐2H‐chromeno[2,3‐b]pyridine‐3‐carbonitrile ( 3b ) showed the most potent antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. Several chromeno[2,3‐b]pyridine derivatives showed equal or more potency against Staphylococcus aureus and Candida albicans.     

Alternating narrow band gap copolymers derived from indeno[1,2‐b]fluorene and thiophene‐cored‐thieno[3,4‐b]pyrazine derivatives—Synthesis,characterization and comparative studies of photochemical stability

Alternating narrow band gap (NBG) conjugated polymers derived from 6,6′,12,12′‐tetraoctylindeno[1,2‐b]fluorene (IF) and 2,3‐dimethyl‐5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DTTP), 2,3‐diphenyl‐5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DPTP) or 2,3‐dioctyl‐5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DOTP), named as PIF‐DTTP, PIF‐DPTP, and PIF‐DOTP, respectively, were synthesized by Suzuki coupling reaction and characterized. The photochemical stabilities of the copolymers and copolymer derived from IF and 5,7‐dithien‐2‐yl‐thieno[3,4‐b]pyrazine (DTP) were investigated by the UV absorptions, PL spectra, FT‐IR spectra, and photovoltaic properties of the copolymers as a function of UV irradiation time. The studies revealed that the degradation of thieno[3,4‐b]pyrazine (TP) ring under UV irradiation can be retarded or eliminated by introducing phenyl group into the 2,3‐positions of TP ring, and indicated that 2,3‐diphenylthieno[3,4‐b]pyrazine could be used as durable electron deficient moiety to achieve donor–acceptor NBG‐conjugated polymers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Efficient One‐Pot Access to 2,9‐Dihydrothiopyrano[2,3‐b]indole Scaffolds Showing Large Stokes Shifts

A simple, mild and efficient one‐pot approach for the construction of 2‐aryl‐3‐nitro‐2,9‐dihydrothiopyrano[2,3‐b]indole derivatives has been realized in CH₂Cl₂ medium at ambient temperature via three‐component tandem reaction of N‐protected‐2‐chloro‐3‐formylindoles, sodium hydrosulfide and β‐substituted nitroolefins/δ‐substituted nitrodienes using DABCO (10 mol%) as an organocatalyst, followed by dehydration in the presence of activated molecular sieves (4 Å). The significant advantages of this protocol are simple operation, shorter reaction time, high atom economy, good to high yields (73% –89%) and wider substrate scope. In addition, all the synthesized compounds have shown the large positive Stokes shift values (5632–6081 cm^?1).     

Isocyanide‐Based Three‐Component Synthesis of Highly Substituted 1,6‐Dihydro‐6,6‐dimethylpyrazine‐2,3‐dicarbonitrile, 3,4‐Dihydrobenzo[g]quinoxalin‐2‐amine,and 3,4‐Dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine Derivatives

A novel and efficient isocyanide‐based multicomponent reaction between alkyl or aryl isocyanides 1 , 2,3‐diaminomaleonitrile ( 2 ), naphthalene‐2,3‐diamines ( 6 ) or benzene‐1,2‐diamine ( 9 ), and 3‐oxopentanedioic acid ( 3 ) or Meldrum's acid ( 4 ) or ketones 7 was developed for the ecologic synthesis, at room temperature under mild conditions, of 1,6‐dihydropyrazine‐2,3‐dicarbonitriles 5a – 5f in H₂O without using any catalyst, and of 3,4‐dihydrobenzo[g]quinoxalin‐2‐amine and 3,4‐dihydro‐3,3‐dimethyl‐quinoxalin‐2‐amine derivatives 8a – 8g and 10a – 10e , respectively, in the presence of a catalytic amount of p‐toluenesulfonic acid (TsOH) in EtOH, in good to excellent yields (Scheme 1).     

Three‐Step Synthesis of 3‐Aryl‐2‐sulfanylthieno[2,3‐b]‐, ‐[2,3‐c]‐, or ‐[3,2‐c]pyridines from the Corresponding Aryl(halopyridinyl)methanones

A convenient three‐step procedure for the synthesis of three types of 3‐aryl‐2‐sulfanylthienopyridines 4, 8 , and 12 has been developed. The first step of the synthesis of thieno[2,3‐b]pyridine derivatives 4 is the replacement of the halo with a (sulfanylmethyl)sulfanyl group in aryl(2‐halopyridin‐3‐yl)methanones 1 by successive treatment with Na₂S?9 H₂O and chloromethyl sulfides to give aryl{2‐[(sulfanylmethyl)sulfanyl]pyridin‐3‐yl}methanones 2 . In the second step, these were treated with LDA (LiNⁱPr₂) to give 3‐aryl‐2,3‐dihydro‐2‐sulfanylthieno[2,3‐b]pyridin‐3‐ols 3 , which were dehydrated in the last step with SOCl₂ in the presence of pyridine to give the desired products. Similarly, thieno[2,3‐c]pyridine and thieno[3,2‐c]pyridine derivatives, 8 and 12 , respectively, can be prepared from aryl(3‐chloropyridin‐4‐yl)methanones 5 and aryl(4‐chloropyridin‐3‐yl)methanones 9 , respectively.     

A Convenient Synthesis of 2,3‐Dihydro‐4H‐thiopyrano[2,3‐b]‐, ‐[2,3‐c]‐, or ‐[3,2‐c]pyridin‐4‐ones by the Reaction of the Corresponding 1‐(Chloropyridinyl)alk‐2‐en‐1‐ones with NaSH

2,3‐Dihydro‐4H‐thiopyrano[2,3‐b]pyridin‐4‐ones 4 were prepared by a three‐step sequence from commercially available 2‐chloropyridine ( 1 ). Thus, successive treatment of 1 with ⁱPr₂NLi (LDA) and α,β‐unsaturated aldehydes gave 1‐(2‐chloropyridin‐3‐yl)alk‐2‐en‐1‐ols 2 , which were oxidized with MnO₂ to 1‐(2‐chloropyridin‐3‐yl)alk‐2‐en‐1‐ones 3 . The reactions of 3 with NaSH?n H₂O proceeded smoothly at 0° in DMF to provide the desired thiopyranopyridinones. Similarly, 2,3‐dihydro‐4H‐thiopyrano[2,3‐c]pyridin‐4‐ones 8 and 2,3‐dihydro‐4H‐thiopyrano[3,2‐c]pyridin‐4‐ones 12 were obtained starting from 3‐chloropyridine ( 5 ) and 4‐chloropyridine ( 9 ), respectively.     

Synthesis of 2‐Aryl‐2,3‐dihydro‐1,8‐naphthyridin‐4(1H)‐ones by Deprotective Cyclization of N‐{3‐[(2E)‐3‐Arylprop‐2‐enoyl]pyridin‐2‐yl}‐2,2‐dimethylpropanamides in Water

A new and convenient method for the preparation of 2‐aryl‐2,3‐dihydro‐1,8‐naphthyridin‐4(1H)‐ones 4 has been developed. Thus, N‐{3‐[(2E)‐3‐arylprop‐2‐enoyl]pyridin‐2‐yl}‐2,2‐dimethylpropanamides 3 are synthesized from commercially available pyridin‐2‐amine using an easily performed three‐step sequence and are subjected to cyclization with deprotection under acidic conditions in H₂O to give the desired products. Similarly, 2‐aryl‐2,3‐dihydro‐1,7‐naphthyridin‐4(1H)‐ones 8 and 2‐aryl‐2,3‐dihydro‐1,6‐naphthyridin‐4(1H)‐ones 12 can be prepared from pyridin‐3‐amine and pyridin‐4‐amine, respectively.     

Synthesis of 2‐Thioxohydropyridine‐3‐Carbonitrile, 2‐Alkylthiopyridine,Thienopyridine, Pyrazolopyridine Derivatives and Their Theoretical Calculations

Cyanothioacetamide ( 1 ) reacted with but‐2‐enal ( 2 ) to give the corresponding 4‐methyl‐2‐sulfanylpyridine‐3‐carbonitrile ( 7 ) which was used as a good starting material for the synthesis of 1‐(3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐yl)ethan‐1‐one ( 10 ), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxamide ( 15 ), 3‐amino‐4‐methylthieno[2,3‐b]pyridine‐2‐carboxylate ( 18 ) and 3‐amino‐4‐methylthieno[2,3‐b]pyridin‐2‐ylarylketone 25a‐c through its reactions with each of (1‐chloroacetone ( 8 ), 3‐chloropentane‐2,4‐dione ( 11 ) or ethyl 2‐chloro‐3‐oxo‐butanoate ( 19 )), 2‐chloroacetamide ( 13 ), ethyl 2‐chloroacetate ( 16 ) and 2‐bromo‐1‐arylethan‐ 1 ‐one 23a‐c , respectively. Considering the data of elemental analyses, IR, ¹HNMR, mass spectra and theoretical calculations, structures of the newly synthesized heterocyclic compounds were elucidated.     

Synthesis of 2‐Aryl‐2,3‐dihydro‐3‐sulfanyl‐1H‐isoindol‐1‐ones by Pummerer‐Type Cyclization of N‐Aryl‐2‐(sulfinylmethyl)benzamides

An efficient method for the synthesis of 2‐aryl‐2,3‐dihydro‐3‐sulfanyl‐1H‐isoindol‐1‐ones 1 via Pummerer‐type cyclization of N‐aryl‐2‐(sulfinylmethyl)benzamides 2 is described. Thus, treatment of these sulfinyl‐benzamides 2 , easily prepared from 2‐(bromomethyl)benzoates 3 in three steps, with Ac₂O at ca. 100° resulted in the formation of the desired isoindolones 1 in generally good yields.     

Chemoselective Route for Synthesis of N‐Aryl‐3‐oxochromeno[2,3‐c]pyrazole‐2(3H)‐carbothioamide Derivatives

A chemoselective route for the synthesis of chromeno[2,3‐c]pyrazole‐2(3H)‐carbothioamide derivatives by a five‐component reaction of salicylaldehyde, malononitrile, NH₂NH₂?H₂O, aryl isothiocyanate, and H₂O in EtOH/AcOH mixture is reported. This new protocol has the advantages of high yields, short reaction times, ease of operation, and simple purification. All structures were confirmed by IR, ¹H‐ and ¹³C‐NMR, and MS analyses. A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Molecular Iodine Promoted Synthesis of New Pyrido[2,3‐d]pyrimidin‐4‐ols

A highly ef?cient synthesis of novel pyrido[2,3‐d]pyrimidin‐4‐ols was developed via an iodine‐catalyzed tandem oxidative cyclization under focused microwave irradiation. Pyrido[2,3‐d]pyrimidin‐4‐ols were obtained from easily available 2‐amino‐4‐aryl‐6‐arylnicotinamides and benzylic amines with good to excellent yields.     

Report on an Unusual Cascade Reaction between Azulenes and 2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone (=4,5‐Dichloro‐3,6‐dioxocyclohexa‐1,4‐diene‐1,2‐dicarbonitrile; DDQ)

The oxidation of 1‐(3,8‐dimethylazulen‐1‐yl)alkan‐1‐ones 1 with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (=4,5‐dichloro‐3,6‐dioxocyclohexa‐1,4‐diene‐1,2‐dicarbonitrile; DDQ) in acetone/H₂O mixtures at room temperature does not only lead to the corresponding azulene‐1‐carboxaldehydes 2 but also, in small amounts, to three further products (Tables 1 and 2). The structures of the additional products 3 – 5 were solved spectroscopically, and that of 3a also by an X‐ray crystal‐structure analysis (Fig. 1). It is demonstrated that the bis(azulenylmethyl)‐substituted DDQ derivatives 5 yield on methanolysis or hydrolysis precursors, which in a cascade of reactions rearrange under loss of HCl into the pentacyclic compounds 3 (Schemes 4 and 7). The found 1,1′‐[carbonylbis(8‐methylazulene‐3,1‐diyl)]bis[ethanones] 4 are the result of further oxidation of the azulene‐1‐carboxaldehydes 2 to the corresponding azulene‐1‐carboxylic acids (Schemes 9 and 10).     

Hydriodic Acid‐Mediated Cyclization of α‐Substituted Secondary 2‐Ethenylbenzamides: Synthesis of 2‐Substituted 2,3‐Dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones and 3,3‐Disubstituted (E)‐1‐(Arylimino)‐1,3‐dihydroisobenzofurans

A new and facile method for the preparation of 2‐substituted 2,3‐dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones 3 and 3,3‐disubstituted (E)‐1‐(arylimino)‐1,3‐dihydroisobenzofurans 6 has been developed. Thus, treatment of N‐alkyl(or aryl)‐2‐(1‐methylethen‐1‐yl)benzamides 2 with concentrated hydriodic acid (HI) in MeCN at room temperature afforded 3 . Similar treatment of N‐aryl‐2‐(1‐phenylethen‐1‐yl)benzamide 5 with concentrated HI at 0° afforded 6 .     

Novel and Stereospecific Synthesis of (2S)‐3‐(2,4,5‐Trifluorophenyl)propane‐1,2‐diol from D‐Mannitol

A stereospecific synthesis of (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol from D ‐mannitol has been developed. The reaction of 2,3‐O‐isopropylidene‐D ‐glyceraldehyde with 2,4,5‐trifluorophenylmagnesium bromide gave [(4R)‐2,2‐dimethyl‐1,3‐dioxolan‐4‐yl](2,4,5‐trifluorophenyl)methanol in 65% yield as a mixture of diastereoisomers (1 : 1). The Ph₃P catalyzed reaction of the latter with C₂Cl₆ followed by reduction with Pd/C‐catalyzed hydrogenation gave (2S)‐3‐(2,4,5‐trifluorophenyl)propane‐1,2‐diol with >99% ee and 65% yield.     

Cyclization vs. Elimination Reactions of 5‐Aryl‐5‐hydroxy 1,3‐Diones: One‐Pot Synthesis of 2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones

2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones were prepared in one step by cyclocondensation of 1,3‐diketone dianions with aldehydes. The use of HCl (10%) for the aqueous workup proved to be very important to avoid elimination reactions of the 5‐aryl‐5‐hydroxy 1,3‐diones formed as intermediates. The TiCl₄‐mediated cyclization of a 2‐aryl‐2,3‐dihydro‐4H‐pyran‐4‐one with 1,3‐silyloxybuta‐1,3‐diene resulted in cleavage of the pyranone moiety and formation of a highly functionalized benzene derivative.