Application of intramolecular cycloaddition/retro cycloaddition reactions for the synthesis of unsymmetrical 2,2′-bipyridine and 2-benzofuropyrazin-2-ylpyridine analogues

1,2,4-Triazines bearing cycloalkeno[c]pyridine substituents at the 5-position, 2a-d, prepared by an intermolecular Diels-Alder reaction of bi-5,5-triazines with cyclic enamines, were provided with an alkynyloxy or a 2-cyanophenoxy group at the 3-position of the triazinyl unit. A subsequent intramolecular Diels-Alder reaction of the former, followed by loss of N₂ leads to two new classes of 2,2′-bipyridine analogues containing different heterocyclic units, namely cycloalkeno[c]pyridine and 2,3-dihydrofuro- or 2,3-dihydropyrano[2,3-b]pyridine 8a-h; the intramolecular reaction of the 2-cyanophenoxy compound gives benzo[4,5]furo[2,3-b]pyrazine 10a-c.     

Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with ethyl chlorooxoacetate in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

Facile access to stereodefined dienoates and cyclopropylenoates containing a trifluoromethyl group

Ethyl (2E,4E)-3-trifluoromethyl-2,4-dienoates 1a-e and ethyl (E)-3-trans-alkylcyclopropyl-4,4,4-trifluoro-2-butenoates 2a-e were prepared from the trans-alkenylboronic acids 3a-e and the trans-cyclopropylboronic acids 4a-e with ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate (5) by the Suzuki cross-coupling reaction in high yields (88-95%). The configurations of both 3a-e or 4a-e and 5 were retained in the reaction.     

Imino Diels-Alder reaction of boronates. Preparation and characterization of new 3,4-dihydroquinoline and 1,2,3,6-tetrahydropyridine derivatives

The preparation of 3,4-dihydroquinolines (2a-d and 3a,b,d), as well as 1,2,3,6-tetrahydropyridines (4a-e) by imino Diels-Alder reaction of boronates (1a-e) with 2,3-dimethylbutadiene is reported. Boronates (1a-d) containing substituents meta and para relative to the imino fragment lead to diastereomeric mixtures of 4-methyl-4-ethenyl-3,4-dihydroquinolines (2, 3) and tetrahydropyridines (4). In contrast, the presence of an electron withdrawing substituent at the para position (1e), favors the iminodienophile behavior giving 4,5-dimethyl-1,2,3,6-tetrahydropyridine (4e) as the main product. The results show that boronates derived from Schiff bases are electron deficient species which can act either as dienophiles or dienes in the reaction with 2,3-dimethylbutadiene to give 3,4-dihydroquinolines and 1,2,3,6-tetrahydropyridines. All products were characterized by NMR and X-ray diffraction analysis of 2b, 2d, 3d and 4c allowed to assign the relative configuration of the newly formed stereogenic centers.     

Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition-palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4H[1]benzopyran-3-yl)-N-phenyl nitrones (7) with allenic esters (8a-c) and allenic ketones (18a-d) furnish benzoindolizines (9a-k, 19a-d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2-C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels-Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels-Alder cycloaddition. An alternative domino route to benzoindolizines (9a,d,g) involving sequential one-pot cycloaddition of azadienes (22a-c) with silyl-enol ether (23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.     

Synthesis and rearrangement of cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones: an access to cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones

2-Substituted-4a-hydroxy-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 2a-c were synthesized by an one-step cyclocondensation from the 5-substituted-2-amino-2-oxazolines 1a-c with ethyl 2-oxocyclohexanecarboxylate in ethanol at room temperature, and easily dehydrated to provide 2-substituted-9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones 3. In refluxing xylene, the reaction conducted with various ethyl 2-oxocycloalkanecarboxylates led to the two isomeric 2-substituted-8/9H-cycloalkyl[1,2-e]oxazolo[3,2-a]pyrimidin-8/9-ones 3 and 2-substituted-5H-cycloalkyl[1,2-d]oxazolo[3,2-a]pyrimidin-5-ones 4. The structure of some compounds was unambiguously established using X-ray crystallography. According to results from the DSC analysis of compound 2a, formation of the thermodynamically stable pyrimidinones 4 could be related to an intramolecular rearrangement of kinetically controlled pyrimidinones 3.     

Synthesis of polyfunctionalized furans from 3-acetyl-1-aryl-2-pentene-1,4-diones

The BF₃-catalyzed cyclization of 3-acetyl-1-aryl-2-pentene-1,4-diones 1a-e in the presence of water in boiling tetrahydrofuran gave bis(3-acetyl-5-aryl-2-furyl)methanes 2a-e in 26-79% yields along with a small amount of 3-acetyl-5-aryl-2-methylfurans 3a-e. The exact structure of 2a was determined by X-ray crystallography. The use of a half volume of the solvent for the reaction of 1a resulted in the formation of 2,4-bis(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-phenylfuran (4) together with 2a and 3a. A similar reaction of 1a was carried out in the presence of 3-acetyl-5-(4-methylphenyl)-2-methylfuran (3d) to afford 4-(3-acetyl-5-phenyl-2-furfuryl)-3-acetyl-5-(4-methylphenyl)-2-methylfuran (5) in 49% yield. The BF₃-catalyzed reaction of 1a with 2,4-pentanedione in dry tetrahydrofuran at 23°C gave 3-(3-acetyl-5-phenyl-2-furfuryl)-4-hydroxy-3-penten-2-one (6a) and 3-(3-acetyl-2-methyl-4-phenyl-5-furyl)-4-hydroxy-3-penten-2-one (7a) in 66 and 24% yields, respectively. The product distribution depended on the reaction temperature. A similar reaction of 1b-e also yielded the corresponding trisubstituted furans 6b-e and tetrasubstituted furans 7b-e in good yields. These results suggested the presence of the furfuryl carbocation intermediate A during the reaction. The one-pot synthesis of 6a and 7a was also achieved by a similar reaction using phenylglyoxal. The deoxygenation of 1a with triphenylphosphine gave 3a in 88% yield, while 1a was treated with concentrated hydrochloric acid to yield 3-acetyl-2-chloromethyl-5-phenylfuran (8) which was quantitatively transformed in ethanol into 3-acetyl-2-ethoxymethyl-5-phenylfuran (9) and in water into 3-acetyl-5-phenylfurfuryl alcohol (10), respectively. In addition, the Diels-Alder reaction of cyclopantadiene with 1a gave the corresponding [4+2] cycloaddition products 11 and 12.     

Asymmetric synthesis of 3-substituted unsaturated prolines from chiral sulfoximine substituted allyl titanium(IV) complexes

An asymmetric synthesis of the 3-substituted Δ^3,4-unsaturated prolines 7a-e and 3-substituted 4-methylene prolines 14a-c starting from the corresponding γ,δ-unsaturated α-amino acids 4a-e and 11a-c, respectively, is described. Amino acid derivatives 4a-e and 11a-d were obtained through aminoalkylation of the corresponding sulfoximine substituted allyl titanium(IV) complexes 2a-e and 10a-d, respectively, with the N-tert-butylsulfonyl imino ester 3. Activation of sulfoximines 4a-e and 11a-c through methylation of the sulfoximine group followed by a KF mediated isomerization of the vinyl aminosulfoxonium salts 5a-e and 12a-c, respectively, to the corresponding allyl aminosulfoxonium salt 6a-e and 13a-c, respectively, and a subsequent intramolecular nucleophilic substitution of the allylic aminosulfoxonium group afforded the enantio- and diastereomerically pure proline derivatives in medium to high yields.     

2-Allyl-N-benzyl substituted α-naphthylamines as building blocks in heterocyclic synthesis. New and efficient syntheses of benz[e]naphtho[1,2-b]azepine and naphtho[1,2-b]azepine derivatives

A new series of 13-acetyl-7,12-dihydro-7-ethylbenz[e]naphtho[1,2-b]azepine (4a-d) and 2-aryl-4-hydroxy-2,3,4,5-tetrahydronaphtho[1,2-b]azepine derivatives (6a-d) have been synthesized from N-allyl-N-benzyl substituted α-naphthylamines (1a-d) by utilizing aromatic amino-Claisen rearrangement, intramolecular Friedel-Crafts alkylation and intramolecular dipolar 1,3-cycloaddition nitrone-olefin reactions.     

Sequential homo-coupling Diels-Alder/retro Diels-Alder reaction of 5,5′-bi-1,2,4-triazine-containing thiamacrocycles as a new route to thiacrown ethers incorporating a 2,2′-bipyridine subunit

A new route to thiacrown ethers 5a-d and 6a-d incorporating a 2,2′-bipyridine subunit is elaborated using, (1) homo-coupling of 1,2,4-triazine sulfides 3a-d tethered to poly(ethylene glycol) chains with potassium cyanide and (2) Diels-Alder/retro Diels-Alder reaction with norbornadiene or 1-pyrrolidino-1-cyclopentene as the key steps.     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

A novel and convenient method for the synthesis of new derivatives of pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione

A novel methodology has been developed for the efficient synthesis of 1,4-pyridopyrrolodiazepine derivatives. The key reaction is the bromination under mild conditions by NBS of compounds resulting via peptide coupling of l-proline methyl ester with 3-aminopyridine-2-carboxylic acid 1, then intramolecular cyclization in the construction of 2-bromo-6a,7,8,9-tetrahydro-5H-pyrido[3,2-e]pyrrolo[1,2-a][1,4]diazepine-6,11-dione 4. This latter is then engaged in cross-coupling reactions to generate 1,4-pyridopyrrolodiazepines derivatives 5a-m, 6a-i, 7, and 8a-c. This strategy provides an efficient method to access a library of compounds based on privileged substructures that are of great interest in drug discovery.     

A tandem decarboxylation and inverse electron-demand Diels-Alder reaction of amino-thiophenecarboxylic acids with 1,3,5-triazines

The scope of 1,3,5-triazine inverse electron-demand Diels-Alder (IDA) reactions was expanded to include aminothiophenecarboxylic acids as latent dienophiles. A series of 2-amino-3-thiophenecarboxylic acids (1a-d) and a 3-amino-2-thiophenecarboxylic acid (5) were introduced as productive dienophiles in IDA reactions with various 1,3,5-triazines (2a-e). This method is useful for the one-step synthesis of both thieno[2,3-d]pyrimidines and thieno[3,2-d]pyrimidines, which should complement existing methods.     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

Gas-phase pyrolysis of benzimidazole derivatives: novel route to condensed heterocycles

Gas-phase pyrolysis of N-(1H-benzimidazol-2-yl)-N′-arylidenehydrazines 1a-e gave the corresponding arylnitriles 2a-e, 2-aminobenzimidazole 3, 2,4,5-triphenylimidazole 4, 1,3-diphenyl-8H-2,3a,8-triazacyclopenta[a]indene 5, and 5,11-diphenyl-6H,12H-dibenzimidazo[1,2-a];1’,2’-d]pyrazine 6. The kinetics and analysis of the products of reaction are reported and used to elucidate the mechanism of the elimination process.     

Imino Diels-Alder reaction of boronates: A new route to 3,4-dihydroquinolines

The synthesis of a series of 3,4-dihydroquinolines (3b-e, 3h and 3i) by Imino Diels-Alder reactions involving sulfolene and boronates 2a-j derived from Schiff bases is described. The reactions are regioselective leading to 4-substituted dihydroquinolines with a cis relative stereochemistry between the phenyl group on the boron atom and the vinyl substituent at position 4, as established by X-ray diffraction analyses of 3b, 3e, 3h and 3i.Boronates 2 containing substituents meta to the imino fragment lead to 4-ethenyl-dihydroquinolines while para substituted derivatives are more reactive and lead to 4-cyclohexenylquinolines 4 formed by a second Diels-Alder reaction with excess of butadiene. The results show that boronates derived from Schiff bases are electron deficient species that react with sulfolene providing a new route to 3,4-dihydroquinolines. Moreover, polarization of the imine bond activates these system toward cycloaddition.     

New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones

N-(1-Ethoxy-2,2,2-trifluoroethyl)anilines 2a-2f, prepared from trifluoroacetaldehyde ethyl hemiacetal and aniline, readily reacted with diethyl malonate in the presence of sodium hydride, giving substituted products 5a-5f in high yields. Compounds 5a-5f subjected to hydrolysis and decarboxylation under specified conditions yielded the 4,4,4-trifluorobutyric acids 6a-6e or 7. Direct ring-closure of 6a-6e with polyphosphoric acid gave 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones 9a-9e.     

Synthesis of poly-substituted pyrroles starting from the Baylis-Hillman adducts

We synthesized poly-substituted pyrrole derivatives 4a-e, 7a-c and 10a-d from the reaction of phenacyl bromide and the aza-Baylis-Hillman adducts 1a-d or their rearranged derivatives 5a-e. The pyrroles were synthesized via the successive N-alkylation, Michael addition, elimination of p-toluenesulfinic acid and oxidative aromatization processes.     

Chemistry of cyclopropenones: synthesis of new pyrrolo[2,1-b]-1,3,4-oxadiazoles

2,3-Diphenylcyclopropenone (1) reacts with ylidene-N-phenylhydrazine-carbothioamides 2a-e to form the pyrrolo[2,1-b]-1,3,4-oxadiazoles 5a-e.