Photochemical Transformations of Some 2‐(5‐Methylthiophen‐2‐yl)‐3‐[(naphthalen‐2‐yl)methoxy]‐4H‐chromen‐4‐ones Involving Type‐II Process

Photo‐irradiation of 2‐(5‐methylthiophen‐2‐yl)‐3‐[(naphthalen‐2‐yl)methoxy]‐4H‐chromen‐4‐ones yielded the fascinating angular tetracyclic products via cyclization involving both 2‐thienyl ring and naphthylmethoxy group via 1,4‐biradical generated in the Norrish type‐II process. The stereochemical dispositions of the products were determined by MM2 energy minimized programme and spectroscopic analysis.     

Photocycloaddition of Cyclohex‐2‐enones to 2‐Methylbut‐1‐en‐3‐yne

Irradiation (350 nm) of 2‐alkynylcyclohex‐2‐enones 1 in benzene in the presence of an excess of 2‐methylbut‐1‐en‐3‐yne ( 2 ) affords in each case a mixture of a cis‐fused 3,4,4a,5,6,8a‐hexahydronaphthalen‐1(2H)‐one 3 and a bicyclo[4.2.0]octan‐2‐one 4 (Scheme 2), the former being formed as main product via 1,6‐cyclization of the common biradical intermediate. The (parent) cyclohex‐2‐enone and other alkylcyclohex‐2‐enones 7 also give naphthalenones 8 , albeit in lower yields, the major products being bicyclo[4.2.0]octan‐2‐ones (Scheme 4). No product derived from such a 1,6‐cyclization is observed in the irradiation of 3‐alkynylcyclohex‐2‐enone 9 in the presence of 2 (Scheme 4). Irradiation of the 2‐cyano‐substituted cyclohexenone 12 under these conditions again affords only traces of naphthalenone 13 , the main product now being the substituted bicyclo[4.2.0]oct‐7‐ene 16 (Scheme 5), resulting from [2+2] cycloaddition of the acetylenic C−C bond of 2 to excited 12 .     

Organocatalytic Asymmetric Conjugate Addition of 3‐Monosubstituted Oxindoles to (E)‐1,4‐Diaryl‐2‐buten‐1,4‐diones: A Strategy for the Indirect Enantioselective Furanylation and Pyrrolylation of 3‐Alkyloxindoles

An asymmetric conjugate addition of 3‐monosubstituted oxindoles to a range of (E)‐1,4‐diaryl‐2‐buten‐1,4‐diones, catalyzed by commercially available cinchonine, is described. This organocatalytic asymmetric reaction affords a broad range of 3,3′‐disubstituted oxindoles that contain a 1,4‐dicarbonyl moiety and vicinal quaternary and tertiary stereogenic centers in high‐to‐excellent yields (up to 98 %), with excellent diastereomeric and moderate‐to‐high enantiomeric ratios (up to 99:1 and 95:5, respectively). Subsequently, cyclization of the 1,4‐dicarbonyl moiety in the resultant Michael adducts under different Paal–Knorr conditions results in two new kinds of 3,3′‐disubstituted oxindoles—3‐furanyl‐ and 3‐pyrrolyl‐3‐alkyl‐oxindoles—in high yields and good enantioselectivities. Notably, the studies presented here sufficiently confirm that this two‐step strategy of sequential conjugate addition/Paal–Knorr cyclization is not only an attractive method for the indirect enantioselective heteroarylation of 3‐alkyloxindoles, but also opens up new avenues toward asymmetric synthesis of structurally diverse 3,3′‐disubstituted oxindole derivatives.     

AgNO3 Catalyzed Regio‐Selective Synthesis of 3‐Alkyl/Aryl‐idene‐3,4‐dihydro‐4‐tosyl‐2H‐1,4‐Benzoxazine: Novel Anti‐Tubercular Scaffolds

A facile and efficient method for the construction of 3‐alkyl/aryl substituted 1,4‐benzoxazine and benzoxazepine via AgNO₃ catalyzed cyclization of propargyloxy sulfonamides and their anti‐tubercular activity against Mycobacterium tuberculosis H₃₇R_V is described. This cyclization proceeds through 6‐exo‐dig manner to generate the products in moderate to good yields.     

Versatile One‐Pot Synthesis of Polysubstituted Cyclopent‐2‐enimines from α,β‐Unsaturated Amides: Imino‐Nazarov Reaction

The imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imines was realized. To this aim, a one‐pot procedure involving reductive alkenyliminylation of α,β‐unsaturated secondary amides with potassium organotrifluoroborates, followed by acid‐catalyzed imino‐Nazarov cyclization of the polysubstituted pentan‐1,4‐diene‐3‐imine intermediates, was studied systematically. This mild, operationally simple, flexible, and high‐yielding protocol efficiently affords polysubstituted pentan‐1,4‐diene‐3‐imines, cyclopentenimines, and α‐amino cyclopentenones, which are useful scaffolds in organic synthesis. The substituent effect at the C2 position of the polysubstituted pentan‐1,4‐diene‐3‐imines was studied by means of density‐functional theory calculations. Results suggested that the electron‐donating group facilitates the imino‐Nazarov cyclization process.     

One‐Pot Syntheses of 2‐(2‐Sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic Acid Derivatives via Reactions of 3‐(2‐Isothiocyanatophenyl)prop‐2‐enoic Acid Derivatives with Thiols or Sodium Sulfide

Two efficient methods for the preparation of 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoates 1a – 1c with thiols in the presence of Et₃N in THF at room temperature, leading to the corresponding dithiocarbamate intermediates 2 , which underwent spontaneous cyclization at the same temperature by an attack of the S‐atom at the prop‐2‐enoyl moiety in a 1,4‐addition manner (Michael addition) to give 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetates in one pot. The second method involves treatment of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoic acid derivatives 1b – 1d with Na₂S leading to the formation of 2‐(2‐sodiosulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or aryl halides to afford derivatives 3 . 2‐(2‐Thioxo‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 6 can be obtained by omitting the addition of halides.     

TiCl3‐Mediated Synthesis of 2,3,3‐Trisubstituted Indolenines: Total Synthesis of (+)‐1,2‐Dehydroaspidospermidine, (+)‐Condyfoline,and (−)‐Tubifoline

2,3,3‐Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl₃‐mediated reductive cyclization of tetrasubstituted alkenes bearing a 2‐nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)‐1,2‐dehydroaspidospermidine featuring a late‐stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π‐electron‐5‐atom electrocyclization and a 1,2‐alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)‐condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2‐alkyl shift. The exclusive formation of (+)‐condyfoline indicates that the 1,2‐alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro‐Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)‐condyfoline to (?)‐tubifoline by way of a retro‐Mannich/1,3‐prototropy/transannular cyclization cascade are also documented.     

Regioselective [3+3] Cyclization of 1,3‐Bis(silyloxy)buta‐1,3‐dienes with 1,1,1‐Trifluoro‐4‐(silyloxy)alk‐3‐en‐2‐ones: New and Convenient Synthesis of Functionalized 5‐Alkyl‐3‐(trifluoromethyl)phenols

Functionalized 5‐alkyl‐3‐(trifluoromethyl)phenols were prepared by formal [3+3] cyclization of 1,3‐bis(silyloxy)buta‐1,3‐dienes with 1,1,1‐trifluoro‐4‐(silyloxy)alk‐3‐en‐2‐ones derived from 1,1,1‐trifluoroalkane‐2,4‐diones. The latter were prepared by condensation of the dianion of 1,1,1‐trifluoropentane‐2,4‐dione with alkyl halides.     

Thermal reactions of N‐alkyl‐2‐benzylaniline and N‐alkyl‐N′‐phenyl‐o‐phenylenediamine: An unusual route to 2‐phenylindole and 2‐phenylbenzimidazole

Thermal cyclization reactions of N‐alkyl‐2‐benzylaniline 1a‐d and N‐alkyl‐N′‐phenyl‐o‐phenylenediamine 2a‐b were carried out expecting to get seven‐membered heterocyclic compounds. However, the results show that aside from the formation of the normally expected six‐membered ring products of acridine 5 , anthracene 6 , and phenazine 8 , thermal cyclization of N‐alkyl‐2‐benzylaniline and N‐alkyl‐N′‐phenyl‐o‐phenylenediamine also resulted to the unexpected formation of 2‐phenylindole 3 and 2,3‐diphenylindole 4 , and 2‐phenylbenzimidazole 7 , respectively.     

Quinolone analogues 2. A facile synthesis of novel 3‐substituted 1‐alkyl‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalines

The reaction of the 2‐(1‐alkylhydrazino)‐6‐chloroquinoxaline 4‐oxides 1a,b with diethyl acetone‐dicarboxylate or 1,3‐cyclohexanedione gave ethyl 1‐alkyl‐7‐chloro‐3‐ethoxycarbonylmethylene‐1,5‐dihydropyridazino[3,4‐b]quinoxaline‐3‐carboxylates 5a,b or 6‐alkyl‐10‐chloro‐1‐oxo‐1,2,3,4,6,12‐hexahydroquinoxalino[2,3‐c]cinnolines 7a,b , respectively. Oxidation of compounds 5a,b with nitrous acid afforded the ethyl 1‐alkyl‐7‐chloro‐3‐ethoxycarbonylmethylene‐4‐hydroxy‐1,4‐dihydropyridazino‐[3,4‐b]quinoxaline‐4‐carboxylates 9a,b , whose reaction with base provided the ethyl 2‐(1‐alkyl‐7‐chloro‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)acetates 6a,b , respectively. On the other hand, oxidation of compounds 7a,b with N‐bromosuccinimide/water furnished the 4‐(1‐alkyl‐7‐chloro‐4‐oxo‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)butyric acids 8a,b , respectively. The reaction of compound 8a with hydroxylamine gave 4‐(7‐chloro‐4‐hydroxyimino‐1‐methyl‐1,4‐dihydropyridazino[3,4‐b]quinoxalin‐3‐yl)‐butyric acid 12 .     

Using Morita–Baylis–Hillman acetates of 2‐azidobenzaldehydes for the synthesis of 2‐alkoxy‐3‐cyanomethylquinolines and alkyl quinoline‐3‐carboxylates

A simple method for the synthesis of several 2‐alkoxy‐3‐cyanomethylquinolines and alkyl quinoline‐3‐carboxylates using iminophosphorane‐mediated cyclization reactions of 3‐(2‐azidophenyl)‐2‐cyanomethylpropenoates and 3‐(2‐azidophenyl)‐2‐nitromethylpropenoates has been developed. These compounds were readily obtained from the Morita–Baylis–Hillman acetates of 2‐azidobenzaldehydes using potassium cyanide or sodium nitrite, respectively. J. Heterocyclic Chem., (2011)     

Photoannelation Reactions of 3‐(Alk‐1‐ynyl)cyclohept‐2‐en‐1‐ones

Irradiation (350 nm) of the newly synthesized 3‐(alk‐1‐ynyl)cyclohept‐2‐en‐1‐ones 1 and 2 leads to the selective formation of tricyclic head‐to‐head dimers. In the presence of 2,3‐dimethylbuta‐1,3‐diene, the (monocyclic) enone 1 affords trans‐fused 7‐alkynyl‐bicyclo[5.2.0]nonan‐2‐ones as major photoproducts, whereas photocycloaddition of benzocyclohept‐5‐en‐7‐one 2 to the same diene gives preferentially the eight‐membered cyclic allene 16 via ‘end‐to‐end’ cyclization of the intermediate allyl‐propargyl biradical 22 . On contact with acid, cycloocta‐1,2,5‐triene 16 isomerizes to cycloocta‐1,3,5‐triene 18 .     

Catenation of 1,3‐Diphosphacyclobutane‐2,4‐diyl Units Having 2,4,6‐Tri‐tert‐butylphenyl Protecting Groups and a P‐sec‐Butyl Group in the Ring

Two and three stable 1‐sec‐butyl‐2,4‐bis(2,4,6‐tri‐tert‐butylphenyl)‐1,3‐diphosphacyclobutane‐2,4‐diyl units were catenated to construct multi‐biradical derivatives by utilizing 1,3‐di‐, 1,4‐di‐, and 1,3,5‐trimethylenebenzenes as bridging groups, respectively. UV/Vis spectroscopic and cyclovoltammetric (CV) properties of the multi‐biradicals indicate a non‐conjugative interaction between the concatenated biradical units.     

Synthesis and analgesic‐antiinflammatory activities of ethyl 2‐[3‐(1‐phenoxy(methoxy)carbonyl‐4‐aryl‐(alkyl)‐1,4‐dihydropyridyl)]acetates

Reaction of ethyl 2‐(3‐pyridyl)acetate 4a or ethyl 2‐methyl‐2‐(3‐pyridyl)acetate 4b , with phenyl chloroformate or methyl chloroform ate, afforded the intermediate pyridinium salt 5 which undergoes regioselective nucleophilic attack at C‐4 upon reaction with a Grignard reagent in the presence of a cuprous iodide catalyst at ?23° to yield the corresponding ethyl 2‐[3‐(1‐phenoxy(methoxy)carbonyl‐4‐aryl(alkyl)‐1,4‐dihydropyridyl)]acetates 6a‐f in 64–96% chemical yield. No product arising from reaction of the ester substituent of the pyridinium salt 5 with the Grignard reagent was observed. The ¹H nmr spectra of 6a‐f exhibited dual resonances for the 1,4‐dihydropyridyl H‐2, H‐5 and H‐6 protons at 25° in deuteriochloroform. These dual resonaces were attributed to two different rotameric configurations resulting from restricted rotation about the nitrogen‐to‐carbonyl carbamate bond due to its double bond character. Compound 6 generally exhibited superior analgesic and antiinflammatory activities, compared to the reference drugs aspirin and ibuprofen, respectively. These structure‐activity correlations indicate the 1,4‐dihydropyridyl ring system present in 6 is a suitable bioisostere for the aryl (heteroaryl) ring present in aryl(heteroaryl)acetic acid non‐steroidal antiinflammatory drugs.     

A challenging synthesis of new 1,3,4‐thiadiazole derivatives starting from 2‐acylamino‐3,3‐dichloroacrylonitriles

Available 2‐acylamino‐3,3‐dichloroacrylonitriles, when treated with hydrazine hydrate, provide 2‐alkyl‐ or 2‐aryl‐5‐hydrazino‐1,3‐oxazole‐4‐carbonitriles that readily add alkyl or aryl isothiocyanates and the adducts formed recyclize on heating. Finally, the synthesis results in 5‐alkyl(aryl)amino‐1,3,4‐thiadiazol‐2‐yl(acylamino)acetonitriles or the products of their further cyclization, 2‐(5‐amino‐1,3‐ oxazol‐2‐yl)‐1,3,4‐thiadiazole derivatives. The structures of the novel substituted 1,3,4‐thiadiazoles are corroborated spectroscopically as well as by X‐ray diffraction method. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:454–458, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20041     

Organophotoredox‐Catalyzed Cascade Radical Annulation of 2‐(Allyloxy)arylaldehydes with N‐(acyloxy)phthalimides: Towards Alkylated Chroman‐4‐one Derivatives

An organophotoredox catalyzed efficient and robust approach for the synthesis of highly important 3‐alkyl substituted chroman‐4‐one scaffold is developed using visible light induced radical cascade cyclization strategy. The reaction is initiated through the generation of alkyl radicals from N‐(acyloxy)phthalimides under photoredox conditions, which subsequently undergo intermolecular cascade radical cyclization on 2‐(allyloxy)arylaldehydes to afford chroman‐4‐one scaffolds. The presented strategy is attractive with regard to mild reaction conditions, operational simplicity, high functional group tolerance and broad substrate scope.     

Synthesis of 2‐Substituted 3‐Alkylidene‐2,3‐dihydro‐1H‐isoindol‐1‐imines through Cyclization of [1‐(2‐Cyanophenyl)alkylidene]aminide Intermediates Generated from the Reaction of 2‐(1‐Azidoalkyl)benzonitriles with NaH

A convenient sequence for the preparation of 3‐alkylidene‐2,3‐dihydro‐1H‐isoindol‐1‐imine derivatives 6 has been developed. Thus, 2‐(1‐azidoalkyl)benzonitriles 2 , readily accessible from 2‐alkylbenzonitriles, are allowed to react with NaH in DMF at 0° to room temperature to generate [1‐(2‐cyanophenyl)alkylidene]aminide intermediates 3 , of which cyclization and the subsequent rearrangement, followed by alkylation with alkyl halides, affords 2‐substituted 1‐alkylidene‐2,3‐dihydro‐1H‐isoindol‐2‐imines 6 in generally moderate yields.     

Synthesis of some fused β‐carbolines including the first example of the pyrrolo[3,2‐c]‐β‐carboline system

Condensation of 1‐methyl‐β‐carboline‐3‐carbaldehyde with ethyl azidoacetate and subsequent thermolysis of the resulting azidopropenoate was used to [c] annulate a pyrrole ring onto the β‐carboline moiety, thus producing the first example of the pyrrolo[3,2‐c]‐β‐carboline ring system. The latter ring system results from cyclization at the C‐4 carbon, whereas cyclization at the N‐2 nitrogen atom also occurs to form a pyrazolo[3,2‐c]‐β‐carboline ring system. Condensation of β‐carboline‐1‐carbaldehyde with ethyl azidoacetate produced a non‐isolable intermediate, which immediately underwent cyclization, however in this case cyclization occurred via attack at the ester and the azide remained intact. The resulting 5‐azidocanthin‐6‐one was transformed to the first examples of 5‐aminocanthin‐6‐ones. β‐Carboline‐1,3‐dicarbaldehyde failed to give an acceptable reaction with ethyl azidoacetate, but did undergo selective condensation with dimethyl acetylene dicarboxylate at the C‐1 carbaldehyde with concomitant cyclization to form a highly functionalized 2‐formyl‐canthine derivative.     

Thermolytic ring closure reactions of 4‐azido‐3‐phenylsulfanyl‐and 4‐azido‐3‐phenylsulfonyl‐2‐quinolones to 12H‐quinolino‐[3,4‐b][1,4]benzothiazin‐6(5H)‐ones

4‐Hydroxy‐3‐phenylsulfanyl‐2‐quinolones 2 and 4‐hydroxy‐3‐sulfonyl‐2‐quinolones 7 , which are readily accessible from 4‐hydroxy‐2‐quinolones 1 and diphenyldisulfide or thiophenol, can be converted to 4‐azido‐3‐phenylsulfanyl‐2‐quinolones 10 or 4‐azido‐3‐phenylsulfonyl‐2‐quinolones 12 via 4‐chloro‐3‐phenylsul‐fanyl‐2‐quinolones 5 or 4‐chloro‐3‐phenylsulfonyl‐2‐quinolones 9 , respectively. Thermolysis of the azides 10 and 12 results in a cyclization reaction to give quinolino[3,4‐b][1,4]benzothiazinone 11 and quino‐lino[3,4‐b][1,4]benzothiazinone dioxides 13 , respectively. The conditions for thermolysis have been studied by differential scanning calorimetry (DSC).     

A Novel Intramolecular Photocyclization of N‐(2‐Bromoalkanoyl) Derivatives of 2‐Acylanilines via 1,8‐Hydrogen Abstraction

The photochemical reactions of different N‐(2‐acylphenyl)‐2‐bromo‐2‐methylpropanamides have been investigated. Irradiation of the N‐unsubstituted anilides 1a – 1c gave the corresponding dehydrobromination, cyclization, and bromo‐migration products 2, 3 , and 4 , respectively (Table 1). Irradiation of the N‐alkyl anilides 1e – 1g afforded the corresponding deacylation and cyclization products 5 and 6 , respectively, whereas irradiation of the N‐alkyl anilides 1i – 1k , carrying 2‐benzoyl groups on the aromatic rings, afforded the unexpected tricyclic lactams 7 (besides 2, 5 , and 6 ). The formation of the cyclization products 6 could be rationalized in terms of an electrocyclic ring closure of the 6π‐electron‐conjugated enamides 2 produced by dehydrobromination of 1 , followed by thermal 1,5‐acyl migration (Path B in the Scheme). The formation of the bridged lactams 7 probably follows a mechanism involving the 1,7‐diradical 8 generated by ζ‐H‐abstraction (1,8‐H transfer) by an excited acyl O‐atom (Path A).