One‐Pot Synthesis of 1,4‐Dihydro‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic Acid Derivatives by the Reaction of 2‐Isothiocyanatophenyl Ketones with Lithium Enolates of Acetates and Tertiary Acetamides

The one‐pot synthesis of 4‐aryl‐1,4‐dihydro‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic acid derivatives 2 was achieved in good yields by the reaction of aryl(2‐isothiocyanatophenyl)methanones 1 with lithium enolates of acetates and tertiary acetamides. (2E)‐1‐(2‐Isothiocyanatophenyl)‐3‐phenylprop‐2‐en‐1‐one ( 3 ) gave 1,4‐dihydro‐4‐[(1E)‐2‐phenylethenyl]‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic acid derivatives 4 in good yields as well.     

1,3‐Dipolar Cycloaddition Reactions of Organic Azides with Morpholinobuta‐1,3‐dienes and with an α‐Ethynyl‐enamine

The cycloaddition of organic azides with some conjugated enamines of the 2‐amino‐1,3‐diene, 1‐amino‐1,3‐diene, and 2‐aminobut‐1‐en‐3‐yne type is investigated. The 2‐morpholinobuta‐1,3‐diene 1 undergoes regioselective [3+2] cycloaddition with several electrophilic azides RN₃ 2 ( a , R=4‐nitrophenyl; b , R=ethoxycarbonyl; c , R=tosyl; d , R=phenyl) to form 5‐alkenyl‐4,5‐dihydro‐5‐morpholino‐1H‐1,2,3‐triazoles 3 which are transformed into 1,5‐disubstituted 1H‐triazoles 4a , d or α,β‐unsaturated carboximidamide 5 (Scheme 1). The cycloaddition reaction of 4‐[(1E,3Z)‐3‐morpholino‐4‐phenylbuta‐1,3‐dienyl]morpholine ( 7 ) with azide 2a occurs at the less‐substituted enamine function and yields the 4‐(1‐morpholino‐2‐phenylethenyl)‐1H‐1,2,3‐triazole 8 (Scheme 2). The 1,3‐dipolar cycloaddition reaction of azides 2a – d with 4‐(1‐methylene‐3‐phenylprop‐2‐ynyl)morpholine ( 9 ) is accelerated at high pressure (ca. 7–10 kbar) and gives 1,5‐disubstituted dihydro‐1H‐triazoles 10a , b and 1‐phenyl‐5‐(phenylethynyl)‐1H‐1,2,3‐triazole ( 11d ) in significantly improved yields (Schemes 3 and 4). The formation of 11d is also facilitated in the presence of an equimolar quantity of tBuOH. The three‐component reaction between enamine 9 , phenyl azide, and phenol affords the 5‐(2‐phenoxy‐2‐phenylethenyl)‐1H‐1,2,3‐triazole 14d .     

Synthesis of (2S)‐2‐(Benzoylamino)‐3‐(heteroaryl)propyl Benzoates

(3E,5S)‐1‐Benzoyl‐5‐[(benzoyloxy)methyl]‐3‐[(dimethylamino)methylidene]pyrrolidin‐2‐one ( 9 ) was prepared in two steps from commercially available (S)‐5‐(hydroxymethyl)pyrrolidin‐2‐one ( 7 ) (Scheme 1). Compound 9 gave, in one step, upon treatment with various C,N‐ and C,O‐1,3‐dinucleophiles 10 – 18 , the corresponding 3‐(quinolizin‐3‐yl)‐ and 3‐(2‐oxo‐2H‐pyran‐3‐yl)‐substituted (2S)‐2‐(benzoylamino)propyl benzoates 19 – 27 (Schemes 1 and 2).     

Novel Synthesis of 2‐Alkylquinolizinium‐1‐olates and Their 1,3‐Dipolar Cycloaddition Reactions with Acetylenes

Several 2‐alkylquinolizinium‐1‐olates 9 , i.e., heterobetaines, were prepared from ketone 11 , the latter being readily available either from pyridine‐2‐carbaldehyde via a Grignard reaction, followed by oxidation with MnO₂, or from 2‐picolinic acid (=pyridine‐2‐carboxylic acid) via the corresponding Weinreb amide and subsequent Grignard reaction. Mesoionic heterobetaines such as quinolizinium derivatives have the potential to undergo cycloaddition reactions with double and triple bonds, e.g., 1,3‐dipolar cycloadditions or Diels? Alder reactions. We here report on the scope and limitations of cycloaddition reactions of 2‐alkylquinolizinium‐1‐olates 9 with electron‐poor acetylene derivatives. As main products of the reaction, 5‐oxopyrrolo[2,1,5‐de]quinolizines (=‘[2.3.3]cyclazin‐5‐ones’) 19 were formed via a regioselective [2+3] cycloaddition, and cyclohexadienone derivatives, formed via a Diels? Alder reaction, were obtained as side products. The structures of 2‐benzylquinolizinium‐1‐olate ( 9a ) and two ‘[2.3.3]cyclazin‐5‐ones’ 19i and 19l were established by X‐ray crystallography.     

Preparation of 1‐substituted‐5‐[(2‐oxo‐2‐phenyl)ethyl]imidazoles

New high yield preparation methods were developed for the pharmaceutically interesting compounds, 1‐benzyl‐, 1‐methyl‐, and 1H‐5‐[(2‐oxo‐2‐phenyl)ethyl]imidazoles 1a‐c , respectively. The title compounds were synthesized by four different methods using various starting materials. Two of the methods involved transformation reactions of the key intermediates, 1‐substituted‐5‐[(2‐nitro‐2‐phenyl)ethenyl]imidazoles 2a‐c and 1‐substituted‐5‐[(2‐nitro‐2‐phenyl)ethyl]imidazoles 3a‐c , while the other two utilized the oxidation of 1‐substituted‐5‐[(2‐hydroxy‐2‐phenyl)ethyl]imidazoles 4a‐c , with chromic oxide, and the umpolung reaction of benzaldehyde followed by a condensation reaction of the umpolung intermediate with imidazolecarboxaldehydes 6a‐c.     

From Blue Azulenes to Blue Heptalenes – New Strongly Polarized π‐Convertible Heptalenes

The 1,5,6,8,10‐pentamethylheptalene‐4‐carboxaldehyde ( 4b ) (together with its double‐bond‐shifted (DBS) isomer 4a ) and methyl 4‐formyl‐1,6,8,10‐tetramethylheptalene‐5‐carboxylate ( 15b ) were synthesized (Schemes 3 and 7, resp.). Aminoethenylation of 4a / 4b with N,N‐dimethylformamide dimethyl acetal (=1,1‐dimethoxy‐N,N‐dimethylmethanamine=DMFDMA) led in DMF to 1‐[(1E)‐2‐(dimethylamino)ethenyl]‐5,6,8,10‐tetramethylheptalene‐2‐carboxaldehyde ( 18a ; Scheme 9), whereas the stronger aminoethenylation agent N,N,N′,N′,N″,N″‐hexamethylmethanetriamine (=tris(dimethylamino)methane=TDMAM) gave an almost 1 : 1 mixture of 18a and 1‐[(1E)‐2‐(dimethylamino)ethenyl]‐5,6,8,10‐tetramethylheptalene‐4‐carboxaldehyde ( 20b ; Scheme 11). Carboxylate 15b delivered with DMFDMA on heating in DMF the expected aminoethenylation product 19b (Scheme 10). The aminoethenylated heptalenecarboxaldehydes were treated with malononitrile in CH₂Cl₂ in the presence of TiCl₄/pyridine to yield the corresponding malononitrile derivatives 23b, 24b , and 26a (Schemes 13 and 14). The photochemically induced DBS process of the heptalenecarboxaldehydes as ‘soft’ merocyanines and their malononitrile derivatives as ‘strong’ merocyanines of almost zwitterionic nature were studied in detail (Figs. 10–29) with the result that 1,4‐donor/acceptor substituted heptalenes are cleaner switchable than 1,2‐donor/acceptor‐substituted heptalenes.     

Synthesis and characterization of bromo‐, arylazo‐, and heterocyclic‐fused troponoids containing a 1,3‐benzodioxole system

A facile synthesis of a series of novel bromo‐, arylazo‐, and heterocyclic fused troponoid compounds containing 1,3‐benzodioxole system is described. The 7‐bromo‐, 5,7‐dibromo‐, and 5‐arylazo‐substituted 3‐[(2E)‐3‐(1,3‐benzodioxol‐5‐yl)prop‐2‐enoyl]tropolones ( 2 , 3 , and 5 , 6 , 7 ) were obtained by direct bromination or azo‐coupling reactions of 3‐[(2E)‐3‐(1,3‐benzodioxol‐5‐yl)prop‐ 2‐enoyl]tropolone ( 1 ) with bromine, and diazonium salts of aniline derivatives, respectively. 3‐[(2E)‐3‐(1,3‐Benzodioxol‐5‐yl)prop‐2‐enoyl]‐5‐bromotropolone ( 4 ) was obtained from 3‐acetyl‐5‐bromotropolone via one‐pot aldol dehydration reaction with piperonal. Tropolones 2, 3 , and 4 were subjected to nucleophilic cyclization with bifunctional hydroxylamine hydrochloride and phenylhydrazine hydrochloride to give the corresponding isoxazolo‐ and pyrazolo‐fused tropones ( 8 , 9 , 10 , 11 , 12 , 13 ), respectively. J. Heterocyclic Chem., (2012).     

Synthesis of (S)‐3‐heteroaryl‐2‐hydroxy‐l‐propyl benzoates by ‘ring switching’ methodology

(S)‐5‐Benzoyloxymethyl‐3‐[(E)‐(dimethylamino)methylidene]tetrahydrofuran‐2‐one (6), prepared in 5 steps from L‐glutamic acid (1), was used as precursor in a one step ‘ring switching’ synthesis of (S)‐2‐hydroxy‐3‐heteroaryl‐l‐propyl benzoates 13‐18, 23, 24. In the reaction of 6 with 2‐aminopyridine (21) and 2‐amino‐4,6‐dimethylpyrimidine (22) the corresponding dimethylamine substitution products (25, 26) were obtained.     

Four Novel Dihydroisocoumarin (=3,4‐Dihydro‐1H‐2‐benzopyran‐1‐one) Glucosides from the Fungus Cephalosporium sp. AL031

Four novel dihydroisocoumarin (=3,4‐dihydro‐1H‐2‐benzopyran‐1‐one) glucosides were isolated from a culture broth of a strain of the fungus Cephalosporium sp. AL031. Their structures were elucidated as (2E,4E)‐5‐[(3S)‐5‐acetyl‐8‐(β‐D ‐glucopyranosyloxy)‐3,4‐dihydro‐6‐hydroxy‐1‐oxo‐1H‐2‐benzopyran‐3‐yl]penta‐2,4‐dienal ( 1 ), (2E,4E)‐5‐[(3S)‐5‐acetyl‐8‐(β‐D ‐glucopyranosyloxy)‐3,4‐dihydro‐6‐methoxy‐1‐oxo‐1H‐2‐benzopyran‐3‐yl]penta‐2,4‐dienal ( 2 ), (3S)‐8‐(β‐D ‐glucopyranosyloxy)‐3‐[(1E,3E,5E)‐hepta‐1,3,5‐trienyl]‐3,4‐dihydro‐6‐hydroxy‐5‐methyl‐1H‐2‐benzopyran‐1‐one ( 3 ), and (3S)‐8‐[(6‐O‐acetyl‐β‐D ‐glucopyranosyl)oxy]‐3‐[(1E,3E,5E)‐hepta‐1,3,5‐trienyl]‐3,4‐dihydro‐6‐methoxy‐5‐methyl‐1H‐2‐benzopyran‐1‐one ( 4 ) by spectroscopic methods, including 2D‐NMR techniques and chemical methods.     

Diastereo‐ and Enantioselective Intramolecular [2+2] Photocycloaddition Reactions of 3‐(ω′‐Alkenyl)‐ and 3‐(ω′‐Alkenyloxy)‐Substituted 5,6‐Dihydro‐1H‐pyridin‐2‐ones

3‐(ω′‐Alkenyl)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 2 – 4 were prepared as photocycloaddition precursors either by cross‐coupling from 3‐iodo‐5,6‐dihydro‐1H‐pyridin‐2‐one ( 8 ) or—more favorably—from the corresponding α‐(ω′‐alkenyl)‐substituted δ‐valerolactams 9 – 11 by a selenylation/elimination sequence (56–62 % overall yield). 3‐(ω′‐Alkenyloxy)‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones 5 and 6 were accessible in 43 and 37 % overall yield from 3‐diazopiperidin‐2‐one ( 15 ) by an α,α‐chloroselenylation reaction at the 3‐position followed by nucleophilic displacement of a chloride ion with an ω‐alkenolate and oxidative elimination of selenoxide. Upon irradiation at λ=254 nm, the precursor compounds underwent a clean intramolecular [2+2] photocycloaddition reaction. Substrates 2 and 5 , tethered by a two‐atom chain, exclusively delivered the respective crossed products 19 and 20 , and substrates 3 , 5 , and 6 , tethered by longer chains, gave the straight products 21 – 23 . The completely regio‐ and diastereoselective photocycloaddition reactions proceeded in 63–83 % yield. Irradiation in the presence of the chiral templates (?)‐ 1 and (+)‐ 31 at ?75 °C in toluene rendered the reactions enantioselective with selectivities varying between 40 and 85 % ee. Truncated template rac‐ 31 was prepared as a noranalogue of the well‐established template 1 in eight steps and 56 % yield from the Kemp triacid ( 24 ). Subsequent resolution delivered the enantiomerically pure templates (?)‐ 31 and (+)‐ 31 . The outcome of the reactions is compared to the results achieved with 4‐substituted 5,6‐dihydro‐1H‐pyridin‐2‐ones and quinolones.     

Synthesis and Cytotoxic Evaluation of Novel 1,2,3‐Triazole‐4‐Linked (2E,6E)‐2‐Benzylidene‐6‐(4‐nitrobenzylidene)cyclohexanones

This work describes the synthesis of novel 1,2,3‐triazole‐4‐linked (2E,6E)‐2‐benzylidene‐6‐(4‐nitrobenzylidene)cyclo‐hexanones starting from cyclohexanone. 1‐(Cyclohex‐1‐en‐1‐yl)piperidine, the enamine from cyclohexanone and piperidine, reacted with 4‐nitrobenzaldehyde to obtain 2‐(4‐nitrobenzylidene)cyclohexanone. Condensation of the latter compound with (prop‐2‐yn‐1‐yloxy)benzaldehyde derivatives under acidic conditions gave (4‐nitrobenzylidene)‐[(prop‐2‐yn‐1‐yloxy)‐benzylidene]cyclohexanones. Finally, ‘click reaction’ of these derivatives and various organic azides led to the title compounds. All compounds were examined by MTT assay for cytotoxic activity in one human breast cancer cell line, MDA‐MB‐231.     

On the features of reactivity of 8-[(1E)-2-phenylethenyl]-substituted thebaine and codeinone derivatives

An improved method for the synthesis of 8-[(1E)-2-phenylethenyl]codeinone dimethyl ketal was described. The ability of [(1E)-2-phenylethenyl] substituent to stabilize effectively the π-system of the ring C is responsible for the essential difference in both the reactivity and the compositions of products formed in the reactions of the corresponding substituted and unsubstituted codeinone and thebaine derivatives.     

A Facile Synthesis of Oxoindenothiazine and Dioxospiro(indene‐2,4′‐thiazine) Derivatives from (Substituted ethylidene)hydrazinecarbothioamides

(E)‐2‐[2‐(1‐Substituted ethylidene)hydrazinyl]‐5‐oxo‐9b‐hydroxy‐5,9b‐dihydroindeno[1,2‐d][1,3]‐thiazine‐4‐carbonitriles and (E)‐5‐oxo‐[(E)‐(1‐substituted ethylidene)hydrazinyl]‐2,5‐dihydroindeno[1,2‐d][1,3]thiazine‐4‐carbonitriles have been obtained from the reaction of 2‐(substituted ethylidene)hydrazinecarbothioamides with 2‐(1,3‐dioxo‐2,3‐dihydro‐1H‐inden‐2‐ylidene)propanedinitrile ( 1 ) in ethyl acetate solution. However, (Z)‐6′‐amino‐1,3‐dioxo‐3′‐substituted‐2′‐[(E)‐(1‐phenylethylidene)hydrazono]‐1,2′,3,3′‐tetrahydrospiro(indene‐2,4′‐[1,3]thiazine)‐5′‐carbonitriles were observed during the reaction of N‐substituted‐2‐(1‐phenylethylidene)hydrazinecarbothioamides with ( 1 ). The structure assignment of products has been confirmed on the basis of ¹H‐, ¹³C‐NMR, and mass spectrometry, as well as theoretical calculations.     

Synthesis of 3‐(4‐Oxo‐4H‐quinolizinyl‐3) and 3‐(4‐Oxo‐4H‐pyridino[1,2‐a]pyrimidinyl‐3) substituted lactic acid derivatives

A one‐step ‘ring switching’ transformation of (S)‐3‐[(dimethylamino)methylidene]‐5‐(methoxycarbonyl)tetrahydrofuran‐2‐one ( 4 ) with 2‐pyridineacetic acid derivatives ( 5–7 ) and 2‐aminopyridines ( 8, 9 ) afforded the corresponding 3‐(4‐oxo‐4H‐quinolizinyl‐3)‐ (15–17) and 3‐(4‐oxo‐4H‐pyridino[1,2‐a]pyrimidinyl‐3)‐2‐hydroxypropanoates ( 18, 19 ), respectively.     

立体选择性合成2-(a-噻吩甲酰基)-3-取代苯基-4-乙氧羰基-5-甲基-反式-2,3-二氢呋喃

溴化(a-噻吩甲酰基)甲基三苯鉮1与3-取代苯甲叉基-2,4-戊二酮 2以碳酸钾为碱,在苯中55℃条件下反应,可以较好的收率、高立体选择性地生成反-2-(a-噻吩甲酰基)-3-取代苯基-4-乙氧羰基-5-甲基-2,3-二氢呋喃3。产物结构均经波谱予以确定。本文还提出了生成产物的可能机理。     

Novel Intramolecular Cyclization of 2‐(Buta‐1,3‐dienyl)benzyl Anions to 6,7(9)‐Dihydro‐5H‐benzocycloheptenyl Anions Leading to Successive Formation of 1,2‐Dihydrocyclopropa[a]naphthalenes

When treated with LiNⁱPr₂ (LDA) at ?78°, 1‐[(methylsulfanyl)methyl]‐2‐[(1Z,3E)‐4‐phenylbuta‐1,3‐dien‐1‐yl]benzene easily cyclized to form benzocycloheptenyl anion, which successively underwent intramolecular nucleophilic substitution to give a cyclopropanaphthalene. Similar LDA‐mediated cyclization also occurred for 4‐phenyl‐ or 4‐methyl‐substituted 1‐[2‐(methoxymethyl)phenyl]buta‐1,3‐dienes to furnish the corresponding benzocycloheptenes and cyclopropanaphthalenes. A 4‐tert‐butyl analog also underwent LDA‐mediated cyclization to give a benzocycloheptene, but not a cyclopropanaphthalene.     

A new synthesis of 4‐cyano‐1,3‐dihydro‐2‐oxo‐2H‐imidazole‐5‐(N1‐tosy1)carboxamide : reactive precursor for thiopurine analogues

N‐[(5‐Cyano‐2‐oxoimidazolidin‐4‐yl)‐iminomethyl]‐p‐toluensulfonamide 3 was prepared in fairly good yield by the base catalyzed cyclisation of N‐[(Z)‐2‐amino‐1,2‐dicycanovinylcarbamoyl]‐p‐toluenesulfon‐amide 2 . The N‐[(Z)‐2‐amino‐1,2‐dicycanovinyl carbamoyl]‐p‐toluenesulfonamide 2 was reacted readily with two molar amount of p‐nitrobenzaldehyde at room temperature in the presence of base to give 7,8‐dihy‐dro‐2‐(4‐nitrophenyl)‐8‐oxo‐9‐tosylpurine‐6‐carboxamide 8 . Thiation of compounds 3 and 8 using Lawesson's reagent in tetrahydrofuran gave novel thioimidazoles 4, 5 , and 6 and thiopurines 9, 10 , and 11 , which have been characterized spectroscopically.     

Two novel organic–inorganic hybrid materials from tetrachloridometallate(II) salts and 4‐[(E)‐2‐(pyridin‐1‐ium‐2‐yl)ethenyl]pyridinium

Two organic–inorganic hybrid compounds have been prepared by the combination of the 4‐[(E)‐2‐(pyridin‐1‐ium‐2‐yl)ethenyl]pyridinium cation with perhalometallate anions to give 4‐[(E)‐2‐(pyridin‐1‐ium‐2‐yl)ethenyl]pyridinium tetrachloridocobaltate(II), (C₁₂H₁₂N₂)[CoCl₄], (I), and 4‐[(E)‐2‐(pyridin‐1‐ium‐2‐yl)ethenyl]pyridinium tetrachloridozincate(II), (C₁₂H₁₂N₂)[ZnCl₄], (II). The compounds have been structurally characterized by single‐crystal X‐ray diffraction analysis, showing the formation of a three‐dimensional network through X—H...Cl_nM⁻ (X = C, N⁺; n = 1, 2; M = Co^II, Zn^II) hydrogen‐bonding interactions and π–π stacking interactions. The title compounds were also characterized by FT–IR spectroscopy and thermogravimetric analysis (TGA).     

Tandem Hydroformylation/Reductive Amination of 3‐Allyl‐2‐methylquinazolin‐4(3H)‐one

The 3‐allyl‐2‐methylquinazolin‐4(3H)‐one ( 1 ), a model functionalized terminal olefin, was submitted to hydroformylation and reductive amination under optimized reaction conditions. The catalytic carbonylation of 1 in the presence of Rh catalysts complexed with phosphorus ligands under different reaction conditions afforded a mixture of 2‐methyl‐4‐oxoquinazoline‐3(4H)‐butanal ( 2 ) and α,2‐dimethyl‐4‐oxoquinazoline‐3(4H)‐propanal ( 3 ) as products of ‘linear’ and ‘branched’ hydroformylation, respectively (Scheme 2). The hydroaminomethylation of quinazolinone 1 with arylhydrazine derivatives gave the expected mixture of [(arylhydrazinyl)alkyl]quinazolinones 5 and 6 , besides a small amount of 2 and 3 (Scheme 3). The tandem hydroformylation/reductive amination reaction of 1 with different amines gave the quinazolinone derivatives 7 – 10 . Compound 10 was used to prepare the chalcones 11a and 11b and pyrazoloquinazolinones 12a and 12b (Scheme 4).     

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.