A novel sulfonic acid functionalized ionic liquid catalyzed multicomponent synthesis of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives in water

Three-component reactions of 4-hydroxycoumarin, aldehydes, and cyclic 1,3-dicarbonyl compounds were prompted by novel sulfonic acid functionalized ionic liquids 1,3-dimethyl-2-oxo-1,3-bis(4-sulfobutyl)imidazolidine-1,3-diium hydrogen sulfate ([DMDBSI]·2HSO₄) in water at reflux temperature to provide a novel series of 10,11-dihydrochromeno[4,3-b]chromene-6,8(7H,9H)-dione derivatives for the first time in high yields.     

An efficient ionic liquid mediated synthesis of substituted 5H[1,3]-thiazolo[2,3-b]quinazoline-3,5-(2H)-dione and 5H-thiazolo[2,3-b]quinazolin-5-one

A new, environmentally benign two-step synthesis of 5H[1,3]-thiazolo[2,3-b]quinazoline-3,5-(2H)-dione and 5H-thiazolo[2,3-b]quinazolin-5-one derivatives has been accomplished stepwise. The substituted 2-aminobenzoic acid upon condensation with thiourea in 1-butyl-3-methylimidazolium bromide at moderate temperature under nitrogen atmosphere yielded 2-thioxo-1H-4-quinazolinones. The resulting intermediate 2-thioxo-1H-4-quinazolinones, when reacted with 2-chloroethanoic acid/2-chloropropanal underwent cyclization to yield the desired product in excellent yields.     

Synthesis of annelated [a]aza-anthracenones and thieno[3,2-g]aza-naphthalenones through ring transformation of 2H-pyran-2-one followed by photocyclization

A concise synthesis of some new classes of heterocycles (4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a-diaza-cyclopenta[a]anthracen-6-carbonitriles and 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a-diazabenzo[a]anthracene-7-carbonitriles) has been developed by the ring transformation of suitably functionalized 2H-pyran-2-one with α-oxoketene cyclic aminals to intermediates (8-aroyl-5-aryl-2,3-dihydro-1H-imidazo[1,2-a]pyridine-7-ylidene)-acetonitriles and (9-aroyl-6-aryl-1,2,3,4-tetrahydropyrido[1,2-a]pyrimidin-8-ylidene)-acetonitriles) followed by their photocyclization either in CHCl₃ or acetonitrile. This reaction was further explored for the synthesis of methyl 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carboxylate, 4-aryl-11-oxo-1,2,3,11-tetrahydro-1,3a,9-triaza-cyclopenta[a]anthracene-6-carbonitriles, 5-aryl-12-oxo-1,3,4,12-tetrahydro-2H-1,4a,10-triazabenzo[a]anthracene-7-carbonitriles, 4-aryl-10-oxo-1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-diazacyclopenta[b]phenanthrene-7-carbonitriles from the similar reactions.     

Synthesis of 4H-1,3-benzoxazin-4-ones from 2,2-diazidobenzofuran-3(2H)-ones

Benzoxazine derivatives are useful building blocks and display various biological activities. We serendipitously discovered and subsequently developed a new one pot method for the synthesis of 2-(dimethyl amino)/2-morpholino/2- (piperidin-1-yl)-4H-benzo[e][1,3]oxazin-4-ones from corresponding substituted 2,2-diazidobenzofuran 3(2H) - ones and N-formyl dimethyl amine (DMF)/N-formylmorpholine/N-formylpiperidine using m-CPBA at 100?°C in moderate to good yields. We also demonstrated the utility of 4H-benzoxazines for the synthesis of other medicinally important compounds such as 2-hydroxyphenyl substituted 1,2,4-triazoles, unsymmetrical 1,3,5-triazines, and 1,2,4-oxadiazoles.     

A novel ionic liquid mediated synthesis of 4(1H)-quinolones, 5H-thiazolo[3,2-a]pyrimidin-5-one and 4H-pyrimido[2,1-b]benzothiazol-4-ones

A new, convenient, environmentally benign two-step synthesis of 4(1H)-quinolones, 5H-thiazolo[3,2-a]pyrimidin-5-one and 4H-pyrimido[2,1-b]benzothiazol-4-ones have been developed by first condensing substituted arylamine/2-aminothiazole/2-aminobenzenethiazole with Meldrum’s acid and trimethylorthoformate in 1-butyl-3-methylimidazolium bromide at a moderate temperature to afford 5-{(substituted aryl/4-methylthiazolyl/substituted benzothiazolyl)methylene}-2,2-dimethyl-1,3-dioxane-4,6-dione. The resulting compounds upon cyclization in 1-butyl-3-methyl tetrafluoroborate/triflate at a moderate temperature gave the title compounds in excellent yields.     

Synthesis and properties of 3-arylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and related compounds: photo-induced autorecycling oxidation of some amines

Novel 3-phenyl- and 3-(4-nitrophenyl)cyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-diones and the corresponding imino derivatives 5a,b and 6a,b were synthesized in modest to moderate yields by the abnormal and normal aza-Wittig reaction of 2-(1,3-diazaazulen-2-ylimino)triphenylphosphorane with aryl isocyanates and subsequent heterocyclization reaction with a second isocyanate. The related cationic compound, 1-methyl-3-phenylcyclohepta[4,5]imidazo[1,2-a]-1,3,5-triazine-2,4(3H)-dionylium tetrafluoroborate 7a, was also prepared. The electrochemical reduction of these compounds exhibited more positive reduction potentials as compared with those of the related compounds of 3,10-disubstituted cyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1H,3H)-dione systems. In a search of the oxidizing ability, compounds 5a, 6a, and 7a were demonstrated to oxidize some amines to give the corresponding imines in more than 100% yield under aerobic and photo-irradiation conditions, while even benzylamine was not oxidized under aerobic and thermal conditions at 100 °C. The oxidation reactions by cation 7a are more efficient than that by 5a and 6a. Quenching of the fluorescence of 5a was observed, and thus, the oxidation reaction by 5a probably proceeds via electron-transfer from amine to the excited singlet state of 5a. In the case of cation 7a, the oxidation reaction is proposed to proceed via formation of an amine-adduct of 7a and subsequent photo-induced radical cleavage reaction.     

A convenient one-pot synthesis of 2-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one derivatives and their further transformations

The trifluoromethyl containing heterocycles, 2-hydroxy-4-aryl-3-(thien-2-oyl)-2-(trifluoromethyl)-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one derivatives 4, were synthesized via a one-pot three-component reaction of aldehyde 1 with 1,3-cyclohexanedione 2 and 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione 3 in the presence of a catalytic amount of Et₃N. The effect of bases and solvents on the reaction efficiency and yield was briefly investigated. Treatment of 4 with an excess amount of NH₄OAc in ethanol afforded 2-trifluoromethyl-1H-quinolin-5-one derivatives 5. Refluxing of 4 with TsOH in CHCl₃ gave the corresponding dehydrated products 8.     

Synthesis and reactions of 1-hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2-(3H)-ones

1-Hydroxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones, as a new type of azaheterocyclic hydroxamic acids, have been synthesized regioselectively from 1-carbamoylmethyl- or 1-(methoxycarbonyl)methyl-2,3,3-trimethyl-3H-indolium salts by reaction with hydroxylamine in the presence of a strong base. The alkylation and reduction with sodium borohydride of these novel heterocycles have been investigated. When treated with protic acids 1-hydroxy- or 1-alkoxy-9,9a-dihydro-1H-imidazo[1,2-a]indol-2(3H)-ones underwent ring opening of the imidazolidine to afford 1-[2-(hydroxyamino)-2-oxoethyl]-2,3,3-trimethyl-3H-indolium salts. The structural assignments are based on extensive ¹H, ¹³C and ¹⁵N NMR spectroscopic studies and single crystal X-ray analyses.     

Preparation and study of chiral boron containing amine-cyano(pyrrolyl-1)borane complexes. Preparation of (−)-(S)-α-phenylethylamine-(−)-cyano(pyrrolyl-1)borane and (+)-(R)-α-phenylethylamine-(+)-cyano(pyrrolyl-1)borane

Several amine-cyano(pyrrolyl)borane complexes [A · BH(NC₄H₄)CN] containing a chiral boron atom were prepared from the reactions of sodium cyanohydrodipyrrolylborate-tridioxane¹ [NaBH(NC₄H₄)₂CN · 3C₄H₈O₂] with amine hydrochlorides as well as by base exchange from the appropriate 4-cyanopyridine complex [4-CNC₅H₄N · BH(NC₄H₄)CN]. Amines with an sp² N atom give stable complexes of a wide range of basicity (pK_a = 0.8?9.7), in contrast to the anines with sp³ hybridized N where only the stronger bases (pK_a ? 7.3) are capable of giving stable complexes (mainly secondary and tertiary amines). These compounds undergo hydrolysis in neutral and alkaline media, while in strong acids they give stable boronium ions by protonation at the α-C atom of the pyrrolyl group. The compounds (?)-(S)-α-phenylethylamine-(?)-cyanopyrrolylborane and (+)-(R)-α-phenylethylamine-(+)-cyanopyrrolylborane have been prepared in pure form; in solution they undergo slow epimerization. Treatment of the appropriate complexes with KH has given the chiral boron-containing borates KBH(NC₄H₄)(CN)X (X = imidazolyl-, pyrazolyl-). Dicyanohydropyrrolylborane was obtained from 4-cyanopyridine-cyanopyrrolylborane and NaCN.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

Synthesis of 8,9-dihydro[1,2,4]triazolo[1,5-a]-quinazolin-6(7H)-one derivatives

Regioselectivity of the reactions of 1H-1,2,4-triazol-3-amines with 2-acyl-5,5-dimethylcyclohexane-1,3-diones and 2-dimethylaminomethylidene-5,5-dimethylcyclohexane-1,3-dione was studied. In all cases, the products were substituted 8,9-dihydro[1,2,4]triazolo[1,5-a]quinazolin-6(7H)-ones whose structure was determined by ¹H and ¹³C NMR spectroscopy.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Synthesis of 6-substituted 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones using the Vilsmeier reaction

The reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of arylalkanone Mannich bases under optimized reaction conditions leads to 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidines in a yield of 50-80%. Functionalization of these dihydropyridopyrimidine(1H,3H)-2,4-diones with the Vilsmeier reagent affords, depending on the reaction conditions, either 6-dimethylaminomethylidene substituted 5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones or the corresponding pyridopyrimidine(1H,3H)-2,4-diones bearing a carboxaldehyde function in position 6 of the heterocycle. Some further transformations of the aldehyde function demonstrate the synthetic potential of the synthesized structures, introducing pharmacologically relevant basic substituents into the side chain of these pyrido[2,3-d]pyrimidine derivatives.     

Synthesis of 4-(2-hydroxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-aryl-4,5-dihydro-1H-pyrrole-3-carboxylates, a new triazafulvalene system

(2E,3Z)-2-(1-Methyl-2,5-dioxoimidazolidin-4-ylidene)-3-[(arylamino- or heteroarylamino)methylene]succinate 5 obtained by [2+2] cycloaddition of (5Z)-5-[(dimethylamino)methylene]-3-methylimidazolidine-2,4-dione (1) and dimethyl acetylenedicarboxylate (2) followed by substitution of the dimethylamino group with aromatic or heteroaromatic amines, afforded by heating in ethanol in the presence of potassium hydroxide, potassium salts 6. Acidification of 6 with hydrochloric acid afforded mixtures of (E)- and (Z)-isomers of methyl 4-(2-hydroxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates. On the other hand, alkylation of compounds 6 with methyl iodide or benzyl bromide produced the corresponding methyl (E)-4-(2-methoxy- or 2-benzyloxy-1-methyl-5-oxo-1H-imidazol-4(5H)-ylidene)-5-oxo-1-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylates 9, derivatives of a new triazafulvalene system.     

Regioselective synthesis of 1H,3H,6H[2]benzopyrano[4,3-d]pyrimidine-2,4-diones and 12H-benzopyrano[3,2-c][1]benzopyran-5-ones by radical cyclization

5-Hydroxy uracils or 4-hydroxy[1]benzopyran-2-ones were refluxed with 2-bromobenzyl bromides in acetone in the presence of anhydrous potassium carbonate to afford a number of 5-(2′-bromobenzyloxy) pyrimidine-2,4-dione (80-92%) or 4-(2′-bromobenzyloxy) benzopyran-7-ones (70-82%) respectively. These were then refluxed with tri-n-butyltin chloride and sodium cyanoborohydride in the presence of a catalytic amount of azobisisobutyronitrile (AIBN) for 3-4 h to give 1H,3H,6H [2]benzopyrano[4,3-d]pyrimidine-2,4-diones (75-85%) or 12H-benzopyrano[3,2-c][1]benzopyran-5-ones (70-85%) respectively.     

Stereochemistry of the thermal isomerizations of (2S,3R-methoxymethyl-2,3-dideuterio-1-(dideuteriomethylene)cyclopropane

The (2S,3R) isomer of 2-methoxymethyl-2,3-dideuterio-1-(dideuteriomethylene)cyclopropane has been synthesized and heated at 198.8°: from the experimentally observed mol fractions of the eight isomers of 2,3,α,α,- and 2,3,3,α - tetradeuterio - 2 - methoxymethyl - 1 - methylenecyclopropane in the pyrolysis product mixture have been derived rate constants for seven distinct modes of isomerization. One-center thermal epimerizations at C(2) and C(3) and the C(2)C(3) two-center epimerization are of kinetic importance. Only two of four observable stereochemical modes for carbon [1,3] shifts are seen: there is inversion of stereochemistry at the migrating C atom, while the C(3)H trans to C(2)-CH₂OCH₃ in starting material becomes syn 4 : 1 C(α)-H in the [1,3] shift product. Stereomutation at C(2) does not occur along the reaction coordinate for [1,3] carbon shifts.     

Temperature dependent selective synthesis of linear 2-bromo and 2-alkoxyfuro[2,3-b]quinolines: reaction of 3-(2,2-dibromovinyl-)quinolin-2(1H)-ones with alcoholic KOH

Base promoted and temperature dependent reactions of 3-(2,2-dibromovinyl)quinolin-2(1H)-ones have been described. At 50 °C, the cyclization reactions afforded 2-bromofuro[2,3-b]quinolines in good yields. However, at elevated temperature (80 °C) the domino reaction proceeded affording 2-alkoxyfuro[2,3-b]quinolines via cyclization and nucleophilic substitution reactions.     

Formation of the same pyrimido[1,2-a]indoles from 1-(oxiran-2-ylmethyl)-1H-indole or [1,3]oxazolo[3,2-a]indole derivatives in its reactions with aromatic amines

Reactions of two isomers—2-chloro-1-(oxiran-2-ylmethyl)-1H-indole-3-carbaldehyde or 2-(chloromethyl)-2,3-dihydro[1,3]oxazolo[3,2-a]indole-9-carbaldehyde with aromatic amines lead to the same products in both cases—hydrochlorides of pyrimido[1,2-a]indole derivatives containing two fragments of an amine per one part of the indole nucleus. Its structure was confirmed by X-ray analysis of the crystals base, obtained by alkali treatment of the reaction product (when aryl is 4-MeOC₆H₄).     

A one-pot synthesis and 1,3-dipolar cycloaddition of [1,2]dithiolo[4,3-b]indole-3(4H)-thiones

Treatment of N-substituted 2-methyl-1H-indoles 1 with S₂Cl₂ and DABCO in chloroform gave the corresponding [1,2]dithiolo[4,3-b]indole-3(4H)-thiones 5 by the addition of triethylamine in high yield. 1,2-Dithiole-3-thiones 5 underwent cycloaddition with one or two DMAD equivalents to afford either 2-(3-thioxo-1,3-dihydro-2H-indol-2-ylidene)-1,3-dithioles 10 or fused 4,5-dihydrothiopyrano[3,2-b]indoles 9.     

A novel,chemoselective one-pot procedure for the preparation of 3H-spiro[isobenzofuran-1,2′-pyrrole]-3,3′(1′H)-dione derivatives via oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles

A one-pot, efficient and chemoselective procedure for the synthesis of new 3H-spiro[isobenzofuran-1,2′-pyrrole]-3,3′(1′H)-dione derivatives has been developed which involves room temperature oxidative cleavage of 3a,8b-dihydroxyindeno[1,2-b]pyrroles themselves synthesized from the reaction of ninhydrin and enaminones in 30% ethanol. A reasonable mechanism is proposed for the oxidation reaction based on the results of this study and our previous related work.