The acid-mediated intramolecular 1,3-dipolar cycloaddition of derived 2-nitro-1,1-ethenediamines for the synthesis of novel fused bicyclic isoxazoles

The discovery of a novel synthesis of new fused bicyclic isoxazoles, for example, N-methyl-3-phenyl-5,6-dihydro-4H-isoxazolo[3,4-c]azepin-8-amine (2a), N-methyl-3-phenyl-4,5-dihydroisoxazolo[3,4-c]pyridin-7-amine (2b) and N-methyl-3-phenyl-4H-pyrrolo[3,4-c]isoxazol-6-amine (2d) in high yield is reported. We speculate that the reaction proceeds via acid-mediated intramolecular 1,3-dipolar cycloaddition from 2-nitro-1,1-ethenediamines 1a,b,d.     

Regioselectivity in the 1,3-dipolar cycloaddition of adamantylidenefulvene and its modification by inclusion in cyclodextrins' solutions

The 1,3-dipolar cycloaddition of adamantylidenefulvene (1) with 2 equiv of nitrile oxides 2a-d gave 1/1 cycloadducts, 3a-d and 4a-d, as the major products, and four other 1/2 minor cycloadducts 5-8a,b. The ratios of 1/1 cycloadducts 3a-d to 4a-d in THF solution were about 1/1 in the four different nitrile oxides 2a-d studied and microwave was found to accelerate the reactions and enhance their yields. It is noteworthy that the regioselectivity of 3a/4a was enhanced to 71/29 in β-cyclodextrin (β-CD) aqueous solution compared to that of 40/60 in the absence of β-CD. The regioselectivity of 3b/4b was further enhanced to 99/1 when 4-tert-butylphenyl hydroximinoyl chloride (9b) was complexed with β-CD and then proceeded to react with 1; this is in sharp contrast with that of 33/67 in the absence of β-CD. The binding constant of 1·β-CD in acetone-d₆/D₂O (1/1) was determined to be 188±9 M⁻¹ by ¹H NMR titration experiments. The binding mode of 1·β-CD was further determined by ROESY experiment. Furthermore, molecular dynamic simulations were carried out to provide information of the complexation modes of 1·β-CD, 3a·β-CD, 4a·β-CD, 9a·β-CD, and 9b·β-CD. It was found that both steric and electrostatic effects play important roles in determining the regio- and stereochemistry of 1,3-dipolar cycloaddition of 1. Finally, β-CD is shown to serve as a chiral shift reagent to differentiate the enantiomers of 4a in ¹H NMR.     

Reaction of (1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile with N-arylisoindolines

In a multistep reaction, 3,3′-(2-aryl-2H-isoindol-1,3-ylene)-di-(1,4-naphthoquinone-2-carbonitriles) 13a-f have been formed in 25-61% yield from a series of N-arylisoindolines 8a-f with (1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile (1) in aerated pyridine. The structure of one of these products (13f) has been unambiguously confirmed by a single crystal X-ray structure analysis. Under otherwise the same conditions, 2-(3-methoxyphenyl)-isoindoline (8g) and 1 gave 38% of [4-(2,3-dihydro-1H-isoindol-2-yl)-2-methoxyphenyl]-1,3-dioxoindan-2-ylidene)acetonitrile (15). Rationales for these conversions involving the known rearrangement of the radical anion of 1 into the radical anion of 1,4-naphthoquinone-2,3-dicarbonitrile (3) are presented.     

Substituted coumarin amidines: useful building blocks for the preparation of [1]benzopyrano[4,3-b]pyridin-5-one and [1]benzopyrano[4,3-d]pyrimidin-5-one derivatives

The synthesis of [1]benzopyrano[4,3-b]pyridin-5-ones 4a-f and 4g-j starting from 3-formylcoumarin and 3-cyanocoumarin N-functionalized amidines 3a-f and 3g-j, respectively, was reported. The ring-closure reaction mechanism, under basic or acidic media, was proposed. Furthermore, the reaction of 3-formylamidines 3a,c-f with ammonium acetate gave good yields of 2-substituted [1]benzopyrano[4,3-d]pyrimidin-5-ones 7.     

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.     

Regio- and stereospecific [3+2] cycloaddition of an unusual nitrone derived from a N-hydroxy-2-pyridone with medium ring enones

Regio- and stereospecific 1,3-dipolar cycloaddition of the nitrone derived from a N-hydroxy-2-pyridone 6 with Z-2-cyclodecenone 7a was accomplished, thus substantiating a possible biomimetic route to pyridomacrolidin 2 from pyridovericin 1 and cephalosporolide B 5. This reaction was further exemplified with different enones (7a-g) similar to cephalosporolide B 5. In all the cases the cycloaddition occurred with high regiochemical control and with high retention of alkene geometry. Both endo and exo modes of cycloaddition were observed. This process can also be extended to aryl conjugated enones as long as no enolisable hydrogens are present.     

Investigations on synthesis of indole based constrained mimetic scaffolds through 1,3-dipolar cycloadditions of the C-(3-indolyl)-N-phenylnitrone with a variety of olefinic and allenic dipolarophiles under microwave irradiation

Monomode microwave assisted regio- and stereo-selective 1,3-dipolar cycloadditions of C-(3-indolyl)-N-phenylnitrone (19) with a number of olefinic dipolarophiles (20a-f) afford isoxazolidines (21-26) in high yields, which are conformationally constrained mimetics of indole-3-propionic acid of biological significance. Similar cycloadducts derived from addition of nitrone (19) to allenic esters (27a-c) undergo domino reorganization to afford potentially biologically active bis-indole derivatives (28, 29). The observed regio- and stereo-selectivities are analysed, inter alia, in terms of HOMO-dipole-LUMO-dipolarophile and involved secondary orbital/steric interactions in the transition states intervening these cycloadditions.     

Synthesis of new condensed nitrogen heterocyclic systems

A cotarnine alkaloid-based synthesis was developed for new heptacyclic condensed diisoquinolines via the double intramolecular pseudosalt bis[1,3]dioxolo[4,5-g;4′,5′-g′][1,3,4]oxadiazolo[2,3-a;5,4-a′]diisoquinoline 6. Substitution of the central O atom in 6 by C, S, or N nucleophiles afforded the first representatives of the new ring systems bis[1,3]dioxolo[4,5-g:4,5-g′]pyrazolo[3,2-a:5,1-a′]diisoquinoline (7a-d), bis[1,3]dioxolo[4,5-g:4,5-g′][1,3,4]thiadiazolo[2,3-a:5,4-a′]diisoquinoline (8), and bis[1,3]dioxolo[4,5-g:4,5-g′][1,2,4]triazolo[3,2-a:5,1-a′]diisoquinoline (9a-d) under simple reaction conditions.     

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.     

Efficient access to chiral N-substituted saccharin analogues via the directed ortho-lithiation of 3-N-arylsulfonyloxazolidin-2-ones

Chiral 3-N-arylsulfonyloxazolidin-2-ones 1a-f, prepared from (l)-amino acids, were reacted with lithium diisopropylamide in anhydrous THF and HMPA. The resulting new, optically active benzisothiazolinone 1,1-dioxides 2a-c and naphthisothiazolinone 1,1-dioxides 2d-f were obtained in good yields.     

Synthetic application of fluorinated vinamidinium salts: Synthesis of fluorinated 1,3-butadienylphosphonates by the reaction with Horner-Wadsworth-Emmons reagents

The reaction of β-fluoro vinamidinium salt 1 with Horner-Wadsworth-Emmons reagents (HWE) such as diethyl(ethoxycarbonyl)methylphosphonate (2a), diethyl(methoxycarbonyl)methylphosphonate (2b), diethyl-2-oxopropylphosphonate (2c), diethyl benzylphosphonate (2d), tetraethyl methylenediphosphonate (2e) and diethyl cyanomethylphosphonate (2f) under basic conditions gave the fluorinated 1,3-butadienylphosphonates 3 in moderate to good yields. The phosphonates 3 could be hydrolyzed with a 10% HCl aqueous solution to afford the corresponding γ-(diethylphosphono)-α-fluoro-α,β-unsaturated aldehydes 7 in good yields. The treatment of the phosphonate 3c with an NH₃ aqueous solution at 70 °C produced the pyridine derivative 8 in 60% yield.     

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.     

A one-pot synthesis of an annelated [a]aza-thieno[3,2-g]naphthalenone through ring transformation followed by photocyclization

A concise synthesis of 4-aryl-10-oxo-1,2,3,10-tetrahydro-9-thia-1,3a-diazadicyclopenta[a,g]naphthalene-6-carbonitriles 5a-f and 5-aryl-11-oxo-1,3,4,11-tetrahydro-2H-10-thia-1,4a-diaza-cyclopenta[b]phenanthrene-7-carbonitriles 5g-i has been delineated through ring transformations of the 2H-pyran-2-one 1, followed by photocyclization of product 4.     

Synthesis of 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles and 4-aryl-3-cyano-5,5-dimethyl Δ-pyrazolines by cycloaddition of 2-diazopropane with iminoethers and propenenitriles

A regiospecific 1,3-dipolar cycloaddition of 2-diazopropane 3 to iminoethers 1a-c, carried out at 0 °C, afforded in two steps the corresponding 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles 5a-c. Under the same conditions, 3-arylpropenenitriles 2a-d led to 3-cyano-5,5-dimethyl Δ¹-pyrazolines 6a-d. Products 4-6 were obtained in good yields (69-85%).     

Phosphorus-nitrogen compounds part 22. Syntheses, structural investigations, biological activities and DNA interactions of new mono and bis (4-fluorobenzyl) spirocyclophosphazenes

The reactions of hexachlorocyclotriphosphazene, N₃P₃Cl₆, with mono (1 and 2) and bis(4-fluorobenzyl) diamines (3-5), FPhCH₂NH(CH₂)_nNHR (RH or FPhCH₂-), produce mono (1a and 2a) and bis(4-fluorobenzyl) monospirocyclophosphazenes (3a-5a). The tetraaminomonospirocyclophosphazenes (1b-2d) are obtained from the reactions of the partly substituted phosphazenes (1a and 2a) with excess pyrrolidine, morpholine and 1,4-dioxa-8-azaspiro[4,5]decane (DASD), respectively. The tetrachlorobis(4-fluorobenzyl) monospirocyclophosphazenes (4a and 5a) with excess pyrrolidine, morpholine and DASD afford the fully substituted bis(4-fluorobenzyl) monospirocyclophosphazenes (4b, 4d-5d) in boiling THF. In addition, monochlorobis(4-fluorobenzyl) monospirocyclophosphazenes (4e and 4f) have also been isolated from the reactions with excess morpholine and DASD in boiling THF. The structural investigations of the compounds have been verified by elemental analyses, MS, FTIR, ¹H, ¹³C, ¹⁹F (for 1d and 2d), ³¹P NMR, HSQC and HMBC techniques. The crystal structures of 3a, 4a, 5a and 2b have been determined by X-ray crystallography. The compounds 2a-5a, 1b-2d, 4b, 4d-5d, 4e and 4f have been screened for antibacterial effects on bacteria and for antifungal activity against yeast strains. The compounds 1b and 4b showed antimicrobial activity against three species of bacteria, Bacillus subtilis, Bacillus cereus and Staphylococcus aureus, and two fungi, Candida albicans and Candida tropicalis. Minimum inhibitory concentrations (MIC) were determined for 1b and 4b. The MIC values were found to be 5000 μM for each bacteria. The most effective compound, 4b has exhibited activity with a MIC of 312 μM for C. albicans and 625 μM for C. tropicalis. DNA-binding and the nature of the interaction with pBR322 plasmid DNA are studied. All of the compounds induce changes on the DNA mobility and intensity. Prevention of HindIII digestion with the compounds indicates that the compounds bind with AT nucleotides in DNA.     

Effect of chain length on the formation of intramolecular and intermolecular products: Reaction of diols with cyclotriphosphazene

The reactions of cyclotriphosphazene, N₃P₃Cl₆ (1), in a 1:1.2 stoichiometry with the sodium derivative of seven diols [ethane- (2a), 1,3-propane- (2b), 1,4-butane- (2c), 1,5-pentane- (2d), 1,6-hexane- (2e), 1,8-octane- (2f) and 1,10-decane- (2g) diol] in THF solution at room temperature have been used to investigate the effect of chain length on the formation of reaction products. Although no new products were found for the reaction of 1 with diols 2a-c compared to those in the literature using other bases and solution conditions, the reactions of 1 with the diols 2d-g gave six different types of products, whose structures have been characterized by elemental analysis, mass spectrometry, ¹H and ³¹P NMR spectroscopy; ansa compounds N₃P₃Cl₄[O(CH₂)_nO], (5d-5g); single-bridged compounds N₃P₃Cl₅[O(CH₂)_nO]N₃P₃Cl₅(6d-6f); double-bridged compounds N₃P₃Cl₄[O(CH₂)_nO]₂N₃P₃Cl₄ (7d-7g, syn and anti) and triple-bridged compounds, N₃P₃Cl₃[O(CH₂)_nO]₃N₃P₃Cl₃ (8d-f). Where suitable single crystals were obtained, X-ray crystallographic studies confirmed the structures of two ansa compounds (5d and 5f), one single-bridged compound (6e), and five double-bridged compounds (meso-anti for 7d, 7e, 7f and meso-syn for 7d and 7f). ³¹P NMR measurements of the reaction mixtures were used to quantify the formation of products for the reactions 1 with all the diols, 2a-g; it is found that, with increasing chain length of the diol, there is a decrease in the products formed by intramolecular reactions (spiro and ansa derivatives) and a concomitant increase in the amounts of products formed by intermolecular reactions (single-, double- and triple-bridged derivatives) of cyclophosphazene.     

Stereoselective synthesis of 2-methylenepyrrolizidines by tandem cyclization of N-propargylaminyl radicals

Tandem cyclization of N-propargylaminyl radicals, generated by N-chlorination of (E)-alk-4-enylamines 2a-d and 2f followed by treatment with tributyltin radical, afforded 2-methylenepyrrolizidines 3a-d and 3f in a highly stereoselective manner. A similar radical cyclization of (Z)-N-propargyl-1-methyl-5-phenylpent-4-enylamine (2e) gave pyrrolizidine 3b having the same stereochemistry as that obtained from the E isomer 2b.     

Synthesis of monofluorinated indolizines and their derivatives by the 1,3-dipolar reaction of N-ylides with fluorinated vinyl tosylates

Monofluorinated indolizines 4, benzo[d]indolizines 7 and 4H-pyrrolo[1,2-a]benzimidazoles 8 were synthesized in moderate yields by 1,3-dipolar reaction between fluorinated vinyl tosylates 2a and N-ylides of pyridinium, isoquinolinium and benzimidazolinium, generated in situ from their halides salts. When the same N-ylides were allowed to react with 2,3,3-trifluoro-1-propenyl tosylate 2b, the unexpected product formylated indolizines and their derivatives 9 were obtained. The reaction mechanism is also proposed.     

Regioselective synthesis of 1- and 4-substituted 7-oxopyrazolo[1,5-a]pyrimidine-3-carboxamides

The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl₃ gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a–h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a–f furnished the 1-alkyl derivatives 17a–f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a–d and 16m,n, selectively.     

Alternative synthesis and novel oxidizing ability of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-dione derivatives

Synthesis of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-diones 7a-g was accomplished by ring opening and ring closure sequences of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives induced by several amines. Furthermore, alternative synthetic methodology for compounds 7a-e was also accomplished by single-step reaction of 2-chlorotropone with 6-aminouracil derivatives under mild conditions. X-ray crystal analysis of 7a was carried out to clarify the structural characteristics. The properties of 7a-e were studied by the UV-vis spectra and reduction potentials (−1.24 to −1.39 V vs Ag/AgNO₃). Novel photo-induced oxidation reaction of 7a-d toward some amines under aerobic conditions was carried out to give the corresponding imines in more than 100% yield [based on compounds 7a-d], suggesting the oxidation reaction occurs in an autorecycling process.