Synthesis and Cytotoxicity of 9‐Substituted Benzo[de]chromene‐7,8‐dione and 5‐Benzyl‐9‐substituted Benzo[de]chromene‐7,8‐dione

New Mansonone analogues of 9‐substitued benzo[de]chromene‐7,8‐dione 5b–e and 5‐benzyl‐9‐substitued benzo[de]chromene‐7,8‐dione 6a–e were prepared through a modified route. The first step involved a bulky base t‐butylamine mediated regioselective deacetylation of 2‐substituted‐1,4‐naphth‐diyl diacetate, resulting in obtaining of monoacetate 4‐acetate 2 in high yield. The mechanism of cyclization, debenzylation, and oxidation for the formation of 5a–e and 6a–e were discussed. The cytotoxicity of the prepared compounds 5 and 6 were comparable with naturally occurring Mansonone F.     

Production of enantiopure chiral aryl heteroaryl carbinols using whole‐cell Lactobacillus paracasei biotransformation

Abstract

Aryl and heteroaryl chiral carbinols are useful precursors in the synthesis of drugs. Lactobacillus paracasei BD87E6, which is obtained from a cereal based fermented beverage, was investigated as whole cell biocatalyst for the bioreduction of different ketones (including aromatic, hetero-aromatic and fused bicyclic ketone) into chiral carbinols, which can be used as a pharmaceutical intermediate. The study shows that bioreduction of aryl, heteroaryl and fused bicyclic ketone (1-5) to their corresponding chiral carbinols (1a-5a) in excellent enantioselectivity (>99%) with high yields. This study gave the first example for an enantiopure production of (S)-6-chlorochroman-4-ol (3a), which has many antioxidant activity, by a biological method. For asymmetric bioreduction of other prochiral ketones, these results open way to use of L. paracasei BD87E6 as biocatalysts. Also, the present process shows a hopeful and alternative green synthesis for the production of enantiopure carbinols in a mild, inexpensive and environmentally friendly process.     

Synthesis of Functionalized Pyrano[3,2‐c]pyridines and Their Transformations to 4‐Hydroxy‐3[(1E)‐N‐hydroxyalkanimidoyl]pyridones

Reaction of 4‐hydroxy‐6‐methyl‐2(1H)‐pyridones 1a and 4‐hydroxy‐1,6‐dimethyl‐2(1H)‐pyridones 1b with diethyl malonates 2a–e leads to the formation of pyrano[3,2‐c]pyridines 4a–j. Degradation of 4a–i affords the corresponding ketones 6a–i. Condensation of ketones 6a–i with hydroxyl amine or phenyl hydrazine hydrochloride is described.     

Synthesis of 1,4‐Diaryl‐piperazine‐2,5‐diones: New Behavior of N,N‐Dimethylformamide Dimethyl Acetal (DMFDMA)

Reactions of chloroacetamides (5) with N,N‐dimethylformamide dimethyl acetal gave 1,4‐diaryl‐piperazine‐2,5‐diones 11a–e in good yield, rather than 1,5‐diaryl‐3,7‐dimethoxy‐1H,5H‐[1,5]diazocine‐2,6‐diones (9a–e).     

Bicyclic N-heterocyclic carbene (NHC) ligand precursors and their palladium complexes

Eight bicyclic amidinium precursors (3), prepared from R,S-tmcp (R,S-tmcp: (1R,3S)-diamino-1,2,2-trimethylcyclopentane) were described. Only five of the precursors (3a–e) could be converted to palladium complexes, (PdX₂(6,7-NHC)PEPPSI) (4) by treatment with PdCl₂, K₂CO₃, and pyridine (additional KBr was used for (PdBr₂(6,7-NHC)PEPPSI)). The salts and complexes were fully characterized by spectroscopic methods and X-ray crystallography.     

Synthesis of 2,3‐Dihydro‐4H‐furo[3,2‐c] chromen‐4‐ones and 2,3‐Dihydronaphtho[2,3‐b]furan‐4,9‐diones by the Radical Cyclizations of Hydroxyenones with Electron-Rich Alkenes using Manganese(III) Acetate

We have obtained dihydrofurans 3a–j in the radical cyclization of 4‐hydroxycoumarin 1a and 2‐hydroxy‐1,4‐naphtoquinone 1b with electron rich alkenes 2a–i by manganese(III) acetate. Methods A and B, which have different molar ratios were studied comparatively in these reactions, and we observed that method B (molar ratio 2:1:3) gave the best results. Treatment of 4‐hydroxycoumarin 1a and electron rich alkenes 2a–e gave 2,3‐dihydro‐4H‐furo[3,2‐c]chromen‐4‐ones 3a–e in 36–86% yields by the method B. Under the same conditions, the reactions of 2‐hydroxy‐1,4‐naphtaquinone 1b with conjugated alkenes 2b and 2f–i afforded 2,3‐dihydronaphtho[2,3‐b]furan‐4,9‐diones 3f–j in an excellent yields.     

Synthesis of Novel 2‐Vinylcyclopropane Phosphonic Acids

2‐Vinylcyclopropane‐1‐phosphonic acid diesters 1a–d were synthesized by the reaction of trans‐1,4‐dibromo‐2‐butene with α‐substituted phosphonic acid diesters. Esterification of 1‐ethoxycarbonyl‐2‐vinylcyclopropane‐1‐carboxylic acid with dimethyl 2‐hydroxyethyl‐phosphonate gave the 2‐vinylcyclopropane phosphonic acid dimethylester 1e. The silylation of phosphonic acid diesters 1a–e by halotrimethylsilanes followed by solvolysis with methanol or water resulted in the formation of phosphonic acids 2a–e. In the case of steric hinderance of the phosphoryl group, monoesters 3c,d were also formed. Furthermore, ethyl carboxylate 1b could be chemoselectively cleaved by aqueous potassium hydroxide to carboxylic acid 4.     

Synthesis of H‐Phosphinates by the UV Light–Mediated Fragmentation‐Related Phosphorylation Using Simple P‐Heterocycles

Photolysis of aryl‐substituted 2,5‐dihydrophosphole oxides (5a–e and 8) in the presence of methanol afforded methyl aryl‐H‐phosphinates (2a–e) in good yields. In the case of 1‐ethyl‐, cyclohexyl‐, or ethoxy‐2,5‐dihydrophosphole oxides, the reaction was much slower (5f and 5h) or did not take place at all (5g). In such instances, the presence of an additional skeletal methyl group (7) or the use of the more strained 7‐phosphanorbornene derivatives (6) promoted the fragmentation‐related phosphorylations. Furthermore, the effect of the ring saturation in 8 and the possible extensions to 2‐phosphabicyclo[3.1.0]hexanes (10a and 10f), a 1,2‐dihydrophosphinine oxide (11), and a 1,2,3,4,5,6‐hexahydrophosphinine oxide (12) were also investigated. Model compounds with P‐phenyl substituent that are of sufficient ring strain (8, 10a, and 11) could be utilized well.     

Synthesis of New Benzoxazaphosphinine/Benzoxazaphosphole/Diazaphosphaphenalene‐2‐sulfides using Lawesson's Reagent

Synthesis of new benzoxazaphosphinine/benzoxazaphosphole/diazaphosphaphenalene 2‐sulfides were accomplished by the reaction of Lawesson's reagent (LR) with 4‐bromo‐2‐[(phenylamino) methyl]phenol (1a), 4‐bromo‐2‐[(4‐chloro/bromo/methoxy/methylphenyl‐amino)methyl]phenol (1b–e), 4‐bromo‐2‐[(benzylamino)methyl]phenol (1f), 2‐amino‐4‐chlorophenol (2a)/2‐amino‐4‐methylphenol (2b), 1,8‐diaminonaphthalene (3) respectively in anhydrous toluene. Products 4a–f, 5a–b and 6 were characterized by IR, ¹H, ¹³C, ³¹P NMR and Mass spectra.     

Synthesis of ent‐Ketorfanol via a C–H Alkenylation/Torquoselective 6π Electrocyclization Cascade

The asymmetric synthesis of ent‐ketorfanol from simple and commercially available precursors is reported. A Rh^I‐catalyzed intramolecular C? H alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2‐dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox‐neutral acid‐catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel–Crafts alkylation.     

Synthesis of 4‐(Indol‐1‐yl)butanals via Rhodium‐Catalyzed Hydroformylation of 1‐Allylindoles

The rhodium‐catalyzed hydroformylation of new 1‐(β‐methallyl) indoles 1a–e carried out with Rh₄ (CO)₁₂ as the catalyst precursor, at 100 atm total pressure and 100°C, produces the 4-(indol‐1‐yl)‐3‐methylbutanals 2a–e as the sole products in high yields. The synthesized 4‐indolylbutanals are stable under the adopted conditions and are isolated and characterized here for the first time. The preparation of the starting 1‐allylindoles is described too.     

Synthesis and Enzyme Inhibitory Activities of Highly Functionalized Pyridylmethyl-C-β-D-Glycosides

Several pyridylmethyl-C-β-D-glycosides (3a–3l, 6a, and 6h) were synthesized by refluxing 3-(β-D-glucopyranosyl)/(β-D-cellobiosyl)-propanones and dicyanobenzylidenes with ammonium acetate in anhydrous toluene in moderate to good yields. The reaction involves a C?C Michael addition of enamine, formed from glycosyl ketone and ammonium acetate, to the dicayanobenzylidene derivative; subsequent dehydrative cyclization; and oxidative aromatization. Two of these prototypes, compounds 3e and 3k, were deacetylated to the respective glucopyranosyl methyl pyridines 4e and 4k with NaOMe/MeOH. The synthesized compounds were screened for their in vitro α-glucosidase inhibitory activities and one of the compounds showed 20% inhibition as compared to standard drug acarbose displaying 39% inhibition.     

Stereoselective formation and rearrangement of morpholinium ylides derived from copper carbenoids

Amino diazoacetoacetates 4a–e and 7a,b were prepared from readily available amino alcohols and subjected to copper-catalyzed carbene-transfer reaction. Substrates 4c–e furnished the morpholin-2-ones 5c–e in good yield via the corresponding cyclic ammonium ylides, albeit with poor diastereoselectivity. Substrates 4a,b failed to provide the corresponding morpholinones, perhaps as a result of steric congestion. Cyclic substrates 7a,b underwent conversion to bicyclic morpholinones 8 and 9 in good yield and with moderate to good diastereoselectivity. This result is rationalized via control of the transiently stereogenic ammonium center of the intermediate bicyclic ylides.     

Efficient One‐Pot Synthesis of Hydroxyflavanones by Cyclization and O‐Demethylation of Methoxychalcones

An efficient one‐pot method for the synthesis of hydroxyflavanones is described. Methoxychalcones are treated with 36% HBr to afford cyclization and regioselective O‐demethylation products (2a–i) while cyclization and complete O‐demethylation products (3a–e) are obtained in the presence of 45% HI.     

Free Radical Cyclization of 1,3‐Dicarbonyl Compounds Mediated by Manganese(III) Acetate with Alkynes and Synthesis of Tetrahydrobenzofurans,Naphthalene, and Trifluoroacetyl Substituted Aromatic Compounds

Furan derivatives were obtained from radical cyclizations of 1,3‐dicarbonyl compounds mediated by Mn(OAc)₃ with phenyl acetylene 2a (14–66% yields). Naphthalene derivates 4a and 4b were produced in the treatments with 2a. In addition to these, trifluoroacetyl substituted naphthalene 4c, benzofuran 4d, and benzothien 4e were obtained in the reactions of trifluoromethyl‐1,3‐dicarbonyls (1 g–i) with 2a.     

Synthesis of α,ω‐Bis(oxazolidinone)polyoxyethylene via a Lithium Bromide–Catalyzed Reaction of Oligoethylene Glycol Diglycidyl Ethers with Isocyanates

The synthesis of bis(oxazolidinone)polyoxyethylene derivatives 2a–h from oligoethylene glycols diglycidyl ethers 1a–e and isocyanates is reported. The reaction was achieved by lithium bromide and tributylphosphine oxide. These bis‐oxazolidinones may have important antibacterial activity.     

Enantioselective Synthesis of a Polyfunctionalized Tetracycle Related to Pentacyclic Triterpenes by Using an Anionic Cycloaddition Reaction

Herein we report a convergent enantioselective synthesis of a polyfunctionalized ABCD tetracycle by using an anionic cycloaddition reaction between a chiral bicyclic CD Nazarov intermediate (see 6 ), derived from the (?)‐Weiland–Mischer ketone, and an achiral cyclohexenone (see 5 ) adequately functionalized to furnish the ring A of pentacyclic triterpenes (Scheme 5). The chiral bicyclic CD Nazarov intermediate forms ring B upon cycloaddition with the achiral cyclohexenone to yield an ABCD tetracycle with a cis‐anti‐trans‐anti‐trans configuration (see 4 ). Further transformations on this adduct allowed reduction of the angular aldehyde function at C(10) to a Me group (→ 17 ) and introduction of an unsaturation at C(5)? C(6) by using the ketone function at C(7) (→ 3 ; Scheme 6).     

Synthesis and liquid crystal properties of a new class of calamitic mesogens based on substituted 2,5‐diaryl‐1,3,4‐thiadiazole derivatives with wide mesomorphic temperature ranges

Liquid crystals based on substituted 2,5‐diaryl‐1,3,4‐thiadiazole derivatives (1a–1f, 3a and 3b) and 1,3,4‐oxadiazole analogues (2a–2f, 4a and 4b) were synthesised and characterised by ¹H, ¹³C nuclear magnetic resonance, Fourier transform infrared, mass spectrometry, high‐resolution mass spectrometry techniques and elemental analyses. The X‐ray crystal structure of 1e revealed that it contains tilted lamellar arrangement of molecules in the crystalline solid. The liquid crystal properties have been investigated by polarised‐light optical microscopy, differential scanning calorimetry and in‐situ variable‐temperature X‐ray diffraction. All compounds (except 2e and 2f) exhibited thermotropic liquid crystal behaviours with various mesophases (smectic A and C, nematic N or soft crystal E phases). Notably, the 1,3,4‐thiadiazole derivatives consistently have wider mesomorphic temperature ranges than those of the respective 1,3,4‐oxadiazole analogues. The solutions of all compounds in CH₂Cl₂ individually displayed one or two absorption bands with λ _max values at 297–355 nm and emitted with λ _max values at 363–545 nm and quantum yields of 0.12–0.73. Structure–property relationships of these compounds are discussed in the contexts of their molecular structures and weak intermolecular interactions.     

Synthesis of Piperidine Derivatives by Reduction of Pyridinium Salts

Piperidine derivatives 1a–e and 2a–f have been prepared by the reduction of 3‐and 4‐substituted pyridinium salts with NaBH₄ in moderate to excellent yields. The reactions regioselectively give 1,2,5,6‐tetrahydropyridines, and the yields depend greatly upon the nature of substituents on the phenyl ring and on the nitrogen atom, the nature and the position of the substituents on the pyridyl ring, and the chain length between the aryloxy and the pyridyl groups.     

Efficient Synthesis of Substituted 2‐Amino‐3‐carbethoxythiophenes

A microwave‐assisted method for the synthesis of a variety of thiophene o‐aminoesters (2a–l) has been developed, starting from an appropriate aldehyde, methyl ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur.