(±)‐2‐Aryl‐2,3‐dihydro‐4(1H)‐quinolinones by a tandem reduction–Michael addition reaction

An efficient synthesis of (±)‐2‐aryl‐2,3‐dihydro‐4(1H)‐quinolinones has been developed from chalcones prepared from 2′‐nitroacetophenone and a series of substituted benzaldehydes. The cyclization sequence is initiated by reduction of the nitro group under dissolving metal conditions using iron powder in concentrated hydrochloric acid. Milder conditions, using acetic acid or acetic acid–phosphoric acid as the reaction medium, were less satisfactory. Procedural details as well as a mechanistic discussion and reaction optimization studies are presented. J. Heterocyclic Chem., (2011).     

Steric and Electronic Requirements in the Synthesis of 2,3‐Dihydro‐4(1H)‐quinolinones by the Tandem Michael‐SNAr Reaction

The steric and electronic requirements have been investigated for the synthesis of 2,3‐dihydro‐4(1H)‐quinolinones by the tandem Michael‐S_NAr reaction. Substrates bearing a single methyl group at the β‐enone carbon gave excellent yields of the title compounds from both the E and Z isomers with X═H or NO₂. Substrates with β,β‐dimethyl substitution at the Michael terminus gave low yields of heterocyclic products in molecules having monoactivated S_NAr aromatic acceptor rings (X═H) and very good yields for diactivated systems (X═NO₂). For these hindered substrates, success in the final cyclization hinges on the ability of the aromatic acceptor to capture the pendant nitrogen nucleophile of the initial Michael adduct before this intermediate can revert to starting materials.     

4H‐1‐Benzopyrans by a tandem SN2‐SNAr reaction

Treatment of 2‐fluoro‐5‐nitrobenzyl bromide with active methylene compounds in the presence of excess potassium carbonate in acetone leads to the formation of highly functionalized 4H‐1‐benzopyrans by a tandem S_N2‐S_NAr reaction sequence. The reaction works well with β‐keto esters, β‐keto sulfones, β‐keto phosphine oxides, β‐keto phosphonates and β‐keto nitriles. The reaction is simple to perform and affords products in 50‐92% yields.     

Ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylates by a tandem addition‐elimination‐SNAr reaction

The ethyl 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2‐(2‐fluorobenzoyl)acetate. Treatment of this β‐ketoester with N,N‐dimethylformamide dimethyl acetal gives a 97% yield of the 2‐dimethylaminomethylene derivative. Reaction of this β‐enaminone with primary amines in N,N‐dimethylformamide at 140°C for 48 h then affords the 1,4‐dihydro‐4‐oxo‐3‐quinolinecarboxylate esters in 60–74% yields by a tandem addition‐elimination‐S_NAr reaction. The synthesis of the starting material as well as procedural details and a mechanistic scenario are presented. J. Heterocyclic Chem., (2011).     

Synthesis of 2,3‐dihydro‐1,3‐thiazin‐4(1H)‐ ones and their remarkably facile recyclization to 2,3‐dihydropyrimidin‐4(1H)‐ones

Functionalized 2,3‐dihydro‐1,3‐thiazin‐4(1H)‐one derivatives have been synthesized by cyclocondensation of 3‐alkyl(aryl)amino‐2‐cyano‐3‐mercaptoacrylamides with aldehydes and ketones under acidic catalysis. 6‐Alkyl(aryl)amino‐5‐cyano‐2,3‐dihy‐ dro‐1,3‐thiazin‐4(1H)‐ones, when treated with a dilute solution of potassium hydroxide, are converted into the potassium salts of isomeric compounds, 1‐alkyl‐ (aryl)‐5‐cyano‐6‐mercapto‐2,3‐dihydropyrimidin‐ 4(1H)‐ones. Alkylation of the latter with dimethyl sulfate in situ furnishes 1‐alkyl(aryl)‐6‐alkylthio‐5‐ cyano‐2,3‐dihydropyrimidin‐4(1H)‐ones, whereas boiling them in ethanol with an excess of hydrochloric acid leads to starting 2,3‐dihydro‐1,3‐thiazin‐4(1H)‐ones. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:426–436, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20129     

6‐Nitro‐1,2,3,4‐tetrahydroquinolines by a tandem reductive amination‐SNAr reaction

A tandem reductive amination‐S_NAr reaction has been developed for the synthesis of 6‐nitro‐1,2,3,4‐tetrahydroquinolines. Treatment of 4‐(2‐fluoro‐5‐nitrophenyl)‐2‐butanone or 3‐(2‐fluoro‐5‐nitrophenyl)‐propanal with primary amines and sodium cyanoborohydride in methanol at room temperature provided good to excellent yields of the substituted tetrahydroquinolines. The reaction proceeded best with the ketone substrate using primary amines that were unbranched at the α‐carbon. The aldehyde also produced the target heterocycles, but these were accompanied by 10‐15% of the uncyclized side chain reductive amination products.     

Nickel boride mediated reductive desulfurization of 2‐thioxo‐4(3H)‐quinazolinones: A new synthesis of quinazolin‐4(3H)‐ones and 2,3‐dihydro‐4(1H)‐quinazolinones

A novel one‐pot approach for the synthesis of aryl substituted quinazolin‐4(3H)‐ones and 2,3‐dihydro‐4(1H)‐quinazolinones has been reported based on the reductive desulfurization of 3‐aryl‐2‐thioxo‐4(3H)‐quinazolinones with nickel boride in dry methanol at ambient temperature.     

Synthesis of 3,4‐dihydro‐1(2H)‐isoquinolinonesxs

Approaches toward the preparative‐scale synthesis of target 3,4‐dihydro‐1(2H)‐isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large‐scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high‐temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)‐isoquinolinone ( 9 ). Catalytic hydrogenation of 9 provided the desired 3,4‐dihydro‐5‐methyl‐1(2H)‐isoquinolinone ( 2 ) in 65 % overall yield. Similar reduction of a commercially available 5‐hydroxy‐1(2H)‐isoquinolinone precursor 10 followed by an O ‐alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4‐dihydro‐1(2H)‐isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.     

Cerous Methanesulfonate Catalyzed Facile Synthesis of 2‐Substituted‐2,3‐dihydro‐4(1h)‐quinazolinones by Grinding Technique

2‐Substituted‐2,3‐dihydro‐4(1H)‐quinazolinones were synthesized in high to excellent yields through direct cyclocondensation of 2‐anthranilamide with aldehydes or ketones in the presence of a recyclable cerous methanesulfonate by grinding technique under aqueous conditions.     

15N NMR spectra of some 3‐substituted 4(1H)‐quinolinones and their 1‐methyl derivatives

¹⁵N NMR spectral data for 3‐substituted (chloro, bromo, acetyl, carboxy, carboethoxy, methylsulfanyl, methylsulfinyl, N,N‐dimethylsulfamoyl, nitro) 4(1H)‐quinolinones and their 1‐methyl derivatives are presented. Copyright © 2003 John Wiley & Sons, Ltd.     

Molecular dynamics of 6‐methyl‐2‐phenyl‐2,3‐dihydro‐4H‐chromen‐4‐one and 6‐methyl‐2‐(4‐nitrophenyl)‐2,3‐dihydro‐4H‐chromen‐4‐one (flavanone) derivatives in a solution studied by NMR spectroscopy

Molecular dynamics of benzoxazepin, oxime, pyrazole, and thiosemicarbazone derivatives of some flavanones have been investigated in a solution using NMR. The results confirm the formation of different O–H···O, O–H···N, N···H–N type intramolecular hydrogen bonds in the pyrazole and oxime molecules. The rotational barrier energy and energy of intramolecular hydrogen bonds have been determined. Copyright © 2013 John Wiley & Sons, Ltd.     

Benzo‐fused heterocycles and carbocycles by intramolecular SNAr and tandem SN2‐SNAr reactions

Benzo‐fused heterocyclic and carbocyclic systems have been synthesized by intramolecular S_NAr and tandem S_N2‐S_NAr reactions. Treatment of 3‐(2‐fluoro‐5‐nitrophenyl)‐1‐propanol with sodium hydride in N,N‐dimethylformamide gave 6‐nitrochroman in 80% yield by an intramolecular S_NAr reaction. Treatment of 2‐(3‐bromopropyl)‐1‐fluoro‐4‐nitrobenzene with benzylamine in N,N‐dimethylformamide gave 1‐benzyl‐6‐nitrotetrahydroquinoline in 98% yield by a tandem S_N2‐S_NAr reaction. Finally, in a similar process, reaction of this same bromide with dimethyl malonate under basic conditions gave 1,1‐bis(methoxycarbonyl)‐6‐nitro‐1,2,3,4‐tetrahydronaphthalene in 80% yield. Further studies exploring ring size effects are also presented.     

(±)‐2,3‐dialkyl‐1,2,3,4‐tetrahydroquinoline‐3‐carboxylic esters by a tandem reduction‐reductive amination reaction

A series of 2‐methyl‐2‐(2‐nitrobenzyl)‐substituted β‐keto ester derivatives has been subjected to reductive cyclization under hydrogenation conditions to assess the importance of the ester group position on the diastereoselectivity of the process. Hydrogenation over 5% palladium‐on‐carbon at 4 atmospheres pressure resulted in formation of (±)‐2,3‐dialkyl‐1,2,3,4‐tetrahydroquinoline‐3‐carboxylic esters with a preference for the product isomer having the C2 alkyl cis to the C3 ester. The product ratios were synthetically useful (6‐16:1), but less than that observed in cyclizations to prepare (±)‐2‐alkyl‐1,2,3,4‐tetrahydroquinoline‐4‐carboxylic esters. The reduced selectivity in the current reactions has been rationalized in terms of the greater conformational mobility around the ester bearing carbon, which decreases the ability of the ester to sterically influence the addition of hydrogen to the final imine intermediate.     

Substituted quinolinones. Part 13 a convenient route to heterocyclization reactions with 3‐substituted 4‐hydroxyquinolin‐2(1H)‐one

The reactivity of 3‐[(dimethylamino)prop‐2‐enoyl]‐4‐hydroxyl‐1‐methylquinolin‐2(1H)‐one ( 2 ) towards different nucleophilic and electrophilic reagents was investigated. The convenient synthesis of several 3‐heterocyclyl‐quinolinones such as 3‐pyridazinyl‐ 10, 11 , 3‐pyranyl 19a,b and 3‐pyrazolylquinolinones 20a,b, 22, 26a,b, 27a,b, 31 and 33 has been described starting from the 3‐acetylquinolinone 1 and enaminone 2 . In addition, certain heterocyclo[c]quinolinones such as pyrimido‐ 12, 14 pyrano‐ 3, 17a,b and pyrazolopyranoquinolinone 29 were obtained in good yields.     

(1S)‐1‐Phenylethanaminium 4‐{[(1S,2S)‐1‐hydroxy‐2,3‐dihydro‐1H,1′H‐[2,2′‐biinden]‐2‐yl]methyl}benzoate

The title molecular salt, C₈H₁₂N⁺·C₂₆H₂₁O₃⁻, contains a dimeric indane pharmacophore that demonstrates potent anti‐inflammatory activity. The indane group of the anion exhibits some disorder about the α‐C atom, which appears common to many structures containing this group. A model to account for the slight disorder was attempted, but this was deemed unsuccessful because applying bond‐length constraints to all the bonds about the α‐C atom led to instability in the refinement. The absolute configuration was determined crystallographically as S,S,S by anomalous dispersion methods with reference to both the Flack parameter and Bayesian statistics on Bijvoet differences. The configuration was also determined by an a priori knowledge of the absolute configuration of the (1S)‐1‐phenylethanaminium counter‐ion. The molecules pack in the crystal structure to form an infinite two‐dimensional hydrogen‐bond network in the (100) plane of the unit cell.     

A convenient preparation of 1,3‐disubstituted dihydro‐2,4‐(1H,3H)pyrimidinediones

The ureas 3 which are obtained from 3‐(benzylamino)propanenitrile ( 1 ) and various isocyanates ( 2 ) cyclize readily upon heating in ethanol, in the presence of hydrochloric acid, to form 3‐substituted 1‐benzyldihydro‐2,4‐(1H,3H)pyrimidinediones ( 11 ) in good yield.     

New conditions for synthesis of (±)‐2‐monosubstituted and (±)‐2,2‐disubstituted 2,3‐dihydro‐4(1H)‐quinazolinones from 2‐nitro‐ and 2‐aminobenzamide

An efficient synthesis of (±)‐2‐monosubstituted and (±)‐2,2‐disubstituted 2,3‐dihydro‐4(1H)‐quinazolinones has been developed using a dissolving metal reduction‐condensative cyclization strategy. Treatment of 2‐nitrobenzamide and an aldehyde or ketone with iron powder in refluxing acetic acid affords high yields of the title compounds. More complex ring systems are available by incorporating additional reactive functionality γ to the carbonyl of the aldehyde or ketone substrate. The scope and limitations of the process along with optimized procedural details are presented. The same target molecules are also accessible by reaction of 2‐aminobenzamide with aldehydes and ketones in refluxing acetic acid. J. Heterocyclic Chem., (2011).