An alternate approach to quinoline architecture via Baylis-Hillman chemistry: SnCl2-mediated tandem reaction toward synthesis of 4-(substituted vinyl)-quinolines

An alternate approach to densely substituted quinolines from the products of S_N2 nucleophilic substitution reaction between the acetyl derivatives of the Baylis-Hillman adducts obtained from 2-nitrobenzaldehydes and the carbonyl group containing carbon nucleophiles is described. Treatment of these compounds with SnCl₂, triggers a tandem reaction wherein reduction of the nitro group is followed by a remarkably regioselective intramolecular cyclization and subsequent dehydrogenation to afford 4-(substituted vinyl)-quinolines.     

Synthesis of substituted 3-methylene-2-pyridones from Baylis-Hillman derivatives and its application for the generation of 2-pyridone substituted spiroisoxazolines

The synthesis of substituted 3-methylene-2-pyridones via S_N2 displacement reaction of nucleophiles bearing a keto group on the acetyl derivative of Baylis-Hillman adducts of acrylonitrile followed by TFA/H₂SO₄-mediated intramolecular cyclization is described. The utility of these pyridone derivatives for the synthesis of new spiroisoxazolines in highly regio- and stereo-selective fashion is also illustrated. The structure of the spiroisoxazolines has been secured via X-ray crystallographic analysis.     

Chiral 2-C-methylene glycosides and carbohydrate-derived pyrano[2,3-b][1]benzopyrans: synthesis via InCl3 catalyzed stereoselective Ferrier rearrangement of 2-C-acetoxymethyl glycal derivatives

2-C-Acetoxymethyl glycal derivatives react with aliphatic alcohols in the presence of InCl₃ (30 mol %) to furnish the corresponding 2-C-methylene glycosides in excellent yields and with exclusive α-selectivity except for the methyl 2-C-methylene glycosides, which are formed in ∼2:1 anomeric ratio in favour of the α-anomer. The reaction of 2-C-acetoxyglycals with phenols, however, produces the corresponding chiral carbohydrate-derived pyranobenzopyran derivatives via initial Ferrier rearrangement followed by tandem cyclization in excellent yields and moderate to high stereoselectivities in favour of the corresponding 10a-R-pyrano[2,3-b][1]benzopyran derivatives.     

Expeditious synthesis of 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones

A convenient synthesis of new 5,6,7,8-tetrahydro-imidazo[1,2-a]pyrimidin-2-ones and 3,4,6,7,8,9-hexahydro-pyrimido[1,2-a]pyrimidin-2-ones from the Baylis-Hillman adducts of acrylonitrile and their derivatives is described. A common strategy employed to achieve the syntheses of title compounds involved generation of diamines from different Baylis-Hillman derivatives followed by treatment with cyanogen bromide at reflux temperature to trigger a double intramolecular cyclization.     

Microwave-assisted Claisen rearrangement of naphthyl 2-propynyl ethers: synthesis of naphthofurans

An efficient two-step approach for the synthesis of naphtho[1,2-b]furans and naphtho[2,1-b]furans has been developed. Various functionalized propargyl alcohols were etherified with α- or β-naphthol under Mitsunobu reaction conditions to give naphthyl 2-propynyl ethers, which underwent a facile microwave-assisted Claisen rearrangement and concomitant anionic cyclization to yield naphthofuran derivatives under basic reaction conditions.     

Studies on the reduction of the nitro group in 3-aryl-2-methylene-4-nitro-alkanoates afforded by the Baylis-Hillman adducts: synthesis of 4-aryl-3-methylene-2-pyrrolidinones and 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylates

The formation of substituted 2-pyrrolidinones and indoles by the reduction of the secondary nitro group in appropriate 3-aryl-2-methylene-4-nitroalkanoates afforded by Baylis-Hillman chemistry via different reducing agents is described. The 3-aryl-2-methylene-4-nitroalkanoate obtained from S_N2 nucleophilic reaction between the acetate of Baylis-Hillman adducts and ethyl nitroacetate upon reduction with indium-HCl furnishes a mixture of cis and trans substituted phenyl-3-methylene-2-pyrrolidinones. In contrast, similar reductions of analogous substrates derived from nitroethane stereoselectively furnished only the trans substituted phenyl-3-methylene-2-pyrrolidinones. On the other hand the SnCl₂·2H₂O-promoted reductions of substrates derived from nitro ethylacetate give oxime derivatives while the ones obtained from nitroethane yield a mixture of cis and trans 4-aryl-3-methylene-2-pyrrolidinones. Alternatively, the SnCl₂·2H₂O-promoted reduction of substituted 2-nitrophenyl-2-methylene-alkanoate furnished from ethyl nitroacetate yield 3-(1-alkoxycarbonyl-vinyl)-1H-indole-2-carboxylate while indium-promoted reaction of this substrate leads to a complex mixture. Analogous reactions with SnCl₂·2H₂O of substituted 2-nitrophenyl-2-methylene-alkanoate obtained from nitroethane yield 4-alkyl-3-methylene-2-quinolones in moderate yields.     

A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction

The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na₂S₂O₄ in dioxane/water at reflux.     

Toward understanding the scope of Baylis-Hillman reaction: synthesis of 3-(2- hydroxyphenyl)indolin-2-ones and polycyclic fused furans

A facile one-pot synthesis of 3-(2-hydroxyphenyl)indolin-2-ones has been developed via the TiCl₄-mediated Baylis-Hillman (B-H) reaction of N-substituted isatins and cyclohex-2-enone, followed by treatment of the in situ generated B-H alcohols with aq HBr. Baylis-Hillman reaction of aromatic cyclic 1,2-diones with cycloalk-2-enones under the influence of TiCl₄ has been successfully performed and the resulting Baylis-Hillman adducts have been conveniently transformed into pentacyclic and hexacyclic fused furan derivatives.     

Synthesis of 3,4-disubstituted 2(1H)-quinolinones via intramolecular Friedel-Crafts reaction of N-arylamides of Baylis-Hillman adducts

3,4-Disubstituted 2(1H)-quinolinones were synthesized starting from the Baylis-Hillman adducts via the following sequential processes: (i) hydrolysis of the Baylis-Hillman adduct to acid, (ii) EDC coupling with anilines, (iii) H₂SO₄-assisted intramolecular Friedel-Crafts cyclization, and the final (iv) DBU-mediated isomerization.     

New atropoisomeric alkenylphenylglycine derivatives: Synthesis of (5R*)- and (5S*)-isomers of (1R*,3aR*,4S*,11S*)-3a,5,9,11-tetramethyl-4,5-dihydro-3aH-1,4-methano[1,3]oxazolo[3,2-a]quinolin-2-one

We synthesized methyl ester of N-(1-methylbut-2-en-1-yl)-N-phenylglycine which underwent acid catalyzed aromatic amino Claisen rearrangement to provide methyl-N-[2-(1-methylbut-2-en-1-yl)phenyl]glycinate. A mixture of syn- and anti-atropisomeric methyl-N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycinates was obtained either by the reaction of this ester with acetyl bromide or by the reaction of the sodium salt of N-acetyl-2-(1-methylbut-2-en-1-yl)-4-methylaniline with methyl bromoacetate. Upon saponification of the synthesized ester mixture the syn-atropisomer of N-acetyl-N-[4-methyl-2-(1-methylbut-2-en-1-yl)phenyl]glycine was isolated by fractional crystallization. Treatment of the obtained acids with acetic anhydride, ethyl chloroformate, dicyclohexylcarbodiimide or isopropenylacetate leads to compounds of 4,5-dihydro-3aH-methano[1,3]oxazolo[3,2-a]quinolin-2-one structure.     

P2O5-Promoted Efficient and Diastereoselective Synthesis of Substituted 5-Methylene-dihydropyran-2,6-diones and 3-Methylene-3,4-dihydropyran-2-ones

A simple, efficient, and diastereoselective synthesis of 5-methylene-dihydropyran-2,6-diones and 3-methylene-3,4-dihydropyran-2-ones from substrates afforded by the S_N2 reaction between the acetyl derivatives of the Baylis–Hillman adducts and methylacetoacetate or acetylacetone or benzoyl acetone via saponification followed by P₂O₅-mediated cyclization is described.     

Synthesis of 3-aryl-3-hydroxypyrrolidin-2-ones and 2-benzyl-9b-hydroxy-3,3a,5,9b-tetrahydro-2H-pyrrolo[3,4-c]quinoline-1,4-dione derivatives from the Baylis-Hillman adducts of isatins

We prepared some 3-aryl-3-hydroxypyrrolidin-2-ones and tricyclic 2-benzyl-9b-hydroxy-3,3a,5,9b-tetrahydro-2H-pyrrolo[3,4-c]quinoline-1,4-diones starting from the Baylis-Hillman adducts of isatin derivatives.     

Convenient and efficient stereoselective synthesis of (2Z)-2-(chloromethyl)alk-2-enoates using iron(III) or indium(III) chloride

The stereoselective synthesis of (2Z)-2-(chloromethyl)alk-2-enoates has been achieved efficiently and in high yields and in short reaction times from Baylis-Hillman adducts, 3-hydroxy-2-methylene-alkanoates, by treatment with FeCl₃ or InCl₃ at room temperature.     

Synthesis of α-C-glycosides via tandem Tebbe methylenation and Claisen rearrangement

A variety of α-C-glycosides may be accessed in an entirely stereoselective fashion from 3-OH glycal esters, by way of the tandem reaction sequence of Tebbe methylenation and Claisen rearrangement. In contrast with previous studies in the corresponding β-series, careful control of conditions for Claisen rearrangement is required in order to avoid loss of integrity of anomeric stereochemistry; thermal rearrangements are best carried out in xylene in a sealed tube.     

A simple approach to highly functionalized benzo[b]furans from phenols and aryl iodides via aryl propargyl ethers

A variety of mono- and disubstituted phenols are alkylated with propargyl bromide to give phenyl 2-propynyl ethers, which were further coupled with aryl iodides under Sonogashira reaction conditions to give 3-phenoxy-1-aryl-1-propyne derivatives. The latter compounds underwent an initial Claisen rearrangement followed by ring closure to give functionalized benzo[b]furans in moderate to good yields.     

ReBr(CO)5-catalyzed sequential addition-cyclization of 1,3-dicarbonyl compounds with electron-deficient internal alkynes affording trisubstituted 2H-pyran-2-ones

The reaction of 1,3-dicarbonyl compounds such as acetoacetate, acetylacetone, dibenzoylmethane, and benzoylacetate with electron-deficient internal alkynes in the presence of catalytic amount of ReBr(CO)₅ in toluene under neutral conditions resulted in the formation of 4,5,6-trisubstituted 2H-pyran-2-ones in moderate to high yield. The reaction took place via a two-step sequence including the rhenium(I)-catalyzed addition of the activated methylenes to alkynes to give enolic 2-alkenyl derivatives, and subsequently dealcoholic cyclization to form 2H-pyran-2-one derivatives.     

Single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo[1,2-c]quinazolin-2(3H)-ones

A single step synthesis of 2,3-dialkyl-6-nitro-quinazolin-4(3H)-imines and 3,5-dialkyl-9-nitro-imidazo-[1,2-c]-quinazolin-2(3H)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitro-benzonitrile was developed. Key intermediates were N,N′-disubstituted amidines obtained by rearrangement of 4,5-dihydrotriazoles; the new heterocyclic rings were formed by spontaneous intramolecular reaction of the amino and cyano groups which are present in the intermediates.     

I2-Catalyzed Cycloisomerization of Ynamides: Chemoselective and Divergent Access to Indole Derivatives

Herein, an I₂-catalyzed unprecedented cycloisomerization of ynamides is developed, furnishing various functionalized bis(indole) derivatives in generally good to excellent yields with wide substrate scope and excellent atom-economy. This protocol not only represents the first molecular-iodine-catalyzed tandem complex alkyne cycloisomerizations, but also constitutes the first chemoselective cycloisomerization of tryptamine-ynamides involving distinctively different C(sp³)−C(sp³) bond cleavage and rearrangement. Moreover, chiral tetrahydropyridine frameworks containing two stereocenters are obtained with moderate to excellent diastereoselectivities and excellent enantioselectivities. Meanwhile, cycloisomerization and aromatization of ynamides produce pyrrolyl indoles with high efficiency enabled by I₂. Additionally, control experiments and theoretical calculations reveal that this reaction probably undergoes a tandem 5-exo-dig cyclization/rearrangement process.     

FeCl3-catalyzed tandem Prins and Friedel–Crafts cyclization: a highly diastereoselective route to polycyclic ring structures

Catalytic FeCl₃ in the presence of 4 Å molecular sieves has been shown to effect highly diastereoselective tandem Prins and Friedel–Crafts cyclization of substituted (E/Z)-6-phenylhex-3-en-1-ol and a variety of aldehydes to provide a range of polycyclic compounds in good to excellent yields. The reaction of an enantioenriched alcohol with an aldehyde provided the cyclization product without loss of optical activity. Furthermore, a Lewis acid catalyzed ring opening resulted in functionalized tetralin derivatives with multiple chiral centers.     

Tandem versus single C-C bond forming reaction under palladium-copper catalysis: regioselective synthesis of α-pyrones fused with thiophene

We herein report a highly convenient protocol for rapid construction of α-pyrone fused with thiophene. This includes one-pot and regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]pyran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes in a simple synthetic operation. The coupling-cyclization reaction was initially studied in the presence of Pd(PPh₃)₂Cl₂ and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C-C bond forming reaction in the presence of palladium catalyst rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling-cyclization-coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C-C bond forming reaction however, can be restricted to the formation of single C-C bond by using 10% Pd/C-Et₃N-CuI-PPh₃ as catalyst system in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was performed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.