A facile tandem construction of C-O and C-C bonds: a novel one-pot transformation of Baylis-Hillman adducts into 2-benzoxepines

A facile and one-pot synthesis of 2-benzoxepines, from Baylis-Hillman adducts that is, alkyl 3-aryl-3-hydroxy-2-methylenepropanoates, via treatment with HCHO in the presence of concd H₂SO₄, involving tandem construction of C-O and C-C bonds via Prins-type and Friedel-Crafts reactions, is described.     

Synthetic applications of Baylis-Hillman chemistry: an efficient and solely stereoselective synthesis of (E)-alpha-methylcinnamic acids and potent hypolipidemic agent LK-903 from unmodified Baylis-Hillman adducts

An efficient and solely stereoselective synthesis of (E)-alpha-methylcinnamic acids has been accomplished in single pot by reduction of the unmodified Baylis-Hillman adducts, methyl-3-hydroxy-3-aryl-2-methylenepropanoates with I(2)/NaBH(4) reagent system at room temperature followed by hydrolysis. The efficacy of this method has been proved in the total synthesis of 1-[p-(myristyloxy)-alpha-methylcinnamoyl]glycerol, LK-903, a highly active hypolipidemic agent.     

Chemo-, regio- and stereoselective addition of triorganoindium reagents to acetates of Baylis-Hillman adducts: a new strategy for the synthesis of (E)- and (Z)-trisubstituted alkenes

The addition of several trialkyl or triarylindium reagents to the acetates of Baylis-Hillman adducts proceeds readily under the catalysis of copper and palladium derivatives. The reactions of trialkylindiums are catalyzed efficiently by CuI whereas additions of triarylindiums produce better results with Pd(PPh₃)₄. The reactions with 3-acetoxy-2-methylenealkanoates provide (E)-alkenes, whereas similar reactions with 3-acetoxy-2-methylenealkanenitriles lead to (Z)-alkenes. All the reactions are highly regio- and stereoselective and high yielding.     

A facile one-pot stereoselective synthesis of trisubstituted (E)-2-methylalk-2-enoic acids from unactivated Baylis-Hillman adducts and a simple access to some important insect pheromones

An efficient one-pot stereoselective synthesis of trisubstituted (E)-2-methylalk-2-enoic acids has been accomplished by treatment of unactivated Baylis-Hillman adducts, 3-hydroxy-2-methylenealkanoates, with Al-NiCl₂·6H₂O in methanol at room temperature followed by hydrolysis. The method has been applied to the synthesis of three important insect pheromones, (4S,2E)-2,4-dimethyl-2-hexenoic acid, (+)-(S)-manicone and (+)-(S)-normanicone.     

Synthesis and hydrogenation of (E)-γ-aryl-γ-morpholino-α-trifluoromethylated allyl alcohols through the reaction of trifluoroacetaldehyde ethyl hemiacetal with enamines

Treatment of trifluoroacetaldehyde ethyl hemiacetal with enamines, derived from acetophenone derivatives, at room temperature gave (E)-1,1,1-trifluoro-4-morpholino-4-aryl-but-3-en-2-ols, which are intermediates for preparation of the β-trifluoromethylated aldol products, 4,4,4-trifluoro-3-hydroxy-1-aryl-butan-1-ones. The structure of the intermediate (E)-1,1,1-trifluoro-4-morpholino-4-(4-nitrophenyl)-but-3-en-2-ols could be assigned by ¹H, ¹³C NMR, IR, and X-ray crystallography. Furthermore, hydrogenation and reductive deamination of the intermediate (E)-1,1,1-trifluoro-4-morpholino-4-aryl-but-3-en-2-ols with hydrogen in the presence of a catalytic amount (10 mol %) of palladium on carbon in trifluoroethanol proceeded smoothly at room temperature to give 1,1,1-trifluoro-4-aryl-2-butanols in good to excellent yields.     

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.     

An efficient stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes from unactivated Baylis-Hillman adducts using NaBH4/CuCl2·2H2O

A convenient and facile stereoselective synthesis of (E)- and (Z)-trisubstituted alkenes has been achieved by treatment of unactivated Baylis-Hillman adducts with NaBH₄ in the presence of CuCl₂·2H₂O at room temperature for 15 min.     

Metallic samarium and iodine promoted facile and efficient syntheses of trisubstituted alkenes from the acetates of Baylis-Hillman adducts

Promoted by samarium metal in the presence of a catalytic amount of iodine, the Baylis-Hillman adducts underwent reductive elimination to form (E)-methylcinnamic ester derivatives. When the iodine was used in 1:1 ratio with metallic samarium, stereospecific syntheses of allylic iodide derivatives, (2Z)-2-(iodomethyl)alk-2-enoates, were achieved. Thus, this gives a new approach to the selective construction of stereo-defined trisubstituted alkenes with the simple Sm/I₂ system.     

Synthesis and cyclo-oligomerization of 2-(bromomethyl)-3-aryl-2-propenoic acid derivatives

2-Bromomethyl-3-aryl-2-propenoic acids have been synthesized from Baylis-Hillman adducts derived from aromatic aldehydes and t-butyl acrylates as new precursors in MBH chemistry. Further triolides were synthesized by the cyclo-oligomerization of 2-bromomethyl-3-aryl-2-propenoic acids in the presence of Cs₂CO₃ demonstrating the synthetic utility of these motifs.     

Acylation of Fischer’s Base with Methyl Aroylpyruvates

Methyl (Z)-4-aryl-2-hydroxy-4-oxobut-2-enoates (methyl aroylpyruvates) reacted with 1,3,3-trimethyl- 2-methylidene-2,3-dihydro-1H-indole (Fischer’s base) to give (2Z,5E)-1-aryl-3-hydroxy-5-(1,3,3-trimethyl-2,3-dihydro-1H-indol-2-ylidene)pent-2-ene-1,4-diones.     

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.     

Chrysanthemyl 2-acetoxy-3-methylbutanoate: the sex pheromone of the citrophilous mealybug, Pseudococcus calceolariae

Headspace volatiles collected from virgin females of the citrophilous mealybug, Pseudococcus calceolariae, contain three compounds not present in the headspace of control samples. The main female-specific compound is identified as [2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropyl]methyl 2-acetoxy-3-methylbutanoate (chrysanthemyl 2-acetoxy-3-methylbutanoate). The other two compounds are identified as [2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropyl]methanol (chrysanthemol) and [2,2-dimethyl-3-(2-methylprop-1-enyl)cyclopropyl]methyl 2-hydroxy-3-methylbutanoate (chrysanthemyl 2-hydroxy-3-methylbutanoate). Traps baited with 100 μg and 1000 μg of chrysanthemyl 2-acetoxy-3-methylbutanoate captured 4- and 20-fold more males than traps baited with virgin females.     

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.     

Studies on the catalytic hydrogenation of Baylis-Hillman derivatives of substituted isoxazolecarbaldehydes. Unusual retention of isoxazole ring during Pd-C-promoted hydrogenation of Baylis-Hillman adducts

Results of the catalytic hydrogenation of Baylis-Hillman adducts obtained from substituted 3-, 4- and 5-isoxazolecarbox-aldehydes and their corresponding acetates in the presence of Raney-Ni and Pd-C are presented. The hydrogenation of Baylis-Hillman adducts of substituted 5-isoxazolecarbaldehydes and 3-isoxazolecarbaldehydes in the presence of Raney-Ni furnishes diastereoselectively syn enaminones over anti and in the presence of boric acid as an additive further enhancement of diastereoselectivity in favor of syn isomer is observed. The Pd-C-promoted hydrogenation of these substrates is also diastereoselective in favor of syn isomer but occurs without the hydrogenolysis of isoxazole-ring. The presence of boric acid as an additive in this hydrogenation exhibits no pronounced effect on diastereoselectivity. The Raney-Ni-mediated hydrogenation of Baylis-Hillman adducts of substituted 4-isoxazolecarbaldehydes yield pyridone derivatives and Pd-C-promoted hydrogenation of the same substrate is diastereoselective to afford the anti isomer of the resulting products. The enaminones derived from Baylis-Hillman adducts of 3- and 5-isoxazolecarbaldehydes serve as versatile precursors for α′-hydroxy-1,3-diketones, which undergo acid-catalyzed ring-closure reaction to afford the furanone derivatives in excellent yields.     

Palladium-catalyzed isomerization of (Z)-1-functionalized-4-acetoxy-2-butenes: Solvent and substituent effects

The Pd(PPh₃)₄-catalyzed isomerization of (Z)-1,4-diacetoxy-2-butene, (Z)-1-(t-butyldimethylsilyloxy)-4-acetoxy-2-butene and (Z)-1-(t-butyldiphenylsilyloxy)-4-acetoxy-2-butene affords the corresponding (E)-isomers and 1,2-difunctionalized-3-butenes. In THF, the formation of the (E)-isomers is mainly due to reaction from an η¹-allylpalladium intermediate while an η³-allylpalladium is the main key intermediate in DMF. The time to reach equilibrium between the products and their respective concentrations depend on the nature of the substituents and the solvent.     

Microwave assisted selective synthesis of (<Emphasis Type="Italic">E</Emphasis>)-1-(4-Chloro-7-hydroxy-2-aryl-2<Emphasis Type="Italic">H</Emphasis>-chromen-6-yl)-3-arylprop-2-en-1-ones and their antimicrobial activity

A series of new (E)-1-(4-chloro-7-hydroxy-2-aryl-2H-chromen-6-yl)-3-arylprop-2-en-1-ones (2a–2f) have been synthesized by selective mono cyclization of 4,6-dicinnamoyl resorcinols (1a–1f) using Vilsmeier–Haack reagent under conventional heating and microwave irradiation. The structures of the synthesized compounds have been elucidated by elemental analysis, IR, ¹H NMR, ¹³C NMR and Mass spectral data. The synthesized compounds were tested in vitro for antimicrobial activity.     

An efficient synthesis of 2-benzoxepines from Morita-Baylis-Hillman adducts using heterogeneous recyclable catalysts

2-Benzoxepines have efficiently been synthesized from Morita-Baylis-Hillman adducts, alkyl 3-aryl-3-hydroxy-2-methylenepropanoates by treatment with HCHO catalyzed by silica supported perchloric acid (HClO4.SiO2) or Amberlyst-15 in CH2Cl2 under reflux for a short period of time (1.5-2.5 h). The catalyst can be recovered and recycled. The antibacterial properties of the new 2-benzoxepines were studied but no activity was found.     

Direct synthesis of methyl 2-diazo-4-aryl-3-butenoates and their application to the enantioselective synthesis of 4-aryl-4-(1-naphthyl)-2-butenoates

An improved one-flask synthesis of various methyl 2-diazo-4-aryl and 4-heteroaryl-3-butenoates, precursors to donor/acceptor substituted carbenoids, is described. Their Rh₂(S-DOSP)₄ catalyzed reaction with 1-acetoxy-3,4-dihydronaphthalene, via a combined C–H activation/Cope rearrangement pathway followed by elimination of acetic acid affords a highly enantioselective (98–99% ee) entry to methyl 4-aryl- and 4-heteroaryl-4-(1-naphthyl)-2-butenoates.     

Ionic liquid [Hmim]HSO4-promoted one-pot oxidative conjugate addition of sulfur-centred nucleophiles to Baylis-Hillman adducts

The first example of the one-pot oxidative conjugate addition of sulfur-centred nucleophiles to Baylis-Hillman adducts is reported. The reaction involves oxidation of Baylis-Hillman adducts with NaNO₃ in the Brønsted acidic ionic liquid [Hmim]HSO₄ to give [E]-α-cyanocinnamaldehydes followed by conjugate hydrothiocyanation/hydrosulfenylation with NH₄SCN/PhSH to afford the corresponding β-thiocyanato (or β-phenylsulfenyl)-α-cyanohydrocinnamaldehydes diastereoselectively in 76-89% yields in a one-pot procedure. After isolation of the product, the ionic liquid [Hmim]HSO₄ could be easily recycled for further use.     

Synthesis and molecular structure of 6-aryl-3-ethoxycarbonyl-4-hydroxypyridazines

EthylZ-5-aryl-2-diazo-5-hydroxy-3-oxopent-4-enoates interact with triphenylphosphine to give 6-aryl-3-ethoxycarbonyl-4-hydroxypyridazines (Ar=Ph, 4-MeC₆H₄, 4-ClC₆H₄). Quantum-chemical calculations (MNDO) were performed to estimate the tautomeric equilibrium in the latter using a 6-phenyl-substituted derivative as an example. Acetylation of the 4-hydroxypyridazines led to 4-acetoxy-6-aryl-3-ethoxycarbonylpyridazines. The structure of the latter was confirmed by an X-ray diffraction analysis of 4-acetoxy-3-ethoxycarbonyl-6-(p-tolyl)pyridazine. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2260–2263, December, 1997.