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.     

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.     

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.     

Z/E Stereoselective synthesis of β-bromo Baylis-Hillman ketones using MgBr2 as promoter via a one-pot three-component reaction

The first time steroselective synthesis of (Z)-β-bromo Baylis-Hillman ketones has been achieved using a one-pot three-component reaction. The new system uses MgBr₂ as both the Lewis acidic promoter and the bromine source for the Michael-type addition with α,β-acetylenic ketones to form an active β-bromo allenolate intermediate, which in turn attacks various aldehydes to afford β-bromo Baylis-Hillman adducts in good yields and Z-selectivity.     

Synthesis of N-tosyl-3,3,4-trisubstituted pyrrolidine derivatives starting from the Baylis-Hillman adducts via radical cyclization

N-Tosyl-3,3-disubstituted-4-vinylpyrrolidine derivatives 3a-c were synthesized via radical cyclization from the modified Baylis-Hillman adducts 2. The required starting materials 2a-c were prepared in moderate yields from the Baylis-Hillman adducts in three steps: (i) acetylation of the Baylis-Hillman adducts, (ii) S_N2′ reaction with tosylamide to prepare 1, and (iii) alkylation with 1,4-dibromo-2-butene.     

Trifluoroacetic acid: a more effective and efficient reagent for the synthesis of 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones and 3-arylmethyl-2-amino-quinolines from Baylis-Hillman derivatives via Claisen rearrangement

Trifluoroacetic acid has been discovered to be a highly effective and efficient reagent for the tandem Claisen rearrangement and cyclization reaction to yield 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones from compounds obtained from the S_N2 reaction between anilines and acetyl derivatives of Baylis-Hillman adducts of acrylates in the presence of DABCO. In contrast, similar compounds obtained from the acetyl derivatives of Baylis-Hillman adduct of acrylonitrile on treatment with trifluoroacetic acid directly furnish 3-arylmethyl-2-amino-quinoline via tandem Claisen rearrangement, cyclization and isomerization.     

Studies on montmorillonite K10-microwave assisted isomerisation of Baylis-Hillman adduct. Synthesis of E-trisubstituted alkenes and synthetic application to lignan core structures by vinyl radical cyclization

The isomerisation of acetates from the Baylis-Hillman adducts with Mont.K10 clay-microwave combination furnished E-trisubstituted alkenes in high yield. The simple Baylis-Hillman adducts with trimethyl orthoformate and unsaturated alcohols under clay catalytic condition gave densely functionalised-isomerized products under solvent free condition. Application of the propargyl derivatives thus obtained from the isomerisation of the Baylis-Hillman adducts with propargyl alcohol has been demonstrated in the synthesis of lignan core structures by tri-n-butyltin hydride mediated vinyl radical cyclization.     

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.     

Synthesis of 4b,5,10a,11-tetrahydroindeno[1,2-b]quinolin-10-ones from Baylis-Hillman adducts

We developed an efficient synthetic method for indenoquinoline skeletons from Baylis-Hillman adducts. 4b,5,10a,11-Tetrahydroindeno[1,2-b]quinolin-10-ones and 7H-indeno[2,1-c]quinolines were prepared from Baylis-Hillman adducts in polyphosphoric acid.     

Baylis-Hillman adducts between pyridine carboxaldehyde derivatives and cyclic enones

Baylis-Hillman (BH) adducts were synthesized using pyridinecarboxaldehyde derivatives and cyclic enones. The Baylis-Hillman reaction was examined by employing various organic tertiary bases and solvents. It was observed that DBU in MeOH as well as imidazole and N-methylimidazole in aqueous MeOH are very effective. These pyridinecarboxaldehydes were reactive and efficient towards the Baylis-Hillman reaction and the resulting adducts are highly stable. The crystal structure for one of the BH adducts was determined.     

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.     

Facile synthesis of 2H-indazole derivatives starting from the Baylis-Hillman adducts of 2-cyclohexen-1-one

Facile synthetic method of 2H-indazole derivatives was developed involving DDQ oxidation of pyrazoles, which were prepared starting from the Baylis-Hillman adducts of 2-cyclohexen-1-one.     

The first application of the Baylis-Hillman reaction in azetidine chemistry: a convenient synthesis of azetidine-3-carbonitriles/carboxylates

The first application of Baylis-Hillman adducts in the synthesis of azetidines is reported. The synthesis involves a one-pot, high yielding and highly diastereoselective annulation of unmodified Baylis-Hillman adducts with N-arylphosphoramidates to afford 1,2-disubstituted azetidine-3-carbonitriles/carboxylates, which are the precursors of biologically versatile azetidine-3-carboxylic acids.     

Synthesis of 3-substituted-4-hydroxyquinoline N-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes

The reaction of the Baylis-Hillman adducts 1b-f derived from o-nitrobenzaldehydes in trifluoroacetic acid in the presence of triflic acid (0.2 equiv.) afforded 3-substituted-4-hydroxyquinoline N-oxides 2b-e and 2a in good to moderate yields. The reaction mechanism was evidenced by the experiment with 1f, the Baylis-Hillman adduct of 2-nitrobenzaldehyde N-tosylimine, as the one involving N-hydroxyisoxazoline as the key intermediate.     

Salt effects on the Baylis-Hillman reaction

The Baylis-Hillman reaction is shown to accelerate in salt solutions of water and the ‘water-like’ structured solvents, like formamide and N-methylformamide in the presence of DABCO. Ethylene glycol, another structured solvent and its salt solutions fail to make any impact on the reaction rates. The salts that are conventionally defined as salting-out or -in do not behave in a similar fashion, when employed in the Baylis-Hillman reactions. The results are supported by solubility measurements. It seems that the cation, anion, nature of solvent and of reactants together ascertain whether a salt will enhance or retard the Baylis-Hillman reaction.     

Bismuth triflate-catalyzed rearrangement of acetates of the Baylis-Hillman adducts into (E)-trisubstituted alkenes

In the presence of a catalytic amount of bismuth triflate, methyl 3-acetoxy-3-aryl-2-methylenepropanoates and 3-acetoxy-3-aryl-2-methylenepropanitriles were smoothly converted into methyl (2E)-2-(acetoxymethyl)-3-arylprop-2-enoates and (2E)-2-(acetoxymethyl)-3-arylprop-2-enenitriles, respectively. A remarkable reversal in stereochemical directions from ester to nitrile was observed. 3-Aryl-3-hydroxy-2-methylenepropanoates and 3-aryl-3-hydroxy-2-methylenepropanitriles could be easily obtained as Baylis-Hillman adducts from methyl acrylate and acrylonitrile, respectively. The overall process is an efficient isomerization of the Baylis-Hillman adducts to the corresponding cinnamyl derivatives. The isomerization reaction proceeded rapidly and afforded smoothly the cinnamyl acetates in moderate to very good yields using catalytic amounts of Bi(OTf)₃·4H₂O (10 mol %).     

Simple access to 2-methylalk-2-enoates and insect pheromones by zinc-promoted reduction of Baylis-Hillman-derived allylic bromides

(E)-2-Methylacrylates are prepared in good yield and high stereoselectivity by zinc-promoted reduction of 2-(bromomethyl)alkenoates derived from Baylis-Hillman adducts. Synthesis of the male ant pheromone (E)-2,4-dimethyl-2-hexenoic acid was performed using this simple methodology.     

An approach to substituted dihydroisoquinolin-1(2H)-ones from Baylis-Hillman adducts

In this communication we describe an easy and straightforward alternative method for the preparation of 3,4-substituted isoquinolin-1(2H)-ones, using Baylis-Hillman adducts as starting material.     

Chemical transformation of Baylis-Hillman adducts: the reaction of methyl 3-arylamino-2-methylene-3-phenylpropanoates in polyphosphoric acid

We synthesized some interesting compounds including 3-benzylidene-3,4-dihydro-1H-quinolin-2-one, 3-benzylquinolin-2-ol, 4-amino-2-benzylideneindan-1-one, and 1-amino-9a,10-dihydro-4bH-indeno[1,2-a]inden-9-one skeletons starting from Baylis-Hillman adducts.     

Remarkable rate acceleration of water-promoted nucleophilic substitution of Baylis-Hillman acetate: a facile and highly efficient synthesis of N-substituted imidazole

Without additional reagents, the Baylis-Hillman acetates 2 underwent nucleophilic substitution reaction with imidazole readily in aqueous THF solution to afford the corresponding N-substituted imidazole derivatives 3 in good to excellent yields. Moreover, the reaction between the in situ generated DABCO salt of Baylis-Hillman acetates 4 and imidazole occurs in aqueous THF providing the S_N2 type products 5. The simpler operational procedure, better stereoselectivity and higher efficiency over conventional method make the present protocol practical for the preparation of imidazole derivatives.