Aza-Baylis-Hillman reactions of diisopropyl azodicarboxylate or diethyl azodicarboxylate with acrylates and acrylonitrile

It has been found that in the Baylis-Hillman reactions of DIAD or DEAD with acrylates or acrylonitrile, the Lewis base and solvent can significantly affect the reaction rate. Using DABCO as Lewis base in DMF or THF, the corresponding aza-Baylis-Hillman adducts 2 or 3 can be obtained in moderate to good yields.     

Reexamination of the traditional Baylis-Hillman reaction

In the Baylis-Hillman reaction of arylaldehydes with methyl vinyl ketone (MVK), we found that, besides the normal Baylis-Hillman adduct 1, the diadduct 2 can also be formed at the same time and the yield of 2 can reach to 55% if increasing the amount of methyl vinyl ketone. But for ethyl vinyl ketone (EVK), methyl acrylate or acrylonitrile, only the normal Baylis-Hillman adduct 4, 7 or 8 was obtained, respectively. The substituent's effects and Lewis base effects were also examined and a plausible reaction mechanism was proposed for the formation of 2.     

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.     

Aza-Morita-Baylis-Hillman reactions of N-(benzylidene)polyfluoroanilines with methyl acrylate and acrylonitrile

Aza-Morita-Baylis-Hillman reactions of N-(benzylidene)polyfluoroanilines 1 with methyl acrylate or acrylonitrile were studied. It was found that Lewis base, solvent and reaction temperature can significantly affect the reaction. Using 3-hydroxyquinuclidine (3-HQD) as a Lewis base in the reactions of 1 with methyl acrylate in DMF, the normal aza-Morita-Baylis-Hillman adducts 3 were formed in moderate to excellent yields. For the reactions of 1 with acrylonitrile, 1,4-diazabicyclo[2.2.2]octane (DABCO) is the best Lewis base giving the corresponding aza-Morita-Baylis-Hillman adducts 4 as the sole product in good to moderate yield. However, upon treatment of 1 with acrolein 2c, the corresponding reaction did not occur even in the presence of a variety of catalysts.     

Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from Baylis-Hillman adducts

Tetrasubstituted pyrazole derivatives 3a-j were synthesized regioselectively in good yields from the reaction of Baylis-Hillman adducts 1a-f and hydrazine hydrochlorides 2a-d in 1,2-dichloroethane.     

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.     

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.     

Synthesis of eight-membered iminocyclitols from d-glucose

The Baylis-Hillman reaction of 3-O-benzyl-α-d-xylo-pentodialdo-1,4-furanose 2 afforded a diastereomeric mixture of l-ido- and d-gluco-configurated α-methylene-β-hydroxy esters 3a and 3b, respectively, in 1:1 ratio. Conjugate addition of benzyl amine on 3a gave adduct 4a as a major product while, addition of benzyl amine to 3b gave only one diastereomer 4b. Reduction of ester functionality in 4a/4b, opening of 1,2-acetonide functionality followed by reductive amino-cyclization under hydrogenation condition afforded azocanes 1c/1d in good yield.     

NaNO2-Ceric ammonium nitrate mediated conversion of acrylic esters and Baylis-Hillman derived acrylic esters into corresponding β-nitro acrylic esters

A variety of acrylic esters, including those derived from Baylis-Hillman reactions, react with NaNO₂-ceric ammonium nitrate to form the corresponding β-nitro alcohols 2 and 5 whose dehydration, via their mesylates, leads to β-nitro acrylic esters, in good to excellent yields. Further, β-nitro acrylic esters containing a mesylate group 6, obtained from the Baylis-Hillman products, react with NaN₃ to form 2-cyano-3-substituted acrylic esters 10 in excellent yields.     

Synthesis of some new tertiary amines and their application as co-catalysts in combination with l-proline in enantioselective Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone

A chiral benzodiazepine derivative 1 was synthesized starting from o-nitrobenzoyl chloride and methyl l-prolinate hydrochloride. Diastereomeric (1R,2R,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3a and (1S,2S,1′S)-(+)-2-[N-methyl-N-(α-phenylethyl)amino]cyclohexanol 3b were synthesized starting from (S)-α-phenylethylamine and cyclohexene oxide via ring-opening, diastereomer separation and N-methylation. (S,S)-octahydrodipyrrolo[1,2-a:1′,2′-d]pyrazin 5 was synthesized from methyl l-prolinate. Chiral tertiary amines 1, 3a, 3b and 5 almost cannot catalyze the Baylis-Hillman reaction between o-nitrobenzaldehyde and methyl vinyl ketone (MVK). However, they functioned as efficient catalysts for this reaction in the presence of l-proline. The corresponding adducts were obtained in good yields with enantioselectivity of 83% ee, 81% ee, 51% ee and 66% ee, respectively.     

Synthesis and bioactivity of novel (3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)phenyl containing acrylate and acrylonitrile derivatives

Fifteen novel (3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)phenyl containing Baylis-Hillman adduct derivatives were designed and synthesized. Evaluation of their biological activities showed that methyl 2-((3-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)phenoxy)(phenyl)methyl)acrylate (2g) exhibited efficient broad-spectrum fungicidal activity, with 100% control of wheat powdery mildew and cucumber downy mildew and 98% control of cucumber anthracnose at 400 g ai/ha. Some of the other title compounds 2, 3 and two Baylis-Hillman bromide intermediates (11a, 11b) had moderate to good fungicidal activity.     

Lewis acid-mediated reactions of 1-cyclopropyl-2-arylethanone derivatives with diethyl 2-oxomalonate and ethyl 2-oxoacetate

TMSOTf-mediated reactions of 2-aryl-1-(1-phenylcyclopropyl)ethanones 1 with diethyl 2-oxomalonate 2 afford a novel method for the synthesis of spiro-γ-lactone derivatives 3 in good to excellent yields via a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H₂O, an aldol-type reaction and a cyclic transesterification mediated by Lewis acid. On the other hand, we found that TMSOTf-mediated reactions of 1-cyclopropyl-2-arylethanones 1 with ethyl 2-oxoacetate 4 could also provide the corresponding spiro-γ-lactone derivatives 5 in moderate yields along with another spiro-γ-lactone derivatives 6 derived from the reaction of 1 with two molecules of ethyl 2-oxoacetate. The plausible reaction mechanisms have also been provided on the basis of control experiments.     

Synthesis of dihydrobenzoimidazo[2,1-a]isoquinolines

A one-pot protocol toward several substituted 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolines 1 starting with 2-allylbenzaldehydes 2 was described. The process was carried out the one-pot condensation/hydroamination reaction of substituted 2-allylbenzaldehydes 2 with 1,2-diaminobenzenes 3 in refluxing toluene in good yields. Skeleton 2 was prepared via one-pot ortho-metalative PhBCl₂-mediated double alkylation of hydroxybenzaldehyde 4 with LDA in moderate yields.     

Reaction of selenofenchone with propiolic acid: first instance of Wagner-Meerwein rearrangement in selone

The reaction of selenofenchone (3a) with propiolic acid in refluxing chloroform produced selenodioxenone (4) along with rearranged product (5b), while 5b was obtained in almost quantitative yield under solvent-free conditions. In the presence of Lewis acid, selenofenchone 3a reacted with methyl propiolate to afford corresponding rearranged adduct (7).     

Convenient synthesis of mono- and di-β-hydroxy-β-bis(trifluoromethyl)-(di)imines from β-hydroxy-β-bis(trifluoromethyl)-ketones and (di)amines

A series of novel β-hydroxy-β-bis(trifluoromethyl)-imines (2a-j) and di(β-hydroxy-β-bis(trifluoromethyl))-diimines (3a-f) were prepared in moderate to good yields via a simple two-step approach: first, β-hydroxy-β-bis(trifluoromethyl)-ketones (1a-c) were obtained by a catalyst-free aldol reaction between liquid hexafluoroacetone sesquihydrate and ketones (acetone, acetophenone, and pinacolone, respectively); then, condensation of the latter fluorinated β-ketols 1a-c with primary amines or diamines was achieved in the presence of Lewis (montmorillonite, InBr₃, La(OTf)₃) or Brönsted (PTSA) acid catalysts. The molecular structures of mono- and di-β-hydroxy-β-bis(trifluoromethyl)-(di)imines 2e,h and 3a,f were determined and found to exhibit strong intramolecular (R)N?H-O hydrogen bonding.     

Reaction of chromone-3-carboxaldehydes with TOSMIC: synthesis of 4-(2-hydroxybenzoyl)pyrroles

Chromone-3-carboxaldehydes 1 react with tosylmethylisocyanide (TOSMIC) in the presence of DBU in THF at room temperature to furnish, after in situ deformylation, good yields of 2-tosyl-4-(2-hydroxybenzoyl)pyrroles 2. When the same reaction is performed with potassium carbonate in methanol under reflux pyrroles 2 are again isolated, but in lower yields. Finally, from the reaction of 1a in the presence of a stronger base (NaOH) only a small amount of the 3-substituted derivative 3a along with polymeric material is isolated.     

Synthesis and substitution reactions of β-alkoxyvinyl bromodifluoromethyl ketones

β-Alkoxyvinyl bromodifluoromethyl ketones 1a, 1b and 1c were synthesized by the reaction of bromodifluoroacetic anhydride with appropriate vinyl ethers in high yields. The acyclic enone 1a reacted with amines to give the corresponding β-aminovinyl bromodifluoromethyl ketones 2 in good yields. The reaction of 1a with electrophilic reagent ICl yielded α-iodoenone 4. The substitution reaction of the cyclic enones 1b and 1c with thio-nucleophiles gave the corresponding difluoromethylene thioethers 6. The three-component reactions of 2 with primary amines and formaldehyde gave multifunctional 1,2,3,4-tetrahydropyrimidine 3 in moderate yields.     

An efficient synthesis of benzofurans and their application in the preparation of natural products of the genus Calea

The intramolecular cyclization of the β-substituted olefins methyl 2-aryloxy-3-dimethylaminopropenoates 3a-3f catalyzed by Lewis acids leads to a short and novel synthesis of benzofurans 2a-2f. When the olefins 4-dimethylamino-3-aryloxy-3-buten-2-ones 4a-4f were used, the cyclization process was faster and provided the corresponding substituted 2-acetylbenzofurans 1a-1f. Among the latter, naturally occurring compounds calebertin (1a), caleprunin A (1b), and caleprunin B (1c) were prepared in good overall yields. These benzofurans were also obtained by direct treatment under MW irradiation of the precursors 1-aryloxypropan-2-ones 7a-7c with DMFDMA, followed by addition of the catalyst, resulting in a route that was one step shorter.     

Straightforward and highly efficient catalyst-free regioselective reaction of thiol to β-nitrostyrene: a concise synthesis of vinyl sulfide and nitro sulfide

Under catalyst-free reaction conditions, solvent-mediated addition of thiol 2 to β-nitrostyrene 1 proceeded with regioselective control to afford either adduct 3 or vinyl sulfide 4 in good to excellent yield. Thermodynamic and autocatalytic reaction mechanisms were proposed to rationalize the products thus formed.     

The influence of the ring size of thiolactams in the Eschenmoser coupling reaction in presence of DBU. Formation of bicyclic thiazolidinones or thioimines

The different behaviors of pyrrolidin-2-thione and piperidin-2-thione under a modified Eschenmoser sulfur contraction reaction protocol using DBU as base was observed. The pyrrolidin-2-thione 1b follows the expected reaction course, leading to thioimines 5a-d, which can be transformed subsequently into the respective by action of a thiophile, while the piperidin-2-thione leads to the formation of bicyclic thiazolidinones 4b-d in moderate to good yields. The β-enaminocarbonyl compound 11 was hydrogenated to afford the respective five-membered analogue of methylphenidate 12.