Facile synthesis of γ-alkylidenebutenolides from Morita–Baylis–Hillman adducts

An expedient synthetic procedure of γ-alkylidenebutenolides was developed via a sequential indium-mediated Barbier-type reaction of Morita–Baylis–Hillman bromide with aldehyde, lactonization, and double-bond isomerization. Various γ-alkylidenebutenolides including bovolide and its derivatives were synthesized in good overall yields.     

Highly efficient one-pot synthesis of fused pyrimidones from 2-heteroaryl amines and Morita–Baylis–Hillman carbonates via intermolecular cyclocondensation

A highly selective and efficient cyclocondensation reaction for construction of various 3-substituted-2H-pyrido[1,2-a]pyrimidin-2-ones and related fused pyrimidones from allylic carbonates and 2-heteroaryl amines has been developed. The transformation involves one-pot sequential aza-Michael addition, intramolecular acyl substitution, and [1,3]-H shift. The method is catalyst free, eco-friendly, scalable, and completes within a short reaction time, with no work-up, no column purification, and demonstrate a broad functional group tolerance.     

Morita–Baylis–Hillman reactions of isatins with allenoates

4-(N,N-dimethylamino)pyridine (DMAP) was found to be a fairly efficient catalyst for the Morita–Baylis–Hillman reactions of isatins with α-substituted allenoates to give the corresponding products in good to high yields with moderate diastereoselectivities under mild conditions.     

Asymmetric Morita–Baylis–Hillman reaction of chiral glyoxylates

The first Morita–Baylis–Hillman reaction of chiral glyoxylic acid derivatives, i.e. N-glyoxyloyl-(2R)-bornane-10,2-sultam and (−)-8-phenylmenthyl glyoxylate is described. The reaction with cyclic α,β-unsaturated ketones proceeded under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride. The adducts were obtained with very high diastereoisomeric excess (over 95% d.e.) and typical yields of 78%. The absolute configuration of the newly created stereogenic center was established by X-ray crystallographic analysis.     

Stereoselective synthesis of benzofulvenes via a palladium-catalyzed cyclization of 1,3-dienes derived from Morita–Baylis–Hillman adducts

A facile synthesis of benzofulvenes was carried out starting from the Morita–Baylis–Hillman adducts of 2-bromobenzaldehyde. The synthesis was carried out via the sequential bromination, Wittig reaction with aldehyde, and Pd-catalyzed intramolecular Mizoroki–Heck reaction. The stereochemistry of benzofulvenes was dependent on the reaction condition, especially on the kinds of base and reaction time, and the substituent of starting materials.     

1,1′-Carbonyldiimidazole mediates the synthesis of N-substituted imidazole derivatives from Morita–Baylis–Hillman adducts

In this Letter, we describe a simple and straightforward method for the synthesis of N-substituted imidazole derivatives. 1,1-carbonyldiimidazole mediates the process, which requires no activation group step. We obtained imidazole derivatives in high yields and with short reaction times. To demonstrate the synthetic significance of the aforementioned compounds, we also describe the synthesis of novel ionic liquids from these derivatives.     

Efficient synthesis of N-allylated 2-nitroiminoimidazolidine analogues from Baylis–Hillman bromides

Various Baylis–Hillman–derived new N-allylated 2-nitroiminoimidazolidine analogs were efficiently prepared using potassium carbonate as base. Simple workup procedure, excellent yields, and mild reaction conditions are the salient features of this method. All the synthesized compounds are screened for their larvicidal activity on fourth instar mosquito larvae, Culex quinquefasciatus.     

Highly regioselective synthesis of 3-alkylthio-2-oxindoles via DABCO-catalyzed allylic α-substitution of Morita–Baylis–Hillman carbonates of isatins with various thiols

The first Lewis base-catalysed allylic sulfuration of Morita–Baylis–Hillman (MBH) adducts derived from ketones (isatins) has been developed, which affords C3-quaternary oxindole derivatives bearing thio-group at 3-position in good to excellent yield (up to 98% yield) under mild reaction conditions. Significantly, the potential utility of the protocol also has been demonstrated by gram-scale synthesis of 3-alkylthio-2-oxindole (3ae), a low catalyst loading (0.3 mol %) and facile conversion of resulting product (3ad) into functionalized pyrrolidinone (5ad).     

Synthesis of chiral allene moiety from Morita–Baylis–Hillman adduct of isatin derivatives via Claisen rearrangement

Chiral allenes are synthesized from Morita–Baylis–Hillman adduct of isatin derivatives via Claisen rearrangement for the first time. The chiral 1,3-substituted allene entity is achieved using (R)-but-3-yn-2-ol. The details of the work are elaborately discussed in this letter.     

Diels–Alder dimerization of Morita–Baylis–Hillman acetates catalyzed by organocatalysts

DABCO-catalyzed dimerization of Morita–Baylis–Hillman acetates to synthesize a series of 3-alkyl-4-(E)-alkenyl-cyclohex-1-ene-1,4-dicarbonyl compounds in excellent yields with modest to excellent diastereoselectivity is reported. A plausible reaction mechanism is also proposed on the basis of previous literature and preliminary investigation the asymmetric version of the reaction.     

Synthesis of functionalized and fused furans and pyrans from the Morita–Baylis–Hillman acetates of nitroalkenes

The Morita–Baylis–Hillman (MBH) acetates derived from nitroalkenes and ethyl glyoxylate have been transformed in one pot at room temperature to highly fused and functionalized furans and pyrans in good to excellent yield. The reaction involves a cascade Michael–oxa-Michael addition of β-dicarbonyl compounds to the MBH acetates in the presence of an amine base such as DABCO. An unusual switching of selectivity in the oxa-Michael addition from 5-exo-trig to 6-endo-trig was observed when the β-dicarbonyl compound was changed from acyclic or six-membered ring cyclic to five-membered ring cyclic system.     

Construction of polycyclic spirooxindoles through [3+2] annulations of Morita–Baylis–Hillman carbonates and 3-nitro-7-azaindoles

A mild and efficient dearomatic [3+2] annulation reaction of 3-nitro-7-azaindoles and Morita Baylis Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindoles containing fused azaindoline architectures and vicinal quaternary centers in excellent yields(up to 96%) with high regio- and diastereoselectivity(dr 19:1). Moderate enantioselectivity(79% ee) was obtained by employing a chiral DMAP-type Lewis base catalyst.     

Direct Umpolung Morita–Baylis–Hillman like α-Functionalization of Enones via Enolonium Species

Herein we report on the umpolung of Morita–Baylis–Hillman type intermediates and application to the α-functionalization of enone C−H bonds. This reaction gives direct access to α-chloro-enones, 1,2-diketones and α-tosyloxy-enones. The latter are important intermediates for cross-coupling reaction and, to the best of our knowledge, cannot be made in a single step from enones in any other way. The proposed mechanism is supported by spectroscopic studies. The key initial step involves conjugate attack of an amine (DABCO or pyridine), likely assisted by hypervalent iodine acting as a Lewis acid leading to formation of an electrophilic β-ammonium-enolonium species. Nucleophilic attack by acetate, tosylate, or chloride anion is followed by base induced elimination of the ammonium species to give the noted products. Hydrolysis of α-acetoxy-enones lead to formation of 1,2-diketones. The α-tosyl-enones participate in Negishi coupling reactions under standard conditions.     

Enantioselective Morita–Baylis–Hillman reaction catalyzed by a chiral phosphine oxide

An application of a hypervalent silicon complex, generated from a chiral phosphine oxide catalyst and silicon tetrachloride, to the enantioselective organocatalytic Morita–Baylis–Hillman reaction is described. A chloride anion liberated from the hypervalent silicon complex smoothly generated a γ-chloro silyl enol ether that subsequently reacted with an aldehyde to afford the Baylis–Hillman adducts in good yields and with good enantioselectivities.     

Transition-metal-free nucleophilic allylic substitutions of Morita–Baylis–Hillman bromides with aliphatic and aromatic amines

A simple protocol for the preparation of functionalized allylic amines under mild, transition-metal-free conditions from the reaction of Morita–Baylis–Hillman (MBH) bromides with amines is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et₃N in aqueous acetone solution and at room temperature affords the corresponding functionalized allyl amines in moderate to good yields (45–87%). The reaction is rapid and carried out at room temperature.     

Computational Evolution Of New Catalysts For The Morita–Baylis–Hillman Reaction**

We present a de novo discovery of an efficient catalyst of the Morita–Baylis–Hillman (MBH) reaction by searching chemical space for molecules that lower the estimated barrier of the rate-determining step using a genetic algorithm (GA) starting from randomly selected tertiary amines. We identify 435 candidates, virtually all of which contain an azetidine N as the catalytically active site, which is discovered by the GA. Two molecules are selected for further study based on their predicted synthetic accessibility and have predicted rate-determining barriers that are lower than that of a known catalyst. Azetidines have not been used as catalysts for the MBH reaction. One suggested azetidine is successfully synthesized and showed an eightfold increase in activity over a commonly used catalyst. We believe this is the first experimentally verified de novo discovery of an efficient catalyst using a generative model.     

Lipase-catalyzed kinetic resolution of Baylis–Hillman products

Lipase-catalyzed kinetic resolution of the various Baylis–Hillman products, α-methylene-β-hydroxy compounds, were examined. When lipase PS was used as a biocatalyst in acetonitrile, transesterification of racemic ethyl 3-hydroxy-2-methylenebutanoate or 3-hydroxy-2-methylenepentanoate proceeded in a practical enantiomeric excess. The resolution by hydrolysis of the acetate derivatives was also tried. In contrast, in case of racemic ethyl 3-acetoxy-2-methylenepentanoate, under the conditions using lipase AK, the E value of the resolution was >321.     

Diastereoselective peroxidation of derivatives of Baylis–Hillman adducts

Cyclic derivatives of Baylis–Hillman adducts were synthesized. Cobalt-catalyzed peroxidation of these cyclic lactones afforded silyl peroxides in diastereomeric ratios ranging from 91:9 to 97:3.     

Transition metal-free direct nucleophilic α-substitution of Morita–Baylis–Hillman alcohols with amines and thiols

An efficient transition metal-free allylic nucleophilic α-substitution of Morita–Baylis–Hillman alcohols with both aliphatic and aromatic amines in refluxing toluene, using activated molecular sieves as additives, is described herein. The reaction proceeded with exclusive α-regioselectivity in moderate to excellent yields with the formation of water as the sole by-product. Under the same conditions, upon treatment of some thiols with the title substrates, allylic sulfides were obtained in excellent yields and high regioselectivity.     

Palladium-catalyzed synthesis of benzo[c]pyrimido[1,6-a]azepine scaffold from Morita–Baylis–Hillman adducts: intramolecular 6-arylation of uracil nucleus

Palladium-catalyzed intramolecular arylation at the C-6 position of uracil moiety was examined. Morita–Baylis–Hillman adducts bearing an uracil moiety at the primary position served an efficient way to a benzo[c]pyrimido[1,6-a]azepine scaffold.