Baylis Hillman Adducts Research Articles

A Facile Anti-selective Synthesis of 3-Nitropyridin-2-ones Using Morita- Baylis Hillman Adduct of Nitroalkene

Background: Amide functionality is an important in many areas of chemistry, including peptide, polymer, and complex molecule synthesis. Furthermore, Morita-Baylis-Hillman (MBH) reaction is well known efficient and economical carbon-carbon bond forming reaction which affords densely functionalized scaffolds. δ-Lactams are important constituents of natural products and have widespread applications from pharmaceuticals to synthetic organic chemistry. To the best of our knowledge, MBH adducts of nitro alkenes and their further oxidized products have not been utilized to construct the target molecule of present investigation. With aim to incorporate nitro group in pyridin-2-ones, we wished to prepare MBH adduct of nitroalkenes, which would be a novel scaffold that can be utilized for synthesis of diverse molecules. Methods: A flame-dried round bottom flask was charged with benzimidazolium salt, α- nitrocinnamaldehyde, phenacyl bromide, and amine in THF/ButOH under positive pressure of nitrogen followed by addition of DBU. The resulting pale yellow solution was stirred for 12-14 h at room temperature and finally after work-up we isolated the desired amide. Then, a mixture of prepared amide and molecular iodine in dichloromethane was stirred at room temperature for 4.5-6 h yields the target lactams. Results: [E]-α-Nitrocinnamaldehydes, prepared from Morita-Baylis-Hillman adduct of nitoalkenes, were converted into functionalized amides (81-95%) under the catalysis of N-heterocyclic carbenes. The reaction proceeds via d3 nucleophile of homoenolate and involves three components coupling strategy. A probe to utilized the prepared amide scaffold for construction of pyridin-2-one was also performed and the reactions gave excellent yields (82-93%) of pure products with highly diastereoselective (>92%) in favor of trans isomer. Conclusion: We have documented an original NHC-catalyzed direct synthesis of α-nitro amides with diverse functionalities, which opens up a new aspect for the utility of MBH adducts of nitroalkenes in organic synthesis. We have also disclosed a new anti-selective synthesis of 3-nitropyridin-2-ones from the prepared amide scaffold. Thus, the envisaged atom-economic strategy for the synthetically important functionalized amides and pharmaceutically important 2-pyridones would be a practical alternative to the existing procedures for their preparations. Keywords: Nitroalkene, Baylis-Hillman adduct, N-heterocyclic carbene, pyridin-2-one, stereoselectivity.

Bioreduction of α‐Acetoxymethyl Enones: Proposal for an SN2′ Mechanism Catalyzed by Enereductase

Abstract(Z)‐3‐Acetoxymethyl‐4‐R‐3‐buten‐2‐ones (R=aryl, alkyl) and (Z)‐3‐methyl‐4‐R‐3‐buten‐2‐ones (R=aryl) were synthesized and submitted to reduction by the yeast Saccharomyces cerevisiae producing the (R)‐ and (S)‐4‐R‐3‐methybutan‐2‐ones, respectively. This stereochemistry control strategy was applied in the syntheses of (R)‐ and (S)‐Tropional® with moderate to high enantiomeric excesses. Other (Z)‐3‐acyloxymethyl‐4‐phenyl‐3‐buten‐2‐ones showed similar behavior to the (Z)‐3‐acetoxymethyl counterpart, and the acylated Morita–Baylis–Hillman adduct 1‐acetoxy‐2‐methylene‐1‐phenylbutan‐3‐one produced a mixture of products, with and without the acetoxy group, via three different reaction pathways. In addition to experiments employing whole cells, those in which isolated enereductases were used suggested that the main pathway through which the loss of the acetoxy group occurs during the biocatalytic cascade is an SN2′‐type reaction, rather than formal hydrogen addition followed by acetic acid elimination. Finally, related ethyl enones were reduced enantioselectively by the yeast Candida albicans, producing both (R)‐ and (S)‐reduction products, depending on the presence of the acetoxy group in the starting material.magnified image

ChemInform Abstract: Phosphine—Thiourea‐Organocatalyzed Asymmetric C—N and C—S Bond Formation Reactions.

Phosphine–thiourea based-organocatalysts derived from l-proline promoted C−N or C−S bond formation of tert-butoxycarbonyloxy-Morita—Baylis—Hillman adducts with phthalimide or alkyl thiols, respectively. Good yields and enantioselectivities up to 93 % were achieved.

Reaction of aryne with aza-Morita–Baylis–Hillman adducts: Synthesis of 4-quinolones and N-arylation products

The reaction of aryne with aza-Morita–Baylis–Hillman (aza-MBH) adducts has been studied. Aryne reacts with aza-MBH adducts through a cascade insertion–cyclization–ene reaction to produce 4-quinolones in 18–44% yields; meanwhile, aza-MBH adducts undergo N-insertion reaction with aryne to afford N-arylation products in 27–77% yields.

Proline-Mediated Baylis–Hillman Reaction of Methyl Vinyl Ketone without a Co-catalyst under Solvent-Free Conditions

A proline-mediated Baylis–Hillman reaction of methyl vinyl ketone with aromatic aldehydes has been carried out without using any co-catalyst, under solvent-free conditions. The reaction works efficiently at 60 °C in the presence of a small amount of water to afford the Baylis–Hillman adducts in reasonable to very good yields over 8–48 h. The absence of a co-catalyst suggests that proline plays a role in the proton-transfer step of the reaction mechanism, in addition to its proposed involvement in the iminium ion formation and conjugate addition. This would, in principle, imply that proline acts as a trifunctional catalyst in the reaction, and mechanistic studies to gain a deeper understanding of this aspect should provide further insights in the future.

ChemInform Abstract: An Efficient Synthesis of α‐Isothiocyanato‐α,β‐unsaturated Esters from Morita—Baylis—Hillman Adducts.

AbstractA facile one‐pot method for the synthesis of the title esters is developed involving the dehydration of the nitroalkane side‐chain of Morita—Baylis—Hillman adducts generating the corresponding nitrile oxide, and the following [3+2] cycloaddition to the C=S bond of thiourea affording a diaminooxathiazole intermediate.

ChemInform Abstract: An Efficient Synthesis of Dihydrobenzo[c]azepines from Morita—Baylis—Hillman Adducts via Pictet—Spengler Reaction.

Various dihydrobenzo[c]azepines were synthesized in good yields via Pictet–Spengler cyclization protocol from tosylamide derivatives of Morita–Baylis–Hillman adducts and 1,3,5-trioxane. The synthesis was carried out in the presence of easily removable montmorillonite K-10 in short time in high yields.

A Single-Flask Synthesis of Morita-Baylis-Hillman Adducts from Ethoxyacetylene and Carbonyl Compounds: Synthesis of Subamolides D and E.

Sequential treatment of (ethoxyethynyl)lithium with aldehydes and/or ketones (2 and 4) and BF3·OEt2 gives rise to β-hydroxyenoates 5 in good to excellent overall yields. Similarly, the combination of 1 (M = Li) and dicarbonyl compounds 6 (X = O) or keto/aldehyde acetals (X = OMe) followed by the addition of a Lewis acid leads to five-, six-, and seven-membered hydroxycycloalkene carboxyates. The utility of this method is demonstrated in the synthesis of the α-alkylidene lactone natural products subamolide D and E.

ChemInform Abstract: Enantioselective Allylic Substitution of Morita—Baylis—Hillman Adducts Catalyzed by Chiral Bifunctional Ferrocenylphosphines.

AbstractAir‐stable chiral ferrocenylphosphines are synthesized and utilized in the asymmetric allylic substitution of Morita—Baylis—Hillman adducts with phthalimide under mild reaction conditions.

Synthesis and activity of novel homodimers of Morita–Baylis–Hillman adducts against Leishmania donovani: A twin drug approach

It is reported here the synthesis of novel Homodimers 12–19 of Morita–Baylis–Hillman adducts (MBHA) from one-pot Morita–Baylis–Hillman Reaction (MBHR) between aromatic aldehydes as eletrophiles and ethylene glycol diacrylate as Michael acceptor (35–94% yields) using cheap and green conditions. The bioactivities were evaluated against promastigote form of Leishmania donovani. All homodimers showed to be more potent than corresponding monomers. It is worth highlighting that the halogenated homodimers 17 and 18 (0.50μM) is almost 400 times more active than the corresponding monomer 10 and 1.24 times more potent than the second-line drug amphotericin B (0.62μM). Moreover, the selectivity index to 18 is very high (SIrb>400) far better than amphotericin B (SIrb=18.73). This is the first report of twin drugs strategy applied on Morita–Baylis–Hillman adducts.

ChemInform Abstract: Synthesis of Hydrazinoheterocycles from Morita—Baylis—Hillman Adducts of Nitroalkenes with Azodicarboxylates.

AbstractA [3 + 2] annulation of hydrazinonitroalkenes, formed under Morita—Baylis—Hillman conditions, with naphthols involving Michael addition and cyclization as the key steps leads to arenodihydrofurans bearing a hydrazinodicarboxylate moiety.

ChemInform Abstract: Synthesis of Poly‐Substituted Benzene from Morita—Baylis—Hillman Adducts via [3 + 1 + 2] Annulation Strategy: Palladium‐Catalyzed Domino Cyclization (5‐exo/3‐exo), Ring‐Expansion by Palladium Rearrangement, and Aromatization.

ChemInform Abstract: Synthesis of Poly‐Substituted Benzene from Morita—Baylis—Hillman Adducts via [3 + 1 + 2] Annulation Strategy: Palladium‐Catalyzed Domino Cyclization (5‐exo/3‐exo), Ring‐Expansion by Palladium Rearrangement, and Aromatization.

Phosphine–Thiourea‐Organocatalyzed Asymmetric C−N and C−S Bond Formation Reactions

AbstractPhosphine–thiourea based‐organocatalysts derived from l‐proline promoted C−N or C−S bond formation of tert‐butoxycarbonyloxy‐Morita—Baylis—Hillman adducts with phthalimide or alkyl thiols, respectively. Good yields and enantioselectivities up to 93 % were achieved.

Rhodium‐Catalyzed [2+2+2] Cycloadditions of Diynes with Morita–Baylis–Hillman Adducts: A Stereoselective Entry to Densely Functionalized Cyclohexadiene Scaffolds

AbstractA rhodium‐catalyzed asymmetric synthesis of 5,5‐disubstituted cyclohexa‐1,3‐dienes has been achieved by [2+2+2] cycloaddition reactions between diynes and Morita–Baylis–Hillman (M‐B‐H) adducts as unsaturated substrates. Products containing two adjacent chiral centres (quaternary and tertiary, respectively) were obtained with complete diastereoselectivity and high enantioselectivity (84–97%) through a kinetic resolution of the M‐B‐H adduct. Furthermore, these highly substituted cyclohexadienes reacted with dienophiles to afford the corresponding Diels–Alder cycloadducts in good yields.magnified image

An Efficient Synthesis of Dihydrobenzo[c]azepines from Morita–Baylis–Hillman Adducts via Pictet–Spengler Reaction

Various dihydrobenzo[c]azepines were synthesized in good yields via Pictet–Spengler cyclization protocol from tosylamide derivatives of Morita–Baylis–Hillman adducts and 1,3,5‐trioxane. The synthesis was carried out in the presence of easily removable montmorillonite K‐10 in short time in high yields.

ChemInform Abstract: Synthesis of 1,3,4‐Trisubstituted Benzenes from Morita—Baylis—Hillman Adducts of α‐Bromocinnamaldehyde via [5 + 1] Annulation Strategy.

ChemInform Abstract: Synthesis of 1,3,4‐Trisubstituted Benzenes from Morita—Baylis—Hillman Adducts of α‐Bromocinnamaldehyde via [5 + 1] Annulation Strategy.

Enantioselective Allylic Substitution of Morita–Baylis–Hillman Adducts Catalyzed by Chiral Bifunctional Ferrocenylphosphines

AbstractA series of air‐stable chiral ferrocenylphosphines (LB1–LB4) were prepared and used in the asymmetric allylic substitution of Morita–Baylis–Hillman (MBH) adducts with phthalimide under mild reaction conditions; the (R,SFc)‐ferrocenylphosphine LB4 afforded the desired amination products 3 in moderate yields with excellent enantioselectivities. The absolute configuration of 3o was confirmed by X‐ray analysis.

An Efficient Synthesis of α‐Isothiocyanato‐α,β‐unsaturated Esters from Morita–Baylis–Hillman Adducts

An Efficient Synthesis of α‐Isothiocyanato‐α,β‐unsaturated Esters from Morita–Baylis–Hillman Adducts

Regioselective addition–elimination of Morita–Baylis–Hillman adducts with 2-naphthol or phenol catalyzed by functionalized ionic liquids: a direct strategy to construct functional alkenes

A highly regioselective addition–elimination of Morita–Baylis–Hillman adducts promoted by base ionic liquids (0.5 mol%) was reported to afford a variety of functional alkenes in excellent yields (up to 99%). This protocol provides a new method to access functional alkenes directly. Recycled base ionic liquids could be reused at least five times and the isolated yield of the product was almost consistent after five runs.

ChemInform Abstract: Synthesis of Highly Diversified 1,2,3‐Triazole Derivatives via Domino [3 + 2] Azide Cycloaddition and Denitration Reaction Sequence.

In this paper, an elegant synthesis of 1,2,3-triazole derivatives via domino [3 + 2] azide cycloaddition and denitration reaction sequence under catalyst free conditions has been described. Treatment of Baylis–Hillman adducts and their cyclic derivatives from nitroolefins with sodium azide in the absence of catalyst smoothly afforded the 1,2,3-triazole derivatives in excellent yields.