A convenient approach to β-heteroarylated (C-N bond) ketones from Cs2CO3 promoted reaction between propargyl alcohols and nitrogen-heterocycles

An efficient and direct approach to β-heteroarylated (C-N bond) ketones is demonstrated. Base promoted redox isomerization of propargyl alcohol to α,β-unsaturated ketone followed by conjugate addition to NH-heteroarenes affords a wide range of β-heteroarylated ketones in good to excellent yields. Aryl, heteroaryl, alkyl C(sp), and terminal alkynes containing unactivated propargyl alcohols effectively undergo redox-isomerization conjugate addition (RICA) with NH-heteroarenes. Reaction of 3-substituted pyrazoles or indazole with propargyl alcohols enables highly regioselective products. A diverse range of NH-bearing nucleophiles such as: pyrazoles, imidazole, triazoles, pyrrole, indoles and aniline participate in this reaction and deliver the corresponding β-heteroarylated ketones.     

Highly enantioselective direct conjugate addition of ketones to nitroalkenes promoted by a chiral primary amine-thiourea catalyst

Primary amine-thiourea derivative 1 is an active and highly enantioselective catalyst for the conjugate addition of ketones to nitroalkenes. Broad substrate scope is described, with nitroalkenes bearing either aromatic or aliphatic substituents and a wide variety of ketones shown to be useful reacting partners. Ethyl ketones react preferentially, generating anti products with methyl-bearing stereocenters with good-to-excellent diastereoselectivity. An enamine mechanism is indicated, with cooperative activation of the electrophile by the thiourea and of the ketone by the primary amine.     

Potassium phosphate or silica sulfuric acid catalyzed conjugate addition of thiols to α,β-unsaturated ketones at room temperature under solvent-free conditions

Potassium phosphate and silica sulfuric acid have been found to be useful and highly efficient catalysts for conjugate addition of thiols to α,β-unsaturated ketones under solvent-free conditions, at room temperature. Silica sulfuric acid (SSA) was found to be suitable for electron-deficient enones while potassium phosphate was found to effect thia-Michael addition with both, electron-deficient as well as electron-rich conjugated ketones.     

Enantioselective palladium-catalysed conjugate addition of arylsiloxanes

The complex formed from Pd(CH(3)CN)(4)(BF(4))(2) and (R,R)-MeDUPHOS is a highly enantioselective catalyst for the asymmetric conjugate addition of aryltriethylsiloxanes to a variety of unsaturated ketones, lactones and lactams.     

Catalytic multicomponent synthesis of highly substituted pyrroles utilizing a one-pot sila-Stetter/Paal-Knorr strategy

[reaction: see text] A multicomponent synthesis of highly substituted pyrroles catalyzed by thiazolium salts has been disclosed. The reaction employs an acyl anion conjugate addition reaction of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. The subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired pyrrole nucleus in an efficient one-pot process.     

Intramolecular cyclization of tert-butyldiphenylallylsilane units and carbonyl groups: allylsilane terminated cyclization versus the ene reaction.

tert-Butyldiphenylsilylcopper reacts with allene to give an allylsilane-vinylcopper intermediate which upon treatment with alpha,beta-unsaturated ketones leads to allylsilane containing ketones resulting from conjugate addition. These oxoallylsilanes bearing the bulky tert-butyldiphenylsilyl group undergo highly selective intramolecular cyclizations when treated with Lewis acid affording unsaturated cyclopentanols. Two reactivity patterns are observed: allylsilane terminated cyclization involving elimination of silicon or an ene reaction without losing the silyl group. The pathway depends on the ability of a hydrogen beta to the carbonyl to be removed in an ene-type process. Alpha,beta-unsaturated acid chlorides lead to silylated cyclopentenones.     

Highly active chiral phosphoramide-Zn(II) complexes as conjugate acid-base catalysts for enantioselective organozinc addition to ketones

A highly efficient enantioselective organozinc (R2Zn) addition to ketones catalyzed by chiral phosphoramide-Zn(II) complexes (1-10 mol %) has been developed. These complexes serve as conjugate Lewis acid-Lewis base catalysts. Chiral phosphoramides are derived from an inexpensive natural amino acid (i.e., L-valine). From a variety of nonactivated aromatic and aliphatic ketones, the corresponding optically active tertiary alcohols were obtained in high yields with high enantioselectivities (up to 98% ee) under the mild reaction conditions.     

Enantioselective organocatalytic conjugate addition of α-nitroacetate to α,β-unsaturated ketones in water

The catalytic enantioselective conjugate addition reaction of α-nitroacetate to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of α-nitroacetate to α,β-unsaturated ketones under aqueous-phase reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are easily converted to chiral δ-keto nitroalkanes and δ-keto esters.     

"Amphiphilic" Cleavage of gamma-Stannyl Ketones with ATPH/RLi: Application to Enone Fragmentation by the Conjugate Addition - Cleavage Sequence

The use of a combined Lewis acid/base system consisting of aluminum tris(2,6-diphenylphenoxide) (ATPH) and MeLi has allowed the electrophilically activated nucleophilic ("amphiphilic") cleavage of C(alpha)-C(beta) bonds in gamma-stannyl ketones. Through combination with the conjugate addition of alpha-stannyl carbanion to enone, this approach constitutes a novel two-step conjugate addition - cleavage sequence that leads to functionalized ketones (see reaction).     

Enantioselective conjugate addition of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones catalyzed by chiral bifunctional organocatalysts

The catalytic enantioselective conjugate addition reaction of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones promoted by chiral bifunctional organocatalysts is described. The treatment of fluorobis(phenylsulfonyl)methane to α,β-unsaturated ketones under mild reaction conditions afforded the corresponding Michael adducts with high enantioselectivity. The conjugate addition adducts are useful for the synthesis of chiral monofluoromethylated compounds.     

Highly enantioselective conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones catalyzed by 9-amino-9-deoxyepiquinine

Asymmetric conjugate addition of 1-bromonitroalkanes to α,β-unsaturated ketones was studied using chiral primary amines as the catalysts. 9-Amino-9-deoxyepiquinine was found to be highly efficient catalyst for the transformation. 4-Bromo-4-nitroketones were obtained with excellent enantioselectivities (97-99% ee) and good yields (61-99%) for a variety of alkyl vinyl ketones. The product could be further debrominated with Bu₃SnH/AIBN to provide chiral 4-nitroketones in good yield and without loss of the optical purity.     

Ceric ammonium nitrate (CAN) as a green and highly efficient promoter for the 1,4-addition of thiols and benzeneselenol to α,β-unsaturated ketones

A mild and efficient process for the 1,4-addition of thiols and benzeneselenols to various α,β-unsaturated ketones using a catalytic amount of CAN with excellent product yields is described. This inexpensive, nontoxic, and readily available catalytic ceric(IV) ammonium nitrate system efficiently catalyzes conjugate addition reactions between thiol derivatives and various α,β-unsaturated ketones under solvent-free conditions. A plausible mechanism for the role of CAN, both as a promoter in free radical chain addition reactions as well as a catalyst for the conjugate addition process is proposed.     

Bismuth trichloride-catalyzed oxy-Michael addition of water and alcohol to α,β-unsaturated ketones

An efficient method was developed for the conjugate addition of water to various α,β-unsaturated ketones by using bismuth(III) chloride as a catalyst. The reactions proceeded smoothly in the presence of a catalytic amount of BiCl₃ (20 mol%) in aqueous media to furnish a variety of synthetically useful β-hydroxyl ketones in moderate to good yields. Apart from water molecule, various alcohols could also be employed as nucleophiles to react with α,β-unsaturated ketones, leading to β-alkoxyl ketones in modest to high yields. In addition, the mild reaction conditions also entailed the conjugate addition reactions to proceed with the tolerance to a range of functional groups.     

Total Synthesis of (−)-Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃-mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (−)-glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Asymmetric conjugate addition of carbonyl compounds to nitroalkenes catalyzed by chiral bifunctional thioureas

Readily available chiral thioureas derived from cyclohexane-1,2-diamine were prepared and found to be highly effective organocatalysts for the conjugate addition of aldehydes and ketones to nitroalkenes. Excellent enantioselectivities and yields were obtained for a variety of aryl and heteroaryl nitroalkenes. The base additives are essential for good yields and excellent enantioselectivities in this transformation. Based on new experimental evidence, a modified catalytic mechanism was proposed to rationalize the important role of the base additives.     

Total Synthesis of (−)‐Glaucocalyxin A

A practically useful method for the formation of the highly oxygenated bicyclo[3.2.1]octane ring system through Mn(OAc)₃‐mediated radical cyclization of alkynyl ketones was developed, which opens up a new avenue for the total synthesis of a number of highly oxidized diterpenoids. Application of this method enabled the first total synthesis of (?)‐glaucocalyxin A. Other salient features of the synthesis include a highly enantioselective conjugate addition/acylation cascade reaction, a Yamamoto aldol reaction, and an intramolecular Diels–Alder reaction to assemble the A/B ring system.     

Enantioselective conjugate radical addition to alpha'-hydroxy enones

Enantioselective conjugate radical addition to alpha'-hydroxy alpha,beta-unsaturated ketones, compounds containing bidentate donors, has been investigated. It has been found that radical additions to alpha'-hydroxy alpha,beta-unsaturated ketones in the presence of Mg(NTf2)2 and bisoxazoline ligand 5a proceeded cleanly, yielding the addition products in high chemical yields and good enantiomeric excesses.     

Chiral ligand-controlled asymmetric conjugate addition of alpha-trimethylsilanylacetate to acyclic and cyclic enones

The reaction of lithium ester enolate with enones provides a challenge for chemoselectivity, that is, discrimination between a conjugate addition and a 1,2-addition. Asymmetric conjugate addition of a lithium enolate of alpha-trimethylsilanylacetate to acyclic and cyclic alpha,beta-unsaturated ketones was mediated by an external chiral ligand to give the corresponding 1,4-adducts in good enantioselectivity of 74% and good chemoselectivity.     

Catalytic enantioselective conjugate allylation of unsaturated methylidene ketones

The use of unsaturated methylidene ketones in catalytic conjugate allylations allows a significant expansion in substrate scope and, with appropriate chiral ligands, occurs in a highly enantioselective fashion.     

Synthesis of β-silyl ketones via reaction of trimethylsilyllthium with unsaturated hydrazones. Application to the synthesis of brevicomin

Trimethylsilyllithium undergoes conjugate addition to dimethylhydrazones of α,β-unsaturated ketones. The resulting metalloenamine intermediates can be alkylated, and the resulting hydrazone products cleaved to give α-substituted-β-silyl ketones. These reactions, together with a silicon-directed Baeyer-Villiger reaction, have been applied to the synthesis of brevicomin.