Α-alkylated Products Research Articles

Novel Brønsted Acid Catalyzed C-C Bond Activation and α-Alkylation of Ketones.

A novel approach for the α-alkylation of ketones was developed using Brønsted acid-catalyzed C-C bond cleavage. Both aromatic and aliphatic ketones reacted smoothly with 2-substituted 1,3-diphenylpropane-1,3-diones to afford α-alkylation products with high yields and with excellent regioselectivity, in which the 1,3-dicarbonyl group acted as a leaving group in the presence of the catalyst TfOH. Mechanism experiments showed that the β-C-C bond cleavage of diketone and the shift of the equilibrium towards the enol formation from ketone are driving forces that induce the desired products.

Nickel-Catalyzed α-Alkylation of Arylacetonitriles with Challenging Secondary Alcohols.

Nickel(II) complex 1 was utilized as a sustainable catalyst for α-alkylation of arylacetonitriles with challenging secondary alcohols. Arylacetonitriles with a wide range of functional groups were tolerated, and various cyclic and acyclic secondary alcohols were utilized to yield a large number of α-alkylated products. The plausible mechanism involves the base-promoted activation of precatalyst 1 to an active catalyst 2 (dehydrochlorinated product) which activates the O-H and C-H bonds of the secondary alcohol in a dehydrogenative pathway.

Iridium-Catalyzed Enantioselective Direct α-C-H Alkylation of Saturated Cyclic Amines with Alkenes.

Enantioselective direct α-C(sp3)-H alkylation of saturated cyclic amines having N-methylbenzimidazolyl as a directing group was realized by using a cationic iridium/chiral diphosphine catalyst. The alkylation of pyrrolidine derivatives with various terminal alkenes proceeded to give α-alkylated products in high yields with high enantioselectivities. Chiral α,α'-dialkylated pyrrolidine derivatives were also synthesized by using an excess of alkenes or by stepwise alkylation.

α-Alkylation of Ketones with Alkenes Enabled by Photoinduced Activation of Silyl Enol Ethers in the Presence of a Small Amount of Water.

Under blue-light irradiation conditions with a photocatalyst [1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene], silyl enol ethers reacted with alkenes in the presence of a small amount of water to afford the α-alkylation products in good to high yields. A thiol cocatalyst was found to expand the substrate scope of the reaction.

Efficient α-Alkylation of Arylacetonitriles with Secondary Alcohols Catalyzed by a Phosphine-Free Air-Stable Iridium(III) Complex.

A well-defined and readily available air-stable dimeric iridium(III) complex catalyzed α-alkylation of arylacetonitriles using secondary alcohols with the liberation of water as the only byproduct is reported. The α-alkylations were efficiently performed at 120 °C under solvent-free conditions with very low (0.1-0.01 mol %) catalyst loading. Various secondary alcohols including cyclic and acyclic alcohols and a wide variety of arylacetonitriles bearing different functional groups were converted into the corresponding α-alkylated products in good yields. Mechanistic study revealed that the reaction proceeds via alcohol activation by metal-ligand cooperation with the formation of reactive iridium-hydride species.

Versatile formation of Ru(II) hydrazone complexes: Structure, theoretical studies and catalytic activity in α-alkylation

New 1-(anthracen-10-yl)methylene)-2-(benzo[d]thiazol-2-yl)hydrazine (BHA) and 1-(anthracen-10-yl)methylene)-2-(quinolin-2-yl)hydrazine (QHA) ligands were reacted with [RuHCl(CO)(E)3] (E = PPh3 or AsPh3) or [RuCl2(AsPh3)3] in a 1:1 mol ratio in chloroform-ethanol medium to synthesis new ruthenium complexes. All the new ruthenium complexes were analyzed by elemental analysis, IR, NMR (1H, 13C and 31P) spectroscopy, ESI-Mass spectrometry and single crystal XRD techniques. The single crystal XRD study reveals the octahedral geometry around the ruthenium ion. The study also shows that the ligands coordinate with the Ru metal as monoanionic bidentate N^N donors in complexes 1, 3 and 4 and as a neutral bidentate N^N donor in complex 2 by forming five or four member chelate rings. The intramolecular interactions in the crystal lattices were studied by Hirshfeld surface analysis. The results indicate that π-stacking contacts play an important role in the crystal lattices. DFT calculations were carried out to explain the solid structures of complexes 1–3. Moreover, the synthesized complexes were screened as catalysts for the α-alkylation of ketones with alcohols. The effect of various parameters, such as base, solvent, temperature, time, substituents and also catalyst loading, on the catalytic activity were analyzed. The results depict that the complex 3 was found to be an efficient catalyst for the synthesis of α-alkylation products.

Manganese(I)-Catalyzed Cross-Coupling of Ketones and Secondary Alcohols with Primary Alcohols.

Catalytic cross-coupling of ketones and secondary alcohols with primary alcohols is reported. An abundant manganese-based pincer catalyst catalyzes the reactions. Low loading of catalyst (2 mol %) and catalytic use of a mild base (5–10 mol %) are sufficient for efficient cross-coupling. Various aryl and heteroaryl ketones are catalytically cross-coupled with primary alcohols to provide the selective α-alkylated products. Challenging α-ethylation of ketones is also attained using ethanol as an alkylating reagent. Further, direct use of secondary alcohols in the reaction results in in situ oxidation to provide the ketone intermediates, which undergo selective α-alkylation. The reaction proceeds via the borrowing hydrogen pathway. The catalyst oxidizes the primary alcohols to aldehydes, which undergo subsequent aldol condensation with ketones, promoted by catalytic amount of Cs2CO3, to provide the α,β-unsaturated ketone intermediates. The hydrogen liberated from oxidation of alcohols is used for hydrogenation of α,β-unsaturated ketone intermediates. Notably either water or water and dihydrogen are the only byproducts in these environmentally benign catalytic processes. Mechanistic studies allowed inferring all of the intermediates involved. Dearomatization–aromatization metal–ligand cooperation in the catalyst facilitates the facile O–H bond activation of both primary and secondary alcohols, and the resultant manganese alkoxide complexes produce corresponding carbonyl compounds, perhaps via β-hydride elimination. The manganese(I) hydride intermediate plays dual role as it hydrogenates α,β-unsaturated ketones and liberates molecular hydrogen to regenerate the catalytically active dearomatized intermediate. Metal–ligand cooperation allows all of the manganese intermediates to exist in same oxidation state (+1) and plays an important role in these catalytic cross-coupling reactions.

Enantioselective Synthesis of Chiral α-Azido and α-Aryloxy Quaternary Stereogenic Centers via the Phase-Transfer-Catalyzed α-Alkylation of α-Bromomalonates, Followed by SN2 Substitution.

A new efficient synthetic method for chiral α-azido-α-alkylmalonates and α-aryloxy-α-alkylmalonates was developed. The enantioselective α-alkylation of diphenylmethyl tert-butyl α-bromomalonate under phase-transfer catalytic conditions [(S,S)-3,4,5-trifluorophenyl-NAS bromide, 50% KOH, toluene, and -40 °C) provided the corresponding α-bromo-α-alkylmalonates in high chemical yields (≤98%) and high optical yields (≤99% ee). The resulting α-alkylated products were converted to α-azido-α-alkylmalonates (≤96%, ≤97% ee) and α-aryloxy-α-alkylmalonates (≤79%, ≤93% ee) by SN2 substitution with sodium azide and aryloxides, respectively.

Oxidative umpolung α-alkylation of ketones.

We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds with dialkylzinc as the alkyl source. The reaction is applicable to all common classes of ketones including 1,3-dicarbonyl compounds and regular ketones via their lithium enolates. The α-alkylated carbonyl products are formed in up to 93% yield. An ionic mechanism is inferred based on meticulous analysis, NMR studies, trapping and crossover experiments, and computational studies.

Deaminative and Decarboxylative Catalytic Alkylation of Amino Acids with Ketones

It cuts two ways: The cationic [Ru-H] complex catalyzes selective coupling of α- and β-amino acids with ketones to form α-alkylated ketone products. The reaction involves CC and CN bond cleavage which result in regio- and stereoselective alkylation using amino acids. A broad substrate scope and high functional-group tolerance is demonstrated.

ChemInform Abstract: Tantalum Catalyzed Hydroaminoalkylation for the Synthesis of α‐ and β‐Substituted N‐Heterocycles.

Abstractα‐Alkylated piperidine, piperazine, and azepane products are prepared in an atom‐economic reaction with excellent regio‐ and diastereoselectivity.

Highly Enantioselective Synthesis of Atropisomeric Anilide Derivatives through Catalytic Asymmetric N-Arylation: Conformational Analysis and Application to Asymmetric Enolate Chemistry

In the presence of (R)-DTBM-SEGPHOS-Pd(OAc)(2) catalyst, N-arylation (aromatic amination) of various o-tert-butylanilides with p-iodonitrobenzene proceeds with high enantioselectivity (88-96% ee) to give atropisomeric N-(p-nitrophenyl)anilides having an N-C chiral axis in good yields. Atropisomeric anilide products highly prefer to exist as the E-rotamer which has trans-disposed o-tert-butylphenyl group and carbonyl oxygen. The application of the present catalytic enantioselective N-arylation to an intramolecular version gives atropisomeric lactam derivatives with high optical purity (92-98% ee). The reaction of the lithium enolate prepared from the atropisomeric anilide and lactam products with various alkyl halides gives alpha-alkylated products with high diastereoselectivity (diastereomer ratio = 13:1 to 46:1).

L-Valinol and l-phenylalaninol-derived 2-phenylamino-2-oxazolines as chiral auxiliaries in asymmetric alkylations

Lithium enolates of N-acyl phenyliminooxazolidine auxiliaries reacted with alkyl halides to produce the α-alkylated products with very high diastereofacial selectivity (up to >99% d.e.). The products were readily cleaved by simple alkaline hydrolysis to give homochiral carboxylic acids and could also be directly converted to aldehydes and other acid derivatives such as esters and amides.

Lithium enediolates and dienediolates of carboxylic acids in synthesis: Alkylation with secondary halides

High yields in the alkylation of dianions of α,β-unsaturated carboxylic acids with secondary halides can be obtained despite elimination reactions occurring. α-Regioselectivity for the alkylation of but-2-enoic acids ( 1–4) is seldom obtained. Although double bond stereoselectivity is higher than 99% for γ-alkylated products, stereoselectivity is rather poor for most of the α-alkylated products.

Synthesis of tertiary alkyl fluoride centers by asymmetric CC(F) bond formation

Asymmetric alkylation of pseudoephedrine α-fluoropropionamide ( 1) affords α-alkylated products efficiently and with excellent stereocontrol at the newly formed tertiary alkyl fluoride center. Mild alkaline hydrolysis of the products provides the corresponding carboxylic acids with high enantiomeric excess.

The Wittig Rearrangement of Chiral S-Methyl Phosphinothioates Promoted by Direct Deprotonation with Lithium Dialkylamides

Abstract Sequential treatment of S-methyl (t-butyl)phenyl- or (1-naphthyl)phenylphosphinothioates with lithium dialkylamides at −78 °C and then with alkyl halides at 0 °C—r.t. gave the corresponding (alkylthiomethyl)phosphine oxides, the Wittig rearrangement products, in moderate to good yields along with small amount of their overreacted α-alkylated products. The corresponding alkylphosphine oxide was obtained only in the reaction of naphthyl derivative. Optically active Wittig rearrangement products were given in 82 and 78% optical yields, respectively.

Fluorinated ketones in the Baylis-Hillman reaction

Hexafluoroacetone, bromopentafluoroacetone, 1,3-dichloro-1,1,3,3-tetrafluoroacetone, and trifluoropyruvic acid methyl ester react with ethyl acrylate, acrylonitrile, acrolein, and methyl vinyl ketone in the presence of 1,4-diazabicyclo[2,2,2]octane with the formation of α-alkylation products.

Addition of organocopper reagents to cyclic sulfites or carbonates of γ,δ-dihydroxy ( E)-α,β-enoates

Reaction of cyclic sulfites or carbonates of γ,δ-dihydroxy ( E)-α,β-enoates with R 2Cu(CN)Li 2, BF 3; RCu(CN)Li, BF 3(R = Me-, n-Bu-) afforded either diastereoselective S N2′products or reductive elimination product depending on reaction conditions. Addition of R 2Cu(CN)Li 2, BF 3(R = Me-, n-Bu-) to cyclic sulfite ( 1) or cyclic carbonate ( 3) (inverse addition) afforded highly regio-, ( E)-stereo- and diastereoselectively α-alkylation products ( 6 and 8). By using this methodology, (2 S, 5 S)- trans-2-methyl-5-hexanolide, the pheromone of the carpenter bee Xylocopa hirutissima was synthesized.

ChemInform Abstract: A NEW SYNTHETIC METHOD OF α,β‐UNSATURATED KETONES VIA REGIOSELECTIVE REACTION OF ALLYL ANION FORMED FROM 2‐MORPHOLINO‐3‐BUTENENITRILES (MASKED ACYL ANION EQUIVALENTS) WITH ALKYL HALIDES FOLLOWED BY HYDROLYSIS

AbstractDie Morpholinobutennitrile (I) werden durch Alkylhalogenide (II) selektiv in α‐Stellung zur Nitrilgruppe alkyliert.

A NEW SYNTHETIC METHOD OF α,β-UNSATURATED KETONES VIA REGIOSELECTIVE REACTION OF ALLYL ANION FORMED FROM 2-MORPHOLINO-3-BUTENENITRILES (MASKED ACYL ANION EQUIVALENTS) WITH ALKYL HALIDES FOLLOWED BY HYDROLYSIS

Abstract Treatment of 2-morpholino-3-butenenitriles and alkyl halides regioselectively afforded products alkylated on α-position to the nitrile group. The hydrolysis of the α-alkylation products gave the α,β-unsaturated ketones in good yields.