TiF-mediated, one-pot, reductive amination of carboxylic acids with borane-ammonia.

A facile one-pot, two-step, reductive alkylation of amines with carboxylic acids has been achieved with BH-NH as an air- and moisture-stable reductant in the presence of TiF. The catalyst is effective for both amidation and reduction steps, and the product amines are isolated in high yields as either the free amines, for those products containing an arylamine, or the borane-complexes. The free amine can be separated from these complexes using BF-EtO, followed by hydrolysis.

Titanium tetrafluoride catalysis for the dehydrative conversion of diphenylmethanols to symmetric and unsymmetric ethers.

In contrast to the conversion of diphenylmethanol to the corresponding halides with an equivalent of titanium tetrachloride or -bromide, catalytic (50 mol%) titanium tetrafluoride converts benzhydrols in diethyl ether or dichloromethane to bis(benzhydryl) ethers within 0.5-1 h at room temperature. Cross ether formation with diphenylmethanols and primary aryl or aliphatic alcohols is achieved in the presence of 25 mol% TiF in refluxing toluene as solvent.

Aryl carbonyls and carbinols as proelectrophiles for Friedel-Crafts benzylation and alkylation.

Friedel-Crafts benzylation/alkylation using benzylic, tertiary, and homobenzylic alcohols; aryl aldehydes, aryl ketones, and the highly challenging aryl carboxylic acids and esters as proelectrophiles has been achieved using borane-ammonia and TiCl, greatly broadening the scope of useable substrates. Incorporation of deactivated aromatic proelectrophiles and specificity for substitution at the benzylic position are demonstrated in the synthesis of various di- and triarylalkane products. Dual protocols allow for the use of standard nucleophilic solvents (benzene, toluene, ) or for stoichiometric addition of more valuable nucleophiles including furans, thiophenes, and benzodioxoles.

Synthesis and Energetic Characterization of Borane-Amines on High-Nitrogen Heterocycles.

Borane-amines have garnered attention over the last several decades in a variety of applications, ranging from hydrogen storage materials to hypergolic fuel systems. An investigation into the synthesis of borane-amines with high-nitrogen content heterocycles was undertaken in this work. Borane-amines were formed by the reaction of BH·MeS in tetrahydrofuran (THF) with the requisite nitrogen-containing heterocycle and isolated by placing the crude reaction mixture in hexanes to precipitate the product.

TiF-catalyzed direct amidation of carboxylic acids and amino acids with amines.

Unlike other metal fluorides, catalytic titanium tetrafluoride enhances the direct amidation of aromatic and aliphatic carboxylic acids and -protected amino acids in refluxing toluene. While aromatic acids were converted to amides with 10 mol% of the catalyst within 24 h, aliphatic acids underwent a faster reaction (12 h), with lower catalyst loading (5 mol%). This protocol is equally efficient with alkyl and aryl amines providing a variety of carboxamides and peptides in 60-99% yields.

Borane-Pyridine: An Efficient Catalyst for Direct Amidation.

Borane-pyridine acts as an efficient (5 mol%) liquid catalyst, providing improved solubility for the direct amidation of a wide range of aromatic and aliphatic carboxylic acids and amines to form secondary and tertiary carboxamides. Tolerance of potentially incompatible halo, nitro, and alkene functionalities has been demonstrated.

One-Pot, Tandem Reductive Amination/Alkylation-Cycloamidation for Lactam Synthesis from Keto or Amino Acids.

Monotrifluoroacetoxyborane-amines, prepared by treating borane-amines with trifluoroacetic acid, have been shown to be efficient reagents for a one-pot, tandem reductive amination/alkylation-cycloamidation of keto or amino acids to achieve the synthesis of 5-aryl or 5-methyl pyrrolidin-2-ones and 6-aryl or 6-methyl piperidin-2-ones.

Catalyst- and Stoichiometry-Dependent Deoxygenative Reduction of Esters to Ethers or Alcohols with Borane-Ammonia.

A facile and selective room temperature deoxygenation of both aromatic and aliphatic carboxylic esters to ethers has been achieved by regulating the stoichiometry of the reductant, BH-NH, and the catalyst, TiCl. This first, practical borane-mediated process is compatible with various potentially sensitive functional groups and is applicable to the deoxygenative ether formation from typically challenging aromatic acid esters. Substituting BF-EtO as the catalyst alters the reaction pathway, reducing the esters to alcohols.

Titanium-Mediated Reduction of Carboxamides to Amines with Borane-Ammonia.

In this study, the successful titanium tetrachloride-catalyzed reduction of aldehydes, ketones, carboxylic acids, and nitriles with borane-ammonia was extended to the reduction (deoxygenation) of a variety of aromatic and aliphatic pri-, sec- and tert-carboxamides, by changing the stoichiometry of the catalyst and reductant. The corresponding amines were isolated in good to excellent yields, following a simple acid-base workup.

Balancing Lewis Acidity and Carbocation Stability for the Selective Deoxyhalogenation of Aryl Carbonyls and Carbinols.

Deoxyhalogenation of aryl aldehydes, ketones, carboxylic acids, and esters has been achieved utilizing an appropriate metal halide Lewis acid acting as a carbonyl activator and halogen carrier in combination with borane-ammonia as the reductant. Selectivity is accomplished by matching the stability of the carbocation intermediate with the effective acidity of the Lewis acid. Substituents and substitution patterns significantly influence the requisite solvent/Lewis acid combination.

Room Temperature Reduction of Titanium Tetrachloride-Activated Nitriles to Primary Amines with Ammonia-Borane.

The reduction of a variety of aromatic and aliphatic nitriles, activated by a molar equivalent of titanium tetrachloride, has been achieved at room temperature using ammonia borane as a safe reductant. The corresponding methanamines were isolated in good to excellent yields following a simple acid-base workup.

A Safer Reduction of Carboxylic Acids with Titanium Catalysis.

Ammonia-borane, shown previously to react with carboxylic acids under reflux to form primary amides, reduces acids to alcohols at room temperature in the presence of catalytic TiCl. The process, which is tolerant of a variety of potentially reactive functional groups, including -protected amino acids, can be employed for the selective reduction of acids in the presence of amides, nitriles and, to some extent, esters. Aliphatic acids can be selectively reduced in the presence of aromatic acids.

Monotrifluoroacetoxyborane-amines: chemoselective reagents for challenging reductive aminations.

Borane-amines undergo exclusive monoacetoxylation to trifluoroacetoxyborane-amines (TFAB-amines), which serve as chemoselective reagents for direct reductive amination of aldehydes and ketones. TFABNEt has been established as mild and highly selective compared to widely-used NaBHCN and Na(AcO)BH, even at higher temperatures with challenging substrates. A mechanism involving polyaminoborane formed dehydroacetoxylation of TFABNH has been described.

TiCl-Catalyzed Hydroboration of Ketones with Ammonia Borane.

Investigation of a variety of Lewis acids for the hydroboration-hydrolysis (reduction) of ketones with amine-boranes has revealed that catalytic (10 mol %) titanium tetrachloride (TiCl) in diethyl ether at room temperature immensely accelerates the reaction of ammonia borane. The product alcohols are produced in good to excellent yields within 30 min, even with ketones which typically requires 24 h or longer to reduce under uncatalyzed conditions. Several potentially reactive functionalities are tolerated, and substituted cycloalkanones are reduced diastereoselectively to the thermodynamic product.

Aminoboranes via Tandem Iodination/Dehydroiodination for One-Pot Borylation.

A rapid synthesis of aminoboranes from amine-boranes utilizing an iodination/dehydroiodination sequence is described. Monomeric aminoboranes are generated exclusively from several substrate adducts, following an E2-type elimination, with the added base playing a critical role in monomer vs dimer formation. Diisopropylaminoborane formed using this methodology has been applied to a one-pot palladium-catalyzed conversion of iodo- and bromoarenes to the corresponding boronates.

Ammonia-borane as a Catalyst for the Direct Amidation of Carboxylic Acids.

Ammonia-borane serves as an efficient substoichiometric (10%) precatalyst for the direct amidation of both aromatic and aliphatic carboxylic acids. generation of amine-boranes precedes the amidation and, unlike the amidation with stoichiometric amine-boranes, this process is facile with 1 equiv of the acid. This methodology has high functional group tolerance and chromatography-free purification but is not amenable for esterification.

Trimethyl Borate-Catalyzed, Solvent-Free Reductive Amination.

Solvent-free reductive amination of aldehydes and ketones with aliphatic and aromatic amines in high-to-excellent yields has been achieved with sub-stoichiometric trimethyl borate as promoter and ammonia borane as reductant.

Amine-boranes as Dual-Purpose Reagents for Direct Amidation of Carboxylic Acids.

Amine-boranes serve as dual-purpose reagents for direct amidation, activating aliphatic and aromatic carboxylic acids and, subsequently, delivering amines to provide the corresponding amides in up to 99% yields. Delivery of gaseous or low-boiling amines as their borane complexes provides a major advantage over existing methodologies. Utilizing amine-boranes containing borane incompatible functionalities allows for the preparation of functionalized amides.

β,γ-Diaryl α-methylene-γ-butyrolactones as potent antibacterials against methicillin-resistant Staphylococcus aureus.

A selected series of racemic α-methylene-γ-butyrolactones (AMGBL) synthesized via allylboration or allylindation reactions were screened against methicillin-resistant Staphylococcus aureus (MRSA) USA300. Unlike natural AMGBLs, such as parthenolide, synthetic analogs bearing aryl moieties at the β- and γ-positions are potent against MRSA. The most potent molecules were comparable to vancomycin and linezolid, the drugs of the last resort for MRSA infections, in their effectiveness with minimum inhibitory concentrations (MICs) ranging from 3.

The role of ammonia in promoting ammonia borane synthesis.

Ammonia promotes the synthesis of pure ammonia borane (AB) in excellent yields from sodium borohydride and ammonium sulfate in tetrahydrofuran under ambient conditions. An examination of the influence of added ammonia reveals that it is incorporated into the product AB, contrary to its perceived function as a catalyst or a co-solvent. Mechanistic studies point to a nucleophilic attack by ammonia on ammonium borohydride with concurrent dehydrogenation to yield AB.

A non-dissociative open-flask hydroboration with ammonia borane: ready synthesis of ammonia-trialkylboranes and aminodialkylboranes.

Under open-flask conditions, ammonia borane hydroborates olefins in refluxing tetrahydrofuran. Unlike conventional hydroboration, the Lewis base (ammonia) is not dissociated from the boron center. Terminal alkenes selectively provide ammonia-trialkylborane complexes.

Factors influencing the cytotoxicity of α-methylene-γ-hydroxy esters against pancreatic cancer.

A systematic study to identify the factors influencing the cytotoxicity of α-methylene-γ-hydroxy esters against three pancreatic cancer cell lines (Panc-1, MIA-PaCa-2, and BxPC-3) has established that, in addition to Michael acceptor abilities, the possibility to lactonize to α-methylene-γ-butyrolactones is as important. The substitution pattern and the number of carbons between the hydroxy and ester moieties also influence the bio-activity.

Facile synthesis of 1-trifluoromethylalkenes via the decarboxylation of α-trifluoromethyl-β-lactones.

DCC-mediated cyclodehydration of α-trifluoromethyl-β-hydroxy acids provides α-trifluoromethylated β-lactone intermediates, without loss of stereoselectivity. These lactones undergo facile decarboxylation providing a simple route to obtain both alkyl and aryl trifluoromethylated alkenes in excellent yields and stereoselectivity.