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 TiCl4, 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, etc.) 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 BH3·Me2S in tetrahydrofuran (THF) with the requisite nitrogen-containing heterocycle and isolated by placing the crude reaction mixture in hexanes to precipitate the product. X-ray crystallography, thermogravimetric analysis (TGA), high resolution mass spectroscopy (HRMS), 1H NMR, 13C NMR, and 11B NMR were utilized for product characterization, while impact and friction sensitivity testing were conducted to identify sensitivity in the synthesized compounds. Most isolated borane-amines, except one, were found to decompose in the atmosphere and were more sensitive to mechanical stimuli than their starting materials; however, all synthesized compounds were found to be hypergolic in the presence of white fuming nitric acid (WFNA).

TiF4-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 N-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, BH3-NH3, and the catalyst, TiCl4. 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 BF3-Et2O as the catalyst alters the reaction pathway, reducing the esters to alcohols. Mechanistic insights are provided by NMR spectroscopy, deuterium labeling, and kinetic isotope studies.

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. Logical combinations of these factors have also been applied for the regioselective conversion of alcohols to alkyl halides.

Dehydroborylation of Terminal Alkynes Using Lithium Aminoborohydrides.

Dehydrogenative borylation of terminal alkynes has recently emerged as an atom-economical one-step alternative to traditional alkyne borylation methodologies. Using lithium aminoborohydrides, formed in situ from the corresponding amine-boranes and n-butyllithium, a variety of aromatic and aliphatic terminal alkyne substrates were successfully borylated in high yield. The potential to form mono-, di-, and tri-B-alkynylated products has been shown, though the mono-product is primarily generated using the presented condition. The reaction has been demonstrated at large (up to 50 mmol) scale, and the products are stable to column chromatography as well as acidic and basic aqueous conditions. Alternately, the dehydroborylation can be achieved by treating alkynyllithiums with amine-boranes. In that respect, aldehydes can act as starting materials by conversion to the 1,1-dibromoolefin and in situ rearrangement to the lithium acetylide.

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 TiCl4. The process, which is tolerant of a variety of potentially reactive functional groups, including N-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. TFAB-NEt3 has been established as mild and highly selective compared to widely-used NaBH3CN and Na(AcO)3BH, even at higher temperatures with challenging substrates. A mechanism involving polyaminoborane formed via dehydroacetoxylation of TFAB-NH3 has been described.

TiCl4-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 (TiCl4) 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. A deuterium labeling study and 11B NMR analysis of the reaction have been performed to verify the proposed hydroboration mechanism.

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. Additionally, modification of the workup allows for isolation of the boronic acid and recovery of the utilized amine.

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.

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. In situ 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. The latter feature has been exploited to prepare hydroxyl- and thiol-containing amides.

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. An intermolecular mechanism proceeding through a triacyloxyborane-amine complex is proposed.

ß,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 ß- 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 3.0 to 5.2 µM. These lactones also exhibited potent antibacterial activity against other clinically important multidrug-resistant Gram-positive bacteria (except enterococci), while also showing high tolerability to mammalian cells. Several of these molecules surpassed vancomycin in their rapid killing of the high MRSA inoculum (2 h vs 12 h) in a standard time-kill kinetics assay, with compounds 1l and 1m significantly reducing the intracellular burden of MRSA by about 98-99%, at low concentrations. Additionally, the compounds surpassed vancomycin in inhibiting staphylococcal protease production, indicating that synthetic methylene lactones warrant further investigations as promising anti-MRSA candidates.

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. On the other hand, internal alkenes afford aminodialkylboranes via a metal-free hydroboration-dehydrogenation sequence. Alkaline hydrogen peroxide oxidation of the products provides the corresponding alcohols in high yields.

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.