Divergent process for the catalytic decarboxylative thiocyanation and isothiocyanation of carboxylic acids promoted by visible light.

A divergent photoinduced selective synthesis of thiocyanate and isothiocyanate derivatives from readily available carboxylic acids was developed using N-thiocyanatosaccharin and a catalytic amount of base or acid. This molecular editing strategy allowed the functionalization of bioactive compounds. A mechanism for the transformation was proposed based on control experiments.

Alkylation of 5-Substituted 1H-Tetrazoles via the Diazotization of Aliphatic Amines.

A new alkylation reaction of monosubstituted tetrazoles via the diazotization of aliphatic amines is reported. This method enables preferential formation of 2,5-disubstituted tetrazoles. A one-pot 1,3-dipolar cycloaddition/diazotization sequence starting from widely available nitriles is also described. Azide residues are quenched in the second step with the nitrite reagent, thus limiting the intrinsic risk associated with trimethylsilyl azide. The reaction conditions were compatible with several functional groups, including thiocyanates, which afford preferentially disubstituted 2-alkyl-5-(substituted-thio)tetrazoles.

Protecting-group-free synthesis of hydroxyesters from amino alcohols.

The synthesis of hydroxyesters from carboxylic acids and unprotected amino alcohols in both continuous flow and batch processes is reported. The formation of a transient diazonium species with a dinitrite reagent is key in this transformation. The reaction conditions are compatible with a variety of functional groups.

Batch and Continuous-Flow Iron(II)-Catalyzed Synthesis of Sulfilimines and Sulfoximines using N-Mesyloxycarbamates.

The synthesis of sulfilimines and sulfoximines with N-mesyloxycarbamates in presence of catalytic iron(II) chloride hydrate is described. The use of 1-butylimidazole as a base proved instrumental in enabling a homogeneous reaction mixture compatible with continuous flow processes. The amination is applicable to a wide range of substrates, and affords the desired product in good to excellent yields within 1 to 60 minutes.

Rhodium(ii)-catalyzed C-H aminations using N-mesyloxycarbamates: reaction pathway and by-product formation.

N-Mesyloxycarbamates are practical nitrene precursors that undergo C-H amination reactions in the presence of rhodium dimer catalysts. Under these conditions, both oxazolidinones and chiral amines have been prepared in a highly efficient manner. Given the elevated reactivity of the intermediates involved in the catalytic cycle, mechanistic details have remained hypothetical, relying on indirect experiments. Herein a density functional theory (DFT) study is presented to validate the catalytic cycle of the rhodium-catalyzed C-H amination with N-mesyloxycarbamates. A concerted pathway involving Rh-nitrene species that undergoes C-H insertion is found to be favored over a stepwise C-N bond formation manifold. Density functional calculations and kinetic studies suggest that the rate-limiting step is the C-H insertion process rather than the formation of Rh-nitrene species. In addition, these studies provide mechanistic details about competitive by-product formation, resulting from an intermolecular reaction between the Rh-nitrene species and the N-mesyloxycarbamate anion.

Chemoselective Synthesis of Amines from Ammonium Hydroxide and Hydroxylamine in Continuous Flow.

The chemoselective amination of alkyl bromides and chlorides with aqueous ammonia and hydroxylamine was achieved in continuous flow to produce primary ammonium salts and hydroxylamines in high yields. An in-line workup was designed to isolate the corresponding primary amine, which was also telescoped in further reactions, such as acylation and Paal-Knorr pyrrole synthesis. Monosubstituted epoxides are also compatible with the reaction conditions.

Mild Esterification of Carboxylic Acids via Continuous Flow Diazotization of Amines.

A new continuous flow protocol for the diazotization of methylamine with 1,3-propanedinitrite in THF is reported. The synthesis of methyl esters was achieved in high yields from a variety of carboxylic acids in 20 min at 90 °C. Additionally, this protocol was extended to other aryl and alkyl amines, namely secondary amines, to produce various substituted esters in high yield using 2-MeTHF as a solvent. The reaction conditions were compatible with many functional groups, namely nitrogen-containing heterocycles, alkynes, alkenes, alcohols, and phenols. Mechanistic investigations reveal that the reaction appears to proceed through a transient diazonium species rather than a diazo intermediate.

Synthesis of oxazolidinones: rhodium-catalyzed C-H amination of N-mesyloxycarbamates.

N-Mesyloxycarbamates undergo intramolecular C-H amination reactions to afford oxazolidinones in good to excellent yields in the presence of rhodium(ii) carboxylate catalysts. The reaction is performed under green conditions and potassium carbonate is used, forming biodegradable potassium mesylate as a reaction by-product. This method enables the production of electron-rich, electron-deficient, aromatic and heteroaromatic oxazolidinones in good to excellent yields. Conformationally restricted cyclic secondary N-mesyloxycarbamates furnish cis-oxazolidinones in high yields and selectivity; DFT calculations are provided to account for the observed selectivity. trans-Oxazolidinones were prepared from acyclic secondary N-mesyloxycarbamates using Rh2(oct)4. The selectivity was reverted with a cytoxazone N-mesyloxycarbamate precursor using large chiral rhodium(ii) carboxylate complexes, affording the corresponding cis-oxazolidinone. This orthogonal selectivity was used to achieve the formal synthesis of (-)-cytoxazone.

Batch and Continuous-Flow One-Pot Processes using Amine Diazotization to Produce Silylated Diazo Reagents.

A novel synthesis of trimethylsilyldiazomethane (TMSCHN2 ) by diazotization of trimethylsilylmethylamine (TMSCH2 NH2 ) is reported using batch and continuous flow synthesis. The latter affords a daily production of 275 g (2.4 mol) of TMSCHN2 . Other silylated methylamines were also successfully reacted under the developed reaction conditions to furnish various silicon-bearing diazomethane reagents. The applicability of the process is highlighted by disclosure of batch and continuous flow one-pot esterification and 1,3-dipolar cycloaddition processes. Furthermore, the high-yielding esterification of carboxylic acids with silylated and substituted methylamines in continuous flow is disclosed. Finally, work-up and purification procedures are reported for the preparation of a 2-MeTHF solution of TMSCHN2 , which can be used in rhodium-catalyzed methylenation and homologation reactions.

Stereoselective synthesis of chiral sulfilimines from N-mesyloxycarbamates: metal-nitrenes versus metal-nitrenoids species.

The synthesis of a variety of chiral sulfilimines and sulfoximines is described. The amination of thioethers with a chiral N-mesyloxycarbamate was achieved in high yields and stereoselectivities using Rh2[(S)-nttl]4 as catalyst in the presence of 4-dimethylaminopyridine (DMAP) and a pyridinium salt, such as bis(DMAP)CH2Cl2 or a viologen salt. These additives proved instrumental to enhance both the yield and the stereochemical discrimination of the reaction. Mechanistic studies and control experiments have elucidated the role of these additives. DMAP served as an apical ligand for the rhodium catalyst: an X-ray crystal structure of the (DMAP)2·[Rh2{(S)-nttl}4] complex was obtained. This complex displayed a lower and irreversible redox potential. Control experiments with preformed Rh(II)-Rh(III) complex suggested such a catalytically active species in the thioether amination process. Diastereoselectivities were influenced by the sulfonyloxy leaving group, ruling out the possibility of a common metal nitrene species and instead suggesting a rhodium-nitrenoid complex. It is believed that the bispyridinium salt played the role of a phase transfer catalyst, influencing both the yield and the diastereoselectivity of the reaction.

Rhodium-catalyzed stereoselective amination of thioethers with N-mesyloxycarbamates: DMAP and bis(DMAP)CH(2)Cl(2) as key additives.

A stereoselective Rh-catalyzed intermolecular amination of thioethers using a readily available chiral N-mesyloxycarbamate to produce sulfilimines in excellent yields and diastereomeric ratio is described. A catalytic mixture of 4-dimethylaminopyridine (DMAP) and bis(DMAP)CH2 Cl2 proved pivotal in achieving high selectivity. The X-ray crystal structure of the (DMAP)2 ⋅[Rh2 {(S)-nttl}4 ] complex was obtained and mechanistic studies suggested a Rh(II) -Rh(III) complex as the catalytically active species.

Palladium-catalyzed Saegusa-Ito oxidation: synthesis of α,ß-unsaturated carbonyl compounds from trimethylsilyl enol ethers.

Palladium-catalyzed Saegusa-Ito oxidation of trimethylsilyl enol ethers is possible using Oxone as a stoichiometric oxidant and sodium hydrogen phosphate as a buffer. Cyclic and acyclic enones as well as α,ß-unsaturated aldehydes are obtained in good to excellent yields.

Stereoselective intermolecular C-H amination reactions.

A novel chiral N-mesyloxycarbamate to perform rhodium-catalyzed stereoselective C-H amination reactions is reported. Chiral benzylic and propargylic amines are produced in good yields and selectivities using ethyl acetate as solvent. The corresponding free amines are easily obtained by cleavage of the chiral reagent, which could also be recovered.

Stereoselective rhodium-catalyzed amination of alkenes.

The first stereoselective rhodium-catalyzed intermolecular aziridination and C-H amination of alkenes to produce chiral carbamate-protected aziridines and allylic amines is described. Good yields and diastereoselectivities were achieved using a readily available chiral N-tosyloxycarbamate and stoichiometric amount of the alkene substrate. Furthermore the protecting group is easy to cleave under mild reaction conditions.

Copper-catalyzed tandem oxidation-olefination process.

A novel catalytic sequence aerobic oxidation-olefination has been developed. A single and inexpensive copper catalyst provides a large range of olefins from alcohols in good to excellent yields. The reaction exhibits excellent functional group compatibility, and the nonbasic reaction conditions allow the transformation of chiral substrates without racemization.

One-pot approach for the synthesis of trans-cyclopropyl compounds from aldehydes. Application to the synthesis of GPR40 receptor agonists.

A novel multicatalytic one-pot process providing trans-cyclopropyl compounds from corresponding aldehydes has been developed and applied to the synthesis of GPR40 small molecule agonists.

Transition-metal-catalyzed chemoselective methylenation of dicarbonyl substrates.

Rhodium- and copper-catalyzed methylenation reactions with trimethylsilyldiazomethane, triphenylphosphine, and 2-propanol were used to react chemoselectively with aldehydes, alkoxymethylketones, and trifluoromethylketones in substrates also containing a less reactive carbonyl group. Terminal alkenes were obtained in high yields, and no protecting group was necessary in the methylenation process.

N-tosyloxycarbamates as reagents in rhodium-catalyzed C-H amination reactions.

Metal nitrenes for use in C-H insertion reactions were obtained from N-tosyloxycarbamates in the presence of an inorganic base and a rhodium(II) dimer complex catalyst. The C-H amination reaction proceeds smoothly, and the potassium tosylate that forms as a byproduct is easily removed by filtration or an aqueous workup. This new methodology allows the amination of ethereal, benzylic, tertiary, secondary, and even primary C-H bonds. The intramolecular reaction provides an interesting route to various substituted oxazolidinones, whereas the intermolecular reaction gives trichloroethoxycarbonyl-protected amines that can be isolated with moderate to excellent yields and that cleave easily to produce the corresponding free amine. The development, scope, and limitations of the reactions are discussed herein. Isotopic effects and the electronic nature of the transition state are used to discuss the mechanism of the reaction.

Copper-catalyzed alkene aziridination with N-tosyloxycarbamates.

Pyridine copper complexes were found as active catalysts for the intramolecular aziridination of allylic N-tosyloxycarbamates and the intermolecular aziridination of styrenes with trichloroethyl N-tosyloxycarbamates. Free aziridines were easily obtained by basic deprotection of the trichloroethyl group.