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 -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 1-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.

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 -mesyloxycarbamates: reaction pathway and by-product formation.

-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.

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.

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.

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

A novel synthesis of trimethylsilyldiazomethane (TMSCHN ) by diazotization of trimethylsilylmethylamine (TMSCH NH ) is reported using batch and continuous flow synthesis. The latter affords a daily production of 275 g (2.4 mol) of TMSCHN .

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.

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,β-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,β-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.

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.

Palladium-catalyzed cross-coupling reactions in one-pot multicatalytic processes.

Palladium-catalyzed cross-coupling reactions have been investigated in multicatalytic processes to synthesize disubstituted alkenes and alkanes from carbonyl derivatives. The use of copper-catalyzed methylenation reactions is the key starting reaction to produce terminal alkenes which are not isolated, but submitted to further structure elongation. Not only is the isolation of the alkene intermediate unnecessary, but also the copper catalyst is a beneficial cocatalyst in the palladium-catalyzed cross-coupling reactions.

Copper-catalyzed methylenation reaction: total synthesis of (+)-desoxygaliellalactone.

The enantioselective total synthesis of (+)-desoxygaliellalactone was achieved in six steps starting from 4-tert-butyldimethylsilyloxybutanal. This synthesis featured a one-pot copper-catalyzed methylenation-Diels-Alder cyclization. The challenging methylenation of aldehyde 4 was studied under various reaction conditions.

De novo synthesis of Troc-protected amines: intermolecular rhodium-catalyzed C-H amination with N-tosyloxycarbamates.

The rhodium-catalyzed intermolecular C-H insertion of the nitrene derived from 2,2,2-trichloroethyl-N-tosyloxycarbamate proceeded in good to excellent yields to produce a variety of Troc-protected amines. With cyclic aliphatic alkanes, it is possible to use only 2 equiv of substrate, whereas the reaction with aromatic alkanes is run neat. Not only does the nitrene insertion proceed in benzylic, secondary, and tertiary C-H bonds but also primary C-H insertion products were obtained in good yields.

Copper-carbene complexes as catalysts in the synthesis of functionalized styrenes and aliphatic alkenes.

(NHC)-Cu (NHC = N-heterocyclic carbene) complexes efficiently catalyzed the methylenation of a variety of aliphatic and aromatic aldehydes and ketones in the presence of trimethylsilyldiazomethane, triphenylphosphine, and 2-propanol. The copper catalysts are not only inexpensive compared to rhodium complexes, but they also exhibit better functional group compatibility with aromatic aldehydes and ketones. Indeed very high yields were obtained for the formation of styrenes containing nitro, trifluoromethyl, amino, and ester groups, as well as for pyridine-, pyrrole-, and indole-substituted alkenes.

Curtius rearrangement of aromatic carboxylic acids to access protected anilines and aromatic ureas.

The reaction of a chloroformate or di-tert-butyl dicarbonate and sodium azide with an aromatic carboxylic acid produces the corresponding acyl azide, presumably through the formation of an azidoformate. The acyl azide undergoes a Curtius rearrangement to form an isocyanate derivative which is trapped either by an alkoxide or by an amine to form the aromatic carbamate or urea. The reaction conditions are compatible with a variety of functional groups and allow the synthesis of a number of aniline derivatives containing alkyl, halide, nitro, ketone, ether, and thioether substituents.