Aldehyde‐Catalyzed Transition Metal‐Free Dehydrative β‐Alkylation of Methyl Carbinols with Alcohols

Different to the borrowing hydrogen strategy in which alcohols were activated by transition metal‐catalyzed anaerobic dehydrogenation, the direct addition of aldehydes was found to be an effective but simpler way of alcohol activation that can lead to efficient and green aldehyde‐catalyzed transition metal‐free dehydrative C‐alkylation of methyl carbinols with alcohols. Mechanistic studies revealed that the reaction proceeds via in situ formation of ketones by Oppenauer oxidation of the methyl carbinols by external aldehydes, aldol condensation, and Meerwein–Ponndorf–Verley (MPV)‐type reduction of α,β‐unsatutated ketones by substrate alcohols, affording the useful long chain alcohols and generating aldehydes and ketones as the by‐products that will be recovered in the next condensation to finish the catalytic cycle.     

An Efficient and Recyclable Catalyst for N‐Alkylation of Amines and β‐Alkylation of Secondary Alcohols with Primary Alcohols: SBA‐15 Supported N‐Heterocyclic Carbene Iridium Complex

A mesoporous silica (SBA‐15)‐supported pyrimidine‐substituted N‐heterocyclic carbene iridium complex was prepared and used as a catalyst for both environmentally friendly N‐alkylation of amines and β‐alkylation of secondary alcohols with primary alcohols. The structure of the supported iridium catalyst was characterized by Fourier transform infrared (FT‐IR), ¹³C and ²⁹Si solid‐state nuclear magnetic resonance (NMR), small‐angle X‐ray scattering (SAXS), transmission electron microscopy (TEM), iridium K‐edge X‐ray absorption near‐edge structure (XANES) and extended X‐ray absorption fine structure (EXAFS) spectroscopic analyses which demonstrated that the coordination environment of the iridium centre and the 3‐dimensional‐hexagonal pore structure of SBA‐15 were retained after the immobilization. The catalyst was found to be highly efficient for both kinds of reaction on a wide range of substrates under mild conditions. Moreover, the supported iridium catalyst was obviously superior to the unsupported one in the N‐alkylation of aniline and β‐alkylation of 1‐phenylethanol with benzyl alcohol as substrate, which indicated that not only the iridium complex moiety but also the support material contributed to the catalytic activity of the supported iridium catalyst in these reactions. The supported iridium catalyst can be easily recycled by simple washing without chemical treatment, and exhibited excellent recycling performance without notable decrease in catalytic efficiency even after twelve test cycles for N‐alkylation of aniline with benzyl alcohol, nine cycles for N‐alkylation of different amines with different alcohols, and eight cycles for β‐alkylation of 1‐phenylethanol with benzyl alcohol, respectively.     

N‐Alkylation of Amines with Alcohols Catalyzed by a Water‐Soluble Cp*Iridium Complex: An Efficient Method for the Synthesis of Amines in Aqueous Media

An efficient and environmentally benign catalytic system for the synthesis of various organic amines catalyzed by the water‐soluble and air‐stable (pentamethylcyclopentadienyl)‐iridium‐ammine iod‐ ide complex, [Cp*Ir(NH₃)₃][I]₂ (Cp*=pentamethylcyclopentadienyl), has been developed. A wide variety of secondary and tertiary amines were synthesized by the N‐alkylation reactions of theoretical equivalents of amines with alcohols in water under air without a base. The synthesis of cyclic amines was also achieved by the N‐alkylation of benzylamine with diols. Furthermore, the recycle use of the present water‐soluble Cp*Ir catalyst was accomplished.     

Transition Metal‐Free Regioselective C‐3 Amidation of Indoles with N‐Fluorobenzenesulfonimide

A direct transition metal‐free regioselective C‐3 amidation of indoles has been developed with the commercially available N‐fluorobenzenesulfonimide (NFSI) as the amino source under external oxidant‐free conditions. This amidation requires only a catalytic amount of base and exhibits excellent functional group tolerance and regioselectivity. The C‐3 regioselectivity was proposed to realize by a free radical mechanism.

     

Direct Amide Synthesis from Alcohols and Amines by Phosphine‐Free Ruthenium Catalyst Systems

Amides are synthesized directly from alcohols and amines in high yields using an in situ generated catalyst from easily available ruthenium complexes such as the (p‐cymene)ruthenium dichloride dimer, [Ru(p‐cymeme)Cl₂]₂, or the (benzene)ruthenium dichloride dimer, [Ru(benzene)Cl₂]₂, an N‐heterocyclic carbene (NHC) ligand, and a nitrogen containing L‐type ligand such as acetonitrile. The phosphine‐free catalyst systems showed improved or comparable activity compared to previous phosphine‐based catalytic systems. The in situ generated catalyst from [Ru(benzene)Cl₂]₂, an NHC ligand, and acetonitrile showed excellent activity toward reactions with cyclic secondary amines such as piperidine and morpholine.     

N‐Heterocyclic Carbene‐Catalyzed Oxidative Amidation of Aldehydes with Amines

The N‐heterocyclic carbene (NHC)‐catalyzed oxidative amidation of aromatic aldehydes with amines in the presence of N‐bromosuccinimide (NBS) as an oxidant has been developed for the synthesis of amides. This amidation strategy is tolerant to both the electronic and the steric nature of the aryl aldehydes employed. The present methodology was extended to chiral amino acid derivatives to generate the corresponding amides in good yields and excellent ee values (>98%).

     

Metal‐Free Oxidative Decarbonylative Coupling of Aliphatic Aldehydes with Azaarenes: Successful Minisci‐Type Alkylation of Various Heterocycles

A metal‐free oxidative decarbonylative coupling of aliphatic aldehydes with various electron‐deficient heterocycles has been developed. This reaction is supposed to be realized via a Minisci‐type mechanism, based on the substrate scope, regioselectivity and radical trapping experiments. The ready availability of aliphatic aldehydes, metal‐free conditions and broad substrate scope should make this method attractive for the late‐stage alkylation of bioactive heterocycles.

     

Ruthenium‐Catalyzed Synthesis of Secondary Alkylamines: Selective Alkylation with Aliphatic Amines

The chemoselective N‐alkylation of tert‐alkylamines applying aliphatic amines is described for the first time. In the presence of the Shvo catalyst 1 , tert‐octylamine 4 and 1‐adamantylamine 5 are alkylated using primary, secondary, and even tertiary amines to give the corresponding monoalkylated tert‐alkylamine in moderate to very good yields and excellent selectivity. This novel reaction proceeds without an additional hydrogen source and ammonia is formed as the only by‐product.     

Transition Metal‐Free Approach to Propynenitriles and 3‐Chloropropenenitriles

A transition metal‐free, facile and efficient one‐pot protocol for the synthesis of propynenitriles from readily available 3‐chloropropenals is disclosed. The reaction conditions have also been optimized for the exclusive formation and isolation of 3‐chloropropenenitriles which are important building blocks in general and are intermediates in the synthesis of propynenitriles. The hallmark of the methodology is the use of non‐toxic reagents, milder, metal‐free and economically benign reaction conditions avoiding a harsh dehydration step while achieving excellent yields.

     

An Efficient Method for the Selective Iridium‐Catalyzed Monoalkylation of (Hetero)aromatic Amines with Primary Alcohols

An efficient multi‐gram scale synthesis protocol of a variety of P,N ligands is described. The synthesis is achieved in a two‐step reaction. First, the amine is deprotonated and subsequently the chlorophosphine is added to yield the corresponding P,N ligand. Deprotonation of the amine is normally achieved with n‐BuLi at low temperature, but for the preparation of ligands with a 2,2′‐dipyridylamino backbone and phosphines with a high steric demand KH has to be employed in combination with reaction temperatures of 110 °C for the salt metathesis step. The reaction of two equivalents of a selected P,N ligand with one equivalent of the iridium complex [IrCl(cod)]₂ (cod=1,5‐cyclooctadiene) affords P,N ligand‐coordinated iridium complexes in quantitative yield. X‐Ray single crystal structure analysis of one of these complexes reveals a monomeric five‐coordinated structure in the solid state. The iridium complexes were used to form catalysts for the N‐alkylation of aromatic amines with alcohols. The catalyst system was optimized by studying 8 different P,N ligands, 9 different solvents and 14 different bases. Systematic variation of the substrate to base and the amine to alcohol ratios as well as the catalyst loading led to optimized catalytic reaction conditions. The substrate scope of the developed catalytic protocol was shown by synthesizing 20 different amines of which 12 could be obtained in isolated yields higher than 90%. A new efficient catalyst system for the selective monoalkylation of primary aromatic and heteroaromatic amines with primary aromatic, heteroaromatic as well as aliphatic alcohols has been established. The reaction proceeds with rather moderate catalyst loadings.     

Copper‐Catalyzed N‐Alkylation of Sulfonamides with Benzylic Alcohols: Catalysis and Mechanistic Studies

The N‐alkylation of sulfonamides with alcohols is efficiently performed in the presence of easily available copper catalysts via hydrogen borrowing methodology. Applying a copper acetate/potassium carbonate system the reaction of sulfonamides and alcohols gave the corresponding secondary amines in excellent yield. In situ HR‐MS analysis indicated that bissulfonylated amines are formed under air atmosphere, which act as self‐stabilizing ligands for the catalytic system. UV‐visible measurements suggest the interaction between the copper centre and the bissulfonylated amine. Reactions of benzyl alcohol‐d₇ with p‐toluenesulfonamide, N‐benzyl‐p‐toluenesulfonamide or N‐benzylidenetoluenesulfonamide revealed that the reaction proceeds via a transfer hydrogenation mechanism and the whole process is micro‐reversible. Competitive reactions of benzyl alcohol and benzyl alcohol‐d₇ with p‐toluenesulfonamide revealed a kinetic isotope effect (kH/kD) of 3.287 (0.192) for the dehydrogenation of benzyl alcohol and 0.611 (0.033) for the hydrogenation of the N‐benzylidene‐p‐toluenesulfonamide intermediate, which suggests that dehydrogenation of the alcohol is the rate‐determining step.     

Hydroxylamine as a Source for Nitric Oxide in Metal‐Free 2,2,6,6‐ Tetramethylpiperidine N‐Oxyl Radical (TEMPO) Catalyzed Aerobic Oxidation of Alcohols

The communication reports on the metal‐free 2,2,6,6‐tetramethylpiperidine N‐oxyl radical (TEMPO) catalyzed aerobic oxidation of various alcohols to aldehydes and ketones. A novel catalyst system that uses 1–4 mol% of TEMPO in combination with 4–6 mol% of aqueous hydroxylamine is introduced. No other additives are necessary and corrosive by‐products are not formed during oxidation. Nitric oxide which is important for the catalytic cycle is generated in situ by reaction of the hydroxylamine with TEMPO. A catalytic cycle for the overall oxidation process is suggested.     

Transition Metal‐Free Trifluoromethylation of N‐Allylamides with Sodium Trifluoromethanesulfinate: Synthesis of Trifluoromethyl‐Containing Oxazolines

A transition metal‐free method for the trifluoromethylation of N‐allylamides has been developed, and the corresponding trifluoromethyl‐containing oxazolines were prepared in moderate to good yields. The protocol uses readily available substituted N‐allylamides as the starting materials, inexpensive and easily stored sodium trifluoromethanesulfinate as the trifluoromethyl source, iodobenzene diacetate as the oxidant, and the procedure involves sequential intermolecular trifluoromethylation of alkenes with sodium trifluoromethanesulfinate and intramolecular cyclization. This is the first example to prepare CF₃‐containing oxazolines. Therefore, the present method should afford an efficient and practical strategy for synthesis of other CF₃‐containing cyclic compounds.

     

Metal‐Free Oxidative Cross Esterification of Alcohols via Acyl Chloride Formation

A novel metal‐free oxidative cross esterification of alcohols has been achieved using trichloroisocyanuric acid as an oxidant. The alcohols were converted in situ into their corresponding acyl chlorides, which were then reacted with primary and secondary aliphatic, benzylic and allylic alcohols and phenols. A wide variety of esters was obtained in satisfactory yields.

     

Indium‐Catalyzed Formal N‐Arylation and N‐Alkylation of Pyrroles with Amines

Under indium Lewis acid catalysis, a nitrogen atom of N‐unsubstituted pyrroles was replaced with a nitrogen atom of primary amines, thereby producing N‐aryl‐ and N‐alkylpyrroles. This system formally introducing such carbon frameworks to the pyrrole nitrogen atom shows unique selectivity: only the H−N(pyrrolyl) unit undergoes the N‐arylation and N‐alkylation even in the coexistence of a similar H−N(indolyl) part; and an aryl–halogen bond remains intact. These are clearly different from the typical method depending on the C−N(pyrrolyl) bond‐forming reaction with organic halides as substrates. From a viewpoint of pyrrole N‐protection–deprotection chemistry, worth noting is that a methyl group on the pyrrole nitrogen atom can be removed, albeit in a formal way.

     

Ruthenium‐Catalyzed β‐Alkylation of Secondary Alcohols with Primary Alcohols

Cyclopentadienyl (Cp), hydrotris(pyrazolyl)borato (Tp), and bipyridine ruthenium complexes were found to be active catalysts for the β‐alkylation of secondary alcohols with primary alcohols. Mechanistic aspects of the Cp and Tp complexes‐catalyzed reactions were investigated; the crucial hydrido complexes were identified. Carbonyl complexes resulting from aldehyde decarbonylation were formed in some cases, and surprisingly, they were also found to be active for the catalytic processes.     

Dimethyl Sulfoxide/Potassium Hydroxide: A Superbase for the Transition Metal‐Free Preparation of Cross‐Coupling Products

Potassium hydroxide (KOH) in dimethyl sulfoxide (DMSO) forms a superbasic medium that allows one to access cross‐coupling products from reactions between aryl halides with various sulfur‐, oxygen‐ and nitrogen‐based nucleophiles under transition metal‐free conditions.     

Formation of Tertiary Amides and Dihydrogen by Dehydrogenative Coupling of Primary Alcohols with Secondary Amines Catalyzed by Ruthenium Bipyridine‐Based Pincer Complexes

Dehydrogenative coupling of primary alcohols with secondary amines to form tertiary amides and dihydrogen (H₂) is efficiently catalyzed by bipyridyl‐based ruthenium pincer complexes (0.2–1 mol%) under neutral conditions (in case of the dearomatized complexes), or with added catalytic amount of base. The reaction is sensitive to steric hindrance; in the case of amidation of bulky secondary amines a less sterically hindered complex is more efficient. Selective acylation of primary amines in the presence of secondary amines was also demonstrated.

     

Tris(acetylacetonato)rhodium(III)‐Catalyzed α‐Alkylation of Ketones, β‐Alkylation of Secondary Alcohols and Alkylation of Amines with Primary Alcohols

The tris(acetylacetonato)rhodium(III) catalyst is shown to be a versatile catalyst in the presence of DABCO (1,4‐diazabicyclo[2.2.2]octane) as ligand for the α‐alkylation of ketones followed by transfer hydrogenation, for the one‐pot β‐alkylation of secondary alcohols with primary alcohols and for the alkylation of aromatic amines in the presence of an inorganic base in toluene.     

Lewis Acid‐Catalyzed Oxidative Allylation: A New Approach for the Synthesis of Homoallylic Alcohols and Amines Directly from Alcohols

A new approach for the synthesis of homoallylic alcohols and amines directly from alcohols via one‐pot sequential oxidation–Barbier reaction and oxidation–condensation–Barbier reactions, respectively, is reported. The protocol involves the one‐pot ferric chloride‐catalyzed oxidation of alcohols to the corresponding aldehydes with chloramine‐T followed by indium‐mediated Barbier allylation with allyl bromide to afford homoallylic alcohols in 70–90% overall yields. The ferric chloride‐catalyzed condensation of aldehydes and oxidation by‐product p‐toluenesulfonamide followed by indium‐mediated Barbier‐type allylation of the resulting aldimines with allyl bromide affords homoallylic amines in 60–80% overall yields in the same reaction vessel. The present work demonstrates a new one‐pot approach toward homoallylic alcohol and amine synthesis directly from alcohols.