Search

A system of three coupled catalytic cycles enabling the one-pot transformation of epoxides to amines via Meinwald rearrangement, imine condensation, and imine reduction is described. This assisted tandem catalysis is catalyzed by B(C6F5)3 resulting in the first tandem Meinwald rearrangement-reductive amination protocol. The reaction proceeds in nondried solvents and yields β-functionalized amines. In particular, β-diarylamines are obtained in high yields.

β-Trifluoromethyl (CF3 ) enones were proved to act as good dienophiles in asymmetric normal-electron-demand Diels-Alder cycloadditions with 2,4-dienals under trienamine catalysis with a chiral secondary amine. The sequential reductive amination transformations with benzylamine produced cis- and trans-fused chiral trifluoromethylated octahydroisoquinolines in a diastereodivergent manner by using NaBH(OAc)3 and NaBH3 CN as the reductants, respectively. Moreover, other types of activated alkenes that bear a CF3 group have also been successfully utilized to construct a diverse range of chiral cyclic frameworks in high stereoselectivity.

A transition-metal- and oxidant-free DNP (2,4-dinitrophenol)-catalyzed atom-economical regio- and diastereoselective synthesis of monofunctionalized α-alkynyl-3-amino-2-oxindole derivatives by C-H bond functionalization of cyclic amines and alkynes with indoline-2,3-diones has been developed. This cascade event sequentially involves the reductive amination of indoline-2,3-dione by imine formation and cross coupling between C(sp(3) )-H and C(sp)-H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α-alkynyl-3-amino-2-oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP-catalyzed metal-free direct C(sp(3) )-H and C(sp)-H bond functionalization providing biologically active α-alkynyl-3-amino-2-oxindole scaffolds.

The ruthenium complex [(η6-cymene)Ru(Cl)(dpmpy)]+ {dpmpy = 2-[2-(dimethylamino)pyrimidin-4-yl]pyridine} is highly reactive in catalyzing the reductive amination of aromatic aldehydes through in situ generated imines with 2-propanol as the hydrogen source following a transfer-hydrogenation mechanism. This transformation does not require any activating additives and is applicable to a broad variety of aldehydes.

An enantioselective hydrogenation of fluorinated hydrazones has been achieved by employing [Pd(R)-DTBM-SegPhos(OCOCF3)2] as the catalyst, providing a general and convenient method toward chiral fluorinated hydrazines. A broad substrate scope including β-aryl-, γ-aryl-, and alkyl-chain-substituted hydrazones worked efficiently in high yields and up to 94% of enantioselectivity. The reductive amination between trifluoromethyl-substituted ketones and benzohydrazides could also proceed smoothly.

In our ongoing efforts in preparing tool compounds for investigating and controlling the biosynthesis of phenazines, we recognized the limitations of existing protocols for C–N bond formation of electron-deficient anilines when using reductive amination. After extensive optimization, we have established three robust and scalable protocols for the reductive amination of ketones with electron-deficient anilines, by using either BH3·THF/AcOH/CH2Cl2 (method A), with reaction times of several hours, or the more powerful combinations BH3·THF/TMSCl/DMF (method B) and NaBH4/TMSCl/DMF (method C), which give full conversions for most substrates within 10 to 25 minutes. The scope and limitations of these reactions have been defined for 12 anilines and 14 ketones.

Reductive amination (RA) is one of the most important transformations in organic chemistry. A versatile and sustainable gas-free RA of aldehydes carried out directly with cheaply available nitroarenes using stoichiometric amounts of non-toxic and entirely renewable formic acid (FA) as the terminal reductant is described herein. A single phase rutile titania supported gold (Au/TiO2-R) catalyst is shown to catalyse efficiently this FA-based direct RA in neat water under mild reaction conditions. The broad scope, mild and neutral conditions, together with CO2 and water as environmental harmless byproducts, make this transformation very useful. Moreover, straightforward examples of the direct construction of bioactive heterocyclic compounds containing a benzimidazole motif were achieved through this protocol.

The highly efficient and direct asymmetric reductive amination of arylacetones catalyzed by an iridium complex for the preparation of enantiomerically pure β-arylamines is described. The monodentate phosphoramidite ligand exhibits superb reactivity (TONs of up to 20 000) and enantioselectivity (up to 99 % ee). Additives played important roles in this reductive coupling reaction.

The combination of commercial easily available Au/TiO2 as catalyst and cost-effective formic acid as reductant was able to render reductive amination of various carbonyl compounds. Aldehydes and ketones were converted into secondary and tertiary amines in good to excellent yields. The supported gold nanoparticles could be easily recycled by simple filtration.

The first enantioselective synthesis of (-)-strychnopivotine from a known and inexpensive phenol has been achieved in 15 steps. The strategy is based on a new diastereoselective aza-Michael-enol-ether cascade desymmetrization of a dienone, guided by a removable lactic acid-derived chiral auxiliary. Synthesis involves a phenol dearomatization, a conjugated silicon addition, a stereoselective double reductive amination, and two Heck-type carbopalladations as key steps. The absolute configuration of the natural compound, which, to date, has been uncertain, was confirmed by using circular dichroism (CD) spectroscopy and X-ray analyses.

A novel regioselective synthesis of 2-aminoquinolines and 2-arylquinoline-3-carbonitriles is described via copper-mediated tandem reaction. Formation of substituted quinolines involves Knoevenagel condensation of ortho-bromobenzaldehyde with active methylene nitriles followed by copper-catalyzed reductive amination and intramolecular cyclization.

The new title catalyst is prepared and used for the one-pot reductive amination of ketones affording a diverse range of secondary amines in predominantly excellent yields.

A broad range of secondary and tertiary amides has been hydrogenated to the corresponding amines under mild conditions using an in situ catalyst generated by combining [Ru(acac)3], 1,1,1-tris(diphenylphosphinomethyl)ethane (Triphos) and Yb(OTf)3. The presence of the metal triflate allows to mitigate reaction conditions compared to previous reports thus improving yields and selectivities in the desired amines. The excellent isolated yields of two scale-up experiments corroborate the feasibility of the reaction protocol. Control experiments indicate that, after the initial reduction of the amide carbonyl group, the reaction proceeds through the reductive amination of the alcohol with the amine arising from collapse of the intermediate hemiaminal.

A highly efficient stereoselective method for the synthesis of functionalized spirooxindole derivatives with three stereogenic centers was realized through an organocatalytic tandem Michael-Michael reaction. By employing (S)-α,α-diphenylprolinol trimethylsilyl ether as the catalyst and N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea as the cocatalyst, the reaction between N-tritylisatylidenemalononitriles and (E)-7-alkyl-7-oxohept-5-enals yields the desired spirooxindole products in good yields (76-95%) and with excellent diastereoselectivities (up to 97 : 3 dr) and enantioselectivities (up to 98% ee), which can be stereoselectively converted into the spiro[indoline-3,8'-isoquinoline] derivative through an intramolecular reductive amination reaction.

Described herein are differences in behavior between a Hantzsch ester and a benzothiazoline as hydrogen donors in the chiral phosphoric acid catalyzed asymmetric reductive amination of ketones with p-anisidine. The asymmetric reductive amination of ketones with a Hantzsch ester as a hydrogen donor provided the corresponding chiral amines exclusively, regardless of the structures of the ketones, whereas a similar transformation with a benzothiazoline provided chiral amines and p-methoxyphenyl-protected primary amines in variable yields, depending on the structures of both the ketones and benzothiazolines. Because a benzothiazoline has an N,S-acetal moiety that is vulnerable to p-anisidine, the primary amine can be formed through transimination of the benzothiazoline with p-anisidine followed by reduction of the resulting aldimine with remaining benzothiazoline.

Described herein is that the catalytic construction of N-substituted five- and six-membered lactams from keto acids with primary amines by reductive amination, using an indium/silane combination. This relatively benign and safe catalyst/reductant system tolerates the use of a variety of functional groups, especially ones that are reduction-sensitive. A direct switch from synthesizing lactams to synthesizing cyclic amines is achieved by changing the catalyst from In(OAc)3 to InI3. This conversion occurs by further reduction of the lactam using the indium/silane pair.

Cinacalcet hydrochloride is the only approved drug acting as calcimimetic, a new class of compounds used in the therapy of secondary hyperparathyroidism and parathyroid carcinoma. Several generic drug manufacturers and research groups from academia have reported alternative approaches to this molecule, mainly from (R)-(+)-1-(1-naphthyl)ethylamine. There are mainly three strategies that have been used to couple this readily accessible enantiopure amine to the other part of the molecule: amide formation followed by reduction, reaction with an aldehyde and reduction of the resulting imine, and nucleophilic substitution with a suitable partner that carries a leaving group. More exotic approaches have also been disclosed. In the present review all of them are discussed. 1 Introduction 2 Synthetic Approaches Involving the Synthesis of an Amide Followed by Its Reduction 2.1 Approaches Involving Saturated Amide 2 from Acid 3 2.2 Approaches Involving Acrylamide 5 2.3 Alternatives Approaches Involving Amides 3 Synthetic Approaches Involving a Reductive Amination 3.1 Processes for the Synthesis of 3-(Trifluoromethyl)cinnamaldehyde (18) and 3-[3-(Trifluoromethyl)phenyl]propanal (20) 3.2 Processes Involving 18 3.3 Processes Involving 20 4 Synthetic Approaches Involving a Substitution Reaction 4.1 Substitutions Involving Alkyl Halides or Pseudohalides 4.2 Substitutions Involving Allyl Halides or Pseudohalides 4.3 Substitution Involving a Propynyl Mesylate 4.4 Direct Substitution without Activating the Hydroxyl Group 5 Miscellaneous Synthetic Approaches 6 Conclusions

We have developed a highly efficient synthetic route to carbazoles that employs sequential C–C/C–N bond formation via Suzuki cross-coupling and Cadogan cyclization using commercially available or easily preparable starting materials. The developed method is compatible with electron neutral, rich or deficient substrates. The synthetic utility of this method was demonstrated by the concise syntheses of four natural products (glycozoline, glycozolicine, glycozolidine and clausenalene).

Imine reductases (IREDs) are NADPH-dependent oxidoreductases that catalyse the asymmetric reduction of cyclic prochiral imines to amines, with excellent stereoselectivity. Since their discovery, stereocomplementary IREDs have been applied to the production of both (S) and (R) cyclic secondary amines, and the expansion in gene sequences recently identified has hinted at new substrate ranges that extend into acyclic imines and even suggest the possibility of asymmetric reductive amination from suitable ketone and amine precursors. Structural studies of various IREDs are beginning to reveal the complexities inherent in determining substrate range, stereoselectivity and mechanism in these enzymes, which represent a valuable emerging addition to the toolbox of available biocatalysts for chiral amine production.

Described herein is a highly enantioselective synthesis of fused piperidine and pyrrolidine derivatives with all-carbon stereogenic centers. The enantioselective reductive amination from Cs-symmetric 1,3-dione derivatives proceeded in a highly stereoselective manner by taking advantage of the desymmetrization approach to afford fused heterocycles with contiguous stereogenic centers in good to excellent enantioselectivities (up to 98% ee).

In this study, two possible regiochemical pathways of aziridine ring opening, termed “regiochemistry-directed branches for 2-substituted aziridines” are described, providing easy access to two classes of compound from a common synthetic intermediate. Application of this synthetic strategy, with stereoselective dihydroxylation and reductive amination as the key steps, allowed the asymmetric synthesis of natural and unnatural polyhydroxylated alkaloids including the calyculin fragment C33–C37, 1,4-dideoxy-1,4-imino-l-ribitol and analogues of hyacinthacine, swainsonine, castanospermine, and deoxynojirimycin. The initial domino reactions consisted of aziridine ring opening and debenzylation, and reductive double annulations were established for the preparation of bicyclic pyrrolizidine and indolizidine—represented by 8-deoxyhyacinthacine and (3R)-methyl-8-deoxyswainsonine—with remarkable stereoselectivity and in high yield.

The facile microwave-assisted protocol allows the synthesis of the title piperidines via reductive amination cyclization reaction of 1,5-diketone (I) with alkylammonium formates.

The reaction can also be conducted under thermal conditions (not shown) and is mentioned to be amenable to a continuous-flow production of cyclohexylamines in gram scale.

A versatile synthesis of 7-azaindoles from substituted 2-fluoropyridines is described. C3-metalation and 1,4-addition to nitroolefins provide substituted 2-fluoro-3-(2-nitroethyl)pyridines. A facile oxidative Nef reaction/reductive amination/intramolecular SNAr sequence furnishes 7-azaindolines. Finally, optional regioselective electrophilic C5-substitution (e.g., bromination or nitration) and subsequent in situ oxidation delivers highly functionalized 7-azaindoles in high overall efficiency.

An unusually strong affinity of unsupported nanoporous gold (AuNPore) towards aldimines and ketimines has been demonstrated. By using PhMe 2 SiH and water as a hydrogen source and AuNPore as a catalyst, ketimines and aldimines can be reduced to the corresponding amines in high chemical yields under mild conditions. This system was also applied to the reductive amination of aldehydes and ketones.

Ruthenium(II)-catalyzed hydrogen transfer from 2-propanol mediates reductive coupling of 1,1-disubstituted allenes with formaldimines with complete branch-regioselectivity, thus representing a new method for hydroaminomethylation beyond classical hydroformylation/reductive amination.

A direct reductive amination procedure for the efficient preparation of tertiary amines (II) under mild reaction conditions employing (Tms)2NH as nitrogen source is developed.

A new method for the synthesis of chiral β-aryl amines via chiral phosphoric acid-catalyzed enantioselective reductive amination of benzyl methyl ketone derivatives with Hantzsch ester was developed. Various chiral β-aryl amines were obtained in high yields and with good to high enantioselectivities. This transformation is applicable to gram-scale reactions, and the catalyst loading can be reduced to 1 mol % without sacrificing any catalytic efficacy. Furthermore, the resulting β-aryl amine was successfully converted into a tetrahydroisoquinoline compound without any loss of enantioselectivity.

Carbonyl compounds are aminated by aromatic amines to give tertiary and secondary amines chemoselectively.

This comprehensive report accounts the development of a highly diastereoselective samarium diiodide-induced cascade reaction of substituted indolyl ketones. The complexity-generating transformation with SmI2 allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra- or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14 % overall yield in ten steps, or 10 % overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI2 -induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids.

Review: recent advances in asymmetric reductive amination by hydrogenation, transfer hdrogenation, organocatalytic and biocatalytic reduction; 103 refs.

The newly developed title complex proves efficient in the reductive amination of various aldehydes and ketones with primary aliphatic and aromatic amines as well as secondary amines.

HF reaction represents a selective method for the synthesis of aldehydes starting from alkenes. Because of versatile aldehydes reactivity, it is possible to perform different domino protocols based on contemporary HF, including Michael's reaction, reductive amination, cyclopropanation, lactonization, and many others. This overview reports on the last 5 years' results obtained on this field.

An efficient one-pot method for the asymmetric reductive amination of ketones in the presence of sodium borohydride is presented.

Chiral amines represent a prominent functional group in pharmaceuticals and agrochemicals and are hence attractive targets for asymmetric synthesis. Since the pharmaceutical industry has identified biocatalysis as a valuable tool for synthesising chiral molecules with high enantiomeric excess and under mild reaction conditions, enzymatic methods for chiral amine synthesis are increasing in importance. Among the strategies available in this context, the asymmetric reduction of imines by NAD(P)H-dependent enzymes and the related reductive amination of ketones have long remained underrepresented. However, recent years have witnessed an impressive progress in the application of natural or engineered imine-reducing enzymes, such as imine reductases, opine dehydrogenases, amine dehydrogenases, and artificial metalloenzymes. This review provides a comprehensive overview of biocatalytic imine reduction and reductive amination of ketones, highlighting the natural roles, substrate scopes, structural features, and potential application fields of the involved enzymes.

As part of our work devoted to the synthesis of organic compounds using “green” processes, we developed several water-soluble catalysts that allow efficiently the synthesis of ketones, amines, alcohols and amides. CuCl 2 ·2H 2 O combined to 2,2′-biquinoline-4,4′-dicarboxylic acid dipotassium salt (BQC) was reported as an active catalyst for the selective oxidation with TBHP of alcohols, alkylarenes and alkynes. We developed also successfully hydrogen transfer reactions. While [Ir(COD)Cl] 2 /BQC proved to be efficient for Oppenauer-type oxidation of secondary alcohols, [Rh(COD)Cl] 2 /P(m-C 6 H 4 SO 3 Na) 3 (TPPTS) showed very good activities for Meerwein–Ponndorf–Verley-type reduction of ketones and aldehydes. Higher alkylated amines and amides were also synthesized respectively, by direct reductive amination of aldehydes with primary and secondary amines catalyzed by water soluble Pd(PhCN) 2 Cl 2 /BQC, and hydration of nitriles with [Rh(COD)Cl] 2 /TPPTS. Many of these catalytic systems are recycled with no significant loss of activity and the final products are isolated in easy manners.

A ruthenium-catalyzed reductive amination without an external hydrogen source has been developed using carbon monoxide as the reductant and ruthenium(III) chloride (0.008–2 mol %) as the catalyst. The method was applied to the synthesis of antianxiety agent ladasten.

The employed calcium hydride seems to react with the formed water and then liberates hydrogen.

The total synthesis of (±)-lycoposerramine-R, a novel skeletal type of Lycopodium alkaloid, was accomplished via the Diels–Alder reaction, the stereoselective introduction of a methyl group, the regio- and stereoselective reductive amination, and the construction of a pyridone ring.

A wide range of primary and secondary amines are used for the direct reductive amination of bio-based 5-hydroxymethylfurfural (I) using the complex dichlorobis(2,9-dimethyl-1,10-phenanthroline)ruthenium(II) as efficient catalyst and H2 as reductant.

The use of a variety of copper salts as well as elemental copper and its oxides can be used to catalyze the dehydrogenation of a range of amine boranes with dimethylamine borane showing high levels of reactivity to the catalyst.

The reaction succeeds using aromatic, heteroaromatic and aliphatic ketones with generally moderate to good reaction yields and high enantioselectivities.

The novel direct reductive amination of aromatic aldehydes furnishes both symmetric and asymmetric secondary benzyl amines in a mild, convenient, acid- and catalyst-free system.

Metal, oxidant and other additive-free novel methods for direct C–H aryloxylation of aliphatic amines are developed. In the presence of excess amine, the course of the reaction was diverted, producing various arylmethylamines via hydride-free formal reductive amination. Involvement of a quinone methide intermediate was revealed from mechanistic studies.

The cheap heterogeneous catalyst, core-shell structured Co3O4 nanocomposite encapsulated with N-doped graphene, allows an efficient domino reductive amination of carbonyl compounds with nitroarenes.

A mild, metal-free approach for the direct reductive N-alkylation of aromatic amines with acetals using the iodine-triethylsilane reductive system is described.

Ultrasound-assisted solventless oxidation/reductive amination of benzyl halides was developed as a facile, efficient, and environmental friendly method toward N-alkylated amines. Aldehydes were formed in situ by oxidation of organic halides with N-methylmorpholine N-oxide (NMO), followed by direct reductive amination with amines using sodium borohydride and montmorillonite K-10 catalyst as the reducing system. This green and simple procedure enables N-alkylated amines to be prepared in good to excellent yields with high selectivity of the monoalkylation.