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%).

     

Rhodium‐Catalyzed Homogeneous Reductive Amidation of Aldehydes

The catalytic reductive amidation of an aldehyde (hexanal) with an amide (acetamide) is reported. Apart from the desired N‐hexylacetamide, the two isomeric unsaturated intermediates as well as hexanol are produced together with higher mass products that arise from aldol condensation and diamide coupling of the aldehyde. Screening of different catalyst precursor salts, ligands and reaction conditions led to the finding that the catalytic system based on the (cyclooctadiene)rhodium chloride dimer, [Rh(cod)Cl]₂, in combination with the ligand xantphos and an acid co‐catalyst results in high selectivity for the desired product. Under optimized conditions nearly full conversion is reached with high selectivity to the desired N‐alkylamide and with a very high N ‐ alkylamide/alcohol ratio, while producing only small amounts of by‐products. The scope of the reaction has been investigated using different amides as well as aldehydes; the results show the general applicability of this novel reaction, but with electron‐withdrawing amides the selectivity to N‐alkylamide is lower. NMR studies showed that the nucleophilic addition of acetamide to hexanal is acid catalyzed, forming N‐(1‐hydroxyhexyl)acetamide in equilibrium with both hexanal and the dehydrated unsaturated imides. A catalytic mechanism is proposed in which a strong acid such as HOTs acts as a co‐catalyst by establishing a rapid chemical equilibrium between the aldehyde, acetamide and the intermediates. Furthermore, it is proposed that the presence of acid causes a change in catalytic species, enabling a cationic Rh/xantphos hydrogenation catalyst to selectively hydrogenate the intermediates to N‐hexylacetamide in the presence of hexanal.     

Storable and Air‐Stable Zirconium Complex‐Catalyzed Highly Enantioselective Darzens Reaction of Diazoacetamide with Aldehydes

An asymmetric Darzens reaction of aldehydes with diazo‐N,N‐dimethylacetamide ( 3 ) catalyzd by an air‐stable and storable chiral zirconium Lewis acid catalyst, which is formed from 3,3′‐diiodobinaphthol and tetrabutoxyzirconium, gives solely the cis‐glycidic amides in high yields with excellent enantioselectivity (up to 97% yield, >99% ee).     

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.

     

Chymopapain‐Catalyzed Direct Asymmetric Aldol Reaction

Chymopapain, a cysteine proteinase isolated from the latex of the unripe fruits of Carica papaya, displays a promiscuous activity to catalyze the direct asymmetric aldol reactions of aromatic and heteroaromatic aldehydes with cyclic and acyclic ketones in acetonitrile in the presence of a phosphate buffer. The excellent enantioselectivities of up to 96% ee and high diastereoselectivities of up to >99:1 (anti/syn) were achieved. The novel catalytic promiscuity of chymopapain widens the applicability of this biocatalyst in organic synthesis.     

Iron‐Catalyzed Amidation of Aldehydes with N‐Chloroamines

A new direct conversion of aldehydes to amides has been realized, in the presence of iron(III) chloride as a catalyst and using tert‐butyl hydroperoxide (TBHP) as an oxidant. Both aliphatic and aromatic aldehydes were successfully reacted with variously mono‐ and di‐substituted N‐chloroamines. The methodology has a wide substrate scope, uses cheap and easily available reagents and is characterized by short reaction times.     

Phenylalanine Ammonia‐Lyase‐Catalyzed Deamination of an Acyclic Amino Acid: Enzyme Mechanistic Studies Aided by a Novel Microreactor Filled with Magnetic Nanoparticles

Phenylalanine ammonia‐lyase (PAL), found in many organisms, catalyzes the deamination of l ‐phenylalanine (Phe) to (E)‐cinnamate by the aid of its MIO prosthetic group. By using PAL immobilized on magnetic nanoparticles and fixed in a microfluidic reactor with an in‐line UV detector, we demonstrated that PAL can catalyze ammonia elimination from the acyclic propargylglycine (PG) to yield (E)‐pent‐2‐ene‐4‐ynoate. This highlights new opportunities to extend MIO enzymes towards acyclic substrates. As PG is acyclic, its deamination cannot involve a Friedel–Crafts‐type attack at an aromatic ring. The reversibility of the PAL reaction, demonstrated by the ammonia addition to (E)‐pent‐2‐ene‐4‐ynoate yielding enantiopure l ‐PG, contradicts the proposed highly exothermic single‐step mechanism. Computations with the QM/MM models of the N‐MIO intermediates from l ‐PG and l ‐Phe in PAL show similar arrangements within the active site, thus supporting a mechanism via the N‐MIO intermediate.     

Enantioselective Synthesis of α‐Hydroxy Ketones via Benzaldehyde Lyase‐Catalyzed C−C Bond Formation Reaction

(R)‐Benzoins and (R)‐2‐hydroxypropiophenone derivatives are formed on a preparative scale by benzaldehyde lyase (BAL)‐catalyzed C−C bond formation from aromatic aldehydes and acetaldehyde in aqueous buffer/DMSO solution with remarkable ease in high chemical yield and high optical purity. The substrate range of this thiamin diphosphate‐dependent enzyme was examined with respect to a broad applicability of this benzoin condensation‐type reaction in stereoselective synthesis.     

Iron‐Catalyzed Efficient Synthesis of Amides from Aldehydes and Amine Hydrochloride Salts

A practical and efficient method for the synthesis of amides has been developed by iron‐catalysed oxidative amidation of aldehydes with amine hydrochloride salts. A wide range of amides have been obtained in good to excellent yields under mild conditions. The application of this novel amide formation reaction to the synthesis of pharmaceutical compounds has been successfully demonstrated.     

Single‐Turnover Kinetics Reveal a Distinct Mode of Thiamine Diphosphate‐Dependent Catalysis in Vitamin K Biosynthesis

MenD, or (1R,2S,5S,6S)‐2‐succinyl‐5‐enolpyruvyl‐6‐hydroxycyclohex‐3‐ene‐1‐carboxylate (SEPHCHC) synthase, uses a thiamine diphosphate (ThDP)‐dependent tetrahedral Breslow intermediate rather than a canonical enamine for catalysis in the biosynthesis of vitamin K. By real‐time monitoring of the cofactor chemical state with circular dichroism spectroscopy, we found that a new post‐decarboxylation intermediate was formed from a multistep process that was rate limited by binding of the α‐ketoglutarate substrate before it quickly relaxed to the characterized tetrahedral Breslow intermediate. In addition, the chemical steps leading to the reactive post‐decarboxylation intermediates were not affected by the electrophilic substrate, isochorismate, whereas release of the product was found to limit the whole catalytic process. Moreover, these intermediates are likely kinetically stabilized owing to the low biological availability of isochorismate under physiological conditions, in contrast to the tight coupling of enamine formation with binding of the electrophilic acceptor in some other ThDP‐dependent enzymes. Together with the unusual tetrahedral structure of the intermediates, these findings strongly support a new ThDP‐dependent catalytic mode distinct from canonical enamine chemistry.     

Highly Enantioselective Co‐Catalytic Direct Aldol Reactions by Combination of Hydrogen‐Bond Donating and Acyclic Amino Acid Catalysts

Highly enantioselective co‐catalytic direct aldol reactions by a combination of simple hydrophobic acyclic amino acid and hydrogen‐bond donating catalysts are presented. The corresponding aldol products are formed in high yields with high regio‐, diastereo‐ (anti or syn) and enantioselectivity (up to 99.5:0.5 er). The catalyst loadings can be decreased to as little as 2 mol%.     

Palladium‐Catalyzed Acylation of 2‐Aryl‐1,2,3‐triazoles with Aldehydes

The palladium‐catalyzed acylation of 2‐aryl‐1,2,3‐triazoles with aldehydes via C H bond activation is described. A wide variety of products was isolated in good to excellent yields. This finding provides a new and useful strategy for the synthesis of aromatic ketones.

     

Nickel‐Catalyzed Reductive Benzylation of Aldehydes with Benzyl Halides and Pseudohalides

The reductive benzylation of aromatic and aliphatic aldehydes with benzylic halides is reported using a nickel/zinc catalyst system. In addition to benzylic halides, the first report on the addition of benzylic triflates, acetates, tosylates and tritylates to aldehydes is also presented. By this new method a range of alcohols was synthesized efficiently from aldehydes and benzylic substrates at room temperature in moderate to high yields. The mild reaction conditions and good functional group tolerance make this nickel‐catalyzed process synthetically useful for the synthesis of diverse benzylic alcohols.

     

(S)‐Selectivity in Phenylacetyl Carbinol Synthesis Using the Wild‐Type Enzyme Acetoin:Dichlorophenolindophenol Oxidoreductase from Bacillus licheniformis

Thiamine diphosphate (ThDP)‐dependent enzymes are well known biocatalysts for the asymmetric synthesis of α‐hydroxy ketones with preferential (R)‐selectivity. Pharmaceutically relevant phenylacetyl carbinol (PAC) has been prepared with absolute (S)‐configuration only on a few occasions using enzyme variants suitably designed through rational site‐directed mutagenesis approaches. Herein, we describe the synthesis of (S)‐phenylacetyl carbinol products with extended reaction scope employing the readily available wild‐type ThDP‐dependent enzyme acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) from Bacillus licheniformis. On a semipreparative scale, cross‐benzoin‐like condensations of methylacetoin (donor) and differently substituted benzaldehydes proceed with almost complete chemoselectivity yielding the target (S)‐1‐hydroxy‐1‐phenylpropan‐2‐one derivatives with high conversion efficiencies (up to 95%) and good enantioselectivities (up to 99%). Ao:DCPIP OR accepts hydroxy‐ and nitrobenzaldehydes and also sterically demanding substrates such as 1‐naphthaldehyde and 4‐(tert‐butyl)benzaldehyde, which are typically poor acceptors in enzymatic transformations. The explorative synthesis of (S)‐phenylpropionyl carbinol mediated by Ao:DCPIP OR via carboligation of benzaldehyde with 3,4‐hexanedione is also reported.

     

Palladium‐Catalyzed Cyclization Reactions of Acetylene‐Containing Amino Acids

Enantiomerically pure acetylene‐containing α‐amino acids were used as versatile starting materials for the synthesis of a variety of heterocycles via Pd‐mediated cyclization reactions. Depending on the protecting group strategy, both the carboxylate and the amine function of the amino acids could participate in the cyclizations, thus giving rise to oxygen heterocycles (α‐aminolactones) and nitrogen heterocycles (cyclic α‐amino acid derivatives), respectively. Beside the straightforward cyclization, cyclization/cross‐coupling reactions were also successfully carried out to provide the corresponding substituted cyclic amino acid derivatives.     

Aluminium(III) Chloride‐Catalyzed Three‐Component Condensation of Aromatic Aldehydes,Nitroalkanes and Sodium Azide for the Synthesis of 4‐Aryl‐NH‐1,2,3‐triazoles

An aluminium(III) chloride‐catalyzed three‐component reaction of aromatic aldehydes, nitroalkanes, and sodium azide has been developed; this reaction sequence can be applied to a broad substrate scope and affords the corresponding 4‐aryl‐NH‐1,2,3‐triazoles in good to excellent yields. The milder reaction conditions and easier operation make this AlCl₃‐catalyzed protocol more advantageous for the synthesis of 4‐aryl‐NH‐1,2,3‐triazoles.

     

Organocatalytic Asymmetric syn‐Aldol Reactions of Aldehydes with Long‐Chain Aliphatic Ketones on Water and with Dihydroxyacetone in Organic Solvents

An on‐water, asymmetric, and direct syn‐aldol reaction of aliphatic ketones with aromatic aldehydes catalyzed by a primary amino acid‐based organocatalyst afforded the syn‐aldol adducts in high yields with excellent diastereo‐ and enantioselectivities (up to > 20/1 dr, >99% ee), and a highly enantioselective syn‐aldol reaction of dihydroxyacetone with a variety of aldehydes in THF proceeded with 14/1 to >20/1 dr and 92 to >99% ee. Water not only accelerated the reaction, but also enhanced the enantioselectivity. This positive water effect might arise from the hydrogen bond formed between a pendant hydroxy group of surface water molecules at the hydrophobic interface with the amide oxygen of the organocatalyst, which increases the acidity of the amide NH and thereby strengthens the related hydrogen bond formed with the aldehyde.