Chemoselective Reductive Nucleophilic Addition to Tertiary Amides,Secondary Amides,and N‐Methoxyamides

As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide carbonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor electrophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nucleophiles to tertiary amides, secondary amides, and N‐methoxyamides that uses the Schwartz reagent [Cp₂ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups.     

Two‐step Synthesis of Multi‐Substituted Amines by Using an N‐Methoxy Group as a Reactivity Control Element

The development of a two‐step synthesis of multi‐substituted N‐methoxyamines from N‐methoxyamides is reported. Utilization of the N‐methoxy group as a reactivity control element was the key to success in this two‐step synthesis. The first reaction involves a N‐methoxyamide/aldehyde coupling reaction. Whereas ordinary amides cannot condense with aldehydes intermolecularly due to the poor nucleophilicity of the amide nitrogen, the N‐methoxy group enhances the nucleophilicity of the nitrogen, enabling the direct coupling reaction. The second reaction in the two‐step process was nucleophilic addition to the N‐methoxyamides. Incorporation of the N‐methoxy group into the amides increased the electrophilicity of the amide carbonyls and promoted the chelation effect. This nucleophilic addition enabled quick diversification of the products derived from the first step. The developed strategy was applicable to a variety of substrates, resulting in the elaboration of multi‐substituted piperidines and acyclic amines, as well as a substructure of a complex natural alkaloid.     

Novel Transition‐Metal (M=Cr,Mo, W,Fe) Carbonyl Complexes with Bis(guanidinato)silicon(II) Ligands

The donor‐stabilized silylene 2 (the first bis(guanidinato)silicon(II ) complex) reacts with the transition‐metal carbonyl complexes [M(CO)₆] (M=Cr, Mo, W) to form the respective silylene complexes 7 – 10 . In the reactions with [M(CO)₆] (M=Cr, Mo, W), the bis(guanidinato)silicon(II ) complex 2 behaves totally different compared with the analogous bis(amidinato)silicon(II ) complex 1 , which reacts with [M(CO)₆] as a nucleophile to replace only one of the six carbonyl groups. In contrast, the reaction of 2 leads to the novel spirocyclic compounds 7 – 9 that contain a four‐membered SiN₂C ring and a five‐membered MSiN₂C ring with a M?Si and M?N bond (nucleophilic substitution of two carbonyl groups). Compounds 7 – 10 were characterized by elemental analyses (C, H, N), crystal structure analyses, and NMR spectroscopic studies in the solid state and in solution.     

Highly Enantioselective Fluorescent Recognition of Both Unfunctionalized and Functionalized Chiral Amines by a Facile Amide Formation from a Perfluoroalkyl Ketone

The H₈BINOL‐based perfluoroalkyl ketone (S)‐ 2 is found to exhibit highly enantioselective fluorescent enhancements toward both unfunctionalized and functionalized chiral amines. It greatly expands the substrate scope of the corresponding BINOL‐based sensor. A dramatic solvent effect was observed for the reaction of the amines with compound (S)‐ 2 . In DMF, cleavage of the perfluoroalkyl group of compound (S)‐ 2 to form amides was observed but not in other solvents, such as methylene chloride, chloroform, THF, hexane, and perfluorohexane. Thus, the addition of another solvent, such as THF, can effectively quench the reaction of compound (S)‐ 2 with amines in DMF to allow stable fluorescent measurement. This is the first example that the formation of strong amide bonds under very mild conditions is used for the enantioselective recognition of chiral amines. The mechanism of the reaction of compound (S)‐ 2 with chiral amines is investigated by using various analytical methods including mass spectrometry as well as NMR and UV/Vis absorption spectroscopy.     

Facile amidation of esters with aromatic amines promoted by lanthanide tris (amide) complexes

The development of catalysts capable of catalyzing amidation of esters with amines to construct amides under mild conditions is of great importance. Compared to aliphatic amines, the direct catalytic amidation of esters with less nucleophilic aromatic amines is rather difficult. Employing simple lanthanide tris (amide) complexes Ln[N (SiMe₃)₂]₃(μ-Cl)Li (THF)₃ as the catalysts, it was found a broad range of aromatic amines and esters were efficiently converted into various amides in good yields under mild conditions. A plausible mechanism for this transformation was experimentally supported as starting from an amide exchange reaction between the lanthanide tris (amide) complex and the substrate amine.     

Metal free amide synthesis via carbon–carbon bond cleavage

A metal-free oxidative coupling of methyl ketones and primary amines to amides has been developed. The reaction tolerates a variety of functional groups, and is operationally simple. The reaction is proposed to go through a radical pathway to form the triiodomethyl ketone intermediate and the amide is formed by the nucleophilic attack of amine on triiodomethyl ketone carbonyl.     

Nickel‐Catalyzed Esterification of Aliphatic Amides

Recent studies have demonstrated that amides can be used in nickel‐catalyzed reactions that lead to cleavage of the amide C?N bond, with formation of a C?C or C?heteroatom bond. However, the general scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel‐catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni‐catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C?N bond cleavage processes.     

Control over the Chemoselectivity of Pd‐Catalyzed Cyclization Reactions of (2‐Iodoanilino)carbonyl Compounds

The factors that control the chemoselectivity of palladium‐catalyzed cyclization reactions of (2‐iodoanilino)carbonyl compounds have been explored by an extensive experimental computational (DFT) study. It was found that the selectivity of the process, that is, the formation of fused six‐ versus five‐membered rings, can be controlled by the proper selection of the initial reactant, reaction conditions, and additives. Thus, esters or amides produce ketones by a nucleophilic addition process, whereas the addition of PhO^? ions leads to the formation of indolines by an α‐arylation reaction. In contrast, the corresponding ketone reactants yield a mixture of both reaction products, the ratio of which depends on the base used, in the presence of phenol. The outcome of the processes can be explained by the formation of a common four‐membered palladacycle intermediate from which the competitive nucleophilic addition and α‐arylation reactions occur. The remarkable effect of phenol in the process, which makes the α‐arylation reaction easier, favored the formation of enol complexes, which are stabilized by an intramolecular hydrogen bond between the hydroxy group of the enol moiety and the oxygen atom of the phenoxy ligand. Moreover, the chemoselectivy of the process can be also controlled by the addition of bidendate ligands that lead to the almost exclusive formation of indoles at expenses of the corresponding alcohols.     

Nucleophilic and Electrophilic Activation of Non‐Heteroaromatic Amides in Atom‐Economical Asymmetric Catalysis

Recent advances in catalytic asymmetric carbon–carbon bond‐forming reactions of non‐heteroaromatic amide substrates are highlighted. Among carbonyl compounds, amides have received limited attention in catalytic asymmetric transformations mainly owing to their lower reactivity. Amides are reluctant to form enolates for nucleophilic addition, and α,β‐unsaturated amides exhibit diminished electrophilicity at the β‐carbon. Recent advances in asymmetric catalysis rendered these amides amenable to enantioselective reactions with perfect atom economy, producing synthetically useful chiral building blocks. This Minireview summarizes recent developments in the field.     

Structural Characterization of N‐Alkylated Twisted Amides: Consequences for Amide Bond Resonance and N−C Cleavage

Herein, we describe the first structural characterization of N‐alkylated twisted amides prepared directly by N‐alkylation of the corresponding non‐planar lactams. This study provides the first experimental evidence that N‐alkylation results in a dramatic increase of non‐planarity around the amide N?C(O) bond. Moreover, we report a rare example of a molecular wire supported by the same amide C=O‐Ag bonds. Reactivity studies demonstrate rapid nucleophilic addition to the N?C(O) moiety of N‐alkylated amides, indicating the lack of n_N to π^*_C=O conjugation. Most crucially, we demonstrate that N‐alkylation activates the otherwise unreactive amide bond towards σ N?C cleavage by switchable coordination.     

Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine

Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine–iodonium complex first forms through N?halogen bonding. This complex reacts with aci‐nitronates to give both α‐iodo‐ and α,α‐diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I⁺ under O₂. In particular, evidence supports α,α‐diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.     

Application of the Cleavable Isocyanide in Efficient Approach to Pyroglutamic Acid Analogues with Potential Biological Activity

Two efficient procedures have been developed for the synthesis of pyroglutamic acid analogues 28, 29, and 34. According to the first method the Ugi (4C3C) reaction is followed by a post-transformation reaction, and the second method involves the Michael addition reaction. The present methodologies demonstrate the applicability of 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (15) as a cleavable isocyanide in the Ugi/ post-transformation reaction and a strong nucleophile in the Michael addition reaction. The framework of pyroglutamic acid analogues has been constructed by the selective cleavage of the C-terminal amide bond and nucleophilic addition to the activated α,β-unsaturated carbonyl group.

     

A Convenient Synthesis of 1‐Alkoxy‐2‐alkyl‐1,2‐dihydroisoquinoline‐3,4‐diones Utilizing the Reaction of 2‐(Dialkoxymethyl)phenyllithiums with Dimethyl Oxalate

A new and convenient method for the preparation of 1,2‐dihydroisoquinoline‐3,4‐diones with alkoxy and alkyl groups at the 4‐ and 3‐positions, respectively, using an easily operated three‐step sequence starting from 2‐(dialkoxymethyl)phenyl bromides has been developed. Thus, the starting materials are treated with BuLi to generate 2‐(dialkoxymethyl)phenyllithiums, which are allowed to react with (COOMe)₂ to give methyl 2‐(dialkoxymethyl)phenyl‐2‐oxoacetates. These are then transformed into the corresponding secondary amides by the reaction with primary amines. Treatment of these keto amides with a catalytic amount of TsOH?H₂O affords the desired products. In order to demonstrate the synthetic utility of these products, transformation of one of them into the corresponding isoquinoline‐1,3,4(2H)‐trione derivative by the oxidation with PCC was achieved.     

Ester‐ and amide‐terminated dendrimers with alternating amide and ether generations

Ester‐terminated polyamide dendrimers up to the third generation and amide‐terminated polyamide dendrimers of the first generation were synthesized by convergent growth. The Williamson ether synthesis and diphenylphosphoryl azide (DPPA) coupling of amines to carboxylic acids were used for the construction of the dendrimers, having alternate ether and amide generations. The methyl ester‐ and N,N‐diethylamide‐terminated dendrimers were readily soluble in common organic solvents while the N‐methylamide‐ and N‐benzylamide‐terminated dendrimers were soluble only in DMF and DMSO. Both the end and internal amide groups of the N,N‐diethylamide‐terminated dendrimer were reduced by LiAlH₄ to form a polyamine dendrimer. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1533–1543, 2000     

Direct Catalytic Asymmetric Aldol Reaction of α‐Alkoxyamides to α‐Fluorinated Ketones

α‐Oxygen‐functionalized amides found particular utility as enolate surrogates for direct aldol couplings with α‐fluorinated ketones in a catalytic manner. Because of the likely involvement of open transition states, both syn‐ and anti‐aldol adducts can be accessed with high enantioselectivity by judicious choice of the chiral ligands. A broad variety of alkoxy substituents on the amides and aryl and fluoroalkyl groups on the ketone were tolerated, and the corresponding substrates delivered a range of enantioenriched fluorinated 1,2‐dihydroxycarboxylic acid derivatives with divergent diastereoselectivity depending on the ligand used. The amide moiety of the aldol adduct was transformed into a variety of functional groups without protection of the tertiary alcohol, showcasing the synthetic utility of the present asymmetric aldol process.     

Diastereoselective [3+2] Annulation of Aromatic/Vinylic Amides with Bicyclic Alkenes through Cobalt‐Catalyzed C−H Activation and Intramolecular Nucleophilic Addition

A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt‐catalyzed C?H activation and intramolecular nucleophilic addition to the amide functional group. Transition‐metal‐catalyzed C?H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C?H bond cleavage may be the rate‐limiting step.     

Tandem Gold Self‐Relay Catalysis for the Synthesis of 2,3‐Dihydropyridin‐4(1 H)‐ones: Combination of σ and π Lewis Acid Properties of Gold Salts

The dual ability of gold salts to act as π‐ and σ Lewis acids has been exploited in a tandem self‐relay catalysis. Thus, triphenylphosphanegold(I) triflate mediated the intramolecular carbonyl addition of the amide functionality of homoprogargyl amides to a triple bond. The formation of a σ complex of the gold salt with the intermediate oxazine promoted a nucleophilic addition followed by a Petasis–Ferrier rearrangement. This tandem protocol, catalyzed by the same gold salt under the same reaction conditions, gave rise to the efficient synthesis of 2,3‐dihydropyridin‐4‐(1 H)‐ones, which contain a cyclic quaternary α‐amino acid unit. The asymmetric version was performed by generating the starting materials from the corresponding sulfinylimines.     

A revision of the alcoholysis and alkanethiolysis of 3‐amino‐6‐chloropyridazine

The synthesis of 3‐amino‐6‐alkoxy‐ and 3‐amino‐6‐alkylthiopyridazines via nucleophilic aromatic substitution on 3‐amino‐6‐chloropyridazine is described. In contrast to literature reports, no pressure tube is required to perform these reactions.     

Polyfluoro-1,2-epoxy-alkanes and - cycloalkanes. Part II. Reactions of decafluoro-1,2-epoxycyclohexane

The epoxy ring of the title compound has been opened by nucleophilic attack using lithium aluminium hydride, sodium methoxide, methyl lithium, sodium azide and potassium cyanide. The primary product incorporated the nucleophile (N) and an alkoxy function, which was fixed by methylation when N = CN. However, in most cases the alkoxide group decomposed to carbonyl, and the ketone was isolated when N was OMe. More nucleophile could be added across this carbonyl group, the resultant substituted alkoxide being isolated as the tertiary alcohol (N = Me) or the methyl ether (N = N₃). With lithium aluminium hydride (N = H), a secondary alcohol was obtained, the fluorine on the ring carbon bearing the alkoxy group being replaced by H; the pathway probably did not involve a free carbonyl group, since the resultant alcohol was a pure stereoisomer. This was shown by nmr, and also since the pure methoxymethyl ether made from it was dehydrofluorinated exclusively to 2H-octafluorocyclohexenyl methoxymethyl ether.     

Palladium‐Catalyzed N‐Alkylation of Amides and Amines with Alcohols Employing the Aerobic Relay Race Methodology

Possibly because homogeneous palladium catalysts are not typical borrowing hydrogen catalysts and ligands are thus ineffective in catalyst activation under conventional anaerobic conditions, they had not been used in the N‐alkylation reactions of amines/amides with alcohols in the past. By employing the aerobic relay race methodology with Pd‐catalyzed aerobic alcohol oxidation being a more effective protocol for alcohol activation, ligand‐free homogeneous palladiums are successfully used as active catalysts in the dehydrative N‐alkylation reactions, giving high yields and selectivities of the alkylated amides and amines. Mechanistic studies implied that the reaction most probably proceeds via the novel relay race mechanism we recently discovered and proposed.