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.     

Highly Selective Addition of a Broad Spectrum of Trimethylsilane Pro‐nucleophiles to N‐tert‐Butanesulfinyl Imines

Addition of organotrimethylsilane reagents to chiral N‐tert‐butanesulfinyl imines can be achieved in good yields and with excellent diastereoselectivities by employing TMSO^?/Bu₄N⁺ as a Lewis base activator in THF. A variety of aliphatic, aromatic, heteroaromatic and organometallic chiral imines were utilised as electrophiles for the synthesis of enantioenriched N‐tert‐butanesulfinyl amides. Remarkably, the same sets of reaction conditions could be used with a highly diverse range of bench‐stable organotrimethylsilane reagents, which highlights the generality and robustness of this methodology.     

Bifunctional‐Thiourea‐Catalyzed Diastereo‐ and Enantioselective Aza‐Henry Reaction

Bifunctional thiourea 1 a catalyzes aza‐Henry reaction of nitroalkanes with N‐Boc‐imines to give syn‐β‐nitroamines with good to high diastereo‐ and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N‐protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N‐Boc‐imines gives R adducts as major products, whereas the same reaction of N‐phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP‐99,994.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem‐Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents

An unprecedent gem‐carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B₂pin₂ to a carbonyl compound generates α‐oxyl‐substituted alkyl boron species. Organolithium and Grignard reagents are then applied as C nucleophiles for the 1,2‐metalate rearrangement process. The organolithium reagents can also be generated by C?H lithiation or halogen/lithium exchange. The use of chiral ligands led to the generation of chiral alkyl boronic esters in enantioenriched form, demonstrating that the enantioselectivity of this transformation is catalyst‐controlled.     

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.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Simple Lanthanide Amides [(Me3Si)2N]3Ln(μ-Cl)Li(THF)3 as Highly Efficient Catalysts for the Nitroaldol Reaction

This contribution is to report the application of simple lanthanide amides [(Me3Si)2N]3Ln(μ-Cl)Li(THF)3 exhibiting a high activity toward catalyzing Henry reaction of aromatic aldehydes with nitroalkanes to give β-nitroalcohols or β-nitroolefins with a very good chemoselectivity by controlling the reaction temperatures and by selecting aromatic aldehydes. It was found that this catalytic system was compatible with a wide range of substrates of aldehydes.     

Two pseudo‐enantiomeric forms of N‐benzyl‐4‐hydroxy‐1‐methyl‐2,2‐dioxo‐1H‐2λ6,1‐benzothiazine‐3‐carboxamide and their analgesic properties

The fact that molecular crystals exist as different polymorphic modifications and the identification of as many polymorphs as possible are important considerations for the pharmaceutic industry. The molecule of N‐benzyl‐4‐hydroxy‐1‐methyl‐2,2‐dioxo‐1H‐2λ⁶,1‐benzothiazine‐3‐carboxamide, C₁₇H₁₆N₂O₄S, does not contain a stereogenic atom, but intramolecular hydrogen‐bonding interactions engender enantiomeric chiral conformations as a labile racemic mixture. The title compound crystallized in a solvent‐dependent single chiral conformation within one of two conformationally polymorphic P2₁2₁2₁ orthorhombic chiral crystals (denoted forms A and B). Each of these pseudo‐enantiomorphic crystals contains one of two pseudo‐enantiomeric diastereomers. Form A was obtained from methylene chloride and form B can be crystallized from N,N‐dimethylformamide, ethanol, ethyl acetate or xylene. Pharmacological studies with solid–particulate suspensions have shown that crystalline form A exhibits an almost fourfold higher antinociceptive activity compared to form B.     

Enantioselective Hydroamidation of Enals by Trapping of a Transient Acyl Species

An enantioselective synthesis of β‐chiral amides through asymmetric and redox‐neutral hydroamidation of enals is reported. In this reaction, a chiral N‐heterocyclic carbene (NHC) catalyst reacts with enals to generate the homoenolate intermediate. Upon highly enantioselective β‐protonation through proton‐shuttle catalysis, the resulting azolium intermediate reacts with imidazole to yield the key β‐chiral acyl species. This transient intermediate provides access to diversified β‐chiral carbonyl derivatives, such as amides, hydrazides, acids, esters, and thioesters. In particular, β‐chiral amides can be prepared in excellent yield and ee (40 chiral amides, up to 95 % yield and 99 % ee). This modular strategy overcomes the challenge of disruption of the highly selective proton‐shuttling process by basic amines.     

Preparation and Application of Solid,Salt‐Stabilized Zinc Amide Enolates with Enhanced Air and Moisture Stability

The treatment of various N‐morpholino amides with TMPZnCl⋅LiCl (TMP=2,2,6,6‐tetramethylpiperidyl) and Mg(OPiv)₂ in THF at 25 °C provides solid zinc enolates with enhanced air and moisture stability (t _1/2 in air: 1–3 h) after solvent evaporation. These enolates undergo Pd‐ and Cu‐catalyzed cross‐couplings with (hetero)aryl bromides as well as allylic and benzylic halides. The arylated N‐morpholino amides were converted into various ketones by LaCl₃⋅2 LiCl mediated acylation with Grignard reagents. The new, solid enolates were used to prepare a potent anti‐breast‐cancer drug candidate in six steps and 23 % overall yield.     

Recent applications of magnesium- and Zinc-TMP amides in the synthesis of bioactive targets

Magnesium- and zinc-TMP amides have come out from relative obscurity to be recognized as important tools in modern synthetic chemistry. Development of LiCl-activated metal amides like TMPMgCl·LiCl and TMP₂Zn·2MgCl₂·2LiCl has been important to obtain new organometallic reagents through highly chemo- and regioselective reactions. Herein, we review how these reagents are applied in the synthesis of important bioactive targets such as natural products and drugs.     

Regio‐ and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)‐Lasiol, (+)‐13‐Norfaranal,and (+)‐Faranal

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr?P(OEt)₃. Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent S_N2 substitutions with allylic bromides (up to >99 % S_N2 regioselectivity). The addition of ZnCl₂ and the use of chiral allylic phosphates allowed to switch the regioselectivity towards S_N2′ substitution (up to >99 % S_N2′ regioselectivity) and to perform highly selective anti‐S_N2′ substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)‐lasiol, (+)‐13‐norfaranal, and (+)‐faranal (up to 98:2 dr, 99 % ee).     

Ferrocene Derivatization Reagents for Optical Resolution of Carboxylic Acids by High-performance Liquid Chromatography with Electrochemical Detection

Abstract

New derivatization methods using chiral ferrocene reagents have been developed for the optical resolution of carboxylic acids by high-performance liquid chromatography with electrochemical detection. Two chiral derivatization reagents, 1-ferrocenylethylamine and 1-ferrocenylpropylamine, were readily prepared from acetylferrocene and propionylferrocene in two steps, respectively. Condensation of carboxylic acids with the chiral reagent was effected in the presence of water-soluble carbodiimide and 1-hydroxybenzotriazole. The diastereomeric amides formed from N-acetylamino acid and α-arylpropionic acid enantiomers were efficiently resolved by reversed-phase chromatography and showed the satisfactory sensitivity at +0.45 V vs. an Ag/AgCl reference electrode with a detection limit of 0.5 pmole (S/N=5).     

Enantioselective Nucleophilic Aromatic Substitution with Small‐Molecule Chiral Selectors

Small‐molecule rationally designed chiral selectors have been shown to influence the stereochemical outcome of a variety of organic transformations. For instance, in a recent report, we demonstrated that a chiral selector (in conjunction with an achiral phase‐transfer catalyst) could selectively inhibit one enantiomer of electron‐deficient aromatic amides from forming Meisenheimer adducts (Scheme 2). We now extend this methodology to performing enantioselective nucleophilic aromatic substitutions. Initial studies involved biphasic kinetic resolutions with a chiral selector in conjunction with an achiral phase‐transfer catalyst (Scheme 3). The results are consistent with previous data taken for biphasic reactions (e.g., Scheme 1) where the chiral selector effectively shields the more highly complexed enantiomer from reaction. With neutral nucleophiles such as amines, the enantioselective nucleophilic aromatic substitutions can also be conducted in single‐phase systems. Several examples are given.     

General One‐Pot Reductive gem‐Bis‐Alkylation of Tertiary Lactams/Amides: Rapid Construction of 1‐Azaspirocycles and Formal Total Synthesis of (±)‐Cephalotaxine

Amides are a class of highly stable and readily available compounds. The amide functional group constitutes a class of powerful directing/activating and protecting group for C? C bond formation. Tertiary tert‐alkylamine, including 1‐azaspirocycle is a key structural feature found in many bioactive natural products and pharmaceuticals. The transformation of amides into tert‐alkylamines generally requires several steps. In this paper, we report the full details of the first general method for the direct transformation of tertiary lactams/amides into tert‐alkylamines. The method is based on in situ activation of amide with triflic anhydride/2,6‐di‐tert‐butyl‐4‐methylpyridine (DTBMP), followed by successive addition of two organometallic reagents of the same or different kinds to form two C? C bonds. Both alkyl and functionalized organometallic reagents and enolates can be used as the nucleophiles. The method displayed excellent 1,2‐ and good 1,3‐asymmetric induction. Construction of 1‐azaspirocycles from lactams required only two steps or even one‐step by direct spiroannelation of lactams. The power of the method was demonstrated by a concise formal total synthesis of racemic cephalotaxine.     

Metallosupramolecular Architectures of Ambivergent Bis(Amino Acid) Biphenyldiimides

The metallosupramolecular chemistry of two enantiopure dicarboxylate ligands has been explored for their potential to form discrete or polymeric interlocked motifs. Consequently, both discrete and polymeric supramolecular complexes have been synthesised, yielding M₂L₂ metallomacrocycles ( 1 and 2 ), a heteroleptic M₂L₃ metallomacrobicycle ( 3 ), a non‐interpenetrated coordination polymer ( 4 ), and highly unusual chiral M₈L₈ squares ( 5 and 6 ). There appears to be a preference for the ligands to form M₂L₂‐type metallomacrocyclic structural units (which feature in 1 – 4 ), although these do not engage in any mechanical interlocking, which is perhaps a combined function of the ligand flexibility and relatively small pi‐surface contrasted to previous analogues. Using copper paddlewheel SBUs, chiral double‐walled squares ( 5 and 6 ) are formed with large internal cavities yet poor stabilities, unexpectedly featuring the paddlewheel motifs at the vertices of the polygonal complex.     

Chiral SiO2 and Ag@SiO2 Materials Templated by Complexes Consisting of Comblike Polyethyleneimine and Tartaric Acid

A facile avenue to fabricate micrometer‐sized chiral (L ‐, D ‐) and meso‐like (dl ‐) SiO₂ materials with unique structures by using crystalline complexes (cPEI/tart), composed of comblike polyethyleneimine (cPEI) and L ‐, D ‐, or dl ‐tartaric acid, respectively, as catalytic templates is reported. Interestingly, both chiral crystalline complexes appeared as regularly left‐ and right‐twisted bundle structures about 10 μm in length and about 5 μm in diameter, whereas the dl ‐form occurred as circular structures with about 10 μm diameter. Subsequently, SiO₂@cPEI/tart hybrids with high silica content (>55.0 wt %) were prepared by stirring a mixture containing tetramethoxysilane (TMOS) and the aggregates of the crystalline complexes in water. The chiral SiO₂ hybrids and calcined chiral SiO₂ showed very strong CD signals and a nanofiber‐based morphology on their surface, whereas dl ‐SiO₂ showed no CD activity and a nanosheet‐packed disklike shape. Furthermore, metallic silver nanoparticles (Ag NPs) were encapsulated in each silica hybrid to obtain chiral (D and L forms) and meso‐like (dl form) Ag@SiO₂ composites. Also, the reaction between L ‐cysteine (Lcys) and these Ag@SiO₂ composites was preliminarily investigated. Only chiral L ‐ and D ‐Ag@SiO₂ composites promoted the reaction between Lcys and Ag NPs to produce a molecular [Ag–Lcys]_n complex with remarkable exciton chirality, whereas the reaction hardly occurred in the case of meso‐like (dl ‐) Ag@SiO₂ composite.     

An Efficient Method for Catalytic Asymmetric Reduction of Diketones and Application of Synthesis to Chiral 2,5- Diphenylpyrrolidine and 2,5-Diphenylthiolane

Asymmetric reduction of diketones with borane reagents generated in situ using cheap and available NaBH_4 andSnCl_2 in the presence of(S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol was successfully achieved to yield the corre-sponding chiral diols with excellent stereoselectivity and enantioselectivity.And the chiral diol was transformedinto optically pure C_2-symmetricl chiral amine or thioether.     

Preparation of planar‐chiral multidonor phosphanylferrocene carboxamides and their application as ligands for palladium‐catalysed asymmetric allylic alkylation

Amide coupling of (S_p)‐2‐(diphenylphosphanyl)ferrocene‐1‐carboxylic acid with appropriate terminal amines mediated by 1‐hydroxybenzotriazole and a carbodiimide affords multi‐donor amides terminally functionalized with planar‐chiral (S_p)‐2‐(diphenylphosphanyl)ferrocen‐1‐yl moieties in good to excellent yields. Palladium catalysts based on these ligands efficiently promote asymmetric allylic alkylation of 1,3‐diphenylallyl acetate with in situ generated dimethyl malonate anion to give the C‐alkylated product with ees up to 93% at room temperature. Copyright © 2010 John Wiley & Sons, Ltd.