Direct Nucleophilic Addition to N‐Alkoxyamides

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long‐standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N‐alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N‐alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N‐alkoxy group formed a five‐membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL‐H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter‐ and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α‐trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five‐ and six‐membered lactams, and macrolactams.     

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.     

Asymmetric Alkenyl C−H Functionalization by CpxRhIII forms 2H‐Pyrrol‐2‐ones through [4+1]‐Annulation of Acryl Amides and Allenes

An efficient Cp^xRh^III‐catalyzed enantioselective alkenyl C?H functionalization/[4+1] annulation of acryl amides and allenes is reported. The described transformation provides straightforward access to enantioenriched α,β‐unsaturated‐γ‐lactams bearing a quaternary stereocenter. The reaction operates under mild conditions, displays a broad functional‐group tolerance, and provides 2H‐pyrrol‐2‐ones with excellent selectivity of up to 97:3 er. Such scaffolds are frequently found in natural products and synthetic bioactive compounds and are of significant synthetic value. It is noteworthy that the allene serves as a one‐carbon unit in the [4+1]‐annulation.     

Electrochemical Oxidative C−H/N−H Coupling between γ‐Lactams and Anilines

A mild method for the direct C?H/N?H coupling between γ‐lactams and anilines through electrochemical oxidation has been developed. The protocol proceeded smoothly without metal catalysts at room temperature to afford γ‐substituted γ‐lactams in good yields. It has been revealed that the quasi‐divided cell which provided high current density on the anode was crucial for this reaction.     

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.     

Ketone Synthesis by Direct,Orthogonal Chemoselective Hydroacylation of Alkenes with Amides: Use of Alkenes as Surrogates of Alkyl Carbanions

Direct functionalization of alkenes and direct transformation of carboxamides are two exciting areas that have attracted considerable attention in recent years. We report herein that secondary amides, the least reactive derivatives of carbonyl compounds, upon activated with triflic anhydride, can serve as effective hydroacylating reagents in partner with alkenes to yield ketones at ambient temperature. The method was applied to the one‐step synthesis of racemic dihydro‐ar‐turmerone. In this method, alkenes serve as surrogates of organometallic reagents, which allows the orthogonal chemoselective reactions. The ready availability of many olefins such as camphene and norbornene permits one‐step ketone synthesis that would require several steps by conventional methods.     

Catalysis in Transamination of 6‐chloro‐2‐(3‐chlorophenyl)‐1H‐benz[de]isoquinoline‐1,3‐(2H)‐dione and its Implications in Laser Tissue Welding

The transamination of 6‐chloro‐2‐(3‐chlorophenyl)‐1H‐benz[de ]isoquinoline‐1,3‐(2H )‐dione with primary alkylamines under pseudo‐first‐order conditions is shown to be unimolecular in both reagents as well as unimolecular in methanol (in methanol solution). The reaction is subject to both general acid and general base catalysis. A termolecular, solvated transition state model and a putative model for the early steps of laser tissue welding with aminonaphthalimide dyes are proposed.     

First Total Synthesis of N‐(3‐Guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide

The first total synthesis of the α‐oxo amide‐based natural product, N‐(3‐guanidinopropyl)‐2‐(4‐hydroxyphenyl)‐2‐oxoacetamide ( 3 ), isolated from aqueous extracts of hydroid Campanularia sp., has been achieved. The α‐oxo amide 12 , prepared via the oxidative amidation of 1‐[4‐(benzyloxy)phenyl]‐2,2‐dibromoethanone ( 9a ) with 4‐{[(tert‐butyl)(dimethyl)silyl]oxy}butan‐1‐amine ( 10a ), has been used as the key intermediate in the total synthesis of 3 as HBr salt. On the way, an expeditious total synthesis of polyandrocarpamide C ( 2c ), isolated from marine ascidian Polyandrocarpa sp., was carried out in four steps.     

A New Route to N‐Aryl 2‐Alkenamides,N‐Allyl N‐Aryl 2‐Alkenamides,and N‐Aryl α,β‐Unsaturated γ‐Lactams from N‐Aryl 3‐(Phenylsulfonyl)propanamides

A series of N‐aryl 2‐alkenamides were produced efficiently by treating N‐aryl 3‐(phenylsulfonyl)‐propanamides with potassium tert‐butoxide in THF at 0°C. With out isolation, it was further treated with an additional equivalent of potassium tert‐butoxide and allyl bromide to give N‐allyl N‐aryl 2‐alkenamides in one pot in good yields. Followed by a ring‐closing metathesis reaction, these N‐allyl N‐aryl 2‐alkenamides were respectively converted into corresponding N‐aryl α,β‐unsaturated γ‐lactams in moderate yields.     

Soluble Polyimides from a New Dianhydride: 5′‐tert‐Butyl‐m‐terphenyl‐3,4,3″,4″‐tetracarboxylic Acid Dianhydride

A novel tert‐butyl‐containing dianhydride was prepared from readily available reagents. It was reacted with various aromatic diamines to prepare a set of polyimides containing tert‐butyl pendent groups. The resulting polyimides exhibit high molecular weights (high inherent viscosity), and a combination of desirable properties, such as good solubility in aprotic amide solvents and cresols, high glass transition temperatures (up to 320 °C), high thermal resistance, film‐forming capability and good mechanical properties.

     

Rhodium(I)‐Catalyzed Enantioselective Activation of Cyclobutanols: Formation of Cyclohexane Derivatives with Quaternary Stereogenic Centers

The activation of carbon–carbon σ bonds is a complementary method to access uncommon and difficult‐to‐prepare organometallic species. Herein, we describe the activation of tert‐cyclobutanols through an enantioselective insertion of a chiral rhodium(I) complex into the C? C σ bond of the cyclobutane, forming a quaternary stereogenic center and an alkyl‐rhodium functionality that initiates ring‐closure reactions. This technology provides access to a variety of substituted cyclohexane derivatives with quaternary stereogenic centers. The formation of different product families can be controlled by the employed set of reaction conditions and additives. In general, high yields and excellent enantioselectivities of up to 99 % ee are obtained.     

Synthesis of 2‐Hydroxy‐1,4‐oxazin‐3‐ones through Ring Transformation of 3‐Hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams and a Study of Their Reactivity

The reactivity of 3‐hydroxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2‐hydroxy‐1,4‐oxazin‐3‐ones through a C3? C4 bond cleavage of the intermediate 4‐formyl‐3‐hydroxy‐β‐lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO₄‐mediated oxidation of 3‐alkoxy‐ and 3‐phenoxy‐4‐(1,2‐dihydroxyethyl)‐β‐lactams, which exclusively leads to the corresponding 4‐formyl‐β‐lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin‐3‐ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin‐3‐ones, morpholin‐3‐ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring‐expansion reaction were provided by means of density functional theory calculations.     

12‐ to 22‐Membered Bridged β‐Lactams as Potential Penicillin‐Binding Protein Inhibitors

As potential inhibitors of penicillin‐binding proteins (PBPs), we focused our research on the synthesis of non‐traditional 1,3‐bridged β‐lactams embedded into macrocycles. We synthesized 12‐ to 22‐membered bicyclic β‐lactams by the ring‐closing metathesis (RCM) of bis‐ω‐alkenyl‐3(S)‐aminoazetidinone precursors. The reactivity of 1,3‐bridged β‐lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring‐opening process by using ab initio calculations. The results predicted that 16‐membered cycles should be more reactive. Biochemical evaluations against R39 DD‐peptidase and two resistant PBPs, namely, PBP2a and PBP5, revealed the inhibition effect of compound 4d , which featured a 16‐membered bridge and the N‐tert‐butyloxycarbonyl chain at the C3 position of the β‐lactam ring. Surprisingly, the corresponding bicycle, 12d , with the PhOCH₂CO side chain at C3 was inactive. Reaction models of the R39 active site gave a new insight into the geometric requirements of the conformation of potential ligands and their steric hindrance; this could help in the design of new compounds.     

Efficient Synthesis of Substituted 3‐Azabicyclo[3.1.0]hexan‐2‐ones from 2‐Iodocyclopropanecarboxamides Using a Copper‐Free Sonogashira Coupling

The copper‐free Sonogashira coupling between N‐substituted cis‐ 2‐iodocyclopropanecarboxamides and terminal aryl‐, heteroaryl‐alkynes or enynes, followed by 5‐exo‐dig cyclization of the nitrogen amide onto the carbon–carbon triple bond, provides a remarkably efficient access to a variety of substituted 4‐methylene‐3‐azabicyclo[3.1.0]hexan‐2‐ones in excellent yields. Protonation of these latter enamides generates bicyclic N‐acyliminium ions that can be involved in Pictet–Spengler cyclizations leading to new 3‐azabicyclo[3.1.0]hexan‐2‐ones, possessing a quaternary stereocenter at C4, with high diastereoselectivities. This strategy constitutes an attractive complementary alternative to the classical route that relies on the addition of organometallic reagents to cyclopropyl imides.     

Transition‐Metal‐Free Reductive Functionalization of Tertiary Carboxamides and Lactams for α‐Branched Amine Synthesis

A new method for the synthesis of α‐branched amines by reductive functionalization of tertiary carboxamides and lactams is described. The process relies on the efficient and controlled reduction of tertiary amides by a sodium hydride/sodium iodide composite, in situ treatment of the resulting anionic hemiaminal with trimethylsilyl chloride and subsequent coupling with nucleophilic reagents including Grignard reagents and tetrabutylammonium cyanide. The new method exhibits broad functional‐group compatibility, operates under transition‐metal‐free reaction conditions, and is suitable for various synthetic applications on both sub‐millimole and on multigram scales.     

Hydrogen‐bonding patterns in three substituted N‐benzyl‐N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)acetamides

The molecules of N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)‐2‐chloro‐N‐(4‐methoxybenzyl)acetamide, C₂₃H₂₆ClN₃O₂, are linked into a chain of edge‐fused centrosymmetric rings by a combination of one C—H...O hydrogen bond and one C—H...π(arene) hydrogen bond. In N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)‐2‐chloro‐N‐(4‐chlorobenzyl)acetamide, C₂₂H₂₃Cl₂N₃O, a combination of one C—H...O hydrogen bond and two C—H...π(arene) hydrogen bonds, which utilize different aryl rings as the acceptors, link the molecules into sheets. The molecules of S‐[N‐(3‐tert‐butyl‐1‐phenyl‐1H‐pyrazol‐5‐yl)‐N‐(4‐methylbenzyl)carbamoyl]methyl O‐ethyl carbonodithioate, C₂₆H₃₁N₃O₂S₂, are also linked into sheets, now by a combination of two C—H...O hydrogen bonds, both of which utilize the amide O atom as the acceptor, and two C—H...π(arene) hydrogen bonds, which utilize different aryl groups as the acceptors.     

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.     

A Novel Asymmetric Synthesis of 3‐(1H‐Pyrrol‐1‐yl)‐Substituted β‐Lactams via a Bismuth Nitrate‐Catalyzed Reaction

The reaction of racemic α‐keto β‐lactams 5a – 5c with the commercially available chiral compound trans‐4‐hydroxy‐L ‐proline ( 6 ) in the presence of a catalytic amount of Bi(NO₃)₃?5 H₂O in EtOH gave a diastereoisomer mixture of β‐lactams with a pyrrole ring at C(3) ( 7 to 12 ). This is the first enantioselective synthesis of optically active β‐lactams (=azetidin‐2‐ones) that possess a pyrrolyl residue at C(3), in a single step.     

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.     

Synthesis of optically active N‐protected α‐aminoketones and α‐amino alcohols

A series of optically active N‐protected α‐aminoketones were synthesized via the Grignard reaction of the Weinreb amides of the N‐tert‐butoxycarbonyl amino acids. Reduction of the α‐aminoketones by sodium borohydride resulted in the corresponding 1,2‐amino alcohols. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:603–606, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10195