Weinreb Amides Research Articles

Synthesis of Enantiomerically Pure β‐Hydroxy Ketones via β‐Keto Weinreb Amides by a Condensation/Asymmetric‐Hydrogenation/Acylation Sequence

An established route to enantiomerically pure β‐hydroxy ketones proceeds through the asymmetric hydrogenation of β‐keto esters, an ester/amide exchange, and the use of the resulting β‐hydroxy amide for the acylation of an organometallic compound. We shortened this route by showing that β‐keto Weinreb amides are hydrogenated with up to 99 % ee in the presence of [Me2NH2]+{[RuCl(S)‐BINAP]2(µ‐Cl)3}– (0.5 mol‐%) at room temp./5 bar. These Weinreb amides were prepared by seemingly obvious yet unprecedented condensations of lithiated N‐methoxy‐N‐methylacetamide with carboxylic chlorides (51–87 % yield). The resulting β‐hydroxy Weinreb amides were used for the acylation of organolithium and Grignard reagents. They thus gave enantiomerically pure β‐hydroxy ketones (28 examples). A selection of these compounds gave anti‐1,3‐diols after another C=O bond hydrogenation, or syn‐1,3‐diols by a Narasaka–Prasad reduction.

ChemInform Abstract: N‐Methoxy‐N‐methylcyanoformamide, a Highly Reactive Reagent for the Formation of β‐Keto Weinreb Amides and Unsymmetrical Ketones.

A rapid and straightforward synthesis of the new and highly reactive reagent N-methoxy-N-methylcyanoformamide from trimethylsilyl cyanide and N-methoxy-N-methylcarbamoylimidazole, is reported. This reagent enables the one-pot preparation of β-carbonyl Weinreb amides from lithium enolates, one-carbon homologated Weinreb amides, and unsymmetrical ketones in one-pot procedures from various organometallic species.

β-Amino functionalization of cinnamic Weinreb amides in ionic liquid.

2-Ns-Protected β-amino Weinreb amides were synthesized by aminochlorination of α,β-unsaturated Weinreb amides in an ionic liquid, 1-n-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([BMIM][NTf2]). Processed without the use of metal catalysts or the need of an inert gas atmosphere, the presented process can be readily performed as a one-pot synthesis at room temperature. Moreover, the preparation has the distinct advantages of the use of 2-NsNCl2 as an inexpensive and stable nitrogen/halogen source and the ionic liquid as a recyclable reaction media. Nine examples were examined, and modest to good isolated chemical yields (40–83%) were obtained.

Lithium Enolates Derived from Weinreb Amides: Insights into Five-Membered Chelate Rings.

Enolization of O-methyl hydroxamic acids (Weinreb amides) in tetrahydrofuran solution with lithium diisopropylamide affords predominantly tetrameric enolates. Aryl substituents on the enolates promote deaggregation. The aggregation states are assigned by using the method of continuous variation in conjunction with 6Li NMR spectroscopy. Decoalescence of the tetramer resonance below -100 °C shows considerable spectral complexity attributed to isomerism of the methoxy-based chelates. Density functional theory calculations were used to examine the consequences of the bite angle of five-membered chelates in cubic tetramers and resulting solvation numbers that were higher than anticipated.

Preparation of cis-Fused Tetrahydropyranyl Lactones via Palladium-Catalysed Cyclocarbonylation of Enediols

The stereoselective palladium-catalysed cyclocarbonylation of hex-5-ene-1,4-diols affords cis-fused bicyclic lactones only. Ring-opening with N,O-dimethylhydroxylamine hydrochloride gives the corresponding Weinreb amides, and their subsequent recyclisation provides advanced synthons for the prospective synthesis of decarestrictine L. The relative configurations of all the prepared tetrahydropyrans are determined by NOESY. The attempted transformations of lactones into methyl ketones leads to an unexpected furan, the formation of which is discussed.

Product Control using Substrate Design: Ruthenium-Catalysed Oxidative C-H Olefinations of Cyclic Weinreb Amides.

A new class of Weinreb amides has been developed as directing groups for the ruthenium-catalysed regioselective oxidative C-H olefination. The new Weinreb amides successfully inhibit the N-O bond reductive cleavage usually associated with the cationic ruthenium system, thereby keeping intact the synthetic utility of Weinreb amides. Mechanistic studies reveal interesting aspects of the directing group capabilities of Weinreb amides when compared to simple amides of similar structures.

ChemInform Abstract: Highly Stereoselective Cyclopropanation of Diazo Weinreb Amides Catalyzed by Chiral Ru(II)—Amm—Pheox Complexes.

AbstractThe first highly stereoselective cyclopropanation of diazo Weinreb amides with olefins using chiral Ru(II)—Pheox‐type catalysts is reported.

ChemInform Abstract: Highly Efficient Synthesis of Functionalized α‐Oxyketones via Weinreb Amides Homologation with α‐Oxygenated Organolithiums.

An efficient, chemoselective homologation of Weinreb amides to the corresponding variously substituted α-oxyketones has been developed via the addition of lithiated α-oxygenated species. This one-step, experimentally easy, high yielding protocol is amenable not only for accessing simple α-oxyketones but also for more complex substituted ones ranging from primary and secondary alkyl-type to aromatic ones. Full delivery of the stereochemical information contained in the starting materials is observed through both the employment of enantioenriched Weinreb amides and optically active organolithium species.

ChemInform Abstract: Lithium Halomethylcarbenoids: Preparation and Use in the Homologation of Carbon Electrophiles

AbstractReview: [37 refs.

Development of acetophenone ligands as potential neuroimaging agents for cholinesterases

Association of cholinesterase with β-amyloid plaques and tau neurofibrillary tangles in Alzheimer’s disease offers an opportunity to detect disease pathology during life. Achieving this requires development of radiolabelled cholinesterase ligands with high enzyme affinity. Various fluorinated acetophenone derivatives bind to acetylcholinesterase with high affinity, including 2,2,2-trifluoro-1-(3-dimethylaminophenyl)ethanone (1) and 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (2). Such compounds also offer potential for incorporation of radioactive fluorine (18F) for Positron Emission Tomography (PET) imaging of cholinesterases in association with Alzheimer’s disease pathology in the living brain. Here we describe the synthesis of two meta-substituted chlorodifluoroacetophenones using a Weinreb amide strategy and their rapid conversion to the corresponding trifluoro derivatives through nucleophilic substitution by fluoride ion, in a reaction amenable to incorporating 18F for PET imaging. In vitro kinetic analysis indicates tight binding of the trifluoro derivatives to cholinesterases. Compound 1 has a Ki value of 7nM for acetylcholinesterase and 1300nM for butyrylcholinesterase while for compound 2 these values are 0.4nM and 26nM, respectively. Tight binding of these compounds to cholinesterase encourages their development for PET imaging detection of cholinesterase associated with Alzheimer’s disease pathology.

Convergent synthesis of 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines by substitution reactions of Weinreb amide group of tetrahydropyrimidines

A method of convergent and stepwise synthesis of novel 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines using the Weinreb amide group is developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc) with N-methoxy-N-methylacrylamide gives 6-unsubstituted 4-dimethylamino-2-phenyltetrahydropyrimidine, which is a synthetic intermediate for 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines. The transformation of the Weinreb amide group to an acyl group via substitution reaction using organolithium reagents, following the elimination of a dimethylamino group using MeI proceeds smoothly, affording 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines in good overall yield. The N-protecting group can be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behaviors were analyzed by 1H NMR spectroscopy.

ChemInform Abstract: A Weinreb Amide Based Building Block for Convenient Access to β,β‐Diarylacroleins: Synthesis of 3‐Arylindanones.

Towards the synthesis of symmetrical and unsymmetrical β,β-diarylacroleins for assembling diarylmethine fragments present in biologically important molecules, we have developed a new Weinreb amide (WA) based building block, derived from propiolic acid. The WA functionality present in this compound allowed the sequential addition of various arylmagnesium bromide reagents in a controlled manner. The developed methodology for the access to β,β-diarylacroleins has been utilised for the synthesis of biologically important 3-arylindanone molecules.

ChemInform Abstract: Cp*CoIII‐Catalyzed Dehydrative C—H Allylation of 6‐Arylpurines and Aromatic Amides Using Allyl Alcohols in Fluorinated Alcohols.

AbstractThe first example of Weinreb amide directed C—H bond functionalization under high‐valent cobalt catalysis is also presented.

N-Methoxy-N-methylcyanoformamide, a Highly Reactive Reagent for the Formation of β-Keto Weinreb Amides and Unsymmetrical Ketones.

A rapid and straightforward synthesis of the new and highly reactive reagent N-methoxy-N-methylcyanoformamide from trimethylsilyl cyanide and N-methoxy-N-methylcarbamoylimidazole, is reported. This reagent enables the one-pot preparation of β-carbonyl Weinreb amides from lithium enolates, one-carbon homologated Weinreb amides, and unsymmetrical ketones in one-pot procedures from various organometallic species.

A new strategy for accessing (S)-1-(furan-2-yl)pent-4-en-1-ol: a key precursor of Ipomoeassin family of compounds and C1–C15 domain of halichondrins

A highly efficient synthesis of (S)-1-(furan-2-yl)pent-4-en-1-ol, known to be an initial precursor of Ipomoeassin family of compounds and C1–C15 domain of halichondrins has been achieved via a sequence involving the use of Weinreb amide formation followed by Weinreb ketone synthesis and finally CBS (Corey–Bakshi–Shibata) reduction. Detailed study on improvement of each step is described. The title compound was converted to a potential cytotoxic agent for further pharmacological studies.

Synthesis of Nα-protected amino/peptide Weinreb amides employing N,N'-carbonyldiimidazole as activating agent; studies on docking and antibacterial activities

Synthesis of Nα-protected amino/peptide Weinreb amides employing N,N'-carbonyldiimidazole as activating agent; studies on docking and antibacterial activities

Mo(CO)6 as a Solid CO Source in the Synthesis of Aryl/Heteroaryl Weinreb Amides under Microwave-Enhanced Condition

The facile transformation of aryl/heteroaryl nonaflates into corresponding amides via Pd-catalyzed aminocarbonylation using Mo(CO)6 as a solid CO source under microwave-enhanced condition is reported. The method was found to be tolerant with respect to a diverse range of electronically biased aryl/heteroaryl nonaflates, and exceptional yields were obtained. The optimized protocol was further extended to a diverse range of amines.

Lithium Halomethylcarbenoids: Preparation and Use in the Homologation of Carbon Electrophiles.

α-Halomethyllithium carbenoids are useful homologating reagents which - reacting under proper reaction conditions as carbanions - enable the installation via nucleophilic addition of a reactive halomethyl fragment onto a preformed carbon-heteroatom bond. The pronounced thermolability represented - since seminal studies by Köbrich - the Achilles' heel of these reagents: the use of Barbier-type methodologies (i.e., the electrophile should be present in the reaction mixture prior to the formation of the carbenoid) was pivotal in order to suppress decomposition through α-elimination processes. Nowadays, the use of low temperatures (-78 °C) guarantees reliable procedures and, significantly, the employment of microreactor technologies allows external trapping to be performed even at higher temperatures as reported by Luisi. We will discuss the α-halomethyllithium-mediated homologations of a series of carbon electrophiles such as carbonyl compounds, imines, esters, Weinreb amides, and isocyanates.

Concise access toward chiral hydroxy phenylpropanoids: formal synthesis of virolongin B; kigelin; kurasoin A; 4-hydroxysattabacin, and actinopolymorphol A

A simple, two step strategy consisting of Sharpless asymmetric dihydroxylation followed by regioselective breaking of CO bond is utilized to target key chiral intermediates of natural products virolongin B, kigelin, kurasoin A, 4-hydroxy-sattabacin, and actinopolymorphol A. Derivatives of enantiopure hydroxy phenyl propanoids and α-hydroxy Weinreb amides are synthesized. The reductive cleavage of CO bond in a regioselective manner is obtained using Pd/C in methanol.

ChemInform Abstract: Stereoselective Synthesis of (Sulfonimidoyl)cyclopropanes with (R)‐PhSO(NTs)CH2Cl and α,β‐Unsaturated Weinreb Amides: Tuning the of Selectivity Between C—Cl and C—S Bond Cleavage.

AbstractThe Weinreb amide group and the counter cation of the base are important for the selective C‐Cl bond cleavage of (R)‐PhSO(NTs)CH2Cl.