An unexpected equilibrium process associated with a standard approach to ynone synthesis

A direct comparison between Weinreb amides and morpholine amides was made with regard to their reactions with alkynyllithium reagents to form ynones. While treatment with stoichiometric alkynyllithium generally effects complete reaction in the case of Weinreb amides, incomplete reactions are obtained from the corresponding morpholine amides. This difference is attributed to an unexpected equilibrium process in the latter case, and it is shown that the use of excess alkynyllithium reagent with morpholine amides provides a synthetically useful synthesis of ynones at 0 degrees C.     

Efficient synthesis of acylsilanes using morpholine amides

[reaction: see text] A general synthesis of acylsilanes from the corresponding morpholine amides and silyllithium species is described. The use of morpholine amides is economical and prevents over-addition by the silyl nucleophile. The procedure cleanly affords acylsilanes in good yields and circumvents the use of stoichiometric copper(I) cyanide typically employed to synthesize these compounds from acid chlorides.     

Palladium-catalyzed intermolecular alpha-arylation of zinc amide enolates under mild conditions

The intermolecular alpha-arylation and vinylation of amides by palladium-catalyzed coupling of aryl bromides and vinyl bromides with zinc enolates of amides is reported. Reactions of three different types of zinc enolates have been developed. The reactions of aryl halides occur in high yields with isolated Reformatsky reagents generated from alpha-bromo amides, with Reformatsky reagents generated in situ from alpha-bromo amides, and with zinc enolates generated by quenching lithium enolates of amides with zinc chloride. This use of zinc enolates, instead of alkali metal enolates, greatly expands the scope of amide arylation. The reactions occur at room temperature or 70 degrees C with bromoarenes containing cyano, nitro, ester, keto, fluoro, hydroxyl, or amino functionality and with bromopyridines. Moreover, the reaction has been developed with morpholine amides, the products of which are precursors to ketones and aldehydes. The arylation of zinc enolates of amides was conducted with catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) or the highly reactive, dimeric, Pd(I) complex [[P(t-Bu)3]PdBr]2.     

Lewis base activation of Lewis acids. Vinylogous aldol addition reactions of conjugated N,O-silyl ketene acetals to aldehydes

N,O-Silyl dienyl ketene acetals derived from unsaturated morpholine amides have been developed as highly useful reagents for vinylogous aldol addition reactions. In the presence of SiCl4 and the catalytic action of chiral phosphoramide (R,R)-3, N,O-silyl dienyl ketene acetal 8 undergoes high-yielding and highly site-selective addition to a wide variety of aldehydes with excellent enantioselectivity. Of particular note is the high yields and selectivities obtained from aliphatic aldehydes. Low catalyst loadings (2-5 mol %) can be employed. The morpholine amide serves as a useful precursor for further synthetic manipulation.     

A Photochemical Protocol for the Synthesis of Weinreb and Morpholine Amides from Carboxylic Acids

In recent years, the development of light-mediated methods for synthetic applications has attracted high interest, because such methods constitute alternative approaches for the production of valuable chemical products. We study herein a photochemical protocol for the synthesis of Weinreb amides and morpholine amides from carboxylic acids. Various carboxylic acids were directly coupled to N,O-dimethylhydroxylamine, upon irradiation with either LED 370 nm or sunlight in the presence of 4-dimethylaminopyridine and bromotrichloromethane, providing Weinreb amides in moderate to high yields. Similarly, morpholine amides were obtained in satisfactory to high yields under sunlight or LED 370 nm irradiation. Thus, the versatile building blocks Weinreb amides and morpholine amides may be efficiently synthesized directly from carboxylic acids by light-mediated approaches, without the need of coupling reagents or pre-activation of carboxylic acids.     

Stereospecific cyclopropanation of highly substituted C-C double bonds promoted by CrCl2. Stereoselective synthesis of cyclopropanecarboxamides and cyclopropyl ketones

We describe herein a CrCl(2)-promoted cyclopropanation of alpha,beta-unsaturated amides. This reaction can be carried out on (E)- or (Z)-alpha,beta-enamides in which the C-C double bond is di-, tri-, or tetrasubstituted. In all cases the process is completely stereospecific and only a single diastereoisomer is obtained. In addition, cyclopropyl ketones were readily prepared by reaction of the cyclopropanecarboxamides (derived from morpholine) obtained with a range of organolithium compounds. A mechanism has been proposed to explain the cyclopropanation reaction.     

2-chloro-4,6-disubstituted-1,3,5-triazines a novel group of condensing reagents

The title, compounds form in reaction with carboxylic acids highly reactive intermediates, which are useful as acylating reagents in the preparation of esters, amides, acid anhydrides, and peptides in 64–98% yield.     

Asymmetric synthesis of beta-amino carbonyl compounds with N-sulfinyl beta-amino Weinreb amides

[reaction: see text] Diverse organometallic reagents readily add to enantiopure N-sulfinyl beta-amino Weinreb amides providing the corresponding, stable, N-sulfinyl beta-amino carbonyl compounds in good to excellent yields. This new methodology represents a general solution to the problem of beta-amino carbonyl syntheses, which are important chiral building blocks and constituents of natural products. N-Sulfinyl beta-amino Weinreb amides are prepared by reaction of the potassium enolate of N-methoxy N-methylacetamide with sulfinimines (N-sulfinyl imines) or lithium N,O-dimethylhydroxylamine with N-sulfinyl beta-amino esters.     

Mild N-deacylation of secondary amides by alkylation with organocerium reagents

Secondary amides are a class of highly stable compounds serving as versatile starting materials, intermediates and directing groups (amido groups) in organic synthesis. The direct deacylation of secondary amides to release amines is an important transformation in organic synthesis. Here, we report a protocol for the deacylation of secondary amides and isolation of amines. The method is based on the activation of amides with Tf₂O, followed by addition of organocerium reagents, and acidic work-up. The reaction proceeded under mild conditions and afforded the corresponding amines, isolated as their hydrochloride salts, in good yields. In combination with the C-H activation functionalization methodology, the method is applicable to the functionalization of aniline as well as conversion of carboxylic derivatives to functionalized ketones.     

Preparation of tertiary amides via aryl, heteroaryl, and benzyl organozinc reagents; scope and limitations

A facile synthetic protocol for the preparation of tertiary amides has been developed. The title compounds have been successfully obtained by the Pd-catalyzed cross-coupling reactions of readily available aryl and benzyl organozinc reagents with the appropriate carbamoyl chlorides.     

Amination of Bis(trimethylsilyl)-1,2-bisketene with secondary amines: formation of aminodihydrofuranones

The bisketene (Me(3)SiC=C=O)(2) (3) reacts rapidly with 1 equiv of secondary amines to form aminodihydrofuranones 11 as the only observable products. This is in contrast to previous studies (J. Org. Chem. 1999, 64, 4690) of the reactions of 3 with primary amines in which 3 with 1 equiv of amine gives ketenyl amides 4, which slowly cyclize to succinimides 7. The kinetics of the reaction of 3 with morpholine obeyed a rate law with the term [morpholine](2), consistent with rate-limiting formation of the enol amide 14 with catalysis by a second amine molecule. The subsequent formation of 11 is attributed to hindrance of ketonization of intermediate enol amides 14. The furanones 11 react with Me(3)SiOTf to form silyloxyfurans 16, and these react with diethyl diazodicarboxylate, forming maleamide derivatives 17.     

Magnesium Aldimines Prepared by Addition of Organomagnesium Halides to 2,4,6-Trichlorophenyl Isocyanide: Synthesis of 1,2-Dicarbonyl Derivatives

The selective addition of organomagnesium reagents to 2,4,6-trichlorophenyl isocyanide leading to magnesiated aldimines is reported. These aldimines react with Weinreb amides, ketones, or carbonates to provide the corresponding carbonyl derivatives after acidic cleavage. This allows for an efficient synthesis of 1,2-dicarbonyl compounds and α-hydroxy ketones.     

Convenient amidation of carboxyl group of carboxyphenylboronic acids

The use of catalysts in the activation of carboxyl groups towards nucleophilic attack and the protection of other functional groups by suitable protecting groups are standard and necessary procedures in amide bond formation. In contrast to the usual methods, various new compounds, amides of APTES ((3-aminopropyl)triethoxysilane, 3-triethoxysilylpropylamine) and carboxyphenylboronic acids, as well as the amides of aniline and carboxyphenylboronic acids, were obtained in good yields by a one-step synthesis under mild conditions without using any coupling reagents or additional catalysts.     

Preparation of tertiary amides from carbamoyl chlorides and organocuprates

[reaction: see text] Reaction of carbamoyl chlorides with cyano-Gilman cuprates affords tertiary amides in good to excellent yields. The reaction is general due to the possibility of using reagents made either from organolithium or from Grignard compounds. The characterization of the main side products allowed for the suggestion of a possible mechanism.     

Long-range deuterium isotope effects on (13)C chemical shifts of intramolecularly hydrogen-bonded N-substituted 3-(cycloamine)thiopropionamides or amides: a case of electric field effects

A series of intramolecularly hydrogen-bonded N-substituted 3-(piperidine, morpholine, N-methylpiperazine)thiopropionamides and some corresponding amides have been studied with special emphasis on hydrogen bonding. The compounds have been selected in order to vary and to minimize the N...N distance. Geometries, charge distributions, and chemical shifts of these compounds are obtained from DFT-type BP3LYP calculations. 1H and 13C 1D and 2D NMR experiments were performed to obtain H,H coupling constants, 13C chemical shifts assignments, and deuterium isotope effects on13C chemical shifts. Variable-temperature NMR studies and 2D exchange NMR spectra have been used to describe the rather complicated conformational behavior mainly governed by the ring flipping of the piperidine (morpholine) rings and intramolecular hydrogen bonding. Unusual long-range deuterium isotope effects on 13C chemical shifts are observed over as far as eight bonds away from the site of deuteriation. The isotope effects are related to the N...N distances, thus being related to the hydrogen bonding and polarization of the N-H bond. Arguments are presented showing that the deuterium isotope effects on 13C chemical shifts originate in electric field effects.     

(S,S)-(+)-pseudoephedrine alpha-iminoglyoxylamide as a chiral glycine cation equivalent: a modular and flexible approach to enantioenriched alpha-amino ketones

We have studied the ability of an alpha-imino glyoxylamide derived from (S, S)-(+)-pseudoephedrine as a valuable chiral electrophile for the preparation of alpha-amino carbonyl compounds. In this context, the addition of Grignard reagents to the azomethine moiety of this chiral electrophile afforded the expected alpha-amino amide adducts in good yields and diastereoselectivities. Moreover, these adducts have been transformed into enantioenriched alpha-amino ketones by exploiting the ability of pseudoephedrine amides to undergo selective monoaddition to the carbamoyl group with organolithium reagents.     

Synthesis of Weinreb amides via Pd-catalyzed aminocarbonylation of heterocyclic-derived triflates

The direct transformation of lactam-, lactone-, and thiolactone-derived triflates into N-methoxy-N-methyl or morpholine Weinreb amides has been realized using Pd-catalyzed aminocarbonylation under CO atmospheric pressure and at room temperature. The carbonylative coupling can be efficiently carried out with 2% of catalyst in the presence of Xantphos as a ligand. The amides smoothly react with nucleophiles to afford acylated aza-, oxa-, and thio-heterocycles. The proposed methodology could be advantageously exploited for the synthesis of dienones in which one of the double bonds is embedded in a heterocyclic moiety, as useful substrates for Nazarov cyclization.     

Concise preparation of 2,2-difluorohomopropargyl carbonyl derivatives. Application to the synthesis of 4,4-difluoroisoquinolinone congeners

A scalable synthesis of 2,2-difluorohomopropargyl esters was achieved using a magnesium-promoted Barbier reaction of substituted difluoropropargyl bromides with alkyl chloroformates. These 2,2-difluorohomopropargyl esters were effective precursors in the synthesis of homopropargylic amides-by aminolysis using AlMe3, as well as of ketones-through the reaction of the corresponding Weinreb amides with Grignard reagents. Ring closing metathesis using difluorinated 1,7-enyne carbonyl compounds furnished six-membered diene products, which were used as susbstrates in a Diels-Alder reaction to afford 4,4-difluoroisoquinolin-3-ones. The [2 + 2 + 2] cycloaddition of alkynes with fluorinated 1,7-diyne amides gave 4,4-difluoro-1,4-dihydro-3(2H)-isoquinolinone derivatives regioselectively.     

Kinetically Controlled,Highly Chemoselective Acylation of Functionalized Grignard Reagents with Amides by N−C Cleavage

The direct transition-metal-free acylation of amides with functionalized Grignard reagents by highly chemoselective N−C cleavage under kinetic control has been accomplished. The method offers rapid and convergent access to functionalized biaryl ketones through transient tetrahedral intermediates. The direct access to functionalized Grignard reagents by in situ halogen–magnesium exchange promoted by the versatile turbo-Grignard reagent (iPrMgCl ⋅ LiCl) permits excellent substrate scope with respect to both the amide and Grignard coupling partners. These reactions enable facile, operationally simple and chemoselective access to tetrahedral intermediates from amides under significantly milder conditions than chelation-controlled intermediates. This novel direct two-component coupling sets the stage for using amides as acylating reagents in an alternative paradigm to the metal-chelated approach, acyl metals and Weinreb amides.     

Stereoselective synthesis of (Z)-alpha-haloacrylic acid derivatives, and (Z)-haloallylic alcohols from aldehydes and trihaloesters or amides promoted by Rieke manganese

A Mn*-promoted sequential process directed toward the synthesis of (Z)-alpha-halo-alpha,beta-unsaturated esters or amides is described. In both cases, the process takes place with complete Z-stereoselectivity. In addition, (Z)-alpha-chloro-alpha,beta-unsaturated ketones and carboxylic acids, and (Z)-haloallylic alcohols were readily prepared from (Z)-alpha-halo-alpha,beta-unsaturated amides derived from morpholine, or esters. A mechanism has been proposed to explain the sequential process and the stereoselectivity observed.