KF/Al2O3‐Mediated N‐Alkylation of Amines and Nitrogen Heterocycles and S‐Alkylation of Thiols

KF/Al₂O₃ efficiently catalyzes N‐alkylation of heterocyclic, primary, and secondary amines and S‐alkylation of thiols with a variety of alkyl halides. The N‐alkylation and S‐alkylation adducts were produced in good to excellent yields and in short times.     

Studies on the synthesis of compounds related to adenosine 3',5'-cyclic phosphate. VII. Synthesis and cardiac effects of N6,N6-dialkyl adenosine 3',5'-cyclic phosphates

A series of novel N6,N6-dialkyl adenosine 3',5'-cyclic phosphates N6,N6-dialkyl cAMPs) was synthesized from 2'-O-p-toluenesulfonyl cAMP (2'-O-tosyl cAMP, 2) and tested for inotropic and chronotropic activities in vitro. Treatment of 2 with excess alkyl halides and sodium hydride followed by detosylation with aqueous NaOH readily gave N6,N6-dialkyl cAMPs (3) in good yields. Various N6,N6-dialkyl cAMPs having different alkyl groups at the N6-position (9-12) were prepared by alkylation followed by detosylation of N6-alkyl-2'-O-tosyl cAMPs (4) which were obtained by the reductive alkylation of 2 with aldehydes in the presence of sodium cyanoborohydride in acetic acid or tosylation of N6-methyl cAMP. The mechanism of the detosylation is briefly discussed. Among the N6,N6-dialkylated derivatives, N6,N6-dipentyl (3f) and N6-ethyl-N6-heptyl (10e) derivatives were found to exhibit a potent positive inotropic effect and a weak positive chronotropic effect. The structure-activity relationships for the position and the length of alkyl residue are discussed.     

A rapid,simple, and mild procedure for alkylation of phenols,alcohols, amides and acids

A general, rapid method is described for alkylation of phenols and alcohols to give ethers, for amides to give N-substituted amides, and for acids to give esters. Differences in optimum reaction times suggest that where two or more such groups as phenol, alcohol, amide, and acid occur in the same molecule, differential alkylation could be effected with suitable substrates. Alkylation with primary alkyl halides was very effective but secondary halides showed evidence for competitive dehydrohalogenation before alkylation was complete and tertiary halides were rapidly dehydrohalogenated with no formation of alkylated derivatives. The method has been applied successfully to N,O-alkylation of peptides for mass spectrometric sequence determination. C-Methylation of peptidic amino-acid residues was observed only on carbon α to a carboxylic ester.     

C‐Propargylation Overrides O‐Propargylation in Reactions of Propargyl Chloride with Primary Alcohols: Rhodium‐Catalyzed Transfer Hydrogenation

The canonical S_N2 behavior displayed by alcohols and activated alkyl halides in basic media (O‐alkylation) is superseded by a pathway leading to carbinol C‐alkylation under the conditions of rhodium‐catalyzed transfer hydrogenation. Racemic and asymmetric propargylations are described.     

Visible‐Light‐Driven N‐Heterocyclic Carbene Catalyzed γ‐ and ϵ‐Alkylation with Alkyl Radicals

The merging of photoredox catalysis and N‐heterocyclic carbene (NHC) catalysis for γ‐ and ?‐alkylation of enals with alkyl radicals was developed. The alkylation reaction of γ‐oxidized enals with alkyl halides worked well for the synthesis γ‐multisubstituted‐α,β‐unsaturated esters, including those with challenging vicinal all‐carbon quaternary centers. The synthesis of ?‐multisubstituted‐α,β‐γ,δ‐diunsaturated esters by an unprecedented NHC‐catalyzed ?‐functionalization was also established.     

Enantioselective copper-catalyzed allylic alkylation with dialkylzincs using phosphoramidite ligands

[reaction: see text]. In the presence of a catalytic amount of copper salts, cinnamyl halides undergo a regio- and enantioselective S(N)2' alkylation with dialkylzincs using chiral phosphoramidites as ligands. An S(N)2':S(N)2 ratio of 85:15 and enantiomeric excesses up to 77% for the chiral S(N)2' products are found. Variation of solvent and reaction temperature revealed that the highest regio- and enantioselectivities are found using coordinating solvents of -40 degrees C.     

Regioselective synthesis of 3-alkylindoles mediated by zinc triflate

Zinc triflate was found to be an effective reagent for the C3-alkylation of indoles by alkyl halides in the presence of Hünig's base and tetrabutylammonium iodide. This new method for indole alkylation proceeds by a S(N)1-like pathway, and is general for allylic, benzylic, and tertiary halides.     

Facile N‐Alkylation/N′‐Arylation Process: A Direct Approach to Aromatic Aminoalkyl Amines

An intriguing C?N transformation involving a catalyst‐free N‐alkylation/N′‐arylation process in a multicomponent reaction with secondary amines, cyclic tertiary amines and electron‐deficient aryl halides has been described. In this case, the N‐alkylation of secondary amines, utilizing cyclic tertiary amines as alkyl group sources, is enabled by a facile C?N cleavage. Such an operationally simple method could facilitate access to aromatic aminoalkyl amines, nitrogen‐containing bioactive molecules, in good to excellent yields.     

Copper-catalyzed alkylation of benzoxazoles with secondary alkyl halides

Copper-catalyzed direct alkylation of benzoxazoles using nonactivated secondary alkyl halides has been developed. The best catalyst is a new copper(I) complex (1), and the reactions are promoted by bis[2-(N,N-dimethylamino)ethyl] ether.     

A Simple Synthesis of Polyfunctionalized 4‐Aminopyrazolidin‐3‐ones as ‘Aza‐deoxa’ Analogs of D‐Cycloserine

A simple five‐step synthesis of fully substituted (4RS,5RS)‐4‐aminopyrazolidin‐3‐ones as analogs of D ‐cycloserine was developed. It comprises a two‐step preparation of 5‐substituted (4RS,5RS)‐4‐(benzyloxycarbonylamino)pyrazolidin‐3‐ones, reductive alkylation at N(1), alkylation of the amidic N(2) with alkyl halides, and simultaneous hydrogenolytic deprotection/reductive alkylation of the primary NH₂ group. The synthesis enables an easy stepwise functionalization of the pyrazolidin‐3‐one core with only two types of common reagents, aldehydes (or ketones) and alkyl halides. The structures of products were elucidated by NMR spectroscopy and X‐ray diffraction.     

Chiral alpha-substituted carbonyls and alcohols from the S(N)2' displacement of cuprates on chiral carbonates: An alternative to the alkylation of chiral enolates

A highly stereoselective sequence of reactions, based on the anti-selective S(N)2' addition of cuprates to allylic carbonates, transforms alkynes or alkenyl halides into carbonyls having alpha-chiral centers. The method, which uses menthone as a chiral auxiliary, is a useful alternative to the alkylation of chiral enolates with the added advantage of allowing for the "alkylation" of sec- and tert-alkyl and aryl groups.     

5H-oxazol-4-ones as building blocks for asymmetric synthesis of alpha-hydroxycarboxylic acid derivatives

5H-Alkyl-2-phenyl-oxazol-4-ones, a little-known heterocyclic ring system, are readily available via a microwave-assisted, sodium fluoride catalyst cyclization of mono-alpha-haloimides, which in turn are accessed by N-acylation of benzamides with alpha-bromo acid halides. Terminally substituted allyl systems serve as excellent substrates for Mo-catalyzed asymmetric allylic alkylation. The resultant products are formed with excellent ees involving a catalyst derived from N,N'-bis-picolinamide of trans-1,2-diaminocyclohexane and cycloheptatriene molybdenum tris(carbonyl). In addition to benzenoid, nonbenzenoid aromatic and vinyl substituents on the allyl carbonate moiety provide good to excellent regio- and diastereoselectivity as well as excellent enantioselectivity. Substituents on the heterocycle include methyl, n-butyl, allyl, isobutyl, isopropyl, and cyclohexyl. The presence of a double bond in the product allows them to be further modified via the chemistry of the double-bond, including metathesis. The products are hydrolyzed under basic conditions to provide alpha-hydroxyamides.     

Novel radical alkylation of carboxylic imides

Although alkylation is one of the most important and fundamental organic reactions, radical-mediated alkylations of carboxylic acid derivatives have not been well studied. The first successful radical alkylation of carboxylic imides is achieved by the addition of an alkyl radical to a ketene O,N-acetal and the subsequent cleavage of N-O bond. It is noteworthy that alkyl halides activated with an electron-withdrawing group undergo alkylations under tin-free conditions due to 1,2-phenyl transfer from silyl to oxygen.     

The selective reaction of aryl halides with KOH: synthesis of phenols, aromatic ethers, and benzofurans

The direct and selective synthesis of phenols from aryl/heteroaryl halides and KOH has been achieved through the use of highly active monophosphine-based catalysts derived from Pd(2)dba(3) and ligands L1 or L2 and the biphasic solvent system 1,4-dioxane/H(2)O. We have also demonstrated a one-pot method of phenol formation/alkylation for the preparation of alkyl aryl ethers from aryl halides. In many instances, this protocol overcomes limitations in existing Pd-catalyzed coupling reactions of aliphatic alcohols with aryl halides. Finally, we demonstrate that substituted benzofurans can be prepared efficiently via a Pd-catalyzed phenol formation/cyclization protocol starting from 2-chloroaryl alkynes.     

On the Alkylation of 5-Fluorouracil-Some Recent Findings

Since its discovery 5-fluorouracil ¹(1,5-FU), an important anticancer drug, has been the subject of study for the preparation of some suitable derivatives² which may have better therapeutic efficacy. These are prepared through silylation method³, mercuri salt method⁴ and direct alkylation method⁵ of 5-FU. It was reported⁵ that the direct alkylation of 5-FU with saturated and allylic type halides under controlled conditions occur at N₃ (3-) and N₁ (1-) position respectively in contrast to alkylation of uracil where N₁ alkylated products are obtained in both cases. The position of alkylation in 5-FU was determined, with analogy from uracil⁶, by the bathochromic shift in UV from the neutral pH to alkaline pH of the 3-substituted product compared to no such shift of the 1-substituted product.     

Formation d'enolates cetoniques par action d'organomagnesiens mixtes dans l'hexamethylphosphorotriamide sur des esters. : Direction des enolisations,limites, utilisation a la preparation de cetones

Alkylmagnesium halides in HMPA react with aliphatic esters to form predominantly the less substituted ketonic enolates. The direction of these enolizations is more selective than that of intermediate ketones. Aliphatic esters are only slightly or not at all enolized under these conditions. Hydrolysis, deuterolysis and alkylation of the ketonic enolates give the corresponding ketones. Benzoic acid derivatives and α-β unsaturated aliphatic and aromatic esters give only low yields of ketonic enolates. The low enolization of the intermediate ketones by these alkylmagnesium halides can explain this result.     

5，6－二取代－3，4－二氢－2－吡啶酮的N－烷基化反应

由四个５，６－二取代－３，４－二氢－２－吡啶酮经烷基化反应合成了九个未见文献报道的Ｎ－取代５，６－二取代－３，４－二氢－２－吡啶酮，并确定了它们的结构。     

Asymmetric Syntheses IV: Enantioselective Synthesis of (R)-Benzylic Amines Via Alkylation of D-Camphor Ketimine

An efficient asymmetric synthesis of (R)-benzylic amines in optical purity 36–90% had been achieved by alkylation of a chiral ketimine prepared from D-camphor and benzylamine. Diastereoselectivity in the alkylation is dependent on the alkyl halides.     

CuPd Nanoparticles as a Robust Catalyst for Electrochemical Allylic Alkylation

An efficient CuPd nanoparticle (NP) catalyst (3 nm CuPd NPs deposited on carbon support) is designed for catalyzing electrochemical allylic alkylation in water/isopropanol (1:1 v/v) and 0.2 m KHCO₃ solution at room temperature. The Pd catalysis was Pd/Cu composition‐dependent, and CuPd NPs with a Pd/Cu ratio close to one are the most efficient catalyst for the selective cross‐coupling of alkyl halides and allylic halides to form C?C hydrocarbons with product yields reaching up to 99 %. This NP‐catalyzed electrochemical allylic alkylation expands the synthetic scope of cross‐coupling reactions and can be further extended to other organic reaction systems for developing green chemistry electrosynthesis methods.     

Alkylation on graphite in the absence of Lewis acids

Graphite is introduced as a convenient catalyst for alkylation of aromatic compounds and alcohols by benzyl, tertiary alkyl, and secondary alkyl halides in the absence of strong Lewis acids. Primary alkyl halides are not active under the reaction conditions.