Dianion of sulfinylacetone as a synthetic equivalent of beta-enolate of propionic acid: a novel synthesis of carboxylic acids from alkyl halides with three-carbon elongation

The reaction of the dianion of phenylsulfinylacetone with alkyl halides afforded beta-keto sulfoxides, which were first chlorinated with hexachloroethane and then treated successively with KH and t-BuLi to give carboxylic acids in three-steps in moderate overall yields from the alkyl halides. This procedure affords a good method for a synthesis of carboxylic acids from alkyl halides with three-carbon elongation.     

Cobalt-Catalyzed Asymmetric Remote Borylation of Alkyl Halides

Enantioselective functionalization of racemic alkyl halides is an efficient strategy to assemble complex chiral molecules, but remains one of the biggest challenges in organic chemistry. The distant and selective activation of unreactive C−H bonds in alkyl halides has received growing interest as it enables rapid generation of molecular complexity from simple building blocks. Here, we reported a cobalt-catalyzed remote borylation of alkyl (pseudo)halides (alkyl−X, X=I, Br, Cl, OTs) with pinacolborane (HBpin) and presented a robust approach for the generation of valuable chiral secondary organoboronates from racemic alkyl halides. This migration borylation reaction is compatible with primary, secondary, and tertiary bromides, offering direct access to a broad range of alkylboronates. The extension of this catalytic system to the borylation of aryl halides was also demonstrated. Preliminary mechanistic studies revealed that this remote borylation involved a radical reaction pathway.     

Photopromoted Carbonylation of Alkyl Halides Under Ambient Conditions

Photopromoted carbonylation of alkyl halides with carbon monoxide can be carried out under ambient conditions with non-precious transition metal complexes(such as cobalt complexes) catalysts.Our preliminary work sowed that alkyl halides can be transformed into alkene and alkane directly under irradiation,but the esters can not be transformed.It is assumed that the carbonylation of alkyl halides may be proceeded in two ways.     

Rapid Synthesis of Alkyloxy Porphyrins Under Microwave Irradiation

Alkyloxy porphyrins have been prepared by direct coupling of 5-para-hydroxyphenyl-10,15,20-triphenylporphyrin and alkyl halides under microwave irradiation within several minutes. The length of the alkyl halides has no obvious effect on the yields and reaction time; however, the steric structure of the alkyl halides has a great impact on the reaction time. All the products were confirmed by ¹H NMR.     

A new method for preparation of organocalcium halides by cocondensation of calcium vapor with solvents

Calcium vapor (atom) when cocondensed with various solvents at 77 K was found to be very reactive toward alkyl and aryl halides. A series of organocalcium halides was prepared in good yields by addition of alkyl or aryl halides to the resultant calcium atom-solvent slurries at ambient temperatures.     

Silver-catalyzed benzylation and allylation reactions of tertiary and secondary alkyl halides with grignard reagents

Treatment of alkyl halides, including tertiary alkyl bromides, with benzylic or allylic Grignard reagent in the presence of a catalytic amount of silver nitrate in ether yielded the corresponding cross-coupling products in high yields. The coupling reactions of tertiary alkyl halides provide efficient access to quaternary carbon centers.     

Cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic and benzylic Grignard reagents and their application to tandem radical cyclization/cross-coupling reactions

Details of cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic Grignard reagents are disclosed. A combination of cobalt(II) chloride and 1,2-bis(diphenylphosphino)ethane (DPPE) or 1,3-bis(diphenylphosphino)propane (DPPP) is suitable as a precatalyst and allows secondary and tertiary alkyl halides--as well as primary ones--to be employed as coupling partners for allyl Grignard reagents. The reaction offers a facile synthesis of quaternary carbon centers, which has practically never been possible with palladium, nickel, and copper catalysts. Benzyl, methallyl, and crotyl Grignard reagents can all couple with alkyl halides. The benzylation definitely requires DPPE or DPPP as a ligand. The reaction mechanism should include the generation of an alkyl radical from the parent alkyl halide. The mechanism can be interpreted in terms of a tandem radical cyclization/cross-coupling reaction. In addition, serendipitous tandem radical cyclization/cyclopropanation/carbonyl allylation of 5-alkoxy-6-halo-4-oxa-1-hexene derivatives is also described. The intermediacy of a carbon-centered radical results in the loss of the original stereochemistry of the parent alkyl halides, creating the potential for asymmetric cross-coupling of racemic alkyl halides.     

The direct synthesis of triorganotin compounds: Process and reaction mechanism

The reaction of tin metal with alkyl halides in the presence of a stoichiometric amount of halide ion rapidly produces very high yields of triorganotin halides. An overview of these reaction conditions and those required for the catalytic preparation of diorganotin dihalides shows that these preparations follow the normal reactivity of the alkyl halides towards nucleophiles. Both processes are satisfactorily explained by a mechanism involving tin halogenoanions as nucleophiles. A similar mechanism also explains the formation of organomagnesium and organozinc halides.     

Symmetrical and Unsymmetrical Coupling of Alkyl Halides Mediated by Grignard Reaction

A simple method for extending the carbon chain via the coupling of alkyl or aryl halides has been developed. The versatility of this reaction has been demonstrated by symmetrical and unsymmetrical coupling of alkyl, alkenyl or alkynyl halides.     

Indium-mediated mild and efficient one-pot synthesis of alkyl phenyl selenides

A mild and convenient one-pot process for synthesizing alkyl phenyl selenides is developed using indium metal. The reaction shows the selectivity for tert-alkyl, benzylic, and allylic halides over primary and secondary alkyl halides.     

Organotin reagents supported on ionic liquid: highly efficient catalytic free radical reduction of alkyl halides

Ionic liquid-supported organotin reagents were prepared in good yield and demonstrated a convenient catalytic free radical reduction of alkyl halides. A variety of alkyl and aryl halides could be reduced in high to excellent yields and selectively to afford the desired products with simple work-up procedure.     

A new approach for generic screening and quantitation of potential genotoxic alkylation compounds by pre-column derivatization and LC-MS/MS analysis

A generic LC-MS/MS method was developed for the analysis of potentially genotoxic alkyl halides. A broad selection of alkyl halides were derivatized using 4-dimethylaminopyridine in acetonitrile. The reaction conditions for derivatization, i.e., solvent, reaction time, temperature and concentration of alkyl halide, active pharmaceutical ingredient (API), and reagent, were optimized for sensitivity and robustness. The interference of the matrix and the API and the presence of water on the derivatization reaction were investigated for a model drug product (paracetamol/caffeine tablets). Hydrophilic interaction liquid chromatography was used to allow a quantitative determination of the derivatives by tandem mass spectrometry. The derivatization reaction was shown to be selective for alkyl halides, although some reactivity was also observed for an aromatic sulfonate, which is also genotoxic. Even though differences in reaction efficiencies have been observed, the enhanced sensitivity obtained by the derivatization allows the majority of the alkyl halides to be detected by MS/MS at relevant levels for genotoxic impurity evaluation, i.e., 10 mg kg(-1). Another key advantage is that for the majority of derivatives, reagent-related fragments are produced, which allows low-level screening for alkyl halides. Highly specific MS detection can be performed using neutral loss and precursor ion scan experiments. The applicability of a generic screening method will make the genotox evaluation less dependent on the quality of assessments based on predictions only, and it will provide essential information during the development of new chemical entities. In addition to screening, target analysis in the low milligrams per kilogram range can be performed. A similar response of the derivatized compounds was obtained in the range of 1-100 mg kg(-1) with a reproducibility better than 10%, which is sufficient for the determination of alkyl halides in APIs and drug products.     

Synthetic approaches to trialkyl(ferrocenylmethyl)ammonium salts as cationic templates for the preparation of ferromagnets on the basis of bimetal oxalates

Trialkyl(ferrocenylmethyl)ammonium salts and their 2-substituted analogs designed for the preparation of molecular ferromagnetics based on bimetallic oxalates were synthesized using classical alkylation of dialkylaminomethylferrocenes by alkyl halides and nucleophilic substitution reaction of 2-substituted dimethylaminomethylferrocene methiodides with trialkylamines. In the case of salts with electron-donating substituents in position 2, only the latter of the two proposed routes is applicable because N-alkylation with alkyl halides is accompanied by competing ferrocenylmethylation of the starting amine. On the contrary, the salts with electron-withdrawing 2-substituents should be prepared preferably by the reaction of amines with alkyl halides, while nucleophilic trialkylamination of methiodides is complicated by deprotonation induced by bases.     

Direct oxidative conversion of alkyl halides into nitriles with molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin in aq ammonia

Various benzylic halides were smoothly and directly converted into the corresponding aromatic nitriles in high yields using molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin, respectively, in aq ammonia. Similarly, primary alkyl halides were also converted into corresponding nitriles in moderate to good yields using molecular iodine and 1,3-diiodo-5,5-dimethylhydantoin in aq ammonia, although a long reaction time was required. The present reaction is a new method for the preparation of aromatic nitriles from benzylic halides and a new method for the conversion of alkyl halides into corresponding nitriles with retention of the number of carbon atoms.     

Synthesis of 1,3-Dialkylimidazolium and 1,3-Dialkylbenzimidazolium Salts

A number of N-alkylimidazoles and N-alkylbenzimidazoles were synthesized by reactions of imidazole and benzimidazole with alkyl halides. The reaction rate increases by a factor of 2 to 3 under conditions of microwave activation. Subsequent treatment of the resulting N-alkylazoles with alkyl halides afforded the corresponding 1,3-dialkylimidazolium and 1,3-dialkylbenzimidazolium halides.     

Copper-Catalyzed Regioselective Borocarbonylative Coupling of Unactivated Alkenes with Alkyl Halides: Synthesis of β-Boryl Ketones

The borocarbonylative coupling of unactivated alkenes with alkyl halides remains a challenge. In this communication, a Cu-catalyzed borocarbonylative coupling of unactivated alkenes with alkyl halides for the synthesis of β-boryl ketones has been developed. A broad range of β-boryl ketone derivatives was prepared in moderate to excellent yields with complete regioselectivity.     

Indium-mediated cleavage of diphenyl diselenide and diphenyl disulfide: efficient one-pot synthesis of unsymmetrical diorganyl selenides, sulfides, and selenoesters

A convenient and efficient method was developed for the synthesis of alkyl phenyl selenides, sulfides, and selenoesters in one-pot reaction by using indium metal. The reaction showed the selectivity for tert-alkyl, benzylic, and allylic halides over primary and secondary alkyl halides. For the reaction of primary and secondary alkyl iodides and bromides, the yields of selenides were improved by the addition of a catalytic amount of iodine.     

Nickel-catalyzed,ring-forming aromatic C–H alkylations with unactivated alkyl halides

The development of a nickel-catalyzed C–H alkylation of aromatic substrates with unactivated alkyl halides is described. This carbocyclization facilitates the synthesis of diverse fused ring systems from simple aromatic substrates and is an attractive alternative to traditional polar or radical-mediated ring formations. The present system uses unactivated primary and secondary alkyl bromides and chlorides, while avoiding the use of precious palladium catalysts and more reactive alkyl halides commonly used in related C–H alkylations.     

Copper‐Catalyzed Regioselective Borocarbonylative Coupling of Unactivated Alkenes with Alkyl Halides: Synthesis of β‐Boryl Ketones

The borocarbonylative coupling of unactivated alkenes with alkyl halides remains a challenge. In this communication, a Cu‐catalyzed borocarbonylative coupling of unactivated alkenes with alkyl halides for the synthesis of β‐boryl ketones has been developed. A broad range of β‐boryl ketone derivatives was prepared in moderate to excellent yields with complete regioselectivity.