Synthesis of O-aminodihydroartemisinin via TMS triflate catalyzed C-O coupling reaction

O-Aminodihydroartemisinin was synthesized for the first time via TMS triflate catalyzed coupling reaction of O-acetylartemisinin. The reaction proceeds with high yield without losing the endoperoxide of the artemisinin backbone. The new coupling reaction was employed to prepare artemisinin O-glycosides with improved water solubility. O-Aminodihydroartemisinin reacts readily with benzaldehyde to give the corresponding oxime derivative, demonstrating the potential of this compound for the preparation of various artemisinin conjugates.     

An efficient route to heteroarene-substituted vinyl- and allyl-silanes via palladium-phosphine complex catalyzed cross-coupling

Heteroarene-substituted vinyl- and allyl-silanes were obtained in good yields by the cross-coupling reaction of either heteroaryl Grignard reagents with halovinyl- and haloallyl-silanes or, alternatively, silyl- and silylmethyl-substituted vinylmetallic reagents with heteroaryl halides in the presence of PdCl₂(dppb) as a catalyst.     

Synthesis of chlorophyll‐a skeleton homologs using grignard reaction with methyl pyropheophorbide‐a

From methyl pyropheophorbide‐a (MPPa) (1), methyl 2‐formylmethyl‐2‐devinyl‐9‐ethylenedioxy‐9‐deoxopyropheophorbide‐a (2) and methyl 3‐acetyl‐9‐ethylenedioxy‐2‐devinyl‐9‐deoxopyropheophorbide‐a (3) were prepared. The Grignard reactions of 2 and 3 were performed using cycloalkyl magnesium bromides to afford cycloalkyl‐substituted sec‐alcohol 4 and tert‐alcohols 9a‐c, respectively. By the deprotection of the ethylenedioxy group, these alcohols were respectively converted to exocyclic ketones 5 and 10a‐c, which were dehydrated to give chlorins 6 and 11a‐c having an alkenyl function at the 2‐position. On the other hand, the oxidation and deprotection of the alcohol 4 gave a diketo chlorin 8.     

Chiral β-dimethylaminoalkylphosphines. Highly efficient ligands for a nickel complex catalyzed asymmetric grignard cross-coupling reaction

Chiral β-dimethylaminoalkylphosphines were prepared starting with amino acids, (S)-alanine, (S)-phenylalanine, (R)-phenylglycine, (S)-valine, and (R)-tert-leucine. The chiral phosphines were found to be highly efficient ligands for a nickel catalyzed asymmetric Grignard cross-coupling reaction (38～94% optical yield).     

Synthesis of the hamigeran skeleton through an electro-oxidative coupling reaction

The tricyclic core of the hamigerans has been prepared through the use of a two-step electrochemical benzannulation reaction. The annulation proceeds through an initial conjugate addition of a phenethyl cuprate to 3-methylcyclopentenone with in situ silylation of the resulting enolate. Anodic oxidation effectively couples the pendant arene and the silyl enolether to produce a key intermediate for the synthesis of the natural products. Careful optimization revealed that the use of ‘alcohol-free’ conditions during the electrolysis was critical to obtain high yields of the annulated product. This method allowed the preparation of the tricyclic core of hamigeran A and B in just four steps from commercially available starting materials.     

Synthesis of Mannich type products via a three-component coupling reaction

The reactions of alkyl nitriles, acetyl chloride, aldehydes and β-ketoesters or simple ketones was studied for the one-pot synthesis of β-acetamido carbonyl compounds. It was observed that the reaction proceeds in the absence of Lewis acids. However, a Lewis acid catalyzes the reaction and several were tested. It was found that whereas Cu(OTf)₂ is suitable for the coupling of β-ketoesters with aldehydes, Sc(OTf)₃ is the best for ketones. A possible mechanism is proposed based on the isolation and characterization of an intermediate.     

Cross-coupling of allylic sulfides and grignard reagents catalyzed by nickel-phosphine complex

Allylic sulfides smoothly couple with Grignard reagents in the presence of Ni(II)-phosphine complexes as catalysts to give the corresponding unsaturated compounds in good yields.     

Development of an efficient and safe process for a grignard reaction via reaction caloremetry

A Grignard reaction of reactantA and phenyl magnesium chloride is used to make a pharmaceutical intermediate at the production scale. The elimination of protecting groups onA was proposed as a means to reduce synthesis costs. This new synthesis route, however, had process efficiency and safety issues associated with it: (1) build-up of unreactedA in the reactor, (2) influence ofA's particle size on the reaction rate, (3) the sensitivity of the reaction rate to the reaction temperature and to the (changing) solvent composition, and (4) the highly exothermic nature of the reaction.The Mettler RC1 Reaction Calorimeter was used to quantify the influence of solvent composition, temperature, and particle size on the reaction rate. Results indicated a dramatic effect of solvent composition and reaction temperature on the reaction rate; for example, over a temperature range of just 30°C, the reaction time decreased from more than a day to just a few minutes. At such high reaction rates, the vessel jacket could not remove the reaction heat sufficiently and the internal temperature rose adiabatically.These results were used to make process design and operation recommendations for safe and efficient plant operation with this modified Grignard reaction system.The authors would like to thank the following for their assistance in this work: E. Daugs for preparing the Grignard reagents, K.L. Gonzales for her help in running the experiments and in the subsequent data work-up; P.M. Russell for his assistance in the design of the slurry addition assembly, and K. Chritz and J. Engel for performing the HPLC analyses of the samples.     

Stereoselective synthesis of amides possessing a vinylsilicon functionality via a ruthenium catalyzed silylative coupling reaction

An effective stereoselective synthesis of E-N-2-(silyl)vinylamides via silylative coupling of vinyl amides such as N-vinylpyrrolidinone, N-vinylphthalimide, and N-vinylformamide with vinyltrisubstituted silanes catalyzed by [RuH(Cl)(CO)(PCy₃)₂] I is described.     

Synthesis of 1-aryl indoles via coupling reaction of indoles and aryl halides catalyzed by CuI/metformin

Ullmann-type C–N coupling reaction has been developed for the synthesis of 1-aryl indole derivatives by indoles and aryl halides in the presence of CuI/metformin (CuI/Met) in DMF. This method is very easy, rapid, and high yielding reaction for the synthesis of 1-aryl indoles. In particular, the metformin, which is used as ligand, is inexpensive and nontoxic that is considered to be relatively environmentally benign.     

Synthesis of indolequinones via a Sonogashira coupling/cyclization cascade reaction

A mild strategy for constructing indolequinone motifs is described on the basis of the Sonogashira reaction and a copper-catalyzed intramolecular cyclization cascade reaction. The first step involves the palladium- and copper-catalyzed reaction between halogenated naphthoquinone and terminal acetylene to generate a coupling product, which then reacts in a copper-catalyzed intramolecular cyclization with the nitrogen functional group adjacent to the carbon-carbon triple bond.     

Synthesis of the cytotrienin A core via metal catalyzed C-C coupling

A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core.     

A mild and practical copper catalyzed amination of halothiophenes

We have found that N,N-dimethylethanolamine (deanol) is a useful solvent and ligand for copper catalyzed amination of a variety of unactivated and activated 2- or 3-halothiophenes. Primary amines, acyclic secondary amines, cyclic secondary amines and acyclic secondary amines with 2-hydroxyethyl functionality react with halothiophenes in moderate to excellent yields. The mildly basic conditions utilized are compatible with many functional groups. The amination of halobithiophenes has also been examined. The aminothiophenes produced by this method are important intermediates in a variety of electronic and optoelectronic materials.     

Synthesis of 2-vinylic indoles and derivatives via a Pd-catalyzed tandem coupling reaction

A novel one-step synthesis of valuable 2-vinylic indoles and their tricycle derivatives is described. This reaction, which utilizes a gem-dibromovinyl unit as a readily available starting material, occurs via an efficient Pd-catalyzed tandem Buchwald-Hartwig/Heck reaction.     

Preparation of functionalized ketones via low temperature grignard reaction

δ-Chloroketones and 5-oxo-9-decenoic acid methyl ester were prepared from 5-chlorovaleryl chloride and methyl 4-(chloroformyl)-butyrate via Grignard reaction in tetrahydrofuran at ?70°.     

Heterogeneous copper-free Sonogashira coupling reaction catalyzed by a reusable palladium Schiff base complex in water

Heterogeneous Sonogashira coupling of terminal alkynes with aryl halides was studied over a polymer-supported macrocyclic Schiff base palladium complex. The cross-coupling reaction proceeded smoothly by adding a piperidine in water medium. The catalyst exhibited effective catalytic activities to afford the corresponding products in good to excellent yields under copper-free conditions. Furthermore, the catalyst could be easily recovered and reused for several times without a significant loss of its activity.