CuCl-catalyzed stereoselective conjugate addition of Grignard reagents to 2,3-allenoates

CuCl was found to be an efficient catalyst for the conjugate addition of 2,3-allenoates with Grignard reagents to synthesize poly-substituted β,γ-unsaturated alkenoates with high stereoselectivity in good to excellent yields. Primary, secondary, and tertiary alkyl, vinyl or phenyl Grignard reagents may all be used.     

Grignard试剂与α-肉桂酰基环二硫缩烯酮的区域选择性加成反 应

乙基、丙基、丁基、苯基和苄基卤化镁等Grignard试剂与具有三个亲电中心的α-肉桂酰基环二硫缩烯酮类化合物2反应,加成反应发生在2中与芳基相邻的碳原子上,生成共轭加成产物3,反应具区域选择性。     

α-肉桂酰基二硫缩烯酮与Grignard试剂的加成反应区域 选择研究-烷硫基对反 应的调控作用

乙基、苯基卤化镁等Grignard试剂与具有三亲电中心的α-肉桂酰基二硫代缩烯酮类化合物1反应,当1中的烷硫基为二乙硫基、1,3-亚丙二硫基、1,4-亚丁二硫基时,Grignard试剂加成到与芳烃相连的碳原子上,得到共轭加成产物2;当1中的烷硫基为二甲硫基时,生成难以分离的混合物。     

Direct Arylation/Alkylation/Magnesiation of Benzyl Alcohols in the Presence of Grignard Reagents via Ni-, Fe-, or Co-Catalyzed sp(3) C-O Bond Activation

Direct application of benzyl alcohols (or their magnesium salts) as electrophiles in various reactions with Grignard reagents has been developed via transition metal-catalyzed sp(3) C-O bond activation. Ni complex was found to be an efficient catalyst for the first direct cross coupling of benzyl alcohols with aryl/alkyl Grignard reagents, while Fe, Co, or Ni catalysts could promote the unprecedented conversion of benzyl alcohols to benzyl Grignard reagents in the presence of (n)hexylMgCl. These methods offer straightforward pathways to transform benzyl alcohols into a variety of functionalities.     

A new source for generation of benzyne and pyridyne: Reactions of O-halophenyl (or 3-bromo-4-pyridyl) phenyl sulfoxides with grignard reagants

o-Chloro- and o-bromophenyl phenyl sulfoxides and (3-bromo-4-pyridyl) phenyl sulfoxide were treated with Grignard reagents to generate benzyne (or 3,4-pyridyne) in THF. The o-iodophenyl derivative, on the other hand, gave mainly o-(arylsulfinyl)phenyl Grignard reagent.     

Reinvestigation of the grignard reactions with formic acid. A convenient method for preparation of aldehydes

Grignard reagents react with formic acid in tetrahydrofuran to produce aldehydes in relatively good yields Various aldehydes such as alkyl, aryl, allyl, benzyl and vinyl aldehydes were prepared from the corresponding Grignard reagents. The reaction with vinyl Grignard reagents proceeded with retention of configuration.     

手性助剂控制的不对称Michael加成立体选择性研究

手性助剂控制的不对称反应是不对称合成的主要方法之一.采用不同空间位阻Evans手性助剂对呋喃基丙烯酸进行立体选择性控制,通过不同空间位阻的格氏试剂对Michael受体1进行不对称1,4-Michael加成反应研究,合成了一系列新的Michael加成产物2a～2h.研究结果表明手性助剂及格氏试剂的空间位阻是影响反应立体选择性的主要因素.当手性助剂及格氏试剂的取代基为芳基时,产物的de值都大于95%,而取代基为烷基、苄基及脂环基时,产物的de值则低于70%.     

Reaction of polyepichlorohydrin with magnesium and grignard reagents

The reaction of polyepichlorohydrin with magnesium in tetrahydrofuran at reflux temperature was studied in the hope of obtaining a polymeric Grignard reagent. The polymeric Grignard reagent could not be obtained, but dechlorination occurred. It was confirmed that the Grignard reagent of polyepichlorohydrin was formed as an intermediate during the dechlorination. The reactions of polyepichlorohydrin with Grignard reagents were carried out in tetrahydrofuran at reflux temperature. Benzylmagnesium chloride and allylmagnesium chloride were used as Grignard reagents. It was found that the chlorine atom in polyepichlorohydrin can be replaced by benzyl and allyl groups. The extent of the substitution increased with increasing concentration of Grignard reagent. Dechlorination and scission of the ether linkage occurred simultaneously as side reactions.     

Synthesis of C2-symmetrical chiral diamines: diastereoselective addition to bis(1,3-oxazolidinyl)alkanes with Grignard reagents

Asymmetric syntheses of C₂-symmetrical chiral 1,4- and 1,5-diamines with stereogenic centers adjacent to the nitrogen atom have been accomplished. Chiral diamines were prepared by diastereoselective alkylations of bisoxazolidine, which was derived from (R)-phenylglycinol. Methyl and phenyl Grignard reagents were employed as alkylating reagents. In addition, tertiary chiral diamines were readily converted to primary diamines in high yield.     

An improved preparation of 3,5-bis(trifluoromethyl)acetophenone and safety considerations in the preparation of 3,5-bis(trifluoromethyl)phenyl Grignard reagent

An improved and efficient bromination of 3,5-bis(trifluoromethyl)benzene was developed. A safe and reliable preparation of the potentially explosive 3,5-bis(trifluoromethyl)phenyl Grignard and 3-trifluoromethylphenyl Grignard reagents, from the precursor bromides, is described. Reaction System Screening Tool (RSST) and Differential Thermal Analysis (DTA) studies suggest these trifluoromethylphenyl Grignard reagents can detonate on loss of solvent contact or upon moderate heating. When prepared and handled according to the methods described herein, these Grignard reagents can be safely prepared and carried on to advanced intermediates.     

Hydroxylated terphenylphosphine ligands for palladium-catalyzed ortho-selective cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents

p-Terphenylphosphines bearing one or two hydroxy groups were used as ligands to palladium in the cross-coupling of dibromophenols, dibromoanilines, and their congeners with Grignard reagents. High ortho-selectivity that cannot be achieved using other phosphine ligands was observed. ortho-Preference was also observed in competitive cross-coupling reactions of two substrates. A significant effect of the concentration of the Grignard reagent on the ortho-selectivity was observed, when the hydroxylated terphenylphosphines were used. Kinetic studies on this effect showed that high concentrations of the Grignard reagent retard the cross-coupling reaction only at the para-position, but not at the ortho-position.     

Remarkable stabilizing effects of silyl group on furfuryl chlorides and furfuryl Grignard reagents

By introducing a silyl group on their 5-position, furfuryl chlorides and the Grignard reagents have been stabilized remarkably and the Grignard reagents have exhibited unusual ambident behavior toward several electrophiles.     

Ligand exchange reactions of aryl pyridyl sulfoxides with grignard reagents: Convenient preparation of 3- and 4-pyridyl grignard reagents and examination of the leaving abilities of pyridyl anions

Aryl 3- and 4-pyridyl sulfoxides undergo ligand exchange in reactions with aryl Grignard reagents to generate 3- and 4-pyridyl Grignard reagents, which, upon treatment with aldehydes or ketones, give the corresponding addition products in moderate-to-good yields. The mechanism for the exchange reaction was investigated by treating optically active 3- and 4-pyridyl p-tolyl sulfoxides with a phenyl Grignard reagent. Inversion of the configuration of the sulfur atom was the stereochemical result of the reactions. In the reactions of phenyl 2-pyridyl sulfoxide with Grignard reagents, the leaving ability of the 2-pyridyl group competes with that of the phenyl group. Both the experimental and MO calculated enthalpy values for deprotonation of α-, β-, and γ-protons of pyridine in the gas phase [1] are in accordance with the following order of the leaving abilities of aryl and pyridyl Grignard reagents: 4-PyMgBr > 3-PyMgBr » PhMgBr > p-TolMgBr > 2-PyMgBr.     

Preparation and addition--elimination reactions of benzyl alpha,beta,beta-trifluoroacrylate. A new stereoselective approach to (Z)-beta-substituted alpha,beta-difluoroacrylates

Benzyl alpha,beta,beta-trifluoroacrylate (1) was prepared in good yield via the reductive Br-F elimination of benzyl 2-bromo-2,3,3,3-tetrafluoropropanoate or the palladium-catalyzed cross-coupling reaction of 1,2,2-trifluorovinylstannane with benzyl chloroformate. On treating 1 with various Grignard reagents or dialkylzinc reagents in the presence of copper(I) salt, the corresponding beta-substituted alpha,beta-difluoroacrylates were obtained in high yields with high Z-selectivity. Additionally, trialkylaluminum reagents were also found to be good nucleophiles, the corresponding addition-elimination products being afforded in good yields but with low stereoselectivity.     

Sequential One‐Pot Addition of Excess Aryl‐Grignard Reagents and Electrophiles to O‐Alkyl Thioformates

The sequential addition of aromatic Grignard reagents to O‐alkyl thioformates proceeded to completion within 30 s to give aryl benzylic sulfanes in good yields. This reaction may begin with the nucleophilic attack of the Grignard reagent onto the carbon atom of the O‐alkyl thioformates, followed by the elimination of ROMgBr to generate aromatic thioaldehydes, which then react with a second molecule of the Grignard reagent at the sulfur atom to form arylsulfanyl benzylic Grignard reagents. To confirm the generation of aromatic thioaldehydes, the reaction between O‐alkyl thioformates and phenyl Grignard reagent was carried out in the presence of cyclopentadiene. As a result, hetero‐Diels–Alder adducts of the thioaldehyde and the diene were formed. The treatment of a mixture of the thioformate and phenyl Grignard reagent with iodine gave 1,2‐bis(phenylsulfanyl)‐1,2‐diphenyl ethane as a product, which indicated the formation of arylsulfanyl benzylic Grignard reagents in the reaction mixture. When electrophiles were added to the Grignard reagents that were generated in situ, four‐component coupling products, that is, O‐alkyl thioformates, two molecules of Grignard reagents, and electrophiles, were obtained in moderate‐to‐good yields. The use of silyl chloride or allylic bromides gave the adducts within 5 min, whereas the reaction with benzylic halides required more than 30 min. The addition to carbonyl compounds was complete within 1 min and the use of lithium bromide as an additive enhanced the yields of the four‐component coupling products. Finally, oxiranes and imines also participated in the coupling reaction.     

Reaction of poly(vinyl chloride) with magnesium and grignard reagents

Reaction of poly(vinyl chloride) with magnesium under various conditions was attempted, but poly(vinyl chloride) did not react with magnesium. The reactions of poly(vinyl chloride) with benzylmagnesium chloride and allylmagnesium chloride as Grignard reagents were carried out in tetrahydrofuran at reflux temperature. It was found that the chlorine atoms in the poly(vinyl chloride) were replaced by benzyl and allyl groups by the coupling reaction, and a small amount of Grignard reagent of poly(vinyl chloride) was formed by the magnesium–halogen exchange reaction. The extent of the substitution increased with increasing reaction time and concentration of the Grignard reagent.     

Regio- and chemoselective addition of alkynyltin reagents to the 2-position of 3-acylpyridines activated by methyl chloroformate: selective synthesis of 2,3-disubstituted 1,2-dihydropyridines

Alkynyltin reagents add to the 2-position of 3-acylpyridines activated by methyl chloroformate regio- and chemoselectively to give 2,3-disubstituted 1,2-dihydropyridines, whereas alkynyl Grignard reagents suffer from a lack of regio- or chemoselectivity.     

Copper-mediated displacements of allylic THP ethers on a bisphosphonate template

The copper-mediated displacement of allylic THP ethers by Grignard reagents has been examined in a system that contains a geminal bisphosphonate ester. With Grignard reagents derived from several aromatic halides or benzyl bromide the displacement proceeds in attractive yields, but more mixed results were obtained from reactions with alkyl halides. In addition to its role as a nucleophile, the Grignard reagent also appears to deprotonate the bisphosphonate to generate an anionic intermediate. Formation of this anion appears to limit competitive nucleophilic attack at the phosphonate group and provides an intermediate that can be trapped by reaction with an electrophilic reagent such as methyl iodide to access a more substituted system.     

Added-metal-free catalytic nucleophilic addition of Grignard reagents to ketones

On the basis of the investigation of the combinational effect of quaternary ammonium salts and organic bases, an added-metal-free catalytic system for nucleophilic addition reactions of a variety of Grignard reagents to diverse ketones in THF solvent has been developed to produce tertiary alcohols in good to excellent yields. By using tetrabutylammonium chloride (NBu(4)Cl) as a catalyst and diglyme (DGDE) as an additive, this system strongly enhances the efficiency of addition at the expense of enolization and reduction. NBu(4)Cl should help to shift the Schlenk equilibrium of Grignard reagents to the side of dimeric Grignard reagents to favor the additions of Grignard reagents to ketones via a favored six-membered transition state to form the desired tertiary alcohols, and DGDE should increase the nucleophilic reactivities of Grignard reagents by coordination. This catalytic system has been applied in the efficient synthesis of Citalopram, an effective U.S. FDA-approved antidepressant, and a recyclable version of this catalytic synthesis has also been devised.     

Synthesis and characterization of polysilabutane having oligo(oxyethylene)phenyl groups on the silicon atom

A new class of polar polysilabutanes with mono- or tri-(oxyethylene)phenyl groups on the silicon atom have been synthesized by anionic polymerization of silacyclobutanes having ω-(t-butyldimethylsilyl-protected) mono- or tri-(oxyethylene)phenyl groups and subsequent deprotection of the silyl groups. The monomers were synthesized by treatment of 1,1-dichlorosilacyclobutane with ω-(t-butyldimethylsilyl-protected) mono- or tri-(oxyethylene)phenyl Grignard reagents. Anionic polymerization of silacyclobutane was performed with butyllithium initiator in THF. t-Butyldimethylsilyl-protecting groups at polymer pendant groups were hydrolyzed with tetrabutyl ammonium fluoride in water-containing THF. The obtained polysilabutanes were soluble in a polar organic solvent such as methanol, and their mass distributions were analysed by matrix-assisted laser-desorption-ionization mass spectrometry (MALDI TOF MS). © 1998 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 36: 225–231, 1998