OCCURRENCE OF LIGAND COUPLING IN THE REACTIONS OF VARIOUS SULFOXIDES WITH GRIGNARD REAGENTS

Abstract

Ligand coupling reactions take place not only between benzyl and 2-pyridyl groups and two 2-pyridyl groups in the treatment of benzyl, alkyl and aryl 2-pyridyl sulfoxides with Grignard reagents, but also between such groups as p-benzenesulfonylphenyl, 4-pyridyl, 2-quinolyl and 2-pyrimidyl, and the benzyl group. There are cases in which ligand exchange precedes ligand coupling, especially with 2-heteroaryl groups. In addition, even some alkyl groups were found to couple with the 2-pyridyl group. The ease of coupling seems to be associated with the electronegativity of the coupling carbon atom of the ligand, when one compares the ¹³C NMR chemical shifts.     

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.     

Preparation of pyridyl grignard reagents and cross coupling reactions with sulfoxides bearing azaheterocycles

Pyridyl Grignard reagents were prepared from the corresponding iodopyridine and EtMgBr. New cross coupling reactions of the Grignard reagents with azaheterocycles took place on the sulfinyl sulfur atom to afford biazaheteroaryls.     

Cross-coupling of alkenyl,aryl or allylic selenides and grignard reagents catalyzed by nickel-phosphine complexes

Alkenyl, aryl or allylic selenides smoothly couple with Grignard reagents in the presence of Ni(II)-phosphine complexes as catalysts to afford the corresponding unsaturated compounds in good yields. The reactivity order of coupling reaction with BuMgBr catalyzed by NiCl₂ [Ph₂PCH₂CH₂CH₂PPh₂] was found to be PhSeMe « PhCl > PhSMe by the competitive reactions.     

Regioselective arylation of 3-bromopyridine

The addition of aryl Grignard reagents to the 1-phenoxycarbonyl salt of 3-bromopyridine affords 2-aryl-5-bromo-1-phenoxycarbonyl-1,2-dihydropyridines and 4-aryl-3-bromo-1-phenoxycarbonyl-1,4-dihydropyridines. The crude dihydropyridines were aromatized with o-chloranil in refluxing toluene to give 4- and 6-aryl-3-bromopyridines. The regioselectivity of this two-step process, 6- vs. 4-substitution, was examined and found to be dependent upon the structure of the Grignard reagent. Unhindered aryl Grignard reagents, e.g., phenyl and 2-naphthyl, gave mainly 6-aryl-3-bromopyridines (49-52%) along with 9% of the 4-substituted isomer and less than 4% of the 2-aryl-3-bromopyridine. Hindered aryl Grignard reagents, e.g., o-tolyl and 1-naphthyl, are less regioselective. When a catalytic amount of cuprous iodide is present during the Grignard reaction, nearly exclusive 1,4-addition results. The crude 4-aryl-3-bromo-1,4-dihydropyridines were aromatized with p-chloranil to provide 4-aryl-3-bromopyridines in good yield and high isomeric purity. The sequential use of the cuprous iodide-catalyzed Grignard reaction and the “normal” Grignard reaction provided a regiospeci-fic synthesis of 3-bromo-6-(p-methoxyphenyl)-4-phenylpyridine from 3-bromopyridine.     

Uncatalysed coupling of an activated aryl chloride with aryllithium and aryl Grignard reagents

Substitution of the chloro group in 2-(2-chlorophenyl)-4,4-dimethyl-2-oxazoline to afford biaryls occurs upon reaction with either aryllithium reagents or aryl Grignard reagents. The reactions with Grignard reagents occur under similar conditions to a previously reported manganese-catalysed procedure. The reactions with lithium reagents, whilst not always affording greater yields of product than the Grignard reagents, involve much shorter reaction times and afford yields, which are comparable with those obtained from the corresponding fluoro derivative.     

Addition of grignard reagents to aryl acid chlorides: an efficient synthesis of aryl ketones

[chemical reaction: see text]. Direct addition of Grignard reagents to acid chlorides in the presence of bis[2-(N,N-dimethylamino)ethyl] ether proceeds selectively to provide aryl ketones in high yields. A possible tridentate interaction between Grignard reagents and bis[2-(N,N-dimethylamino)ethyl] ether moderates the reactivity of Grignard reagents, preventing the newly formed ketones from nucleophilic addition by Grignard reagents.     

Ligand coupling through σ-sulfurane — complete retention of geometric configuration of allylic and vinylic groups in the reactions of allylic and vinylic sulfoxides with Grignard reagents

The reaction of p-benzenesulfonylphenyl crotyl sulfoxide with Grignard reagents is considered to proceed via formation of an incipient σ-sulfurane to afford the coupling product, p-benzenesulfonyl-crotylbenzene, in which the geometric configuration of crotyl group was completely preserved. No rearrangement was observed in the coupling reaction of p-benzenesulfonylphenyl α-methylallyl sulfoxide. Such a complete retention of geometric configuration was also found in the reactions of 2-pyridyl and p-benzenesulfonylphenyl styryl sulfoxides with Grignard reagents.     

Facile synthesis of 4-substituted pyridines using grignard reagents

N-t-Butyldimethylsilylpyridinium triflate $\text{2}$ reacted with Grignard reagents at 4-position with almost complete regioselectivity ($\text{>}$99%) to afford the corresponding 1,4-dihydropyridine derivatives ($\text{3}$), which are easily oxidized by oxygen to give 4-substituted pyridines ($\text{4}$: 58 – 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.     

Nucleophilic substitution by grignard reagents on sulfur mustards

With proper activation of the leaving group, sulfur mustards react with Grignard reagents with neighboring group participation of the sulfur atom. 2,6-Dichloro-9-thiabicyclo[3.3.1]nonane is especially useful in this regard, providing clean reactivity with organomagnesium nucleophiles on a topologically constrained scaffold.     

The reaction of hexafluoropropene oxide with grignard reagents

The reactions of hexafluoropropene oxide and equimolar amounts of Grignard reagents lead to the formation of 2-halotetrafluoropropanoyl fluorides which were converted to the methyl or ethyl ester for isolation purposes. Treatment of hexafluoropropene oxide with excess Grignard reagent formed an unsaturated ketone of the type R₂CCFCOR (RCH₃ or CH₂CH₃; a route by which this product is formed is postulated.     

Synthesis of novel 1-phenyl-1H-indole-2-carboxylic acids. II. Preparation of 3-dialkylamino, 3-alkylthio, 3-alkylsulfinyl,and 3-alkylsulfonyl derivatives

The synthesis of novel indole-2-carboxylic acids with amino- and sulfur-containing substituents in the indole 3-position is described. An Ullmann reaction with bromobenzene converted 1H-indoles with 3-(acetylamino)- and 3-(diethylamino)-substituents into 1-phenyl-1H-indoles. Reaction of 3-unsubstituted indoles with thionyl chloride provided indole 3-sulfinyl chlorides, which reacted with alkyl and aryl Grignard reagents to form the corresponding sulfoxides. The indole sulfoxides thus obtained were reduced to sulfides or oxidized to sulfones.     

Highly enantiomerically enriched alpha-haloalkyl Grignard reagents

alpha-Chloro- and alpha-bromoalkyl Grignard reagents 11 and 30 with > 97% ee (enantiomeric excess) were generated by a sulfoxide/magnesium exchange reaction from the enantiomerically and diastereomerically pure sulfoxides 25 and 27. The resulting alpha-haloalkyl Grignard reagents are configurationally stable at -78 degrees C. Racemization sets in at or above -60 degrees C, especially when the solution contains bromide ions. In the absence of halide ions, the configurational stability extends up to -20 degrees C, when chemical decomposition commences.     

Stéréochimie des réactions de réactifs de grignard au niveau de l'atome de silicium d'un cyclosilane asymétrique

The stereochemistry of coupling reactions of Grignard reagents and symetrical organomagnesium compounds with the silicon atom of 1,2,3,4-tetrahydro-2-(1-naphthyl)-2-silanaphthalene is studied. The results show that the electrophilic at the leaving group, by the metal atom is not a main factor for the retention of the configuration. It is possible to give a first explanaion of the stereochemical pathway of these reactions by considerig the “hard and soft” character of the attacking organometallic as well as polarisability of the leaving group.     

Addition of indolyl and pyrrolyl grignard reagents to 1-acylpyridinium salts

Certain indolyl and pyrrolyl Grignard reagents add to 1-acyl salts of 4-methoxy-3-(triisopropylsilyl)pyridine to give the corresponding 1-acyl-2-heteroaryl-2,3-dihydro-4-pyridones in good to high yield. When the 1-acyl group contained a chiral auxiliary, (+/-)-trans-2-(alpha-cumyl)cyclohexyloxy, addition of the indolyl Grignards resulted in a separable mixture of diastereomeric 2,3-dihydro-4-pyridones.     

New polyfunctional magnesium reagents for organic synthesis

The iodine-magnesium exchange reaction allows the preparation of polyfunctional aryl, heteroaryl, or alkenyl magnesium reagents at low temperature. These reagents display the typical reactivity of Grignard compounds and undergo various copper-catalyzed reactions such as allylation or 1,4-addition. Using this halogen-metal exchange reaction, it was possible to generate polyfunctional magnesium reagents on the solid phase.     

Reaction of 6-phenyl-2-(p-toluenesulfonyl)-3(2H)pyridazinone with grignard reagents

6-Phenyl-2-(p-toluenesulfonyl)-3(2H)pyridazinone (I) reacted with Grignard reagents to give 5-substituted 4,5-dihydro-3(2H)pyridazinones II and two types of dihydropyridazines, III and IV. The ratio of II, III, and IV was sensitively dependent on the reaction conditions. Further, by quenching the reaction mixture with alcohol, the ring-opened product VII was mainly isolated.     

A comparison of some friedel-crafts and grignard reactions of optically active phenyloxirane

The Friedel-Crafts reactions of optically active phenyloxirane with toluene and anisole were examined for stereospecificity. The enantiomeric ratios of the diarylethanol products were determined and compared to those of the same products obtained from the reaction of p-tolyl and p-methoxyphenyl Grignard reagents with optically active phenyloxirane. The p-tolyl Grignard and Friedel-Crafts products gave similar enantiomeric ratios (approximately 64:36 and 60:40, respectively). However, in the p-methoxyphenyl products from the Grignard and Friedel-Crafts reactions, different enantiomers predominated (ratios of 33:67 and 62:38, respectively).     

Nickel-catalyzed cross-coupling reaction of grignard reagents with alkyl halides and tosylates: remarkable effect of 1,3-butadienes

A new method for the cross-coupling reaction of Grignard reagents with alkyl chlorides, bromides, and tosylates has been developed by the use of a nickel catalyst in the presence of a diene as an additive. This reaction proceeds efficiently at 0-25 degrees C in THF using primary and secondary alkyl and aryl Grignard reagents. Nickel complexes bearing no phosphine ligands, such as NiCl2, Ni(acac)2, and Ni(COD)2, afford the coupling products in good yields, whereas NiCl2(PPh3)2 and NiCl2(dppp) were less effective. 1,3-Butadiene shows the highest activity as an additive for the present coupling reaction. A plausible reaction pathway was proposed.