Grignard substitution

Nickel catalysts also catalyze Grignard substitution to allylic compounds including allyl alcohol [230-233] ethers [230,231,234,235 Eq. (106) 231] amines, albeit in a low product yield [231] sulfides [231,236,237], including thioacetals [238] thiols [231] selenides [239] carboxylates [240] phosphates [94,121] and halides [Eq. (107) 230], most likely via intermediate / -allyl-Ni species. Monosubstitution of bis-allyl ether was possible [Eq. (108) 235]. Most of the literatures cited in the foregoing disclosed regiochemical outcome associated with these allylic substitutions. 

The activation energy for exchange appears to be lower than that for Grignard substitution. The exchange is more pronounced in tetrahydrofuran than in diethyl ether. Although frequently, the exchange is of no consequence, it can significantly alter final product distribution in some sterically constrained systems. 

An elegant insertion-ring-expansion reaction, that involves halide exchange, ring-opening, and Grignard substitution, is the formation of silaoxacyclohexanes [22]. 

It is of interest to note that, although the Grignard substitution and ring-opening reactions involving the trans-fused system 163 occurred under relatively mild conditions, potential reactions based on the cis-fused system 165 (in which R and R have the same significance) failed to occur. 

Grignard substitution on allylbromide gave allyl derivative 3 while chlorodimethylvinylsilane and methylacetate gave olefin intermediates 1-2 via substitution with the aryllithium derivative. Formation of bis-TFVE olefin 2 is illustrative of the pronounced reactivity of TFVE-Li toward organic electrophiles. Addition of methyl acetate to a solution of TFVE-Li, followed by protonation, yields the tertiary alcohol [p-F2C=CFOC6H4]2C(CH3)OH, which undergoes rapid dehydration to afford the bis-TFVE olefin 2. Isolated yields of 1-3 after short path... 

Grignard reagent comes from the substitution products it gives with various reactive substrates. When the low-temperature adduct is heated in an autoclave at 90 to 170 C for 3 to 6 hr, it does not rearrange to 2-ethylthiazole (12) as is the case in the pyridine series (436). 

The reaction of Grignard reagents with epoxides is regioselective m the same sense Attack occurs at the less substituted carbon of the ring... 

Phenyllithium can be used in Grignard-type reactions involving attachment of phenyl group, eg, in the preparation of analgesics and other chemotherapeutic agents (qv). It also may be used in metal—metal interconversion reactions leading, eg, to phenyl-substituted siUcon and tin organics. 

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

In general, Grignard reagents are useful in the synthesis of mixed hydridochlorosilanes because these reagents can effect stepwise substitution of the halogen, eg,... 

Organometalhcs. Halosilanes undergo substitution reactions with alkali metal organics, Grignard reagents, and alkylaluininums. These reactions lead to carbon—siUcon bond formation. 

The synthesis involves the nickel-catalyzed coupling of the mono-Grignard reagent derived from 3-alkyl-2,5-diiodothiophene (82,83). Also in that year, transition-metal hahdes, ie, FeCl, MoCl, and RuCl, were used for the chemical oxidative polymerization of 3-substituted thiophenes (84). Substantial decreases in conductivity were noted when branched side chains were present in the polymer stmcture (85). 

The reaction involves nucleophilic substitution of for OR and addition of R MgX to the carbonyl group. With 1,4-dimagnesium compounds, esters are converted to cyclopentanols (40). Lactones react with Grignard reagents and give diols as products. 

In some instances a carbon-carbon bond can be formed with C-nucleophiles. For example, 3-carboxamido-6-methylpyridazine is produced from 3-iodo-6-methylpyridazine by treatment with potassium cyanide in aqueous ethanol and l,3-dimethyl-6-oxo-l,6-dihydro-pyridazine-4-carboxylic acid from 4-chloro-l,3-dimethylpyridazin-6-(lH)-one by reaction with a mixture of cuprous chloride and potassium cyanide. Chloro-substituted pyridazines react with Grignard reagents. For example, 3,4,6-trichloropyridazine reacts with f-butyl-magnesium chloride to give 4-t-butyl-3,5,6-trichloro-l,4-dihydropyridazine (120) and 4,5-di-t-butyl-3,6-dichloro-l,4-dihydropyridazine (121) and both are converted into 4-t-butyl-3,6-dichloropyridazine (122 Scheme 38). 

Isopyrazole quaternary salts (363) are key intermediates leading to the highly substituted A -pyrazolines. Lithium aluminum hydride gives the pentasubstituted derivatives (364 R = H) and Grignard reagents provide access to the fully substituted A -pyrazolines (364 R H) (68BSF3866, 70BSF1121). 

Benzo[6]thiophene, 2-(aryloxymethyl)-3-chloromethyl-synthesis, 4, 872 Benzo[6]thiophene, 2-arylthio-synthesis, 4, 931 Benzo[6]thiophene, 2-bromo-reaction with potassamide, 4, 829-830 synthesis, 4, 934 Benzo[6]thiophene, 3-bromo-Grignard reagents, 4, 831 reactions, 4, 830 synthesis, 4, 934 Benzo[6]thiophene, 4-bromo-synthesis, 4, 878, 934 Benzo[6]thiophene, 5-bromo-electrophilic substitution, 4, 797 Benzo[6]thiophene, 6-bromo-synthesis, 4, 878, 934 Benzo[6]thiophene, 5-t-buty 1-3-methyl-synthesis, 4, 880... 

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