Methyl iodide homologation

The principal competing reactions to ruthenium-catalyzed acetic acid homologation appear to be water-gas shift to C02, hydrocarbon formation (primarily ethane and propane in this case) plus smaller amounts of esterification and the formation of ethyl acetate (see Experimental Section). Unreacted methyl iodide is rarely detected in these crude liquid products. The propionic acid plus higher acid product fractions may be isolated from the used ruthenium catalyst and unreacted acetic acid by distillation in vacuo. 

Effect of Operating Conditions. Yield data, summarized in Figures 1 and 2, point to acetic acid homologation activity being sensitive to at least four operating variables, viz. ruthenium and methyl iodide concentrations, syngas composition and operating pressure. 

Deuteration studies with acetic acid-d4 (99.5% atom D) as the carboxylic acid building block, ruthenium(IV) oxide plus methyl iodide-d3 as catalyst couple and 1/1 (C0/H2) syngas, were less definitive (see Table III). Typical samples of propionic and butyric acid products, isolated by distillation in vacuo and glc trapping, and analyzed by NMR, indicated considerable scrambling had occurred within the time frame of the acid homologation reaction. 

Syngas Homologation of Acetic Acid. To a N2-flushed liquid mix of acetic acid (50.0 gm) and methyl iodide (5.67 gm, 40 mmole), set in a glass liner is added 0.763 gm of ruthenium(IV) oxide, hydrate (4.0 mmole). The mixture is stirred to partially dissolve the ruthenium and the glass liner plus contents charged to a 450 ml rocking autoclave. The reactor is sealed, flushed... 

Unsubstituted 2//-pyran (6) was converted to dienyl sulfide 510a along with a small amount of the methyl homolog 510b by treating with sodium in HMPTA or naphthylsodium in THF followed by alkylation with methyl iodide. The conversion probably proceeded via a short-lived anion.419... 

The 2-substituted thiothiazolines have also been shown to be convenient reagents for effecting the iodomethylation and iodopropenylation of alkyl halides (72TL2743). After alkylation of the anion of 2-methylthiothiazoline or 2-allylthiothiazoline, the product is simply stirred with methyl iodide in DMF to furnish the homologated iodide (607 Scheme 134). 

The cumbersome route in Scheme 269 had been prompted by frustrated attempts to prepare the dianion of acid 32 on the microscale. A reexamination of this reaction on a larger scale showed that warming of a THF solution of 32 with two equivalents of LDA at 50 °C for 2 h led to an orange solution of dianion. Addition of methyl iodide then gave rise to a single diastereomerically pure homologous acid, 41, in nearly quantitative yield (Scheme 3). The stereochemical identity of 41 was reasonably assumed to be erythro from its conversion to the natural product 1. The possibility of epimerization at some stage in this process was ruled out by the clean conversion of threo acid 37 to 9-epiartemisinin 29. 

Most recently, our total synthesis was streamlined further. Since the Claisen rearrangement which provided 32 required excess base, and was followed in a separate step by dianion formation, it seemed reasonable that the two steps could be combined. For example, treatment of acetate 30 with several equivalents of base should lead directly to the dianion of 32, which could then be alkylated in situ to provide the homologated acid 41. Indeed, treatment of 30 with four equivalents of LDEA (-78 to 50 °C) provided the desired dianion of 32, which upon cooling and admission of methyl iodide, gave the acid 41 in 57% yield. 

Several authors have demonstrated the feasibility of the alkylation of a MSMA substrate to obtain the homologous RSMA via reaction of the corresponding a-silylcarbanion with an alkyl halide. Treatment with LDA of (allyl)(pyrrazolylmethyl) silane gives a carbanion that on trapping with methyl iodide, leads to the unique formation of the corresponding RSMA derivative without traces of compounds that could have resulted from the allylic system. However, when. v-butyllithium is used instead of LDA, partial methylation of this system also occurs.66... 

Although several studies have examined the effects of various promoters and ligands on the methanol homologation reaction, none has identified a system with substantially improved selectivity. However, there are many claims that iodide accelerates the rate of the reaction 62-64). While the possible sources of this enhancement have been discussed in Section IV,B, it should be noted that the systems from which these interpretations were extracted are by no means simple. Qualitative comparisons among the various studies of promoted and unpromoted systems are difficult for the reasons given above, but, in addition, because the variety of forms by which iodine is introduced (e.g., I2, CH3I, or iodide salts) apparently produce different effects (57, 63, 64). Also, many of the systems involve two promoter components (e.g., triphenylphosphine + methyl iodide or tri-p-tolylphosphine + I2X which further complicates the interpretations as to the role(s) of the halide. 

AJthaugh various propiisals for the ni chani m of methanol homologation exist, the course of the reaction is still not fully understood. This is especially true for the activation of methanol with a concomitant C-0 bond scission. Also, the folc of the iodine promoter and of ligands remains unclear. This situation is controversial to the closely-related carbonylation of methanol to acetic acid with rhodium catalysts, where the oxidative addition of the intermediate methyl iodide to a rhodium (1) is a generally-accepted reaction path [SR]. 

The role of iodine promoters in methanol homologation still remains unclear. Controversial reports can be found in the literature describing methyl iodide 3 an intermediate that can be formed at reaction conditions (of. Equation (20)). 

Berty et ai. excluded methyl iodide as an intermediate, since it could not be homologated in anhydrous benzene, as was mentioned earlier [17), Based on data by Mizorokj et al. from the cobalt-catalyzed carbonylation of ntetbanol to acetic acid [64], Bahmiann et ai. proposed that the activating effect of iodine did not ensue via methyl iodide fomiation [5. Activation was correlated 10 the lahilization of the coordination sphere of cobalt carbonyls by iodine ligands and the sequence (21) (25) was suggested. 

The assumption of alkyl iodides would also offer an explanation for the marked difference in reactivity of methanol and ethanol in alctrfiol homologation. It has been recently siiown that methyl iodide reacts signiHcantly faster in oxidative addition to rhodium(l) than ethyl iodide [69]. 

In a new variation for the two-carbon homologation of alkyl halides to give aldehydes, 2,4,4,6-letraniethyl-5,6-dihydro-l,3-(4H)-oxazine is first converted into the stable, crystalline methiodide salt (S) by treatment with 4.0 eq. of methyl iodide in the dark for 20 hr. The salt (5) is treated with sodium hydride in dry DMF at room temperature. The alkyl halide is then added and the reaction mixture is stirred at SO-5S° until... 

There are two possible pathways to homologate methanol with carbon dioxide the CO2 insertion path and CO insertion path (Scheme 2). As for the former, Fukuoka et al. reported that the cobalt-ruthenium or nickel bimetallic complex catalyzed acetic acid formation from methyl iodide, carbon dioxide and hydrogen, in which carbon dioxide inserted into the carbon-metal bond to form acetate complex [7]. However, the contribution of this path is rather small because no acetic acid or its derivatives are detected in this reaction. Besides, the time course... 

Phenylthiomethyllithium (2a) was used for the homologation of primary halides in a two-step sequence first halogen displacement by reagent (2a) or the organocuprate derivative (in the case of allylic compound) and then replacement of the phenylthio group by iodo by heating the sulfide with a large excess of methyl iodide in 1 M sodium iodide solution in DMF (Scheme 16). 

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