Acetic acid homologation

Figure 1. Acetic acid homologation (%) acetic acid, propionic acid, (A) butyric acids, and (V) valeric acids A, effect of Ru (operating conditions acetic acid, 417 mmol Mel, 20 mmol 220°C 476 atm constant pressure CO/H2 = 1/1) B, effect of Mel (operating conditions acidic acid, 417 mmol Ru(IV) oxide, 2.0 mmol 220°C 476 atm constant pressure CO/Ht = 1/1)...

Formic acid exhibits many of the typical chemical properties of the aHphatic carboxyHc acids, eg, esterification and amidation, but, as is common for the first member of an homologous series, there are distinctive differences in properties between formic acid and its higher homologues. The smaller inductive effect of hydrogen in comparison to an alkyl group leads, for example, to formic acid = 3.74) being a considerably stronger acid than acetic acid... 

The structural homology between intermediate 4 and isostrych-nine I (3) is obvious intermediates 3 and 4 are simply allylic isomers and the synthetic problem is now reduced to isomerizing the latter substance into the former. Treatment of 4 with hydrogen bromide in acetic acid at 120°C results in the formation of a mixture of isomeric allylic bromides which is subsequently transformed into isostrychnine I (3) with boiling aqueous sulfuric acid. Following precedent established in 194810 and through the processes outlined in Scheme 8a, isostrychnine I (3) is converted smoothly to strychnine (1) upon treatment with potassium hydroxide in ethanol. Woodward s landmark total synthesis of strychnine (1) is now complete. 

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

Reactions of 2,3-dioxo-l,2,3,5,6,7-hexahydropyrido[l,2,3-carboxylic acids and the homologous acetic and propionic acids, prepared by basic hydrolysis of the corresponding ester, with amines, 28% NH4OH, and hydroxylamine derivatives in the presence of l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide and hydroxybenztria-zole <1995BML1527>, 1995BML1533>, and in the presence of NEt3 and A, A -bis(2-oxo-3-oxazolidinyl)phosphinic... 

Where acetic is the starting acid (eq. 1), homologation selectively yields the corresponding C3+ aliphatic carboxylic acids. Since acetic acid is itself a "syngas" chemical derived from methanol via carbonylation (2,3), this means the higher MW carboxylic acids generated by this technique could also be built exclusively from C0/H2 and would thereby be in-depent of any petroleum-derived coreactant. 

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. 

For catalyst combinations containing initial I/Ru ratios 5, the product solutions also show strong new bands at 1999 and 2036 cm characteristic (6) of ruthenium pentacarbonyl. Where acetic acid homologation is run at [RuJ > 0.2 M, then another ruthenium iodocarbonyl, Ru(C0)3I2, may be isolated from the product mix as a yellow crystalline solid. A typical spectrum of this material is illustrated in Figure 3b. 

Homologation of 13C-Enriched Acetic Acid CataIyst RuO2-10CH3I... 

Homologation of Acetic Acid-d4 Catalyst RuO2-10CH3I-d3... 

Figure 3. Acetic acid homologation A, IR spectrum of typical product solution, [Ru(C03)I3] ...

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... 

Dienes can be obtained from silylallenes by protodesilylation using boron trifluo-ride-acetic acid complex (equation 29)62. Since silylallenes can be obtained by the reaction of propargyl acetate with cuprous reagent derived from chloromethyltrimethylsilane, this reaction sequence constitutes conversion of propargylic acetate to butadiene through one carbon homologation. 

The double bond in indole and its homologs and derivatives is reduced easily and selectively by catalytic hydrogenation over platinum oxide in ethanol and fluoroboric acid [456], by sodium borohydride [457], by sodium cyanoborohydride [457], by borane [458,459], by sodium in ammonia [460], by lithium [461] and by zinc [462]. Reduction with sodium borohydride in acetic acid can result in alkylation on nitrogen giving JV-ethylindoline [457]. 

Pyrazole was hydrogenated over palladium on barium sulfate in acetic acid to 4,5-dihydropyrazole (A -pyrazoline), and 1-phenylpyrazole at 70-80° to 1-phenylpyrazolidine [478]. In benzopyrazole (indazole) and its homologs and derivatives the six-membered ring is hydrogenated preferentially to give... 

Catalytic hydrogenation over palladium in acetic acid and sulfuric acid at room temperature and 2.5 atm reduced nitroacetophenones and their homologs and derivatives all the way through the alkyl anilines in yields of 78.5-95% [904]. 

Homologation via a-Haloenolates. Organoboranes can also be used to construct carbon-carbon bonds by several other types of reactions that involve migration of a boron substituent to carbon. One such reaction involves a-halocarbonyl compounds.19 For example, ethyl bromoacetate reacts with trialkylboranes in the presence of base to give alkylated acetic acid derivatives in excellent yield. The reaction is most efficiently carried out with a 9-BBN derivative. These reactions can also be effected with B-alkenyl derivatives of 9-BBN to give /i,y-unsaturatcd esters.20... 

While the direct carbonylation is well accepted by industry, the reductive and oxidative carbonylations are still in the research and development stage. Using Texaco technology (j, 7/ ) the combined synthesis of ethene and ethanol is feasible via homologation of acids according to Figure 3. Ethene can also be obtained from the reductive carbonylation of methyl acetate to ethyl acetate followed by pyrolysis (2 ). Both routes, so far, lack selectivity. 

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