Synthesis of acids

Ethyl cyanoacetate (Section 111,131) is sometimes preferable to diethyl malonate for the synthesis of acids. It forms a sodio derivative with sodium ethoxide ... 

Diallylsulfonium salts undergo intramolecular allylic rearrangement with strong bases to yield 1,5-dienes after reductive desulfurization. The straight-chain 1,5-dienes may be obtained by double sulfur extrusion with concomitant allylic rearrangements from diallyl disulfides. The first step is achieved with phosphines or phosphites, the second with benzyne. This procedure is especially suitable for the synthesis of acid sensitive olefins and has been used in oligoisoprene synthesis (G.M. Blackburn, 1969). 

These interesting reactions, however, have limited interest for the synthesis of acids. 

The customary method for the laboratory synthesis of acid anhydrides is the reac tion of acyl chlorides with carboxylic acids (Table 20 1)... 

The chemical inertness of the three-membered ring permitted many conversions of functional groups in diazirines. Esterifications, cleavage of esters and acetals, synthesis of acid chlorides, oxidation of hydroxy groups to carboxyl groups as well as Hofmann alkenation all left the three-membered ring intact (79AHC(24)63). 

Suggest a synthesis of acid (15) used in an. vestigation of oxidation reactions. 

On page 94 appeared a problem on the synthesis of acid (1), needed for conversion to ketone (2), The problem under investigation was sterlc hindrance in nucleophilic additions to ketones and a crowded ketone with a chiral centre was needed. 

In some cases, substrate racemization can be achieved by an appropriate change of a functional group. A good example of this strategy is the synthesis of acid 10, which is the key intermediate for roxifiban - a potent selective antagonist of the platelet plycoprotein Ilb/IIa receptor (Scheme 5.8) [27, 28]. 

Although the synthesis of acid 3 developed by our Medicinal Chemistry colleagues proceeded in a single step from commercial starting materials the yield was modest, and there were significant safety concerns about the use of sodium hydride in DMF on a larger scale. After some experimentation it was found that use of the ester in conjunction with just 1 equiv of KHMDS as base gave a clean... 

Three methods are known for the synthesis of acid anhydrides from carboxylic acids by means of azolides ... 

Hydroxycarbonylation and alkoxycarbonylation of alkenes catalyzed by metal catalyst have been studied for the synthesis of acids, esters, and related derivatives. Palladium systems in particular have been popular and their use in hydroxycarbonylation and alkoxycarbonylation reactions has been reviewed.625,626 The catalysts were mainly designed for the carbonylation of alkenes in the presence of alcohols in order to prepare carboxylic esters, but they also work well for synthesizing carboxylic acids or anhydrides.137 627 They have also been used as catalysts in many other carbonyl-based processes that are of interest to industry. The hydroxycarbonylation of butadiene, the dicarboxylation of alkenes, the carbonylation of alkenes, the carbonylation of benzyl- and aryl-halide compounds, and oxidative carbonylations have been reviewed.6 8 The Pd-catalyzed hydroxycarbonylation of alkenes has attracted considerable interest in recent years as a way of obtaining carboxylic acids. In general, in acidic media, palladium salts in the presence of mono- or bidentate phosphines afford a mixture of linear and branched acids (see Scheme 9). 

Fauq, A.H., Kache, R., Khan, M.A., and Vega, I.E. (2006) Synthesis of acid-cleavable light isotope-coded affinity tags (ICAT-L) for potential use in proteomic expression profiling analysis. Bioconjugate Cbem. 17, 248-254. 

Synthesis of acid 129 starts from the commercially available 6-heptenoic acid (122), which upon reaction with (4S)-benzyloxazolidin-2-one (123) as the chiral auxiliary group yields the intermediate 124, hydroxymethylation of which affords compound 125. Hydrolysis of compound 125 followed by condensation with O-benzylhydroxylamine gives rise to the hydroxamate (126), which is then converted into (Claclam 127 via an intramolecular Mitsunobu reaction. Hydrolysis of the (Claclam 127 affords acid 128, which is subsequently formylated at the benzyloxyamine moiety to give the required intermediate acid (129) in quantitative yield, as depicted in Scheme 26. 

The selectivity and mildness of the Pd(0)-catalyzed deprotection of allyl (All) esters and the allyloxycarbonyl (Aloe) urethanes117 181 reaction also allowed for the successful and efficient application of this blocking group technology in the synthesis of acid- and base-labile lipidated pepti-... 

The adducts (94) of triphenylphosphine and alkylphenyl-AT-p-tosylsulphilimines also act as dehydrating agents, and have been employed in the synthesis of acid anhydrides, esters, and amides.90-91... 

The approach to polyketide synthesis described in Scheme 5.2 requires the relatively nontrivial synthesis of acid-sensitive enol acetals 1. An alternative can be envisioned wherein hemiacetals derived from homoallylic alcohols and aldehydes undergo dia-stereoselective oxymercuration. Transmetallation to rhodium could then intercept the hydroformylation pathway and lead to formylation to produce aldehydes 2. This proposal has been reduced to practice as shown in Scheme 5.6. For example, Yb(OTf)3-cata-lyzed oxymercuration of the illustrated homoallyhc alcohol provided organomercurial 14 [6]. Rhodium(l)-catalyzed hydroformylation of 14 proved successful, giving aldehyde 15, but was highly dependent on the use of exactly 0.5 equiv of DABCO as an additive [7]. Several other amines and diamines were examined with variation of the stoichiometry and none proved nearly as effective in promoting the reaction. This remarkable effect has been ascribed to the facilitation of transmetallation by formation of a 2 1 R-HgCl DABCO complex and the unique properties of DABCO when both amines are complexed/protonated. 

The above reagents serve as condensing reagents and have different reactivities for peptides 279, p-lactams 281, esters, thioesters, and mixed phosphates, as well as for the direct preparation of 3-acyl-2(3F/)-oxazolones. The bis(2-oxo-3-oxazohnyl)phosphinate 282 is useful for Zr(IV)-catalyzed phosphorylation of alcohols, leading to the general synthesis of acid- and base-labile mixed phosphate esters 284 (Fig. 5.67). ... 

Synthesis of Acid-Labile Phosphate Alkyl Ester Derivatives of Fmoc-Protected... 

Scheme 24 Synthesis of acid stable platinum-NHC-complexes...

In the synthesis of acidic peptide such as BMP, aspartic acid and glutamic acid residues were stepwisely elongated. In case of the practical synthesis of peptide containing a many acidic amino acid residues, multi reaction procedure for long duration may be required. 

One important advantage of the use of ROOH/transition-metal reagents over the traditional organic peracids is that they are particularly useful in the synthesis of acid-sensitive epoxides. 

Since it is known that the introduction of Al species leads to the synthesis of acidic Al-substituted MCM-41 materials, which are useful catalyst supports [2-4,13,14], the formation of Al-substituted MCM-41 mesoporous structure in fluoride medium is... 

Synthesis of Acid-Prepared Mesoporous Spheres (APMS).3 Tetraethylorthosilicate (TEOS, 5.65 g, 27.1 mmol) was added to a solution of cetyltrimethylammonium bromide (CTAB, 1.20 g, 3.30 mmol) in aqueous acid (4.40 g cone. HC1, 55.5 g H20). This mixture was stirred for 1 hour and then transferred to a teflon-lined Parr autoclave and heated at 150 °C for 40 minutes. The mixture was cooled and filtered to recover a white powder. APMS could also be prepared at temperatures between 80 and 230 °C by adjusting the heating time (lower temperatures, longer times). 

Crafts alkylation and acylation (Section 22-4E and 22-4F), the Gattermann-Koch reaction for preparation of aldehydes from arenes and carbon monoxide (Section 22-4F), and the Kolbe-Schmitt, Reimer-Tiemann, and Gattermann reactions for synthesis of acids and aldehydes from arenols (Section 26-1E). 

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