From carboxylic acids tertiary

SECONDARY AND TERTIARY ALKYL KETONES FROM CARBOXYLIC ACID CHLORIDES AND LITHIUM PHENYLTHIO(ALKYL)CUPRATE REAGENTS tert-BUTYL PHENYL KETONE... 

The reaction depicted was run in THF at 0 C, other solvents having been found to be inferior. The S-(2-pyridyl) thioates may be prepared through reaction of the corresponding acid chloride and 2-pyridine-thiol in the presence of a tertiary amine. They are also available directly from carboxylic acids by reaction with 2,2 -dipyridyl disulfide (Aldrithiol-2) and triphenylphosphine. In the case illustrated above, protection of the ketone would seem unnecessary if Grignard addition was selective for the thiol ester however, the starting material, 5-(2-pyridyl) y-oxopentanethioate, is not stable to the lactonization shown in equation (18). 

Kende has demonstrated that the mixed anhydride from carboxylic acids and diphenylphosphinic chloride would acylate Grignard reagents to afford ketones in moderate to good yield. Tertiary carbinols were not observed unless excess Grignard reagent was added. The intermediate anhydrides were generally isolated and made free of triethylamine hydrochloride before addition of the nucleophile. The reaction shown in equation (52) gave improved yields over the simple addition of methyllithium to the carboxylic acid. ... 

Gancet, C Preparation of Esters of Carboxylic Acids Directly From Carboxylic Acids and Alcohols Using a Catalyst System Comprising a Sulfonic Acid and a Polymer-Bound Tertiary Amine. European Patent 1,167,337, Jan 2, 2002. 

Mixed anhydrides can be obtained by those of the above methods in which acid chlorides are used. Further, formation of anhydrides from carboxylic acids and acetic anhydride involves mixed anhydrides as intermediates, and in some cases these can be isolated, e.g., the mixed formic acetic anhydride.977 This anhydride can replace the unstable formic anhydride itself, for only the reactive formyl group is transferred in its reactions this fact has been utilized in the preparation of numerous formic esters, which in turn can be transformed into esters of tertiary alcohols that are otherwise difficult of access (see page 376). 

Esterification. Activated esters derived from carboxylic acids with the title reagent react with alcohols (including tertiary alcohols) to give esters. 

Sbcondaby and Tertiary Alkyl Ketones from Carboxylic Acid Chlobides and Lithium Phenylthio alkyl)odi>bate Reagents ... 

Esters of tertiary alcohols may not be prepared from carboxylic acids containing acidic a-protons using this modified procedure, since deprotonation and subsequent condensation, competes. However, the use of stoichiometric 1,8-Diazabicyclo[5.4.0]-undec-7-ene as base has been shown to provide good yields of i-butyl esters even for acids with acidic a-protons (eq 3). This procedure was unsuccessful for pivaUc acid or for IV-acyl-a-amino acids. 

JV-Acylbenzotriazoles (7), generated from carboxylic acids (5) and N(l-methanesulfonyl)benzotriazole (6), react with ammonium hydroxide, primary and secondary amines to form primary (8), secondary (9), and tertiary (10) amides in high yields (Scheme 3) (2000JOC8210). The utility of this simple chemistry is beautifully illustrated by the synthesis of a range of improved mosquito repeUants (2008PNAS7359). 

A variety of non-volatile tertiary amine bases, which would either completely favor the ammonium phosphate salt and/or form an ammonium phosphate salt that could be removed prior to distillation by precipitation and filtration, were evaluated. Only l,8-his(dimethylamino) naphthalene, known for its bidentate nature [255], which most probably favors the formation of the ammonium phosphate salt, furnished benzyl isocyanate in good yield and with high purity [256). About 75% of the ammonium phosphate salt was removed by precipitation and filtration prior to distillation. Consequently, a simple method for the synthesis of high purity isocyanates from carboxylic acids was developed using DPPA and 1,8-his(dimethylamino) naphthalene. Yields evaluated for the monoisocyanates ranged from 60% to 81.5% (Table 4.17) [256]. 

It is not necessary to use ketenes themselves in the cycloaddition reaction with enamines. Opitz and coworkers have demonstrated that the adducts can be obtained in good yield from carboxylic acid chlorides and enamines in the presence of a tertiary amine as the hydrogen chloride scavenger . 

Deshmukh et al. demonstrated that triphosgene can also be used to prepare dialkylcar-bamoyl azides from tertiary amines and sodium azide. Alternatively, acyl azides (e.g. 303) can be converted via a one-step procedure from carboxylic acids using bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) (Scheme 3.46). ... 

Aldehydes and Ketones from Carboxylic Acids. Reduction of the derived acylimidazole (2) with Lithium Aluminum Hydride achieves conversion of an aliphatic or aromatic carboxylic acid to an aldehyde (eq 6). Diisobutylaluminum Hydride has also been used, allowing preparation of a-acylamino aldehydes from iV-protected amino acids. Similarly, reaction of (2) with Grig-nard reagents affords ketones, with little evidence for formation of tertiary alcohol. 

Synthesis of Amides from Carboxylic Acids/ In the corresponding amidation process (eq 2) there is a requirement for the addition of 1 equiv of a tertiary amine (Tri-n-butylamine) to ensure efficient utilization of the amine component (R R NH). Once again, carboxyl activation is achieved using a 2-halopyridinium salt (2) but, unlike the esterification reaction, amidation is best carried out as a two-step one-pot process. 

The nature of the base, CmHijN, varies. When produced from pure Mupinine, m.p. 68-9°, it furnishes on oxidation only 3-methylpyridine-2-carboxylic acid (XV) and pyridine-2 3-dicarboxylic acid. If, however, lupinine, m.p. 63-3°, is used, the resulting pyridine base on oxidation furnishes in addition 2-n-butylpyridine-6-carboxylic acid (XVI) and 6-methylpyridine-2-carboxylic acid (XVII). The conclusion is drawn that lupinine, m.p. 63-3°, is a mixture of 1-lupinine (XI) with aZlolupinine (XII), each of these components furnishing its own lupinane (XIII and XIV), and that these two lupinanes contribute to the final degradation product, the tertiary pyridine base, CioHuN, the two isomerides 2-w-Ijutyl-3-inethylpyridine (XVIII) and 2-w-butyl-6-raethylpyridine (XIX) respectively. These interrelationships are shown by the following scheme —... 

This tertiary ester was developed to reduce aspartimide and piperidide formation during the Fmoc-based peptide synthesis by increasing the steric bulk around the carboxyl carbon. A twofold improvement was achieved over the the standard Fbutyl ester. The Mpe ester is prepared from the acid chloride and the alcohol and can be cleaved under conditions similar to those used for the r-butyl ester. ... 

A variant of the Williamson ether synthesis uses thallium alkoxides. The higher reactivity of these can be of advantage in the synthesis of ethers from diols, triols and hydroxy carboxylic acids, as well as from secondary and tertiary alcohols on the other hand however thallium compounds are highly toxic. 

According to the above reaction scheme the carbonylation reaction has to be carried out in two steps In the absence of water the olefin is first converted at 20-80°C and 20-100 bar by the aid of mineralic acid and carbon monoxide into an acyliumion. In a second step the acyliumion reacts with water to the carboxylic acid. The mineral acid catalyst is recovered and can be recycled. The formation of tertiary carboxylic acids (carboxylic acids of the pivalic acid type) is enhanced by rising temperature and decreasing CO pressure in the first step of the reaction. Only tertiary carboxylic acids are formed from olefins that have at the same C atom a branching and a double bond (isobutylene-type olefins). 

As mentioned in the Introduction, rearrangements of the intermediate alkyl cation in the Koch synthesis may compete with the carbonylation. Under the kinetically controlled conditions prevailing in the Koch synthesis of carboxylic acids, the rearrangements occur only from a less stable to a more stable carbonium ion, e.g. from a secondary to a tertiary ion. The reverse rearrangements—from a more stable to a less stable... 

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