Carboxylic acids amine synthesis

Friedlander synthesis, 2, 444 as antipyretic, 1, 172 Quinoline-4-carboxylic acids amination, 2, 236 Beyer synthesis, 2, 475 Pfitzinger synthesis, 2, 446... 

Typically MCRs allow the synthesis of very many derivatives of a special scaffold. Since the number of possible products increases exponentially with the multiplicity of the MCR, very large chemical spaces can be inspected. These very large chemical spaces are not realistically accessible by classical sequential syntheses. As realized by Ugi in 1961 starting with 1000 each of the educts carboxylic acid, amines, aldehydes and isocyanides 10004 products are accessible [4]. In this seminal paper the roots of combinatorial chemistry are described. The authors noted that MCRs have huge variability. Although the paper describes the essentials of combinatorial chemistry, the time was not right for the great advances that only started 30 years later. 

The simplest, and one of the most remarkable, new enzyme mimics has emerged from a piece of lateral thinking by Menger and Fei. [9] No synthesis is involved. These authors simply mixed long-chain carboxylic acids, amines, alcohols and alkylimidazoles, of the sort known to form aggregates, and eventually micelles, in aqueous solution then screened large numbers of such mixtures for catalytic activity. The test reaction was the hydrolysis of the reactive ester 9 (X = O), which is easily followed above pH 7 by the release of the p-nitrophenolate chromophore. Some of the mixtures used effected the hydrolysis of 9 (X = O) at rates too fast to measure manually. Remarkably this was also true in the presence of a single component when this was the hexadecanoate anion, and this system also effects the hydrolysis of the p-nitroanilide (9, X = NH). 

The trityl linkers were introduced to permit anchoring of carboxylic acids and other nucleophiles to a solid support and to effect cleavage reactions under very mild acidic conditions [64-67]. Various trityl resins, such as Ib-le (Table 1), have been developed that differ in the substitution pattern of the aromatic ring substituents in order to modify the cleavage properties by their influence on the stability of the trityl cation. For carboxylic acids, amines, and phenols, the chlorotrityl resin Ic affords a more stable anchor [65-67] than does resin lb. Similarly, resin le, which contains both fluoro and carbonyl ring substituents, proved to be very stable toward nucleophiles and was fully compatible with piperidine / / -Fmoc (9-fluorenylmethoxycar-bonyl) deprotections used in a model peptide synthesis. Cleavage of acids from le could be effected using dilute TFA in dichloromethane [68]. 

Amides from Carboxylic Acids Peptide Synthesis. Analogous to ester formation, reaction of equimolar amounts of a carboxylic acid and (1) in THF, DMF, or chloroform, followed by addition of an amine, allows amide bond formation. The method has been applied to peptide synthesis (eq 5). One equivalent of (1) is added to a 1M solution of an acylamino acid in THF, followed after 1 h by the desired amino acid or peptide ester. The amino acid ester hydrochloride may be used directly instead of the free amino acid ester. An aqueous solution of the amino acid salt can even be used, but yields are lower. 

Most primary amines are suitable for peptoid synthesis. Protection is required if the amine carries a side-chain fimctionahty such as carboxylic acid, amine, thiol, and/or heterocyclic compound. The review by Gulf and Ouellette [15] lists several amines which successfully have been used for peptoid synthesis. 

Hofmann s amine synthesis can be applied to both aliphatic and aromatic carboxylic acid amides, benzamide, C HsCONH, thus giving aniline, C4H5NH,. 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

The octylphenol condensate is used as an additive to lubricating oils and surface-active agents. Other uses of dimer are amination to octylamine and octyldiphenylamine, used in mbber processing hydroformylation to nonyl alcohol for phthalate production and carboxylation via Koch synthesis to yield acids in formulating paint driers (see Drying). 

Phenanthridine-6-carboxylic acids synthesis, 2, 415 Phenanthridines amination, 2, 236 bromination, 2, 320 hydrogenation, 2, 328 nitration, 2, 319 nomenclature, 2, 5 5-oxides... 

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

With its structure known, the synthesis of a peptide can then be undertaken— perhaps to obtain a larger amount for biological evaluation. A simple amide might be formed by treating an amine and a carboxylic acid with dicyclo-hexylcarbodiimide (DCC Section 21.7), but peptide synthesis is a more difficult problem because many different amide bonds must be formed in a specific order rather than at random. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

As has been outlined for the Strecker synthesis, the Ugi reaction also proceeds via initial formation of a Schiff base from an aldehyde and an amine. The imine intermediate is attacked by the isocyanidc, a process which is supported by protonation of the imine by the carboxylic acid component. The resulting a-amino nitrilium intermediate is immediately trapped by the carboxylate to give an 6>-acyl imidiate. All steps up to this stage are reversible. Only the final oxygen to nitrogen acyl shift is irreversible and delivers the A-acyl-a-amino amide as the thermodynamically favored product which contains two amide groups. 

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