Synthesis from acid amides

Acid amide-triphenylphosphine dihalide adducts (4) have found wide application in organic synthesis. - Synthetic equivalents are adducts (5) from acid amides and triphenylphosphine/CCU, which are prepared in situ from the educts. - With these reagents the following transformations have been performed dehydration of amides or aldoximes to nitriles, preparation of isonitriles from secondary form-amides, preparation of imidoyl halides from amides or acylhydrazines and preparation of ketene imines from amides. Using polymer-supported triphenylphosphine the work-up procedure is much easier to achieve. Triphenylphosphine can be replaced by tris(dialkylamino)phosphines. - Instead of CCI4 hexa-chloroethane, hexabromoethane or l,l,2,2-tetrabromo-l,2-dichloroethane can be used " the adducts thus formed are assumed to be more effective than those from the triphenylphosphine/CCU system. 

APA may be either obtained directly from special Penicillium strains or by hydrolysis of penicillin Q with the aid of amidase enzymes. A major problem in the synthesis of different amides from 6-APA is the acid- and base-sensitivity of its -lactam ring which is usually very unstable outside of the pH range from 3 to 6. One synthesis of ampidllin applies the condensation of 6-APA with a mixed anhydride of N-protected phenylglydne. Catalytic hydrogenation removes the N-protecting group. Yields are low (2 30%) (without scheme). 

A/-Chloro fatty acid amides have been synthesized from the direct halogenation of the amide in boiling water (28). They are useful as reactive intermediates for further synthesis. Fluorination has also been reported by treating the fatty amide with fluorine-containing acid reagents at 200 °C to reach a fluorinated amide with less reactivity toward fluorocarbon polymers (29). 

R = H) is made similarly from its ester (789 R = Et), itself prepared by several obvious steps (see (i) below) from the pyrimidine (788) which can be made by primary synthesis (66AP362). 4-Aminopyrimidine-5-carbonitrile (790 R = CN), which may be made by primary synthesis, undergoes hydrolysis in alkali to the amino acid (790 R = C02H) it may be made similarly from the amide (790 R = CONH2) (53JCS331). 

Emphasis in recent applications of the method has been placed on the synthesis of tetra- and penta-cyclic structures containing a di-hydro-j8-carboline system or its equivalent. Thus the tetracyclic system 100 was obtained from the amide (99) of tryptamine and hip-puric acid. ... 

The structure of 82 was established by alkaline ring cleavage to benzilic acid amide and by hydrogenolysis to (C6H5)2CH—CONH— COCfiHs. These reactions also served to eliminate 83 as the structure of the 169° compound. The other possible isomeric structure, (C6H5)2C(CN)0C0C6H5, which could have formed after 0-acylation, was ruled out by its independent synthesis from bromodiphenyl-acetonitrile and silver benzoate. 

The application of / -(diphenylphosphinyl)benzenesulphonic acid (58) to the synthesis of esters of amino-acids has made the work-up much simpler, since the resultant oxide is water-soluble. Diphenylphosphinyl isocyanate (59) can be prepared from diphenylphosphinic amide. 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

The chemistry of pepper has long been studied and the pungent principle of black pepper—a piperidine alkaloid, piperine 134—was isolated as early as 1877 (201). Its synthesis from the acid and piperidine was accomplished in 1882. (202). The corresponding pyrrolidine alkaloid trichostachyne (135) was isolated some 100 years later from several Piper species (see below). The cooccurence of piperidine and pyrrolidine alkaloids is a common feature of the chemistry of pepper. In many cases, the crude alkaloid extract is first cleaved with acids or bases and then each alkaloid is reconstituted by selective amidation. For the sake of unity, this chapter will be limited to comments on pyrrolidines, even in cases where they are minor alkaloids. 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

G Galavema, R Corradini, A Dossena, R Marchelli. Diaminomethane dihydrochloride, a novel reagent for the synthesis of primary amides of amino acids and peptides from active esters. Int J Pept Prot Res 42, 53, 1993. 

The ease of the Strecker synthesis from aldehydes makes a-aminonitriles an attractive and important route to a-amino acids. Fortunately, the microbial world offers a number of enzymes for carrying out the necessary conversions, some of them highly stereoselective. Nitrilases catalyze a direct conversion of nitrile into carboxylic acid (Equation (11)), whereas nitrile hydratases catalyze formation of the amide, which can then be hydrolyzed to the carboxylic acid in a second step (Equation (12)). In a recent survey, with a view to bioremediation and synthesis, Brady et al have surveyed the ability of a wide range of bacteria and yeasts to grow on diverse nitriles and amides as sole nitrogen source. This provides a rich source of information on enzymes for future application. 

Secondary nitramides are relatively stable in highly acidic media and so their synthesis from the direct nitration of A -substituted amides with nitric acid and its mixtures is feasible. The synthesis of primary nitramides from the nitration of A -unsubstituted amides is usually not possible in acidic media, although this class of compounds have no practical value as explosives anyway. 

Intestinal bacteria produce enzymes that can chemically alter the bile salts (4). The acid amide bond in the bile salts is cleaved, and dehydroxylation at C-7 yields the corresponding secondary bile acids from the primary bile acids (5). Most of the intestinal bile acids are resorbed again in the ileum (6) and returned to the liver via the portal vein (en-terohepatic circulation). In the liver, the secondary bile acids give rise to primary bile acids again, from which bile salts are again produced. Of the 15-30g bile salts that are released with the bile per day, only around 0.5g therefore appears in the feces. This approximately corresponds to the amount of daily de novo synthesis of cholesterol. 

In 2001, De Luca and GiacomeUi " reported a new simple and high-yielding one-flask synthesis of Weinreb amides from carboxylic acids and A-protected amino acids that uses different 1,3,5-triazine derivatives (such as 236) as the coupling agents (Scheme 104). The method allows the preparation of Weinreb amides 237 and hydroxamates as O-benzyl and 0-silyl hydroxamates that can be easily transformed into hydroxamic acids. 

Due to the vast numbers and rapidity of novel developments in solid-phase synthesis over the past ten years, a number of reports currently found in the literature deal with solid-phase syntheses of lanthionine peptides. There are at least two different approaches to synthesize lanthionine peptides in which the sulfide bond links amino acid halves that are not direct neighbors within the peptide chain (Scheme 10). One obvious approach, method A, is based on the coupling of a preformed, orthogonally protected lanthionine monomer to the N-terminus of a peptide oxime resin. 48 This is then followed by acid-catalyzed cyclization and simultaneous release from the resin during amide bond formation with the C-terminal carboxy group via the peptide cyclization method on oxime resin (see Section 6.73.2.2). The alternative approach is lanthionine formation after peptide synthesis from amino acid derivatives, such as serine and cysteine (method B). 

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