Amides, acidity acyloxy

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. The following mechanism has been postulated ... 

Fig. 8.20. Two-step activation ofN-[(acyloxy)methyl] prodrugs, a) Cleavage of the ester bond, which may be enzymatic and/or nonenzymatic, is followed by decomposition of the N-(hy-droxymethyl) intermediate, b) For (V-(hydroxymethyl) derivatives of amides and imides, the decomposition is base-catalyzed, c) For N-(hydroxymethyl) derivatives of amines, the decomposition can be uncatalyzed or undergo acid or base catalysis (modified from [214]).

This view has been challenged with more recent evidence indicating that AT-[(acyloxy)methyl] derivatives of both primary and secondary amides (8.170, Fig. 8.21) undergo decomposition by the same mechanisms, namely a) an acid-catalyzed process involving protonation followed by formation of an /V-acyliminium species (Fig. 8.21, Reaction a) b) a pH-independent heterolytic cleavage forming the same /V-acyliminium species (Fig. 8.21, Reaction b) and c) a base-catalyzed pathway, which for /V-[(acyloxy)methyl] derivatives of AT-methylamides is the normal mechanism (Fig. 8.21, Reaction c), but for AT-[(acyloxy)methyl] derivatives of primary amides involves substrate deprotonation followed by /V-acy limine formation (Fig. 8.21, Reaction d) [218],... 

Fig. 8.21. Mechanisms of cleavage ofN-[(acyloxy)methyl] derivatives of primary amides (8.170, R = H) and secondary amides (8.170, R = methyl) via an acid-catalyzed pathway (.Reaction a), a pH-independent pathway (.Reaction b), and base-catalyzed pathways (Reactions c and d) [218].

Chloro-4,6-dimethoxy-l,3,5-triazine (100) reacts with iV-methylmorpholine at 20 °C to yield an isolable quaternary triazinylammonium salt (101 R = Me, R, R = C4H8O). This salt can then be reacted with a carboxylic acid to yield a 2-acyloxy-4,6-dimethoxy-l,3,5-triazine (102), which, in turn, can be reacted with an amine to yield an amide (103). This sequence of reactions provides an explanation for the activation (formation of reactive ester) of the carboxylic acid function by 2-chloro-4,6-disubstituted-l,3,5-triazines (100) in the presence of hindered amines. Several other hindered amines may replace iV-methylmorpholine in the process, but unhindered amines such as triethylamine and tributylamine were inactive. ... 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

Free acids require still an additional hydride equivalent because their acidic hydrogens combine with one hydride ion of lithium aluminum hydride forming acyloxy trihydroaluminate ion. Complete reduction of free carboxylic acids to alcohols requires 0.75 mol of lithium aluminum hydride. The same amount is needed for reduction of monosubstituted amides to secondary amines. Unsubstituted amides require one full mole of lithium aluminum hydride since one half reacts with two acidic hydrogens while the second half achieves the reduction. 

The amide carbonyl vibrational frequencies of A-acyloxy-Af-alkoxyamides are similar to that observed for the twisted l-aza-2-adamantanone (98, 1731 cm ) . It is apparent from the extensive data available for both A-chlorohydroxamic esters (Table 2, Section in.B.2) and Af-acyloxy-A-alkoxyamides that when an amide nitrogen lone pair loses conjugation with the carbonyl (either through twisting/pyramidalization or, in the case of anomeric amides, pyramidalization alone), the configuration is analogous to an ester rather than a ketone. As with esters, acid halides and anhydrides or diacyl peroxides , the carbonyl stretch frequency is higher than that of ketones and aldehydes... 

Alkoxy-2-hydroxybenzylamides (Entry 13, Table 3.9) can also be cleaved by treatment with TFA (see also Section 16.1.5). If the phenolic hydroxyl group is acy-lated, however, acidolysis proceeds more slowly. Hence, 4-alkoxy-2-(acyloxy)benzyl-amides can serve as linkers that are stable towards both acids and bases, but which can be activated towards acidolysis by saponification to the corresponding 4-alkoxy-2-hydroxybenzylamide [211],... 

Diastereofacial selectivity in the a-allylation of cyclic a-acyloxy amides 259 derived from succinic or phthalic anhydride can be controlled by the Lewis acid. Thus, while TiCLt gives 260, allylation promoted by SnCLt affords 261393. No rationalization has been offered. 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

Initially, a loosely bound hydrogen bonded adduct 10 is formed, from the carboxyhc acid 8 and the carbonyl compound 6. The next step is the formation of the a-adduct 11 by reaction of the isocyanide with the nucleophilic carboxylate and the electrophilic protonated carbonyl compound. a-Adduct 11 then rearranges to give oc-acyloxy amide 9. 

Review. New synthetic reactions based on the onium salts of aza-arenes have been reviewed (75 references). The reactions discussed involve activation of carboxylic acids or alcohols with 2-haIopyridinium, benzoxazolium, benzothiazolium, and pyridinium salts to afford 2-acyloxy or 2-alkoxy intermediates, which can be transformed into esters, amides, thiol esters, (macrocyclic) lactones, acid fluorides, olefins, allenes, carbodiimides, isocyanates, isothiocyanates, and nitriles under appropriate conditions. 

Cyanuric chloride has been used for the preparation of acyl chlorides, amides, and peptides. Conversion of cyanuric chloride into 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT, 6) leads to a reagent that upon reaction with carboxylic acids produces the highly reactive 2-acyloxy-4,6-dimethoxy-l,3,5-triazines.P l The resulting active ester is a powerful acylating agent for alcohols and amines. The activation is performed in presence of a base, preferentially NMM, which leads to intermediate formation of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 7)P l (Scheme 5). This addition product is readily prepared from the commercially available CDMT (6) and NMM in THF and can be stored as solid compound in the cold.P P l It offers the advantage that it can be used in a one-... 

Simple alkyl or aryl esters Alkyl esters containing an amino or amido group, or another functionality (Acyloxy)methyl or (acyloxy)ethyl esters Esters of diacylaminopropan-2-ols N,N-Dialkyl hydroxylamino derivatives Amides of amino acids... 

Alkoxy bromides are obtained by treating a compound containing aC=C bond with A-bromoacetamide297 or another bromo amides (e.g., N,N-di-bromobenzenesulfonamide302,303), not in an aqueous medium but in anhydrous methanol or ethanol at 0-20° acyloxy bromides are obtained in glacial acetic acid.297,304... 

Kaminski has noted that partial substitution of chlorine atoms in TCT 3 by methoxy or phenoxy groups changes the course of the reaction with carboxylic acids <1985TL2901>. In fact, instead of the expected acyl chlorides, the reaction between 2-chloro-4,6-dialkoxy-[l,3,5]-triazine 295 and carboxylic acids gave highly reactive 2-acyloxy-4,6-dialkoxy-[l,3,5]-triazine 296, which, under further treatment with amines, alcohols, and carboxylic acid anions, afforded amides, esters, and anhydrides, respectively (Scheme 57). 

Azetidinyl-4-ketones are closer than azetidinyl-4-carboxylic esters to the target 4-acyloxy derivatives 11, 29, 36. Thus, Hanessian s version of the threonine route [29], utilizing a-keto anions, can be considered an improvement over Shiozaki s a-carboxyanion strategy, especially when its aptitude for being scaled-up for industrial production is considered. The key-step, cyclization of amide 68a (prepared from epoxyacid 64 and fV-anisylphenacylamine) to azeti-dinone 28a, is carried out by simple treatment with K2CO3 at ambient temperature silylation, CAN-mediated cleavage and oxidation with mono-perphthalic acid complete the sequence to synthon 29b. 

Initially, Passerini proposed that the reaction involved an addition of carboxylic acid to carbonyl compound, giving acyloxy hemiacetal, which then reacted with isonitrile to form the final product. However, current views about this reaction favor the following consecutive processes the protonation of the carbonyl compound from carboxylic acid, followed by the attack of isonitrile to give a nitrilium ion, the nucleophilic addition of carboxylate, acyl group transfer, and the final amide tautomerization. A general mechanism for this reaction is shown here. ... 

Through further followup studies, Passerini expanded the scope of substrates to include a number of aldehydes and ketones as the carbonyl component and a variety of isonitriles including saturated alkyl isocyanides. Passerini also examined reactions where two components were combined into a single bifunctional substrate such as levulinic acid (8), where the carboxylic acid is proximally connected to a ketone. The reaction of levulinic acid with phenyl isocyanide gave amide 9 with the acyloxy moiety of the generic product now a y-lactone. ... 

Alternatively, cyclic enol ethers can serve as the electrophile in Passerini-type reactions as they undergo protonation by strong Bronsted acids to produce oxocarbeniums as the reactive partner. More recently, acyl cyanides have been demonstrated to participate as the carbonyl component in Passerini reactions, giving a-acyloxy-a-cyano amides in good yields. ... 

Mutagenic A-acyloxy-A-alkoxybenzamides undergo 5n2 reactions at the amide nitrogen with A-methylaniline and ring-substituted anilines.Hammett correlations for various reaction series are presented. These reactions model the possible mode of interaction between the mutagens and nucleic acids, which may be responsible for their biological activity. 

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