Carboxylic acid hydrazides, reaction with

As in Section 5.06.9.1, the assignments are sometimes arbitrary. Important routes to oxadiazoles, aminooxadiazoles, oxadiazolinones, and oxadiazolinethiones involving the reaction of hydrazides RCONHNH2 with carboxylic acids, acyl chlorides, alkyl esters, or trialkyl orthoesters are described in Section 5.06.9.2.1, reactions with carbon disulfide... 

Neidlein. R.. Jochheim, M., Krieger, C., and Kramer, W., Synthesis of l,3-dithietane-2,4-diylideneWr)cyanomethylphosphonates) and -phenylphosphinates and their reaction with carboxylic acid hydrazides, Heterocycles, 39, 185, 1994. 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

Biotin-hydrazide also may be used to couple with carboxylate-containing molecules. Hydrazidcs can be coupled with carboxylic acid groups by using the carbodiimide reaction (Chapter 3, Section 1.1). The carbodiimide activates a carboxylate to an o-acylisourea intermediate. Biotin-hydrazide can react with this intermediate via nucleophilic addition to form a stable covalent bond. 

Monothiodiacylhydrazines 127, derived from the acylation of thiosemicarbazides or as intermediates in the reactions of (1) thiohydrazides with carboxylic acids and their derivatives (see Section 5.10.9.2.2(i)) or (2) hydrazides with thiocarbonyl compounds (see Section 5.10.9.2.3(i)), cyclize in the presence of an acid catalyst to give 1,3,4-thiadiazoles 128 (Equation 39, Table 4). 

Palladium-catalyzed carbonylation reactions with aryl halides are powerful methods of generating aromatic amides, hydrazides, esters and carboxylic acids [25]. We have previously reported the exploitation of Mo(CO)6 as a robust carbon monoxide-releasing reagent in palladium-catalyzed carbonylation reactions [26-29]. This stable and inexpensive solid delivers a fixed amount of carbon monoxide upon heating or by the addition of a competing molybdenum coordinating ligand (for example DBU). This allows for direct liberation of carbon monoxide in the reaction mixture without the need for external devices. 

FIGURE 7 Schematic of different coupling methods used (a) reaction between meleimide and thiol functions (b) formation of disulfide bond (c) reaction between carboxylic acid and primary amine group (d) reaction between hydrazide and aldehyde functions (e) cross-linking between two primary amine functions. (Reproduced from ref. 150 with permission of Elsevier.)... 

Haptens containing amino groups can be coupled directly to carriers containing carboxyl groups, or the amino group can be converted to a carboxylic acid by reaction with succinic anhydride. - When a keto or an aldehyde group is present in the hapten, it can be converted to a carboxyl via reaction with 0-(carboxymethyl)hydroxylamine or with hydrazides. Haptens containing double bonds can be made to react directly with mer-captoacetic or mercaptopropionic acid, or a two-step reaction may be performed bromination followed by reaction with mercaptocarboxylic acid. ... 

The products of the reaction between carboxylic acid hydrazides and carbon disulfide cyclize very readily to Zl4-l,3,4-oxadiazoline-2-thiones (LXXXIII) (see Section II.7). The intermediates, the acyl- or benzoyl-dithiocarbazic acids may, however, also be isolated and reacted with alkyl halides to give S-alkyl dithiocarbazates (LXXXVIIIa) which also cyclize easily either to thiadiazoline or oxadiazoline rings according to the reaction circumstances (see Section II.7). 

The palladium-catalyzed carbonylation reaction with aryl halides is a powerful method for generating aromatic amides, hydrazides, esters, and carboxylic acids... 

Hydrazides (s. a. Carboxylic acid hydrazides) reduction with borane 26,56 Hydrazine (s. a. Wolff-Kishner reduction) 26,15 reaction with dicarboxylic acid anhydrides 8, 482... 

One of the most commonly used methods to obtain 2-amino-l, 3,4-thiadiazolines is the heterocyclization of thiosemicarbazides. An efficient one-pot synthesis of 2-amino-l,3,4-thiadiazoles 125 features the in situ formation of thiosemicarbazides 123 by the reaction of carboxylic acid hydrazides 121 with trimethylsilyl isothiocyanate (TMSNCS) 122, followed by cyclodehydration of thiosemicarbazides 123 under acidic conditions (13RSC6813). 

The amides and hydrazides of pyridine-carboxylic acids arc of some importance, though their chemistry is not marked by unusual properties. Nicotinamide is, of course, an important compound, and isonicotinic acid hydrazide (isoniazid) is an antitubercular drug. Substituted derivatives are used as antidepressants. In general, however, these compounds show normal chemical behaviour. The amides undergo hydrolysis, dehydration and Hofmann bromination without difficulty. Their reduction has been much studied as a route to pyridine aldehydes. The Sonn-Muller reduction is not very satisfactory in this series, but the McFadyen-Stevens reaction is useful . Nicotinic acid diethylamide gives only poor yields of the aldehyde upon reduction with lithium aluminium hydride, but yields from the methyl-phenylamide are high. Most satisfactory is the reduction of nicotinic acid dimethylamide with lithium diethoxyaluminium hydride . 

Thiazole carboxylic acid hydrazides were prepared in a similar way (444, 445). Thus by refluxing thioacetamide or thiobenzamide with y-bromoaceto acetic ester arylhydrazones (83) for several hours in alcohol the 4-carboxythiazole derivatives (84) listed in Table II-ll were obtained (Scheme 36) (656). This reaction is presumed to proceed via dehydration of the intermediate, thiazoline-S-oxide. 

A.ldehyde Syntheses. Aromatic (Ar) carboxylic acids are reduced to the corresponding aldehydes by a sequence of steps known as the McFadyen-Stevens reaction. The acid is converted to the hydrazide, derivatized with benzenesulfonylchloride, then decomposed to the aldehyde in hot glycol in the presence of a base ... 

Carboxylic acid hydiazides are prepared from aqueous hydrazine and tfie carboxylic acid, ester, amide, anhydride, or halide. The reaction usually goes poody with the free acid. Esters are generally satisfactory. Acyl halides are particularly reactive, even at room temperature, and form the diacyl derivatives (22), which easily undergo thermal dehydration to 1,3,4-oxadiazoles (23). Diesters give dihydtazides (24) and polyesters such as polyacrylates yield a polyhydrazide (25). The chemistry of carboxyhc hydrazides has been reviewed (83,84). 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

Reaction of benzimidazole-2-carboxylic acid hydrazide 590 with carbon disulfide gave triazine 591 (86JPR515) (Scheme 121). 

The acyl azide intermediates are prepared either by reaction of sodium azide with a reactive acylating agent or by diazotization of an acyl hydrazide. An especially convenient version of the former process is treatment of the carboxylic acid with ethyl chloroformate to form a mixed anhydride, which then reacts with azide ion.265... 

Most proteins contain an abundance of carboxylic acid groups from C-terminal functionalities and aspartic and glutamic acid side chains. These groups are readily modified with bis-hydrazide compounds to yield useful hydrazide-activated derivatives. Both carbohydrazide and adipic acid dihydrazide have been employed in forming these modifications using the carbodi-imide reaction (Wilchek and Bayer, 1987). 

Hydrazide groups can react with carbonyl groups to form stable hydrazone linkages. Derivatives of proteins formed from the reaction of their carboxylate side chains with adipic acid dihydrazide (Chapter 4, Section 8.1) and the water-soluble carbodiimide EDC (Chapter 3, Section 1.1) create activated proteins that can covalently bind to formyl residues. Hydrazide-modified enzymes prepared in this manner can bind specifically to aldehyde groups formed by mild periodate oxidation of carbohydrates (Chapter 1, Section 4.4). These reagents can be used in assay systems to detect or measure glycoproteins in cells, tissue sections, or blots (Gershoni et al., 1985). 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

The reactions of hydrazides with the respective carboxylic acids afforded oxadiazole derivatives 123 <1996JME2753>, 124 <2000BML1645>, 125 <2003JFC163>, and 126 <2004EJM535>. The reactions... 

---