Carboxylic acids, amides prepared

TABLE XXVn. l-Methyl-l,6-dihydropyrazolo[3,4-c]pyridin-7-ones Prepared by Cyclization of Vicinal 4-(Alkyn- l-yl)pyrazole-5-carboxylic Acid Amides [90IZV2089]. 

Many procedures for the formation of carboxylic acid amides are known in the literature. The most widely practiced method employs carboxylic acid chlorides as the electrophiles which react with the amine in the presence of an acid scavenger. Despite its wide scope, this protocol suffers from several drawbacks. Most notable are the limited stability of many acid chlorides and the need for hazardous reagents for their preparation (thionyl chloride, oxalyl chloride, phosgene etc.) which release corrosive and volatile by-products. Moreover, almost any other functional group in either reaction partner needs to be protected to ensure chemoselective amide formation.2 The procedure outlined above presents a convenient and catalytic alternative to this standard protocol. 

Activated NHS esters of carboxylic acids are prepared by reacting the acid with NHS in the presence of DCC (Table 4, Figure 16). A-Hydroxysuccinimide esters are stable when kept under anhydrous and slightly acidic conditions, and they react rapidly with amino groups to form an amide in high yield. 

The Alper group [163] reported on a highly efficient double carbohydroamination for the preparation of a-amino carboxylic acid amides 6/1-345, starting from aryl iodides and a primary amine 6/1-344, in usually high yield (Scheme 6/1.88) both, aryl iodides with electron-donating and electron-withdrawing groups can be used. 

The instability of primary nitramines in acidic solution means that the nitration of the parent amine with nitric acid or its mixtures is not a feasible route to these compounds. The hydrolysis of secondary nitramides is probably the single most important route to primary nitramines. Accordingly, primary nitramines are often prepared by an indirect four step route (1) acylation of a primary amine to an amide, (2) A-nitration to a secondary nitramide, (3) hydrolysis or ammonolysis with aqueous base and (4) subsequent acidification to release the free nitramine (Equation 5.17). Substrates used in these reactions include sulfonamides, carbamates (urethanes), ureas and carboxylic acid amides like acetamides and formamides etc. The nitration of amides and related compounds has been discussed in Section 5.5. 

Carboxylic acids are prepared hy the hydrolysis of acid chlorides and acid anhydrides, and acid- or hase-catalysed hydrolysis (see Section 5.6.1) of esters, primary amides and nitriles (see Section 5.6.1). 

An alternative to the azlactone procedure for the preparation of short-chain dehydropeptides 19 is offered by the direct condensation of an a-oxo acid 17 on heating with one equivalent of a carboxylic acid amide or by the treatment of an a-oxo acid 17 with a nitrile in the presence of dry HC1 gas (Scheme 6). If the former reaction proceeds with the condensation of two molecules of amide per molecule of a-oxo acid, then the corresponding a,a-bis(acylamino) aliphatic acid 18 is formed, which on warming with acetic acid results in partial deamidation with formation of the corresponding dehydropeptide 19. 

Substituted aromatic carboxylic acid amides of the type ArCONHR and Ar-CONR2 are only slowly attacked by aqueous alkali and are characterised by hydrolysis under acidic conditions 70 per cent sulphuric acid (prepared by carefully adding 4 parts of acid to 3 parts of water) is the preferred reagent. Use the general procedure which has been outlined on p. 1229 characterise the acidic and basic components. 

Benzyl-6-oxoperhydropyrido[2,l-c][l,4]oxazine-4-carboxylic acid was prepared from the 7-unsubstituted derivative by alkylation with PhCH2Br in the presence of lithium bis(trimethylsilyl)amide in THF at -78°C (96MIP8). The reaction of 1,3, 4,6,7,116-hexahydro[l,4]thiazino[3,4-a]-isoquinolin-4-one (45) with a Vielsmeier-Haack reagent afforded 3-formyl-4-chloro-l,6,7,llh-tetrahydro[l,4]thiazino[3,4-a]isoquinoIine (111) (81CP 1101857). 

The user should bear in mind that the pairs of functional groups alcohol, ester carboxylic acids, ester amine, amide and carboxylic acid, amide can be interconverted by simple reactions. Compounds of the type RCH(OAc)CH2OAc (ester-ester) would thus be of interest to anyone preparing the diol RCH(OH)CH2OH (alcohol-alcohol). 

Final purification by use of metal complexes was also applied in the syntheses of the ligands XS4—H4. These ligands exclusively contain thiolate donors and were prepared by Hahn et al. (23) using 2,3-dimercaptobenzoic acid as starting material (Scheme 8). Isopropyl or benzyl protection of the thiol functions, conversion into the acyl chlorides, reaction with a,oo-diamines, and deprotection of the sulfur atoms enabled the connection of two 1,2-benzene-dithiol units via carboxylic acid amide bonds. 

Preparation of 5-benzyl-ll-hydroxy-5H-benzo[b]carbazole-l-carboxylic acid amide... 

The preparation of Step 1 co-reagent, 4-amino-5-pyridine-3-yl-lH-pyrazol-3-carboxylic acid amide, (I), was provided by the author and illustrated in Eq. 2. 

The a-chloro-a-sultinyl ketone 20 was prepared from methyl benzoate and chloromethyl phenyl sulfoxide 19 after in situ a-lithiation. Compound 20 is dimetallated by KH and f-BuLi to give the keto dianion 21, which is converted into a potassium/lithium ynolate 22 (equation 7). The resulting metal ynolates are converted into thioesters, carboxylic acids, amides and esters (Section V). 

Carboxylic acids, amides, and hydrazides were prepared from esters 412, 456, and 457 (77MI1 81BEP883216 84H2285). 

The requisite W-methoxy-W-methylamides may be pre >ared from acid chlorides by employing a slight excess of the commercially available W,G-dimetiiylhydroxylamine hydrochloride in the presence of pyridine. They have also been pre >ared from acylimidazoles and from mixed anhydrides of carboxylic acids. Once prepared, these systems X)ssess stability equivalent to that of most tertiary amides and, in... 

Removal of water by distillation shifts the equilibrium point to favor formation of the amide. For preparation of the amide by this method the ammonium salt of the carboxylic acid is prepared and dehydrated, melted, allowed to cool, and then pulverized. The powdered material is placed in a distilling flask and heated. Another method is to add solid ammonium carbonate to the carboxylic acid, and distill directly. 

A still unresolved problem is the structure of the often used adducts from phosphorus trihalides and carboxylic acid amides, which might be described by the formulae (8) or (9). With the aid of in situ generated adducts of acid amides and PX3 amidines, isonitriles, quinazolinones, alkyl chlorides, aminomethylenediphosphonic acids, carbamoyl halides, triformylaminomethane, 1,3,4-oxadia-zoles, sulfides (from sulfoxides), nitriles (from primary nitro compounds)" and bromoqui-nolines (from methoxyquinolines)" have been prepared. 

Phosgene and tertiary carboxylic acid amides form very labile adducts (17 equation 6 not yet isolated or used for preparative purposes as such), which decompose with loss of CO2 very rapidly to give amide chlorides (see Section 2.7.2.2.1.i). Decomposition with evolution of CO2 is a common fate of primary adducts of carbonic acid chloride derivatives. Primary adducts from DMF and chloroformic acid esters (18), for example, decompose immediately to give alkoxymethyleneiminium chlorides, which react to give alkyl chlorides and DMF (equation 7). Adducts (19) from secondary and tertiary carboxamides... 

The preparation of acyliminium ions is not restricted to aldehyde or ketone derivatives as starting materials, but can also use the more highly oxidized carboxylic acid amides as precursors, e.g. reduction of imides (66) affords (67 Scheme 33). For constitutionally unsymmetrical imides, regiocontrol can be achieved in many cases by the choice of the appropriate hydride-transfer reagent. ... 

The thia2olidin-5-one-2-thiones (CLXIII) which can be prepared by refluxing 5-imino thiazohdine-2-thiones (CLXII) with acids (method A), can also be obtained directly from carbon disulfide and a-amino carboxylic acid amides (CLXXVIII) (method B). 

---