Acid amides Dehydration

Dehydration of the corresponding acid amides. This process usually requires phosphorus pentoxide (correctly termed phosphoric anhydride) as a dehydrating agent. 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

A series of N-substituted narceine amides (Section III,D,1) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the ( )-narceine imide (117) type (100). Similar transformations were performed in the hydrastine series (101). JV-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (Z)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5). 

The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113) (5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111) 121). Narceine amide (149) was prepared from (Z)-narceine enol lactone (101) in likewise fashion 100,122) and dehydrated to narceine imide (116). A large number of N-alkylated narceine amides was synthesized from (Z)-narceine enol lactone (101) and primary amines by Czech investigators for... 

A carboxylic acid cannot be directly converted to an acid amide by the action of an amine. Hence the need of a dehydrating agent like DCC. The acid is converted to a compound with a better leaving group. 

Alkynenitriles, RC=CC=N, are generally prepared by dehydration of acid amides. RC=CC(=0)NH2, with phosphorous pentoxide. For HC=CC=N and NsCChCChN [130] this is the only available method it requires the previous synthesis of the carboxylic esters and their conversion into the acid amides. In principle it should be possible to prepare these useful... 

In contrast, the isourea-mediated p-elimination method from Thr peptides gave a mixture of Z- and E-isomers in a 3 2 ratio. 104 Similarly to AAla, peptides containing AAbu can also be synthesized by N-hydroxylation/dehydration 147 or by N-chlorination/dehydrochlorina-tion. 122-124 Another method, reported by Smelka et al. 148 involves the synthesis of dipeptides 60 with a C-terminal AAbu by condensing the Na-protected a-amino acid amides 58 with the a-oxo acid 59 (Scheme 20). The ratio of Z/E-isomers is 10 1. We have used Miller s method to prepare peptides containing AAbu. 351... 

Dehydration of pyridine-3-carboxylic acid amide (Nicotinamide) Dehydration of nicotinamide was carried out at different temperatures using conditions similar to those employed for benzamide. The results are shown in Fig.4. The reaction followed zero order kinetics and rate of reaction is very comparable to that of dehydration of benzamide. The kinetic constants are given in Table 2. In contrast with benzamide dehydration of nicotinamide in the absence of catalyst was negligible. 

The latter, on reaction with methylamine yielded via the P-epoxide 373, the trans-a aminoalcohol 374, which was N-acylated to the amide 375. Acid-catalysed dehydration of the tertiary alcohol 375, led to the olefin 375, from which the key radical precursor, the chlorothioether377 was secured in quantitative yield by reaction with N-chlorosuccinimide. In keeping with the earlier results recorded for structurally related compounds, 377 on heating in the presence of ruthenium dichloride and triphenylphosphine also underwent a 5-exo radical addition to generate the cyclohexyl radical 378 which recaptured the chlorine atom to furnish the a-chloro-c/5-hydroindolone 379. Oxidation of thioether 379 gave the corresponding sulfoxide 380, which on successive treatment with trifluoroacetic anhydride and aqueous bicarbonate led to the chloro-a-ketoamide 381. The olefin 382 resulting from base induced dehydrochlorination of 381, was reduced to the hydroxy-amine 383, which was obtained as the sole diastereoisomer... 

Ferrini and Marxer65 have recently shown that vinylene carbonate reacts with primary amides, in the presence of polyphosphoric acid, to yield 2-substituted oxazole derivatives. Yields are low (2-34%), and phenoxy- and phenyl-acetamide, p-methylbenzamide, and salicylamide do not give oxazole derivatives. Although the reaction has been interpreted according to Scheme 3, the nucleophilic attack of a nitrile molecule (from the amide dehydration), with a nitrilium salt as intermediate (Scheme 4), cannot be excluded.06... 

Fig. 7.2. Phosphorus pent-oxide-mediated dehydration of nicotinic acid amide (A) to nicotinic nitrile (B) with the reagent forming polyphospho-ric acid (HP0 )r...

Fig. 7.4. Triftuoromethane-sulfonic acid an hydride/pyridine-mediated dehydration of primary carboxylic acid amides (A) to give the corresponding nitriles (B) with the reagents converting into pyridinium trifluormethanesulfonate pyrH F3C-S03 .

Hemiaminals are available from HFA and amines. A series of similar reactions has been carried out with ammonia (187,189), amines (189), aliphatic, aromatic (258), and fluoroaliphatic acid amides (169). The hemiaminals 95 can be dehydrated with phosphorus oxychloride in pyridine to form 2-hexafluoropropaneimines 96 (187). 

Substituted succinic anhydrides, and related anhydrides are formed under acidic conditions. Dicarboxylic acids are dehydrated with acetyl chloride, trifluoroacetic anhydride, or sulfuric acid (hydrolysis of amide and condensation). ... 

Amides - nitriles. Primary acid amides are dehydrated to nitriles by treatment with titanium tetrachloride and a base (triethylamine, N-mcthylmorpholine) in THF at 0°. Yields range from 65 to 95%. 

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. 

Dehydration of23 diaUa xycarboxylic acid amides... 

There are other applications of these derivatives. For example, imines can be reduced to amines (equation 1), oximes can undergo rearrangement under strongly acidic (or dehydrating) conditions to form amides (equation 2), and the treatment of tosylhydrazones with strong bases can provide an excellent method for reductive elimination to form alkenes (equation 3). ... 

Semiplenamides A 359 to G 365, a series of new anandamide-like fatty acid amides, were isolated from a 1997 Papua New Guinea collection of the marine cyanobacterium Lyngbya semiplena, and all these new metabolites displayed toxicity in the brine shrimp model system. Only semiplenamides A 359, B 360, and G 365 showed weak affinity for the rat cannabinoid CBl receptor. Semiplenamide A 364 was also a moderate inhibitor (IC50 = 18.1 pM) of the anandamide membrane transporter (AMT). Novel 5y -aldol/dehydration methodology was developed for the stereoselective synthesis of the core ( )-a, P-unsaturated amide functionality of this class of natural product, and employed for the efficient synthesis of semiplenamide... 

That the amide might be dehydrated by the sulfuric acid reaction mixture seems to be ruled out by the fact that benzamide shows a molar freezing point depression of two in sulfuric acid solution. Dehydration would cause a molar freezing point depression of four. Accordingly, it seems more likely58 that dehydration of the intermediate XC occurs before rearrangement since a series of steps similar to those outlined in equations 25 to 29 would lead to the nitrile directly ... 

Esters are cleaved to the acid chloride and the alkyl chloride, acid amides are dehydrated to nitriles. Yields for the most part are satisfactory. 

Since, as has just been done, the acid-amide may be made by dehydrating the ammonium salt of an acid, thus, in a single operation the nitrile may be obtained directly from the ammonium salt, if it is treated with a powerful dehydrating agent, e.g. ammonium acetate heated with phosphoric anhydride ... 

The thiadiazoles are formed during the acid catalyzed dehydration of (XCa) or (XCb) which are themselves the reaction products of an intramolecular attack of the thioxo group on the carbonium ion (LXXXIX) that is formed by the protonization of the amide carbonyl function (LXXXVIIIa). 

Monomethyl phthalate, BOP, ZnCB, DIPEA, CH3CN, sonication, 16 h, 53-95 % yield. These conditions result in racemization free protection of amino acid amides and esters. PyBOP can also be used as a dehydrating agent. ... 

---