Amidines amide acetals

Bonds typically hydrolyzed include carboxylic and phosphoric esters, amides, acetals, amidines, as well as metal ion complexes. (When a nucleophilic substitution reaction uses the solvent as the nucleophile, the reaction is often referred to as solvolysis.)... 

It was found inadvisable to use more than four molecules of form-amide [ (47) when R = H] per molecule of anthranilic acid and the condensation produces best results when the mixture is heated at 120 -130°C for 2 hr followed by further heating at 170°-180 C for 2 hr. Other variants of this reaction involve the use of ammonium o-acylaminobenzoates, anthranilic acid in the presence of nitriles and acetic anhydride, o-acetamidonitrile with acetic anhydride or hydrogen peroxide, anthranilic esters and aliphatic or aromatic amides or amidines, isatoic anhydride with amides or amidines, and anthranilic esters with aryl iminochlorides in acetoned The mechanism proposed by Bogert and Gotthelf has had experimental supporR and is represented in Scheme 12. 

The reaction of chlorodiphenoxymethane with dimethylamine yields the amide acetal (459 equation 214). Dialkoxymethyl groups can be transferred by means of dialkoxyalkyltriethylammonium tetraflu-oroborate (460 equation 215) to primary amines and amides, amidines, secondary amines and amides once or twice to give amide acetals (461) and (462) Azodiazoles, e.g. (463) and (464) (Scheme 85), add to ketene dimethylacetal to give lactam acetals. ... 

Aluminum bromide, 10,42,140 Aluminum chloride, 10-15,140,357 Aluminum cyclohexoxide, 15 Aluminum hydride, 357 AluminumOII) iodide, 106 Aluminum isopropoxide, 15-16 Amberlite-15, 266 Amberiite IR 120, 267 Amide acetals, 527-528 Amides, 424,456 Amidines, bicyclic, 16-18 Amine oxides, 270 p-Aminoacetophenone, 18 Amino adds, 252, 273, 368 Aminoalkenylation, 95 4-Aminobenzoic add, 45 2-Amino-3-cyano-5-chloromethylpyrazine 1-oxide, 459... 

Rablen ° investigated carbonyl substituent effects by using a series of isodesmic reactions designed to separate resonance and polar effects. He found the oxygen tt contributions to be about 6 kcal/mol, as opposed to about 14 kcal/mol for nitrogen. The order of the polar effect is F > O > N > C, whereas that for the resonance effect is N > O > F. His analysis suggests that the stabilization in acetate (O donor) is about one-third resonance and two-thirds electrostatic. On the other hand, in amides and amidines, the order is reversed, roughly two-thirds resonance and one-third electrostatic. 

Triazines 5 with three different 2,4,6-substituents are conveniently prepared by cyclocondensation of acylamidines 4 with amidines [172]. Acylamidines result from amides and amide acetals. 

Amidines from amide acetals. N-Dimethyl-acetamide diethyl acetal added to a stirred suspension of 2-amino-6-carbethoxy-3-hy-droxy-4-pyrone in abs. acetone, and the product isolated after 3-4 hrs. N-(6-carbethoxy -3- hydroxy -4- pyron-2- yl)-N, N -dimethylacetamidine. 

Treatment of the intermediate with acetic anhydride affords the acetamide (57-2). Reaction of the product with a base leads to an attack of the nitrogen on the secondary side chain amide on the newly introduced amide carbonyl with the formation of the cychc amidine. There is thus obtained the antiarrhythmic agent actisomide (57-3) [59]. 

The initial synthetic approach to conivaptan HCl (1) employed by the Yamanouchi discovery group26 commenced with commercially available benzazepinone 10. Acylation of 10 with p-nitrobenzoyl chloride provided benzamide 11. Subsequent hydrogenation of 11 over palladium on carbon yielded aniline 12, which was in turn condensed with biphenyl-2-carbonyl chloride to provide bis(amide) 13. Bis(amide) 13 was subsequently heated with copper(II) bromide in boiling chloroform/ethyl acetate to furnish a-bromoketone 14. It is interesting that condensation of a-bromoketone 14 with acetamidine hydrochloride in the presence of potassium carbonate in boiling acetonitrile afforded not only the desired imidazobenzazepine product (1 53% yield, 2 steps) but also the related oxazolobenzazepine 15 (7% yield, 2 steps), which presumably resulted from nucleophilic attack of the benzazepinone oxygen on the amidine moiety followed by loss of ammonia. Separation of oxazolobenzazepine byproduct 15 from imidazobenzazepine 1 by silica gel chromatography followed by treatment of the purified imidazobenzazepine free-base with hydrochloric acid then provided conivaptan HCl (1). 

Simultaneously, Woodward and co-workers (21) confirmed structure X for the alkaloid by chemical methods. They first recorded the caly-canine synthesis already mentioned. The intermediate tetraaminodi-aldehyde, first postulated by Robinson and Teuber (10), was also the basis for their structural speculations. The mercuric acetate oxidation product (dehydrocalycanthine) of Marion and Manske (13), formed by loss of two hydrogens, was smoothly converted by the action of alcoholic alkali into methylamine, and the resulting amide alcohol was written as XI. It was concluded that dehydrocalycanthine is an ene-imine, the relevant portion of the molecule being shown as XII. Other structures derivable from the tetraaminodialdehyde would more probably generate on amidine, and this would be impossible with X because of steric strain at a bridgehead double bond. 

---