TV-Acyl Derivatives

Marked differences in the UV spectra of 1-alkyl- and l-acyl-dibenz[f>,/]azepines support the view that the TV-acyl derivatives are best described as the polar canonical dibenz-azepinium mesomers (32), in which the nitrogen lone pair is delocalized onto the oxygen,... 

The oxidation of AT-substituted 5/f-dibenz[6,/]azepines with MCPBA is complex and depends upon the nature of the TV-substituent. TV-Acyl derivatives do not form the AT-oxide but suffer epoxidation of the 10,11-bond. A/ -Aryl derivatives undergo hydroxylation of the phenyl ring, whereas AT-alkyl congeners, with the exception of the AT-methyl compound, yield mixtures of diphenylamines and acridones. The N-oxide is obtained from the Af-methyl derivative along with ring-opened and ring-contracted products (81CPB1221). 

The first representative of this group, a /3-acylamino-a,/8-unsaturated ester, yielded 67 through pyrolysis in diphenyl ether205-207 [Eq. (53)]. A modification of this method used a Schiff s base instead of die TV-acyl derivative of a j8-amino-a,j8-unsaturated acid.208 Similarly, enamino esters react with benzoyl chloride to yield 6//-l,3-oxazines.209... 

Yata, N., et al. 1985. Enhanced rectal absorption of sodium ampicillin by TV-acyl derivatives of collagen peptide in rabbits and rats. J Pharm Sci 74 1058. 

Coumarins, too, fluoresce, notably when an electron-releasing group is present at the 7-position. For example, TV-acyl derivatives of some 7-aminocoumarins serve as fluorescent markers for the detection of proteinases (80MI22403). Coumarins show a propensity to absorb UV light and this results in a number of applications. A particularly simple illustration is the use of umbelliferone, 7-hydroxycoumarin, in sun-screen lotions. 

The coupling protocol proved successful for all the TV-acyl derivatives tested in aqueous media, even if the decarbonylation processes were too fast, as shown in Scheme 8.9. 

TV-Acyl derivatives of heterocycles can often be quaternized by hard alkylating agents, such as trialkyloxonium fluoroborates ° or methyl fluorosulfonate. The quaternary salt is not usually isolated, but N-alkylated derivatives are obtained whose structures are generally different from those obtained by alkylation of anions (Sections IV,C,2). This method, due to Olofson and Kendall, has been used with success in azapentalenes [Eqs. (34) and (35)1, where the products 384 and 385 are different from those obtained by alkylation of the anions 361 and 364, respectively (Scheme 16). 

The pharmacologically active and commercially important 5//-dibenz[/>,/]azepines 40 are available by base-catalyzed dehydrobromination of their 5-acyl- 10-bromo-l 0.11-dihydro derivatives 38,118 followed by hydrolysis of the isolable tV-acyl compounds 39 29.119-121... 

TV-Acyl indoles derived from amides have been employed for the conversion of lactones into protected hydroxyacids. Thus, (chloromethyl)alumi-num 2-(2-propenyl)anilide reacts (120) with 1,4- and 1,5-lactones, as for example per-O-terZ-butyldimethylsilyl-D-ribono-1,4-lactone (104), to afford hydroxyamides. After protection of the free hydroxyl group, these amides were converted by ozonolysis into TV-acyl indoles, 105, which were readily saponified to the acid 106. 

As with mass spectral data, detailed information of the UV spectra of azepines is confined to a few sources and for information on particular systems recourse has to be made to the primary literature. Available are compilations of UV data on TV-acyl- and TV-sulfonyl-1//-azepines (B-69MI51600,69JOC2866), benzazepines (74AHC(17)45), dibenz[T>,/]azepines and their 10,11-dihydro derivatives (74CRV101), and the azatropolones (13) and their 1,5-dihydro derivatives (79H(12)1427). 

Since TV-acylation is a reversible process, it has allowed the regiospecific alkylation of, for example, imidazoles to give the sterically less favored derivative. This principle is illustrated in Scheme 12 (80AHC(27)24l). 

When the derivatives are required to convert to the parent 5-FU in vivo, appropriate substituents were introduced across the carbonyl groups in the chemical modification [20-25]. Though the first synthesis of acryloyl derivatives of 5-FU, which is the simplest polymerizable derivative, was done by Gebelein, the monomer has not been purified and collected [23]. In the present case, as shown in Scheme 2, silylated 5-FU was used instead of just 5-FU so as to give selectivity to the 1 TV-acylation similar to that of the acryloyl derivatives of thymine [9]. For the preparation of acryloyl-5-FU (AFU), methacryloyl-5-FU (MAFU) and / -vinylbenzoyl-5FU (VBFU), trimethylsilylated 5-FU (1) was allowed to react with acryloyl chloride, methacryloyl chloride and vinyl-benzoyl-chloride, respectively. The reaction was carried out in water-free acetonitrile solution after the addition of acid chloride at room temperature the solution was stirred for 30 min. This procedure afforded AFU in 16%, MAFU in 56%, and VBFU in 63% yield. 

Weaker hydrazine derived nucleophiles may also participate in the amination reaction as has been reported by H. Katayama.105 They found that TV-acyl hydrazines 63 underwent a clean intramolecular cyclization to give the desired indol[l,2-A]indazole derivatives 64 using DPEphos as the ligand. 

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