Dibenzazepine

In systems of proper geometry, nucleophiles within a side chain may be well connected for attack on ring atoms. For example, an aminomethyl group at the 5-position of a dibenzazepine-2-one was found to attack the carbonyl group (Section 5.16.3.5.2). Such reactions should be possible in rings of any size. 

Dibenzazepin-2-one, 5-aminomethyl-transannular nucleophilic attack, 7, 25 Dibenzazepin-2-ones tautomerism, 7, 503 Dibenz[6,dJazepinones phenanthridinones from, 2, 507 synthesis, 7, 530 Dibenz[6,d]azepinones, hydrosynthesis, 7, 536 Dibenz[6,eJazepinones synthesis, 7, 529, 530 5H-Dibenz[c,eJazepin-7-ones synthesis, 7, 529... 

Protoporphyrin-IX, N-methyl-, 4, 396 Protoporphyrins, 4, 382 photooxygenation, 4, 402 Prototropic tautomerism polyheteroatom six-membered rings, 3, 1055 Prozapine properties, 7, 545 Pschorr reaction carbolines from, 4, 523 dibenzazepines from, 7, 533 dibenzothiophenes from, 4, 107 phenanthridines from, 2, 433 Pseudilin, pentabromo-synthesis, 1, 449 Pseudoazulene synthesis, 4, 526 Pseudobases in synthesis reviews, 1, 62 Pseudocyanines, 2, 331 Pseudothiohydantoin synthesis, 6, 296 Pseudouracil structure, 3, 68 Pseudoyangonin IR spectra, 3, 596 Pseudoyohimbine synthesis, 2, 271 Psicofuranine biological activity, 5, 603 as pharmaceutical, 1, 153, 160... 

Of the four dibenzazepines, 5//-dibenz[h,d]azepine (19), 5//-dibenz [h,e]azepine (20), 5//-dibenz[h,/]azepine (21), and 6//-dibenz[c,e]azepine (22), only 21 is known as such (74CRV101 84JHC197), while 22 exists as the nonaromatic 5//-tautomer (81LA240). 

A solution of 5-(3-toluene-p-sulfonvloxvpropvl)dibenzazepine (9.2 g) and 1-(2-hvdroxy-ethyDpiperazine (8.6 g) in anhydrous toluene (50 cc) is heated at boiling point under reflux for 4 hours. 

After cooling, distilled water (75 cc) is added. The aqueous phase is decanted. The toluene solution is washed with distilled water (25 cc) and then extracted with N-hydrochloric acid (40 cc). The hydrochloric acid solution is made alkaline to phenolphthalein with sodium hydroxide (d = 1.33). The base which separates is extracted with chloroform (50 cc). The chloroform solution is dried over anhydrous sodium sulfate and then evaporated to dryness. There are obtained 5-[3-(4-/3-hydroxyethylpiperazino)propyll-dibenzazepine (7.95 g),thedi-hydrochloride of which, crystallized from ethanol, melts at about 210°C. 

Similar problems arise with the four isomeric dibenzazepines 4-7. since only 5//-dibenz-[6,d]azepine (4) and 5//-dibenz[/>,./]azepine (7) can be drawn as fully benzenoid ring structures. Even so, 5//-dibenz[/ ,t/]azepines are rare and are known only as the 7-oxo derivatives.4 In contrast, 5//-dibenz[6,e azepine (5) and 6//-dibenz[r,t>]azepine (6) exist only as the 11//- 5a and 5H- 6a isomers, respectively. In fact, there is no chemical or spectrosopic evidence for the isomerization of 5//-dibenz[e,e]azepine,5 or its 6-oxide,6 to the 6//-dibenz[r, e]azcpinc isomer (6). In addition, an X-ray crystal structure of 7-methoxy-5//-dibenz[e,e]azepine supports unequivocally the benzenoid rather than the quinonoid form.7 9//-Tribenz[6,d /]azepine (8) has only recently been prepared.8... 

Thermolysis of 2,2 -bis(azidomethyl)biphenyl (33) in an inert solvent produces a mixture of phenanthridine (21 %) and 5//-dibenz[c,e]azepine (29% bp 138—140°C/0.08 Torr). The yield of dibenzazepine is increased to 57% by carrying out the thermolysis under reduced pressure over glass beads.86 The mechanism of this unique reaction has been discussed. 

There are no methods for the preparation of benz- and dibenzazepines by ring transformation of other seven-membered rings. Interconversions between tautomeric forms of these systems are dealt with in Section 3.2.1.5.8. 

The formation of dibenzazepines by dehydrogenation of their hydro derivatives is much more common than with the benzazepines. 

A detailed study of the dehydrogenation of 10.1 l-dihydro-5//-benz[6,/]azcpinc (47) over metal oxides at 550 C revealed that cobalt(II) oxide, iron(III) oxide and manganese(III) oxide are effective catalysts (yields 30-40%), but formation of 5//-dibenz[7),/]azepinc (48) is accompanied by ring contraction of the dihydro compound to 9-methylacridine and acridine in 3-20 % yield.111 In contrast, tin(IV) oxide, zinc(II) oxide. chromium(III) oxide, cerium(IV) oxide and magnesium oxide arc less-effective catalysts (7-14% yield) but provide pure 5H-dibenz[b,/]azepine. On the basis of these results, optimum conditions (83 88% selectivity 94-98 % yield) for the formation of the dibenzazepine are proposed which employ a K2CO,/ Mn203/Sn02/Mg0 catalyst (1 7 3 10) at 550 C. 

Remarkably few examples of the electrophilic substitution of benz- and dibenzazepines by heterofunctional groups (e.g., N02 and halogen) have been reported. 

Tautomerism of benz- and dibenzazepines is much less common than with monocyclic azepines since, as pointed out in the introduction, with most of these bi- and tricyclic systems the number of tautomers in which the carbocyclic ring retains its benzenoid character is severely restricted. Rare examples in the benzazepine series are the thermal isomcrizations of butyl l-aryl-5//-2-benzazepine-5-carboxylates 1 (X = H, Cl, F) to their 3//-tautomers 2,7S and of 3-ethoxy-1-phenyl-5//-2-benzazepines 3 (R = Me, Bn) to the 1//-tautomers 4.240... 

Oxidation of 5//-dibenz[7>,/]azepine (12) with Fremy s salt [ON(S03K)2] yields a mixture of acridine-9-carbaldehyde (13) and 2//-dibenz[A,/]azepin-2-one (14).215 The dibenzazepin-2-one 14 is also obtained in 46% yield with bis(trifluoroacetoxy)pentafluoroiodobenzene [PhI(OCOCF3)2] in acetonitrile as the oxidant.221... 

The cycloaddition of alkynes and alkenes to nitrile oxides has been used in the synthesis of functionalised azepine systems <96JHC259>, <96T5739>. The concomitantly formed isoxazole (dihydroisoxazole) ring is cleaved by reduction in the usual way. Other routes to 1-benzazepines include intramolecular amidoalkylation <96SC2241> and intramolecular palladium-catalysed aryl amination and aryl amidation <96T7525>. Spiro-substituted 2-benzazepines have been prepared by phenolic oxidation (Scheme 5) <96JOC5857> and the same method has been applied to the synthesis of dibenzazepines <96CC1481>. 

There is no shortage of these. The established ones belong to four main chemical groups (Fig. 17.1), the phenothiazines, thioxanthenes, butyrophenones and dibenzazepines. 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

It is of interest to note that attachment of a basic side chain on carbon of an isomeric dibenzazepine affords a compound in which anticholinergic activity predominates, elantrine (50). Reaction of anthra-quinone (45) with the Grignard reagent from 3-chloro-N,N-dimethylaminopropane in THF in the cold results in addition to but one of the carbonyl groups to yield hydroxyketone 46. This is then converted to oxime 47 in a straightforward manner. Treatment of that intermediate with a mixture of phosphoric and polyphosphoric acids results in net dehydration of... 

Competitive inhibitors of GST Pl-1 fall under two categories non-glutathione-and glutathione-based compounds. The former group covers a broad range of chemical structures such as tricyclic-based dibenzazepines, polyphenolic natural products, alkaloids, pyrimethamine, and dyes. The latter group, as its name indicates, covers compounds whose main structure or backbone is that of GSH. 

Tricyclic antidepressants such as imipramine (25), clomipramine (26), amitriptyline (27), and doxepine (28) were found to be weak inhibitors of GST Pl-1 in vitro. Inhibition of GST Pl-1 was enhanced with the introduction of a chloro group on the dibenzazepine ring (25 40% inhibition at 15 mM 26 70% inhibition at 10 mM). The same result was observed with the substitution of an oxygen for a carbon in the heptadiene ring (27 18% inhibition at 10 mM 28 48% inhibition at 15 mM) [35],... 

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