2.3- Benzoxazepine derivative

The Meisenheimer rearrangement of substituted tetrahydroisoquinoline IV-oxides <1996CHEC-II(9)183> has been further exploited as a convenient approach for the synthesis of 2,3-benzoxazepine derivatives <1997MI13>. 

Kamei K, Maeda N, Nomura K, Shibata M, Katsuragi-Ogino R, Koyama M, Nakajima M, Inoue T, Ohno T, Tatsuoka T. Synthesis, sar studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-htla receptor agonists with neuroprotective effect discovery of piclozotan. Bioorg Med Chem 2006 14 1978-1992. 

Via (N—C—C—C—O—C—C) intermediates (type c). Salicylamide (351 R = H) can be converted to 1,4-benzoxazepine derivatives, e.g. its reaction with 2-chloropheny-lacetic acid gives (351 R = CH(Ph)C02H) which on treatment with acetyl chloride cyclizes to the 3,5-dione (352). Similarly reaction of (351 R = H) with phenacyl bromide gives (351 R = CH2COPh) which undergoes acid-catalyzed cyclization to give (353). 

Treatment of the 1,2,4-triazino[5,6-methyl iodide affected methylation and intramolecular rearrangement to give the mesoionic l,2,4-triazolo[l,6-c] quinazolinone (632) (73MI1). 

The reaction of deprotonated 2-aminophenol 115 with an alkynyl-substituted Fischer carbene 277 gave a cyclic complex 279 in 40% yield, most probably via an intermediate adduct 278 (X = 0). On the other hand, complex 280, obtained from 115 and 277 without base, was heated in tetrahydrofuran to afford benzoxazepine derivative 281 (38%) and benzoxacinone 282 (36%) with reverse regiochemistry (Scheme 49) <2003CEJ4943>. 

The acid-catalysed reaction of acetonitrile with either the benzo-l,2,3-dioxathepane 2-oxide 308 [01JGU150] or the dihydro-2,3,4-benzodioxasilepine 308a [01JGU295] affords the benzoxazepine derivative 309, although in very low yield from the latter alkaline hydrolysis then yields the amino alcohol 310. 

Selected spectroscopic data have also been reported for the 1,3-benzoxazepine derivative (14) <90HCA739>. In this case, the signal at 6 7.57 in the H NMR spectrum was assigned to H-5 in the parent system, 1,3-benzoxazepine, H-5 and H-4 appeared as doublets (/=8 Hz) at S 6.57 and S 6.25, respectively <79TL376l>. 

A ring construction approach has also been used to make the 4,5-dihydro-3,l-benzoxazepine derivative (56), utilizing electrophilic attack on the allylic double bond in (55), followed then by intramolecular nucleophilic attack by the amide oxygen on the intermediate carbocation (Equation... 

Photolysis of the substituted quinoline A -oxide (82) afforded the 3,1-benzoxazepine derivative (83), as a stable solid (Equation (10)) <79CPB946>. 

F. Ji, M.-F. Lv, W.-B. Yi, C. Cai, Adv. Synth. Catal. 2013,355, 3401-3406. Synthesis of 1,4-benzoxazepine derivatives via a novel domino aziridine ring-opening and isocyanide-insertion reaction. 

J. Shirai, T. Matsumoto and I. Kamo, Benzoxazepine Derivatives and Use Thereof, EP2123644 (Al), 25 November 2009. 

Matyus et al. described a cascade Knovenagel/1,5-hydride transfer/cyclization reactions of 4-aryl-2-phenyl-1,4-benzoxazepine derivatives 19, which furnished fused 0,A -heterocycles 20 containing tetrahydro-l,4-benzoxazepine and tetrahydroquinoline moieties with high yields and diastereoselectivity (Scheme 9) [92]. Basically, under thermal conditions, the benzylidene intermediate I generated in situ... 

Scheme 14.21 1,4-Benzoxazepine derivative synthesis by domino aziridine ring-opening/...

Further, these newly synthesized products were evaluated as antioxidants and lipid peroxidation (LPO) inhibitors in vitro. One compound from both the groups, benzoxazepine and benzodiazepine, (R = Me) were found to be the most potent inhibitors of lipoxygenase and LPO, respectively. The amino substituent containing benzoxazepine derivative showed most encouraging antioxidant property. Benzodiazepine (R = R = 4-CIC6H4) derivative was also evaluated as anti-inflammatory agent in vivo. 

The parent 1,4-benzoxazepine is very unstable it and its simple derivatives have been reported only recently. 

The 3-phenyl derivative 3a was similarly obtained by cyclodehydration of O-phenacylsalicylam-ide.33 An analogous reaction of O-acetonylsalicylamide gives 3-methyl-l,4-benzoxazepin-5(4//)-one (3b).34 The 2-phenyl compound can also be obtained from the corresponding salicylamide derivative in 56% yield.420... 

The benzoxazepinone 2 is converted into 5-methoxy-l,4-benzoxazepine (8a) by trimethyl-oxonium tetrafluoroborate.32 An analogous reaction of 3-phenylbenzoxazepinonc 3 with tri-cthyloxonium tetrafluoroborate gives the 5-cthoxy derivative 8b. The thione 6 undergoes methylation at sulfur to yield the (methylsulfanyl)benzoxazepine 9.32... 

Nitration of 9-methylpyrido[2,3-(t][l,5]benzoxazepin-5(6//)-one with nitronium tetrafluoro-borate gives exclusively the 7-nitro derivative 3, which is reduced to the amine 4 with iron/acetic acid.41... 

Baeyer-Villiger oxidation of the anti-tumour alkaloid acronycine and its 2-nitro derivative, led to the chromeno[5,6-b][4,l]benzoxazepin-8-one 144 (R = H) and 144 (R = NO2) respectively <00NPL183>. 

Oxazolidin-5-ones (11.110) are structurally related to oxazolidines, combining the motifs of a lactone and an O-Mannich base. These derivatives have already been discussed in Sect. 8.7.5. However, they serve here as a transition to [3,1 ]benzoxazepin-4-ones as an example of potential prodrugs. Thus, [3,l]benzoxazepin-4-one derivatives (11.111, R = H or Me, R = H, Me, Et, or Ph) were prepared from diclofenac (11.112) [137]. These prodrugs were stable for at least a few hours in simulated gastric juice, but, when administered to rats elicited an anti-inflammatory response comparable to that of diclofenac. One compound (11.111, R = Me, R = Et) was even more active than diclofenac without producing the gastric mucosal injury (ulcers) caused in all rats by diclofenac itself. Here again, there was no indication of whether the mechanism of hydrolysis is chemical or enzymatic. 

As Scheme 120 shows, more benzoxazepines are available by aza-Wittig cyclization of o-acyloxy-2-azidoacetophenone (331). The benzoyloxy derivatives, however, eliminate triphenylphosphane oxide but afford an acyclic product (332) for steric reasons (90S455). 

Af-Phenylpyrrole generates a di-lithio derivative which after trapping with acetone and treatment with silica gel produces tetramethyl pyrrolo-benzoxazepine... 

The ester derivative of pyrrolo-benzoxazepine 403 (Scheme 84) has been transformed into ketone 404 with methyl lithium, while ester 406 was synthesized by esterification with acetyl bromide of alcohol 405, prepared by LAH reduction of 403 (1996JMC3435). 

Reactions of this type have been widely used for the synthesis of 1,5-benzoxazepines by the reactions of o-aminophenols and their derivatives with a variety of functionalized three-carbon chains. Thus reaction with 3-bromo-l-chloropropane gives (360) and reaction with 3-chloropropionyl chloride gives the analogous 4-oxo derivative. Similarly a,/3-unsatur-ated Icetones give (361), /3-ketoesters give (362), l,3-oxazolid-5-ones give (363), and the reaction of the sodium salt of N-methanesulfonyl-o-aminophenol with epichlorohydrin gives... 

A-Acyl-l,3,4,5-tetrahydro-2,1 -benzoxazepines (268) are synthesized from the A-chloro derivatives (267). The reaction proceeds via initial ipso attack followed by 1,2-carbon migration (84JCS(P1)2255, 87T2577, 90T7247). 

Benz-fused analogues are also covered in this chapter. The possible benz-fused parent systems are 2,1-benzothiaze-pine 4, 1,2-benzoxazepine 5, 3,2-benzoxazepine 6, 2,3-benzoxazepine 7, 2,1-benzothiazepine 8, 1,2-benzothiazepine 9, 3,2-benzothiazepine 10, and 2,3-benzothiazepine 11 derivatives of some of these systems are included. A major reference series has reviewed seven-membered heteroarenes with two or more heteroatoms <1997HOU(E9d)299>, while the syntheses of benzoxazepines, including 2,3-, 3,2-, and 2,1-skeletons, have also been reviewed <1997MI1>. 

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