Synthesis of azepines

As shown for the aziridines, BETMIP (68) has proved to be useful in the synthesis of azepines (Scheme 118). Treatment with methylenephosphorane leads to a phosphonium salt which in turn is deprotonated with BuLi and cyclized with benzene-l,2-dialdehyde in a Wittig and aza-Wittig step to form benzazepine 326 (93JOC1987). 

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

The addition of allylmagnesium halides (2 equiv.) to 1,3-azadienes affords after in situ alkylation dihomoallylamines, which are useful intermediates in the synthesis of azepines or related heterocycles. Activation of the C=N moiety of aldimines by 1-benzotriazolyltrimethylsilane minimizes side reactions. The mechanism involves reversible addition of BtTMS (216) to the imine 217 followed by displacement of the benzotriazolyl group by a Grignard reagent (equation 148). ... 

The Beckmann and Schmidt reactions are applicable to the synthesis of azepines fused to other heterocyclic and carbocyclic systems, such as pyridoazepinones (70JA203, 76AP550, 78JHC249), indoloazepinones (78CB1780) and the 14v aromatic azabenzazulen-nones (204) (80BCJ3232). The general chemistry of azaazulenes has been reviewed <81H(15)547>. 

Dieckmann cyclizations of diesters of type (210) are catalyzed by potassium f-butoxide in toluene, sodium in xylene, or sodium hydride in DMF, and produce 1-benzazepinones in good yields. The method is also applicable to the synthesis of azepines fused to other heterocycles, e.g. pyrrolo[2,3-6]azepin-4-ones (211) (81H(16)399). 

Nitrenes insertion is effective for the synthesis of azepines by thermolysis of o-styryl azidocinnamates (86JCS(P1)1113). Thus, the vinylazidocinnamate (209) yields the 3-benzazepine (210) (90JCS(P1)2929). 

Another synthesis of azepines from azides involved the photolysis or thermolysis of aryl azides in the presence of nucleophiles. The photolysis of phenyl azide in diethylamine yielded (34%) 2-diethylamino-3/f-azepine (311) °. In the same manner 2-substituted azepines were obtained from phenyl azide and liquid ammonia, aniline and hydrogen sulphide . 

In the synthesis of azepines, the seven-membered heterocyclic ring is produced (a) by ring enlargement of six-membered ring systems, (b) by ring closure of suitable acyclic precursors. 

RCM was also successfully applied for the synthesis of wide range of nitrogen-containing heterocycles. Pioneered by Dixneuf and Osipov," this approach was first applied for the synthesis of azepines 68 (Fig. 10.29). RCM reaction of 4-azanona-dienes-1,8 catalyzed by Grubs-type ruthenium catalysts results in high-yield formation of the corresponding azepines. 

The Beckmann rearrangement has been a popular method for the synthesis of azepine systems based upon caprolactam. A recent example is the synthesis of 7,8-... 

The [4 + 3] annulation of Fischer chromium carbene complexes with azadienes offers a facile synthesis of azepines <94CC32l>. Thus, 3-iminoprop-l-enylamine6 (195) react with the a, -unsatu-rated Fischer complexes (196) to furnish the azepines (1 ) as sole stereoisomers. The mechanism is considered to involve the formation of the aziridine (197) which undergoes an aza-Cope rearrangement followed by a 1,3 proton shift (Scheme 25). 

The intramolecular aza-Wittig reaction has been described previously as a convenient route for the synthesis of azepines, and, in a bimolecular equivalent, the reaction of 2-formyl-6-dimethyl-aminofulvene with phenyl-substituted vinyliminophosphoranes in a one-pot reaction offers a facile synthesis of phenyl-substituted 5-azaazulene (201) <91TL6727>. 

In a new synthesis of azepines, it has been shown that 2/f-pyrones react with 2-aminocinnamates to form 2,3-dihydro-l/f-azepine derivatives <89HCA457> in a reaction which has potential for the synthesis of a number of polycyclic azepines (Scheme 26). 

Organocatalysts were also reported in the synthesis of azepines. In this way, a-ketoamides 8 were reacted with a,p unsaturated aldehydes 9 and a prolinol catalyst 11 to form oxobridged azepine derivatives 10 with good stereocontrol. 

Scheme 4.14 Gold catalyzed synthesis of azepines via an intermoleciilar Diels-Alder cvcloadditinn.

Other methods exploited for the synthesis of azepine derivatives included ring-closing metathesis (13CEJ16746), alkylation of a primary amine with a 1,6-dihalohexane (13ARK240), and hydroamination of aminohexenes (13JA7235). 

A review of synthesis of azepines by [l,7]-electrocyclization reactions of unsaturated azomethine ylides and azatriene anions has been published. ... 

Two years later, Ftirstner et al. developed a synthesis of azepine 277 based on a selective Sharpless asymmetric epoxidation of divinylcarbinol (Scheme 2.60) [89]. The resulting epoxide 272 was then regioselectively opened with allylamine to give the corresponding diene. Protection of the secondary amine with an N-Boc group provided the precursor 275 for RCM. CycUzation proceeded in 94% yield using [Mo]-I catalyst (CH2CI2, 30 min, reflux, 94%). Subsequent conversion of the... 

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