4.5- Dihydroazepines

In 1995, and regrettably missed in last year s review, Klotgen and Wiirthwein described the formation of the 4,5-dihydroazepine derivatives 2 by lithium induced cyclisation of the triene 1, followed by acylation <95TL7065>. This work has now been extended to the preparation of a number of l-acyl-2,3-dihydroazepines 4 from 3 <96T14801>. The formation of the intermediate anion and its subsequent cyclisation was followed by NMR spectroscopy and the stereochemistry of the final product elucidated by x-ray spectroscopy. The synthesis of optically active 2//-azepines 6 from amino acids has been described <96T10883>. The key step is the cyclisation of the amino acid derived alkene 5 with TFA. These azepines isomerise to the thermodynamically more stable 3//-azepines 7 in solution. 

In a series of three papers, Noguchi and co-workers have reported their continuing studies on the formation of heterocycle-fused azepine systems <96X13081, 96X13097, 96X13111>. A typical example is the conversion of the aldehyde 15 into the azepines 16 and 17 (Scheme 3). Xhe reaction also proceeds with imines when the dihydroazepine prior to bridging can be isolated. Mechanistic and stereochemical aspects of the reaction have been explored. 

A-Methylphthalimide (288) undergoes photoaddition in acetonitrile to ds-but-2-ene (289) to give d.s-l,6,7-trimethyl-3,4-benzo-6,7-dihydroazepine-2,5-dione (290).238 Evidence supports a concerted [ 2 + J2] pathway to the intermediate 291. Similar additions to other alkenes have been reported.239 Electron transfer quenching has been shown to compete with cycloaddition... 

If AAs are heated in acetic anhydride in the presence of 1,2-dicyanocyclo-butene as a dipolarophile, 4,5-dihydroazepines are formed in good yields. For example, the reaction with Ala is actually considered a cycloaddition of the intermediate mesoionic derivative (Scheme 43) (80JHC1593). 

Additional heterocyclic ring systems, such as benzofurans [125], dihydropyrroles and dihydroazepines [41], piperidines and dihydropyrimidines 36 [126], and fused oxazole derivatives [127], have been described (Eq. 7). The formation of epoxides and aziri-dines, formally emanating from ylides, was recently reported by Doyle et al. [77]. Rho-dium(II)-catalyzed isomiinchnone cycioaddition followed by Lewis acid-mediated ring opening has been used as an entry into the protoberberine azapolycyclic ring structure [128]. 

The reaction of l-methyl-2-(methylmercapto)-2-pyrroline (282) with DMAD is known to give a dihydroazepine derivative (283) (Eq. (38)1. The recent report of the reaction of 1-methyl-2-pyrrolidone dimethyl-acetal (284) with DMAD to give products like 286, 287, 288, and 289 may be interpreted as essentially the reaction of the enamine system (285) (Scheme 45). Other examples of the reaction of enamines include the reaction of the pyrrolidinopentenone (290) to give the phthalate (293)... 

Martin et al. (115) found that miinchnone 38 reacts with isopropyhdenecyclo-butenone (204) to form dihydroazepine 205. At room temperature the two bis(adducts) 206 and 207 were isolated, although the regiochemistry of the cycloaddition has not been established. 

Turchi (118) also reported cycloaddition reactions between milnchnones 215 and 209 to afford dihydroazepine 216 in high yield. Further cyclization of 216 gave tricycle 217. Likewise, diester 218 reacts with miinchnone 38 to give dihydroazepine 219. 

Further study with Rh2(OAc)4-catalyzed reaction styryldiazoacetate 188 and cinnamaldehyde derived imine 189 found the formation of dihydropyrrole 190 and dihydroazepine 191 in high yields and with high stereocontrol. No aziridine products were observed in these cases (Equation (29)). ... 

Not unexpectedly the 5a,9a-dihydro-l-benzazepine (64) on heating isomerizes to the conjugated 2,3-dihydro isomer (78JOC315). Likewise, 19F NMR spectra reveal that after 24 hours at 25 °C, 30% of the unconjugated bis-(trifluoromethyl)dihydroazepine (65) (see Section 5.16.4.2.1(ii)) is converted via prototropic shift to the conjugated 2,3-dihydro-3iT-azepine (67JA605). 

The action of anions on 4-(chloromethyl)-l,4-dihydropyridines provides a useful route to 4//-azepines (Section 5.16.4.2.3). However, in several instances the 4,5-dihydro-4//-azepines (170) suffer further cyclization to the 2,5-bridged azepines (171 X=NH, NMe, NCH2Ph, S, Se) via an intramolecular Michael type addition at the 2,3-double bond (68JCS(C)23ii, 79CJC44). Occasionally, e.g. (170 X = p-MeC6H4S), the 4,5-dihydroazepine can be isolated. 

Muscaflavin, a yellow pigment from the poisonous mushroom Amanita muscaria has the unusual dihydroazepine-amino acid structure (288) (81LA2164). 

In a related rearrangement with simultaneous oxidation by palladium on carbon in toluene at 1103C, dihydroazepines 13 were formed in 80-100% yield.82... 

Methyl 6-azatricyclo[3.2.0.02,4]heptane-6-carboxylate afforded methyl 2,5-dihydroazepine-l-carboxylate (1) on heating in refluxing xylene.83... 

The fused dihydroazepine derivative (119), however, behaves differently, and undergoes rapid isomerization to 9-cyano-9-aza-bicyclo[6.1.0]nona-2,4,6-triene (120) on photolysis in pentane solution.106 The mechanism of this reaction is not clear, but the process is thought to be a concerted one, involving a 1,5-migration of the NON bridge. There is no evidence for the intermediacy of a tricyclic species (such as 121), but the possibility cannot be excluded. 

A bridging reaction, identical to that discussed for dihydroazepines, has been observed in oxygen heterocycles. This was first reported for muconic anhydride107 more recently, 2,3-dihydrooxepin (122) has been converted into 2-oxabicyclo[3.2.0]hept-6-ene (123) in 80% yield... 

A lithium-induced cyclization of the imine-diene 267, followed by N-alkylation (e.g., with EX = EtBr) or iV-acylation (e.g. with EX = PhCOCl), to form the 4,5-dihydroazepines 268 in poor to fair yields has been reported (Equation 36) <1995TL7065>. By using the different imine-dienes 269 but the same conditions as for 267 to form the anionic intermediate for the 1,7-electrocyclization, the N-substituted 2,3-dihydroazepines 270 were obtained (Equation 37) <1996T14801>. NMR spectroscopy was used to monitor the progress of these reactions. 

Substituted 4,5-dihydroazepines 321 (e.g., R1 = Bn, R2 = R3 = H, R4 = M e 82% yield) may be prepared in high yield by a rhodium-mediated hetero-[5+2]-cycloaddition of the cyclopropyl imines derived from 318 on reaction with the primary amines 319, with dimethyl acetylenedicarboxylate 320 (Equation 48) <2002JA15154>. 

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