Azepanes, rearrangement

The Co-catalyzed reaction of azepane 264 n = 3) at 220 °C and 54 atm of CO gave the normal ring-expansion product 265 ( = 3) in 42% yield (Scheme 39). However, when Ru3(CO)i2 was used as co-catalyst of Co2(CO)s under the same conditions, azepanone 266 ( = 3) was obtained as the sole product in 72% yield (Scheme 39).The attempted reaction only with Ru3(CO)i2 as catalyst under the same conditions resulted in the recovery of the substrate 264 (n = 3). Thus, this unique rearrangement requires both Co and Ru catalysts. A proposed mechanism for the formation of 266 is illustrated in Scheme 40, which proposes that the origin of the lactam oxygen is the carbonyl oxygen of the A7-pivaloylmethyl group of pyrrolidine 264. ... 

Azepan-2-one (hexano-6-lactam, --caprolactam, 28) is industrially the most important azepine derivative. It is used in the production of perlon and is synthesized by Beckmann rearrangement of cyclohexanone oxime. Structurally related to caprolactam is the CNS stimulant pentetrazole 29 (1,5-pentamethylenetetrazole, see p 217). 

Subsequent experiments showed that piperidine with D-fructose gave D-glu-cose, and that morpholine, dicyclohexylamine as well as tertiary amines converted D-fructose into D-psicose without detectable formation of Heyns rearrangement products. Employing secondary amines such as pyrrolidine, the corresponding Heyns rearrangement products could be obtained very easily, contrasting results with other cyclic amines, for example, piperidine, hexame-thylene imine (azepane) and other open-chain amines such as dimethyl-, diethyl-, or methylbenzylamine, which did not react [105]. 

Scheme 43 Synthesis of 5-substituted azepane-2-carboxylate by the Beckmann rearrangement.

Beckmann Rearrangement The Beckmann rearrangement of oxime constitutes another approach to the insertion of nitrogen into the C-C=0 bond. Wishka and coworkers developed an asymmetric synthesis of (25,55)-5-substituted azepane-2-carboxylate 12 based on this reaction [8]. Condensation of ketone 8 with hydroxylamine afforded oxime 9. Treatment of 9 with TsCl triggered the Beckmann rearrangement to afford the desired lactam 10 as the sole product. Compound 10 was then converted to 12 by ozonolysis of the enolether 11 (Scheme 4.3). 

Caprolactam scaffold represents a bioactive moiety in many drugs [99]. Fox and coworkers have described the synthesis of 3-(acylamino)azepan-2-one derivatives as stable broad-spectrum chemokine inhibitors resistant to metabolism in vivo [100]. Azepan-2-ones are also reported as valuable inhibitors of metallic proteinase [101]. The synthesis of N-alkyl-2-(2-oxoazepan-l-yl)-2-arylacetamide derivatives is carried out by a three-component Ugi reaction in water. The reaction of 6-aminohexanoic acid 133, aromatic aldehydes 51, and isocyanide derivatives 134 in water under reflux without any catalyst affords N-alkyl-2-(2-oxoazepan-l-yl)-2-arylacetamides 135 (Scheme 45) [102]. The first step of the reaction leads to the formation of imines 136 by the reaction of 6-aminohexanoic acid 133 and aldehydes 51 (Scheme 46). The nucleophilic attack of the isocyanide 134 on protonated imine 137 leads to the formation of nitrilium carboxylate intermediate 138, which xmdergoes cyclization through attack of carboxylate on nytrilium carbon to give an intermediate cyclic product 139. The latter product undergoes a Mumm rearrangement to yield the final product 135 via the intermediate 140. 

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