2- azepane, reaction

Piperidine ring-expansion methodology and aziridinium ion intermediate formation has been demonstrated to provide good regio- and stereochemical control in the synthesis of substituted azepanes. Reaction of 298 with azide ion afforded 300 from preferential attack from behind by the azide ion at the methine carbon in the intermediate 299 (Scheme 38) <2002J(P1)2080>. 

An example of an intriguing ring-size dependency of the reaction pathway is that of the cyclization of vinylogous urethanes 328a-c with cinnamaldehyde (08T883). Pyrrolidine- and azepane-based esters 328a and c, respectively, give via aza-[3+3] annulation the expected... 

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. ... 

Isomerization of the enantiopure hydroxylated azepane 42, after hydroxyl group activation, afforded either the ring-contracted piperidine derivative 45 (on O-mesylation to 43 followed by internal displacement to the aziridinium ion intermediate 44 and subsequent chloride ion induced ring opening) or the chiral ethylene-bridged morpholines 48 via 47 and an intramolecular Mitsunobu reaction of 46 (Scheme 4) <1996TL1613>. 

A dominant feature of the type c ring-construction approach to azepine systems has been ruthenium-catalyzed ringclosing metathesis reactions. Examples include the synthesis of the azepine derivative 157 from 156 using either the Grubbs type I catalyst 159 or type II 160. The diene precursor 156 was prepared in turn from 154 via 155, as shown in Scheme 21. Hydrogenation of the C-C double bond in 157 afforded the azepane 158 <2005SL631>. 

Thus, reaction of N-Cbz-protected a-, fl- or y-amino aldehydes 190 with 1,3-dicarbonyl compound 191 in the presence of benzyl enol ether 192 followed by hydrogenation led to substituted pyrrolidines, piperidines and azepanes as a mixture of diastereomers in >95% chemical purity in most cases. 

This microwave-accelerated double alkylation reaction was applicable to a variety of aniline derivatives and dihalides, furnishing N-aryl azacycloalkanes in good to excellent yields [89]. The reaction was applicable to alkyl chlorides, bromides and iodides and was extended to include hydrazines [90]. This improved synthetic methodology provided a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted-2,3-dihydro-Iff-isoindoles, 4,5-dihydro-pyrazoles, pyrazolidines, and 1,2-dihydro-phthalazines [91]. The mild reaction conditions tolerated a variety of functional groups such as hydroxyls, carbonyls, and esters. 

In the preparation of polyhydroxylated azepane as potential glycosidase inhibitors, Dha-vale [28] described a short synthetic route utilizing the Henry approach. The nitroaldol reaction of l,2-0-isopropylidene-3-0-benzyl-a-D-xylo-pentodialdose 36 and nitromethane in the presence of triethylamine at room temperature afforded a-D-gluco- and /3-L-ido- nitroal-dose 37, the precursors to (2S, 3R, 4R, 5R) and (2S, 3R, 4R, 55) tetrahydroxyazepanes 38 and 39, in a 88 12 ratio in 95% yield (O Scheme 13). 

Depazay and co-workers have described the synthesis of a series of polyhydroxylated pyrrolidine, piperidine and azepanes derived from D-mannitol as novel mimetics of somatostatin [8]. The synthesis of one piperidine 116 is shown in O Scheme 9. The authors used reaction of tr) tamine with the D-mannitol derived bis-epoxide 112 followed by protection of the indole nitrogen with a Boc group to prepare the L-gulo-piperidine 113, the azepane 114 also being formed. Selective protection of the primary alcohol followed by reaction with hydrazoic acid... 

Meldrum s acid is best introduced into a bicyclo[n.l. OJalkylamine system by its reaction with bicyclic A,0-acetals. Various amines such as morpholine, piperidine, pyrrolidine, dimethylamine, benzylamine, or azepane can be used for this reaction with c/j-bicyclic systems. Azepane as amino component is essential for the analogous reaction of a trans-bi-cyclo[9.1.0]dodecanone A,0-acetal. Both cw-bicyclo[n.l.0]alkane isomers 5 possessing Meldrum s acid either in the exo-position or in the enrfo-position were synthesized as sterically... 

In contrast to the synthesis of dimorpholino aminals 5 without isomerization of the bicyclic skeleton, either a cis- or a tran -aminal was prepared as a pure isomer by the reaction of l-[(la,lla,12a)-12-(azepan-l-yl)bicyclo[9.1.0]dodec-12-yl]pyrrolidine-2,5-dione (6) with azepane. Shorter reaction times and lower temperatures gave the cw-aminal cis-1 while higher temperatures and a longer reaction time gave the trans-aminaX trans-1 ... 

The synthetic power of Ru-catalysed ring closing metathesis reactions has continued to be realized, for example, in the synthesis of the azepine derivative 4 from 3, which was prepared in turn from 1 via 2. Reduction of 4 afforded the azepane 1 <05SL631>. 

All these reactions confirm the high versatility of glycosylenamines, which can be easily transformed into 1,4- and 1,6-anhydro-iminosugars, bicychc compoimds that can be used in the preparation of pyrrohdines, pyrrohzidines, piperidines and azepanes. 

Pyrrole Mannich bases have been prepared as potential antipsychotic agents that do not have the extrapyramidal side effects (EPS). In one case, A -methylpyrrole was amidomethylated with l-(hydroxymethyl)azepan-2-one, which was assembled by condensation between the seven-membered lactam and formaldehyde. The amidomethylated 7V-methylpyrrole then underwent the Mannich reaction with arylpiperazine and formaldehyde in the presence of trifluoroacetic acid (TEA). The pyrrole Mannich bases synthesized in this manner exhibited a high affinity for the serotonin 5-HT-lA and 5-HT-lB binding sites. Although these arylpiperazines interact weakly with dopamine D-1 and D-2 receptors, they were reasonably potent in an in vivo model in the rat CAR (conditioned avoidance responding), an indication of potent antipsychotic activity. 

A series of polyoxygenated azepane derivatives 5 were created from azi-dolactol 4 via a Staudinger/aza-Wittig-type cyclization followed by reaction with -alkylmagnesium halides, en route to the synthesis of a library of potent glucosidase inhibitors (140BC8977). 

A chiral selenophosphoramide catalyst was employed for the intramolecular cyclization of an alkenyl sulfonamide to achieve the enantioselective formation of N-heterocycles including an azepane derivative via a mechanism proposed to include formation of a three-membered sulfur-containing ring (14JA8915). A [4 + 3]-cycloaddition reaction of methyl coumalate 12 with an azomethine ylide, formed from imine esters 13 yielded functionalized azepine derivatives 14 (14OL4508). 

The ring-expansion reaction of the trifluoroacetate derivative of piperidine 4, which after hydrolysis gives azepane 5, occurs slowly compared to that of the corresponding pyrrolidine analogs (13SL1529). 

---