Azacycles

The following order of initiation rate constants was found by Grubbs et al. for 71a and some precatalysts containing one phosphine ligand 56d< 56k 71a<56h (cf. Scheme 15 for structures of 56d,h,k) [48b, 55]. Thus, 71a shows a rate of initiation comparable to that of 56k but three orders of magnitude higher than that of 56d. Nevertheless, 56d appears to be more reactive in RCM reactions than 71a [56]. Wakamatsu and Blechert were the first to report that the activity of precatalysts related to 71a can be dramatically enhanced by modification of the benzylidene unit [56]. For example, RCM of 75 using 1 mol% of BINOL-derived complex 71b yields the azacyclic product 76 in quantitative yield within 20 min (Eq. 10), whereas with 56d only 4% of 76 was obtained under these conditions [56]. 

Scheme 25 Sequential formation of 13- and 8-membered azacycles in Martin s total synthesis of ircinal A (129) and related manzamine alkaloids [78]...

Scheme 26 Sequential formation of 8- and 15-membered azacycles in total synthesis of enf-nakadomarin A (145) [80]...

Benzo-, Dibenzo-, and Other Fused Cycl[3.2.2]azines and Azacycl[3.2.2]azines 838... 

Synthetic routes to the various classes of azacycl[3.2.2]azines generally follow along very similar lines to the above. For example, l-azacycl[3.2.2]azines (imida/o[ 5,1,2-tv/] indolizines), 356, may be obtained by the [8+2] cycloaddition... 

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-c /]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier-Haack-Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[l,5- ]pyridine have been unsuccessful. 

Aminoallenes constitute an important class of functionalized allenes with interesting chemical properties. They are known as attractive substrates for constructing three- to six-membered azacycles [78]. In 1999, Ohno and co-workers reported the stereoselective synthesis of chiral a-aminoallenes 179 and 181 by RCu(CN)M-medi-ated anti-SN2 substitution of chiral 2-ethynylaziridines 178 and 180 (Scheme 4.47) [79]. The X-ray data and specific rotations of the allenes were consistent with a net anti-S- 2 substitution reaction. 

Diarylamides with arenes activated by electron-donating substituents can be converted to azacycles by anodic oxidation through phenolic oxidative coupling reactions that can be a key step in the synthesis of alkaloids (Schemes 16 and 17). According to the nature of substituents and the experimental conditions, either spiro compounds [22] or non-spiro compounds [23, 24] were obtained. 

An anodic azacyclization, producing tropane-related 11-substituted dibenzo[a,d]cycloheptimines 123, was recently developed by Karady et al. [136, 137]. This two-electron process is initiated by anodic oxidation of the O-substituted hydroxylamine 119 in nucleophilic solvent. It is proposed that the first one-electron oxidation leads to the aminium radical cation 120 which adds rapidly to the double bond. The electron-rich carbon radical 121 is readily oxidized to the carbocation 122. Selective nucleophilic attack on 122 from the less hindered exo-side yields the 11- substituted product 123. Depending on the... 

The stereoselective construction of nitrogen heterocycles remains a topic of intense synthetic interest [39]. Evans and Robinson described the combination of the stereospecific aUylic amination with ring-closing metathesis as a strategy for the constmction of mono- and disubstituted azacycles, which they demonstrated with the stereospecific construction of cis- and tra s-2,5-disubstituted pyrrolines [40]. Furthermore, this approach provided an ideal system for the determination of whether the enantiospecific rhodium-catalyzed aUyhc amination with an enantiomerically enriched nucleophile experiences a matched and a mismatched reaction manifold. 

New azacyclic diterpenoid compounds were also prepared in good yields by ring expansion and only one isomer of the lactam 363 product was obtained (equation 142). However, when the oxime was tosylated, a nitrile compound resulting from ring opening was obtained in good yield (72%) as a result of the Beckmann degradation reaction. 

The Lee group originated rhodium alkenylidene-mediated catalysis by combining acetylide/alkenylidene interconversion with known metal vinylidene functionalization reactions [31], Thus, the first all-intramolecular three-component coupling between alkyl iodides, alkynes, and olefins was realized (Scheme 9.17). Prior to their work, such tandem reaction sequences required several distinct chemical operations. The optimized reaction conditions are identical to those of their original two-component cycloisomerization of enynes (see Section 9.2.2, Equation 9.1) except for the addition of an external base (Et3N). Various substituted [4.3.0]-bicyclononene derivatives were synthesized under mild conditions. Oxacycles and azacycles were also formed. The use of DMF as a solvent proved essential reactions in THF afforded only enyne cycloisomerization products, leaving the alkyl iodide moiety intact. 

While enantioselective transition metal catalysis continues to be important, several useful all-organic catalysts have been developed over the past few years. Tomislav Rovis of Colorado Stale University has reported (J. Am. Chem. Soc. 2004, /26, 8876) that the triazolium salt 5 catalyzes the enantioselective Stetter-type cyclization of 4 to 6. The cyclization also works well for the enantioselective construction of azacyclic, thiacyclic and carbocyclic rings. 

Five- and six-membered azacyclic rings are the basic building blocks of pharmaceutical synthesis. Several powerful methods for the construction of such rings that recently have been developed are highlighted here. 

Azacycles can also be constructed by C-C bond construction. The enantiomerically-pure amide 8 is easily prepared by photolysis of pyridine followed by acetylation and enzymatic desymmetrization. 

When l-benzoyl-2-phenyl-4,8-diazapentalene (8) was treated with dimethyl acetylenedicarboxylate under dehydrogenating conditions, 1-phenyl-2-benzoyl-5,6-dicarbomethoxy-2a-azacycl[2,2,2]azine (9a) was... 

Azacycl[3,2,2] azine (19) has been prepared by the reaction sequence given in Eq. (4).21... 

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