Cyclazines 3.3.3 Cyclazine, aromaticity

The reaction of the same ylide 63 with dimethyl acetylenedicarboxylate (DMAD) in chloroform afforded the cyclazine 67, through aromatization of monoadduct 66 the azocine 69, which is formed through a second nucleophilic attack with ring expansion in the bis-adduct 68 and the pyrrolo derivative 71, which is formed by evolution of the bis-adduct 70 through a retro-Diels-Alder reaction (Scheme 3) <2001JOC1638>. 

Despite its 10-electron aromatic Jt-system, indolizine apparently participates as an eight-electron system in its reaction with acetylene dicarboxylate, although the process may be stepwise and not concerted. By carrying out the reaction in the presence of a noble metal as catalyst, the initial adduct is converted into an aromatic cyclazine. 

Four chapters in the present volume bring older reviews up to date. Those on the quinoxalines (Cheeseman and Werstiuk) and on hetero-aromatic quaternization (Zoltewicz and Deady) carry forward contributions on the same subjects in Volumes 2 (1963) and 3 (1964), respectively, of this Series, while those on the phenanthrolines (L. A. Summers) and the isatogens and indolones (Hiremath and Hooper) deal with topics previously covered elsewhere. The cyclazines, a relatively new field of chemistry, are reviewed by Flitsch and Kramer, and the azapentalenes— the wide variety of nitrogen-containing heterocycles formed by the fusion of two aromatic five-membered rings—are collected into one chapter by Elguero, Claramunt, and A. J. H. Summers. 

Cyclazines (229) are stable aromatic compounds, the synthesis of which may involve indolizines, 3H-pyrrolizines or pyridines. Their chemistry has been investigated extensively. 

Other products from pyridine and its 3- and 4-methyl and 3,5-dimethyl derivatives and MP are cyclazines (e.g., 100),291 which are probably formed from indolizines of type 97 by further reaction with MP and subsequent aromatization. This type of reaction has been achieved by heating appropriate indolizines with DMAD293 or MP in the presence of palladized charcoal, and the direction of the addition, as shown below, has been established in several instances.294 Heating MP with diethyl-2-pyridylmethylene malonate gave the pyrrolo[2,l,5- /]indolizine corresponding to 100, no trace of the expected indolizine intermediate (cf. 97) being observed.292... 

Bromination of l,3,6-triazacycl[3,3,3]azine (11.112, R = X = H) occurs at the 4-position and then at the 7- and 9-positions. Calculations predict this (73ACS242I) but the reason can be easily seen by comparison of the transition states for 4- and 7-substitution (11.113 and 11.114). Aromaticity is created in both transition states, so reaction should be rapid. However, the triazanaphthalene lOir-ring in 11.113 is more stable than the tetrazanaphthalene lOir-ring in 11.114. Bromination of the 4-cyano-3-methyl-substituted cyclazine occurs at the 7- and 9-positions (72ACS624), and of9-ethoxycarbonyl-2-methyl-l,3,4,7-tetrazacycl[3,3,3]azine (11.115] at the 6-position (73ACS2421). 

The dienophile is the usual sort of unsaturated carbonyl compound—but count the electrons used from the indolizine. The nitrogen lone pair is not used but all the other eight are, so this is a most unusual [2 + 8] cycloaddition. The first formed product is not aromatic (it is not fully conjugated) but it can be dehydrogenated with palladium to make a cyclazine. 

Now count the electrons in the cyclazine—there are ten electrons round the outer edge and the nitrogen lone pair is not part of the aromatic system. Cyclazines have NMR spectra and reactions that suggest they are aromatic. 

The cyclazines (a trivial name) are tricyclic fused molecules containing a central nitrogen and a peripheral rr-system. The definition of aromaticity in these compounds is not as straightforward as for the simple bicycfic molecules discussed above, and a more detailed analysis of the molecular orbitals may be required. 

In contrast, (3.3.3)cyclazine has no aromatic resonance stabilisation and is unstable and highly reactive, displaying some diradical character. However, its hexa-aza analogue is extremely stable, this stabilisation being attributed to perturbation of the molecular orbitals by the electronegative atoms leading to a much... 

In assessing the aromaticity of various cyclazines, 1,6a-diaza[2.2.2]cyclazines (46) (Table 6) turns out to be diatropic in nature from a comparison of the chemical shifts of the protons H-5 and H-6. 

It is important to note that the ring proton of [2,2.3]cyclazines (219) and (221) appears at a lower field than the corresponding ring protons of indolizines since the ring current increases, as is seen in polynuclear aromatic hydrocarbons (PAH). Methyl protons of both methyl and methylthio groups on the cyclazine ring are also shown at lower field, compared with those of the corresponding indolizine derivatives. 

The authors conclude that [2.2.3]cyclazine (219) is intermediate in aromaticity between the polynuclear aromatic hydrocarbons and peripheral conjugated aromatic compounds involving delocalized 10 tt or 14 tc electrons. They also state that the resulting [2.2.3]cyclazines and benzo[2.2.3]-cyclazines are strongly dlatropic and claim that further theoretical study is required before the details of these novel conjugated systems can be fully understood. 

Indolizine can participate with its Sit-electron perimeter in a cycloaddition with acetylene dicarboxylate (presumably in stepwise and not in concerted fashion) to give the adduct 5. By performing this reaction in the presence of Pd/C, additional dehydrogenation converts 5 to the aromatic cyclazine derivative 6 [215] ... 

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