Cycl azines

Thomas and Long488 also measured the rate coefficients for detritiation of [l-3H]-cycl[3,2,2]azine in acetic acid and in water and since the rates relative to detritiation of azulene were similar in each case, a Bronsted correlation must similarly hold. The activation energy for the reaction with hydronium ion (dilute aqueous hydrochloric acid, = 0.1) was determined as 16.5 with AS = —11.3 (from second-order rate coefficients (102At2) of 0.66, 1.81, 4.80, and 11.8 at 5.02, 14.98, 24.97, and 34.76 °C, respectively). This is very close to the values of 16.0 and —10.1 obtained for detritiation of azulene under the same condition499 (below) and suggests the same reaction mechanism, general acid catalysis, for each. 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

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

With the exception of cycl[3.2.2]azines and their analogues (Sections 12.16.6.3-12.16.6.5) and systems containing a... 

The most frequently used synthetic route to cycl[3.2.2]azines involves the reaction of an indolizine with a dienophile, for example, DMAD, in the presence of a dehydrogenating agent such as palladium-on-carbon (Scheme 85), although the scope of the reaction is limited by the presence of substituents in one or both of the reactants, and/or the reaction conditions. If C-3 and C-5 of the indolizine are unsubstituted, the cyclazine is the main product a 3,4-dihydrocyclazine may sometimes be isolated as a by-product (see below). 

A third method for the synthesis of cycl[3.2.2]azines, from iV-(aroylmethyl)pyridinium salts via indolizines, involves intramolecular (reductive) McMurry coupling of the latter. For example, 3,5-dibenzoylindolizines, obtained from 2-benzoyl-iV-phenacylpyridinium bromide as shown (Scheme 91), are cyclized using zinc and titanium(iv) chloride to give the 3,4-diphenylcyclazines 352 in high yield (>90%). The reaction cannot be applied, however, to... 

The initial step in Scheme 91 presumably involves deprotonation of the phenacyl substituent to give a pyridinium ylide. Such ylides may be generated as reactive (unstable) intermediates in the synthesis of cycl[3.2.2]azines from iV-(trimethylsilylmethyl)-2-pyridones (Scheme 92) in the presence of an excess of DMAD, the cyclazine is the major product <2003S1398>. 

Cycl[3.2.2]azines which are highly functionalized in the six-membered ring may be obtained in good yield from... 

Cycl[3.2.2]azines may also be obtained by the cycloaddition of a bifunctional three-carbon unit to a 3//-pyrrolizine. Vinamidinium salts have been used for this purpose <1984CB1649>, although the reactions require the use of a strong base (sodium hydride) and extended reaction times. They appear to proceed via a stepwise mechanism, since intermediates (the conjugated enamines 354 and 355) have been isolated in certain cases (Scheme 94). 

Table 1 13C chemical shifts (S) of cycl[3.2.2]azine analogues (in CDCI3)... 

Two series of benzo-fused cycl[3.2.2]azines, viz the benzo [a]-, 365, and benzo(g]-cycl[3.2.2]azines, 366, and three dibenzo-analogues, 367-369, are theoretically possible (Figure 6). These have attracted attention since the benzo-analogues have a... 

Synthetic routes to the benzocyclazines are analogues of those which lead to the cyclazines themselves. Representatives of the benzoh ]cycl[3.2.2]azine (indolizi no [3,4,5- ] isoindole, 365) ring system result from cycloaddition of, for example, DMAD to pyrido[2,l-tf]isoindole-6-carbonitrile 370 <1986H(24)3071> (Scheme 100). An alternative synthesis, which starts from the cyclazine 371 and involves construction of the additional benzenoid ring by a double Horner-Wadsworth-Emmons type of reaction, apparently gives the tetracyclic product 365 in only very low yields (Scheme 101) <1988H(27)2251>. 

Benzo[g]cycl[3.2.2]azines or pyrrolizino[3,4,5- 3]isoquinolines, for example, 366, are similarly obtained by cycloaddition of DMAD to pyrrolo[2,l- ]isoquinolines <1985CPB3038>, and l-aza-benzo[ ]cycl[3.2.2]azines are prepared by cycloaddition of DMAD to imidazo[2,l- ]iso-quinolines <1985H(23)2531> (Scheme 102). In all of the above cases, as with the simpler cyclazines, the ester functions are removable by hydrolysis in aqueous alkali followed by... 

As already mentioned in Section 12.16.1, this chapter covers a large number of diverse ring systems, and it has therefore been convenient to divide the material into several sections, according to the nature of these systems. Except for the cycl[3.2.2]azines (Section 12.16.6), an in-depth study of the properties of each individual ring system appears not to have been undertaken, and so the emphasis in each section has been on the diversity of available synthetic routes to these stmctural types. The same approach has been adopted in the chapter which follows (11.17), where the number and diversity of ring systems covered is even greater. 

Although most of the fundamental studies of cycl[3.2.2]azines were reported in CHEC(1984) (see Section 12.16.6.3 for leading references), there is continuing interest - synthetic, spectroscopic, and theoretical - in these and their benzo- and dibenzo-fused analogues, all of which may be considered as bridged analogues of [10]-, [14]-, and [18]-annulenes, respectively. The same level of theoretical interest continues to apply to those />m -fused systems with a hypervalent sulfur or selenium at the 5 5 ring junction (Section 12.16.6.6). 

Whereas much of the interest in cycl[3.2.2]azines (Section 12.16.6, Chapter 12.16) relates to the declocalized lOjt-electron system around the periphery, and the extent of aromatic stabilization thereby conferred on these molecules, the same is obviously not true of cycl[3.3.2]azines, which have an 11-atom periphery. Nevertheless the synthetic methods which lead to representatives of this latter ring system have some features in common with those of the former. Also, within the review period, several alkaloids containing reduced cycl[3.3.2]azine rings have been identified and synthesized, just as in the cycl[3.2.2]azine series, and some points of similarity exist between those compounds containing the two different ring systems. 

Table 5. Theoretical Possibilities for Cycl[a,b,c]azines with 9 < m < 12...

The chemistry of cyclazines has not previously been reviewed. It is our aim to survey the methods of synthesis of these compounds and to show that the chemistry of cyclazines has stimulated discussion on theories of condensed -systems. This latter point may be illustrated by an example Early molecular orbital (MO) studies on cycl[3,3,3]azine (2) predicted a resonance energy greater than that for the highly stable... 

HMO-treatment reveals a closed-shell system for the dianion of 6, thus indicating stabilization for isoelectronic cycl[2,2,2]azines with an additional nitrogen atom in a peripheral position, e.g., 7. Compounds of this type can be prepared by cycloaddition reactions. 

Cycl[3,2,2]azines (1) are stable aromatic compounds that have been investigated extensively (Table I). 

Most of the methods of forming cycl[3,2,2]azine derivatives involve indolizines. Other precursors are 3//-pyrrolizines and pyridines. 

---