Cycloadditions cyclazines

Acyl-substituted quinolizinium ylide 63 was obtained by treatment of its 1,2-dihydro analogue with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ). Its 1,3-dipolar cycloaddition with an acetylenic ester in excess was regioselective and was accelerated in polar solvents yielding the intermediate adduct 64 and finally the corresponding cyclazine 65, as shown in Scheme 2 <2001JOC1638>. 

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... 

Most of the methods of formation of [2.2.3]cyclazines have been described already the intramolecular condensation of indolizines in Sections 3.08.1 and 3.08.4, the cycloaddition to indolizines in Section 3.08.3.5, the cycloaddition to methylenepyrrolizines in Section 3.08.6.2.1 and a multistep synthesis from 2-formylpyrrole and l,2-bis(hetero) substituted ethylenes in Section 3.08.6.3.1. 

The antiaromatic 5-thia[2.3.3]cyclazines (262) represent 7r-systems with a heteroatom in the six-membered ring. They have been prepared by cycloaddition (see Section 3.08.6.2.2 for details) of acrylonitrile or ethyl acrylate to the 1,3-dipole formed from (263) with a base which gave (264) under dehydrogenating conditions. Conversion to the thiacyclazines (262) followed conventional routes (80CL947). 

Cycloaddition reactions have been used for the transformation of [3.3.3]cyclazine derivatives. DMAD in boiling benzene converted (265c) into the red Diels-Alder adduct (281a). This readily formed a dihydro derivative (281b), which lost ethylene above 220 °C to give... 

Cycloaddition of methyl propiolate to 4-imino-4//-pyrido[ 1,2-a]py-rimidin-4-imine 481 in the presence of 5% palladium-on-charcoal catalyst as dehydrogenating agent yielded cyclazine derivative 482 in 12% yield (Scheme 27) (87YZ344). A similar reaction with dimethyl acetylenedicar-boxylate gave a mixture of addition (483), cycloaddition (484), and dehydrogenated (485) products in 16%, 23%, and 37% yields, respectively. 

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. 

Cyclazines can be prepared by cyclisation of bicyclic precursors, for example (3.2.2)cyclazine is prepared via a cycloaddition reaction on indolizine (28.1), or by cyclocondensation. " ... 

Reactions of indolizines with electron deficient alkenes and alkynes were studied. Cycloaddition reactions with dimethyl alkynedicarboxylate yield cycl(2.2.3)azine derivatives (22)-(24), adducts (25), and (2.3.4)cyclazines (26) <84H(22)705>. 

Through an unusual [8 + 2] cycloaddition of 4,8-diazapentalene (193 Ar = Ph) with DMAD under dehydrogenating conditions, Boekelheide and Fedoruk synthesized the cyclazine (41a) (Table 5) (Scheme 17) <66PNA(55)1385>. A simple course of reactions converts (41a) to (41b) (Table 5). 

The synthesis of [2.2.3]cyclazines, aza[2.2.3]cyclazines and their derivatives has also been covered. The attention of the reviewers has been focused on the study of the developments in the synthesis of several benzocyclazines and azacyclazines by the [8 -I- 2] cycloaddition reaction of the dimethyl acetylene dicarboxylate with various types of indolizines. The synthesis of indolizines, imidazo[l, 2-a]pyridines, and related compounds, which are key intermediates for the synthesis of cyclazines, is also described <88H(27)225i>. 

The [8 -I- 2] cycloaddition of 3-imino-3/f-pyrrolizine derivatives with DMAD has been also used to prepare 5-aza[2,2,3]cyclazines. Treatment of (538) with DMAD gave the dimethyl 4-cyano-3-methylthio-5-aza[2.2.3]cyclazine-6,7-dicarboxylate (539) in good yield. The 3-amino-5-aza-[2.2.3]cyclazine derivatives (541) have also been prepared from the corresponding l-amino-3-imino-377-pyrrolizine derivatives (540) (Equation (17)). 

Calicenes, 397 Coronene, hexahydro, 327 Cyclazines, 330 Cycloaddition reactions of... 

S2Sa. Since the imine 525b was not a precursor of the cyclazine 524, it was concluded that C-S bond breaking must precede C-C and C-N bond formation, as would be the case if 3,5-didehydroimidazo[l,5-a]pyridine (525c) were an intermediate. An alternative explanation involving a [2-h8] cycloaddition of the reactants followed by elimination of lithium thioethoxide was also considered, however, but has not yet been disproven. Precedent for such cycloaddition-elimination reactions exists in the closely related pyrrocoline system. ... 

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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