Science of Synthesis

Tominaga, Y., Science of Synthesis, (2004) 17, 1025.

The cyclazine with the smallest ring structure is a [2.2.2]cyclazinium salt (‌2‌), a basic compound among the [2.2.2]cyclazine derivatives, which has not been synthesized.[‌8‌] Compound ‌2‌ is not an aromatic compound, because it is an 8π-electron system. It is possible to obtain an aromatic compound that becomes a 10π-electron system and is theoretically stable, if 2π-electrons are added to its 8π-electron system. Aza- or thia-analogues of [2.2.2]cyclazines with other heteroatoms in the peripheral conjugate system have been prepared from a theoretical viewpoint.[‌19‌–‌29‌] The aza[2.2.2]cyclazines ‌8‌, ‌9‌, and ‌11‌, as shown in ‌Scheme 2‌, were prepared by the 1,3-dipolar cycloaddition reaction of the azapentalene ring system ‌12‌ with a dipolarophile reagent, such as dimethyl acetylenedicarboxylate to give ‌13‌ and then ‌8‌.[‌19‌] The 1-thia[2.2.2]cyclazine ‌10‌ has been synthesized in a stepwise manner from pyrrolothiazole ‌14‌ via ‌15‌ by a similar method to the preparation of [2.2.3]cyclazine from 5-methylindolizine.[‌22‌] Part of the experimental synthesis of [2.2.2]cyclazine derivatives is not shown in this section, because that part of the preparation is accomplished by steps similar to those that are used for the [2.2.3]cyclazine series.

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References