Past exam of the chemistry course of the year 4 of the natural sciences course of the University of Cambridge / 2022 / Paper 2 / Section I / 35

TODO — user-deferred biology. This biological subquestion is intentionally left unsolved under the current scope.

TODO — user-deferred biology. This biological subquestion is intentionally left unsolved under the current scope.

TODO — user-deferred biology. This biological subquestion is intentionally left unsolved under the current scope.

TODO — user-deferred biology. This biological subquestion is intentionally left unsolved under the current scope.

TODO — user-deferred biology. This biological subquestion is intentionally left unsolved under the current scope.

K is ethyl 4-(4-methylbenzoyl)-1H-pyrrole-2-carboxylate. AlCl${}_3$ activates the aroyl chloride to an acylium-like electrophile. Pyrrole attacks through C4, forming a sigma complex; deprotonation restores aromaticity and work-up releases the ketone from its Lewis-acid complex.

Unsubstituted pyrrole normally favours an $\alpha$ position, but the ester at C2 changes the regioselectivity. Attack at C5, or at C3, permits important sigma-complex contributors with positive charge at the ester-bearing C2, which is strongly destabilized by the electron-withdrawing ester. C4 substitution avoids that particularly unfavourable contributor. The C2 ester therefore directs the acylation towards C4, overriding the simple unsubstituted-pyrrole rule. Combining the starting ester with a p-toluoyl group while replacing a ring hydrogen gives ${\mathrm{C}}_{15}{\mathrm{H}}_{15}\mathrm{N}{\mathrm{O}}_3$, as required.

Sulfuryl chloride converts the aryl thiol into an electrophilic sulfur reagent, conveniently represented as $\mathrm{ArSCl}$ after chlorination and dehydrogenation. Triethylamine traps the generated acid. The pyrrole's two $\alpha$ positions are already occupied; its less deactivated remaining carbon, C4, attacks electrophilic sulfur, displacing chloride. Loss of the C4 proton restores the aromatic ring and gives the C4 arylthio-substituted pyrrole.

The net new bond is C(pyrrole)–S(aryl). Sulfur is retained from the thiol and becomes a thioether; the transformation is not sulfonylation by transfer of sulfuryl chloride's SO${}_2$ group. Possible disulfide formation during thiol chlorination does not change the electrophilic-sulfenylation logic of the final ring substitution.

Silver carbonate promotes deprotonation of the methylene group in methyl isocyanoacetate, giving the nucleophilic carbon $\mathrm{Me}{\mathrm{O}}_2\mathrm{C}-\mathrm{C}{\mathrm{H}}^{-}-\mathrm{N}\equiv \mathrm{C}$. It adds to the alkyne carbon farther from the electron-withdrawing sulfone. This creates the new bond between the future pyrrole C2 and methyl-bearing C3 and leaves the vinyl anion at the sulfone-bearing carbon, future C4.

The vinyl anion then attacks the terminal carbon of the isocyanide intramolecularly, closing a five-membered ring with atom sequence C2–C3–C4–C5–N. Proton transfers place one of the starting methylene hydrogens on nitrogen and the other on C5, giving an aromatic pyrrole. The product has CO${}_2$Me at C2, methyl at C3 and the retained arylsulfonyl group at C4. This is an addition–cyclization–aromatization sequence: the isocyanide contributes both ring nitrogen and the otherwise unsubstituted ring carbon, rather than acting as a cyanide leaving group.