The Fe+-mediated [4+2] cycloaddition of dienes with alkynes has been examined by four-sector ion-beam and ion cyclotron resonance mass spectrometry. Prospects and limitations of this reaction were evaluated by investigating several Me-substituted ligands. Me Substitution at C(2) and C(3) of the diene, i.e., 2-methylbuta-1,3-diene, 2,3-dimethylbuta-1,3-diene, hardly disturbs the cycloaddition. Similarly, variation of the alkyne by use of propyne and but-2-yne does not affect the [4 + 2] cycloaddition step, but allows for H/D exchange processes prior to cyclization. In contrast, Me substituents in the terminal positions of the diene moiety (e.g., penta-1,3-diene, hexa-2,4-diene) induce side reactions, namely double-bond migration followed by [3+2] and [5+2] cycloadditions, up to almost complete suppression of the [4+2] cycloaddition for 2,4-dimethylhexa-2,4-diene. Similarly, alkynes with larger alkyl substituents (pent-1-yne, 3,3-dimethylbut-1-yne) suppress the [4+2] cycloaddition route. Stereochemical effects have been observed for the (E)- and (Z)-penta-1,3-diene ligands as well as for (E, E)- and (E,Z)-hexa-2,4-diene. A mechanistic explanation for the different behavior of the stereoisomers in the cyclization reaction is developed. Further,the regiochemical aspects operative in the systems ethoxyacetylene/pentadiene/Fe+ and ethoxyacetylene/isoprene/Fe+ indicate that substituents avoid proximity.