The synthesis and evaluation of a series of C3-substituted 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) analogues of the CC-1065 and duocarmycin alkylation subunits are detailed, including methyl and the full series of halogens. Introduction of the key substituent was accomplished through directed metalation of the seco-CBI core followed by reaction of the resultant aryllithium with an appropriate electrophile. C3-Bromo and iodo substituents were only effectively installed on the hindered aryllithium intermediate using a novel halogen source, 1-bromo- and 1-iodophenylacetylene, that should prove generally useful beyond the studies we describe. X-ray crystal structures of the series show substantial distortion in the vinylogous amide due to unfavorable steric interactions between the C3-substituent and the N(2)-carbamate. In the halogen series, the N2-C2a bond length and the torsional angle chi(1) smoothly increase with the increasing size of the C3 substituent indicative of decreasing vinylogous amide conjugation through the series (H > F > Cl > Br > I). Unlike N-Boc-CBI, this series of substituted CBI analogues proved remarkably reactive toward solvolysis even at pH 7, where the reaction is uncatalyzed and the reactivity order (I > Br > Cl > F > H) follows a trend consistent with the extent of vinylogous amide conjugation and stabilization. The implications of these observations on the source of catalysis for the DNA alkylation reaction of the natural products are discussed.