Regiodivergent Synthesis of 11H‐Indolo[3,2‐c]quinolines and Neocryptolepine from a Common Starting Material

Abstract

A large number of diversely functionalized analogs of the bioactive natural products neocryptolepine and isocryptolepine have been prepared from a series of 3-bromoquinoline derivatives. The neocryptolepines were obtained by a Pd 0catalyzed CÀ C bond coupling followed by CÀ N bond formation in yields up to 80 %, whereas the indoloquinolines were prepared by a Suzuki-Miyaura cross-coupling followed by azidation-photochemical cyclization in yields ranging from traces to 95 % yield.

Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds

“…These studies showed that in addition to substrate 31 , substituted indoloquinolines were R 1 was either trifluoromethoxy (95 % yield), methyl (91 % yield), or fluorine (84 % yield) with the remaining R‐groups being hydrogen was formed in good yields (Scheme 13). [30] Other functional groups in this position gave relatively poor yields. For example, when R 1 was a methoxy group the indoloquinoline was only formed in 49 % yield.…”

“…Irradiating aryl azide 45 in α,α,α-trifluorotoluene with a 125 W medium-pressure mercury lamp at room temperature at primarily 254 nm gave a clean conversion to the desired product in 95 % yield after a simple work-up. [30] The conditions developed for the photolytic conversion of aryl azide 45 to indoloquinoline 31 was also used in order to prepare a range of analogues of compound 31. These studies Scheme 10.…”

“…At the end these explorations did not return ideal conditions achieving our ultimate goal of tunable conditions, however, during our solvent screening we discovered the ideal solvent for converting aryl azide 45 to substrate 31 (Scheme 12). Irradiating aryl azide 45 in α,α,α‐trifluorotoluene with a 125 W medium‐pressure mercury lamp at room temperature at primarily 254 nm gave a clean conversion to the desired product in 95 % yield after a simple work‐up [30] …”

“…When we reversed the order of reactions and subjected 3‐bromo‐ N ‐methylquinolinium iodide ( 46 ) and boronic acid 29 to the palladium catalyzed Suzuki‐Miyaura cross‐coupling conditions a cascade reaction took place resulting In the formation of neocryptolepine ( 2 ) in good yield over the three steps (80 %, when X=I) (Scheme 14). [30] Changing the counter ion to OTf − or MeSO 4 − resulted in a dramatic drop in yield possibly due to different properties of the counter ion, although the exact nature of the counter ion's role was never resolved. A potential reason could however be that the counter ion is instrumental in stabilizing a key intermediate in the reaction, a phenomenon which is well documented within gold catalysis [32] …”