Abstract
2-Substituted tetrahydroquinoline moieties are frequently found in biologically active molecules. Several of these compounds are naturally occurring and many relatively simple synthetic 2-substituted tetrahydoroquinolines are already used or have been tested as potential drugs. Consequently, 2-substituted tetrahydroquinolines have been a significant subject of synthetic studies of biologically active compounds. Herein, we described a new efficient synthesis of 2-substituted tetrahydroquinolines achieved by the domino reaction of N-indanyl(methoxy)amines, which consists of three types of reactions: elimination of an alcohol, rearrangement of an aryl group, and addition of an organolithium or magnesium reagent. The synthetic utility of this approach is demonstrated by the syntheses of (±)-galipinine and (±)-martinellic acid. The domino reaction of N-indanyl(methoxy)amine (5) with various organometallic reagents proceeded smoothly to afford 2-substituted tetrahydroquinolines 6a-e in very short reaction time. We next investigated the domino reaction of substituted N-indanyl(methoxy)amines 7a-d. As shown in Table 2, these reactions also proceeded effectively to give 8a-h in good yields. In order to demonstrate the synthetic potential of this methodology, we performed syntheses of (±)-galipinine (16) and (±)-martinellic acid (17). The domino reaction of 5 with allylmagnesium bromide and N-methylation proceeded to give tetrahydroquinoline 11 in good yield. Then, olefin isomerization of 11 followed by cross metathesis with 14 and subsequently hydrogenation provided (±)-galipinine (16). We next applied the methodology to a formal synthesis of (±)-martinellic acid (17). The tricyclic methoxyamine 22 for the domino reaction was prepared from commercially available acetal 19. With the substrate for key reaction in hand, we next investigated the domino reaction of 22 with allylmagnesium bromide. The reaction, proceeded smoothly and stereoselectively to give the desired pyrroloquinoline. 23 in 94% yield as a sole product The brornination of 23 followed by hydroboration-oxidation of the resulting 'bromide 24 aftrded pyrrolot3,2-clquinoline 25, which is a. key intermediate used in the synthesis of (±)martinellic acid (17).
