Naphthalenes and Quinolines by Domino Reactions of Morita–Baylis–Hillman Acetates

Abstract

An efficient synthetic route to highly functionalized naphthalenes and quinolines has been developed using domino reactions between Morita–Baylis–Hillman (MBH) acetates and active methylene compounds (AMCs) promoted by anhydrous K2CO3 in dry N,N-dimethylformamide (DMF) at 23 °C. The substrates incorporate allylic acetates positioned adjacent to a Michael acceptor as well as an aromatic ring activated toward a SNAr ring closure. A control experiment indicated that the initial reaction was an SN2’-type displacement of a side chain acetoxy by the AMC anion to afford the alkene product bearing the added nucleophile trans to the SNAr aromatic ring acceptor. Thus, equilibration of the alkene geometry of the initial product was required prior to cyclization. Products were isolated in good to excellent yields. Numerous cases (24) are reported, and several mechanistic possibilities are discussed.

Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates

“…Finally, the difluoro-substituted substrate 7 showed dual reactivity under anaerobic versus aerobic conditions, giving dihydroquinolines 18 in the absence of O 2 and quinolones 19 when O 2 was present ( Table 3 ). As in our previous work [ 1 ], it was also noted that the 2-fluoropyridine (and 2,5-difluorophenyl) precursors were less reactive, requiring higher temperatures and longer reaction times (1 h, 23 °C and 5–6 h, 90 °C) for complete conversion. This appears to reflect the decreased activation of these acceptor rings in the final S N Ar ring-closing step.…”

“…While steric congestion around the alkene terminus is lower in carbocation E , it is difficult to envision any selectivity in producing only the Z alkene 16 with the added amine trans to the S N Ar acceptor. In our studies, here and elsewhere [ 1 ], a product having the added nucleophile cis to the acceptor ring was not observed. This could potentially rule out this mechanistic option, unless the cyclization of 17 is sufficiently fast that it is not possible to observe or isolate this intermediate.…”

“…The current project sought to develop an efficient route to dihydroquinolines and dihydronaphthyridines from MBH acetates. This work differs from our earlier contribution [ 1 ] in providing a route to the title heterocycles wherein a dihydropyridine is fused to a preexisting ring and cannot aromatize. The sequence was initiated by addition of a nitrogen rather than a carbon nucleophile and required mild heating, but no added base.…”

“…The Michael acceptors embedded in the side chains were either acrylate esters or acrylonitriles. These precursors were prepared by a Morita-Baylis-Hillman reaction using 1 equiv of the aromatic aldehyde, 2 equiv of the activated alkene and 1.2 equiv of 1,4-diazabicyclo[2.2.2]octane (DABCO) [ 1 ] in acetonitrile (2 days, 23 °C) to afford 86–98% yields. Acylation of the alcohol adducts with no allylic inversion was achieved in ≥95% yield after 30 min at 0 °C by treatment with acetic anhydride and catalytic trimethylsilyl trifluoromethanesulfonate, as has been previously described [ 1 , 24 ].…”

“…We recently disclosed a synthesis of 1,3,6-trisubstituted naphthalenes and 6,8-disubstituted quinolines from Morita-Baylis-Hillman (MBH) acetates and active methylene compounds (AMCs) in DMF with K 2 CO 3 at 23–90 °C [ 1 ]. This process formally involved S N 2′ displacement of the acetoxy group by the stabilized AMC anion, a second deprotonation, S N Ar cyclization and elimination to give the aromatic product.…”