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

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward SNAr ring closure. A control experiment established that the initial reaction was an SN2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the SNAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O2, the expected dihydroquinolines were formed, while in the presence of O2, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed.


Comment
The displacement ellipsoids were drawn at the 50% probability level.

Experimental
A colorless, plate-shaped crystal of dimensions 0.044 x 0.196 x 0.258 mm was selected for structural analysis. Intensity data for this compound were collected using a D8 Quest -geometry diffractometer with a Bruker Photon II CMOS area detector [1,2] and an Incoatec Is microfocus Mo K source ( = 0.71073 Å ). The sample was cooled to 100(2) K. Cell parameters were determined from a least-squares fit of 7723 peaks in the range 2.85 <  < 28.73°. A total of 21066 data were measured in the range 2.848 <  < 28.786° using and oscillation frames. The data were corrected for absorption by the empirical method [3] giving minimum and maximum transmission factors of 0.6236 and 0.7458. The data were merged to form a set of 3242 independent data with R(int) = 0.0490 and a coverage of 99.8%.
The orthorhombic space group P212121 was determined by systematic absences and statistical tests and verified by subsequent refinement. The structure was solved by direct methods and refined by full-matrix least-squares methods on F 2 [4,5]. The positions of hydrogens bonded to carbons were initially determined by geometry and were refined using a riding model. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atom displacement parameters were set to 1.2 times the isotropic equivalent displacement parameters of the bonded atoms. A total of 172 parameters were refined against 3242 data to give wR(F 2 ) = 0.0766 and S = 1.007 for weights of w = 1/[ 2 (F 2 ) + (0.0220 P) 2

Comment
The displacement ellipsoids were drawn at the 50% probability level.

Experimental
A yellow, plate-shaped crystal of dimensions 0.028 x 0.152 x 0.248 mm was selected for structural analysis. Intensity data for this compound were collected using a D8 Quest -geometry diffractometer with a Bruker Photon II CMOS area detector [1,2] and an Incoatec Is microfocus Mo K source ( = 0.71073 Å ).
The sample was cooled to 100(2) K. Cell parameters were determined from a least-squares fit of 7081 peaks in the range 2.76 <  < 25.64°. A total of 21764 data were measured in the range 2.758 <  < 25.821° using and  oscillation frames. The data were corrected for absorption by the empirical method [3] giving minimum and maximum transmission factors of 0.5330 and 0.6463. The data were merged to form a set of 2763 independent data with R(int) = 0.0762 and a coverage of 99.9%.
The monoclinic space group Cc was determined by systematic absences and statistical tests and verified by subsequent refinement. The structure was solved by dual-space methods and refined by full-matrix least-squares methods on F 2 [4,5]. The positions of hydrogens bonded to carbons were initially determined by geometry and were refined using a riding model. The hydrogens bonded to N3 was located on a difference map, and its position was refined independently. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atom displacement parameters were set to 1.

Comment
The displacement ellipsoids were drawn at the 50% probability level.

Experimental
A colorless, block-shaped crystal of dimensions 0.106 x 0.272 x 0.280 mm was selected for structural analysis. Intensity data for this compound were collected using a D8 Quest -geometry diffractometer with a Bruker Photon II CMOS area detector [1,2] and an Incoatec Is microfocus Mo K source ( = 0.71073 Å ). The sample was cooled to 110(2) K. Cell parameters were determined from a least-squares fit of 9898 peaks in the range 2.91 < < 32.61°. A total of 39073 data were measured in the range 2.468 < < 32.644° using and  oscillation frames. The data were corrected for absorption by the empirical method [3] giving minimum and maximum transmission factors of 0.7806 and 0.8623. The data were merged to form a set of 6040 independent data with R(int) = 0.0288 and a coverage of 99.9 %. The orthorhombic space group P212121 was determined by systematic absences and statistical tests and verified by subsequent refinement. The structure was solved by direct methods and refined by full-matrix least-squares methods on F2 [4,5]. The positions of hydrogens were initially determined by geometry and were refined using a riding model. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atom displacement parameters were set to 1.2 (1.5 for methyl) times the isotropic equivalent displacement parameters of the bonded atoms. A total of 227 parameters were refined against 6040 data to give wR(F 2 ) = 0.0896 and S = 1.005 for weights of w = 1/[ 2 (F 2 ) + (0.0580 P) 2