Unprecedented regio and stereocontrol in Povarov reaction of benzylidene-(3-nitrophenyl)amine

Abstract

Typically, Povarov reactions of imines derived from aromatic amines and aromatic aldehydes show poor exo/endo-stereoselectivity and to date no data is available on the regioselectivity of the cyclisation when 3-substituted imines are employed. We have demonstrated that reaction using acyclic enamides as the alkene component with 3-nitro substituted imines is completely regioselective and gave only the 5-nitro substituted tetrahydroquinoline. As a bonus the reaction also became completely exo-selective with the stereochemistry of the E-alkene preserved in the tetrahydroquinoline product.

One-Pot Diastereoselective Synthesis of Tetrahydroquinolines from Star Anise Oil in a Choline Chloride/Zinc Chloride Eutectic Mixture

“…Therefore, in the case of m -chloro-substituted intermediate G, the electron density at the para-position (with respect to the Cl position) could be much greater than that at the ortho-position; in contrast, the electron density at the para-position of m-nitro-substituted intermediate G could be much lesser than that at the ortho-position. Similar results were reported by Stevenson and Graham . In light of these results, theoretical studies on the regioselectivity of this particular reaction are currently underway.…”

“…Similar results were reported by Stevenson and Graham. 65 In light of these results, theoretical studies on the regioselectivity of this particular reaction are currently underway.…”

Multicomponent reaction access to complex quinolines via oxidation of the Povarov adducts

“…In this context, it is possible to obtain a wide variety of complex tetrahydroquinolines through the Povarov MCR (the interaction of anilines, aldehydes and activated olefin inputs under acid catalysis) [ 4 – 8 ]. Interestingly, this process allows cyclic enol ethers and enamines to be used as electron-rich alkenes, leading to heterocycle-fused tetrahydroquinolines, usually as a mixture of stereoisomers [ 9 – 13 ]. Unfortunately, no general methods for enantioselective Povarov reactions have been developed (for examples of catalytic enantioselective transformations operating in particular systems, see [ 14 – 15 ]), and this constitutes a serious drawback in the use of this reaction for library preparation, as one reaction affords several products, when ideally it should give only one.…”

“…One of the most commonly used is DDQ, which affords quinolines in acceptable yields. The main advantages of this oxidizing agent lie in its chemoselectivity and a requirement for relatively mild conditions, allowing it to be used in the presence of a wide range of substituents of the starting tetrahydroquinoline, such as O-, N- and C-linked residues ( Scheme 2 ) [ 8 – 9 12 – 13 16 – 18 ]. Unfortunately, the alternative oxidation–elimination products ( 5 and 8 ) are often observed, therefore suggesting an acid catalyzed process.…”

The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

“…The Povarov reaction and its variants can be catalyzed by a wide variety of Brønsted and Lewis acids: BF 3 ·Et 2 O, 33 34 35 36 37 38 39 40 BiCl 3 , 41–44 CAN, 45 46 47 48 49 50 51 cerium sulfate, 52 Amberlyst 15, 53 phthalic acid, 54 p -toluenesulfonic acid 55 56 and its supramolecular analogue CX4SO 3 H, 57 ferric sulfate, 58 59 60 iodine, 61 62 63 InCl 3 , 64 65 66 67 68 69 NH 4 Br, 70 Sc(OTf) 3 , 71 72 73 74 75 and Sc(III)-loaded resin, 76 Y(OTf) 3 , 77 78 79 80 81 bistriflimide, 28 TFA 82 and zinc chloride. 83 Moreover, mixed catalytic systems may be employed, such as Ca(OTf) 2 /Bu 4 NPF 6 84 and CeCl 3 /NaI.…”