Coupling quinoline

Quinoline derivatives have been substituted by nucleosides <94JCS(P1)2931> and by ert-butyl groups <95JOC(60)5390> via radical substitution reactions. Palladium-catalyzed cross coupling method has been used to couple quinoline triflates with acetylene <95T(51)3737>. 4-Quinolones, in contrast to 2-quinolones, react with peroxodisulfate anions in aqueous base to form 3-hydroxyquinolines via the 3-sulfate ester <95JCR(S)164>. 

In respect to the Suzuki and the Negishi couplings, quinoline stannanes provide an easy entry to highly substituted derivatives. As a highlighted example, 2-trimethylstannyl-5,8-dimethoxyquinoline reacts with appropriately substituted pyridyltriflate in the presence of palladium tetrakis-(triphenylphospine), lithium chloride, and copper bromide to produce 2-pyridylquinoline, an advance intermediate for the total syntheses of antitumor compounds streptonigrin and lavendamycin. ... 

This coupling works best when the halogen at the 7-position is bromine rather than chlorine or fluorine. This represents the first appUcation of this coupling reaction to the intact quinoline nucleus and thus represents an important advance in quinolone chemistry. 

The Doebner reaction is a three component coupling of an aniline (1), pyruvic acid (2), and an aldehyde (3) to provide a 4-carboxyl quinoline (4). That product can be decarboxylated to furnish quinoline 5. 

Doebner also found that under certain conditions (specifically cold ether), the result of the three-component coupling was not the quinoline but diketopyrrolidine 10." ... 

The preparation and use of derivatized Meldrum s acid has led to an alternative preparation of 2-substituted quinolines (49 and 50) and the preparation of pyridopyrimidines (52). When Meldrum s acid derivatives are used (as shown in this example) decarboxylation occurred under the cyclization conditions. Three component coupling has been used to readily assemble the desired 3-anilino-acrylate from reaction of Meldrum s acid, (EtO)3CH and an aniline (e.g. 54 or 55).< ... 

Dialkylquinolinyl boranes 83 and 86 were prepared from halogen/metal exchange of 3-bromoquinoline (70) with n-BuLi followed by quenching with Et2BOMe and Br-9-BBN, respectively. They are then coupled with bromides 84 and 87 to give 3-substituted quinoline derivatives 85 and 88, respectively (85H2375). 

Due to their successful synthesis of 2-(4 -chlorophenyl)-4-iodoquinoline from the corresponding precursor acetylene, Arcadi et al. (99T13233) developed a one-step synthesis of 2,4-disubstituted quinolines via palladium-catalyzed coupling reactions. An example is the Heck reaction of 4-iodoquinoline (131) with a-acetamidoacrylate (132). This one-pot synthesis yielded adduct 133 in 50% overall yield after purification via flash chromatography. 

Cacchi and Palmier (83T3373) investigated a new entry into the quinoline skeleton by palladium-catalyzed Michael-type reactions. They found that phenyl mercurial 134 was a useful intermediate for the synthesis of quinoline derivatives, and that by selecting the reaction conditions the oxidation level of the heterocyclic ring in the quinoline skeleton can be varied. On such example is shown in Scheme 16. PdCla-catalyzed coupling between organomercurial reagent 134 and enone 135 delivered adduct 136 which was subsequently cyclized to quinoline 137 under acidic conditions. 

In summary, palladium-mediated reactions, especially cross-coupling reactions have found many applications in quinoline synthesis. It is noteworthy that due to the a and S activation for the C(2) and C(4) positions, even 2-chloro- and 4-chloro-quinolines are viable substrates for palladium-catalyzed reactions under standard conditions. With the advent of the palladium chemistry and more commercially available organometallic substrates, more palladium-mediated quinoline syntheses are to be added to the repertoire of quinoline chemistry. 

Scheme 19 Synthesis of quinolines by iron(III)-catalyzed three-component coupling/hydroaryla-tion of aldehydes, alkynes, and amines...

General procedure for Heck coupling. A mixture of POPd (16.0 mg, 6 mol%), quinoline derivative (0.56 mmol), tert-butyl acrylate (356 mg, 2.8 mmol), and base (0.61 mmol) was stirred in 5 mL of anhydrous DMF at 135 °C for 24 h. The reaction mixture was allowed to cool to room temperature, quenched with water, and extracted with Et20. The combined organic layers were washed with water, dried over MgS04, and the solvents were removed under vacuum. The crude products were purified by flash chromatography on silica gel. 

It is of primary interest to avoid corrosive mineral acids in synthetic processes. This can easily be achieved by use of acidic solid supports coupled with microwave irradiation. This has been applied to the preparation of quinolines [53] (Scheme 8.35). This procedure is a safe, green alternative to the use of H2S04 at more than 150 °C. In the same way, quinoxaline-2,3-diones were prepared [54] by use of single-mode irradiation. Previous attempts in solution led to explosions, but the authors successfully used solvent-free conditions with acidic supports or catalysts (the best being p-toluenesulfonic acid) and irradiation times of 3 min (Scheme 8.36). 

Aniinophenyl)-a,(J>-ynones react with nitrile oxides by domino [3 + 2] cycloaddition/annulation reactions, giving rise to isoxazolo[4,5-c]quinolines in satisfactory yields (434). Nitrile oxides undergo addition to allylzinc bromide to generate 5-butenylisoxazolines in good yields. The domino reaction combines 1,3-cycloaddition with Wurtz coupling (435). 

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