3- substituted tetrahydroquinolines

The asymmetric addition of different types of nucleophiles at the C-l position of 3,4-dihydroisoquinolines were highlighted in a number of publications. Schreiber et al. described an enantioselective addition of terminal alkynes 136 to 3,4-dihydroisoquinolinium bromide 137 in the presence of triethylamine, catalytic copper bromide, and QUINAP <06OL143>. The resulting 1-substituted tetrahydroquinolines 138 were isolated in high yield and high enantiomeric excess in most cases. 

Zhang W, Guo YP, Liu ZG, Jin XL, Yang L, Liu ZL (2005) Photochemically catalyzed Diels-Alder reaction of arylimines with N-vinylpyrrohdinone and N-vinylcarbazole by 2,4,6-triphenylpyrylium salt synthesis of 4-heterocycle-substituted tetrahydroquinoline derivatives. Tetrahedron 61 1325-1333... 

Bismuth(III) Bromide-Catalyzed Synthesis of Substituted Tetrahydroquinoline Derivatives... 

Substituted tetrahydroquinoline derivatives are of considerable interest due to the range of their biological activities and presence in a variety of natural products... 

Scheme 5 Bismuth(III) bromide-catalyzed synthesis of substituted tetrahydroquinoline derivatives...

Rogers JL, Emat JJ, Yung H, Mohan RS (2009) Environmentally friendly organic synthesis using bismuth compounds Bismuth(III) bromide catalyzed synthesis of substituted tetrahydroquinoline derivatives. Catal Commun 10 625-626... 

The Lewis acid-catalyzed three-component reaction of dihydropyridines, aldehydes, and />-substituted anilines efficiently yields highly substituted tetrahydroquinolines in a stereoselective manner, through a mechanism believed to be imine formation followed by formal [4-1-2] cycloaddition (Scheme 41). The 1,4-dihydropyridine starting materials were also prepared in situ by the nucleophilic addition of cyanide to pyridinium salts, creating in effect a one-pot four-component reaction <20030L717>. 

The Brpnsted acid catalyzed hydrogenation of quinolines with Hantzsch dihydropyridine as reducing agent provides a direct access to a variety of substituted tetrahydroquinolines (Table 4.2). The mild reaction conditions of this metal-free reduction of heteroaromatic compounds, high yields, operational simplicity and practicability, broad scope, functional group tolerance and remarkably low catalyst loading render this environment-friendly process an attractive approach to optically active tetrahydroquinolines and their derivatives (Table 4.3) (see page 176). ... 

The enantioselective synthesis of 3-substituted tetrahydroquinolines was achieved with 98% ee starting from o-nitrocinnamyl intermediates and using rhodium-catalyzed asymmetric hydrogenation, with subsequent cyclization yielding the heterocycle (Scheme 10) <20010L2053>. In an analogous fashion, Sharpless epoxidation of similar o-nitrocinnamyl alcohols yields 3-substituted tetrahydroquinolines with 90% ee. 

A -Arylfluoroalkylimines can act as heterodienes, involving the unsaturation of the aryl substituent, when they react with enol ethers in the presence of Lewis acids. The reaction is highly stereoselective and provides trifluoromethyl-substituted tetrahydroquinolines, e.g. 6 and 7. Such imines also react in a similar way with cyclopentadiene however, with highly reactive dienes, such as 1 -methoxy-3-(trimethylsiloxy)buta-l.3-diene, they act as dienophiles (see Section... 

In a similar manner a series of substituted tetrahydroquinolines were synthesized using a Lewis acid catalyzed intramolecular halo-arylation. This process was shown to be a regio- and stereoselective method that provided products in moderate to high yield <05TL8599>. 

There are few examples of enantioselective reductions of imines bearing chiral substituents. According to Polniaszek and Dillard [139], reduction ofimmin-ium salts 6.23 by NaBHLj, followed by hydrogenolysis, leads to nonracemic-substituted tetrahydroquinolines. To observe a high asymmetric induction, it is necessary to introduce a 2,6-dichlorophenyl group on the chiral substituent (Figure 6.19). 

Carling, R.W., Leeson, P.D., Moseley, A.M., Smith, J.D., Saywell, K., Tricklebank, M.D., Kemp, J.A., Marshall, J.R., Foster, A.C., Grim-wood, S., 1993. Anticonvulsant activity of glycine-site NMDA antagonists 2. Trans 2-carboxy-4-substituted tetrahydroquinolines. Bioorg. Med. Chem. Lett. 3, 65-70. 

The synthesis of azatitanacyles was achieved intermolecularly from the reaction of imines 63 and Grignard reagents in the presence of Ti(0-/-Pr)4. Treatment of the titanium species with electrophiles yielded the corresponding substituted tetrahydroquinoline 64 in good yields <04TL9037>. 

The three component condensation employing aldehydes, anilines and electron-rich olefins leading to substituted tetrahydroquinolines 93 constitutes an attractive approach for combinatorial and parallel synthesis (Scheme 3.6.13). 

Functionalized 3-substituted tetrahydroquinolines were prepared in highly enantioselective fashion from o-nitrocinnamyl intermediates prepared from 53 (Scheme 4). Rhodium catalyzed asymmetric hydrogenation of 54 afforded intermediate 55 (-98% ee) which was converted to tetrahydroquinoline 56. Similarly, Sharpless epoxidation of 57 afforded intermediate 58 (-90% ee) which was converted to tetrahydroquinoline 59 <010L2053>. Trans- and cis- i-hydroxy-4-phenyl-l,23,4-tetrahydroquinolines were prepared from the corresponding aniline and (2/ , VR ) or (2, l 5 )-2-(a-bromobenzyl)oxirane with good selectivity. These tetrahydroquinoline derivatives can be converted to 4-phenylquinolines <01H1249>. 

FIGURE 23.10 Optimization of activity and specificity of 7-substituted tetrahydroquinolines by MLR. 

The aza-Diels-Alder reaction can also be used as a convenient method for the synthesis of substituted tetrahydroquinolines by in situ generation of azadiene compounds, generated from the appropriate carbonates, and its reaction with dienophiles. ... 

A variety of 2-aryl-substituted tetrahydroquinolines were already synthesized with excellent enantioselectivities under the conditions developed by Rueping s group, but 2-alkyl-substituted tetrahydroquinolines in lower enantioselectivities (87-91% ee). With the use of this new phosphoric acid, Du reported that a low catalyst loading (0.2 mol%) was sufficient to obtain excellent enantioselectivities of up to 98% ee for 2-aryl- and 2-alkyl-substituted quinolines. Best results were obtained with i-Pr and cyclohexyl derivatives, likely due to the increased steric effects. 

Michael addition of MeN02 to enone (168), followed by cyclization, has been reported to produce substituted tetrahydroquinolines (169) in <20 1 dr and >98% ee upon a reaction catalysed by various bifunctional thioureas. The first step, that is, the key Michael addition, is believed to involve the activation of both substrates (170), which however portrays a coordination that is the opposite to the generally accepted mechanism. ... 

Normally, the A-arylimine is obtained by reaction of aldehyde and aniline in acidic condition. Either tetrahydroquinoline or its corresponding substituted quinoline can be generated in the Povarov reaction, depending on the reaction conditions. For instance, DDQ-promoted dehydrogenation, vacuum distillation under acidic condition, oxidation by air or Mn(OAc)3, and Pd/C-catalyzed aromatization of tetrahydroquinoline, provides the corresponding substituted quinolines in good to excellent yield. Since some tetrahydroquinolines are unstable under the reaction conditions, the corresponding substituted quinolines could be isolated as the sole products. Electron-rich olefin, such as vinyl enol ethers, vinyl sulfides, and silyl enol ethers, are widely used as dienophiles in the cycloaddition of A-aryl aldimines to obtain substituted tetrahydroquinolines. To access natural... 

Using Ln(OTf)3 catalyst, Batey demonstrated that the three-component Povarov reaction generated highly functionalized C-2 aliphatic-substituted tetrahydroquinolines 45, which were inaccessible previously using the traditional Povarov reaction, due to the instability of the aliphatic iV-arylaldimine. It is interesting that cyclopentadiene was used as the dienophile in this new process. ... 

Recently, Jacobsen developed a new strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a chiral urea 95 interacts with the highly reactive intermediate through a network of noncovalent interactions. This interaction leads to an attenuation of the reactivity of the iminium ion and allows high enantioselectivity in the Povarov reaction, giving lactam-substituted tetrahydroquinoline derivatives 98 in excellent enantioselectivities and diastereoselectivities. ... 

Reagent-free synthesis of 2,3,4-poly-substituted tetrahydroquinolines application to the formal synthesis of (+/-)-martinellic acid and martinelline. 

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