5.6.7.8- tetrahydroquinoline alkene

Lanthanide triflates catalyze the Diels-Alder reaction of imines, generated from anilines and aldehydes, with both dienes and alkenes [26]. Thus N-benzyl-ideneaniline in the presence of Yb(OTf)3 (Scheme 6.16) reacts in organic solvent with open-chain dienes, such as Danishefsky s diene, to give tetrahy-dropyridine derivatives, while with cyclopentadiene and vinylethers and vinylthioethers it works like azadiene in both organic solvent and aqueous medium, affording tetrahydroquinoline derivatives. 

Kwong and Lee [39] prepared various chiral 2,2 6, 2"-terpyridines and tested them as copper ligands for the cyclopropanation of alkenes. High enantioselectivities were obtained, the presence of bulky alkyl groups at the 8-position of the tetrahydroquinoline ring being crucial (structure 29 in Scheme 17). Thus when = Bu, up to 90% ee for the trans and 94% for the cis isomer were obtained by performing the reaction at 0 °C (transIds = 69/31). 

A partially soluble polyallylscandium triflamide ditriflate 45 was prepared and used to catalyze a three-component coupling reaction.67 An aldehyde, an aromatic amine, and an alkene were mixed in the presence of the catalyst to afford tetrahydroquinolines (equation 17). The catalyst was recovered from the reaction mixtures by precipitation with hexane and could be recycled without loss of activity. Another polymer-supported scandium catalyst was prepared by treating Nafion with scandium chloride to afford the Nafion-scandium catalyst 46.68 This catalyst was used in allylation reactions of carbonyl compounds by tetraallyltin (equation 18). It could be easily recovered by filtration and reused without appreciable loss of activity. 

Figure 15.14. Preparation of tetrahydroquinolines from anilines, aldehydes, and alkenes.

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

Fig. 6.10. The resin (15 g) was partitioned into 60 aliquots of 250 mg in 60 glass vials, and each was treated with an aniline and an olefin as 0.5 M solutions in acetonitrile in the presence of 2% TFA at room temperature for 24 h. The resin in each vial was filtered, washed, and dried and the product cleaved from the support with 15% TFA-DCM. The library individuals were obtained as solids (>80% by HPLC) after evaporation and trituration of the crude residue with Et20, with the yields reported in Table 6.1. The reactions proceeded well for alkenes 6.3-6.7 (60-84% yields), the only detectable impurities being the corresponding Schiff bases (5-10%). Alkene 6.8 gave poor yields of the desired product or failed to react completely in some cases (see Table 6.1). All of the tetrahydroquinolines were obtained as single diastereomers, as shown for compounds 6.14 and 6.15 (Fig. 6.10).

The synthesis of functionalized 8-hydroxy-l,2,3,4-tetrahydroquinolines 77 has been reported by Dai and co-workers [119] in moderate to good yields via an aza-Diels-Alder reaction of an 2-aminophenol, a substituted benzaldehyde and a cyclic alkene catalyzed by TFA under controlled microwave irradiation in acetonitrile. In general, when electron deficient aromatic aldehydes were used, the adducts could be isolated in 39-59% yields with a predominance of the trans isomer (Scheme 58). 

Virantmycin is a tetrahydroquinoline alkaloid that has inhibitory activity against DNA and RNA viruses. A total synthesis of virantmycin making use of a key type II aziridine has elucidated the absolute stereochemistry at C-2 and C-3 <1996T10609>. An intramolecular photocyclization of an azide onto a Z-alkene produces type II aziridine 351 in excellent yield. A three-step reduction/selective reoxidation procees yields key aziridine alcohol 352 in 76% overall yield (Scheme 71). The alcohol is methylated and the ester hydrolyzed without harm to the azirdine. A TFA-induced ring opening of the aziridine by chloride provides the natural product virantmycin in good yield. This entire process was also carried out with the -alkene to produce /)(-virantmycin, thus proving the stereochemistry at C-2 and C-3. 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have been examined. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, benzaldehyde was treated with aniline and Danishefsky s diene. The desired three-component reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in 83 % yield (Eq. 9) [24b]. Under the same reaetion conditions, cyclopentadiene was used instead of Danishefsky s diene to afford the corresponding tetrahydroquinoline derivative (Eq. 10). Different combinations of aldehydes, amines, and alkenes are possible in these reactions, and afford diverse tetrahydroquinoline derivatives in high yields. 

Styryl derivatives of 2-aminofurans, as well as alkenyl compounds, also undergo intramolecular cycloaddition and the alkene function can be introduced by Stille coupling of a suitably functionalised aryl iodide. This approach is illustrated by the tetrahydroquinoline synthesis summarised in Scheme 26 (99JOC3595). The iodo derivative 143 is readily prepared from the carbamate ester 142 (67% yield) and Stille coupling with vinyltributyltin gives the styrene 144 (72% yield). Intramolecular cycloaddition and dehydration is then achieved simply by heating compound 144 in toluene under reflux (24 h) to give the tetrahydroquinoline 145 in 79% yield. 

An inverse electron demand aza D A reaction of electron rich alkenes with N aryl imines as 2 azadiene (Povarov reaction) provides tetrahydroquinolines. Reactions catalyzed by chiral phosphoric acids yielded different absolute ste reochemical outcomes when ethyl vinyl efher and enecarbamate are employed as electron rich alkenes, although chiral phosphoric acids have the same axial chirality in both cases (see Scheme 3.26). 

The reverse eledron-demand aza-Diels-Alder reaction of eledron-rich alkenes with 2-azadienes was catalyzed by 21 j to give tetrahydroquinoline derivatives in favor of the ds-isomer with excellent enantioselectivities (Equation 10.44) [91]. 

Aniline that is orf/io-substituted with a hexa-2,5-dienyl side-chain undergoes catalytic, palladium-assisted cyclization to 2-propylquinoline (Scheme 34) this is only one of a series of ring-closure reactions involving palladium-promoted nucleophilic attack on an alkene. A tetrahydroquinoline (55) is produced by the action of trifluoroacetic acid on the hydroxylamine (54). This method has also been used to prepare l,4-benzoxazines. ... 

Condensations with alkenes. In the presence of LiBp4 iminium species are generated. Trapping of these species with dienes and alkenes provides tetrahydropy-ridinium salts or 1,2,3,4-tetrahydroquinolines. 

Anodic oxidation of N, N.-dimethylaniline in methanol yields the -methoxylated derivative (72), which reacts with substituted alkenes in the presence of Lewis acid to give a wide range of tetrahydroquinolines (e.g. 73).94- The adduct (75) from N-methylaniline and allene-1,3-dicarboxylic acid dimethyl ester (7 ) can be converted into the 4-quinolone (76) on treatment with polyphosphoric acid. 95 The use of nitrobenzenes as quinoline precursors is exemplified by the reaction sequence depicted in Scheme 17. The transition-metal-catalysed transformation is thought to involve the reduction of the nitrobenzene to the corresponding aniline via a nitrene intermediate.96... 

Polymeric catalysts. A very useful modification of the catalyst is obtained by ligand exchange with a (polyallyl)triflamide, forming polymer-bound scandium triflamide bistriflate. The catalyst has been used in the combinatorial synthesis of a tetrahydroquinoline library from anilines, aldehydes, and alkenes. A related catalyst prepared from ScClj-bHjO and Nafion is effective in several useful synthetic reactions, including allylation, Diels-Alder reaction, and Friedel-Crafts acylation. ... 

Aziridine-2-carboxylic esters are preparecf from hexahydro-l,3,5-triazines with alkyl diazoacetates in the presence of SnCl,. A-Tosylmethylanilines apparently also undergo ionization to generate iminium species that are interceptable by alkenes 1,2,3,4-Tetrahydroquinolines are formed. ... 

The titanium (Il)-alkene complex reacts with the A-propargylated anthranilic acid derivative to provide the quinolinone 37 <97JA6984>. The reaction also works well with N-allyl derivatives giving the cyclopropyl-fused tetrahydroquinoline. 

Intramolecular addition reactions of arenes and aryl olefins with secondary and primary amines have proven to be of broader scope than the analogous reactions with tertiary amines. The intramolecular addition of nonconjugated o-allylanilines 51 to yield the 2-methylindolines 52 was reported by Koch-Pomeranz et al. in 1977. Intramolecular electron transfer from the singlet aniline to the ground state alkene followed by N-H proton transfer to the alkene terminal carbon was proposed to account for the regioselective formation of indolines. Proton transfer to the internal carbon would yield tetrahydroquinolines, which were... 

The [Ir(ppy)2bpy] complex photo-catalyses inter- and intramolecular C-H functionalisation reactions of tertiary amines under the visible light irradiation. Oxygen behaves as a chemical switch, triggering different reaction pathways and leading to different products from the same starting material. In anaerobic conditions, the intermolecular addition of iV,iV-dimethyl-anilines to electron-deficient alkenes yields y-amino nitriles. Aerobic conditions, on the other hand, favour a radical addition/ cyclisation reaction, leading to tetrahydroquinoline derivatives. The intramolecular version of the radical addition produces unexpectedly indole-3-carboxaldehyde derivatives. ... 

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