Aromatic tetrahydroquinoline

Tetrahydroisoquinoline is a stronger base than tetrahydroquinoline. The unshared electron pair of tetrahydroquinoline is delocalized into the aromatic ring, and this substance resembles aniline in its basicity, whereas tetrahydroisoquinoline resembles an alkylamine. 

It can be assumed that, in the presence of InCl3 and water, the cyclic enol ethers 2-618 form a hydroxy aldehyde which reacts with the aniline to give an aromatic im-inium ion. This represents an electron-poor 1,3-butadiene which can undergo a hetero-Diels-Alder reaction [323] with another molecule of 2-618 to give a mixture of the diastereomeric tetrahydroquinolines 2-619 and 2-620. 

A variety of natural products and pharmaceutical agents contain a tetrahydroquinoline moiety [31]. Recently, a simple and general access to these heterocycles by a so-far unknown domino reaction of aromatic nitro compounds 7-65 and 2,3-dihydrofuran mediated by indium in water has been described by Li and coworkers (Scheme 7.19) [32]. It is assumed that the process is initiated by reduction of the nitro group in 7-65 to give the aniline 7-66 on treatment with indium in... 

Asymmetric aza Diels-Alder reactions provide a useful route to optically active heterocyclics such as piperidines and tetrahydroquinolines.45 Although successful examples of diastereoselective approaches had been reported as early as 10 years ago,46 only recently have enantioselective reactions been accomplished.47 For example, the reaction of chiral amine-derived aromatic imine 115 with Brassard s diene 116 gives adduct 117 with up to 95% diaster-eoselectivity (Scheme 5-37).48... 

Zhang J, Li C-J (2002) InCl3-catalyzed domino reaction of aromatic amines with cyclic enol ethers in water a highly efficient synthesis of new L2,3,4-tetrahydroquinoline derivatives. J Org Chem 67 3969-3971... 

Sridharan V, Avendano C, Menendez JC (2007) CAN-catalyzed three-component reaction between anilines and alkyl vinyl ethers stereoselective synthesis of 2-methyl-1,2,3,4-tetrahydroquinolines and studies on their aromatization. Tetrahedron 63 673-681... 

Imines derived from aniline and glyoxylic acid esters can be regarded as electron-poor 2-azadienes, in which an aromatic carbon—carbon double bond takes part of the diene system. In this context, Prato and Scorrano et al. were able to achieve the [4 + 2] cycloaddition of ethyl N-phenyl glyoxylate imines with dihydrofuran and indene leading to hexahydrof-uro[3,2-c]- and tetrahydro-7//-indeno[2,l-c]quinolines, respectively, in moderate to good yields (88JHC1831). Similarly, tetrahydroquinoline derivatives were formed by [4 + 2] cycloaddition of 1,2-bis(trimethylsily-... 

The enantioselective hydrogenation of olefins, ketones and imines still represents an important topic and various highly enantioselective processes based on chiral Rh, Ru or Ir complexes have been reported. However, most of these catalysts failed to give satisfactory results in the asymmetric hydrogenation of aromatic and heteroaromatic compounds and examples of efficient catalysts are rare. This is especially the case for the partial reduction of quinoline derivatives which provide 1,2,3,4-tetrahydroquinolines, important synthetic intermediates in the preparation of pharmaceutical and agrochemical products. Additionally, many alkaloid natural products consist of this stmctural key element. 

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. 

Protonated phenols and phenol ethers formed in superacids can be trapped by aromatics (benzene, naphthalene, tetrahydroquinoline). The products are either cyclohexenone derivatives301 [Eq. (5.112)] or aryl-substituted phenols. In the reaction of phloroglucinol with benzene, the diphenyl-substituted derivative is the main product [Eq. (5.113)], whereas 1,3,5-trimethoxybenzene gives selectively the monophenyl derivative (80% yield). Protonated dicationic species, such as 76, detected by Olah and Mo302 using NMR, were suggested to be intermediates in these processes. 

The procedure has also been applied for the hydroxylation of aromatic amines. Aniline and its /V-alkyl-substimted derivatives show similar behavior under similar conditions to afford the meta-substi tuted aminophenols as the major hydroxylated product.627 Product formation was interpreted by the attack of protonated hydrogen peroxide on the anilinium ion protected by /V-protonation from oxidation or degradation. Indoles, indolines, and tetrahydroquinoline have also been successfully hydroxylated with H202 in HF-SbF5 with the hydroxyl group meta to the nitrogen function.559,628 Hydroxylation of tryptophane and tryptamine derivatives affords pretonine and serotonine derivatives in 42% and 38% yields, respectively.629... 

A 1,3-dipolar cycloaddition using oxime derivatives yielded the tetrahydroquinoline derivative 25 (Equation 58) <2005S3423>. It was advantageous that the product precipitated out of the aqueous reaction medium in excellent yield. Carbenoid-insertion reactions have been demonstrated to produce the ring-extended quinolone structure 26 from simple substituted anilines (Equation 59) <2003TL7433>. The C-H insertion onto the aromatic ring can vary. 

An InCl3-catalyzed domino reaction of aromatic amines and cyclic enol ethers has been reported and gives rise in good yields to a range of 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines <2002JOC3969>. 

The use of aromatic imines to produce tetrahydroquinolines has been shown to be promoted by the use of bismuth(m) chloride and triflate catalysts <2000SL1160>. 

A three component coupling reaction of A-acetyl-2-azetine, aromatic imines and aromatic amines allows a rapid stereoselective entry to 2,3,4-trisubstituted tetrahydroquinolines, via fused tricyclic azetidines 1 <02CC444>. Fused heterocycles 1 were formed through an aza Diels-Alder reaction between aromatic imines and A-acetyl-2-azetine, which acts as an enamide substrate. This strategy has been used for the formal synthesis of luotonin A <02TL5469>. 

Tetrahydroquinoline derivatives can be obtained by cycloaddition of aromatic imines or immonium salts with enamines having an a-hydrogen186,187. Anodic oxidation of A,A-dimethylaniline 323 in methanol to a-methoxylated compound 324 and subsequent... 

In a new synthetic protocol Shi et al. synthesized 1,2,3,4-tetrahydroquinolines 107 by a Lewis acid-catalyzed reaction of arylvinylidenecyclopropanes 108 and ethyl(arylimino)acetates 109 <070L1805>. When R3 is an electron-rich aromatic group, the... 

The authors first considered the attachment of the aldehyde component to the SP using the AMEBA (acid-sensitive methoxy benzaldehyde) PS resin (100). 4-Carboxy-benzaldehyde and two different amines were reacted to produce the resin-bound intermediates 6.1 and 6.2 on a 100-g scale according to the reaction scheme shown in Pig. 6.9, with good yields resulting from an optimization of the reaction conditions. Resin-bound 6.1 was reacted with the standard olefin (cyclopentadiene, 6.3) and an aromatic amine (aniline, 6.9) and, after optimization of the reaction conditions, the desired tetrahydroquinoline 6.14 was obtained in good yield and purity after cleavage. 

A series of A-substimted 4-aryl-4,6,7,8-tetrahydroquinoline-2,5(l//,3/f)-diones 63 has been synthesized by Tu and co-workers [110] through a rapid one-pot four-component reaction of an aldehyde, Meldrum s acid, a 1,3-cyclohexanedione and an amine in ethanol under microwave irradiation. This method allows the introduction of substiments at the nitrogen of octahydroquinolones 63. The reaction has a wide scope as different aromatic aldehydes and a variety of amines (including aliphatic and aromatic) are well tolerated in this four-component condensation (Scheme 47). 

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). 

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