Tetrahydroquinoline, formation

The mechanism of tetrahydroquinoline formation by the Povarov reaction has been debated. A stepwise mechanism involves ionic intermediate 13, followed by an intramolecular electrophilic substitution. A concerted hetero Diels-Alder reaction was proposed where a concerted asynchronous transition state 14 was suggested. 

The most surprising observation from low temperature reactions was the formation of adducts between good donor solvents (Tetralin, octahydrophenanthrene, tetrahydroquinoline) and acceptor radicals. The resulting adducts were not of a single predominant structure. In particular, several isomers of toluene-Tetralin were formed as well as di-Tetralin. Several of these reactions were done with D -Tetralin which permitted the firm identification of the Tetralin moiety in the adducts. GLC-MS studies indicated that the Tetralin may be bonded to phenyl, benzyl, benzyloxy- or phenoxy-groups, depending on the acceptor used. 

The antibacterial agent flumequine 280 was synthetized in optically active form by starting with resolution of the two enantiomers of a suitably substituted racemic tetrahydroquinoline through formation of the (lf )-3-bromocamphor-8-sulfonates. After N-alkylation of the (2K)-tetrahydroisoquinoline enantiomer 277 with diethyl ethoxymethylene-malonate to give 278, the quinolizidine system 279 was formed by acylation onto the peri-position. This compound was finally hydrolyzed to afford 280 (Scheme 60) <1999TA1079>. 

BJ Marsden, TM Nguyen, PW Schiller. Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence. Int J Pept Prot Res 41, 313, 1993. 

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

Reduction of quinolines in acid solution at a lead cathode or by dissolving zinc leads to attack on the heterocyclic ring with the formation of 4,4-coupled products, together with the tetrahydroquinoline [82,83]. In the case of 2- and 4-methyl substituted quinolines, dimeric products are obtained in 10 90 % yields. In these processes, dimerization of the one-electron addition product is in competition with further reduction to give the 1,4-dihydroquinoline, The latter is an enamine and it... 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

NJC641>. Similarly, the reaction of nitroarenes with TiOj, as a photocatalyst, in the presence of alcohols leads to the formation of the tetrahydroquinoline <99TL1145>. 

A few pyrolytic methods of synthesis are known, leading directly to the formation of pyridine rings by formation of the /3, y-bond. Alkylpyridines are obtained when unsaturated imines (116) or (117) are passed over heated zeolites (80IZV655) or alumina (72IZV2263). More dehydrogenation is achieved by the use of nickel or alumina, as in the synthesis of tetrahydroquinolines (118) or octahydrophenanthridine (119) (78IZV1446). 

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 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... 

Recently Liu and coworkers used (porphyrin)iron(III) chloride complex 96 to promote 1,5-hydrogen transfer/SHi reactions of aryl azides 95, which provided indolines or tetrahydroquinolines 97 in 72-82% yield (Fig. 24) [148]. The reaction starts probably with the formation of iron nitrenoids 95A from 95. These diradicaloids undergo a 1,5- or 1,6-hydrogen transfer from the benzylic position of the ortho-side chain. The resulting benzylic radicals 95B react subsequently with the iron(IV) amide unit in an Sni reaction, which liberates the products 97 and regenerates the catalyst. /V,/V-Dialkyl-w// o-azidobenzamides reacted similarly in 63-83% yield. For hydroxy- or methoxy-substituted indolines 97 (R2=OH or OMe) elimination of water or methanol occurred from the initial products 97 under the reaction conditions giving indoles 98 in 74—78% yield. 

HDN of Quinoline. Satterfield et al.(8) proposed that there are two pathways for the HDN of the coal liquid model compound quinoline using a NiHMocatalyst. One pathway involves the successive formation from quinoline of 1,2,3,4-tetrahydroquino-line, o-propylaniline and then ammonia plus n-propylbenzene. A second pathway involves the successive formation of 5,6,7,8-tetrahydroquinoline, decahydroquinoline, propylcyclohexylamine... 

Carbon-sulfur bond formation by oxidative cyclization of a thiourea derivative using bromine will in the case of (521) furnish a thiazolo[/,/]quinoline (522 Z = NH). The same imine is obtained from 8-mercapto-l,2,3,4-tetrahydroquinoline on treatment with cyanogen bromide with phosgene the 2-oxo derivative (522 Z = 0) is formed (63JOC2581). 

Formation of the cis isomer increased to 65% when quinoline was hydrogenated in acetic acid added by a large quantity of hydrochloric acid.72 Booth and Bostock obtained practically pure cw-decahydroquinoline by hydrogenation of quinoline in concentrated hydrochloric acid over platinum black (eq. 12.47).75 Vierhapper and Eliel showed that the hydrogenation in the strongly acidic medium proceeds mostly via 5,6,7,8-tetrahydroquinoline as intermediate, which probably is related to the high stereoselectivity in the formation of the cis isomer.37... 

Vigorous chemical reduction (e.g., Sn, HC1 or Zn, HC1) affects complete reduction of the heterocyclic ring, e.g., 1-methylquinolinium ion yields 1-methyl-1,2,3,4-tetrahydroquinoline however, a common and often efficient method for the preparation of saturated piperidines is the catalytic reduction of pyridines, pyridine A-oxidcs, or pyridinium salts <2001CHE797, 2003T2953, 2004AGE2850>. Ammonium formate and palladium on carbon also convert pyridine A-oxidcs into piperidines <2001JOC5264>. 

An intramolecular cycloaddition reaction results in the simultaneous formation of two new rings. Examples include the formation of a tetrahydroquinoline derivative (Section 4.4.2.3.4), the asymmetric synthesis of 1,2-oxazine derivatives (Section 4.3.2.4.2), and the preparation of a hcxahydrothiazino 2,3vz]quinolinc (Section 4.6.3.4) by intramolecular... 

In this cyclization reaction, as mentioned above, 3,4-dihydroquino-line 81 is generated as the initial product (Scheme 36). If this 3,4-di-hydroquinoline 81 could be reduced prior to the disproportionation, then 1,2,3,4-tetrahydroquinoIine 83a should be obtained. Accordingly, the cyclization of 80a was attempted in the presence of a reducing reagent, sodium cyanoborohydride (Na[BH3(CN)]), and 2-methyl-l,2,3,4-tetrahydroquinolin-8-ol (83a) was produced in 78% yield without the formation of quinoline 82a (Scheme... 

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