Tetrahydroquinoline, reductive

Many synthetic methods have been developed for the preparation of quinolines and 1,2,3,4-tetrahydroquinolines due to the interesting biological properties of quinoline-type alkaloids. Most of the synthetic methods are based on the elaboration of aniline derivatives and, as for the synthesis of tetrahydroquinolines, reduction of the corresponding quinolines is the main approach. Only a few methods have been reported for the construction of the quinoline skeleton by N-C(8a) bond formation as the key step, such as oxidative cyclization of 2-(3-aminopropyl)benzene-1,4-diol 89 with K2[Fe(CN)e] (Scheme 42)... 

Reduction. Quinoline may be reduced rather selectively, depending on the reaction conditions. Raney nickel at 70—100°C and 6—7 MPa (60—70 atm) results in a 70% yield of 1,2,3,4-tetrahydroquinoline (32). Temperatures of 210—270°C produce only a slightly lower yield of decahydroquinoline [2051-28-7]. Catalytic reduction with platinum oxide in strongly acidic solution at ambient temperature and moderate pressure also gives a 70% yield of 5,6,7,8-tetrahydroquinoline [10500-57-9] (33). Further reduction of this material with sodium—ethanol produces 90% of /ra/ j -decahydroquinoline [767-92-0] (34). Reductions of the quinoline heterocycHc ring accompanied by alkylation have been reported (35). Yields vary widely sodium borohydride—acetic acid gives 17% of l,2,3,4-tetrahydro-l-(trifluoromethyl)quinoline [57928-03-7] and 79% of 1,2,3,4-tetrahydro-l-isopropylquinoline [21863-25-2]. This latter compound is obtained in the presence of acetone the use of cyanoborohydride reduces the pyridine ring without alkylation. 

Julolidine has been prepared by the reaction of trimethylene chlorobromide with formanilide, aniline, methylaniline, and tetrahydroquinoline by the reduction of 8,10-diketojuloli-... 

Sodium borohydride reduction of 4-substituted isoquinolinium salts led to vinylogous cyanamides, ureas, and urethanes, as well as the corresponding tetrahydroquinolines (640). Hydrogenation of /8-acylpyridinium salts (641) to vinylogous ureas was exploited in syntheses of alkaloids (642), leading, for instance, to lupinine, epilupinine, and corynantheidine (643, 644). Similarly, syntheses of dasycarpidone and epidasycarpidone were achieved (645) through isomerization of an a,/0-unsaturated 2-acylindole and cyclization of the resultant enamine. 

Reactions of 3- and 4-piperidone-derived enamines with a dienester gave intermediates which could be dehydrogenated to tetrahydroquinolines and tetrahydroisoquinolines (678). The methyl vinyl ketone annelation of pyrrolines was extended to an erythrinan synthesis (679). Perhydrophenan-threnones were obtained from 1-acetylcyclohexene and pyrrolidinocyclo-hexene (680) or alternatively from Birch reduction and cyclization of a 2-pyridyl ethyl ketone intermediate, which was formed by alkylation of an enamine with a 2-vinylpyridine (681). 

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

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... 

Xie and co-workers developed a simple route for the synthesis of 3-aryl-l,2,3,4-tetrahydroquinolines 79 using a direct intramolecular reductive ring closure strategy <06TL7191>. The yields for the key reductive ring closure were moderate however, the simplicity of their route leads to an efficient synthesis of a variety of tetrahydroquinolines 79. 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

Numerous y-secretase inhibitors featuring sulfonamide- and sulfone-based scaffolds have been disclosed. Bicyclononane thiophene sulfonamide 40 reduced brain Ap in transgenic mice by 50% after a dose of 100 mg/kg [100]. High potency (A p IC50 = 0.5 nM) and improved oral activity (ID50 = 17 mg/kg) was found in a series of related sulfamides represented by 41 [101]. Tetrahydroquinoline (42) and piperidine (43-44) sulfonamides have been developed [102-104]. Elaboration of the piperidine series with the cyclopropyl substituent present in 44 improved in vitro potency (Aft IC50 = 2.1 nM in membrane assay) and in vivo activity in transgenic mice (plasma Ap = 2% of control after oral dose of 30 mg/kg). Reductions of A p in the cortex were reported to be comparable to those observed in plasma. 

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... 

Hydroxy-l,2,3,4-tetrahydroquinolines 304 were obtained by cyclization of oxime 2,4-dinitrophenyl ethers 303 in the presence of system NaBH3CN/NaH/l,4-dioxane (equation 131) . If the reductive cyclization was followed by oxidation with DDQ (2,3-dichloro-4,5-dicyano-p-benzoquinone) the corresponding 8-hydroxyquinolines 305 were obtained . ... 

Reduction of quinoline with lithium in liquid ammonia in the absence of a proton source gives mainly 1,2,3,4-tetrahydroquinoline. However, if methanol is present throughout the reaction the main product is 5,8-dihydroquinoline (45 R = H). 6-Methoxyquinoline gives (45 R = OMe) together with some 6-methoxy-7,8-dihydroquinoline (46 R = OMe) as main products (Scheme 32) (71JOC279). 

A roundabout route is used to prepare tetrahydroquinolines with reduced carbocyclic rings since direct reduction, as noted above, adds hydrogen to the heterocyclic ring. The key reaction in this scheme involves a variant of the Hantzsch pyridine synthesis. Condensation of the imine (37-1) from dihydroresorcinol with ethoxymethylenepropionaldehyde (37-2) can be envisaged as proceeding through... 

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. 

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 reductive route used to prepare heterocyclic enamines has the advantage of avoiding the hydroxylation reaction sometimes found in the mercuric acetate oxidation of saturated heterocyclic amines [126]. The lithium-n-propyl-amine reducing system has been used by Leonard to reduce julodine to A5-tetrahydrojulolidine (66% yield) and l-methyl-l,2,3,4-tetrahydroquinoline to a mixture of enamines (87% yield), consisting of l-methyl-A8-octahydro-quinoline and 1-methyl-A9-octahydroquinoline [135] (Eqs. 51, 52). 

Vigorous chemical reduction (e.g. Sn-HCl or Zn-HCl) effects complete reduction of the heterocyclic ring, e.g. 1-methylquinolinium ion yields 1-methyl-1,2,3,4-tetrahydroquinoline. Reversible reduction of the pyridinium ring of coenzymes I and II (335 Y = H and P03H2, respectively) is important physiologically (B-97MI502-07). 

Reductions with noble metal catalysts proceed smoothly (at 20°C) when the bases are in the form of hydrochlorides the free bases tend to poison the catalyst. A pyridine ring is reduced more easily than a benzene ring thus, 2-phenylpyridine gives 2-phenylpiperidine (384), quinoline gives 1,2,3,4-tetrahydroquinoline (385) and acridine gives 9,10-dihydroacridine (386). 

Heating 2,3,4,4a,5,6-hexahydro-l//-pyrimido[l,2-a]quinoline (55) in 0.1 N hydorchloric acid yielded ring-opened product (56). Reduction of compound 55 in ethanol containing 5% HC1 at room temperature and normal pressure over Pt02 catalyst afforded l-(3-aminopropyl)-l,2,3,4-tetrahydroquinoline (57) (63YZ682). 

Quinoline may be reduced rather selectively, depending on the reaction conditions. Catalytic reduction with platinum oxide in strongly acidic solution at ambient temperature and moderate pressure gives a 70% yield of 5,6,7,8-tetrahydroquinoline. Further reduction of this material with sodium-ethanol produces 90% of fratrr-decahydroquinoline. 

That hydrogen is set free is proved by the reduction of some of the quinoline derivative to a tetrahydroquinoline derivative. A mixture of two aldehydes, or of an aldehyde and a ketone, may be employed. (B., 20, 1098.)... 

Reduction of 8-nitro-l,2,3,4-tetrahydroquinoline 342 with aqueous TiCl3 in acetone gave 2,3,6,7-tetrahydro-lH,5H-pyrido[l/2,3-de]quinoxa-line-2,3-dione 343 after a spontaneous cyclization (06CTM733). 

Acidic media in the hydrogenation of quinolines may be avoided by the use of Rh/Al2C>3 as catalyst. Selective reduction may then be effected in hexafluoroisopropanol or methanol <2004SL2827>. Use of methanol leads to the isolation of the corresponding 1,2,3,4-tetrahydroquinoline while performing the hydrogenation in hexafluoroisopropanol results in total reduction to the decahydro product. 

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