Tetrahydroisoquinoline derivatives, formed

The Pictet-Spengler reaction is an acid-catalyzed intramolecular cyclization of an intermediate imine of 2-arylethylamine, formed by condensation with a carbonyl compound, to give 1,2,3,4-tetrahydroisoquinoline derivatives. This condensation reaction has been studied under acid-catalyzed and superacid-catalyzed conditions, and a linear correlation had been found between the rate of the reaction and the acidity of the reaction medium. Substrates with electron-donating substituents on the aromatic ring cyclize faster than the corresponding unsubstituted compounds, supporting the idea that the cyclization process is involved in the rate-determining step of the reaction. 

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

Incubation of tryptamine derivatives with 5-methyl-tetrahydrofolic acid and an enzyme preparation from brain gives tryptolines. Dopamine and its derivatives form related tetrahydroisoquinolines such as the product that arises from reaction with acetaldehyde (see Eq. 30-5). This product has been found in elevated amounts in alcoholics (who synthesize excess acetaldehyde), in phenylketonurics, and in L-dopa-treated patients with Parkinson disease.1136... 

Polystyrene-bound o-quinodimethanes, which are formed upon thermolysis of ben-zocyclobutanes, can be converted into 1,2,3,4-tetrahydroisoquinoline derivatives by reaction with /V-sulfonylimines. Reaction of o-quinodimethanes with electron-poor nitriles leads to the formation of 1,4-dihydroisoquinolines, which undergo elimination with simultaneous release of isoquinolines into solution (Entry 7, Table 15.25). 

The Bobbitt modified Pomeranz-Fritsch reaction allows the preparation of enantiopure tetrahydroisoquinolines. During the studies directed toward the total synthesis of ET 743 and its analogues, S.J. Danishefsky and co-workers utiiized this transformation for the preparation of a key tetrahydroisoquinoline intermediate. The cyclization precursor was efficiently synthesized from the enantiopure benzylamine derivative by A/-alkylation with excess diethylbromoacetal. The resulting compound was subjected to QN hydrochloric acid at 0 °C and slowly warmed to ambient temperature overnight. The desired tetrahydroisoquinoline was formed as a 4 1 mixture of diastereomers. 

Formation of tetrahydroisoquinoline derivatives by condensation of (3-arylcthylamines with carbonyl compounds and cyclization of the Schiff bases formed. 

It seems likely that the ring system of the homoerythrina alkaloids is derived by a route analogous to that involved in the formation of the erythrina alkaloids for which a l-benzyl-l,2,3,4-tetrahydroisoquinoline precursor has been established (36, 37). On the basis of this analogy the homoerythrina skeleton could be formed from a sequence of an oxidative coupling reaction through a l-phenethyl-l,2,3,4-tetrahydroisoquinoline derivative, as shown in Chart 18. 

Asymmetric intramolecular conjugate addition of chiral enolates to form pyrrolidine, piperidine, indoline, and tetrahydroisoquinoline derivatives with contiguous quaternary and tertiary stereocenters 06YZ617. 

In 2010, Enders et al. reported on an organocatalytic, one-pot, three-component reductive amination/aza-Michael sequence. They used bis(2,4,6-triisopropyl-phenyl)-l,l -binaphthyl-2,2 -diyl hydrogenphosphate (TRIP) 319 as the organocatalyst and 2-binaphthyl substituted benzathioazole derivatives 320 as the reducing agent and t-BuOH was used as the base. After alkylative cyclization, substituted tetrahydroisoquinoline derivatives 318 were formed in high yields with excellent stereoselectivity (Scheme 40.69). 

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). 

Reduction of dihydro compounds to the tetra- or hexa-hydro derivatives is usually possible. For example, dihydroisoquinolines of type (484) form the corresponding tetrahydroisoquinolines with H2/Pd or with Na/Hg-EtOH. 

In relation to their biosynthesis, it was proposed that A-B units of Et s are most likely formed by condensation of two Dopa-derived building blocks and that the tetrahydroisoquinoline ring in unit B is closed by condensation (Pictet-Spengler) with a serine(or glycine)-derived aldehyde, as in the case of the related saframycins. S-Adenosylmethinonine is the likely source of the methyl groups. A plausible route for the formation of unit C was proposed later [75]. This was partially demonstrated by incorporation of radiolabeled tyrosine and cysteine by Kerr and Miranda [80] and by incorporation of labeled methionine, glycine and tryptophan by Morales and Rinehart [81]. 

The C-N bond cleavage of a benzo tetrahydroisoquinoline compound with lithium metal followed by aqueous quenching formed a naphthalene derivative Equation (1) <2000T8375>. An isoquinolinium ring system has been converted into a highly functionalized 1,2-disubstituted benzene compound. Ring opening of the quaternary salt was... 

In at least one case, a substituted aminoacetal has been used. Wacker and Fritz31 reported the use of D-glucosamine [Eq. (14)] to form derivatives of tetrahydroisoquinoline. Carbons 1 and 2 of the sugar became carbons 3 and 4 of the isoquinoline, and the acetal oxygen became the 4-oxy substituent. This area of work has been retarded by the lack of readily available 2-aminoaldehyde acetals other than the simple acetaldehyde derivative. 

Quinolines generally produce 1,2-dihydroqulnolines with aluminum hydrides. Diisobutylaluminum hydride and Red-Al have been used to reduce quinolines and quinoline-A -boranes (42 Scheme 9). The reactions are believed to proceed via aminoalanes or boranes and the dihydroquinolines produced are quenched and trapped as the carbamates by the addition of chloroformate esters. Minor amounts of 1,4-dihydro- and 1,2,3,4-tetrahydro-quinolines are also formed. The possession of a 2-substituent hinders reaction. At low temperatures the kinetic product, i.e. (43), is favored, but at higher temperatures reduction at the 4-position predominates which subsequently produces the tetrahydro derivative (44). A similar approach has been employed with isoquinoline, generating 1,2-disubstituted tetrahydroisoquinolines (45 Scheme 9). ... 

Hydrogenation with homogeneous catalysis has received increasing attention over the last few decades. Hexarhodium hexadecacarbonyl (181 Scheme 35) under water gas shift conditions forms 1,2,3,4-tetrahydroquinoline (128) or N-formyl-1,2,3,4-tetrahydroisoquinoline (182) with the parent hete-roaromatic. When hydrogen is substituted for carbon monoxide, 4-methylquinoline is reduced to 4-methyl-5,6,7,8-tetrahydroquinoline (183) exclusively.Isoquinoline behaves similarly generating A/-formyl-l,2,3,4-tetrahydroisoquinoline (184). Similar reductions under water gas shift or synthesis gas conditions using transition metal carbonyls derived from Mn, Co and Fe, have been recorded.Promotion by phase transfer agents is observed in some cases. 

Kolbe reactions of heterocyclic compounds have been studied in only a few cases. Anodic oxidation of l-azabicyclo[2.2.2]octane-2-carboxylic acid under Kolbe conditions produced 2-methoxy-l-azabicyclo[2.2.2]octane [454]. The primary radical, formed by loss of an electron from the carboxylate ion, decarboxylates and is oxidized further to a carboca-tion, which is attacked by a methoxide ion. A similar pseudo-Kolbe reaction is found in the anodic decarboxylation of 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid derivatives to 3,4-dihydroisoquinolines [455]. 

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