3- Aryl-3,4-dihydroisoquinolines

Aryl-3,4-dihydroisoquinolines.2 Isoquinolines are generally prepared by the Bis-chlcr-Napicralski reaction, but this classical route is not useful in the case of 3-aryl-isoquinolincs. In a modified procedure, the precursor, (phenylcthyl)amidc (1), is treated with oxalyl chloride to form a, which on treatment with FeCI, forms an N-acy-liminium ion b. This ion cyclizes to 2, which is converted into 3,4-dihydroisoquinolinc 3 by treatment with sulfuric acid in methanol. Overall yields of 3 are in the range 55-90%. 

Kametani s group has applied the diazomethane ring expansion reaction of 3,4-dihydroisoquinoline methiodides to the preparation of isopavines. The carbon insertion reaction with the 3-aryl-3,4-dihydroisoquinoline methiodide 13 supplied a crude aziridinium iodide which upon standing in 6N hydrochloric acid for a week underwent successive ring expansion and closure, probably through the quinone methide 14, to furnish reframidine in 20% yield from the aziridine salt ... 

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

Peroxidase and laccase enzymes were used to catalyze the decarboxylation of various tetrahydroisoquinoline-1-carboxylic acids to give high yields of the corresponding 3,4-dihydroisoquinolines (204). Compounds such as 125 (Scheme 29) are derived from Pictet-Spengler ring closure via a-keto acid and aryl amine condensation and are of biogenetic importance. The possible relevance of iso-... 

Other synthetic routes to benzazepines involving ring expansion of six-membered heterocycles include the action of diazomethane (77CPB321), sulfonium ylides (77H(7)37> or acyl halides (75T1991) on quaternary 3,4-dihydroisoquinolines that of sulfoxonium ylides on quaternary quinolines (74IJC(B)1238) and the zinc-acetic acid reduction of quaternary 1-acyltetrahydroisoquinolines (77BSF893). Photoaddition of acyl- or aryl-nitrenes to the exocyclic alkene bond of 2-methylene-1,2-dihydroquinolines results in ring expansion to... 

The interaction between ammonia and l-R1-3-aryl-substituted ben-zo[c]pyrylium salts 30, as well as 3,4-diaryl-substituted indeno[e l,2-]-benzo[c]pyrylium, and other substituted cations having a similar fragment is more complicated, especially in hydroxyl-containing solvents. In these cases, mixtures in different ratios are obtained that contain isoquinolines 138, 3-hydroxy-3,4-dihydroisoquinolines 137, OR-adducts 109, anhydro-bases 119, diketones 29, a-naphthylamines 140, and a-naphthols 141 (88UP2). 

Grigg et al. [61] have recently reported a one-pot reaction involving the initial three-component condensation with a 2-halo-benzylamine 112, ethyl glyoxylate 113 and an aryl boronic acid 114, followed by Pd cyclization in the presence of carbon monoxide to give 116, or in the presence of allene to form dihydroisoquinoline amino acid derivatives 117 (Scheme 7.15). 

There is a discrepancy in the literature concerning 1,2-dihydro-isoquinoline itself. Thus, Huckel and Graner54 report its trimerization to 31 (m.p. 138°, the same melting point that Packham and Jackman11 ascribe to the monomer). It is thought63 that in a nonpolar solvent, 1,2-dihydroisoquinoline is relatively stable, but in methanol, protonation and trimerization occur certainly the mass spectrum of the compound (m.p. 138°) described by Packham and Jackman indicates that it is trimeric.63 The series of 1,2-dialkyl-1,2-dihydroisoquinolines described by Bradley and Jeffry30 was purified by distillation under reduced pressure. The stability of these compounds is quite remarkable in view of the known tendency for 1,2-dihydroisoquinolines to undergo disproportionation. Some other 1,2-dialkyl-1,2-dihydroisoquinolines have been described,7 as well as 1-aryl derivatives.7 The derivative (32) when heated with triethyl phosphite is transformed by an unknown mechanism, in 37% yield, into 33.64... 

The copper(I) iodide promoted cyclization of 7V-(2-haloaryl)-substituted enaminones is a good method to yield indoles and carbazoles. This type of intramolecular arylation is a reasonable alternative to the route via benzyne (see Section A.l.f) (equation 106). The method could be extended to 7V-(2-haloaryl)alkyl-substituted enaminones which give the expected dihydroisoquinolines whereas a nucleophilic attack of the nitrogen instead of the /1-carbon give the undesired indoles159 (equation 107). 

Aryl-ethanamines react with aldehydes easily and in good yields to give imines. 1,2,3,4-Tetrahydro-isoquinolines resnlt from their cyclisation with acid catalysis. Note that the lower oxidation level imine, versus amide, leads to a tetrahydro- not a dihydroisoquinoline. Routine dehydrogenation easily converts the tetrahydro-isoqninolines into fnlly aromatic species. 

Hydroxy-substituted A -(2-arylethy)amides 51 lead to isoquinolines 48 under Bischler-Napieralski conditions. In this case, dehydrogenation is not required Pictet-Gams synthesis), because H2O elimination occurs at the dihydroisoquinoline step. The starting materials 51 are available e.g. from aryl-4,5-dihydrooxazoles (e.g. 57). 

Nitrogen Heterocycles.- Intramolecular Wittig reactions have been used to construct heterocyclic rings in, for example, the synthesis of N-alkyl-3-pyrrolines (193) (Scheme 18) and that of 2-methyl-3-(aryl/alkyl)-l-oxo-l,2-dihydroisoquinolines (195) by a one-pot synthesis from the amides (194) (Scheme 19). ... 

The much more important 1S,3S isomer 116 could also be obtained by nucleophilic alkylation of the 1-unsubstituted dihydroisoquinoline 117, for example, with CH3Li, stereoselectively occurring from the p face (70). Again, 117 was easily accessible from the chiral aryl isopropylamine 113 (see Scheme 27). 

The same logic can be followed on the nucleophilic attack of alkyl or aryl groups on C2 position of quinoline and Cl position of isoquinoline cores by organometalic species (lithium or Grignard reagents). The reaction seems to proceed in two steps as this is demonstrated in the alkylation of isoquinolile below. Addition at the Cl position gives a dehydroisoquinoline-A-lithio derivatives, which can be hydrolyzed to furnish an isolable 1-substituted 1,2-dihydroisoquinoline. It was followed by an oxidation process to yield the full aromatized product. ... 

In 2009, Baudoin and co-workers reported a new strategy for the synthesis of dihydroisoquinolines, involving sequential C(sp )-H arylation and 6-... 

Disubstituted 3,4-dihydroisoquinolines are easily prepared via cycli-zation of l-(2-aryl-2-isocyanoalkyl)-2-bromobenzenes in the presence of butyl lithium (Scheme 64) (13H389). The precursors to the l-(2-aryl-2-isocyanoalkyl)-2-bromobenzenes were themselves prepared l-bromo-2-(bromomethyl)benzenes and (l-isocyanoalkyl)benzenes in the presence of butyl lithium. The reaction sequence proceeded well with l-bromo-2-(bromomethyl)benzenes containing chlorides (47-58% yields) and methoxy groups (57-58% yields). Additionally, the (l-isocynaoalkyl)benzenes could contain various substituents without a decrease in yields. Trapping of the anion to introduce functionality at C-1 failed. 

Dihydroisoquinoline esters undergo an oxidative [3 + 2] cycloaddition with nitroolefines or N-sulfuryl aldimines when treated with a cobalt catalyst (Scheme 69) (130BC6691). This cycloaddition provides a fairly robust approach to dihydropyrrolo[l,2-rj]isoquinolines. Nitroolefins with a number of aryl substituents underwent reaction with the dihydroiso-quinolines.The aryl groups could have either electron-donating (methoxy)... 

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