Aromatization dihydroisoquinoline

Detailed mechanistic studies by Fodor demonstrated the intermediacy of both imidoyl chlorides (6) and nitrilium salts (7) in Bischler-Napieralski reactions promoted by a variety of reagents such as PCI5, POCI3, and SOCh)/ For example, amide 1 reacts with POCI3 to afford imidoyl chloride 6. Upon heating, intermediate 6 is converted to nitrilium salt 7, which undergoes intramolecular electrophilic aromatic substitution to afford the dihydroisoquinoline 2. Fodor s studies showed that the imidoyl chloride and nitrilium salt intermediates could be generated under mild conditions and characterized spectroscopically. Fodor also found that the cyclization of the imidoyl chlorides is accelerated by the addition of Lewis acids (SnCU, ZnCh), which provides further evidence to support the intermediacy of nitrilium salts. ... 

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. 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

I.2. Oxidation of Amines Oxidation of primary amines is often viewed as a particularly convenient way to prepare hydroxylamines. However, their direct oxidation usually leads to complex mixtures containing nitroso and nitro compounds and oximes. However, oxidation to nitrones can be performed after their conversion into secondary amines or imines. Sometimes, oxidation of secondary amines rather than direct imine oxidation seems to provide a more useful and convenient way of producing nitrones. In many cases, imines are first reduced to secondary amines which are then treated with oxidants (26). This approach is used as a basis for a one-pot synthesis of asymmetrical acyclic nitrones starting from aromatic aldehydes (Scheme 2.5) (27a) and 3,4-dihydroisoquinoline-2-oxides (27b). 

This method is very useful for the construction of 1-substituted 3,4-dihydroisoquinolines, which if necessary can be oxidized to isoquinolines. A P-phenylethylamine (l-amino-2-phenylethane) is the starting material, and this is usually preformed by reacting an aromatic aldehyde with nitromethane in the presence of sodium methoxide, and allowing the adduct to eliminate methanol and give a P-nitrostyrene (l-nitro-2-phenylethene) (Scheme 3.17). This product is then reduced to the p-phenylethylamine, commonly by the action of lithium aluminium hydride. Once prepared, the p-phenylethylamine is reacted with an acyl chloride and a base to give the corresponding amide (R = H) and then this is cyclized to a 3,4-dihydro-isoquinoline by treatment with either phosphorus pentoxide or phosphorus oxychloride (Scheme 3.18). Finally, aromatization is accomplished by heating the 3,4-dihydroisoquinoline over palladium on charcoal. 

Through a slight modification the Pomeranz-Fritsch synthesis can be made particularly useful for the preparation of 1,2-dihydroisoquinolines. The imine is first reduced with sodium borohydride in 98% ethanol to the corresponding benzylamine, prior to cyclization, by treatment with 6 M hydrochloric acid. When electron-donating groups (such as a methoxyl) are present in the aromatic unit of the benzylamine, the ring-... 

Soufiaoui and co-workers (19) reported an intermolecular 1,3-dipolar cycloaddition of tosyl azide with the 1,2-dihydroisoquinoline 81 to give the triazohne 82, which, on extrusion of nitrogen followed by aromatization via elimination of H2 or... 

Isoquinoline synthesis Bischler-Napieralski synthesis is used to synthesize isoquinolines. (3-phenylethylamine is acylated, and then cyclodehy-drated using phosphoryl chloride, phosphorus pentoxide or other Lewis acids to yield dihydroisoquinoline, which can be aromatized by dehydrogenation with palladium, for example in the synthesis of papaverine, a pharmacologically active isoquinoline alkaloid. 

Aromatization of l-(perfluoroalkyl)-3,4-dihydroisoquinolines to the corresponding isoquinolines is accomplished by catalytic dehydrogenation using palladium on charcoal (Table 16).260... 

Evidently, the stability of 3-hydroxy-3,4-dihydroisoquinolines 137, formed as the result of heterocyclization, is also determined by the anne-lated benzenoid ring. The lower tendency toward aromatization for these compounds, compared to monocyclic analogs, leads to the ability of 137 to react as a cyclic azomethine. The addition of a molecule of nucleophile to the C=N bond causes opening of the isoquinoline ring and formation of a new ring system (for instance, a-naphthols 141 in alkaline aqueous solutions). Such conversions occur even under conditions of the recyclization reaction of 2-benzopyrylium salts, namely, on heating 137 in alcoholic ammonia a mixture of isoquinoline 138 and a-naphthylamine 140 results (88MI1). 

Tetralone 213 may be considered as the specific analog of 3-hydroxy-3,4-dihydroisoquinolines 137 (Section III,C,4,a,i). Its isolation is more evidence of the lower tendency toward aromatization in recyclization products of benzo[c]annelated pyrylium salts in comparison with monocyclic cations. 

The 3,4-dihydroisoquinoline system is also encountered in this family of alkaloids. The assignment of chemical shifts to the aromatic carbon atoms of the substituted 3,4-dihydroisoquinolines (21-25 in Fig. 3 and Table III) followed directly from the application of the appropriate substituent parameters to the shifts reported for 20 (22) and from a consideration of the resonance effect of the carbon-nitrogen double bond. This latter point is especially evident in the methiodide salts, 24 and 25, where charge delocalization causes C-4a, C-6, and C-8 to appear at lower field than their counterparts C-8a, C-l, and C-5, respectively. Carbon-1 was readily recognized as the lowest field resonance because of its imine character. 

The aromatization of the dihydroisoquinoline was achieved under micro-wave-assisted conditions, irradiating the intermediate in CHCI3 at 120 °C for 5 min with DDQ as the oxidizing agent (Scheme 23). It is noteworthy that the use of DDQ, MnC>2 or Pd - C in various solvents under conventional heating conditions was not successful. The authors completed the total synthesis by an AICI3-mediated lactonization to furnish lamellarin D in a total of eight steps with 18% overall yield. 

Agbalyan et al 9 recently employed this reaction in the synthesis of several 3,4-dihydroisoquinoline derivatives with unsaturated substituents in the 1-position. The Madrid group50 has shown that (with the exception of benzyl thiocyanate) aliphatic and aromatic thiocyanates yield 1-alkylthio- and l-arvlthio-3,4-dihydroisoquinolines as expected (cf. Table V). 

The imidazolyl-annelated dihydroisoquinoline 78 was accessible from the cyclization of imidazole 79. The outcome of intramolecular substitutions on pyridines turned out to be strongly dependent on the linker between the aromatic cores (Scheme 30). With a c/.v-configured alkene in place, as in 80, the expected benzoisoquinoline 81 was isolated in excellent yield. The frans-configured alkene and the saturated C2-alkane were shown to be less suitable tethers due to the formation of side products. 

When exposed to air, or better to manganese dioxide, 1,2-dihydroisoquinolines are readily oxidized to isocarbostyrils,8,105 whereas with iodine,77 mercuric acetate,78 or jV-bromosuccinimide,106 the products are the fully aromatic isoquinolinium salts. 

Disproportionation to an equimolecular mixture of the 1,2,3,4-tetrahydroisoquinoline and the fully aromatic derivative is a common consequence of the interaction of 1,2-dihydroisoquinolines with acids. It is possible that protonation at C-4 occurs first (Scheme II), but with... 

Employment of pyrido[3,4-d]pyridazine derivatives (18) as azadienes in inverse electron-demand Diels-Alder reactions with 1-pyrrolidino-l-cyclopentene, or its six-membered homologue, provides a good route to the isoquinolines (19) after aromatization of the dihydroisoquinoline intermediates (Equation (2)) <92TL7173>. 

An important method for making derivatives of isoquinoline is the Bischler-Napieralski synthesis. Acyl derivatives of /3-phenylcthylaminc arc cyclized by treatment with acids (often P2O5) to yield dihydroisoquinolines, which can then be aromatized. 

In 1952, Ritter and Murphy reported cases of intramolecular Ritter behavior resulting in formation of dihydroisoquinolines from reactions of methyleugenol with nitriles such as veratronitrile (equation 30). Such reactions involve nucleophilic attack by the aromatic ring on the nitrilium ion and are enhanced by... 

The Beckmann rearrangement-cyclization sequence terminated by aromatic moieties is fairly general. Recent examples of isoquinoline and dihydroisoquinoline synthesis exhibit two-step sequences using phosphorus pentachloride and phosphorus pentoxide via the cyclization of the intermediate imidoyl chlorides (equation 34). ... 

In order to obtain analogs of 1,2-dihydroisoquinolines in which the aromatic carbocycle is replaced by various heteroaromatic systems, the furopyridines (19), the thieno[3,2-c]pyridines (20), and the thieno[2,3-c]-pyridines (21) were synthesized (70BSB301 71JHC57). By Grignard coupling of 4-chloro-19 with allylmagnesium chloride in the presence of catalytic... 

The dihydroisoquinoline 83 gave with 2 N HCl the isoquinolinium salt 85, which was formed under the reaction conditions from 84 by dehydration, followed by aromatization (73AP648). Compound 86, having benzyl groups in... 

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