Bischler-Napieralski synthesis of isoquinolines

This reaction corresponds to the Bischler-Napieralski synthesis of isoquinoline (see p 343) and proceeds as an intramolecular S Ar process by way of nitrilium ions as intermediates. By an anlogous reaction, biphenyl-2-isocyanates 29, derived from 2-aminobiphenyl, on treatment with polyphosphoric acid, cyclize to yield phenanthridones 30. 

This reaction corresponds to the Bischler-Napieralski synthesis of isoquinoline (cf p. 413) and proceeds as an intramolecular SgAr process by way of nitrilium... 

The plan was to disconnect reserpine into indole 80 and tri-O-methylgallic acid (81). Indole 80 was to be converted to reserpine using a variant of the well-known Bischler-Napieralski synthesis of isoquinoline derivatives. This transformation (80 79) generates a stereogenic center and thus, there... 

The mechanism of the Staudinger reaction was mentioned above in another computational study of this reaction, a biradical transition structure has been predicted. Finally, the Bischler-Napieralski synthesis of isoquinolines is well-known experimentally the activation energy for the cyclization process has been calculated by ab initio means, together with the effect on this energy of various substituents. ... 

This method [Eq. (10)] was first used in 1930 by Kondo and Tanaka60 for the preparation of 4-hydroxy-5-methoxytetrahydroisoquinoline from j8-hydroxy-j8-(o-methoxyphenyl)ethylamine and methylal (mixed in aqueous HC1). Such ethanolamine derivatives are frequently used in the Bischler-Napieralski synthesis of isoquinolines61 as the Pictet-Gams modification. In this case, the reaction proceeds with dehydration to yield completely aromatic isoquinolines directly. Preparations of the ethanolamines have been reviewed.62... 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

An approach to the isoindole[l,2-a]isoquinoIine skeleton found in jamtine (328) and nuevamine (329) involves a Bischler-Napieralski synthesis of the isoquinoline portion... 

This approach to the isoquinoline ring, albeit a reduced isoquinoline, is mechanistically similar to the Bischler-Napieralski synthesis, in that it involves electrophilic attack of an iminium cation on to an aromatic ring. In this case, the imine intermediate is formed by reacting a phenylethylamine with an aldehyde. 

Alternatively, a P-methoxy-P-phenylethylamine can be used to circumvent the oxidation step after the conventional Bischler-Naperialski cyclization. Here, when treated with the phosphorus reagent the amide (R = OMe) undergoes both cyclization and the elimination of methanol to give the isoquinoline (R = H) directly. This is known as the Pictet-Gams modification of the Bischler-Napieralski synthesis. 

The Pictet-Gams modification of the Bischler-Napieralski synthesis has also been reviewed (5loR(6)74, 81HC(38-l)l6i). As shown in equation (32), the additional unsaturation is achieved by elimination of ROH before the cyclization. The commonest examples use j8-hydroxy or /3-methoxy substituents on the phenethylamide. Papaverine (107) is an example of an isoquinoline obtained from both precursors (09CB2943, 27AP(265)l). The precursors can be made from 5-aryloxazolines by reaction with an acid chloride and... 

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. 

As in the Skraup quinoline synthesis, loss of two hydrogen atoms is necessary to reach the fully aromatic system. However, this is usually accomplished in a separate step, utilising palladium catalysis to give generalised isoquinoline 6.14. This is known as the Bischler-Napieralski synthesis. The mechanism probably involves conversion of amide 6.12 to protonated imidoyl chloride 6.15 followed by electrophilic aromatic substitution to give 6.13. (For a similar activation of an amide to an electrophilic species see the Vilsmeier reaction, Chapter 2.)... 

Step 4. This isoquinoline formation is of course an example of the Bischler-Napieralski synthesis, although phosphorus trichloride was actually used in this example, not phosphorus oxychloride. 

The methods discussed in this chapter have made possible the facile synthesis of isoquinoline derivatives oxygenated at the 7-position, the 5,8-positions, the 6,7-positions, the 7,8-positions, and the 6,7,8-positions [Eq. (7)] or having carbon substituents at the 6-position [Eq. (6)]. The starting materials are readily available aromatic aldehydes, and the reactions are experimentally simple. These methods are not suitable for the preparation of isoquinolines with oxygen at the 5-position, the 6-position, or the 5,6-positions. These must still be prepared by the Bischler-Napieralski method,61 the Pictet-Spengler method,83 or the Dieckmann route shown in Eq. (22). 

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. 

The first total synthesis of ( + )-dauricine was reported by Kametani and Fukumoto in 1964 (18,19). Arndt-Eistert reaction of homoveratryl-amine with the acid chloride XIX afforded the amide XXII. Bischler-Napieralski cyclization of the above amide gave the dihydro isoquinoline derivative XXIV, the methiodide of which when reduced with zinc dust and ethanol-hydrochloric acid afforded + )-dauricine. The identity of the synthetic product with ( )-dauricine w as concluded through a comparison of its physical properties (spectra and chromatographic behavior) with those of an authentic sample of the alkaloid. Melting-point determination of a mixture of derivatives of the two specimens is not recorded. 

The isoquinoline syntheses, which utilize intramolecular S Ar reactions for building the heterocycle, are of greater preparative importance [116]. For instance, on treatment with strong protic acids (H2SO4, polyphosphoric acid), Lewis acid or POCI3, A-(2-arylethyl)amides 46 cyclize giving 1-substituted 3,4-dihydroisoquinolines 47 Bischler-Napieralski synthesis) ... 

The isoquinoline ring, although common in natural products, is not as important among pharmaceuticals as is the quinoline ring. Several synthetic methods are available, but we will discuss only the most commonly used one, the Bischler-Napieralski synthesis that was reported in 1893. With some modifications, it is stiU of great value today for the synthesis of isoquinolines. The process is simple and involves the reaction of an acyl derivative (an amide) of a 2-arylethylamine with phosphorus oxychloride or phosphorus pentoxide (Scheme 9.54). The... 

The Bischler-Napieralski cyclization of a brominated tetrahydrobenzyl-isoquinoline formamide was employed to obtain the desired 2,3,9,10-substitution pattern required for a synthesis of cheilanthifoline ... 

The Bischler-Napieralski reaction [20] and the Pictet-Gams reaction [22] are both known as typical methods for the construction of the isoquinoline framework as described in Sect 2. Gambon et al. synthesized l-(trifluoromethyl)isoquinolines via the Bischler-Napieralski reaction of A(-(phenethyl)trifluoroacetamides, [104] whereas Simig et al. utilized the Pictet-Gams reaction of Af-(2-aryl-3,3,3-trifluoro-2-methoxypropyl)amides of acetic or cinnamic acids for the synthesis of 4-(trifluo-romethyl)isoquinolines (Scheme 30) [105]. 

BISCHLER NAPIERALSKI Isoquinoline synthesis Isoqutnoline synthesis Irom amides of phenethylamines... 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

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