Pomeranz-Fritsch synthesis of isoquinolines

Numerous modifications to the Pomeranz-Fritsch synthesis of isoquinolines have been studied over the years without much success.42 Some of these cyclizations, had they been successful, would have generated 1,2-dihydroisoquinolines it is possible, at least in some cases, that the overall sequence failed because the conditions of cyclization were too harsh for the 1,2-dihydroisoquinolines formed to survive. 

The Pomeranz-Fritsch synthesis of isoquinolines from the acetals (286) often gives oxazoles as by-products. Isoquinoline formation is favoured by the presence of electronreleasing groups in the benzene ring and suppressed when the ring is deactivated. Nitroaryl-methylene compounds (286 X = NOz), for example, give only oxazoles (equation 102). 

Pomeranz-Fritsch Synthesis. Isoquinolines are available from the cyclization of benzalaminoacetals under acidic conditions. 

The Pomeranz-Fritsch synthesis [Eqs. (1) and (2)]1 is the only isoquinoline synthesis involving a simple two-step sequence from common starting materials. Furthermore, it is one of the few methods which can be used to prepare isoquinolines substituted in the 7- and 8-positions. The first step, Schiff base formation [Eq. (1)], takes place readily, but the ring closure [Eq. (2)] is difficult. The yields vary markedly with the concentration of H2S04 and are generally low. Frequently the reaction fails completely. Most of the work described in this chapter was undertaken to circumvent these problems and to realize the potential promise of the synthesis. 

Pomeranz-Fritsch reaction Synthesis of isoquinolines from aromatic aldehydes and 2,2-dialkoxvethylamine. 358... 

Gensler, W. J. Synthesis of isoquinolines by the Pomeranz-Fritsch Reaction. Org. React. 1951, VI, 191-206. 

Bevis, M. J., Forbes, E. J., Naik, N. N., Uff, B. C. Synthesis of isoquinolines, indoles, and benzothiophene by an improved Pomeranz-Fritsch reaction, using boron trifluoride in trifluoroacetic anhydride. Tetrahedron 1971, 27,1253-1259. 

Another method for the synthesis of isoquinoline derivatives is the Pomeranz-Fritsch reaction. Simple aniline derivatives can be used but this is very useful for acid sensitive substrates such as thiophene and pyrrole... 

This reaction was first and concurrently reported by Pomeranz and Fritsch in 1893. It is the synthesis of isoquinolines via an acid-promoted electrophilic cyclization of benza-laminoacetals prepared from aromatic aldehydes and aminoacetals. Therefore, this reaction is known as the Pomeranz-Fritsch cycUzation, Pomeranz-Fritsch isoquinoline synthesis, Pomeranz-Fritsch reaction," Pomeranz-Fritsch ring closure, Pomeranz-Fritsch ring synthesis, or Pomeranz-Fritsch synthesis. ... 

Numerous classical isoquinoline syntheses utilize intramolecular SeAr reactions for the construction of the hetero ring. Among them are the Bischler-Napiehaiski synthesis, the Pictet-Gams and Pictet-Spengler syntheses, and the Pomeranz-Fritsch synthesis. 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

The first synthesis of a derivative of 2,8-phenanthroline was reported by Merz, Weidlich, and Fink13 in 1964. They prepared 5,6-dimethoxy-2,8-phenanthroline (34) (isolated as the dipicrate) in very low yield by conducting a double Pomeranz-Fritsch isoquinoline synthesis on 4,5-dimethoxyisophthalaldehyde. The parent compound was prepared 2 years later12 in 25-35% yield, along with 1,9-phenanthroline (4%), by the photocyclization of trans-1 (3-pyridyl)-2-(4-pyridyl)ethylene in benzene. This reaction was used by Hiinig and his colleagues15 to prepare an N,N -dimethyl diquaternary salt of 2,8-phenanthroline by methylating the crude product from the irradiation reaction. 

Phenanthroline was first claimed to have been synthesized by a double Pomeranz-Fritsch isoquinoline synthesis.11 It has recently been prepared12 in about 12% yield by the irradiation of trans-l,2-di(3-pyridyl)ethylene in benzene, along with 1,8-phenanthroline (12-20%) and 1,10-phenanthroline (1-2%). The melting point is quite different from that recorded earlier by Ruggli and Schetty.11 This latter method has subsequently been used15 to prepare an AT, AT -dimethyl diquaternary salt of 3,8-phenanthroline by methylating the crude product from the irradiation reaction. 

Schlittler, E., Muller, J. A new modification of the isoquinoline synthesis according to Pomeranz-Fritsch. Helv. Chim. Acta 1948, 31,914-924. 

Electrophilic cyclisation, in which the heterocyclic ring is formed in the manner of the Pomeranz-Fritsch isoquinoline synthesis, offers a potential route to benzoisoquinolines. Cyclisation of the N-2-... 

When the )V-tosylaceta (3.2) is heated with dilute hydrochloric acid and dioxan, a surprisingly facile detosylating-dehydrogenative cyclization occurs to give the isoquinolines in high yields—a valuable variation of the Pomeranz-Fritsch reaction. It has been used in a synthesis of the medicinally important ellipticine [2870]. 

An alternative synthesis to the Pomeranz-Fritsch method has been developed for 7- and 5,7-substituted isoquinolines. As an extension to the photolysis of... 

A preparative improvement is achieved by combining the arylaldehyde and aminoacetal to give the secondary amine 60 in a reductive amination. Its tosylate 62 cyclizes in an acid medium to the 1-tosyl-1,2-dihydroisoquinoline 63 with elimination of ROH. Subsequent loss of toluenesulfinic acid leads to isoquinoline. The synthesis of compoimd 64 shows that 1,2,3,4-tetrahydroisoquinolines can also be obtained by a Pomeranz-Fritsch methodology ... 

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