Pomeranz-Fritsch Reaction

The Pomeranz-Fritsch reaction involves the preparation of isoquinolines 4 via the acid-mediated cyclisation of the appropriate aminoacetal intermediate 3. The best yields are usually obtained when the benzaldehyde portion 1 has electron-donating substituents in the 3- or 3,4- positions relative to the aldehyde. 

Of the well-known methods to prepare isoquinolines, including the Pictet-Spengler and Bischler-Napieralski cyclisation, the Pomeranz-Fritsch reaction is the only direct generally accepted method for the construction of the fully unsaturated isoquinoline ring system. 

Toward the end of the 19 century both Pomeranz and Fritsch independently reported the preparation of isoquinolines by the reaction of aminoacetaldehyde dimethyl acetal 2 (R = Me) with aromatic aldehydes 1 followed by cyclisation in acidic media. Unfortunately yields were often poor and not always reproducible. This has prompted the search for various improvements and modifications on the original theme, including the use of reagents other than strong mineral acid which tends to destroy the intermediate imine.  

The most plausible mechanism involves condensation between aldehyde 1 and amine 5 to give the corresponding imine 6. Cyclisation and subsequent elimination yields the fully unsaturated isoquinoline ring structure 4. 

The Bobbitt modification is the most widely used variation of the Pomeranz-Fritsch reaction. This modification involves cyclisation of benzylaminoacetal 10, usually prepared from the classical Pomeranz-Fritsch imine 9, to yield 4-hydroxy derivatives 11. The success of this method can be attributed to avoiding treatment and thus (partial) destruction of imine 10 under strongly acidic conditions. 

The Pomeranz-Fritsch reaction involves the initial condensation of an aryl aldehyde with 2-aminoaldehyde acetal to provide aldimine, which is then isolated and cyclized under strong acid conditions to afford the isoquinoline framework. The most known variation of this reaction is using benzylamine and glyoxal diethylacetal as the coupling pair for the initial condensation (known as the Schlitter-Muller variation), which is able to provide 1-substituted isoquinolines.  

The mechanism of the reaction involves intramolecular electrophilic substitution of aryl group on the acetal side as shown in the scheme. Based on that, electron-donating groups on the aromatic ring (especially para- to the position of ring closure) greatly enhance the ability of aromatic ring to cyclize.  

Usually, the reaction is poor in yield limited by the imine hydrolysis in the strong acidic conditions used for the cyclization. Two solutions were used to overcome this drawback i. The use of milder acidic conditions (e.g., trifluoroactic acid/boron trifluoride mixture) and ii. Carrying out the cyclization on the amine oxidation state (Bobbit and Jackson variation). 

Isoquinoline synthesis via acid-mediated cyclization of the appropriate ami-noacetal intermediate. 

Pomeranz, C. Monatsh. 1893, 14, 116. Cesar Pomeranz (1860-1926) received his Ph.D. degree at Vienna, where he was employed as an associate professor of chemistry. 

Fritsch, P. Ber. Dtsch. Chem. Ges. 1893, 26, 419. Paul Fritsch (1859—1913) was bom in Oels, Silesia. Fie studied at Munich where he received his doctorate in 1884. Fritsch eventually became a professor at Marburg after several junior positions. 

Hudson, A. Pomeranz-Fritsch Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 480-486. (Review). 

R = usually an electron-donating group (EDG), H, alkyl, aryl, 0-alkyl, Cl, Br R = H, alkyl R = Me, Et orotic acid H2SO4, HCI, 

Formation of oxazole if R - EWG (the oxidation is performed by the cone. H2SO4)  

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. 

The total synthesis of (+)-4-hydroxycrebanine was accomplished by J.-l. Kunitomo et al., who used the Bobbitt modification of the Pomeranz-Fritsch reaction as the key ring-forming step. The aromatic ketone substrate was first condensed with aminoacetaldehyde diethylacetal to afford a Schiff base that was immediately reduced to the corresponding amino compound in high yield. Exposure of this intermediate to concentrated HCI for several days gave rise to the tetrahydroisoquinoline as a mixture of two diastereomers. 

The shortest synthesis of papaverine was achieved in the laboratory of R. Hirsenkom starting from racemic stilbene oxide and using a modified Pomeranz-Fritsch reaction The aminolysis of the stilbene oxide led to the formation of the cyclization precursor, which upon treatment with excess benzoyl chloride, underwent cyclization to give the N-benzoyl 1,2-dihydroisoquinoline derivative. Reduction under Wolff-Kishner conditions afforded papaverine. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 206, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 220, Springer International Publishing Switzerland 2014 

Simple permutation where the amine and the aldehyde switch places for the two reactants in comparison to the Pomeranz-Fritsch reaction. 

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The Jackson modification involves cyclisation of iV-tosylated amine 12 and provides a complementary method to the classical Pomeranz-Fritsch reaction for entry into the fully unsaturated ring system 13. Amine 12 can be prepared from either the Pomeranz-Fritsch-Bobbitt imine 10 or reaction of benzylhalide 14 and the corresponding sodium anion 15. ... 

The Schlittler-Muller variation of the Pomeranz-Fritsch reaction involves reaction of diethoxyethanal 17 with benzylamine 16 to prepare the desired imine 18. Intermediate 18 is subsequently cyclised to substituted isoquinoline 19. The advantage here lies in the fact that the initial condensation can still take place between an aldehyde and an amine. 

A number of Lewis acids have been utilized in the Pomeranz-Fritsch reaction, including polyphosphoric acid and boron trifluoride-trifluoroacetic anhydride. Under the latter conditions yields were best when electron-donating groups were present in the 3- or 3, 4- position of imine 20, whereas unactivated aldehydes failed to cyclise at all. ... 

Diazaphenanthrene 53 has been prepared via the Schlittler-Muller variation of the Pomeranz-Fritsch reaction in moderate yield. ... 

Polyhalo ketones, reductive dehalogenation of, 29, 2 Pomeranz-Fritsch reaction, 6, 4 Prevost reaction, 9, 5 Pschorr synthesis, 2, 6 9, 7 Pnmmerer reaction, 40, 3 Pyrazolines, intermediates in diazoacetic ester reactions, 18, 3 Pyridininm chlorochromate, 53, 1 Pyrolysis ... 

Schlittler-Mtiller Reaction (Modification of the Pomeranz-Fritsch Reaction)... 

POMERANZ-FRITSCH REACTION. Formation of isoquinolines by the acid-catalyzed cyclization of benzalaminoacetals prepared from aromatic aldehydes and aminoacetal. 

Pomensm-Fritseh reaetkm. In the Pomeranz-Fritsch reaction, i.soquinolines are formed by the cyclization of bcnzalaminoacetals (I) with concentrated sulfuric acid as... 

POMERANZ-FRITSCH REACTION Boron trifluoride-Trifluoroacetic anhydride. 

The asymmetric variant of the Pomeranz-Fritsch reaction was used by D. Rozwadowska and co-workers in the total synthesis of (-)-salsolidine. ... 

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

Pomeranz-Fritsch reaction The acid catalyzed cyclization of benzalaminoacetals to form isoquinolines. 358... 

Related reactions Pictet-Spenglertetrahydroisoquinoline synthesis, Pomeranz-Fritsch reaction ... 

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. 

Katritzky, A. R., Yang, Z., Gundy, D. J. A mild and efficient synthesis of intermediates for the Pomeranz-Fritsch reaction. Heteroatom Chem. 1994, 5, 103-106. 

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