Pomeranz—Fritsch cyclization

Dyke and Tiley have successfully used the Bobbitt modification of the Pomeranz-Fritsch cyclization in a synthesis of berberastine. The deoxybenzoin 21 was condensed with aminoacetaldehyde dimethyl acetal and the resulting Schiff base was reduced with borohydride to give amine 22. The remaining key steps were a Mannich condensation and a Pomeranz-Fritsch acid-catalyzed cyclization  

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A full paper has now appeared on the preparation of 5-hydroxylated tetra-hydroprotoberberines utilizing the Pomeranz-Fritsch cyclization. An alterna-... 

The Bobbitt variation of the Pomeranz-Fritsch cyclization to obtain 4-hydroxytetrahydroisoquinolines continues to be a useful approach. " Jackson and co-workers have worked out a superior method for the preparation of substituted isoquinolines which involves cyclization, under mildly acidic conditions, of acetal sulfonamides. ... 

Super polyphosphoric acid (PPA 4- P2O5) is an effective reagent in the Pomeranz-Fritsch cyclization, replacing the usual 6N HCl. Thus when imine acetal 4, prepared from o-methylacetophenone and aminoacetaldehyde dimethyl acetal, was heated briefly with super PPA, a 30% yield of 1,8-dimethylisoquino-line was obtained. The product was then oxidized and decarbonylated to supply 8-methylisoquinoline. ... 

A practical route to the benzylisoquinolines utilizes the Jackson modification of the Pomeranz-Fritsch cyclization (see Sec. 1.2.3), followed by C-1 alkylation of the isoquinoline intermediate using a Reissert compound. For example, takatonine was prepared in 59% overall yield from 3,4,5-trimethoxy-benzaldehyde by the sequence shown in Scheme 2.3. ... 

The diphenyl ether 1 was converted to the morpholinamide 2, which after cyclization to the enamine 3 and hydrolysis furnished the tricyclic ketone 4. Interestingly, in the modified Pomeranz-Fritsch cyclization step, one of a pair of ethoxyl rather than hydroxyl racemates was isolated. Catalytic hydrogenolysis and reductive iV-methylation completed the synthesis shown below ... 

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-... 

A modification of the Pomeranz-Fritsch synthesis <1983JCXI3344> is used in the preparation of thieno[2,3- l-pyridine and its 2-substituted derivatives. An aryl aldehyde undergoes condensation with aminoacetaldehyde dimethyl acetal giving a Schiff base which cyclizes to form an imine product. The imine is treated with ethyl chloroformate followed by triethyl phosphate to form an intermediate carbonate-phosphonate, which then cyclizes to the thienopyr-idine product (Scheme 22) <2004S1935>. Very low product yields (2-17%) are obtained for alkyl- and phenyl-substituted thieno[2,3- ]pyridines however, the unsubstituted product and 2-halogenated derivatives give moderate yields (28-44%). 

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

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

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. 

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

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 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. 

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

Regarding synthetic studies, the syntheses of ( )-latifine (437) (200), of ( )-cherylline (440) and ( )-latifine (437) (201), and of ( )-0,0-dimethylcherylline (445) and ( )-6>,0-dimethyllatifine (446) (202) have been performed using the Pomeranz-Fritsch-type cyclization (Scheme 51), the Bischler-Napieralski-type reaction (Scheme 52), and intramolecular nucleophilic addition of aryllithium (generated by butyllithium) to a carbonyl group (Scheme 53). 

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]. 

As noted previously, 7,8-dioxygenated tetrahydroisoquinoline alkaloids may be synthesized by a modified Pomeranz-Fritsch reaction. Application of the Bischler-Napieralski or Pictet-Spengler reactions usually leads to cyclization in an undesired sense, e.g., in (29 X = H) to the 2- rather than to the 6-position. This can be avoided by blocking the 2-position with a bromine function. Thus homopetaline (30 R = CH2CH2C6H4-p-OMe) has been synthesized from (29 R = CH2CH2C6H4-p-OMe) in four steps, the bromo-substituent being removed by catalytic hydrogenation over Raney nickel in the final step.41... 

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 ... 

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. ... 

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. ... 

Jackson modification and Schlittler-Muller modification. The Fischer modification involves the treatment of benzalaminoacetal with fuming sulfuric acid, whereas Bobbitt modification produces tetrahydroisoquinoline derivative through the hydrogenation of an imine intermediate in situ to an aminoacetal, which in turn is converted into product by the acid-promoted cyclization and hydrogenation. This modification for tetrahydroisoquinoline is also known as the Pomeranz-Fritsch-Bobbitt cyclization. The Schlittler-Muller modification involves the preparation of benzalaminoacetal from benzyl amines and gly-oxal semiacetal. In addition, this reaction has been extended to prepare other types of aromatic heterocycles, such as thieno[2,3-c] and thieno[3,2-c]pyridines by intromolecular cyclization to thiophene ring. ... 

Construction of the required spiro system was performed through a modified Pomeranz-Fritsch sequence (see Scheme 25.1). The nitrogen function had to be acetylated before cyclization with formation of ring B could be carried out. The sodium borohydride reduction to furnish ochrobirine proceeded with a high degree of specificity. 

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