Pictet-Gams isoquinoline synthesis

Isoquinolines from acylated aminomethyl phenylcarbinols using phosphorus pen-toxide. 

P2O5 actually exists as P4O10, an adamantane-like structure. 

Ardabilchi, N. Fitton, A. O. Frost, J. R. Oppong-Boachie, F. Tetrahedron Lett. 1977, 4107. 

The isoquinoline framework is derived from the corresponding acyl derivatives of P-hydroxy-P-phenylethylamines. Upon exposure to a dehydrating agent such as phosphorus pentaoxide, or phosphorus oxychloride, under reflux conditions and in an inert solvent such as decalin, isoquinoline frameworks are formed. 

Pictet, A. Gams, A. Ber. Dtsch. Chem. Ges. 1909, 42, 1973, 2943. Ame Pictet (1857—1937), bom in Geneva, Switzerland, carried out a tremendous amount of work on alkaloids. 

Holsworth, D. D. Pictet—Gams Isoquinoline Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hohoken, NJ, 2005, 457—465. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 200, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 214, Springer International Publishing Switzerland 2014 

An Alternative to Pictet—Gams Reaction Triggered by Hendriekson Reagent Isoquinolines and p-Carbolines from amides  

FjCSOT PhjP PPhj F3CSO3 Hendrickson reagent 

Gabler, M. Nouroozian, M. Schulz, P. Tetrahedron Lett. 1994, 35, 9697-9700. 

To understand the unpredictable nature of the Pictet-Gams reaction, Hartwig and Whaley conducted the first mechanistic studies in 1949. Their work focused on substituent effects when directly attached to the ethylamine side chain. They also investigated a variety of dehydration agents in order to identify optimal reaction conditions. It was determined that formation of the isoquinoline structure was virtually impossible when alkyl or phenyl substituents were placed in the 4-position of the ethylamine side chain. 

Hartwig and Whaley suggested that when substituents are placed in the 4-position of the ethylamine side chain, an oxazoline intermediate (7) is formed a side reaction that was first mentioned by Krabbe in 1940. However, Hartwig and Whaley did not isolate the putative intermediate. 

Hartwig and Whaley also demonstrated that increasing the size of the alkyl side chain off the 3-position, resulted in low yields of expected product. In fact, when Ri is larger than a propyl group, the expected products were not isolated (n-butyl gave a 1% of the corresponding isoquinoline ). Furthermore, isoquinolines were formed more 

In 1968, the aforementioned reaction was repeated and found to produce a rearranged product (11). This was the first report of aryl migration with the Pictet-Gams conditions. The expected product was l-methyl-3-phenyl isoquinoline, but only 1-methyl-4-isoquinoline (11) was observed. Interestingly, the authors did not suggest a mechanism for the formation of the isolated product. 

In 1977 Fitton et al. conducted the first detailed study that shed light on the true mechanism of the Pictet-Gams reaction. It was postulated that all Pictet-Gams reactions create an oxazoline intermediate (15) by the mechanism shown below  

In 1977, a postulated mechanism involving the formation of an oxazoline intermediate was described by Fritton. The mechanism managed to explain the unexpected products observed when different 3-positioned alkyl groups were used. 

Nowadays, several modifications of the Pictet-Gams reaction exist in the literature, constituting the reaction as the method of choice for the synthesis of isoquinoline frameworks when acid labile substituents are not present in the molecule. Modifications include the use of cinnamic esters, instead of 2-phenyl-2-hydroxy ethanamines, as starting materials 

Special concern was also given in the development of milder reaction conditions using mixtures of trifluoroacetic anhydride and 2-chloropyridine or DMAP for electrophilic amide activation. 

The Pictet-Gams reaction was used for the synthesis of difficult accessible isoquinoline derivatives as the tri-isoquinoline artificial receptor of resorcinol.  

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Pictet-Gams isoquinoline synthesis. Formation of isoquinolines by cychzation of acylated aminomethyl phenyl carbinols or their ethers with phosphorus pentoxide in toluene or xylene. 

Cf. Bradsher Reaction Pechmann Condensation Pictet-Gams Isoquinoline Synthesis Pictet-Hubert Reaction Skraup Reaction. 

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