Pictet-Gams Reaction

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. 

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 2000, Simig et al. began to conduct structure activity relationships on 25 by employing the Pictet-Gams reaction. Compound 25 had been identified as an anxiolytic agent that does not show sedative side-effects. ... 

However, when carrying out the synthetic route, as shown below, isoquinoline production was not realized. Rather, the oxazolidine intermediate (27) was isolated. Fortunately, an X-ray of the intermediate was obtained that proved unambiguously, that 2-oxazolidines were an intermediate in the Pictet-Gams reaction. 

Even though the Pictet-Gams reaction requires strong acid and high temperatures to form the desired isoquinoline framework, it remains the method of choice when acid labile substituents are not present in the molecule. This is particularly true now that the mechanism has also been elucidated and the reaction more predictable. 

Isoquinolines have been shown to useful as artificial receptors for resorcinol. The Pictet-Gams reaction offers a short and efficient route to the complex triisoquinoline (33) artificial receptor. 

The extent of kinetically controlled formation of the carboxonium ions 31 depends on the nature of R1 and Yy. The possible existence of 31 allows formation of acylated enols 32 (Y = R3CO), which are analogous with w-acylaminostyrene derivatives. As is known, the latter compounds easily undergo an intramolecular acid-catalyzed cyclization to isoquinolines (the Pictet-Gams reaction) (80T1279). 

On the basis of data obtained in the previous paragraphs, one can propose that formation of 5-oxoniachrysenes 67 (R2 = H) occurs via the primary O-formylation of 66 followed by cyclization of esters 70 (R2 = R3 = H), which is similar to the Pictet-Gams reaction (80T1279). Obviously, this mechanism can also be applied to the acylation of 66 with R2COOH (R2 does not equal H) in PPA in contrast to the scheme of formation of 2-benzopyrylium cations 30 from benzyl ketones 28 (Section II, C, 2). 

Oxazoles.—Formation. ci)-Diazoacetophenone reacts with benzonitrile in the presence of trifluoromethanesulphonic acid to give 2,5-diphenyloxazole (514). Bi-, ter-, and quater-oxazoles have been synthesized from a-metallated isocyanides thus lithiobenzyl isocyanide (PhCHLiNC) and dimethyl oxazole-3,4-dicarboxylate afford compound (515). Stable methylene-oxazolines (516 R = Me or Ph) are obtained by heating the iminesHN=C(Ph)OCHRC=CH. The fluorinated oxazoline (518) results from the action of benzonitrile on the oxiran (517), and also from the reaction of bis(trifluoromethyl)carbene with the benzoylimine (CF3)2C=NCOPh/ Treatment of 2-acylamino-l-aryl-alkan-l-ols (519) under the conditions of the Pictet-Gams reaction, i.e. with phosphorus pentoxide in boiling toluene or xylene, results in cis- and trans-2-oxazolines (520), rather than isoquinolines, as claimed previously. The spiro-oxazolines (521 R = Me or Ph) are formed when the lithiated di-isocyanide CN—CH2CH2CHLi—NC is treated with acetone or benzophenone, respec-tively. ... 

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... 

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

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

The Pictet-Gams reaction, [22] which is known as a variation of the Bischler-Napieralski reaction, enabled a sequential reaction consisting of cyclization and aromatization to give l-benzyl-5-fluoroisoquinoline from A -[2-(2-fluorophenyl)-2-methoxyethyl]-2-phenylacetamide (Scheme 7) [21],... 

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]. 

Scheme 30 Syntheses of 1- or 4-(trifluoromethyl)isoquinotines via the Bischler-Napieralski reaction or the Pictet-Gams reaction...

---