Pictet reactions

The reaction conditions applied are usually heating the amine with a slight excess of aldehyde and a considerable.excess of 2d-30hydrochloric acid at 100 °C for a few hours, but much milder ( physiological ) conditions can be used with good success. Diols, olefinic double bonds, enol ethers, and glycosidic bonds survive a Pictet-Spengler reaction very well, since phenol and indole systems are much more reactive than any of these acid sensitive functional groups (W.M. Whaley, 1951 J.E.D. Barton, 1965 A.R. Battersby, 1969). 

Synthetic Isomerides of Laudanine. In 1903 Pictet and Kramers, in an attempt to synthesise laudanine, reduced trimethylpapaveroline methochloride (jjro/opapaverine methoehloride, p. 195) with tin and hydrochloric acid and obtained a base, m.p. 76°, not identical with laudanine, and which was named tsolaudanine. On repeating this work Spath and Epstein obtained dZ-codamine and the reactions involved are discussed under codamine below. 

One important variation of the Bischler-Napieralski reaction is the Pictet-Gams modification, in which p-hydroxy or -alkoxy phenethylamides 38 are converted to isoquinolines 39. This transformation is covered in detail in section 9.12 of this text. 

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 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 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 Pictet-Hubert reaction describes the construction of the phenanthridine nucleus (2) by dehydration of acyl-o-xenylamines (1). The application of zinc chloride at high temperature facilitates the dehydration/ This reaction is also referred as the Morgan-Walls Reaction. 

The synthetic utility of the Pictet-Hubert reaction is limited. This is due to the requirement of having a substituent in the para position of the A ring (10) or no substituent on the A ring. Substituents present in the meta position of the A ring (12)... 

The Pictet-Hubert reaction has found utility in the production of phenanthridine molecules that act as DNA-intercalator antitumor and antiviral agents (17). 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

In 1911, Ame Pictet and Theodor Spengler reported that P-arylethyl amines condensed with aldehydes in the presence of acid to give tetrahydroisoquinolines. Phenethylamine 6 was combined with dimethoxymethane 7 and HCl at elevated temperatures to give tetrahydroisoquinoline 8. Soon after, the Pictet-Spengler reaction became the standard method for the formation of tetrahydroisoquinolines. 

The Pictet-Spengler reaction is an acid-catalyzed intramolecular cyclization of an intermediate imine of 2-arylethylamine, formed by condensation with a carbonyl compound, to give 1,2,3,4-tetrahydroisoquinoline derivatives. This condensation reaction has been studied under acid-catalyzed and superacid-catalyzed conditions, and a linear correlation had been found between the rate of the reaction and the acidity of the reaction medium. Substrates with electron-donating substituents on the aromatic ring cyclize faster than the corresponding unsubstituted compounds, supporting the idea that the cyclization process is involved in the rate-determining step of the reaction. 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

One complication of the Pictet-Spengler condensation of benzylisoquinolines 24 is regiochemical control in the closure of ring C when activating substituents are present on the D ring. Experimentally, the ring-closure reaction yields predominantly the 10,11-disubstituted product 23 rather than the 9,10-disubstituted product 25. ... 

The oxa-Pictet-Spengler reaction has been used with success to prepare dihydrofurano[2,3-c]pyrans and isochromans from l-(3-furyl)alkan-2-ols and 2-(3 ,4 -dihydroxy)phenylethanol, respectively. Furanyl alcohol 32 reacted with isobutyraldehyde 33 in the presence of p-toluenesulfonic acid to give the corresponding CI5-5,7-diisopropyl 4,5-dihydro-7H-furano[2,3-c]pyran 34 in good yield. ... 

A formal Pictet-Spengler condensation to give 2,3-dihydro-lH-2-benzazepine-3-carboxylic acid 36 was achieved in quantitative yield via a sigmatropic rearrangement of ci5-2,3-methanophenylalanine 35 in the presence of paraformaldehyde and hydrochloric acid at room temperature. It is interesting to note that homophenylalanine 38 did not cyclize to give 37, even under vigorous reaction conditions. 

Several factors influence the diastereoselectivity of the Pictet-Spengler condensation to form 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-P-carbolines (39 and 40, respectively). The presence or absence of an alkyl substituent on the nitrogen of tryptophan has a large influence on the relative stereochemistry of the tetrahydro-P-carboline products formed from a condensation reaction with an aldehyde under various reaction conditions. 

One of the most common methods for introducing asymmetry into a Pictet-Spengler condensation reaction is to append a non-racemic auxiliary onto the indole amine or... 

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

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. 

Reaction of tryptamine with simple ketones has not been widely explored. Acetone in the presence of benzoyl chloride has been reported to yield 2-benzoyl-1,1 -dimethyl-1,2,3,4-tetrahydro-j8-carbo-line. That the keto group is much less reactive than the aldehyde group is indicated by the fact that j8-keto aldehydes, in the form of their acetals or sodium salts, react with tryptamine at the aldehyde function to yield the conjugated enamine 24, which undergoes ring closure via an intramolecular Michael addition. The potentialities of this interesting modification of the Pictet-Spengler reaction have not yet been fuUy explored. 

There can be little doubt that the crucial, acid-catalyzed step in these cyclization reactions, analogous to that in the Pictet-Spengler type ring closure, involves the charged species 64 (cf. 11). 

The second line of circumstantial evidence quoted in support of this hypothesis is the ready formation of l,2,3,4-tetrahydro-/3-carboline derivatives under pseudo-physiological conditions of temperature, pH, and concentration. Tryptamine and aldehydes, trypt-amine and a-keto acids, and tryptophan and aldehydes condense at room temperature in a Pictet-Spengler type intramolecular Mannich reaction in the pH range 5.2-8.0 (cf. Section III, A, 1, a). It was argued that experiments of this type serve as models for biochemical reactions and may be used in evidence. 

The initial synthesis of papaverine is due to Pictet, and fittingly enough involved as its key step the name reaction. Acylation of veratrylamine (109) with dimethoxyphenylacetylchlo-ride affords the amide (110). Cyclization by means of phosphorus oxychloride constitutes the same reaction and affords the dihy-droisoquinoline (111). Dehydrogenation by means of a noble metal catalyst affords papaverine (107). ... 

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