Pictet- Spengler reaction

The Pictet-Spengler reaction is a modification of the Bischler-Napieralski reaction. It is probably the most used method for the synthesis of 1,2,3,4-tetrahydro isoquinoline core. Therefore, phenylethyl amines are used in reaction with carbonyl compounds in the presence of protic or Lewis acids. 

Reaction of phenylethyl amine with aldehyde or ketone forms intermediate imine, which under the acidic conditions is protonated to give the highly reactive iminium ion. Electrophilic substitution on the aromatic ring provides 1,2,3,4-tetrahydro isoquinoline after rapid loss of a proton and 

As in the case of the Bischer-Napieralski reaction, regiochemical and stereochemical issues also exist in the Pictet-Spengler reaction. Electrophilic substitution occurs on the more electron-rich carbon of the aromatic ring, whereas phenylethyl amines possess a substituent in a-position leads to a modest preference of anti-positioned substituent in the Cl position of the 

In another example, variation in one of the starting components by using the carboxylic salt of a-epoxide in reaction with P-phenethylamine (dopamine) under the Pictet-Spengler conditions was used for the synthesis of trimethoquinol. This compound is one of a small group of compounds devoid of an aminoalcohol moiety that acts as a P-adrenergic agonist investigated as a potent bronchodilator.  

An analogous methodology was used for the synthesis of selective ACE inhibitor quinapril. Condensation of 5-phenylaIanine with formaldehyde in the presence of sulfuric acid produced an intermediate imine, which was readily cyclized to for predominantly only one enantiomer of the tetrahydroisoquinoline core. Protection of carboxylic acid moiety was followed by acylation with the appropriate acid to form quinapril after deprotection. 

Subsequently, the same group showed that ji-indolyl hydroxylactams 283 could also be applied to a Pictet-Spengler reaction under chiral thiourea catalysis. In the presence of TMSCl, P-indolyl hydroxylactams were converted to chlorolactams 

SCHEME 2.76 Chiral thiourea-catalyzed asymmetric acyl-Pictet-Spengler reaction. 

SCHEME 2.77 Chiral thiourea-catalyzed Pictet-Spengler reaction of 3-indolyl hydroxy-lactams. 

SCHEME 2.78 Regio- and enantioselective Pictet-Spengler reaction of pyrrolo-hydroxylactams. 

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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). 

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. 

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. ... 

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. 

The Pictet-Spengler reaction has mainly been investigated as a potential source of polycyclic heterocycles for combinatorial apphcations or in natural product synthesis [149]. Tryptophan or differently substituted tryptamines are the preferred substrates in a cyclocondensation that involves also aldehydes or activated ketones in the presence of an acid catalyst. Several versions of microwave-assisted Pictet-Spengler reactions have been reported in the hter-ature. Microwave irradiation allowed the use of mild Lewis acid catalysts such as Sc(OTf)3 in the reaction of tryptophan methyl esters 234 with different substituted aldehydes (aliphatic or aromatic) [150]. Under these conditions the reaction was carried out in a one-pot process without initial formation of the imine (Scheme 86). 

An interesting modification of the Pictet-Spengler reaction has been described by Besson and co-workers that employed the degradation of DMSO under microwave irradiation [154]. DMSO undergoes decomposition by prolonged microwave heating, generating dimethyl sulfide, dimethyl disulfide. 

Scheme 86 Microwave-assisted one-pot Pictet-Spengler reaction...

The Bischler-Napieralski and Pictet-Spengler reactions continue to produce new dihydro- and tetrahydroisoquinolines <96TL(37)5453,957(51)12159,96H(43)1605>. 

Treatment of the protected aldehyde 342 with a TFA/water/chloroform mixture results in the formation of a 10-membered intermediate iminium cation intramolecular attack of this electrophile at C-2 of the indole (an intramolecular Pictet-Spengler reaction) gives the isolated tetracyclic product 343 in good yield (Equation 124) <1995T4841>. 

Carbolines (see also Section 12.17.3.3) can be prepared by a Pictet-Spengler reaction between tryptophan derivatives and aldehydes. This general reaction gives compounds such as 405, which provide the starting point for the synthesis of a range of fused pyrazinocarbolines, as shown in Scheme 94. 

A few intriguing developments in the area of tetrahydro-P-carboline synthetic methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS1086> and an enantioselective Pd-catalyzed intramolecular allylic alkylation of indoles <06JACS1424>. A one-step synthesis of 1-substituted-P-carbolines from L-tryptophan has appeared that bypassed the tetrahydro intermediate <06T10900>. 

A modified Pictet-Spengler reaction has been applied to the synthesis of thiazolo-quinolines 58 <06T3228>. Condensation of anilines 53 with aryl aldehydes 54 followed by endo cyclization results in the formation of thiazoloquinolines 58 under a variety of traditional Pictet-Spengler protocols such as 2% trifluoroacetic acid in dichloromethane. 

Chen et al. reported a more environmentally friendly version of the Pictet-Spengler reaction <06H1651>. In this report, a series of 2-phenylsulfonyl-l,2,3,4-... 

Scheme 6.232 Lewis acid-catalyzed Pictet-Spengler reactions.

Yen and Chu subsequently also disclosed a related Pictet-Spengler reaction involving tryptophan and ketones for the preparation of 1,1-disubstituted indole alkaloids [417]. In the approach shown in Scheme 6.234, tryptophan was reacted with numerous ketones (12 equivalents) in toluene in the presence of 10 mol% of trifluoroacetic acid catalyst. Using microwave irradiation at 60 °C under open-vessel conditions, the desired products were obtained in high yields. Compared to transformations carried out at room temperature, reaction times were typically reduced from days to minutes. Subsequent treatment with isocyanates or isothiocyanates led to tetrahydro-/8-carbolinehydantoins. 

Scheme 6.234 Trifluoroacetic acid-mediated Pictet-Spengler reactions.

The pyrrolo[3, 4 2,3]azepino[4,5,6-cd] indole-8,10-dione system can be accessed by reaction, under conditions used for the Pictet-Spengler reaction, of the imines from condensation of 3-amino-4-(3-indolyl) pyrrolin-2,5-diones with aldehydes or ketones. Cyclisation to the pyrrolo-P-carbolines did not occur under the conditions <00JHC1177>. 

An efficient catalyst of the Pictet-Spengler reaction was found to be the Yb(OTf)3-TMSCl system (678). 

The first two reported syntheses of manzamine C utilized the two most common approaches to the /J-carboline ring system—the Pictet-Spengler reaction [13,14] and the Bischler-Napieralski reaction [15]. These two reactions are illustrated in Fig. 3. 

The Pictet-Spengler reaction has also seen much use in the synthesis of lavendamycin methyl ester. Both Hibino [31] and Behforouz [32] used it as a key step in their syntheses of this molecule (Fig. 10). In Hibino s synthesis, /i-methyltryptophan ethyl ester 27 was condensed with quinoline aldehyde 28 to give the corresponding lelrahydro- -carbohnc, which was aromatized by heating with palladium on carbon in xylenes, giving /1-carboline 29 in 75% yield. A five-step sequence (which included conversion to the methyl ester for easier comparison with known compounds) yielded bromoquinone 24 in 27% yield for the five steps. This completed Hibino s formal total synthesis of lavendamycin methyl ester, since this was the same intermediate used in Kende s synthesis. 

Other routes to the key imine intermediate of the Pictet-Spengler reaction have also been reported. For example, Molina and coworkers [34] generated imine intermediate 34 by reaction of azide 32 with aldehyde 33 in the presence of tributylphosphine, via the corresponding iminophosphorane (Fig. 11). Use of triphenylphosphine was unsuccessful in the formation of an iminophosphorane. Without isolation, the intermediate was heated at 165 °C in a sealed tube with palladium on carbon, giving /J-carboline 35 in 45% yield. This com-... 

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