Isoquinoline reactions with carbonyl compounds

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. 

For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

The success achieved with the Rh(II)-catalyzed transformations of -oximino diazo carbonyl compounds prompted our group to study some additional systems where the C-N 7i-bond was configurationally locked so that azomethine ylide formation would readily occur. Toward this end, we investigated the Rh(II)-catalyzed behavior of isoxazoline 186 in the presence of DMAD. This reaction afforded the azomethine-derived cycloadduct 187 as a 4 1 mixture of diastereomers in 65% yield. A similar transformation occurred using the a-diazoacetophenone derivative 188 which produced isoxazolo[3,2-a]isoquinoline 189 as a 2 1 mixture of diastereomers in 82% yield.84... 

Plants have taken advantage of this successful synthetic principle for their enzymatic production of isoquinoline (as well as p-carboline ) alkaloids. In the chemical laboratory, this synthetic approach has been exploited for nearly 80 years in numerous biomimetic-type syntheses. This special form of the Mannich reaction requires electron-rich aromatics, if possible with ftee phenolic oxygen functions in ortho or para positions (Scheme 9). As for the carbonyl compound, aldehydes or 1,2-dicarbonyls (and very recently 1,2,3-tricarbonyls - ) are preferred. Due to the mild physiological reaction conditions required with such ideally reactive partners (often pH = 7, room temperature, aqueous medium), this condensation was also found to play a role in human organisms, leading to endogenous mammalian alkaloids... 

One of the most powerful methods for the construction of tetrahydroisoquinoline systems is the Pictet-Spengler cyclisation. The reaction consists of the condensation of a b-phenylethylamine derivative with a carbonyl compound, generating an imine (Schiffs base), which undergoes cyclisation via an intramolecular electrophilic aromatic substitution yielding the isoquinoline derivative. The Pictet-Spengler reaction is traditionally carried out in a protic solvent with acid catalysts, usually acetic acid or trifluoroacetic acid. 

The number of alkaloids based on the 1-substituted tetrahydroisoquinoline skeleton is legion and the structural variation which this skeleton affords, particularly in the case of 1-benzylisoquinolines, is rich. The 1-substituted isoquinoline skeleton of each kind probably arises by the common step of condensing a j8-arylethylamine with an appropriate carbonyl compound, for which the Pictet-Spengler reaction provides an analogy. In some cases the participation of a carbonyl compound is established but in others it is still speculative. Recently progress has been made in this area in studies on the biosynthesis of lophocerine, the Papaver alkaloids, and to some extent the cryptostyline alkaloids with their novel 1-phenylisoquinoline structures. 

Nitrogen heterocycles can also b e prepared by silver(I)-catalyzed cyclization reaction. Asao, Yamamoto, and their colleagues have shown synthesis of 1,2-dihydro-isoquinoline derivatives by addition of pronucleophiles to ortho-alkynylaryl ald-imines employing AgOTf as a catalyst [29]. For example, treatment of imine (19) with 2 equiv of nitromethane (20) in the presence of 3 mol% of the catalyst at 80 °C, 1,2-dihydroisoquinoline derivative (21) is produced in 85% yield (Scheme 18.7). Terminal alkynes and carbonyl compounds possessing activated methylene groups are also usable as the pronucleophiles [29]. 2-Alkoxyazetidines are efficiently synthesized by Ag(fod)-catalyzed [2-F2] cycloadditions of imines to (alkoxymethylene)... 

Later, Wu and co-workers demonstrated a practical and novel approach to H-pyrazolo [5,l-a]-isoquinoline-l-carboxylates 24. The AgOTf-catalyzed one-pot tandem reaction proceeded with 2-alkynylbenzaldehyde 20, sulfonohydrazide, and a,p-unsaturated carbonyl compounds 23 via a [3 h- 2] cyclization under mild conditions in good yield (Scheme 7.11) [66]. 

Alkaloid synthesis from yic-tricarbonyl compounds. Wasserman s group1 has used the strongly electrophilic character of the central carbonyl of a Wc-tricarbonyl system for synthesis of several alkaloids. Thus several isoquinoline alkaloids can be prepared by reaction of a phenethylamine with the tricarbonyl 1. 

The reaction to make the isoquinoline ring can be carried out chemically under very mild conditions providing that we use an aldehyde as the carbonyl component. Then it works very well with rather similar compounds,... 

Similar phenol couplings have been attempted in the laboratory with compounds in the benzyl isoquinoline series but the nitrogen atom interferes if it is at all basic. When it has a carbonyl substituent the reactions do work reasonably well, but the yields are poor. Nature is still much better at this reaction than we are. 

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