Reissert compounds synthesis

B. Reaction of Reissert Compounds Synthesis of Isoquinoline Alkaloids... 

The Reissert method15—conversion of an isoquinoline to a 2-benzoyl-1,2-dihydroisoquinaldonitrile (Reissert compound), alkylation, and hydrolysis—has enjoyed wide success in the synthesis of benzyliso-quinoline and related alkaloids.16,17 In particular, aporphines are prepared conveniently by converting isoquinolines to I-(o-nitrobcnzyl)-isoquinolines via a Reissert sequence, followed by A7-alkylation, reduction, and Pschorr cyclization.17... 

Several syntheses of secoquettamines have been performed. Seco compounds 234 and 235 were semisynthesized from quettamine (236) by Hofmann and Emde degradations, respectively (179). Chattopadhyay and Shamma (184) conducted a total synthesis of these bases with the intermediacy of quettamine (236) (Scheme 36). In this approach Reissert compound 237 served as substrate. On reaction with 4-benzyloxybenzaldehyde 237 supplied the addition product 238, which after N-methylation and sodium borohydride reduction afforded amino carbinol 239. Compound 239 was cyclized to... 

A. Synthesis and Reactions of 3,4-Dihydro-P-carboline Reissert Compounds... 

The chemistry of Reissert compounds has been the subject of numerous general reviews (3-10). In 1973 Popp gave a summary on the use of Reissert compounds in the synthesis of isoquinoline alkaloids and related compounds (7). We now wish to summarize new results that have appeared from 1973 to the end of 1985 for the application of Reissert compounds in the synthesis of isoquinoline as well as indole alkaloids. 

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

Jackson et al. (22) reported the biomimetic total synthesis of ( )-cularine (67) itself (Scheme 11). Benzyolation of isoquinoline 68 in the presence of potassium cyanide gave Reissert compound 69, the anion of which was alkylated with 3-benzyloxy-4-methoxybenzyl chloride, resulting in intermediate 70. After al-... 

Among the great number of different approaches for the synthesis of phthal-ideisoquinoline alkaloids the application of Reissert compounds, developed first by Kerekes et al. (42,43), proved to be one of the most efficient and suitable methods (Scheme 24). Treatment of isoquinoline Reissert compounds 26 or 28 with sodium hydride in dimethylformamide resulted in the formation of the corresponding Reissert anions, which were reacted with dimethoxy- or meth-ylenedioxy-substituted o-formylbenzoic acid ester derivatives 178 and 179, respectively. The presumed mechanism of this reaction involves an initial reaction... 

A new synthesis of dibenzo[a,g]quinolizinium derivatives also makes use of an aldehyde cyclization (Scheme 80) (75JAP(K)7596599). In one example, a benzyl bromide bearing an acetal-masked aldehyde group in the ortho position (126) was allowed to react with the anion (127) generated by the action of phenyllithium on a Reissert compound. The condensation product was heated with alkali to cleave the benzoyl and cyano groups to yield the isoquinoline (128), then the acetal was cleaved and the resulting aldehyde cyclized to (129), presumably under acid conditions. 

Makosza118 has also shown that Reissert compounds, A-benzoyl-1,2-dihydroisoquinaldenitrile (67), can be alkylated in the presence of NaOH and TEBA. Alkaline hydrolysis of alkylated 68 will give isoquinoline derivatives, which are starting materials for the synthesis of alkaloids. 

This section deals with transformations of heterocyclic rings and includes not only addition of carbenes and nitrenes, but also rearrangements frequently following these additions. Also included are topics such as the synthesis of Reissert compounds as well as miscellaneous oxidations and reductions. 

Koizumi et al.266 have reported the synthesis of Reissert compounds under PT conditions. Ulf and Budrham267 report the same reaction with phthalazines (171). 

Amino groups in compounds of type (23, Z=NH) are frequently derived from nitro groups. In the Reissert indole synthesis, o-nitrotoluene undergoes Claisen condensation with oxalic ester to yield the pyruvic ester (24). When this is reduced with Zn-AcOH the corresponding amino derivative spontaneously cyclizes to the 2-ethoxycarbonylindole (25) (63OS(43)40). 

A second synthesis of cordrastine starts from a Reissert compound, the 6,7-dimethoxy-analogue of (9), which was condensed with 2-methoxycarbonyl-3,4-dimethoxybenzaldehyde the product was hydrolysed, lactonized, hydrogenated, and N-methylated.118... 

Only one example of an attachment of heteroarenes by addition/elimination strategy has been devised [77, 111]. Although arenes are more or less resistant toward addition, heteroaromatic systems such as isoquinolines 118 are prone to addition of nucleophiles. Subsequent reaction with addition of electrophiles furnishes the so-called Reissert compounds 120. These are stable compounds which can, for example, be alkylated. In solid-phase synthesis the electrophile chosen was a polymer-based acid chloride. Detachment can be achieved by simple addition of hydroxide ions (Scheme 6.1.30). 

Reissert compounds, 9, I 24, 187 Ring closure of ortlio-substituted t-anilines, heterocycles by, 14, 211 Ring-opening of flve-membered heteroaromatic anions, 41, 41 Ring synthesis of heteroaromatic nitro compounds, 25, 113 Ring transformations and cyclizations on reaction of azines with bifunctional nucleophiles, 43, 301 of five-membered heterocycles, 56, 49... 

Although the number and variety of isoquinolines investigated does not approach that of the quinoline series, it would appear that the synthesis of isoquinoline Reissert compounds is general when the methylene chloride-water solvent system is used. A possible exception is 1-substituted isoquinolines where a steric effect, similar to that... 

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