Tetrahydroisoquinolines ketone reactions

Reactions of 3- and 4-piperidone-derived enamines with a dienester gave intermediates which could be dehydrogenated to tetrahydroquinolines and tetrahydroisoquinolines (678). The methyl vinyl ketone annelation of pyrrolines was extended to an erythrinan synthesis (679). Perhydrophenan-threnones were obtained from 1-acetylcyclohexene and pyrrolidinocyclo-hexene (680) or alternatively from Birch reduction and cyclization of a 2-pyridyl ethyl ketone intermediate, which was formed by alkylation of an enamine with a 2-vinylpyridine (681). 

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. 

The reaction of cyclohexylidenemalononitrile with CS2 under phase transfer conditions gives a 5,6,7,8-tetrahy-droisothiochroman-l-thione. Under the same conditions, reaction with isothiocyanates produces the corresponding 1-imine, but tetrahydroisoquinoline thiones and/or ketones are also formed, often in the major quantities, and this detracts from the synthesis (Scheme 187) <2000JHC1233>. 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

Synthesis of i-Keto-, 2,3,4 -tetrahydroisoquinolines These ketones have been prepared by four different routes a Dieck-mann condensation [Eq. (22)], ring closure of benzylglycine derivatives [Eq. (23)], ring closure of substituted nitriles [Eq. (24)], and a Grignard reaction on 4-hydroxy-JV-alkylisoquinolinium salts [Eq. (25)]. Earlier unsuccessful attempts at their synthesis have been summarized.52,58... 

The total synthesis of (+)-4-hydroxycrebanine was accomplished by J.-l. Kunitomo et al., who used the Bobbitt modification of the Pomeranz-Fritsch reaction as the key ring-forming step. The aromatic ketone substrate was first condensed with aminoacetaldehyde diethylacetal to afford a Schiff base that was immediately reduced to the corresponding amino compound in high yield. Exposure of this intermediate to concentrated HCI for several days gave rise to the tetrahydroisoquinoline as a mixture of two diastereomers. 

Using iV-silylaldimines as electrophiles, aminoalcohols (41) are obtained as reaction products, which after chlorination followed by cyclization under basic conditions lead to the formation of tetrahydroisoquinolines (42) (Figure 1) (00JHC1061). When ketones derived from D-fructose, and D-glucose, as well as (9-ethoxymethyl-substituted estrone and (-)-menthone are used as electrophiles, diols (36f)-(36i)... 

Some biosynthetic studies involving incorporation of labelled tyrosine, cysteine, methionine, glycine and tryptophane [68,69], have already been performed on the ecteinascidins, to partially confirm the proposed biosynthetic origin of the A and B units from Dopa units. Further studies are in progress to test the hypothesis that the electrophilic ketone in an intermediate such as Et 594 or Et 596 can be condensed in a Pictet-Spengler reaction with a Dopa derivative to form the third tetrahydroisoquinoline group (C unit) in Et 729 or Et 743 [68]. 

Indeed, photoredox catalysis with Ru polypyridine complexes has emerged as a powerful tool for redox reactions including formation of carbon-carbon bonds based on oxidation of sp C-H bonds via single-electron-transfer (SET) processes. Results that are closely related to those shown in Schemes 33,34, and 35, where the carbon-carbon bond formation resulted from the benzyUc sp C-H oxidative activation in the presence of BuOOH, have been recently reported for the regioselective functionalization of tetrahydroisoquinolines with cyanide and a variety of nucleophiles arising from ketones, nitroalkanes, allyltrimethylsilane, silyl enol ethers, 1,3-dicarbonyl compounds under photocatalytic conditions [67-70] as illustrated in Scheme 62 [67]. Other applications of Ru(bipy)3Cl2 in photocatalytic cycUzation reactions involving carbon-carbon btmd formation have appeared [71, 72]. 

Pictet-Spengler Cyclization Hegediis et al. carried out the one-step synthesis of tetrahydroisoquinolines 50 via Pictet-Spengler cyclization between p-phenylethylamine and ketones/aldehydes in the presence of E4a zeolite in ethanol (Scheme 36) [140]. Ersorb-4 (E4) zeolite is a weakly acidic zeolite-type adsorbent with a small pore size (4A) that seems to show good activity in different condensation reactions. E4a xmder study was obtained by ionic exchange of E4. When the reaction was carried out over montmorillonite KPIO catalyst, which is more acidic than E4a, no product was observed as KPIO is unable to bind the water formed during the reaction. 

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