1.2- Dihydroisoquinolines enamine reactions

A methylene base formed from quinaldine ethiodide, l-ethyl-2-methyl-ene-1,2-dihydroisoquinoline (129), exhibits a number of reactions characteristic of enamines (207,209). On treatment with benzoylchloride a dialkylated product (130) is produced by C and subsequent O benzoylation (210). 

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

Nucleophilic addition takes place at C-1, and this is considerably enhanced if the reaction is carried out upon an isoquinolinium salt. Reduction with lithium aluminium hydride [tetrahydroaluminate(III)] in THF (tetrahydrofuran), for example, gives a 1,2-dihydroisoquinoline (Scheme 3.15). These products behave as cyclic enamines and if isoquinolinium salts are reacted with sodium borohydride [tetrahy-droboronate(III)] in aqueous ethanol, further reduction to 1,2,3,4-tetrahydroisoquinolines is effected through protonation at C-4 and then hydride transfer from the reagent to C-3. 

Members of the tetracyclic dibenzopyrrocoline alkaloid family can be prepared by the intramolecular ring closure of l-(o-halobcnzyl)-tetrahydroisoquinoline derivatives. (3.38.)47 The analogous transformation of dihydroisoquinolines (3.39.) proceeds probably through the isomeric enamine form obtained by the tautomeric shift of the double bond 48 The palladium-carbene catalyst system applied in these reactions was also effective in the preparation of indoline, indolizidine and pyrrolizidine derivatives 49... 

The reduction of isoquinolinium ions has been extensively investigated with borohydride and aluminum hydride ions. The use of boro-hydride ion in a protonic solvent normally leads to the formation of 1,2,3,4-tetrahydroisoquinolines, whereas the reduction with aluminum hydride ion in an aprotic medium generally gives a 1,2-dihydroiso-quinoline. This 1,2-dihydroisoquinoline contains an enamine system and may undergo further reaction on treatment with acid. The 1,2-and 3,4-dihydroisoquinolines as well as isoquinolinium ions are reduced by the borohydride ion in a protonic medium to the 1,2,3,4-tetrahydroisoquinolines. 

Various heterocyclic compounds contain an a,)3-unsaturated amine moiety in their structure, for example, indoles, 1,2,3,4-tetrahydro-pyridines, 1,4-dihydroquinolines, and 1,2-dihydroisoquinolines. It is the purpose of this review to summarize our knowledge of the chemistry of 1,2-dihydroisoquinolines and to evaluate those reactions that may be interpreted in terms of enamine character. 

Methyl-1,2-dihydroisoquinoline has been reacted8,66 with a variety of acid chlorides (Table III) the expected vinylogous amides (64) were isolated in most cases. 2-Benzyl-l,2-dihydroisoquinoline behaves similarly. The acylation reaction fails with simple aliphatic acid chlorides. Sometimes, the reaction of the enamine with the acid in the presence of dicyclohexylcarbodimide succeeds. The 1,2-dihydro-isoquinoline (65) also reacts with ethoxalyl chloride to yield 66.86... 

The Vilsmeier reaction,103 which has been successfully applied104 to the formation of 3-acylindoles, has yielded the 4-formyl-1,2-dihydroisoquinolines (76)—(78).105—10 d. Reactions with Aldehydes. Cyclopentanone enamine gives the... 

Thermal [l,3]-sigmatropic rearrangements of enamines have also been reported75. Compound 78 obtained from the reaction of dihydroisoquinoline and phenyl isocyanate,... 

Sequential reaction of azines with alkyl hthium compounds and chloroformates usually affords the expected Reissert-type products 136, together with minor amounts of doubly acylated compounds 135 (Scheme 18b). Isoquinoline is likely to react directly with the alkyl-lithium compound to generate the alkylated lithio-enamine intermediate E, and this species may account for the formation of dihydroisoquinolines 135 and 136, through interaction with the electrophihc partner. Mamane recently expanded this concept by replacing the acylating agent with different electrophiles. These combinations lead exclusively to isomers 134 (Scheme 18) [118-120]. 

The structures of all currently approved gastric acid secretion inhibitors that act as inhibitors of the sodium-potassium pump consists of variously substituted pyiidylsulfonyl-benzimidazoles. A structurally very distinct compound based on a pyrimidine moiety has much the same activity as the benzimidazole-based drugs. In yet another convergent synthesis, reaction of (3-phenethylamine (53) with acetic anhydride affords amide 54. Treatment with polyphosphoric acid (PPA) then leads to ring closure to form the dihydroisoquinoline (55). Sodium borohydride then reduces the enamine function to afford fragment 56. 

Qulnolinium salts (68 Scheme 15) can undergo attack at either the 2- or 4-position. The former normally predominates and the latter leads to 1,2,3,4-tetrahydroquinolines (69). 3-Substituents generally produce mixtures of the 1,2- and 1,4-dihydro adducts. Isoquinolinium salts (70 Scheme 15) produce both 1,2-dihydrolsoqulnolines (71) and 1,2,3,4-tetrahydroisoquinolines (72). Reduction in protlc solvents normally produces the tetrahydro adducts, in anhydrous pyridine or dimethylformamide the reduction generally stops at the 1,2-dihydroisoquinoline. Reaction of the enamine system of 1,2-dihydroisoqui-nollnes with electrophiles has been used as a method for generation of 4-substituted isoquinolines. 

The reduction of isoquinolinium salts in aprotic solvents with LAH leads to the formation of 1,2-dihydroisoquinolines (195), in which the enamine system can undergo subsequent reaction with electrophiles. This type of reactivity has been exploited in the synthesis of alkaloids. ... 

In 2007, Ding and Wn reported a cascade reaction combining enamine and Ag catalysis for the synthesis of 1,2-dihydroisoquinoline derivatives [42]. Initially, the nncleophilic enamine derived from the ketone and proUne attacked the imine that arose from the aldehyde and the amine, forming the Mannich base 140, which then participated in a hydroamination reaction toward pendant alkyne to build the final prodnct (Scheme 9.46). 

An example of a cascade reaction combining enamine and silver catalysis for synthesis of 1,2-dihydroisoquinoline derivatives is shown in Fig. 8.26. In the first step, nucleophilic enamine formed from the ketone and proline reacts with the imine, which is generated from the aldehyde and the amine. As a result, the Mannich base is formed, which then undergoes a hydroamination reaction in the presence of silver catalyst. 

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