Cyclodehydration isoquinoline

Cyclodehydration. This reagent is superior to polyphosphate ester (PPE) for synthesis of benzimadazoles, indoles, and isoquinolines. 

Azine approach. Oxazolo[3,2-a]pyridinium salts (210) were first obtained from the cyclodehydration reaction of l-phenacyl-2(lii)-pyridinone in sulfuric acid (67JHC66). These salts can also be prepared from 2-halo-l-phenacylpyridinium derivatives (211) by treatment with a base which causes ylide formation and hence cyclization by intramolecular substitution (69JOC2129, 76CB3646). It is recommended that a bulky tertiary amine is used as base in order to avoid opening of the ring or substitution of the 2-halo substituent in the starting material (211). Isoquinoline and quinoline analogues have also been prepared by these methods. 

To obtain the [l,2,4]triazolo[4,3- ]isoquinoline series it was not possible to displace the halogen atom of 3-chloroisoquinoline with hydrazine. However, 3-hydrazinoisoquinoline 2-oxide could be prepared from the corresponding 3-chloro 2-oxide, and it could be selectively reduced by titanium trichloride to 3-hydrazinoisoquinoline, a relatively unstable compound (78JHC463). This hydrazino derivative was unresponsive to the usual carboxylic acid type ring closures generally used to make fused [4,3-x] systems. The desired products (299) could be obtained by cyclodehydration of the monoacylhydrazino compounds (300) with polyphosphoric acid. These derivatives (299) were, however, unstable and had to be characterized as their perchlorate salts (301 Scheme 32) (78JHC463) to eliminate the o-quinoid structure. 

A side-chain t-alcohol group as in (99.4) undergoes cyclodehydration when heated with sulphuric acid. Annulation of a phenylethanol with a nitrile and sulphuric acid can give fairly high yields of an isoquinoline the usefulness of nitriles in the synthesis of heterocycles has been reviewed [3332a]. 

The first step of this cyclodehydration brought about by POCI3 is akin to the Vilsmeier reaction. It proceeds via chloroimines 49 (or their conjugate acids) and the electrophilic nitrilium ions 50, which are isolable as hexachloroantimonates. The 3,4-dihydroisoquinolines can be transformed to isoquinolines 48 by conventional methods, e.g. catalytic dehydrogenation. 

Many biologically active derivatives are based on the dihydrobenzodiazepine structure. The tranquilizer medazepam is of this type its synthesis (Scheme 9.56) is of interest because of its close resemblance to the Bischler-Napieralski isoquinoline synthesis, in that an amide is subjected to cyclodehydration with PPA. Here, a second nitrogen atom must be present in the side chain, as in the starting amide 9.114. This product is the tranquilizer medazepam (9.115). 

A cyclodehydration methodology has been developed, leading to the imidazole [2,l-fl]isoquinoline ring system (Scheme 16). The chemistry is thought to involve dicationic, superelectrophilic intermediates. For example, the ketone (65) provides the... 

Compound 183 undergoes B—N cyclodehydration to give the expected isoquinoline 184. Sodium borohydride as a reductive agent was ineffective. However, sodium cyanoborohydride reduction of 184 after prolonged interaction provides tetrahydroisoquinoline 185, which was transformed into an amido ester 186 with ethyl acrylate via Michael addition. The latter can be converted to the desired tricyclic system 187 via Dieckmann cycli-zation.As expected (i-kcto ester 187 is a mixture ofketo—enol tautomers, as proven by its spectroscopic data and a positive FeCls-MeOH test. It is likely that this is the first successful way for the syntheses of l,l-dimethylbenzo[a] quinolizidin-2-ones (Scheme 50) (83JOC1075). 

Cyclodehydration of isoquinoline derivative (46) may proceed via a thietanium ion, and thermolysis of thiabicyclo-octene (47) may involve a 2-thietanone intermediate. ... 

Cyclodehydrations. The Pictet-Gams modification of the Bischler-Napieralski reaction is an important method for the preparation of isoquinolines. This reaction relies on the dehydration of molecules such as (2) with P2O5 at high temperature... 

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