Isoquinoline formation

Bischler-Napieralski reaction conditions can be attributed, again, to the destabilizing ability of the trifluoromethyl group to the cationic transition state of the acid catalyzed elimination. Formation of compound 29 was ultimately accomplished by base catalyzed methanol elimination-conditions conditions that are quite unusual for isoquinoline formation. 

Unexpected oxazoline formation was observed during a study to prepare nonsedating anxiolytic 1-styrylisoquinolines 27a-h from 2-(trifluoromethyl)aryl-ethylamines 25a-h under Pictet-Gams conditions (POCI3 in refluxing toluene). This deviation from the normal reaction pathway was hypothesized to result from the electron-withdrawing effect of trifluoromethyl group that inhibited the formation of a benzylic cation required for isoquinoline formation (Scheme 8.12). 

Step 4. This isoquinoline formation is of course an example of the Bischler-Napieralski synthesis, although phosphorus trichloride was actually used in this example, not phosphorus oxychloride. 

The Pomeranz-Fritsch synthesis of isoquinolines from the acetals (286) often gives oxazoles as by-products. Isoquinoline formation is favoured by the presence of electronreleasing groups in the benzene ring and suppressed when the ring is deactivated. Nitroaryl-methylene compounds (286 X = NOz), for example, give only oxazoles (equation 102). 

NCS catalyzes isoquinoline formation via an asymmetric Pictet-Spengler reaction (ii). The reaction entails an acid-catalyzed electrophilic addition of an iminium ion. The mechanism is a two-step process in which the iminium ion is generated first from the condensation reaction between the aldehyde carbonyl (such as 4-HPAA) and dopamine. Two types of NCS (CjNCSl and CjPRlOA) have been isolated from Coptis japonica cells and characterized [21]. CjPRlOA has been sufficiently expressed in an active form in E. coli. Conversely, CjNCSl forms a larger complex in plant cells. Therefore, the recombinant enzyme expressed in E. coli cells has considerably lower activity than that of the native enzyme. 

Disconnection at positions C-4 or C-1 (i/j) in the 3,4-dihydroisoquinoline 40 lead to formation of the synthons 39 or 41, from which suitably functionalized educts for isoquinoline formation by SsAr cycUzation reactions may arise. 

This principle of isoquinoline formation has been verified for other biselectrophiles analogous to 44, for example, derivatives 45 of (2-cyano)phenylacetic acid ... 

Larock developed a powerful approach to isoquinolines which involves copper-catalyzed hydroamination of A -ferf-butyl-2-(l-alkynyl)benzaldimine accompanied by elimination of ferf-butyl group (Eq. 4) [55-59]. Asao and Yamamoto reported a novel synthesis of 1,2,3-trisubstituted isoquinolines through attack of a carbon nucleophile to the carbon-nitrogen double bond of iV-alkyl-2-(l-alky-nyl)benzaldimine and simultaneous hydroamination catalyzed by transition metal [60]. They also achieved isoquinoline synthesis by transition metal-free three-component coupling (Eq. 5) [61]. Takemoto and Yanada reported a related isoquinoline formation by a catalysis of carbophilic Lewis acids such as indium(III), Ni(II), or Au(I)/Ag(I) [62, 63]. Oikawa succeeded in palladium-catalyzed three-component... 

Isoquinolinylpalladium(II) intermediates of type 27 (Scheme 19.7) are useful precursors of 4-substituted isoquinolines. For example, when the reaction was carried out under a CO atmosphere in the presence of R X (aryl iodides/acyl chlorides) [8] or ROH [9], the corresponding ketones 29 or esters 31 were produced through carbony-lation (Scheme 19.8). Additionally, palladium(II)-catalyzed isoquinoline formation followed by a Heck reaction under oxidative conditions (CUCI2/O2) effectively produces 4-alkenylisoquinolines 33 [10]. 

In addition to tert-butylimines, aldoximes and related compounds are efficient substrates for isoquinoline formation. Silver(I) and gold(I) complexes promote 6-endo-dig cyclization of benzaldoximes 34 to produce isoquinoline-Ai-oxides 35 (Scheme 19.9) [11], A related synthesis of isoquinolinium-2-yl amides 37 using hydrazide derivatives 36 was also reported [12], The interesting synthetic potential of 0-alkyl oxime redox chemistry was demonstrated in isoquinoline synthesis using 38 and AgOTf (10 mol %)/TfOH (5 mol %) [13],... 

In this section, useful cascade reactions, including the reaction between C=X and alkynes, which are not presented in the sections above, are introduced briefly. As mentioned in Section 19.2.1, isoquinoline formation proceeds through cationic iso-quinolinium intermediates 160 (Scheme 19.39). Many cascade reactions based on the electrophilic reactivity of 160 were reported in the literature, including intermolec-ular nucleophilic addition to produce 161 (path A), a second cyclization through... 

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