Nucleophilic bases, isoquinoline

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

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). 

Nucleophilic Reactions of Aromatic Heterocyclic Bases Heterocyclic aromatic compounds containing a formal imine group (pyridine, quinoline, isoquinoline, and acridine) also react readily with nucleophilic reagents. A dihydro-derivative results, which is readily dehydrogenated to a new heteroaromatic system. Since the nucleophile always attacks the a-carbon atom, the reaction formally constitutes an addition to the C=N double bond. An actual localization of the C=N double bond in aromatic heterocyclic compounds is incompatible with molecular orbital theory. The attack of the nucleophilic reagent occurs at a site of low 77-electron density, which is not... 

There is some question about the mechanism involved in an extensive series of nucleophilic reactions discovered by Umezawa and Hoshino and their co-workers.58,77 78 In these reactions, the 4,7-diacetoxy compound (30) was treated, in base, with alcohols (to yield 31), amines (to yield 32), mercaptans (to yield 33), KCN (to yield 34), nitromethane (to yield 35), malononitrile (to yield 36), malonic ester (to yield 37), cyclohexanone (to yield 38), acetophenone (to yield 39), and dimethyl sulfoxide (to yield 40). The reaction with cyclopentanone was anomalous in that a dimer of the ketone reacted with the isoquinoline. Since the acetoxy group on C-7 was almost always lost and the reaction failed when a 7-methoxy group was present, a quinone methide intermediate (41) was proposed. Some of the reactions were done in aqueous or alcoholic base and some were done under anhydrous conditions with NaH. 

A base-catalyzed intramolecular nucleophilic substitution reaction on isoquinoline Reissert compounds (222) is the basis of a benzo[a]quinolizidine synthesis developed by Popp et al. (Scheme 42) <72JHC541>. 

Methods that rely on alkynes and alkenes for the synthesis of isoquinoline core are based on two basic modes for their cyclization. The first uses electrophilic reagents as activators of alkynes or alkenes for the cyclization process, while the second method uses a nucleophilic atom usually nitrogen in reaction with the alkyne or alkene moiety. 

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... 

Jun et al. demonstrated a Rh(I)-catalyzed cyclization of an N-benzyl aromatic ketimine with diphenylacetylene to provide isoquinoline 44 [27]. The chelation-assisted C-H activation strategy was employed for the first time for isoquinoline synthesis. However, the reaction required a high temperature (150 C) and led to two different isoquinoline derivatives 44 and 44. Based on the experimental results, the authors proposed a plausible reaction mechanism that involved ortho-alkenylation, 6. r-electrocyclization, intermolecular nucleophilic substitution, and dehydrogenative aromatization (Eq. (5.43)). 

Recently, a dual organocatalysis approach, namely, the combination of the achiral nucleophilic Lewis base catalyst DMAP (23) and the chiral anion-binding thiourea catalyst 27, was applied to the Steglich rearrangement to provide a,a-disubstituted amino acid derivatives 24 in a highly enantioselective fashion (Scheme 43.5) [14]. Notably, replacement of the nucleophilic codiamino acid derivatives with excellent enantiomeric excesses (88-93% ee). 

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