Isoquinoline reactions with electrophiles

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

The lone-pair electron on the nitrogen is responsible for electrophilic reactions on its side. Thus, heterocyclic nitrogen atom of quinoline and isoquinolines react with electrophiles, as alkyl halides, alkyl sulfates, alkyl-toluene-p-sulfonates, etc., providing quinolinium and isoquinolinium salts. 

Reactions with Electrophiles. The structure of isoquinoline 1 is the result of fusing benzene and pyridine together. Electrophilic aromatic substitution predominately occurs on the benzene ring under acidic conditions and usually addition takes place at the 5-position but can sometimes add to the 8-position. The rate of electrophilic aromatic substitution is slower for isoquinoline compared to naphthalene. The nitrogen in isoquinoline reacts similar to a pyridine nitrogen and will add a variety of electrophilic species such as 0-(2,4-dinitrophenyl)hydroxylamine 2 to aminate the nitrogen (eq 1). Friedel-Crafts acylation and alkylation do not work due to the formation of IV-acyl or IV-alkyl isoquinolinium salts. 

The [4 + 2] cycloaddition of benzo-l-azadienes with electrophilic carbon—carbon double bonds has been implemented by de Meijere and coworkers (90CC574) in this case, the authors used N-unsubstituted benzo-phenone imine and cyclopropylideneacetates, and the reaction represents a new isoquinoline ring synthesis. 

Charge effects may also play an extremely important role in controlling the reactions of co-ordinated amines with electrophilic reagents. This is very clearly seen in the alkylation reactions of nucleophilic sites remote from the metal. On electrostatic grounds we would expect the reaction of positively charged complexes with electrophiles to be less favoured than the reaction of neutral or anionic complexes, and this is indeed the case. Consider the attempted alkylation of the non-co-ordinated isoquinoline rings in the cop-per(n) complexes 5.14 and 5.15. Compound 5.14 is derived from salicylaldehyde and... 

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). 

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. 

Thiazoles are deactivated towards electrophilic substitution, and thus direct reaction with hydride re-ductants to give thiazolines should be facilitated. There are indeed some examples of this type of reaction, but it is more common to reduce N-alkylated thiazolium salts (209). These compounds are converted first by reaction with sodium borohydride into 4-thiazolines (210), which in protic solvents become protonated and undergo further reduction to yield thiazolidines (211). Similarly the isoquinoli-nium salt (213), formed by the acid-promoted cyclization of the isoquinoline (212), is converted into the tetrahydroisoquinoline (214) (presumably via an intermediate 1,2-dihydroisoquinoline) by reaction with sodium borohydride. ... 

Following the dipole moments presented, quaternary alkylations on nitrogen take place readily. But unlike pyridine, both quinoline and isoquinoline heterocyclic nitrogen promote the reaction with nucleophiles. What is more, electrophilic substitution takes place much more easily than in pyridine, and the substituents are generally located in carbocyclic ring preferentially in the more activated positions of the benzene ring, with a positional selectivity in the case of quinolines in the order of C8 > C5 > other positions. 

Quinolines and isoquinolines can also react with electrophiles at the pyridine side. This can be rationalized by a different reaction mechanism involving the prior introduction of a nucleophile in the heterocyclic quinoline/isoquinoline ring followed by an electrophilic substitution involving attack on the intermediate enamine. Notable is the electrophilic bromination of isoquinoline hydrobromide in a solvent like nitrobenzene that provides 81% yield of 4-bromoisoquinoline, in contrast to the bromination or chlorination of an isoquinoline-aluminum chloride complex that affords 78% of 5-bromoisoquinoline. Exhaustive bromination or chlorination under Lewis acid conditions usually yields mixtures of 5,8-halogenated isoquinolines along with 5,7,8-trisubstituted derivatives. ... 

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. 

Since heteroaromatic compounds sometimes exhibit interesting physical properties and biological activities, construction of substituted heteroaromatics has drawn some attention. Heteroaromatics can be divided into two major categories. One is the tt-electron-sufhcient heteroaromatics, such as pyrrole, indole, furan, and thiophene those easily react with electrophiles. The other is the 7r-electron-deficient heteroaromatics, such as pyridine, quinoline, and isoquinoline those have the tendency to accept the nucleophilic attack on the aromatic ring. Reflecting the electronic nature of heteroaromatics, the TT-electron-deflcient ones are usually used as the electrophiles.t The rr-electron-sufficient heteroaromatics having simple structures, such as 2-iodofuran and 2-iodothio-phene, have also been utilized as the electrophiles. Not only the electronic nature of the heteroaromatics but also coordination of the heteroatom to the palladium complexes influence catalytic activity. This is another reason why the couphng reaction did not proceed efficiently in some cases. 

Ye S, Wang H, Wu J (2011) l-(Isoquinolin-l-yl)urealibrary generation via three-component reaction of 2-alkynylbenzaldoxime, carbodiimide, with electrophile. ACS Comb Sci 13 120-125... 

This reaction works with aryl, allylic and 1-alkynyl halides, but not vinylic halides. A vinylic group can be introduced into the 4 position of an isoquinoline by using PdBr2 as the electrophile and an alkene (Scheme 9).10 This process... 

The synthesis of 3-aryltetrahydroisoquinolines was accomplished by electrophilic aromatic substitution of polysubstituted phenols and phenyl ethers with Lewis acid-generated tosyliminium ions of 2-tosyl-3-methoxytetrahydroisoquinoline derivatives <00SL801>. In addition isoquinoline was reported to react with N-tosylated (R)- or (S)-amino acid fluorides to afford optically active dihydroimidazoisoquinolinones. The reaction proceeds via acylation followed by attack of the tosylamino group at Cl of the intermediate 2-tosylaminoacylisoquinolinium salt <00TL5479>. 

Nitration of isoquinoline with nitric and sulfuric acids occurs preferentially at positions 5 and 8, the former predominating, in the approximate ratio of 9 1 at 0 °C. The amount of 8-nitro isomer is slightly increased at higher temperatures. Electrophilic localization energies predict the reactivity order 5>8>others. Over the range 71—85% sulfuric acid it has been shown that the reaction proceeds via the isoquinolinium cations (Scheme 6) (63CI(L)1283, 60T(8)23, 57JCS2521). 

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