Nucleophilic aromatic substitutions isoquinoline

Furthermore, pyrazole 366 reacts with phthalazine (Scheme 132) to afford pyrazolo[3, 4 4,5]pyrido[6,l-a]phthalazine (367). From a mechanistic viewpoint, no 1,6-dipolar cyclization occurs. Instead, an intramolecular nucleophilic aromatic substitution to the heteroarene is likely. Isoquinoline leads to zwitterionic 368 (94JOC3985). 

Chloropyrazolo[3,4- ]quinoline, 3-chloropyrazolo[3,4-acid-induced nucleophilic aromatic substitution (SnH) of H-3 in A -hydroxypyrazolo[3,4-first cases of nucleophilic aromatic substitution of a fused pyrazole <2002JOC585>. 

Reactions with Nucleophiles. NucleophiUc aromatic substitution (SnAt) is a common reaction for isoquinoUne. The nucleophile usually adds to the 1- or 3-position on the isoquinoUne ring with addition to the 1-position being about 10 times faster than the 3-position when ethoxide is the nucleophile. SNAr reactions involving A-methyl-isoquinoline are accelerated by as much as 10 times compared to the isoquinoUne. ... 

The azanaphthalenes (benzopyridines) quinoline and isoquinoline contain an electron-poor pyridine ring, susceptible to nucleophilic attack, and an electron-rich benzene ring that enters into electrophilic aromatic substitution reactions, usually at the positions closest to the heterocyclic unit. 

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. 

Nucleophilic reagents attack pyridine at the a-position to form an adduct that rearomatizes by dissociation (Scheme 1). Only very strong nucleophiles, e.g. NH2-, RLi, LAH, Na-NH3, react, and for the second step to afford a substitution product (5), conditions that favour hydride loss are required. Adducts formed with hydride ions (from LAH) or carbanions (from lithium alkyls) are relatively more stable than the others at low temperature, and dihydropyridines (6) can be obtained by careful neutralization. Fusion of a benzene ring to pyridine increases reactivity towards nucleophiles, and attack is now found at both a- and y-positions in quinoline (7) and at C-l in isoquinoline (8). This may be attributed to a smaller loss of aromaticity in forming the initial adduct than in pyridine, and thus a correspondingly decreased tendency to rearomatize is also observed. Acridine reacts even more easily, but nucleophilic attack is now limited to the y -position (9), as attachment of nucleophiles at ring junctions is very rare. 

Oxidation of the pyridine nitrogen increases the propensity of the aromatic ring for nucleophilic attack at the 2- and 4-positions. a-Benzotriazolyl-substituted pyridines, quinolines, and isoquinolines may be prepared by treatment of the A -oxide with 1-tosylbenzotriazole in the presence of triethylamine in toluene or xylene under reflux <2001H1703> (Equation 78). 

This type of chemistry is also observed with 1-methyl isoquinoline 6.28. However 3-methyl isoquinoline is much less activated because delocalisation of charge in 6.29a,b involves disruption of aromaticity of the benzenoid ring. This phenomenon is closely related to the reluctance of 3-halo isoquinolines to undergo nucleophilic substitution. 

Af-Methyl-jV-(l-methylpropyl)-l(2-fluoro-5-nitrophenyl)isoquinoline-3-carboxamide, 323, possessing high affinity and selectivity for PBBS (peripheral-type benzodiazepine binding sites)312 in living man, has been labelled313 with n.c.a. fluorine-18, obtained via lsO(p, n)18F nuclear reaction, by an aromatic nucleophilic substitution process (equation 139). (n.c.a. = no carrier added)... 

Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with Ai-oxide azaindoles (Reissert-Henze reaction. Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61,62]. Following similar mechanistic trends, V-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, W-tosylated isoquinoline [63, 64] and W-fluoropyridinium salts [65] are also reactive substrates in Reissert-Henze type processes. 

The same logic can be followed on the nucleophilic attack of alkyl or aryl groups on C2 position of quinoline and Cl position of isoquinoline cores by organometalic species (lithium or Grignard reagents). The reaction seems to proceed in two steps as this is demonstrated in the alkylation of isoquinolile below. Addition at the Cl position gives a dehydroisoquinoline-A-lithio derivatives, which can be hydrolyzed to furnish an isolable 1-substituted 1,2-dihydroisoquinoline. It was followed by an oxidation process to yield the full aromatized product. ... 

An aryne multicomponent reaction involving isoquinoline and 5-bromo-1-methylisatin resulted in spirooxazino isoquinolines (Scheme 66).The reaction occurs with a number of iV-substituted isatins. Quinoline can replace the isoquinoline as well. Carbonyls other than the isatins can trap the anion as well. A variety of aromatic, aliphatic, and heteroaromatic aldehydes can function as the electrophile. When pyridine replaces isoquinoUne as the nucleophilic trap, the reaction forms an oxindole but not an oxazino pyridine derivative (14SL608). 

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. 

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)). 

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