1-Alkylated isoquinoline heterocycles

Isoxazolinoisoquinoline heterocycles and several Cl-alkylated isoquinolines were thus obtained [141]. 

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. 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

Reissert compounds (l-acyl-l,2-dihydro-2-quinolinecarbonitriles) have been prepared on cross-linked polystyrene and C-alkylated in the presence of strong bases (Entry 8, Table 15.25). Treatment of polystyrene-bound C-alkylated Reissert compounds with KOH leads to the release of isoquinolines into solution (Entry 9, Table 15.25). The reaction of support-bound quinoline- and isoquinoline /Y-oxides with acy-lating agents followed by treatment with electron-rich heteroarenes and enamines has been used to prepare alkylated and arylated derivatives of these heterocycles (Entry 10, Table 15.25 see also Table 15.26). 

Chemical Properties. The presence of both a carbocycfic and a heterocyclic ring facilitates a broad range of chemical reactions for (1) and (2). Quaternary alkylation on nitrogen takes place readily, but unlike pyridine both quinoline and isoquinoline show addition by subsequent... 

Heterocyclic coupling components that have been coupled with diazotized ami-nophenyltrimethylammonium chloride are l-alkyl-6-hydroxy-2-pyridone [93], 1-amino-3-hydroxy-isoquinoline [94], and 2,4-diamino-6-hydroxypyrimidine [95], The trialkylammoniumaryl residue may also be connected to the aromatic diazo component via a sulfone or a sulfonamido function [96], Disazo dyes in this series (e.g., 34) [77901-21-4] may also be generated from monoazo dyes that still contain a primary amino group by dimerization using phosgene [97] or cyanuric chloride [98],... 

The decreasing reactivity of the most familiar aromatic heterocyclic compounds with nucleophilic reagents may be illustrated by the following sequence quinoxaline > acridine > phenanthridine > isoquinoline > quinoline > pyridine. Acridine is alkylated in the 4-position, phenanthridine and quinoxaline in the a-position, isoquinoline in the 1-position, and quinoline and pyridine in the 2- or 4-positions. Weaker nucleophilic reagents seem to enter the 4-position of the pyridine and quinoline rings. If the addition occurs readily and in good yield, the intermediate dihydro derivative may sometimes be isolated otherwise, the product of the subsequent oxidation results. In synthetic work the dihydro derivative is usually directly oxidized. 

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 quinolines, isoquinolines, and pyridines are structurally diverse with a large number of alkyl-substituted isomers. Direct isotopic measurements have not been made on nitrogen heterocycles. 

Two asymmetric syntheses of phenethylisoquinolines have been reported. Simple exchange between isoquinoline 125 and imine 126 gave the chiral formamidine 127. Methylation of 127 with /ert-butyllithium gave the lithiated formamidine, which was alkylated with 3,4-dimethoxyphenethyl iodide and hydrazinolyzed to give the (S)-(-)-isoquinoline 128 in 95% enantiomeric excess (e.e.) (74). The e.e. of 128 was determined by chiral-column HPLC analysis, as developed by Pirkle and applied to chiral N-heterocycles and other amines (75). 

A number of polymers containing a heterocyclic group have been prepared using the Reissert alkylation sequence. Thus, for example, the reaction of the isoquinoline Reissert anion (26) with poly(vinylbenzyl chloride) and sodium hydride gave 36, which on hydrolysis with base gave A... 

Isoquinolines are precursors of many alkaloids, and asymmetric alkylations of these heterocycles have been successfully carried out with the same two auxiliaries... 

The immediate products of addition of alkyl and aryl Grignard reagents and alkyl- and aryllithiums are dihydro-quinolines and -isoquinolines and can be characterised as such, but can be oxidised to afford the C-substituted, re-aromatised heterocycles illustrated below is a 2-arylation of quinoline. ... 

A number of polymers containing a heterocyclic group have been prepared using the Reissert alkylation sequence.92 94 Thus, for example, the reaction of the isoquinoline Reissert anion (26) with polyfvinylbenzyl chloride) and sodium hydride gave 36, which on hydrolysis with base gave 37.92,93 A similar condensation takes place with quinoline, phenanthridine, and benzo-[/Jquinoline Reissert compounds.94 The Reissert anion 26 has also been alkylated with a mixture of m- and p-vinylbenzyl chloride and the product polymerized to a polymer of type 37.93 Copolymerization has also been studied.93... 

Friedel-Crafts alkylation and acylation reactions are quite versatile. They form the basis of several named reactions that have been used to synthesize heteroatom-containing compounds such as quinolines, isoquinolines, indoles, and many others. This section will examine several more common transformations that will show the scope and utility of these processes. It will also introduce a modest amount of heterocyclic chemistry into our synthetic discussion. 

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. 

As in the case of quinolines, isoquinolines can be prepared by metal-mediated annotation processes. Reaction of t-butylimines of iodo-benzaldehydes with acetylenes in the presence of palladium catalyst affords 3,4-disubstituted isoquinolines. The power of this reaction relies on its ability to introduce different type of substituents on 4-position of the heterocycle by using the formed intermediate palladium complex in the cross-coupling reaction with aryl and alkyl halides or alkenes. This methodology was successfully applied to the total synthesis of decumbenine... 

Alkyl salts of quinoline and isoquinoline are particularly easily reduced in the heterocyclic ring, either catalytically or with a borohydride in protic solution. 

Although the intramolecular SrnI reaction has been studied to a lesser extent as compared to the intermolecular process, it has been shown to represent a highly useful route for the synthesis of various heterocyclic compounds. For example, the SrnI cyclization of N-alkyl-N-acyl-o-haloaniUnes and N-acyl-N-methyl-o-chlorobenzylamines (Equation 13.5) gives N-aUcylindol-2-one and 1,4-dihydro-2H-isoquinolin-3-ones in moderate to good yields [21]. lodoketone 1 reacts under SrnI conditions to provide the complex heterocyclic compound 2 with excellent yield (Equation 13.6) [22]. 

The NMR data which also include /nx couplings have been collected by Pazderski for 105 complexes of Pd(II), Pt(II), Au(III), Co(III), Rh(III), Ir(III), Pd(IV) as well as Pt(IV) complexes with simple azines such as pyridine, 2,2 -bipyridine, 1,10-phenanthroline, quinoline, isoquinoline, 2,2 -biquinoline, l,2 6,2 -terpyridine and their alkyl or aryl derivatives. A short review on the formation and structure of heterocycles obtained from condensation of trifluoromethanesulphonamide with different carbonyl compounds has been written by Shainyan and Meshcheryakov. It contains NMR data including proton-proton couplings. A brief review (in Chinese) on NMR has been written by Li et al ... 

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