Isoquinolines metalation

Isoquinoline 2-oxide was converted by bromine in acetic anhydride in the presence of sodium acetate into the 4-bromo 2-oxide, presumably via an addition-elimination process (84MI2). Metallic derivatives have been used occasionally to prepare bromoisoquinolines, as in the formaton of 79, a process accompanied by ring-opening [87JCS(PI)1865]. 

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. 

An appropriately functionalized isoquinoline (38) bearing a benzyl group is prepared from an aromatic aldehyde (37). The benzyl position is metalated with LDA and the resulting carbanion is reacted with a highly substituted methyl benzoate to produce a ketone (39). The isoquinoline nitrogen is alkylated with ethyl a-bromoacetate and the resulting quaternary salt is cyclized... 

Figure 7 shows SNIFTIRS spectra for isoquinoline molecules adsorbed on mercury. The reference spectrum in each case was obtained at 0.0V vs. a SCE reference electrode at this potential the molecules are believed to be oriented flat on the metal surface. The vibrational frequencies of the band structure (positive values of absorbance) are easily assigned since they are essentially the same as those reported by Wait et al. (22) for pure isoquinoline. The differences in the spectra are that the bands for the adsorbed species exhibit blue shifting of 3-4 cm" relative to those of the neat material, and the relative intensities of the bands for the adsorbed species are markedly changed. 

There was a lack of any potential dependence in the frequencies of the vibrational modes of the adsorbed isoquinoline. The explanation of this may be the fact that mercury has no available vacant p- or d-orbitals into which back-bonding (which is observed for adsorbates on d metals) can occur. 

Another type of reaction which occurs at a metal surface and which is most conveniently discussed in this section is catalytic hydrogenation. Pyridine is reduced rather more easily than benzene, and quinoline and isoquinoline give the 1,2,3,4-tetrahydro derivatives. 

Like the related organolithium-pyridine adducts (see Section II,D,2,d), the dihydropyridyl metal adducts considered in this Section are found to be good hydride donors toward a number of carbonyl and other compounds.152 Hydride transfer from such adducts has also been shown to occur toward a variety of azaheterocyclic substrates, thus generating, in turn, the corresponding adducts. Such a transfer has been carried out with pyridine, (V.AT-dimethylnicotinamide, quinoline, isoquinoline, 2,2 -bipyridyl and its isomers, and 1,10-phenanthroIine.158... 

In l,2,3-triazolo[5,l-a]isoquinoline (520), the N-3 atom appears to direct metalation to the peri C-4 position, as seen from the products 521 derived from electrophile quench experiments (Scheme 158) [85JCS(P1)1897]. With TMSC1, besides 60% of 521 (E=TMS), 23% of 1,5-disubstituted... 

Early publications on [VO(/3-diketonato)2] have been reviewed.355 More recently, complexes with benzoyl m-nitroacetanilide, benzoyl acetanilide545 and l,l -(l,3-phenylene)-bis(butane-1,3-dione546 have been synthesized. Other [VO(/S-dik)2] adducts have been isolated, for example [VO(acac)2] adducts with a series of pyridine N-oxides547 and several pyridine carboxamides, 48 and [VO(bzac)2] adducts with pyridine, methylamine, isoquinoline and 4-picoline.549 Equilibrium constants of 1 1 and 2 1 adducts of pyrazine with [VO(tfacac)2] have been determined (equation 38).550 In the 2 1 complex, the pyrazine bridge between two equatorial sites of adjacent vanadium atoms promotes a weak exchange interaction. The nitroxide radical 2,2,6,6-tetramethylpiperidinyl N-oxide also forms an adduct with [VO(hfacac)2] in which there is a strong interaction between the electrons on the metal and nitroxide.551... 

Transition metals also catalyze isotopic exchange reactions. Platinum is the most active catalyst for most heterocycles. The mechanism may involve metallation, addition, o--addition and ir-complex formation. a-Hydrogen exchange in pyridine is favored over 3- and 7-positions, particularly by a cobalt catalyst whereas platinum is much less selective. In isoquinoline both the 1- and 3-position protons are exchanged at almost the same rates with very little exchange at any other position. In 3-substituted pyridines exchange is preferred at the 6-position, the more so as the size of the 3-substituent increases (73AHC(15)140). 

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... 

The iodination of pyridine, quinoline, and isoquinoline via a-metalation using lithium di-fert-butyltetramethylpi-peridinozincate (TMP-zincate) proceeds smoothly at room temperature using iodine as the electrophile. The chemoselective deprotonative zincation generated 2-iodopyridine 70 and 1-iodoisoquinoline 71 in 76% and 93% yield, respectively. Quinoline metalated preferentially at the 8-position to give 61% yield of the 8-iodo derivative 72 and 26% yield of 2-iodoisoquinoline 73 (Equations 25-27) <1999JA3539>. 

Although the transition-metal-catalyzed reaction of a-diazocarbonyl compounds with aromatic molecules has received much attention in recent years,104 the metal-catalyzed behavior of these compounds with N-containing heteroaromatics has not been extensively studied. An early example involved the preparation of isoquinoline-carboethoxymethylide... 

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