Acids, isoquinoline salt formation

The iridicycle catalysts also catalyse the TH of A-heterocycles (including quinolines, isoquinolines, indoles and pyridinium salts) in water under mild conditions a solution of formic acid and sodium formate is employed in the reaction. TONs of up to 7500 and catalyst loadings as low as 0.01 mol% were used [206]. 

Physical Properties. Both (1) and (2) are weak bases, showing 4.94 and 5.40, respectively. Their facile formation of crystalline salts with either inorganic or organic acids and complexes with Lewis acids is in each case of considerable interest. Selected physical data for quinoline and isoquinoline are given in Table 1. Reference 4 greatly expands the range of data treated and adds to them substantially. 

Completion of the synthesis of quinapril involves amide bond formation between 26 and a tetrahydroisoquinoline fragment. Two complementary protected 1,2,3,4-tetrahydro-3-isoquinoline subunits 27 and 28, each available in a single step from commercially available (6)-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, were utilized (Scheme 10.7). Coupling with 26 using DCC and HOBt in dichloromethane afforded the penultimate compounds 29 and 30 as maleate salts. Cleavage of the f-butyl ester of 29 and treatment with HCl provided quinapril. Alternatively, hydrogenation of 30 under standard conditions cleanly removed the benzyl ester, and quinapril (3) was isolated after formation of the hydrochloride salt. 

Azine approach. Oxazolo[3,2-a]pyridinium salts (210) were first obtained from the cyclodehydration reaction of l-phenacyl-2(lii)-pyridinone in sulfuric acid (67JHC66). These salts can also be prepared from 2-halo-l-phenacylpyridinium derivatives (211) by treatment with a base which causes ylide formation and hence cyclization by intramolecular substitution (69JOC2129, 76CB3646). It is recommended that a bulky tertiary amine is used as base in order to avoid opening of the ring or substitution of the 2-halo substituent in the starting material (211). Isoquinoline and quinoline analogues have also been prepared by these methods. 

Deprotonation to the enamine anion, selective coupling with the allylic terminus of dibromide 114, followed by an intramolecular enamine alkylation, afforded reduced isoquinoline 119. A rather elegant conversion to aminoaldehyde 122 ensued. Immonium ion formation in 119 via protonation with perchloric acid at first yielded the kinetic trans isomer, which underwent equilibration upon reflux in methanol to give the corresponding crystalline cis product 120. Diazomethane treatment led to aziridinium salt 121, which upon exposure to DMSO, ring opened with concomitant oxidation in a Komblum fashion to the aldehyde 122.63 Treatment with Lewis acid effected B-ring closure, thus... 

A novel preparative synthesis of aporphines which should prove of appreciable utility in the future involves the cathodic cyclization of a l-(o-iodo-benzyl)isoquinoline methiodide salt. Gottlieb and Neumeyer have shown that electrolysis of l-(o-iodobenzyl)isoquinoline methiodide in dry acetonitrile containing tetraethylammonium bromide, and using a mercury cathode, furnished an 867o yield of the yellow didehydroaporphine which was reduced over Adams catalyst in methanolic hydrochloric acid to produce aporphine hydrochloride. The formation of didehydroaporphine proceeds via two one-electron reduction steps as shown below. 10,11-Dimethoxyaporphine was also prepared by this route. 

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. 

On the way to further extension of the scope of Cp Co "-catalyzed C-H functionalization, Glorius and coworkers developed a condensation reaction of 2-arylpyridine derivatives and diazoesters to form unique polycyclic heteroaromatics having 6//-pyrido[2,l-a]isoquinolin-6-one skeletons (Scheme 10.15) [38]. The reaction is achieved by the combination of a bench-stable Co precatalyst [Cp Co(CO)l2] [39], a silver salt (AgSbFg), and an acetate source (KOAc) in trifluoroethanol. The in situ-formed Cp Co catalyst is proposed to play a dual role in this condensation reaction. First, it promotes formal carbene insertion into the ortho C-H bond through pyridine-directed C-H metalation, cobalt-carbene formation, carbene insertion into the aryl-Co bond, and protodemetalation. Second, it acts as a Lewis acid to facilitate nucleophilic attack of the pyridine moiety to the ester group, which eventually leads to the product through aromatization and elimination of methanol. The thus-synthesized polycyclic heteroarenes exhibit bright and color-tunable fluorescence in solution and in the solid state. 

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