7,8-Disubstituted isoquinolines

Various cyclizations of alkynylbenzaldimines (e.g., 174) are particularly useful in the synthesis of isoquinolines as summarized in Scheme 101 . The use of electrophiles and base yields 3,4-disubstituted isoquinolines 175 <2002JOC3437> whereas the palladium-catalyzed carbonylation affords 4-aroylquinolines 173 <2002JOC7042>. Cyclization followed by Heck reaction gives rise to 4-alkenyl substituted isoquinolines 176 (Scheme 101) <2002TL3557>. 

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... 

Larock and Dai developed the synthesis of isoquinolines via palladium-catalyzed coupling of organic halides with 2-(l-allqmyl)benzaldimines. Starting from N-tert-butyl-2-(l-alkynyl)benzaldimines and aiyl, allylic, benzylic, alkynyl halides, as well as a vinylic halide, the corresponding 3,4-disubstituted isoquinolines with aryl, allylic, benzylic, 1-alkynyl, and vinylic substituents, respectively, in the 4-position were produced in good yields. The reaetion appears to require an aiyl group on the end of the acetylene furthest from the imine functionality. 

Kobayashi and co-workers have described a new synthesis of a range of 1,4-disubstituted isoquinoline derivatives 117 <06S2934>. Initially, a lithium halogen exchange of 118 was performed to form 119, followed by treatment with a variety of nitriles 120 resulting in 1,4-disubstituted isoquinolines 117. 

Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives <06BCJ 1126 06S2934>. The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1 -amino-4-substituted isoquinolines 121 in moderate yields. 

F. Cularine.—New syntheses of ( )-cularine (ISO) and its derivatives using intramolecular Ullmann186 and phenolic oxidative coupling187,188 reactions as key steps have been reported. It is well known that 7,8-disubstituted isoquinolines cannot be prepared by the Bischler Napieralski reaction. This problem was circumvented (Scheme 14) by using an ethoxycarbonylamino-/ -phenethyl-amide (177) in order to activate the para-position and thus to effect the required cyclization reaction (177) — (178).186 Conventional steps then led to the phenol (179) which under Ullmann reaction conditions gave (+)-cularine (180). 

Mycoplasmal infection may also play a role in the etiology of rheumatoid diseases [556,557]. Since copper complexes of 1,10-phenanthroline, 2,9-dime-thyl-l,10-phenanthroline, 1,3-disubstituted isoquinolines, and 2,2 -bipyridine have been shown to be effective antimycoplasmal agents [558-561], this approach to understanding the effectiveness of therapy and the physiological response associated with elevated blood copper levels in arthritic diseases also merits study. 

Kametani et al. (544,545) and other workers (546-561) endeavored to carry out the synthesis of cularine alkaloids by phenolic oxidation (bio-genetic type of synthesis) of the corresponding derivatives of laudanosine. The paper (549) describes the synthesis of these bases via the 6-ethoxycar-bamido-3,4-dihydroisoquinolines, which were converted to 6-amino-isoquinoline. By Ullmann reaction it gives the compound 52 and ( )-cularine (51) (Scheme 18). Cularine-type alkaloids were also synthesized by the intramolecular Ullmann reaction of 7,8-disubstituted isoquinoline obtained by the usual Bischler-Napieralski reaction from the phenolic bromoamide (pathway a) (544, 548). However, in the papers referred to (557,558,561), the rings A, C, and D were formed first (pathway b), and only then was the ring formed during the synthesis of cularine. 

Meyers and coworkers have shown that the simple modification of replacing the t-butoxy group with the smaller methoxy group allowed deprotonation of the remaining benzylic proton in 1-substituted tetrahydroisoquinolines [61]. Subsequent alkylation of the resulting carbanion afforded a,a-disubstituted isoquinolines 74 in high yields of 85-90% with good diastereoselectivities of up to 93 7 (Scheme 21). The stereochemical course of the reactions has been sununa-rized [62-65]. 

Biologically important heteroarenes are readily prepared by the reaction of ketone, ester or amide enolates with ortho-substituted aryl halides [11]. The ortho-substituent can subsequently be used for further synthetic manipulations. For example, the reaction of o-iodo or o-bromoaniline with enolates generated from aliphatic or aromatic ketones under SrnI conditions provides 2,3-disubstituted indoles in moderate to excellent yields (Equation 13.2) [12, 13]. 2,3-Disubstituted isoquinolin-l-ones (Equation 13.3) and isoquinolines are readily prepared using o-iodobenzamide and o-iodobenzylamine as radical precursors by the same approach [14]. 

A series of bisbenzylisoquinolines has been prepared through alkylation of 6,7-disubstituted isoquinoline Reissert compounds with diaryl ethers such as 8, 9, and 10. ... 

When the 1-monoximes or dioximes of 4-acetyl-l-tetralones are hydrogenated in the presence of palladium, mixtures of diastereoisomeric 1-aminotetralones are formed. The m-aminoketone isomers readily form dehydrobenzoisoquinuclideines (3,4-disubstituted-1,4-dihydro-1,4-ethano-isoquinolines). Quaternary immonium salts prepared from these bicyclic imines are then converted by bases to bicyclic enamines [2,4-disubstituted-3-alkylidene-1,4-ethano-1,2,3,4-tetrahydroisoquinolines (25)]. 

An asymmetric synthesis of 1-aryltetrahydroisoquinolines 79 from chiral amide 78 was reported <96TL(37)4369>. Optically active cis- or rranj-1,3-disubstituted tetrahydro-isoquinolines can he prepared hy a modification of this procedure. 

A base peak corresponding to a 6,7 (or 7,8)-disubstituted isoquinolinium ion is the prime criterion in considering a pavine or an isopavine structure. In the case of a pavine, the presence of the expected peaks may only confirm the structure deduced by other spectral and chemical means. In isopavines, however, mass spectroscopy is an exceptionally powerful tool in differentiating this group from the pavine alkaloids, as well as from other related isoquinoline bases. 

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... 

Cyclocondensation of 2-aminoquinoline and iminium derivatives 315 in boiling 1,2-dichloroethane yielded l-(disubstituted amino)-3//-pyrimido[l,2-a]quinolin-3-ones (224) containing traces of isomeric 3-(disubstituted amino)-l//-pyrimido[l,2-a]quinolin-l-ones (149) (95MI1). Similar reactions of 1-aminoisoquinoline with compounds 315 afforded 4-(disubstituted amino)-2//-pyrimido[2,l-a]isoquinolin-2-ones (33, R = Rj = Et, -(CH2)5-, -CH2CH2OCH2CH2-) (12-20%) together with a few percent (1.4-12%) of isomeric 2-(disubstituted amino)-4//-pyrimido[2,l-a]iso-quinolin-4-ones (34, R = R1 = Et, -(CH2)5-, -CH2CH2OCH2CH2-) (95MI1). 

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