Isoquinolines, carboxylation

Recently, Jankowski et al. [80] reported the application of MW to the Diels-Alder synthesis of N-methyloctahydroisoquinoline adducts, which are important intermediates in the synthesis of medicinally important compounds, such as HIV protease inhibitor isoquinoline carboxylate pharmaceuticals. The reaction of the arecoline 67 or its isomer 70 with Danishefsky s diene 68 in toluene (Scheme 4.32) was studied under both conventional and MW heating in sealed tubes, i. e. at elevated pressure. 

Scheme 4.32 Diels-Alder synthesis of isoquinoline carboxylates.

Zwitterionic analogs of SNC 80 designed by replacement of the diethylamide benzamide ring by various 7-yl-3,4-dihydro-2(l//)-isoquinoline-carboxylic acids have recently been described in the literature as selective peripheral 8 opioid receptor agonists [40]. 

Halogenated and Metallated Isoquinolines and Their Hydrogenated Derivatives Isoquinoline Carboxylic Acids and Their Hydrogenated Derivatives... 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

Isoquinoline reacts with aliphatic carboxylic acids photolyticaHy or with a silver catalyst to give excellent yields of alkylation products by decarboxylation (155). This method is useful in the synthesis of 2-benzoyhsoquinolines bearing a variety of aromatic substituents in the 1-position (156). 

Polycyclic derivatives have been prepared by straightforward amide formation. The tetracyclic amide 166 was obtained by reductive cyclization of 3-o-nitrophenylindole-2-carboxylic acid (165).22 When l-(2 -ethoxycarbonylskatyl)isoquinoline (167) was heated the pentacyclic j8-carboline derivative 168 was formed. If,... 

Lithiation of 2-(2-alkylphenyl)-l,2,3,4-tetrahydropyrimidines 427 with 1.3 M BuLi in the presence of A/, A/, A, A -tetramethylethylenediamine, then with 1.3 M -BuLi, followed by the addition of a carboxylic acid methyl ester, and treatment of the reaction mixture with pTSA afforded 3,4-dihydro-2/f-pyrimido[2,l-u]isoquinolines 428 after chromatographic work-up (98JMC1050). 

Treatment of (11 aS)-3-isopropyl-11 a-methyl-4-phenyl-1,6,11,11 a-tetrahy-dro[l,4]oxazino[4,3-6]isoquinolin-l-one (243) with 6N HCl in a pressure tube, then the reaction of the work-up residue with propylene oxide gave (3S)-3-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (244) (99S704). 

Cyclocondensation of 2-(2-chloroacetyl)-l, 2,3,4-tetrahydroisoquinoline-3-carboxylate 418 (R =N02, R = Me) with liquid NH3 in MeOH in a stainless steel pressure vessel at room temperature overnight gave 8-nitro-2,3,4,6,1 1,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione (419, R=H, R =N02) (97MIP4). (1 la/i)-2-Cycloalkyl-8-hydroxy-2,3,4,6,ll, 1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones 419 (R = cycloalkyl, R = OH) were prepared in the reactions of (3/i)-2-chloroace-tyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (418, R = OH, R = Et) with cycloalkylamines (98MIP7). 

Thermolysis of the vinyl azide 11 in toluene furnishes a mixture of ethyl 2-phenyl-l//-3-benz-azepine-4-carboxylate(12), ethyl 4-(2-phenylvinyl)indole-2-carboxylate(13) and ethyl 1-benzyl-isoquinoline-3-carboxylate (14).82... 

Ethyl 1 -phenyl-1,8b-dihydroazirino[2,l- ]isoquinoline-3-carboxylate (2), obtained by decomposition of azide 1 (see Section 3.2.1.1.1.1.) in the presence of triethyl phosphite, on heating under reflux in toluene, rearranges quantitatively to the 3//-3-benzazepine 3.82... 

A Diels-Alder reaction of arynes with 1,2,4-triazines 102 allows the preparation of isoquinolines substituted with electron-withdrawing groups in the nitrogen-containing ring. The isoquinoline-1-carboxylic esters bearing additional substituents are of particular interest because they are not readily available by the usual routes [100,101] (Scheme 2.42). 

The majority of nonsteroidal antiinflammatory agents contain an acidic carboxyl group. A series of experimental agents in this class have been prepared in which the acidic proton is supplied by a highly enolizable proton from a function such as a p-dicarbonyl incorporated into a heterocyclic system. As an example, an acylated, highly oxidized isoquinoline moiety can fulfill this function (see also the benzo-thiazines below). Toward this end, reaction of... 

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