Isoquinoline and Its Derivatives

The ubiquity of the isoquinoline stmcture among namral products might lead to the expectation of a correspondingly large number of therapeutics that incorporate this nucleus. The relatively small number of isoquinolines that show useful biological activity is thus somewhat of a surprise. It should be added that the examples below are included more for illustration of the chemistry of this heterocyclic system than for their therapeutic importance, since most have long since passed out of use. 

A dihydroisoquinoline was at one time investigated in some detail as an antiviral compound. Acylation of 3-phenethylamine (52-1) with 2-(4-chlorophenoxy)acetyl 

A commercial NSAID and some of its analogues that depend on an enolized heterocyclic ring for an acidic proton are considered in more detail later in this chapter. The preparation of a simplihed example starts by conversion of homophtha-lic acid (56-1) with ammonia to its imide (56-2). Reaction of that product with pam-chlorophenylisocyanate (56-3) in the presence of triethylamine results in the addition 

---

IsoquinoUne was converted to 1,2,3,4-tetrahydroisoquinoline in 89% yield by reduction with sodium in liquid ammonia and ethanol [473], and to a mixture of 70-80% cis- and 10% trans-decahydroisoquinoline by catalytic hydrogenation over platinum oxide in acetic and sulfuric acid [474]. Without sulfuric acid the hydrogenation stopped at the tetrahydro stage. Catalytic hydrogenation of isoquinoline and its derivatives is the topic of a review in Advances in Catalysis [439]. 

B-76MI20603 S. F. Dyke Isoquinoline and Its Derivatives , in Rodd s Chemistry of Carbon... 

Aniline [AMINES - AMINES, AROMATIC - ANILINE AND ITS DERIVATIVES] (Vol 2) -for quinolines [QUINOLINES AND ISOQUINOLINES] (Vol 20)... 

The Bohlmann bands at 2805 and 2761 cm-1 in the infrared spectra indicated trans-fusion of the heterorings in 3,3-diethyl-l,3,4,6,7,116-hexahydro-2//-pyrimido[2,l-a]isoquinoline (69YZ649). The presence of Bohlmann bands in the infrared spectra of l,3,4,6,ll,llu-hexahydro-2//-pyrimido[l,2-6]-isoquinoline and its 2-oxo derivative justified the trans-type ring junction of the heterorings [68JCS(CC)1423]. 

EUP161917,85EUP164247 91JMC19). l,3,4,6,7,116-Hexahydro[l,4]ox-azino[3,4-a]isoquinoline and its 4-oxo derivative were obtained by cycliza-tion of 3-[o-(2-chloroethyl)phenyl]morpholine and l-[(2-chloroethoxy)-methyl]-l,2,3,4-tetrahydroisoquinoline on the action of ferf-BuOK, and by cyclization of 2-[o-(3-morpholinyl)phenyl]acetyl chloride on the action of NEt3 (67BRP1094470,67NEP6611733). 

In this series of compounds (5) and its derivatives have been the most extensively studied. The parent compound is stable towards mineral acid but in the presence of 4.5N potassium hydroxide solution [l,2,4]triazolo[5,l-a]isoquinoline (7) was obtained. The mechanism for this conversion is similar to that for isomerization of [l,2,4]triazolo[4,3-n]pyridines described earlier and is given in Scheme 3 (71RTC1225). Oxidation of both (5) and (7) with potassium permanganate give 3-(2-carboxyphenyl)-[l,2,4]triazole (121) (71CB3925). 

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). 

Phenethylamine and its derivatives are the most likely precursors of the isoquinoline system. Their sources are undoubtedly /S-phenylalanine and its nuclear substituted derivatives, from which they can arise by carboxylase-catalyzed decarboxylation. 

Although probably not significant, it is interesting that the first applications of inverse-detected 2D NMR techniques in the study of marine alkaloids were applied to quinoline-based alkaloids. There have also been a sizeable number of isoquinoline and acridine-derived marine alkaloids reported. Thus, we will begin our survey of marine alkaloids with these groups. 

Palacios F, Alonso C, Rodriguez M, Rodriguez M, Martinez de Marigorta E, Rubiales G (2005) Preparation of 3-(fluoroalkyl)-2-azadienes and its application in the synthesis of (fluo-roalkyl)isoquinoline and -pyridine derivatives. Eur J Org Chem 9 1795-1804... 

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

Both of these approaches have been attempted, and both are substantially equivalent for heterocyclic (e.g. quinoline and isoquinoline) and homocyclic (naphthalene) systems. Consequently, in the subsequent discussion it is fruitful to include the available work on naphthalene derivatives. In the case of the fused six-membered rings, Eq. (3) is not applied because it does not permit treatment of the 5- and 8-positions, and the available series as a whole are too short to make this treatment useful. 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

With pyridine and its alkyl derivatives, and in contrast to chlorination, substantial nuclear fluorination occurred before the side chain was attacked (87TL255). Direct fluorination of isoquinoline was unsuccessful but 2-methylcarbostyril gave the 4-fluoroderivative in 54% yield (82H429). 

---