Of isoquinolines

A 90% yield of isoquinoline (>95% pure) was reported by treating a cmde fraction with hydrochloric acid followed by addition of an alcohoHc solution of cupric chloride in a mole ratio of 1 2 CUCI2/isoquinoline (40). A slighdy lower yield of 2-methylquinoline [91-63-4] (97.5% pure) was obtained from bituminous coal using 30% aqueous urea to form a clathrate (41). 

The oxidation of isoquinoline has also been examined using mthenium tetroxide. In this instance, the surprising observation that phthaUc acid is the only significant product (58%) was made this fact is both important and difficult to explain (145). Isoquinoline is also oxidized to its N-oxide by peracids. Isoquinoline N-oxide [1532-72-5] has also been obtained from 2-(2,4-dinitrophenyl)isoquinolinium chloride [33107-14-1] by refluxing with hydroxjiamine hydrochloride in concentrated hydrochloric acid (146). 

The N-oxides of isoquinolines have proved to be excellent intermediates for the preparation of many compounds. Trialkylboranes give 1-alkyl derivatives (147). With cyanogen bromide in ethanol, ethyl N-(l- and 4-isoquinolyl)carbamates are formed (148). A compHcated but potentially important reaction is the formation of 1-acetonyLisoquinoline and 1-cyanoisoquinoline [1198-30-7] when isoquinoline N-oxide reacts with metbacrylonitrile in the presence of hydroquinone (149). Isoquinoline N-oxide undergoes direct acylamination with /V-benzoylanilinoisoquinoline salts to form 1-/V-benzoylanilinoisoquinoline [53112-20-4] in 55% yield (150). A similar reaction of AJ-sulfinyl- -toluenesulfonamide leads to l-(tos5larriino)isoquinoline [25770-51-8] which is readily hydrolyzed to 1-aminoisoquinoline (151). 

Hydroisoquinolines. In addition to the ring-closure reactions previously cited, a variety of reduction methods are available for the synthesis of these important ring systems. Lithium aluminum hydride or sodium in Hquid ammonia convert isoquinoline to 1,2-dihydroisoquinoline (175). Further reduction of this intermediate or reduction of isoquinoline with tin and hydrochloric acid, sodium and alcohol, or catalyticaHy using platinum produces... 

Ha.loisoquinolines, The Sandmeyer reaction is commonly used to prepare chloroisoquinolines from the amino compound. The corresponding hydroxy compounds are also used by treatment with chlorides of phosphoms. The addition of bromine to a slurry of isoquinoline hydrochloride in nitrobenzene gives a 70—80% yield of 4-bromoisoquinoline [1532-97-4J. Heating 1-chloroisoquinoline [19493-44-8] with sodium iodide andhydriodic acid gives 1-iodoisoquinoline [19658-77-6] (179). 

A number of isoquinoline derivatives have fungicidal properties, eg, 1,2,3,4-tetrahydroisoquinoiines bearing acyl nitrogen substituents like (36) [41910-26-3] (189). Substituted isoquinolines (37) have proved to be effective in controlling undesired vegetation, insects, acarina, and fungi (190). 

GABRIEL COLMAN Rearrangement Synthesis of isoquinolines by rearrangement ol phthahmides. 

For other more recent methods for the synthesis of isoquinolines see... 

Fluonnation of isoquinoline gave a mixture of partly and fully fluorinated compounds of which perfluoro-3,4,5,6,7,8-hexahydroisoqumoline and perfluoromethylcyclohexane were fully identified [28] (equation 11)... 

The Pomeranz-Fritsch reaction involves the preparation of isoquinolines 4 via the acid-mediated cyclisation of the appropriate aminoacetal intermediate 3. The best yields are usually obtained when the benzaldehyde portion 1 has electron-donating substituents in the 3- or 3,4- positions relative to the aldehyde. 

Toward the end of the 19 century both Pomeranz and Fritsch independently reported the preparation of isoquinolines by the reaction of aminoacetaldehyde dimethyl acetal 2 (R = Me) with aromatic aldehydes 1 followed by cyclisation in acidic media. " Unfortunately yields were often poor and not always reproducible. This has prompted the search for various improvements and modifications on the original theme, including the use of reagents other than strong mineral acid which tends to destroy the intermediate imine. ... 

The reactions of (174) with various amines has been studied." " Hydrolysis of the hexamine salt of (174) gave not the symmetric diamine but (184) via a cyclic intermediate. The pyrolysis of 5-methyl-2-thenyltrimethyl ammonium hydroxide (185) is claimed to give (186) through a 1,6 Hofmann elimination reaction. The Bischler-Napieralski cyclization has been applied to acetyl derivatives of 2-(2-thienyl) ethylamine and 2-(3-thienyl) ethylamine for the preparation of sulfur analogs of isoquinoline. ... 

It is difficult to treat the effect of a heteroatom on the localization energies of aromatic systems, but Brown has derived molecular orbital parameters from which he has shown that the rates of attack of the phenyl radical at the three positions of pyridine relatively to benzene agree within 10% with the experimental results. He and his co-workers have shown that the formation of 1-bromoisoquinoline on free-radical bromination of isoquinoline is in agreement with predictions from localization energies for physically reasonable values of the Coulomb parameters, but the observed orientation of the phcnylation of quinoline cannot be correlated with localization ener-... 

Treatment of isoquinoline tV-oxide (55) with sodium hydride in dimethyl sulfoxide results in ring expansion, albeit in poor yield, to the 3//-3-benzazepine 56, along with a trace of naphthalene (0.8%), and much tar.26... 

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). 

Chlorination. When 75 was treated with chlorine in the presence of aluminium chloride, initial chlorination took place at the 5-position, but the reaction was rather unselective 5,8-di-, 5,7,8-tri-, and 5,6,7,8-tetra-chloroisoquinolines were also formed (64JOC329). Perchlorination has been achieved by initial reaction of the isoquinoline-aluminium chloride complex with chlorine, as above, followed by treatment with phosphorus pentachloride at 270°C in an autoclave [66JCS(C)2328]. Treatment of 1,8-dimethylisoquinoline with NCS gave the 5-chloro derivative (91NKK-1193). Meisenheimer reaction of isoquinoline 2-oxides with phosphoryl chloride gave 1-chloroisoquinoline (84MI2). 

Fluorination. Attention has been focused on the direct fluorination of isoquinolines activated by conversion into 2-methylisocarbostyril (80). With gaseous fluorine (diluted to 10% with argon) in acetic acid a 54% yield of the 4-fluoro derivative was obtained. (Scheme 40). With methylene chloride as the solvent, only the 4-chloro analogue was formed [82H( 17)429]. Fluoroisoquinolines have also been made by displacement of nitro groups, and from diazonium fluoroborates (87JHC181). Hepta-chloroisoquinoline was converted into a perfluoro derivative by heating it in an autoclave with anhydrous potassium fluoride [66JCS(C)2328]. 

Synthesis in m-cresol. The dianhydride (1.35 mmol) is added to a stirred solution of 1.35 mmol of die diamine in die appropriate amount of m-cresol containing 6 drops of isoquinoline under N2 at room temperature. After 3 h, it is heated to reflux (ca. 200° C) and maintained at that temperature for 3 h. During this time, the water of imidization is distilled from die reaction mixture along with 1 to 3 mL of m-cresol. The m-cresol is continually replaced to keep the total volume of the solution constant. After die solution is allowed to cool to room temperature, it is diluted witii 20 mL of m-cresol and then slowly added to 1 L of vigorously stirred 95% ethanol. The precipitated polymer is collected by filtration, washed witii ethanol and ether and dried under reduced pressure at 125°C for 24 h. 

Isoquinoline must be completely dissolved prior to the addition of N-bromosuccinimide. N-Bromosuccinimide (99%) was purchased from Aldrich Chemical Company, Inc. and recrystallized2 and air-dried prior to use. Recrystallization is essential in order to obtain high yield and pure product. The use of more NBS than stated (i.e., more than 1.1 equiv for the synthesis of 5-bromoisoquinoline and 1.3 equiv for the synthesis of 5-bromo-8-nitroisoquinoline) to obtain complete transformation of isoquinoline should be avoided as this leads to formation of 5,8-dibromoisoquinoline, which cannot easily be separated from 5-bromoisoquinoline and which will also lead to a lower yield of 5-bromo-8-nitroisoquinoline. 

Previously published methods for electrophilic bromination of isoquinoline"" lead to mixtures of isomers only separable with difficulty, use expensive additives or large excesses of reactants, or involve multistep procedures. 

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 intramolecular Diels-Alder reaction of 78 was investigated during the synthesis of isoquinoline alkaloids [65ij. No reaction occurred when solid-phase conditions were used (Florosil in DCM and CaCli) or when a variety of Lewis acids were employed (SnCU, BF3, RAICI2, Ti(z — Pr)4-TiCl4). A 56 % yield of 79 was obtained by carrying out the cycloaddition in toluene in a sealed tube at 200 °C. jS-CD catalysis in water under milder conditions (Equation 4.11) improved the conversion to 84 %. 

Intramolecular Diels-Alder reaction of substituted fiirans has been investigated as a route to the synthesis of isoquinoline alkaloids. Tetrahydroisoquinoline 81 was prepared from furan 80 in 40% yield <95JCS(P1)2393>. 

The transformation of isoquinoline has been studied both under photochemical conditions with hydrogen peroxide, and in the dark with hydroxyl radicals (Beitz et al. 1998). The former resulted in fission of the pyridine ring with the formation of phthalic dialdehyde and phthalimide, whereas the major product from the latter reaction involved oxidation of the benzene ring with formation of the isoquinoline-5,8-quinone and a hydroxylated quinone. 

The degradation of isoquinoline by Pseudomonas diminuta strain 7 is initiated by an oxidoreductase that contains [2Fe-2S] centers and the cofactor molybdopterin cytosine dinucleotide (Lehmann et al. 1994). 

Lehmann M, Tshisuaka B, Fetzner S, Roger P, Lingens F (1994) Purification and characterization of isoquinoline 1-oxidoreductase from Pseudomonas diminuta 7, a molybdenum-containing hydroxylase. JBiol Chem 269 11254-11260. 

The oxidoreductase from Pseudomonas diminuta strain 7 that carries out hydroxylation of isoquinoline at C2 is a molybdenum enzyme containing [Fe-S] centers, which is comparable to the aldehyde oxidoreductase from Desulfovibrio gigas (Lehmann et al. 1994). 

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