Isoquinoline preparation

Reaction of 9-hydroxy-2-methyl-6-phenyl-l,2,3,6,7,llh-hexahydro-4//-pyrazino[2,l-a]isoquinoline, prepared from its 9-methoxy derivative in 48% HBr, with 5-chloro-l-phenyl-l//-tetrazole in the presence of K2C03 in DMSO yielded the 9-(l-phenyl-l//-tetrazol-5-yloxy) derivative, which then gave its 9-unsubstituted derivative by hydrogenation over 5% Pd-C (88USP4782058). 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

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). 

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). 

Uses. Isoquinoline and isoquinoline derivatives are usehil as corrosion inhibitors, antioxidants, pesticides, and catalysts. They are used in plating baths and misceUaneous appHcations, such as in photography, polymers, and azo dyes (qv). Numerous derivatives have been prepared and evaluated as pharmaceuticals. Isoquinoline is a main component in quinoline stiH residue bases, which are sold as corrosion inhibitors and acid inhibitors for pickling iron and steel. 

The preparation of benzo fused pyrido[3,2- i]pyrimidines has furnished the only examples of the classic reaction of this type, the Bischler-Napieralski, involving the cyclization of 5-aryl-4-acylaminopyrimidines to 6-alkylpyrimido[4,5-c]isoquinolines, e.g. (157)->(158) (73YZ330). As often found in this reaction, the presence of activating substituents appears necessary (78CPB245). 

As exemplified in the present procedure, the reaction has been optimized and extended in scope it affords functionalized benzocyclobutenes as well as substituted isoquinolines in high yields. Benzocyclobutenes have been used as intermediates in the synthesis of many naturally occurring alkaloids, - steroids,polycyclic terpenoids,and anthracycline antibiotics. The traditional routes leading to the preparation of benzocyclobutenes have been... 

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)]. 

The Reissert-Henze reaction offers a method to prepare cyanopyridines and extends the Reissert and Kaufmann reactions in the quinoline and isoquinoline series. 

The Gabriel-Colman reaction has been used to prepare 3-alkyl isoquinoline 1,4-diols. Phthalimides 8 and 9 rearrange as expected when treated with alkoxides. Further treatment with sodium ethoxide results in decarboxylation and the expected isoquinolinone 1,4-diols 12 and 13. 

The Gabriel-Colman reaction can be used to prepare isoquinoline-1,4-diols regioselectively by the use of unsymmetrically substituted phthalimides. Reaction of phthalimide 32 with sodium ethoxide in ethanol provides a 1 7 mixture of 33 34. It was rationalized that attack at carbon b is preferred because of its greater steric accessibility and diminished electron density compared to carbon a. In spite of the reasonable regioselectivity observed m this reaction, the Gabriel-Colman reaction has not been substantially investigated in the preparation of non-symmetrically substituted isoquinolines. 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

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. 

Of the well-known methods to prepare isoquinolines, including the Pictet-Spengler and Bischler-Napieralski cyclisation, the Pomeranz-Fritsch reaction is the only direct generally accepted method for the construction of the fully unsaturated isoquinoline ring system. 

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 Schlittler-Muller variation of the Pomeranz-Fritsch reaction involves reaction of diethoxyethanal 17 with benzylamine 16 to prepare the desired imine 18. Intermediate 18 is subsequently cyclised to substituted isoquinoline 19. The advantage here lies in the fact that the initial condensation can still take place between an aldehyde and an amine. 

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. ... 

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,... 

The 4-unsaturated-5-oxazolones provide convenient starting materials for the synthesis of other nitrogen-containing heterocyclic systems. The preparation of tetrazoles and isoquinolines is discussed in Sections II,B, 1 and II,B,2,b. 

The aporphinoid alkaloid PO-3 (129) was also prepared by intermolecular benzyne cycloaddition between 1-methylene isoquinolines 148 and arynes derived from 147 (Scheme 53). The alkaloid was finally isolated by means of preparative thin layer chromatography (91JOC2984). 

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

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