Amines isoquinoline synthesis

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. 

An attempt to utilize this conversion of amines into aldehydes in an isoquinoline synthesis was not successful.439 Instead, reaction between 2-(3,4-dimethoxyphenyl)ethylamine and isatin afforded only the spiro compound 150.439 Reaction between isatin and 2-(3-hydroxy-4-methoxyphenyl)ethylamine gave a mixture of two spiro compounds, while a reaction of isatin, this amine, and benzylamine gave 6-hydroxy-7-methoxy-l-phenyl-1,2,3,4-tetrahydroisoquinoline.439... 

Isocyanophosphonates, aldol reactions, 227 Isoquinoline synthesis, enamide reactions, 33 Isomerization allylic amines, 9, 95 olefins, 118, 171 see also specific compounds Isopulegol, 102 Isotactic polymers, 174 chloral, 182 photoirradiation, 347 methacrylates, 181 propylene, 174 Isotacticity, 177... 

The general synthesis of phenanthridines, which are benzoisoquinolines, are patterned on isoquinolines. The lithiation route is similar to the one, where, for an isoquinoline synthesis, a p-phenylethyl amine (75) is the starting compound. The starting compound now is a 2-amino biphenyl (79). Interestingly, it is no more necessary to convert the primary amine to its dimethyl derivative. 

Another classical approach is the Pictet-Spengler isoquinoline synthesis. 66c x is variation generates an iminium salt from an amine and an aldehyde (a Schiff base), which cyclizes with an aromatic ring to complete the reaction. A synthetic example is taken from Liang s synthesis of chrysotricine.1 2 xhg reaction of amine 279 with aldehyde 280, in the presence of trifluoroacetic acid, initially gave an iminium salt (281). Subsequent Friedel-Crafts cyclization of the iminium salt gave the isoquinoline product (282 in 70% yield). The amino groups of amino acid derivatives also serve as excellent partners in this reaction.1 3... 

A similar isoquinoline synthesis has recently been reported using a rhodium catalyst to effect a one-pot coupling of an aryl ketone, an amine, and an internal alkyne (Eq. 53) [114]. 

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 Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Amide (1) was needed for a synthesis of an isoquinoline. Disconnecting the amide reveals the amine (2) which could be made by reduction of an unsaturated nitro compound. The a, -disconnection is simple. 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

A palladium-catalyzed three-component reaction with 2-iodobenzoyl chloride or methyl 2-iodobenzoate, allene and primary aliphatic or aromatic amines to prepare fV-substituted 4-methylene-3,4-dihydro-1 (27/)-isoquinolin-1 -ones was disclosed <02TL2601>. A synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via a Cp2TiMe2-catalyzed, intramolecular hydroamination/cyclization of aminoalkynes was also reported <02TL3715>. Additionally, a palladium-catalyzed one-atom ring expansion of methoxyl allenyl compounds 79 to prepare compounds 80 that can serve as precursors to isoquinolones was reported <02OL455,02SL480>. 

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