Isoquinoline amination

Cu(CgHgN 1( 3 >2 mw 403.88, N 27.75%, yel gfeeri crysts irip — explodes ac 197—200° bums in (lame sol in ethylenediamine with violet color freeing some (Sfi-quinoline darkens in warm acid. It is insensitive to impact. It was prepd by dissolving Cu azide in an isoquinoline amine soln in ale, by the addn of NaN CO an amine soln of the Cu " salt in... 

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]. 

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

The Pictet-Gams method involves the cyclization of P-hydroxy- or P-methoxy- P-phenethylamides, and produces the isoquinoline derivative rather than the reduced form. A further extension of method is based on a metboxyetbyl amine. 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

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 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. 

The most plausible mechanism involves condensation between aldehyde 1 and amine 5 to give the corresponding imine 6. Cyclisation and subsequent elimination yields the fully unsaturated isoquinoline ring structure 4. 

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. 

In another example reaction of aldehyde 22 and amine 23 gave imine 24 which cyclised under strongly acidic conditions to yield the corresponding isoquinoline 25 in good yields It is interesting that the aldehyde portion 22 is not benzaldehyde derived. 

Condensation between aldehyde 40 and amine 29 followed by sodium borohydride reduction of the resultant imine and cyclisation yielded isoquinoline 41 in good yield. Cyclisation occurred exclusively at the more electron-rich aromatic group. 

Tosylation of secondary amine 48 gave desired precursor 49 which was cyclised under prolonged acidic conditions to yield a mixture of linear and angular fully unsaturated isoquinolines 50 and 51. ... 

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. ... 

The rate of amination and of alkoxylation increases 1.5-3-fold for a 10° rise in the temperature of reaction for naphthalenes (Table X, lines 1, 2, 7 and 8), quinolines, isoquinolines, l-halo-2-nitro-naphthalenes, and diazanaphthalenes. The relation of reactivity can vary or be reversed, depending on the temperature at which rates are mathematically or experimentally compared (cf. naphthalene discussion above and Section III,A, 1). For example, the rate ratio of piperidination of 4-chloroquinazoline to that of 1-chloroisoquino-line varies 100-fold over a relatively small temperature range 10 at 20°, and 10 at 100°. The ratio of rates of ethoxylation of 2-chloro-pyridine and 3-chloroisoquinoline is 9 at 140° and 180 at 20°. Comparison of 2-chloro-with 4-chloro-quinoline gives a ratio of 2.1 at 90° and 0.97 at 20° the ratio for 4-chloro-quinoline and -cinnoline is 3200 at 60° and 7300 at 20° and piperidination of 2-chloroquinoline vs. 1-chloroisoquinoline has a rate ratio of 1.0 at 110° and 1.7 at 20°. The change in the rate ratio with temperature will depend on the difference in the heats of activation of the two reactions (Section III,A,1). 

Bromoisoquinoline can be aminated under vigorous conditions (concentrated NH4OH, 165°, 16 hr), - but attempted methoxyla-tion (methanolic methoxide, 235°, 7 hr) gave isoquinoline (50% yield) via the reductive reaction observed with 6- and 8-bromo-quinoline. ... 

Reaction of 2-chloro-6,7-dihydro-4//-pyrimido[6,1 -a]isoquinolin-4-ones with liquid NH3 in a pressure bomb at 85 °C for 4h, and with primary and secondary amines in boiling CHCI3 (98MIP15), and anilines in boiling i-PrOFI (00MI17) yielded 2-amino-6,7-dihydro derivatives or their 2,3,6,7-tetrahydro-2-imino tautomers. 

In principle, the quaternization reactions are extremely simple the amine (or phosphine) is mixed with the desired haloalkane, and the mixture is then stirred and heated. The following section refers to the quaternization of l-alkylimidazoles, as these are the most common starting materials. The general techniques are similar, however, for other amines such as pyridine [9], isoquinoline [10], 1,8-diazabi-cyclo[5,4,0]-7-undecene [11], 1-methylpyrrolidine [12], and trialkylamines [13], as... 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

Among the amines that have been resolved with (-)-DAG are a-phenylethylamine (a-methylbenzenemethanamine),s [R-(R, R )]-2-amino-l-(4-nitrophenyl)-l, 3-propanediol,61,2,3,4,5,6,7,8-octahydro-l-(4-methoxyphenylmethyl)isoquinoline, 3-methoxymorphinan, 1,2,3,4-tetrahydro-7-methoxy-4-phenylisoquinoline, 3-hydroxy-A7-methyl-... 

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. 

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