3 -Aminoquinolines, reaction with

Reaction of 2-aminoquinoline derivatives with BrCH2C0C02Et gave imidazoquinoline-2-carboxylate 473 which upon hydrolysis with sodium hydroxide gave the corresponding acid which had been tested against the passive cutaneous anaphylaxis (78GEP2802493, 78BEP858605) (Scheme 79). 

Reaction of 8-aminoquinoline 567 with 3,4-dichlorodithiazolium chloride gave the quinolyl iminodithiazole 568 whose thermal rearrangement gave 569 via a molecular rearrangement process (96MI2775) (Scheme 95). 

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

Nucleophilic substitution occurs at C-2, and to a lesser extent C-4, as might be predicted from similar reactions with pyridine. Chichibabin amination occurs rather more readily than with pyridine, giving 2-aminoquinoline. A typical hydride abstraction process occurs when qninoline is heated with sodinm... 

Alkylpyridines are aminated preferentially at the 2-position, but reaction is slower than in the parent system. Quinoline is difficult to aminate and only a low yield of 2-aminoquinoline (32%) is obtained from reaction with sodamide in toluene. When dimethylaniline is employed as solvent, 2-amino-3,4-dihydroquinoline (24%) becomes the major product, and the yield of 2-aminoquinoline drops to 7%. The best yields of 2-aminoquinoline (53-69%) have been obtained by using barium or potassium amide in liquid ammonia. Use of the potassium salt also produces a 10% yield of the 4-amino isomer. The... 

Reaction of 2-aminoquinoline either with ethyl 3-chloropropionate for 1 h at 100°C (63YZ682) or with methyl acrylate in the presence of acetic anhydride for 8 h at 120°C (71KGS482) gave 2,3-dihydro-l//-pyrimido[l,2-a]quinolin-3-one (58). 

Although other condensation reactions with 4-aminopyridine are reported to fail, they have in most cases succeeded with 4-aminoquinoline.59 Dey and Joullie87 have prepared a series of trifluoro-methylbenzo[A]-l,6-naphthyridines by condensing ethyl trifluoro-methylacetoacetate with 4-aminoquinaldine. 

Reaction of lithiated 3-enaminophosphonj tes of aniline and isocyanates with subsequent cyclization of the resulting amides with triphenylphosphine/triethylamine leads to the 3-phosphonyl-4-aminoquinolines (Equation 92) <1999T5947>. Aniline reaction with /3-diketones < 1999H(51 )2171 > and ethoxymethylenemalonates <1999JFC(94)7> also leads to quinoline formation. The Vilsmeier reaction conditions can also be applied to the synthesis of quinolines with the use of a-oxoketene /V -anilinoacetals (Equation 93) <2003JOC3966>. 

For instance, both quinoline and isoquinoline undergo the Chichibabin reaction (with formal hydride elimination, see Chapter 5) to give 2-aminoquinoline 6.23 and 1-aminoisoquinoline 6.24 respectively. Halogen substituents ortho to the nitrogen atoms are easily displaced, as in the preparations of 6.25 and 6.26. 

In an intramolecular reaction with jV,jV-diethylformamide or AyV-dimethylacetamide diethyl acetal, enaminones are known to react at the nitrogen to form amidines42. The corresponding products from acetamide acetals can be converted to 2-aminoquinolines by condensation with DMF acetals or to 1,4-dihydroquinolines by cycloaddition with diethyl maleate (see Section II.A.5) (equation 26). 

Steinhaus, R.K., Baskin, S.I., Clark, J.H., Kirby, S.D. (1990). Formation of methemoglobin and metmyoglobin using 8-aminoquinoline derivatives or sodium nitrite and subsequent reaction with cyanide. J. Appl. Toxicol. 10 345-51. 

Heating the aminoacetal (2.1) with ethanolic hydrogen chloride produces a quinoline [2612], but sulphuric acid causes the cyclization to follow another course (see Chapter 3, Section II. 1). n-Aminoaldehydes are cyclized by heating with a reactive methylene-containing ketone, ester or nitrile but in the reaction with the pyrazole aldehyde (2.2), yields seem to depend greatly on the nature of the A -substituent for example, when R = R = CN, the product is obtained in either 3.6% or 83% yields according to whether R is methyl or phenyl [2798]. The chemistry of a-cyanothioacetamide (2.4), which is used in the conversion of 2-aminobenzaldehyde (2.3) to 2-aminoquinoline-3-thiocarboxamide [2926], has been reviewed [3331]. 

A synthesis of 7,8-dioxygenated isoquinolines (found in cularine alkaloids) requires o-metallation of the Af-protected -phenylethylamine. The primary amine is protected by reaction with two equivalents of trimethylsilyl chloride. Phenylhydroxylamine and the allenic nitrile (53.7) react in boiling ethanol over 48 h to give a high yield of 4-aminoquinoline—an important intermediate for the synthesis of some antimalarial drugs. 

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