Quinolines sodium hydride

Nitroquinoline (138) undergoes direct cyclocondensation with aromatic hydra-zones 139 in the presence of sodium hydride in DMF to give low yields of the corresponding [l,2,4]triazino[6,5-fc]quinolines 140 and pyrazolo[3,4-/] quinolines... 

An interesting reaction of dimsyl anion 88 is the methylation of polyaromatic compounds. Thus naphthalene, anthracene, phenanthrene, acridine, quinoline, isoquinoline and phenanthridine were regiospecifically methylated upon treatment with potassium t-butoxide and DMSO in digyme or with sodium hydride in DMSO123-125. Since ca. 50% of D was found to remain in the monomethyl derivative 93 derived from 9-deuteriophenanthrene 92, the mechanistic route shown in Scheme 2 was suggested125. 

Kuroda and Suzuki used reaction of 267a with 2-bromoaniline leading to anilide 312 as the first step of their sequence in the preparation of 1H-imidazo[4,5-c]quinolin-4(5//)-ones (Scheme 77) (91TL6915). Reaction of 267a with amines usually does not require any catalyst and/or base, but in this case use of sodium hydride was reported. The anilide 312 was sequentially alkylated, first with methyl iodide in ethanol with potassium hydroxide at room temperature and then with different alkyl iodides in acetone at reflux to provide intermediate 313. This compound was then cyclized via palladium catalyzed reaction leading to product 314. This reaction provides a new entry to l//-imidazo[4,5-c]quinolin-4(5//)-ones that are of current interest as antiasthmatic agents. 

Cyclization of quinoline derivatives 185 in DMSO on the action of cesium carboxate at 85°C afforded diesters 186 [95T11125]. No cyclization product could be obtained when a piperazono group was present in 185 (R = piperazino). Cyclization in the presence of sodium hydride gave lower yield. When the potassium salt of 185 was applied in the presence of 20 mol%... 

Sodio malononitrile, prepared from malononitrile with 57% sodium hydride in dimethylacetamide, and l-(3-chloropropyl)isatoic anhydride (398) at room temperature for 30 min, then at 120°C for 18 h, gave 6-oxo-l,2,3,4-tetrahydro-6//-pyrimido [1,2-a quinoline-5 -nitrile (399) (76JOC825). 

Sodium hydride reduction of quinoline in HMPA leads to a 2 3 mixture of 1,2-dihydroquinoline (82) and 1,4-dihydroquinoline (83) isolated as the A-methoxycarbonyl derivatives. In situ produced copper hydride reagents react with pyridinium species with high regioselectivity generating 1,4-dihydropyridine... 

Dehydrohalogenation Benzyltrimethylammonium mcsitoate. r-Butylamine. Calcium carbonate. j Uidine. Diazabicyclo[3.4.0]nonene-5. N.N-Dimethylaniline (see also Ethoxy-acetylene, preparation). N,N-Dimelhylformamide. Dimethyl sulfoxide-Potassium r-but-oxide. Dimethyl sulfoxide-Sodium bicarbonate. 2,4-Dinitrophenylhydrazine. Ethoxy-carbonylhydrazine. Ethyldicyclohexylamine. Ethyidiisopropylamine. Ion-exchange resins. Lithium. Lithium carbonate. Lithium carbonate-Lithium bromide. Lithium chloride. Methanolic KOH (see DimethylTormamide). N-PhenylmorphoKne. Potassium amide. Potassium r-butoxide. Pyridine. Quinoline. Rhodium-Alumina. Silver oxide. Sodium acetate-Acetonitrile (see Tetrachlorocyclopentadienone, preparation). Sodium amide. Sodium 2-butylcyclohexoxide. Sodium ethoxide (see l-Ethoxybutene-l-yne-3, preparation). Sodium hydride. Sodium iodide in 1,2-dimethoxyethane (see Tetrachlorocyclopentadienone, alternative preparation) Tetraethylammonium chloride. Tri-n-butylamine. Triethylamine. Tri-methyiamine (see Boron trichloride). Trimethyl phosphite. 

Coutts cZ al. (41) reported that LTA oxidation in AcOH of ( )-2-tri-fluoroacetyl - ], 2,3,4 - tetrahydro - 6- methoxy -1 - (3,4,5 - trimethoxybenzyl) iso-quinolin-7-ol (60) gives p-quinol acetate 61, TFA treatment in CHiCL of which affords in 35% yield ( )-6-trifluoroacetyl-l-hydroxy-2,9,10,11-tetramethoxynoraporphine (62). Further methylation of 62 with methyl iodide and sodium hydride gave ( )-6-trifluoroacetyI-l, 2,9,10,11-pentamethoxynoraporphine (63) (Scheme 8). 

The reaction of benzo[f]quinoline with methylsulphinyl carbanion prepared from dimetl lsulphoxide and sodium hydride leads to the 5-methyl and the 6-methyl derivatives in a 1 4 ratio. Although benzo[flquinoline-4-oxide gives a high yield of phenanthrene under these conditions, the carbanion generated using potassium t-butoxide as the base leads to alkylation at C-3 and to simultaneous deoxygenation (Y. Hamada and I. Takeuchi. J. org. Chem.. 1977. fa, 4209). 

Phenanthroline-l-oxide loses the /7-oxide function on brief treatment with the carbanion derived from dimethylsulphoxide and sodium hydride to give benzo[h]quinoline in 48% yield. Prolonged reaction results in methylation of the benzoquinoline at the 5-and the 6-position (Y. Hamada et al, Chem. pharm. Bull. Japan, 1979, 1535). 

Reissert compounds of the type 33 (n = 330,49 and 430) undergo an intramolecular alkylation on treatment with sodium hydride in dimethyl-formamide to give the tricyclic compounds (34). A similar reaction also takes place in the quinoline series.30 When 33 (n = 3) and isopropyl bromide are treated with sodium hydride, cyclization to 34 (n = 3) takes place rather than alkylation with the isopropyl bromide however, treatment of 33(n = 3) and carbon disulfide-methyl iodide with sodium hydride gives 35 rather than cyclization.30 Alkaline peroxide converts the nitrile 34 (n = 3) into an amide, and acid or base hydrolysis gives 4-(l-isoquinolyl)butyric acid.30... 

A number of polymers containing a heterocyclic group have been prepared using the Reissert alkylation sequence.92 94 Thus, for example, the reaction of the isoquinoline Reissert anion (26) with polyfvinylbenzyl chloride) and sodium hydride gave 36, which on hydrolysis with base gave 37.92,93 A similar condensation takes place with quinoline, phenanthridine, and benzo-[/Jquinoline Reissert compounds.94 The Reissert anion 26 has also been alkylated with a mixture of m- and p-vinylbenzyl chloride and the product polymerized to a polymer of type 37.93 Copolymerization has also been studied.93... 

The anion of the isoquinoline Reissert compound (26) has also been alkylated with a wide variety of other alkyl halides.519-35 38 48-62-66,90 93 The alkylation product from 26 and allyl chloride undergoes isomerization to 38 on base-catalyzed hydrolysis.90 The phthalazine Reissert compound (3) has also been alkylated, in the presence of sodium hydride, with methyl iodide39 and with benzyl halides40 to give, after hydrolysis, 1-substituted phthalazines. A phthalazine analog of 34 (n = 3) has been prepared.1511 An additional example of the alkylation of the quinoline Reissert compound in the 4-position has appeared.943... 

Treatment of the isoquinoline Reissert compound (2) with sodium hydride in dimethylformamide,96 with 50% aqueous sodium hydroxide-TEBA chloride,61 or with 50% aqueous sodium hydroxide-TBA chloride963 and an activated aryl halide, such as 2,4-dinitrofluorobenzene,96 2-bromo-3-nitropyridine,96 4-nitrochlorobenzene,61 t-butyl 2-chloro-5-nitrobenzoate,61 2-chloro-3-nitropyridine,963 4-chloro-3-nitropyridine,96a or 9-chloroacri-dine96b leads to the arylation product 43. Arylation of the quinoline Reissert compound (1) with 4-nitrofluorobenzene in the presence of sodium hydride in dimethylformamide leads to 44.96 It should be noted that alkylation of... 

Step G 4-[Ortho-(2, 3 -Dihydroxypropyloxycarbonyl)-Phenyl]-Amino-S-Trifluoromethyl-quinoline Acetonide - 100 cc of toluene were added to 80 cc of 2,2-dimethyl-4-hydroxy-methyl-1,3-dioxolane and the toluene was distilled off under reduced pressure to eliminate the water present. To the anhydrous 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane thus obtained, 0.25 gram of an oily 50% suspension of sodium hydride and then 21.3 grams of 4-... 

In cases where R is a benzyloxy substituent, the use of strong non-aqueous acids, particularly sulfuric and trifluoroacetic acids, provides a convenient means of preparing the hydroxy quinolines XVII by deben-zylation (1J). The hydroxy compounds may be acetylated by standard techniques to afford XVIII. Formation of the sodium salt of XIV using sodium hydride in DMF, followed by reaction with an alkyl halide, leads to the 3-substituted compounds (XIX). 

Walser et al. have employed a combination of the Friedlander method and nucleophilic displacement of aromatic fluorines in the synthesis of quinolinoquinolines and benzochromenoquinolines. 4-(2-Fluorophenyl) quinoline 11 reacts with ethyl acetoacetate to 5deld 12 (83%) that is reduced to 13 followed by treatment with sodium hydride to give benzochrome-noquinoline 14 in 75% yield. However, hydrol5 is of 12 to 15 followed by sodium hydride leads to quinolinoquinoline 16 in 77% yield (Scheme 6) (75JHC737). 

Methylation. The reaction of 1,10-phenanthroline-JV-oxide with methylsulfinyl carbanion has been reported. Liberation of the A oxide moiety occurred when the compound was treated with sodium hydride in dimethylsulfoxide for 0.5 h, resulting in the formation of benzo[A]quinoline as a sole product in 48% yield. Prolonging the reaction time to 4 h led to a mixture of three products corresponding to further methylation at the 5- and 6-positions of the quinoline ring (eq 4). ... 

The intramolecular cycUzation takes place smoothly in the 6-endo-trig fashion on treatment with a base (sodium hydride or triethylamine) of N-[ortho-0, i-difluoroaUyl)phenyl] substituted p-toluenesulfonamides 55. As a result 2-fluoro-quinolines 56 are formed in high yields (Scheme 21) [32],... 

Reduction of quinoline with lithium aluminum hydride gives 1,2-dihydroquinoline. Neutral pyridines bearing electron-withdrawing substituents are also reduced by sodium borohydride (Scheme 32). 

Different hydrogenolytic reactivity of trifluoromethyl groups with respect to their position on the quinoline ring is observed. All C-F bonds in 2-, 4- and 6-(trifluoromethyl)quinoline are hydrogenolyzed by lithium aluminum hydride (Table 4), but the 3-trifluoromethyl isomer gave 3-(difluoromethyl)-l,2-dihydroquinoline (10) under the same experimental conditions in contrast to these results, sodium borohydride surprisingly reduces 3-(trifluoromethyl)quinoline to the corresponding 3-methylquinoline (Table 4).149... 

Numerous reducing agents were tried at this point unsuccessfully. For example, lithium aluminum hydride destroyed the substrate, whereas DIBAH or lithium borohydnde in THF and sodium borohydride in ethanol led to reduction of the quinoline system. On the other hand, both potassium borohydride (either with or without 18-crown-6) and zinc borohydride (with or without ethanol) produced no reaction at all. Lithium triethylborohydride resulted in de-methoxylation, and sodium borohydride in refluxing THF gave a 45% yield of diol 16 together with overreduced product. 

As would be expected, the weaker reducing agent, sodium boro-hydride, has received little attention for the reduction of quinolines. The reaction of 2-chloro-3,7-dicarbomethoxy-5,6-benzoquinoline (80) has been reported by Walker to yield 3,7-dicarbomethoxy-5,6-benzo-1,4-dihydroquinoline (81) on reaction with sodium borohydride.96 The success of this reaction may depend upon the electron-withdrawing properties of the carbomethoxy groups. 

---