Chloroquinoline derivative

The concise formal total synthesis of mappicine was accomplished using an intramolecular hetero Diels-Alder reaction as the key step by M. lhara and co-workers. Introduction of the necessary acetylenic moiety at the C2 position was achieved by the Sonogashira cross-coupling of a 2-chloroquinoline derivative with TMS-acetylene. Several substituents at the C3 position were investigated, and it was found that the unprotected hydroxymethyl substituent gave almost quantitative yield of the desired disubstituted alkyne product. 

Meth-Cohn et al. [18] demonstrated that treatment of acetanilides with the Vilsmeier-Haack reagent (POCI3/DMF) provided chloroquinoline derivatives. As such, treatment of... 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

Basic alumina catalyzed C-C bond formation between 2-hydroxy-1,4-naphthoquinone 345 and 2-chloroquinoline derivative 344 in CH2CI2 under MWI for 120-165 s to give 346 in 94-98% yields (Scheme 69) (00MI2). Conventional heating required 4-6 h to give 70-82% yields (80TL5011). 

Like the chloronitrobenzenes, a chloroquinoline reacts faster with sodium p-tolylsulfide when the chloro group is para to the aza-group than when it is orthoy the factor involved being about 10. However, a strikingly different behavior is noted in the much lower BS-/ BO- ratio which is 2.5 for 4-chloroquinoline ( para isomer) and 0.24 for 2-chloroquinoline ( ortho isomer). For p-chloronitro-benzene this ratio is 38, and for 2,4-dinitrochlorobenzene it is 1950. Thus far there is no case in which the reaction of a chloronitrobenzene derivative with sodium methoxide is faster than that with sodium phenylsulfide. 

Deactivation in the anion formed under the reaction conditions prevents alkoxy-dechlorination of 4-chloro-2-quinolone (222) with boding alkoxide solution while 4-chloroquinoline and its 2-ethoxy and 2-anilino derivatives react. 4-Chloro-iV -methyl-2-quinolone reacts readily. 

The reactivities of 4- and 2-halo-l-nitronaphthalenes can usefully be compared with the behavior of azine analogs to aid in delineating any specific effects of the naphthalene 7r-electron system on nucleophilic substitution. With hydroxide ion (75°) as nucleophile (Table XII, lines 1 and 8), the 4-chloro compound reacts four times as fast as the 2-isomer, which has the higher and, with ethoxide ion (65°) (Table XII, lines 2 and 11), it reacts about 10 times as fast. With piperidine (Table XII, lines 5 and 17) the reactivity relation at 80° is reversed, the 2-bromo derivative reacts about 10 times as rapidly as the 4-isomer, presumably due to hydrogen bonding or to electrostatic attraction in the transition state, as postulated for benzene derivatives. 4-Chloro-l-nitronaphthalene reacts 6 times as fast with methanolic methoxide (60°) as does 4-chloroquinoline due to a considerably higher entropy of activation and in spite of a higher Ea (by 2 kcal). ... 

The effect of solvent on the rate, E, and dS can be derived from the data on haloquinolines and their A-oxides (Tables X and XI), on halonitronaphthalenes (Tables XII and XIII), and on halodinitro-naphthalenes (Table XVI). Depending on the nature of the reaction, the relative reactivity of two compounds can be substantially different in different solvents. For example, piperidination of 2-chloroquinoline (Table X, lines 3 and 4) compared to 2-chloroquinoxaline (Table XV,... 

Chloroquinoline (401) reacts well with potassium fluoride in dimethylsulfone while its monocyclic analog 2-chloropyridine does not. Greater reactivity of derivatives of the bicyclic azine is evident also from the kinetic data (Table X, p. 336). 2-Chloroquinoline is alkoxylated by brief heating with methanolic methoxide or ethano-lic potassium hydroxide and is converted in very high yield into the thioether by trituration with thiocresol (20°, few hrs). It also reacts with active methylene carbanions (45-100% yield). The less reactive 3-halogen can be replaced under vigorous conditions (160°, aqueous ammonia-copper sulfate), as used for 3-bromoquino-line or its iV-oxide. 4-Chloroquinoline (406) is substituted by alcoholic hydrazine hydrate (80°, < 8 hr, 20% yield) and by methanolic methoxide (140°, < 3 hr, > 90% yield). This apparent reversal of the relative reactivity does not appear to be reliable in the face of the kinetic data (Tables X and XI, pp. 336 and 338) and the other qualitative comparisons presented here. 

Alteration of the relative reactivity of the ring-positions of quinoline is expected and observed when cyclic transition states can intervene. Quinoline plus phenylmagnesium bromide (Et20,150°, 3 hr) produces the 2-phenyl derivative (66% yield) phenyllithium gives predominantly the same product along with a little of the 4-phenylation product. Reaction of butyllithium (Et 0, —35°, 15 min) forms 2-butylquinoline directly in 94% yield. 2-Aryl- or 6-methoxy-quinolines give addition at the 2-position with aryllithium re-agents, and reaction there is so favored that appreciable substitution (35%) takes place at the 2-position even in the 4-chloroquinoline 414. Hydride reduction at the 2-position of quinoline predominates. Reaction of amide ion at the 2-position via a cyclic... 

Ring expansions of 3-aryl-7-azido-2-chloroquinolines, e.g. 21, in potassium methoxide-meth-anol/dioxane yield mixtures of the expected 3-aryl-2-chloro-7-methoxy-9//-pyrido[2,3-f]pyrid-ines, e.g. 22, and the 2,7-dimethoxy derivatives, e.g. 23, formed by nucleophilic displacement of the 2-chloro group.154 ... 

Electronegative groups do not invariably prevent nuclear bromination, but reaction conditions must be much more severe, and the orientation of substitution may be affected by the substituent. Thus 6-nitroquinoline was brominated in sulfuric acid at 100°C to give the 8-bromo product (71) in 51% yield 8-methyl-5-nitroquinoline gave a 69% yield of the 7-bromo derivative (72) under similar conditions, whereas 7-chloroquinoline was transformed into the 5-bromo product (93%) (88CHE892) (Scheme 35). In a sealed tube reaction with bromine, 8-nitroquinoline gave a mixture... 

Quinolylphosphines have been prepared from the reaction of 8-chloroquinoline and potassium diphenylphosphide, or the quinolyl-lithium derivative and a chlorophosphine. ... 

Blackie, M.A.L., Beagley, P., Chibale, K., Clarkson, C., Moss, J.R. and Smith, P.J. (2003) Synthesis and antimalarial activity in vitro of new heterobimetallic complexes Rh and Au derivatives of chloroquine and a series of ferrocenyl-4-amino-7-chloroquinolines. Journal of Organometallic Chemistry, 688(1-2), 144-152. 

Pyrazolopyrazoloquinoline derivatives can be prepared by treatment of pyrazolidin-3-one with 2-chloroquinoline-3-carbaldehyde, which gives firstly the zwitterionic compound 283. Reduction with sodium borohydride followed by ring closure in basic media gives the fused tricyclic heterocycles (Scheme 77) <1991T9599>. 

Low-valent cobalt pyridine complexes, electrogenerated from CoCl2 in DMF containing pyridine and associated with a sacrificial zinc anode, are also able to activate aryl halides to form arylzinc halides.223 This electrocatalytic system has also been applied to the addition of aryl bromides containing an electron-withdrawing group onto activated alkenes224 and to the synthesis of 4-phenylquinoline derivatives from phenyl halides and 4-chloroquinoline.225 Since the use of iron as anode appeared necessary, the role of iron ions in the catalytic system remains to be elucidated. 

Upon microwave ( rw) irradiation, benzotriazole and its derivatives react readily with 2-chloropyridine to afford products 113-115 in 87%, 72%, and 70% yield, respectively (Scheme 9). 2-Chloroquinoline reacts similarly. 2-Bromopyridine and 2-bromoquinoline give generally lower yields in these reactions <20060L415>. 

In contrast with the azoles, diazoles and their benzo derivatives tend to react with dichlorocarbene to yield the tris(diazolyl)methanes, presumably via the initial formation of the N-dichloromethyl derivative [6, 13]. Only in more activated polymethyl derivatives does reaction occur at a ring carbon atom. In a similar manner (7.7.1.B), 2-chloropyridine and 2-chloroquinoline react with dichlorocarbene at the ring nitrogen atom to yield, after nucleophilic displacement of the chloro group, the 1 -dichloromethyl-2-oxo derivatives (13-25%) [14] (Scheme 7.38). 2-Chlorobenzothiazole reacts in an analogous manner, but other pyridine and quinoline derivatives fail to react. It is also noteworthy that the dichloromethyl group is unusually stable and is not converted into the formyl group. 

However, there are some cases when an unpaired electron is localized not on the n, but on the o orbital of an anion-radical. Of course, in such a case, a simple molecular orbital consideration that is based on the n approach does not coincide with experimental data. Chlorobenzothiadiazole may serve as a representative example (Gul maliev et al. 1975). Although the thiadiazole ring is a weaker acceptor than the nitro group, the elimination of the chloride ion from the 5-chlorobenzothiadiazole anion-radical does not take place (Solodovnikov and Todres 1968). At the same time, the anion-radical of 7-chloroquinoline readily loses the chlorine anion (Fujinaga et al. 1968). Notably, 7-chloroquinoline is very close to 5-chlorobenzothiadiazole in the sense of structure and electrophilicity of the heterocycle. To explain the mentioned difference, calculations are needed to clearly take into account the o electron framework of the molecules compared. It would also be interesting to exploit the concept of an increased valency in the consideration of anion-radical electronic structures, especially of those anion-radicals that contain atoms (fragments) with available d orbitals. This concept is traditionally derived from valence-shell expansion through the use of d orbital, but it is also understandable in terms of simple (and cheaper for calculations) MO theory, without t(-orbital participation. For a comparative analysis refer the paper by ElSolhy et al. (2005). Solvation of intermediary states on the way to a final product should be involved in the calculations as well (Parker 1981). 

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