Chloroquinoline ring

The noticeable rate enhancement due to a microwave-specific effect is consistent with a reaction mechanism in which the kinetic rate-determining step is nucleophilic attack of an amino group on the chloroquinoline ring (Scheme 3.16). 

The relation of activation by para vs. ortho ring-nitrogen in bicy-clics is altered by these special cases. For example, 4-chloroquinazoline (4-Cl-l,3-diaza) is much more reactive than the 2-chloro isomer (2-Cl-l,3-diaza) for two reasons, one being the poor activation in 2-Le-3-aza compounds. 4-Chloro-l,8-naphthyridine will be decreased in reactivity relative to its 2-chloro isomer due to the very poor activation in 4-Le-8-aza compounds and it may be only slightly more reactive than the mono-aza analog 4-chloroquinoline. The greater reactivity at the 2-position of 2,4-dichloro-l,8-naphthyri-dine 3 can be ascribed to this 4-Le-8-aza effect. ... 

The monoazanaphthalenes provide a good illustration of the effect of henzo-fusion onto an azine and of the variation of the effect with the position of fusion. A benzo ring can be fused onto 2-chloro-pyridine at the 3,4- [leading to 1-chloroisoquinoline (393)], at the 4,6- [forming 3-chloroisoquinoline (394)], or at the 5,6-position [yielding 2-chloroquinoline (395)]. The first and the last fusions... 

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... 

In a six-step synthesis of (5)-camptothecin (20010L4255), the final step involved a C-ring closure using the Heck reaction. As shown in Scheme 17, 2-chloroquinoline 146 was treated with 15% (PPh3)2Pd(OAc)2 and two equivalents KOAc in CH3CN at 100 °C, affording (5)-campotothecin (147) in 64% yield. 

Preparation o the key intermediate for the chloroquinoline series starts with Shiff base formation of metachloroaniline with ethyl oxaloacetate (66). Heating of the intermediate leads to cyclization into the aromatic ring and consequent formation of the quinoline ring (67). Saponification of the ester to the acid... 

Inclusion of the carbon atoms of an aromatic ring in the side chain sequence is apparently quite consistent with antlmalarial activity. Thus, reaction of p-acetamidophenol with formaldehyde and diethylamine affords the Mannich product, 79. This is then converted to the diamine (80) by saponification. Alkylation with the chloroquinoline, 70, affords amidoquine (81). The same sequence starting with the Mannich product in which pyrrolidine has been used as the amine (82) gives amopyroquine (83). 

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 ... 

A potential advantage of the SRN1 mechanism is that it is not particularly sensitive to the nature of other aromatic ring substituents, although EWG substituents favor the nucleophilic addition step. For example, chloropyridines and chloroquinolines are excellent reactants.182 A variety of nucleophiles undergo the reaction, although not always in high yield. The nucleophiles that have been found to participate in... 

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>. 

Later, starting from /V-(3-nitrophenyl)aminomethylenemalonate (752, R = H), Cidda and Sleiter prepared 5- and 7-nitro-4-chloroquinolines in 1 2 ratio in several steps. In the first step of the thermal ring closure in... 

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). 

Indole can be reacted with dichiorocarbene to yield 3-chloroquinoline (Scheme 7.12). Initially, the carbene adds across the C-2-C-3 double bond to form a cyclopropanoindole this product then ring expands with elimination of hydrogen chloride cf. pyrrole. Section 6.1.3). 

Nuclei for tricyclic antidepressants and tranquilizers, for example clomacran (89) (64USP3131190), almost invariably contain the three rings fused in a linear array. An exception to this general rule is fantridone (90), an antidepressant obtained by alkylation of the anion of phenanthridone with 3-chloro-iV,iV-dimethylpropylamine (68BRP1135947). Similar activity is shown by a relatively simple quinoline derivative (91), which is derived from 2-chloroquinoline and piperazine (70GEP2006638). 

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