Synthesis of Quinolines and Isoquinolines

Three of the more generally important approaches to quinoline and three to isoquinoline compounds from non-heterocyclic precursors, are summarised in this section. 

Anilines react with 1,3-dicarbonyl compounds to give intermediates which can be cyclised with acid. 

Condensation of a 1,3-dicarbonyl compound with an arylamine gives a high yield of a / -amino-enone, which can then be cyclised with concentrated acid. ° Mechanistically, the cyclisation step can be viewed as an electrophilic substitution by the O-protonated amino-enone, as shown, followed by loss of water to give the aromatic quinoline. 

An example of this approach which provides 4-unsubstituted 3-nitroquinolines, is shown below.  

This closely related synthesis uses /3-ketoesters and leads to quinolones. Anilines and /9-ketoesters can react at lower temperatures to give the kinetic product, a / -aminoacrylate, cyclisation of which gives a 4-quinolone. At higher temperatures, / -ketoester anilides are formed and cyclisation of these affords 2-quinolones. / -Aminoacrylates, for cyclisation to 4-quinolones, are also available via the addition of anilines to acetylenic esters or by reaction with diethyl ethoxymethylenemalonate (Et0CH = C(C02Et)2 ArNHCH = C(C02Et)2).  

2 Quinolines from arylamines and a,P-unsaturated carbonyl compounds 

R1 = aryl, alkyl piperidine R2 = R3 = allyl, benzyl R4 = aryl, alkyl AuBr3 53-99 119 

R1 = aryl, alkyl cyclic amine R4 — phenyl, naphthyl, silyl Agh 47-99 120 

R1 = aryl, t-Bu aryl amine R4 — phenyl RuC13 CuBr 64-96 121 

The proposed mechanism involves the initial rearrangement of alkynyl imine 137 into allenyl imine 138. Subsequent coordination of copper(I) to the terminal bond of the allene triggers intramolecular attack of the aromatic ring, a process that finally leads to quinolines 139 via several intermediates. 

Addition of Organometallic Reagents to I mines 8.8.2.1 Allylmetal Reagents 

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For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

The quinoline derivatives (100) to (103) exemplify two important overall strategies by which the heterocyclic ring may be constructed, indicated by (105) and (106). The isoquinoline derivative (104) has been selected to illustrate the overall strategy shown in (107). It should be pointed out however that a range of other strategies have been employed for the synthesis of quinolines and isoquinolines and the reader s attention is directed to specialist texts.27... 

A number of recently described routes take rather different approaches to the synthesis of quinolines and isoquinolines, for example ozonolyses of indenes, as shown below provides homophthalaldehydes which are at exactly the right oxidation level for aromatic pyridine ring closure with ammonia. Another method for the generation of equivalent species depends on the side-chain lithiation of ortho-methylaraldehyde cyclohexylamine imines, then acylation with a Weinreb amide. 

A number of recently described routes take rather different approaches to the synthesis of quinolines and isoquinolines for example, ozonolyses of indenes... 

Examples of this cyclisation-oxidation strategy include the synthesis of pyridotriazine 5.32 (page 42) and syntheses of quinolines and isoquinolines (Chapter 6). Some examples of nucleophilic and electrophilic fragments are shown in Table 1.1. Several points arise from the table. 

Cyanadons. Aluminum complexes of BINOLs (1) that are armed at C-3 and C-3 with diarylphosphine oxide groups possess both Lewis acid and base centers. Asymmetric cyanation of aldehydes and mines with MeaSiCN, and of quinolines and isoquinolines in a manner analogous to the Reissert reaction is successful (ee 70-90%). The asymmetric Strecker synthesis is applicable to conjugated aldimines and the higher reactivity of Me SiCN than HCN in the presence of 10 mol% of PhOH enables its use in catalytic amount while supplying stoichiometric HCN as the cyanide source. 

A protic-solvent-mediated cycloisomerization of quinoline and isoquinoline propargylic alcohols to give azacycles has found apphcation in the synthesis of the Erythrina alkaloids 3-demethoxyerythratidinone and cocculidine (Scheme 95). ... 

The main methods used for the synthesis of quinolines, isoquinolines and their derivatives... 

An intramolecular cyclization of iV-anilino- and iV-benzyl-substituted propargyl trimethylsilyl ethers with Lewis acid catalysis provides the quinolines and isoquinolines, respectively <20040L2361>. An intramolecular aza-Diels-Alder reaction has been used as a key step in the synthesis of luotonin (Scheme 69) <20040L4913>. An analogous reaction afforded the dihydroquinoline as a single diastereomer (Equation 132) <2000TL5715>. 

The next section deals with the synthesis of hererocycles where a heterocyclic ring is fused to a benzene ring, the 6/5 system, indole, and the 6/6 systems, quinoline and isoquinoline. 

Thus, radical addition reactions provide a useful means of functionalising pyridines, quinolines and isoquinolines, particularly when it is reasonable to employ the heteroaromatic base in excess. Intramolecular variants of the reaction are devoid of that limitation and have been widely exploited in the synthesis of nitrogen-containing heteroaromatics. The mildness of the reaction conditions have found favour in natural products total synthesis and medicinal chemistry programs. These bare testament to the reactions worth and have raised its stature from academic curiosity to useful synthetic tool. 

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