Quinolines closure

A variety of aryl systems have been explored as substrates in the Knorr quinoline synthesis. Most notable examples are included in the work of Knorr himself who has demonstrated the high compatibility of substituted anilines as nucleophilic participants in that reaction. In the case of heteroaromatic substrates however, the ease of cyclization is dependent on the nature and relative position of the substituents on the aromatic ring." For example, 3-aminopyridines do not participate in ring closure after forming the anilide... 

Ring closure of l-(2-chloroethyl)-6-fluoro-4-oxo-l,4-dihydroquinoline-2-carboxylate on the action of K2CO3 in DMF at 100 °C for afforded 8-fluoro-l,2-dihydro-4//,6//-[l,4]oxazino[4,3-a]quinoline-4,6-dione (01SL833). 

The reaction is often used to effect ring closure.The Friedldnder quinoline synthesis is an example ... 

The photocyclization of enamides to quinolines or isoquinolines has become an important reaction in the synthesis of alkaloids 219,358). It has recently been applied in the preparation of the isoquinoline alkaloid polycarpine 359). The principle of the reaction is demonstrated in the preparation of dihydroquinolines 360> (3.39) and of spirocyclohexaneisoquinoline derivatives (3.40) 361K In each case the electrocyclic ring closure product undergoes a subsequent 1,5-hydrogen shift. 

A series of transformations via nitrene formation similar to the previously discussed case was also found under flash vacuum thermolytic (FVT) conditions by the same team as shown in Scheme 8 <2003JOC1470>. 9-Phenyltetrazolo[l,5- ]quinoline 29 underwent nitrene 30 and cyclic carbodiimide 31 formation, and this intermediate - similar to the previous case - could open up to the isoquinoline nitrene 32 in which, however, proximity of the nitrene to the phenyl substituents allowed the ring closure to the stable tetracyclic ring system 33 which was obtained in 73% yield. 

The thermal ring closure of 4-benzothiazolylaminomethylenemalonates (629) in boiling Dowtherm A for 10-30 min gave thiazolo[5,4-/i]quinoline-carboxylates (630) in 61-78% yields [77JAP(K)83596, 77JAP(K)125196 79CPB1],... 

The thermal ring closure of N-( 1,2,3,4-tetrahydrodibenzofuran-8-yl)-aminomethylenemalonate (664) in boiling Dowtherm A for 30 min afforded 7,8,9,10-tetrahydrobenzofuro[3,2-/i]quinoline-3-carboxylate (665) in good yield (69GEP1908542 70GEP2021100 71BRP1240446). 

The ring closure of diethyl (benzo[/]quinolin-l-yl)methylenemalonate (148) was carried out by heating in polyphosphoric acid at 90-110°C to give ethyl naphtho[ 1,2,3-//]quinolizine-6-carboxylate (723) (84USP4456606). 

V-(3-trifluoromethylphenyl)aminomethylenemalonate (749, R = 3-CF3) proved unsuccessful in boiling phosphoryl chloride. The thermal cycliza-tion of ZV-ethyl-N-arylaminomethylenemalonates (749) and their ring closure in acetic acid, in acetic anhydride with zinc chloride, or in a melt of aluminium chloride were likewise unsuccessful (71JHC357). The corresponding quinoline was not obtained in a one-pot version when N-ethylani-line and EMME were reacted in polyphosphoric acid. Table V shows the yields of quinoline-3-carboxylic acid derivatives obtained from /V-ethyl-N-phenyl- and iV-ethyl-7V-(3,4-methylenedioxyphenyl)aminomethylene-malonates (749, R = H and 3,4-0CH20) under various acidic cyclization conditions. 

Acidic conditions are more favorable than thermal ring-closure for the formation of 5-substituted isomers. The isomeric ratio of 5- and 7-substi-tuted quinolines is less sensitive to conditions of ring closure in the case of A/r-(3-alkoxy- or 3,4-dialkoxy- or 3,4-alkylenedioxophenyl)aminomethy-lenemalonates (see Table V and following discussion). 

The ring closure of arylaminomethylenemalonates (762) in a 1 3 mixture of polyphosphoric acid and phosphoryl chloride at 70°C for 4 hr afforded quinoline-3-carboxylates (763) in 56-78% yields (87JHC399). 

The ring closure of (V-[4-ethyl-3-(2-chlorophenoxy)methylphenyl]ami-nomethylenemalonate (757, R = 2-ClPhOCH2, R1 = Et) in polyphosphate (prepared from phosphorus pentoxide and ethanol in xylene at 100°C) at 150°C for 30 min afforded quinoline-3-carboxylate (759, R = 2-ClPhOCH2, R1 = Et) in 74% yield (79EGP136742). 

The thermal ring closure of /V-(3-chlorophenyl)aminomethylenemalo-namate (781, R = Cl) to quinoline-3-carboxamide (782, R = Cl) in 50-59% yields was carried out in boiling diphenyl ether (46JA1251, 46JA1253) in a higher dilution than for its diester derivative (250) (46JA1204). A similar reaction took place with phenylaminomethylenemalonate (781, R = H) (50JCS607). 

The ring closure of A-(3-chlorophenyl)aminomethylenemalona-mate (781, R = Cl) and the 4-chloro derivative in boiling benzene on the action of phosphoryl chloride for 6-10 hr afforded the corresponding 4-(arylamino)quinoline-3-carboxylate (e.g., 783) in 57-65% yield... 

The ring closure of N-isopropyl- or /V-cyclopropyl-A/-(substituted phenyl Jaminomethylenemalonates (785) in polyphosphoric acid at 100-110°C for 1 hr gave quinoline-3-carboxylates (786) in good yields (85JAP(K)28964, 85JAP(K)126271). 

At the same time, the ring closure of A-(l,3-benzodioxan-7-yl)amino-methylenemalonate (830, R = H) in boiling phosphoryl chloride for 12 hr gave a mixture of l,3-dioxino[4,5-g]quinoline (831) and l,3-dioxino[4,5-/Iquinoline (832, R = H), with an excess of the linear product (831) (72MI5). Starting from the methyl derivative of compound 830 (R = Me), the angular product (832, R = Me) was prepared in 40% yield (72MI4). 

The ring closure of N- 1,4-benzoxazin-6-yl)aminomethylenemalonates (80) in boiling diphenyl ether for 30 min gave mixtures of isomeric 1,4-oxazino[2,3-g]quinoline-8-carboxylates (865) and l,4-oxazino[3,2-/]quin-oline-6-carboxylates (866) in good yields, with an excess of the linearly anelated ring systems (865) [88IJC(B)649]. 

Heeramaneck and Shah obtained 3-phenylbenzo[/]quinoline-2-carbox-ylate (908) in good yield on the ring closure of diethyl phenyl(2-naphthyla-mino)methylenemalonate by heating in the melt at 185-195°C (37JCS867). 

The 6-benzofuranylaminomethylenemalonate (928) can be regarded as both a /we/o-alkoxy-substituted and an aromatic ring condensed phenyla-mine derivative. On thermal ring closure in boiling Dowtherm A for 30 min, a 1 1 mixture of furo[3,2-g]quinoline-6-carboxylate (929) and furo [2,3-/]quinoline-8-carboxylate (930) was obtained in 70-80% yield (70GEP2021100 71BRP1240446), indicating that both the alkoxy substituted and the aromatic moiety exerted an influence. 

The ring closure of 5-indazolylaminomethylenemalonate (948, R = H) in a 6 5 mixture of polyphosphoric acid and phosphoryl chloride for 4 hr afforded 9-chloropyrazolo[4,3-/ quinoline-8-carboxylate (950) in 97% yield [78YZ1063, 79JAP(K)32496]. 

Cyclization of diethyl [3-(4-acetyl-l-piperazinyl)-4-fluorophenyl-l,3-thiazetidin-2-ylidene]malonate (1291) in polyphosphoric acid at 120°C for 1 hr gave a mixture of l,3-thiazeto[3,2-a]quinoline-3-carboxylate (1292, R = Et 25%) and 3-carboxylie acid (1292, R = H 20%) (87BRP2190376). Ring closure was also carried out in fuming sulfuric acid at 100°C for 5 min to afford l,3-thiazeto[3,2-fl]quinoline-3-carboxylic acid (1292, R = H) in 98% yield. 

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

Base-induced isomerization of propargyl amide 29a gives chiral ynamide 30a, which is subjected to ring-closure metathesis to afford cyclic enamide 31a. Diels-Alder reaction of 31a with dimethyl acetylene dicarboxylate (DMAD) gives quinoline derivative 32. In a similar manner, propargyl amide 29b is converted into ynamide 30b, RCM of which gives bicyclic compounds 31b and 31b in a ratio of 1 to 1 (Scheme 10). 

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