Ether cyclization thermal

A -Aryl-A -(ethoxyearbonyl)iinidamides and 2-alkyl-l-aryl-3-(ethoxycarbonyl)isothioureas 12 cyclize thermally to yield 2-substituted quinazolin-4(3//)-ones 13. When an A-aryl-A -(ethoxy-carbonyl)imidamide is boiled briefly in quinoline, ethanol is evolved and the corresponding 2-arylquinazolin-4(3//)-one is formed in 49-88% yield. Presumably elimination of ethanol yields an imidoyl isocyanate which undergoes cyclization to form the 2-arylquinazolin-4(3//)-one. These cyclizations are most likely simple thermal processes, since they proceed equally well when diphenyl ether is used instead of quinoline or when the imidamide is heated at 50-70 C above its melting point in the absence of a solvent.This reaction is also suitable for the synthesis of benzo-fused quinazolin-4(3//)-ones. °... 

Figure 11-16. Thermal ether cyclizations Lewis acid catalyzed ether cyclizations,...

Nearly every substitution of the aromatic ring has been tolerated for the cyclization step using thermal conditions, while acid-promoted conditions limited the functionality utilized. Substituents included halogens, esters, nitriles, nitro, thio-ethers, tertiary amines, alkyl, ethers, acetates, ketals, and amides. Primary and secondary amines are not well tolerated and poor yield resulted in the cyclization containing a free phenol. The Gould-Jacobs reaction has been applied to heterocycles attached and fused to the aniline. 

Another approach involves utilization of the amines for addition of a fused pyridine ring to the benzothiadiazole skeleton. The Gould-Jacobs reaction of 4-amino-2,l,3-benzothiadiazole 60 with diethyl ethoxymethylenemalonate gave the substitution product, and, after thermal cyclization in diphenyl ether, afforded the... 

Replacement of one of the ethereal oxygen atoms by a methylene group is compatible with anticoccidial activity. For example, condensation of substituted aniline 35 with dimethyl ethoxymethylenemalonate affords aminoacrylate 36. Thermal cyclization in diphenyl ether gives neguinate (37).11... 

Some examples of the lateral cyclization of suitable O-allyl and O-propargyl derivatives were discussed in CHEC-11(1996) <1996CHEC-II(8)747>. Thermal reaction of silyl diazoacetate 303 in xylene provides unspecific decomposition and a minor amount (about 2%) of a colorless solid can be precipitated with ether. The X-ray diffraction analysis identified the structure 305, which is a product of the lateral criss-cross cycloaddition of primarily formed azine 304 (Scheme 43) <2000T4139>. 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

However, it was claimed that the thermal cyclization of (7,8-difluoro-3-fluoromethyl-2,3-dihydro-1,4-benzoxazin-4-yl)methylenemalonate (560) in diphenyl ether at 250°C for 30 min gave pyridoH J-c/el-M-benzox-azine-6-carboxylate (561) in 71% yield [86JAP(K)204188]. 

The thermal cyclization of )V-[2-(disubstituted amino)phenyl]amino-methylenemalonates (568, R1 + H,R2 + H) by heating in boiling diphenyl ether for 5-18 min afforded quinolines (569, R1 + H, R2 =h H) in 53-81% yields [75JCS(P 1)2409]. 7V-[2-(Substituted amino)phenyl]aminomethy-lenemalonates (568, R + H, R2 = H) failed to cyclize to the corresponding quinolines (569, R1 + H, R2 = H) when heated in diphenyl ether, but their JV-(p-tosyl) derivatives (568, R2 = 4-MePhS02) gave the expected products (569, R2 = 4-MePhS02) in 72-77% yields. 

It was later claimed that the thermal cyclization of bis(aminomethylene-malonates) (601, R = H, Me, Cl, N02, R1 = Et) by heating in refluxing diphenyl ether for 15-30 min under nitrogen afforded 8-(substituted amino)quinoline-3-carboxylates (603) in 31-75% yields (78USP4123536). In the cases of the methyl and chloro derivatives (601, R = Me, Cl, R1 = Et), l,10-phenanthroline-3,8-dicarboxylates (602, R = Me, Cl, R1 = Et) could also be isolated as byproducts in 3-4% yields. 

Y = CH2), respectively, by thermal cyclization in boiling diphenyl ether (70JMC1110). 

The thermal cyclization of A-(l,2,5-benzothiadiazol-4-yl)aminomethy-lenemalonate in diphenyl ether at 250-280°C gave l,2,5-thiadiazolo[3,4-/j]quinoline (635) in good yield (76KGS61 84MI2). 

N-(Pyrazolopyrimidin-7-yl)aminomethylenemalonates (640) were thermally cyclized when heated in diphenyl ether at 240°C for 7 min to give pyrazolopyridopyrimidinecarboxylates (641) in 73-75% yields (77GEP26 50780). 

Anthraquinonylaminomethylenemalonates (658, R = H, OMe) and 1,5-bis(aminomethylenemalonate) (191) in boiling diphenyl ether readily gave tetracyclic and pentacyclic pyridine derivatives (659 and 660) in good yields (59MI2). At the same time, the thermal cyclization of the 4-hydroxy derivative (658, R = OH) and 1,4-bis(aminomethylenemalonate) [658, R = —NHCH=C(COOEt)2] did not yield the expected condensed tetracyclic pyridine derivatives. 

Aqui et al. investigated the cyclization of diethyl A-(3-substituted phe-nyl)aminomethylenemalonates (251) under different cyclization conditions (75JHC557). For cyclization, they applied a 4 7 mixture of concentrated sulfuric acid and acetic anhydride, polyphosphoric acid, polyphosphate (prepared from phosphorus pentoxide and diethyl ether in chloroform), phosphoryl chloride, and Dowtherm A (see Table VI). They found the most effective cyclization conditions were thermal cyclization (heating in Dowtherm A) and polyphosphate. 

Shah and Coats prepared a series of 7-substituted quinoline-3-carboxyl-ates (759, R1 = H) in 63-98% yields by thermal cyclization of diethyl N-( 3-substituted phenyl)aminomethylenemalonates (757, R1 = H) in diphenyl ether at 250-260°C (77JMC1001). /V-(3-Cyanophenyl)aminomethylenema-lonate (757, R = CN, R1 = H) gave 7-cyanoquinoline-3-carboxylate (759, R = CN, R1 = H) (76PHA145 77JMC1001) and not the 5-cyano isomer (758, R = CN, R1 = H) as stated earlier (47JA374). The thermal cyclization of (3-sulfonamidophenyl)aminomethylenemalonate (757, R = H2NS02, R1 = H) was unsuccessful (77JMC1001). 

Isomeric 6- and 8-chloro-7-fluorothiazolo[3,2-a]quinolines (768 and 769) were prepared in 29-66% yields by the thermal cyclization of [(2-sub-stituted ethyl)thio][(3-chloro-4-fluorophenyl)amino]methylenemalonates (767) in diphenyl ether at 250°C for 5 min (82EUP58392). 

The thermal cyclization of A/-(3-chloro-5-methoxyphenyl)aminomethy-lenemalonate (779) in boiling diphenyl ether for 20 min gave 7-chloro-5-methoxyquinoline-3-carboxyIate (780) (47JA371). 

The thermal cyclization of 4-fluoro-3-(l-pyrrolyl)phenylaminomethy-lenemalonate (757, R = l-pyrrolyl, R1 = F) in diphenyl ether at 250°C for 5 min gave 6-fluoro-7-(l-pyrrolyl)quinoline-3-carboxylate (759, R = 1-pyrrolyl, R1 = F) in 55% yield (86FRP2574404). 

The thermal cyclization of [(3-chloro-4-fluorophenyl)amino][4-methoxy-phenyl)methylthio]methylenemalonate (789, R = Cl, R1 = 4-MeOC6H4) in diphenyl ether at 250°C for 3 min gave 2-substituted quinoline-3-carbox-ylate (790, R = Cl, R = 4-MeOC6H4) in 66% yield (82EUP58392). 

The thermal cyclization of (methoxymethylthio)(3,4-difluorophenyl-amino)methylenemalonate (789, R = F, R1 = MeOCH2) by heating in diphenyl ether at 240°C for 5-10 min yielded 6,7-difluoro-2-(methoxy-methy thio)quinoIine-3-carboxyIate (790, R = F, R1 = MeOCH2 (87BRP2190376). 

The thermal cyclization of m-phenylenediamine derivatives (799) by heating in diphenyl ether afforded angular l,7-phenanthroline-3,9-dicarboxylate (800), if a substituent was not present at position 2 of the phenyl ring of 799 (R = H), but the linear pyrido[3,2-g]quinolinecarbox-ylate (801, R = Me, R1 = R2 = H) was prepared from the 2-methyl-substituted derivative (799, R = Me, R1 = R2 = H) (72GEP2220294). 

Cruickshank et al. reported that the thermal cyclization of 5-benzofuran-ylaminomethylenemalonate (808) in boiling diphenyl ether for 30 min gave a 10 1 mixture of the linearly and angularly fused tricycles (809 and 810) in 75% yield, while in the case of 6-benzofuranylaminomethylenemalonate (811), only formation of the linear product (812) could be detected (70JMC1110). 

The thermal cyclization of 2- and 3-thienylaminomethylenemalonates (883) in boiling Dowtherm A or in boiling diphenyl ether for 0.25-1.5 hr... 

The thermal cyclization of 3-acridinylaminomethylenemalonates (921) by heating in diphenyl ether at 260-270°C for 20 min afforded pyrido[2, 3-c]acridine-2-carboxylates (922) in good yields [77JAP(K)3099, 77USP 4060527]. 

Later, Corelli et al. reported that the thermal cyclization of 3-carbazol-ylaminomethylenemalonates (941) by heating in boiling diphenyl ether for 1 hr afforded the angular pyrido[2,3-c]carbazolecarboxylates (942) in 67-80% yields (87FES641). 

Pyrido[l,2-a]pyrimidine-3-carboxylate (1002) R = R1 = H) was prepared in 94% and 40% yields by the thermal cyclization of 2-pyridylamino-methylenemalonate (1001, R = R1 = H) in boiling diphenyl ether (52JA5491 77GEP2648770 80M1P2). 

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