Thermal ring closure

The oldest known industrially used synthesis is carried out in a solvent and involves several intermediate steps. It is not necessary to isolate the intermediates, and the reaction can proceed in one vessel [4], 

The starting material is succinic dialkylester, which is easily obtained from maleic anhydride. Cyclization is accomplished with sodium alcoholate in a high boiling solvent or solvent mixture (such as diphenylether/diphenyl) to afford the succinylosuccinic dialkylester 54  

A newer synthetic pathway, found by Lonza, involves chlorinating diketene to form the y-chloroacetoacetic ethylester, followed by condensation to afford the succinylosuccinic diethylester [5]  

The typical quinacridone synthesis may be exemplified by the manufacture of unsubstituted quinacridone. 

Succinylosuccinic dialkylester is treated with two equivalents of aniline to yield the 2,5-dianilino-3,6-dihydroterephthalic dialkylester 55. Without separating the intermediate, the ring is closed thermally (at 250°C) in the same reaction medium to afford the a-modification of dihydroquinacridone 56 [4, 6]  

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The most satisfactory method involving this type of intramolecular electrophilic cyclization was the thermal ring-closure of aminomethylenemalonates (e.g., 119, R = COOEt) to yield the pyrido[3,2-d]pyrimidine-2,4,8(l/7,3/f,5/f)-trione (120, R = COOEt). 

Benzothiazepin-5(4/7)-one (2) is obtained by the thermal ring closure of the thiosalicylamide derivative l.49... 

Benzodiazepines 7 are formed by the thermal ring closure of a-(2-alkenylaryl)diazoal-kanes in 1,2-dimethoxycthane.134... 

This chapter deals with thermal ring-closure reactions of dienes and polyenes resulting in carbocyclic compounds the formation of heterocycles is mentioned only occasionally. The account is highly selective, concentrating on recent work, since two comprehensive general reviews have appeared1,2. Other pertinent reviews are cited at appropriate places in the text. 

The thermal ring-closure of butadienes to cyclobutenes proceeds in a conrotatory fashion (equation 2) but this reaction is only observed in special cases because, in general, the equilibrium lies on the side of the open-chain isomer. 

The stereoselectivity of the thermal ring-closure of the dodecatrieneones 42 is determined by the nature of the remote group R. trans-Fused products 43 predominate over cw-products 44 and their ratio increases as R varies from MeO through Me to H (equation 29). If the reactions are catalysed by diethylaluminium chloride only fraws-compounds are formed. The homologues 45 behave similarly34. In contrast, the 7-azadeca-l,3,9-trienes 46 (X, Y = H2 or O) yield more of the cis- than the traws-fused compounds, regardless of the nature of X and Y (equation 30)35. 

Irradiation of trans, cis, trans 1,6 dimethylhexa-1,3,5 triene (I) gives rise to trans-5, 6 dimethylcyclohexa 1,3 diene (II) while thermal ring closure gives rise to cis 5, 6 dimethyl cyclohexa 1,3 diene III. 

The thermal ring closure of Af-(het)arylaminomethylenemalonates gave bi- or polycondensed 4-hydroxypyridine-3-carboxy lates. This type of reaction is named the Gould-Jacobs reaction. (The reaction is illustrated in Scheme 40). The cyclized products may exhibit oxo-enol tautomerism. In this review, the hydroxy form is generally depicted. This type of tautomerism was discussed in an excellent review (76MI1). 

The thermal ring closure of AM 1 -ethyl-4-oxo-1,4-dihydroquinolin-7-yl)aminomethylenemalonate (605) in diphenyl ether at 260°C for 1 hr afforded l,7-phenanthroline-3,9-dicarboxylic acid 9-ethyl ester (606) in 23% yield (88USP4719302). 

Thermal ring closure of A/-(4-oxo-l,4-dihydroquinolinyl-5-yl)amino-methylenemalonate (607) gave a mixture of ethyl 1,7-phenanthroline-3-carboxylate (608, R = H)and l,7-phenanthroline-3,9-dicarboxylic acid 3-ethyl ester (608, R = COOH) in 17% and 23% yields, respectively (88USP4719302). 

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). 

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). 

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... 

Lee et al. reported that the thermal ring closure of diethyl A-(3-cyano-4-fluorophenyl)aminomethylenemalonate (757, R= CN, R1 = F) in Dowtherm A led to the formation of 5-cyano-6-fluoro-4-hydroxyquinoline-3-carboxylate (759, R = CN, R1 = F) in very good yield (89MI1). 

The thermal ring closure of diethyl /V-(3-aminophenyl)aminomethylene-malonate (757 R = NH2, R1 = H) and its 4-fluoro derivative (757, R = NH2, R1 = F) in boiling diphenyl ether in the presence of acetic anhydride gave the corresponding ethyl 7-acetamido-4-hydroxyquinoline-... 

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). 

Ujhidy and co-workers studied the thermal ring closure of )V-(3-chloro-phenyl)aminomethylenemalonate (250) to 7-chloro-4-hydroxyquinoline-3-carboxylate (759, R = Cl, R1 = H) in Dowtherm A containing 5% or 10% of paraffin oil at 230°C, 235°C, 240°C, 245°C, 250°C, and 255°C in different reactors (a continuous tank reactor, a batch tank reactor, a cascade of... 

Albrecht reported that the thermal ring closure of the isomeric 5-benzo-furanylaminomethylenemalonate (807, R = H) in boiling Dowtherm A for... 

The thermal ring closure of 6- and 7-chromanylaminomethylenemalo-nates (823 and 825) in Dowtherm A at 240°C for 15 min gave only linear products (824 and 826) in 78% and 70% yields, respectively (70GEP1936393 72BRP1283900). 

The thermal ring closure of 5-indolinylaminomethylenemalonate (850) by heating in Dowtherm A at reflux temperature for 20 min afforded the linear pyrrolo[2,3-g]quino inecarboxylate (851) in 33% yield (77MI4). 

The thermal ring closure of AKl,3-benzodithiol-5-yl)aminomethylene-malonate (860) in Dowtherm A at 253-258°C led to a 7.3 1 mixture of 1,3-dithiolo[4,5-g]quinolinecarboxylate (861) and l,3-dithiolo[4,5-/]quinoli-necarboxylate (862) in 81% yield (86M1339). The cyclization of diethyl N-(3,4-dimethylthiophenyl)aminomethylenemalonate under similar conditions afforded only ethyl 6,7-dimethylthio-4-hydroxyquinoline-3-carbox-ylate. 

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. 

When position 2 of the pyridine moiety of 3-pyridylaminomethylene-malonates (983) was substituted, the thermal ring closure occurred in position 4 to yield 4-hydroxy-l,7-naphthyridine-3-carboxylates (984) (66BRP1022214 69USP3429887 70BRP1182369, 70USP3506668, 70USP 3517014 84EUPI15469). 

The thermal ring closure of (V-(furo[2,3-6]pyridin-5-yl)aminomethy-lenemalonate (990) in boiling Dowtherm A for 12 min afforded furo[2, 3- ]-1,5-naphthyridinecarboxylate (991) in 77% yield (77MI6). 

From a study of the thermal ring closure of 2-pyridylaminomethylene-malonates (1001) by heating in diphenyl ether, Lappin found that pyri-do[l,2-a]pyrimidine-3-carboxylates (1002) were formed from those malo-... 

The thermal ring closure of /V-(5-nitro-6-diethylamino-2-pyridyl)amino-methylenemalonate (1001, R = Et2N, R1 = 5-NO,) by heating in boiling Dowtherm A for 10 min gave 1,8-naphthyridine (1003, R = Et2 N R1 = N02) in 51% yield (79YZ155). 

The thermal ring closure of 1-isoquinolinylaminomethylenemalonates (1058) by heating in diphenyl ether at 235-260°C for 5-15 min gave pyrim-ido[2,l-a]isoquinoline-3-carboxylates (1059) in 67-83% yields [78USP-4127720 84JAP(K) 172472]. 

The thermal ring closure of NA4H-1,2,4-benzothiadiazine 1,1-dioxide-3-yl)aminomethylenemalonates (1086) in Dowtherm A at 200°C for 8 hr... 

The thermal ring closure of isopropylidene N-[amino(thio)carbonyl]ami-nomethylenemalonates (439, X = O, S) in boiling diphenyl ether for 5 min afforded uracil and thiouracil (1193, X = O, S) in 68% and 70% yields, respectively (84SC96I). 

The reaction of 2-amino-5,7-dimethyl-1,8-naphthyridine and EMME in boiling Dowtherm A for 45 min gave the pyrido[l,2-o]-1,8-naphthyridine derivative (1602) in 40% yield. The same product (1602) was obtained in 44% yield in the reaction of N-( 1,8-naphthyridin-2-yl)aminomethylene-malonate (1603) and EMME in boiling Dowtherm A for 1 hr. The thermal ring closure of 1603 was unsuccessful. An ethanolic suspension of 1603 was treated with concentrated aqueous ammonium hydroxide at reflux for 24 hr to give 2-aminopyrido[ 1,2-a]-1,8-naphthyridine (1604) in quantitative yield (80FES1052). 

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