Cyclization thermal

Acyclic enediynes undergo thermal cycloaromatization at temperatures above 200°C. The influence of aromaticity and electronic factors on the 

The theory of distance is used extensively because of its simplicity. Calculations using the density functional theory (DFT) also revealed a correlation between spontaneous Bergman cyclization and the c-d distance between the acetylenic branches [226]. 

Electronic Effects in the Formation of Diradicals. Syntheses of Naphthalenes and Acenes 

The factors determining the activity of enediynes in the cycloaroma-tization reaction have been studied in detail [25, 27]. When assessing Bergman cycloaromatization, it is difficult to consider the effect of any one factor separately from the others. Often two factors, the c-d distance and the stress factor in the cycle reinforce each other and control the generation of diradicals at a physiologically acceptable temperature. A series 

The same mechanism applies to the intramolecular H-abstraction in the formation of p-diradicals in natural enediyne antibiotics [236]. However, it is notable that the activation energy determined by different 

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Unsaturated hydrazones, unsaturated diazonium salts or hydrazones of 2,3,5-triketones can be used as suitable precursors for the formation of pyridazines in this type of cyclization reaction. As shown in Scheme 61, pyridazines are obtainable in a single step by thermal cyclization of the tricyanohydrazone (139), prepared from cyanoacetone phenylhydrazone and tetracyanoethylene (76CB1787). Similarly, in an attempted Fischer indole synthesis the hydrazone of the cyano compound (140) was transformed into a pyridazine (Scheme 61)... 

Quinazoline alkaloids are found in at least six botanical families of which the Rutaceae are the most important in this respect. Thus, arborine was isolated from Glycosmis arborea in 1952 and in the following year appeared its structure (990) and synthesis by thermal cyclization of the phenylacetyl derivative (989) of (V-methylanthranilamide (53JCS3337>. The same plant material yields three related alkaloids, glycosmicine (991), glycorine (992) and glycosminine (993) (63T1011>. 

Buta-1,3-diene, 1 -(2 -furyl)-pyrolysis, 4, 600 Buta-1,3-diene, 1-mercapto-thiophenes from, 4, 887 Buta-1,3-diene, 1 -(1 -methyl-2-pyrrolyl)-thermal cyclization, 4, 285 Buta-1,3-diene, l-(2-thienyl)-electrocyclization, 4, 748 Butadienes... 

There are also examples of electrocyclic processes involving anionic species. Since the pentadienyl anion is a six-7c-electron system, thermal cyclization to a cyclopentenyl anion should be disrotatory. Examples of this electrocyclic reaction are rare. NMR studies of pentadienyl anions indicate that they are stable and do not tend to cyclize. Cyclooctadienyllithium provides an example where cyclization of a pentadienyl anion fragment does occur, with the first-order rate constant being 8.7 x 10 min . The stereochemistry of the ring closure is consistent with the expected disrotatory nature of the reaction. 

Imine formation by reaction of aniline 58 and dione 49 under thermal conditions gave a mixture of imines. Cyclodehydration using PPA gave nearly a 1 1 mixture of isomers 59 and 60. These authors attempted thermal cyclization conditions (similar to Gould-Jacobs type conditions) to affect cyclization of this mixture and failed. Also, these authors reported difficulty in the clean formation of the imine. They observed large amounts of the A -acetyl compound presumably coming from fragmentation of the imine at the reported temperature... 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

In 1885, Just reported the reaction of sodium diethylmalonate with Af-phenylbenzimino chloride to provide 11. Thermal cyclization provided 12. This work was virtually untouched for several decades, but laid the groundwork for further development. 

Condensation of Af-aryliminochlorides with malonic ester followed by thermal cyclization, as initially reported by Just, was found to be a general method for the preparation of 2, 3, 4-substituted quinolines. Various substituents on the aryl ring of the iminochloride proved uneventful, even though the conditions required to generate the iminochloride utilized PCI5. 

Alternatively, cyclization has been accomplished using various acids which dramatically altered the selectivity in the cyclization, a cyclization that failed under thermal conditions as in the preparation of 59 and 60. Often, the yield of the acid-promoted reaction was lower than the thermally-promoted cyclization. Of course, the temperature in which acid-promoted reactions were conducted was much lower than the normal 250 °C required for thermal cyclization. The selectivity was altered when an acid was used as in 58 —> 59 and 60, suggesting a change in mechanism. 

Thermal cyclization of the 3-nitro anilide 107 gave a 1 1 mixture of 108 and 109 in excellent yield, though one would expect the nitro group to be more sterically demanding than a hydrogen An interesting difference in the reported... 

The thermal cyclization of 2-alkynylbenzenediazonium salts represented by 2 to provide the 4-hydroxycinnoline derivatives 3 respectively is regarded as the von Richter cinnoline synthesis. " ... 

The same methodology was also used starting from the ethyl 6-amino-7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate, prepared by reduction of the nitro derivative. The requisite nitro derivative was prepared by nitration of ethyl 7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate. A second isomer was prepared from 4-chloro-3-nitroaniline by reaction with diethyl ethoxymethylene-malonate, subsequent thermal cyclization, and further ethylation because of low solubility of the formed quinolone. After separation and reduction, the ethyl 7-amino-6-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate 32 was obtained. The ort/io-chloroaminoquinolones 32,33 were cyclized to the corresponding 2-substituted thiazoloquinolines 34 and 35, and the latter were derivatized (Scheme 19) (74JAP(K)4, 79CPB1). 

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... 

By analogy, thermal cyclization was described also for 6-nitro-2 -hydroxy-biphenyl-2-carboxylic acids, e.g. 14, obtained by other methods. The same product 15 was also formed from lactone 17, prepared by oxidation of fluorenone 16 (Scheme 2). If the reaction was performed in DMF, the corresponding dimethylamide was isolated (82KGS703, 86KGS852, 87KGS314, 89MI1). 

Treatment of 228 with 2,4-dinitrofluorobenzene (227) provided 230. The assumed intermediate A -benzoyl-A -(2,4-dinitrophenyl)-A -phenylhydrazine (229) underwent the denitrocyclization reaction in its enol form (80JOC3677). Similar reaction is probably involved also in the thermal cyclization of antraquinone 231 leading to 232 (Scheme 35), which took place even during attempts to crystallize the compound (60T107). 

Thermal cyclization of 2-vinyl-N,N-dialkylanilines 138 afforded 139 with creation of a new chiral center in 98% purity (89JOC199). In case of pyrrolidine with methyl or methoxymethyl substituent, cyclization with ZnCl2 occurs via an irreversible 1,5-hydrogen shift in boiling acetonitrile (87JA3136) or BuOH (91RTC115) to afford the diastereoisomers 140 (33%), 141 (35%) and 142 (6%) (87JA3136) (Scheme 27). 

Thermal cyclization of the arylaminomethylenemalonate afforded quinoline 3-carboxylate 630 whose reaction with 1,1-dibromoethane gave oxazolo[5,4,3-(/]quinoline 631. Acid hydrolysis and reaction with N-methylpiperazine gave 632 whose bactericidal activity is superior to that of pipemidic acid (82JAPK57203085) (Scheme 108). 

Pyrrolo[l,2-a]azepin-9-one (12), which in acid solution exists as the cation 13, is prepared by thermal cyclization of ( , )-4-(dimethylaniino)buta-l,3-dienyl pyrrol-2-yl ketone (ll)7. 

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