Aromatic cyclodehydration

By contrast to the bases, the cationic species have long been known. In addition to Fozard and Jones bicyclic salts already described (307, 308), benzo-fused derivatives were synthesized in the context of the aromatic cyclodehydration series by Bradsher s group (Scheme 71). Different from the 2-propenylpyridinium salts 316 just mentioned, the cycHzation of 2-benzylpyridinium 318 salts does not give indolizines unless under basic conditions in the acidic medium morphanthridizinium salts, such as 319a and b, are formed (59JA2547). This cyclization (after iodo-chloro metathesis) takes place in several days but in the case of the... 

The aromatic cyclodehydration (46CRV(38)477> of suitable quaternary salts bearing carbonyl groups has provided convenient access to both benzo[a]- and benzo[6]-quinoIizinium (acridizinium) salts and their benzo analogs, each of the two systems requiring a different approach. The two approaches can be classified according to their synthetic purpose as type A or type B. 

The first synthesis of the benzo[6]quinolizinium ion (Scheme 98, Table 9, example 1) was by hydrobromic acid-catalyzed cyclization of the quaternary salt formed between 2-pyridinecarbaldehyde and benzyl bromide. Aromatic cyclodehydration has continued to the present as almost the only method used for the preparation of the acridizinium ion, its derivatives and benzo analogs. Because of its instability, 2-pyridinecarboxaldehyde has been replaced by more efficient derivatives. The first of these was the oxime (example 2) which not only gave a better overall yield, but also made possible the isolation of a crystalline intermediate (181 Z = NOH). The disadvantages are that it is not suitable for high temperature cyclizations involving polyphosphoric acid, and some products (182) (e.g. example 10, Table 10) may tend to form double salts with hydroxylamine hydrobromide. 

Using the more versatile tool of aromatic cyclodehydration (Scheme 98), Sawa and Ikekawa have prepared a variety of dibenzo[a,g]quinolizinium derivatives for use in cancer chemotherapy. Their results are described in a large number of Kokai (e.g. 75JAP(K)75154295). From these, it is clear that the compounds of greatest interest bear a hydroxy group or hydroxy derivative at position 8. In a German patent (75GEP2520524) it was claimed that 8-hydroxy-9-methoxydibenzo[a,g]quinolizinium bromide (231) increased the survival time of mice infected with sarcoma 180 and leukemia 1210 by 100% and 240% respectively. 

Aromatic cyclodehydration. Bradsher17 introduced this name for reactions in which intramolecular condensation is accompanied by dehydration to give an aromatic system. In an extensive investigation of such reactions he has used almost consistently hydrobromic acid in refluxing acetic acid as the acid catalyst. Only a few typical examples are cited. 

Aromatic cyclodehydration has been used in the preparation of several indolo[2,3-a]acridizinium salts (43) (Chart V). Reaction of l-formyl-)3-carboline (LXIX) with benzyl bromides in dimethyl formamide at room temperature provided the quaternary salts (LXX R = H or OMe) which were smoothly converted to the desired indolo-[2,3-a]acridizinium salts (LXXI) by action of polyphosphoric or concentrated hydrochloric acid (when R = OMe). 

The intramolecular Bradsher cyclization refers to the acid-catalyzed aromatic cyclodehydration of ort/zo-acyl diaryImethanes to form anthracenes. On the other hand, the intermolecular Bradsher cycloaddition often involves the Diels-Alder reaction of a pyridium with a vinyl ether or vinyl sulfide. 

Many polycyclic aromatic compounds have been synthesized by a cyclization reaction known as the Bradsher reaction or aromatic cyclodehydration. This method can be illustrated by the following synthesis of 9-methylphenanthrene ... 

Early reports from the Bradsher group highlighted new routes to anthracene derivatives iP In the event, conversion of chloride 49 to ketone 6 was accomplished by treatment with cuprous cyanide followed by 1,2-addition of a Grignard reagent. The cyclized product 7 was obtained by heating with hydrobromic acid. It was reported later that liquid sulfur dioxide as solvent was effective in facilitating the aromatic cyclodehydration. " ... 

This particular reaction was observed for the first time by Bergmann during the hydrolysis of o-benzylbenzaldehyde in boiling hydrochloric acid, when he isolated a small amount of anthracene. A very similar reaction, perhaps the first case of aromatic cyclodehydration was reported by Zincke and Breuer in 1884, when they observed the formation of P-phenylnaphthalene fi om phenylacetaldehyde in boiling sulphuric acid (50%). Zincke postulated that aldol condensation of two molecules of... 

Bradsher and Sinclair attempted an aromatic cyclodehydration at lower temperature for heat-sensitive substrates and reported the cyclization of o-benzylbenzophenone (11) to 9-phenylanthracene (12) in the presence of a vigorously stirred fine suspension of phosphorous pentoxide in liquid sulfur dioxide at -10 °C with a moderate yield (53%) of 12 being obtained. ... 

In an innovation, Newman applied polyphosphoric acid (PPA) in place of the usual mixture of hydrobromic acid and acetic acid. PPA had been used earlier in the aromatic cyclodehydration for preparation of phenanthrene derivatives. Newman applied PPA under thermal conditions for the aromatic cyclodehydration of an unactivated ketone 16 to afford 17, an aromatic carcinogen, in moderate yield. In contrast, the use of a mixture of hydrobromic and acetic acids failed to give the cyclized product. 

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