O-Xylylenes

The benzocyclobutene ring stmcture is a latent reactive diene because it tautomerizes to o-xylylene on heating according to the foUowiag ... 

Caution This reaction should be carried out in a good hood because hydrogen is evolved and o-xylylene dibromide is a powerful lachrymator (Note 6). 

A solution of 52.8 g. (0.20 mole) of o-xylylene dibromide (Note 6) in 300 ml. of purified dimethylformamide is added dropwise with stirring at such a rate as to maintain a temperature of 60-70° (Note 7). Subsequently the reaction mixture is stirred at room temperature for 3 hours and then poured into 600 ml. of ice water in a 2-1. Erlenmeyer flask. After standing at room temperature overnight the product is collected by suction filtration, pressed on the funnel, and washed twice with 100-ml. portions of water. The crude product is air-dried on filter paper for 2-3 hours and is then dissolved in 1.21. of boiling 95% ethanol. The solution is filtered through a heated funnel, and the filtrate is refrigerated overnight. The crystals are collected on a Buchner funnel and washed on the funnel with 100 ml. of cold 95% ethanol. The product is dried over phosphorus pentoxide in a vacuum desiccator. The yield of white crystals of 2-(% tolylsulf onyl)-dihydroisoindole is 41-46 g. (75-84%), m.p. 174-175° (dec.). 

Precautions to be observed in handling o xylylene dibromide are described in Org. Syntheses, Coll. Vol. 4, 984 (1963). The dibromide was purchased from Eastman Organic Chemicals, recrystallized from 95% ethanol (3 ml./g.), and dried over potassium hydroxide in a vacuum desiccator, m.p. 89-91°. 

TolyIsulfonyl)dihydroisoindole has been prepared by alkylation of /Moluenesulfonamide with o-xylylene dibromide in the presence of sodium methoxide in ethanol.2 3... 

Ji-Toldaldehyde, 2-bromo-, 46,13 />-ToJuenesult onamide, alkylation with o-xylylene dibromide, 47, 111 -Toluenesulfonvlbromide, 45, 88 -Toluenesulfonyl chloride m prepara tion of methvl isocyanide, 46,... 

Although the o-xylylene complex is thermally unstable, it was characterized at — 50 °C by its 1H- and 13C-NMR spectra showing the exocyclic methylene at 5 = 5.04,4.42 ppm (JH) and 5 = 144.8 ppm (13C) using C6D5CD3 as the solvent. Its reaction with benzoyl chloride on the exocyclic carbon leaves a very acidic methylene group which transfers a proton onto the adjacent methylene unit. The double bond is benzoylated again in in situ and a di-cation of the [bis(arene)Fe]2+ type is obtained [47] Scheme VIII. 

The higher solubility of several quaternary ammonium salts of glyphosate in polar aprotic organic solvents such as acetonitrile was discovered (2), which permitted their reaction in solution with various alkyl halides. For example, GLY(n-Bu4N)2H reacted with either o-xylylene dichloride or 1,5-dibromopentane to produce the interesting quaternary glyphosate derivatives 81 and 82, whose structures have been confirmed by x-ray analysis (2). 

On the contrary. Chapman and McMahon found that H-transfer in o-tolylcar-bene can be directly observed at very low temperatures, through several different spectroscopic methods. Irradiation of Ar matrix isolated diazo compound 50 at 4.2 to 10 K gave triplet carbene 51, which could be characterized by EPR, IR, and UV/VIS spectroscopy. The various spectra of 51 slowly decayed at temperatures as low as 4.2 K (tin ca. 64 h), and o-xylylene (52) could be observed to grow correspondingly... 

An additional notable mode of the reactivity of these quinone methide complexes is formation of metal stabilized p- and o-xylylenes.10... 

PPP calculations indicate the lowest triplet state of o-xylylene to be 8000 cm-1 above the ground state singlet. 

Low intensity ultrasound has also been applied to the Simmons-Smith cyclopropanation of olefins with zinc-diiodomethane (237). This reaction normally will not occur without activation of mossy Zn with I2 or Li, and was difficult to scale-up due to delayed initiation. Yields upon sonication are nearly quantitative, activation of the Zn is unnecessary, and no delayed exotherms are observed. In reactions with another class of organic dihalides, ultrasonic irradiation of Zn with a,a -dibromo-o-xylene has proved a facile way to generate an o-xylylene-like species [Eq. (49)],... 

When zinc and a,a -dibromo-o-xylene are irradiated with ultrasonic waves at room temperature, synthetically useful quantities of the reactive intermediate, o xylylene, are generated which can be treated in situ with activated olefins to give good yields of cycloaddition products(30). Chew and Ferrier used this methodolgy to generate a-xylylene for the synthesis of optically pure functionalized hexahydroanthracenes(31). The reaction with lithium takes a different course(19). Rather than generate the -xylylene intermediate, ionic species are produced. The two fates of a, a -dibromo-o-xylene are presented in the scheme below ... 

Successes in producing reactive intermediates like o-xylylene and carbene and in preparing bimetal lies in high yields using ultrasound led us to attempt to generate West s novel compound, tetramesityldisilene the first example of a stable species with a silicon-silicon double bond(32). We prepared this species in one step and trapped it with methanol(33). The disilene is reactive towards lithium, however, and we have found it very difficult to obtain consistent results. Most often, hexamesitylcyclotrisilane is isolated in very good yield(34). 

Although 1, -elimination of o xylene polyhalides with sodium iodide, zinc, copper, or iron metal is a fundamental method for the formation of o-xylylene intermediates, it is difficult to carry out the reaction under mild conditions such as at room temperature. o Trimethylsilylmethyl)-benzyltrimethylammonium halides were devised for this purpose and were shown to generate the o-xylylene at room temperature. However, we have successfully generated o-xylylene at room temperature by the reaction of a, 0,-dibromo o-xylene with metallic nickel(51). The Diels-Alder reaction of... 

Organometallic reactions leading to condensed pyrans containing three or more rings have been achieved by cyclooligomerization processes and by intramolecular coupling. The former type of reaction is based on intramolecular trapping of o-xylylenes produced in cobalt-catalyzed cyclization... 

The thermal reaction of the compound (318) may be chosen as an example to show the usefulness of the benzocyclobutene — o-xylylene rearrangement in alkaloid synthesis U1). On heating (318) at 120 °C, an intermediate product (319) was formed, which cyclized to give the compound (320). This method formulated the key step in the total synthesis of the alkaloid chelidonine (321) ni). 

Steroid molecules can be constructed by applying the benzocyclobutene-o-xylylene method. When the compound (329) was heated in o-dichlorobenzene at 180 °C for 14 hours, the compound (330) was isolated, which could be converted by a number of steps to the steroid acetate (331) u4). 

The steroid estrone (332) contains a benzene ring and thus provides the best structural feature for the synthetic application of the benzocyclobutene-o-xylylene method. Indeed, many successful applications of this methodology have been recorded 115 -118). 

From these examples, one should recognize that the building of the complex steroid skeleton of estrone has been made rather simple when various o-xylylene generation and trapping methods are applied ll5 118). 

As indicated by the aforementioned examples U5-U8>5 the most useful feature of the intramolecular trapping of o-xylylenes generated from benzocyclobutenes is the control of stereochemistry so that high purity of ( )-estrone could be obtained. Subsequent molecular manipulation of synthetic estrone may give rise to alternative routes to other medicinally important steroid drugs. 

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