Intermediate benzyne

Recent developments in the synthesis of dibenzopyrrocolines have centered mainly on variations of the benzyne approach. Potassium amide in liquid ammonia treatment of the bromobenzylisoquinoline 1 affords the dibenzopyrrocoline 2 along with the corresponding aporphine 3.  

In the absence of a C-7 phenol in the cyclization precursor, the reaction proceeds further and styrenes such as 4 are isolated, presumably by oxidation of the Hofmann elimination product.  

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The carbon that bears the leaving group and a carbon ortho to it become equiva lent m the benzyne intermediate Thus when chlorobenzene 1 is the substrate the ammo group may be introduced with equal likelihood at either position... 

Although nucleophilic aromatic substitution by the elimination-addition mecha nism IS most commonly seen with very strong amide bases it also occurs with bases such as hydroxide ion at high temperatures A labeling study revealed that hydroly SIS of chlorobenzene proceeds by way of a benzyne intermediate... 

A benzyne intermediate is impossible because neither of the carbons ortho to the intended leaving group bears a proton... 

Preparation of phlorogluciaol or its monomethyl ether by reaction of a halogenated phenol with an alkaU metal hydroxide in an inert organic medium by means of a benzyne intermediate has been patented (142). For example, 4-chlororesorcinol reacts with excess potassium hydroxide under nitrogen in refluxing pseudocumene (1,2,4-trimethylbenzene) with the consequent formation of pure phlorogluciaol in 68% yield. In a version of this process, the solvent is omitted but a small amount of water is employed (143). 

An early ease in whieh the existenee of benzyne as a reaetion intermediate was established was in the reaction of chlorobenzene with potassium amide. Carbon-14 label in the starting material was found to be distributed in the aniline as expeeted for a benzyne intermediate. ... 

The reaction of an alicyclic enamine with benzyne intermediate yields simple arylation products and/or 1,2-cycloaddition products, depending upon the reaction conditions 102). This is illustrated by the reaction of l-(N-pyrrolidino)cyclohexene with benzyne (86) (obtained from fluoro-benzene and butyl lithium or o-bromofluorobenzene and lithium amalgam), which produces benzocyclobutene 87 102). 

Only one benzyne intermediate can form from p-bromotoluene two different benzyne... 

Benzyne, intermediate in preparation of phenyl t butyl ether, 46, 90 methods for generation of, 46, 112 trapping by tetraphenylcyclopenta-dienone, 46,112... 

It has been found that aryl groups can also be introduced into the a-position of sulphoxides. Corey and Chaykovsky have demonstrated that chlorobenzene reacts at room temperature with an excess of sodium methylsulphinyl carbanion to give methyl benzyl sulphoxide in 41% yield. The authors believe that a benzyne intermediate may be involved in the reaction400,401 (equation 174). 

Basicities 565-567 Basis orbitals 2-5 Benzisothiazolinone dioxides 163 Benzofurans 638 Benzoic acids, pKa values of 586 Benzoxathiazine 2-oxides 71 Benzyne intermediates 306 Beta scales 559... 

The following intermediates in the synthesis of naturally occurring materials have been synthesized by reactions based on a benzyne intermediate. The benzyne precursor is shown. By retrosynthetic analysis identify an appropriate co-reactant that would form the desired compound. 

A mixture of sodamide, bromoanisole, and l-methoxy-2-methyl-l-(trimethylsilyl-oxy)-l-butene were reacted at room temperature at a 50 millimolar scale. After some two horns, with slight emission of ammonia, the reaction suddenly became exothermic, with violent gas emission and on one occasion a fire. This was a modest scale-up of a literature procedure for synthesis of 2-alky lbenzoic acids, via a benzyne intermediate. It is advised that this reaction be employed only on smaller scale, with safety precautions. The reaction must pass through a benzocyclobutane intermediate, this, or another, high energy species might accumulate and then decompose. 

An approach to dibenzothiophenes involving a benzyne intermediate has been developed, wherein the required precursor 5, which is available in three steps from 2-fluorothiophenol, underwent lithiation giving the species 6, which could thereafter be treated with various electrophiles rendering the final products 7 <06JOC6291>. 

Another reaction that is catalyzed by a base is that which leads to the formation of the benzyne intermediate. In this case, the strong base is the amide ion, NH2 . 

The triple bond in the benzyne intermediate is very reactive toward a wide range of nucleophiles. The reaction of acetaldehyde with methanol to produce a hemiacetal is also a base-catalyzed reaction. In this reaction, the methoxide ion, CH30, is the base ... 

Ortho substitution also allows one to control other steps in the cycloaromatization cascade. For example, mira-molecular hydrogen-atom (H-atom) abstraction from the ortho-OCH3 group effectively intercepts the p-benzyne intermediate in the Bergman cycloaromatization of 2,3-diethynyl-l-methoxybenzene before this... 

For the formation of indoles 2 and 3 we assumed that amines 1 first reacted with fBuLi at -110°C to give N-(2-lithioallyl)amines 4, through halogen-metal exchange 23 this was confirmed by deuteration and isolation of the deuteriated amine 5 a (Scheme 2). Intermediate 4, which is stable for several hours at —110 °C, probably undergoes proton-abstraction ortho to the fluorine atom by the additional equivalents of fBuLi when the temperature is raised to — 40 °C giving the intermediate 6. The subsequent elimination of LiF produces a benzyne intermediate 7, which is efficiently... 

Scheme 2. Anionic cyclization of A/-(2-lithioallyl)-/V-2-fluoroanilines 1 via benzyne intermediates 7.

Fusion of arenesulfonates with sodium hydroxide leads to phenols. Although the exact mechanism for this well known reaction is not certain, a benzyne intermediate has been ruled out by showing that cine substitution does not occur (Buzbee, 1960 Oae et al., 1966). 

Elimination-addition goes through a benzyne intermediate, and the nucleophile can add to either benzyne C, so both 3- and 4-bromotoluene should give mixtures of products if this mechanism is operative. 

The photochemistry of borazine delineated in detail in these pages stands in sharp contrast to that of benzene. The present data on borazine photochemistry shows that similarities between the two compounds are minimal. This is due in large part to the polar nature of the BN bond in borazine relative to the non-polar CC bond in benzene. Irradiation of benzene in the gas phase produces valence isomerization to fulvene and l,3-hexadien-5-ynes Fluorescence and phosphorescence have been observed from benzene In contrast, fluorescence or phosphorescence has not been found from borazine, despite numerous attempts to observe it. Product formation results from a borazine intermediate (produced photochemically) which reacts with another borazine molecule to form borazanaphthalene and a polymer. While benzene shows polymer formation, the benzyne intermediate is not known to be formed from photolysis of benzene, but rather from photolysis of substituted derivatives such as l,2-diiodobenzene ... 

Mixtures of xanthone (246) and 3,4-benzocoumarin (247) result when 2-aryliodoniobenzoates 245 are heated at higher temperature. This reaction involves fragmentation of 245 to benzyne, carbon dioxide, and iodoarene. Thus, in the absence of trapping agents, the benzyne intermediate reacts with 245 to form cyclized products 246 and 247 (64JOC1637) (Scheme 63). 

An elimination/addition reaction is another distinct type of reaction mechanism that occurs in aromatic systems. In these mechanisms, the elimination involves the loss of an HX molecule. While this may seem like a dehydrohalo-genation as seen in Organic Chemistry 1, it really is a different reaction. The HX loss leads to the formation of a benzyne intermediate (see Figure 8-2). The mechanism ends with addition to the bond formed by the loss of HX. 

The intramolecular trapping of a benzyne intermediate has been used as a novel route to 7-lithiated benzoxazoles (Scheme 89)(82JOC2804). 

Scheme 11.9 illustrates some of the types of compounds that can be prepared via benzyne intermediates. 

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of ( )-cryptowoline (2) and the related dehydro base 39 by Bennington and Morin (7). ( )-6 -Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylformamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to ( )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide. 

It has been proved that the benzyne intermediate can be easily prepared from o-iodobenzoic acid and potassium peroxydisulfate in sulfuric acid. Water-soluble vicinal diols are converted into their corresponding aldehydes in the presence of Ag(I) catalyst. ... 

Cycloaddition of benzyne intermediates with aminothiazadienes provide access to substituted 2,4-diamino-4//-l,3-benzothiazines 196 in high yields. The benzynes are prepared by the treatment of (phenyl)[o-(trimethylsilyl)aryl]-iodonium triflates with 1.5 equiv of tetrabutylammonium fluoride (Scheme 20). Interestingly, 3-substituted-l,2-benzisothiazoles 197 are obtained when 4 equiv of tetrabutylammonium fluoride is used <2005H(65)1615>. 

The synthesis of 273 proceeds through a benzyne intermediate (Scheme 55) <2005TL7443>. An enzymatic cyclization has also been reported (Scheme 56) <1990TL6907>. 

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