Benzyne, from aminobenzotriazole

Benzyne generation. Several reagents [e.g., lead(IV) acetate, etc.] have been used to generate benzyne from 1-aminobenzotriazole. (V-Iodosuccinimide is now recognized as a superior reagent for this purpose. 

Carbene reactions are also involved when electron-deficient acetylenes are heated with carbon disulphide.Full details have now been published for these addition reactions, in which intermediates of type (70 R = CF, or C02Me) are postulated. Generation of benzyne, from 1-aminobenzotriazole and lead tetra-acetate, in the presence of carbon disulphide, also leads to a 1,3-dithiole carbene, and hence to a variety of complex products. ... 

Figure 7.20. Mechanistic alternatives for the P450-catalyzed generation of benzyne from l-aminobenzotriazole.

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

Benzyne, generated either by oxidation of 1-aminobenzotriazole with lead tetraacetate or by decomposition of benzenediazonium-2-carboxylate, was efficiently trapped by (2) to give 88% of the 1,2-benzisoselenazole (26) however, it was trapped in only 5-10% yield by (1). The series of adducts analogous to (26), prepared from benzyne and substituted benzoselenadiazoles (81JCS(P1)607), occurred via attack of the benzyne at the selenium atom followed by reorganization of the intermediate according to Scheme 6. Benzyne addition to dimethylthiadiazole produced methyl derivatives of quinoline and 1,2-benzisothiazole (82CC299). 

With benzyne, formed in situ from 1-aminobenzotriazole, the 2,5-diphenyl-l,3-dithiolium-4-olate (Section III,A,l,d) gives l,3-diphenylbenzo[c]thio-phene in 3b% yield. 

Another method of producing benzyne is from the decomposition of 1-aminobenzotriazole, after it has been oxidised with lead tetraacetate. The oxidation converts the amino group to the nitrene intermediate, and this fragments. Even though there is some doubt over whether nitrenes can exist as true intermediates in these circumstances, suggest a mechanism that utilises their involvement in order to achieve the desired result. 

In the first reported reaction of benzyne with oxazoles, the isolated products were 2 1 benzyne oxazole adducts. In that reaction, the benzyne was generated in situ in a thermal process carried out at 101 °C. The initially formed adduct loses a nitrile to give an isobenzofuran, which adds a second molecule of benzyne. When benzyne is generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, the initial cycloadducts (59) are formed in essentially quantitative yield <90JOC929>. They can be handled at room temperature and can be decompose at elevated temperatures to isobenzofuran (60), which in the presence of other dienophiles leads to a variety of useful products (Scheme 16). 

Benzyne is also formed almost quantitatively on oxidation of l-aminobenzotriazole with NBS (2 equivalents) in the presence of tetracyclone, 1,2,3,4-tetraphenylnaphthalene is obtained in 88% yield. In the absence of a trap, o-dibromobenzene is obtained in 52% yield. No dimer is formed. Bromine is known to be an efficient scavenger of benzyne generated from this precursor.3... 

EHphenyl ether is often used as a high-boiling solvent but it can take part in an intramolecular cyclization under some conditions. The reaction is rapid in the presence of a palladium salt (review [B-41]) and an acid such as methanesul-phonic or trifluoroacetic add or of boron trifluoride. Addition of 4-phenyl-oxazole to benzyne (generated from 1-aminobenzotriazole and LTA) is more eflSdent when both reagents are simultaneously introduced through two syringes on opposite sides of the reaction vessel. 

The oxidation of 1-aminobenzotriazole (ABT) by chemical reagents yields benzyne, an exceedingly reactive species, and two molecules of nitro-gen . The finding that benzyne, or its equivalent, is bound across two of the nitrogens of the prosthetic heme isolated from inactivated P450 enzymes suggests that the enzyme-catalyzed oxidation of ABT follows the same reaction trajec-tory 3 > The benzyne may add directly to the... 

Figure 7.19. Two alternative mechanisms for addition of the benzyne released from l-aminobenzotriazole (ABT) to the heme. The heme porphyrin framework is represented by a square of nitrogens, each of which represents one of the four nitrogens of the porphyrin.

Azulene (201) reacts with benzyne to give cycloadduct 202, the yield being best (33%) when 1 was generated via Pb(OAc)4 oxidation of 1-aminobenzotriazole . The product is derived from addition across the cyclopentadiene moiety of 201. Although a concerted cycloaddition is possible, reaction may take place via electrophilic attack of benzyne at Cl of azulene (known to be prone to electrophilic attack) to form zwitterionic intermediate 203, followed by ring closure at C3a. 

The reactivity of functionalised crosslinked polymers may significantly differ from that of analogous soluble reagents. Polymer-bound benzyne, generated by Pb(OAc)4-oxidation of resin-bound 1-aminobenzotriazole 3, for example was converted into aryl acetates 4. This reaction was not observed if an analogous 1-aminobenzotriazole derivative 6 was oxidised in solution, where the formation of dimers (7 and 8) was predominant (Scheme 1.6.3). 

Rickborn and co-workers ° ° isolated the cycloadduct 164 from 4-phenylox-azole through careful manipulation of the experimental conditions (Fig. 3.50). They generated benzyne at 0°C from 1-aminobenzotriazole and lead tetraacetate. Compound 164 was stable at room temperature but, on heating, eliminated benzo-nitrile to give isobenzofuran 162, which could be trapped with A -methylmaleimide to afford a quantitative yield of the tetracyclic derivative 166 as an 88 12 mixture of endo and exo isomers. The cyclic aminal 164 was also sensitive to acid and rearranged to 4-hydroxy-3-phenyl-isoquinoline 165 on exposure to silica gel or a catalytic amount of trifluoroacetic acid. The benzyne cycloadditions were also carried out on 4-(4-nitrophenyl)oxazole and 4-(4-methoxyphenyl)oxazole. A fourfold rate increase was seen for the cycloaddition of the nitrophenyl-substituted oxazole relative to the methoxyphenyl analog, indicating a concerted process with little contribution from a polar intermediate. 

The practice of using an insoluble polymer to isolate and kinetic-ally stabilize a reactive intermediate has been addressed in several reports, most commonly using DVB cross-linked polystyrene as a support. In these cases, the three dimensional structure of the polymer and rigidity of the polymer backbone diminish intramolecular reactivity between two sites on the same polymer bead. Physical constraints preclude any significant reaction between two different polymer beads. Similar, less dramatic reduced intramolecular reactivity has also been noted for reactive intermediates bound to linear polystyrene. For example, o-benzyne bound to linear polystyrene has been shown by Mazur to have enhanced stability relative to non-polymer-bound -benzyne (35). In this case, o-benzyne was generated by lead tetraacetate oxidation of a 2-aminobenzotriazole precursor, 1. Analysis of the reaction products after cleaving the benzyne derived products from the polymer by hydrolysis showed a 60% yield of aryl acetates was obtained (Equation 11). In contrast, the monomeric aryne forms only coupled products under similar conditions. Further comparisons of the reactivity of -benzyne bound to insoluble 2% or 20%... 

Aminobenzotriazole (11) is utilized as a precursor of the reactive intermediate benzyne, which is generated from 11 by oxidation with Pb(OAc)4 and then trapped in situ, for example, by dienophiles. 

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