[1608-42-0]  · C7H4N2O2  · Benzenediazonium-2-carboxylate  · (MW 148.12)

(benzyne precursor6)

Alternate Name: 2-carboxybenzenediazonium hydroxide inner salt.

Solubility: insol most organic solvents.

Preparative Method: obtained by diazotization of anthranilic acid;1 the most useful diazotization agent is Isopentyl Nitrite (caution, heart stimulant!).

Handling, Storage, and Precautions: can be generated in situ,2 handled as a suspension of the inner salt1 or the hydrochloride3 in ethers or halogenated hydrocarbons, or isolated as a dry solid.1 Solid benzenediazonium 2-carboxylate decomposes explosively on being heated or scraped against a hard surface. The use of the wet compound is safer, but explosions have been reported during experiments using a slurry of the inner salt4 or the hydrochloride.5 The safest procedure is generation in situ by aprotic diazotization, but yields are lower. Preparation and handling should be carried out with good shielding.

Generation of Benzyne.6

Benzenediazonium-2-carboxylate decomposes on heating to afford benzyne (eq 1). The decomposition temperature depends on the solvent used.6 This is one of the simplest and most commonly used procedures for the generation of benzyne for synthetic purposes. When diazotization is carried out in situ, secondary products derived from the reaction of benzyne with the starting materials are obtained. Better yields are obtained if the diazonium salt is prepared previously in a separate flask. However, the scale of work is limited to a few grams by safety reasons. Application of this procedure to the generation of substituted benzynes is limited by the availability of starting anthranilic acids. Most of these reactions are carried out in refluxing DME, THF, or 1,2-dichloroethane.

Nucleophilic Additions.6

Most nucleophiles react with benzyne to afford an intermediate aryl carbanion, which can be protonated or trapped with another electrophile. Even ethers, which are frequently used as solvents in these reactions, react with benzyne. For example, THF reacts with benzyne to afford an intermediate betaine, which can undergo attack by nucleophiles (eq 2).7

When nucleophile and electrophile belong to the same molecule, annulation takes place. For example, when benzyne is generated from benzenediazonium-2-carboxylate in the presence of enol ethers or enol acetates, benzocyclobutenes are obtained by a formal [2 + 2] cycloaddition (eq 3).8 These benzocyclobutenes can then be used to generate o-quinodimethanes. Halogenated benzocyclobutenes can be obtained in a similar way (eq 4).9

The benzyne dimer biphenylene is a frequent secondary product in benzyne reactions (eq 5).6

The high reactivity of benzyne with nucleophiles makes it necessary to protect nucleophilic centers when other types of reaction, such as cycloadditions, are desired. In particular, nucleophilic nitrogens react very fast with benzyne to afford intermediate betaines, which can undergo a variety of transformations. For example, the aporphine alkaloid nuciferine is transformed into a phenanthrene in moderate yield (eq 6).10

[4 + 2] Reaction with Acyclic Dienes.6

Due to the low yields in the first attempts at cycloadditions between benzyne and acyclic dienes,7 this reaction was rarely used in synthesis until the 1980s. Its resurrection began with the synthesis of anthracyclinones by reaction of benzyne with an exocyclic diene (eq 7).11

Benzyne generated from benzenediazonium 2-carboxylate has been reacted with styrenes to afford low yields of phenanthrenes and/or dehydrophenanthrenes.12 This reaction has been applied in recent years to the synthesis of aporphinoids. When benzyne was generated in a solution of a protected 1-methylene-1,2,3,4-tetrahydroisoquinoline in DME, the corresponding dehydroaporphine was obtained, the initial dehydrophenanthrene cycloadduct having undergone oxidation under the reaction/work-up conditions. Substituted anthranilic acids can be used as precursors of substituted benzynes, but the yield of the cycloaddition is lower. Remarkably, the reaction works regioselectively when o-substituted benzynes are used (eq 8).13

[4 + 2] Reaction with Cyclic Dienes.6

Benzyne generated from benzenediazonium-2-carboxylate reacts with most heterocyclic dienes. A typical example is the reaction with furan, which is frequently used as a trapping agent for benzyne (eq 9).14 Lower yields of cycloadducts are obtained with the less reactive thiophene (see (2-carboxyphenyl)phenyliodonium hydroxide).15 Silacyclopentadienes also react with benzyne to afford bicyclic compounds (eq 10).16

A sequence of Diels-Alder/retro-Diels-Alder reactions occurs when benzyne is generated in the presence of 1,2-diazines.6 Eq 11 shows a particular case which includes a Diels-Alder/retro-homo-Diels-Alder sequence.17

Bridged hydrocarbons can be easily constructed by cycloaddition of benzyne with cyclic dienes such as dimethylfulvene (eq 12).18 Even aromatic compounds take part in these reactions. Eq 13 shows the formation of benzobarrelene by cycloaddition of benzyne with an anisole derivative.19

Benzyne cycloaddition is often the method of choice for the synthesis of triptycenes, azatriptycenes, and related compounds (see 2-Bromofluorobenzene and 2-Bromoiodobenzene). In eq 14 an azatriptycene is obtained by the addition of benzenediazonium-2-carboxylate to a refluxing solution of the diene in DME.20 Benzenediazonium-2-carboxylate hydrochloride has been used to generate benzyne in the key cycloaddition step of the synthesis of complex triptycene derivatives. Propene oxide is added to the reaction mixture to trap the HCl. Remarkably, almost quantitative yields were obtained in this cycloaddition step.21

When benzyne is generated from benzenediazonium-2-carboxylate in the presence of isoquinolopyrroline-2,3-diones, the major products are protoberberines (eq 15).22 This procedure has also been used for the synthesis of compounds with a yohimban skeleton. The mechanism of these transformations seems to be rather complex.7 Naphthopyrroline-2,3-diones react in a similar way with benzyne to afford benzophenanthridines (eq 16). This procedure too can be used with substituted anthranilic acids.23 A different approach to the same group of isoquinoline alkaloids is based on the cycloaddition of benzyne to a pyrone to form a bicyclic intermediate which loses CO2 in a retro-Diels-Alder reaction (eq 17).24 Good yields were also obtained using substituted anthranilic acids.

1,3-Dipolar Cycloaddition.

Benzyne generated from benzenediazonium-2-carboxylate also undergoes cycloaddition with 1,3-dipoles such as N-oxides (eq 18).25 2-Isopentoxy-1,3-benzodithiole is obtained by 1,3-dipolar cycloaddition of carbon disulfide to benzyne, followed by addition of isopentyl alcohol (eq 19).26

The reactivity of benzyne generated from benzenediazonium-2-carboxylate with dienes can be modified by the addition of Ag+. 1,3,5-Cycloheptatriene reacts with benzyne to afford, in 36% yield, a mixture of two products, one resulting from an ene reaction and the second by formal [2 + 2] cycloaddition (eq 20).27 In the presence of Ag+ only the [4 + 2] adduct was obtained, although the yield fell to 20% (eq 21).27

Related Reagents.

1,2,3-Benzothiadiazole 1,1-Dioxide; Diphenyliodonium Carboxylate.

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3. Stiles, M.; Miller, R. G.; Burkhardt, U. JACS 1963, 85, 1792.
4. Matuszak, C. A. Chem. Eng. News 1971, 49(24), 39.
5. Sullivan, J. M. Chem. Eng. News 1971, 49(16), 5.
6. Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic: New York, 1967.
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8. Wasserman, H. H.; Solodar, J. JACS 1965, 87, 4002.
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15. Del Mazza, D.; Reinecke, M. G. JOC 1988, 53, 5799.
16. Gilman, H.; Cottis, S. G.; Atwell, W. H. JACS 1964, 86, 5584.
17. Moerck, R. E.; Battiste, M. A. CC 1972, 1171.
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19. Bender, C. O.; Cassis, I. M.; Dolman, D.; Heerze, L. D.; Schultz, F. L. CJC 1984, 62, 2769.
20. Markgraf, J. H.; Davis, H. A.; Ernst, P. S.; Hirsch, K. S.; Leonard, K. J.; Morrison, M. E.; Myers, C. R. T 1991, 47, 183.
21. Chen, Y-S.; Hart, H. JOC 1989, 54, 2612.
22. Cobas, A.; Guitián, E.; Castedo, L. JOC 1992, 57, 6765.
23. Martín, G.; Guitián, E.; Castedo, L.; Saá, J. M. JOC 1992, 57, 5907.
24. Pérez, D.; Guitián, E.; Castedo, L. JOC 1992, 57, 5911.
25. Seidl, H.; Huisgen, R.; Knorr, R. CB 1969, 102, 904.
26. Nakayama, J.; Seki, E.; Hoshino, M. JCS(P1) 1978, 468.
27. Crews, P.; Beard, J. JOC 1973, 38, 529.

Luis Castedo, Concepción González, & Enrique Guitián

CSIC & University of Santiago de Compostela, Spain

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