Other Transformations with Benziodoxoles


Up to ten years ago, cyclic hypervalent iodine reagents, such as benziodoxoles, had been only scarcely employed for the introduction of new functional groups in organic chemistry. In fact, the most frequently used cyclic hypervalent iodine reagents were iodine (V) compounds, such as IBX and Dess-Martin periodinane in oxidation reactions. With our work on alkyne transfer and the work of Togni and co-workers on trifluoromethylation, the exceptional properties of benziodoxoles reagents for atom-transfer reactions have become for the first time truly apparent (Chem. Commun. 2011, 47, 102. DOI:10.1039/C0CC02265) . It is our conviction that these properties will also be useful for the transfer of other functional groups. In view of a first step in this direction, we were particularly interested in the  azido-  and cyano- benziodoxole reagents, two further “treasures” first synthesized in the Zhdankin group. Indeed, cyanides and azides are among the most versatile functional groups in organic chemistry. Most methods used to introduced them in organic molecules are based on the nucleophilicity of the azide and cyanide ions, and more general and versatile electrophilic synthons are urgently needed. In 2017, our group further introduced Indole-BX and Pyrrole-BX as new reagents for the Umpolung of indoles and pyrroles. Of course, the research for new, yet undisclosed reagents continues to be an important topic of research in our group, and both modifications of the benziodoxole core structure and the transfered functionality offer exciting opportunities for further development.


With azidobenziodoxole reagents, we discovered a fast and clean azidation of cyclic ketoesters without the addition of any additive (Org. Lett. 2013, 15, 3246. DOI:10.1021/ol401229v) . We preferred the use of the dimethyl reagent, as it was both more efficient and safer to use (smooth decomposition vs explosion for the carboxy reagent). Nevertheless, the azidation did not work in the case of non-cyclic ketoesters or ketones as substrates. In this case, we found that it was possible to further activate the reagent using zinc triflate as catalyst. Under these conditions, both non-cyclic ketoesters and silyl enol ethers could be azidated successfully.

Our next goal was to develop an azidation of non-activated olefins. In 2017, we developed two complementary approaches for the azidolactonization of olefins, using either photoredox or Lewis acid catalysis.(Chem. Eur. J. 2017, 23, 9501. DOI:10.1002/chem.201702599) .

As Azidobenziodoxolone (ABX) is a stronger oxidant, it was an ideal reagent for the generation of azide radicals in presence of a copper photocatalyst and blue LED. The formed azide radical can then react with an olefin, generating a benzylic radical, followed by oxidation to the carbocation and attack of the carboxylic acid to give 1,2-azidolactones. Unfortunately, ABX is unstable and can explode spontaneously (see Stability Data). In contrast, Azidodimethylbenziodoxole (ADBX) could be activated by a Lewis acid to give the corresponding iodonium. Reaction wiht the olefin, followed by lactonization, 1,2-aryl shift and azidation gave then the observed 1,1-azidolactones.


With cyanobenziodoxoles, we were able to develop a new method for the synthesis of thiocyanates starting from thiols (Chem. Eur. J. 2015, 21, 2662. DOI:10.1002/chem.201406171 ). As was the case for the related alkynylation reaction, this transformation is extremely efficient, with often quantitative yields obtained in a few minutes. Both the dimethyl and the carboxy reagents worked well. Many functional groups such as acids, alcohols or aromatic amines are tolerated. The cyanation of thiols displayed a broad generality, as it could be applied in the case of aromatic, heteroaromatic, aliphatic or glycosidic thiols.


After having developed the efficient alkynylation of carboxylic acids using EBX reagents under photoredox conditions, we wondered if a similar approach could be also successful for other benziodoxolones. In particular, the conversion of carboxylic acid is usually a multi-step procedure generating large amounts of waste. In 2016, we developed a one-step decarboxylative cyanation of carboxylic acid using CBX and an iridium photocatalyst. The reaction worked well for amino- and oxy- acids, but not for simple aliphatic acids. Mechanism investigations combining experiments and computational chemistry shown that the alkynylation and cynation reaction, although similar on the first look, follow different mechanisms: The alkynylation proceeds via a radical, whereas the cyanation most probably involves an iminium intermediate (Chem. Sci. 2017, 8, ASAP. DOI:10.1039/C6SC04907A ).


The efficient azidation and cyanation of ketoesters derived from indanones with benziodoxol(on)e reagents gave access to the starting materials needed for an enantioselective decarboxylative allylation reaction. The corresponding homoallylic azides and nitriles could be obtained in high yield and enantioselectivity using a palladium catalyst and Trost’s chiral diphosphine ligands (Org. Lett. 2015, 17, 5832. DOI:10.1021/acs.orglett.5b03002 ).


In 2017, an important breakthrough was achieved at LCSO with the discovery of Indole- and Pyrrole- BX reagents, the first examples of benziodoxoles with this type of heterocycles (Chem. Eur. J. 2017, 23, 14702. DOI:10.1002/chem.201703723 ). These new reagents were bench stable and could be used in the rhodium and ruthenium catalyzed C-H functionalization of arenes. These transformations could not be realized with other reagents. As often in science, the new reagents were discovered serendipitously when attempting new domino reactions (Helv. Chim. Acta 2017, 100, e1700221. DOI:10.1002/hlca.201700221 ).


Togni’s work on trifluoromethylation and our work on alkynylation had amply demonstrated the utility of benziodoxole reagents. Most certainly, these reagents will be also highly useful for the transfer of other functional groups. Indeed, exciting new examples have started to emerge in azidation, cyanation, fluorination and many other transformations (Angew. Chem., Int. Ed. 2016, 55, 4436. DOI: 10.1002/anie.201509073 ).