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. 2017 Mar 1;8(3):1790-1800.
doi: 10.1039/c6sc04907a. Epub 2016 Dec 22.

Room temperature decarboxylative cyanation of carboxylic acids using photoredox catalysis and cyanobenziodoxolones: a divergent mechanism compared to alkynylation

Franck Le Vaillant  1 , Matthew D Wodrich  1 , Jérôme Waser  1
Affiliations

Room temperature decarboxylative cyanation of carboxylic acids using photoredox catalysis and cyanobenziodoxolones: a divergent mechanism compared to alkynylation

Franck Le Vaillant et al. Chem Sci. .

Abstract

The one-step conversion of aliphatic carboxylic acids to the corresponding nitriles has been accomplished via the merger of visible light mediated photoredox and cyanobenziodoxolones (CBX) reagents. The reaction proceeded in high yields with natural and non-natural α-amino and α-oxy acids, affording a broad scope of nitriles with excellent tolerance of the substituents in the α position. The direct cyanation of dipeptides and drug precursors was also achieved. The mechanism of the decarboxylative cyanation was investigated both computationally and experimentally and compared with the previously developed alkynylation reaction. Alkynylation was found to favor direct radical addition, whereas further oxidation by CBX to a carbocation and cyanide addition appeared more favorable for cyanation. A concerted mechanism is proposed for the reaction of radicals with EBX reagents, in contrast to the usually assumed addition elimination process.

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Figures

Fig. 1
Fig. 1. Importance of aliphatic nitriles in pharmaceuticals.
Scheme 1
Scheme 1. Applications and classical methods for nitriles synthesis.
Scheme 2
Scheme 2. More efficient methods to convert carboxylic acids to nitriles.
Scheme 3
Scheme 3. Screening of cyanation reagents.
Scheme 4
Scheme 4. Scope of carboxylic acids. Reaction conditions: carboxylic acid (5, 0.30 mmol, 1.0 equiv.), CBX reagent (4a, 0.45 mmol, 1.5 equiv.), 6 (4.5 μmol, 0.015 equiv.), CsOBz (0.45 mmol, 1.5 equiv.), 4 Å molecular sieves (30 mg), THF (1.5 mL), 25–34 °C, blue LEDs irradiation for 5 to 18 h. Isolated yield after purification by column chromatography is given.
Scheme 5
Scheme 5. Sun light experiment (A), scale up (B) and synthesis of key building blocks (C).
Scheme 6
Scheme 6. Speculative mechanism for the decarboxylative cyanation and alkynylation reactions.
Scheme 7
Scheme 7. Experiments supporting the existence of a carbon centered radical intermediate II.
Fig. 2
Fig. 2. Reaction free energy profile at the [PBE0-dDsC/TZ2P//M06/def2-SVP level for the alkynylation (A) and cyanation (B) of protected proline 5a for paths b–d.
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