Cyanuric Fluoride

[675-14-9]  · C3F3N3  · (135.05)

(reagent used for conversion of carboxylic acids to acid fluorides; deoxygenation of alkyl sulfoxides; and activation of alkenyl boronic acids for 1,4-addition reactions)

Alternate Name: 2,4,6-trifluoro-1,3,5-triazine, cyanuryl fluoride.

Physical Data: mp -38°C; bp 72-74°C; d 1.574 g mL-1.

Form Supplied in: colorless liquid.

Purification: the commercial reagent is generally used as received.

Handling, Storage, and Precautions: highly toxic; very toxic by inhalation, in contact with skin, and if swallowed. Causes burns. Readily absorbed through the skin. Lachrymator. In case of accident or if you feel ill, seek medical advice immediately (show the label when possible). In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. Do not breath vapor. Wear suitable protective clothing, gloves, and face/eye protection. Refrigerate. Moisture sensitive; keep container tightly closed. Disposal: dissolve or mix with a combustible solvent and incinerate.

Acid Fluoride Synthesis

Cyanuric fluoride first appeared as a reagent for the mild and direct conversion of carboxylic acids into acid fluorides. This method represented a significant advancement for the preparation of acid fluorides.1 Previously reported methods include treatment of acid chlorides with potassium fluoride,2 potassium hydrogen fluoride,3 or potassium fluorosulfinate.4 Acid fluorides were also prepared from carboxylic acids using sulfur tetrafluoride,5 diethyl(2-chloro-1,1,2-trifluoroethyl)amine,6 thionyl fluoride,7 benzoyl fluoride,8 and selenium tetrafluoride.9 These methods are less direct and are often incompatible with other functional groups in the substrate.

In a typical procedure,1 a solution of 0.4 equiv of cyanuric fluoride in acetonitrile is added to a mixture of 1.0 equiv each of a carboxylic acid and pyridine in acetonitrile at room temperature. After being stirred for 1 h, the reaction is subjected to a standard aqueous work-up which then provides the desired acid fluoride in generally high yields for a variety of carboxylic acid starting materials (eq 1). Each mole equivalent of cyanuric fluoride reacts to give three moles of acyl fluoride.

The ability to prepare acid fluorides under these mild conditions opened up a number of synthetic applications. Perhaps the most significant application to date is the increased use of acid fluorides as activated intermediates in peptide bond formation.10,11 The use of Fmoc amino acid chlorides as activated N-protected peptide building blocks has been limited by the propensity of t-butyl ester- or ether-protected side chains (e.g. serine, threonine, glutamate, aspartate) to cyclize onto the acid chloride with the loss of t-butyl chloride. Carpino et al. have shown that the corresponding amino acid fluorides are not subject to this same side reaction.10 The general reactivity pattern for acid fluorides compared with acid chlorides is that they are less sensitive to uncharged oxygen nucleophiles such as water or methanol but display similar reactivity to charged or nitrogen nucleophiles. The Fmoc amino acid fluorides were prepared from the corresponding Fmoc amino acids under similar conditions to those described above and were isolated as white crystalline solids. A number of the exemplified amino acids contained protected acid and amide side chains (eq 2 and 3).

Acid fluorides have the additional advantage that they are more reactive in peptide coupling reactions of hindered amino acid derivatives. This is due at least in part to the small size of the fluoride leaving group.12 Hindered acid fluorides like Fmoc-Aib-F can be prepared in the usual way with cyanuric fluoride.

Reduction of Acids to Alcohols

The mild conditions required for the conversion of carboxylic acids to acid fluorides has resulted in a method for the reduction of carboxylic acids to alcohols by way of the acid fluorides.13 A variety of carboxylic acids were converted to acid fluorides under standard conditions. A quick aqueous work-up was followed by NaBH4 reduction (eq 4). This mild reaction sequence has the distinct advantage over NaBH4-I2 in that it is compatible with N-protected amino acids. The resulting alcohols are obtained in generally high yields with no observable loss in enantiomeric purity.

Other Uses

A recent use for cyanuric fluoride is the activation of alkenyl boronic acids for the 1,4 addition of a,b-unsaturated ketones.14,15 Hara et al. have shown that alkenyl boronic acids when treated with cyanuric fluoride undergo 1,4 addition to unsaturated ketones.14 Presumably, this reaction takes place via the alkenyl fluoro alkoxy borane intermediate followed by coordination of the carbonyl oxygen to the boron and intramolecular carbon-carbon bond formation (eq 5). Selective 1,4 additions to a,b,a,b-unsaturated ketones could be achieved by introducing substituents on one of the double bonds (eq 6).15

Cyanuric fluoride has also been used as a reagent for the selective deoxygenation of sulfoxides (eq 7 and 8).16 Stirring the sulfoxide with cyanuric fluoride in dioxane followed by aqueous work-up gave good yields of the corresponding sulfides.

Finally, cyanuric fluoride has been used in solid-phase synthesis as a method for activating a carboxylic acid functionality on solid support for loading a nucleophile onto a resin.17,18 For example, in 1998 Böhm et al. demonstrated carboxypolystyrene activation as the acyl fluoride followed by resin loading with a primary amine linker (eq 9).17 In 1999, Sams et al. employed a similar method to activate substituted benzoic acids loaded onto Wang resin with N-methylmorpholine (NMM) in dichloromethane. The resulting acyl fluorides were coupled with derivatives of N-hydroxyamidine in the presence of N-methylmorpholine (eq 10).18

1. Olah, G. A.; Nojima, M.; Kerekes, I., Synthesis 1973, 487.
2. Pittman, A. G.; Sharp, D. L., J. Org. Chem. 1966, 31, 2316.
3. Olah, G. A.; Kuhn, S.; Beke, S., Chem. Ber. 1956, 89, 862.
4. Seel, F.; Lange, J., Chem. Ber. 1958, 91, 2553.
5. Hasek, W. R.; Smith, W. C.; Engelhardt, V. A., J. Am. Chem. Soc. 1960, 82, 543.
6. Yarovenko, N. N.; Radsha, M. A., J. Gen. Chem. USSR (Engl. Transl.) 1959, 29, 2125.
7. Roberts, H. L., British Patent 908177 (1963) (Chem. Abstr. 1963, 58, 5579.)
8. Olah, G. A.; Kuhn, S. J., Org. Synth. 1965, 45, 3.
9. Olah, G. A.; Nojima, M.; Kerekes, I., J. Am. Chem. Soc. 1974, 96, 925.
10. Carpino, L. A.; Sadat-Aalaee, D.; Chao, H. G.; DeSelms, R. H.; J. Am. Chem. Soc. 1990, 112, 9651.
11. Carpino, L. A.; Beyermann, M.; Wenschuh, H.; Bienert, M., Acc. Chem. Res. 1996, 29, 268.
12. Wenschuh, H.; Beyermann, M.; Krause, E.; Brudel, M.; Winter, R.; Schümann, M.; Carpino, L. A.; Bienert, M., J. Org. Chem. 1994, 59, 3275.
13. Kokotos, G.; Noula, C., J. Org. Chem. 1996, 61, 6994.
14. Hara, S.; Shudoh, H.; Ishimura, S.; Suzuki, A., Bull. Chem. Soc. Jpn. 1998, 71, 2403.
15. Hara, S.; Ishimura, S.; Suzuki, A., Synlett 1996, 993.
16. Olah, G. A.; Fung, A. P.; Gupta, B. G. B.; Narang, S. C., Synthesis 1980, 221.
17. Böhm, G.; Dowden, J.; Rice, D. C.; Burgess, I.; Pilard, J.-F.; Guilbert, B.; Haxton, A.; Hunter, R. C.; Turner, N. J.; Flitsch, S. L., Tetrahedron Lett. 1998, 39, 3819.
18. Sams, C. K.; Lau, J., Tetrahedron Lett. 1999, 40, 9359.

David A. IN, Barda

Eli Lilly and Company, Indianapolis, IN, USA

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