In medicinal chemistry, the chemical group known as the amide is king. Amides consist of a nitrogen atom linked to a carbonyl group (C=O), and featured in all but four of the top 40 bestselling drugs in 2018 (see go.nature.com/30f709w). Writing in Nature, Scattolin et al.1 expand the range of amides available for drug discovery by showing how to synthesize a previously inaccessible group of compounds known as N-trifluoromethylamides, in which the amide is closely associated with three fluorine atoms.

Read the paper: Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas

Amides are prevalent in medicinally important compounds not only because they are particularly stable, but also because they are polar (they contain regions of high positive and negative electrical charge density), which allows amide-containing drugs to interact with biological receptors and enzymes. In these respects, the use of amides in drugs follows nature’s example — amide groups provide the links between amino-acid residues in proteins. But drugs don’t just have to interact with biological targets; they must also resist rapid metabolic degradation in the complex environment of the human body.

One well-established way to protect molecules from such degradation involves the use of fluorine atoms. Like amides, carbon–fluorine (C–F) bonds are polar and unreactive. But, unlike amides, they are almost entirely alien to biology — which means that metabolic enzymes struggle to degrade them rapidly. This makes the incorporation of fluorine atoms an effective way to increase the metabolic stability, as well as other desirable properties, of drug compounds2.

Combining amide groups with fluorine atoms can be a particularly fruitful strategy for drug development — indeed, the bestselling drug of all time, cholesterol-reducing atorvastatin, contains both an amide and a fluorine substituent, albeit in different parts of the molecule. But the synthesis of molecules in which amides and fluorine atoms are closely associated is far from straightforward. Attempts to assemble fluorinated amides typically require reaction conditions that can cause the degradation of sensitive chemical groups in the target molecule.

Scattolin et al. describe a practical solution for the synthesis of an otherwise almost inaccessible family of fluorinated amides that contain an N-trifluoromethyl group (N–CF 3 ; Fig. 1). The authors cleverly overcome the reluctance of fluoride ions to take part in useful reactions by using a relatively reactive salt, silver fluoride, to promote bond formation between two reagents that will be familiar to organic chemists but are rarely combined. The first of these is a sulfur-containing compound called an isothiocyanate (Fig. 1) — more specifically, the compound that promotes the classical Edman degradation reaction, used in early methods for determining the amino-acid sequence of proteins. Researchers from the same group as Scattolin et al. previously used3,4 silver ions to promote the replacement of sulfur atoms by fluorine. Silver fluoride has the same role in the present work: it rips out sulfur from the Edman reagent and replaces it with three fluorine atoms, forming an intermediate compound that contains a trifluoromethyl (CF 3 ) group.

Figure 1 | The synthesis of N-trifluoromethylamide compounds. N-trifluoromethylamides contain a trifluoromethyl group (red) attached to an amide group (blue), and have been almost impossible to make. R1 and R2 represent any chemical group. Scattolin et al.1 report a practical synthesis of these compounds, which are of interest for drug discovery. The authors treated an isothiocyanate with silver fluoride (AgF), producing an intermediate compound in which a trifluoromethyl group is attached to a nitrogen atom. This intermediate reacts with bis(trichloromethyl) carbonate (CO(OCCl 3 ) 2 ) in the presence of silver fluoride to make a carbamoyl fluoride. Treating this compound with magnesium-containing reagents known as Grignard reagents (R2MgX, where X is a halogen atom) produces N-trifluoromethylamides. Side products of the reactions are not shown.

The second reagent is bis(trichloromethyl) carbonate (Fig. 1), which is often used to make amides and amide-like derivatives5. The authors report that, when used in combination with silver fluoride, this carbonate traps the typically highly unreactive CF 3 -containing intermediate to form a compound called a carbamoyl fluoride. It is this compound that forms the conceptual breakthrough of Scattolin and colleagues’ work.

The carbamoyl fluoride already contains the carbon–nitrogen bond of the target amide, thereby sidestepping the usual difficulties associated with making fluorinated amides. Moreover, it is stable enough to be isolated, but reactive enough to act as a building block for the synthesis of a range of N-trifluoromethylamides — which Scattolin et al. prepare by reacting the carbamoyl fluoride with various magnesium-containing compounds known as Grignard reagents (Fig. 1). The authors show that chemical groups called ureas and carbamates can also be made in this final step, widening the applicability of the chemistry beyond fluorinated amides.

In this work, Scattolin and colleagues have impressively choreographed the reactions of several seemingly incompatible, highly reactive reagents, perfectly controlling which meets which, and when. The authors demonstrate that their method can be used to make not only simple N-trifluoromethylamide molecules, but also chemically sensitive ones such as those based on amino acids, drug scaffolds and the monomers used to make polymeric materials.

A radical approach to diversity

The reported reactions will enable medicinal chemists to prepare previously unavailable compounds for testing in drug-discovery programmes — some of these compounds might well display new biological activities. The addition of a methyl group to the nitrogen atom of an amide in drug candidates has long been used to alter the conformations adopted by those molecules6, thereby altering their biological activities; the ability to make N-trifluoromethylamides will broaden the scope of that strategy.

There are, however, drawbacks to the new chemistry that will need to be addressed before it can be used on the industrial scales needed to manufacture a drug. The main issue is that the reactions require substantial quantities of the necessary reagents: every fluorine atom introduced into a molecule, plus two more that are expelled during the reaction, is accompanied by an atom of silver, meaning that five atoms of silver are needed for every molecule of product. This is acceptable for the initial stages of drug discovery (lead development and optimization), which typically involve only milligram to gram quantities of drug candidates. However, it would not be sustainable for synthesizing compounds on the kilogram scales needed for testing in clinical trials, let alone for industrial manufacturing processes, because of the cost and large amount of waste produced. Another breakthrough will be needed to find a way of synthesizing N-trifluoromethylamides sustainably on such large scales.

Looking beyond medicinal chemistry, Scattolin and co-workers’ findings reveal that isothiocyanate groups can act as precursors of trifluoromethyl groups bonded to nitrogen atoms. Their reactions might find much wider use in chemical synthesis, where the ability to make trifluoromethyl-substituted nitrogen compounds could facilitate the design and synthesis of catalysts or materials with new properties.