Journal Article

Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization

Hartwig, John F., Sharma, Ankit

2015

Overview

Most currently used catalysts for the amination of C–H bonds are ill suited to the functionalization of complex molecules; here it is shown that a mild, selective, iron-catalysed azidation of tertiary C–H bonds is suitable for the amination of complex molecules containing a range of functional groups. Convenient C–H amination in complex molecules Synthetic chemists are keen to identify catalysts that directly convert C–H bonds to C–N bonds. Natural enzymes are not available for this amination reaction and most currently used chemical catalysts are ill-suited for the functionalization of complex molecules. In this manuscript, the authors report an iron catalysed, highly selective azidation of tertiary C–H bonds under conditions with substrate as the limiting reagent. The reaction tolerates aqueous environments and is suitable for 'late-stage' functionalization of complex structures, as demonstrated by the azidation of tetrahydrogibberellic acid, a complex and medicinally relevant molecule. Many enzymes oxidize unactivated aliphatic C–H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C–H bonds 1 , 2 . The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the –N(Me)CH 2 – group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time 3 , 4 . For such reasons, synthetic chemists have sought catalysts that directly convert C–H bonds to C–N bonds. Most currently used catalysts for C–H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C–H bonds, or reagents containing specialized groups on the nitrogen atom 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Among C–H bond amination reactions, those forming a C–N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation 15 . Here we report a mild, selective, iron-catalysed azidation of tertiary C–H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen ‘click’ cycloadditions and the Staudinger ligation 16 , 17 , 18 , 19 . We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment—for example, to fluorescent tags or ‘handles’ for affinity chromatography—directly on complex molecular structures.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 639/638/403 / 639/638/77 / Amination / Azides - chemistry / Biochemistry / Carbon / Carbon - chemistry / Catalysis / Chemical bonds / Chemical research / Chemical tests and reagents / Electrons / Humanities and Social Sciences / Hydrogen / Hydrogen - chemistry / Indicators and Reagents - chemistry / Iron - chemistry / Ketones / letter / Mass spectrometry / multidisciplinary / Nitrogen / Nitrogen - chemistry / Reagents / Science / Structure