In the previous chapters, a key strategy to selectively activate the C–H bond is presented by employing a Lewis-basic directing group, which brings the metal catalyst in close proximity to the target. While this concept has obvious benefits which justify its raison d'être, the auxiliary often needs to be present within the molecule or additional reaction steps are required to install or modify existing functional groups to meet this purpose. In addition, this prerequisite inherently limits the valuable approach for the activation of only selected C–H bonds. In contrast, to functionalize C–H bonds distant to the directing group or to transform unactivated aliphatic hydrocarbons without any Lewis-basic functional groups at all, chemists have developed innovative concepts that can be classified as undirected C–H functionalization.[23g, 25c, 166] Among others,[167] hydrogen atom abstraction via homolytic bond cleavage has proven to be particularly powerful within this context.[24,
168] Generally, these free radical pathways include photochemical irradiation,[169]
electrochemistry[170] or highly oxidizing chemical intermediates.[171] However, controlling the site- and chemoselectivity in intermolecular alkane functionalizations remains a key challenge and is commonly dictated by the inherent electronic properties or steric environment of the C–H bond. To overcome these limitations, transition-metal catalysis has become prevalent within the last decades to significantly improve the selectivity and efficiency of C–H functionalizations. In this context, biological systems have evolved powerful enzymes that are capable of selective C–H functionalizations for inter alia C–H oxygenations[172] or C–H halogenations.[173] Inspired by this toolbox,[174] scientist have put large efforts in the development of biomimetic metal-catalyzed C–H transformations to achieve oxidation and group transfer reactions in a more controlled fashion.[24a-d, 24f, 166d, 170d, 175]
1.2.1 Undirected C(sp3)–H Azidation
Organic azides[176] have been recognized as key structural motifs in numerous molecules of interest to medicinal chemistry,[177] material sciences,[178] peptide chemistry or molecular biology.[179] Due to the vast utility of azide-containing molecules,[180] a plethora of functional group interconversion strategies have been developed, exploiting organic halides, alcohols or epoxides, among others.[176e, 181] However, more step-economical methods that directly install the azido-group into otherwise inert C(sp3)–H bonds continue to be scarce.[182]
In 1992, Magnus disclosed a pioneering study on metal-free C(sp3)–H azidation in the β-position of enol ethers to afford 112, with the aid of potentially explosive hypervalent iodine reagents and TMSN3 as the azide source (Scheme 33a).[183] Based on this reagent combination, the substrate scope was later extended to the azidation of other functional groups such as carbamates and ureas,[184] among others.[185] Encouraged by these findings, notable contributions for metal-free C–H azidations of aliphatic substrates 111 with the aid of stoichiometric amounts of hypervalent iodine reagents were independently reported by Kita,[186] Zhdankin[187] and Bols.[188] More recently, Tang devised a metal-free C–H azidation of unactivated hydrocarbons 111 with K2S2O8 as a strong oxidant and sulfonyl azide 115 as the electrophilic azide source, to deliver the desired azidation products 113 (Scheme 33b).[189] In 2016, Chen disclosed photoredox-catalyzed C(sp3)–H azidations of tertiary C–H bonds under visible-light irradiation using the Zhdankin reagent[187a] 116 as the azide source (Scheme 33c).[190] Likewise, photocatalytic azidations of benzylic C–H bonds were subsequently reported by Greaney[191] and Kamijo.[192]
Scheme 33. Metal-free and photoredox-catalyzed C(sp3)–H azidation.
A general approach for the photocatalytic azidation of unactivated C–H bonds was later devised by Alexanian and Nicewicz (Scheme 33d).[169b] The method encompassed an essential phosphate salt, sulfonyl azide 117 and an acridinium photoredox catalyst 118,
powered by blue LED irradiation. Moreover, the reaction conditions allowed for a broad substrate scope, including unactivated cyclic hydrocarbons. In the case of unsymmetrical, acyclic hydrocarbons, C–H azidation occurred at the inherently more electron-rich C–H bond with moderate regioselectivities. Detailed Stern-Volmer plot analysis was suggestive of a SET process from the phosphate salt to the photoexcited catalyst 118*, thus generating an oxygen-centered radical. Next, the highly oxidizing radical abstracts the most electron-rich C–H bond from substrate 111, producing a carbon-centered radical, which upon trapping by the sulfonyl azide transfer reagent 117 affords the desired organic azides 113.
In spite of these notable contributions, the site-selectivity of metal-free H atom abstractors such as alkoxyl, iodanyl[193] or sulfate radicals are inherently limited to the innate reactivity of the substrate. These radicals are typically highly electrophilic and therefore abstract the most electron-rich, less polarized, and weakest C–H bonds in terms of bond dissociation energy.[15, 194] In contrast, a specifically designed metal catalyst can bypass these restrictions and thereby significantly enhance the reactivity profile for aliphatic C–H functionalizations.[182d]
In 2014, Bollinger employed a modified iron-dependent wild-type halogenase SyrB2 for the direct azidation of aliphatic C–H bonds.[175h] In this proof-of-concept study, a high-valent iron(IV)-oxo active center abstracted the C4-hydrogen from L-threonine, followed by azidation via a radical-rebound mechanism. However, this approach was limited to the functionalization of substrates that were directly bonded to the carrier protein. Although early attempts to develop biomimetic iron- or manganese-catalyzed C–H azidations of unactivated C(sp3)–H bonds date back to 1983, these approaches suffered from low efficiency and large excesses of chemical oxidants.[195] In contrast, from 2010 onwards, Groves developed a series of highly efficient manganese-catalyzed C–H halogenations[196]
that showed reactivity beyond typical hydroxylation of the previously used manganese porphyrin complexes.[197] Inspired by these findings, the same group elegantly devised an efficient and selective manganese-catalyzed C–H azidation of aliphatic hydrocarbons 111 with user-friendly NaN3 as the azide source, and a biphasic solvent mixture (Scheme 34).[198] The manganese catalysis was characterized by low catalyst loadings of 1.5–
5 mol %, high functional group tolerance and efficient transformation of activated, as well as unactivated hydrocarbons 111 to the corresponding organic azides 113. The synthetic utility of the approach was highlighted by late-stage diversification[199] of bioactive and pharmaceutically-relevant compounds.
Scheme 34. Manganese-catalyzed aliphatic C–H azidation. [a] Azide 113 to oxygenated 125 product ratios: 2–4:1. [b] Yield was determined relative to starting material by GC-MS.
Moreover, based on previous reports and mechanistic studies by experiment and DFT-calculations, the authors proposed a catalytic cycle of the manganese-catalyzed C–H azidation (Scheme 34b). Initially, PhIO-mediated oxidation of the manganese(III) complex 119 generates the manganese(IV)-oxo complex 120. The highly oxidizing species 120 now undergoes hydrogen atom transfer (HAT) with substrate 111 to afford the carbon-centered radical 121 and a manganese(IV) species 122. Finally, azide transfer takes place between an azidomanganese(IV) complex 123 and radical 121 via a heteroatom rebound mechanism, thus forming the desired C–N3 product 113. Despite the broad synthetic
applicability of the method, a major drawback is the use of super-stoichiometric amounts of hypervalent iodine reagents[200] and the relatively poor levels of chemoselectivity.
Concurrently, Hartwig reported iron-catalyzed C–H azidations of aliphatic substrates 111 with a chiral iron PyBOX catalyst and the Zhdankin azidation reagent 116 (Scheme 35).[201]
The mild reaction conditions enabled broad functional group tolerance and the strategy was later also applied to the late-stage diversification of drugs and other complex organic molecules.[202] However, in contrast to Groves’ report, iron-catalyzed C–H azidations were limited to the functionalization of tertiary and benzylic C–H bonds.
Scheme 35. Iron-catalyzed C–H azidation of tertiary and benzylic C–H bonds.
Although detailed mechanistic studies were not conducted, the authors proposed that the reaction proceeds through a radical pathway, since radical traps such as BHT or TEMPO completely inhibited the catalysis. Moreover, kinetic studies with deuterated ethylbenzene-d10 and the non-deuterated compound revealed a large KIE of 5.0. Based on the obtained diastereomeric excess for some azidated products 113 and the relatively mild reaction conditions when comparing to Zhdankin’s report,[187a] Hartwig proposed a key catalyst-mediated azide-transfer step. With these observations in hand, the hydrogen abstraction likely proceeds by oxo-radical 127, followed by azidoiron(III)-catalyzed azide transfer to afford the azidated products 113.
In addition to these notable contributions, other metal-catalyzed C(sp3)–H azidations were reported, which however were limited to activated C–H bonds such as benzylic,[203]
allylic[204] or acidic β-keto ester substrates.[205]