Organogermanes as Orthogonal Coupling Partners in Synthesis and Catalysis

Abstract

Conspectus Since the advent of metal-catalyzed cross-coupling technology more than 40 years ago, the field has grown to be ever-increasingly enabling, yet the employed coupling partners are largely still those that were originally employed in the context of Pd-catalyzed cross-coupling, namely, arylboronic esters/acids, aryl silanes, aryl stannanes, or organometallic reagents (RMgX, RZnX). Aryl germanes have little precedent in the literature; they were historically explored in the context of Pd0/PdII-catalyzed cross-coupling reactions but were found to be much less reactive than the already established reagents. Consequently, few efforts were made by the community on their further mechanistic or synthetic exploration. In 2019, our group described trialkyl aryl germanes as robust, convenient, and nontoxic reagents. Although structurally similar to trialkyl aryl stannanes or silanes, the GeEt3 site does not engage in the traditional transmetalation mode of PdII complexes. Our studies instead provided strong support for an unprecedented and orthogonal reactivity of organogermanes that follows electrophilic aromatic substitution (SEAr)-type reactivity. This mode of bond activation allowed us to devise a number of synthetic strategies in which the Ge functionality was for the first time more reactive and exclusively functionalized in preference over several of the established coupling partners (e.g., silanes, boronic acids/esters, halogens). Within the past year we have showcased the unique reactivity of organogermanes in C–C and C–X bond-forming transformations. Because of the exquisite mode of bond activation, the new strategies offer access to complementary chemical transformations, tolerating other cross-coupling enabling functionalities, and allow for their further downstream diversification. We have for instance demonstrated that organogermanes can be coupled efficiently with aryl halides under Pd nanoparticle conditions with tolerance of all other established cross-coupling partners, while under homogeneous Pd0/PdII catalysis all of the other established groups can be functionalized preferentially over the Ge functionality. We similarly were able to harness this orthogonal reactivity mode in oxidative gold catalysis, where organogermanes proved to be more reactive than the established silanes or boronic esters. We have also developed an orthogonal approach for metal-free halogenation of organogermanes with convenient halogenation agents, offering access to the chemo- and regioselective installation of valuable halide motifs in the presence of alternative groups that can also engage in electrophilic halogenations. In this Account, we wish to provide an overview of (i) the historic versus current reactivity findings and synthetic utility of organogermanes, (ii) the current state of mechanistic understanding of their reactivity, and (iii) the synthetic repertoire and ease of installing the germanium functionality in organic molecules.

Base-Mediated Direct C–H Germylation of Heteroarenes and Arenes

“…The identification of alternative cross coupling partners in synthesis and catalysis is imperative to meet existing selectivity challenges in the modular construction of molecules, expand coupling scope, and/or overcome limitations of established coupling partners in relation to their efficiency or stability. , For example, while boronic acids/esters are arguably the most popular and widely used coupling partners in the context of Pd-catalyzed cross coupling, the instability of certain heterocyclic, especially 2-pyridyl, or highly fluorinated motifs, such as pentafluoroaryl boronic acids (see Figure ), pose challenges for the construction of their derivatives, which in turn are of relevance in the medicinal, agrochemical, and materials arenas . In this context, aryl germanes have recently been identified as promising alternatives . They are nontoxic andin contrast to boronic acidsproved to be highly robust to acids and bases as the corresponding pentafluoroaryl or 2-pyridyl motifs, for example .…”

“…However, the wider impact and applicability of aryl germanes as coupling partners and enabling functionality greatly depends on the ease of accessibility of aryl germanes. In this context, traditional syntheses of aryl germanes rely largely on halogenated precursors, which are either transformed at low temperature via metal–halogen exchange to the corresponding organometallic reagents and quenched with Ge-electrophiles , or coupled under Pd catalysis to the corresponding aryl germanes, albeit with limited scope (Figure B). The direct functionalization of C–H bonds under transition-metal catalysis is limited in scope and in need of high temperature as well as a directing group. , We recently reported the formal C–H germylation of arenes and styrenes via thianthrenium and dibenzothiophenium salts as enabling intermediates (Figure ).…”

Modular Generation of (Iodinated) Polyarenes Using Triethylgermane as Orthogonal Masking Group

“…CÀ Br, CÀ Cl, CÀ OTf, CÀ B(OR) 2 , CÀ SiR 3 ) under Pdnanoparticle, [18] Au-catalysis [19] or with electrophilic halogenation [20] (Figure 1, bottom). [21] The non-toxic, [22] and easily installed GeEt 3 functionality [23] offers high stability to a range of reaction conditions including air, moisture, as well as acidic and basic media. [18] Since the [Ge]-transmetalation is associated with an unsurmountable activation barrier as well as lack of driving force on [L n Pd II (Ar)] intermediates, [18] the [GeEt 3 ] unit is unreactive in homogeneous L n Pd 0 /L n Pd II cross-couplings.…”

Co-Catalyzed E-(β)-Selective Hydrogermylation of Terminal Alkynes

“…Despite enormous success in this area, the need for more rapid, selective, advanced synthetic methodologies drives search for new coupling partners. Recently, organogermanes [1][2][3][4][5] have emerged as perspective coupling partners to circumvent limitations of traditional organozinc and organomagnesium reagents 6,7 (low functional group tolerance); organosilanes 8 (low reactivity), organostannanes [9][10][11] (acute toxicity: endocrine disruptors, immunotoxicants, carcinogens and obesogens); and organoboronic acids 12,13 (acid/base sensitivity). In this regard, vinylgermanes are of particular interest as versatile synthetic building blocks due to their low toxicity, 14 resistance to protonolysis, 15 and benchtop stability.…”