The Germanes Have It

A couple of weeks ago I attended the 20th annual Bristol Synthesis Meeting at the Victoria rooms in Bristol, UK.1 Always an excellent event, and this one was no exception. I was intrigued by a presentation given by Franziska Schoenebeck from the University of Aachen, Germany on the application of organogermanes in cross coupling chemistry. I’ve always been interested in use of the more esoteric chemical elements in organic synthesis, the reason I guess why the talk was particularly interesting to me. Germanium, as the name implies, was discovered in Freiberg, Germany in 1886 by Clemens Winkler.2 Franziska’s research really is going back to the elemental grass roots as it were.3,5

Trialky aryl germanes don’t appear very frequently in the synthetic literature, particularly in the area of Pd catalysed cross coupling chemistry. They are much less reactive than aryl boronic acid/esters, aryl silanes and their insidious cousins the aryl stannanes,4 and do not engage in traditional transmetallation with Pd(II) complexes.5  Computational studies have shown that concerted transmetallation (generating LPdII(Ar)(X)) is highly disfavoured, with no thermodynamic driving force for this process. In fact, electrophilic activation is preferred energetically- but the bar is very high.5

In short, they don’t do anything – even with very active ligated Pd catalysts. This might be considered by many to be somewhat limiting, however the Schoenebeck group have leveraged this apparent reticence and developed orthogonal coupling strategies by exploiting a different mechanism of activation. What this also means is that differential reactivity over established C-C coupling methodology using aryl halides, boronates and silanes is possible and presents an opportunity for diversification.  Reaction of Pd2dba3 with stochiometric AgBF4 enables coupling of ArGeEt3 with aryl iodides (and not chlorides, bromides or triflates) through generation of Pd nanoparticles and electrophilic substitution rather than oxidative addition (Figure 1).6

 

Figure 1: Pd nanoparticle generation and electrophilic activation

Subsequent papers by the Schoenebeck group describe selective light-activated gold catalysed arylation of aryl germanes using electron rich aryl diazonium salts (Figure 2, 10 mol% [(PPh3)AuCl], blue LED, MeCN, rt). Orthogonal activation of the various substituents on the substate aryl ring can be used to build fairly complex biaryl systems, the germanium system remaining resistant to standard cross coupling conditions and only activated using the photo-activated gold catalyst  (Figure 2).7

Figure 2: Orthogonal activation of substituted aryl germanes

Gold-catalysed C-H arylation of electron poor substrates has also been described but remains somewhat limited.8a Gold chemistry seems to be something of a recurring theme: gold catalyzed C−H functionalization of polyfluoroarenes with aryl germanes has been used to prepare polyfluorinated biaryls- key building blocks for advanced materials including organic light emitting diodes (OLED’s).8b Obviously plenty of money to be had at Aachen…

The Schoenebeck group have also published a method for chemoselective Csp3 alkylation of alkyl germanes under photoredox conditions (Giese-type additions).9

A perceived limitation of the chemistry is synthetic access to the required stable, non-toxic germane substrates. The Schoenebeck have developed a simple approach to these intermediates via C-H functionalisation of aryl sulphonium salts (thianthrenium)10a with triethylgermaine (Et3Ge-H) and an iodine-bridged Pd(I) dimeric complex (Figure 3).10b An alternative approach via direct C-H germylation of arenes and heteroarenes using lithium tetramethylpiperidine (LiTMP) and Et3GeCl at room temperature has also been developed (Figure 3).10c

Figure 3: Pd-catalyzed germylation of aryl tetrafluorothianthrenium salts and base-mediated coupling

Aryl germaines have been used for the selective introduction of iodine and bromine via concerted electrophilic aromatic substitution at germanium.11 N-Iodo or N-Bromo-succinimides are used as halogen sources (2 eqv. X+, DMF, rt). Mechanistically the germanium is halogenated in a concerted SEAr electrophilic aromatic substitution process (Figure 4). Unlike ArSnBu3, which reacts rapidly and smoothly with selectfluor, the trialkylgermaine group was stable to nucleophilic and electrophilic fluorinating agents, giving another point of orthogonality in aryl halogenation. The former is used for late-stage F18 incorporation.12

Figure 4: ArGeE3 halogenation

Adding another string to the bow, the team at Aachen have just published an orthogonal C-O coupling of aryl germanes with alcohols to generate aryl ethers (Figure 5).13a One of the reasons this is notable and will be popular is that 17% of the 200 top-selling drugs in 2021 contain an aryl ether linkage- particularly methoxy. Examples include Tramadol and venlafaxine.

The reaction uses Pd(OAc2) and is driven by formation of high-valency Pd complexes generating an electron deficient metal centre to activate the germanium. As I mentioned above computational analysis of oxidative addition of arylgermanes to Pd show it to be an endergonic process. On the other hand ligand-free Pd salts present a driving force for arylation (calculated activation energy:-15.2 kcal/mol, exergonic). To this end reaction of ArGeEt3 with electrophilic Pd(TFA)2 (formed from the acetate by salt exchange) followed by oxidation of [ArPdII] with a hypervalent iodine reagent PhI(TFA)2 works a treat. In the presence of an alcohol (ROH) the PhI(OR)2 iodane is generated (releasing TFA) and the aryl ether is formed (Figure 6). Primary, secondary and tertiary alkyl alcohols as well as carboxylic acids could successfully coupled with C−GeEt3 with Pd loadings of 1-0.1 mol%. 5 equivalents of alcohol were required. The reaction was shown to have similar orthogonality potential to that described above.

Figure 5: Ge selective orthogonal C-O bond formation

 

Figure 6: mechanism for ArOR formation

The germanium atoms in the process end up as germanium trifluoroacetate. In one experiment described in the paper’s supplementary information addition of a Grignard reagent to the crude reaction mixture generated a modest yield of ArGeEt3 (p-FPhMgBr, 40% yield) suggesting a recovery option.13b A room temperature conversion without the forcing conditions usually required for an Ullman-type coupling is great. A traditional copper (I) catalyzed coupling using a 3,4,7,8-tetramethyl-1,10-phenanthroline ligand and an aryl halide, a process developed by Buchwald et al, requires prolonged heating at high temperature. It does, however, require less alcohol substrate (typically 1.5 eqv).13c

To finish I thought I’d add an interesting fact about germanium. It was the first element used in transistors.2Apparently it has the ability to conduct electrical current in one direction only. In 1942, when development work was initiated, there was one problem- the germanium supply. The Germans had it. So, the US government were forced to develop an extraction process using waste generated from zinc smelting in Oklahoma. By 1948 the first transistor radios, containing germanium, were on sale to the public.

I think you’ll agree- some interesting chemistry with an unusual element.

See you next time.

References:

  1. Bristol Synthesis meeting 2023
  2. John Emsley, Nature’s Building Blocks: An A-Z Guide to the Elements, Oxford University Press, New York, 2nd Edition, 2011, p197-201
  3. Schoenebeck research group: publications
  4. The Stille reaction 38 years later: P. Espinet et al, ACS Catal.2015, 5, 3040–3053
  5. Organogermanes as orthogonal coupling partners in synthesis and catalysis: F. Schoenebeck et al, Acc. Chem. Res. 2020, 53, 2715−2725
  6. Orthogonal Nanoparticle catalysis with organogermanes: F. Schoenebeck et al, Angew. Chem. Int. Ed.2019, 58, 17788-17795
  7. Modular and selective arylation of aryl germanes (C-GeEt3) over C-Bpin, C-SiR3 and halogens enabled by light-activated gold catalysis: F. Schoenebeck et al, Angew. Chem. Int. Ed. 2020, 59, 15543-15548
  8. Gold-catalyzed C-H functionalization with aryl germanes: F. Schoenebeck et al, Catal. 2019, 9, 9231-9236; b) Gold-catalysed chemoselective couplings of polyfluoroarenes with aryl germanes and downstream diversification: F. Schoenebeck et al, J. Am. Chem. Soc. 2020, 142, 7754-7759
  9. Modularity in the Csp3 space- aryl germanes as orthogonal molecular handles for chemoselective diversification: F. Schoenebeck et al ACS. Catal. 2022, 12, 4833-4839
  10. a) General blog review of Thianthrene-https://www.scientificupdate.com/process-chemistry-articles/thianthrenium-is-back-and-this-time-its-vinyl/b) Germylation of arenes via Pd(I) dimer enabled sulfonium salt functionalization: F. Schoenebeck et al, Org. Lett. 2020, 22, 4802-4805; c) Base-mediated direct C-H germylation of heteroarenes and arenes: F. Schoenebeck et al, Org. Lett 2021, 23, 6010-6013
  11. Orthogonal stability and reactivity of aryl germanes enables rapid and selective (multi)halogenations: F. Schoenebeck et al, Angew. Chem. Int. Ed. 2020, 59, 18717-18722
  12. Silver-mediated fluorination of functionalized aryl stannanes: T. Ritter et al, J. Am. Chem. Soc. 2009, 131, 1662-1663
  13. a) Orthogonal C-O bond construction with organogermanes: F. Schoenebeck et al, Am. Chem. Soc. 2023, 145, 7729-7735; b) Supplementary information, p52, https://pubs.acs.org/doi/10.1021/jacs.3c01081?goto=supporting-info; c) An improved Cu-based catalyst system for the reaction of alcohols with aryl halides: S. Buchwald et al, J. Org. Chem. 2008, 73, 284-286