Orthogonal Stability and Reactivity of Aryl Germanes Enables Rapid and Selective (Multi)Halogenations

Abstract While halogenation is of key importance in synthesis and radioimaging, the currently available repertoire is largely designed to introduce a single halogen per molecule. This report makes the selective introduction of several different halogens accessible. Showcased here is the privileged stability of nontoxic aryl germanes under harsh fluorination conditions (that allow selective fluorination in their presence), while displaying superior reactivity and functional‐group tolerance in electrophilic iodinations and brominations, outcompeting silanes or boronic esters under rapid and additive‐free conditions. Mechanistic experiments and computational studies suggest a concerted electrophilic aromatic substitution as the underlying mechanism.


Iodination General Procedure 2 (GP 2)
Aryl germane (1.0 equiv.) and N-iodosuccinimide (NIS; 1.0 equiv.) were added to the reaction vial in air, dissolved in DMF (0.3 M) and stirred at room temperature or at 50 °C for 4 h. After completion of reaction (monitored by GC-MS or TLC), the reaction was quenched by addition of aqueous solution of Na2S2O3 (sat.), the organic phase was separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried with MgSO4, the solvent was removed under reduced pressure and the crude product mixture was purified over silica column chromatography. Some of the iodinated compounds are not isolable due to their high volatility.
An 1 H NMR (quant.) or 19 F NMR (quant.) yield is given in those cases and the further analysis was performed using the crude reaction mixture.

1-Iodo-4-methylbenzene
Prepared according to GP 2 at room temperature. The yield was determined by quantitative 1 H NMR (96%). Due to its high volatility, the title compound was not isolated.

5-Iodo-1,2,3-trimethoxybenzene
Prepared according to GP 2 at room temperature. The title product was obtained after purification by column chromatography (n-pentane/Et2O, 5:1) as a white These data are in agreement with those reported previously in the literature. [9] 1-Iodonaphthalene Prepared according to GP 2 at room temperature. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (77. 4  These data are in agreement with those reported previously in the literature. [10] 1-Iodo-4-methoxybenzene These data are in agreement with those reported previously in the literature. [6] 1-Iodo-2-methoxybenzene Prepared according to GP 2 at room temperature. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (66.2 mg, 0.283 mmol, 94%). These data are in agreement with those reported previously in the literature. [3]

S13
These data are in agreement with those reported previously in the literature. [11] 1-Iodo-4-chlorobenzene These data are in agreement with those reported previously in the literature. [11] 1-Iodo-4-fluorobenzene Due to its high volatility, the title compound was not isolated.

4-Iodo-3,5-dimethylisoxazole
Prepared according to GP 2 at 50 °C; reaction time 24 h. The yield was determined by quantitative 1 H NMR (97%). Due to its high volatility, the title compound was not isolated. The resolution of the NMR made it impossible to assign the correct 13 C NMR shifts.

3-Iodobenzo[b]thiophene
Prepared according to GP 2 at room temperature. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (70. 8  These data are in agreement with those reported previously in the literature. [10] 1 C atom missing in the 13 C NMR. This is in line with literature reports.

2-Iodothiophene
Prepared according to GP 2 at room temperature. The yield was determined by quantitative 1 H NMR (97%). Due to its high volatility, the title compound was not isolated.

3-Iodothiophene
Prepared according to GP 2 at room temperature. The yield was determined by quantitative 1 H NMR (97%). Due to its high volatility, the title compound was not isolated.

Synthesis of Aryl Germanes General Procedure 3 (GP 3)
Triethylgermanium chloride (1.05 equiv.) and the corresponding aryl iodide or aryl bromide (1.0 equiv.) were dissolved in anhydrous and degassed THF (0.2 M) under argon, iPrMgCl (1.2 M in THF; 1.2 equiv.) was added slowly and the reaction was stirred for 3 h at room temperature (ArI) or for 12 h at 60 °C (ArBr). The reaction was quenched by addition of aqueous solution of NH4Cl (sat.), the organic phase was separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over MgSO4, the solvent was removed under reduced pressure and the crude product mixture was purified by silica column chromatography.

General Procedure 4 (GP 4)
Triethylgermanium chloride (1.0 equiv.) and the corresponding aryl Grignard reagent (1.1 equiv.) were dissolved in anhydrous and degassed THF (0.2 M) under argon and stirred for 3 h at room temperature. The reaction was quenched by addition of aqueous solution of NH4Cl (sat.), the organic phase was separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over MgSO4, the solvent was removed under reduced pressure and the crude product mixture was purified by silica column chromatography.

Note:
Our group meanwhile developed a formal C-H germylation strategy. Synthesis from prefunctionalized arenes (as followed herein) is hence not strictly necessary.

Triethyl(phenyl)germane
Prepared according to GP 2. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (629 mg, 2.65 mmol, 89%). These data are in agreement with those reported previously in the literature. [12] Triethyl(4-fluorophenyl)germane Prepared according to GP 4. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (732 mg, 2.87 mmol, 96%). These data are in agreement with those reported previously in the literature. [12] Triethyl(4-methoxyphenyl)germane Prepared according to GP 4. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (785 mg, 2.94 mmol, 98%). These data are in agreement with those reported previously in the literature. [12] Triethyl(thiophen-2-yl)germane Prepared according to GP 4. The title product was obtained after purification by column chromatography (n-hexane/EtOAc, 5:1) as a colorless oil (589 mg, 2.43 mmol, 81%). These data are in agreement with those reported previously in the literature. [12] Triethyl(4-iodophenyl)germane These data are in agreement with those reported previously in the literature. [13] Triethyl(4-bromophenyl)germane Prepared according to GP 3. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (820 mg, 2.61 mmol, 87%). These data are in agreement with those reported previously in the literature. [13]

Triethyl(4-chlorophenyl)germane
Prepared according to GP 3. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (797 mg, 2.94 mmol, 98%). These data are in agreement with those reported previously in the literature. [13] Triethyl(2-methoxyphenyl)germane Prepared according to GP 3. The title product was obtained after purification by column chromatography (n-pentane) as a colorless oil (689 mg, 2.58 mmol, 86%). These data are in agreement with those reported previously in the literature. [14] Triethyl(mesityl)germane

Trimethyl(4-(triethylgermyl)phenyl)silane
Triethyl(4-iodophenyl)germane (1.09 g, 3.0 mmol, 1.0 equiv.) was added to a round bottom flask and dissolved in anhydrous and degassed THF (20 mL) under argon. iPrMgCl (2.0 M in THF, 1.8 mL, 3.6 mmol, 1.2 equiv.) was added dropwise at 0 °C and the reaction was stirred for 30 min. Tetramethyl orthosilicate (899 μL, 6.0 mmol, 2.0 equiv.) was added and the mixture was stirred at room temperature for 12 h. The reaction was quenched by addition of aqueous solution of NH4Cl (sat.), the organic phase was separated and the aqueous phase was extracted with DCM (3x20 mL). The combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. The title product was obtained after purification by column chromatography (n-hexane) as a colorless oil (576 mg, 1.86 mmol, 62%). These data are in agreement with those reported previously in the literature. [12] Triethyl(4-(tributylstannyl)phenyl)germane Triethyl(4-iodophenyl)germane (276 mg, 0.76 mmol, 1.0 equiv.) was added to a round bottom flask and dissolved in anhydrous and degassed THF (3 mL) under argon. nBuLi (2.5 M in toluene, 0.46 mL, 1.14 mmol, 1.5 equiv.) was added dropwise at -78 °C and the reaction was stirred for 30 min. Tributyltin chloride (227 μL, 0.836 mmol, 1.1 equiv.) was added and the mixture was stirred while warming to room temperature for 12 h. The reaction was quenched by addition of aqueous solution of NH4Cl (sat.), the organic phase was separated and the aqueous phase was extracted with DCM (3x20 mL). The combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. The title product was obtained after purification by column chromatography (n-hexane) as a colorless oil (132 mg, 0.251 mmol, 33%). These data are in agreement with those reported previously in the literature. [12]     These data are in agreement with those reported previously in the literature. [15]
The characterization data matches the one previously reported in this manuscript (see S25).

Compatibility of Functional Handles in Halogenation Approaches
To

Tolerance of Functional Handles in Fluorination Approaches
To test the tolerance of the GeEt3-, SnBu3-, B(OH)2-, B(pin)-and SiMe3-site towards established fluorination approaches, the corresponding starting materials (0.03 mmol, 1 equiv.) and the corresponding reagents (for details see Table S1) were dissolved in the DMF-d7 and stirred under reaction conditions as specified. The procedures were adopted from literature. [16] The reaction mixtures were analyzed by calibrated GC-MS and quantitative 1 H NMR (using mesitylene as internal standard). The results are shown in Table S1.

Selective Fluorination of SnBu3 vs. GeEt3
Triethyl ( Table   S2 and S3.  1 C atom missing in the 13 C NMR. This is in line with literature reports.

Linear Free Energy Relationship Analysis (Hammett Plot)
The reaction was performed according to GP 1. It was monitored using a Mettler Toledo ReactIR ® 15 equipped with a 6.3 mm probe. The relative absorption data over time was normalized to yields obtained by calibrated GC-MS (using mesitylene as internal standard) or quantitative 1 H or 19 F NMR analysis (using mesitylene or 1,4-difluorobenzene as internal standard). Figure S1: Determination of initial reaction rates.

Robustness Screen
The reaction was performed according to GP 1. In addition, an additive (1.0 equiv., for details see Table S5) was added to the reaction mixture. The tolerance of the reaction towards each additive was shown by quantification of yield of product (Y), remaining additive (A) and remaining starting material (SM) using calibrated GC-MS with mesitylene as internal standard. The results are shown in Table S5 (green: >66%; yellow 34-66%; red <34%). The vast majority of the additives is well tolerated. Due to their low molecular weight and resulting low boiling point, it was impossible to quantify some of the additives via GC-MS (marked in grey). However, also in those cases the reaction proceeded with high efficiency.

Robustness Screen for ArB(pin) and ArSiMe3
The reaction was performed according to GP 1 with ArFG (FG = GeEt3, B(pin) or SiMe3; 0.03 mmol, 1 equiv.). To investigate the tolerance of the reaction, different additives were added to the reaction mixture (see table below for details). The reaction was stirred for 1 h at rt and subsequently analyzed by calibrated GC-MS using mesitylene (1 equiv.) as internal standard. The results are shown in Table S6.

EPR Analysis
The reaction was performed according to GP 1. EPR measurements of the reaction mixture were performed every 20 min aiming to detect paramagnetic species which would indicate a SET type mechanism. No paramagnetic species were detected.
Additionally, the reaction was performed according to GP 1 with either 2,2,6,6tetramethylpiperidinyloxyl (TEMPO) or N-tert-butyl-α-phenylnitrone (PBN) as spin probe/spin trap. After 2 h of reaction time, the reaction mixture was analyzed by EPR. In all experiments with various amounts of TEMPO as spin probe no TEMPO-related adducts were detected (GC-MS). Additionally, EPR measurements did not show any change in the TEMPO signal.

PBN (unambiguously confirmed by GC-MS analysis). This observation is in line with literature
reports. [22] The quantitative yield confirmed that the aryl germane did not form significant amount of aryl radicals which might be trapped by the spin trap.
The reaction was performed according to GP 1. It was monitored using a Mettler Toledo ReactIR ® 15 equipped with a 6.3 mm probe. The relative absorption data over time was normalized to yields obtained by calibrated GC-MS (using mesitylene as internal standard). Images were created using the CYLview software. [24] Figure S7: Gibbs free energies computed at the CPCM (DMF) M06/6-311++G(d,p) (SDD)//ωB97XD/def2SVP level of theory. Energies are given relative to starting materials.