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

Abstract While the modular construction of molecules from suitable building blocks is a powerful means to more rapidly generate a diversity of molecules than through customized syntheses, the further evolution of the underlying coupling methodology is key to realize widespread applications. We herein disclose a complementary modular coupling approach to the widely employed Suzuki coupling strategy of boron containing precursors, which relies on organogermane containing building blocks as key orthogonal functionality and an electrophilic (rather than nucleophilic) unmasking event paired with air‐stable PdI dimer based bond construction. This allows to significantly shorten the reaction times for the iterative coupling steps and/or to close gaps in the accessible compound space, enabling straightforward access also to iodinated compounds.


Experimental Techniques
All reactions involving air-or moisture-sensitive reagents or intermediates were carried out in dried glassware under an argon atmosphere and were performed either in an argon-filled glovebox or by using standard Schlenk techniques unless otherwise stated. Kugelrohr distillation was performed using a Büchi Glass Oven B-585 Kugelrohr apparatus.

Characterization
All 1 H, 13 C and 19 F NMR spectra were recorded on Bruker Avance Neo 600, Varian VNMRS 600, Varian VNMRS 400 or Varian Mercury 300 spectrometers at ambient temperature. Chemical shifts (δ) are reported in parts per million (ppm) and were referenced to residual solvent peak (for 1 H and 13 C) or by the instrument internally after locking and shimming to the deuterated solvent (for 19 F). Coupling constants (J) are given in Hertz (Hz). 2.5 mol%) were placed into a vial. The vial was evacuated and backfilled with argon three times before dry toluene (1 mL) was added. A freshly prepared solution of appropriate organozinc (0.3 mmol, 1.5 equiv.) was added in one portion. The reaction mixture was stirred for 5 min before the reaction was quenched with pentane or hexane (1 mL). The mixture was filtered through a plug of silica eluting with hexane/DCM (1:1, 10 mL) and the obtained filtrate was concentrated under reduced pressure.
Bromination: The crude was dissolved in MeCN (2 mL), NBS (0.3 mmol, 1.5 equiv.) was added and the mixture was stirred at 60 °C for 1 hour. Volatiles were removed under reduced pressure and the residue was filtered through a short pad of silica gel eluting with hexane. Volatiles were removed under reduced pressure to give the crude bromoarene.
2 nd Coupling: The crude bromoarene was transferred into a vial, which was then evacuated and backfilled with argon three times. Dry toluene (0.1 M, 2 mL) was added, followed by the addition of freshly prepared organozinc reagent (0.5 equiv.; to quench excess brominating agent, alternatively the crude bromoarene can be purified by column chromatography prior to the second coupling) and [Pd(μ-I)(P t Bu3)]2 (0.006 mmol, 3.0 mol%; added as a solid under a stream of argon). More of the organozinc reagent (1.5 equiv.) was then added dropwise over 10 min via syringe pump. The reaction mixture was stirred for additional 5 min before the reaction was quenched with hexane (1 mL) and a spatula tip of ammonium pyrrolidine-1-dithiocarboxilic acid was added to precipitate palladium. [4] The mixture was filtered through a plug of silica eluting with hexane/DCM (1:1, 10 mL). After evaporation of all volatiles the product was purified by column chromatography on silica gel.
Amination: In an argon-filled glovebox, a 4 mL glass-vial was charged with KOEt (0.8 mmol, 4.0 equiv.), [Pd(μ-I)(P t Bu3)]2 (0.01 mmol, 5 mol%), amine (0.3 mmol, 1.5 equiv.), bromoarene (0.2 mmol, 1.0 equiv.) and dry THF (1 mL). If the amine and/or the bromoarene were a liquid, they -S4 -were added as a solution in THF. The vial was sealed, and the mixture was stirred for 1.5 hours at 50 °C. The solution was filtered through a plug of silica gel, eluting with EtOAc (10 mL). The solvent was removed under reduced pressure and the crude purified by column chromatography on silica gel.

General procedure B -Sequential synthesis (1 mmol scale)
C-C Coupling: The appropriate aryl bromide (1.0 equiv., 1 mmol) and [Pd(μ-I)(P t Bu3)]2 (2.5 mol%) were placed into 25 mL round bottom flask. The flask was evacuated and backfilled with argon three times before dry toluene (0.2 M, 5 mL) was added. A freshly prepared solution of organozinc reagent (1.5 equiv.) was added slowly to the reaction mixture via syringe pump over 15 min while the mixture was stirred gently. The reaction mixture was stirred for additional 5 min before the reaction was quenched with pentane or hexane and a spatula tip ammonium pyrrolidine-1-dithiocarboxilic acid was added to precipitate palladium. [4] The mixture was filtered through a plug of silica eluting with Et2O, the filtrate was concentrated under reduced pressure.
Bromination: The crude aryl germane was dissolved in MeCN (0.2 M) or HFIP (0.2 M, for electron deficient or sterically hindered aryl germanes) and NBS (2.0 equiv.) was added. The reaction was stirred at 60 °C for 1.5 hours. After that time, the mixture was allowed to cool to room temperature, filtered through a plug of silica gel, eluting with Et2O. Volatiles were removed under reduced pressure and the crude material was purified by column chromatography on silica gel.
For sequential coupling the C-C coupling and bromination steps were repeated, followed by a final iodination.
Iodination: The crude obtained from cross-coupling was dissolved in HFIP (0.2 M) and NIS (2.0 equiv.) was added. The reaction was stirred at 60 °C for 24 hours. After that time, the mixture was allowed to cool to room temperature, filtered through a plug of silica, concentrated under reduced pressure and the crude material was purified by column chromatography on silica gel.

General procedure C -Iodination of Germanes in DMF
According to Fricke et al. [5] , to a solution of aryl germane (1.0 equiv.) in DMF (0.1 M) was added NIS (2.0 equiv.) and the reaction mixture was stirred at 60 °C, until the starting material was fully consumed (monitored via GC-MS). After cooling to ambient temperature, H2O (10 mL) and DCM (15 mL) were added and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with saturated aq. Na2S2O3 (25 mL) and 10% w/w aq. LiCl (25 mL), dried over Na2SO4 and concentrated under reduced pressure. The product was purified by chromatography on silica gel.

General procedure D -Iodination of Germanes in HFIP
To a solution of aryl germane (1.0 equiv.) in HFIP (0.1 M) was added NIS (2.0 equiv.) and the reaction mixture was stirred at 60 °C, until the starting material was fully consumed (monitored via GC-MS).
After cooling to ambient temperature, the reaction mixture was diluted with DCM (20 mL). The organic layer was washed with saturated aq. Na2S2O3 (25 mL), dried over Na2SO4 and concentrated under reduced pressure. The product was purified by chromatography on silica gel.
Note: During the course of this investigation direct C-H germylations have become available, [6] which offer alternatives to the general procedures E and F presented herein.

General procedure E -Synthesis of aryl germanes with i PrMgCl•LiCl
According to Fricke et al. [5] the appropriate aryl halide was weighed into an oven dried Schlenk flask and dissolved in dry THF (0.2 M). The solution was cooled to 0 °C and a solution of i PrMgCl•LiCl (1.0 equiv., 1.3 M in THF) was added dropwise to the stirred solution. After the addition was complete, GeEt3Cl (1.0 equiv.) was added and the reaction mixture stirred at ambient temperature. After full -S6 -conversion was observed (monitored via GC-MS), saturated aq. NH4Cl was added and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The product was purified by column chromatography on silica gel.

General procedure F -Synthesis of aryl germanes with n BuLi
According to Fricke et al. [5] the appropriate aryl halide (1.0 equiv.) was placed to an oven dried Schlenk flask and dissolved in THF (0.25 M). The solution was then cooled to -78 °C and n Buli (2.5 M in hexane, 1.0 equiv.) was added dropwise stirred for 30 min at the same temperature. Et3GeCl (1.0 equiv.) was added and the reaction was stirred overnight, while warming up to ambient temperature. The reaction was quenched with saturated aq. NH4Cl and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography on silica gel.

General procedure G -Preparation of organomagnesium and -zinc reagents
Organomagnesium Reagents: In an oven dried flask magnesium powder (1.5 equiv.) and dry LiCl (1.1 equiv.; previously dried under high vacuum using a Bunsen burner and allowing to cool under high vacuum) were suspended in dry THF (1 M). A solution of aryl bromide or iodide in THF (1 M) was added and the mixture was stirred overnight. The obtained mixture was filtered through a syringe filter and stored at ambient temperature in the glovebox (no decomposition was observed for months). The organomagnesium reagent was titrated following Knochel's protocol. [7] -S7 -Organozinc Reagents: Solutions of ZnCl2 (1M in THF, 1.1 equiv.) and LiCl (0.5M in THF, 1.1 equiv.; only added if a commercial organomagnesium reagent was employed) were added to a solution of aryl magnesium halide (in THF, 1.0 equiv.) in a 16 mL vial under argon atmosphere and stirred for 10 min. The organometallic species was then used without further analysis.
Preparation of the ZnCl2 solution: [8] To an oven dried Schlenk tube equipped with a stir-bar was added anhydrous ZnCl2 (1.36 g, 10 mmol) under argon atmosphere. Upon melting under high vacuum using a Bunsen burner, the tube was allowed to cool to room temperature and was then refilled with argon.

Aryl germane starting materials
Note: During the course of this investigation direct C-H germylations have become available, [6] which offer alternatives to the general procedures E and F presented herein. with those previously reported. [5] (2-bromo-6-chlorophenyl)triethylgermane: An oven dried round bottom flask equipped with a magnetic stirrer was evacuated and refilled with argon three times.

Recycling of germanium masking group
During our investigation on the halogenation of arylgermanes with NBS as halogenating reagent we observed the formation of germanium containing by-products. The major by-product was identified as a succinimide-GeEt3 species followed by low amounts of Et3GeBr and Et3GeCl. While the succinimide-GeEt3 species is likely formed due to an excess of NBS, we assumed that the formation of the halogenated germanes Et3GeX (X = Br, Cl) occurs due to the presence of the corresponding anions in solution (derived from ZnCl2, organomagnesium bromide). Since isolation of the succinimide-GeEt3 species proved difficult, we intended to increase the formation of Et3GeBr by adding an excess of NH4Br to the reaction mixture. Indeed, the succinimide-GeEt3 formation was fully suppressed and high amounts of Et3GeBr (and minor amounts of Et3GeCl) were observed ( Figure S1).
The mixture of germanium halides (Et3GeBr and Et3GeCl) was then isolated by Kugelrohr distillation (see below). Subsequently, NBS (3 equiv.) and NH4Br (5 equiv.) were added. The reaction was stirred at 60 °C for 1.5 hours. After that time, the mixture was allowed to cool to room temperature, filtered through a plug of silica gel, washed with Et2O and concentrated under reduced pressure.
Attention! During the reaction Et3GeCl and Et3GeBr are formed, both are volatile, and one must make sure that the pressure is higher than 200 mbar and that the temperature remains below 40 °C.
(c) Distillation: The obtained crude mixture was subjected to Kugelrohr distillation (70 °C, 10 mbar, 2 hours, ice bath cooling). The distilled fractions were combined yielding a mixture of Et3GeCl and Et3GeBr, while the remainder of the distillation (i.e. the halogenated arene) was purified by column chromatography (pentane) and directly used for further coupling.
(d) Germylation: The obtained distillate (mixture of Et3GeCl and Et3GeBr) was placed into a 25 mL round bottom flask equipped with a magnetic stir bar. The flask was closed with a septum and gently purged with argon for 2 min. Subsequently, THF (1 M) was added followed by the appropriate organomagnesium reagent (2.0 equiv. with regard to [Ge]). After stirring overnight saturated aq.