Solid-Phase Synthesis and Catalytic Screening of Polystyrene Supported Diphosphines

Supporting information

Solid-Phase Synthesis and Catalytic Screening of Polystyrene Supported Diphosphines

Michiel C. Samuels, Frank J. L. Heutz, Arnald Grabulosa and Paul C. J. Kamer*

School of Chemistry, University of St Andrews

St. Andrews, Fife, KY16 9ST, United Kingdom

E-mail:

Supporting information

Contents

General Experimental S-3

Synthesis of sodium ethoxide[6] S-3

Synthesis of tert-butylchloro-ethylphosphinite1 S-3

Synthesis of resin-bound tert-butylphosphine-borane 6 S-3

General procedure for immobilised phosphine-sulfates 8a-f S-4

General Procedure for the Preparation of Lithium Phosphides S-5

General procedure for immobilised diphosphine boranes 9a-g S-5

General Procedure for Asymmetric Hydrogenation Experiments S-6

31P Gel-Phase NMR Spectra for the synthesis towards immobilised phosphine 6 S-7

31P Gel-Phase NMR Spectra of immobilised phosphine-sulfates 8a-f S-9

31P Gel-phase NMR spectra of immobilised diphosphines 9a-g S-11

Representative FT-IR Spectra of Resins S-18

References S-20

General Experimental

All reactions and manipulations were carried out under inert conditions using standard Schlenk techniques or in an MBraun glovebox unless stated otherwise. All glassware was dried prior to use to remove traces of water. All chemicals were obtained from commercial suppliers and used as received unless otherwise stated. Toluene was distilled from sodium, diethyl ether and THF were distilled from sodium/benzophenone and triethylamine, dichloromethane and acetonitrile were distilled from calcium hydride. Polystyrene-Br (50-100 mesh, 2.17 mmol∙g−1, 2% cross-linked DVB) was obtained from Sigma-Aldrich. Cyclic sulfates are prepared according to literature: 1,3-propadiol cyclic sulfate i,[1] l,4-butanediol cyclic sulfate ii,[2] (2R,4R)-2,4-pentanediol cyclic sulfate iii,[3] (2R,5R)-2,5-hexanediol cyclic sulfate iv,[4] (2S,5S)-2,5-hexanediol cyclic sulfate v,[4] (3R,6R)-3,6-octadiol cyclic sulfate vi.[5]

NMR spectra were recorded on a Bruker AVANCE II 400. Gel-phase 31P{1H} NMR spectra of all resins were recorded unlocked and without additional shimming using dry THF as solvent and chemical shifts are reported relative to 85% H3PO4 in water. IR spectra were recorded on a Shimadzu IRAffinity-1 FTIR spectrometer. Elemental analyses were measured by Mikroanalytisches Laboratorium Kolbe in Mülheim an der Ruhr, Germany. GC measurements where performed on a Thermo Trace GC ultra, see further experimental details for columns and conditions.

Synthesis of sodium ethoxide[6]

A Schlenk flask was loaded with freshly cut sodium (1.17g, 50.90 mmol) and cooled to 0°C. Freshly distilled ethanol (70mL) was added slowly resulting in gas evolution. After 1h at 0°C, the reaction mixture was allowed to warm up to room temperature until all sodium had reacted. After 1h, the excess of ethanol was removed in vacuo at 60°C. The resulting solid was dried in vacuo for an additional 1.5h at 80°C, yielding sodium ethoxide as a white fine powder quantitatively (3.46g, 50.90mmol).

Synthesis of tert-butylchloro-ethylphosphinite1

tert-Butylchloroethoxyphosphine1 was prepared by addition of a cooled (0°C) suspension of freshly prepared sodium ethoxide (3.46g, 50.90mmol, 1.1eq.) in 50mL of toluene via a Teflon cannula to a cooled (0°C) solution of t-BuPCl2 (46mL, 46mmol, 1.0M in Et2O) in 75mL of toluene. The flask was rinsed with toluene (2x25mL) and the reaction was stirred at 0°C for 2hours. Resulting in a mixture of t-BuP(OEt)Cl 1 (70%, δ31P{1H} NMR(162 MHz, in toluene) = 209ppm) and t-BuP(OEt)2 2 (25%, δ31P{1H} NMR(162 MHz, in toluene) = 187ppm), which was used as such in the subsequent reaction.

Synthesis of resin-bound tert-butylphosphine-borane 6

Step 1

p-Bromopolystyrene (5.09g, 11.04mmol, loading 2.17mmol/g) was allowed to swell in 50mL of toluene for 1 hour. After addition of n-butyllithium (30mL, 78mmol, 2.6M in toluene), the suspension was heated for 4 hours at 60°C with slow stirring, after which the supernatant was removed and the resulting yellow resin 3 was washed with toluene (3x30mL).[7] The obtained resin was used as such in a subsequent reaction.

Step 2

To the lithiated polystyrene resin 3 (5.09g, 11.04mmol), suspended in 20mL of toluene, the crude reaction mixture of t-BuP(OEt)Cl 1 was added via transfer of the supernatant with a Teflon cannula. The resin decoloured slowly and after overnight stirring at room temperature, the resin was washed with toluene (3x30mL), yielding resin4. δ31P{1H} NMR (162 MHz, toluene) = 129.1 (br). The obtained resin was used as such in the subsequent reaction.

Step 3

The crude resin4 from the previous reaction was suspended in 10mL of toluene and diisobutylaluminum hydride (30mL, 36mmol, 1.2M in toluene) was added at room temperature. After 3 days, the resin was washed consecutively with toluene (3 x 30mL), Et2O (2 x 30mL), and toluene (2 x 30mL), yielding resin5. δ31P{1H} NMR (162 MHz, toluene) = −7.0 (br). The obtained resin was used as such in the subsequent reaction.

Step 4

The crude resin5 from the previous reaction was suspended in 30mL of toluene and BH3·SMe2 (15mL, 30mmol, 2M in toluene) was added at room temperature. After gentle stirring for 2hours followed by washing with toluene (3 x 30mL) Et2O (2 x 30mL) and toluene (2 x 30mL), resin6 was obtained (5.94g, 12.28mmol; calculated loading: 2.07 mmol/g resin). δ31P{1H} NMR (162 MHz, toluene) = 28.8 (br); IR (KBr): ν˜ = 2367 cm−1 (BH3); elemental analysis (%): P, 7.29.

General procedure for immobilised phosphine-sulfates 8a-f

Step 1

Resin-bound phosphine-borane 6 (500 mg) was swollen in THF (20 mL). Next, LDA (2.0 M in THF/heptane/ethylbenzene, 10 eq.) was added under gentle stirring to avoid mechanical abrasion of the resin. Upon addition the resin colored dark brown and was allowed to react for 3 hours. Next, the supernatant solution was removed and the resin was washed subsequently with three 10 mL portions of THF followed by three 10 mL portions of Et2O. The obtained resin 7 was used as such in the subsequent reaction. δ31P{1H} NMR (162 MHz, toluene) = -16.0 (br).

Step 2

Propanediol cyclic sulfate (129.8mg, 939.6µmol, 1.5eq.) was azeotropically dried with portions of toluene (3 x 0.5mL) and dissolved in 1mL of THF. The solution of cyclic sulfate was transferred to the Schlenk tube with the suspension of lithiated resin 7 (303mg, 627.8µmol, loading: 2.07mmol/g) in 2mL of THF. After reacting 18hours at room temperature, the light yellow resin was washed with portions of THF and Et2O (3 x 7 mL respectively). The white resin 8 was suspended in 7 mL of THF to be used in the subsequent reaction.

8a: white resin, 31P{1H} NMR (162 MHz, THF): +32.5ppm; IR (KBr): ν˜ = 2381 (BH3), 1640 and 1260 (S=O) cm−1; elemental analysis (%): P, 3.44; S, 3.31.

8b: white resin, 31P{1H} NMR (162 MHz, THF): +32.2ppm; IR (KBr): ν˜ = 2379 (BH3), 1639 and 1262 (S=O) cm−1; elemental analysis (%): P, 4.01; S, 2.89.

8c: white resin, 31P{1H} NMR (162 MHz, THF): +39.8ppm; IR (KBr): ν˜ = 2374 (BH3), 1651 and 1259 (S=O) cm−1; elemental analysis (%): P, 4.11; S, n.d.

8d: white resin, 31P{1H} NMR (162 MHz, THF): +40.7ppm; IR (KBr): ν˜ = 2374 (BH3), 1651 and 1259 (S=O) cm−1; elemental analysis (%): P, 3.91; S, 3.24.

8e: white resin, 31P{1H} NMR (162 MHz, THF): +40.7ppm; IR (KBr): ν˜ = 2370 (BH3), 1657 and 1261 (S=O) cm−1; elemental analysis (%): P, 4.35; S, n.d.

8f: white resin, 31P{1H} NMR (162 MHz, THF): +39.5ppm; IR (KBr): ν˜ = 2374 (BH3), 1655 and 1258 (S=O) cm−1; elemental analysis (%): P, 3.98; S, n.d.

General Procedure for the Preparation of Lithium Phosphides

S-20

Phosphane (~1.0 eq.) was introduced into a dry Schlenk vessel, dissolved in dry THF and cooled to −78 °C. 1.0 equivalent of n-BuLi (1.6 M in hexanes) was added dropwise, upon addition the solution colored bright yellow or orange. After 1 hour the cooling bath was removed and the reaction mixture was allowed to warm up to room temperature and was left for an additional amount of time until full conversion was confirmed by 31P{1H} NMR. The lithium phosphides were directly used in subsequent reactions.

Lithium Phenyl Phosphide

The lithium phosphide was obtained from phenylphosphane (0.35 g, 3.18 mmol, 1.05 eq.) and n-BuLi (1.9 mL, 1.6 M in hexanes, 1 eq.) in dry THF (5 mL) as a bright yellow solution (0.5 M). 31P{1H} NMR (162 MHz, THF): δ=−112.4 (s) ppm.

Lithium Di(o-tolyl) Phosphide

The lithium phosphide was obtained from di(o-tolyl)phosphane (0.43 g, 2.00 mmol, 0.99 eq.) and n-BuLi (0.80 mL, 1.6 M in hexanes, 1.0 eq.) in THF (5 mL) as a bright orange solution (0.4 M). 31P{1H} NMR (162 MHz, THF):δ=−41.1 (s) ppm.

General procedure for immobilised diphosphine boranes 9a-g

Step 1

To the resin 8 (220mg, 358.6µmol, loading: 1.63mmol/g) suspended in 7mL of THF was added freshly prepared lithium diphenylphosphide solution (5mL, 0.5M, 1mmol, 11eq.). After reacting 4 days at room temperature, the resin 9 was washed with portions of THF and Et2O (3 x 7mL respectively).

9a: white resin, in situ 31P{1H} NMR (162 MHz, THF): +31.4ppm, −18.8ppm.

9b: white resin, in situ 31P{1H} NMR (162 MHz, THF): +31.7ppm, −16.4ppm.

9c: white resin, in situ 31P{1H} NMR (162 MHz, THF): +40.3ppm, +1.6ppm and −2.7ppm.

9d: white resin, in situ 31P{1H} NMR (162 MHz, THF): +40.2ppm, −1.6ppm.

9e: white resin, in situ 31P{1H} NMR (162 MHz, THF): +40.3ppm, −1.7ppm.

9f: white resin, in situ 31P{1H} NMR (162 MHz, THF): +38.7ppm, −7.6ppm and −8.4ppm.

9g: white resin, in situ 31P{1H} NMR (162 MHz, THF): +40.2ppm, −28.4ppm.

Step 2

The white resin 9-BH3 was obtained by suspending resin 9 in 10mL of THF following by addition of 1mL of BH3·SMe2 complex (2M in toluene, 2mmol). After 18 hours, the white resin 9-BH3 was washed with 5mL portions of THF, THF/H2O (5:1), THF, Et2O and dried under reduced pressure.

9a-BH3: white resin, 31P{1H} NMR (162 MHz, THF): +31.4ppm, +15.4ppm; IR (KBr): ν˜ = 2379 (BH3) cm−1; elemental analysis (%): P, 5.52.

9b-BH3: white resin, 31P{1H} NMR (162 MHz, THF): +31.4ppm, +15.9ppm; IR (KBr): ν˜ = 2379 (BH3) cm−1; elemental analysis (%): P, 6.13.

9c-BH3: white resin, 31P{1H} NMR (162 MHz, THF): +41.2ppm, +26.0ppm; IR (KBr): ν˜ = 2374 (BH3) cm−1; elemental analysis (%): P, 5.80.

9d-BH3: white resin, 31P{1H} NMR (162 MHz, THF): +40.3ppm, +24.5ppm; IR (KBr): ν˜ = 2378 (BH3) cm−1; elemental analysis (%): P, 6.40.

9e-BH3: white resin, 31P{1H} NMR (162 MHz, THF): +40.1ppm, +24.5ppm; IR (KBr): ν˜ = 2374 (BH3) cm−1; elemental analysis (%): P, 5.96.

9f-BH3: white resin, 31P{1H} NMR (162 MHz, THF): +38.4ppm, +22.9ppm; IR (KBr): ν˜ = 2374 (BH3) cm−1; elemental analysis (%): P, 5.86.

9g-BH3: white resin, 31P{1H} NMR (162 MHz, THF): +40.3ppm, +26.0ppm; IR (KBr): ν˜ = 2363 (BH3) cm−1; elemental analysis (%): P, 6.52.

Step 3

For the deprotection, resin 9-BH3 was suspended in 10 mL of THF and a solution of 1,4-Diazabicyclo[2.2.2]octane (DABCO, 10 eq.) in THF (5 mL) was added. The reaction was heated to 40°C and left overnight without stirring. After complete deprotection was confirmed by 31P NMR, the supernatant solution was removed and the resin was washed subsequently with three 5 mL portions of THF followed by three 5 mL portions of Et2O. The product was dried in vacuo yielding a white deprotected resin−bound diphosphine. The product 9* was used directly in asymmetric hydrogenation experiments without further purification.

9b*: white resin, in situ 31P{1H} NMR (162 MHz, THF): +1.5ppm, −16.1ppm.

9c*: white resin, in situ 31P{1H} NMR (162 MHz, THF): +19.7ppm, +1.6ppm and −2.7ppm.

9d*: white resin, in situ 31P{1H} NMR (162 MHz, THF): +18.6ppm and +17.1ppm, −1.9ppm.

9e*: white resin, in situ 31P{1H} NMR (162 MHz, THF): +18.4ppm and +17.2ppm, −1.9ppm.

9f*: white resin, in situ 31P{1H} NMR (162 MHz, THF): +10.3ppm, −7.3ppm and −8.1ppm.

9g*: white resin, in situ 31P{1H} NMR (162 MHz, THF): +18.6ppm, −28.3ppm.

General Procedure for Asymmetric Hydrogenation Experiments

The hydrogenation experiments were performed in a stainless steel autoclave charged with an insert suitable for 10 reaction vessels including Teflon mini stirring bars. In a typical experiment, a reaction vessel was charged with a deprotected resin-bound diphosphine (2.5 mg, approximately 3.0 μmol) and a solution of [Rh(COD)2]BF4 (3.0 μmol) in CH2Cl2 (1 mL) and the heterogeneous mixture was allowed to stir gently for 4 h. The supernatant solution was removed and the resulting orange resin was washed subsequently with three 1 mL portions of THF followed by three 1 mL portions of Et2O. Next, a solution of substrate (0.5 mL, 0.18 M, 30 eq.) in THF was added to the reaction vessel. Subsequently, the autoclave was purged three times with 5 bar of H2 and then pressurized to 1.2 bar. The reaction mixtures were gently stirred at 25 °C. After 16 h, the autoclave was depressurized and the reaction mixtures were filtered over a plug of silica. Prior to GC measurements substrate II and its products were derivatized using (trimethylsilyl)diazomethane (2 M in diethyl ether), in essence yielding substrate III. The conversion and the enantiomeric excess were determined by chiral GC using the following column and conditions:

I: Permabond-L-Chirasil-Val column: T0 = 90 °C, ΔT = 8 °C min−1 to 170 °C, tR (I) = 2.4 min. tR (R) = 3.3 min, tR (S) = 3.7 min.

III: Permabond-L-Chirasil-Val column: T0 = 90 °C, ΔT = 8 °C min−1 to 150 °C, hold for 15 min, then ΔT = 8 °C min−1 to 180 °C, hold for 15 min, tR (R) = 14.2 min. tR (S) = 15.6 min, tR (III) = 26.7 min.

31P Gel-Phase NMR Spectra for the synthesis towards immobilised phosphine 6

31P{1H} NMR of reaction mixture 1 and 2 (162 MHz, toluene).

31P{1H} NMR of resin 4 (162 MHz, toluene).

31P{1H} NMR of resin 5 (162 MHz, toluene).

31P{1H} NMR of resin 6 (162 MHz, toluene).

31P{1H} NMR of resin 7 (162 MHz, THF).

31P Gel-Phase NMR Spectra of immobilised phosphine-sulfates 8a-f