Supporting Information a Convenient Chromatography-Free Method For

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 Supporting Information A Convenient Chromatography-Free Method for the Purification of Alkenes Produced in the Wittig Reaction Peter A. Byrne, Kamalraj V. Rajendran, Jimmy Muldoon and Declan G. Gilheany Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland 241. 2. 3. 4. 5. 6. General Experimental Synthesis of phosphonium salts 11 15 34 Procedures for Wittig reactions & phosphine oxide removal Characterisation of purified alkenes Reduction of phosphine chalcogenides Synthesis & isolation of neomenthyl chloride and reduction of phosphine oxide-by-product 37 42 7. 8. NMR spectra of phosphonium salts NMR spectra of purified alkenes and regenerated phosphines from Wittig reactions 56 <ul style="display: flex;"><li style="flex:1">9. </li><li style="flex:1">NMR spectra of phosphines produced by reduction of phosphine </li></ul>chalcogenides 85 90 91 10. NMR spectra of purified products from Appel-type reactions 11. References 1Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 1. General Experimental All chemicals were supplied by Aldrich, with the exception of Zeoprep silica, 2- methylbenzaldehyde (o-tolualdehyde, Fluka), (tert-butoxycarbonylmethyl)- triphenylphosphonium bromide (Fluka), 1 mol L-1 LiAlH4 in THF (Acros Organics) and Merck standardised alumina 90. All chemicals were used without further purification except diethyl ether, toluene, and THF, which were processed through an Innovative Technology Inc. Pure Solv-400-3-MD solvent purification (Grubbs still) system and stored in Strauss flasks under a nitrogen atmosphere, and ethyl acetate and dichloromethane, which were degassed by passing a stream of dry nitrogen gas (oxygenfree) through the solvent for one hour for the purposes of work-ups in phosphine syntheses. All benzaldehydes (supplied by Aldrich) were checked by NMR for the presence of carboxylic axids, but no trace of acid was found and so the benzaldehydes were used without further purification. Phosphonium salts were dried in a vacuum dessicator over P2O5 and, together with KHMDS, NaHMDS, and commercial (tert- butoxycarbonylmethyl)triphenylphosphonium bromide, were stored in an MBraun glove box under an atmosphere of argon. Oxalyl chloride was stored under an atmosphere of nitrogen in a Young’s flask, and dispensed by nitrogen-flushed syringe. 1,2-O- isopropylidene-3-O-methyl-α-D-xylopentodialdofuranose-(1,4) was placed in a Schlenk flask under argon gas, and dissolved in dry THF to give a 0.5 mol L-1 solution. This solution was stored in the Schlenk flask under nitrogen at -18 ˚C in a freezer. 2- methylbenzaldehyde (o-tolualdehyde) was stored under nitrogen in a sealed Fluka® vessel. NMR chemical shifts are reported in parts per million (ppm), and coupling constants (J) are reported in hertz (Hz). All NMR samples were made up using CDCl3 as solvent. NMR spectra were obtained on Varian Inova and VNMRS 300, 400, 500 and 600 MHz spectrometers, the latter of which is equipped with a triple resonance probe. Double <ul style="display: flex;"><li style="flex:1">13 </li><li style="flex:1">31 </li></ul>decoupled C {1H, P} NMR spectra of new phosphonium salts were obtained on the 600 MHz instrument. 1H and 13C NMR chemical shifts were measured relative to tetramethylsilane. 31P NMR chemical shifts were measured relative to an external orthophosphoric acid standard. 19F NMR chemical shifts were measured relative to 2Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 CCl3F. In the reporting of characterisation details, the NMR signals due to aromatic hydrogen “j” (where j = 1-6) of a benzyl group are referred to as ArH-j and those due to phenyl hydrogens as PhH-j, and likewise the corresponding carbons are referred to as <ul style="display: flex;"><li style="flex:1">1</li><li style="flex:1">13 </li></ul>ArC-j and PhC-j respectively. Assignments of signals in H and C NMR spectra was <ul style="display: flex;"><li style="flex:1">13 </li><li style="flex:1">31 </li></ul>done by reference to C{1H, P}, COSY, g HSQCAD, and gHMBCAD NMR spectra. The 1D DPFGSE-NOE NMR technique (Double Pulse Field Gradient Spin Echo Nuclear Overhauser Effect NMR spectroscopy) was used to detect NOE contacts. High resolution mass spectra were obtained on a LCT electrospray ionisation mass spectrometer or a GCT Premier GC/MS mass spectrometer by electronic or chemical ionisation. Samples were dissolved in acetonitrile or methanol. Melting points were obtained using a Reichert Thermovar melting point apparatus, and are uncorrected. Flash column chromatography was carried out using Aldrich neutral alumina (Brockmann grade I) or Zeoprep silica. TLC was done using Merck pre-coated alumina 90 or silica 60 F-254 plates. Realisation of plates was done by UV irradiation. All reactions described here were carried out under an atmosphere of nitrogen. The inert atmosphere was established inside a reaction flask by the standard Schlenk pump and fill technique,1 using a Schlenk manifold that allowed each of five silicone rubber tubes to each be open either to vacuum or to the nitrogen supply by means of a three-way tap (third position is closed to both vacuum and nitrogen). The reaction flask was typically flame dried and attached to the Schlenk manifold by one of the silicone rubber tubes, and evacuated by application of a vacuum pump (Edwards RV5 rotary vane pump) while hot. The flask was allowed to cool under vacuum and then filled with nitrogen. It was then evacuated and re-filled a further two times. This technique was also applied to establish a nitrogen atmosphere in the tubing connected to a sealed Schlenk flask that already contained an inert atmosphere (nitrogen or argon gas). The flask could be opened to the nitrogen supply after the connecting tubing had been evacuated and re-filled three times. When not in use, the the open end of each length of silicone rubber tubing was fitted with a syringe barrel with an attached needle. The needle was inserted through a rubber septum into a conical flask containing dry KOH pellets, and the tip was embedded in amongst the pellets. In this manner the tubing was kept free of ambient moisture. 3Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 2. Synthesis of phosphonium salts P-(iso-butyl)triphenylphosphonium bromide2 Ph P Br MeCN 80 oC P Br Ph Ph <ul style="display: flex;"><li style="flex:1">Ph </li><li style="flex:1">Ph </li></ul>Ph Triphenylphosphine (4.26 g, 16.2 mmol), dry acetonitrile (10 ml), and 1-bromo-2- methylpropane (2 ml, 18.4 mmol) were added to a flame dried Schlenk flask under an atmosphere of nitrogen. Stirring gave a clear solution. The flask was fitted with a reflux condenser (flame dried and connected to nitrogen supply) and the reaction mixture was heated to 80 ˚C for 3 days under a gentle flow of nitrogen. The progress of the reaction was periodically checked by taking a 31P NMR spectrum of a small sample of the reaction mixture diluted with CDCl3. After 3 days, the acetonitrile solvent was removed, and the residue was recrystallised from hot chloroform/ethyl acetate to give white crystals of the product in a yield of 5.5 g (13.8 mmol, 85%). The white crystals thus obtained were placed in a dessicator under nitrogen and dried using phosphorus pentoxide and calcium chloride, and then placed in a glove box under an atmosphere of argon. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 6H, PhH-2), 7.79 (m, 3H, PhH-4), 7.71 (m, 6H, PhH-3), 3.80 (dd, J = 12.9, 6.2, 2H, PCH2), 2.18 – 1.99 (m, 1H, CHMe2), 1.08 (d, J = 6.7, 6H, CH(CH3)2).2 31P NMR (162 MHz, CDCl3): δ 23.0. 13C NMR (101 MHz, CDCl3) δ 134.9 (d, J = 3.0, PhC-4), 133.7 (d, J = 10.0, PhC-2), 130.4 (d, J = 12.5, PhC-3), 119.0 (d, J = 85.3, PhC-1), 30.5 (d, J = 47.4, P-CH2), 24.6 (d, J = 4.3, CHMe2), 24.34 (d, J = 9.2, CH(CH3)2).2 4Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 iso-Butyldiphenylphosphine3 <ul style="display: flex;"><li style="flex:1">P</li><li style="flex:1">THF </li></ul>P Ph Ph Ph <ul style="display: flex;"><li style="flex:1">Cl </li><li style="flex:1">MgBr </li></ul>Ph Chlorodiphenylphosphine (8.5 ml, 46.0 mmol) was transferred from a Young’s flask to a flame-dried Schlenk tube under a nitrogen atmosphere, and dissolved in dry THF (60 ml). The yellow solution was cooled to 0 ˚C and a 2.0 mol L-1 solution of iso-propyl magnesium chloride in Et2O (29 ml, 58 mmol) was added dropwise. The solution became cloudy as addition neared completion. Once addition of the Grignard reagent was complete, the reaction mixture was allowed to warm to room temperature. 31P NMR (inert atmosphere) of a small sample (0.3 ml) of the reaction mixture diluted with dry degassed CDCl3 (0.5 ml) showed it to contain only phosphine (δP = -20 ppm). The reaction mixture was quickly poured into a degassed mixture of CH2Cl2 (150 ml) and saturated NH4Cl solution (150 ml) under a nitrogen atmosphere in a separatory funnel. All remaining manipulations were carried out under inert atmosphere. The biphasic mixture was shaken, and then the organic layer was allowed to drain into a flame-dried round bottom flask (connected to nitrogen supply) containing Na2SO4. After shaking the resulting mixture, the supernatatnt solution was transferred by cannula into a frit, and filtered into a Schlenk flask connected to the frit to remove the drying agent. The solvent was removed from the filtrate in vacuo. The resulting yellow oil was purified by vacuum distillation (10-2 mbar, bath temperature 156 ˚C) using a short range distillation apparatus, giving a clear oil (7.5 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.38 (m, 4H), 7.36 – 7.27 (m, 6H), 1.99 (d, J = 7.0, 2H), 1.68 (dd, J = 14.3, 7.1, 1H), 1.02 (dd, J = 14.0, 6.2, 6H).3 31P NMR (121 MHz, CDCl3) δ -19.9 (lit.3 -19.4) 5Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 Di(iso-butyl)diphenylphosphonium bromide Br MeCN 70 oC <ul style="display: flex;"><li style="flex:1">P</li><li style="flex:1">Br </li></ul>Ph Ph P Ph Ph iso-Butylduphenylphosphine (4.8 ml, 20 mmol) and iso-butyl bromide (6.5 ml, 60 mmol) were dissolved in dry acetonitrile in a flame dried Schlenk flask fitted with a reflux condenser under a nitrogen atmosphere. The solution was stirred for one week at 70 ˚C. Reaction progress was monitored periodically by taking a 31P NMR spectrum of a small sample of the reaction mixture. Once all the phosphine was consumed, the solvent was removed in vacuo, and the residue was crytallised from hot chloroform/ethyl acetate. The resulting white crystals were dried under vacuum in a dessicator containing CaCl2 and P2O5 and stored under argon gas in a glove box. Yield = 6.8 g (90%). 1H NMR (500 MHz, cdcl3) δ 8.00 – 7.93 (m, 4H), 7.81 – 7.75 (m, 2H), 7.73 – 7.66 (m, 4H), 3.35 (dd, J = 12.8, 6.5, 4H), 1.98 – 1.85 (m, 2H), 0.96 (dd, J = 6.7, 0.8, 12H). 13C NMR (101 MHz, CDCl3) δ 134.6 (d, J = 3.0), 133.3 (d, J = 9.4), 130.2 (d, J = 12.0), 118.9 (d, J = 80.9), 30.7 (d, J = 46.6), 24.3 (dd, J = 18.6, 6.8). 31P NMR (162 MHz, CDCl3) δ 26.0. HRMS: Calc. for [M]+ = C20H28P 299.1929; found 299.1928 (0.2 ppm). MP (crystallised from CHCl3/EtOAc) 183-184 °C. 6Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 Benzylmethyldiphenylphosphonium bromide4 Br Et2O Br P Ph Ph P Ph Ph A Schlenk flask was charged with nitrogen using the standard Schlenk pump and fill technique.1 Methyldiphenylphosphine5 (3.50 ml, 18.6 mmol) was transferred from a Young’s flask to the Schlenk flask by nitrogen-flushed syringe. Dry diethyl ether (30 ml) was added to give a clear solution of the phosphine. Benzyl bromide (2.5 ml, 21 mmol) was then added by syringe. The solution turned a cloudy white colour upon addition. The solution was left to stir for 2 days, after which time a white solid was observed in the flask. The solid was isolated by filtration under suction. This solid was recrystallised from hot chlorform/ethyl acetate and the crystals isolated by filtration under suction. The filtrate was retained and yielded further crystals after standing for a period. The crystals (6.51g , 94% yield) were dried in a vacuum dessicator over P2O5 and CaCl2 for several days before being transferred to a glove box under argon. 1H NMR (500 MHz, CDCl3): δ 7.91 (m, 4H, ArH-2), 7.70 (m, 2H, ArH-4), 7.60 (m, 4H, <ul style="display: flex;"><li style="flex:1">PhH-3), 7.27 (m, 2H, ArH-2), 7.20 (m, 1H, ArH-4), 7.13 (m, 2H, ArH-3), 4.91 (d, 2JPH </li><li style="flex:1">=</li></ul>15.4, 2H, CH2), 2.70 (d, 2JPH = 13.7, 3H, CH3). 31P NMR (202 MHz, CDCl3): δ 23.8. 13C NMR (126 MHz, CDCl3): δ 134.5 (d, 4JPC = 3.2 Hz, PhC-4), 132.9 (d, 2JPC = 9.9 Hz, <ul style="display: flex;"><li style="flex:1">3</li><li style="flex:1">4</li></ul>PhC-2), 130.8 (d, 3JPC = 5.6 Hz, ArC-2), 129.8 (d, JPC = 12.6 Hz, PhC-3), 128.7 (d, JPC = 3.6 Hz, ArC-3), 128.1 (d, 5JPC = 4.2 Hz, ArC-4), 127.4 (d, 2JPC = 9.2 Hz, ArC-1), 118.7 (d, 1JPC = 85.0 Hz, PhC-1), 30.5 (d, 1JPC = 47.6 Hz, CH2), 7.1 (d, 1JPC = 56.4 Hz, CH3). HRMS (m/z): Calc. for [M]+ = C20H20P 291.1303; found 291.1296 (2.4 ppm). 7Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 2-Methoxybenzylmethyldiphenylphosphonium chloride Cl <ul style="display: flex;"><li style="flex:1">Et2O </li><li style="flex:1">Cl </li></ul>P Ph Ph P Ph Ph OMe OMe A Schlenk flask was charged with nitrogen using the standard Schlenk pump and fill technique.1 Methyldiphenylphosphine5 (4.1 ml, 4.3 g, 21.6 mmol) was transferred from a Young’s flask to the Schlenk flask by nitrogen-flushed syringe. Dry diethyl ether (35 ml) was added to give a clear solution of the phosphine. 2-methoxybenzyl chloride (3.3 ml, 3.7 g, 23.8 mmol) was then added by syringe. The solution turned a cloudy white colour upon addition. The solution was left to stir for 2 days, after which time a white solid was observed in the flask. The solid was isolated by filtration under suction. This solid was recrystallised from hot chlorform/ethyl acetate and the crystals isolated by filtration under suction. The filtrate was retained and yielded further crystals after standing for a period. The crystals (7.52 g, 98% yield) were dried in a vacuum dessicator over P2O5 and CaCl2 for several days before being transferred to a glove box under argon. 1H NMR (500 MHz, CDCl3): δ 7.82 (m, 4H, PhH-2), 7.71 (m, 2H, PhH-4), 7.64 (m, 1H, ArH-6), 7.60 (m, 4H, PhH-3), 7.23 (m, 1H, ArH-4), 6.87 (m, 1H, ArH-5), 6.66 (m, 1H, <ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">2</li></ul>ArH-3), 4.79 (2H, d, JPH = 15.2, CH2), 3.20 (s, 3H, OCH3), 2.75 (d, JPH = 13.6, 3H, CH3), 31P NMR (202 MHz, CDCl3): δ 22.9. 13C NMR (126 MHz, CDCl3): δ 156.8 (d, JPC = 5.6, ArC-5), 134.5 (d, JPC = 2.8, PhC-4), 133.0 (d, JPC = 10.1, PhC-2), 132.8 (d, JPC = 5.6, ArC-6), 130.0 (d, JPC = 3.9, ArC-4), 1129.7 (d, JPC = 12.3, PhC-3), 121.3 (d, JPC = 3.4, ArC-5), 119.7 (d, JPC = 83.6, PhC-1), <ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">1</li></ul><ul style="display: flex;"><li style="flex:1">115.9 (d, JPC = 7.0, ArC-1), 110.3 (d, JPC = 3.3, ArC-3), 54.8 (s, OCH3), 25.4 (d, JPC </li><li style="flex:1">=</li></ul>48.8, CH2), 8.0 (d, 1JPC = 56.7, CH3). HRMS (m/z): Calc. for [M]+ = C21H22PO 321.1408; found 321.1410 (0.6 ppm). MP (crystallised from CHCl3/EtOAc) 188-191 °C. 8Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012 2-Fluorobenzylmethyldiphenylphosphonium bromide Br Ph <ul style="display: flex;"><li style="flex:1">Et2O </li><li style="flex:1">Br </li></ul>P Ph Ph P F Ph FA Schlenk flask was charged with nitrogen using the standard Schlenk pump and fill technique.1 Methyldiphenylphosphine5 (3.8 ml, 4.05 g, 20 mmol) was transferred from a Young’s flask to the Schlenk flask by nitrogen-flushed syringe. Dry diethyl ether (32 ml) was added to give a clear solution of the phosphine. 2-fluorobenzyl bromide (2.65 ml, 4.16 g, 22 mmol) was then added by syringe. The solution turned a cloudy white colour upon addition. The solution was left to stir for 2 days, after which time a white solid was observed in the flask. The solid was isolated by filtration under suction. This solid was recrystallised from hot chlorform/ethyl acetate and the crystals isolated by filtration under suction. The filtrate was retained and yielded further crystals after standing for a period. The crystals (7.59g, 97% yield) were dried in a vacuum dessicator over P2O5 and CaCl2 for several days before being transferred to a glove box under argon.

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