Supporting Information. Reduction of Tertiary Phosphine Oxides with DIBAL-H

Transcription

1 Supporting Information Reduction of Tertiary hosphine Oxides with DIBAL-H Carl A. Busacca*, Ravinder Raju, Nelu Grinberg, Nizar Haddad, aul-james Jones, Heewon Lee, Jon C. Lorenz, Anjan Saha, and Chris H. Senanayake Dept. of Chemical Development, Boehringer-Ingelheim harmaceuticals, Inc. 900 Ridgebury Rd., Ridgefield, CT Table of Contents. General Comments and References General rocedure for NMR Reactions NMR Figures from Manuscript Text Experimental rocedures and Compound Characterization. NMR Spectra.. S2-S4 S5 S5-S6 S7-S29 S30-S113 S1

2 General Comments. 1 H NMR spectra were recorded at 400, 500, or 600 MHz, 31 NMR spectra were recorded at 202 or 162 MHz, 13 C NMR spectra were recorded at 100, 125, or 150 MHz, and 19F NMR spectra were recorded at 376 MHz. 31 and 19 F NMR chemical shifts were calibrated vs. external 85% H 3 O 4 (δ: 0.0 ppm) and neat C 6 F 6 (δ: ppm), respectively, contained in coaxial insert tubes (Wilmad WGS-5BL). 1 H and 13 C chemical shifts were calibrated vs. the deuterated solvent used. All NMR spectra were collected on spectrometers equipped with a 5 mm BBI probe ( 1 H, 13 C, 31 ) or a 5 mm QN probe ( 19 F), each with z-gradient, at 30 o C, unless otherwise indicated. Where multiplicity is determined for 13 C data, any multiplicity listed first (s,d,t,q) refers to multiplicity with respect to 1 H. If coupling to other nuclei is present ( 19 F, 31, etc.), that coupling constant is listed second, and normally explicitly described. Accurate mass measurements were performed on a Time of Flight mass spectrometer (LC/MSD TOF) operating in a positive electrospray ionization mode with the capillary voltage of 3 kv. The mass spectrometer was tuned and calibrated using a tuning mix prior to sample analysis. Samples were introduced to the mass spectrometer by flow injection using an HLC system. All reagents were used as received unless stated otherwise. Compounds 1, 9, 11, 13, 15, 17, 19-20, 23-24, 43, 46, 48, 49, and DH were commercially available. Of these, 48, and 49 were chromatographed before use. Compound 9 was prepared by the method of Busacca 1, compound 44 was prepared by the method of Willis using excess sulfur in hme 2, and 54 was prepared by the method of Hayashi. 3 DIBAL-H both neat and in solution was used as received, as was TIBAO/hMe. Several items deserve special comment. Neat DIBAL-H is quite pyrophoric, so we used the commercial solutions in cyclohexane, toluene, and CH 2 Cl 2 extensively, which are much easier to handle. In all cases, good inert atmosphere and syringe transfer technique are needed. Needles should immediately be rinsed with hexane or better yet CH 2 Cl 2 (non-flammable) after handling DIBAL-H neat or in solution. Organolauminum solutions will degrade standard septum closures on bottles, so these should be inspected regularly, or use the small metal S2

3 cylinders with ball valves (such as Aldrich -Sure/ac) for longevity. A 19/35 septum may be inverted and wired on to these valves for convenient use. When ball valves are closed, they are truly closed. These DIBAL-H reductions are somewhat exothermic, and they generate gas. The gas is probably a mixture of H 2 with lesser amounts of isobutane and isobutene 1, so reactor venting will be needed for reactions performed on a larger scale. The workup of these reductions is quite important. The reactions are generally diluted with additional organic solvent, then cooled to 0 o C and quenched with aqueous NaOH. The additional organic solvent is added prior to the quench so that any dissolved oxygen inadvertently introduced with this solvent will lead to minimal oxidation of the product, since the environment is still strongly reducing at this point. The quench must be done slowly, particularly for the first ~10% of the NaOH addition. This quench is quite vigorous, with exotherms and gas evolutions typical of hydride quenches. This initial quench seems to correspond to quenching the active hydride, NOT quenching the C-Al bonds present. The last hydrolysis of the C-Al bonds requires a few minutes at ambient temperature to go to completion, and we incompletely quenched several of these reductions at low temperature before we learned this. Aqueous NaOH solutions of 3-6N concentration are the key to effective hydrolysis and formation of two clear phases free of any gels. We pass the organic solution from the aqueous/organic partition through a pad of silica gel without concentrating it first. This is critical, because we have shown by aluminum analysis that omitting this step can lead to crude products containing about 1% aluminum by weight. In addition, these crude materials are made highly insoluble by the extracted aluminum matrix, making further chromatographic purification difficult. Simply passing the dilute solution through silica gel appears to remove all aluminum. We normally chose solvents such as MTBE and CH 2 Cl 2 for this silica gel treatment so that the very non-polar phosphines and phosphine borane products will readily elute, while any phosphine oxide or other polar impurities will be retained. As phosphines become more electron-rich, they become more prone to air oxidation. We generally converted phosphines containing one or more alkyl groups to the phosphine borane in situ for this reason. hosphine borane formation is not instantaneous upon addition of BH 3 /THF. Less basic phosphines and more hindered phosphines react more slowly, and monitoring by 31 NMR is best for a new substrate, where S3

4 formation of a new line-broadened 31 resonance (quadrupolar line broadening by boron) usually in the range of ~ δ 0 to 25 ppm shows the desired product has been formed. It appears that phosphine borane formation is slower in the presence of the organoaluminum species than it is when only the phosphine itself is present. resumably, some time is required for the superior Lewis acid (BH 3 ) to displace the weaker organoaluminum Lewis acids from the phosphine. Standard 31 NMR acquisition pulse sequences use a delay, d1, of about 2 seconds. This rarely causes problems because 31 has 100% isotopic abundance and good signal to noise can be obtained in scans on standard samples. Quantitative 31 NMR requires a longer d1, however, to pick up slowly relaxing nuclei. In most cases we saw no significant difference between d1= 2 seconds and d1= seconds, though for careful quantitation, the longer delay should be used. 1) Busacca, C.A.; Lorenz, J.C.; Grinberg, N.; Haddad, N.; Hrapchak, M.; Latli, B.; Lee, H.; Sabila,.; Saha, A.; Sarvestani, M.; Shen, S.; Varsolona, R.; Wei, X.; Senanayake, C.H. Org. Lett. 2005, 7(19), ) Chapman, C.J.; Frost, C.G.; Gill-Carey, M..; Kociok-Kohn, G.; Mahon, M.F.; Weller, A.S.; Willis, M.C. Tetrahedron:Asymmetry 2003, 14(6), ) Shimada, T.; Kurushima, H.; Hiroaki, C.; Cho, Y.-H.; Hayashi, T. J. Org. Chem. 2001, 66(26), S4

5 General rocedure for Solvent Screening by NMR. A 5 mm X 7 inch screw-cap NMR tube with TFE septum (Wilmad 535-TR-7) was charged with 46 mg diphenylethyl phosphine oxide 1 (0.20 mmol, 1 eq.) and 0.80 ml solvent. The NMR tube was then agitated on a vortex mixer for ~ 2 minutes, generally giving a suspension. To this was then added by syringe 0.14 ml neat DIBAL-H (CAUTION: yrophoric!, 0.80 mmol, 4 eq.). This mixture was then agitated for a full 5 minutes on the vortex mixer, generally giving a clear, colorless solution, with evolution of gas. The tube was then aged at ambient temperature with an Ar line through the NMR tube septum. 31 spectrum were then acquired with proton decoupling and a d1 delay of 5-10 seconds, and the signals integrated to determine percent conversion. NMR Figures from Manuscript Text. h h O 13 CH J C = 73 Hz ppm h h O 13 CH 3 1 J C = 73 Hz ppm FIGURE 1. Isotopically Labeled TO 5: A: NMR, 31 acetone d 6. B: 13 C NMR, acetone d 6, methyl region. See manuscript text for discussion. S5

6 1 J C = 76 Hz 1 J C = 74 Hz ppm ppm ppm ppm FIGURE 2. NMR: Reductions of C-Labeled TO. A: h 13 2 CH 3 =O + DIBAL-H, 4h 30 o C, C 6 D 12.B: h 13 2 CH 3 =O + DIBAL-H + c-hex 3 =O, 4h 30 o C, C 6 D 12. Resonance at δ -24 ppm is product h 13 2 CH 3. Chemical shifts calibrated vs. 85% H 3 O 4 (0 ppm) external reference. See manuscript text for discussion ppm Figure NMR: Reduction of h 2 Et=O at 120 o C. roduct is at δ -11 ppm. See manuscript text for discussion DH(O2) + c-hex3=o, + DIBAL-H, 2h 90C, mes-d Current Data arameters NAME cb56q EXNO 1 ROCNO 1 F2 - Acquisition arameters Date_ Time INSTRUM spect ROBHD 5 mm ABBO BB- ULROG zg30 TD SOLVENT Tol NS 64 SWH Hz FIDRES Hz AQ sec RG 2890 DW usec DE 6.50 usec TE K D sec TD0 1 NUC usec L db SFO MHz F2 - rocessing parameters SI SF MHz WDW EM LB 1.00 Hz C 1.40 Figure NMR: Reduction of DH(O 2 ) to DH with DIBAL-H + c-hex 3 =O. Two hours at 90 o C in mesitylene d 12. DH is at δ -16 ppm. Decoy/Al complex is at ~ δ 65 ppm. See manuscript test for discusion. S ppm

7 2 BH 3 Diphenylethylphosphine borane. 2. A 100 ml 3-neck flask was charged with 0.50 g phosphine oxide 1 (2.1 mmol, 1 eq.), then evacuated/ar filled (2X). 8.7 ml 1M DIBAL-H/C 6 H 12 (8.7 mmol, 4 eq.) was then added via syringe. The resulting mixture was then placed in a pre-equilibrated 72 o C oil bath under Ar. After 14 hours, the mixture was cooled to ambient temperature, then 3.3 ml 1M BH 3 /THF (3.3 mmol, 1.5 eq.) was added via syringe. After 2h at 23 o C, 31 NMR indicated complete conversion to the phosphine borane. 16 ml CH 2 Cl 2 was then added by syringe. After 5 minutes, the reaction mixture was cooled to ~ 0 o C, then 13 ml 6N NaOH was slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via syringe. The mixture was then allowed to warm to ambient temperature and stirred for 15 minutes. The mixture was then transferred to a separatory funnel. The layers were separated and the aqueous phase reextracted with CH 2 Cl 2 (1 X 15 ml). The combined organic phases were dried (MgSO 4 ), and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel eluting with ~ 100 ml 1:1 hexane:ch 2 Cl 2. The solvents were then removed, first under house vacuum, then under high vacuum, to give 0.45 g phosphine borane 2 (91%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 4H), (m, 6H), 2.28 (dq, J = 7.6, 18 Hz, 2H), 1.18 (dt, J = 7.5, 18 Hz, 3H), 1.07 (q, 1 J HB = 91 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: (d, J C = 8.9 Hz), (d, J C = 2.4 Hz), (s, 1 J C = 54 Hz), (d, J C = 9.7 Hz), 18.6 (t, 1 J C = 38 Hz), 7.00 (q). 31 NMR (202 MHz, CDCl 3 ) δ: (J B = 49 Hz). HRMS (M-BH 3 +H) + C 14 H 16 : calculated , observed , difference = ppm. O 5 13 CH 3 Diphenyl- 13 C-methyl phosphine oxide. 5. A flask was charged with 64 ml 0.5M h 2 K/THF (32 mmol, 1 eq.), which was then cooled to -10 o C under Ar. 5.00g 13 CH 3 I (35 mmol, 1 eq.) was then added dropwise via syringe over 10 minutes. After 30 minutes, the bath was removed, and the resultant slurry allowed to warm to ambient temperature. After 12h, the mixture was cooled to 0 o C, then quenched by the slow S7

8 addition of 75 ml H 2 O. The mixture was extracted with Et 2 O (2 X 75 ml), dried (MgSO 4 ), and the solvents removed in vacuo to give a colorless oil. The oil was dissolved in 20 ml MTBE and filtered through a plug of silica gel eluting with additional MTBE. The MTBE was then concentrated to give 7.00 g of a colorless oil which was used immediately. This oil was dissolved in 50 ml acetone and cooled to 0 o C under Ar. 4.0 ml 50% aq. H 2 O 2 (70 mmol, ~2 eq.) ws then added via addition funnel over 10 minutes. After 15 minutes, the reaction mixture was concentrated in vacuo, giving 8 g of a white solid. The solid was nearly fully dissolved in 150 ml boiling MTBE, then filtered hot to remove a small amount of an insoluble impurity. The filtrate was then concentrated in vacuo to give a solid, which was recrystallized from 5 ml boiling EtOAc to give 2.0 g 5 (29% over 2 steps) as colorless needles, which were crushed in a mortar and pestle. Mp C; 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 4H), (m, 2H), (m, 4H), 2.03 (dd, J = 13, 129 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: (s, 1 J C = 101 Hz, 2 J CC = 5.6 Hz), (d, J C = 2.6 Hz), (d, J C = 9.7 Hz), (d, J C = 12 Hz), 16.7 (q, 1 J C = 73 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: (J C = 73 Hz). Anal. Calcd for. C CH 13 O. 0.1[H 2 O] (see 1 H NMR spectrum): C, 71.75; H, Found: C, 71.81; H, HRMS (M+H) + C CH 14 O: calculated , observed , difference = ppm. Triphenylphosphine from h 3 =O A 100 ml 3-neck flask equipped with a thermocouple and addition funnel was evacuated/ar filled (2 X), then charged with 8.0 ml 1M DIBAL-H/C 6 H 12 (8.0 mmol, 4 eq.) by syringe. To this mixture was then added [0.566 g h 3 =O (2.00 mmol, 1 eq.) g c-hex 3 =O (2.00 mmol, 1 eq.)] added neat, at once. The internal temperature rose to a maximum of 32 o C. The flask was then placed in a pre-equilibrated 72 o C oil bath under Ar. After 7 hours, the reaction mixture was cooled to ambient temperature, and 8 ml MTBE was added. After 5 minutes, the mixture was cooled to 0 o C, then 12 S8

9 ml 6N NaOH was slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via the addition funnel. The resultant mixture was stirred vigorously for 5 minutes at 0 o C, then allowed to warm to 23 o C. After 15 minutes, the mixture was transferred to a separatory funnel and the phases were separated. The aqueous layer was then reextracted with MTBE (2 X 10 ml). The combined organics were then dried (MgSO 4 ) and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel eluting with ~ 50 ml MTBE. The eluant was concentrated in vacuo and chromatographed on silica gel eluting with 9:1 Hexane:CH 2 Cl 2 to give 0.48 g triphenylphosphine 12 (91%) as a colorless solid. Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 15H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s, J C = 11 Hz), (d, J C = 20 Hz), (d), (d, J C = 7 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: HRMS (M+H) + C 18 H 16 : calculated , observed , difference = ppm. Triphenylphosphine from h 3 =S A flask was charged with 294 mg h 3 =S (1.00 mmol, 1 eq.) and 4.0 ml hme ml 1.5M DIBAL-H/hMe (4.00 mmol, 4 eq.) was then added by syringe, and the flask placed in a pre-equilibrated 50 o C oil bath under Ar. After 14h, the reaction mixture was cooled to 0 o C and cautiously quenched by the slow addition of 10 ml 3N NaOH. The resulting mixture was extracted with EtOAc (2 X 15 ml), dried (MgSO 4 ), and the solvents (unconcentrated) filtered through a small plug of silica gel, eluting with a further 40 ml EtOAc. The solvents were then removed in vacuo to give a solid which was recrystallized from EtOAc to give 230 mg 12 (88%) as a colorless solid. Spectra identical to that reported above. S9

10 Me BH 3 14 Diphenylmethyl phosphine borane. 14. A 3-neck 250 ml flask with addition funnel was charged with 2.00 g diphenylmethyl phosphine oxide 13 (9.20 mmol, 1 eq.), then 37 ml 1M DIBAL-H/cyclohexane (37 mmol, 4 eq.) was then added via syringe under Ar. The resulting solution was then placed in a pre-equilibrated 72 o C oil bath under Ar. The mixture was aged 8 hours at 72 o C, then cooled to ambient temperature, and then 14 ml 1M BH 3 /THF (14 mmol, 1.5 eq.) was added via syringe. The mixture was aged one hour at ambient temperature, then 40 ml CH 2 Cl 2 was added via syringe. The reaction mixture was then cooled to 0 o C, then the addition funnel was charged with 83 ml 6N NaOH. The NaOH solution was then added slowly (CAUTION:Vigorous reaction!). The bath was removed, the mixture allowed to warm to ambient temperature, and aged 15 minutes at ambient temperature. The mixture was transferred to a separatory funnel, where the upper phase was the organic phase. The phases were separated, and the lower aqueous phase was reextracted with 40 ml CH 2 Cl 2, giving a lower organic phase. All the organic extracts were combined, dried (MgSO 4 ), and filtered. The filtrate (unconcentrated) was then passed through a 50 g pad of silica gel, using 200 ml CH 2 Cl 2 as additional eluant. The solvents were then removed, first under house vacuum, then under high vacuum, to give 1.96 g phosphine borane 14 (99%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 4H), (m, 6H), 1.89 (d, J = 10 Hz, 3H), 1.04 (q, 3H, 1 J HB = 92 Hz). 13 C NMR (125 MHz, CDCl 3 ) δ: (d, J C = 7.6 Hz), (d, J C = 2.3 Hz), (d, J C = 8.0 Hz), 11.9 (q, 1 J C = 32 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: HRMS (M-BH 3 +H) + C 13 H 14 : calculated , observed , difference = ppm. Diphenylcyclohexyl phosphine borane BH 3 A 100 ml 3-neck flask equipped with a thermocouple and addition funnel was charged with 0.50 g phosphine oxide 15 (1.8 mmol, 1 eq.), and 0.52 g c-hex 3 =O (1.8 mmol, 1 eq.). The flask was then evacuated/ar filled (2 X), then 7.2 ml 1M DIBAL-H/C 6 H 12 S10 (7.2 mmol, 4 eq.) was than added via syringe. The reaction mixture was then placed in a pre-equilibrated 72 o C oil bath under Ar. After 16 hours, the mixture was cooled to ambient temperature, then

11 2.3 ml 1M BH 3 /THF (2.3 mmol, 1.5 eq.) was added via syringe. The resultant mixture was then stirred 1 hour at 23 o C, at which time 31 NMR showed complete conversion to the phosphine borane. 14 ml MTBE was then added via syringe. After 5 minutes, the reaction mixture was cooled to 0 o C, then 11 ml 6N NaOH was then slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via addition funnel. The bath was then removed and the reaction mixture allowed to warm to 23 o C. After 15 minutes, it was transferred to a separatory funnel and the phases separated. The aqueous phase was reextracted with MTBE (1 X 15 ml). the combined organics were then dried (MgSO 4 ) and filtered. The filtrate was then passed through a pad of silica gel eluting with ~ 100 ml MTBE. The solvents were then removed in vacuo and the residue chromatographed on silica gel eluting with 4:1 Hex:CH 2 Cl 2 to give g phosphine borane 16 (90%) as a colorless solid. Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 4H), (m, 6H), 2.41 (q, J = 13 Hz, 1H), (m, 2H), (m, 3H), (m, 2H), (m, 4H), 0.97 (q, 3H, 1 J HB = 89 Hz). 13 C NMR (100 MHz, CDCl 3 ) δ: (d, J C = 8.4 Hz), (d, J C = 2.3 Hz), (d, J C = 9.6 Hz), (s), 33.8 (d, 1 J C = 36 Hz), 26.7 (t, J C = 12 Hz), 26.5 (t), 25.8 (t, J C = 1.2 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 18 H 24 B: C, 76.62; H, Found: C, 76.50; H, HRMS (M-BH 3 +H) + C 18 H 22 : calculated , observed , difference = ppm. Biphenyl-2-dicyclohexyl phosphine oxide. 21. O 2 21 A 100 ml flask was charged with 1.75 g biphenyl-2-dicyclohexylphosphine (5.00 mmol, 1 eq.) and 40 ml acetone. To the resulting solution was then added 0.50 ml 50% aq. H 2 O 2 via syringe. After 3 hours, the volatiles were removed in vacuo (25 o C/house vacuum), and the residue dissolved in 20 ml boiling 4:1 hexane:et 2 O, and allowed to cool to ambient S11

12 temperature. The crystals thus formed were filtered, washed with a small amount of hexane, and air dried to give 1.71 g of phosphine oxide 21 (93%) as a colorless crystalline solid. Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 1H), (m, 2H), (m, 3H), (m, 3H), (m, 22H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s, J C = 9 Hz), (s, J C = 2.1 Hz), (d, J C = 6.1 Hz), (d, J C = 10 Hz), (d, J C = 2.4 Hz), (s, 1 J C = 81 Hz), (d), (d), (d), (d, J C = 9.8 Hz), 38.0 (d, 1 J C = 65 Hz), (t), (t), (t), (t), (t), (t), 26.1 (t), 25.5 (t). 31 NMR (162 MHz, CDCl 3 ) δ: Anal. Calcd for. C 24 H 31 O. [1.5 H 2 O]: : C, 73.26; H, Found: C, 72.98; H, HRMS (M+H) + C 24 H 32 O: calculated , observed , difference = ppm. O Me henyl-methyl-t-butyl phosphine oxide. 22. A 100 ml flask was charged with 2.00 g phenyl-t-butyl phosphineoxide 1 (11.0 mmol, 1 eq.) 22 and 18 ml anhydrous DMSO at 23 o C under Ar ml 12N KOH (14.7 mmol, 1.34 eq.) was then added via syringe, causing a yellow solution to form. This solution was aged 15 minutes, then 0.92 ml MeI (14.7 mmol, 1.34 eq.) was then added via syringe over 5 minutes, giving a colorless solution. The mixture was aged 15 minutes, then 25 ml H 2 O was added. The mixture was then extracted with Et 2 O (2 X 100 ml), and the organic phases were discarded. The ph of the aqueous phase was then adjusted to 1.0 with 6N HCl, and then extracted with EtOAc (2 X 150 ml). The combined organics were washed with H 2 O (1 X 200 ml), dried (MgSO 4 ), and the solvents removed in vacuo to give a viscous yellow oil, which crystallized on standing. The resultant solid was then recrystallized from 5 ml boiling hexane to give 0.80 g 22 (37%) as a light yellow solid. Mp C; 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 2H), 7.54 (t, J = 7.2 Hz, 1H), (m, 2H), 1.76 (d, 2 J H = 12.2 Hz, 3H), 1.14 (d, 3 J H = 15 Hz, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s, 1 J C = 90 Hz), (d, J C = 8 Hz), (d, J C = 11 Hz), 32.3 (s, 1 J C = 71 Hz), 24.1 (q), 10.1 (q, 1 J C = 66 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for C 11 H 17 O. [0.5 H 2 O]: C, 64.38; S12

13 H, Found: C, 64.58; H, HRMS (M+H) + C 11 H 18 O: calculated , observed , difference = ppm. Me BH 3 Me 25 henyl-dimethyl phosphine borane. 25. A 100 ml 2-neck flask equipped with an addition funnel was charged with 0.50 g phosphine oxide 19 (3.2 mmol, 1 eq.), then evacuated/ar filled (2 X). 13 ml 1M DIBAL-H/C 6 H 12 (13 mmol, 4 eq.) was then added via syringe. The resultant mixture was then placed in a pre-equilibrated 72 o C oil bath under Ar. After 4 hours, the reaction was cooled to ambient temperature, then 4.9 ml 1M BH 3 /THF (4.9 mmol, 1.5 eq.) was added by syringe. The mixture was then stirred for one hour, then 15 ml CH 2 Cl 2 was added via syringe. The reaction mixture was then cooled to 0 o C, and 20 ml 6N NaOH was slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via the addition funnel. The cold bath was then removed and the mixture allowed to warm to ambient temperature. After 15 minutes, the mixture was transferred to a separatory funnel. The aqueous phase was then reextracted with CH 2 Cl 2 (1 X 15 ml). The combined organics were then dried (MgSO 4 ), and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel, eluting with ~ 70 ml CH 2 Cl 2. The solvents were then removed, first under house vacuum, then under high vacuum, to give 0.48 g of phosphine borane 25 (97%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 2H), (m, 3H), 1.57 (d, 2 J H = 10 Hz, 6H), 0.82 (qd, 1 J HB = 95 Hz, 2 J H = 15 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: (d, J C = 2.4 Hz), (d, J C = 9.5 Hz), (d, J C = 10 Hz), 12.7 (q, 1 J C = 39 Hz). 31 NMR (162 MHz, CDCl 3 ) δ: HRMS (M-BH 3 +H) + C 8 H 12 : calculated , observed , difference = ppm. henyldicyclohexyl phosphine borane BH 3 A 50 ml 2-neck flask was charged with 0.50 g phosphine oxide 20 (1.70 mmol, 1 eq.) and 5.7 ml of ethylcyclohexane. To the resulting suspension, stirring under Ar at ambient temperature, was then added 1.20 ml neat DIBAL-H (6.90 mmol, 4 eq.) via syringe. The reaction mixture was then placed in a pre-equilibrated 125 o C oil bath under Ar. After 15 hours, S13

14 the reaction mixture was cooled to ambient temperature. 2.6 ml 1M BH 3 /THF (2.6 mmol, 1.5 eq.) was then added, and the mixture stirred for 2 hours at 23 o C. 10 ml CH 2 Cl 2 was then added via syringe, and the mixture cooled to 0 o C under Ar. 11 ml 6N NaOH was then slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via syringe. The bath was then removed, and the reaction mixture allowed to warm to ambient temperature. After 15 minutes, the mixture was transferred to a separatory funnel, and the layers separated. The aqueous phase was reextracted with CH 2 Cl 2 (1 X 20 ml). The combined organics were then dried (MgSO 4 ), and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel eluting with ~ 50 ml CH 2 Cl 2. The solvents were then removed, first under house vacuum, then under high vacuum, to give g phosphine borane 26 (90%) as a colorless solid. Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 2H), (m, 3H), 1.84 (q, J = 11 Hz, 2H), (m, 2H), (m, 8H), (m, 10H), 0.39 (q, J = 85 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: (d, J C = 7.5 Hz), (d, J C = 2.3 Hz), (d, J C = 9.1 Hz), (s, 1 J C = 48 Hz), 31.3 (d, 1 J C = 34 Hz), 26.8 (t, J C = 2.9 Hz), 26.7 (t), 26.5 (t), 26.2 (t, J C = 2.7 Hz), 25.9 (t, J C = 1.0 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 18 H 30 B: C, 75.01; H, Found: C, 74.89; H, HRMS (M-BH 3 +H) + C 18 H 28 : calculated , observed , difference = ppm. Me BH 3 henyl-methyl-t-butyl phosphine borane. 28. A 100 ml 3-neck flask equipped with a thermocouple and addition funnel was charged 28 with 0.48 g phosphine oxide 22 (2.40 mmol, 1 eq.), and 0.69 g c-hex 3 =O (2.40 mmol, 1 eq.). The flask was then evacuated/ar filled (2 X), then 9.6 ml 1M DIBAL-H/C 6 H 12 (9.6 mmol, 4 eq.) was added via syringe. The reaction mixture was then placed in a pre-equilibrated 72 o C oil bath under Ar. After 7 hours, the mixture was cooled to ambient temperature, then 3.6 ml 1M BH 3 /THF (3.6 mmol, 1.5 eq.) was added via syringe. The resultant mixture was then stirred 2 hours at 23 o C, at which time 31 NMR showed complete conversion to the phosphine borane. 15 ml MTBE was then added via syringe. S14

15 After 5 minutes, the reaction mixture was cooled to 0 o C, then 16 ml 6N NaOH was slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via addition funnel. The bath was then removed and the reaction mixture allowed to warm to 23 o C. After 15 minutes, it was transferred to a separatory funnel and the phases separated. The aqueous phase was reextracted with MTBE (1 X 15 ml). The combined organics were then dried (MgSO 4 ) and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel eluting with ~ 100 ml MTBE. The solvents were then removed, first under house vacuum, then under high vacuum, to give g phosphine borane 28 (89%) as a colorless oil, which crystallized on standing. Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 2H), (m, 3H), 1.58 (d, J = 9.6 Hz, 3H), 1.12 (d, J = 14 Hz, 9H), 0.73 (q, J = 97 Hz, 3H). 1 H NMR (500 MHz, DMSO d 6 ) δ: 7.71 (m, 2H), 7.46 (m, 3H), 1.56 (d, J = 9.4 Hz, 3H), 1.11 (d, J = 14 Hz, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ: (d, J C = 8.2 Hz), (d, J C = 2.5 Hz), (d, J C = 9.4 Hz), (s, 1 J C = 50 Hz), 28.4 (s, 1 J C = 33 Hz), 25.2 (q, 2 J C = 3 Hz), 5.2 (q, 1 J C = 37 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: ( 1 J B = 57 Hz). HRMS (M-BH 3 +H) + C 11 H 18 : calculated , observed , difference = ppm. 29 BH 3 Tri-n-butyl phosphine borane. 29. A 100 ml 2-neck flask equipped with an addition funnel was charged with 0.50 g phosphine oxide 23 (2.30 mmol, 1 eq.), then evacuated/ar filled (2 X). 9.2 ml 1M DIBAL-H/C 6 H 12 (9.2 mmol, 4 eq.) was then added via syringe. The resultant mixture was then placed in a pre-equilibrated 72 o C oil bath under Ar. After 4 hours, the reaction was cooled to ambient temperature, then 3.4 ml 1M BH 3 /THF (3.4 mmol, 1.5 eq.) was added by syringe. The mixture was then stirred for one hour, then 12 ml CH 2 Cl 2 was added via syringe. The reaction mixture was then cooled to 0 o C, and 13 ml 6N NaOH was slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via the addition funnel. The S15

16 cold bath was then removed and the mixture allowed to warm to ambient temperature. After 15 minutes, the mixture was transferred to a separatory funnel. The lower aqueous phase was then reextracted with CH 2 Cl 2 (1 X 12 ml). The combined organics were then dried (MgSO 4 ), and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel, eluting with ~ 70 ml CH 2 Cl 2. The solvents were then removed, first under house vacuum, then under high vacuum, to give 0.48 g of phosphine borane 29 (97%) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 6H), (m, 12H), 0.87 (t, J = 7.1 Hz, 9H), 0.13 (q, 1 J HB = 98 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 24.5 (t, J C = 2.0 Hz), 24.1 (t, J C = 13 Hz), 22.6 (t, 1 J C = 35 Hz), 13.3 (q). 31 NMR (162 MHz, CDCl 3 ) δ: ( 1 J B = 71 Hz). HRMS (M-BH 3 +H) + C 12 H 28 : calculated , observed , difference = ppm. Me BH 3 Me Me 30 Trimethyl phosphine borane. 30. A 3-neck 100 ml flask was charged with 0.50 g trimethylphosphine oxide 24 (5.4 mmol, 1 eq.) and the flask cooled to 0 o C under Ar ml 1.0M DIBAL-H/cyclohexane 21.7 mmol, 4 eq.) was then slowly added by syringe. The resultant mixture was stirred for 15 minutes at 0 o C, then the bath was removed, and the mixture allowed to warm to 23 o C. The mixture was aged 15 hours, then 8.1 ml 1.0M BH 3 /THF (8.1 mmol, 1.5 eq.) was added slowly at ambient temperature. After 30 minutes, 31 NMR of an aliquot showed phosphine borane formation was complete. 20 ml MTBE was then charged, and the mixture cooled to 0 o C under Ar. 33 ml 6N NaOH was then added very slowly (CAUTION: Vigorous reaction!) by syringe. The bath was then removed, the mixture allowed to warm to ambient temperature, and stirred for 15 minutes at 23 o C. The mixture was then transferred to a separatory funnel, the phases were separated, and the aqueous phase reextracted with 20 ml MTBE. The combined organic extracts were dried (MgSO 4 ) and filtered, and the filtrate (unconcentrated) was passed through a 30 g pad of silica gel, using 200 ml CH 2 Cl 2 as additional eluant. The solvents were removed in vacuo, first under house vacuum, then under high vacuum, to S16

17 give g (99%) of phosphine borane 30 as a colorless solid. Mp 101 C; 1 H NMR (400 MHz, CDCl 3 ) δ: 1.27 (d, J = 11 Hz, 9H), 0.42 (qd, 2 J H = 16, 1 J HB = 95 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: 12.8 (q, 1 J C = 38 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: ( 1 J B = 63 Hz). HRMS (M-BH 3 +H) + C 3 H 10 : calculated , observed , difference = ppm. F 3 C O F 3 C CF 3 31 Tri-(p-Trifluoromethylphenyl)phosphine oxide. 31. A 100 ml 2-neck flask was charged with 1.00g tertiary phosphine (2.14 mmol, 1 eq.) and 15 ml CH 2 Cl 2. The resulting solution was then cooled to 0 o C. To this solution was then added 0.12 ml 50% aq. H 2 O 2 (2.14 mmol, 1 eq.) via syringe. After 45 minutes, HLC indicated the oxidation was complete. 30 ml H 2 O was added, the phases were separated, and the aqueous phase reextracted with CH 2 Cl 2 (1 X 20 ml). The combined organic phases were then dried (MgSO 4 ), and the solvents removed in vacuo to give a solid. This solid was then chromatographed on silica gel eluting with 50:1 CH 2 Cl 2 :MeOH to give 1.00g phosphine oxide 31 (97%) as a colorless solid. Mp C; 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 12H). 13 C NMR (125 MHz, CDCl 3 ) δ: (s, 1 J C = 102 Hz), (s, 2 J CF = 35 Hz, 4 J C = 3 Hz), (d, 2 J C = 10 Hz), (d, 3 J CF = 4 Hz, 3 J C = 12 Hz), (s, 1 J CF = 271 Hz). 19 F NMR (376 MHz, CDCl 3 ) δ: NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 21 H 12 F 9 O: C, 52.30; H, Found: C, 51.90; H, HRMS (M+H) + C 21 H 13 F 9 O: calculated , observed , difference = ppm. Cl Tri-(p-chlorophenyl)phosphine oxide. 32. O A 100 ml 2-neck flask was charged with 3.00g tertiary phosphine (8.20 mmol, 1 eq.) and 40 ml CH 2 Cl 2. The resulting solution was then cooled to 0 o C. To this Cl Cl 32 solution was then added 0.47 ml 50% aq. H 2 O 2 (8.20 mmol, 1 eq.) via syringe. After 30 minutes, 31 NMR indicated the oxidation was complete. 50 ml H 2 O was added, the phases were separated, and the aqueous phase reextracted with CH 2 Cl 2 (1 X 40 ml). The combined organic phases were S17

18 then dried (MgSO 4 ), and the solvents removed in vacuo to give a solid. This solid was then chromatographed on silica gel eluting with 50:1 CH 2 Cl 2 :MeOH to give 2.80 g phosphine oxide 32 (90%) as a colorless solid. Mp C; 1 H NMR (500 MHz, CDCl 3 ) δ: 7.58 (dd, J = 8.4, 12 Hz, 6H), 7.47 (dd, J = 2.1, 8.4 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s, 4 J C = 3.3 Hz), (d, J C = 11 Hz), (s, 1 J C = 106 Hz), (J C = 13 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 18 H 12 Cl 3 O: C, 56.65; H, Found: C, 56.56; H, HRMS (M+H) + C 18 H 13 Cl 3 O: calculated , observed , difference = ppm. CF 3 Tri-(p-Trifluoromethylphenyl)phosphine. 36. A 100 ml 3-neck flask equipped with a thermocouple and addition funnel was F 3 C CF 3 36 charged with 0.50 g phosphine oxide 31 (1.00 mmol, 1 eq.), and 0.30 g c- Hex 3 =O (1.00 mmol, 1 eq.). The flask was then evacuated/ar filled (2 X), then 4.0 ml 1M DIBAL-H/C 6 H 12 (4.0 mmol, 4 eq.) was added via syringe. The reaction mixture was then placed in a pre-equilibrated 72 o C oil bath under Ar. After 14 hours, the mixture was cooled to ambient temperature, then 8.0 ml MTBE was added via syringe. After 5 minutes, the reaction mixture was cooled to 0 o C, then 6 ml 6N NaOH was slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via addition funnel. The bath was then removed and the reaction mixture allowed to warm to 23 o C. After 15 minutes, it was transferred to a separatory funnel and the phases separated. The aqueous phase was reextracted with MTBE (1 X 8 ml). The combined organics were then dried (MgSO 4 ) and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel eluting with ~ 300 ml hexanes. The solvents were then removed, first under house vacuum, then under high vacuum, to give g phosphine 36 (93%) as a colorless solid. Mp 70 C (dec.); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.65 (d, J = 7.8 Hz, 6H), 7.43 (t, J = 7.6 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s, 1 J C = 14 Hz), (d, J C = 20 Hz), (s, 2 J CF = 32 Hz), (d, 6 lines, J CF + J C ), (s, 1 J CF = 272 Hz). 19 F NMR S18

19 (376 MHz, CDCl 3 ) δ: NMR (202 MHz, CDCl 3 ) δ: HRMS (M+H) + C 21 H 13 F 9 : calculated , observed , difference = ppm. Cl Tri-(p-chlorophenyl)phosphine. 37. A 3-neck 50 ml flask was charged with 0.50 g of phosphine oxide 32 (1.3 mmol, 1 eq.) and g c-hex 3 =O (1.3 mmol, 1 eq.). To this mixture under Ar was Cl 37 Cl then added 5.2 ml 1 M DIBAL-H/cyclohexane (5.2 mmol, 4 eq.) via syringe. The flask was then placed in a pre-equilibrated 72 o C oil bath, and aged for 15 hours. The reaction mixture was then cooled to ambient temperature and 10 ml MTBE added via syringe. The mixture was then cooled to 0 o C and quenched by the very slow addition (CAUTION!:Vigorous reaction! Gas evolution!) of 8 ml 6N NaOH. The cold bath was then removed, and the mixture allowed to warm to ambient temperature, and aged for a full 20 minutes at ambient temperature. The mixture was then transferred to a separatory funnel, the phases were separated, and the aqueous phase reextracted with 10 ml MTBE. The combined organic phases were dried (MgSO 4 ) and filtered. The filtrate (unconcentrated) was then passed through a 25 g pad of silica gel, using 200 ml hexanes as additional eluant. The organic solvents were removed in vacuo to give g of tertiary phosphine 37 (98%) as a colorless solid. Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: (d, J = 8 Hz, 6H), (t, J = 8 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s), (d, J C = 21 Hz), (s, J C = 11 Hz), (d, J C = 7.2 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 18 H 12 Cl 3 : C, 59.13; H, Found: C, 59.19; H, HRMS (M+H) + C 18 H 13 Cl 3 : calculated , observed , difference = ppm. S19

20 F Me O henyl-(3,5-difluorophenyl)-methyl phosphine oxide. 41. A 3 neck 1L flask with addition funnel, thermocouple, and inert gas inlet was charged F 41 with 39.5 ml 3,5-difluorobromobenzene (343 mmol, 2.2 eq.) and 150 ml THF. The resulting solution was cooled in a CO 2 /acetone bath. When the internal temperature reached -70 o C, ml 2M i-rmgcl/thf (343 mmol, 2 eq.) was added dropwise via addition funnel over 40 minutes. The cold bath was then removed and the mixture allowed to warm to ambient temperature. HLC of a quenched aliquot showed only 90% conversion, so a further 17.2 ml 2M i-rmgcl/thf was added at 0 o C, and again allowed to warm to 23 o C. The reaction mixture was again cooled to -70 o C, then 25 ml ethylphenyl phosphinate (94%, 156 mmol, 1 eq.) in 25 ml THF was then added dropwise via addition funnel over 10 minutes. The bath was removed and the mixture allowed to warm to 23 o C. The mixture was then cooled to 0 o C, then cautiously quenched by the addition of 200 ml 3N HCl. The phases were separated, and the aqueous phase reextracted with 250 ml EtOAc. The combined organics were washed with H 2 O (1 X 500 ml), sat d NaHCO 3 (1 X 500 ml), dried (MgSO 4 ), and the solvents removed, first under house vacuum, then under high vacuum to give 37 g of a viscous, light yellow oil. This oil was dissolved in 25 ml EtOAc and filtered through a pad of silica gel (700 cm 3 ) eluting with 1.5 L EtOAc to give 32g (86%) of the intermediate secondary phosphine oxide (SO) as a colorless oil. Anal. Calc d for C 12 H 9 F 2 O MH + : , Found: A 3-neck 100 ml flask was equipped with an addition funnel and a short path condenser to a chilled (-78 o C) receiver. The flask was charged with 4.60 g of the SO (18.2 mmol, 1 eq.) and 20 ml CH 2 Cl 2. To the solution was then added 12.8 ml 2M Cl 3 /CH 2 Cl 2 (25.6 mmol, 1.4 eq.) via addition funnel over 15 minutes under Ar. After 2h, chlorophosphine formation was complete. The volatiles were then removed by distillation at ambient temperature into the chilled receiver, using house vacuum first, then high vacuum. After 15 minutes at ~ 1mm Hg, a mobile, light yellow oil remained in the reaction flask. Vacuum was released to Ar, then 12 ml THF was added via addition funnel, and the resulting solution was cooled to 0 o C under Ar. 12 ml 3M MeMgBr/THF (36 mmol, 2 eq.) was then added dropwise via addition funnel over 15 minutes. The mixture was aged 15 minutes at 0 o C, and formation of the tertiary phosphine was complete. The mixture was then cautiously S20

21 quenched by the addition of 30 ml 3N HCl. 30 ml MTBE was added, and the phase were separated, and the aqueous phase reextracted with 30 ml MTBE. The combined organic phases were washed with H 2 O (1 X 50 ml), 0.5N NaOH (1 X 50 ml), dried (MgSO 4 ), and the solvents removed in vacuo. The residue was then dissolved in 25 ml THF, cooled to 0 o C, and then 1.6 ml 50% H 2 O 2 (28 mmol, 1.5 eq.) was added dropwise via syringe. The bath was then removed, and the reaction mixture allowed to warm to 23 o C. 50 ml MTBE and 50 ml H 2 O were added, the phases separated, and the aqueous phase reextracted with 50 ml MTBE. The combined organics were washed with 0.5N HCl (1 X 50 ml), dried (MgSO 4 ), and the solvents removed in vacuo to give a white solid. The solid was suspended in 20 ml boiling hexane, then EtOAc was slowly added until a clear solution was just obtained (~15 ml EtOAc). On cooling, 2.60 g 41 (57% from SO intermediate) was obtained as a colorless crystalline solid. Mp C; 1 H NMR (500 MHz, CDCl 3 ) δ: (m, 2H), (m, 1H), (m, 2H), (m, 2H), (m, 1H), 2.03 (d, 2 J H = 13 Hz, 3H). 13 C NMR (125 MHz, CDCl 3 ) δ: (s, 8 lines, 1 J CF = 253 Hz, J CF, C = 11 Hz, 19 Hz), (s, 6 lines, 1 J C = 97 Hz, J CF, C = 6.6 Hz, 6.6 Hz), (s, 1 J C = 103 Hz), (d, J C = 3 Hz), (d, J C = 10 Hz), (d, J C = 12 Hz), (d, 8 lines, J CF + J C ), (d, 6 lines, J CF + J C ), 16.0 (q, 1 J C = 74 Hz). 19 F NMR (376 MHz, CDCl 3 ) δ: NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 13 H 11 F 2 O: C, 61.91; H, Found: C, 61.56; H, HRMS (M+H) + C 13 H 12 F 2 O: calculated , observed , difference = ppm. F Me O (+)-henyl-(3,5-difluorophenyl)-methyl phosphine oxide. (+) mg of racemic 41 was chromatographed on a Chiralak Ad-H SFC column, F (+)-41 21mm X 250 mm, 5 micron particle size, ambient temperature, isocratic with 96/4 hexanes/i-roh at 35 ml/minute, 40 minute run time, analysis wavelength 230 nm. The retention time (RT) of the enatiomers were 27 and 30 minutes, giving partial (non-baseline) separation of the two enantiomers. Following multiple injections, the later eluting fractions were pooled and concentrated in vacuo to give 25 mg of a colorless solid. Analytical chiral HLC showed the material to be 79% ee. The S21

22 optical rotation of the later eluting peak was: α D = + 10 (c 1.66, CH 2 Cl 2 ). Analytical chiral HLC was carried out on a Chiralpak AD-H column, 4.6 X 250 mm, 5 micron particle size, 97/3 heptane/i-roh, 2.0 ml/minute, isocratic at 20 o C, 5 μl injection volume, 30 minute run time, analysis wavelength 230 nm. The first peak eluted (RT 19.6 minutes) was the (-)-isomer, while the (+)-isomer eluted with RT 21.1 minutes. F Me henyl-(3,5-difluorophenyl)-methyl phosphine. 42. A 3-neck 50 ml flask was charged with 0.50 g of phosphine oxide 41 (2.00 mmol, 1 F 42 eq.) and 0.59 g c-hex 3 =O (2.00 mmol, 1 eq.). To this mixture under Ar was then added 8.0 ml 1 M DIBAL-H/cyclohexane (8.0 mmol, 4 eq.) via syringe. The flask was then placed in a pre-equilibrated 72 o C oil bath, and aged for 15 hours. The reaction mixture was then cooled to ambient temperature and 16 ml MTBE added via syringe. The mixture was then cooled to 0 o C and quenched by the very slow addition (CAUTION!:Vigorous reaction! Gas evolution!) of 12 ml 6N NaOH. The cold bath was then removed, and the mixture allowed to warm to ambient temperature, and aged for a full 20 minutes at ambient temperature. The mixture was then transferred to a separatory funnel, the phases were separated, and the aqueous phase reextracted with 10 ml MTBE. The combined organic phases were dried (MgSO 4 ) and filtered. The filtrate (unconcentrated) was then passed through a 25 g pad of silica gel, using 200 ml hexanes as additional eluant. The organic solvents were removed in vacuo to give g of tertiary phosphine 42 (98%) as a colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 2H), (m, 3H), 6.92 (t, J = 5.9 Hz, 2H), 6.76 (t, J = 9.0 Hz, 1H), 1.66 (d, J = 3.9 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s, 8 lines, 1 J CF = 249 Hz, J CF, C = 8 Hz, 12 Hz), (s, 6 lines, J CF + J C ), (d, J = 20 Hz), (d), (d, J = 7 Hz), (d, 6 lines, J CF + J C ), (d, J = 25 Hz), 29.8 (s), 12.2 (q, 1 J C = 15 Hz). 19 F NMR (376 MHz, CDCl 3 ) δ: NMR (162 MHz, CDCl 3 ) δ: HRMS (M+H) + C 13 H 12 F 2 : calculated , observed , difference = ppm. S22

23 (rac)-bina (S 2 ) 44. This follows the method of Willis. 2 S h 2 h 2 S A 50 ml flask equipped with a reflux condenser was charged with 2.00 g racemic BINA (3.21 mmol, 1 eq.), g sulfur (7.07 mmol, 2.2 eq.), and 25 ml C 6 H 6. The resultant slurry was then heated to reflux under Ar. After 3 hours, an additional 20 ml 44 C 6 H 6 was added to aid solubility. After 6 hours total time at reflux, 31 NMR showed reaction complete to the bis-phosphine sulfide. The reaction mixture was then cooled, and the volatiles removed in vacuo. The resultant solid was suspended in 15 ml hot C 6 H 6 and filtered hot. After air-drying on the frit for ~ 15 minutes, 1.55 g of bis-sulfide 44 (70%) was obtained as a nearly-colorless solid. Mp > 313 o C. 1 H NMR (500 MHz, CDCl 3 ) δ: 7.79 (dd, J = 1.6, 8.7 Hz, 2H), (m, 8H), 7.48 (dd, J = 7.3, 12 Hz, 2H), 7.40 (m, 2H), (m, 4H), (m, 2H), 6.73 (d, J = 8.6 Hz, 2H), 6.65 (t, J = 7.6 Hz, 2H). 13 C NMR (125 MHz, CDCl 3 ) δ: (s, J C = 5 Hz), (s, J C = 5 Hz), (s), (s), (s, J C = 2 Hz), (s, J C = 12 Hz), (d, J C = 10 Hz), (d, J C = 11 Hz), (s, 1 J C = 84 Hz), (d, J C = 3 Hz), (d, J C = 3 Hz), (d), (d), (s, 1 J C = 84 Hz), (d), (d), (d), (d), (d), (d), (d), (d). 31 NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 44 H 32 2 S 2 : C, 76.95; H, Found: C, 76.95; H, HRMS (M+H) + C 44 H 33 2 S 2 : calculated , observed , difference = ppm. (rac)-bina. 45. h 2 h 2 A flask was charged with 343 mg racemic 44 [BINA(S 2 ) 2 ] (0.50 mmol, 1 eq.) and 3.0 ml hme. To this mixture, stirring at 23 o C under Ar, was then added 2.67 ml 1.5M 45 DIBAL-H/hMe (4.00 mmol, 8 eq.). The resultant mixture was then placed in a preequilibrated 100 o C oil bath under Ar. After 4h, the reaction mixture was cooled to 0 o C, then cautiously quenched by the slow addition of 25 ml 3N NaOH, followed by 25 ml EtOAc. The aqueous phase was reextracted with 25 ml EtOAc, and the combined organics dried (MgSO 4 ), and the solvents (unconcentrated) filtered through a small plug of silica gel, eluting with a further 60 ml EtOAc. The solvents were then removed in vacuo to give a solid which was triturated with hexane, then filtered and air-dried to give S23

24 249 mg 12 (80%) as a colorless solid. Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: 7.89 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.35 (t, J = 7.1 Hz, 2H), (m, 20H), 6.92 (t, J = 6.7 Hz, 2H), 6.83 (d, J = 8.3 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ: (d), (d), (d), (d), (d), (s), (s), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d), (d). 31 NMR (202 MHz, CDCl 3 ) δ: HRMS (M+H) + C 44 H 33 2 : calculated , observed , difference = ppm. Triphenylarsine. 47. A flask was charged with 1.00 g triphenylarsine oxide (3.10 mmol, 1 eq.) and 20 ml As 47 hme at 23 o C under Ar ml 1.5M DIBAL-H/hMe (12.4 mmol, 4 eq.) was then added via syringe, causing an exotherm accompanied by gas evolution. After 30 minutes, TLC showed the reaction was complete to a product which co-eluted with commercial h 3 As. The reaction mixture was poured slowly into a mixture of [25 cm 3 ice + 25 ml 3N NaOH], and the resultant mixture extracted with CH 2 Cl 2 (2 X 100 ml). The combined organics were dried (MgSO 4 ), and the solvents removed in vacuo to give a semi-solid. This material was then chromatographed on silica gel eluting with 4:1 Hex:EtOAc to give, after drying under high vacuum, 868 mg of an oil which rapidly crystallized on standing to give 47 as a colorless solid (91%). Mp C; 1 H NMR (400 MHz, CDCl 3 ) δ: (m, 9H), (m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ: (s), (d), (d), (d). HRMS (M+H) + C 18 H 16 As: calculated , observed , difference = ppm. S24

25 dppe bisborane. 50. H 3 B BH 3 A 50 ml 2-neck flask was charged with 0.50 g dppe-mono-oxide (1.2 mmol, 1 eq.), and was then evacuated/ar filled (2 X). To the flask was then added 4.8 ml 1M DIBAL- H/C 6 H 12 (4.8 mmol, 4 eq.) via syringe. The flask was then placed in a pre-equilibrated o C oil bath under Ar. After 6 hours, 31 NMR indicated the reaction was complete. The reaction mixture was cooled to ambient temperature, then 3.60 ml 1M BH 3 /THF (3.60 mmol, 3 eq.) was then added via syringe. After 1 hour, 31 NMR of an aliquot showed formation of the bis-borane was complete. 15 ml MTBE was then added. After 5 minutes, the reaction mixture was cooled to 0 o C, then 10 ml 6N NaOH was slowly added (CAUTION!:Vigorous reaction! Gas evolution!) via syringe. The bath was then removed, and the mixture allowed to warm to ambient temperature. After 15 minutes, it was transferred to a separatory funnel. The phases were then separated and the aqueous phase reextracted with 15 ml MTBE. The combined organics were then dried (MgSO 4 ), and filtered. The filtrate (unconcentrated) was then passed through a pad of silica gel eluting with ~ 50 ml CH 2 Cl 2. The solvents were then removed in vacuo to give a solid. This solid was then chromatographed on silica gel eluting with 1:1 CH 2 Cl 2 :Hexane to give g dppe bisborane 50 (92%) as a colorless solid. Mp C; 1 H NMR (500 MHz, CDCl 3 ) δ: 7.69 (br s, 8H), (m, 12H), 2.45 (s, 4H), (br m, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ: (d, J C = 4.7 Hz), (d), (d, J C = 5.0 Hz), (s, 1 J C = 55 Hz), 19.5 (t, 1 J C = 37 Hz). 31 NMR (202 MHz, CDCl 3 ) δ: Anal. Calcd for. C 26 H 30 BB2 2 : C, 73.29; H, Found: C, 73.17; H, HRMS (M- BH 3 +H) + C26H 28 B 2 : calculated , observed , difference = ppm. S25