Organic Syntheses, Vol. 83, p.1 (2006).
PREPARATION OF ENANTIOMERICALLY PURE (R,R)-BozPHOS
[(2R,5R)-1-{2-[(2R,5R)-2,5-dimethylphospholan-1-yl]phenyl}-2,5-dimethylphospholane 1-oxide]
Submitted by Alexandre Côté, Jean-Nicolas Desrosiers, Alessandro A. Boezio, and André B. Charette1.
Checked by Scott E. Denmark and Justin I. Montgomery.
1. Procedure
(2R,5R)-1-{2-[(2R,5R)-2,5-dimethylphospholan-1-yl]phenyl}-2,5-dimethylphospholane 1-oxide (R,R)-BozPHOS. A flame-dried, 100-mL, one-necked, round-bottomed flask equipped with an egg-shaped magnetic stirring bar and a rubber septum is charged with (R,R)-Me-DuPHOS (1 g, 3.26 mmol) (Note 1) in a glove-box under argon. Anhydrous THF (32 mL) (Note 2) is added to the flask via a syringe under argon and the resulting colorless solution is cooled in a 0 °C ice bath for 15 min before BH3·DMS 10 M (360 µL, 3.6 mmol) (Note 3) is added dropwise (Note 4) via a syringe. The colorless mixture is stirred for 45 min under argon at 0 °C and H2O2 35% wt. (3 × 1.15 mL, 39.2 mmol) (Note 5) is added dropwise via syringe (Note 6) at 0 °C under argon in three portions with an interval of 30 min between each addition. The mixture is stirred for an additional 45 min at room temperature, and the reaction is quenched by the dropwise addition via cannula of a saturated aqueous solution of Na2SO3 (40 mL) at 0 °C over 30 min (Note 7). The mixture is transferred to a 250-mL separatory funnel and the aqueous layer is extracted with ethyl acetate (3 × 100 mL), and the combined extracts are dried over Na2SO4 (50 g), filtered and concentrated by rotary evaporation (30 °C, 50 mmHg) to afford a white foam (1.115 g) (Note 8). The crude product and DABCO (550 mg, 4.9 mmol) (Note 9) are placed in a 100-mL, one-necked, round-bottomed flask equipped with an egg-shaped magnetic stirring bar and a rubber septum. The flask is purged under argon, then anhydrous benzene (32 mL) (Note 10) is added. The colorless reaction mixture is stirred for 5 h in a 50 °C oil bath and then the solvent is removed by rotary evaporation (25 °C, 40 mmHg) to afford a white residue. The crude product is purified on silica gel (Notes 11, 12) to afford 977 mg (93% yield, >99% ee) of the title compound as a white solid (Notes 13 and 14).
2. Notes
1. (R,R)-Me-DuPHOS was purchased from Strem Chemicals, Inc. Although, it could be briefly manipulated under moisture and oxygen, it was stored under argon atmosphere in a glove-box to prevent any undesired oxidation. It was used without any prior purification.
2. Anhydrous THF was obtained by filtration through a drying column on a GlassContour system (Irvine, CA).
3. Borane·dimethyl sulfide (BH3·DMS) was purchased from Aldrich Chemical Company, Inc. and was used without prior purification.
4. The addition lasted 1 minute.
5. H2O2 35% wt. was purchased from Aldrich Chemical Company, Inc. and was used without prior purification.
6. One minute was needed for each addition.
7. The reaction is exothermic and a gas is evolved.
8. The crude product can be stored overnight under argon in a −20 °C freezer with no degradation.
9. DABCO was purchased from Aldrich Chemical Company, Inc. and was recrystallized from a 1:1 mixture of MeOH and hexanes.
10. Anhydrous benzene was obtained by filtration through a drying column on a GlassContour system (Irvine, CA).
11. The product was dissolved in dichloromethane (2 mL) and charged on a column (3 × 15 cm) of 60 g of UltraPure silica gel (40–63 µm) purchased from Silicycle. The product was eluted with 600 mL of 5% MeOH in EtOAc and collected with 8 mL fractions. The desired product was obtained in fractions 16–30, which were combined and concentrated by rotary evaporation (30 °C, 30–50 mmHg). The desired product can be visualized on TLC with a UV lamp or by developing with a KMnO4 solution.
12. No over-oxidation occurred during the chromatography, but the pure compound is typically stored under argon.
13. The physical properties are as follows: Rf 0.33 (5% MeOH in EtOAc) mp 125–127 °C; HRMS (ESI+) m/z calc. for C18H29P2O [M+ + 1]: 323.1694, found: 323.1688; Elemental Analysis calc. for C18H28P2O: C, 67.07; H, 8.75, found: C, 67.13; H, 9.00; IR (neat) cm−1 730, 738, 758, 1116, 1130, 1159, 1253, 1374, 1455, 2860, 2925; 1H NMR pdf (400 MHz, C6D6) δ: 0.85 (dd, J = 17.3, 7.4 Hz, 3 H), 0.91–1.03 (m, 1 H), 1.06 (dd, J = 9.1, 7.1 Hz, 3 H), 1.26–1.37 (m, 2 H), 1.28 (dd, J = 17.6, 8.3 Hz, 3 H), 1.30 (dd, J = 13.7, 6.9 Hz, 3 H), 1.64–1.76 (m, 2 H), 1.84–2.06 (m, 4H), 2.41–2.52 (m, 1 H), 2.58–2.71 (m, 1 H), 2.71–2.83 (m, 1 H), 7.05 (tddd, J = 7.5, 2.6, 1.3, 0.5 Hz, 1 H), 7.13 (tt, J = 7.4, 1.5 Hz, 1 H), 7.27–7.34 (m, 1 H), 7.45–7.50 (m, 1 H); 13C NMR (100 MHz, C6D6) δ: 13.1 (dd, JC-P = 2.9, <1 Hz), 17.5 (d, JC-P = 8.8 Hz), 18.6 (d, JC-P = 3.9 Hz), 20.6 (d, JC-P = 36.1 Hz), 31.7 (dd, JC-P = 67.9, <1 Hz), 31.8 (d, JC-P = 9.8 Hz), 32.2 (dd, JC-P = 8.8, 1.9 Hz), 34.4 (d, JC-P = 11.7 Hz), 35.0 (d, JC-P = 13.6 Hz), 36.5 (d, JC-P = 6.8 Hz), 36.8 (dd, JC-P = 66.9, 4.9 Hz), 36.9 (d, JC-P = 2.0 Hz), 128.5 (d, JC-P = 10.8 Hz), 130.9 (dd, JC-P = 2.9, <1 Hz), 131.5 (dd, JC-P = 11.2, 9.3 Hz), 134.2 (dd, JC-P = 10.7, 2.9 Hz), 140.3 (dd, JC-P = 82.0, 33.2 Hz), 144.0 (dd, JC-P = 37.1, 9.3 Hz); 31P NMR (202 MHz, C6D6) δ: 8.99 (d, J = 4.6 Hz), 62.05 (d, J = 4.6 Hz); [α]D20 −221.6 (c = 0.836, EtOH). The enantiomeric excess of the product is determined by HPLC analysis at 254 nm [Chiralpak AD, 95:5 hexanes: i-PrOH, 1 mL/min: (R,R) tr (major) = 7.3 min, (S,S) tr (minor) = 10.1 min)] or determined by SFC analysis [Chiralpak AD, 20% i-PrOH, 150 bar CO2, 1 mL/min, 65° Cl.
14. The checkers found that the appearance of the NMR spectra was highly concentration dependent. The spectra reported were taken as follows: 1H NMR, 4 mg/1.0 mL; 13C NMR, 309 mg/1.5 mL.
Waste Disposal Information
All hazardous materials should be handled and disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The hemilabile ligand BozPHOS is useful for the copper-catalyzed asymmetric addition of diorganozinc reagents to N-diphenyl-phosphinoylimines.2-5 This bis-phosphine monoxide ligand can be prepared from both enantiomers of the commercially available Me-DuPHOS by mono-oxidation. Various methods have been reported to oxidize bidentate phosphines.6 Among them, Grushin's method involving palladium acetate7 was unsuitable because it afforded a mixture of the unreacted bis-phosphine, its mono-oxide (40%), its bis-oxide and an unidentified phosphonium salt. The procedure described above employs a selective mono-protection of the bis-phosphine with BH3·DMS followed by a mono-oxidation with H2O2. During this process, no bis-oxidation is obtained even if an excess of H2O2 is used. Traces of unreacted Me-DuPHOS can be separated easily by silica gel flash chromatography since BozPHOS is air stable. The procedure described above can be accomplished on a 0.5 to 10 g-scale to obtain BozPHOS in an 87 to 93% yield.
References and Notes
  1. Département de Chimie, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal (Québec) Canada, H3C 3J7.
  2. Desrosiers, J.-N.; Côté, A.; Boezio, A. A.; Charette, A. B. Subsequent procedure in this volume, 2004.
  3. Boezio, A. A.; Pytkowicz, J.; Côté, A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125, 14260–14261.
  4. Côté, A.; Boezio, A. A.; Charette, A. B. Angew. Chem. Int. Ed. 2004, 43, 6525–6528.
  5. Côté, A.; Boezio, A. A.; Charette, A. B. Proc. Natl. Acad. Sci. USA 2004, 101, 5405–5410.
  6. Grushin, V. V. Chem. Rev. 2004, 104, 1629–1662.
  7. Grushin, V. V. J. Am. Chem. Soc. 1999, 121, 5831–5832.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

(R,R)-Me-DuPHOS: Phospholane 1,1'-(1,2-phenylene)bis[2,5-dimethyl-, [2R-[1(2'R∗,5'R∗),2a,5b]]-; (147253-67-6)

DABCO:1,4-Diazabicyclo[2.2.2]octane; (280-57-9)

(R,R)-BozPHOS: Phospholane, 1-[2-[(2R,5R)-2,5-dimethyl-1-oxido-1-phospholanyl]phenyl]-2,5-dimethyl-, (2R,5R)-; (38132-66-8)

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