Org. Synth. 2006, 83, 1
DOI: 10.15227/orgsyn.083.0001
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. Charette
1.
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: R
f 0.33 (
5% MeOH in
EtOAc) mp
125–127 °C; HRMS (ESI
+)
m/z calc. for C
18H
29P
2O [M
+ + 1]: 323.1694, found: 323.1688; Elemental Analysis calc. for C
18H
28P
2O: 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, C
6D
6) 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, C
6D
6) 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, C
6D
6) 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) t
r (major) = 7.3 min, (S,S) t
r (minor) = 10.1 min)] or determined by SFC analysis [Chiralpak AD,
20% i-PrOH, 150 bar CO
2, 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.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
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.
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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