Rapid synthesis of an electron-deficient t-BuPHOX ligand: Cross-coupling of aryl bromides with secondary phosphine oxides

Article abstract of DOI:10.1016/j.tetlet.2010.08.039

Herein an efficient and direct copper-catalyzed coupling of oxazoline-containing aryl bromides with electron-deficient secondary phosphine oxides is reported. The resulting tertiary phosphine oxides can be reduced to prepare a range of PHOX ligands. The p

Full text of DOI:10.1016/j.tetlet.2010.08.039

Tetrahedron Letters 51 (2010) 5550–5554
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Tetrahedron Letters
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Rapid synthesis of an electron-deficient t-BuPHOX ligand: cross-coupling
of aryl bromides with secondary phosphine oxides
⇑
Nolan T. McDougal, Jan Streuff, Herschel Mukherjee, Scott C. Virgil, Brian M. Stoltz
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology,
Pasadena, CA 91125, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein an efficient and direct copper-catalyzed coupling of oxazoline-containing aryl bromides with elec-
tron-deficient secondary phosphine oxides is reported. The resulting tertiary phosphine oxides can be
reduced to prepare a range of PHOX ligands. The presented strategy is a useful alternative to known
methods for constructing PHOX derivatives.
Received 13 May 2010
Revised 11 August 2010
Accepted 12 August 2010
Available online 17 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Phosphinooxazoline (PHOX) ligands have found broad applica-
tions in transition metal catalysis.1 Developed by Pfaltz,2 Helm-
chen,3 and Williams,4 PHOX ligands have become a preeminent
class of P,N-ligands,5 with t-BuPHOX (L1, Scheme 1) representing
a most prominent example.6 We have recently demonstrated the
utility of t-BuPHOX in palladium-catalyzed enantioselective
decarboxylative alkylation7 and protonation8 reactions. We, how-
ever, became aware of examples where t-BuPHOX provided only
moderate results with respect to yields and enantioselectivities,
and designed an electronically-modified version of this ligand, p-
(CF3)3-t-BuPHOX (L2). In some cases, the electron-withdrawing tri-
fluoromethyl groups affected the reactivity of the corresponding
transition metal complex, leading to significantly shorter reaction
times and enhanced selectivities. For example, we were able to
achieve 99% yield and 87% ee in our palladium-catalyzed, enantio-
selective allylic alkylation reaction of allyl enol carbonate 1 within
only 10 min at 25 °C with the use of (S)-L2, while the use of (S)-L1
required 120 min reaction time to give 96% yield and 88% ee.9 Fur-
ther, this ligand was successfully applied in the catalytic asymmet-
ric total synthesis of (+)-elatol where the key allylic alkylation of
chloroallyl enol carbonate 2 was performed with (R)-L2, resulting
in 82% yield of product in 87% ee, compared to only ꢀ81% ee and
a poor 23% yield with the use of (S)-L1.10 Moreover, we recently
published a palladium-catalyzed, enantioselective enolate alkyl-
ation cascade, which provides products with up to 99% enantio-
meric excess,11 where (S)-p-(CF3)3-t-BuPHOX was far superior to
(S)-t-BuPHOX for the alkylation of b-keto ester 3.
secondary phosphines are not commercially available. Similarly,
substituted secondary phosphines (e.g., bis(4-(trifluoromethyl)
phenyl)phosphine) are difficult to prepare in the required purity
due to their propensity to oxidize upon exposure to air.14 Although
the preparation of synthetically challenging PHOX variants was
possible using our previously described conditions, a more efficient
and higher yielding protocol was desired. Therefore a synthetic
strategy for the synthesis of p-(CF3)3-t-BuPHOX (L2) that avoids
phosphine intermediates was needed. We envisioned a preparative
route toward this electron-deficient PHOX ligand in which an oxaz-
oline-containing aryl bromide is joined directly with a secondary
phosphine oxide.15,16 Herein, we demonstrate a copper-catalyzed
coupling of aryl halides to secondary phosphine oxides for the syn-
thesis of electron-deficient PHOX ligands.
Oxazoline-containing aryl bromide 4 and secondary phosphine
oxide 5 can be readily synthesized on multi-gram scale (Scheme 2).
Aryl bromide 4 was prepared using modified conditions from a
published route,10 requiring only one purification by flash chroma-
tography. The treatment of (S)-t-leucinol with acid chloride 67 in
the presence of sodium carbonate provided amide 7 in 93% yield.17
Subsequent mesylation of the free hydroxyl of 7, followed by
in situ mesylate displacement results in the formation of oxazoline
4 in 99% yield.18 Bis(4-(trifluoromethyl)phenyl)phosphine oxide
519 is produced in 80% yield by careful exposure of 4-(trifluoro-
methyl)phenylmagnesium bromide 8, synthesized via the Leazer
method,20 to diethyl phosphite.21 Unlike the related secondary
phosphine, phosphine oxide 5 can be purified by column chroma-
tography and is stable to air at room temperature for several
months.
Previously, we published a convenient and scalable synthesis
for t-BuPHOX,12 using an Ullmann-type coupling developed by
Buchwald.13 While this approach proved useful for the coupling
of aryl halides and secondary phosphines, most substituted
Our modification to Buchwald’s copper iodide-catalyzed condi-
tions for the coupling of secondary phosphines with aryl bro-
mides9,12 was tested for the coupling of secondary phosphine
oxide 5 with oxazolinyl aryl bromide 4 (Table 1, entries 1 and 2).
Gratifyingly, when a catalytic amount of CuI (12.5 mol %) was used
in combination with N,N0-dimethylethylenediamine as ligand and
⇑
Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 564 9297.
E-mail address: stoltz@caltech.edu (B.M. Stoltz).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.039

N. T. McDougal et al. / Tetrahedron Letters 51 (2010) 5550–5554
5551
CF3
O
O
F3C
P
N
P
N
t-Bu
t-Bu
CF3
L2: (S)-p-(CF3)3-t-BuPHOX
L1: (S)-t-BuPHOX
O
(S)-Ligand (12.5 mol %)
Pd2(dba)3 (5 mol %)
O
O
O
THF, 25 °C
(S)-L1: 96% yield, 120 min
(S)-L2: 99% yield, 10 min
88% ee
87% ee
1
Cl
O
(R)-Ligand (12.5 mol %)
Pd(dmdba)2 (10 mol %)
O
O
O
Cl
PhH
HO
Cl
Br
i-BuO
i-BuO
−81% ee
(S)-L1: 23% yield, 24 °C
(R)-L2: 82% yield, 11 °C
(+)-elatol
2
87% ee
CN
Ph
CN
(1.0 equiv)
(S)-Ligand (12.5 mol %)
Pd2(dba)3 (5 mol %)
O
O
O
Ph
O
Ph
+
O
p-dioxane, 40 °C, 48 h
NC CN
NC CN
3
(S)-L1: 82% yield, 3.1:1 d.r.
(S)-L2: 91% yield, 6.1:1 d.r.
63% ee
87% ee
42% ee
77% ee
Scheme 1. PHOX ligands and their use in synthesis and methodology development.
Cs2CO3 as base, secondary phosphine oxide 5 could be successfully
coupled with aryl bromide 4 to produce 9 in 57% yield (entry 1).
Reaction times could be reduced, and product yields improved to
65% with the use of a stoichiometric amount of CuI at a higher reac-
tion concentration (entry 2).22 To our satisfaction, secondary phos-
phine oxide 5 could be coupled with other aryl bromides 10–12 in
moderate to good yields using catalytic amounts of CuI (entries 3–
5). Similarly, bis(3,5-bis(trifluoromethyl)phenyl)phosphine oxide
(13) could be coupled with oxazoline-containing aryl bromides
using catalytic loadings of CuI (entries 6 and 7).
The resulting triarylphosphine oxides 9 and 14–18 can be
smoothly purified by column chromatography and reduced to the
corresponding PHOX ligands via silane reduction.23 For example,
reduction of 9 to the desired p-(CF3)3-t-BuPHOX ligand was accom-
plished with neat diphenylsilane, yielding L2 in 86% isolated yield
(Scheme 3).24
CF3
Cl
CF3
Br
O
CF3
Br
6 (1.1 equiv)
MsCl (1.2 equiv)
Et3N (2.4 equiv)
OH
Na2CO3 (3.0 equiv)
OH
H2N
H
N
O
CH2Cl2 /H2O
23 °C, 10 h
(93% yield)
CH2Cl2
0 → 50 °C, 20 h
(99% yield)
t-Bu
Br
N
O
t-Bu
t-Bu
7
4
t-leucinol
H
EtO
P
O
H
OEt
(0.33 equiv)
F3C
P
O
MgBr
Br
Mg (1.03 equiv)
Et2O
0 → 30 °C, 2 h
Et2O
0 → 20 °C, 18 h
(80% yield)
F3C
F3C
CF3
8
5
Scheme 2. Synthesis of oxazoline-containing aryl bromide 4 and secondary phosphine oxide 5.

5552
N. T. McDougal et al. / Tetrahedron Letters 51 (2010) 5550–5554
Table 1
Copper-catalyzed coupling of aryl bromides with secondary phosphine oxidesa
R1
R1
NHCH3
CuI, H3CHN
Cs2CO3
H
+
Ar
P
O
O
O
R3
R3
R3
R3
PhCH3, 110°C
Ar
Br
N
Ar
P
O N
Ar
R2
R2
Entry
1
Aryl bromide
Secondary phosphine oxide
Product
Yieldb (%)
57
CF3
H
CF3
F3C
P
O
2c
65
O
O
Br
N
F3C
P
O N
CF3
t-Bu
t-Bu
4
5
9
CF3
H
F3C
F3C
F3C
P
O
O
O
Ph
Ph
Ph
Ph
Br
N
10
F3C
P
O
N
3
85
t-Bu
t-Bu
CF3
H
5
5
14
O
CF3
P
O
O
Ph
Ph
Ph
Ph
F3C
P
O N
Br
N
4
62
i-Pr
i-Pr
11
CF3
H
15
CF3
CF3
CF3
Br
P
O
O
O
Ph
Ph
Ph
Ph
5
N
12
F3C
P
O N
55
46
36
CF3
i-Pr
i-Pr
5
16
CF3
O N
F3C
F3C
H
P
F3C
O
O
Ph
Ph
O
Ph
Ph
t-Bu
6
Br
N
P
t-Bu
F3C
F3C
F3C
CF3
10
13
CF3
17
CF3
Br
F3C
F3C
CF3
H
P
O
F3C
O
O
Ph
Ph
Ph
Ph
7
N
P
O N
F3C
CF3
i-Pr
i-Pr
F3C
F3C
13
12
CF3
18
a
Reactions were performed with aryl bromide (1.0 equiv), secondary phosphine oxide (1.3 equiv), CuI (12.5 mol %), N,N0-dimethylethylenediamine (87.5% mol %), and
Cs2CO3 (3.7 equiv) in PhCH3 (0.1 m) at 110 °C for 38–42 h.
b
Yield of isolated product.
c
Reaction was performed with 1.0 equiv of CuI and 3.0 equiv of N,N0-dimethylethylenediamine in PhCH3 (0.25 M) for 15 h.
In conclusion, we have developed a rapid synthesis of p-(CF3)3-
t-BuPHOX (L2) that results in an overall 51% yield starting from (S)-
t-leucine under relatively mild conditions in four linear steps. The
route utilizes a copper iodide-catalyzed coupling of oxazoline-con-
taining aryl bromide 4 to secondary phosphine oxide 5, followed
by a silane-mediated reduction of the resulting triarylphosphine

N. T. McDougal et al. / Tetrahedron Letters 51 (2010) 5550–5554
5553
CF3
CF3
O
O
Ph2SiH2 (7.0 equiv)
F3C
P
O N
F3C
P
N
140 °C, 13 h
(86% yield)
t-Bu
t-Bu
CF3
CF3
9
L2: (S)-p-(CF3)3-t-BuPHOX
Scheme 3. Reduction of 9 to afford (S)-p-(CF3)3-t-BuPHOX.
16. For Cu-catalyzed couplings of secondary phoshine oxides with aryl halides,
see: (a) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2006, 12, 3636–
3646; (b) Huang, C.; Tang, X.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2006, 71,
5020–5022; (c) Jiang, D.; Jiang, Q.; Fu, H.; Jiang, Y.; Zhao, Y. Synthesis 2008,
3473–3477.
oxide, to prepare the phosphinooxazoline core structure. We be-
lieve that the copper-catalyzed coupling of aryl bromides to sec-
ondary phosphine oxides provides a convenient alternative to the
coupling of air-sensitive secondary phosphines for the preparation
of tertiary phosphines.
17. (S)-2-Bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-5-(trifluoromethyl)benzamide
(7): To a 250 mL, round-bottomed flask charged with a magnetic stirring bar and
(S)-t-leucinol (2.10 g, 17.9 mmol, 1.0 equiv) was added methylene chloride
(60 mL). To the mixture was added a solution of sodium carbonate (5.70 g,
53.8 mmol, 3.0 equiv) in water (45 mL). The biphasic mixture is vigorously
stirred at 23 °C. To the mixture was added 2-bromo-5-(trifluoromethyl)benzoyl
chloride 69 (5.66 g, 19.7 mmol, 1.1 equiv) dropwise over 15 min. The reaction
mixture was vigorously stirred at 23 °C for 10 h. The layers were separated, and
the aqueous layer was extracted with methylene chloride (4 ꢁ 50 mL). The
combined organic layers were stirred with a 1 N potassium hydroxide solution in
methanol (10 mL) for 30 min, then acidified to neutral pH with 1 N hydrochloric
acid (ꢂ8 mL). To the mixture was added water (15 mL), and the layers were
separated. The aqueous layer was extracted with methylene chloride
(4 ꢁ 20 mL). The combined organic layers were washed with brine, dried over
sodium sulfate, and concentrated. The resulting residue 7 (6.10 g, 16.6 mmol,
93% yield) was found to be pure by 1H NMR, and used without further
purification. Analytical data matched literature values for the corresponding
(R)-enantiomer.10
Acknowledgments
This publication is based on the work supported by Award No.
KUS-11-006-02, made by King Abdullah University of Science
and Technology (KAUST). Additionally, the authors wish to thank
NIH-NIGMS (R01 GM 080269-01), the German Academic Exchange
Service (DAAD, postdoctoral fellowship to J.S.), Abbott Laborato-
ries, Amgen, the Gordon and Betty Moore Foundation, and Caltech
for financial support.
References and notes
18. (S)-2-(2-Bromo-5-(trifluoromethyl)phenyl)-4-tert-butyl-4,5-dihydrooxazole (4):
To a flame-dried, 250 mL three-necked flask charged with a magnetic stirring
bar and (S)-2-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)-5-(trifluorome
1. For reviews, see: (a) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151–
4202; (b) Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109, 2505–2550.
2. von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566–568.
3. Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769–1772.
4. Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993,
34, 3149–3150.
5. For a review, see: (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345;
See also: (b) Pfaltz, A. Acta Chem. Scand. B 1996, 50, 189–194; (c) Williams, J. M.
J. Synlett 1996, 705–710; (d) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen,
H. Pure Appl. Chem. 1997, 69, 513–518.
6. For selected examples of the use of t-BuPHOX in asymmetric reactions, see: (a)
Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1996, 35, 200–202; (b)
Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595–602; (c) Sagasser, I.; Helmchen,
G. Tetrahedron Lett. 1998, 39, 261–264; (d) Loiseleur, O.; Hayashi, M.; Keenan,
M.; Schmees, N.; Pfaltz, A. J. Organomet. Chem. 1999, 576, 16–22; (e) Nilsson, P.;
Gold, H.; Larhed, M.; Hallberg, A. Synthesis 2002, 1611–1614; (f) Hiroi, K.;
Kazuhiro, W. Tetrahedron: Asymmetry 2002, 13, 1841–1843; (g) Schulz, S. R.;
Blechert, S. Angew. Chem., Int. Ed. 2007, 46, 3966–3970; (h) Cook, M. J.; Rovis, T.
J. Am. Chem. Soc. 2007, 129, 9302–9303; (i) Linton, E.; Kozlowski, M. C. J. Am.
Chem. Soc. 2008, 130, 16162–16163.
thyl)benzamide
7 (6.10 g, 16.6 mmol, 1.0 equiv) were added methylene
chloride (86 mL) and freshly distilled triethylamine (5.60 mL, 40.0 mmol,
2.4 equiv). The solution was cooled to 0 °C in an ice bath, and methanesulfonyl
chloride (1.50 mL, 19.4 mmol, 1.2 equiv) was added dropwise over 3 min. A
reflux condenser was attached to the flask, and the reaction mixture was
heated to 50 °C with stirring for 20 h. The crude reaction mixture was allowed
to cool to ambient temperature, and an aqueous saturated sodium bicarbonate
solution (30 mL) was added with vigorous stirring for 5 min. The layers were
separated, and the aqueous phase was extracted with methylene chloride
(3 ꢁ 20 mL). The combined organic layers were washed with brine, dried over
magnesium sulfate, and concentrated. The resulting residue was subjected to
silica gel chromatography, and eluted with hexanes/ethyl acetate (9:1 ? 6:1)
to afford 4 (5.76 g, 16.4 mmol, 99% yield) as a colorless oil. Analytical data
matched literature values.9
19. Grayson, M.; Farley, C. E.; Streuli, C. A. Tetrahedron 1967, 23, 1065–1078.
20. Leazer, J. L., Jr.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.; Vickery, T.; Bachert, D. J.
Org. Chem. 2003, 68, 3695–3698.
21. Bis(4-(trifluoromethyl)phenyl)phosphine oxide (5): To a flame-dried, 50 mL flask
charged with magnesium metal (607 mg, 25.0 mmol, 3.1 equiv) was added
diethyl ether (12 mL). The mixture was cooled to 0 °C and 4-bromobenzotrifluoride
(3.38 mL, 24.2 mmol, 3.0 equiv) was added dropwise over 25 min, during
7. (a) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044–15045; (b)
Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed.
2005, 44, 6924–6927; (c) Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew. Chem., Int.
Ed. 2008, 47, 6873–6876.
which the mixture changed from colorless to yellow to black.
A reflux
8. (a) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006,
128, 11348–11349; (b) Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M.
Org. Lett. 2008, 10, 1039–1042.
9. Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org. Lett. 2007, 9, 2529–
2531.
condenser was attached to the flask, and the mixture was allowed to warm to
23 °C over 20 min, and then heated to 30 °C for 90 min. The Grignard solution
was transferred via cannula to a flame-dried, 25 mL flask to remove excess
magnesium metal. The resulting Grignard solution was cooled to 0 °C, and
diethyl phosphite (1.04 mL, 8.05 mmol, 1.0 equiv) was added dropwise over
5 min. The reaction mixture was allowed to slowly warm to 23 °C with stirring
over 18 h. The reaction mixture was cooled to 0 °C and treated with 2 m
aqueous hydrochloric acid (10 mL). The mixture was allowed to warm to
ambient temperature and extracted with ethyl acetate (3 ꢁ 25 mL). The
combined organic layers were washed with brine, dried over sodium sulfate
and concentrated. The resulting residue was subjected to silica gel
chromatography, and eluted with hexane/ethyl acetate (1:1 ? 1:9), to give 5
(2.18 g, 6.46 mmol, 80% yield) as a pale yellow solid. Mp: 67–69 °C (lit. 65–
67 °C); Rf = 0.29 (hexane/ethyl acetate, 1:1); 1H NMR (300 MHz, CDCl3) d 8.19
(d, JHP = 492 Hz, 1H), 7.83–7.90 (m, 4H), 7.78–7.82 (m, 4H); 31P NMR (121 MHz,
CDCl3) d 17.80 (JPH = 490 Hz); 19F NMR (282 MHz, CDCl3) d ꢀ63.35; FTIR (neat
film, NaCl) 3482, 3042, 2341, 1401, 1325, 1171, 1128, 1103, 1062, 1018, 942,
832, 711 cmꢀ1; HRMS (FAB, Pos) m/z calcd for C14H10OPF6 [M+H]+: 339.0373,
found 339.0387.
10. White, D. E.; Stewart, I. C.; Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008,
130, 810–811.
11. Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2, 192–196.
12. Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86, 181–193.
13. Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315–2318.
14. (a) Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Hrapchak, M.; Latli, B.;
Lee, H.; Sabila, P.; Saha, A.; Sarvestani, M.; Shen, S.; Varsolona, R.; Wei, X.;
Senanayake, C. H. Org. Lett. 2005, 7, 4277–4280; (b) Busacca, C. A.; Lorenz, J. C.;
Sabila, P.; Haddad, N.; Senanyake, C. H. Org. Synth. 2007, 84, 242–261.
15. For Pd-catalyzed couplings of secondary phosphine oxides with aryl halides
and aryl triflates, see: (a) Xu, Y.; Li, Z.; Xia, J.; Guo, H.; Huang, Y. Synthesis 1984,
781–782; (b) Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J. Org. Chem.
1993, 58, 1945–1948; (c) Kabachnik, M. M.; Solntseva, M. D.; Beletskaya, I. P.
Russ. Chem. Bull. 1997, 46, 1491; (d) Toffano, M.; Dobrota, C.; Fiaud, J.-C. Eur. J.
Org. Chem. 2006, 650–656.

5554
N. T. McDougal et al. / Tetrahedron Letters 51 (2010) 5550–5554
22. (S)-2-(2-(Bis(4-(trifluoromethyl)phenyl)phosphoryl)-5-(trifluoromethyl)phenyl)-
4-tert-butyl-4,5-dihydro-oxazole (9): To a 50 mL Schlenk flask charged with a
magnetic stirring bar, CuI (976 mg, 5.12 mmol, 1.0 equiv), and bis(4-
9H); 31P NMR (121 MHz, CDCl3) d 27.96; 19F NMR (282 MHz, CDCl3) d ꢀ63.26,
ꢀ63.26, ꢀ63.42; FTIR (neat film, NaCl) 3435, 2105, 1644, 1479, 1399, 1323,
1173, 1131, 1062 cmꢀ1; HRMS: HRMS (FAB, Pos) m/z calcd for C28H24O2PNF9
(trifluoromethyl)phenyl)phosphine oxide
5
(2.25 g, 6.66 mmol, 1.3 equiv)
[M+H]+: 608.1401, found 608.1414; ½a 2D5
= ꢀ56.3 (c 1.03, CH2Cl2).
ꢃ
was added toluene (15 mL) under an Ar atmosphere. To the mixture was
added N,N0-dimethylethylenediamine (1.65 mL, 15.4 mmol, 3.0 equiv) and the
resulting mixture was stirred for 20 min. To the mixture were then added (S)-
2-(2-bromo-5-(trifluoromethyl)phenyl)-4-tert-butyl-4,5-dihydrooxazole 4
(1.79 g, 5.12 mmol, 1.0 equiv), Cs2CO3 (6.18 g, 19.0 mmol, 3.7 equiv), and 5 mL
toluene. The Schlenk flask was sealed and the reaction mixture was heated to
110 °C with stirring for 15 h. The crude reaction mixture was allowed to cool to
ambient temperature and concentrated under reduced pressure. 1H NMR of the
mixture showed ꢂ70% conversion into the desired product with formation of
ꢂ30% of debrominated 4. The concentrated reaction mixture was subjected to
silica gel chromatography, and eluted with hexanes/ethyl acetate (3:1 ? 1:1)
to provide 9 (1.97 g, 3.33 mmol, 65% yield) as white crystals. Mp: 159–161 °C;
Rf = 0.60 (hexane/ethyl acetate, 1:1); 1H NMR (300 MHz, CDCl3) d 8.20 (br s,
1H), 7.80–8.03 (m, 4H), 7.72 (s, 1H), 7.70–7.78 (m, 5H), 3.89 (dd, J = 17.1,
8.7 Hz, 1H), 3.86 (dd, J = 18.9, 8.7 Hz, 1H), 3.38 (app t, J = 9.6 Hz, 1H), 0.71 (s,
23. Koch, G.; Lloyd-Jones, G. C.; Loiseleur, O.; Pfaltz, A.; Pretot, R.; Schaffner, S.;
Schnider, P.; von Matt, P. Recl. Trav. Chim. Pays-Bas 1995, 114, 206–210.
24. (S)-2-(2-(Bis(4-(trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-
tert-butyl-4,5-dihydrooxazole, (L2): To
a flame-dried 50 mL Schlenk tube
charged with magnetic stirring bar and (S)-2-(2-(bis(4-(trifluoromethyl)
a
phenyl)phosphoryl)-5-(trifluoromethyl)phenyl)-4-tert-butyl-4,5-dihydro-
oxazole 9 (2.02 g, 3.33 mmol, 1.0 equiv) under an Ar atmosphere was added
diphenylsilane (4.30 mL, 23.3 mmol, 7.0 equiv). The Schlenk tube was sealed
and the clear solution was heated to 140 °C with stirring for 13 h. The crude
reaction mixture was allowed to cool to ambient temperature, then subjected
directly to silica gel chromatography, and eluted with hexanes and methylene
chloride (3:1), to provide ligand L2 as
a colorless, semi-crystalline oil.
Crystallization was induced with pentane (4 mL) at ꢀ20 °C to yield L2
(1.69 g, 2.86 mmol, 86% yield) as colorless crystals. Analytical data matched
literature values.9,10