P-Chiral phosphine oxide catalysed reduction of prochiral ketimines using trichlorosilane

Article abstract of DOI:10.1016/j.tetasy.2016.01.001

Twelve P-chiral phosphine oxides were screened for their ability to act as a chiral Lewis base catalyst for the asymmetric hydrosilylation of ketimines, providing chiral amines in good conversion and yield, but relatively poor enantioselectivity (ee <30%). Mechanistic studies paralleling work on chiral sulfinamides have shown a non-linear relationship of catalyst enantioselectivity and the chiral amine product.

Full text of DOI:10.1016/j.tetasy.2016.01.001

Tetrahedron: Asymmetry 27 (2016) 136–141
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
P-Chiral phosphine oxide catalysed reduction of prochiral ketimines
using trichlorosilane
⇑
Christopher J. A. Warner, Andrew T. Reeder, Simon Jones
Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Twelve P-chiral phosphine oxides were screened for their ability to act as a chiral Lewis base catalyst for
the asymmetric hydrosilylation of ketimines, providing chiral amines in good conversion and yield, but
relatively poor enantioselectivity (ee <30%). Mechanistic studies paralleling work on chiral sulfinamides
have shown a non-linear relationship of catalyst enantioselectivity and the chiral amine product.
Ó 2016 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Received 18 December 2015
Accepted 4 January 2016
Available online 15 January 2016
1. Introduction
2. Results and discussion
The synthesis of enantiomerically enriched amines is an area of
great interest, the longstanding importance stemming from the
widespread presence of this functional group in a wide variety of
natural products and pharmaceutically active compounds.1,2
Amongst methodologies developed to reduce ketimines, the use
of trichlorosilane as a reductant has received growing interest in
recent years.3,4 Trichlorosilane needs to be activated by coordina-
tion with a Lewis base, such as DMF, to generate a hexa-coordinate
hydridosilicate complex, which is believed to be the active reduc-
ing species. In 2001, Matsamura reported the first enantioselective
reduction of a ketimine using N-formyl proline as a chiral Lewis
base, giving enantiomerically enriched amines in moderate yields
with up to 66% ee.5 Several other N-formyl derived organocatalysts
Our previously published work has detailed a new route for the
efficient preparation of P-chiral phosphine oxides in an enantiose-
lective manner via reaction of a P-chiral N-phosphinoyl oxazolidi-
none 1 with a Grignard reagent.24 Several of the phosphine oxides
2–7 from this work were utilised, and a further subset 8–12 pre-
pared by use of the appropriate Grignard reagent, all with excellent
enantioselectivity, as determined by chiral phase HPLC (Scheme 1).
O
P
O
O
P
R1MgBr
oC, THF
R1
Me
O
N
Me
0
120 mins
ˇ
then followed, including those developed by Malkov and Kocov-
6–8
Matsumura,9 and Sun,10–14 in addition to imidazole15–17
´
sky,
and picolinoyl amides.18 Other than amides, only a small selection
of other Lewis base catalysts have been evaluated, the most suc-
cessful being S-chiral sulfinamides developed by Sun19–21 In con-
trast, phosphorus derived reagents have received much less
attention. Sugiura et al. identified BINAPO as an effective
organocatalyst for the synthesis of enantioenriched 4H-1,3-oxazi-
(see Table 1 for a
complete list of R1)
R
1 = (2-iPrC H ), , 91%
8
4
6
(2,4,6-MeOC H ), , 53%
9
6
(2-Me-4-FC6H3)2, 10, 80%
(4-MeOC6H4), 11, 25%
(2-Me-4-MeOC6H3) , 12, 78%
Scheme 1. Synthesis of phosphine oxides 8–12.
nes via
a trichlorosilane mediated reductive cyclisation of
N-acylated-b-amino enones.22 Benaglia et al. reported the potential
of a range of chiral phosphinamides derived from proline to promote
the hydrosilylation of b-enamino esters.23 However, neither of
these cases involve direct 1,2-reduction of a non-conjugated C@N
bond catalysed by a P-chiral phosphine oxides. Herein describes
preliminary investigations in this area.
These compounds were then screened as potential catalysts in
the trichlorosilane mediated reduction of the benchmark N-PMP
ketimine 13 at both 10 mol % and 1 mol % loading (Scheme 2,
Table 1).
In every case, the phosphine oxides demonstrated excellent
reactivity at 10 mol % loading, with each catalyst enabling com-
plete conversion to the N-PMP amine 14 after 4 h. The catalyst
loading was also reduced to 1 mol %, but this lowered the reactivity
⇑
Corresponding author. Tel.: +44 (0)114 2229483.
E-mail address: simon.jones@sheffield.ac.uk (S. Jones).
http://dx.doi.org/10.1016/j.tetasy.2016.01.001
0957-4166/Ó 2016 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

C. J. A. Warner et al. / Tetrahedron: Asymmetry 27 (2016) 136–141
PMP
137
and resulted in amine 13 being isolated in a lower yield, albeit with
similar selectivity. Although the reactivities were good, the enan-
tioselectivities were poor in comparison to other reported cata-
lysts. Species containing an ortho-methoxy displayed the highest
selectivity (Table 1, entries 2 and 8), but incorporation of an iso-
propyl group at this position was less well-tolerated resulting in
a decrease in enantioselectivity to 16% ee (Table 1, entry 7). The
PMP
HN
N
XX mol% catalyst
2 equiv. Cl3SiH
CH2Cl2, 0 oC, 4 hr
13
14
Scheme 2. Asymmetric reduction of ketimine 13.
Table 1
Evaluation of P-chiral catalysts as described in Scheme 2a
Entry
Catalyst
10 mol % loading
Yieldc (%)
1 mol % loading
Yieldc (%)
Conversionb (%)
eed (%)
Conversionb (%)
eed (%)
O
P
Me
Me
Me
1
100
91
22
73
41
43
21
2
O
P
MeO
2
3
100
100
90
81
29
12
78
68
28
10
3
O
P
Me
Me
Me
Me
39
41
Me
4
O
P
O
O
4
100
85
11
79
10
5
O
P
5
6
7
100
100
100
88
90
87
10
19
16
77
75
64
39
41
39
11
19
17
6
O
Me
P
7
O
P
Me
8
O
P
MeO
Me
8
9
100
100
94
88
28
20
81
72
48
41
27
18
MeO
O
Me
9
O
Me
Me
P
F
10
(continued on next page)

138
C. J. A. Warner et al. / Tetrahedron: Asymmetry 27 (2016) 136–141
Table 1 (continued)
Entry
Catalyst
10 mol % loading
1 mol % loading
Yieldc (%)
Conversionb (%)
Yieldc (%)
eed (%)
Conversionb (%)
eed (%)
O
P
Me
Me
10
100
92
7
77
37
35
7
MeO
MeO
11
O
P
Me
11
100
91
23
74
21
12
a
All reactions performed on 1 mmol scale using 1 mL of CH2Cl2 with either 1 or 10 mol % loading of catalyst.
b
c
Refers to amine 14, determined by comparison of appropriate integrals in the 1H NMR spectrum of the crude reaction mixture.
Refers to yield of isolated product 14.
d
Determined by chiral phase HPLC analysis of amine 14.
use of an o-tolyl group also reduced the enantioselectivity to 22%
ee (entry 1). The crucial requirement of an o-methoxy group is also
exemplified by the other methoxy-aryl catalysts (Table 1, entries 4,
10 and 11), all of which are significantly less selective.
Of the successful S-chiral sulfinamide catalysts developed by
Sun, only two 15 and 17 have been evaluated in the reduction of
PMP-ketimine 13 (Fig. 1).
evaluated under standard reaction conditions (Scheme 2), the
product amine was only obtained in 69% conversion and with
12% ee using 10 mol % catalyst. Although there are slight differ-
ences in substrate and the amount of catalyst used, this is reason-
ably in-line with the data obtained with Sun’s sulfinimide. When
further comparison is made with the analogue missing the NH
group (Table 1, entry 6), there does not appear to be any particular
need for this functional group, and in some ways it might even be
considered detrimental.
i-Pr
O
S
OH
H
N
N
H
N
S
O
P
O
O
P
O
O
i-Pr
BnNHLi
Me
Ph
N
H
O
N
0
oC, THF
10 mins
F
Me
15
16
97% yield, 91% ee
at 20 mol%
β
only used with -enamino esters at
10 mol%
1
19
87% (> 98% ee)
O
S
with N-PMP-ketimine at 10 mol%
O
O
69% (12% ee)
S
N
H
S
N
Ph
N
H
H
18
with N-Ph-ketimine at 20
mol%
17
92% yield, 92% ee at 10 mol%
42% (27% ee)
Figure 1. Activity and selectivity of Sun’s sulfinamide catalysts 15 and 17 with
imine 13.
Scheme 3. Asymmetric synthesis of phosphinamide 19 and comparison of its
activity to sulfinamide 18.
In general, the catalytic activities of the phosphine oxides were
comparable to the sulfinamides, however the enantioselectivities
were significantly lower. The two sulfinamide catalysts 15 and
17 used to reduce acetophenone derived ketimines differ from
the phosphine oxides in several ways, primarily as a consequence
of using the Ellman chiral sulfinamide to construct these species.25
The combined stereo-discriminatory effect of the t-butyl group, the
lone pair and the oxygen atom is apparently sufficient to induce
excellent levels of enantioselectivity. Each also bears an acidic
NH group adjacent to the stereogenic sulfur atom and is benzylic.
Sun’s closest analogue to those evaluated herein is benzyl sulfi-
namide 18, which although evaluated with the N-Ph ketimine, gave
the amine product in 42% yield and with 27% ee using 20 mol %
loading of catalyst. In an attempt to directly compare the sulfur
and phosphorus variants, phosphonamide 19 was prepared by
the careful addition of lithium benzylamide to oxazolidinone 1
(Scheme 3). The product phosphinamide was isolated in 87% yield
and with excellent enantioselectivity (>98% ee). However, when
In comparing these data, it does highlight the crucial need for
an oxygen substituent on the aromatic ring, correctly spaced rela-
tive to the stereogenic centre. Since the NH group was not deemed
to be important, an attempt was made to access catalyst 23 con-
taining the key structural elements found in Sun’s catalyst
(Scheme 4). Thus, 2-benzyloxybenzaldehyde 20 was converted
into gem-dibromoalkene 21 and this was treated with n-BuLi to
generate the lithio-alkyne in situ, which was immediately reacted
with oxazolidinone 1. However, alkyne 22 was only isolated in a
disappointingly low 28% yield and with 53% ee. This low ee usually
results from a slow reaction rate of the organometallic with the N-
phosphinoyl oxazolidinone 1, leading to an in situ racemisation
pathway.24,26 Despite numerous attempts, the enantioselectivity
of the phosphine oxide 22 could not be improved, and further
development of this chemistry was abandoned.

C. J. A. Warner et al. / Tetrahedron: Asymmetry 27 (2016) 136–141
OBn
139
(0.2 mm, Merck DC-alufolien Kieselgel 60 F254). Plates were visu-
alised using UV light or by dipping in KMnO4 solution, followed
by exposure to heat. Flash column chromatography was performed
on silica gel (Merck Kieselgel 60 F254 230–400 mesh), unless other-
wise stated. 1H and 13C NMR spectra were measured using CDCl3 as
solvent unless otherwise stated, on a Bruker AV-250 or AV-
400 MHz machine with an automated sample changer. Chemical
shifts for carbon and hydrogen are given on the d scale. Coupling
constants were measured in Hertz (Hz). 13C NMR spectra were
recorded using the JMOD method. Specific rotations were per-
formed on an Optical Activity Ltd. AA-10 automatic polarimeter
OBn
Br
CBr4, PPh3
O
Et3N, CH2Cl2
78%
Br
20
21
n-BuLi, THF
-78 oC, then
oxazolidinone 1
28%
O
P
O
OH
OBn
P
Me
Me
at 589 nm (Na line). [
a
]
D
values are given in 10À1 deg cm2 gÀ1
.
Infrared spectra were recorded on a Perkin–Elmer 100 FT-IR
machine using attenuated total reflectance (ATR). Peaks between
1600 and 4000 cmÀ1 with an absorbance of >10% are quoted. Mass
spectra were either recorded on a micromass autospec (EI+) or
Waters LCT Classic (TOF ES+). HPLC was carried out on a Gilson
analytical system using chiral phase analytical columns
(4.8 mm  250 mm). Melting points (mp) were measured on a Gal-
lenkamp melting point apparatus and are uncorrected.
23
53% ee
22
Scheme 4. Attempted synthesis of phosphine oxide 23.
The low enantioselectivity, coupled with Sun’s observations of a
non-linear effect with sulfinamide catalysts20 prompted an
evaluation of this effect for these systems. The relationship
between the enantioselectivity of the o-anisyl catalyst (Table 1,
entry 2) and that of product amine 14 was plotted (Fig. 2), exhibit-
ing a negative [ML2] non-linear system in which two ligands were
required in the stereoselective step of the reduction.27,28
Experimental details and general procedures for the synthesis
of P-chiral phosphine oxides
2 to 7 have been previously
reported.24
4.2. General procedure A for the preparation of diaryl methyl P-
chiral phosphineoxides from the N-phosphinoyloxazolidinone 1
35
30
25
20
15
10
5
N-Phosphinoyl oxazolidinone 1 (297 mg, 1 mmol) was dis-
solved in anhydrous THF (5 mL) and the solution cooled to 0 °C.
The Grignard reagent (2 mmol) in THF (concentration indicated
in individual experiments) was then added dropwise, after which
the reaction mixture was warmed to room temperature and stirred
for 45 min. Next, 1 M HCl solution (5 mL) was added drop-wise and
the aqueous phase was extracted with CH2Cl2 (3 Â 10 mL). The
organic phases were combined, washed with brine (10 mL) and
dried over MgSO4. After filtration and removal of the solvent in
vacuo, the crude phosphine oxide was purified as described in
the individual experimental details. Racemic samples of the phos-
phine oxide for HPLC analysis were prepared in the same way but
substituting methylphenyl phosphinic chloride for the N-phosphi-
noyl oxazolidinone.
0
0
20
40
60
80
100
Catalyst ee (%)
4.2.1. (SP)-(2-Isopropylphenyl)methylphenylphosphine oxide
829
Figure 2. The non-linear relationship of the ee of P-chiral phosphine oxide (Table 1,
entry 2) and amine 14.
Prepared according to the general procedure using isopropy-
lphenylmagnesium bromide (2 mL, 1 M in THF, 2 mmol), followed
by purification by flash column chromatography using a gradient
eluent of 75% EtOAc/petroleum ether 40–60 to 5% MeOH/CH2Cl2
giving recovered oxazolidinone 1 as a yellow crystalline material
(143 mg, 91%) and the phosphine oxide 8 as a white solid
3. Conclusion
In conclusion, P-chiral phosphine oxides can act as catalysts and
offer some degree of stereocontrol for the Lewis base mediated
reaction of trichlorosilane with ketimines. However, crucial to
the development of a catalyst capable of delivering high levels of
enantioselectivity with P-chiral stereocontrol elements is judicious
design of the supporting scaffold; work is currently underway to
develop such systems.
(108 mg, 42%); mp 140–141 °C; [
a
]
D
25 = À34.0 (c 1.0, CHCl3) >99%
ee; dH (250 MHz, CDCl3) 0.85 [3H, d, J 6.8, 1 Â CH(CH3)2), 1.14
[3H, d, J 6.8, 1 Â CH(CH3)2], 2.06 (3H, d, JP–H 13.0, PCH3), 3.48 [1H,
heptet, J 6.8, CH(CH3)2], 7.27–7.76 (9H, m, ArCH); dP (121 MHz,
CDCl3) 31.2; Chiral phase HPLC (CHIRALPAK-AS, 95:5 hexane/pro-
pan-2-ol at 1.0 mL minÀ1, 210 nm) tR 29.8 (minor isomer) and
40.2 (major isomer). No melting point or specific rotation data
are reported in the literature, otherwise all is in accordance.
4. Experimental
4.1. General
4.2.2. (SP)-Methylphenyl(2,4,6-trimethoxyphenyl)phosphine
oxide 9
Prepared according to the general procedure using 2,4,6-
trimethoxyphenylmagnesium bromide (4 mL, 0.5 M in THF,
2 mmol), followed by purification by flash column chromatography
on silica gel using a gradient eluent of 75% EtOAc/petroleum ether
Dry solvents were obtained either from the Grubbs dry solvent
system or by distillation. All other reagents were used as supplied
without purification, unless specified. Glassware was flame dried
and cooled under vacuum before use. Thin layer chromatography
was performed on aluminium backed plates pre-coated with silica

140
C. J. A. Warner et al. / Tetrahedron: Asymmetry 27 (2016) 136–141
40–60 to 5% MeOH/CH2Cl2 affording the recovered oxazolidinone 1
as a yellow crystalline material (133 mg, 86%) and the phosphine
135.2 (d, JC–P 99.7, ArC), 144.2 (d, JC–P 9.4, ArC), 162.3 (d, JC–P 3.0,
ArC); dP (101 MHz, CDCl3) 30.9; m/z (TOF ES+) 261.1036 (MH+,
100%, C15H18O2P requires 261.1039); Chiral phase HPLC (Cellu-
ose-1, 90:10 hexane/propan-2-ol at 1 mL minÀ1, 210 nm) tR 17.3
(minor isomer) and 19.9 (major isomer).
oxide
9 as a white solid (162 mg, 53%); mp 133–134 °C;
[a
]
D
25 = À28.1 (c 1.0, CHCl3) >99% ee; mmax (ATR)/cmÀ1 2360, 1599,
1577; dH (400 MHz, CDCl3) 1.98 (3H, d, JP–H 14.0, PCH3), 3.58 (6H,
s, 2 Â OCH3), 3.82 (3H, s, OCH3), 6.06 (2H, d, J 3.6, 2 Â ArCH),
7.35–7.41 (3H, m, ArCH), 7.64–7.67 (2H, m, ArCH); dC (101 MHz,
CDCl3) 21.8 (d, JC–P 76.0, PCH3), 55.4 (OCH3), 55.5 (2 Â OCH3),
91.0 (ArCH), 91.1 (ArCH), 103.0 (d, JC–P 108.0, ArC), 127.8 (d, JC–P
13.0, 2 Â ArCH), 129.2 (d, JC–P 10.0, 2 Â ArCH), 130.0 (d, JC–P 3.0,
ArCH), 138.9 (d, JC–P 107.0, ArC), 164.0 (2 Â ArC), 165.0 (ArC); dP
(101 MHz, CDCl3) 27.1; m/z (TOF ES+) 307.1105 (MH+, 100%.
4.3. General procedure B for the asymmetric reduction of the
PMP-ketimine 13
The PMP-ketimine 13 (225 mg, 1.00 mmol) and catalyst
(0.1 mmol) were dissolved in CH2Cl2 (1 mL) and the solution
cooled to 0 °C. Trichlorosilane (0.20 mL, 2.0 mmol) was then added
dropwise and the reaction mixture stirred for 4 h. The reaction
solution was quenched via the addition of 1 M aqueous HCl solu-
tion (1 mL), diluted with CH2Cl2 (5 mL) and basified with a 1 M
aqueous NaOH solution (10 mL). The organic phase was separated,
and the aqueous phase extracted with CH2Cl2 (3 Â 5 mL). The com-
bined organics were washed with brine (10 mL), before being dried
over MgSO4, filtered and concentrated in vacuo to yield the crude
material. Purification of the crude product by flash column chro-
matography eluting on silica gel with 10% EtOAc/petroleum ether
afforded the desired amine 14 as a golden yellow solid.
C
16H20O4P requires 307.1099); Chiral phase HPLC (Celluose-1,
90:10 hexane/propan-2-ol at 1 ml minÀ1, 210 nm) tR 35.5 (minor
isomer) and 38.5 (major isomer).
4.2.3. (SP)-(2-Methyl-4-fluorophenyl)methylphenylphosphine
oxide 1030
Prepared according to the general procedure from 2-methyl-4-
fluorophenylmagnesium bromide (1.7 mL, 1.4 M in THF, 2 mmol),
followed by purification by flash column chromatography on silica
gel using a gradient eluent of 75% EtOAc/petroleum ether 40–60 to
5% MeOH/CH2Cl2, affording the recovered oxazolidinone
1
(150 mg, 97%) as a white solid and the phosphine oxide 10 as a
4.3.1. (SP)-N-Benzyl-methylphenyl-phosphinic amide 1932
A solution of benzylamine (0.25 mL, 2.3 mmol) in dry THF (5 mL)
at À78 °C was treated with a solution of n-BuLi (1.15 mL, 2.00 M in
hexanes, 2.30 mmol) and stirred at À78 °C for 40 min and then for a
further 10 min at 0 °C. A solution of phosphinoyloxazolidinone 1
(0.223 g, 0.755 mmol) in dry THF (5 mL) was added to the solution
of the lithium amide over a period of 10 min at 0 °C. The reaction
mixture was stirred for a further 45 min at this temperature before
being quenched with a saturated aqueous solution of NH4Cl (2 mL).
This mixture was diluted with CH2Cl2 (25 mL) and the layers were
separated and the aqueous portion was extracted with CH2Cl2
(2 Â 15 mL). The combined organic layers were washed with a sat-
urated aqueous solution of NH4Cl (2 Â 10 mL) and brine (10 mL),
before being dried over MgSO4, filtered and concentrated in vacuo
to give the crude material as a yellow oil. Purification by chromatog-
raphy eluting on basic alumina with 10% propan-2-ol/CH2Cl2
afforded the title compound 19 as a white waxy solid (0.102 g,
white solid (200 mg, 80%); mp 134–135 °C (lit.30 98–102 °C for
racemate); [
a
]
24 = À24.2 (c 1.0, CHCl3) 99% ee; dH (250 MHz, CDCl3)
D
2.04 (3H, d, JP–H 13.1, PCH3), 2.38 (3H, s, CH3), 6.91–7.05 (2H, m,
ArCH), 7.42–7.75 (6H, m, ArCH); dP (101 MHz, CDCl3) 30.6; dF
(235 MHz, CDCl3) À107.9; Chiral phase HPLC (Cellulose 1, 96:4
hexane/propan-2-ol at 1.0 mL minÀ1, 210 nm) tR 30.9 (minor iso-
mer) and 32.8 (major isomer). No specific rotation value is
reported in the literature, otherwise all data are in accordance.
4.2.4. (SP)-(À)-(4-Methoxyphenyl)methylphenylphosphine
oxide 1131
Prepared according to the general procedure from 4-anisylmag-
nesium bromide (3 mL, 1 M in PhMe, 3 mmol), followed by purifica-
tion by flash column chromatography on silica gel using an eluent of
5% MeOH/CH2Cl2 to afford the title compound 11 as a white crys-
talline solid (62 mg, 25%); mp 119–120 °C (lit.31 120–121 °C);
[
a
]
25 = À8.1 (c 1.0 in MeOH) >99% ee, lit.31 = b+7.0 (c 0.99, MeOH)
87%); mp 76–77 °C (lit.32 73–74 °C); [
a
]
D
25 = À6.1 (c 0.9, CHCl3) 98%
D
for the (RS)-enantiomer, >95% ee); dH (250 MHz, CDCl3) 1.94 (3H,
d, JP–H 13.2, PCH3), 3.79 (3H, s, OCH3), 6.90–6.96 (2H, m, ArCH),
7.37–7.47 (3H, m, ArCH), 7.57–7.66 (4H, m, ArCH); dP (121 MHz,
CDCl3) 29.7; Chiral phase HPLC (Cellulose 1, 90:10 hexane/pro-
pan-2-ol at 1.0 mL minÀ1, 210 nm) tR 21.7 (major isomer) and 24.1
(minor isomer). Data are in accordance with the literature.
ee; mmax (ATR)/cmÀ1 3167, 3055, 2888, 1629, 1569; dH (400 MHz,
CDCl3) 1.64 (3H, d, JP–H 14, PCH3), 3.03–3.10 (1H, m, NH), 3.91 (1H,
ddd, JP–H 14.2, J 8.3, 7.7, CHH), 4.10 (1H, ddd, JP–H 14.2, J 7.7, 6.5,
CHH), 7.18–7.27 (5H, m, ArCH), 7.41–7.52 (3H, m, ArCH), 7.81–
7.86 (2H, m, ArCH); dC (100 MHz, CDCl3) 16.3 (d, JC–P 93.1, PCH3),
44.4 (NCH2), 127.4 (ArCH), 127.7 (2 Â ArCH), 128.5 (ArCH), 128.6
(2 Â ArCH), 128.7 (ArCH), 131.7 (ArCH), 131.8 (ArCH), 131.9
(d, JC–P 2.3, ArCH), 133.2 (ArC), 139.6 (d, JC–P 8.1, ArC); dP
(162 MHz, CDCl3) 31.1; m/z (TOF ES+) 246.1047 (100%, MH+,
4.2.5. (SP)-(2-Methyl-4-methoxyphenyl)methylphenylphosphine
oxide 1231
Prepared according to the general procedure from 2-methyl-4-
methoxyphenylmagnesium bromide (2 mL, 1 M in THF, 2 mmol),
followed by purification by flash column chromatography on silica
gel using a gradient eluent of 75% EtOAc/petroleum ether 40–60 to
5% MeOH/CH2Cl2 afforded the recovered oxazolidinone 1 (148 mg,
94%) and the phosphine oxide 12 as a white solid (203 mg, 78%);
C14H17NOP requires 246.1048); Chiral phase HPLC (Celluose-1, 90:10
hexane/propan-2-ol at 1 mL minÀ1, 254 nm) tR 13.9 (major isomer)
and 16.8 (minor isomer).
4.3.2. 1-(2,2-Dibromoethenyl)-2-(phenylmethoxy)benzene 21
Triphenylphosphine (3.51 g, 13.4 mmol) was added portionwise
to a solution of carbon tetrabromide (2.22 g, 6.69 mmol) in dry
CH2Cl2 (30 mL) at 0 °C and then stirred for a further 20 min at this
temperature. 2-Benzyloxybenzaldehyde 20 (709 mg, 3.34 mmol)
was then added to the mixture followed immediately by triethy-
lamine (0.47 mL, 3.34 mmol). The reaction was stirred for 30 min
at 0 °C before being poured onto a saturated aqueous solution of
NaHCO3 (15 mL). The subsequent layers were separated and the
aqueous phase was extracted with CH2Cl2 (2 Â 30 mL). The com-
bined organic layers were sequentially washed with a saturated
aqueous solution of NaHCO3 (10 mL), a saturated aqueous solution
mp 135–137 °C (lit.31140.0–140.5 °C for racemate); [
(c 0.95, CHCl3) >99% ee, lit.31
a]
25 = À21.6
D
[
a]
D
26 = +1.75 (c 0.92, MeOH) for 23%
ee for the (Rp)-enantiomer); mmax (ATR)/cmÀ1 2973, 2907, 2839,
1601, 1566; dH (400 MHz, CDCl3) 2.00 (3H, d, JP–H 13.1, PCH3),
2.32 (3H, s, CH3), 3.81 (3H, s, OCH3), 6.72–6.82 (2H, m, ArCH),
7.39–7.51 (3H, m, ArCH), 7.57–7.67 (3H, m, ArCH); dC (100 MHz,
CDCl3) 17.4 (d, JC–P 74.0, PCH3), 21.5 (d, JC–P 4.0, CH3), 55.2
(OCH3), 110.5 (d, JC–P 13.1, ArCH), 117.4 (d, JC–P 11.0, ArCH), 123.0
(d, JC–P 105.0, ArC), 128.5 (d, JC–P 11.8, 2 Â ArCH), 130.3 (d, JC–P
9.9, 2 Â ArCH), 131.3 (d, JC–P 2.3, ArCH), 133.4 (d, JC–P 12.7, ArCH),

C. J. A. Warner et al. / Tetrahedron: Asymmetry 27 (2016) 136–141
141
of NH4Cl (2 Â 10 mL), and brine (10 mL), before being dried over
Supplementary data
MgSO4, filtered and concentrated in vacuo to give a crude material
as a yellow oil. Purification by flash column chromatography elut-
ing on silica gel with 5% EtOAc/petroleum ether afforded the title
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.01.
001.
compound 21 as a colourless oil (959 mg, 78%); mmax (ATR)/cmÀ1
)
3065, 3029, 2868, 1597; dH (400 MHz, CDCl3) 5.18 (2H, s, CH2Ph),
7.00 (1H, dd, J 8.3, 0.7, ArCH), 7.08 (1H, td, J 7.6, 0.8, ArCH), 7.35–
7.52 (6H, m, ArCH), 7.79 (1H, s, HC@CBr2), 7.83 (1H, dd, J 7.7, 1.4,
ArCH); dC (100 MHz, CDCl3) 70.4 (CH2Ph), 90.0 (ArCO), 112.4
(CHCBr2), 120.7 (ArCH), 125.0 (2 Â ArC), 127.2 (ArCH), 128.1
References
1. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55–
68.
2. Henkel, T.; Brunne, R. M.; Müller, H.; Reichel, F. Angew. Chem., Int. Ed. 1999, 38,
643–647.
3. Guizzetti, S.; Benaglia, M. Eur. J. Org. Chem. 2010, 2010, 5529–5541.
4. Jones, S.; Warner, C. J. A. Org. Biomol. Chem. 2012, 10, 2189–2200.
5. Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura, Y.
Tetrahedron Lett. 2001, 42, 2525–2527.
(2 Â ArCH), 128.8 (ArCH), 129.4 (ArCH), 130.0 (ArCH), 133.1 (ArCH),
136.8 (ArC), 155.8 (CBr2); m/z (EI+) 367.9235 (5%, M+, C15
H Br2O
12
79
requires 367.9230), 287 (5), 196 (20), 169 (28), 91 (100).
6. Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kocovsky, P. Org. Lett. 2004, 6,
2253–2256.
7. Malkov, A. V.; VrankovaÌ, K.; StoncÌŒius, S.; KocÌŒovskyÌ, P. J. Org. Chem. 2009,
74, 5839–5849.
4.3.3. (SP)-[2-(2-Benzyloxyphenyl)ethynyl]methylphenylphosphine
oxide 22
A solution of 1-(2,2-dibromoethenyl)-2-(phenylmethoxy)ben-
zene 21 (0.13 g, 0.71 mmol) in dry THF (2 mL) at À78 °C was trea-
8. Malkov, A. V.; Stewart-Liddon, A. J. P.; McGeoch, G. D.; Ramirez-Lopez, P.;
Kocovsky, P. Org. Biomol. Chem. 2012, 10, 4864–4877.
9. Matsumura, Y.; Ogura, K.; Kouchi, Y.; Iwasaki, F.; Onomura, O. Org. Lett. 2006, 8,
3789–3792.
10. Wang, Z.; Ye, X.; Wei, S.; Wu, P.; Zhang, A.; Sun, J. Org. Lett. 2006, 8, 999–1001.
11. Wang, Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett. 2006, 8, 3045–3048.
12. Zhou, L.; Wang, Z.; Wei, S.; Sun, J. Chem. Commun. 2007, 2977–2979.
13. Wang, Z.; Wei, S.; Wang, C.; Sun, J. Tetrahedron: Asymmetry 2007, 18, 705–709.
14. Wang, Z.; Wang, C.; Zhou, L.; Sun, J. Org. Biomol. Chem. 2013, 11, 787–797.
15. Jones, S.; Zhao, P. Tetrahedron: Asymmetry 2014, 25, 238–244.
16. Gautier, F.-M.; Jones, S.; Li, X.; Martin, S. J. Org. Biomol. Chem. 2011, 9, 7860–
7868.
17. Gautier, F.-M.; Jones, S.; Martin, S. J. Org. Biomol. Chem. 2009, 7, 229–231.
18. Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y. Tetrahedron Lett. 2006, 47,
3751–3754.
19. Pei, D.; Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Org. Lett. 2006, 8, 5913–5915.
20. Pei, D.; Zhang, Y.; Wei, S.; Wang, M.; Sun, J. Adv. Synth. Catal. 2008, 350, 619–
623.
21. Liu, X.-W.; Wang, C.; Yan, Y.; Wang, Y.-Q.; Sun, J. J. Org. Chem. 2013, 78, 6276–
6280.
22. Sugiura, M.; Kumahara, M.; Nakajima, M. Chem. Commun. (Cambridge, U. K.)
2009, 3585–3587.
23. Bonsignore, M.; Benaglia, M.; Annunziata, R.; Celentano, G. Synlett 2011, 1085–
1088.
24. Adams, H.; Collins, R. C.; Jones, S.; Warner, C. J. A. Org. Lett. 2011, 13, 6576–
6579.
ted with
a solution of n-BuLi (0.32 mL, 2.2 M in hexanes,
0.70 mmol) and stirred at À78 °C for 5 min. The flask was then
removed from the cold bath and stirred for a further 30 min before
being re-cooled to À78 °C. A solution of phosphinoyloxazolidinone
1 (0.10 g, 0.35 mmol) in dry THF (1.5 mL) was then added at À78 °C
over a period of 15 min. The reaction was stirred at À78 °C for 5 h
before being quenched with a saturated aqueous solution of NH4Cl
(2 mL). This mixture was diluted with CH2Cl2 (25 mL) and the lay-
ers were separated and the aqueous portion was extracted with
more CH2Cl2 (2 Â 15 mL). The combined organic layers were
washed with brine (10 mL), before being dried over MgSO4, filtered
and concentrated in vacuo to give the crude material as an orange
oil. Purification by flash column chromatography eluting on silica
gel with 20% petroleum ether/EtOAc afforded the title compound
22 as white waxy solid (34 mg, 28%); mp 93–94 °C; [
a
]
24 = À1.6
D
(c 0.6, CHCl3) 53% ee; mmax (ATR)/cmÀ1 3058, 3031, 2907, 1599,
1589; dH (400 MHz, CDCl3) 1.93 (3H, d, JP–H 14.4, PCH3), 5.15 (2H,
s, CH2Ph), 6.94–7.00 (2H, m, ArCH), 7.30–7.48 (8H, m, ArCH),
7.49–7.57 (2H, m ArCH), 7.86–7.94 (2H, m, ArCH); dC (100 MHz,
CDCl3) 20.9 (d, JC–P 85.4, PCH3), 70.5 (CH2Ph), 87.7 (d, JC–P 164.8,
PC„C), 100.4 (d, JC–P 30.8, ArC), 110.0 (d, JC–P 3.4, ArC„C), 112.4
(ArCH), 120.9 (ArCH), 127.2 (2 Â ArCH), 128.1 (ArCH), 128.5 (ArCH),
128.6 (2 Â ArCH), 128.7 (ArCH), 130.0 (ArCH), 130.1 (ArCH), 132.0
(d, JC–P 3.0, ArCH), 132.1 (ArCH), 133.0 (ArC), 134.2 (ArCH), 136.3
(ArC), 160.5 (ArC); dP (162 MHz, CDCl3) 11.1; m/z (TOF ES+) 693
(35%), 347.1198 (100, MH+, C22H20O2P requires 347.1195); Chiral
25. Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997, 119, 9913–9914.
26. Liu, L.-J.; Chen, L.-J.; Li, P.; Li, X.-B.; Liu, J.-T. J. Org. Chem. 2011, 76, 4675–4681.
27. Guillaneux, D.; Zhao, S.-H.; Samuel, O.; Rainford, D.; Kagan, H. B. J. Am. Chem.
Soc. 1994, 116, 9430–9439.
28. Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922–2959.
29. Bergin, E.; O’Connor, C. T.; Robinson, S. B.; McGarrigle, E. M.; O’Mahony, C. P.;
Gilheany, D. G. J. Am. Chem. Soc. 2007, 129, 9566–9567.
30. Rajendran, K. V.; Kennedy, L.; Gilheany, D. G. Eur. J. Org. Chem. 2010, 2010,
5642–5649.
31. Oshiki, T.; Imamoto, T. Bull. Chem. Soc. Jpn. 1990, 63, 3719–3721.
32. Ellis, K.; Smith, D. J. H.; Trippett, S. J. Chem. Soc., Perkin Trans. 1 1972, 1184.
phase HPLC (Celluose-1, 90:10 hexane/propan-2-ol at 1 mL minÀ1
,
254 nm) tR 21.8 (minor isomer) and 25.0 (major isomer).
Acknowledgements
We thank the University of Sheffield (CJAW) and the EPSRC
(ATR, EP/K007955/1) for financial support.