P-stereogenic phosphorus compounds: Effect of aryl substituents on the oxidation of arylmethylphenylphosphanes under asymmetric appel conditions

Article abstract of DOI:10.1002/ejoc.201000733

The effects of aryl ring substitution on the dynamic resolution of aryl(methyl)phenylphosphanes under asymmetric Appel reaction conditions have been studied. As expected, substitution at the ortho position strongly affects the degree ofstereoselection tha

Full text of DOI:10.1002/ejoc.201000733

FULL PAPER
DOI: 10.1002/ejoc.201000733
P-Stereogenic Phosphorus Compounds: Effect of Aryl Substituents on the
Oxidation of Arylmethylphenylphosphanes under Asymmetric Appel Conditions
Kamalraj V. Rajendran,[a] Lorna Kennedy,[a] and Declan G. Gilheany*[a]
Keywords: Phosphorus / Phosphanes / Asymmetric synthesis / Stereoselectivity / Oxidation / Substituent effects
The effects of aryl ring substitution on the dynamic resolution
of aryl(methyl)phenylphosphanes under asymmetric Appel
reaction conditions have been studied. As expected, substi-
tution at the ortho position strongly affects the degree of
stereoselection that can be achieved. Unexpectedly, how-
ever, there was no variation of stereoselectivity with the elec-
tronic nature of the para substituents, which suggests that
there are two selection processes in operation. An unusual
halogen-exchange process was observed in the arylphenyl-
phosphinous chlorides on route to the required tertiary phos-
phane substrates.
previously reported success in the dynamic resolution of a
variety of P-stereogenic aryl(methyl)phenylphosphanes un-
der asymmetric Appel conditions (Scheme 1).[36] This is an
oxidation/reduction/dehydration system[37] in which a race-
mic tertiary phosphane interacts with a source of positively
charged chlorine, for example, hexachloroacetone (HCA),
and a chiral non-racemic alcohol.
Introduction
The asymmetric synthesis of non-symmetrically substi-
tuted phosphorus compounds (variously referred to as P-
stereogenic, P-chiral or P-chirogenic) is a venerable topic.[1]
Its history is rich and varied with many well-known phos-
phorus chemists making important contributions down
through the years.[2–7] Early methods were based on resolu-
tion (for which there is no general method) or on the gener-
ation and separation of diastereomers.[3–5] Better progress
was made when methods for the generation of unequal
amounts of diastereomers were developed. Among
others,[8–14] it is reasonable to single out Mislow and co-
workers whose method, based on menthyl phosphinates,[15]
has been used widely.[4,16] Later, the method of Jugé, Genet
and co-workers,[17,18] based on cyclic phosphoramidate pre-
cursors, came to prominence and has been used exten-
sively.[19] Both these methods were used to good effect by
Imamoto and co-workers.[20–23] More recent strategies in-
clude desymmetrisation, enzymatic resolution and catalytic
asymmetric synthesis.[7,24–31] Most recently, the method via
optically pure H-phosphinates, also pioneered by Mislow
and co-workers,[32] has benefited from a recent, very signifi-
cant improvement in methodology.[33–35]
Scheme 1. Asymmetric oxidation under Appel conditions.
The dynamic nature of the resolution allows high enan-
tiomeric excesses to be obtained at full conversion. Pre-
viously, there have been very few reported successes of ki-
netic resolution (KR) or dynamic kinetic resolution (DKR)
in such systems,[38–40] one of the few reported cases being
that of Perlikowska et. al.[38] who reported up to 39 % ee in
the KR of P-stereogenic tertiary phosphanes and 70 % ee
for a single example of the first DKR of a chlorophos-
phane. In our case, enantiomeric excesses of up to 82 %
were achieved (Scheme 2) and some indications were ob-
tained of the factors that influence the stereoselectivity of
the reaction. It was clear that the presence of an ortho sub-
stituent in the aryl group was necessary for enantio-
selectivity. Also, certain indications were obtained relating
to the choice of suitable chiral alcohol, with cyclic second-
Despite all this progress in the asymmetric synthesis of
P-stereogenic phosphanes, the successful synthesis of any
particular example is not assured. It is still the case that
relatively few P-stereogenic ligands for transition-metal ca-
talysis have been studied because they are difficult to syn-
thesise.[4,7] For this reason we began to explore the possibil-
ity of kinetic resolution of phosphanes and their oxides. We
[a] Centre for Synthesis and Chemical Biology, School of Chemis-
try and Chemical Biology, University College Dublin,
Belfield, Dublin 4, Ireland
Fax: +353-1-7162127
E-mail: declan.gilheany@ucd.ie
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Eur. J. Org. Chem. 2010, 5642–5649

P-Stereogenic Phosphorus Compounds
ary alcohols such as menthol being found to be the most addition to minimise significant exothermicity (Scheme 5).
effective. To take this study further we have synthesised a This is reasonably successful if the aryl group is somewhat
set of new phosphanes with different ortho and para substit- bulky and so is suitable for most ortho-substituted cases.
uents (see Schemes 3 and 4) and subjected them to asym- However a balance has to be struck such that the reaction
metric oxidation under Appel conditions.
of the aryl Grignard with dichloro(phenyl)phosphane is not
too slow, otherwise certain exchange reactions can occur.
Also, if the starting material [dichloro(phenyl)phosphane] is
not used up in the reaction, it may react with the methyl-
magnesium chloride giving dimethyl(phenyl)phosphane.
Scheme 5. Synthesis of the required phosphanes.
In one case, 2d, this methodology could not be used and
the older method of Mislow and co-workers was applied.
Samples of all the phosphanes synthesised were then oxi-
dised to the corresponding racemic oxides with hydrogen
peroxide and CSP-HPLC conditions developed to allow the
separation of the enantiomers of each oxide.
Scheme 2. Some enantioselectivities previously obtained under the
asymmetric Appel conditions shown in Scheme 1.
Halogen Exchange in Halophosphanes
In all cases, during the synthesis of the phosphanes we
observed two signals in the 31P NMR spectrum of the reac-
tion mixture[42] at the intermediate stage but after the ad-
dition of methylmagnesium chloride only a single signal
corresponding to the expected tertiary phosphane was ob-
served. We investigated this further in the case of the o-CF3
derivative, which shows the two signals in a 1:2 ratio at δ =
75.4 and 66.2 ppm, respectively. The reaction mixture from
the initial Grignard addition was filtered from excess salts,
which were further extracted with diethyl ether. After evap-
oration of the combined extracts, the residue was purified
by vacuum distillation. The 31P NMR spectrum still showed
Scheme 3. Phosphanes studied with varying ortho substituents.
1
the same two peaks (but now in a 2:1 ratio) and the H
and 13C NMR spectra showed only aromatic protons and
carbons, respectively. Most significantly, electron ionisation
mass spectra showed peaks at 287.9886 and 289.9854 in a
1:3 ratio and at 331.935 and 333.935 in a 1:1 ratio. From
these results we concluded that the compounds are proba-
bly as shown in Scheme 6, formed by a halogen-exchange
reaction. A similar observation was previously made by
Wehmschulte and co-workers.[43]
Scheme 4. Phosphanes studied with varying para substituents.
Results and Discussion
Synthesis of Phosphane Precursors
Previously the method of Mislow and co-workers[15] had
been the most common procedure for the synthesis of race-
mic phosphanes in our laboratory. This route gives the
phosphane oxide, which then has to be reduced to the de-
sired phosphane. However, we found[41] that methyl(phen-
yl)(o-tolyl)phosphane could be prepared directly from
dichloro(phenyl)phosphane in by two Grignard reactions at
low temperatures and we have now applied, with proper
care, this methodology to the synthesis of many of the
phosphanes required in this work. The aryl Grignard rea-
gent is added first and its double addition can be minimised
Scheme 6. Products of the halogen-exchange reaction.
Asymmetric Appel Reaction
The asymmetric Appel reaction was performed with a
by control of stoichiometry, a low temperature and slow set of chiral alcohols similar to those used previously. The
Eur. J. Org. Chem. 2010, 5642–5649
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K. V. Rajendran, L. Kennedy, D. G. Gilheany
FULL PAPER
reactions have to be performed carefully, especially with re- Table 2. Enantiomeric excesses[a] obtained in the asymmetric Appel
reaction[b] (Scheme 1) with para-substituted phosphanes
(Scheme 4).
gard to the low temperatures used, the exclusion of moist-
ure and to the order and rate of addition of the reagents.
Alcohol
para substituent
The reaction was successful if phosphane and alcohol were
mixed initially with the subsequent addition of HCA at
F
Cl
H
Me
OMe
–78 °C. Alternatively, the selectivity was almost the same if 1[c]
73
60
51
38
72
60
57
82 (S)
71 (S)
65 (S)
69 (S)
–67 (R)
–76
–68
–54
–57
69
64
52
56
–59
2
the alcohol and HCA were mixed first followed by the ad-
dition of phosphane at –78 °C. However, phosphane and
HCA may not be premixed. The enantiomeric excesses ob-
tained from the oxidation of the phosphanes with the dif-
ferent chiral alcohols (Scheme 7) are given in Tables 1 and
2.
3
4
5
–67
[a] Obtained by CSP-HPLC; the absolute configurations were not
determined except where noted. A negative ee indicates that the
major enantiomer was eluted second. [b] Phosphane (0.11 mmol),
alcohol (1.2 equiv.), HCA (1 equiv.) at –78 °C. All yields are Ͼ95 %
(as judged by 31P NMR). [c] All the reactions with (+)-menthol
were repeated with (–)-menthol. Comparable results were obtained
but with opposite configuration.
stituent (methyl) gives the best selectivity with most of the
alcohols studied, whereas the most bulky (tert-butyl) gives
the poorest selectivity in most cases.
To try to separate the electronic and steric effects we
turned to para substitution. To ensure consistency and rea-
sonable degrees of enantioselectivity, it was necessary to
study a series of compounds having a constant substituent
at the ortho position and we chose the methyl series. The
results, given in Table 2, unexpectedly and disappointingly
showed that the stereoselectivity could not be improved by
variation of the electronic nature of the para substituent.
Thus, in almost all cases lower selectivity (sometimes signif-
icantly so) was obtained with both electron-withdrawing
and -donating substituents relative to the unsubstituted
case. It is difficult to envisage how a selection process could
be affected in the same direction by both EWGs and EDGs.
We therefore believe that there is another process occurring
that affects the selectivity. One possibility would be a ra-
cemisation process, for example, involving the chloride ion
that is present. Assuming that one of these selectivity-affect-
ing processes is promoted by an EDG and the other by an
EWG then explains the observed trends in selectivity.
Scheme 7. Chiral alcohols reported in Tables 1 and 2 drawn in such
a way that the enantiomers shown all give the same sense of selec-
tion in the asymmetric Appel reaction.
Table 1. Enantiomeric excesses[a] obtained in the asymmetric Appel
reaction[b] (Scheme 1) of ortho-substituted phosphanes (Scheme 3).
Alcohol
ortho substituent
Br 2,3-Benzo[c] Ph
CF3
Me
tBu NMe2
1[d]
2
3
4
5
–71
–67
–58
–06
72
60
57
–59
–51
–54
–36
45
64
64
55
50
82 (S) –57
71 (S) –40
65 (S) –36
69 (S) –19
–71
–46
–43
–55
–67
–41 –67 (R)
6
13
16
[a] Obtained by CSP-HPLC; the absolute configurations were not
determined except where noted. A negative ee indicates that the
major enantiomer was eluted second. [b] Phosphane (0.11 mmol),
alcohol (1.2 equiv.), HCA (1 equiv.) at –78 °C. All yields are Ͼ95 %
(as judged by 31P NMR). [c] Refers to compound 1c in Scheme 3.
[d] All the reactions with (+)-menthol were repeated with (–)-men-
thol. Comparable results were obtained but with opposite configu-
ration.
Conclusions
The synthesis and asymmetric oxidation of a series of
The data in Table 1 strongly suggest that there is no elec- novel ortho- and para-substituted aryl(methyl)phenylphos-
tronic effect of ortho substitution. For example, both the phanes has been carried out. During the syntheses we found
electron-rich NMe2 and the electron-deficient CF3 substitu- that there are two intermediate diarylhalophosphane spe-
ents give very similar selectivity with menthol. It might be cies present as a result of halogen exchange between chloro
that they give the opposite configurations but the fact that and bromo substituents. Asymmetric oxidation under Ap-
they have the same magnitude of selection is highly sugges- pel conditions with different chiral alcohols clearly shows
tive. However, this conclusion still must remain provisional that substitution at the ortho position in aryl(methyl)phen-
because we were not able to determine the absolute configu- ylphosphanes strongly affects the degree of stereoselection.
rations of the products. In addition, the electronic effects of Unexpectedly, selectivity was reduced by para substitution
ortho substituents are always compromised by steric effects with both electron-withdrawing and -donating groups,
and it is apparent that steric effects have a significant role which suggests that there are at least two selection processes
in the stereochemical outcome of this reaction. The trends in operation. Among several alternatives it is possible that
are not clear cut and, again, we are lacking absolute config- there is a racemisation process involving the chloride ion.
urations, but it is certainly the case that the least bulky sub- We will address this issue in subsequent studies. Finally, we
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Eur. J. Org. Chem. 2010, 5642–5649

P-Stereogenic Phosphorus Compounds
and the product was isolated as a colourless oil (2.3 g, 64 %); b.p.
note that it is the P-stereogenic phosphanes themselves that
are the more desirable products. These can be obtained
from the oxides made in this work by known stereoselective
reduction techniques (e.g., with silanes[3]) but these are
sometimes capricious when substituents are changed and
we will also address this issue in subsequent work.
180 °C at 1.3 Torr. 1H NMR (CDCl3, 300 MHz): δ = 7.53–7.24 (m,
2
9 H, Ar), 2.53 (s, 3 H, ArCH3), 1.75 (d, JPH = 4.1 Hz, 3 H,
CH3) ppm. 31P NMR (CDCl3, 121 MHz): δ = –36.2 ppm (ref.[36]
–35.2 ppm).
A similar procedure was followed to synthesise the other phospha-
nes.
Methyl(phenyl)(2-trifluoromethylphenyl)phosphane (1a): 2-Bromo-
(trifluoromethyl)benzene (3.8 g, 17.5 mmol, 1 equiv.) was added to
magnesium (0.45 g, 18.7 mmol, 1.1 equiv.). The aryl Grignard rea-
gent was then treated with dichloro(phenyl)phosphane (3.1 g,
17.5 mmol, 1 equiv.) and subsequently methylmagnesium chloride
(6.8 mL of a 3.0  solution in THF, 20.4 mmol, 1.2 equiv.) and the
crude phosphane was purified by high-vacuum distillation and the
product was isolated as a colourless oil (2.5 g, 53 %); b.p. 160 °C at
1.3 Torr. 1H NMR (CDCl3, 300 MHz): δ = 7.64–7.42 (m, 9 H, Ar),
Experimental Section
General: Melting points were determined with a Reichert Thermo-
var melting-point apparatus. Elemental analyses were carried out
at the Microanalytical Laboratory, University College Dublin.
Routine electrospray mass spectra were obtained with a Micromass
Quattro spectrometer. High-resolution mass spectra were recorded
with a Waters Micromass GCT system either by chemical ionis-
ation (CI) or electron ionisation (EI) also at UCD. The NMR spec-
tra were recorded at 25 °C with Varian VNMRS 300, 400,
500 MHz spectrometers. 13C NMR spectra (31P-decoupled) were
recorded with a VNMRS 600 MHz spectrometer. All NMR spectra
of potentially air-sensitive compounds were recorded under nitro-
gen. High-performance liquid chromatography was performed on
a Shimadzu LC 10AT system with an autosampler coupled to a
Shimadzu SPD 10A UV/Vis detector. HPLC grade solvents, pur-
chased from Aldrich and Lennox Supplies, Ireland, were used as
supplied. All samples were filtered through an Acrodisc CR 13 mm
syringe filter with 0.2 µm PTFE prior to injection. IR spectra were
recorded with a Varian 3100 FTIR Excalibur series spectrometer.
2
1.76 (d, JPH = 3.6 Hz, 3 H, PCH3) ppm. 13C NMR {1H, 31P}
(CDCl3, 151 MHz): δ = 139.9, 139.5, 134.3, 133.3 131.6, 128.6,
128.4, 128.2, 126.0, 125.9, 124.4 (q, J = 275.2 Hz), 12.8 ppm. 31P
NMR (CDCl3, 121 MHz): δ = –32.8 ppm. MS (electrospray): m/z
= 269 [M + H]+. HRMS (EI): calcd. for [M]+ 268.0629; found
268.0641.
Methyl(1-naphthyl)phenylphosphane[45] (1c): 2-Naphthyl bromide
(4.02 g, 20 mmol, 1 equiv.) was added to magnesium (0.5 g,
20 mmol, 1.1 equiv.). The formed Grignard reagent was then
treated with dichloro(phenyl)phosphane (3.40 g, 19 mmol) and
methylmagnesium chloride (6.3 mL, 19 mmol) to yield a yellow-
tinted oil. The phosphane was purified by column chromatography
on silica using ethyl acetate. A white solid (4.15 g, 87 %) was ob-
Unless otherwise stated all the reactions were carried out under N2
in dry glassware using Schlenk-line techniques, All “dry” solvents
were dried and distilled by standard procedures[44] or were pro-
cessed through a Grubbs-type still, a Pure Solv-400-3-MD solvent
purification system, supplied by Innovative Technology Inc.
1
tained. H NMR (CDCl3, 300 MHz): δ = 8.58–8.22 (m, 1 H, Ar),
7.42–7.24 (m, 2 H, Ar), 7.17–7.00 (m, 3 H, Ar), 6.97–6.78 (m, 4 H,
2
Ar), 6.78–6.61 (m, 2 H, Ar), 1.14 (d, JPH = 4.4 Hz, 3 H,
CH3) ppm. 31P NMR (CDCl3, 121 MHz): δ = –36.1 ppm (ref.[45]
–37.1 ppm).
General Method for the Synthesis of the Required Phosphanes by
Direct Substitution at Phosphorus
Exemplar: Methyl(phenyl)(o-tolyl)phosphane[36] (2e): A dry 100 mL
two-necked round-bottomed flask fitted with reflux condenser, ni-
trogen inlet and outlet and septum was charged with magnesium
turnings (0.5 g, 18.7 mmol, 1.1 equiv.). 2-Bromotoluene (3.0 g,
17 mmol, 1 equiv.) was dissolved in THF (10 mL) and approx.
2 mL of this solution was added to the flask through a syringe. The
mixture was heated at reflux with vigorous stirring until the reac-
tion initiated, at which point the remainder of the solution was
added over approximately 30 min, also through a syringe. After this
time the reaction was heated at reflux for a further 2 h. The reac-
tion was allowed to cool to room temperature and was then trans-
ferred through a syringe into a pressure-equalised dropping funnel
attached to a flame-dried and -degassed 100 mL round-bottomed
flask, which had been charged previously with dichloro(phenyl)-
phosphane (3.0 g, 17 mmol, 1 equiv.) and anhydrous THF (10 mL).
This solution was cooled to –78 °C using a dry ice/acetone mixture
and the Grignard solution was added dropwise over 1 h. The flask
was warmed to room temperature and was then stirred for 1 h.
A solution of methylmagnesium bromide in THF (3.0 , 6.2 mL,
18.7 mmol, 1.1 equiv.) was added over approximately 30 min, and
the mixture was then stirred at room temperature overnight. The
reaction was quenched slowly at 0 °C with degassed saturated am-
monium chloride solution (100 mL) and extracted with dichloro-
methane (3ϫ100 mL) that had been stored over anhydrous magne-
sium sulfate for 30 min under nitrogen. The extracts were filtered
through a sintered funnel under nitrogen, the solvent removed in
vacuo, the crude phosphane purified by high-vacuum distillation
Biphenyl-2-yl(methyl)phenylphosphane[46] (1d): Biphenyl-2-yl bro-
mide (5.22 g, 20 mmol, 1 equiv.) was added to magnesium (0.57 g,
20 mmol, 1 equiv.). The aryl Grignard reagent was then treated
with dichloro(phenyl)phosphane (3.96 g, 22 mmol, 1 equiv.) and
subsequently methylmagnesium chloride (7.34 mL, 22 mmol,
1 equiv.). The product was purified by column chromatography on
silica using an ethyl acetate mobile phase to yield the pure phos-
1
phane as a clear oil (4.75 g, 78 %). H NMR (CDCl3, 300 MHz):
2
δ = 7.23–7.45 (m, 14 H, Ar), 1.44 (d, JPH = 3.9 Hz, 3 H,
CH3) ppm. 31P NMR (CDCl3, 121 MHz): δ = –32.7 ppm (ref.[46]
–34.2 ppm).
(2-tert-Butylphenyl)(methyl)phenylphosphane (1f): 1-Bromo-2-tert-
butylbenzene[47] (4.2 g, 20.1 mmol, 1 equiv.) was added to magne-
sium (0.5 g, 22.1 mmol, 1.1 equiv.). The aryl Grignard reagent was
then treated with dichloro(phenyl)phosphane (3.6 g, 20.1 mmol,
1 equiv.) and subsequently methylmagnesium chloride (8.0 mL of a
3.0  solution in THF, 24.12 mmol, 1.2 equiv.). The crude phos-
phane was purified by high-vacuum distillation and the product
was isolated as a colourless oil (3.3 g, 64 %); b.p. 200 °C at 1.3 Torr.
1H NMR (CDCl3, 300 MHz): δ = 7.12–7.54 (m, 9 H, Ar), 1.73 (s,
9 H, tert-butyl-CH3), 1.64 (d, 2JPH = 5.7 Hz, 3 H, PCH3) ppm. 13
C
NMR {1H, 31P} (CDCl3, 151 MHz): δ = 155.8, 143.2, 136.5, 130.8,
130.6, 128.1, 126.9, 126.5, 125.4, 125.3, 32.6, 26.9, 13.6 ppm. 31P
NMR (CDCl3, 121 MHz): δ = –31.9 ppm. MS (electrospray): m/z
= 257.1 [M + H]+. HRMS (CI): calcd. for [M + 1]+ 257.1459; found
257.1449.
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K. V. Rajendran, L. Kennedy, D. G. Gilheany
FULL PAPER
Dimethyl-[2-(methylphenylphosphanyl)phenyl]amine (1g): 2-Bromo- Halogen Exchange in Halophosphanes
N,N-dimethylaniline (2 g, 9.8 mmol, 1 equiv.) was added to magne-
Chloro(2-trifluoromethylphenyl)phenylphosphane: 2-Bromo(trifluoro-
sium (0.26 g, 10.8 mmol, 1.1 equiv.). The aryl Grignard reagent was
then treated with dichloro(phenyl)phosphane (1.7 g, 9.8 mmol,
1 equiv.) and subsequently methylmagnesium chloride (4.0 mL of a
3.0  solution in THF, 11.8 mmol, 1.2 equiv.). The crude phos-
phane was purified by high-vacuum distillation and the product
was isolated as a colourless oil (1.2 g, 50 %); b.p. 185 °C at 1.3 Torr.
1H NMR (CDCl3, 300 MHz): δ = 7.02–7.45 (m, 9 H, Ar), 2.65 [s,
6 H, N(CH3)2], 1.63 (d, 2JPH = 4.8 Hz, 3 H, PCH3) ppm. 13C NMR
{1H, 31P} (CDCl3, 151 MHz): δ = 158.2, 141.6, 132.5, 132.3, 131.6,
129.4, 128.2, 128.0, 124.5, 120.5, 45.5, 12.6 ppm. 31P NMR
(CDCl3, 121 MHz): δ = –35.1 ppm. MS (electrospray): m/z = 244.2
[M + H]+. HRMS (EI): calcd. for [M]+ 243.1177; found 243.1187.
methyl)benzene (2 g, 9.2 mmol, 1 equiv.) was added to magnesium
(0.2 g, 9.8 mmol, 1.1 equiv.). The aryl Grignard reagent was then
treated with dichloro(phenyl)phosphane (1.6 g, 9.2 mmol, 1 equiv.).
The solvent was removed in vacuo. Dry diethyl ether (100 mL) was
added to the reaction mixture to precipitate the magnesium salts,
which were filtered through a sintered funnel under nitrogen. The
solvent was removed in vacuo, the crude phosphane was purified
by high-vacuum distillation and the product was isolated as a
colourless oil (1.2 g, 64 %); b.p. 135 °C at 1.3 Torr. 1H NMR
(CDCl3, 300 MHz): δ = 7.86–7.18 (m, 9 H, Ar) ppm. 13C NMR
{1H, 31P} (CDCl3, 151 MHz): δ = 139.9, 139.5, 134.3, 133.3, 131.6,
128.6, 128.4, 128.2, 126.0, 125.9, 124.4 (q, J = 275.2 Hz) ppm. 31P
NMR (CDCl3, 121 MHz): δ = 75.9, 66.5 ppm. HRMS (EI): calcd.
for C13H9BrF3P [M]+ 331.9577, 333.9558; found 331.9356,
333.9352; calcd. for C13H9ClF3P [M]+ 288.0082, 290.0053; found
287.9886, 289.9954.
(4-Fluoro-2-methylphenyl)(methyl)phenylphosphane (2a): 1-Bromo-
4-fluoro-2-methylbenzene (4.7 g, 9.8 mmol, 1 equiv.) was added to
magnesium (0.6 g, 27.5 mmol, 1.1 equiv.). The aryl Grignard rea-
gent was then treated with dichloro(phenyl)phosphane (4.6 g,
25 mmol, 1 equiv.) and subsequently methylmagnesium chloride
(10 mL of a 3.0  solution in THF, 30 mmol, 1.2 equiv.). The crude
phosphane was purified by high-vacuum distillation and the prod-
uct was isolated as a colourless oil (3.9 g, 65 %); b.p. 180 °C at
1.3 Torr. 1H NMR (CDCl3, 300 MHz): δ = 7.43–6.95 (m, 8 H, Ar),
2.48 (s, 3 H), 1.64 (d, 2JPH = 10.9 Hz, 3 H, PCH3) ppm. 13C NMR
{1H, 31P} (CDCl3, 151 MHz): δ = 163.2 (d, J = 247.5 Hz), 144.9,
139.8, 133.3, 132.3, 131.9, 128.5, 128.2, 116.8, 113.0, 21.5,
12.5 ppm. 31P NMR (CDCl3, 121 MHz): δ = –37.4 ppm. MS (elec-
trospray): m/z = 233.39 [M + H]+. HRMS (CI): m/z calcd. for [M
+ 1]+ 233.0895; found 233.0895.
(4-Methoxy-2-methylphenyl)(methyl)phenylphosphane (2d) by Re-
duction of the Oxide: (4-Methoxy-2-methylphenyl)(methyl)phenyl-
phosphane oxide (0.37 g, 1 mmol, 1 equiv.) was added to a flame-
dried round-bottomed flask under vacuum and flushed with nitro-
gen three times, fitted with a magnetic stirring bar, nitrogen inlet/
outlet, condenser and rubber septum, and dissolved in toluene
(5 mL/g approx.). Trichlorosilane (0.54 g, 4 mmol, 4 equiv.) was
added dropwise through a syringe. The reaction was heated to
70 °C for 12 h using an oil bath. The reaction was allowed to cool
and quenched with 20 equiv. of aqueous degassed sodium hydrox-
ide (2 ). The organic material was extracted with dichlorometh-
ane, dried with sodium sulfate and the solvent removed in vacuo
to yield a clear oil. The compound was purified by chromatography
on silica with a dichloromethane (DCM) mobile phase to give a
clear oil (0.31 g, 76 %). 1H NMR (CDCl3, 600 MHz): δ = 7.30–
7.19 (m, 6 H, Ar), 6.82–6.72 (m, 2 H, Ar), 3.81 (s, 3 H, OCH3),
(4-Chloro-2-methylphenyl)(methyl)phenylphosphane (2b): 2-Bromo-
5-chlorotoluene (5.00 g, 24 mmol, 1 equiv.) was added to magne-
sium (0.60 g, 25 mmol, 1.1 equiv.). The aryl Grignard reagent was
dropped onto dichloro(phenyl)phosphane (4.35 g, 24 mmol,
1 equiv.) at –78 °C over a period of 2 h and the mixture was then
stirred for a further hour. Methylmagnesium chloride (8 mL,
24 mmol) was added as the temperature rose to room temperature.
This reaction mixture was stirred for 2 h. The reaction was worked
up as stated for 2e. A caramel-coloured oil was recovered, which
was then purified by column chromatography on silica with 100 %
dichloromethane as the mobile phase. This gave a clear oil (4.77 g,
2
2.42 (s, 3 H, CH3), 1.57 (d, JPH = 4.1 Hz, 3 H, PCH3) ppm. 13C
NMR {1H, 31P} (CDCl3, 151 MHz): δ = 160.1, 144.1, 140.1, 132.1,
131.8, 128.5, 128.3, 128.0, 115.6, 111.6, 55.1, 21.4, 12.4 ppm. 31P
NMR (CDCl3, 241 MHz): δ = 38.3 ppm. HRMS (CI): calcd. for
C15H17OP [M + 1]+ 245.1095; found 245.1089.
General Method for the Synthesis of Racemic Phosphane Oxides and
Their Separation on Chiral HPLC Columns
1
80 %). H NMR (CDCl3, 600 MHz): δ = 7.44–7.31 (m, 5 H, Ar),
2
7.30–7.18 (m, 3 H, Ar), 2.41 (s, 3 H, CH3), 1.60 (d, JPH = 4.3 Hz,
Exemplar: (؎)-Methyl(phenyl)(o-tolyl)phosphane Oxide[36] (Oxo-
2e): Hydrogen peroxide (1.14 mL, 35 wt.-%, 0.4 g, 11.6 mmol,
1.5 equiv.) was added dropwise to a stirred solution of phosphane
(2.2 g, 10.2 mmol, 1 equiv.) in acetone (30 mL, degassed) at 0 °C
(ice bath). After the addition was complete the solution was stirred
overnight. Water (60 mL) and dichloromethane (120 mL) were
added and the organic layer was separated. The aqueous layer was
extracted with dichloromethane (2ϫ60 mL) and the combined or-
ganic layers were dried (Na2SO4), filtered and concentrated under
reduced pressure to yield a white solid. Column chromatography
on silica gel was carried out with dichloromethane followed by
dichloromethane/methanol (95:5) to yield a white solid (1.24 g,
53 %); m.p. 113–114 °C (ref.[36] m.p. 114–115 °C). 1H NMR
(CDCl3, 300 MHz): δ = 7.71-7.61 (m, 3 H, Ar), 7.53–7.40 (m, 4 H,
3 H, CH3) ppm. 13C NMR {1H, 31P} (CDCl3, 151 MHz): δ = 144.0,
139.5, 136.6, 134.6, 132.2, 131.7, 130.0, 128.6, 128.50, 126.2, 21.1,
12.2 ppm. 31P NMR (CDCl3, 241 MHz):
δ = –36.8 ppm.
C14H14ClP (248.69): calcd. C 67.61, H 5.67, Cl 14.26, P 12.45;
found C 67.50, H 5.82, Cl 14.50, P 12.26. HRMS (CI): calcd. for
C14H14ClP [M + 1]+ 249.0600; found 249.0588.
(2,4-Dimethylphenyl)(methyl)phenylphosphane (2c): 1-Bromo-2,4-
methylbenzene (4.8 g, 26 mmol, 1 equiv.) was added to magnesium
(0.7 g, 28.6 mmol, 1.1 equiv.). The aryl Grignard reagent was then
treated with dichloro(phenyl)phosphane (4.7 g, 26 mmol, 1 equiv.)
and subsequently methylmagnesium chloride (10.4 mL of a 3.0 
solution in THF, 31.3 mmol, 1.2 equiv.). The crude phosphane was
purified by high-vacuum distillation and the product was isolated
1
as a colourless oil (3.7 g, 61 %); b.p. 185 °C at 1.3 Torr. H NMR
2
Ar), 7.35–7.21 (m, 2 H, Ar), 2.39 (s, 3 H, Ar-CH3), 2.01 (d, JPH
(CDCl3, 300 MHz): δ = 7.45–7.09 (m, 8 H, Ar), 2.45 (s, 3 H), 2.39
= 13.0 Hz, 3 H, CH3) ppm. 31P NMR (CDCl3, 121 MHz): δ =
2
(s, 3 H), 1.64 (d, JPH = 4.1 Hz, 3 H, PCH3) ppm. 13C NMR {1H,
32.5 ppm (ref.[36] 31.8 ppm). IR: ν = 3379, 1593, 1474, 1180 (P=O),
˜
31P} (CDCl3, 151 MHz): δ = 142.3, 140.6, 138.5, 134.2, 132.2,
131.9, 131.0, 130.5, 128.4, 126.9, 21.2, 21.0, 12.2 ppm. 31P NMR
(CDCl3, 121 MHz): δ = –37.4 ppm. MS (electrospray): m/z =
229.30 [M + H]+. HRMS (EI): calcd. for [M]+ 228.1068; found
228.1059.
1138, 1112 cm–1. HPLC (CHIRALPAK® AD column, 90:10 hep-
tane/EtOH, 1 mL/min): Rt = 13.8, 21.3 min.
A similar procedure was followed to synthesise the other phos-
phane oxides.
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Eur. J. Org. Chem. 2010, 5642–5649

P-Stereogenic Phosphorus Compounds
(؎)-Methyl(phenyl)(2-trifluoromethylphenyl)phosphane
Oxide
31.7 ppm. IR: ν = 3372, 1723, 160.5, 1438, 1187 (P=O), 1071,
˜
(Oxo-1a): From the phosphane (1 g, 3.7 mmol, 1 equiv.) in a yield
1037 cm–1. HRMS (EI): calcd. for [M]+ 244.1017; found 244.1008.
1
of 0.68 g, 65 %. H NMR (CDCl3, 300 MHz): δ = 7.93–7.12 (m, 9 HPLC (CHIRALPAK® OD column, 90:10 pentane/EtOH, 1 mL/
H, Ar), 2.1 (d, 2JPH = 10.2, Hz, 3 H, P-CH3) ppm. 13C NMR {1H,
31P} (CDCl3, 151 MHz): δ = 134.9, 134.4, 132.1, 131.9, 131.7,
min): Rt = 15.3, 16.9 min.
Synthesis of Phosphane Oxides via Phosphanyl Chloride
131.6, 131.4, 130.0, 128.4, 127.4, 123.5 (q,
J = 274.2 Hz),
16.63 ppm. 31P NMR (CDCl , 121 MHz): δ = 31.6 ppm. IR: ν =
General Method: Magnesium turnings (1.1 equiv.) were placed in a
flame-dried three-necked round-bottomed flask fitted with a con-
denser, nitrogen in/outlet, pressure-equalising dropping funnel,
magnetic stirring bar and stoppers. All joints were greased and the
vessel was placed under vacuum using an oil pump and then
flushed with nitrogen. This procedure was repeated three times. The
aryl bromide (1 equiv.) was added to the dropping funnel and dis-
solved in dry THF (20 mL/g approx.). Approximately one third was
added to magnesium and stirred until the reaction had initiated,
which could be observed in different ways depending on the sub-
strate used, for example, the evolution of heat, a colour change
and/or effervescence from the magnesium. The remainder of the
aryl bromide solution was then added slowly (approx. 50 mL/h)
and the reaction was heated at reflux until all the magnesium was
consumed (approx. 2 h). The reaction was allowed to cool and
methyl(phenyl)phosphanyl (1 equiv.) chloride was added dropwise
through a syringe. The reaction was heated at reflux overnight and
then allowed to cool and quenched with saturated ammonium chlo-
˜
3
3223, 1679, 1591, 1574, 1127 (P=O), 1132 cm–1. HRMS (EI): calcd.
for [M]+ 284.0578; found 284.0582. HPLC (CHIRALPAK® OD
column, 95:5 pentane/EtOH, 1 mL/min): Rt = 17.5, 20.6 min.
(؎)-(2-tert-Butylphenyl)(methyl)phenylphosphane Oxide (Oxo-1f):
From the phosphane (1 g, 3.9 mmol, 1 equiv.) in a yield of 0.62 g,
58 %; m.p. 137–140 °C. 1H NMR (300 MHz, CDCl3): δ = 8.23–
2
6.40 (m, 9 H, Ar), 2.06 (d, JPH = 12.9 Hz, 3 H, PCH3), 1.55 (s, 9
H, tert-butyl-CH3) ppm. 13C NMR {1H, 31P} (CDCl3, 151 MHz):
δ = 156.2, 144.1, 133.3, 131.2, 130.5, 129.9, 127.5, 126.8, 124.25,
123.9, 31.06, 24.8, 13.3 ppm. 31P NMR (CDCl3, 300 MHz): δ =
37.4 ppm. IR: ν = 3329, 1635, 1591, 1455, 1167 (P=O), 1138, 1123,
˜
1082 cm–1. HRMS (EI): calcd. for [M]+ 272.1330; found 272.1322.
HPLC (CHIRALPAK® OD column, 98:2 pentane/EtOH, 1 mL/
min): Rt = 19.6, 21.1 min.
(؎)-Methyl(phenyl)[2-(dimethylamino)phenyl]phosphane
Oxide
(Oxo-1g): From the phosphane (1 g, 4.1 mmol, 1 equiv.) in a yield
1
of 0.72 g, 67.9 %; m.p. 117–120 °C. H NMR (CDCl3, 300 MHz): ride[15] (20 mL/g). The organic material was extracted with dichlo-
δ = 7.95–6.67 (m, 9 H, Ar), 2.23 [s, 6 H, N(CH3)2], 2.04 (d, 2JPH
=
romethane, dried with sodium sulfate and the solvent removed un-
10.4 Hz, 3 H, PCH3) ppm. 13C NMR {1H, 31P} (CDCl3, 151 MHz): der reduced pressure.
δ = 154.3, 136.7, 132.5, 131.2, 130.4, 129.9, 127.5, 127.1, 124.2,
(؎)-Methyl(2-naphthyl)phenylphosphane Oxide (Oxo-1c):[48] Using
122.1, 44.3, 12.3 ppm. 31P NMR (CDCl3, 121 MHz): δ = 29.5 ppm.
magnesium (0.27 g, 10 mmol, 1 equiv.), 2-naphthyl bromide (2.34 g,
10 mmol, 1 equiv.) and methyl(phenyl)phosphanyl chloride (1.67 g,
10 mmol, 1 equiv.), a yellow soft solid was obtained. The material
was purified by column chromatography on silica with a 1:1 ethyl
acetate/dichloromethane mobile phase. The pure product was a
white solid (1.59 g, 63 %); m.p. 151–152 °C (ref.[48] 150–152 °C). 1H
NMR (CDCl3, 300 MHz): δ = 8.44 (d, J = 8.2 Hz, 1 H, Ar), 8.03
IR: ν = 3342, 1663, 1585, 1522, 1169 (P=O), 1118, 1044 cm–1.
˜
HRMS (EI): calcd. for [M]+ 259.1126; found 259.1118. HPLC
(CHIRALPAK® OD column, 95:5 pentane/EtOH, 1 mL/min): Rt
= 14.1, 16.2 min.
(؎)-(4-Fluoro-2-methylphenyl)(methyl)phenylphosphane
Oxide
(Oxo-2a): From the phosphane (1 g, 4.3 mmol, 1 equiv.) in a yield
1
of 0.74 g, 69.1 %; m.p. 98–102 °C. H NMR (CDCl3, 300 MHz): δ (d, J = 8.2 Hz, 1 H, Ar), 7.91 (m, 2 H, Ar), 7.73 (dd, J = 6.7,
= 7.64–6.84 (m, 8 H, Ar), 2.29 (s, 3 H, Ar), 1.96 (d, 2JPH = 13.1 Hz, 12.1 Hz, 2 H, Ar), 7.60–7.37 (m, 6 H, Ar), 2.17 (d, 2JPH = 13.1 Hz,
3 H, PCH3) ppm. 13C NMR {1H, 31P} (CDCl3, 151 MHz): δ = 3 H, CH3) ppm. 31P NMR (CDCl3, 121 MHz): δ = 33.1 ppm.
163.8 (d, J = 253.0 Hz), 144.8, 133.8, 132.6, 132.9, 130.7, 129.3,
HPLC CHIRALPAK® AS-H column, 90:10 heptane/EtOH, 1 mL/
min): Rt = 9.7, 11.11 min.
127.7, 118.0, 111.4, 20.3, 16.6 ppm. 31P NMR (CDCl3, 121 MHz):
δ = 31.0 ppm. IR: ν = 3052, 2973, 1724, 1583, 1483, 1183 (P=O),
˜
(؎)-Biphenyl-2-yl(methyl)phenylphosphane Oxide[41] (Oxo-1d): Bi-
phenyl-2-yl bromide (4.94 g, 20 mmol, 1 equiv.) was treated with
magnesium (0.57 g, 20 mmol, 1 equiv.) and methyl(phenyl)phos-
phinyl chloride (3.05 g, 20 mmol, 1 equiv.) to yield a yellow tinted
1107, 1072 cm–1. HRMS (CI): calcd. for [M + 1]+ 249.0845; found
249.0836. HPLC (CHIRALPAK® AD column, 90:10 pentane/
EtOH, 1 mL/min): Rt = 19.0, 21.0 min.
(؎)-(4-Chloro-2-methylphenyl)(methyl)phenylphosphane
Oxide soft solid. The material was purified by column chromatography
(Oxo-2b): From the phosphane (0.5 g, 2.4 mmol, 1 equiv.) in a yield on silica with a 1:1 ethyl acetate/dichloromethane mobile phase.
1
of 0.54 g, 99 %. H NMR (CDCl3, 600 MHz): δ = 7.53–7.43 (m, 3 The pure product was a white solid (3.9 g, 63 %); m.p. 87–89 °C
1
H, Ar), 7.34 (m, 1 H, Ar), 7.34 (m, 2 H, Ar), 7.12 (m, 1 H, Ar),
(ref.[41] 87–89 °C). H NMR (CDCl3, 300 MHz): δ = 7.84 (dd, J =
2
2
7.17 (m, 1 H, Ar), 2.2 (s, 3 H, CH3), 1.95 (d, JPH = 13.1 Hz, 3 H,
7.6, 13.1 Hz, 1 H, Ar), 7.54–6.98 (m, 13 H, Ar), 1.50 (d, JPH
=
CH3) ppm. 13C NMR {1H, 31P} (CDCl3, 151 MHz): δ = 143.9,
13.3 Hz, 3 H, CH3) ppm. 31P NMR (CDCl3, 121 MHz): δ =
138.1, 134.1, 132.8, 131.7, 130.3, 130.2, 128.6, 21.1, 17.1 ppm. 31P
26.9 ppm. HPLC (CHIRALPAK® AS-H column, 90:10 heptane/
NMR (CDCl , 241 MHz): δ = 30.6 ppm. IR: ν = 3361, 2973 (w, EtOH, 1 mL/min): Rt = 12.3, 18.7 min.
˜
3
C–H) 1585, 1437 (m, aromatic C=C) 1178 (s, P=O) cm–1. HRMS
(؎)-(4-Methoxy-2-methylphenyl)(methyl)phenylphosphane
Oxide
(Oxo-2d): 4-Methoxy-2-methylphenyl bromide (1.16 g, 10 mmol,
1 equiv.) was treated with magnesium (0.17 g, 10 mmol, 1 equiv.)
and methyl(phenyl)phosphanyl chloride (0.97 g, 10 mmol, 1 equiv.)
to give a clear crude oil. The phosphane oxide was purified by
(CI): calcd. for [M + 1]+ 265.0543, 267.0520; found 265.0549,
267.0409. HPLC (CHIRALPAK® AS-H, 83:17 heptane/EtOH,
1 mL/min): Rt = 8.3, 15.5 min.
(؎)-(2,4-Dimethylphenyl)(methyl)phenylphosphane Oxide (Oxo-2c):
From the phosphane (1 g, 4.3 mmol, 1 equiv.) in a yield of 0.65 g,
recrystallisation from toluene to give a white solid (0.77 g, 54 %);
1
61 %. M.p 125–128 °C. 1H NMR (CDCl3, 300 MHz): δ = 7.67– m.p. 144–146 °C. H NMR (CDCl3, 400 MHz): δ = 7.83–7.32 (m,
2
6.90 (m, 8 H, Ar), 2.35 (s, 3 H), 2.33 (s, 3 H), 2.04 (d, JPH
=
6 H, Ar), 6.87–6.60 (m, 2 H, Ar), 3.83 (s, 3 H, OCH3), 2.34 (s, 3
10.9 Hz, 3 H, PCH3) ppm. 13C NMR {1H, 31P} (CDCl3, 151 MHz): H, Ar-CH3), 2.00 (d, JPH = 13.1 Hz, 3 H, CH3) ppm. 13C NMR
2
δ = 142.4, 141.8, 135.5, 134.1, 132.6, 131.3, 130.3, 130.2, 128.5,
{1H,31P} (CDCl3, 151 MHz): δ = 162.4, 144.2, 135.2, 133.4, 131.4,
126.1, 21.3, 21.2, 17.6 ppm. 31P NMR (CDCl3, 300 MHz): δ =
130.4, 125.6, 121.1, 117.6, 110.6, 21.5, 17.4 ppm. 31P NMR
Eur. J. Org. Chem. 2010, 5642–5649
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5647

K. V. Rajendran, L. Kennedy, D. G. Gilheany
(CDCl3, 161 MHz): δ = 31.9 ppm. C15H17O2P (260.27): calcd. C Centre for Synthesis and Chemical Biology (CSCB) and University
FULL PAPER
69.22, H 6.58, P 11.90; found C 68.93, H 6.47, P 12.04. HRMS
(CI): calcd. for C15H17O2P [M + 1]+ 261.1033; found 261.1044.
HPLC (CHIRALPAK® AS-H column, 90:10 heptane/EtOH,
1 mL/min): Rt = 15.4, 17 min.
College Dublin. Thanks to Celtic Catalysts Ltd. for gifts of com-
pounds 1b and oxo-1b.
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Asymmetric Appel Reaction
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Predrying of Stock Solutions: The alcohol, phosphane and HCA
were dried thoroughly before preparing the stock solution as fol-
lows. The individual alcohols (1.2 equiv.) were weighed into flame-
dried and degassed round-bottomed flasks with dry toluene. The
toluene was removed using a rotary evaporator with a membrane
pump to remove water through the azeotrope. This process was
repeated three times and dry solvent (from Grubbs’ system) was
added to the vessels to make up to their respective concentrations
(0.132 ) and the flask was capped. Molecular sieves (4 Å), which
were flame-dried until red hot, were added to flame-dried Young’s
flasks. The flasks were heated with a heat gun focusing on the mo-
lecular sieves for 2 min each and then flushed with nitrogen. This
was repeated. The vessels were then put under vacuum again and
flushed with nitrogen. The Young’s flask screw crown was removed
with a good flow of nitrogen and replaced with a rubber septum.
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removed by syringe from the round-bottomed flask and placed on
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screw caps of the Young’s flasks were removed with a good flow
of nitrogen and replaced with rubber septa. Distilled HCA
(1 equiv.) was weighed into the Young’s flasks and dry toluene
(from Grubbs’ system) was added to the vessels to give 0.11  solu-
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Exemplar Reaction with Methyl(phenyl)(o-tolyl)phosphane (2e): The
phosphane (1e; 0.11 , 1 equiv.) and alcohol solutions (0.132 ,
1.2 equiv.) were removed by syringe and added to the flame-dried
degassed Schlenk flask fitted with a stirring bar. A rubber septum
was put over the Schlenk arm and the Schlenk flask was then im-
mersed in a dry ice/acetone bath and cooled to –78 °C. A HCA
stock solution (0.11 , 1 equiv.; 0.1 mL/min approx.) was added
through the syringe. When all the HCA had been added, the reac-
tion was stirred at –78 °C for 1 h. The reaction was then removed
from the cold bath, allowed to warm to room temperature and
then stirred for a further 24 h under nitrogen. Triphenylphosphane
sulfide (as an internal standard, 0.11 , 3 mL) was added to each
reaction and stirred. A portion (0.5 mL) of the mixture was re-
moved, diluted to 2 mL with HPLC solvent (HPLC grade solvents
purchased from Aldrich were used as supplied) and filtered through
a PTFE syringe filter into a HPLC vial. High-performance liquid
chromatography was performed with a Shimadzu LC 10 AT system
with an autosampler coupled to a Shimadzu SPD 10A UV/Vis de-
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Acknowledgments
For financial support, we thank the Science Foundation Ireland
(SFI) (Grants RFP/06/CHO013 and RFP/08/CHE1251), the UCD
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P-Stereogenic Phosphorus Compounds
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Received: May 20, 2010
Published Online: August 26, 2010
Eur. J. Org. Chem. 2010, 5642–5649
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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