Evaluation of bifunctional chiral phosphine oxide catalysts for the asymmetric hydrosilylation of ketimines

Article abstract of DOI:10.1016/j.tet.2019.130733

A series of bifunctional phosphine oxides have been prepared and evaluated as catalysts for the trichlorosilane mediated asymmetric hydrosilylation of ketimines. bis-Phosphine oxides, hydroxy-phosphine oxides, and biaryl phosphine oxides all demonstrated good catalytic activity, but poor to moderate enantioselectivity. A bis-P-chiral phosphine oxide displayed the highest enantioselectivity of 60%.

Full text of DOI:10.1016/j.tet.2019.130733

Journal Pre-proof
Evaluation of bifunctional chiral phosphine oxide catalysts for the asymmetric
hydrosilylation of ketimines
Christopher J.A. Warner, Sian S. Berry, Simon Jones
PII:
S0040-4020(19)31119-6
https://doi.org/10.1016/j.tet.2019.130733
TET 130733
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 August 2019
Revised Date: 15 October 2019
Accepted Date: 22 October 2019
Please cite this article as: Warner CJA, Berry SS, Jones S, Evaluation of bifunctional chiral phosphine
oxide catalysts for the asymmetric hydrosilylation of ketimines, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.130733.
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Evaluation of bifunctional phosphine oxide catalysts for the asymmetric
hydrosilylation of ketimines
Christopher J. A. Warner,a Sian S. Berrya and Simon Jones a*
Department of Chemistry, University of Sheffield, Dainton Building, Brook Hill, Sheffield. S3 7HF.
UK.
Graphical Abstract

Evaluation of bifunctional chiral phosphine oxide catalysts for the
asymmetric hydrosilylation of ketimines
Christopher J. A. Warner,a Sian S. Berrya and Simon Jonesa*
a Department of Chemistry, Dainton Building, University of Sheffield, Brook Hill, Sheffield
S3 7HF, UK
*
Corresponding
author.
Tel.:
+44
(0)114-2229483;
e-mail
address:
simon.jones@sheffield.ac.uk
Dedication
This paper is dedicated to the outstanding achievements of Professor Stephen Davies in
organic chemistry, for being an incredible mentor and advisor, and for his continual support
and friendship over the years.
Keywords
Hydrosilylation; Asymmetric Catalysis; Phosphine Oxide; Organocatalysis
Abstract
A series of bifunctional phosphine oxides have been prepared and evaluated as catalysts for
the trichlorosilane mediated asymmetric hydrosilylation of ketimines. bis-Phosphine oxides,
hydroxy-phosphine oxides, and biaryl phosphine oxides all demonstrated good catalytic
activity, but poor to moderate enantioselectivity. A bis-P-chiral phosphine oxide displayed
the highest enantioselectivity of 60%.
1

Introduction
Non-symmetrically substituted phosphorus compounds are commonplace throughout organic
chemistry both as chiral ligands and more recently as organocatalysts.[1–5] Despite their
prevalence, the majority of examples reported utilise a P-chiral phosphine as the catalytic
moiety, with very few reports of the application of the analogous P-chiral phosphine oxides.
The earliest report of the use of a P-chiral phosphine oxide detailed the application as a
ligand for asymmetric transfer hydrogenation of ketones,[6] and subsequent studies have
shown applicability in a number of synthetic applications, including Diels-Alder reactions,[7]
enantioselective allylation of α-hydrazono esters,[8] desymmetrisation of diaryl meso-
epoxides,[9] reductive aldol condensations,[10] and reductive cyclisation of N-acylated-β-
amino enones.[11] The latter two transformations make use of trichlorosilane as a reductant,
a reagent known for susceptibility for activation by Lewis base catalysts, a majority of which
are amide based.[12] However, Sun has used S-chiral sulfoxides to affect asymmetric
hydrosilylation of ketimines,[13] further developing initial disclosures with a second
generation bis-S-chiral sulfoxide that delivered consistently higher reactivity and
selectivity.[14] Sun’s group also went on to develop an organocatalyst with both carbon and
sulfur stereogenic centres to promote the enantioselective hydrosilylation of 1,4-
benzooxazines.[15]
Work from our laboratories has developed imidazole derived organocatalysts for the
asymmetric hydrosilylation of ketimines that operate very effectively at exceptionally low
catalyst loading,[16] and proposed a dual activation model for this behaviour based on
catalysts containing both Lewis basic and Brønsted acidic functionality.[17] We have also
explored the use of P-chiral phosphine oxides as catalysts for this reaction.[18] Although
these species displayed potent catalytic activity, they struggled to deliver enantioselectivities
of greater than 28% ee. Notably, these phosphine oxides displayed a negative non-linear
effect, which is in-line with that observed with S-chiral catalysts developed by Sun. In this
work we describe efforts to bring together these key design elements; dual activation to
provide a catalyst which displays no non-linear effects.
Results and Discussion
Initial studies sought to accrue data to validate the proposed dual activation hypothesis. A
series of potential catalysts were targeted bearing phosphine oxide and alcohol functional
groups with different length spacers between these. Achiral diphenyl bis-phosphine oxide
catalysts 1–7 were synthesised with chain lengths varying from two to nine carbon atoms,
2

following established literature precedent.[19] Thus, the appropriate alkyldihalide was treated
with triphenylphosphine to form the bis-phosphonium salt, followed by reaction with
concentrated sodium hydroxide to afford the desired catalysts in excellent yield (Scheme 1).
The hydroxy-phosphine oxides 8–10 were prepared adopting a similar route used for the bis-
phosphine oxides, but instead starting with the appropriate halohydrin or halo-acetate
(Scheme 1).
Scheme 1. Synthesis of bis-phosphine oxides 1-7 and hydroxy-phosphine oxides 8-10.
The prepared catalysts 1–10 were then trialled in the reduction of a benchmark ketimine
substrate 11 to the PMP-amine 12 under standard previously employed reaction conditions
(Scheme 2 and Table 1). For the bis-phosphine oxides 1–7, there appears to be an optimum
chain length of six-carbon atoms that delivers the highest conversion (Table 1, compare
entries 1–7). The smaller subset of hydroxy-phosphine oxides provided fairly consistent
conversion, with the highest observed with the five-carbon linker (Table 1, entries 8-10).
Scheme 2. Reduction of PMP-ketimine 11 using the achiral phosphine oxide catalysts.
Table 1. Conversion of ketamine 11 to amine 12 according to Scheme 2.a
entry catalyst
conversion / %b
O
40
Ph2P
1
PPh2
O
55
2
3

O
59
Ph2P
3
4
5
PPh2
O
65
81
O
Ph2P
PPh2
O
O
Ph2P
O
PPh2
74
63
75
78
81
6
7
8
9
10
a All reactions performed according to Scheme 2 at a 1 mmol scale using 1 mL of solvent; b determined by
comparison of appropriate integrals of starting material and product in the 1H NMR spectrum of the unpurified
reaction mixture. Data refers to the average of two reactions.
Next, a series of easily accessible enantiopure phosphine oxides were targeted, two being
based on a conformationally flexible sidechain 13 and 14, and the others on a more rigid
binaphthyl framework, 15 and 16. Oxidation of the commercially available enantiopure
phosphines with hydrogen peroxide gave the bis-phosphine oxides 13–16 in excellent yield
following known literature precedent.[20,21]
Scheme 3. Synthesis of chiral bis-phosphine oxides 13–16.
A series of biaryl catalysts were also synthesised incorporating a Brønsted acidic hydroxyl
group also based upon a binaphthyl framework. Following known literature precedent, the
mono ortho-tolyl and para-methoxy catalysts 21 and 22 were both successfully synthesised
from commercially available (R)-BINOL 17 via a common bis-BINOL triflate 18 (Scheme
4).[22]
4

Scheme 4. Synthesis of biaryl-hydroxy BINOL catalysts 21 and 22.
Analysis of these catalysts under the standard reduction conditions (Scheme 2) demonstrated
that all reduced the PMP-ketimine 11 but with varying degrees of efficiency. The catalyst
bearing a two carbon linker was more effective than the achiral counterpart (compare Table
1, entry 1 verses Table 2, entry 1) which may be due to the chiral version exhibiting gauche
interactions of the methyl groups when the phosphine oxides are anti-periplanar, preferring a
syn-periplanar arrangement that promotes a dual activation mechanism. This effect is also
mirrored in the catalyst with stereogenic phosphorus centres; with no methyl groups on the
backbone, the reactivity drops (Table 2, entries 1 & 2). Although only small, a better
enantioselectivity is observed with stereogenic phosphorus centres rather than carbon
centered ones on the backbone. In contrast, (S)-BINAPO derived catalysts 21 and 22 both
performed excellently as catalysts, but delivered very similar enantioselectivities depending
on the nature of the aryl phosphine oxides used (Table 2, entries 3 & 4). In contrast the
hydroxy-BINOL phosphine oxides where considerably less reactive, with no significant
improvement in enantioselectivity (Table 2, entries 5 & 6).
Table 2. Conversion of ketamine 2 to amine 1 according to Scheme 2.a
entry
catalyst
conversion / %b
ee / %c
1
85
3
2
3
66
16
15
100
4
100
19
5

O
P(o-tol)2
5
6
55
70
13
11
OH
O
P(p-OMe)2
OH
a All reactions performed according to Scheme 2 at a 1 mmol scale using 1 mL of solvent; b determined by
comparison of appropriate integrals of starting material and product in the 1H NMR spectrum of the unpurified
reaction mixture. Data refers to the average of two reactions; c enantiomeric excess determined by chiral phase
HPLC analysis.
Further hydroxy-phosphine oxide catalysts were prepared based on a more conformationally
mobile framework bearing a stereogenic alcohol centre. Thus, the commercially available
chloro-nitrile 23 was treated with phenylmagnesium bromide to afford the chloro-ketone 24
in excellent yield (Scheme 5).[23] This was reduced using an oxazaborolidine derived from
(1R, 2S)-amino indanol and trimethylborate at 0 °C,[24] and the resulting alcohol 25
protected as a TBS ether 26. Formation of the phosphonium salt and subsequent oxidation to
the phosphine oxide using 3 M NaOH afforded the TBS protected catalyst that was
deprotected with TBAF to form the target molecule 27 in six steps. In order to determine the
enantioselectivity of catalyst 27, a racemic version of the catalyst was synthesised in
analogous fashion using the racemic alcohol derived from the sodium borohydride reduction
of chloro-ketone 24. Analysis of the enantioselectivity of the catalyst by chiral HPLC
analysis showed a 91% ee, which was sufficient to enable its use. A shorter 3-carbon
analogue 29 was also synthesised through the ring opening of an enantiomerically pure
epoxide with a lithium phosphinate derived from methyl diphenyl phosphine oxide 28.[25]
6

Scheme 5. Synthesis of hydroxy-phosphine oxide catalysts 27 and 29.
Table 3. Reduction of the PMP-ketimine 11 using chiral hydroxy-phosphine oxide catalysts 27 and 29a
entry
catalyst
conversion / %b
ee / %c
1d
82
10
2
73
10
a All reactions performed according to Scheme 1 at a 1 mmol scale using 1 mL of solvent; b determined by
comparison of appropriate integrals of starting material and product in the 1H NMR spectrum of the unpurified
reaction mixture. Data refers to the average of two reactions; c enantiomeric excess determined by chiral phase
HPLC analysis; d Catalyst used was 91% ee.
Screening of the phosphine oxides 27 and 29 under benchmark conditions (Scheme 2)
demonstrated very similar conversion to the PMP-amine 12 after 4 hours to those obtained
with the achiral linear variant of the catalysts. However, in both cases, the amine 12 was
obtained in a 10% ee in both cases. This indicates that a stereogenic centre located at these
positions on the carbon chain has only a small effect on the overall enantioselectivity.
As already noted, use of P-chiral phosphine oxides demonstrated negative [ML2] non-linear
effects similar to observed by Sun and co-workerswith an analogous S-chiral sulfoxide. Thus,
7

a P-chiral phosphine oxide that delivered the highest enantioselectivity was selected and a
bis-phosphine oxide prepared with an appropriate 6-carbon linker that was shown to be the
most effective chain length in earlier experiments (Table 1, entry 5). Controlled addition of
the P-chiral oxazolidinone 30 to a solution of but-3-enylmagnesium bromide employing
previously developed methodology for the synthesis of P-chiral phosphine oxides gave the
desired P-chiral phosphine oxide 31 as a single enantiomer (>99% ee as determined by chiral
HPLC analysis).[26] Treatment of this with 10 mol% of Grubbs-Hoveyda second generation
catalyst followed by immediate hydrogenation afforded the desired catalyst 32 in good yield
over two steps (Scheme 6)
OMe
i) 10 mol% GH-II
CH2Cl2,
O
O
P
O
P
O
P
MgBr
O
H3C
H3C
N
THF, 0 oC
syringe pump
addn
P
MeO
O
ii) H2 cube
i-Pr
OMe
MeO
H2 (1 atm), rt
30
31
32
64% over 2 steps
91%
As a catalyst, Scheme 2 a
88% conversion, 60% ee
Scheme 6. Synthesis of P-chiral bis-phosphine oxide catalyst 32. a Reaction performed according to Scheme 1
at a 1 mmol scale using 1 mL of solvent.
The bis-phosphine oxide catalyst 32 was evaluated under the standard reduction conditions
(Scheme 2), undergoing 88% conversion to the N-PMP amine 12. Analysis of the
enantioselectivity of the reduction showed a 60% ee and is consistent with the hypothesis that
two phosphine oxide moieties were required to enable high enantiocontrol. To further
confirm this, a non-linear relationship study was again undertaken on catalyst 32 (Fig. 1),
where scalemic mixtures of the catalyst 32 were accessed by mixing the opposing enantiomer
of the bis-phosphine oxide, prepared in analogous fashion using the N-phosphinoyl
oxazolidinone derived from (R)-valine. The observation of a direct linear relationship
between the enantioselectivity of the catalyst and the enantioselectivity of the resultant N-
PMP amine 12 confirmed that the reaction now proceeded through a pathway whereby only a
single molecule of the catalyst 32 was present in the transition state, and confirms a need to
have stereogenic elements at either end of the catalyst system.
8

70
60
50
40
30
20
10
0
0
20
40
60
80
100
Catalyst 32 ee / %
Figure 1. Probing non-linear activity of catalyst 32 using reaction conditions according to Scheme 2.
In the recently disclosed dual activation model with the organocatalyst derived from
imidazole, trichlorosilane is coordinated to the Lewis basic amide and the hydroxyl group,
whilst the protonated imidazole activates the imine substrate. One can propose a similar
model for the bis-phosphine oxide 32 where each terminus can act as a Lewis base or a
Bronsted acid. The same model overlays well with a catalyst system developed by Sun and
co-workers based on chiral sulfoxides that displays similar non-linear effects.
Catalysts
O
S
O
S
Ph
Ph
OH
O
P
N
Me
N
N
N
P
H
H
O
O
OMe
N
MeO
Me
O
HN
S
Ph
H
Me
Cl
Cl
Si
Cl
N
O
N
O
N
O
H
Cl
Ph
S
Si
Cl
P
O
H
O
H
Me
O
P
NH
H
Si
Cl
Cl
H
O
N
N
N
MeO
MeO
MeO
Figure 2. Dual activation models for the imidazole, phosphine oxide, and sulfoxide catalysts.
Conclusion
P-Chiral phosphine oxides offer potential for acting as effective catalysts for the asymmetric
reduction of ketimines. Symmetric variants offer good reactivity and selectivity but
refinements are needed in order to improve the levels of selectivity further. Potential exists
for the synthesis of P-chiral omega-hydroxy hybrids that may offer further advantages over
those presented here.
9

Experimental
General procedure A for the preparation of the achiral bis-phosphine oxide catalysts
The dibromoalkane (5 mmol) and triphenyl phosphine (2.60 g, 10 mmol) were dissolved in
MeCN (20 mL) and the solution heated to reflux for 18 h. Upon cooling to room temperature
the solvent was removed in vacuo to afford the crude phosphonium salt. The phosphonium
salt was redissolved in a solution of MeOH (10 mL) and aqueous 6 M KOH solution (10 mL)
and heated at reflux for a further 24 h. The solvent was removed in vacuo to afford the crude
bis-phosphine oxide. Purification of the crude material occurred as described within the
individual experimental details.
1,2-bis(Diphenylphosphinyl)ethane 1[27]
Prepared according to general procedure A from 1,2-dibromoethane (0.4 mL, 5 mmol).
Recrystallisation of the crude compound from MeOH: EtOAc afforded the title compound as
a white crystalline solid (2.02 g, 95%); m.p. 273–274 °C (lit.[27] 273–276 °C); δH (400 MHz,
CDCl3) 2.51 (4 H, d, JP-H 1.8, 2 × CH2), 7.41–7.53 (12 H, m, ArCH), 7.66–7.73 (8 H, m,
ArCH); δP (101 MHz, CDCl3) 32.5. All data is in accordance with that in the literature.
1,3-bis(Diphenylphosphinyl)propane 2[27]
Prepared according to general procedure A from 1,3-dibromopropane (0.5 mL, 5 mmol).
Recrystallisation of the crude material from MeOH: EtOAc afforded the title compound as a
white solid (1.61 g, 72%); m.p. 140–141 °C (lit.[27] 139–140 °C); δH (400 MHz, CDCl3)
1.92–2.08 (2 H, m, CH2), 2.45–2.56 (4 H, m, 2 × CH2), 7.39–7.52 (12 H, m, ArCH), 7.65–
7.72 (8 H, m, ArCH); δP (101 MHz, CDCl3) 32.2. All data is in accordance with the literature.
1,4-bis(Diphenylphosphinyl)butane 3[27]
Prepared according to general procedure A from 1,4-dibromobutane (0.6 mL, 5 mmol).
Recrystallisation of the crude material from MeOH: EtOAc afforded the title compound as a
white crystalline solid (1.81 g, 80%); m.p. 267–268 °C (lit.[27] 267–269 °C); δH (400 MHz,
CDCl3) 1.67–1.79 (4 H, m, 2 × CH2), 2.21–2.28 (4 H, m, 2 × CH2), 7.42–7.53 (12 H, m,
ArCH), 7.66–7.73 (8 H, m, ArCH); δP (101 MHz, CDCl3) 31.8. All data is in accordance with
the literature.
1,5-bis(Diphenylphosphinyl)pentane 4[28,29]
10

Prepared according to general procedure A from 1,5-dibromopentane (0.7 mL, 5 mmol).
Recrystallisation of the crude material from MeOH: EtOAc afforded the title compound as a
white crystalline solid (1.64 g, 67%); m.p. 119–120 °C (lit.[29] 119–120 °C); δH (400 MHz,
CDCl3) 1.55–1.69 (6 H, m, 3 × CH2), 2.15–2.26 (4 H, m, 2 × CH2), 7.44–7.48 (12 H, m,
ArCH), 7.66–7.74 (8 H, m, ArCH); δP (101 MHz, CDCl3) 32.2. All data is in accordance with
the literature.
1,6-bis(Diphenylphosphinyl)hexane 5[28]
Prepared according to general procedure A from 1,6-dibromohexane (0.8 mL, 5 mmol).
Recrystallisation of the crude material from MeOH : EtOAc afforded the title compound as a
white crystalline solid (1.53 g, 64%); m.p. 196–197 °C (lit.[28] 196.9–197.2 °C); δH (400
MHz, CDCl3) 1.35–1.42 (4 H, m, 2 × CH2), 1.54–1.65 (4 H, m, 2 × CH2), 2.19–2.26 (4 H, m,
2 × CH2), 7.44–7.56 (12 H, m, ArCH), 7.69–7.76 (8 H, m, ArCH); δP (101 MHz, CDCl3)
32.1. All data is in accordance with that of the literature.
1,7-bis(Diphenylphosphinyl)heptane 6[28]
Prepared according to general procedure A from 1,7-dibromoheptane (0.9 mL, 5 mmol).
Recrystallisation of the crude material from MeOH: EtOAc afforded the title compound as a
white crystalline solid (2.01 g, 80%); m.p. 90–91 °C (lit.[28] 90–91 °C); δH (250 MHz,
CDCl3) 0.84–0.92 (2 H, m, CH2), 1.23–1.43 (4 H, m, 2 × CH2), 1.50–1.67 (4 H, m, 2 × CH2),
2.17–2.30 (4 H, m, 2 × CH2), 7.42–7.58 (12 H, m, ArCH), 7.68–7.78 (8 H, m, ArCH); δP
(101 MHz, CDCl3) 32.3. All data is in accordance with the literature.
1,9-bis(Diphenylphosphinyl)nonane 7[30,31]
Prepared according to general procedure A from 1,9-dibromononane (2.62 g, 5 mmol).
Recrystallisation of the crude compound from MeOH: EtOAc afforded the title compound as
a white crystalline solid (1.80 g, 70%); m.p. 123–125 °C (lit.[30] 123–125 °C); δH (250 MHz,
CDCl3) 1.10–1.38 (10 H, m, 5 × CH2), 1.52–1.68 (4 H, m, 2 × CH2), 2.19–2.30 (4 H, m, 2 ×
CH2), 7.43–7.56 (12 H, m, ArCH), 7.70–7.78 (8 H, m, ArCH); δP (101 MHz, CDCl3) 32.4.
All data is in accordance with the literature.
General procedure B for the formation of the diphenylphosphine oxide moiety from the
halogenated alcohol or ester
The halogenated alcohol or ester (7 mmol) was added dropwise to a suspension of sodium
iodide (1.00 g, 7 mmol) and triphenylphosphine (2.00 g, 7.0 mmol) in acetonitrile (20 cm³)
11

and the reaction mixture heated at reflux for 24 hours. The solution was cooled to room
temperature and the solvent removed in vacuo to yield the phosphonium salt. The salt was
dissolved in a 30% aqueous solution of NaOH (20 cm³) and methanol (10 cm³) and heated at
reflux for 12 hours. The reaction mixture was poured into a saturated solution of ammonium
chloride (20 cm³) and the aqueous phase extracted with dichloromethane (3 × 30 cm³). The
organic layers were combined, washed with brine (10 cm³) and dried over magnesium sulfate.
Removal of the solvent in vacuo afforded the crude material. Purification of the crude
material occurred as described in the individual experimental details.
3-(Diphenylphosphinyl)-1-propanol 8[32]
Prepared in accordance to general procedure B using 3-chloro-propan-1-ol (0.7 cm³, 7 mmol).
Trituration of the crude material from diethyl ether (20 cm³) gave the title compound as a
white crystalline solid (0.60 g, 24%); m.p. 95 °C (lit.[32] 95–96 °C); δH (400 MHz, CDCl3)
1.83–1.93 (2 H, m, CH2), 2.42 (2 H, dt, J 11.5 7.3, PCH2), 3.69–3.72 (2 H, m, CH2OH), 4.23
(1 H, br s, OH), 7.45–7.55 (6 H, m, ArCH), 7.72–7.77 (4 H, m, ArCH); δP (101 MHz, CDCl3)
34.7. All data is in accordance with the literature.
4-(Diphenylphosphinyl)butan-1-ol 9[33]
Prepared according to general procedure B using 4-iodobutyl benzoate[33] (2.00 g, 7 mmol).
Purification of the crude material by flash column chromatography on silica gel using an
eluent of 100% ethyl acetate afforded the title compound as a colourless oil (270 mg, 19%);
δH (400 MHz, CDCl3) 1.65–1.79 (4 H, m, CH2), 2.28–2.38 (2 H, m, CH2), 2.90 (1 H, br s,
OH), 3.65 (2 H, t, J 5.8, CH2OH), 7.28–7.55 (6 H, m, ArCH), 7.67–7.78 (4 H, m, ArCH); δP
(101 MHz, CDCl3) 33.7. All data is in accordance with that of the literature.
5-(Diphenylphosphinyl)pentan-1-ol 10[34]
Prepared according to general procedure B using 5-bromopentan-1-ol (1.00 g, 7 mmol).
Purification of the crude material by flash column chromatography on silica gel using an
eluent of 100% ethyl acetate afforded the title compound as a colourless oil (700 mg, 39%);
δH (400 MHz, CDCl3) 1.43–1.75 (6 H, m, 3 × CH2), 1.95 (1 H, br s, OH), 2.21–2.34 (2 H, m,
CH2), 3.61 (2 H, t, J 6.3, CH2OH), 7.42–7.54 (6 H, m, ArCH), 7.70–7.78 (4 H, m, ArCH); δH
(101 MHz, CDCl3) 32.7. All data is in accordance with that of the literature.
General procedure for the asymmetric reduction of the PMP-ketimine 11
The PMP-ketimine 11 (225 mg, 1.00 mmol) and catalyst (0.1 mmol) were dissolved in
CH2Cl2 (1 cm³) and the solution cooled to 0 °C. Trichlorosilane (0.20 cm³, 2.0 mmol) was
added dropwise and the reaction mixture stirred for 4 hours. The reaction solution was
12

quenched through addition of 1M aqueous HCl solution (1 cm³), diluted with CH2Cl2 (5 cm³)
and basified with a 1M aqueous NaOH solution (10 cm³). The organic phase was separated,
and the aqueous phase extracted with CH2Cl2 (3 × 5 cm³). The combined organics were
washed with brine (10 cm³), before being dried over MgSO4, filtered and concentrated in
vacuo to yield the crude material. Purification of the crude product by flash column
chromatography eluting on silica gel with 10% EtOAc / petroleum ether afforded the desired
amine 12 as a golden yellow solid; m.p. 64 °C (lit.[16] 65 °C); δH (400 MHz, CDCl3) 1.52
(3H, d, J 6.7, CH3CHN), 3.80 (3H, s, OCH3), 3.83 (1H, bs, NH), 4.42 (1H, q, J 6.7,
CH3CHN), 6.48 [2H, (AX)2, ArCH], 6.70 (2H, (AX)2, ArCH], 7.20 – 7.25 (5H, m, ArCH);
HPLC tR = 7.9 min. (R isomer), 8.6 min. (S isomer) (Chiralpak AD, 95/5 hexane/propan-2-
ol); All data is in accordance with the literature.
(2R, 3R)-(+)- 2,3-bis(Diphenylphosphinyl)butane 13[35]
(2R, 3R)-(+)-bis(Diphenylphosphino)butane (200 mg, 0.5 mmol) was dissolved in CH2Cl2
(10 cm³) and the reaction solution cooled to 0 °C. Hydrogen peroxide (35 wt. %, 0.5 cm³)
was added dropwise and the reaction mixture stirred for 18 hours. The solution was poured
into water (10 cm³) and the organic phase separated. The aqueous layer was extracted with
dichloromethane (3 × 10 cm³) and the organic phases combined, washed with a saturated
aqueous solution of sodium sulfite (15 cm³) and dried over magnesium sulfate. Filtration,
then removal of the solvent in vacuo afforded the title compound as a white crystalline solid
that required no further purification (203 mg, 94%); m.p. 183 °C (lit.[35] 183–184 °C); [α]D25
+39.0 (c 2.0 in CH2Cl2, lit.[35] +39.4 c 2.0 in CH2Cl2); δH (250 MHz, CDCl3) 1.29–1.39 (6 H,
m, 2 × CH3), 2.87 (2 H, qd, J 7.1, 5.1, 2 × CH), 7.28–7.81 (20 H, m, ArCH); δP (101 MHz,
CDCl3) 36.7. All data is in accordance with the literature.
(1R, 1R')-(-)-1,1'-(1,2-Ethanediyl)bis[1-(2-methoxyphenyl)-1-phenyl-phosphine oxide
14[36]
(1R, 1R’)-(-)-bis[(2-Methoxyphenyl)phenylphosphino]ethane (100 mg, 0.2 mmol) was
dissolved in anhydrous CH2Cl2 (5.0 mL) and the solution cooled to 0 °C. Hydrogen peroxide
(35 wt. %, 0.1 mL) was added dropwise and the solution warmed to room temperature and
stirred for 12 hours. The reaction was poured into water (3.0 mL) and the organic phase
separated. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and the organic phases
combined, washed with a saturated aqueous solution of sodium bisulfite (10 mL) and dried
with MgSO4. Filtration and removal of the solvent in vacuo afforded a white crystalline solid
as the title compound which required no further purification (100 mg, 96%); m.p. 206 °C;
13

[α]2D5 -44.5 (c 1.0 in MeOH); δH (400 MHz, CDCl3) 2.57–2.74 (4 H, m, 2 × CH2), 3.57 (6 H,
s, 2 × OCH3), 6.79–6.82 (2 H, m, ArCH), 7.08 (2 H, t, J 7.3, ArCH), 7.37–7.49 (8 H, m,
ArCH), 7.72–7.77 (4 H, m, ArCH), 7.97–7.99 (2 H, m, ArCH); δP (121 MHz, CDCl3) 32.2.
All data is in accordance with that of the literature.
(S)-2,2'-Bis-(Diphenylphosphinyl)-1,1'-binaphthyl 15[37]
(S)-2,2'-bis-(Diphenylphosphino)-1,1'-binaphthyl (300 mg, 0.5 mmol) was added to
dichloromethane (10 cm³) and the solution cooled to 0 °C. Hydrogen peroxide (35 wt.%, 0.2
cm³) was added dropwise and the mixture stirred for 18 hours. The solution was poured into
water (10 cm³) and the organic phase separated. The aqueous layer was extracted with diethyl
ether (3 × 15 cm³) and the combined organic phases washed with a saturated aqueous solution
of sodium sulfite (10 cm³) and dried over magnesium sulfate. Filtration and removal of the
solvent in vacuo afforded a white crystalline solid that required no further purification (290
mg, 95%); m.p. 261 °C (lit.[37] 260.5–261.5 °C); [α]2D5 -390 (c 1.0 in C6H6, lit.[37] -391.2 c
0.5 in C6H6); δH (250 MHz, CDCl3) 6.78–6.85 (4 H, m, ArCH), 7.26–7.51 (20 H, m, ArCH),
7.69–7.77 (4 H, m, ArCH), 7.82–7.89 (4 H, m, ArCH); δP (250 MHz, CDCl3) 28.3. All data is
in accordance with the literature.
(S)-2,2'-bis(di-o-Tolylphosphinyl)-1,1'-binaphthyl 16
(S)-(−)-2,2′-bis(di-o-Tolylphosphino)-1,1′-binaphthyl (100 mg, 0.1 mmol) was dissolved in
dichloromethane (5 cm³) and the solution cooled to 0 °C. Hydrogen peroxide (35 wt. %, 0.2
cm³) was added dropwise and the reaction mixture stirred for 18 hours. The solution was
poured into water (10 cm³) and the organic layer separated. The aqueous layer was extracted
with diethyl ether (3 × 15 cm³) and the combined organic phases washed with a saturated
solution of sodium sulfite (10 cm³) and dried over magnesium sulfate. Filtration and removal
of the solvent in vacuo afforded the title compound as a white crystalline solid that required
no further purification (100 mg, 98%); m.p. 268 °C; [α]2D5 -421 (c 1.0 in C6H6); υmax (ATR)/
cm-1 3658, 3379, 3046, 2920, 2865, 1601, 1553. 1501; δΗ (400 MHz, CDCl3) 2.33 (12 Η, d,
JP-H 23.4, 4 × CΗ3), 6.85–6.91 (4 Η, m, ArCΗ), 6.99–7.05 (8 Η, m, ArCΗ), 7.27–7.31 (4 Η,
m, ArCΗ), 7.37–7.55 (8 Η, m, ArCΗ), 7.81–7.86 (4 Η, m, 4 × ArCΗ), 7.82–7.85 (4 Η, m, 4 ×
ArCΗ); δC (100 MHz, CDCl3) 21.5 (d, JP-H 2.1, 4 × CH3), 125.9 (ArCH), 127.1 (ArCH),
127.3 (ArCH), 127.4 (ArCH), 127.7 (ArCH), 128.2 (d, JP-H 13.5, ArCH), 128.5 (2 × ArCH),
128.7 (2 × ArCH), 129.6 (ArC), 130.4 (d, JP-H 28.4, ArC), 131.4 (ArC), 132.0 (d, JP-H 10.1,
ArCH), 132.5 (d, JP-H 12, ArCH), 133.7 (d, JP-H 11.4, ArC), 133.9 (d, JP-H 2.5, ArC), 141.1 (d,
14

JP-H 7.9, ArC), 141.2 (d, JP-H 7.9, ArC), 142.9 (d, JP-H 6.1, ArC), 143.0 (d, JP-H 6.1, ArC); δP
(101 ΜΗz, CDCl3) 28.4; m/z (ESI+) 711.2559 (100%, MH+, C48H41O2P requires 711.2576).
(R)-1,1'-Binaphthyl-2,2'-diyl bis(trifluoromethanesulfonate) 18[38]
(R)-BINOL 17 (1.00 g, 4 mmol) was dissolved in a solution of dichloromethane (20 cm³) and
freshly distilled pyridine (1.0 cm³, 13 mmol) and the mixture cooled to 0 °C. Triflic
anhydride (3.00 g, 2.0 cm³, 12 mmol) was added dropwise over a period of 30 minutes and
the mixture warmed to room temperature and stirred for six hours. The solution was diluted
with ethyl acetate (50 cm³) and the organic phase was separated. The aqueous phase was
extracted with ethyl acetate (3 × 10 cm³) and the combined organic layers washed
sequentially with an aqueous solution of 5% HCl (20 cm³), aqueous saturated sodium
hydrogen carbonate solution (20 cm³) and brine (20 cm³). The organic phase was dried over
sodium sulfate, filtered and the solvent removed in vacuo to yield an orange oil. Purification
of the crude material by column chromatography on silica gel using an eluent of 5% ethyl
acetate: petroleum ether 40–60 °C furnished the title compound as a white crystalline solid
(3.03 g, 100%); m.p. 75 °C (lit.[38] 76–78 °C); [α]2D5 -146.2 (c 1.0 in CHCl3, lit.[38] -147.7 c
1.01 in CHCl3); δH (400 MHz, CDCl3) 7.27–7.29 (2 H, m, ArCH), 7.41–7.46 (2 H, m,
ArCH), 7.59–7.65 (4 H, m, ArCH), 8.03 (2 H, d, J 8.0, ArCH), 8.17 (2 H, d, J 9.0, ArCH); δF
(235 MHz, CDCl3) -74.57 (2 × CF3). All data is in accordance with that of the literature.
(R)-2-[bis-(o-Tolylphosphinyl)]-
19[39]
2’-[(trifluoromethanesulfonoyl)oxy]-1,1'-binaphthyl
(R)-1,1'-Binaphthyl-2,2'-diyl-bis-trifluoromethanesulfonate 18 (0.60 g, 1 mmol) was added to
a stirred solution of bis-(2-methylphenyl)-phosphine oxide (0.60 g, 3 mmol), palladium
acetate (0.06 g, 0.3 mmol) and diphenylphosphoryl butane (0.10 g, 0.3 mmol) under an
atmosphere of argon. N,N-Diisopropylethylamine (0.70 g, 1.0 cm³, 6 mmol) was added
dropwise and the reaction mixture heated to 120 °C for 12 hours. Upon cooling to room
temperature, the solution was diluted with ethyl acetate (50 cm³) and washed successively
with water (3 × 20 cm³), 1N HCl (20 cm³) and an aqueous saturated solution of NaHCO3 (20
cm³). The organic layer was dried over magnesium sulfate, filtered, and the solvent removed
in vacuo to yield an orange oil. Purification of the crude material by flash column
chromatography on silica gel using an eluent of 40% ethyl acetate: petroleum ether 40–60 °C
afforded the title compound as a white crystalline solid (630 mg, 74%); m.p. 78 °C (lit.[39]
123–125 °C); [α]2D5 +62.2 (c 0.5 in CHCl3, lit.[39] +9.1 (c 0.99, CHCl3); δH (400 MHz,
CDCl3) 2.15 (3 H, s, CH3), 2.48 (3 H, s, CH3), 6.90–7.13 (7 H, m, ArCH), 7.25–7.31 (3 H, m,
15

ArCH), 7.35–7.45 (5 H, m, ArCH), 7.61 (1 H, app. t, J 7.1, ArCH), 7.87 (1 H, app. d, J 8.1,
ArCH), 7.97–8.01 (3 H, m, ArCH); δF (235 MHz, CDCl3) -75.0; δP (101 MHz, CDCl3) 33.9.
Data is in general agreement with the literature.
(R)-2-[bis-(4-Methoxyphenyl)phosphinyl]-2’-[(trifluoromethanesulfonyl)oxy]-1,1’-
binaphthyl 20[40]
(R)-1,1'-Binaphthyl-2,2'-diyl-bis-trifluoromethanesulfonate 18 (0.60 g, 1 mmol) was added to
a stirred solution of bis(4-methoxyphenyl)phosphine oxide (0.60 g, 3 mmol), palladium
acetate (0.06 g, 0.3 mmol) and 1,4-bis(diphenylphosphino)butane (0.10 g, 0.3 mmol) under
an atmosphere of argon. N,N-Diisopropylethylamine (0.70 g, 1.0 cm³, 6 mmol) was added
dropwise and the reaction mixture heated to 120 °C for 12 hours. Upon cooling, the solution
was diluted with ethyl acetate (50 cm³) and washed successively with water (3 × 20 cm³), 1N
HCl (20 cm³) and a 1M aqueous solution of NaHCO3 (20 cm³). The organic layer was dried
over magnesium sulfate, filtered, and the solvent removed in vacuo to yield an orange oil.
Purification of the crude material by flash column chromatography on silica gel using an
eluent of 40% ethyl acetate: petroleum ether 40–60 °C afforded the title compound as a white
crystalline solid (700 mg, 87%); m.p. 81 °C (lit.[40] 80–81 °C); [α]2D5 +66.1 (c 0.7 in CHCl3,
lit.[40] +66.2 c 0.7 in CHCl3); δH (400 MHz, CDCl3) 3.79 (3 H, s, OCH3), 3.81 (3 H, s,
OCH3), 6.66–6.69 (2 H, m, ArCH), 6.77–6.80 (2 H, m, ArCH), 7.01 (1 H, d, J 8.6, ArCH),
7.12 (1 H, d, J 8.6, ArCH), 7.18–7.23 (1 H, m, ArCH), 7.30–7.39 (6 H, m, ArCH), 7.45 (1 H,
ddd, J 8.2, 6.9, 1.2, ArCH), 7.56–7.60 (1 H, m, ArCH), 7.78 (1 H, dd, J 11.4, 8.6, ArCH),
7.84 (1 H, d, J 8.3, ArCH), 7.90 (1 H, d, J 9.0, ArCH), 7.96 (1 H, d, J 8.3, ArCH), 8.04 (1 H,
dd, J 8.8, 2.2, ArCH); δF (235 MHz, CDCl3) -75.0; δP (101 MHz, CDCl3) 27.9. All data is in
accordance with the literature.
(R)-2’-[bis-(o-Tolylphosphinyl]-[1,1’-binapthalen]-2-ol 21[39]
(R)-2-[bis-(o-tolylphosphinyl)]- 2’-[(trifluoromethanesulfonoyl)oxy]-1,1'-binaphthyl 19 (0.30
g, 0.4 mmol) was added to a solution of dioxane (10 cm³) and methanol (5.0 cm³) at room
temperature. A 3 M solution of NaOH (3.0 cm³) was introduced in a single portion and the
solution stirred at room temperature for 24 hours. The reaction was acidified to pH 1 using
concentrated HCl (5.0 cm³) and the aqueous phase extracted with ethyl acetate (3 × 10 cm³).
The organic phases were combined, washed with brine (10 cm³) and dried over magnesium
sulfate. Filtration and removal of the solvent in vacuo yielded a yellow oil. Purification of the
crude material by flash column chromatography on silica gel using an eluent of 50% ethyl
acetate: petroleum ether 40–60 °C afforded the title compound as a white crystalline solid
16

(210 mg, 96%); m.p. 162 °C, lit.[39] 150–152 oC; [α]D25 +135.0 (c 0.7 in CHCl3, lit.[39] -59.8
c 1.11, CHCl3); δH (400 MHz, CDCl3) 2.03 (3 H, s, CH3), 2.72 (3 H, s, CH3), 6.21 (1 H, d, J
8.5, ArCH), 6.52–6.63 (2 H, m, ArCH), 6.74–6.81 (2 H, m, ArCH), 7.03–7.25 (6 H, m,
ArCH), 7.47–7.52 (6 H, m, ArCH), 7.70 (1 H, d, J 8.5, ArCH), 7.91–8.00 (2 H, m, ArCH),
9.33 (1 H, s, OH); δP (121 MHz, CDCl3) 37.3. All data is in general agreement with the
literature.
(R)-2’-[bis-(4-Methoxyphenyl)phosphinyl]-[1,1’-binapthalen]-2-ol 22[22]
(R)-2-[bis(4-Methoxyphenyl)phosphinyl]-2’-[(trifluoromethanesulfonyl)oxy]-1,1’-binaphthyl
20 (0.30 g, 0.4 mmol) was added to a solution of dioxane (10 cm³) and methanol (5.0 cm³) at
room temperature. A 3 M solution of NaOH (3.0 cm³) was introduced in one portion and the
solution stirred at room temperature for 24 hours. The reaction was acidified to pH 1 using
concentrated HCl (5.0 cm³) and the aqueous phase extracted with ethyl acetate (3 × 10 cm³).
The organic phases were combined, washed with brine (10 cm³) and dried over magnesium
sulfate. Removal of the solvent in vacuo yielded a yellow oil. Purification of the crude
material by flash column chromatography on silica gel using an eluent of 50% ethyl acetate:
petroleum ether 40 60 °C afforded the title compound as a white crystalline solid (215 mg,
100%). m.p. 178 °C; [α]2D5 -126.0 (c 0.7 in CHCl3, lit.[22] +126.3 c 0.7 in CHCl3 for the (S)-
enantiomer); δH (400 MHz, CDCl3) 3.55 (3 H, s, OCH3), 3.89 (3 H, s, OCH3), 6.21–6.24 (2
H, m, ArCH), 6.43 (1 H, app. d, J 8.6, ArCH), 6.92–6.96 (1 H, m, ArCH), 7.05 (2 H, app. dd,
J 8.6, 2.3, ArCH), 7.10–7.16 (4 H, m, ArCH), 7.20–7.24 (1 H, m, ArCH), 7.38–7.45 (2 H, m,
ArCH), 7.50–7.56 (2 H, m, ArCH), 7.67 (1 H, app. d, J 8.6, ArCH), 7.81–7.92 (4 H, m,
ArCH) 9.40 (1 H, s, OH); δP (121 MHz, CDCl3) 31.3. No melting point data is reported
within the literature, all other data is in accordance.
5-Chloro-1-phenyl-pentan-1-one 24[41]
5-Chlorovaleronitrile 23 (5.00 g, 5.0 cm³, 43 mmol) was added to THF (20 cm³) and the
solution cooled to 0 °C. Phenyl magnesium bromide (29.0 cm³, 3 M in THF, 86 mmol) was
added dropwise over a period of 90 minutes and the reaction mixture warmed to room
temperature and stirred overnight. A 10% aqueous solution of HCl (25 cm³) was added and
the resulting suspension heated at reflux for 3 hours. The mixture was cooled to room
temperature and the aqueous phase extracted with dichloromethane (3 × 30 cm³). The organic
layers were combined, washed with 1M NaOH solution (20 cm³) and dried over magnesium
sulfate. Filtration and removal of the solvent in vacuo yielded a yellow solid.
Recrystallisation of the crude material from n-hexane afforded the title compound as a white
17

crystalline material (7.05 g, 81%); m.p. 50–51 °C (lit.[41] 50 °C); δH (400 MHz, CDCl3)
1.90–1.93 (4 H, m, CH2), 3.03 (2 H, t, J 6.8, CH2CO), 3.60 (2 H, t, J 6.1, CH2Cl), 7.48 (2 H,
t, J 7.5, ArCH), 7.58 (1 H, t, J 7.5, ArCH), 7.96 (2 H, d, J 7.5, ArCH). All data is in
accordance with that of the literature.
(S)-5-Chloro-1-phenyl-pentan-1-ol 25[41]
Trimethyl borate (0.1 cm³, 0.5 mmol) was added dropwise to a solution of (1R, 2S)-(+)-1-
amino-2-indanol (0.80 g, 0.5 mmol) in THF (2.0 cm³) at 0 °C and the mixture stirred for 30
minutes. BH3.DMS (0.50 cm³, 5 mmol) was added dropwise and stirring continued for a
further 45 minutes. The ketone 159 (900 mg, 4 mmol) dissolved in THF (5 cm³) was
introduced by syringe pump (1.8 cm³ / hr) at 0 °C and the mixture warmed to room
temperature and stirred for a further 90 minutes following complete addition of the ketone 24.
Methanol (5.0 cm³) was added in a single portion and the aqueous phase extracted with
dichloromethane (3 × 15 cm³). The organic layers were combined, washed with 1M HCl (10
cm³), brine (10 cm³) and dried over magnesium sulfate. Filtration and removal of the solvent
in vacuo yielded a yellow oil. Purification of the crude material by flash column
chromatography on silica gel using an eluent of 3% ethyl acetate: petroleum ether 40–60 °C
afforded the title compound as a white fluffy solid (800 mg, 83%). A racemic version of the
alcohol rac-25 was prepared through treatment of the ketone 24 with sodium borohydride.
m.p. 37 °C; [α]2D5 -17.4 (c 1.0 in C6H6, lit.[41] -14.16 c 1.90, C6H6, 94% ee for (S)-
enantiomer); δH (400 MHz, CDCl3) 1.40–1.51 (1 H, m, CHH), 1.51–1.57 (1 H, m, CHH),
1.70–1.87 (5 H, m, 2 × CH2 and OH), 3.54 (2 H, t, J 6.8, CH2Cl), 4.70 (1 H, t, J 6.8, CHOH),
7.28–7.41 (5 H, m, ArCH); δC (100 MHz, CDCl3) 23.3 (CH2), 32.5 (CH2), 38.2 (CH2), 44.9
(CH2Cl), 74.4 (CHOH), 125.9 (2 × ArCH), 127.7 (ArCH), 128.6 (2 × ArCH), 144.6 (ArC).
No melting point or 13C NMR data is reported within the literature for this enantiomer,
otherwise all other data is in accordance. The enantioselectivity of this compound could not
be assayed at this stage.
(S)-tert-Butyl(5-chloro-1-phenylpentyloxy)dimethylsilane 26
(S)-5-Chloro-1-phenyl-pentan-1-ol 25 (1.00 g, 5 mmol) was added to a solution of 4-
diaminomethylpyridine (0.20 g, 2 mmol) and triethylamine (2.00 g, 2.0 cm³, 15 mmol) in
dichloromethane (20 cm³). The solution was cooled to
0
°C and tert-
butyl(chloro)dimethylsilane (2.00 g, 10 mmol) added in a single portion. The reaction
mixture was stirred for 18 hours before being poured into water (10 cm³). The organic phase
was separated and aqueous layer extracted with diethyl ether (3 × 15 cm³). The organic layers
18

were combined, washed with 1M NaOH (10 cm³), brine (10 cm³) and dried over magnesium
sulfate. Filtration and removal of the solvent in vacuo yielded a yellow oil. Purification of the
crude material by flash column chromatography on silica gel using an eluent of 10% ethyl
acetate: petroleum ether 40–60 °C afforded the title compound as a colourless oil (936 mg,
60%). A racemic version of the molecule rac-26 was prepared in analogous fashion from the
racemic alcohol 25; [α]2D5 -33.0 (c 0.5 in CHCl3); υmax (ATR)/ cm-1 3121, 3061, 1515; δH (400
MHz, CDCl3) -0.12 (3 H, s, SiCH3), 0.05 (3 H, s, SiCH3), 0.91 [9 H, s, (CH3)3], 1.37–1.55 [6
H, m, (CH2)3], 3.52 (2 H, t, J 6.9, CH2Cl), 4.66 (1 H, dd, J 7.5 4.8, CH), 7.22–7.34 (5 H, m,
ArCH); δC (100 MHz, CDCl3) -5.0 (SiCH3), -4.6 (SiCH3), 18.3 (C[CH3]3), 23.0 (CH2), 25.7
(3 × CH3), 32.6 (CH2), 40.1 (CH2), 44.9 (CH2), 74.8 (CH), 125.8 (2 × ArCH), 126.9 (2 ×
ArCH), 128.0 (ArCH), 145.5 (ArC); m/z (TOF) 317.1751 (100%, MH+, C17H2935ClOSi
requires 313.1754).
(S)-5-(Diphenylphosphinyl)-1-phenylpentan-1-ol 27
(S)-tert-Butyl(5-chloro-1-phenylpentyloxy)dimethylsilane 26 (0.10 g, 0.4 mmol) was added
to a stirred suspension of triphenylphosphine (0.10 g, 0.4 mmol) and sodium iodide (0.06 g,
0.4 mmol) in acetonitrile (5.0 cm³) and the solution heated to reflux for 18 hours. The solvent
was removed in vacuo to afford the crude phosphonium salt that was immediately dissolved
in a 30% NaOH solution (10 cm³) and heated to reflux for a further 24 hours. The aqueous
phase was extracted with dichloromethane (3 × 10 cm³), washed with an aqueous solution of
NaHCO3 (10 cm³) and dried over magnesium sulfate. Removal of the solvent in vacuo
yielded a yellow oil. The crude material was dissolved in THF (10 cm³) and cooled to 0 °C.
TBAF (1.5 cm³, 1M in THF, 0.8 mmol) was added dropwise and the solution warmed to
room temperature and stirred for 24 hours. The reaction mixture was poured into water (5.0
cm³) and ethyl acetate (10 cm³) and the organic layer separated. The aqueous phase was
extracted with ethyl acetate (3 × 10 cm³) and the organic layers combined, washed with 1M
NaOH (10 cm³), brine (10 cm³) and dried over magnesium sulfate. Filtration and removal of
the solvent in vacuo yielded a yellow oil. Purification of the crude material by flash column
chromatography on silica gel using an eluent of 50% ethyl acetate: petroleum ether 40–60 °C
afforded the title compound as a colourless oil (45 mg, 33%). A racemic version of the
catalyst rac-27 was prepared in analogous fashion from the TBS ether rac-26; tR 10.5 min (S
isomer) and 13.2 min (R isomer) (Celluose-1, 1: 1 hexane: propan-2-ol); [α]2D5 -4.0 (91% ee
from HPLC, c 0.2 in CHCl3); υmax (ATR) / cm-1 3430, 1641, 1515; δH (400 MHz, CDCl3)
1.41–1.85 (5 H, m, CH2), 2.18–2.30 (3 H, m, CH2), 4.64–4.67 (1 H, m, CHOH), 7.26–7.36 (4
19

H, m, ArCH), 7.46–7.56 (6 H, m, ArCH), 7.71–7.75 (4 H, m, ArCH); δC (100 MHz, CDCl3)
21.3 (d, JC-P 4.0, CH2), 27.0 (d, JC-P 14.0, CH2), 29.5 (d, JC-P 71.0, CH2), 38.6 (CH2P), 73.7
(CHOH), 125.9 (2 × ArCH), 127.1 (ArCH), 128.2 (2 × ArCH), 128.5 (2 × ArCH), 128.7 (2 ×
ArCH), 130.6 (d, JC-P 4.0, 2 × ArCH), 130.7 (d, JC-P 4.0, 2 × ArCH), 131.65 (ArCH), 131.68
(ArCH), 132.3 (d, JC-P 8.4, ArC), 133.4 (d, JC-P 8.4, ArC), 145.2 (ArC); δP (121 MHz, CDCl3)
32.4; m/z (TOF ES+) 365.1671 (100%, MH+, C23H26O2P requires 365.1670), 347 (35, M+-
H2O).
(S)-3-(Diphenylphosphinyl)-1-phenylpropan-1-ol 29[33]
Methyl diphenylphosphine oxide[42] 28 (0.50 g, 2 mmol) was dissolved in anhydrous THF
(10 cm³) and the solution cooled to 0 °C. n-Butyl lithium (2.0 cm³, 2M in hexanes, 4 mmol)
was added dropwise and the reaction mixture stirred for 90 minutes. (S)-2-Phenyloxirane (0.3
cm³, 2.5 mmol) was introduced and the solution warmed to room temperature and stirred
overnight. The mixture was poured into a saturated ammonium chloride solution (10 cm³)
and the aqueous phase extracted with diethyl ether (3 × 15 cm³). The organic layers were
combined, washed with brine (15 cm³) and dried over magnesium sulfate. Removal of the
solvent in vacuo afforded a yellow oil. Purification of the crude material by flash column
chromatography on silica gel using an eluent of 10% methanol: ethyl acetate afforded the title
compound as a white solid (604 mg, 78%). m.p. 127 °C (lit.[33] 144–145 °C for racemate);
[α]2D5 -11.5 (c 0.7 in CHCl3); δH (CDCl3, 400 MHz) 1.99–2.20 (2 H, m, CH2), 2.33–2.50 (2 H,
m, CH2), 2.65 (1 H, br s, OH), 4.86 (1 H, dd, J 7.3, 4.2, CH), 7.25–7.35 (5 H, m, ArCH),
7.46–7.57 (6 H, m, ArCH), 7.70–7.77 (4 H, m, ArCH); δP (CDCl3, 101 MHz) 32.7. No data is
reported on the enantiomerically pure compound.
(SP)-Phenyl-(2-anisyl)-but-3-ene phosphine oxide 31[42]
N-Phosphinyl oxazolidinone[26] 30 (120 mg, 0.3 mmol) was dissolved in THF (2.0 mL) and
added by syringe pump (1.0 mL / hr) to a solution of but-3-enylmagnesium bromide (4 mL, 1
M in THF, 4 mmol) and THF (4.0 mL). Once addition was complete the reaction mixture was
quenched through addition of a saturated aqueous solution of ammonium chloride (5.0 mL)
and the aqueous phase extracted with CH2Cl2 (3 × 10 mL). The organic layers were
combined, washed with brine (10 mL) and dried over MgSO4. Filtration and removal of the
solvent in vacuo yielded a crude yellow oil. Purification of the crude material by flash
column chromatography on silica gel using a gradient eluent of 75% EtOAc: petroleum ether
40–60 °C to 5% MeOH: CH2Cl2 afforded the oxazolidinone (44 mg, 91%) as a white solid
and the phosphine oxide 31 as a colourless oil (63 mg, 77%); tR 10.5 (minor isomer) and 18.8
20

(major isomer) (Celluose-1, 90: 10 hexane: propan-2-ol, 210 nm); [α]2D5 +23.0 (c 1.0 in
CHCl3); υmax / cm-1 (ATR) 3076, 2976, 1640, 1590; δH (400 MHz, CDCl3) 2.22–2.60 (4 H, m,
2 × CH2), 3.76 (3 H, s, OCH3), 4.93–5.04 (2 H, m, CH=CHH), 5.84 (1 H, ddt, J 16.8, 10.2,
6.4, CH=CHH), 6.88 (1 H, dd, J 8.3 5.4, ArCH), 7.08–7.12 (1 H, m, ArCH), 7.39–7.52 (4 H,
m, ArCH), 7.75–7.81 (2 H, m, ArCH), 7.97–8.03 (1 H, m, ArCH); δC (101 MHz, CDCl3) 25.7
(d, JC-P 3.0, CH2), 28.5 (d, JC-P 73.0, CH2), 55.3 (OCH3), 110.8 (d, JC-P 6.6, ArCH), 114.8
(CH=CHH), 119.3 (d, JC-P 95.7, ArC), 121.2 (d, JC-P 10.6, ArCH), 128.2 (d, JC-P 11.8, 2 ×
ArCH), 130.6 (d, JC-P 9.7, 2 × ArCH), 131.3 (d, JC-P 2.4, ArCH), 133.5 (ArC), 133.9
(CH=CHH), 134.5 (d, JC-P 5.2, ArCH), 137.8 (d, JC-P 16.3, ArCH), 159.7 (d, JC-P 5.0, ArC);
δP (101 MHz, CDCl3) 31.4; m/z (TOF ES+) 287.1195 (100%, MH+, C17H20O2P requires
287.1201). No data is reported in the literature.
1,6-bis[(SP)-(2-Methoxyphenyl)(phenyl)phosphinyl]hexane 32
Phosphine oxide 31 (90 mg, 0.3 mmol) was added to a solution of CH2Cl2 (3 mL) and
Hoveyda-Grubbs II catalyst (18 mg, 0.03 mmol) and the solution heated at reflux for 18 h.
Upon cooling to room temperature, the volatiles were removed in vacuo and the residue
purified by flash column chromatography on silica gel using a gradient eluent of 100%
EtOAc to 5% MeOH: CH2Cl2 to afford a yellow oil. The oil (54 mg, 0.1 mmol) was dissolved
in MeOH (2 mL) and subjected to a single cycle through a Pd/C Thalesnano Catcart H-
CubeTM under 1 atmosphere of hydrogen at 30 °C. Removal of the solvent in vacuo afforded
the title compound as a colourless oil (50 mg, 61% over 2 steps); [α]2D5 +42.0 (c 1.0 in
CHCl3); υmax / cm-1 (ATR) 3062, 2929, 1588, 1575; δH (400 MHz, CDCl3) 1.30–1.65 (8 H, m,
4 × CH2), 2.22–2.47 (4 H, m, 2 × CH2), 3.72 (6 H, s, 2 × OCH3), 6.82–6.90 (2 H, m, ArCH),
7.07–7.10 (2 H, m, ArCH), 7.40–7.50 (8 H, m, ArCH), 7.72–7.77 (4 H, m, ArCH), 7.95–8.00
(2 H, m, ArCH); δC (101 MHz, CDCl3) 21.4 (d, JC-P 3.0, CH2), 28.7 (CH2), 29.4 (CH2), 30.5
(d, JC-P 3.0, CH2), 55.3 (2 × OCH3), 110.7 (d, JC-P 6.6, 2 × ArCH), 120.5 (d, JC-P 95.9, 2 ×
ArC), 121.1 (d, JC-P 10.6, 2 × ArCH), 128.1 (d, JC-P 11.7, 4 × ArCH), 130.5 (d, JC-P 9.6, 4 ×
ArCH), 131.2 (2 × ArCH), 133.8 (2 × ArCH), 134.1 (d, JC-P 75.3, 2 × ArC), 134.5 (d, JC-P
5.2, ArCH), 159.7 (d, JC-P 5.0, 2 × ArC); δP (101 MHz, CDCl3) 32.0; m/z (TOF ES+)
547.2190 (100%, MH+, C32H37O4P2 requires 547.2167).
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23

Highlights
•
•
•
•
A series of achiral and chiral, non-racemic bifunctional phosphine oxides have been
prepared.
The target compounds were evaluated as catalysts in the hydrosilylation of a
benchmark ketimine.
Almost all acted as very effective catalysts, although enantioselectivities were
generally poor.
A bifunctional P-chiral catalyst gave the best enantioselectivity, helping to reinforce a
dual activation model.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: