When Chirality Meets “Buchwald-Type” Phosphines: Synthesis and Evaluation in Frustrated Lewis Pair-, Lewis Base- and Palladium-Promoted Asymmetric Catalysis

Article abstract of DOI:10.1002/ejoc.201600727

We describe the synthesis of axially chiral “Buchwald ligand”-like biphenylphosphines in highly enantioenriched form. These monodentate phosphines, biphenyl analogues of Hayashi's MOP ligands, were evaluated in phosphine-promoted organocatalysis and in hydrosilylations catalyzed by palladium or by frustrated Lewis pairs. As expected, the title phosphines appeared best suited for transition metal catalysis where they provided higher asymmetric induction.

Full text of DOI:10.1002/ejoc.201600727

DOI: 10.1002/ejoc.201600727
Full Paper
Chiral Phosphines
When Chirality Meets “Buchwald-Type” Phosphines: Synthesis
and Evaluation in Frustrated Lewis Pair-, Lewis Base- and
Palladium-Promoted Asymmetric Catalysis
Mickaël J. Fer,[a] Joséphine Cinqualbre,[a] Julien Bortoluzzi,[a] Matthieu Chessé,[a]
Frédéric R. Leroux,[a] and Armen Panossian*[a]
Abstract: We describe the synthesis of axially chiral “Buchwald organocatalysis and in hydrosilylations catalyzed by palladium
ligand”-like biphenylphosphines in highly enantioenriched or by frustrated Lewis pairs. As expected, the title phosphines
form. These monodentate phosphines, biphenyl analogues of appeared best suited for transition metal catalysis where they
Hayashi's MOP ligands, were evaluated in phosphine-promoted provided higher asymmetric induction.
Introduction
trophiles, was possible and opened access to various enantio-
pure biphenyls.[6c] The remaining question was whether or not
a phosphorus electrophile could be used in this strategy with
retention of axial stereoenrichment and, in the case of chlorodi-
arylphosphine electrophiles, without preponderant formation
of undesired dibenzophospholes.[6a,6b]
The importance of axially chiral biaryls, especially in catalysis,
has motivated intense work towards enabling their synthetic
access.[1] Among such agents, efforts focussed on binaphthyl-
based bidentate phosphorus ligands have seen tremendous
success in asymmetric catalysis.[2] Hayashi et al. have also dem-
onstrated the high efficiency of simply monodentate binaphth-
ylphosphines –MOP ligands– in transition metal-catalyzed
asymmetric reactions.[3] On the other hand, much less effort
has been applied to the study of enantiopure axially chiral bi-
phenylmonophosphines; only a few examples have been re-
ported, including monodentate ligands – i.e. the biphenyl
equivalents of Hayashi's MOP ligands.[4] Considering the re-
markable results achieved by Buchwald et al. and others in cata-
lytic reactions mediated by the corresponding achiral biphenyl-
phosphine ligands,[5] as well as our own interest in the synthesis
of C1-symmetric biphenylphosphines and atropisomerically
pure biphenyls,[6] we decided to tackle the synthesis of such
atropo-enantiopure biphenylphosphines (Figure 1, a). We were
interested in assessing the latter structures in catalysis, and to
comparing them with binaphthyl analogues. Indeed, biphenyls
are expected to allow for better structural and electronic tuning
in closer vicinity to the chiral aryl–aryl bond and the phos-
phorus function (Figure 1, b). Consequently, a highly modular
and perfectly enantioselective route to these biphenylphos-
phines was required. We thus decided to take advantage of our
Figure 1. Binaphthyl- vs. biphenylphosphines.
Results and Discussion
previously developed sulfoxide-based deracemization/desym- We chose to start from 2,2′-dibromo-6-chlorobiphenyl (1) as the
metrization strategy. From atropisomerically pure biarylsulfox- platform from which to access desired atropo-enantiopure bi-
ides, we had shown that a chemo- and enantioselective sulfox- phenylphosphines, as well as their racemic counterparts and
ide/lithium exchange, followed by trapping with various elec- corresponding oxides (Scheme 1). The racemic synthesis of bi-
phenylphosphines 3 was carried out by means of regioselective
[a] CNRS - Université de Strasbourg (ECPM), UMR 7509,
bromine/lithium exchange using BuLi and subsequent trapping
with chlorophosphines under standard reaction conditions. This
strategy delivered the desired compounds in 26–65 % yields,
depending on the chlorophosphines used and the air-stability
COHA25, Rue Becquerel, 67087 Strasbourg, France
E-mail: armen.panossian@unistra.fr
http://coha-lab.org
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600727.
of corresponding products 3 (Table 1). Chlorodicyclohexylphos-
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phine gave the best results, whereas the p-tolyl and 1-napththyl to phosphines 3. Furthermore, from racemic and enantiopure
analogues afforded complex reaction mixtures from which nei- compounds 3a,c we also prepared phosphines 3′a,b using a
ther phosphine ( )-3e or ( )-3g could be isolated. Diisopropyl- Suzuki–Miyaura coupling at the brominated position under
phosphine ( )-3b was found to be particularly oxidizable and, microwave conditions (80 °C, 1 h); complete retention of axial
consequently, also proved elusive. All the remaining phosphines chirality was validated by chiral HPLC analyses of the corre-
could be handled without need of a glovebox although they sponding phosphine oxides (aR)-4′a,b (Table 1, Entries 12–15).
were rather air-sensitive when not in the solid state. In such
cases, they could be taken up in pentane and concentrated to
yield the desired compounds as solids.
Additionally, we synthesized phosphine 6 and its oxide 7, in
both racemic and enantiopure forms. In this case, the sulfoxide/
lithium exchange–trapping sequence was even more critical, as
the key biaryllithium intermediate was substituted at positions
2, 2′, 6 and 6′ by relatively small substituents[7] (respectively Li/
Cl/H/Me, structure C in Figure 2). We had previously shown that
intermediate A, leading to 3 and 5, was configurationally stable
at –78 °C for at least 10 min, whereas B, bearing very small
substituents, partially racemized even when trapped after only
5 min at –100 °C (Figure 2).[6c] We were pleased to see that C
did not undergo racemization since (aR)-6 was produced with
an er of 98:2 [measured on (aR)-7], starting from (aR)-5 with a
96:4 er.
Table 1. Synthesis of axially chiral biphenylphosphines.[a]
Entry
R
3
Yield [%]
65
4
Yield [%]
er[b]
1
2
3
4
5
6
7
8
Cy
iPr
Ph
oTol
pTol
( )-3a
( )-3b
( )-3c
( )-3d
( )-3e
( )-4a
( )-4b
( )-4c
( )-4d
( )-4e
( )-4f
( )-4g
(aR)-4a
(aR)-4c
(aR)-4d
(aR)-4f
( )-4′a
( )-4′b
(aR)-4′a
(aR)-4′b
76
–
82
85
–
–
–
–
–
–
[c]
–
54
32
[d]
–
4-F-C6H4 ( )-3f
1-Naphth ( )-3g
Cy
Ph
oTol
26
86
–
–
–
[d]
–
(aR)-3a
(aR)-3c
(aR)-3d
52
55
26
37
51
61
54
62
76
81
92
76
76
89
83
87
> 99:1
99:1
98:2
98:2
–
9
10
11
12
13
14
15
4-F-C6H4 (aR)-3f
Cy
Ph
Cy
Ph
( )-3′a
( )-3′b
(aR)-3′a
(aR)-3′b
–
> 99:1
> 99:1
[a] See Experimental Section and Supporting Information for details. [b] Enantio-
meric ratio (er) determined on the phosphine oxide by chiral phase HPLC analysis
(CP-HPLC). [c] Phosphine 3b was very air-sensitive and could not be isolated pure.
[d] Phosphines 3e and 3g could not be isolated from complex mixtures.
Figure 2. Configurational stability of atropisomerically enriched biphenyl-
lithiums.
The synthesis of the target atropo-enantiopure phosphines
proceeded efficiently, with yields comparable to those obtained
during the racemic synthesis (Table 1, Entries 8–11). To deter-
mine the enantiomeric excess of phosphines (aR)-3a,c,d,f, we
We then evaluated the newly synthesized biphenylphos-
converted them to their corresponding phosphine oxides 4 phines in different catalytic processes, to estimate their poten-
which enabled easier separation of enantiomers by CP- HPLC. tial for asymmetric induction in reactions where they should
Gratifyingly, no loss of axial stereoenrichment was observed, behave as simple monodentate Lewis bases or act as hemilabile
underscoring the efficiency of the synthetic protocol leading ligands. We first examined their ability to activate hydrosilanes
Scheme 1. Synthesis of racemic and enantiopure axially chiral biphenylphosphines 3, 3′ and 6, and phosphine oxides 4, 4′ and 7.
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in the presence of tris(pentafluorophenyl)borane (BCF, 8), a typi-
cal feature of FLPs.[8] The mixtures of phosphines 3a, 3c or 3d
with 8 were converted in all cases, at least partially, into the
standard Lewis adducts having 11B NMR signals at approxi-
mately –3.5 ppm, and a sensible upfield shift in the 19F NMR
spectra.[9] However formation of these complexes was reversi-
ble since, upon addition of dimethylphenylsilane, we observed
the disappearance of their signals and the appearance of char-
acteristic 11B NMR signals representing the corresponding
hydridoborate salts at approximately –25 ppm, shaped as dou-
1
blets with JB-H = about 92 Hz, and a 29Si NMR signal at δ =
16.4 ppm for the salt derived from (aR)-3c.[9] With this informa-
tion in hand, we evaluated the series of compounds 3a,c,d in
FLP-catalyzed hydrosilylation. Indeed, Klankermeyer and co-
workers had shown that the phosphine component plays a
non-innocent role in the hydrosilylation of imines and ket-
ones.[10] Moreover, Du et al. have recently reported that the
phosphine is essential for both activity and stereoselectivity in
the hydrosilylation of related 1,2-dicarbonyl compounds.[11]
Borane 8, associated with 3a, 3c or 3d, showed catalytic activity
in the hydrosilylation of acetophenone and of the correspond-
ing N-phenylimine. Yet, as expected from the mechanism of
such hydrosilylations,[12] the presence of chiral information
solely on the Lewis base (or competitive pathways where the
phosphine does not participate), led to formation of the prod-
ucts in racemic form (Scheme 2, a).
We also assessed (aR)-3a,c,d in chiral phosphine-catalyzed
reactions.[13] These species showed no activity at room temp.
in Lu's [3 + 2] annulation[14] between ethyl buta-2,3-dienoate
and diethyl fumarate. However, unlike the case with (aR)-3a,
triarylphosphines (aR)-3c and (aR)-3d proved to be active at
60 °C affording the desired cyclopentene in 57–60 % yield and
with very modest 10–11 % ee values (Scheme 2, b). Interest-
ingly, the activity pattern was reversed in the aza-Morita–Baylis–
Hillman reaction[15] of methyl vinyl ketone with N-tosyl-ben-
zaldimine (Scheme 2, c), as only (aR)-3a was active at room
temp. even though only the racemic product was generated in
this case. At 60 °C, the use of diphenyl-substituted phosphine
(aR)-3c ultimately afforded the aza-MBH adduct with 12 % ee;
the more congested di-o-tolyl analogue (aR)-3d remained inac-
tive. On the other hand, the three phosphines of interest were
found to be efficient at effecting the conjugate borylation[16] of
methyl crotonate; although, in all cases, only racemic products
were generated (Scheme 2, d).
Last but not least, we evaluated (aR)-3a,c,d, (aR)-3′a,b and
(aR)-6 in the palladium-catalyzed hydrosilylation of styrene, an
emblematic application of Hayashi's analogous MOP li-
gands.[3,17] All phosphines enabled successful conversion of
styrene cleanly in 63–92 % yields (Scheme 2, e). Gratifyingly,
encouraging asymmetric inductions were also obtained. Phos-
phines (aR)-3a and (aR)-3c, bearing cyclohexyl and phenyl
groups, respectively, at phosphorus, gave the same 54 % ee of
the product, with identical (R) configuration, whereas the use
of o-tolyl derivative (aR)-3d afforded a poor 8 % ee, with the
reversed absolute configuration. When the 2′-Br substituent on
Scheme 2. Evaluation of axially chiral enantiopure biphenylphosphines in ca-
talysis.
Phosphine (aR)-6, bearing the PPh2 group on the non-chlorin-
ated aromatic ring, led to the opposite enantiomer (42 % ee)
with regard to (aR)-3c. This could be rationalized by the fact
the biphenyl backbone was replaced by a phenyl group, [phos- that the larger o-substituent of the non-phosphorus ring, re-
phines (aR)-3′a,b], the alcohol was obtained in racemic form. spectively Br and Cl in (aR)-3c and (aR)-6, point in opposite
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2 equiv.) was added dropwise to a solution of iodobenzene
(1 equiv.) in dry Et2O (4 mL/mmol iodobenzene)]. The solution was
stirred at –78 °C for 10 min then the desired chlorodialkyl- or chloro-
diarylphosphine (3 equiv.) was added dropwise if liquid, or as a THF
solution if solid. The reaction mixture was allowed to reach 25 °C
overnight and was then quenched by addition of sodium thio-
sulfate. The aqueous layer was extracted with DCM (3 × 15 mL) and
the combined organic layers were dried with Na2SO4, filtered and
concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel. When the air-sensitive compound was ob-
tained as an oil, it could be taken up in pentane and concentrated
repeatedly to turn into a more stable solid. The enantiomeric ratio
of the phosphine was determined by chiral phase HPLC analysis of
the corresponding phosphine oxide.
directions in each analogue; yet, less obvious parameters influ-
encing asymmetric induction cannot be ruled out.
Conclusions
We successfully accessed
a series of atropo-enantiopure
monodentate biphenylphosphines, with complete control of ax-
ial chirality, and via a synthetic route whose potential for modu-
larity was demonstrated in our previous work and confirmed in
this paper. These phosphines exhibited activity in FLP- or Lewis
base-catalysis, but afforded low asymmetric inductions. This
outcome was suspected due to the remoteness of the chiral
environment provided by the phosphines with respect to the
substrate in FLP-catalyzed hydrosilylations. Similarly, the confor-
mational flexibility around the biphenyl–phosphorus bond of
the phosphines was anticipated to give modest enantioselectiv-
ity in phosphine-catalyzed reactions, which was confirmed by
our results and is coherent with the need for a second binding
site as in Shi's catalysts.[18] On the other hand, we expected
better asymmetric inductions in Pd-catalyzed reactions, where
monodentate biarylphosphines are known to behave as hemila-
bile bidentate ligands due to Pd–arene interactions, thus rigidi-
fying chiral transition states. The encouraging enantioselectivi-
ties (up to 77:23 er) obtained in the hydrosilylation of styrene
corroborate this hypothesis. With these preliminary results in
hand, we are currently tuning biphenyl backbone substituents
and those of the phosphorus group so as to achieve optimal
stereo-induction in catalysis, where axially chiral biphenylphos-
phines may complement or even outcompete their established
binaphthyl congeners.
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)dicyclohexylphosphine ( )-
3a: Compound ( )-3a was synthesized according to general proce-
dure GP1 starting from biphenyl ( )-1 (560 mg, 1.62 mmol, 1 equiv.)
and chlorodicyclohexylphosphine (1.1 mL, 4.85 mmol, 3 equiv.).
After work up, the residue was purified by flash chromatography
on silica gel (pentane/DCM, 10:0 to 7:3) to yield ( )-3a as a white
powder (490 mg, 65 % yield): Rf = 0.11 (cyclohexane/DCM, 8:2); m.p.
71 °C. IR (film): ν = 2922 (s), 2849 (s), 1719 (m), 1414 (m), 750 (s) cm–1
.
˜
1H NMR: δ = 7.60 (dd, J = 7.9, 1.2 Hz, 1 H), 7.44 (d, J = 7.6 Hz, 1 H),
7.40 (dd, J = 7.9, 1.0 Hz, 1 H), 7.32–7.23 (m, 2 H), 7.19 (t, J = 7.7 Hz,
1 H), 7.07 (dd, J = 7.5, 1.8 Hz, 1 H), 1.95–1.78 (m, 1 H), 1.76–1.49 (m,
10 H), 1.49–1.38 (m, 1 H), 1.28–0.85 (m, 10 H) ppm. 13C NMR: δ =
147.0 (d, J = 31.3 Hz), 140.6 (d, J = 6.5 Hz), 138.4 (br. s), 134.5 (d,
J = 7.6 Hz), 132.6 (d, J = 2.6 Hz), 132.4, 131.3 (d, J = 1.8 Hz), 129.8,
129.4, 128.4, 126.6, 124.5 (d, J = 1.8 Hz), 35.7 (d, J = 14.9 Hz), 34.1
(d, J = 12.7 Hz), 30.9 (d, J = 15.0 Hz), 30.3 (d, J = 12.4 Hz), 30.0 (d,
J = 17.2 Hz), 29.4 (d, J = 6.2 Hz), 27.6 (d, J = 4.7 Hz), 27.5, 27.3 (d,
J = 5.1 Hz), 27.2 (d, J = 6.6 Hz), 26.5 ppm. 31P{1H} NMR: δ = –8.0
(s) ppm. HRMS ESI+ calcd. for C24H30BrClP+ [M + H]+ 463.0952, found
463.0964.
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)dicyclohexylphosphine
(aR)-3a: Compound (aR)-3a was synthesized according to general
procedure GP2 starting from sulfoxide (S,aR)-2 (400 mg, 0.98 mmol,
1 equiv.) and chlorodicyclohexylphosphine (653 μL, 2.98 mmol,
3 equiv.). The crude material was purified in a fashion analogous to
that applied to the racemic compound to afford the aR derivative
as a white powder (238 mg, 52 % yield); Additional data for (aR)-
3a: [α]D = –80 (c = 1.0, DCM).
Experimental Section
General: NMR spectra were recorded in CDCl3, at the following
frequencies for each nucleus: 1H NMR (400 MHz), 13C NMR (100
MHz), 31P NMR (172 MHz), 11B NMR (128 MHz) and 19F NMR (377
MHz); except for compound 4c, whose 1H NMR sepctrum was re-
corded in C6D6 (400 MHz).
GP1: General Procedure for the Introduction of Dialkyl- and Di-
arylphosphinyl Groups on Racemic Biphenyls: At –78 °C, butyl-
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)diphenylphosphine ( )-3c:
Compound ( )-3c was synthesized according to general procedure
GP1 starting from biphenyl ( )-1 (500 mg, 1.44 mmol, 1 equiv.) and
chlorodiphenylphosphine (777 μL, 4.33 mmol, 3 equiv.). After work
up, the residue was purified by flash chromatography on silica gel
(pentane/DCM, 10:0 to 7:3) to yield ( )-3c as a white powder
(351 mg, 54 % yield): Rf = 0.36 (cyclohexane/DCM, 85:15); m.p.
lithium (1.55–1.60
solution of 2,2′-dibromo-6-chlorobiphenyl ( )-1 (1 equiv.) in freshly
distilled THF (0.5 ). After 15 min at –78 °C, the desired chlorodi-
M in hexane, 1 equiv.) was added dropwise to a
M
alkyl- or chlorodiarylphosphine (3 equiv.) was added dropwise if
liquid, or as a THF solution if solid. The reaction mixture was al-
lowed to reach 25 °C overnight and was then quenched by addition
of sodium thiosulfate. The aqueous layer was extracted with DCM
(3 × 15 mL) and the combined organic layers were dried with
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel. When the air-sensitive
compound was obtained as an oil, it could be taken up in pentane
and concentrated repeatedly to turn into a more stable solid.
152 °C. IR (film): ν = 3056 (m), 1587 (m), 1463 (m), 1428 (w) cm–1
.
˜
1H NMR: δ = 7.59 (dd, J = 8.0, 0.8 Hz, 1 H), 7.41 (dd, J = 8.0, 1.2 Hz,
1 H), 7.26–7.07 (m, 12 H), 7.04 (td, J = 7.2, 0.8 Hz, 1 H), 6.93 (ddd,
J = 7.6, 2.8, 0.8 Hz, 1 H), 6.68 (dd, J = 7.6, 1.6 Hz, 1 H) ppm. 13C
NMR: δ = 144.9 (d, J = 31.7 Hz), 140.5 (d, J = 14.6 Hz), 139.4 (d, J =
6.9 Hz), 136.8 (d, J = 12.4 Hz), 136.1 (d, J = 11.7 Hz), 134.5 (d, J =
7.0 Hz), 134.1 (d, J = 20.4 Hz, 2 C), 133.8 (d, J = 19.7 Hz, 2 C), 132.5,
132.2, 132.1, 132.0, 129.7 (d, J = 30.6 Hz, 2 C), 129.1 (d, J = 28.1 Hz,
2 C), 128.7, 128.6, 128.5, 128.4, 126.8, 124.4 ppm. 31P{1H} NMR: δ =
–8.6 (s) ppm. HRMS ESI+ calcd. for C24H18BrClP+ [M + H]+ 451.0013,
found 451.0013.
GP2. General Procedure for the Sulfoxide/Lithium Exchange.
Synthesis of Enantioenriched Phosphines: A pre-cooled solution
of
(S,aR)-2-bromo-2′-chloro-6′-(p-tolylsulfinyl)biphenyl
(S,aR)-2
(1 equiv.) in dry THF (c = 0.1
M
) was added to a solution of phenyl-
lithium (2 equiv.) in Et2O at –78 °C. [Note: preparation of the phenyl-
lithium solution: At –78 °C, tert-butyllithium (1.7 in pentane,
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)diphenylphosphine (aR)-
3c: Compound (aR)-3c was synthesized according to general proce-
M
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dure GP2 starting from sulfoxide (S,aR)-2 (450 mg, 1.10 mmol,
1 equiv.) and chlorodiphenylphosphine (597 μL, 3.33 mmol,
3 equiv.). The crude compound was purified in a fashion analogous
to that applied to the racemic compound to afford the aR derivative
as a white powder (276 mg, 55 % yield); Additional data for (aR)-3c:
[α]D = –75 (c = 1.0, DCM).
ford the aR derivative as a white powder (177 mg, 37 % yield); Addi-
tional data for (aR)-3f: [α]D = –26 (c = 1.0, DCM).
( )-(2′-Chloro-6-methylbiphenyl-2-yl)diphenylphosphine ( )-6:
Compound ( )-6 was synthesized according to general procedure
GP1 starting from ( )-2-bromo-2′-chloro-6′-methylbiphenyl ( )-5[6c]
(206 mg, 0.73 mmol, 1 equiv.) and chlorodiphenylphosphine
(422 μL, 2.19 mmol, 3 equiv.). After work up, the residue was puri-
fied by flash chromatography on silica gel (pentane/DCM, 10:0 to
7:3) to yield ( )-6 as a white powder (120 mg, 42 % yield): Rf = 0.38
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)-di-o-tolylphosphine ( )-
3d: Compound ( )-3d was synthesized according to general proce-
dure GP1 starting from biphenyl ( )-1 (418 mg, 1.21 mmol, 1 equiv.)
and chlorodi-o-tolylphosphine (900 mg, 4.85 mmol, 3 equiv.) in THF
(2 mL). After work up, the residue was purified by flash chromatog-
raphy on silica gel (pentane/DCM, 10:0 to 7:3) to yield ( )-3d as a
white powder (185 mg, 32 % yield): Rf = 0.56 (cyclohexane/DCM,
(cyclohexane/DCM, 8:2); m.p. 134 °C. IR (film): ν = 3051 (w), 1430
˜
1
(s), 744 (s), 691 (s) cm–1. H NMR: δ = 7.44 (t, J = 7.3 Hz, 1 H), 7.34
(t, J = 7.5 Hz, 1 H), 7.24 (m, 13 H), 7.14 (dd, J = 4.5, 7.5 Hz, 1 H),
7.07 (d, J = 7.5 Hz, 1 H), 1.76 (s, 3 H) ppm. 13C NMR: δ = 145.2,
145.1, 140.0 (d, J = 6.8 Hz), 139.1, 137.6, 137.5 (d, J = 4.0 Hz), 137.3,
137.2, 136.8 (d, J = 12.3 Hz), 134.5, 134.3, 134.3, 134.2 (d, J =
20.8 Hz), 133.9, 133.6 (d, J = 20.1 Hz), 129.7 (d, J = 5.8 Hz), 129.5,
128.7 (d, J = 10.7 Hz), 128.5 (d, J = 7.3 Hz), 128.4, 128.3, 128.1 (d,
J = 14.1 Hz), 128.0, 126.7, 29.9 ppm. 31P{1H} NMR: δ = –14.3 (s) ppm.
HRMS ESI+ calcd. for C25H21ClP+ [M + H]+ 387.1064, found 387.1091.
85:15); m.p. 139 °C. IR (film): ν = 3055 (w), 1587 (m), 1428 (m), 754
˜
1
(s), 748 (s) cm–1. H NMR: δ = 7.67 (d, J = 8.0 Hz, 1 H), 7.50 (d, J =
8.0 Hz, 1 H), 7.30–7.10 (m, 7 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.01 (t, J =
7.6 Hz, 1 H), 6.90 (dd, J = 7.6, 2.0 Hz, 1 H), 6.86 (dd, J = 7.2, 3.6 Hz,
1 H), 6.72 (dd, J = 7.2, 4.0 Hz, 1 H), 6.50 (d, J = 7.2 Hz, 1 H), 2.37 (s,
3 H), 2.06 (s, 3 H) ppm. 13C NMR: δ = 144.8 (d, J = 32.0 Hz), 143.4
(d, J = 28.4 Hz), 143.0 (d, J = 25.9 Hz), 139.7 (d, J = 14.6 Hz), 139.2
(d, J = 6.9 Hz), 135.0, 134.9 (d, J = 11.7 Hz), 134.7 (d, J = 6.5 Hz),
134.5 (d, J = 13.8 Hz), 133.5, 132.4, 131.9 (2 C), 131.6, 130.2 (d, J =
4.0 Hz), 130.0 (d, J = 5.1 Hz), 129.8, 129.3 (d, J = 6.5 Hz, 2 C), 129.0,
128.8, 126.5, 126.1 (d, J = 6.5 Hz), 124.6, 21.7 (d, J = 20.7 Hz), 21.4
(d, J = 24.1 Hz) ppm. 31P NMR{1H}: δ = –27.7 (s) ppm. HRMS ESI+
calcd. for C26H22BrClP+ [M + H]+ 479.0326, found 479.0368.
(aR)-(2′-Chloro-6-methylbiphenyl-2-yl)diphenylphosphine (aR)-
6: At –78 °C, butyllithium (461 μL, 1.59
M in hexane, 0.73 mmol,
1 equiv.) was added dropwise to a solution of (aR)-2-bromo-2′-
chloro-6′-methylbiphenyl (aR)-5[6c] (206 mg, 0.73 mmol, 1 equiv.) in
freshly distilled THF (4 mL). After 10 min at –78 °C chlorodiphenyl-
phosphine (422 μL, 2.19 mmol, 3 equiv.) was added. The reaction
mixture was allowed to reach 25 °C overnight and then quenched
by addition of water (10 mL). The aqueous layer was extracted with
DCM (3 × 15 mL) and the combined organic layers were dried with
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (pentane/DCM, 10:0
to 7:3) and the derivative (aR)-6 was obtained as a slightly yellow
solid. Additional data for (aR)-6: [α]D = –18 (c = 1.0, DCM).
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)-di-o-tolylphosphine (aR)-
3d: Compound (aR)-3d was synthesized according to general proce-
dure GP2 starting from sulfoxide (S,aR)-2 (450 mg, 1.10 mmol,
1 equiv.) and a solution of chlorodi-o-tolylphosphine (827 mg,
3.33 mmol, 3 equiv.) in THF (2 mL). The crude material was purified
in a fashion analogous to that applied to the racemic compound
to afford the aR derivative as a white powder (276 mg, 26 % yield);
Additional data for (aR)-3d: [α]D = –52 (c = 0.8, DCM).
GP3. General Procedure for Suzuki–Miyaura Coupling: An oven-
dried 10 mL microwave reaction vial was charged with the 2′-
bromobiphenyl-2-ylphosphine (1 equiv.), phenylboronic acid
(2 equiv.), cesium fluoride (4 equiv.) and Pd(PPh3)4 (10 mol-%). The
vial was purged with argon. Dry and degassed THF (15 mL) was
added, and argon was bubbled for 5 min into the resulting yellow
reaction medium, which was stirred at 80 °C under microwave irra-
diation during 1 h. After cooling, the mixture was poured into 5 %
aq. HCl and extracted three times with DCM (3 × 5 mL). The com-
bined organic layers were washed twice with water and brine, dried
with Na2SO4, filtered and concentrated in vacuo. The resulting resi-
due was purified by column chromatography on silica gel (elution
precised below) to afford the desired coupling product.
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)bis(p-fluorophenyl)phos-
phine ( )-3f: Compound ( )-3f was synthesized according to gen-
eral procedure GP1 starting from biphenyl ( )-1 (544 mg,
1.57 mmol, 1 equiv.) and a solution of chlorobis(p-fluorophen-
yl)phosphine (1.2 g, 4.71 mmol, 3 equiv.) in THF (2 mL). After work
up, the residue was purified by flash chromatography on silica gel
(pentane/DCM, 10:0 to 7:3) to yield ( )-3f as a white powder
(199 mg, 26 % yield): Rf = 0.46 (cyclohexane/DCM, 85:15); m.p.
1
142 °C. IR (film): ν = 3056 (w), 1586 (s), 1492 (s), 1221 (s) cm–1. H
˜
NMR: δ = 7.80 (dd, J = 8.0, 1.2 Hz, 1 H), 7.63 (dd, J = 8.0, 0.8 Hz, 1
H), 7.43 (t, J = 8.0 Hz, 1 H), 7.40–7.33 (m, 2 H), 7.32–7.23 (m, 5 H),
7.15 (t, J = 8.8 Hz, 4 H), 7.07 (ddd, J = 7.6, 3.2, 1.2 Hz), 6.87 (ddd,
J = 7.6, 3.2, 1.2 Hz) ppm. 13C NMR: δ = 164.8 (d, J = 8.4 Hz), 162.3
(d, J = 8.4 Hz), 144.7 (d, J = 31.7 Hz), 140.1 (d, J = 14.2 Hz), 139.6
(d, J = 6.9 Hz), 136.2 (d, J = 8.0 Hz), 135.9 (d, J = 8.1 Hz), 135.8 (d,
J = 7.6 Hz), 135.6 (d, J = 8.0 Hz), 134.7 (d, J = 7.0 Hz), 132.6, 131.9,
131.9, 131.8, 131.7, 131.6, 131.5, 130.2, 129.8, 129.4, 126.8, 124.3,
116.1 (d, J = 7.7 Hz), 115.8 (d, J = 7.7 Hz) ppm. 31P{1H} NMR: δ =
–13.8 (t, JP-F = 4.8 Hz) ppm. 19F{1H} NMR: δ = –111.6 (d, JF-P = 4.8 Hz),
–112.2 (d, JF-P = 4.8 Hz) ppm. HRMS ESI+ calcd. for C24H16BrClF2P+
[M + H]+ 486.9824, found 486.9792.
( )-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)dicyclohexylphosphine
( )-3′a: Compound ( )-3′a was synthesized according to general
procedure GP3 starting from phosphine ( )-3a (51 mg, 0.11 mmol,
1 equiv.). After work up, the residue was purified by flash chroma-
tography on silica gel (cyclohexane/DCM, 9:1) to furnish ( )-3′a as
a white film (25 mg, 51 % yield): Rf = 0.15 (cyclohexane/DCM, 8:2).
1
IR (film): ν = 3069 (w), 1548 (w), 1143 (m), 746 (s), 695 (s) cm–1. H
˜
NMR: δ = 7.50–7.39 (m, 3 H), 7.41–7.36 (m, 2 H), 7.34–7.29 (m, 1 H),
7.24–7.20 (m, 3 H) 7.17–7.09 (m, 3 H), 1.69–1.52 (m, 6 H), 1.48–1.22
(m, 6 H), 1.17–0.88 (m, 10 H) ppm. 13C NMR: δ = ; 147.6 (d, J =
31.3 Hz), 141.5, 141.0 (d, J = 2.2 Hz), 137.7 (d, J = 6.6 Hz), 135.5 (d,
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)bis(p-fluorophenyl)- J = 8.1 Hz), 132.3, 131.5, 131.4, 130.0, 129.8 (2 C), 129.5, 128.3, 127.9
phosphine (aR)-3f: Compound (aR)-3f was synthesized according
to general procedure GP2 starting from sulfoxide (S,aR)-2 (398 mg,
0.98 mmol, 1 equiv.) and chlorobis(p-fluorophenyl)phosphine
(755 mg, 2.94 mmol, 3 equiv.). The crude material was purified in a
fashion analogous to that applied to the racemic compound to af-
(2 C), 127.8, 126.5, 126.3, 36.8 (d, J = 16.7 Hz), 33.2 (d, J = 13.5 Hz),
30.7 (d, J = 13.5 Hz), 29.8, 29.0 (d, J = 6.2 Hz), 28.2 (d, J = 13.2 Hz),
27.7 (d, J = 10.1 Hz), 27.6, 27.0 (2 C), 26.5, 26.4 ppm. 31P{1H} NMR:
δ = –8.6 ppm. HRMS ESI+ calcd. for C30H35ClP [M + H]+ 461.2159,
found 461.2146.
Eur. J. Org. Chem. 0000, 0–0
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5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(aR)-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)dicyclohexylphos-
phine (aR)-3′a: Compound (aR)-3′a was synthesized according to
general procedure GP3 starting from phosphine (aR)-3a (35 mg,
0.08 mmol, 1 equiv.). After work up, the residue was purified by
flash chromatography on silica gel (cyclohexane/DCM, 9:1) to fur-
nish (aR)-3′a as a white film (19 mg, 54 % yield).
a white powder (45 mg, 76 % yield); Additional data for (aR)-4a:
[α]D = –62 (c = 1.0, DCM); CP-HPLC Chiralpak IA column (hexane/2-
propanol 95:5, flow rate: 0.5 mL/min, λmax = 207 nm) tR = 26.1 min,
er > 99:1.
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)diphenylphosphine Oxide
( )-4c: Compound ( )-4c was synthesized according to general pro-
cedure GP4 starting from phosphine ( )-3c (110 mg, 0.12 mmol,
1 equiv.). After work up, the residue was purified by flash chroma-
tography on silica gel (cyclohexane/EtOAc, 5:5 to 3:7) to furnish ( )-
4c as a white powder (93 mg, 82 % yield): Rf = 0.17 (cyclohexane/
Additional data for (aR)-3′a: [α]D = –7 (c = 0.2, DCM).
( )-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)diphenylphosphine ( )-
3′b: Compound ( )-3′b was synthesized according to general pro-
cedure GP3 starting from phosphine ( )-3c (70 mg, 0.16 mmol,
1 equiv.). After work up, the residue was purified by flash chroma-
tography on silica gel (cyclohexane/DCM, 95:5) to furnish ( )-3′b as
a white film (42 mg, 61 % yield): Rf = 0.31 (cyclohexane/DCM, 9:1).
EtOAc, 4:6); m.p. 176 °C. IR (film): ν = 2990 (m), 1581 (m), 1431
˜
1
(w) cm–1. H NMR (C6D6): δ = 7.75 (ddd, J = 11.6, 8.0, 1.2 Hz, 2 H),
7.61 (ddd, J = 11.6, 7.6, 1.2 Hz, 2 H), 7.43 (dd, J = 7.6, 1.2 Hz, 1 H),
7.30 (dd, J = 13.2, 7.6 Hz, 1 H), 7.24 (br. d, J = 8.0 Hz, 1 H), 7.09 (br.
d, J = 8.0 Hz, 1 H), 7.04–6.84 (m, 8 H), 6.66 (td, J = 7.6, 7.6, 2.4 Hz,
1 H), 6.58 (td, J = 8.0, 8.0, 1.6 Hz, 1 H) ppm. 13C NMR: δ = 143.4 (d,
J = 9.1 Hz), 137.0 (d, J = 4.0 Hz), 136.7 (d, J = 12.8 Hz), 135.1, 134.1,
133.1, 133.1, 132.9, 132.6, 132.3, 132.2, 131.9, 131.8, 131.7, 131.5,
131.4, 131.4, 131.3, 129.6, 128.8 (d, J = 13.5 Hz), 128.5 (d, J =
16.1 Hz), 128.2 (d, J = 12.1 Hz), 126.4, 125.1 ppm. 31P{1H} NMR: δ =
26.6 (s) ppm. CP-HPLC Chiralpak IA column (hexane/2-propanol
IR (film): ν = 3290 (m), 1421 (s), 1148 (s), 730 (m) cm–1. 1H NMR: δ =
˜
7.47 (m, 2 H), 7.38–7.27 (m, 7 H), 7.25–7.15 (m, 7 H), 7.14–7.07 (m,
3 H), 6.82–6.74 (m, 3 H) ppm. 13C NMR: δ = 145.7 (d, J = 14.2 Hz),
141.4 (d, J = 15.0 Hz), 140.5 (d, J = 15.0 Hz), 138.0 (d, J = 14.3 Hz),
136.9 (d, J = 6.6 Hz), 136.6, 136.4, 135.1 (d, J = 7.3 Hz), 134.3, 134.1,
133.9, 133.8, 133.2, 132.9, 132.5, 131.3, 129.9, 129.8, 129.7, 129.6,
128.9, 128.7, 128.6, 128.5 (2 C), 128.4 (2 C), 128.2, 127.8, 126.7 (d,
J = 7.6 Hz) ppm. 31P{1H} NMR: δ = –11.8 ppm. HRMS ESI+ calcd. for
C30H23ClP [M + H]+ 449.1220, found 449.1188.
95:5, flow rate: 0.5 mL/min, λmax = 207 nm) tR1 = 48.9 and tR2
=
53.0 min. C24H17BrClOP: C 61.63, H 3.66; found C 61.56, H 3.77.
(aR)-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)diphenylphosphine
(aR)-3′b: Compound (aR)-3′b was synthesized according to general
procedure GP3 starting from phosphine (aR)-3c (30 mg, 0.07 mmol,
1 equiv.). After work up, the residue was purified by flash chroma-
tography on silica gel (cyclohexane/DCM, 95:5) to furnish (aR)-3′b
as a white film (18.5 mg, 62 % yield).
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)diphenylphosphine Oxide
(aR)-4c: Compound (aR)-4c was synthesized according to general
procedure GP4 starting from phosphine (aR)-3c (26 mg,
0.057 mmol, 1 equiv.). The crude material was purified in a fashion
analogous to that applied to the racemic compound to afford the
aR derivative as a white powder (21.8 mg, 81 % yield); Additional
data for (aR)-4c: [α]D = –48 (c = 1.0, DCM); CP-HPLC Chiralpak IA
Additional data for (aR)-3′b: [α]D = –15 (c 0.5, DCM).
column (hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax
207 nm) tR = 48.9 min, er = 99:1.
=
GP4. General Procedure for the Oxidation of Phosphines: The
title phosphine (1 equiv.) was stirred in a mixture of acetone/30 %
aqueous hydrogen peroxide solution (10:1 v/v, final concentration
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)di-o-tolylphosphine Oxide
( )-4d: Compound ( )-4d was synthesized according to general
procedure GP4 starting from phosphine ( )-3d (40 mg, 0.081 mmol,
1 equiv.). After work up, the residue was purified by flash chroma-
tography on silica gel (cyclohexane/EtOAc, 6:4 to 3:7) to furnish ( )-
4d as a white powder (35 mg, 85 % yield): Rf = 0.43 (cyclohexane/
0.25
M) at room temperature overnight. After addition of water
(5 mL), the aqueous layer was extracted with DCM (3 × 15 mL) and
the combined organic layers were dried with Na2SO4, filtered and
concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel.
EtOAc, 4:6); m.p. 168 °C. IR (film): ν = 2921 (m), 2951 (m), 1591 (m),
˜
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)dicyclohexylphosphine Ox-
ide ( )-4a: Compound ( )-4a was synthesized according to general
procedure GP4 starting from phosphine ( )-3a (57 mg, 0.12 mmol,
1 equiv.). After work up, the residue was purified by flash chroma-
tography on silica gel (cyclohexane/EtOAc, 5:5 to 3:7) to furnish ( )-
4a as a white powder (45 mg, 76 % yield): Rf = 0.17 (cyclohexane/
1419 (w), 754 (s) cm–1
.
1H NMR: δ = 7.71–7.07 (m, 1 H), 7.45–7.32
(m, 5 H), 7.31–7.23 (m, 2 H), 7.13–6.93 (m, 5 H), 6.85 (dd, J = 14.4,
7.6 Hz, 1 H), 6.80 (dd, J = 7.6, 1.2 Hz, 1 H), 2.48 (s, 3 H), 2.43 (s, 3
H) ppm. 13C NMR: δ = 143.9–143.6 (m, 3 C), 137.8 (d, J = 3.3 Hz),
136.6 (d, J = 12.8 Hz), 134.8, 133.8, 132.9–132.8 (m, 3 C), 132.1–
131.8 (m, 4 C), 131.6–131.5 (m, 2 C), 131.0 (d, J = 5.1 Hz), 130.9,
130.1 (d, J = 4.8 Hz), 129.2, 128.6 (d, J = 13.5 Hz), 126.1, 125.2–125.0
(m, 2 C), 22.2 (d, J = 3.7 Hz), 22.1 (d, J = 3.3 Hz) ppm. 31P{1H} NMR:
δ = 33.8 (s) ppm. CP-HPLC Chiralpak IA column (hexane/2-propanol
EtOAc, 4:6); m.p. 128 °C. IR (film): ν = 2923 (s), 2849 (m), 1412 (m),
˜
1
1168 (s), 754 (s) cm–1. H NMR: δ = 7.84 (ddd, J = 11.6, 7.6, 0.8 Hz,
1 H), 7.68–7.63 (m, 1 H), 7.48 (td, J = 7.6, 7.6, 2.0 Hz, 1 H), 7.42 (td,
J = 7.6, 7.6, 1.2 Hz, 1 H), 7.32 (td, J = 7.6, 7.6, 1.6 Hz, 1 H), 7.15 (dd,
J = 7.2, 1.6 Hz, 1 H), 1.81–1.50 (m, 11 H), 1.49–0.90 (m, 11 H) ppm.
13C NMR: δ = 142.2 (d, J = 7.3 Hz), 140.5 (d, J = 14.6 Hz), 139.1 (d,
J = 2.2 Hz), 136.3 (d, J = 11.7 Hz), 133.5, 132.7, 132.6, 132.3 (d, J =
1.5 Hz), 131.2 (d, J = 8.1 Hz), 130.7, 129.8, 128.9 (d, J = 10.9 Hz),
126.9, 125.1, 38.4 (d, J = 46.0 Hz), 37.2 (d, J = 46.3 Hz), 26.8–26.1 (6
C), 25.8, 25.7 ppm. 31P{1H} NMR: δ = 50.6 (s) ppm. CP-HPLC Chiralpak
95:5, flow rate: 0.5 mL/min, λmax = 207 nm) tR1 = 28.0 min and tR2
=
30.5 min. HRMS ESI+ calcd. for C26H22BrClOP+ [M + H]+ 495.0275,
found 495.0309.
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)di-o-tolylphosphine Ox-
ide (aR)-4d: Compound (aR)-4d was synthesized according to gen-
eral procedure GP4 starting from phosphine (aR)-3d (20 mg,
0.04 mmol, 1 equiv.). The crude material was purified in a fashion
analogous to that applied to the racemic compound to afford the
aR derivative as a white powder (19.1 mg, 92 % yield); Additional
data for (aR)-4d: [α]D = –62 (c = 1.0, DCM); CP-HPLC Chiralpak IA
IA column (hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax
=
207 nm) tR1 = 26.0 min and tR2 = 29.1 min. HRMS ESI+ calcd. for
C24H30BrClOP+ [M + H]+ 479.0901, found 479.0913.
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)dicyclohexylphosphine
Oxide (aR)-4a: Compound (aR)-4a was synthesized according to
general procedure GP4 starting from phosphine (aR)-3a (57 mg,
0.12 mmol, 1 equiv.). The crude material was purified in a fashion
column (hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax
=
207 nm); tR = 28.3 min, er = 98:2.
( )-(2′-Bromo-6-chlorobiphenyl-2-yl)bis(p-fluorophenyl)phos-
analogous to that applied previously to afford the aR derivative as phine Oxide ( )-4f: Compound ( )-4f was synthesized according
Eur. J. Org. Chem. 0000, 0–0
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6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
to general procedure GP4 starting from phosphine ( )-3f (40 mg,
0.082 mmol, 1 equiv.). After work up, the residue was purified by
flash chromatography on silica gel (cyclohexane/EtOAc, 5:5 to 3:7)
to furnish ( )-4f as a white powder (35 mg, 86 % yield): Rf = 0.17
135.6, 132.5, 131.1, 130.4, 130.1, 129.9, 129.8, 129.7 (2 C), 128.9,
128.2 128.1, 128.0 (2 C), 126.6 (d, J = 10.5 Hz), 38.2 (d, J = 64.6 Hz),
36.5 (d, J = 65.1 Hz), 26.6–26.4 (3 C), 25.8–25.7 (3 C), 25.2, 24.8, 20.9,
20.8 ppm. 31P{1H} NMR: δ = 52.8 ppm. CP-HPLC Chiralpak IA column
(hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax = 207 nm)
tR1 = 16.5 min and tR2 = 18.1 min. HRMS ESI+ calcd. for C30H35ClOP
[M + H]+ 477.2109, found 477.2100.
(cyclohexane/EtOAc, 4:6); m.p. 132 °C. IR (film): ν = 2912 (m), 2906
˜
(m), 1594 (m), 1390 (w) cm–1. 1H NMR: δ = 7.70–7.60 (m, 3 H), 7.51–
7.36 (m, 4 H), 7.23–7.18 (m, 3 H), 7.13–7.09 (m, 2 H), 7.07–6.97 (m,
3 H) ppm. 13C NMR: δ = 166.1 (dd, J = 24.0, 2.9 Hz), 163.6 (dd, J =
24.0, 3.0 Hz), 143.2 (d, J = 9.1 Hz), 136.8, 136.8 (d, J = 11.3 Hz), 134.6
(t, J = 11.6 Hz), 133.8 (t, J = 9.1 Hz), 133.5, 133.2, 133.1, 132.6, 132.1,
132.0, 132.1, 129.9, 129.1, 128.9, 128.7 (d, J = 2.9 Hz), 128.1 (d, J =
2.9 Hz), 127.6 (d, J = 2.9 Hz), 127.1 (d, J = 2.9 Hz), 126.6, 125.1,
116.2–115.6 (m) ppm. 31P{1H} NMR: δ = 25.5 (t, JP-F = 2.6 Hz) ppm.
CP-HPLC Chiralpak IA column (hexane/2-propanol 95:5, flow rate:
0.5 mL/min, λmax = 207 nm) tR1 = 39.0 min and tR2 = 44.1 min.
HRMS ESI+ calcd. for C24H16BrClF2OP+ [M + H]+ 502.9773, found
502.9811.
(aR)-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)dicyclohexylphos-
phine Oxide (aR)-4′a: Compound (aR)-4′a was synthesized accord-
ing to general procedure GP4 starting from phosphine (aR)-3′a
(12 mg, 0.026 mmol, 1 equiv.). The crude material was purified in a
fashion analogous to that applied to the racemic compound to af-
ford the aR derivative as a white film (8.6 mg, 83 % yield); Additional
data for (aR)-4′a: [α]D = –12 (c = 0.2, DCM); CP-HPLC Chiralpak IA
column (hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax
207 nm) tR = 16.5 min, er > 99:1.
=
( )-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)diphenylphosphine Ox-
ide ( )-4′b: Compound ( )-4′b was synthesized according to gen-
eral procedure GP4 starting from phosphine ( )-3′b (9.7 mg,
0.021 mmol, 1 equiv.). After work up, the residue was precipitated
(aR)-(2′-Bromo-6-chlorobiphenyl-2-yl)bis(p-fluorophenyl)-
phosphine Oxide (aR)-4f: Compound (aR)-4f was synthesized ac-
cording to general procedure GP4 starting from phosphine (aR)-3f
(40 mg, 0.082 mmol, 1 equiv.). The crude reaction was purified in a
fashion analogous to that applied previously to afford the aR deriva-
tive as a white powder (35 mg, 76 % yield); Additional data for (aR)-
4f: [α]D = –13 (c = 0.7, DCM); CP-HPLC Chiralpak IA column (hexane/
2-propanol 95:5, flow rate: 0.5 mL/min, λmax = 207 nm) tR =
38.1 min, er = 98:2.
in pentane to furnish ( )-4′b as a white film (8.9 mg, 89 % yield): IR
1
(film): ν = 3292 (m), 1439 (s), 1161 (s), 726 (m) cm–1. H NMR: δ =
˜
7.70–7.60 (m, 1 H), 7.60–7.47 (m, 4 H), 7.46–7.30 (m, 9 H), 7.26–7.18
(m, 3 H), 7.17–7.11 (m, 3 H), 7.06–7.02 (m, 1 H), 6.58 (d, J = 7.6 Hz,
1 H) ppm. 13C NMR: δ = 141.8, 140.9, 134.7 (d, J = 3.6 Hz), 133.5 (d,
J = 3.7 Hz), 132.8, 132.8, 132.7, 132.6, 132.5, 132.3, 132.3, 132.2 (d,
J = 5.9 Hz), 132.1, 132.0 (d, J = 3.5 Hz), 131.9 (d, J = 3.2 Hz), 131.8,
131.7, 130.3, 129.9, 129.6 (2 C), 129.0, 128.9, 128.9 (d, J = 13.2 Hz),
128.5 (d, J = 12.1 Hz), 128.1, 127.9, 127.5 (2 C), 126.6 (d, J =
5.4 Hz) ppm. 31P{1H} NMR: δ = 34.7 ppm. CP-HPLC Chiralpak IA
( )-(2′-Chloro-6-methylbiphenyl-2-yl)diphenylphosphine Oxide
( )-7: Compound ( )-7 was synthesized according to general proce-
dure GP4 starting from phosphine ( )-6 (30 mg, 0.078 mmol,
1 equiv.). After work up, the residue was purified by flash chroma-
tography on silica gel (cyclohexane/EtOAc, 10:0 to 6:4) to furnish
( )-7 as a white film (27 mg, 86 % yield): Rf = 0.23 (cyclohexane/
column (hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax
=
207 nm) tR1 = 71.0 min and tR2 = 75.4 min. HRMS ESI+ calcd. for
EtOAc, 6:4). IR (film): ν = 3293 (m), 1439 (s), 1161 (s), 719 (m) cm–1
.
C30H23ClOP [M + H]+ 465.1170, found 465.1210.
˜
1H NMR: δ = 7.70 (d, J = 11.7 Hz, 1 H), 7.68 (d, J = 11.7 Hz, 1 H),
7.61 (t, J = 7.6 Hz, 1 H), 7.46–7.42 (m, 9 H), 7.27–7.22 (m, 2 H), 7.17
(dd, J = 7.8, 3.5 Hz, 1 H), 6.99 (d, J = 3.8 Hz, 1 H), 6.98 (s, 1 H), 6.88
(dd, J = 6.5, 2.9 Hz, 1 H), 2.00 (s, 3 H) ppm. 13C NMR: δ = 143.9 (d,
J = 8.0 Hz), 139.2, 137.9 (d, J = 3.3 Hz), 134.5 (d, J = 13.1 Hz), 133.4,
132.9, 132.5, 132.3, 132.2, 132.1, 132.0, 131.9, 131.8, 130.7, 130.3,
129.9, 129.1, 128.8 (d, J = 12.4 Hz), 128.5 (d, J = 12.4 Hz), 128.3,
127.6 (d, J = 12.4 Hz), 126.4, 110.9, 109.7 (d, J = 5.1 Hz), 20.7 ppm.
31P{1H} NMR: δ = 28.2 ppm. CP-HPLC Chiralpak IA column (hexane/
(aR)-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)diphenylphosphine
Oxide (aR)-4′b: Compound (aR)-4′b was synthesized according to
general procedure GP4 starting from phosphine (aR)-3′b (11 mg,
0.025 mmol, 1 equiv.). The crude material was purified in a fashion
analogous to that applied to the racemic compound to afford the
aR derivative as a white film (9.9 mg, 87 % yield); additional data
for (aR)-4′b: [α]D = –8 (c = 0.1, DCM); CP-HPLC Chiralpak IA column
(hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax = 207 nm) tR =
75.4 min, er > 99:1.
2-propanol 95:5, flow rate: 0.5 mL/min, λmax = 207 nm) tR1
=
42.0 min and tR2 = 54.0 min. HRMS ESI+ calcd. for C25H20ClOP (M+)
GP5. General Procedure for the FLP-Catalyzed Hydrosilylation
of Acetophenone and Acetophenone N-Phenylimine
402.0935, found 402.0982.
(aR)-(2′-Chloro-6-methylbiphenyl-2-yl)diphenylphosphine Ox-
ide (aR)-7: Compound (aR)-7 was synthesized according to general
procedure GP4 starting from phosphine (aR)-6 (35 mg, 0.090 mmol,
1 equiv.). The crude material was purified in a fashion analogous to
that applied before to afford the aR derivative as a white film
(29 mg, 80 % yield); Additional data for (aR)-6: [α]D = +3 (c = 1.0,
DCM); CP-HPLC Chiralpak IA column (hexane/2-propanol 95:5, flow
rate: 0.5 mL/min, λmax = 207 nm) tR = 52.5 min, er = 98:2.
Hydrosilylation of Acetophenone: A dry Schlenk tube was trans-
ferred into a glovebox under vacuum and was charged successively
with tris(pentafluorophenyl)borane (22.4 mg, 0.044 mmol,
0.1 equiv.) and the appropriate phosphine (0.044 mmol, 0.1 equiv.).
Acetophenone (53 mg, 0.44 mmol, 1 equiv.) was added as a solution
in C6D6 (1 mL). The resulting solution was stirred for 10 min at room
temperature and dimethylphenylsilane (80 μL, 0.53 mmol,
1.2 equiv.) was added dropwise resulting in an instantaneous
slightly exothermic reaction. The solution was stirred at room tem-
( )-(6-Chloro-[1,1′:2′,1′′-terphenyl]-2-yl)dicyclohexylphosphine
Oxide ( )-4′a: Compound ( )-4′a was synthesized according to perature for 18 h. The crude mixture was quenched by addition of
general procedure GP4 starting from phosphine ( )-3′a (10 mg,
0.021 mmol, 1 equiv.). After work up, the residue was precipitated
in pentane to furnish ( )-4′a as a white film (7.9 mg, 76 % yield): IR
TBAF (1 M in THF, 1.32 mL, 1.32 mmol, 3 equiv.) at room temperature
and stirring for 1 h. It was then concentrated in vacuo, and purified
by flash chromatography on silica gel (cyclohexane/EtOAc, 9:1 to
8:2) to furnish 1-phenylethanol as a colorless oil (yields are reported
in Scheme 2, a). Spectral data were in agreement with literature.
(film): ν = 2925 (s), 2832 (m), 1403 (m), 1163 (s), 748 (s) cm–1 1H
.
˜
NMR: δ = 7.65–7.63 (m, 1 H), 7.52–7.47 (m, 2 H), 7.40–7.33 (m, 3 H),
7.32–7.26 (m, 2 H), 1.77–1.49 (m, 8 H), 1.49–1.31 (m, 2 H), 1.23–0.72 Rf = 0.20 (cyclohexane/EtOAc, 8:2). The enantiomeric ratio was
(m, 12 H) ppm. 13C NMR: δ = 145.1, 140.9 (d, J = 26.3 Hz), 138.1, measured by CP-HPLC on a Chiracel OD-H column (hexane/2-prop-
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anol 95:5, flow rate: 0.5 mL/min, λmax = 204 nm); tR1 = 16.2 min,
tR2 = 18.2 min. All runs depicted in Scheme 2 (a) afforded the race-
mic product.
(cyclohexane/EtOAc, 95:5 to 8:2) to furnish methyl 3-(pinacolato-
boranyl)butanoate: Rf = 0.67 (cyclohexane/EtOAc, 8:2). Spectral data
were in agreement with literature.
Hydrosilylation of Acetophenone N-Phenylimine: The hydrosilyl-
ation of acetophenone N-phenylimine was carried out on a 0.16–
0.47 mmol scale without notable changes on conversions or yields,
following the same procedure as for acetophenone except for the
TBAF quench which was avoided. After concentration of the crude
reaction in vacuo, the residue was purified by flash chromatography
on silica gel (cyclohexane/Et2O, 5:1) to afford N-(1-phenylethyl)anil-
ine as a colorless oil (yields are reported in Scheme 2, a). Spectral
data were in agreement with literature. The enantiomeric ratio was
measured by CP-HPLC on a Chiralpak IB column (hexane/2-propanol
Enantiomeric Excess Determination. Boronic Ester Conversion
to Corresponding Benzoate: To the crude borylation product
(0.5 mmol, 1 equiv.) in THF (2 mL) and water (2 mL), sodium per-
borate (769 mg, 2.5 mmol, 5 equiv.) was added in one portion. The
reaction mixture was stirred vigorously for 18 h at room tempera-
ture, diluted with water and then extracted with dichloromethane
(3 × 20 mL). The combined organic layers were dried with Na2SO4,
filtered and concentrated in vacuo. At 0 °C, to a solution of crude
methyl 3-hydroxybutanoate (0.5 mmol, 1 equiv.) in dry DCM (5 mL),
pyridine (100 μL, 1.01 mmol, 2 equiv.) and benzoyl chloride (115 μL,
2.5 mmol, 5 equiv.) were successively added dropwise. The mixture
was stirred 1 h at room temperature and was then quenched at
0 °C by addition of a saturated aqueous solution of NaHCO3 (10 mL).
The aqueous phase was extracted with DCM (3 × 15 mL) and the
combined organic layers were dried with Na2SO4, filtered and con-
centrated in vacuo. The resulting oily residue was purified by flash
chromatography on silica gel (cyclohexane/EtOAc, 9:1 to 8:2) to af-
ford methyl 3-(benzoyloxy)butanoate as a colorless oil (yields over
3 steps are reported in Scheme 2, d). Rf = 0.45 (cyclohexane/EtOAc,
8:2). Spectral data were in agreement with literature. The enantio-
meric ratio was measured by CP-HPLC on a Chiralpak IB column
(hexane/2-propanol 98:2, flow rate: 0.5 mL/min, λmax = 208 nm);
tR1 = 12.8 min, tR2 = 13.3 min. All runs depicted in Scheme 2 (d)
afforded the racemic product.
95:5, flow rate: 0.5 mL/min, λmax = 210 nm); tR1 = 10.1 min, tR2
=
12.5 min. All runs depicted in Scheme 2 (a) afforded the racemic
product.
GP6. General Procedure for Lu's [3 + 2] Annulation of Ethyl
Buta-2,3-dienoate with Diethyl Fumarate: In a dried Schlenk tube
flushed with argon, to a mixture of diethyl fumarate (74 mg,
0.43 mmol, 2 equiv.) and the appropriate phosphine catalyst
(0.02 mmol, 0.1 equiv.) in dried, degassed toluene (700 μL), was
added under argon atmosphere ethyl buta-2,3-dienoate (25 μL,
0.22 mmol, 1 equiv.). The solution was stirred at room temperature
or at 60 °C for 18 h. The crude mixture was concentrated in vacuo,
and purified by flash chromatography on silica gel (cyclohexane/
EtOAc, 9:1 to 8:2) to afford the annulation product as a colorless oil
(yields are reported in Scheme 2, b): Rf = 0.22 (cyclohexane/EtOAc,
8:2). Spectral data were in agreement with literature. The enantio-
meric ratio was measured by CP-HPLC on a Chiralpak IB column
(hexane/2-propanol 95:5, flow rate: 0.5 mL/min, λmax = 211 nm);
tR1 = 12.5 min, tR2 = 15.7 min.
GP9. General Procedure for Palladium-Catalyzed Hydrosilyl-
ation of Styrene and Determination of Enantiomeric Excess: A
dry Schlenk tube flushed with Ar was charged with styrene (50 mg,
0.48 mmol, 1 equiv.), allylpalladium chloride dimer (4.4 mg,
0.012 mmol, 2.5 mol-%) and the appropriate phosphine ligand
(0.024 mmol, 5 mol-%). The mixture was stirred for 20 min and
quickly sonicated to furnish a clean yellow solution. Trichlorosilane
(100 μL, 0.96 mmol, 2 equiv.) was then slowly added and the mix-
ture took instantaneously a black coloration. It was stirred until
complete conversion (followed by 1H NMR) and concentrated in
vacuo. The crude material was redissolved in DCM, transferred into
a 10 mL flask and volatiles were removed. The crude compound
was purified by bulb-to-bulb distillation (high vacuum) to furnish
the corresponding trichloro(1-phenylethyl)silane with 63–92 %
yields as a colorless oil. Spectral data were in agreement with litera-
ture.
GP7: General Procedure for the Phosphine-Catalyzed Aza-Mo-
rita–Baylis–Hillman Reaction of N-Tosyl-Benzaldimine with
Methyl Vinyl Ketone: To a solution of N-tosyl-benzaldimine
(30.0 mg, 0.12 mmol) and the appropriate phosphine catalyst
(0.01 mmol, 0.1 equiv.) in THF (1.0 mL) was added methyl vinyl
ketone (11 μL, 0.14 mmol, 1.2 equiv.). The reaction mixture was
stirred at room temperature or 60 °C. When the reaction was com-
pleted, as monitored by 1H NMR, the solvent was removed in vacuo
and the residue was purified by flash chromatography on silica gel
(cyclohexane/EtOAc, 9:1 to 7:3) to afford N-(1-phenylethyl)aniline as
a white solid (yields are reported in Scheme 2, c): Rf = 0.35 (cyclo-
hexane/EtOAc, 7:3). Spectral data were in agreement with literature.
The enantiomeric ratio was measured by CP-HPLC on a Chiralpak
IA column (hexane/2-propanol 80:20, flow rate: 0.5 mL/min, λmax
208 nm); tR1 = 17.1 min, tR2 = 18.4 min.
=
Enantiomeric Excess Determination. Alkyltrichlorosilane Con-
version to Corresponding Alcohol by Fleming–Tamao Oxid-
ation: The reaction scale for ee determination is based on yield of
the previous step. The freshly distilled alkyltrichlorolsilane (72–
105 mg, 0.3–0.44 mmol, 1 equiv.) was dissolved in a mixture of
THF (8 mL) and MeOH (8 mL). K2CO3 (248–364 mg, 1.8–2.64 mmol,
6 equiv.), KF (104–153 mg, 1.8–2.64 mmol 6 equiv.) and 30 % aque-
GP8: General Procedure for Phosphine-catalyzed Conjugate
Borylation of Methyl Crotonate and Determination of Enantio-
meric Excess: A dry Schlenk tube flushed with argon was charged
with the appropriate phosphine catalyst (0.05 mmol, 0.1 equiv.),
cesium carbonate (25 mg, 0.08 mmol, 0.15 equiv.) and bis(pinacol-
ato)diboron (140 mg, 0.55 mmol, 1.1 equiv.). Freshly distilled THF ous solution of hydrogen peroxide (300 μL) were then successively
(2 mL) was then added and the mixture was stirred for 10 min at added. The resulting suspension was vigorously stirred overnight.
room temperature to dissolve the phosphine and the borane rea- Water (10 mL) was then added and the mixture was extracted with
gents completely. Methyl crotonate (50 mg, 0.50 mmol, 1 equiv.) Et2O (3 × 15 mL), dried with Na2SO4, filtered and concentrated in
and MeOH (100 μL, 2.5 mmol, 5 equiv.) were then successively vacuo. The resulting oily residue was purified by column chroma-
added and the reaction mixture was stirred at 70 °C until complete
conversion (followed by H NMR). The reaction mixture was cooled
to room temperature and concentrated in vacuo. After filtration
through a silica pad, the crude compound was directly engaged in
tography on silica gel (cyclohexane/EtOAc, 8:2) to afford 1-phenyl-
ethanol as an oil (yields are given in Scheme 2, e). Spectral data
were in agreement with literature. The enantiomeric ratio was meas-
ured by CP-HPLC on a Chiracel OD-H column (hexane/2-propanol
1
the oxidation step for determination of enantiomeric excess. Alter- 95:5, flow rate: 0.5 mL/min, λmax = 204 nm); tR1 = 16.2 min, tR2
nately, it could be purified by flash chromatography on silica gel 18.2 min.
=
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Acknowledgments
This work was supported by the Centre National de la Recher-
che Scientifique (CNRS), as well as the University of Strasbourg
Institute for Advanced Study (USIAS) and the International Cen-
tre for Frontier Research in Chemistry (IcFRC) (project AxLAB
2014). The authors thank Dr. D. Bourissou and Dr. G. Bouhadir
(LHFA, UMR 5069, Toulouse) for the recording of 29Si NMR spec-
tra and for fruitful discussions.
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Keywords: Organocatalysis · Asymmetric catalysis ·
Homogeneous catalysis · Enantioselectivity · Palladium ·
Axial chirality · Atropoisomerism · Biaryls · Phosphines
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Received: June 14, 2016
Published Online: ■
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Chiral Phosphines
Axially chiral “Buchwald ligand”-like bi-
phenylphosphines were prepared in
highly enantioenriched form and were
evaluated in phosphine-promoted or-
ganocatalysis and hydrosilylations cata-
lyzed by Pd or by frustrated Lewis pairs
(FLPs). The title phosphines are best
suited for transition metal catalysis where
asymmetric induction proved much
higher.
M. J. Fer, J. Cinqualbre, J. Bortoluzzi,
M. Chessé, F. R. Leroux,
A. Panossian* ...................................... 1–10
When Chirality Meets “Buchwald-
Type” Phosphines: Synthesis and Eval-
uation in Frustrated Lewis Pair-, Lewis
Base- and Palladium-Promoted Asym-
metric Catalysis
DOI: 10.1002/ejoc.201600727
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