The synthesis of new HetPHOX ligands and their application to the intermolecular asymmetric heck reaction

Article abstract of DOI:10.1002/ejoc.200800761

The synthesis of six members of the HetPHOX ligand class and the application of palladium complexes of these ligands to the intermolecular asymmetric Heck reaction is described, The tert-leucinol-derived ligands proved the most enantioselective, with pall

Full text of DOI:10.1002/ejoc.200800761

FULL PAPER
DOI: 10.1002/ejoc.200800761
The Synthesis of New HetPHOX Ligands and Their Application to the
Intermolecular Asymmetric Heck Reaction
Martin O. Fitzpatrick,[a] Helge Muller-Bunz,[a] and Patrick J. Guiry*[a]
Keywords: Asymmetric catalysis / Heck reaction / N,P ligands / HetPHOX ligands
The synthesis of six members of the HetPHOX ligand class
and the application of palladium complexes of these ligands
to the intermolecular asymmetric Heck reaction is described.
hexenylation and naphthylation, respectively, of 2,3-di-
hydrofuran. As an aid to the explanation of the observed
selectivity a palladium complex of the most enantioselective
The tert-leucinol-derived ligands proved the most enantiose- ligand was prepared and an X-ray crystal structure obtained.
lective, with palladium complexes of these ligands affording
ee values of up to 96, 95 and 94% in the phenylation, cyclo-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The standard Heck reaction is the substitution of a vi-
nylic hydrogen by an alkenyl or aryl group catalysed by Pd0
complexes. Since its discovery in 1968 by Heck,[1–3] this
elaboration of substituted alkenes by direct C–C bond for-
mation at the vinylic carbon centre has evolved into a
powerful synthetic transformation. The potential of the in-
tramolecular reaction, and in particular its asymmetric
variant, has been exploited in the key steps of many total
syntheses.[4,5] The intermolecular variant has not seen wide
application to date although Hayashi did employ it in the
synthesis of a platelet-activating factor antagonist.[6] Since
the first enantioselective intermolecular Heck reactions by
Hayashi using the diphosphane ligand BINAP,[7] there has
been a recent emphasis on the application of new classes of
chiral ligands. The first use of P,N ligands in this reaction
was reported by Pfaltz who described the arylation and cy-
clohexenylation of 2,3-dihydrofuran (1).[8] The use of palla-
dium complexes of the tert-leucinol-derived “PHOX” li-
gand 5 in the coupling of 2,3-dihydrofuran (1) and cyclo-
hexenyl triflate (2) afforded 3 in ee values of up to 99%,
Scheme 1. Only trace amounts of the thermodynamic prod-
uct 4 were formed compared to BINAP,[7] thus demonstrat-
ing a low amount of double-bond isomerisation after the
initial migratory insertion step.
Scheme 1.
recent research has focussed on applying heterocyclic ana-
logues of the PHOX ligands (HetPHOX ligands) to asym-
metric catalysis[14] including the phenylation and cyclohex-
enylation of 2,3-dihydrofuran (1).[9a,9b] Palladium com-
plexes of HetPHOX ligand 6 induced high levels of enantio-
selectivity of up to 95% in the cyclohexenylation of 1,
Scheme 1. In this article, we wish to report the synthesis of
a wider range of HetPHOX ligands and the application of
their palladium complexes to the phenylation, cyclohexenyl-
ation and naphthylation of 2,3-dihydrofuran (1). We now
report in full on the preparation of four novel HetPHOX
ligands 7c–f and their application, along with two existing
HetPHOX ligands 7a–b,[14] to the intermolecular asymmet-
ric Heck reaction, Figure 1.
Given the success of this ligand class, much effort was
directed toward designing new chiral P,N ligands for this
transformation. The groups of Guiry,[9] Gilbertson,[10]
Hashimoto,[11] and Hou[12] have all developed highly selec-
tive P,N systems with varying chiral scaffolds.[13] Our more
[a] Centre for Synthesis and Chemical Biology, School of Chemis-
try and Chemical Biology, UCD Conway Institute, University
College Dublin,
Belfield, Dublin 4, Ireland
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Novel HetPHOX ligands 7c–f.
Eur. J. Org. Chem. 2009, 1889–1895
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1889

M. O. Fitzpatrick, H. Muller-Bunz, P. J. Guiry
FULL PAPER
Ligand Synthesis
Using proton sponge as base (Entry 1) provided the best
result with complete conversion and 93% ee favouring the
(R)-enantiomer.[17] Relatively moderate conversions were
observed using PMP and tributylamine as bases (Entries 2
and 6), although enantioselectivities remained consistently
high. Where it was possible to measure the ee of the
thermodynamic product 8, results were comparable to those
for the kinetic isomer 10. For example when DIPEA was
used as base the ee of 11 was found to be 93% (R).[17]
Two points of possible diversification of the HetPHOX
ligands were identified. Firstly, the substituent on the oxaz-
oline ring could be varied to include phenyl as well as iso-
propyl and tert-butyl. The second variation could be
achieved at phosphorus with the expectation that introduc-
ing o-tolyl and p-fluorophenyl substituents would vary the
sterics and electronics of the donor phosphorus atom and
thus the reactivity of the ligand.[14]
The synthesis of diphenylphosphane-derived HetPHOX
ligands has been reported previously by directed metalation
and quenching with chlorodiphenylphosphane of the corre-
sponding thiophene-oxazoline 8.[9,16] In order to expand the
series we performed a similar directed metalation and
quench with the appropriate chlorodiarylphosphane to af-
ford the required ligands 7c–f in moderate yields, Scheme 2.
Table 1. Asymmetric phenylation of 2,3-dihydrofuran (1) using pal-
ladium complexes of ligand 7a.
Entry
Ligand
Base
Conversion[a] 10/11[b]
ee 10 (%)[c]
(R)
(%)
1
2
3
4
5
6
7a
7a
7a
7a
7a
7a
PS
PMP
Cy2NMe
DIPEA
Et3N
100
51
100
100
83
91:9
96:4
98:2
85:15
90:10
89:11
93
95
92
94
96
91
Bu3N
43
[a] Conversions were determined using achiral GC with tri-n-dec-
ane as internal standard. [b] Product ratios were also determined
using achiral GC. [c] Enantiomeric excesses were determined using
chiral GC [γ-CD-TFA, 30 m, 80–90 °C, 0.3 °C/min, 90–120 °C,
2 °C/min, 10 min, 15 psi, injection temp. 200 °C, detection temp.
220 °C, tR (S)-10 = 33.52 min, tR (R)-10 = 34.78 min].
Scheme 2.
It was decided to use three bases to test the remaining
five ligands in the phenylation of 2,3-dihydrofuran (1). PS,
Cy2NMe and DIPEA were chosen as bases as these pro-
vided the highest conversions in our initial study. Using the
same reaction conditions palladium complexes derived in
situ from Pd2(dba)3 (4 mol-% Pd) and a twofold excess of
ligands 7b–f were tested in the phenylation of 2,3-dihy-
drofuran (1), Scheme 4, Table 2.
Asymmetric Phenylation of 2,3-Dihydrofuran
Following from the work carried out in this research
group,[9a,9b] where ligand 6 had proven successful, toluene
was chosen as the solvent for these transformations. The
initial reactions used palladium complexes of ligand 7a
(4 mol-%) derived in situ from Pd2(dba)3 (4 mol-% Pd) and
a twofold excess of ligand (8-mol-%) at 80 °C for 7 days,
Scheme 3.
Scheme 4.
Ligands 7b–f provided moderate to excellent conversions
with good to excellent ee values [favouring the (R)-product
10] in the phenylation of 2,3-dihydrofuran (1). Again the
major product formed was the kinetic isomer 10 although
Scheme 3.
The aim of these initial reactions was to screen a variety in a few cases there were significant amounts (up to 18%)
of bases: 1,8 bis(dimethylamino)naphthalene (PS), of thermodynamic product 11 formed (Entries 11 and 12).
1,2,2,6,6-pentamethylpiperidine (PMP), dicyclohexylme- Palladium complexes of ligand 7c, which contained an iso-
thylamine, diisopropylethylamine (DIPEA), triethylamine, propyl-substituted oxazoline, proved the most active and se-
and tributylamine. The results of the base screen, Table 1, lective catalyst system, giving complete conversion and an
show that good to excellent conversions and excellent enantiomeric excess of 92% when PS was used as base (En-
enantioselectivities were achieved in all cases for this initial try 4). In this case only 2% of isomer 11 was formed. The
study. As is consistent with many P,N ligands[9–13] low two phenylglycinol-derived ligands, 7b and 7d, proved only
amounts of the thermodynamic product 11 were observed. slightly less active and selective producing conversions of 95
1890
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Eur. J. Org. Chem. 2009, 1889–1895

HetPHOX Ligands for Intermolecular Asymmetric Heck Coupling
Table 2. Asymmetric phenylation of 2,3-dihydrofuran (1) using pal-
ladium complexes of ligands 7b–f.
Table 3. Asymmetric cyclohexenylation of 2,3-dihydrofuran (1)
using palladium complexes of ligands 7a–f.
Entry
Ligand
Base
Conversion[a] 10/11[b]
ee 10 (%)[c]
(R)
Entry
Ligand Base
Conversion[a]
(%)
3/4[b]
ee 3 (%)[c]
(R)[17]
(%)
1
2
3
4
5
6
7
8
7b
7b
7b
7c
7c
7c
7d
7d
7d
7e
7e
7e
7f
PS
58
95
53
100
100
68
78
92
81
34
36
46
28
32
38
85:15
86:14
87:13
98:2
96:4
95:5
92:8
87:13
95:5
85:15
82:18
83:17
90:10
87:13
88:12
67
88
76
92
92
91
78
69
70
78
81
82
68
71
70
1
2
3
4
5
6
7
8
7a
7a
7a
7b
7b
7b
7c
7c
7c
7d
7d
7d
7e
7e
7e
7f
PS
93
99
77
60
78
72
99
95
94
96
72
96
75
50
58
75
57
38
98:2
94:6
90:10
96:4
92:8
91:9
91:9
93:7
97:3
93:7
90
95
94
68
88
86
93
77
90
24
21
36
80
80
73
74
35
81
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
9
9
10
11
12
13
14
15
10
11
12
13
14
15
16
17
18
99:1
94:6
85:15
80:20
75:25
87:13
70:30
65:35
7f
7f
Cy2NMe
DIPEA
[a] Conversions were determined using achiral GC with tri-n-dec-
ane as internal standard. [b] Product ratios were also determined
using achiral GC. [c] Enantiomeric excesses were determined using
chiral GC [γ-CD-TFA, 30 m, 80–90 °C, 0.3 °C/min, 90–120 °C,
2 °C/min, 10 min, 15 psi, injection temp. 200 °C, detection temp.
220 °C, tR (S)-10 = 33.52 min, tR (R)-10 = 34.78 min].
7f
7f
[a] Conversions were determined using achiral GC with tri-n-dec-
ane as internal standard. [b] Product ratios were also determined
using achiral GC. [c] Enantiomeric excesses were determined using
chiral GC [γ-CD-TFA, 30 m, 80–90 °C, 0.3 °C/min, 90–120 °C,
2 °C/min, 10 min, 15 psi, injection temp. 200 °C, detection temp.
220 °C, tR (S)-3 = 21.82 min, tR (R)-3 = 23.36 min].
and 92% and ee values of 88 and 69%, respectively, when
dicyclohexylmethylamine was used as base (Entries 2 and
8). However, when the substituent on the phosphorus was
changed to p-fluorophenyl, ligands 7e–f, the activity of the
palladium complexes dropped significantly. Conversions be-
tween 28 and 46% were observed although enantio-
selectivities remained high with ligand 7e proving the most
selective giving an ee of 82%.
To conclude, the most active and selective catalyst for the
phenylation of 2,3-dihydrofuran was that formed with li-
gand 7a. Excellent conversions and enantioselectivities of
up to 96% for the predominant kinetic product 10 were
observed.
Excellent enantioselectivities and conversions were ob-
served in many cases for this transformation. Palladium
complexes of ligand 7a proved both the most active and
selective with almost complete conversion and 95% ee
achieved when dicyclohexylmethylamine was used as base
(Entry 2). Indeed, varying the base only had a slightly nega-
tive effect on the ee (Entries 1 and 3). Varying the substitu-
ent at the 4-position on the oxazoline from tert-butyl to
isopropyl had little effect on the activity or selectivity of the
catalysts. Palladium complexes of ligand 7c proved highly
reactive providing conversions from 94–96% while the ac-
companying ee values were also high, ranging from 77–93%
(Entries 7–9). The two phenylglycinol-derived ligands pro-
vided varying results: ligand 7b, which possesses a diphenyl-
phosphane group, promoted conversion of up to 78% and
ee of up to 88% (Entry 5). However, the di-o-tolylphos-
phane analogue (ligand 7d), gave excellent conversions (up
to 96%), although the enantioselectivities were poor, with
36% being the best ee achieved (Entry 12) and variation of
base gave 21–24% ee (Entries 10 and 11).
Asymmetric Cyclohexenylation of 2,3-Dihydrofuran
The efficacy of palladium complexes (4 mol-%) derived
from Pd2(dba)3 (4 mol-% Pd) and a twofold excess of li-
gands 7a–f, once again generated in situ, was tested in the
coupling of cyclohexenyl triflate (2) and 2,3-dihydrofuran
(1), Scheme 5, Table 3.
The regioselectivity of the reaction is excellent with the
favoured kinetic product 3 formed over the thermodynamic
product 4 in ratios of up to 99:1 (Entry 11). However, when
palladium complexes of the p-fluorophenylphosphane-de-
rived ligands 7e–f were employed, appreciable amounts of
the thermodynamic product 4 (up to 35%) were observed
(Entry 18). It is also worth noting here that (as was the case
in the phenylation) overall conversions with these ligands
7e–f were decreased although the ee values remained mod-
erately high (up to 80%, Entry 13).
In summary, similar trends to those observed in the
phenylation of 2,3-dihydrofuran (1) were observed for this
Scheme 5.
Eur. J. Org. Chem. 2009, 1889–1895
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1891

M. O. Fitzpatrick, H. Muller-Bunz, P. J. Guiry
FULL PAPER
transformation. Palladium complexes of all ligands pro- 7–9). When dicyclohexylmethylamine was employed as base
duced predominately product 3. The t-leucinol-derived di- the palladium complex of 7c afforded almost complete con-
o-tolylphosphane ligand 7a proved the most efficacious in version and 88% ee (Entry 8).
inducing excellent levels of enantioselectivity (up to 95%)
The two phenylglycinol-derived ligands 7b and 7d pro-
and conversion (up to 99%) in the cyclohexenylation of 2,3- vided quantitative product in all cases. Moderate regioselec-
dihydrofuran (1).
tivities (from 70:30 to 81:19) were observed with the di-
phenylphosphane ligand 7b (entries 4–6) with an optimal ee
of 66% (Entry 5) whereas the di-o-tolylphosphane-contain-
ing ligand 7d gave near perfect regioselectivities of greater
than 99:1 (Entries 10–12) and an optimal ee of 72% (Entry
12).
The two p-fluorophenylphosphane-derived ligands 7e
and 7f showed similar trends in reactivity and selectivity as
observed in our phenylation and cyclohexenylation studies
as conversions dropped to between 35 and 49% (Entries
13–18). However, ligand 7f induced very high enantio-
selectivities of up to 92% ee when DIPEA was used as base
(Entry 18).
Asymmetric Naphthylation of 2,3-Dihydrofuran
The enantiodifferentiating ability of ligands 7a–f in the
coupling of 2-naphthyl triflate (12) and 2,3-dihydrofuran (1)
was tested, Scheme 6, Table 4.[18]
In all cases, the predominant product formed was the
kinetic product 13 with product ratios of greater than 99:1
obtained in some cases. However, in certain cases, particu-
larly with ligands 7e and 7f, appreciable amounts of prod-
uct 14 were formed (Entries 13–18). Where it was possible
to analyse the thermodynamic product 14, ee values similar
to the kinetic product 13 were observed once again favour-
ing the (R)-enantiomer.[19]
We believe that the selectivity model recently proposed
for related P,N ligands by Hou[20] is followed in our studies.
A palladium dichloride complex of ligand 7a, the ligand
that consistently afforded the highest ee values across the
range of transformations studied, was prepared and crystals
suitable for analysis by X-ray diffraction were grown,
Scheme 7, Figure 2 and Table 5.[21] A syn conformation
Scheme 6.
Table 4. Asymmetric naphthylation of 2,3-dihydrofuran (1) using
palladium complexes of ligands 7a–f.
Entry
Ligand
Base
Conversion[a] 13/14[b]
ee 13 (%)[c]
(R)
(%)
1
2
3
4
5
6
7
8
7a
7a
7a
7b
7b
7b
7c
7c
7c
7d
7d
7d
7e
7e
7e
7f
PS
84
99
98:2
91:9
92
94
94
54
66
66
82
88
88
54
68
72
60
50
38
86
87
92
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
PS
Cy2NMe
DIPEA
94
98:2
100
100
100
88
80:20
70:30
81:19
98:2
99
94:6
9
95
99:1
10
11
12
13
14
15
16
17
18
100
100
100
47
35
34
46
20
49
Ͼ99:1
99:1
98:2
80:20
79:21
85:15
80:20
70:30
81:19
Scheme 7.
7f
7f
[a] Conversions were determined using achiral GC with tri-n-dec-
ane as internal standard. [b] Product ratios were also determined
using achiral GC. [c] Enantiomeric excesses were determined using
chiral HPLC (Chiralcel-OD 0.46ϫ25 cm, hexane/IPA, 99:1, 1 mL/
min, 25 °C), tR (S)-13 = 12.65 min, tR (R)-13 = 16.95 min.
Similar trends to those observed in the phenylation and
cyclohexenylation reactions were observed with this trans-
formation. Palladium complexes of ligand 7a were once
again highly successful promoting excellent conversions of
up to 99% and ee values of up to 94% (Entries 1–3). Varia-
tion of the oxazoline 4-substituent from tert-butyl to iso-
propyl had only a slightly deleterious effect on the conver-
sions and ee values observed (compare Entries 1–3 and Figure 2. X-ray crystal structure of 16.
1892 Eur. J. Org. Chem. 2009, 1889–1895
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HetPHOX Ligands for Intermolecular Asymmetric Heck Coupling
GC-2010 gas chromatograph equipped with a Shimadzu C-R3A
chromatopac integrator and a Chiraldex γ-TFA chiral column
[30 m, 0.25 mm (diam.)ϫ0.25 µm] with helium as carrier gas and
a flame-ionising detector. All reagents were purchased from Sigma–
Aldrich and used as received. Dry solvents were used from a Pure-
sol Grubbs solvent system and degassed by bubbling nitrogen
through them. Anhydrous chlorobenzene was purchased from
Sigma–Aldrich and used without further purification. Oxygen-free
nitrogen was obtained from BOC gases and was used without fur-
ther drying. Crystal data were collected using a Bruker SMART
APEX CCD area detector diffractometer. A full sphere of recipro-
cal space was scanned by phi-omega scans. Pseudo-empirical ab-
sorption correction based on redundant reflections was performed
by the program SADABS (X-1). The structures were solved by di-
rect methods using SHELXS-97 (X-2) and refined by full-matrix
least-squares on F2 for all data using SHELXL-97 (X-3). Hydrogen
atoms were added at calculated positions and refined using a riding
model. Their isotropic temperature factors were fixed to 1.2 times
(1.5 times for methyl groups) the equivalent isotropic displacement
parameters of the carbon atom the H-atom is attached to. Aniso-
tropic thermal displacement parameters were used for all non-hy-
drogen atoms. X-1: G.M. Sheldrick, SADABS, Bruker AXS Inc.,
Madison, WI 53711, 2000.
with the (S)-tert-leucinol-derived ligand is adopted, which
as reported by Hou[20] should lead to (R)-configured prod-
ucts and this is what is seen experimentally in our studies.
Table 5. Selected bond lengths and angles of 16.
Pd–P bond length [Å]
Pd–N bond length [Å]
P–Pd–N bond angle [°]
Pd–Cl (trans to N) [Å]
Pd–Cl (trans to P) [Å]
2.233
2.052
88.6
2.292
2.372
Conclusions
Six HetPHOX ligands have been applied to the intermo-
lecular asymmetric Heck coupling of 2,3-dihydrofuran (1)
with a range of triflates. Excellent selectivity for the (R)-
enantiomer was observed with ee values up to 95%. Palla-
dium complexes of ligand 7a proved the most successful in
all three test reactions. In general, the di-o-tolylphosphane-
derived ligands proved more active than the p-fluorophen-
ylphosphane-derived ligands although enantioselectivities
remained consistently high throughout. Results in this
study are comparable to results obtained previously in this
group with palladium complexes of HetPHOX ligand 6,
where conversions of up to 97% and ee values of up to 95%
were observed, Scheme 1.[9a,9b]
X-2: G. M. Sheldrick, SHELXS-97, University of Göttingen, 1997.
X-3: G. M. Sheldrick, SHELXL-97-2, University of Göttingen,
1997. Racemic samples of 2-phenyl-2,5-dihydrofuran (10),[9] 2-cy-
lohex-1Ј-en-yl-2,5-dihydrofuran (3),[9] and 2-naphthalen-2Ј-yl-2,5-
dihydrofuran (13)[18] were prepared and analysed according to lit-
erature reports. Conversions for asymmetric reactions were mea-
sured using burn ratios with tri-n-decane as internal standard.
General Procedure for the Preparation of Di-ortho-tolylphosphane-
Derived Ligands 7c–d: Thiophene-2-oxazoline (2 mmol) 8 was dis-
solved in diethyl ether (5 mL) and the solution was cooled to
–78 °C. A solution of 2.5  n-butyllithium in hexanes (1.6 mL,
4 mmol) was added dropwise. After addition the reaction was kept
at –78 °C for a further 30 min, then warmed to 0 °C and stirred at
this temperature for 30 min. The reaction was then recooled to
–78 °C and chloro-di-ortho-tolylphosphane (0.99 g, 4 mmol) was
carefully added. The reaction was warmed to room temperature
and stirred overnight. It was then quenched with water (5 mL). The
phases were separated and the aqueous phase was extracted with
diethyl ether (2ϫ5 mL). The organic layers were combined, dried
with sodium sulfate and concentrated in vacuo. Purification was
performed using column chromatography on silica gel with pen-
tane/diethyl ether, 9:1 as the eluent.
Experimental Section
1
General: H NMR (300, 400, 500 and 600 MHz) and 13C (75, 100,
125 and 150 MHz) spectra were recorded with Varian VNMRS
(Varian NMR System) spectrometers at 400, 500 and 600 MHz and
Varian Inova 300 and 500 MHz spectrometers at room temperature
in CDCl3 or [D6]DMSO using tetramethylsilane (TMS) as an in-
ternal standard. Chemical shifts (δ) are given in parts per million
and coupling constants are given in absolute values expressed in
Hertz. Please see below for position numbers on the molecular skel-
etons of compounds 7a–f to aid in the assignment of the NMR
peaks obtained.
(S)-2-[3-(Di-o-tolylphosphanyl)thiophen-2-yl]-4-isopropyl-4,5-dihydro-
oxazole (7c): (0.34 g, 42%) was isolated as a white solid; Rf = 0.3
(pentane/diethyl ether); m.p. 90–93 °C. [α]D = –165 (c = 0.95,
1
3
HRMS was obtained using a Micromass/Waters LCT instrument.
Infra-red spectra were recorded with a Varian Infra-red FT spec-
trometer. Optical rotation values were measured with a Perkin–El-
mer 343 polarimeter at room temperature. Melting points were de-
termined in open capillary tubes with a Gallenkamp melting point
apparatus and are uncorrected. Thin-layer chromatography (TLC)
was carried out on plastic sheets pre-coated with silica gel 60 F254
(Merck). Column-chromatography separations were performed
using Merck Kieselgel 60 (0.040–0.063 mm). Elemental analyses
were performed by Mr. Adam Coburn, School of Chemistry and
Chemical Biology, University College Dublin. HPLC analysis was
performed using a LC 2010A machine equipped with a UV/Vis
detector employing Chiracel® OD and AD columns from Daicel
Chemical Industries. GC analysis was performed using a Shimadzu
CHCl3). H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 5.1 Hz, 1
H, H5Ј), 7.27–7.15 (m, 4 H, PAr2), 7.10–7.00 (m, 2 H, PAr2), 6.82–
6.75 (m, 2 H, PAr2), 6.35 (dd, J = 5.1, JH,P = 0.7 Hz, 1 H, H4Ј),
3
3
4.20 (dd, 3J = 9.38, 7.9 Hz, 1 H, H5a), 4.02–3.95 (m, 1 H, H5b),
3.90 (app. t, 3J = 7.9 Hz, 1 H, H4), 2.46 (d, JH,P = 1.5 Hz, 3 H,
3
Ar-CH3), 2.42 (d, JH,P = 1.5 Hz, 3 H, Ar-CH3), 1.53 [sep., 3J =
3
6.8 Hz, 1 H, CH(CH3)2], 0.69 [app. t, 3J = 6.8 Hz, 6 H, (CH3)2]
ppm. 13C NMR (100 MHz, CDCl3): δ = 158.4 (d, JC,P = 3.5 Hz,
3
C2), 142.6–142.1 (m, 2 C, ArC-CH3), 140.3 (d, JC,P = 26.5 Hz,
2
C2Ј), 136.2 (d, 1JC,P = 10.5 Hz, PC-oTol), 135.5 (d, 1JC,P = 10.5 Hz,
PC-oTol), 133.6 (2 C, C-p-P), 132.7 (d, JC,P = 27 Hz, C4Ј), 132 (d,
2
1JC,P = 23 Hz, C3Ј), 130.0–129.8 (m, 2 C, C-m-P), 128.6 (d, JC,P
=
=
3
6.8 Hz, C-m-P, 2 C), 127.7 (d, JC,P = 2 Hz, C5Ј), 126 (d, JC,P
3
2
12 Hz, C-o-P, 2 C), 73.1 (C4), 70.4 (C5), 32.8 [CH(CH3)2], 21.3 (d,
Eur. J. Org. Chem. 2009, 1889–1895
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1893

M. O. Fitzpatrick, H. Muller-Bunz, P. J. Guiry
FULL PAPER
3JC,P = 10 Hz, Ar-CH3), 21.1 (d, 3JC,P = 10 Hz, Ar-CH3), 18.3 (iPr
(S)-4-tert-Butyl-2-{3-[bis(4-fluorophenyl)phosphanyl]thiophen-2-yl}-
CH3), 18.1 (iPr CH3) ppm. 31P NMR (162 MHz, CDCl3): δ = –30.2 4,5-dihydrooxazole (7f): (0.28 g, 33%) was isolated as a sticky white
ppm. IR (KBr disc): ν = 3056, 2960, 1639 cm–1. HRMS calcd.
solid, Rf = 0.25 (pentane/diethyl ether, 9:1). [α]D = –156.7 (c = 0.52,
˜
1
3
for C24H26NOPS (M + 1) 408.1551; found 408.1539. C24H26NOPS
(407.52): calcd. C 70.74, H 6.43, N 3.44; found C 70.44, H 6.40, N
3.41.
CHCl3). H NMR (600 MHz, CDCl3): δ = 7.31 (d, J = 5.0 Hz, 1
H, H5Ј), 7.30–7.22 (m, 4 H, PAr2H’s), 7.04–6.99 (m, 4 H, PAr2H’s),
6.34 (dd, 3J = 5.0, JH,P = 0.8 Hz, 1 H, H4Ј), 4.17 (dd, 3J = 9.9,
3
8.1 Hz, 1 H, H5a), 4.04 (app. t., J = 8.1 Hz, 1 H, H5b), 3.96 (dd, J
3
= 9.9, 8.1 Hz, 1 H, H4), 0.68 (s, 9 H, 3CH3) ppm. 13C NMR
(S)-2-[3-(Di-o-tolylphosphanyl)thiophen-2-yl]-4-phenyl-4,5-dihydro-
oxazole 7d (0.36 g, 38%) was isolated as a white solid, Rf = 0.33
(pentane/diethyl ether); m.p. 70–72 °C. [α]D = –96 (c = 1.04,
1
(150 MHz, CDCl3): δ = 164.2 (d, JC,F = 12 Hz, F-CAr), 162.5 (d,
1JC,F = 12 Hz, F-CAr), 157.9 (d, JC,P = 4 Hz, C1), 141 (d, JC,P
=
3
2
1
3
26 Hz, C2Ј), 135.9–135.7 (m, 2 C, C-o-F), 135.2–134.9 (m, 2 C, C-
o-F), 133.9–133.7 (m, P-CAr), 133.1 (C4Ј), 133.1–133.0 (m, P-CAr),
CHCl3). H NMR (500 MHz, CDCl3): δ = 7.34 (d, J = 5.1 Hz, 1
H, H5Ј), 7.30–7.15 (m, 7 H, Ar H’s), 7.12–7.06 (m, 2 H, Ar H’s),
6.87–6.81 (m, 4 H, Ar H’s), 6.41 (d, 3J = 5.1 Hz, 1 H, H4Ј), 5.33
(dd, 3J = 9.5, 8.3 Hz, 1 H, H4), 4.62 (dd, 3J = 11, 8.3 Hz, 1 H,
1
131.9 (d, JC,P = 22 Hz, C3Ј), 127.7 (C5Ј), 115.8–115.5 (m, 4 C, C-
o-P), 77.0 (C4), 68.9 (C5), 33.8 (CCH3), 25.6 [3 C, (CH3)3] ppm. 31
P
H5a), 3.98 (t, J = 8.3 Hz, 1 H, H5b), 2.47 (d, JC,P = 1.1 Hz, 3 H,
3
3
NMR (162 MHz, CDCl3): δ = –17 (app t, J = 4.3 Hz) ppm. 19F
NMR (376 MHz, CDCl3): δ = –112.8–112.7 (m), –112.3–112.2 (m)
Ar-CH3), 2.39 (d, JC,P = 1.1 Hz, 3 H, Ar-CH3) ppm. 13C NMR
3
(125 MHz, CDCl3): δ = 160 (d, JC,P = 3.6 Hz, C2), 142.7–142.4
3
ppm. IR (KBr disc): ν = 2957, 2917, 2349 cm–1. HRMS calcd. for
˜
(m, 2 C, ArC-CH3), 142.2 (Ph C), 141.3 (d, JC,P = 27 Hz, C2Ј),
2
C23H22F2NOPS (M
+
1) 430.1206, found 430.1219.
136.1–135.5 (m, 2 C, P-CoTol), 133.7 (2 C, C-p-P), 132.8 (d, 2JC,P
=
C23H22F2NOPS (429.47): calcd. C 64.32, H 5.16, N 3.26; found C
64.14, H 5.17, N 3.16.
17 Hz, C4Ј), 131.5 (d, JC,P = 23 Hz, C3Ј), 130.1–130.0 (m, 2 C, C-
1
3
m-P), 128.7 (m, 2 C, C-o-P), 128.4 (m, 2 C, C-m-P), 128.2 (d, JC,P
General Procedure for Asymmetric Heck Reactions: A solution of
Pd2(dba)3 (2.3 mg, 0.002 mmol) and ligand (0.008 mmol) in toluene
(0.5 mL) was stirred at room temperature under nitrogen until it
was evident by the appearance of a transparent solution that the
complex had formed (ca. 1 h). A solution of the required triflate
16, 19 or 22 (0.13 mmol) and tri-n-decane (13 µL, 0.11 mmol) in
toluene (0.5 mL) was added. This was followed by the addition
of 15 (50 µL, 0.65 mmol) and the relevant base (0.78 mmol). The
reaction vessel was sealed and heated to 80 °C for 7 d with precipi-
tation of Base.HOTF proving the reaction was proceeding. The re-
action was cooled to room temperature and pentane (10 mL) was
added. The resulting suspension was filtered through 2 cm of silica
with further elution using diethyl ether (10 mL). This solution was
the concentrated and the yield calculated using GC (Se-30, 11 psi,
50 °C, 4 min, 15 °C/min, 170 °C, 10 min) by the internal standard
method. The determination of the ee values was carried out as
described above. Absolute configuration was assigned by compari-
son with literature values.[2,14]
= 2 Hz, C5Ј), 127.1 (Ph C), 126.4 (2 C, Ph C), 126.1 (2 C, Ph C),
74.9 (C4), 70.2 (C5), 21.3 (d, 2JC,P = 23 Hz, Ar-CH3), 21.2 (d, 2JC,P
= 23 Hz, Ar-CH3) ppm. 31P NMR (121 MHz, CDCl3): δ = –30.4
ppm. IR (KBr disc): ν = 3057, 2850, 1637 cm–1. HRMS calcd.
˜
for C27H24NOPS (M + 1) 442.1394; found 442.1396. C27H24NOPS
(441.53) calcd. C 73.45, H 5.48, N 3.17; found C 73.10, H 5.51, N
3.13.
General Procedure for the Preparation of Di-p-fluorophenylphos-
phane-Derived Ligands 7e–f: Thiophene-2-oxazoline 8 (2 mmol)
was dissolved in diethyl ether (5 mL) and the solution was cooled
to –78 °C. A solution of 2.5  n-butyllithium in hexanes (1.6 mL,
4 mmol) was added dropwise. After addition the reaction was kept
at –78 °C for a further 30 min, then warmed to 0 °C and stirred at
this temperature for 30 min. The reaction was then recooled to
–78 °C and chloro-di-p-fluorophenylphosphane (0.88 mL, 4 mmol)
was carefully added. The reaction was warmed to room tempera-
ture and stirred overnight. It was then quenched with water (5 mL).
The phases were separated and the aqueous phase was extracted
with diethyl ether (2ϫ5 mL). The organic layers were combined,
dried with sodium sulfate and concentrated in vacuo. Purification
was performed using column chromatography on silica gel with
pentane/diethyl ether, 9:1 as the eluent.
Preparation of the Palladium Dichloride Complex 16 of Ligand 7a:
Ligand 7a (6.6 mg, 0.016 mmol) and bis(acetonitrile)dichloropalla-
dium(II) (3.76 mg, 0.015 mmol) were stirred in CH2Cl2 (1 mL) in
a Schlenk tube for 1 h at room temperature. Diethyl ether (1 mL)
was than added slowly down the side of the Schlenk tube and two
layers were formed. The mixture was then left for crystals to form.
The palladium dichloride complex 16 (7.6 mg, 85%) was isolated
as a yellow solid. [α]D = +202 (c = 0.2, CHCl3). 1H NMR
(S)-2-{3-[Bis(4-fluorophenyl)phosphanyl]thiophen-2-yl}-4-isopropyl-
4,5-dihydrooxazole (7e): (0.31 g, 37%) was isolated as a sticky oil.
RF = 0.28 (pentane/diethyl ether, 9:1). [α]D = –118.8 (c = 2.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (m, 5 H, 4
3
(500 MHz, CDCl3): δ = 7.70 (d, J = 4.9 Hz, 1 H, H5Ј), 7.53–7.44
3
(m, 3 H, PAr2H’s), 7.33 (app dd., J = 6.6, 6.3 Hz, 1 H, PAr2 CH),
3
7.15–7.05 (m, 2 H, PAr2H’s), 6.86 (ddd, 3J = 14.0, 7.8, JH,P
=
3
PAr2H’s, H5Ј), 7.05–6.98 (m, 4 H, PAr2 CH’s), 6.35 (dd, J = 5.1,
0.8 Hz, 1 H, PAr2H), 6.60 (app dd., 3J = 3.9, 3.4 Hz, 1 H, H4Ј),
6.36–6.28 (m, 1 H, Ar H), 5.42 (dd, 3J = 8.9, 4.3 Hz, 1 H, H5a),
4.57–4.59 (m, 2 H, H4,5b), 3.05 (s, 3 H, Ar-CH3), 2.76 (s, 3 H, Ar-
CH3), 0.71 [s, 9 H, (CCH3)3] ppm. 13C NMR (125 MHz, CDCl3):
δ = 159.2 (C2), 145.2 (Ar-C-CH3), 143.4 (Ar-C-CH3), 134.2 (C5Ј),
133.8 (C2Ј), 133.0–132.1 (7 C, C2Ј, C4Ј, C5Ј, 4ϫ PAr2 C), 131.5 (PAr2
C), 126.5 (PAr2 C), 125.9 (PAr2 C), 122.6–122.0 (2 C, 2ϫ C-i-P),
73.4 (C4), 72.0 (C5), 34.4 [C(CH3)3], 25.5 [(CH3)3], 24.4 (Ar-CH3),
24.2 (Ar-CH3) ppm. 31P NMR (162 MHz, CDCl3): δ = 3.9 ppm.
IR (KBr disc): δ = 2912, 1701, 1622 cm–1. ESI-HRMS calcd. for
C25H28Cl2NOPPdS (M + 1 – HCl) 562.0353; found 562.0369.
3JH,P = 1.0 Hz, 1 H, H4Ј), 4.23 (dd, 3J = 9.1, 7.7 Hz, 1 H, H5a),
4.02–3.90 (m, 2 H, H4,5b), 1.61–1.54 [m, 1 H, CH(CH3)2], 0.74 (d,
3
3J = 6.7 Hz, 3 H, CH3), 0.70 (d, J = 6.7 Hz, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3: δ = 164.5 (d, 1JC,F = 12 Hz, F-CAr), 162.0
1
3
(d, JC,F = 12 Hz, F-CAr), 155.6 (d, JC,P = 4 Hz, C2), 141.0 (d,
2JC,P = 26 Hz, C2Ј), 135.9–135.5 (m, 2 C, C-o-F), 135.3–134.9 (m,
2 C, C-o-F), 133.7–133.5 (m, P-CAr), 133.0 (C4Ј), 133.0–132.8 (m,
P-CAr), 131.9 (d, JC,P = 22 Hz, C3Ј), 127.8 (C5Ј), 115.8–115.4 (m,
1
4 C, C-o-P), 73.2 (C4), 70.5 (C5), 32.8 [CH(CH3)2], 18.4 (iPr CH3),
18.1 (iPr CH3). 31P NMR (162 MHz, CDCl3): δ = –17 (app. t, J =
4.3 Hz) ppm. 19F NMR (376 MHz, CDCl3) δ = –112.8–112.7 (m),
–112.3–112.2 (m) ppm. IR (KBr disc): ν = 2960, 2873, 2349 cm–1.
Supporting Information (see footnote on the first page of this arti-
cle): Relevant 1H, 13C, 31P and 19F NMR spectra and GC and
HPLC traces are included.
˜
HRMS calcd. for C22H20F2NOPS (M + 1) 416.1050; found
416.1056.
1894
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1889–1895

HetPHOX Ligands for Intermolecular Asymmetric Heck Coupling
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graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Received: August 1, 2008
Published Online: March 10, 2009
Eur. J. Org. Chem. 2009, 1889–1895
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1895