A new class of readily available and conformationally rigid phosphino-oxazoline ligands for asymmetric catalysis

Article abstract of DOI:10.1016/j.tet.2005.03.111

A new class of conformationally rigid phosphino-oxazoline ligands 3 were synthesized via an efficient ortho-substitution of phenyl glycinol as the key step. Divergent synthetic routes for easy ligand modulation, as well as a procedure suitable for scale-u

Full text of DOI:10.1016/j.tet.2005.03.111

Tetrahedron 61 (2005) 6460–6471
A new class of readily available and conformationally rigid
phosphino-oxazoline ligands for asymmetric catalysis
*
Duan Liu, Qian Dai and Xumu Zhang
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 5 November 2004; revised 28 January 2005; accepted 4 March 2005
Available online 11 May 2005
Abstract—A new class of conformationally rigid phosphino-oxazoline ligands 3 were synthesized via an efficient ortho-substitution of
phenyl glycinol as the key step. Divergent synthetic routes for easy ligand modulation, as well as a procedure suitable for scale-up synthesis,
were established. The catalytic potential of ligands 3 has been demonstrated in the highly enantioselective Ir-catalyzed hydrogenation of
alkenes and Pd-catalyzed allylic substitution and intermolecular Heck reactions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Numerous chiral P,N-ligands have been reported for asym-
metric catalysis by a number of groups during the past
decades.3 However, for most of these ligands, the application
scope is limited regarding both the reaction type and
enantioselectivity. Discovering readily available new P,N-
ligands with high catalytic efficiency in various type of
transformations is still needed. Ligand 1 (PHOX), invented by
Pfaltz/Helmchen/Williams, has proven to be a superior ligand
in a number of transition metal catalyzed reactions.4 Burgess
also obtained very good enantioselectivities in Pd-catalyzed
allylic alkylation reactions and Ir-catalyzed hydrogenation of
several unfunctionalized olefins with ligand 2 (JM-Phos),5
although this ligand is fairly conformationally flexible with an
ethylene linker. Recently, we have designed many confor-
mationally rigid chiral bisphosphine ligands for achieving
high enantioselectivities in asymmetric hydrogenation.6
Bidentate ligand with a more rigid linker reduces the number
of conformations in the transition state of the stereo-
determining step and consequently enhances the enantioface
differentiation.7 On the basis of this consideration, we
envisioned that ligands 3 might be superior to JM-Phos due
to their more rigid 1,2-phenyl linker. Furthermore, ligands 3
are structurally highly resemble the PHOX, it would be of
interest for a comparison with PHOX in their catalytic
behavior. We have previously communicated the divergent
syntheses of a series of ligands 3a–e and their utilities in
Ir-catalyzed highly enantioselective hydrogenation of unfunc-
tionalized alkenes and a,b-unsaturated esters.8 In this article,
we want to give full details of the ligand synthesis including
a new procedure suitable for scale-up ligand preparation.
In addition to previously reported Ir-catalyzed hydrogenation
reactions, evaluations of this new class of P,N-ligands
in Pd-catalyzed asymmetric allylic substitution and inter-
molecular Heck reactions are also discussed.
Discovering metal-catalyzed asymmetric transformations is
among the most attractive frontiers in modern organic
chemistry.1 Since, chiral ligand has a significant influence
on the metal catalyst reactivity and enantioselectivity,
searching ligands with appropriate steric and electronic
natures is one of the major tasks in asymmetric catalysis.
Hetero-bidentate ligands, especially those bearing a phos-
phorus and a nitrogen as the donor atoms (called P,N-
ligands), have become a particularly interesting ligand
family because of the good p-acceptor character of
phosphorus atom and the good s-donor ability of nitrogen
atom, the combination of which can help to stabilize the
intermediate oxidation states during the catalytic cycle.2 In
addition, independent structural alternation on each of the P
and N donor site makes it convenient to build a ligand set for
optimization of a given reaction (Fig. 1).
Figure 1.
Keywords: Ligand; Catalysis; Enantioselectivity.
*
Corresponding author. Tel: C1 814 865 4221; fax: C1 814 865 3292;
e-mail: xumu@chem.psu.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.111

D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
6461
Scheme 1. Divergent synthesis of ligands 3a–e.
2. Results and disccussion
would be based on ortho-substitution of phenyl glycinol.
Thus, developing an efficient method of ortho-substitution
of phenyl glycinol was desirable. Although the a-N,N-
dimethyl amino group is commonly used as an ortho-
directing group for metallation of aromatic rings,11 direct
use of primary amines for such a purpose was much less
explored and was not used to construct chiral ligands.12
Polniaszek et al. prepared (2-chloro or 2,6-dichlorophenyl)
ethylamine from phenylethylamine via ortho-lithiation
2.1. Synthesis of phosphino-oxazoline ligands
The inexpensive enantiopure phenyl glycinol is widely used
as a building block for the preparation of chiral ligands and
auxilaries.4,9 However, ortho-substituted phenyl glycinol
derivatives are rarely used due to the lack of efficient
synthesis.10 One of the most direct ways to make ligands 3

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D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
Scheme 2. Preparation of Ir-complexes with P,N-ligands 3a–e.
directed by the in situ generated N-lithiosilylamine.13 After
modification of their method, we successfully carried out,
for the first time, an ortho-lithiation of silyl-protected
phenyl glycinol. Subsequent reaction with I2 or different
phosphine chlorides efficiently gave rise to (2-iodo or
2-phosphino) phenyl glycinol derivatives, which are novel
and highly modular chiral synthons for ligand synthesis. On
the basis of this method, two different routes were
developed for making ligands 3 (Scheme 1). In route A,
(R)-phenyl glycinol (4) was protected with TBSCl to give an
intermediate 5, which was directly subjected to ortho-
lithiation with 3 equiv of n-BuLi. Subsequent iodination
followed by aqueous workup afforded aryl iodide 6.
Oxazoline formation using literature methods4 gave the
key intermediate 7. Lithium–halogen exchange of 7 with
t-BuLi followed by reaction with Ph2PCl afforded the
desired ligand 3a. Presumably, variation of the phosphine
chloride in the last step would allow a facile tuning of the
phosphine site. In route B, a phosphine chloride, instead of
I2, was used as the electrophile after the ortho-lithiation
step. Subsequent protection of the phosphine with sulfur
followed by aqueous workup generated a phosphine sulfide
8, which could be converted into a series of oxazolines 9
with various R2 substituents by reaction with essentially
unlimited carboxylic acids. Reduction of 9 with Raney-Ni14
afforded ligands 3b–e. The combination of both routes
provides convenient ways of tuning either the phosphine site
or the oxazoline site from intermediates 7 or 8. This is useful
for building a ligand set to optimize a particular reaction.
attempted applying readily available and inexpensive
carboxylic acid chlorides for the amide intermediates
formation. We were pleased to find that this method
provided comparable yields of the oxazolines 9a–c and 9e
(42–47%) after subsequent one-pot mesylation and substi-
tution reactions, considering that the starting material 10 of
only 90% purity was used. 9a–d were then reduced with
Raney-Ni to afford 3a–d in high yields, respectively. Thus,
an overall three step synthesis of ligands 3 was established.
Ligand 3a was then prepared in 3.7 g scale through route C
and this indicates that the new procedure is scalable.
2.2. Ir-Catalyzed asymmetric hydrogenations
Various P,N-ligands have exhibited superior reactivities and
selectivities in Ir-catalyzed asymmetric hydrogenation of
unfunctionalized alkenes.15 To evaluate the catalytic
properties of ligands 3 in asymmetric hydrogenation, their
Ir-complexes 11 were prepared according to a literature
procedure,16 in which a weakly coordinating group BARF
(tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) was used as
the counter ion. These complexes are air-stable and can be
stored in air for months without losing their catalytic
properties (Scheme 2).
Methylstilbene (12a), a typical substrate for Ir-catalyzed
asymmetric hydrogenation of unfunctionallized olefins, was
initially tested with complexes 11a–e under 50 bar of H2
pressure at rt in CH2Cl2. As shown in Table 1, all the
catalysts gave excellent enantioselectivity (97–99% ee),
except for 11b (83% ee). Although the conversions were not
satisfactory with 11a, 11b, and 11c, high conversions were
obtained with 11d and 11e (entries 7 and 8). Pressure and
temperature effects were examined with 11a on the same
substrate (entries 1–4). Increasing the H2 pressure dramati-
cally improved the conversion, while the enantioselectivity
did not change significantly. Performing the reaction at an
elevated temperature also resulted in a great increase in
conversion. Pfaltz et al. reported that the formation of
inactive hydride-bridged Ir-trimers during the catalytic
cycle might be one of the major reasons for the deactivation
of catalyst and isolated a trimeric Ir(PHOX)-hydride
complex after treating the corresponding Ir-complex with
H2 (Fig. 2).15a On the basis of this hypothesis and our
observations, we suppose that: (1) a relatively larger R2
substituent on the oxazoline ring might be beneficial not
only for the enantioselectivity, but also for the reactivity; (2)
more electron-donating ligands might form more reactive
It is noteworthy that relatively expensive reagents EDC and
HOBT were used in the preparation of oxazoline derivatives
7 and 9. This renders a negative cost effect to scale-up
ligand synthesis. In addition, both 6 and 8, which are fairly
polar intermediates, need to be purified by column
chromatography before transformations to 7 and 9,
respectively. This adds another problem to the practicability
of ligand synthesis. Solving these problems is critical for
potential application of ligands 3 in catalysis. Route C in
Scheme 1 outlines a slightly revised procedure for the
synthesis of several ligands of 3. After ortho-substitution of
4 with a diphenylphosphino group and subsequent sulfur
protection, the crude product was treated with HCl (conc.)
in MeOH to afford amino alcohol 10, which can be purified
by conventional washing and extraction procedures under
different pH conditions. Therefore, 10 (90% pure by NMR)
was obtained in 56% yield, which could be directly used for
the next step. In instead of using EDC and HOBT, we

D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
Table 1. Asymmetric hydrogenation of methylstilbene derivatives with 11a
6463
Entry
Substrate
Catalyst
H2 pressure (bar)
Temperature
Conversion (%)b
ee (%)c
1
2
3
4
5
6
7
8
12a
12a
12a
12a
12a
12a
12a
12a
12a
12b
12b
12b
11a
11a
11a
11a
11b
11c
11d
11e
11e
11a
11d
11e
10
50
90
50
50
50
50
50
100
100
100
100
rt
rt
rt
50 8C
rt
rt
rt
rt
rt
31
64
94
98
77
68
98
O99
O99
O99
O99
O99
98
98
97
98
83
97
97
99
98
97
97
90
9
10
11
12
rt
rt
rt
a For a general procedure, see Section 4.
b The conversions were determined by GC.
c The enantiomeric excesses were determined by chiral HPLC (Chiralcel OJ-H) or chiral GC (Chiralselect 1000). The absolute configuration was assigned by
comparison of the retention times of two enantiomers with reported data.15g
Figure 2. Formation of a hydride-bridged Ir-trimer.
catalyst or more stable catalytic species by preventing the
formation of the hydride-bridged Ir-trimer, presumably
through a trans-effect; (3) increasing the H2 pressure might
accelerate the desired catalytic cycle relative to the
formation of the Ir-trimer; (4) a higher reaction temperature
might either accelerate the desired catalytic cycle or
possibly decelerate the formation of the Ir-trimer. These
hypotheses can give us some guidance for further ligand
modification and optimization of reaction conditions for a
particular substrate. Another methylstilbene derivative 12b
Table 2. Asymmetric hydrogenation of b-methylcinnamic esters with 11a
Entry
Substrate
Catalyst
H2 pressure (bar)
Temperature
Conversion (%)b
ee (%)c
1
2
3
4
5
6
7
8
14a RZH
14a RZH
14a RZH
11a
11d
11e
11a
11d
11e
11d
11d
11d
11d
11d
11d
11d
100
100
100
100
100
100
100
100
100
100
100
100
100
rt
rt
rt
rt
rt
rt
50 8C
50 8C
50 8C
50 8C
50 8C
50 8C
50 8C
O99
O99
O99
32
58
94
90
O99
87
O99
O99
96
98
99
91
89
91
85
96
99
98
98
99
94
95
14b RZp-F
14b RZp-F
14b RZp-F
14b RZp-F
14a RZH
14c RZp-Cl
14d RZp-CH3
14e RZm-CH3
14f RZp-OCH3
14g RZp-OCF3
9
10
11
12
13
84
a For a general procedure, see Section 4.
b The conversions were determined by GC.
c The enantiomeric excesses were determined by chiral HPLC (Chiralcel OJ-H) or chiral GC (Chiralselect 1000). The absolute configuration was assigned by
comparison of the retention times of two enantiomers with reported data.15g

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D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
Table 3. Pd-Catalyzed asymmetric allylic alkylation of 16
Entry
Ligand
Temperature
Time (h)
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8b
3a
3b
3c
3d
3a
3a
3d
3a
rt
rt
rt
rt
0 8C
40 8C
40 8C
40 8C
12
12
12
12
12
4
97
93
86
91
85
97
90
73
93(S)
2(S)
93(S)
97(S)
88(S)
98(S)
97(S)
98(S)
4
12
a The ee values were determined by chiral HPLC (Chiral AD column) and the absolute configuration was assigned by comparison of the sign of the optical
rotation with reported data.4c
b 0.1 mol% of [Pd(C3H5)Cl]2 and 0.2 mol% of 3a were used.
was then examined as the substrate with a few of the best
catalysts (11a, 11d, and 11e). Complete conversions and
very high enantioselectivities were obtained with 11a and
11d (entries 10 and 11), while 11e, the most reactive
catalyst, gave a little lower selectivity (entry 12). Thus, the
overall results for asymmetric hydrogenation of biaryl
alkenes with ligands 3 compare favorably with those
obtained with JM-Phos 2 (95% ee for 12a and 93% ee for
12b).15i
anion of dimethyl malonate (17) as a nucleophile was
first tested with ligands 3a–d. Under standard reaction
conditions with [Pd(p-C3H5)Cl]2 as a catalyst precursor,
BSA as a base and KOAc as an additive in CH2Cl2 at rt, all
the catalysts derived from 3a–d provided product 18 in very
good yields (86–97%) and high enantiomeric excesses
(93–97%) (Table 3, entries 1–4), except that the catalyst
derived from ligand 3b showed essentially no enantioselec-
tivity for this transformation. Lowering the reaction
temperature has proven to be effective to improve the
enantioselectivities in some allylic substitutions.19 Thus, we
carried out the same reaction with ligand 3a at 0 8C instead
of rt. Surprisingly, not only the yield was diminished as
expected, but also the enantioselectivity dropped from
93–88% (entry 1 vs entry 5). On the opposite, when we
increased the reaction temperature from rt to 40 8C, product
18 was obtained in the same yield but a higher ee value of
98% (entry 6). While for ligand 3d, little difference was
observed regarding both yields and ee values of 18 at a
higher temperature (entry 7). In general, higher temperature
increases the catalyst reactivity. Thus, this relatively
uncommon property of ligand 3a (higher ee at higher
temperature) prompted us to test the possibility of lowering
the catalyst loading for this reaction, which is generally used
in 1–10 mol%, while maintaining high enantioselectivity.
As shown in entry 8, when the reaction was carried out with
only 0.2 mol% of Pd catalyst at 40 8C for 12 h, product 18
was obtained in 73% yield without any diminishment of
enantioselectivity (98% ee). Such a low catalyst loading
(S/CZ500) is rarely reported for Pd-catalyzed allylic
substitution reactions with P,N-ligands, showing the
superior reactivity of the catalyst of ligand 3a. However,
further decreasing the catalyst loading to 0.1 mol% was not
satisfactory with only 38% yield of 18.
Asymmetric hydrogenation of b-methyl cinnamic esters,
followed by reduction of the ester function, can efficiently
form chiral 3-arylbutanols, which are important inter-
mediates for the synthesis of aromatic sesquiterpenes of
the bisabolane family.17 Few systems have been reported to
be highly selective for this type of substrates.15a,g We were
certainly interested in examining these important hydro-
genation substrates with the air-stable catalysts 11. Methyl-
(E)-b-methyl cinnamate (14a) was initially selected as the
substrate to screen ligands and reaction conditions.
Complete conversions and extremely high enantioselec-
tivities were observed with complexes 11a and 11d under
100 bar at rt (entries 1–3). The ee values are significantly
higher than that with PHOX as a ligand (84% ee). However,
when substrate 14b having a para-fluoro substituent on the
phenyl ring was subjected to hydrogenation, the conversion
was not complete even at elevated temperature. The best
result (96% ee and 90% conversion) for 14b were obtained
with 11d at 50 8C under 100 bar (entry 7). We therefore used
11d as catalyst and these optimized conditions for
hydrogenation of several other aryl-(E)-b-methylcinnamic
esters 14c–g. Excellent ee values (94–99%) were obtained
regardless of the substitution pattern on the phenyl ring,
which were comparable to the best reported to date.15a,g The
reactivities seemed quite substrate dependent. However, no
obvious trend could be observed.
To test the substrate scope and limitations of our new
catalysts in allylation reactions of dimethyl malonate, a
couple of more demanding substrates 19 and 20 were tested
with ligand 3a. Under standard reaction conditions, products
21 and 22 were obtained in good yields but disappointing ee
values (Scheme 3). For the reaction of a cyclic substrate
19,20 only 36% ee was observed. For the reaction of an
unsymmetric substrate 20,21 the product was obtained as a
mixture of two regio-isomers in 4:1 ratio with 20% ee for
2.3. Pd-Catalyzed asymmetric C–C bond formations
2.3.1. Asymmetric allylic substitutions. Our next explora-
tion of ligands 3 in asymmetric catalysis was focused on
Pd-catalyzed allylic substitutions, a extensively studied
reaction due to its synthetic potential.18 A typical substrate
1,3-diphenylpropenyl acetate (16) in conjunction with the

D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
6465
Scheme 3.
the major isomer 2-(1-methyl-3-phenylallyl) malonic acid
dimethyl ester (22a). These results indicate this transform-
ation is highly substrate dependent.
proton sponge, another commonly used base in this
transformation, did not promote the reaction at all (entry
8) (Table 4).
2.3.2. Asymmetric intermolecular Heck reaction. To
further demonstrate the utility of ligand 3, Pd-catalyzed
asymmetric intermolecular Heck reaction22 of 2,3-dihydro-
furan (23) and phenyl triflate (24) was also investigated.
Under typical conditions with Pd2(dba)3$dba as the catalyst
precursor and N,N-diisopropylethylamine as a base in
benzene, ligands 3a and 3d provided product 25 in good
yield and high ee value (entries 1 and 4). While much poorer
yield and ee value of 25 were observed with 3b and 3c
(entries 2 and 3), implying that a bulky substituent R2 on the
oxazoline ring of the ligand is beneficial for both higher
reactivity and enantioselectivity in this reaction. Another
regioisomer 26, generated via C–C double bond migration
in this reaction, was not observed under these conditions.
Changing the catalyst precursor from Pd2(dba)3$dba to
Pd2(dba)3$CHCl3 resulted in a mixture of 25 and 26 (93:7),
though the overall yield and the ee value of the major
product 25 were not affected significantly (entry 1 vs entry
5). Using THF in place of benzene as a solvent improved
both yield and ee value of 25 (entry 1 vs entry 6 and entry 5
vs entry 7). Therefore, 25 was obtained almost quantita-
tively in 94% ee (entry 6), which is comparable to the best
obtained with other P,N-ligands. Somewhat surprisingly,
3. Conclusion
In summary, we have established a novel and efficient
method of ortho-substitution of phenyl glycinol. Using this
strategy as the key step, a new class of conformationally
rigid phosphino-oxazoline ligands 3 were synthesized via
divergent synthetic routes. A procedure that is suitable for
scale-up ligand preparation was also developed, making this
new class of ligands readily available from inexpensive
phenyl glycinol. Their catalytic potential has been demon-
strated in the highly enantioselective Ir-catalyzed hydro-
genation of alkenes and Pd-catalyzed allylic substitution
and intermolecular Heck reactions.
4. Experimental
4.1. General methods
All reactions and manipulations were performed in a
nitrogen-filled glovebox or using standard Schlenk tech-
niques, unless otherwise noted. THF, ether, and benzene
Table 4. Pd-Catalyzed intermolecular Heck reactiona
Entry
Ligand
Pd complex
Base
Solvent
Yield(%)(25:26)b
ee(%)c
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3a
3a
3a
3a
Pd2(dba)3$dba
Pd2(dba)3$dba
Pd2(dba)3$dba
Pd2(dba)3$dba
Pd2(dba)3$CHCl3
Pd2(dba)3$dba
Pd2(dba)3$CHCl3
Pd2(dba)3$dba
iPr2EtN
Benzene
Benzene
Benzene
Benzene
Benzene
THF
87(O99:1)
32(O99:1)
45(O99:1)
91(O99:1)
90 (93:7)
99(O99:1)
93 (93:7)
No reaction
91
88
78
90
90 (86)
94
93 (91)
n/a
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
Proton sponge
THF
Benzene
a For a typical reaction precedure, see Section 4.
b The total isolated yield of 25 and 26. The ratio of 25:26 was determined by GC.
c The enantiomeric excesses of major isomer 25. The data in parentheses were enantiomeric excesses of the minor isomer 26, if detectable. They were all
determined by chiral GC (b-DEX 120 column). The absolution configuration of 25 was assigned by comparison of the sign of the optical rotation with
reported data.23

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D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
were dried and distilled from sodium-benzophenone ketyl
under nitrogen. Methylene chloride was dried over CaH2
under nitrogen. Column chromatography was performed
product 9a was isolated by flash column chromatography
(hexane/EtOAcZ90:10) as a white solid (3.03 g, 65%).
[a]2D0K66.6 (c 1.6, CHCl3); 1H NMR (360 MHz, CDCl3) d
7.85–7.74 (m, 5H), 7.56–7.46 (m, 7H), 7.14 (m, 1H), 6.87
(dd, JZ7.8, 14.7 Hz, 1H), 4.80 (dd, JZ3.6, 8.0 Hz, 1H),
3.60–3.47 (m, 2H), 1.73 (s, 2H), 0.83 (s, 9H), K0.04 (s, 3H),
K0.07 (s, 3H); 13C NMR (75 MHz, CDCl3) d 147.2 (d, JZ
9.0 Hz), 133.5–131.6 (m), 130.2 (d, JZ10.2 Hz), 128.6 (d,
JZ1.2 Hz), 128.4 (d, JZ1.6 Hz), 126.8 (d, JZ12.7 Hz),
66.9, 53.6 (d, JZ7.0 Hz), 25.8, 18.2, K5.3, K5.5; 31P NMR
(145 MHz, CDCl3) d 42.11; HRMS (MCC1) m/z calcd for
C26H35NOSiPS 468.19408, found 468.19092.
1
using sorbent silica gel 60 A (230!450 mesh). H, 13C, and
˚
31P were recorded on Bruker AM-300, AMX-360, and
APX-400 spectrometers. Chemical shifts were reported in
ppm up field to tetramethylsilane with the solvent resonance
as the internal standard. MS spectra were recorded on a
KRATOS mass spectrometer MS 9/50 for LR-ESI and HR-
ESI or LR-APCI and HR-APCI. GC analysis was carried on
Helwett–Packard 6890 gas chromatography using chiral
capillary columns. HPLC analysis was carried on
WatersTM 600 chromatography.
4.1.3. 2-(tert-Butyl-dimethyl-silanyloxy)-(1R)-[2-(dicy-
clohexyl-phosphinothioyl)-phenyl]-ethylamine (8b). To
a suspention of (R)-a-methylbenzylamine 4 (0.343 g,
2.50 mmol, 1 equiv) in 10 mL THF at K78 8C was added
n-BuLi (2.5 M solution in hexane, 2 mL) dropwise. The
resulting purple solution was stirred at K78 8C for 30 min
before a solution of TBSCl (0.791 g, 5.25 mmol) in 5 mL
THF was added at the same temperature. The reaction
mixture was allowed to warm to rt naturally and was stirred
overnight. After removing the THF solvent under reduced
pressure, the residue was redissolved in 15 mL ether. To this
solution at K78 8C was added n-BuLi (2.5 M solution in
hexane, 3 mL) dropwise. The reaction mixture was allowed
to slowly warm to rt during 3 h and was stirred at rt for 1 h.
Dicyclohexylchlorophosphine (0.873 g, 3.75 mmol) was
slowly added at K78 8C and the resulting solution was
allowed to warm to rt and was stirred overnight. Sulfur
(0.240 g, 7.50 mmol) was added at rt and the mixture was
stirred for 1 h before water was added. After usual work up,
the product 9b was isolated by flash column chromato-
graphy (hexane/EtOAcZ90:10) as a yellow oil (0.660 g,
55%). [a]2D0K48.6 (c 1.1, CHCl3); 1H NMR (CDCl3,
360 MHz) d 8.00 (br s, 1H), 7.72–7.69 (m, 1H), 7.52–7.47
(m, 1H), 7.38–7.34 (m, 1H), 5.18 (br s, 1H), 3.82–3.70 (m,
2H), 2.41–2.35 (m, 2H), 2.11–2.08 (m, 2H), 1.87–1.19 (m,
20H), 0.95 (s, 9H), 0.11 (s, 6H); 13C NMR (CDCl3,
90 MHz) d 147.1, 133.5 (m), 130.9, 128.5 (m), 127.0, 126.6,
126.5, 126.3, 68.2, 53.1, 39.8 (d, JZ44.6 Hz), 39.3 (d, JZ
48.9 Hz), 27.0, 26.8, 26.4–26.1 (m), 25.7, 25.5, 18.0, K5.4,
K5.5; 31P NMR (CDCl3, 145 MHz) d 61.43 (br s); HRMS
(MCC1) m/z calcd for C26H46NOSiPS 480.28798, found
480.28543.
4.1.1. 2-(tert-Butyl-dimethyl-silanyloxy)-(1R)-(2-iodo-
phenyl)-ethylamine (6). To a suspention of (R)-a-methyl-
benzylamine 4 (1.37 g, 10.0 mmol) in 40 mL of THF at
K78 8C was added n-BuLi (2.5 M solution in hexane,
8 mL) dropwise. The resulting purple solution was stirred at
K78 8C for 30 min before a solution of TBSCl (tert-
butyldimethylsilyl chloride) (3.17 g, 21.0 mmol) in 20 mL
of THF was added at the same temperature. The reaction
mixture was allowed to warm to rt naturally and was stirred
overnight. After removing the THF solvent under reduced
pressure, the residue was redissolved in 50 mL of ether. To
this solution at K78 8C was added n-BuLi (2.5 M solution
in hexane, 12 mL) dropwise. The reaction mixture was
allowed to slowly warm to rt during 3 h and stirred at rt for
1 h. I2 (5.08 g, 20.0 mmol) was added at K78 8C and the
reaction mixture was allowed to warm to rt and stirred at rt
for 1 h. 10% Na2S2O3 solution (20 mL) was added and the
resulting mixture was stirred vigorously for 10 min. After
usual work up, the product 7 was isolated by flash column
chromatography (hexane/EtOAcZ80:20) as a brown oil
(2.27 g, 60%). [a]D20K49.4 (c 0.82, CHCl3); 1H NMR
(CDCl3, 360 MHz) d 7.79 (dd, JZ1.1, 7.9 Hz, 1H), 7.57
(dd, JZ1.6, 7.8 Hz, 1H), 7.32 (dt, JZ1.0, 7.8 Hz, 1H), 6.93
(dt, JZ1.7, 7.7 Hz, 1H), 4.33 (dd, JZ3.6, 7.9 Hz, 1H), 3.80
(dd, JZ3.6, 9.9 Hz, 1H), 3.42 (dd, JZ7.9, 9.9 Hz, 1H), 1.82
(s, 2H), 0.91 (s, 9H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR
(CDCl3, 90 MHz) d 144.5, 139.5, 129.1, 128.3, 99.9, 67.6,
60.9, 26.1, 18.4, K5.1, K5.2; HRMS (MCC1) m/z calcd
for C14H25NOSiI 378.07447, found 378.07638.
4.1.2. 2-(tert-Butyl-dimethyl-silanyloxy)-(1R)-[2-(di-
phenyl-phosphinothioyl)-phenyl]-ethylamine (8a). To a
suspention of (R)-a-methylbenzylamine
4
(1.37 g,
4.2. General procedure for preparation of oxazolines 7
and 9b–e
10.0 mmol, 1 equiv) in 40 mL THF at K78 8C was added
n-BuLi (2.5 M solution in hexane, 8 mL) dropwise. The
resulting purple solution was stirred at K78 8C for 30 min
before a solution of TBSCl (3.17 g, 21.0 mmol) in 20 mL
THF was added at the same temperature. The reaction
mixture was allowed to warm to rt naturally and stirred
overnight. After removing the THF solvent under reduced
pressure, the residue was redissolved in 50 mL ether. To this
solution at K78 8C was added n-BuLi (2.5 M solution in
hexane, 12 mL) dropwise. The reaction mixture was
allowed to slowly warm to rt during 3 h and stirred at rt
for 1 h. Diphenylchlorophosphine (4.42 g, 20.0 mmol) was
slowly added at K78 8C and the resulting solution was
allowed to warm to rt and stirred overnight. Sulfur (0.960 g,
30.0 mmol) was added at rt and the mixture was stirred for
1 h before water was added. After usual work up, the
A mixture of 8a (437 mg, 0.934 mmol), EDC$HCl (1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride) (357 mg, 1.87 mmol), HOBT$H2O (1-hydroxy-benzo-
triazole
hydrate)
(126 mg,
0.934 mmol),
1-
adamantanecarboxylic acid (168 mg, 0.934 mmol), and
TEA (triethylamine) (0.53 mL, 3.7 mmol) in 10 mL DMF
was stirred at 70 8C overnight. To the cooled mixture was
added 10 mL 2 N HCl solution followed by 20 mL EtOAc.
The resulting mixture was stirred at rt for 30 min and then
the two layers were separated. The aqueous layer was
extracted with EtOAc (10 mL!2). The combined organic
layer was washed with water and brine, dried with Na2SO4.
After removal of the solvent, the resulting residue was
purified by column flash chromatography (hexane/EtOAc/

D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
6467
CH2Cl2Z70:20:10) to give condensation product as a white
solid (336 mg). To a mixture of the above condensation
product (316 mg, 0.613 mmol), DIPEA (N,N-diisopropyl-
ethylamine) (0.73 mL, 2.5 mmol) and TEA (0.51 mL,
6.1 mmol) in 10 mL CH2Cl2, was added methanesulfonyl
chloride (95 mL, 1.2 mmol) at 0 8C. The resulting mixture
was allowed to warm to rt and stirred overnight. After
removal of the solvent and the excessive DIPEA and TEA
under reduced pressure, 9d was isolated by column flash
chromatography (hexane/EtOAcZ85:15) as a white solid
(235 mg, 54% two steps).
131.6 (d, JZ2.9 Hz), 130.5 (d, JZ83.4 Hz), 128.8–128.4
(m), 126.7 (d, JZ12.5 Hz), 75.3, 66.6 (d, JZ7.0 Hz), 39.6,
36.5, 35.3, 27.8; 31P NMR (CDCl3, 145 MHz) d 42.30;
HRMS (MCC1) m/z calcd for C31H33NOPS 498.20150,
found 498.19902.
4.2.5. 2-tert-Butyl-(4R)-[2-(dicyclohexyl-phosphino-
thioyl)-phenyl]-4,5-dihydro-oxazole (9e). This compound
was produced from 8b and dimethyl acetic acid following
the general procedure as a colorless oil (52%). [a]2D0K78.0
1
(c 0.50, CHCl3); H NMR (CDCl3, 300 MHz) d 7.54–7.49
(m, 2H), 7.37–7.31 (m, 2H), 6.53 (m, 1H), 4.94 (t, JZ
9.5 Hz, 1H), 3.92 (t, JZ8.0 Hz, 1H), 2.54 (m, 1H), 2.31 (m,
1H), 2.09 (m, 1H), 1.91–1.13 (m, 19H), 1.34 (s, 9H); 13C
NMR (CDCl3, 75 MHz) d 175.7, 149.2, 131.7 (d, JZ
2.6 Hz), 131.3, 128.6 (d, JZ9.0 Hz), 126.3 (d, JZ10.5 Hz),
125.0 (d, JZ63.8 Hz), 76.2, 66.5 (d, JZ3.7 Hz), 41.2 (d,
JZ48.2 Hz), 36.5 (d, JZ51.2 Hz), 33.3, 27.9, 26.6–25.2
(m); 31P NMR (CDCl3, 145 MHz) d 57.27 (br); HRMS
(MCC1) m/z calcd for C25H39NOPS 432.24845, found
432.24619.
4.2.1. 2-tert-Butyl-(4R)-(2-iodo-phenyl)-4,5-dihydro-oxa-
zole (7). This compound was produced from 6 and dimethyl
acetic acid following the general procedure as a colorless oil
(60%). [a]2D0K87.5 (c 1.3, CHCl3); 1H NMR (CDCl3,
360 MHz) d 7.79 (dd, JZ1.2, 7.9 Hz, 1H), 7.32 (dt, JZ1.2,
7.7 Hz, 1H), 7.20 (dd, JZ1.7, 7.8 Hz, 1H), 6.94 (dt, JZ1.8,
7.6 Hz, 1H), 5.37 (dd, JZ7.8, 10.3 Hz, 1H), 4.76 (dd, JZ
8.5, 10.3 Hz, 1H), 3.85 (t, JZ8.1 Hz, 1H), 1.32 (s, 9H); 13C
NMR (CDCl3, 90 MHz) d 176.3, 146.0, 139.2, 129.1 (d, JZ
22.0 Hz), 128.6, 127.4, 98.3, 74.3, 72.8, 33.6, 28.1; HRMS
(MCC1) m/z calcd for C13H17NOI 330.03494, found
330.03633.
4.2.6. 2-tert-Butyl-(4R)-(2-diphenylphosphanyl-phenyl)-
4,5-dihydro-oxazole (3a). To a solution of 7 (94 mg,
0.286 mmol) in 4 mL ether was added t-BuLi (1.7 M
solution, 0.34 mL) at K78 8C. The reaction mixture was
stirred at K78 8C for 30 min before diphenylchloropho-
sphine (2.43 g, 11.0 mmol) was added slowly. The solution
was allowed to warm to rt and was stirred overnight. Water
was added. The aqueous layer was separated and extracted
with CH2Cl2. The combined organic layers were dried with
Na2SO4 and concentrated. The residue was purified by flash
column chromatography to give 3a as a white solid (40%).
[a]2D0K50.9 (c 2.0, CHCl3); 1H NMR (CD2Cl2, 360 MHz) d
7.40–7.26 (m, 12H), 7.19 (dt, JZ1.5, 7.5 Hz, 1H), 6.93–
6.89 (m, 1H), 5.82–5.75 (m, 1H), 4.24 (dd, JZ8.4, 10.2 Hz,
1H), 3.64 (dt, JZ0.5, 8.4 Hz, 1H), 1.28 (s, 9H); 13C NMR
(CD2Cl2, 90 MHz) d 175.8, 148.4 (d, JZ24.0 Hz), 136.9 (d,
JZ10.2 Hz), 135.4–134.2 (m), 130.0–129.3 (m), 127.9 (br
s), 126.8 (br s), 75.4 (d, JZ4.4 Hz), 67.5 (m), 33.9, 28.3; 31P
NMR (CD2Cl2, 145 MHz) d K14.97; HRMS (MCC1) m/z
calcd for C25H27NOP 388.18248, found 388.17930.
4.2.2. 2-Benzhydryl-(4R)-[2-(diphenyl-phosphinothioyl)-
phenyl]-4,5-dihydro-oxazole (9b). This compound was
produced from 8a and diphenyl acetic acid following the
general procedure as a white solid (52%). [a]2D0C35.4 (c
0.65, CHCl3); 1H NMR (CDCl3, 360 MHz) d 7.83–7.71 (m,
4H), 7.56–7.45 (m, 7H), 7.41–7.24 (m, 11H), 7.16 (m, 1H),
6.87 (dd, JZ7.7, 14.8 Hz, 1H), 5.91 (t, JZ9.1 Hz, 1H), 5.26
(s, 1H), 4.72 (t, JZ9.6 Hz, 1H), 3.96 (t, JZ8.5 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) d 169.4, 146.8 (d, JZ8.5 Hz),
139.2 (d, JZ8.7 Hz), 133.1–130.1 (m), 129.0–128.5 (m),
127.2 (d, JZ4.2 Hz), 127.0 (d, JZ12.5 Hz), 76.3, 66.8 (d,
JZ7.2 Hz), 51.2; 31P NMR (CDCl3, 145 MHz) d 42.38;
HRMS (MCC1) m/z calcd for C34H29NOPS 530.17020,
found 530.17347.
4.2.3. 2-(3,5-Di-tert-butyl-phenyl)-(4R)-[2-(diphenyl-
phosphinothioyl)-phenyl]-4,5-dihydro-oxazole (9c). This
compound was produced from 8a and 3,5-di-tert-butylben-
zoic acid following the general procedure as a white solid
(50%). [a]2D0C34.0 (c 1.1, CHCl3); 1H NMR (CDCl3,
360 MHz) d 7.92–7.76 (m, 6H), 7.57–7.49 (m, 9H), 7.19 (t,
JZ7.4 Hz, 1H), 6.95 (dd, JZ7.7, 14.8 Hz, 1H), 6.03 (t, JZ
8.9 Hz, 1H), 4.72 (t, JZ9.7 Hz, 1H), 4.07 (t, JZ8.5 Hz,
1H), 1.35 (s, 18H); 13C NMR (CDCl3, 90 MHz) d 166.6,
151.1, 147.5 (d, JZ8.5 Hz), 133.4–131.6 (m), 130.7,
129.6–129.0 (m), 127.1, 125.9, 123.0, 75.9, 68.0, 35.2,
31.6; 31P NMR (CDCl3, 145 MHz) d 42.30; HRMS (MCC
1) m/z calcd for C35H39NOPS 552.24845, found 552.24701.
4.3. General procedure for preparation of ligands 3b–e
To a N2-flushed Schlenk flask was loaded about 1 g of
Raney-Ni 2800 slurry. The Raney-Ni was washed sequen-
tially with methanol (3 mL!3), ether (3 mL!3), and dried
degassed CH3CN (3 mL!3). To this flask was then
transferred a solution of 9d (190 mg, 0.382 mmol) in
6 mL CH3CN. The resulting mixture was stirred under N2
at rt for 1 d. The mixture was filtered under N2. The Raney-
Ni solid was washed with CH3CN (3 mL!3). The
combined filtrate was concentrated under reduced pressure
and the residue was passed through a short silica gel plug
under N2 to give pure product 3d as a white solid (91%).
4.2.4. 2-Adamantan-1-yl-(4R)-[2-(diphenyl-phosphino-
thioyl)-phenyl]-4,5-dihydro-oxazole (9d). [a]2D0C9.35 (c
0.77, CHCl3); 1H NMR (CDCl3, 360 MHz) d 7.83–7.66 (m,
4H), 7.52–7.40 (m, 7H), 7.32 (dd, JZ4.8, 6.8 Hz, 1H),
7.12 (m, 1H), 6.85 (ddd, JZ0.7, 7.8, 14.8 Hz, 1H), 5.74 (t,
JZ9.0 Hz, 1H), 4.49 (dd, JZ9.0, 9.9 Hz, 1H), 3.78
(t, JZ8.4 Hz, 1H), 1.98 (s, 3H), 1.91 (s, 6H), 1.69 (s, 6H);
13C NMR (CDCl3, 75 MHz) d 175.5, 147.4 (d, JZ8.5 Hz),
133.0 (d, JZ5.5 Hz), 132.7–132.3 (m), 131.9–131.7 (m),
4.3.1. 2-Benzhydryl-(4R)-(2-diphenylphosphanyl-phen-
yl)-4,5-dihydro-oxazole (3b). This compound was pro-
duced from 9b following the general procedure as a white
solid (94%). [a]D20K67.9 (c 0.66, CHCl3); 1H NMR
(CD2Cl2, 360 MHz) d 7.44–7.21 (m, 23H), 6.98–6.95 (m,
1H), 5.97 (dt, JZ5.6, 9.4 Hz, 1H), 5.24 (s, 1H), 4.38 (dd,

6468
D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
JZ8.6, 10.3 Hz), 3.74 (t, JZ8.6 Hz); 13C NMR (CD2Cl2,
90 MHz) d 169.3, 147.9 (d, JZ24.4 Hz), 140.4 (d, JZ
3.6 Hz), 136.7 (d, JZ10.3 Hz), 135.5–134.0 (m), 130.1–
126.9 (m), 75.6 (d, JZ5.3 Hz), 68.0, 51.7; 31P NMR
(CD2Cl2, 145 MHz) d K15.10; HRMS (MCC1) m/z calcd
for C34H29NOP 498.19813, found 498.19772.
in 200 mL of ether. To this solution at K78 8C was added
n-BuLi (2.5 M solution in hexane, 48 mL) dropwise. The
reaction mixture was allowed to slowly warm to rt during
3 h and stirred at rt for 1 h. Diphenylchlorophosphine
(17.7 g, 0.08 mol) was slowly added at K78 8C and the
resulting solution was allowed to warm to rt and stirred
overnight. Sulfur (3.84 g, 0.12 mol) was added at rt and the
mixture was stirred for 1 h. The solvent was removed and
the residue was dissolved in 100 mL of methanol followed
by addition of 20 mL of conc. HCl. The mixture was heated
at 50 8C for 4 h. After removal of methanol the yellow solid
residue was redissolved in 150 mL of water and washed
with ether (80 mL!3). The aqueous layer was then
basicified by adding 60 mL of 4 N NaOH solution. The
precipitate was dissolved in CH2Cl2 and extracted from the
aqueous layer. After removal of the solvent, the crude
product 10 was obtained as an offwhite solid (7.88 g, 56%,
4.3.2. 2-(3,5-Di-tert-butyl-phenyl)-(4R)-(2-diphenylpho-
sphanyl-phenyl)-4,5-dihydro-oxazole (3c). This com-
pound was produced from 9c following the general
procedure as a white solid (95%). [a]2D0K48.3 (c 0.87,
CHCl3); 1H NMR (CD2Cl2, 360 MHz) d 7.95 (d, JZ1.8 Hz,
2H), 7.67 (t, JZ1.8 Hz, 1H), 7.50–7.47 (m, 1H), 7.43–7.34
(m, 1H), 7.24 (dt, JZ1.3, 7.5 Hz, 1H), 7.01 (ddd, JZ1.1,
4.4, 7.6 Hz, 1H), 6.11 (ddd, JZ5.9, 8.7, 14.5 Hz, 1H), 4.48
(dd, JZ8.4, 10.2 Hz, 1H), 3.90 (t, JZ8.5 Hz, 1H), 1.42 (s,
18H); 13C NMR (CD2Cl2, 90 MHz) d 166.1, 151.7, 148.2 (d,
JZ23.9 Hz), 137.0 (m), 135.6–133.9 (m), 130.2–126.3 (m),
123.3, 75.4 (d, JZ4.2 Hz), 68.6, 35.5, 31.9; 31P NMR
(CD2Cl2, 145 MHz) d K14.83; HRMS (MCC1) m/z calcd
for C35H39NOP 520.27638, found 520.27501.
1
about 90% purity shown by NMR); H NMR (360 MHz,
CDCl3) d 7.68–7.72 (m, 4H), 7.41–7.49 (m, 8H), 7.10 (m,
1H), 6.81 (m, 1H), 4.69 (dd, JZ1.3, 6.6 Hz, 1H), 3.48 (d,
JZ6.9 Hz, 2H), 1.88 (s, 2H); 13C NMR (75 MHz, CDCl3) d
132.3–132.9 (m), 129.0–129.3 (m), 127.4 (d, JZ13.1 Hz),
67.1, 53.9; 31P NMR (145 MHz, CDCl3) d 42.4.
4.3.3. 2-Adamantan-1-yl-(4R)-(2-diphenylphosphanyl-
phenyl)-4,5-dihydro-oxazole (3d). [a]2D0K66.1 (c 0.75,
CHCl3); 1H NMR (CDCl3, 300 MHz) d 7.31–7.05 (m, 12H),
6.79 (ddd, JZ0.9, 4.4, 7.8 Hz, 1H), 5.74 (ddd, JZ5.1, 8.3,
13.4 Hz, 1H), 4.15 (dd, JZ8.5, 10.3 Hz, 1H), 3.53 (t, JZ
8.3 Hz, 1H), 1.96 (s, 3H), 1.90 (s, 6H), 1.66 (s, 6H); 13C
NMR (CDCl3, 75 MHz) d 175.2, 147.8 (d, JZ24.3 Hz),
136.4–136.1 (m), 134.7, 134.4, 134.0, 133.7, 133.5, 129.7,
129.2, 128.9, 128.8, 128.7, 127.6, 126.1 (d, JZ5.7 Hz), 74.6
(d, JZ5.0 Hz), 66.8 (d, JZ24.2 Hz), 39.9, 36.8, 35.6, 28.2;
31P NMR (CDCl3, 145 MHz) d K15.14; HRMS (MCC1)
m/z calcd for C31H33NOP 466.22943, found 466.22620.
4.4.2. 2-tert-Butyl-(4R)-[2-(diphenyl-phosphinothioyl)-
phenyl]-4,5-dihydro-oxazole (9a). A mixture of 10
(7.88 g, 22.3 mmol), trimethyl acetyl chloride (3.0 mL,
24.5 mmol), and TEA (13.0 mL, 89.2 mmol) in 200 mL of
CH2Cl2 was stirred at 0 8C for 2 h. 10 equiv of TEA
(32.5 mL, 0.223 mol), 4 equiv of DIPEA (15.6 mL,
89.2 mmol) and 2 equiv of methanesulfonyl chloride
(3.45 mL, 44.6 mmol) was added sequentially at the same
temperature. The resulting mixture was allowed to warm to
rt during 2 h and stirred for another 24 h. TLC showed the
completion of the reaction. After removal of the solvent and
the excessive TEA and DIPEA under reduced pressure, 9a
was isolated by column flash chromatography (hexane/
EtOAcZ85:15) as a white solid (4.4 g, 47% yield).
4.3.4. 2-tert-Butyl-(4R)-(2-dicyclohexylphosphanyl-
phenyl)-4,5-dihydro-oxazole (3e). This compound was
produced from 9e following the general procedure as a
colorless oil (90%). [a]2D0K70.9 (c 0.53, CHCl3); 1H NMR
(CD2Cl2, 360 MHz) d 7.49–7.47 (m, 1H), 7.37–7.24 (m,
3H), 6.02 (ddd, JZ5.7, 8.4, 14.1 Hz, 1H), 4.76 (dd, JZ8.3,
10.3 Hz, 1H), 3.79 (t, JZ8.3 Hz, 1H), 2.00–0.85 (m, 31H);
13C NMR (CD2Cl2, 75 MHz) d 175.2, 151.0 (d, JZ
25.3 Hz), 133.2 (d, JZ20.8 Hz), 133.1 (d, JZ3.4 Hz),
129.5, 126.7, 126.2 (d, JZ6.3 Hz), 75.9 (d, JZ7.2 Hz), 67.9
(d, JZ25.9 Hz), 35.2 (d, JZ12.9 Hz), 34.0 (d, JZ11.7 Hz),
33.7, 31.3–30.9 (m), 30.0 (d, JZ10.2 Hz), 29.2 (d, JZ
6.2 Hz), 28.1, 27.7–27.3 (m), 26.8 (d, JZ3.9 Hz); 31P NMR
(CD2Cl2, 145 MHz) d K14.46; HRMS (MCC1) m/z calcd
for C25H39NOP 400.27638, found 400.27262.
4.4.3. 2-tert-Butyl-(4R)-(2-diphenylphosphanyl-phenyl)-
4,5-dihydro-oxazole (3a). To a N2-flushed Schlenk flask
was loaded about 20 g of Raney-Ni 2800 slurry. The Raney-
Ni was washed sequentially with methanol (30 mL!3),
ether (30 mL!3), and dried degassed CH3CN (30 mL!3).
To this flask was then transferred a solution of 9a (4.4 g,
10.5 mmol) in CH3CN (100 mL). The resulting mixture was
stirred under N2 at rt for 1 d. The reaction mixture was
filtered under N2 and washed with CH3CN (50 mL!3). The
combined filtrate was concentrated under reduced pressure
and the residue was passed through a short silica gel plug
under N2 to give 3a as a white solid (3.66 g, 90% yield).
4.4. Multigram scale synthesis of ligand 3a via route C
4.5. General procedure for preparation of complex 11a–e
4.4.1. 2-Hydroxyl-(1R)-[2-(diphenyl-phosphinothioyl)-
phenyl]-ethylamine (10). To a suspention of (R)-a-
methylbenzylamine 4 (5.46 g, 0.04 mol) in 150 mL of
THF at K78 8C was added n-BuLi (2.5 M solution in
hexane, 32 mL) dropwise. The resulting purple solution was
stirred at K78 8C for 30 min before a solution of TBSCl
(12.7 g, 0.084 mol) in 80 mL of THF was added at the same
temperature. The reaction mixture was allowed to warm to
rt naturally and stirred overnight. After removing the THF
solvent under reduced pressure, the residue was redissolved
To a Schlenk tube was added 3d (76 mg, 0.163 mmol),
[Ir(COD)Cl]2 (54.8 mg, 0.0816 mmol) and dried CH2Cl2
(3 mL). The resulting red solution was heated under N2 at
50 8C for 1 h. TLC indicated that 3d was consumed
completely. After the solution was cooled to rt, Na[BARF]
(217 mg, 0.245 mmol) was added followed by H2O (3 mL).
The resulting mixture was stirred vigorously for 30 min.
The two layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 mL!2). The combined organic

D. Liu et al. / Tetrahedron 61 (2005) 6460–6471
6469
layer was dried with Na2SO4 and evaporated. The residue
was purified by flash column chromatography (hexanes/
CH2Cl2Z1:1) to give 11d as an orange solid (57%).
(anion) m/z calcd for C32H12BF24 863.06434, found
863.07146.
4.6. General procedure for enantioselective
hydrogenations
4.5.1. Compound 11a. This compound was produced from
2a following the general procedure as a yellow solid (52%);
1H NMR (CDCl3, 360 MHz) d 7.74 (s, 8H), 7.60–6.54 (m,
8H), 7.46–7.31 (m, 6H), 7.25–7.17 (m, 3H), 7.05 (ddd, JZ
1.2, 7.9, 10.9 Hz, 1H), 5.81 (dd, JZ3.7, 9.7 Hz, 1H), 4.96
(m, 1H), 4.94 (dd, JZ4.2, 9.4 Hz, 1H), 4.81 (t, JZ9.7 Hz,
1H), 4.26 (m, 1H), 4.16 (m, 1H), 3.22 (m, 1H), 2.50–2.33
(m, 2H), 2.24 (m, 1H), 2.13–2.00 (m, 2H), 1.71 (m, 1H),
1.55 (m, 1H), 0.93 (s, 9H); 31P NMR (CDCl3, 145 MHz) d
15.55; HRMS (cation) m/z calcd for C33H38NOPIr
688.23150, found 688.22827; HRMS (anion) m/z calcd for
C32H12BF24 863.06434, found 863.06754.
a-Methylstilbene (25.9 mg, 0.133 mmol) and Ir-complex
11d (1 mg, 0.614 mmol) was dissolved in CH2CH2
(2 mL). This solution was then transferred into an
autoclave. The hydrogenation was performed at rt under
50 bar of H2 (or under reaction conditions described in
Tables 1 and 2) for 12 h. After carefully releasing the
hydrogen, the reaction mixture was directly passed
through a short silica gel plug and flashed with ether.
After evaporation, the residue was directly used for
chiral HPLC analysis to measure the enantiomeric
excess and for GC to measure the conversion.
4.5.2. Compound 11b. This compound was produced from
2b following the general procedure as a red solid (50%); 1H
NMR (CD2Cl2, 360 MHz) d 7.77–6.78 (m, 34H), 5.93 (d,
JZ7.2 Hz, 2H), 5.76 (dd, JZ5.6, 9.7 Hz, 1H), 5.20–5.11
(m, 2H), 4.90–4.80 (m, 2H), 3.95 (m, 1H), 3.80 (m, 1H),
3.00 (m, 1H), 2.53–2.45 (m, 2H), 2.35–2.19 (m, 2H), 1.90
(m, 1H), 1.75 (m, 1H), 1.52–1.34 (m, 2H); 31P NMR
(CD2Cl2, 145 MHz) d 16.33; HRMS (cation) m/z calcd for
C42H40NOPIr 798.24715, found 798.24948; HRMS (anion)
m/z calcd for C32H12BF24 863.06434, found 863.07128.
4.7. General procedure for enantioselective allylic
substitutions
In a schlenk tube, allylpalladium chloride dimer (4.57 mg,
0.0125 mmol), ligand 3a (9.68 mg, 0.025 mmol) and solid
potassium acetate (4.9 mg, 0.05 mmol) were dissolved in
2 mL of CH2Cl2. The solution was stirred at rt for 15 min.
Dimethyl malonate (0.172 mL, 1.5 mmol) and N,O-bis(tri-
methylsilyl) acetamide (0.37 mL, 1.5 mmol) and a solution
of rac-(E)-1-acetoxy-1,3-diphenyl-2-propene (17) (126 mg,
0.5 mmol) in 1 mL of CH2Cl2 were added subsequently.
The reaction mixture was stirred at rt for 12 h. The solvent
was removed under vacuum and the residue was passed
through a short silica gel column (EtOAc/hexanesZ1:9) to
give product 18.
4.5.3. Compound 11c. This compound was produced from
2c following the general procedure as an orange solid
(63%); H NMR (CD2Cl2, 360 MHz) d 7.79 (m, 2H), 7.73
1
(s, 9H), 7.62 (m, 1H), 7.56 (br s, 4H), 7.50–7.36 (m, 12H),
7.22 (m, 1H), 6.04 (dd, JZ4.2, 9.1 Hz, 1H), 5.21 (dd, JZ
4.4, 9.5 Hz, 1H), 5.07 (t, JZ9.4 Hz, 1H), 5.04 (m, 1H), 4.08
(m, 1H), 3.87 (m, 1H), 3.52 (m, 1H), 2.54–2.39 (m, 2H),
2.30 (m, 1H), 2.22–2.14 (m, 2H), 1.90 (m, 1H), 1.70–1.64
(m, 2H), 1.31 (s, 18H); 31P NMR (CD2Cl2, 145 MHz) d
12.47; HRMS (cation) m/z calcd for C43H50NOPIr
820.32540, found 820.32552; HRMS (anion) m/z calcd for
C32H12BF24 863.06434, found 863.06159.
4.7.1. 2-(1,3-Diphenyl-allyl) malonic acid dimethyl ester
(18). H NMR (360 MHz, CDCl3) d 7.15–7.29 (m, 10H),
1
6.45 (d, JZ15.8 Hz, 1H), 6.31 (dd, JZ15.7, 8.5 Hz, 1H),
4.24 (dd, JZ10.3, 8.8 Hz, 1H), 3.93 (d, JZ10.9 Hz, 1H),
3.70 (s, 3H), 3.65 (s, 3H). The ee of product was analyzed
via chiral HPLC (AD column; eluting with 90:10 hexanes/
2-propanol).
4.5.4. Compound 11d. 1H NMR (CD2Cl2, 360 MHz) d 7.75
(s, 8H), 7.66–7.58 (m, 8H), 7.43–7.38 (m, 5H), 7.35–7.26
(m, 4H), 7.05 (m, 1H), 5.84 (dd, JZ3.5, 9.8 Hz, 1H), 5.05
(m, 1H), 5.01 (dd, JZ4.0, 9.4 Hz, 1H), 4.84 (t, JZ9.6 Hz,
1H), 4.35 (m, 1H), 4.28 (m, 1H), 3.23 (m, 1H), 2.52–2.36
(m, 3H), 2.25 (m, 1H), 2.16–2.01 (m, 2H), 1.84–1.74 (m,
7H), 1.64–1.52 (m, 4H), 1.41–1.36 (m, 6H); 31P NMR
(CD2Cl2, 145 MHz) d 15.89; HRMS (cation) m/z calcd for
C39H44NOPIr 766.27845, found 766.27163; HRMS (anion)
m/z calcd for C32H12BF24 863.06434, found 863.07188.
4.7.2. 2-Cyclohex-2-enylmalonic acid dimethyl ester (21).
1H NMR (360 MHz) d 5.68–5.71 (m, 1H), 5.43–5.46 (m,
1H), 3.66 (s, 6H), 3.21 (d, JZ9.5 Hz, 1H), 2.82–2.84 (m,
3H), 1.27–1.92 (m, 6H). The ee of product was analyzed via
chiral GC (Supelco Chiral Select 1000 column).
4.7.3. Compounds 22a and 22b. 1H NMR showed an
inseparable mixture of 22a and 22b (80:20) was obtained.
2-(1-Methyl-3-phenylallyl) malonic acid dimethyl ester
4.5.5. Compound 11e. This compound was produced from
2e following the general procedure as an orange solid
(58%); 1H NMR (CD2Cl2, 360 MHz) d 7.74 (m, 8H), 7.65–
7.51 (m, 7H), 7.39 (m, 1H), 5.67 (d, JZ7.2 Hz, 1H), 5.28
(dd, JZ1.2, 10.2 Hz, 1H), 5.06 (m, 1H), 4.92 (m, 1H), 4.43
(dd, JZ7.5, 10.2 Hz, 1H), 3.76 (m, 1H), 3.56 (m, 1H), 2.97
(m, 1H), 2.60–2.51 (m, 2H), 2.39–2.10 (m, 5H), 1.94–1.63
(m, 12H), 1.52–1.32 (m, 19H); 31P NMR (CD2Cl2,
145 MHz) d 9.00; HRMS (cation) m/z calcd for
C33H50NOPIr 700.32540, found 700.32349; HRMS
1
(22a); H NMR (360 MHz, CDCl3) d 7.11–7.21 (m, 5H),
6.31 (d, JZ15.8 Hz, 1H), 5.98 (dd, JZ15.8, 8.5 Hz, 1H),
3.60 (s, 3H), 3.53 (s, 3H), 3.25 (d, JZ8.9 Hz, 1H), 2.97–
1
3.00 (m, 1H), 1.05 (d, JZ6.8 Hz, 3H); H NMR for 2-(1-
phenyl-but-2-enyl) malonic acid dimethyl ester (22b) can be
found in literature.21a The ee of 22a was analyzed via
chiral HPLC (OJ-H column; eluting with 95:5 hexanes/
2-propanol).

6470
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11. (a) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.;
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¨
(b) Almena Perea, J. J.; Borner, A.; Knochel, P. Tetrahedron
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2-Phenyl-2,5-dihydrofuran (25). In a schlenk tube,
[Pd2(dba)3$dba] (8.61 mg, 0.015 mmol), ligand 3a
(11.61 mg, 0.03 mmol) were dissolved in 3 mL of THF.
The solution was stirred at 70 8C for 15 min. Phenyl
triflate (24) (80.7 mL, 0.5 mmol), 2,3-dihydrofuran (23)
(0.19 mL, 2.5 mmol) and N,N-diisopropylethylamine
(0.26 mL, 1.5 mmol) were added subsequently. The
reaction mixture was stirred at 70 8C for 3 d. The solvent
was removed under reduced pressure and the residue was
purified by a silica gel column (EtOAc/hexanesZ1:9) to
12. Burns, S. A.; Corriu, R. J. P.; Huynh, V.; Moreau, J. J. E.
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14. Gilbertson, S. R.; Fu, Z. Org. Lett. 2001, 3, 161.
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(b) Kallstrom, K.; Hedberg, C.; Brandt, P.; Bayer, A.;
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1
afford 25; H NMR (360 MHz, CDCl3) d 7.20–7.25 (m,
5H), 5.92 (m, 1H), 5.79 (m, 1H), 5.70 (m, 1H), 4.76 (m,
1H), 4.69 (m, 1H). The product was analyzed via chiral
GC (Supelco b-DEX 120 column).
Acknowledgements
This work was supported by the National Institute of Health.
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