Effective chiral ferrocenyl phosphine-thioether ligands in enantioselective palladium-catalyzed allylic alkylations

Article abstract of DOI:10.1002/adsc.200900086

Chiral ferrocene-derived phosphine-thioether mixed donor ligands supported by heterocycles effected the palladium-catalyzed enantioselective allylic alkylations with excellent yields and enantioselectivities (up to 96% ee). With cyclic and unsymmetrical a

Full text of DOI:10.1002/adsc.200900086

FULL PAPERS
DOI: 10.1002/adsc.200900086
Effective Chiral Ferrocenyl Phosphine-Thioether Ligands in
Enantioselective Palladium-Catalyzed Allylic Alkylations
Hong Yee Cheung,a Wing-Yiu Yu,a Terry T. L. Au-Yeung,a Zhongyuan Zhou,a
and Albert S. C. Chana,*
a
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis,
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Peopleꢀs
Republic of China
Fax : (+852)-23-649-932; e-mail: bcachan@polyu.edu.hk
Received: February 9, 2009; Published online: June 3, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900086.
Abstract: Chiral ferrocene-derived phosphine-thio- 87% ee were obtained. Based on X-ray crystallo-
ether mixed donor ligands supported by heterocycles graphic and NMR studies, the origin of the observed
effected the palladium-catalyzed enantioselective al- enantioselectivities is discussed.
lylic alkylations with excellent yields and enantiose-
lectivities (up to 96% ee). With cyclic and unsymmet- Keywords: allylic alkylation; asymmetric catalysis;
rical allylic acetates as substrate, the corresponding enantioselectivity; ferrocenes; phosphine-thioether
alkylated products with enantioselectivities up to ligands
Introduction
series of phosphinite-thioether ligands supported by
some readily available carbohydrates, and these P/S
The design and synthesis of new chiral ligands is a ligands were effective for asymmetric allylic substitu-
central activity in asymmetric catalysis studies. Exten- tions[5q] and asymmetric hydrosilylation of ketones.[5r]
sive efforts have been devoted to developing chiral Extensive studies showed that ferrocene is an appeal-
C2-symmetrical homobidentate ligands such as P/P, ing building block for designing novel chiral ligands
N/N and O/O ligands, and highly effective asymmetric because of the easy implementation of the central
catalysis has been reported using these ligand sets.[1] and planar chiralities.[8] Enders described a family of
The development of heterobidentate ligands equipped enantiopure ferrocenyl P/S ligands which were highly
with a strong and a weak heteroatom pair such as effective for asymmetric allylic substitutions.[9] Ac-
P/N[2] and P/O[3] is receiving increasing attention. cording to the recent works by Carretero and co-
Such coordinations have been proved to be effective workers,[10] Fesulphos which contained only planar
for achieving high enantioselectivities through steric
and electronic differentiations.[4] However, there are
few examples on the study of chiral P/S ligands for
asymmetric catalysis.[5–10] Unique to this class of li-
gands, the coordination of the sulfur donor to the
metal center would create a stereogenic center at
sulfur, near the reaction site in addition to other ste-
reogenic carbon centers.[6] For example, Evans and
co-workers showed that phosphinite-thioethers[7] were
excellent ligands for the Pd-catalyzed asymmetric al-
lylic substitution of cyclic and acyclic allylic acetates
(FigACHTUNGTRENNUNG
ure 1).[7a,b] The same series of ligands was also
found to effect Rh-catalyzed asymmetric hydrogena-
tion of dehydroamino acids and asymmetric hydrosi-
lylation of ketones.[7c] Diꢁguez and Pꢂmies reported a Figure 1. Examples of effective P/S ligands.
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Effective Chiral Ferrocenyl Phosphine-Thioether Ligands
FULL PAPERS
Ugiꢀs amine as a starting material (Figure 2). Through
extensive structure-activity studies, ligand L8 with a
benzimidazole scaffold was found to be highly effec-
tive for asymmetric allylic substitutions[14] giving up to
96% ee. A related study on the Pd-catalyzed asym-
metric intermolecular indole alkylation has been com-
municated elsewhere.[15]
Results and Discussion
Ligand Synthesis
Figure 2. Modular design of bidentate ligands supported by
ferrocene and heterocycles.
Ugiꢀs amine has been proven to be a versatile precur-
sor for the preparation of diverse chiral ferrocenyl di-
phosphine ligands.[16] This is exemplified by the ele-
chirality was developed for enantioselective allylic gant synthesis of Josiphos,[17] BoPhoz[18] and Wal-
substituti
ACHTUNGTRENNUNG
Alder reactiACHTUNGTRENNUNG
dipolar cycloaddition.[10h–m]
Ugiꢀs amine with tartaric acid[20] or other chiral auxil-
The development of highly efficient and practical iaries,[21] we recently developed a highly enantioselec-
chiral ligands for asymmetric C C bond formation is tive synthesis of (S)-Ugiꢀs amine (>99% ee) on a 150-
À
a long-standing research interest for many scientists. gram scale by asymmetric hydrogenation of acetylfer-
Previously we showed that chiral diphosphine ligands rocene, followed by nucleophilic substitution.[12j] By
P-Phos[11] with heteroaromatic scaffolds are excellent virtue of the synthetic versatility of Ugiꢀs amine, we
ligands for asymmetric hydrogenations[12] as well as devised a three-step modular synthetic approach to
some C C bond formation reactions.[13] Notably, these prepare a library of novel air- and moisture-stable P/S
À
ligands are air-stable compared to the analogous ferrocenyl ligands L1–L9 containing a heterocyclic
BINAP ligand. Following this approach, we envi- motif.
sioned a new class of ferrocenyl P/S ligands with het-
As shown in Scheme 1, diastereoselective ortho-
erocyclic scaffolds to have good air/moisture stability substitution of (S)-Ugiꢀs amine with various disulfides
and to be excellent ligands for asymmetric catalysis. gave amino-thioethers 1.[22] Treating 1 with imidazole,
In this work, we describe the preparation of structur- benzimidazole or 1,2,4-triazole in AcOH afforded op-
ally diverse ferrocenyl P/S ligands containing hetero- tically pure compounds 2–4 in good to excellent
cycles using a modular synthetic approach with (S)- yields. Lithiation of 2–4 followed by trapping with
Scheme 1. Synthesis of P/S ligand L1–L9.
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ClPPh2 afforded ligands L1–L9 in overall 48–76% and Bu4NCl showed similar reactivities but slightly
yields. Ligands L1–L9 are air-stable solids and can be lower enantioselectivities (50–52% ee).
handled and stored without protection from air. The
With MeCN as solvent, we turned to examine the
molecular structure and absolute configuration of L9 effect of the substituents on the thioether group [R=
has been unambiguously defined as (S,Rp) by X-ray p-Tol (L2), Me (L3), Et (L4), i-Pr (L5), Cy (L6) and
crystallography (See Supporting Information).
t-Bu (L7)]. Ligand L2 (R=p-Tol) afforded the same
level of reactivity and enantioselectivity as L1 (63%
ee, entry 5). With smaller primary alkyl substituents
such as L3 (R=Me) and L4 (R=Et), higher enantio-
selectivities of 87% and 90% ee, respectively, were
Ligand Screening and Reaction Optimization
To begin the search for effective ligands for the Pd- achieved with complete conversions (entries 6 and 7).
catalyzed asymmetric allylic alkylation, we employed Ligands L5 (R=i-Pr) and L6 (R=Cy) with secondary
1,3-diphenyl-2-propenyl acetate 5 as a model sub- alkyl substituents led to slightly lower enantioselectiv-
strate and dimethyl malonate as the nucleophile. The ities (81% and 83%, respectively; entries 8 and 9). An
reaction was performed in the presence of [PdACTHNUTRGNEUNG
(h3- ee value of 15% was observed when using L7 contain-
C3H5)Cl]2 (2.5 mol%), ligand (5 mol%), N,O-bis(tri- ing a t-Bu substituent (entry 10). Having found that
methylsilyl)acetamide (BSA, 2 equiv.) and a catalytic the ligand L4 with an ethyl substituent produced
amount of LiOAc as additive in various solvents higher enantioselectivity, ferrocenyl ligands L8 and
(CH2Cl2, THF, toluene, MeCN). With ligand L1, com- L9 supported by different heterocycles (benzimi-
plete reactions were achieved in polar solvents within
ACHTUNGTRENdNUGN azole and 1,2,4-triazole, respectively) were then ex-
2 h, while only 52% conversion was attained with tol- amined for this reaction (entries 11 and 13). It was
uene as solvent (Table 1, entries 1–4). Up to 62% ee found that L9 afforded the alkylated product with
of (S)-6a was obtained with MeCN as solvent 82% ee, albeit with a shorter time (1 h) for complete
(entry 4); other solvents such as CH2Cl2, THF and tol- reaction (entry 13). However, ligand L8 supported by
uene produced lower enantioselectivity (37–59% ee). benzimidazole furnished the best enantioselectivity of
Other additives such as NaOAc, KOAc, ZnACHTUNTRGNEUNG(OAc)2 93% ee in 3 h (entry 11). Further improvement to
95% ee was attained when the reaction temperature
was lowered to 08C (entry 12).
With the optimized reaction conditions in hand, the
asymmetric allylic alkylation of 5 with different nucle-
ophiles was studied and the results are summarized in
Table 2. Excellent reactivities and enantioselectivities
Table 1. Optimization of reaction conditions with ligands
L1–L9.[a]
Table 2. Scope of nucleophiles.[a]
Entry Ligand Solvent Temp.
[oC]
Time Conv.
[h]
ee
[%][b]
[%][c,d]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L8
L9
CH2Cl2 r.t.
THF r.t.
2
2
2
2
2
2
2
2
2
2
3
15
1
99
99
52
99
99
99
99
99
99
99
99
99
99
59
59
37
62
63
87
90
81
83
15
93
95
82
toluene r.t.
MeCN r.t.
MeCN r.t.
MeCN r.t.
MeCN r.t.
MeCN r.t.
MeCN r.t.
MeCN r.t.
MeCN r.t.
Entry NuH
Product Yield [%][b] ee [%][c]
1
2
3
6a
6b
6c
98
97
95
95
95
94
9
4
5
6
6d
6e
6f
95
94
96
95
96
10
11
12
13
MeCN
0
MeCN r.t.
[a]
96
Conditions:
1,3-diphenyl-2-propenyl
acetate
5
(0.1 mmol),
[Pd (2.5 mol%),
ACHTUNGTRENNUNG
ligand
[a]
(5 mol%), dimethyl malonate (2 equiv.), BSA (2 equiv.),
LiOAc (5 mol%) in solvent (1 mL).
Determined by H NMR analysis of the crude mixture.
Conditions:
1,3-diphenyl-2-propenyl
acetate
5
(0.1 mmol), [PdACTHNUTRGNEUNG
(h3-C3H5)Cl]2 (2.5 mol%), L8 (5 mol%),
[b]
[c]
[d]
1
NuH (2 equiv.), BSA (2 equiv.), LiOAc (5 mol%) in
MeCN (1 mL).
Isolated yield.
Determined by chiral HPLC (see Experimental Section).
Absolute configuration was assigned to be (S) by com-
parison with the literature results.[7]
[b]
[c]
Determined by chiral HPLC (See Experimental Section).
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Effective Chiral Ferrocenyl Phosphine-Thioether Ligands
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were achieved with both bulky and substituted malo- tion with unsymmetrical allylic substrates such as 9
nates. The corresponding alkylated products 6a–6e and 11 bearing a larger and a smaller substituent on
were obtained in quantitative yields and 94–96% ee each terminus. The development of Pd-catalyzed allyl-
(entries 1–5). The diketone 3-methyl-2,4-pentane- ic substitution of unsymmetrical substrates with high
dione was also an effective nucleophile for the Pd-cat- regioselectivity and enantioselectivity is a current in-
alyzed allylic alkylation reaction, and adduct 6f was terest since, in the Pd-catalyzed allylic alkylations, nu-
formed in 96% ee with excellent yield (entry 6).
cleophiles would preferentially attack at the least hin-
dered allylic carbon to give achiral linear or less hin-
dered products.[24,25] Recently, bulky and electronically
poor phosphorus ligands were found to be efficient in
the allylic alkylation of achiral linear or racemic
Cyclic and Unsymmetrical Allylic Substrates
Development of the highly enantioselective allylic al- branched allylic acetate 11, and highly regioselective
kylation of non-sterically demanding cyclic substrates and enantioselective branched alkylated products 12a
remains a challenge; few examples with enantioselec- were obtained.[23b,e,24e,g]
tivities >90% ee have been reported.[7b,23] In this
To investigate the regio- and enantioselectivity of
work, the reaction of cyclic allylic acetates 7a–c of dif- the allylic substitution of unsymmetrical substrates
ferent ring size with dimethyl malonate in the pres- using our catalyst system, we employed 9 as substrate,
ence of 2.5 mol% [Pd
was examined (Table 3). Good to excellent chemical workers.[26] It was found that the allylic alkylation of
yields were obtained for all cyclic substrates tested. unsymmetrical substrate 9 with 2.5 mol% of [Pd
(h3-
(h3-C3H5)Cl]2 and 5 mol% L8 which has been extensively studied by Pfaltz and co-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Cycloheptenyl acetate 7c afforded the alkylated prod- C3H5)Cl]2 and 5 mol% of L8 afforded the regioisom-
uct 8 in 96% yield and 87% ee in 3 h at ambient tem- ers 10a and 10b in an 87/13 ratio with excellent yield
perature (entry 3).
in 3 h. The less hindered major product 10a was
Many ligands documented in the literature are formed with 43% ee. The minor product 10b was also
known to exhibit excellent enantioselectivity for the formed by the nucleophile attacking the more hin-
allylic alkylation of 1,3-diphenyl-2-propenyl acetate 5; dered site; a higher enantioselectivity of 71% ee was
however, they are usually less successful for the reac- observed (Scheme 2).
Employing the same reaction conditions, cinnamyl
acetate 11a was converted to an inseparable mixture
of 12a and 12b in 80% total yield (12a/12b=68/32),
Table 3. Allylic alkylation of cyclic allylic substrates.[a]
product 12a was formed in 57% ee (Scheme 3). Re-
placing 11a with a branched racemic regioisomer 11b,
branched product 12a was also obtained as the minor
isomer (12a/12b=35/65) with improved enantioselec-
tivity (76% ee) and 87% total yield.
Entry
n
Product
Yield [%][b]
ee [%][c,d]
Mechanistic Proposal
1
2
3
0
1
2
8a
8b
8c
84
93
96
76
64
87
In order to gain insight into the allylic substitution re-
action, complexes 13a and 13b were prepared by re-
[a]
acting [PdACTHNUTRGNEUNG
(h3-C3H5)Cl]2 and [Pd(h3-PhC3H3Ph)Cl]2
Conditions: allylic acetate 7 (0.3 mmol), [Pd
(2.5 mol%), L8 (5 mol%), dimethyl
(1.5 equiv.), BSA (1.5 equiv.), LiOAc (5 mol%) in MeCN
(1 mL).
Isolated yield.
ACHTUNGTRENNUNG
malonate
with L8 in CH2Cl2, respectively, followed by the addi-
tion of TlPF6 to the resulting reaction mixture for
counterion exchange (Scheme 4).
[b]
[c]
[d]
[Pd(L8)ACHTUNGTRNEUNG
(h3-C3H5)]PF6 (13a) was recrystallized by
1
Determined by H NMR analysis by using Eu
(hfc)3.
slow diffusion of hexane into a CH2Cl2 solution, and a
single crystal was obtained for X-ray diffraction anal-
Absolute configurations were assigned to be (R) by com-
parison with the literature results.[7]
Scheme 2. Allylic alkylation of unsymmetrical allylic substrate 9.
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Scheme 3. Allylic alkylation of unsymmetrical allylic substrates 11.
several attempts. On a 31P NMR study, complex 13a
in CD2Cl2 solution showed two peaks at dP =11.3 and
9.8 ppm with an integral ratio of 3.2:1, indicative of
the presence of two diastereomeric p-allyl complexes.
While chelation of both P- and S-donor atoms of L8
to the palladium metal center was confirmed by X-
ray crystallography, the endo- and exo-h3-allyl palladi-
um isomers should account for the occurrence of the
two 31P NMR signals.
Scheme 4. Preparation of Pd-(h3-allyl) complexes 13.
Selected bond distances and bond angles of the two
ysis (Figure 3). However, we failed to prepare a single isomeric endo-13a and exo-13a are depicted in
crystal of [Pd(L8)(h3-PhC3H3Ph)]PF6 (13b) despite Table 4. The Pd atom of 13a adopted a highly distort-
Figure 3. Molecular structures of [Pd(L8)ACTHNUTRGNEUNG
(h3-C3H5)]PF6 complex (13a): endo isomer (left) and exo isomer (right) (hydrogen
atoms and anion are omitted for clarity).
Table 4. Selected bond lengths (ꢄ) and angles (deg) of complex endo-13a and exo-13a.
Bond Length (ꢄ)
Bond Angle (deg)
À
À
À
Pd(1) P(1)
Pd(1) S(1)
2.3237(5)
2.3883(5)
P(1) Pd(1) S(1)
C(34) Pd(1) C(36)
105.891(17)
À
À
À
68.87(11) (endo)
70.93(11) (exo)
91.49(8) (endo)
91.75(8) (endo)
97.20(7) (exo)
85.99(8) (exo)
68.87(11) (endo)
70.93(11) (exo)
À
À
À
Pd(1) C(34)
2.221(2) (endo)
2.168(3) (endo)
2.179(3) (endo)
2.237(2) (exo)
2.175(3) (exo)
2.231(2) (exo)
CACTHNGUTRENN(UG 34’) Pd(1) CACHTNUGTRENNUNG
À
À
À
Pd(1) C(35)
À
À
À
Pd(1) C(36)
S(1) Pd(1) C(34)
À
À
À
Pd(1) C
A
P(1) Pd(1) CACTHUGNETRNNU(G 36’)
À
À
À
Pd(1) C
A
S(1) Pd(1) CACTHUGNETRNNU(G 34’)
À
À
À
Pd(1) C
A
C(36) Pd(1) C(34)
À
À
CACTHNUTRGENN(UG 36’) Pd(1) CACHTUNGTERN(NUGN 34’)
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Effective Chiral Ferrocenyl Phosphine-Thioether Ligands
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Figure 4. Side view of Pd(L8)Cl2 (left) and [Pd(L8)ACTHNUTRGNEUNG
(h3-C3H5)]PF6 (13a) (right) complexes.
ed square-planar coordination in which the bond expected to exert some steric interaction for coordi-
À
À
angle P(1) Pd(1) S(1) is 105.8918 and the bond angle nation of the 1,3-diphenyl-2-propenyl ligand to the
À
À
À
C(36) Pd(1) C(34) of the endo-isomer and C
(36’)
metal center. Yet the ethyl substituent of the thioeth-
À
Pd(1) C
(34’) of the exo-isomer are 68.878 and 70.938, er group should be more flexible and is oriented away
respectively. The stronger trans influence of the phos- from the palladium center.
phine moiety than the thioether group resulted in
longer allylic carbon bonds Pd(1) C(34) with 2.221 ꢄ alized by a proposed mechanism (Scheme 5). Nucleo-
The observed enantiofacial selection can be ration-
À
À
for endo-isomer and Pd(1) C
the exo-isomer. The Pd-allylic carbon distances trans relief of steric strain between the allylic phenyl group
G
to the S-donor were found to be shorter: Pd(1)
and the lower Cp ring of the ferrocene motif. There-
C(36)=2.179 ꢄ (endo) and Pd(1) C
(exo).
bly slower because, upon the nucleophilic addition, a
According to VT 31P NMR analysis of 13b in large steric strain would be developed in forming the
CD2Cl2, two peaks at dP =14.8 and 11.8 ppm were ob- energetically unfavorable palladium-olefin complex.
served with an integral ratio of 1:1 (see Supporting
Information). This finding suggested that endo- and
exo-isomers existed equally in rapid equilibrium. Conclusions
However, it should be noted that the trans influence
of the P-donor is larger than that of the S-donor, nu- In summary, a series of chiral phosphine-thioether
cleophilic addition should occur at the terminal allylic mixed donor ligands L1–L9 supported with ferrocene
carbon trans to P-donor.[5x] Since excellent enantiose- and heterocyclics is described. They are effective in
lectivities (94–96% ee) were observed for the allylic palladium-catalyzed asymmetric allylic alkylations
substitutions of 1,3-diphenyl-2-propenyl acetate, this with a variety of allylic substrates and nucleophiles.
implies that one isomer should be more reactive than Excellent yields and enantioselectivities (up to 96%
the other one and the endo-exo interconversion must ee) were attained. Variation of the substituents of the
be faster than the nucleophilic addition.
thioether moiety was crucial in the stereocontrol in
By inspection of the structures of [Pd(L8)ACHTUNGTERNNNUG
(h3- the catalysis. The origin of the stereochemical out-
C3H5)]PF6 (13a) and Pd(L8)Cl2 (Figure 4), the ferro- come of the alkylated products is discussed with the
cene motif should play an important role in the ste- aid of X-ray crystallography, NMR and observed
reochemical control of the product formation. It was enantioselectivity. Studies on expanding this class of
found that the lower Cp ring of ferrocene was tilted ligand by further tuning of phosphine-thioether donor
toward the palladium center. The ferrocene motif is sets and heterocyclic scaffolds, as well as development
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were recorded on a Perkin–Elmer 341 polarimeter in a
10 mm cell. Melting points were measured on a Bꢅchi Melt-
ing Point B-545 machine. The X-ray crystal structure was
determined using a Brꢅker CCD area detector diffractome-
ter. HPLC analyses were performed on an HP1100 instru-
ment using Chiralcelꢆ OD-H, AD-H and OJ-H columns
(0.46 cm diameter ꢇ 25 cm length). Compounds 1–3, L1–L8
and Pd(L8)Cl2 were reported elsewhere.[15] [Pd(h3-
PhC3H3Ph)Cl]2 was prepared according to the reported pro-
cedure.[27]
Ligand Synthesis
1-{(S)-1-[(R)-2-(Ethylthio)ferrocenyl]ethyl}-1H-ACTHNUGTRNEUNG[1,2,4]-
triazole (4): A mixture of thioether 1d (1 g, 3.15 mmol) and
1,2,4-triazole (1.74 g, 25.2 mmol) in degassed glacial AcOH
(11 mL) was stirred at 808C for 6 h. The reaction mixture
was quenched with an excess of saturated NaHCO3 solution
and extracted with CH2Cl2 (15 mLꢇ3). The combined or-
ganic layers were washed with brine and dried over anhy-
drous Na2SO4, filtered and evaporated under reduced pres-
sure. The crude product was purified by flash column chro-
matography to afford compound (S,Rp)-4; yield: 94%; red
oil; Rf =0.36 (EtOAc/hexane/Et3N=1/1/0.01); [a]2D0: +157.78
(c 1.22, CH2Cl2); 1H NMR (500 MHz, CDCl3): d=7.89 (s,
1H), 7.84 (s, 1H), 5.78 (q, 1H, J=7.0 Hz), 4.53 (br s, 1H),
4.46–4.45 (m, 1H), 4.34 (t, 1H, J=2.0 Hz), 4.19 (s, 5H),
2.03–1.96 (m, 1H), 1.89 (d, 3H, J=7.0 Hz), 1.86–1.79 (m,
1H), 0.89 (t, 3H, J=7.5 Hz); 13C NMR (125 MHz, CDCl3):
d=151.56, 141.54, 88.28, 79.08, 76.09, 70.38, 68.69, 67.57,
53.95, 30.95, 20.81, 14.51; IR (cmÀ1) 3095, 2977, 2925, 2869,
1666, 1558, 1499, 1453, 1374, 1272, 1195, 1137, 1106, 1051,
1033, 1004, 958, 823, 764, 706, 681, 661; MS (ESI): m/z=
342.04 [M+H]+; HR-MS (ESI): m/z=342.0749, calcd. for
C16H20N3SFe [M+H]+: 342.0727.
Scheme 5. Proposed mechanism of the asymmetric allylic al-
kylation with L8.
of other bidentate ligands with this modular frame-
work design, and their applications in other asymmet-
ric catalyses are currently underway.
1-{(S)-1-[(R)-2-(Ethylthio)ferrocenyl]ethyl}-2-(diphenyl-
phosphino)-1H-ACHTUNTRGNEUNG[1,2,4]triazole (L9): To a solution of 4 (0.5 g,
1.47 mmol) in THF (18 mL) was added dropwise n-BuLi
(0.92 mL, 1.6M solution in hexane) at À788C, and the mix-
ture was stirred for 30 min under a nitrogen atmosphere.
ClPPh2 (291 mL, 1.62 mmol) was then added dropwise to the
reaction mixture at 08C. The reaction mixture was stirred
for further 4 h at room temperature, and then evaporated
under reduced pressure. The residue was purified by flash
column chromatography to afford L9; yield: 59%, yellow
solid; Rf =0.45 (EtOAc/hexane/Et3N=1/3/0.01). A single
crystal for X-ray crystallographic analysis was grown by
slow diffusion of hexane into a solution of L9 in CH2Cl2.
[a]20: +89.18 (c 1.04, CH2Cl2); mp 160–1628C; 1H NMR
(50D0 MHz, CDCl3): d=7.95 (s, 1H), 7.74–7.68 (m, 2H),
7.49–7.46 (m, 2H), 7.38–7.37 (m, 6H), 6.44 (p, 1H, J=
7.0 Hz), 4.61 (s, 1H), 4.41 (s, 1H), 4.35–4.33 (m, 1H), 4.21
(s, 5H), 1.73–1.66 (m, 4H), 1.44–1.37 (m, 1H), 0.70 (t, 3H,
J=7.0 Hz); 13C NMR (125 MHz, CDCl3): d=153.69, 153.55,
152.15, 152.12, 134.51, 134.46, 134.34, 134.17, 133.69, 133.53,
133.46, 133.42, 129.55, 129.36, 128.71, 128.65, 128.40, 128.34,
88.81, 79.01, 75.85, 70.22, 68.55, 68.37, 68.36, 53.69, 53.58,
30.53, 20.69, 14.29; 31P NMR (202 MHz, CDCl3): d=À35.0;
IR: n=3072, 3048, 2996, 2977, 2923, 1470, 1436, 1385, 1313,
1278, 1261, 1244, 1217, 1178, 1105, 1090, 1069, 1040, 1029,
1000, 973, 954, 888, 841, 828, 817, 757, 745, 697 cmÀ1; MS
Experimental Section
General Considerations
All the reactions were carried out under a nitrogen atmos-
phere using oven-dried glassware. Unless otherwise noted,
commercial reagents were used as received without purifica-
tion. Toluene was distilled from sodium under a nitrogen at-
mosphere. Tetrahydrofuran (THF) was distilled from
sodium/benzophenone ketyl under a nitrogen atmosphere.
Acetonitrile (MeCN), dichloromethane (CH2Cl2) and
hexane were distilled from CaH2 under a nitrogen atmos-
phere. Thin layer chromatography was performed on silica
gel plates. Silica gel (Merck, 230–400 mesh) was used for
flash column chromatography. H, 13C and 31P NMR spectra
1
were recorded on a Varian (500 MHz) or Brꢅker (400 MHz)
spectrometer. Chemical shift (d) are given in ppm and are
referenced to residual solvent peaks (1H NMR and
13C NMR) or to an 85% H3PO4 in D2O externally
(31P NMR). Coupling constants (J) were reported in hertz
(Hz). Mass spectra and high resolution mass spectra (HR-
MS) were obtained on a VG MICROMASS, Fison VG plat-
form, Finnigan Model Mat 95 ST instrument, or Brꢅker
APEX 47e FT-ICR mass spectrometer. Optical rotations
1418
asc.wiley-vch.de
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1412 – 1422

Effective Chiral Ferrocenyl Phosphine-Thioether Ligands
FULL PAPERS
(ESI): m/z= 526.11 [M+H]+; HR-MS (ESI): m/z=
526.1179, calcd. for C28H29N3PSFe [M+H]+: 526.1169.
d=7.34–7.16 (m, 15H), 6.77 (dd, 1H, J=15.5, 8.5 Hz), 6.33
(d, 1H, J=15.5 Hz), 4.29 (d, 1H, J=9.0 Hz), 4.25–4.11 (m,
2H), 4.02–3.91 (m, 2H), 3.25 (d, 1H, J=13.5 Hz), 3.10 (d,
1H, J=13.5 Hz), 1.19 (t, 3H, J=7.0 Hz), 1.01 (t, 3H, J=
7.5 Hz); 13C NMR (125 MHz, CDCl3): d=170.2, 170.1,
139.3, 137.4, 136.8, 132.1, 130.3, 129.9, 129.5, 128.5, 128.4,
127.8, 127.2, 127.1, 126.7, 126.3, 64.1, 61.1, 61.0, 54.8, 40.9,
13.9, 13.7; EI-MS: m/z=442 [M]+.
General Procedure for Pd-Catalyzed Asymmetric
Allylic Alkylation
(h3-C3H5)Cl]2 (0.91 mg, 2 mmol) and the ap-
A solution of [PdACHTUNGTRENNUNG
propriate ligand (4 mmol) in CH2Cl2 (100 mL) was stirred for
15 min under a nitrogen atmosphere in a Teflon-lined screw-
capped vial. To this catalyst was added allylic acetate
(0.1 mmol) in MeCN (1.0 mL), and the mixture was stirred
for further 5 min. After addition of nucleophile (0.2 mmol),
BSA (49 mL, 0.2 mmol) and LiOAc (catalytic amount), the
reaction mixture was stirred for the corresponding time and
temperature indicated. The resulting mixture was diluted
with CH2Cl2 and quenched with saturated aqueous NH4Cl
solution. The aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography
to afford the corresponding product.
(E)-Ethyl 2-carboethoxy-2-formamido-3,5-diphenylpent-4-
enoate (6e):[29] Yield: 94%, colorless oil. Rf =0.5 (EtOAc/
hexane=1/1). 96% ee by HPLC (Chiralcel AD-H, i-PrOH/
hexane=10/90, 1.0 mLminÀ1, 254 nm): Rt =15.3 min (major)
1
and 22.5 min (minor); H NMR (500 MHz, CDCl3): d=8.18
(s, 1H), 7.37–7.23 (m, 10H), 6.87 (bs, 1H), 6.77 (dd, 1H, J=
16.0, 7.5 Hz), 6.32 (d, 1H, 16.0 Hz), 4.78 (d, 1H, J=7.0 Hz),
4.36–4.24 (m, 2H), 4.17–4.01 (m, 2H), 1.27 (t, 3H, J=
7.5 Hz), 1.18 (t, 3H, J=7.5 Hz); 13C NMR (125 MHz,
CDCl3): d=166.9, 166.4, 159.8, 137.8, 137.3, 136.7, 129.5,
128.4, 128.3, 128.2, 127.6, 127.1, 126.4, 68.3, 62.8, 62.5, 53.1,
14.1, 13.9; EI-MS: m/z=395 [M]+.
(E)-3-Acetyl-3-methyl-4,6-diphenyl-5-hexen-2-one (6f):[30]
Yield: 96%, colorless oil. Rf =0.2 (EtOAc/hexane=1/9).
96% ee by HPLC (Chiralcel OJ-H, i-PrOH/hexane=10/90,
1.0 mLminÀ1, 254 nm): Rt =16.8 min (S) (minor) and
(E)-Methyl
2-carbomethoxy-3,5-diphenylpent-4-enoate
(6a):[7b] Yield: 98%, colorless oil. Rf =0.3 (EtOAc/hexane=
1/9). 95% ee by HPLC (Chiralcel AD, i-PrOH/hexane=10/
90, 1.0 mLminÀ1, 254 nm): Rt =10.7 min (R) (minor) and
1
23.1 min(R) (major); H NMR (500 MHz, CDCl3): d=7.31–
7.18 (m, 10H), 6.46 (d, 1H, J=15.5 Hz), 6.38 (dd, 1H, J=
15.5, 8.0 Hz), 4.69 (d, 1H, J=8.5 Hz), 2.15 (s, 3H), 1.93 (s,
3H), 1.49 (s, 3H); 13C NMR (125 MHz, CDCl3): d=206.5,
205.7, 139.7, 136.9, 133.2, 129.6, 128.5, 128.3, 127.8, 127.5,
127.0, 126.3, 71.5, 51.5, 27.9, 27.5, 15.8; EI-MS: m/z=306
[M]+.
1
15.0 min (S) (major); H NMR (500 MHz, CDCl3): d=7.33–
7.19 (m, 10H), 6.48 (d, 1H, J=16.0 Hz), 6.33 (dd, 1H, J=
15.5, 8.5 Hz), 4.26 (dd, 1H, J=10.5, 8.5 Hz), 3.97 (d, 1H, J=
11.0 Hz), 3.71 (s, 3H), 3.52 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=168.2, 167.8, 140.2, 136.8, 131.8, 129.1, 128.7,
128.5, 127.9, 127.6, 127.2, 126.4, 57.6, 52.6, 52.4, 49.2; EI-MS:
m/z=324 [M]+.
(R)-Dimethyl 3-cyclopentenylmalonate (8a):[7b] Yield:
84%, colorless oil. Rf =0.24 (EtOAc/hexane=1/19). [a]2D0:
(E)-Ethyl
2-carboethoxy-3,5-diphenylpent-4-enoate
1
(6b):[28] Yield: 97%, colorless oil. Rf =0.2 (EtOAc/hexane=
1/10). 95% ee by HPLC (Chiralcel AD-H, i-PrOH/hexane=
5/95, 1.0 mLminÀ1, 254 nm): Rt =15.0 min (R) (minor) and
+72.08 (c 1.61, CH2Cl2); 76% ee by H NMR using Eu
G
1
chiral shift reagent. H NMR (500 MHz, CDCl3): d=5.82–
5.80 (m, 1H), 5.64–5.62 (m, 1H), 3.71 (s, 6H), 3.37–3.34 (m,
1H), 3.26 (d, 1H, J=9.5 Hz), 2.36–2.29 (m, 2H), 2.14–2.08
(m, 1H), 1.60–1.55 (m, 1H); 13C NMR (125 MHz, CDCl3):
d=169.1, 169.0, 133.0, 131.3, 56.6, 52.4, 52.3, 45.4, 31.7, 27.7;
EI-MS: m/z=198 [M]+.
1
20.5 min (S) (major); H NMR (500 MHz, CDCl3): d=7.31–
7.17 (m, 10H), 6.48 (d, 1H, J=16.0 Hz), 6.34 (dd, 1H, J=
15.5, 8.5 Hz), 4.27 (t, 1H, J=9.5 Hz), 4.17 (q, 2H, J=
7.0 Hz), 3.99–3.92 (m, 3H), 1.20 (t, 3H, J=7.0 Hz), 1.00 (t,
3H, J=7.0 Hz); 13C NMR (125 MHz, CDCl3): d=167.8,
167.3, 140.2, 136.8, 131.6, 129.3, 128.6, 128.4, 127.9, 127.4,
127.0, 126.3, 61.5, 61.3, 57.7, 49.2, 14.1, 13.7; EI-MS: m/z=
352 [M]+.
(R)-Dimethyl 3-cyclohexenylmalonate (8b):[7b] Yield:
93%, colorless oil. Rf =0.24 (EtOAc/hexane=1/19). [a]2D0:
1
+32.18 (c 1.0, CH2Cl2); 64% ee by H NMR using Eu
G
1
chiral shift reagent. H NMR (500 MHz, CDCl3): d=5.76–
5.72 (m, 1H), 5.49–5.47 (m, 1H), 3.71 (s, 3H), 3.70 (s, 3H),
3.25 (d, 1H, J=9.5 Hz), 2.90–3.84 (m, 1H), 1.98–1.91 (m,
2H), 1.77–1.65 (m, 2H), 1.58–1.49 (m, 1H), 1.37–1.30 (m,
1H); 13C NMR (125 MHz, CDCl3): d=168.8, 168.7, 129.6,
127.2, 56.7, 52.3, 52.2, 35.3, 26.5, 24.8, 20.8; EI-MS: m/z=
212 [M]+.
(E)-Phenylmethyl
2-carbophenylmethoxy-3,5-diphenyl-
pent-4-enoate (6c):[28] Yield: 95%, colorless oil. Rf =0.4
(Et2O/CH2Cl2/hexane=1/1/5). 94% ee by HPLC (Chiralcel
AD-H, i-PrOH/hexane=10/90, 1.0 mLminÀ1, 254 nm): Rt =
1
24.1 min (minor) and 29.8 min (major); H NMR (500 MHz,
CDCl3): d=7.34–7.24 (m, 18H), 7.12–7.11 (m, 2H), 6.49 (d,
1H, J=16.0 Hz), 6.39 (dd, 1H, J=15.5, 8.5 Hz), 5.17 (dd,
2H, J=17.5, 12.5 Hz), 5.00 (dd, 2H, J=17.5, 12.5 Hz), 4.38
(dd, 1H, J=11.0, 9.0 Hz), 4.13 (d, 1H, J=11.0 Hz);
13C NMR (125 MHz, CDCl3): d=167.5, 167.1, 140.0, 136.6,
135.1, 135.0, 131.8, 128.9, 128.7, 128.5, 128.4, 128.3, 18.2,
128.1, 128.0, 127.9, 127.5, 127.1, 126.4, 67.3, 67.1, 57.7, 49.2;
EI-MS: m/z=476 [M]+.
(R)-Dimethyl 3-cycloheptenylmalonate (8c):[7b] Yield:
96%, colorless oil. Rf =0.21 (EtOAc/hexane=1/19). [a]2D0:
1
+7.48 (c 1.78, CH2Cl2); 86.8% ee by H NMR using Eu
G
1
chiral shift reagent. H NMR (500 MHz, CDCl3): d=5.82–
5.77 (m, 1H), 5.57–5.54 (m, 1H), 3.71 (s, 3H), 3.69 (s, 3H),
3.44 (d, 1H, J=8.5 Hz), 3.03–2.99 (m, 1H), 2.12–2.10 (m,
2H), 1.93–1.89 (m, 1H), 1.66–1.56 (m, 3H), 1.37–1.28 (m,
2H); 13C NMR (125 MHz, CDCl3): d=169.1, 168.9, 132.8,
132.7, 56.7, 52.3, 52.2, 39.6, 30.9, 30.1, 28.3, 26.2; EI-MS:
m/z=226 [M]+.
(E)-Ethyl
2-carboethoxy-2-benzyl-3,5-diphenylpent-4-
enoate (6d):[29] Yield: 95%, colorless oil. Rf =0.5 (Et2O/
CH2Cl2/hexane=1/1/5). 95% ee by HPLC (Chiralcel AD-H,
i-PrOH/hexane=3/97, 1.0 mLminÀ1, 254 nm): Rt =9.4 min
(E)-Methyl
2-carbomethoxy-3-methyl-5-phenylpent-4-
1
(major) and 12.9 min (minor); H NMR (500 MHz, CDCl3):
enoate (10a):[5f,31] Yield: 98% (inseparable mixture with
Adv. Synth. Catal. 2009, 351, 1412 – 1422
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1419

Hong Yee Cheung et al.
FULL PAPERS
10b), colorless oil. Rf =0.21 (EtOAc/hexane=1/10). 43% ee
by HPLC (Chiralcel OD-H, i-PrOH/hexane=1/99,
0.5 mLminÀ1, 254 nm): Rt =18.7 min (major) and 19.8 min
(minor); 1H NMR (500 MHz, CDCl3): d=7.34–7.19 (m,
5H), 6.45 (d, 1H, J=15.5 Hz), 6.12 (dd, 1H, J=16.0,
8.5 Hz), 3.75 (s, 3H), 3.67 (s, 3H), 3.40 (d, 1H, J=9.0 Hz),
3.16–3.09 (m, 1H), 1.19 (d, 3H, J=6.5 Hz); EI-MS: m/z=
262 [M]+.
metric Synthesis, (Eds.: G.-Q. Lin, Y.-M. Li, A. S. C.
Chan), John Wiley & Sons, New York, 2001; c) New
Frontiers in Asymmetric Catalysis, (Eds.: K. Mikami,
M. Lautens), Wiley, Hoboken, New Jersey, 2007; d) S.
Castillꢈn, C. Claver, Y. Dꢉaz, Chem. Soc. Rev. 2005, 34,
702; e) W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029;
f) H. U. Blaser, C. Malan, B. Pugin, F. Spindler, H.
Steiner, M. Studer, Adv. Synth. Catal. 2003, 345, 103;
g) K. V. L. Crꢁpy, T. Imamoto, Adv. Synth. Catal. 2003,
345, 79; h) K. V. L. Crꢁpy, T. Imamoto, Top. Curr.
Chem. 2003, 229, 1.
(E)-Methyl
2-carbomethoxy-3-phenylhex-4-enonate
(10b):[24c] Yield: 98% (inseparable mixture with 10a), color-
less oil. Rf =0.21 (EtOAc/hexane=1/10). 71% ee by HPLC
(Chiralcel OD-H, i-PrOH/hexane=1/99, 0.5 mLminÀ1,
215 nm): Rt =14.9 min (minor) and 16.0 min (major);
1H NMR (500 MHz, CDCl3): d=7.34–7.19 (m, 5H), 5.61–
5.53 (m, 2H), 4.04 (dd, 1H, J=11.0, 7.5 Hz), 3.82 (d, 1H,
J=11.0 Hz), 3.73 (s, 3H), 3.48 (s, 3H), 1.63 (d, 3H, J=
5.0 Hz); EI-MS: m/z=262 [M]+.
[2] For a recent review on P/N ligands, see: a) P. J. Guiry,
C. P. Saunders, Adv. Synth. Catal. 2004, 346, 497; b) G.
Chelucci, G. Orrꢊ, G. Pinna, Tetrahedron 2003, 59,
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[3] a) G. Knuhl, P. Sennhenn, G. Helmchen, J. Chem. Soc.
Chem. Commun. 1995, 1845; b) S. R. Gilbertson, P.
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4, 1615; d) K. Suzuki, S. Ishii, K. Kondo, T. Aoyama,
Synlett 2006, 648.
Dimethyl 1-phenyl-2-propenylmalonate (12a):[32] Yield:
87% (inseparable mixture with 12b), colorless oil. Rf =0.21
(EtOAc/hexane=1/10). 76% ee by HPLC (Chiralcel OJ-H,
iPrOH/hexane=3/97, 0.7 mLminÀ1, 220 nm): Rt =44.2 min
1
(major) and 52.2 min (minor); H NMR (500 MHz, CDCl3):
[4] a) T. G. Appleton, H. C. Clark, L. E. Manzer, Coord.
Chem. Rev. 1973, 10, 335; b) S. Murray, F. Hartley,
Chem. Rev. 1981, 81, 365.
d=7.32–7.21 (m, 5H), 6.03–5.96 (m, 1H), 5.14–5.08 (m,
2H), 4.11 (dd, 1H, J=11.0, 8.5 Hz), 3.87 (d, 1H, J=
11.5 Hz), 3.75 (s, 3H), 3.49 (s, 3H); EI-MS: m/z=248 [M]+.
[5] Recent examples on chiral P/S ligands: a) F. L. Lam,
T. T.-L. Au-Yeung, F. Y. Kwong, Z. Zhou, K. Y. Wong,
A. S. C. Chan, Angew. Chem. 2008, 120, 1300; Angew.
Chem. Int. Ed. 2008, 47, 1280; b) F. L. Lam, T. T.-L.
Au-Yeung, H. Y. Cheung, S. H. L. Kok, W. S. Lam,
K. Y. Wong, A. S. C. Chan, Tetrahedron: Asymmetry
2006, 17, 497; c) J. W. Faller, J. C. Wilt, Org. Lett. 2005,
7, 633; d) J. W. Faller, J. C. Wilt, Organometallics 2005,
24, 5076; e) J. W. Faller, J. C. Wilt, J. Parr, Org. Lett.
2004, 6, 1301; f) G. A. Molander, J. P. Burke, P. J. Car-
roll, J. Org. Chem. 2004, 69, 8062; g) T. Kanayama, K.
Yoshida, H. Miyabe, Y. Takemoto, Angew. Chem. 2003,
115, 2100; Angew. Chem. Int. Ed. 2003, 42, 2054; h) A.
Lledꢈ, J. Solꢂ, X. Verdaguer, A. Riera, M. A. Maestro,
Adv. Synth. Catal. 2007, 349, 2121; i) J. Solꢂ, A. Riera,
X. Verdaguer, M. A. Maestro, J. Am. Chem. Soc. 2005,
127, 13629; j) X. Verdaguer, A. Lledꢈ, C. Lꢈpez-Mos-
quera, M. A. Maestro, M. A. Pericꢂs, A. Riera, J. Org.
Chem. 2004, 69, 8053; k) X. Verdaguer, M. A. Pericꢂs,
A. Riera, M. A. Maestro, J. Mahia, Organometallics
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Pericꢂs, A. Riera, M. A. Maestro, J. Mahia, J. Am.
Chem. Soc. 2000, 122, 10242; m) H. Nakano, K. Taka-
hashi, Y. Suzuki, R. Fujita, Tetrahedron: Asymmetry
2005, 16, 609; n) H. Nakano, J. Yokoyama, Y. Okuya-
ma, R. Fujita, H. Hongo, Tetrahedron: Asymmetry
2003, 14, 2361; o) H. Nakano, Y. Suzuki, C. Kabuto, R.
Fujita, H. Hongo, J. Org. Chem. 2002, 67, 5011; p) H.
Nakano, Y. Okuyama, M. Yanagida, H. Hongo, J. Org.
Chem. 2001, 66, 620; q) E. Guimet, M. Diꢁguez, A.
Ruiz, C. Claver, Tetrahedron: Asymmetry 2005, 16, 959;
r) M. Diꢁguez, O. Pꢂmies, C. Claver, Tetrahedron:
Asymmetry 2005, 16, 3877; s) O. Pꢂmies, G. P. F. van
Strijdonck, M. Diꢁguez, S. Deerenberg, G. Net, A.
Ruiz, C. Claver, P. C. J. Kamer, P. W. N. M. van Leeu-
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Diꢁguez, G. Net, A. Ruiz, C. Claver, Organometallics
2000, 19, 1488; u) L. Routaboul, S. Vincendeau, J.-C.
General Procedure for the Synthesis of Pd-allyl
Complexes
A mixture of ligand (0.06 mmol) and Pd-allyl complex
(0.03 mmol) in CH2Cl2 (3 mL) was stirred for 3 h at room
temperature under a nitrogen atmosphere. TlPF6 (23 mg,
0.066 mmol) was then added and the solution was stirred
overnight at room temperature. The white precipitate was
filtered and the filtrate was evaporated under reduced pres-
sure.
[Pd(L8)
ACHTUNGTRENNUNG(C3H5)]PF6 ACHTUNGTERN(NUGN 13a): L8 (34.0 mg, 0.06 mmol) and
[PdACHTUNGTRENNUNG(allyl)Cl]2 (11.0 mg, 0.03 mmol) were used with in accord
with the general procedure. 31P NMR (162 MHz, CD2Cl2):
d=11.3 and 9.8 (3.2:1); HR-MS (ESI): m/z=721.0710,
calcd. for C36H36N2PSFePd [MÀPF6]+: 721.0721.
[Pd(L8)
ACHTUNGTRENNUNG(PhC3H3Ph)]PF6 ACHTUGNTREN(NUGN 13b): L8 (34.0 mg, 0.06 mmol)
and [PdACHTUNGTRENNUNG(PhC3H3Ph)Cl]2 (20.0 mg, 0.03 mmol) were used in
accord with the general procedure. 31P NMR (162 MHz,
CD2Cl2): d=14.8 and 11.8 (1:1); HR-MS (ESI): m/z=
873.1365, calcd. for C48H44N2PSFePd [MÀPF6]+: 873.1347.
Acknowledgements
We thank the University Grants Committee Areas of Excel-
lence Scheme (AoE/P-10/01); Hong Kong Research Grants
Council (Project# PolyU5001/08P); The Hong Kong Poly-
technic University ASD Fund for financial support.
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Adv. Synth. Catal. 2009, 351, 1412 – 1422

Effective Chiral Ferrocenyl Phosphine-Thioether Ligands
FULL PAPERS
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