Asymmetric Allylic Alkylation and Hydrogenation with Transition Metal Complexes of Diphosphite Ligands Based on (1S,2S)-Trans-1,2-cyclohexanediol

Article abstract of DOI:10.1007/s10562-017-1986-8

Abstract: The preparation of new palladium complexes in situ that were composed of a series of chiral diphosphite ligands, which were derived from (1S,2S)-trans-1,2-cyclohexanediol, have been described. It was found that (1S,2S)-bis[(S)-1,1′-binaphthyl-2,

Full text of DOI:10.1007/s10562-017-1986-8

Catal Lett (2017) 147:893–899
DOI 10.1007/s10562-017-1986-8
Asymmetric Allylic Alkylation and Hydrogenation
with Transition Metal Complexes of Diphosphite Ligands Based
on (1S,2S)-Trans-1,2-cyclohexanediol
Zengbo Pang1,2 · Mi Tian1,2 · Haifeng Li1 · Lailai Wang1
Received: 24 November 2016 / Accepted: 21 January 2017 / Published online: 23 February 2017
© Springer Science+Business Media New York 2017
Abstract The preparation of new palladium complexes
in situ that were composed of a series of chiral diphosphite
ligands, which were derived from (1S,2S)-trans-1,2-cyclohex-
anediol, have been described. It was found that (1S,2S)-bis[(S)-
1,1′-binaphthyl-2,2′-diyl]phosphite-cyclohexanediol was the
suitable ligand in the Pd-catalyzed allylic alkylation, and up
to 75% ee for (E)-dimethyl 2-(1,3-diphenylallyl)malonate
was obtained. In compared with the results of the asymmet-
ric allylic alkylation, (1S,2S)-bis[(R)-1,1′-binaphthyl-2,2′-diyl]
phosphite-cyclohexanediol was proved to be the most effi-
cient ligand in the Rh-catalyzed asymmetric hydrogenation
of dimethyl itaconate and enamides with up to 99% ee. The
stereochemically matched combinations between the diol
skeleton and diaryl moieties of the ligands were essential for
inducing high enantioselectivities in the two transformations.
It was found that the sense of the enantiodiscrimination of the
products was mainly determined by the configuration of the
binaphthyl phosphite moieties.
Graphical Abstract
MeOOC
COOMe
Ph
OAc
Ph
COOMe
COOMe
[Pd(n -allyl)Cl]2, 2b
98% yield, 75% ee (S)2b
+
Ph
BSA/NaOAc
*
Ph
COOMe
NHAc
COOMe
NHAc
MeOOC
*
(R) 2a
100% conv., 99% ee
MeOOC
[Rh(cod)2]BF4, 2a
H2, CH2Cl2
*
100% conv., 99% ee (S) 2a
Br
Br
O
*
P
P
O
a: (R)ax
b: (S)ax
O
O
O
c: (R)ax
O
O
O
O
=
d: (S)ax
O
O
O
*
2a-d
Electronic Supplementary Material The online version
Keywords Phosphite ligands · Allylic alkylation ·
of this article (doi:10.1007/s10562-017-1986-8) contains
Hydrogenation · Cyclohexanediol
supplementary material, which is available to authorized users.
* Lailai Wang
1 1 Introduction
wll@licp.cas.cn
1
State Key Laboratory for Oxo Synthesis and Selective
One of the main aims in organic synthesis is the catalytic
enantioselective formation of C–C bonds [1, 2]. In this
respect, the Pd-catalyzed asymmetric allylic alkylation
with several stabilized nucleophiles and the Rh-catalyzed
Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou 730000, China
2
University of Chinese Academy of Sciences, Bejing 100039,
China
Vol.:(0123456789)
1 3

894
Z. Pang et al.
asymmetric hydrogenation are two kinds of efficient and
versatile methods [3–9]. Up to now, many kinds of chiral
ligands, especially mixed bidentate donor ligands, such as
P-P,[10–13] P-N,[14–21] P-S,[22–24] P–O ligands,[25,
26] have been synthesized, and successfully applied in
these transformations. In recent years, owing to their syn-
thetic availability, high resistance to oxidation, and their
low cost,[27] more and more attention has been devoted to
phosphite ligands for these reactions and achieved magnifi-
cent results [28–30]. In spite of huge achievements in this
field, however, further research is still needed to develop
the new catalytic systems which can catalyze a wide range
of substrates with good activity and good enantioselectivity.
In our previous work, we synthesized bidentatephosphite
ligands 1a–d (Fig. 1) using (1R,2R)-trans-1,2-cyclohexane-
diol 3 as the diol skeleton. These ligands were successfully
employed in the Rh-catalyzed asymmetric hydrogenation
of α,β-unsaturated carboxylic acid derivatives and enam-
ides with up to 99% ee [31]. The correct assembly of cen-
tral chirality in the scaffold and axial chirality of the biaryl
phosphite moieties was very important for achieving higher
enantioselectivity in this reaction. Ligands 2a–b (Fig. 1)
were synthesized by changing the configuration of the
chiral diol skeleton, and applied them in the Cu-catalyzed
asymmetric conjugate addition, good catalytic activity and
enantioselectivity was received when complex 2b/CuTc
was used as the catalyst [32]. Considering the backbone
and the biaryl phosphite moiety flexibility of ligands 1a-d
and 2a-b play an important role in affecting the activity and
enantioselectivity of the transformations,[32–35] we won-
dered whether the ligands 2a-b would be suitable for the
Pd-catalyzed asymmetric allylic alkylation.
Cl]2 and NaOAc as a base. At the same time, ligands 2a-
d were applied in the Rh-catalyzed asymmetric hydro-
genation. Fortunately, 99% ee for dimethyl itaconate and
N-(1-(4-bromophenyl)vinyl)acetamide were obtained
when 2a/[Rh(cod)2]BF4 were used as the catalyst.
2 Materials and Methods
2.1 General Procedures
NMR spectra were recorded on Bruker 300 MHz or Bruker
1
400 MHz spectrometers. H and 13C NMR spectra were
reported in parts per million (ppm) with TMS (δ=0.00 ppm)
as an internal standard. 31P NMR spectra were reported in
ppm with 85% H3PO4 as an external reference. Proton chem-
ical shifts (δ) and coupling constants (J) were reported in
ppm and Hz, respectively. Spin multiplicities were given as
s (singlet), d (doublet), t (triplet) and m (multiplet). HRMS
were recorded on a Bruker microTOF-QII mass instru-
ment. All non-aqueous reactions and manipulations were
performed under an N2 atmosphere with standard Schlenk
techniques. Reactions were monitored by thin layer chroma-
tography (TLC, silica gel GF254 plates). Column chroma-
tography separations were conducted on silica gel (200–300
mesh). Reagents NEt3, THF, Et2O, hexane, 1,4-dioxane and
toluene were distilled with Na and benzophenone as an indi-
cator. CH3CN and CH2Cl2 were dried over CaH2 before use.
H8-Binaphthol was prepared according to a literature proce-
dure [36]. All the other chemicals were obtained commer-
cially and used without further purification.
In order to enrich the types of phosphite ligands,
ligands 2c and 2d (Fig. 1), which derived from (1S,2S)-
trans-1,2-cyclohexanediol, were also synthesized. To our
delight, ligand 2b gave excellent yields (up to 98%) and
good enantioselectivities (ee up to 75%) in a CH2Cl2/THF
mixture (v/v,1:1) using catalytic precursor [Pd(π-allyl)
2.2 Synthesis of Diphosphites 2a–d
As shown in Scheme 1, bidentatephosphite ligands
2c and 2d were synthesized stereospecifically in one
step
from
(1S,2S)-trans-1,2-cyclohexanediol,
and
2,2′-dihydroxy-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl
biaryl moieties
diphosphite ligands
diOH skeleton
O
P
*
*
*
*
O
O
OH
OH
DMAP, NEt3
THF
O
O
5a: (R)ax
ligands 2a-d
P Cl
5a-d
diOH
4
+
O
O
*
5b: (S)ax
O
O
P
O
1a-d
3
4
O
P
O
O
O
O
O
5c: (R)ax
5d: (S)ax
O
O
O
=
OH
OH
O
O
O
O
O
P
2a-d
5a: (R)ax 5b: (S)ax
5c: (R)ax 5d: (S)ax
Scheme 1 The synthesis of diphosphite ligands 2c and 2d based on
(1S,2S)-trans-1,2-cyclohexanediol
Fig. 1 The diphosphite ligands derived from (1R,2R)-trans-1,2-cy-
clohexanediol and (1S,2S)-trans-1,2-cyclohexanediol
1 3

Asymmetric Allylic Alkylation and Hydrogenation with Transition Metal Complexes of Diphosphite…
895
phosphochloridites 5c-d, by starting from 2,2′-dihydroxy-
5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthol. Diphosphite
ligands 2a-b were synthesized stereospecifically accord-
and was used directly without further purification.
Treatment of compound 4 (77.6 mg, 0.67 mmol), 5d
(530.1 mg, 1.48 mmol), and DMAP (17.8 mg, 0.15 mmol)
as described for the synthesis of ligand 2c afforded
ligand 2d, which was purified by flash chromatography
(Rf =0.44, n-hexane:toluene=1:1) to produce a white solid
(211.8 mg, 42% yield). [α]D20 =+147 (c 0.13, CH2Cl2); Mp
109–110°C; 1H NMR (400 MHz, DMSO-d6) δ 7.12 (s, 2H,
Ar), 7.05 (dd, J=17.6, 8.2 Hz, 4H, Ar), 6.88 (d, J=7.4 Hz,
2H, Ar), 4.15 (s, 2H, CH), 2.76 (s, 8H, CH2), 2.58 (s, 4 H,
CH2), 2.10 (d, J=10.6 Hz, 6H, CH2), 1.71 (s, 16H, CH2),
1.46 (s, 6H, CH2) ppm. 13C NMR (100 MHz, DMSO-d6)
δ 146.27, 145.77, 137.25, 134.96, 133.78, 129.82, 129.36,
127.71, 119.33, 119.02, 77.12, 76.92, 32.73, 28.81, 27.67,
27.54, 23.36, 22.45, 22.36, 22.34, 22.23 ppm. 31P NMR
(161 MHz, DMSO-d6) δ 142.59 ppm. HRMS (ESI+): calcd
for C46H50NaO6P2 [M+Na]+783.2975; found: 783.2965.
1
ing to the literature procedures,[33] and their H NMR,
13C NMR, 31P NMR, and HRMS were consistent with the
expectation for them. All of the ligands were stable dur-
ing the purification of neutral silica gel under a nitrogen
atmosphere with reasonable yields.
2.2.1 (1S,2S)‑bis[(R)‑1,1′‑H8‑binaphthyl‑2,2′‑diyl]
phosphite‑cyclohexanediol 2c
To a 100 mL Schlenk flask equipped with a condenser
were added 1.0 g of (R)-H8-binaphthol, 20 mL of tolu-
ene, and 12 mL of PCl3. Under a nitrogen atmosphere the
mixture was refluxed for 20 h. After removal of the excess
PCl3 and toluene, the residue was dissolved in 20 mL of
toluene, and then was transferred to another Schlenk flask,
and toluene was removed in vacuo to obtain the com-
pound (R)-1,1′- H8-binaphthyl-2,2′-diyl-chlorophosphite
5c as a white powder, which was used directly in the fol-
lowing step without further purification. To a stirred solu-
tion of compound 4 (77.5 mg, 0.67 mmol), compound
5c (529.9 mg, 1.48 mmol), and 4-dimethylaminopyri-
dine (DMAP) (17.4 mg, 0.15 mmol) in THF (10 mL) at
−15°C, NEt3 (0.32 mL) was slowly added using a syringe
over 2 min., and the solution was stirred for 0.5 h at
−15°C. The mixture was then stirred at room temperature
for 1 h. THF was distilled off in vacuo, and then toluene
(20 mL) was added. The solid was removed by filtration
through a pad of silica gel, and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (Rf =0.47, n-hexane:toluene=1:1), and
furnished ligand 2c as a white foamy solid (231.1 mg,
45% yield). [α]D20 =−137 (c 0.12, CH2Cl2); Mp 95–96°C;
1H NMR (400 MHz, DMSO-d6) δ 7.13 (d, J=8.0 Hz,
2H, Ar), 7.06 (d, J=8.0 Hz, 2H, Ar), 6.98 (d, J=8.0 Hz,
2H, Ar), 6.85 (d, J=8.2 Hz, 2H, Ar), 4.05 (s, 2H, CH),
2.86–2.70 (m, 8H, CH2), 2.69–2.56 (m, 4H, CH2), 2.13
(ddd, J=28.0, 16.8, 8.2 Hz, 6H, CH2), 1.81–1.68 (m,
12H, CH2), 1.63 (s, 2H, CH2), 1.58–1.30 (m, 8H, CH2)
ppm. 13C NMR (101 MHz, DMSO-d6) δ 145.95, 145.45,
136.93, 134.64, 133.46, 129.50, 129.04, 127.39, 119.01,
118.70, 76.80, 76.60, 32.41, 28.49, 27.35, 27.22, 23.04,
22.13, 22.04, 22.02, 21.91 ppm. 31P NMR (162 MHz,
DMSO-d6) δ 144.99 ppm. HRMS (ESI+): calcd for
C46H50NaO6P2 [M+Na]+783.2975; found: 783.2947.
2.3 Representative Procedure for the Pd-Catalyzed
Allylic Alkylation of 1,3-Diphenyl-2-propenyl
acetate 6a
To a flame dried Schlenk tube, [Pd(π-allyl)Cl]2 (0.9 mg,
0.0025 mmol) and ligand 2a (3.7 mg, 0.005 mmol) were
added under nitrogen, followed by addition of mixed sol-
vent (CH2Cl2/THF=1:1) 2 mL. The solution was stirred
at 40°C for 0.5 h. Then 1,3-diphenyl-2-propenyl acetate
6a (0.083 mmol) was added, and the mixture was stirred
for 10 min before the addition of nucleophile (0.25 mmol),
BSA (0.062 mL, 0.25 mmol), and anhydrous NaOAc
(8.2 mg, 0.10 mmol). After being stirred for 12 h at room
temperature, water (10 mL) was added and the mixture
was extracted with CH2Cl2 (3×10 mL). And the combined
organic phase was dried over anhydrous Na2SO4. The sol-
vent was removed under vacuum, and the residue was puri-
fied by flash chromatography using petroleum ether/EtOAc
20:1 (v/v) as eluant to afford the desired product. The enan-
tiomeric excess of the products were determined by HPLC
analysis with a Chiralpak AD-H column (0.46×25 cm).
2.4 Representative Procedure for the Rh-Catalyzed
Asymmetric Hydrogenation
After stirring a solution of [Rh(cod)2]BF4 (0.0025 mmol)
and ligand 2a (0.00275 mmol) in degassed CH2Cl2 (1 mL)
at room temperature for 1 h, a solution of the correspond-
ing substrate (0.25 mmol) in degassed CH2Cl2 (2 mL) was
added. The mixture was transferred via syringe into a stain-
less autoclave that had been previously purged with argon.
The hydrogenation was carried out in the autoclave at room
temperature for 6 h. After releasing H2, the reaction mix-
ture was passed through a short silica gel column to remove
the catalyst. After evaporation of the solvent under reduced
2.2.2 (1S,2S)‑bis[(S)‑1,1′‑H8‑binaphthyl‑2,2′‑diyl]
phosphite‑cyclohexanediol 2d
(S)-1,1′-H8-Binaphthyl-2,2′-diyl-chlorophosphite
5d
was synthesized by the same procedure as that of 5c,
1 3

896
Z. Pang et al.
pressure, the residue was purified by flash chromatogra-
phy on silica gel. The data on conversion and enantio-
meric excess of the product were determined by GC with
a gamma-DEX 225 column (30 m×0.25 mm×0.25 μm
moieties in comparison with ligand 2a, gave 65% yield and
29% ee (S) (Table 1, entry 2). Ligand 2c gave 43% yield
and 13% ee (R) for the product 8a (Table 1, entry 3), in
contrast, the configuration of the H8-binaphthyl moiety was
opposite to that of 2c and gave 18% ee (S) (Table 1, entry
4) when ligand 2d was used. Based on the data of the yields
and enantioselectivities, ligand 2b was screened as the most
efficient ligand. Moreover, it was found that the sense of
enantioselectivity was mainly determined by the configura-
tion of the binaphthyl or H8-binaphthyl moiety of ligands
2a–d, and an (R)-binaphthyl fragment gives an (R)-product,
and conversely an (S)-product for an (S)-binaphthyl.
film
thickness)
CP-Chirasil-DEX
CB
column
(25 m×0.25 mm×0.25 μm film thickness) or AT FFAP
(30 m×0.25 mm×0.25 μm film thickness). The absolute
configuration was determined by comparison with authen-
tic samples [37].
3 Results and Discussion
Using the catalyst prepared in situ from [Pd(π-allyl)
Cl]2 and ligand 2b, the AAA of substrate 6a and dime-
thyl malonate 7a with a variety of solvents was investi-
gated, and a profound solvent effect on the reaction was
observed. Enantioselectivities 34% ee (S) and 37% ee (S)
were obtained in CH3CN and Et2O, respectively (Table 1,
entries 5–6). 52% yield and 43% (S) ee were obtained when
using THF as the solvent (Table 1, entry 7). Toluene was
proven to be the unbeneficial solvent for this transforma-
tion (Table 1, entry 8). In order to further improve the yield
and enantioselectivity, we attempted to use mixed solvents
in this reaction. The yield increased from 65 to 85% and up
to 61% ee (S) was received, when 2 mL of THF was added
into 2 mL of CH2Cl2 (Table 1, entry 9).
3.1 Pd-catalyzed Asymmetric Allylic Alkylation
We first examined the effects of ligands 2a–d on the reac-
tion. The transformation was proceeded smoothly in
the presence of [Pd(π-allyl)Cl]2 (0.0025 mmol), ligand
(0.005 mmol), N,O-bis-(trimethylsilyl)acetamide (BSA,
0.25 mmol), and a catalytic amount of KOAc as base in
CH2Cl2 at room temperature for 24 h. The results were
summarized in Table 1. 52% yield and 22% ee (R) were
obtained when using 2a/[Pd(π-allyl)Cl]2 as the catalyst
(Table 1, entry 1). Ligand 2b, which bore (S)-binaphthyl
Table 1 The effect of ligand structures and solvents on the enanti-
oselectivity for the allylic alkylation of (E)-1,3-diphenyl-2-propenyl
acetate 6a with dimethyl malonate 7a
Palladium
catalyst
precursors,
such
as
[Pd2(dba)3]·CHCl3, Pd(TFA)2, Pd(OAc)2, and so on, were
examined (Table 2, entries 1–5). Similar results were
received when [Pd2(dba)3]·CHCl3 and Pd(CH3CN)2Cl2
MeOOC
COO
Me
OAc
Ph
COOMe
COOMe
[Pd(n -allyl)Cl]2/ligands
BSA/KOAc, r.t.
+
Ph
Ph
Ph
8a
7a
6a
Table 2 Screening of Pd salts in asymmetric allylic alkylation
Entry
Ligands
Solvent
Yielda(%)
%eeb (conf.)
MeOOC
COOMe
OAc
Ph
Pd salts,2b
COOMe
COOMe
+
1
2
3
4
5
6
7
8
2a
2b
2c
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
Et2O
THF
Toluene
52
65
43
56
95
30
52
n.d
85
84
91
22 (R)
29(S)
13 (R)
18 (S)
34 (S)
37 (S)
43 (S)
n.d
BSA/KOAc, r.t.
Ph
Ph
Ph
7a
6a
8a
Yielda(%)
%eeb (conf.)
2d
2b
2b
2b
2b
2b
2b
2b
Entry
Pd salts
L/Pd
1
2
3
4
5
6
7
[Pd2(dba)3]·CHCl3
Pd(TFA)2
Pd(OAc)2
1.0
1.0
1.0
1.0
1.0
0.5
2.0
62
61
48
n.d
65
71
75
32 (S)
42 (S)
28 (S)
n.d
33 (S)
40 (S)
47 (S)
Pd(acac)2
9
10
11
CH2Cl2/THF
CH2Cl2/CH3CN
THF/CH3CN
61 (S)
28 (S)
30 (S)
Pd(CH3CN)2Cl2
[Pd(π-allyl)Cl]2
[Pd(π-allyl)Cl]2
Reaction conditions: [Pd(π-allyl)Cl]2 (0.0025 mmol), ligand
(0.005 mmol), compound 6a (0.083 mmol), compound 7a
(0.25 mmol), BSA (0.25 mmol), KOAc (0.1 mmol), solvent (4 mL),
25°C, 24 h
Reaction conditions: Pd salts (0.0025 mmol), ligand (0.0025-
0.01 mmol), compound 6a (0.083 mmol), compound 7a (0.25 mmol),
BSA (0.25 mmol), KOAc (0.1 mmol), solvents CH2Cl2/THF (4
mL,v/v), 25°C, 12 h
aIsolated yield
aIsolated yield
bThe enantiomeric excess of compound 8a was determined by HPLC
analysis (column Chiralpak AD-H 0.46×25 cm). The absolute con-
figuration of 8a was determined by comparison with authentic sample
bThe enantiomeric excess and the absolute configuration of the prod-
ucts were determined using the same conditions as noted in Table 1
1 3

Asymmetric Allylic Alkylation and Hydrogenation with Transition Metal Complexes of Diphosphite…
897
were used as the precursors (Table 2, entries 1 vs. 5).
The activity obtained with Pd(TFA)2 was lower than
[Pd2(dba)3]·CHCl3, but the enantiomeric excess was higher
(Table 2, entry 2 vs. 1). Both low activity and enantiose-
lectivity were gained when Pd(OAc)2 was used (Table 2,
entry 3). No product was even detected in this reaction
when using Pd(acac)2 instead of [Pd(π-allyl)Cl]2 (Table 2,
entry 4). Based the above results, [Pd(π-allyl)Cl]2 was
proven to be the most suitable catalyst precursor. Then the
effects of ligand-to-palladium ratio on the catalytic activi-
ties and enantioselevtivities of the transformation were
investigated. The results showed that reducing or increas-
ing the loading of ligand had a detrimental effect on the
reaction (Table 2, entries 6–7). High enantioselectivity
(61% ee) was obtained when the loading of ligand was 1.0
equiv (Table 1, entry 13). The trade-off between activities
and enantioselectivities was optimum with [Pd(π-allyl)Cl]2
and a ligand-to-palladium ratio of 1:1.
were received when lithium acetate and cesium acetate
were used in this reaction (Table 3, entries 5–6). Up to
75% ee was obtained when sodium acetate was used as
the base (Table 3, entry 7). These results indicated that
base had an important influence on the ee values. Con-
sidering the yield and ee value, NaOAc among the bases
screened was found as the most befitting base in conjunc-
tion with N,O-bis-(trimethylsilyl)acetamide. By lowering
the reaction temperature from 25 to −10 °C, the ee values
of product 8a decreased from 75 to 70%, and the yield
significantly decreased (Table 3, entries 7–9).
Then, the scope of alkylation substrate and malonates
was explored in the Pd-catalyzed AAA, and the results
were collected in Table 4. Several substituted aromatic
allylic acetates, containing either electron-donating groups
Table 4 Scope of substrates for Pd-catalyzed asymmetric allylic
alkylation
Next, the role of bases in allylic alkylation of com-
pound 6a and 7a was probed, and the results were sum-
marized in Table 3. High yield but poor ee were obtained
when potassium bicarbonate was used (Table 3, entry 1).
Potassium carbonate or caesium carbonate, instead of
potassium bicarbonate gave (S)-8a in 61 and 76% yields
with 43 and 42% ee, respectively (Table 3, entries 2–3).
Using lithium carbonate as the base, the reaction gave a
higher enantioselectivity (51%) as compared to caesium
carbonate (Table 3, entry 4). Similar enantioselectivities
R
R
OAc
Ar
[Pd(n -allyl)Cl]2,2b
+ CH2R2
Ar
BSA/NaOAc, r.t.
Ar
* Ar
6
8
7
Entry Ar
R
Product Yielda(%) %eeb (conf.)
1
2
3
4
5
6
7
8
Ph
Ph
COOEt
8b
97
99
68
86
99
68
98
99
64
98
99
37
72
61
51
99
99
64
99
99
53 (S)
42 (S)
29 (S)
21 (S)
33 (S)
48 (S)
63 (S)
53 (S)
56 (S)
60 (S)
48 (S)
4 (S)
COOBn 8c
COOMe 8d
COOEt
2-BrC6H4
2-BrC6H4
2-BrC6H4
3-BrC6H4
3-BrC6H4
3-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
2-MeC6H4 COOMe 8 m
2-MeC6H4 COOEt 8n
2-MeC6H4 COOBn 8o
3-MeC6H4 COOMe 8p
3-MeC6H4 COOEt
8e
Table 3 Screening of bases in asymmetric allylic alkylation
COOBn 8 f
COOMe 8 g
MeOOC
COOMe
Ph
OAc
Ph
[Pd(n -allyl)Cl]2,2b
COOMe
COOMe
COOEt
8h
+
Ph
BSA/base, r.t.
COOBn 8i
Ph
7a
9
COOMe 8j
6a
8a
10
11
12
13
14
15
16
17
18
19
20
COOEt
8k
Entry
Base
T (°C)
Yielda (%)
%eeb (conf.)
COOBn 8l
1
2
3
4
5
6
7
8
9
KHCO3
K2CO3
Cs2CO3
Li2CO3
LiOAc
CsOAc
NaOAc
NaOAc
NaOAc
25
25
25
25
25
25
25
0
82
61
76
87
79
86
98
90
82
30 (S)
43 (S)
42 (S)
51 (S)
40 (S)
41 (S)
75 (S)
74 (S)
70 (S)
4 (S)
2 (S)
48 (S)
60 (S)
52 (S)
53 (S)
62 (S)
40 (S)
8q
3-MeC6H4 COOBn 8r
4-MeC6H4 COOMe 8 s
4-MeC6H4 COOEt
8t
4-MeC6H4 COOBn 8u
−10
Reaction conditions: [Pd(π-allyl)Cl]2 (0.0025 mmol), ligand 2b
(0.005 mmol), compound 6 (0.083 mmol), compound 7 (0.25 mmol),
BSA (0.25 mmol), NaOAc (0.1 mmol), CH2Cl2/THF (4 mL,v/v),
25°C, 12 h
Reaction conditions: [Pd(π-allyl)Cl]2 (0.0025 mmol), ligand
2b (0.005 mmol), compound 6a (0.083 mmol), compound 7a
(0.25 mmol), BSA (0.25 mmol), base (0.1 mmol), CH2Cl2/THF (4
mL,v/v), -10-25°C, 12 h
aIsolated yield
aIsolated yield
bThe enantiomeric excess and the absolute configuration of the prod-
ucts were determined using the same conditions as noted in Table 1
bThe enantiomeric excess and the absolute configuration of the prod-
ucts were determined using the same conditions as noted in Table 1
1 3

898
Z. Pang et al.
or electron-withdrawing groups at the ortho-, meta- or
para-position of the phenyl ring, were subjected to the
optimal set of reaction conditions. Moderate to good ees
were received when the electron-withdrawing groups at the
meta- orpara-position of the phenyl ring. (Table 4, entries
6–11 vs. 3–5). It was demonstrated that the nucleophile
have a significant impact on the reaction outcome. Com-
pared with dimethyl and dibenzyl malonate, when diethyl
malonate was used as the nucleophile, better ee values were
received (Table 4, entries 7, 10 vs. 6, 8, 9, 11). The same
trend was also observed when the electron-donating groups
groups at the meta- or para-position of the phenyl ring
(Table 4, entries 12–20). The results also suggested that
the electronic property of the substrate did not have a sig-
nificant impact on the reaction outcome when the substitu-
ent group at the meta- and para-posotion of the pheny ring
(Table 4, entries 6–11 vs. 15–20). And excellent yields and
good enantioselectivities were obtained when using diethyl
malonate as the nucleophile (Table 4, entries 7, 10, 16, 19).
and (1R,2R)-trans-1,2-cyclohexanediol were matched in
Rh-catalyzed asymmetric hydrogenation (Scheme 2). This
result was different from our previous conclusion in the
asymmetric allylic alkylation.
Ligand 2a proved to be effective for the hydrogenation
of N-(1-phenylvinyl)acetamide 11a (Scheme 2). The same
ee values but the opposite configuration for the product 12a
was received when 1b/[Rh(cod)2]BF4 was used as the cata-
lyst [31].
The Rh-catalyzed asymmetric hydrogenation of other
enamides (11b, 11c, 11e and 11f), which were not exam-
ined in our previous work,[31] were assessed. As shown
in Fig. 2, the hydrogenation appeared to be insensitive to
the position of the substituent on the phenyl ring. Moreo-
ver, the enantioselectivity was also obviously affected by
the presence of either electron-donating or electron-with-
drawing groups on the phenyl ring. Therefore, high enanti-
oselectivity was obtained by introducing the electron-with-
drawing groups at the para positions of the aryl group. To
our delight, up to 99% ee was obtained when using 11h as
the substrate. This is another successful case for substrate
11h that ever reported with phosphite ligands [38–41]. The
stereochemically matched combinations of (1S,2S)-trans-
1,2-cyclohexanediol backbone and (R)-binaphthyl in the
ligand 2a and (1R,2R)-trans-1,2-cyclohexanediol back-
bone and (S)-binaphthyl in the ligand 1b, were essential
for inducing high enantioselectivity. It is worth noting that,
unlike aromatic allylic acetates and dimethyl itaconate,
an (R)-binaphthyl fragment gives an (S)-product and con-
versely an (R)-product for an (S)-binaphthyl when enamide
was used as the substrate.
3.2 Rh-catalyzed asymmetric hydrogenation
It is noted that, for ligands 2a, (R)-BINOL was matched
cooperatively to the corresponding (1S,2S)-trans-1,2-cy-
clohexanediol skeleton, while for ligands 1b, (S)-BINOL
[Rh(cod)2]BF4, 2a/1b
COOMe
COOMe
MeOOC
MeOOC
CH2Cl2, H2 (10 atm), r.t., 6h
9
10
99% ee (R) 2a
99% ee (S) 1b
[Rh(cod)2]BF4, 2a/1b
NHAc
NHAc
4 Conclusion
CH2Cl2, H2 (10 atm), r.t., 4h
12a
91% (S) 2a
91% (R) 1b
11a
In summary, the newly catalytic systems, which were read-
ily constituted from a catalytic precursor [Pd(π-allyl)Cl]2
and ligands 2a-d, were successfully developed in the allylic
alkylation with up to 75% ee. The matched combination
Scheme 2 Rh-catalyzed asymmetric hydrogenation of dimethyl ita-
conate 9 and N-(1-phenylvinyl)acetamide 11a
Fig. 2 Selected results for
the asymmetric Rh-catalyzed
*
*
NHAc
*
NHAc
12d
*
NHAc
hydrogenation of substrates
11b–h using [Rh(cod)2]BF4/2a
catalytic system
NHAc
Cl
12e
12b
100%, 68% (S)
12c
100%, 89% (S)
100%, 90% (S)
100%, 60% (S)
*
*
*
NHAc
NHAc
NHAc
12f
Cl
Br
12h
12g
Cl
100%, 82% (S)
100%, 99% (S) 2a
100%, 99% (R) 1b
100%, 97% (S) 2a
100%, 99% (R) 1b
1 3

Asymmetric Allylic Alkylation and Hydrogenation with Transition Metal Complexes of Diphosphite…
899
15. Coll M, Pamies O, Dieguez M (2012) Dalton Trans 41:3038
of the chirality at C-1 and C-2 centers of (1S,2S)-trans-
1,2-cyclohexanediol backbone and (S)-binaphthyl moieties
was fundamental to obtain higher enantioselectivity and
activity using ligand 2b. The [Rh(cod)2]BF4/ ligands 1b
and 2a complexes respectively were found to be effective
in the asymmetric hydrogenation of dimethyl itaconate and
enamides, reaching up to 99% ee for dimethyl 2-methylsuc-
cinate and N-(1-(4-bromophenyl)ethyl)acetamide under the
optimal conditions. It is noted that ligand 1b is enantiomer
of ligand 2a, and for ligands 1b, (S)-BINOL and (1R,2R)-
trans-1,2-cyclohexanediol were matched, and (R)-BINOL
was matched cooperatively to the corresponding (1S,2S)-
trans-1,2-cyclohexanediol skeleton for ligands 2a. Moreo-
ver, the sense of the enantiodiscrimination of the products
was mainly determined by the configuration of the binaph-
thyl phosphite moieties. Additional studies highlighting the
potential of these ligands in other asymmetric reactions are
currently underway.
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1 3