Chiral P,Olefin Ligands with Rotamers for Palladium-Catalyzed Asymmetric Allylic Substitution Reactions

Article abstract of DOI:10.1055/s-0039-1690901

We synthesized a series of phosphine-olefin-type chiral aminophosphines, and we confirmed that these each exists as two rotamers at the C(aryl)-N(amine) bond. We also investigated the ability of these aminophosphines to act as chiral ligands for Pd-catalyzed asymmetric allylic substitution reactions, such as the alkylation of allylic acetates with malonates or indoles, and we found they gave high enantio-selectivities (up to 98% ee).

Full text of DOI:10.1055/s-0039-1690901

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–G
cluster
A
en
T. Mino et al.
Cluster
Synlett
Chiral P,Olefin Ligands with Rotamers for Palladium-Catalyzed
Asymmetric Allylic Substitution Reactions
Takashi Mino*a,b,c
R3
a R1 = OMe, R2 = H, R3 = R4 = Ph
Daiki Yamaguchia
Manami Kumadaa
Junpei Youdaa
Hironori Saitoa
Junya Tanakaa
b R1 = Me, R2 = H, R3 = R4 = Ph
N
R4
c R1–R2 = –(CH=CH)2–, R3 = R4 = Ph
d R1 = OMe, R2 = H, R3 = 1-Naph, R4 = Ph
e R1 = OMe, R2 = H, R3 = 2-Naph, R4 = Ph
f R1 = OMe, R2 = H, R3 = Ph, R4 = H
R1
R2
PPh2
(S)-6
Ph
Ph
O
O
R2
Yasushi Yoshidaa,b,c
Masami Sakamotoa,b
Pd/(S)-6d
Pd/(S)-6a
OAc
Ph
R1O
Ph
OR1
R
N
Ph
H
O
O
Ph
R
R1O
OR1
a Graduate School of Engineering, Chiba University, 1-33,
Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
N
H
R2
up to 94% ee
up to 98% ee
b Molecular Chirality Research Center, Chiba University, 1-33,
Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
c Soft Molecular Activation Research Center, Chiba University,
1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
tmino@faculty.chiba-u.jp
Published as part of the Cluster The Power of Transition Metals:
An Unending Well-Spring of New Reactivity
Received: 16.03.2020
Accepted after revision: 29.03.2020
Published online: 16.04.2020
the aminophosphine (aR)-4, were ineffective as chiral li-
gands in a Pd-catalyzed asymmetric allylic substitution re-
action.4a
DOI: 10.1055/s-0039-1690901; Art ID: st-2020-u0157-c
Our previous work
Abstract We synthesized a series of phosphine–olefin-type chiral ami-
nophosphines, and we confirmed that these each exists as two rotam-
ers at the C(aryl)–N(amine) bond. We also investigated the ability of
these aminophosphines to act as chiral ligands for Pd-catalyzed asym-
metric allylic substitution reactions, such as the alkylation of allylic ace-
tates with malonates or indoles, and we found they gave high enantio-
selectivities (up to 98% ee).
H
N
Ph
N
Ph
R1
R2
PPh2
R1
R2
PPh2
(aR)-1
(aR)-2
a: R1 = MeO, R2 = H
b: R1 = Me, R2 = H
c: R1–R2 = –(CH=CH)2–
a: R1 = Me, R2 = H
b: R1 –R2 = –(CH=CH)2–
c: R1 = i-Pr, R2 = H
Key words phosphines, ligands, rotamers, asymmetric catalysis, pal-
ladium catalysis, allylic acetates
Chiral ligands are important molecules that effect asym-
metric inductions in various transition-metal-catalyzed re-
actions such as Pd-catalyzed asymmetric allylic substitu-
tion reactions.1 Phosphine–olefin-type chiral ligands have
been developed and successfully used for transition-metal-
catalyzed asymmetric reactions.2,3 We recently reported
the synthesis of phosphine–olefin-type chiral ligands (aR)-
1 and (aR)-2 with C(aryl)–N(amine) bond axial chirality
(Figure 1).4,5 In these ligands, one substituent of the nitro-
gen atom at the axially chiral C(aryl)–N(amine) bond was a
bulky alkyl group, such as a 1- or 2-adamantyl group. We
also synthesized the aminophosphine 3, which has a less-
hindered substituent, in this case a cyclohexyl group; this
compound did not display axial chirality of the C(aryl)–
N(amine) bond.5 We also reported that analogues of amino-
phosphine (aR)-1c without an internal olefin group, such as
N
Ph
N
Ph
MeO
PPh2
PPh2
3
(aR)-4
Figure 1 Axially chiral-type P,olefin ligands 1 and 2, achiral-type P,ole-
fin ligand 3, and axially chiral-type P,N ligand 4
Miyano’s group reported the synthesis of such P,N li-
gands as the aminophosphine (S)-5, obtained from N-meth-
yl-[(1S)-1-phenylethyl]amine (Figure 2). They also reported
that a 1H NMR analysis of (S)-5 showed the existence of two
conformational isomers, both of which were inseparable at-
ropisomers as rotamers at the C(aryl)–N(amine) bond.
However, (S)-5 was not an effective chiral ligand for Pd-cat-
alyzed asymmetric allylic substitution.6
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
T. Mino et al.
Cluster
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R3
Previous work (Miyano’s group)
Ph
R3
NH
MeO
P(O)Ph2
NHLi
THF
N
7a
PPh2
(S)-8d (R3 = 1-Naph) 59%
(S)-8e (R3 = 2-Naph) 86%
(S)-5
R3
This work
R3
N
Ph
PhCH=CHCH2Br
K2CO3
MeO
P(O)Ph2
HSiCl3, Et3N
(S)-6d 65%
(S)-6e 67%
a R1 = OMe, R2 = H, R3 = R4 = Ph
N
R4
b R1 = Me, R2 = H, R3 = R4 = Ph
m-xylene, Δ
R1
R2
PPh2
MeCN, Δ
c R1–R2 = –(CH=CH)2–, R3 = R4 = Ph
d R1 = OMe, R2 = H, R3 = 1-Naph, R4 = Ph
e R1 = OMe, R2 = H, R3 = 2-Naph, R4 = Ph
f R1 = OMe, R2 = H, R3 = Ph, R4 = H
(S)-9d 31%
(S)-9e 72%
(S)-6
Scheme 2 Preparation of aminophosphines (S)-6d and (S)-6e
Figure 2 Chiral P,N ligand 5 and chiral P,olefin ligands 6
Chiral aminophosphine (S)-6f was prepared from phos-
phine oxide (S)-8a through N-alkylation with allyl bromide
and reduction of the resulting phosphine oxide (S)-9f
(Scheme 3). We confirmed that aminophosphines (S)-6a–f
each exist as two rotamers (ratio: 60:1 to 2:1) by 31P and/or
1H NMR analysis in CDCl3.
For our investigations into phosphine–olefin-type chiral
ligands with axial chirality, we were interested in phos-
phine–olefin-type ligands that exist as two rotamers. Here,
we report the synthesis of phosphine–olefin-type chiral
aminophosphines (S)-6 from [(1S)-1-phenylethyl]amine or
its derivatives. We also report the application of these prod-
ucts as chiral ligands for Pd-catalyzed asymmetric allylic
substitution reactions with high enantioselectivities (up to
98% ee).
Chiral aminophosphines (S)-6a–c were prepared in
three steps from the corresponding phosphine oxides 77,8
through an SNAr reaction with the nucleophilic lithium am-
ide from [(1S)-1-phenylethyl]amine followed by N-alkyla-
tion with cinnamyl bromide and reduction of the resulting
phosphine oxides 9a–c with trichlorosilane–triethylamine
(Scheme 1).
Ph
N
CH2=CHCH2Br
MeO
P(O)Ph2 HSiCl , Et N
3 3
K2CO3
(S)-8a
(S)-6f
50%
m-xylene, Δ
MeCN, Δ
(S)-9f
84%
Scheme 3 Preparation of aminophosphines (S)-6f
We investigated the ability of aminophosphines (S)-6 to
act as chiral ligands for such Pd-catalyzed asymmetric allyl-
ic substitution reactions as the alkylation of allylic acetates
with malonates.10 The reaction of 1,3-diphenylprop-2-enyl
acetate with dimethyl malonate was performed as a model
Ph
Ph
NHLi
THF
OMe
NH
R1
R2
P(O)Ph2
R1
R2
P(O)Ph2
reaction (Table 1). The reaction with
2 mol% of
[Pd(C3H5)Cl]2 and 4 mol% of (S)-6a as a catalyst (Pd/ligand =
1:1) and 10 mol% of NaOAc as a base in toluene containing
3.0 equivalents of N,O-bis(trimethylsilyl)acetamide (BSA) at
room temperature for 24 hours gave the corresponding
product (S)-10a in 85% yield and 84% ee (Table 1, entry 1).
We also tested (S)-6b–f as chiral ligands in this reaction,
and we found that (S)-6d was the most effective ligand with
a high enantioselectivity (93% ee; entry 4). We then exam-
ined the effect of changing the base in the reaction with (S)-
6d in toluene (entries 4, 7, and 8). When LiOAc or KOAc was
used as the base, the enantioselectivity decreased to 76 and
91% ee, respectively. We next investigated the effects of var-
ious solvents (entries 4 and 9–12). When THF was used as
the solvent, the enantioselectivity of the product decreased
dramatically to 58% ee (entry 9), but when the reaction was
carried out in dichloromethane or acetonitrile, the enantio-
selectivity of the product decreased slightly (entries 10 and
11). When the reaction was carried out in (trifluoro-
methyl)benzene, the enantioselectivity increased to 94% ee
7a R1 = MeO, R2 = H
7b R1 = Me, R2 = H
(S)-8a 75%
(S)-8b 71%
(S)-8c 83%
7c R1–R2 = –(CH=CH)2–
Ph
N
Ph
P(O)Ph2
PhCH=CHCH2Br
K2CO3
R1
R2
HSiCl3, Et3N
(S)-6a 50%
(S)-6b 51%
(S)-6c 35%
m-xylene, Δ
MeCN, Δ
(S)-9a 84%
(S)-9b 59%
(S)-9c 79%
Scheme 1 Preparation of aminophosphines (S)-6a–c
We similarly prepared the chiral aminophosphines (S)-6d
and (S)-6e from phosphine oxide 7a by using [(1S)-1-(1-
naphthyl)ethyl]amine or [(1S)-1-(2-naphthyl)ethyl]amine,
respectively, instead of [(1S)-1-phenylethyl]amine (Scheme
2).9
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

C
T. Mino et al.
Cluster
Synlett
(entry 12). By using the optimized conditions (entry 12),
we then examined the scope of the allylic alkylation of vari-
ous malonates with allylic esters in the presence of (S)-6d
and NaOAc in (trifluoromethyl)benzene at room tempera-
ture for 24 hours.11 The reaction of 1,3-diphenylprop-2-
enyl acetate with diethyl malonate instead of dimethyl
malonate gave the corresponding product (S)-10b in 81% ee
(entry 13). On using di-tert-butyl malonate, the enantiose-
lectivity of the product decreased dramatically to 59% ee
(entry 14). On the other hand, the reactions of dibenzyl
malonate and diethyl methylmalonate gave the correspond-
ing products (S)-10d and (R)-10e with 79 and 76% ee, re-
spectively (entries 15 and 16). When the reaction was car-
ried out with 1,3-di(4-chlorophenyl)prop-2-enyl acetate
instead of 1,3-diphenylprop-2-enyl acetate, the corre-
sponding product (S)-10f was obtained at a similar level of
enantioselectivity (93% ee; entry 17). On the other hand,
with 1,3-diphenylprop-2-enyl pivalate instead of the ace-
tate, the enantioselectivity of product 10a decreased to 81%
ee (entry 18).
Next, we investigated the ability of aminophosphines
(S)-6 to act as chiral ligands for the Pd-catalyzed asymmet-
ric allylic substitution reaction of indoles.12 The reaction of
1,3-diphenylprop-2-enyl acetate with indole was per-
formed in the presence of 3 mol% of [Pd(C3H5)Cl]2 and 6
mol% of ligand (Pd/ligand = 1:1) as a model reaction (Table
2). The reaction with (S)-6a as a ligand and two equivalents
of K2CO3 as a base in acetonitrile at 40 °C for 18 hours gave
the corresponding product (R)-11a in 66% yield with good
enantioselectivity (95% ee) (Table 2, entry 1). We tested the
other aminophosphines (S)-6b–f in this reaction and found
that aminophosphine (S)-6a was the most effective ligand
Table 1 Palladium-Catalyzed Asymmetric Allylic Substitution Reactions in the Presence of (S)-6a
OAc
[Pd(C3H5)Cl]2 (4 mol% Pd)
Ph
Ph
(S)-6 (4 mol%)
base (10 mol%)
BSA (3 equiv)
O
O
+
R2
O
O
R1O
Ph
OR1
R1O
OR1
Ph
solvent (0.5 M), r.t., 24 h
R2
10
3 equiv
Entry
Ligand
R1
Me
R2
Solvent
Base
Product
Yieldb (%)
eec (%)
1
2
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(S)-6e
(S)-6f
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
(S)-6d
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
THF
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
LiOAc
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10b
10c
10d
10e
10f
85
73
62
87
76
90
92
85
80
76
90
86
63
61
78
52
83
84
84
51
28
93
88
83
76
91
58
84
88
94
81
59
79
76
93
81
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
4
5
6
7
8
KOAc
9
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
10
11
12
13
14
15
16
17d
18e
CH2Cl2
MeCN
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
t-Bu
Bn
Et
Me
Me
Me
H
H
10a
a The reactions were carried out on 0.2 mmol scale of the allyl ester in various solvents (0.4 mL) at r.t. with 3.0 equiv of malonate and BSA in the presence of base
(10 mol%), (S)-6 (4 mol%) and [Pd(C3H5)Cl]2 (2 mol%; 4 mol% Pd).
b Isolated yield.
c Determined by HPLC analysis on a chiral column.
d This reaction was carried out using 1,3-di(4-chlorophenyl)prop-2-enyl acetate instead of 1,3-diphenylprop-2-enyl acetate.
e This reaction was carried out using 1,3-diphenyl-2-propenyl pivalate instead of 1,3-diphenyl-2-propenyl acetate.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

D
T. Mino et al.
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(entry 1). We next investigated the effects of various sol-
vents with K2CO3 (entries 1 and 7–10). The use of THF, di-
chloromethane, or (trifluoromethyl)benzene as a solvent
instead of acetonitrile gave (R)-11a with a similar level of
enantioselectivity (entries 7–9). When the reaction was
carried out in toluene, the enantioselectivity of (R)-11a rose
to 97% ee (entry 10). We also changed the base for the reac-
tion in toluene (entries 10–13). On using Na2CO3 and Cs2CO3
as a base, the enantioselectivity of (R)-11a decreased (en-
tries 11 and 12). When the reaction was carried out with
KOAc instead of K2CO3, the product (R)-11a was obtained at
a similar level of enantioselectivity (97% ee) and in a good
yield (74%) (entry 17).
carried out with 1,3-diphenylprop-2-enyl pivalate instead
of the acetate, product (R)-11a was obtained at a similar
level of enantioselectivity (98% ee; entry 13).
Table 3 Palladium-Catalyzed Asymmetric Allylic Alkylation of Indoles
in the Presence of (S)-6aa
4
3
5
[Pd(C3H5)Cl]2 (6 mol% Pd)
(S)-6a (6 mol%)
Ph
R
2
Ph
6
N
H
KOAc (2 equiv)
7
+
R
OAc
N
PhMe (1.0 M), 40 °C, 18 h
H
Ph
Ph
1.2 equiv
11
Entry
R
Product
Yieldb (%)
eec (%)
Table 2 Optimization of the Palladium-Catalyzed Asymmetric Allylic
Substitution Reaction of Indole in the Presence of (S)-6a
1
2
H
11a
11b
74
54
71
56
68
73
74
67
58
64
46
85
64
97
91
82
77
95
97
97
95
97
94
94
96
98
6-Me
[Pd(C3H5)Cl]2 (6 mol% Pd)
(S)-6 (6 mol%)
Ph
3
6-MeO
6-BnO
6-O2N
6-F
11c
11d
11e
11f
Ph
N
H
base (2 equiv)
4
+
OAc
N
solvent (1.0 M), 40 °C, 18 h
5
H
Ph
Ph
6
1.2 equiv
11a
7
6-Cl
11g
11h
11i
Entry
Ligand
Base
K2CO3
Solvent
Yieldb (%)
eec (%)
8
6-Br
5-Br
4-Br
7-Br
2-Ph
H
9
1
2
(S)-6a
(S)-6b
(S)-6c
(S)-6d
(S)-6e
(S)-6f
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
(S)-6a
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
66
72
73
76
79
52
81
76
62
60
78
66
74
95
84
85
87
89
73
94
95
95
97
93
93
97
10
11
12
13d
11j
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOAc
11k
11l
3
4
11m
5
a The reactions were carried out on 0.2 mmol scale of indole derivative in
PhMe (0.4 mL) at 40 °C with 1.2 equivalents of the allyl ester and 2 equiva-
lents of KOAc in the presence of (S)-6a (6 mol%) and [Pd(C3H5)Cl]2 (3 mol%;
6 mol% Pd).
6
7
8
CH2Cl2
PhCF3
PhMe
PhMe
PhMe
PhMe
b Isolated yield.
c Determined by HPLC analysis on a chiral column.
d This reaction was carried out using 1,3-diphenylprop-2-enyl pivalate in-
stead of 1,3-diphenylprop-2-enyl acetate.
9
10
11
12
13
According to the observed stereochemical outcome as
well as our previous relevant reports,4,5 we propose a possi-
ble pathway for product formation (Scheme 4). We recently
reported that the chiral ligands (aR)-1 with C(aryl)–
N(amine) bond axial chirality gave (S)-products 10 in a Pd-
catalyzed asymmetric allylic substitution reactions with
malonates.4a We also reported that the chiral ligands (aR)-1
and (aR)-2 gave (R)-products 11 in allylic substitution reac-
tions with indoles.4b,5 In the case of (S)-6a, these reactions
gave (S)-products 10 and (R)-products 11, respectively. A
single-crystal X-ray analysis of (S)-9a,14 a derivative of (S)-
6a oxidized at the phosphorus atom, showed that torsion at
the C(aryl)–N(amine) bond provides a stable (pseudo-aR)-
type rotamer (see Supplementary Information, Figure S1).
As shown in Scheme 4, the pseudo-axial chirality of (S)-6a
at the C(aryl)–N(amine) bond also seems to provide a
(pseudo-aR)-type rotamer II that is more stable than the
corresponding (pseudo-aS)-type rotamer I. Such Pd(II) com-
a The reactions were carried out on a 0.2 mmol scale of indole in various
solvent (0.4 mL) at 40 °C with 1.2 equivalents of 1,3-diphenylprop-2-enyl
acetate and 2 equivalents of base in the presence of (S)-6 (6 mol%) and
[Pd(C3H5)Cl]2 (3 mol%; 6 mol% Pd).
b Isolated yield.
c Determined by HPLC analysis on a chiral column.
Using the optimized conditions (Table 2, entry 17), we
examined the scope of the allylic alkylation of various in-
doles with 1,3-diphenylprop-2-enyl acetate in the presence
of (S)-6a in toluene with KOAc at 40 °C (Table 3).13 The reac-
tions of the 6-substituted indoles gave the corresponding
products (R)-11b–h in good to high enantioselectivities
(77–97% ee; Table 3, entries 2–8). The reactions with bro-
moindoles and 2-phenylindole also proceeded with high
enantioselectivities (entries 9–12). When the reaction was
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

E
T. Mino et al.
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Synlett
plexes as M-type A and W-type B intermediates are formed
from (pseudo-aR)-type (S)-6a. Intermediate B is favored
over intermediate A due to the steric effect. A nucleophile
preferentially attacks the carbon at the position trans to the
phosphorus of the ligand from the outside.3p,15 Finally, (S)-
products 10 or (R)-products 11 are obtained from Pd(0)
complex C.
Funding Information
This work was supported by Grants-in-Aid for Scientific Research (C)
(Nos. 26410109 and 18K05117) from the Japan Society for the Pro-
motion of Science (JSPS).
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Supporting Information
Supporting information for this article is available online at
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https://doi.org/10.1055/s-0039-1690901.
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MeO
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References and Notes
P
N
H
(1) For selected reviews, see: (a) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz,
B. M. Acc. Chem. Res. 2015, 48, 740. (b) Trost, B. M. Tetrahedron
2015, 71, 5708. (c) Trost, B. M. Org. Process Res. Dev. 2012, 16,
185. (d) Guerrero Rios, I.; Rosas-Hernandez, A.; Martin, E. Mole-
cules 2011, 16, 970. (e) Diéguez, M.; Pàmies, O. Acc. Chem. Res.
2010, 43, 312. (f) Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2,
1476. (g) Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal. 2004, 346,
497. (h) Trost, B. M. J. Org. Chem. 2004, 69, 5813. (i) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921. (j) Graening, T.;
Schmalz, H.-G. Angew. Chem. Int. Ed. 2003, 42, 2580. (k) Trost, B.
M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(pseudo-aR)-type (II)
(pseudo-aS)-type (I)
OAc
Ph
Ph
PdII
Pd0
AcO
N
MeO
Me
Ph
P
MeO
P
N
Me
Ph
H
H
(2) For a review, see: Feng, X.; Du, H. Chin. J. Org. Chem. 2015, 35,
259.
A
(3) (a) Kamikawa, K.; Tseng, Y.-Y.; Jian, J.-H.; Takahashi, T.;
Ogasawara, M. J. Am. Chem. Soc. 2017, 139, 1545. (b) Gandi, V.
R.; Lu, Y.; Hayashi, T. Tetrahedron: Asymmetry 2015, 26, 679.
(c) Liu, Y.; Feng, X.; Du, H. Org. Biomol. Chem. 2015, 13, 125.
(d) Ogasawara, M.; Tseng, Y.-Y.; Arae, S.; Morita, T.; Nakaya, T.;
Wu, W.-Y.; Takahashi, T.; Kamikawa, K. J. Am. Chem. Soc. 2014,
136, 9377. (e) Wang, H.-L.; Hu, R.-B.; Zhang, H.; Zhou, A.-X.;
Yang, S.-D. Org. Lett. 2013, 15, 5302. (f) Liu, Z.; Du, H. Org. Lett.
2013, 15, 740. (g) Liu, Y.; Cao, Z.; Du, H. J. Org. Chem. 2012, 77,
4479. (h) Cao, Z.; Liu, Z.; Liu, Y.; Du, H. J. Org. Chem. 2011, 76,
6401. (i) Shintani, R.; Narui, R.; Tsutsumi, Y.; Hayashi, S.;
Hayashi, T. Chem. Commun. 2011, 47, 6123. (j) Liu, Z.; Cao, Z.;
Du, H. Org. Biomol. Chem. 2011, 9, 5369. (k) Cao, Z.; Liu, Y.; Liu,
Z.; Feng, X.; Zhuang, M.; Du, H. Org. Lett. 2011, 13, 2164. (l) Liu,
Z.; Du, H. Org. Lett. 2010, 12, 3054. (m) Stemmler, R. T.; Bolm, C.
Synlett 2007, 1365. (n) Duan, W.-L.; Iwamura, H.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2007, 129, 2130. (o) Kasák, P.;
Arion, V. B.; Widhalm, M. A. Tetrahedron: Asymmetry 2006, 17,
3084. (p) Shintani, R.; Duan, W.-L.; Okamoto, K.; Hayashi, T. Tet-
rahedron: Asymmetry 2005, 16, 3400. (q) Shintani, R.; Duan, W.-
L.; Nagano, T.; Okada, A.; Hayashi, T. Angew. Chem. Int. Ed. 2005,
44, 4611. (r) Marie, P.; Deblon, S.; Breher, F.; Geier, J.; Böhler, C.;
Rüegger, H.; Schönberg, H.; Grützmacher, H. Chem. Eur. J. 2004,
10, 4198.
Nu
Pd0
PdII
Nu
AcO
N
MeO
MeO
P
P
N
Me
Ph
Me
Ph
H
H
B
C
Nu
Ph
Ph
(S)-10 or (R)-11
Scheme 4 Possible stereochemical pathway
In conclusion, we found two rotamers at the C(aryl)–
N(amine) bond exist for the phosphine–olefin-type chiral
aminophosphines (S)-6 (ratio: 60:1 to 2:1). A Pd-catalyzed
asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl
acetate with malonates using the aminophosphine (S)-6d
as a chiral ligand gave the desired products (S)-10 with
good enantioselectivities (up to 94% ee). We also found that
a Pd-catalyzed asymmetric allylic alkylation of 1,3-diphen-
ylprop-2-enyl acetate with indoles in the presence of the
chiral ligand (S)-6a gave the desired products (R)-11 with
high enantioselectivities (up to 98% ee).
(4) (a) Mino, T.; Youda, J.; Ebisawa, T.; Shima, Y.; Nishikawa, K.;
Yoshida, Y.; Sakamoto, M. J. Oleo Sci. 2018, 67, 1189. (b) Mino,
T.; Nishikawa, K.; Asano, M.; Shima, Y.; Ebisawa, T.; Yoshida, Y.;
Sakamoto, M. Org. Biomol. Chem. 2016, 14, 7509.
(5) Mino, T.; Yamaguchi, D.; Masuda, C.; Youda, J.; Ebisawa, T.;
Yoshida, Y.; Sakamoto, M. Org. Biomol. Chem. 2019, 17, 1455.
(6) Hattori, T.; Komuro, Y.; Hayashizaka, N.; Takahashi, H.; Miyano,
S. Enantiomer 1997, 2, 203.
(7) Mino, T.; Tanaka, Y.; Sakamoto, M.; Fujita, T. Tetrahedron: Asym-
metry 2001, 12, 2435.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

F
T. Mino et al.
Cluster
Synlett
(8) (a) Mino, T.; Tanaka, Y.; Sakamoto, M.; Fujita, T. Heterocycles
2000, 53, 1485. (b) Hattori, T.; Sakamoto, J.; Hayashizaka, N.;
Miyano, S. Synthesis 1994, 199.
(9) [2-(Diphenylphosphoryl)-6-methoxyphenyl][(1S)-1-phenyl-
ethyl]amine [(S)-8a]
method of full-matrix least–squares, where the final R and Rw
were 0.0327, 0.0875, respectively, for 4982 reflections.
[2-(Diphenylphosphino)-6-methoxyphenyl][(1S)-1-phenyl-
ethyl][(2E)-3-phenylprop-2-en-1-yl]amine [(S)-6a]
To a mixture of phosphine oxide (S)-9a (1.09 g, 2.0 mmol) and
Et3N (3.1 mL, 22 mmol) in m-xylene (10 mL) was added HSiCl3
(2.0 mL, 20 mmol) at 0 °C under Ar. The mixture was stirred at
120 °C for 24 h then cooled to r.t. and diluted with Et2O. The
reaction was quenched with 2 M aq NaOH, and the organic layer
was washed with brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by chromatography
[silica gel, hexane–EtOAc (50:1)]. to give a white solid; yield
A 1.6 M solution of BuLi in hexane (9.4 mL, 15.0 mmol) was
slowly added to a solution of [(1S)-1-phenylethyl]amine (1.82 g,
15.0 mmol) in THF (35 mL) at –80 °C. Phosphine oxide 7a (1.69
g, 5.0 mmol) was added at r.t., and the mixture was stirred for
21 h at r.t. The mixture was then diluted with Et2O, and the
reaction was quenched with sat. aq NH4Cl. The organic layer
was washed with brine, dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by chromatography
[silica gel, hexane–EtOAc (2:1)] to give a beige solid; yield: 1.60
g (75%, 3.74 mmol); mp 124–126 °C; []D20 +99.1 (c 0.50, CHCl3).
1H NMR (300 MHz, CDCl3):  = 7.68–7.53 (m, 6 H), 7.50–7.41 (m,
4 H), 7.36 (br s, 1 H), 7.15–7.12 (m, 2 H), 7.06–7.03 (m, 3 H),
6.79 (d, J = 7.1 Hz, 1 H), 6.56 (dt, J = 3.6 and 7.8 Hz, 1 H), 6.42
(ddd, J = 1.4, 7.7, 14.0 Hz, 1 H), 5.10 (t, J = 6.1 Hz, 1 H), 3.69 (s, 3
H), 1.33 (d, J = 6.8 Hz, 3 H). 13C NMR (75 MHz, CDCl3):  = 150.7
20
0.530 g (50%. 1.0 mmol); mp 55–56 °C; []D +59.6 (c 0.51,
CHCl3); rotamer ratio = 20:1.
1H NMR (300 MHz, CDCl3):  (major rotamer) = 7.66 (d, J = 8.0
Hz, 2 H), 7.37–7.04 (m, 19 H), 6.86 (dd, J = 1.0, 8.1 Hz, 1 H), 6.53
(ddd, J = 1.3, 2.8, 7.6 Hz, 1 H), 6.04–5.94 (m, 1 H), 5.85 (d, J = 15.9
Hz, 1 H), 4.59 (q, J = 6.5 Hz, 1 H), 3.83 (s, 3 H), 3.58–3.42 (m, 2
H), 0.89 (d, J = 6.7 Hz, 3 H);  (minor rotamer) = 7.66 (d, J = 7.4
Hz, 2 H), 7.37–7.04 (m, 19 H), 6.64 (dd, J = 1.0, 8.1 Hz, 1 H),
6.42–6.39 (m, 1 H), 6.09 (d, J = 16.1 Hz, 1 H), 5.76–5.68 (m, 1 H),
4.81 (q, J = 6.5 Hz, 1 H), 3.75 (s, 3 H), 3.58–3.42 (m, 2 H), 1.50 (d,
J = 6.9 Hz, 3 H). 13C NMR (75 MHz, CDCl3):  = 159.3 (d, JCP = 3.9
Hz), 147.1, 141.9 (d, JCP = 4.2 Hz), 141.1 (d, JCP = 22.0 Hz), 138.7
(d, JCP = 11.6 Hz), 146.4, 144.1 (d, JCP = 5.5 Hz), 133.0 (d, JCP
103.9 Hz), 132.6 (d, JCP = 104.5 Hz), 132.2 (d, JCP = 10.1 Hz) (2 C),
132.0 (d, JCP = 9.9 Hz) (2 C), 131.8 (d, JCP = 2.5 Hz), 131.7 (d, JCP
2.5 Hz), 128.4 (d, JCP = 12.2 Hz) (4 C), 127.9 (2 C), 126.2 (2 C),
126.0, 125.6 (d, JCP = 11.0 Hz), 117.5 (d, JCP = 15.5), 115.6 (d, JCP
=
=
=
(d, JCP = 14.4 Hz), 138.5 (d, JCP = 15.1 Hz), 137.6, 134.2 (d, JCP =
2.5 Hz), 115.5 (d, JCP = 104.2 Hz), 55.5, 55.4, 24.6. 31P NMR (121
MHz, CDCl3):  = 37.5. EI-MS: m/z (%): 427 (M+, 30), 412 (100).
HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C27H27NO2P:
428.1774; found: 428.1766.
[2-(Diphenylphosphoryl)-6-methoxyphenyl][(1S)-1-phenyl-
ethyl][(2E)-3-phenylprop-2-en-1-yl]amine [(S)-9a]
To the solution of the phosphine oxide (S)-8a (2.14 g, 5.0 mmol)
in MeCN (50 mL) at r.t. were added K2CO3 (3.46 g, 25 mmol) and
cinnamyl bromide (1.18 g, 6.0 mmol) in MeCN (20 mL), and the
mixture was stirred at 60 °C for 22 h. The mixture was then fil-
tered and concentrated under reduced pressure. The residue
was purified by chromatography [silica gel, hexane–EtOAc
(5:1)] to give a white solid; yield: 2.29 g (84%, 4.22 mmol); mp
169–171 °C; []D20 +53.1 (c 0.36, CHCl3).
20.5 Hz) (2 C), 134.0 (d, JCP = 20.5 Hz) (2 C), 130.1, 129.0,
128.2(8) (d, JCP = 2.0 Hz) (2 C), 128.2(6), 128.2(2) (d, JCP = 1.0 Hz)
(2 C), 128.1(4) (2 C), 128.0(9) (d, JCP = 1.0 Hz) (2 C), 128.0(3),
128.0(1) (2 C), 126.9, 126.6, 126.4 (2 C), 126.1 (2 C), 111.9, 61.6,
56.3, 55.1, 23.5. 31P NMR (121 MHz, CDCl3):  (major rotamer) =
−16.0;  (minor rotamer) = −14.1. EI-MS: m/z (%) = 527 (M+, 8.2),
422 (100). HRMS (ESI-Orbitrap): m/z [M
36H35NOP: 528.2451; found: 528.2441.
+
H]+ calcd for
C
(10) For recent examples, see: (a) Li, S.; Zhang, J.; Li, H.; Feng, L.;
Peng Jiao, P. J. Org. Chem. 2019, 84, 9460. (b) Imrich, M. R.;
Maichle-Mö ssmer, C.; Ziegler, T. Eur. J. Org. Chem. 2019, 3955.
(c) Hu, Y.-L.; Wang, Z.; Yang, H.; Chen, J.; Wu, Z.-B.; Lei, Y.; Zhou,
L. Chem. Sci. 2019, 10, 6777. (d) Baumann, T.; Brückner, R.
Angew. Chem. Int. Ed. 2019, 58, 4714. (e) Qiu, Z.; Sun, R.; Teng, D.
Org. Biomol. Chem. 2018, 16, 7717. (f) Borràs, C.; Elias-Rodri-
guez, P.; Carmona, A. T.; Robina, I.; Pàmies, O.; Diéguez, M.
Organometallics 2018, 37, 1682. (g) Argüelles, A. J.; Sun, S.;
Budaitis, B. G.; Nagorny, P. Angew. Chem. Int. Ed. 2018, 57, 5325.
(h) Biosca, M.; Margalef, J.; Caldentey, X.; Besora, M.; Rodriguez-
Escrich, C.; Saltó, J.; Cambeiro, X. C.; Maseras, F.; Pàmies, O.;
Diéguez, M.; Pericàs, M. A. ACS Catal. 2018, 8, 3587. (i) Chang, S.;
Wang, L.; Lin, X. Org. Biomol. Chem. 2018, 16, 2239.
(j) Naganawa, Y.; Abe, H.; Nishiyama, H. Chem. Commun. 2018,
54, 2674. (k) Szulc, I.; Kołodziuk, R.; Zawisza, A. Tetrahedron
2018, 74, 1476. (l) Yao, L.; Nie, H.; Zhang, D.; Wang, L.; Zhang, Y.;
Chen, W.; Li, Z.; Liu, X.; Zhang, S. ChemCatChem 2018, 10, 804.
(m) Sartorius, F.; Trebing, M.; Brückner, C.; Brückner, R. Chem.
Eur. J. 2017, 23, 17463. (n) Ogasawara, M.; Tseng, Y.-Y.; Uryu, M.;
Ohya, N.; Chang, N.; Ishimoto, H.; Arae, S.; Takahashi, T.;
Kamikawa, K. Organometallics 2017, 36, 4061.
1H NMR (300 MHz, CDCl3):  = 7.84–7.73 (m, 4 H), 7.47–7.38 (m,
8 H), 7.24–7.01 (m, 10 H), 6.66 (ddd, J = 1.2, 7.7, 13.9 Hz, 1 H),
5.83 (d, J = 15.9 Hz, 1 H), 5.33 (ddd, J = 7.0, 7.0, 15.9 Hz, 1 H),
4.67 (q, J = 6.0 Hz, 1 H), 3.73 (dd, J = 7.5, 7.6 Hz, 1 H), 3.67 (s, 3
H), 3.26 (dd, J = 6.5, 15.1 Hz, 1 H), 1.11 (d, J = 6.7 Hz, 3 H). 13C
NMR (75 MHz, CDCl3):  = 160.1 (d, JCP = 11.5 Hz), 145.3, 143.8
(d, JCP = 4.4 Hz), 137.8, 134.7 (d, JCP = 106.6 Hz), 134.0 (d, JCP
=
105.3 Hz), 133.0 (d, JCP = 103.8 Hz), 132.1 (d, JCP = 9.0 Hz) (2 C),
131.1(931) (d, JCP = 2.6 Hz), 131.1(925) (d, JCP = 9.4 Hz) (2 C),
131.0 (d, JCP = 2.8 Hz), 129.5, 128.9, 128.5 (2 C), 128.2 (d, JCP
=
12.2 Hz) (2 C), 128.1 (d, JCP = 11.7 Hz) (2 C), 128.0 (2 C), 127.6 (2
C), 126.7 (d, JCP = 12.4 Hz), 126.4, 126.3, 126.2 (d, JCP = 3.3 Hz),
126.0 (2 C), 115.6 (d, JCP = 2.3 Hz), 62.3, 56.9, 55.1, 22.4. 31P NMR
(121 MHz, CDCl3):  = 27.5. EI-MS: m/z (%) = 543 (M+, 0.15), 438
(100). HRMS (ESI-Orbitrap): m/z [M + H]+ calcd for C36H35NO2P:
544.2400; found: 544.2388.
X-ray diffraction analysis: Colorless plate crystals (0.20 × 0.10 ×
0.020 mm3) from hexane–CHCl3; monoclinic space group P21, a
= 12.4152(3) Å, b = 8.9538(2) Å, c = 13.5274(3) Å,  =
103.4670(10)°, V = 1462.40(6) Å3, Z = 2,  = 1.235 g/cm3,  (Cu
K) = 1.54178 mm–1. The structure was solved by the direct
(11) Palladium-Catalyzed Allylic Alkylation of Malonates;
General Procedure
BSA (0.15 mL, 0.60 mmol) and the appropriate allylic ester (0.20
mmol) were added to a mixture of [Pd(C3H5)Cl]2 (1.48 mg, 4
mol), (S)-6d (4.64 mg, 8 mol), and NaOAc (1.64 mg, 20 mol)
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

G
T. Mino et al.
Cluster
Synlett
in PhCF3 (0.4 mL) at r.t. under Ar, and the mixture was stirred for
10 min. A dialkyl malonate (0.60 mmol) was added, and stirring
was continued for 24 h at r.t. The mixture was then diluted with
Et2O and water. The organic layer was washed with brine then
dried (MgSO4), filtered, and concentrated in a rotary evaporator.
The residue was purified by column chromatography [silica gel,
hexane–EtOAc (10:1)].
indole (0.2 mmol), the appropriate 1,3-diarylprop-2-enyl
acetate (60.6 mg, 0.24 mmol), (S)-6a (6.3 mg, 12 mol),
[Pd(C3H5)Cl]2 (2.2 mg, 6 mol), and KOAc (39.3 mg, 0.4 mol) at
r.t. under Ar, and the mixture was stirred for 18 h at 40 °C. The
reaction was quenched with H2O, and the mixture was diluted
with Et2O. The organic layer was washed with H2O and brine
then dried (MgSO4), filtered, and concentrated in a rotary evap-
orator. The residue was purified by column chromatography
[silica gel, hexane–EtOAc–Et3N (20:2:1)].
Dimethyl
[(1S,2E)-1,3-Diphenylprop-2-en-1-yl]malonate
[(S)-10a]16
20
Colorless oil; yield: 55.7 mg (86%, 0.172 mmol, 94% ee); []D
–21.6 (c 0.51, CHCl3). HPLC [Daicel CHIRALPAK AD-H, 0.46 × 25
cm,  = 254 nm, hexane–i-PrOH (90:10), 0.5 mL/min]: tR = 26.3
min (minor), 33.3 min (major). 1H NMR (400 MHz, CDCl3):  =
7.34–7.18 (m, 10 H), 6.48 (d, J = 15.8 Hz, 1 H), 6.33 (dd, J = 8.4,
15.7 Hz, 1 H), 4.27 (dd, J = 8.1, 8.6 Hz, 1 H), 3.95 (d, J = 10.8 Hz, 1
H), 3.70 (s, 3 H), 3.52 (s, 3 H). 13C NMR (101 MHz, CDCl3):  =
168.2, 167.8, 140.2, 136.8, 131.9, 129.1, 128.7, 128.5, 127.9,
127.6, 127.2, 126.4, 57.7, 52.7, 52.5, 49.2. EI-MS: m/z (%) = 324
(M+, 13).
3-[(1R,2E)-1,3-Diphenylprop-2-en-1-yl]-1H-indole [(R)-11a]4
Yellow solid; yield: 48.0 mg (74%, 0.146 mmol, 97% ee); mp
20
118–120 °C; []D –35.3 (c 0.19, CHCl3). HPLC [Daicel CHIRAL-
PAKIB, 0.46 × 25 cm,  = 254 nm, hexane–EtOH (99:1), 0.7
mL/min]: tR = 56.3 min (major), 63.9 min (minor). 1H NMR (400
MHz, CDCl3):  = 7.98 (br s, 1 H), 7.43–7.15 (m, 13 H), 7.04–7.00
(m, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 6.73 (dd, J = 7.4, 15.8 Hz, 1 H),
6.43 (d, J = 15.9 Hz, 1 H), 5.12 (d, J = 7.3 Hz, 1 H). 13C NMR (101
MHz, CDCl3):  = 143.3, 137.5, 136.6, 132.5, 130.5, 128.5 (2 C),
128.4, 127.1, 126.8, 126.4, 126.3, 122.6, 122.1, 119.9, 119.4,
118.7, 111.1, 46.2. EI-MS: m/z (%) 309 (M+, 100).
(12) For examples, see: (a) Qiu, Z.; Sun, R.; Yang, K.; Teng, D. Mole-
cules 2019, 24, 1575. (b) Zhang, L.; Xiang, S.-H.; Wang, J.; Xiao, J.;
Wang, J.-Q.; Tan, B. Nat. Commun. 2019, 10, 566. (c) Yamamoto,
K.; Shimizu, T.; Igawa, K.; Tomooka, K.; Hirai, G.; Suemune, H.;
Usui, K. Sci. Rep. 2016, 6, 36211. (d) Feng, B.; Pu, X.-Y.; Liu, Z.-C.;
Xiao, W.-J.; Chen, J.-R. Org. Chem. Front. 2016, 3, 1246. (e) Xu, J.-
X.; Ye, F.; Bai, X.-F.; Zhang, J.; Xu, Z.; Zheng, Z.-J.; Xu, L.-W. RSC
Adv. 2016, 6, 45495. (f) Mino, T.; Ishikawa, M.; Nishikawa, K.;
Wakui, K.; Sakamoto, M. Tetrahedron: Asymmetry 2013, 24, 499.
(g) Hoshi, T.; Sasaki, K.; Sato, S.; Ishii, Y.; Suzuki, T.; Hagiwara, H.
Org. Lett. 2011, 13, 932. (h) Cheung, H. Y.; Yu, W.-Y.; Lam, F. L.;
Au-Yeung, T. T.-L.; Zhou, Z.; Chan, T. H.; Chan, A. S. C. Org. Lett.
2007, 9, 4295.
(14) CCDC 1938333 contains the supplementary crystallographic
data for compound (S)-9a. The data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(15) For examples, see: (a) Brown, J. M.; Hulmes, D. I.; Guiry, P. J. Tet-
rahedron 1994, 50, 4493. (b) Sprinz, J.; Kiefer, M.; Helmchen, G.;
Reggelin, M.; Huttner, G.; Walter, O.; Zsolnai, L. Tetrahedron Lett.
1994, 35, 1523.
(16) (a) Mino, T.; Asakawa, M.; Shima, Y.; Yamada, H.; Yagishita, F.;
Sakamoto, M. Tetrahedron 2015, 71, 5985. (b) Tanaka, Y.; Mino,
T.; Akita, K.; Sakamoto, M.; Fujita, T. J. Org. Chem. 2004, 69,
6679.
(13) Palladium-Catalyzed Allylic Alkylation of Indoles; General
Procedure
PhMe (0.2 mL) was added to a mixture of indole or a substituted
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G