Palladium-Catalyzed Asymmetric Suzuki-Miyaura Cross Coupling with Homochiral Phosphine Ligands Having Tetrahydro-1 H -imidazo[1,5-a ]indole Backbone

Article abstract of DOI:10.1055/s-0036-1589407

Amphiphilic polystyrene-poly(ethylene glycol) resin-supported chiral imidazoindole phosphines (PS-PEG-L?), (3R,9aS)-2-aryl-3-(2-dialkylphosphino)phenyltetrahydro-1H-imidazo[1,5-a]indol-1-one, bearing PPh₂, P(t-Bu)₂, and P(c-Hex)₂ groups were designed and prepared with a view toward using them in aqueous heterogeneous asymmetric Suzuki-Miyaura biaryl coupling. The asymmetric coupling of 2-substituted 1-iodonaphthalenes and 2-substituted naphthalen-1-ylboronic acid took place in water under heterogeneous conditions in the presence of 10 mol% palladium of PS-PEG-L?-Pd complexes to give up to 94% ee of (S)-2,2′-disubstituted 1,1′-binaphthyls.

Full text of DOI:10.1055/s-0036-1589407

SYNTHESIS
0
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1
1
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1
0
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
Y. Uozumi et al.
Paper
Synthesis
Palladium-Catalyzed Asymmetric Suzuki–Miyaura Cross Coupling
with Homochiral Phosphine Ligands Having Tetrahydro-1H-imid-
azo[1,5-a]indole Backbone
Yasuhiro Uozumi*a,b,c,d
Yutaka Matsuurab
Toshimasa Suzukab
Takayasu Arakawab,c
Yoichi M. A. Yamadad
Pd-L*
(10 mol% Pd)
( Pd/L* = 1/1)
B(OH)2
88–94%
10 examples
61–99% yield
R
R
R
+
TBAF (10 equiv)
R
in H2O
80 °C, 24 h
X
X = Cl, Br, I
R = Me, OMe, OEt, CO2Me, NO2, P(O)(OEt)2
R = Me, OMe, OEt
a Hubei Key Laboratory of Natural Products Research and Development,
China Three Gorges University, Yichang 443002, P. R. of China
b Institute for Molecular Science (IMS), Myodaiji, Okazaki 444-8787, Japan
c SOKENDAI (The Graduate University for Advanced Studies),
Okazaki 444-8787, Japan
d Riken Center for Sustainable Resource Science, 2-1 Hirowasa,
Wako 351-0198, Japan
O
H
O
PS
N
O
O
N
H
C
(CH2)3
N
n
L*
PCy2
uo@ims.ac.jp
The authors would like to dedicate this article to Professor Dieter Enders
on the occasion of his 70th birthday.
Received: 30.09.2016
Accepted after revision: 07.10.2016
Published online: 27.10.2016
We have continued our efforts to develop new amphiphilic
polymer resin-supported chiral phosphine ligands and
found that those bearing tetrahydro-1H-imidazo[1,5-a]in-
dol-1-one backbone (e.g., PS-PEG-L*1–L*3, Figure 1) are
very effective for several types of aquacatalytic asymmetric
reactions including palladium-catalyzed asymmetric π-al-
lylic substitution, the Tsuji–Trost reaction,2 and the cross-
coupling of aryl halides and aryl boronic acids – the Suzuki–
Miyaura coupling.3 Here we describe in detail the develop-
ment of the unimmobilized and immobilized chiral phos-
phine ligands bearing the tetrahydro-1H-imidazo[1,5-a]in-
dol-1-one backbone (Figure 1) and their application to the
asymmetric Suzuki–Miyaura coupling reaction.4
DOI: 10.1055/s-0036-1589407; Art ID: ss-2016-z0676-op
Abstract Amphiphilic polystyrene-poly(ethylene glycol) resin-sup-
ported chiral imidazoindole phosphines (PS-PEG-L*), (3R,9aS)-2-aryl-3-
(2-dialkylphosphino)phenyltetrahydro-1H-imidazo[1,5-a]indol-1-one,
bearing PPh2, P(t-Bu)2, and P(c-Hex)2 groups were designed and pre-
pared with a view toward using them in aqueous heterogeneous asym-
metric Suzuki–Miyaura biaryl coupling. The asymmetric coupling of 2-
substituted 1-iodonaphthalenes and 2-substituted naphthalen-1-ylbo-
ronic acid took place in water under heterogeneous conditions in the
presence of 10 mol% palladium of PS-PEG-L*-Pd complexes to give up
to 94% ee of (S)-2,2′-disubstituted 1,1′-binaphthyls.
Key words asymmetric catalysis, biaryls, cross-coupling, palladium,
Suzuki–Miyaura coupling, catalysis in water, heterogeneous catalysis
The triarylphosphine ligand, (3R,9aS)-3-[2-(diphenyl-
phosphino)phenyl]-2-phenyltetrahydro-1H-imidazo[1,5-
a]indol-1-one (L*1), the homogeneous counterpart of the
Catalytic asymmetric organic transformations have at-
tracted significant interest due to their synthetic utility,
and development of those catalyzed by transition metal
complexes containing optically active ligands is one of the
most exciting and challenging research subjects to date. Or-
ganophosphorus compounds having a homochiral back-
bone are recognized as one of the most versatile and suc-
cessful classes of ligands in transition-metal-catalyzed
asymmetric reactions. On the other hand, over the past two
decades, we have demonstrated that a wide variety of or-
ganic transformations can be performed in water by use of
amphiphilic polystyrene-poly(ethylene glycol) copolymer
(PS-PEG) resin-supported transition metal catalysts, and
therefore readily immobilizable chiral phosphine ligands
are required for the realization of aqueous- and heteroge-
neous-switching of given catalytic asymmetric reactions.1
O
H
O
PS
N
O
O
N
H
C
(CH2)3
N
n
PS-PEG-L*1 (R = Ph)
PS-PEG-L*2 (R = t-Bu)
PS-PEG-L*3 (R = c-Hex)
PR2
L*1-3
O
O
H
H
L*1 (R = Ph)
L*2 (R = t-Bu)
L*3 (R = c-Hex)
N
N
N
N
PR2
PR2
α-L*1–3
Figure 1 Tetrahydro-1H-imidazo[1,5-a]indolephosphines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
Y. Uozumi et al.
Paper
Synthesis
polymeric ligand PS-PEG-L*1, was prepared from the (S)-
indoline-2-carboxanilide and 2-(diphenylphosphi-
ring (P,N-chelating fashion), and two chloride atoms. The
bite angle of the imidazoindole phosphine ligand L*1 to
palladium ∠[N(1)-Pd-P] is 96.2° (Figure 2). As can be seen
from the schematic structure of L*1-PdCl2 complex shown
in Figure 2 B, the fused benzene ring of the indole moiety
and one of the P-phenyl groups are situated in the regions
of the second and the fourth quadrants (from the view
point of metal side) to construct the effective chiral sur-
roundings.
1
no)benzaldehyde (2a).5 Thus, the reaction of anilide 1 and
2a in refluxing methanol gave imidazoindolephosphine li-
gand L*1 (48%) along with its diastereomeric isomer α-L*1
(27%) (Scheme 1).
O
H
PPh2
MeOH, Δ
N
H
L*1 + α-L*1
48% 27%
+
N
H
(– H2O)
CHO
O
H
1
2a
N
Scheme 1 Preparation of L*1
N
ClCH2CH2Cl, reflux
L*1 + PdCl2
PdCl2
recrystallized from CH2Cl2
P
It has been reported that sterically demanding basic
phosphine ligands having bulky alkyl P-substituents (e.g.,
P-tert-butyl, P-cyclohexyl) promote several palladium-
catalyzed coupling reactions, including Suzuki–Miyaura
coupling and Hartwig–Buchwald amination, of less reactive
aryl chloride substrates.6 2-[Bis(tert-butyl)phosphino]phe-
nyl and 2-[bis(cyclohexyl)phosphino]phenyl groups were
readily introduced at the C3 position of the chiral imidazo-
indole skeleton via the condensation of indoline carboxani-
lide 1 with 2-[bis(tert-butyl)phosphino]benzaldehyde (2b)
and 2-[bis(cyclohexyl)phosphino]benzaldehyde (2c), to af-
ford the P-alkylimidazoindolephosphine ligands L*2 and
L*3 in 26% and 32% yield, respectively (Scheme 2), while the
minor diastereomeric isomers α-L*2 and α-L*3 were diffi-
cult to isolate because of their instability in air.
Ph2
L*1-PdCl2
Scheme 3 Preparation of L*1-PdCl2
Figure 2 A: ORTEP drawing of L*1-PdCl2. The ellipsoids are drawn at
30% probability level. All hydrogens are omitted for simplicity. B: Sche-
matic structure of L*1-PdCl2 from the view point of metal side. Two
chloride ligands and a backside-half of L*1 (-CON(C6H5)CHC6H4-) are
omitted for simplicity. Selected bond length (Å): Pd–Cl(1) = 2.356(4),
Pd–Cl(2) = 2.265(5), Pd–P = 2.231(4), Pd–N(1) = 2.12(1). Selected an-
gles (degree): ∠[N(1)–Pd–P] = 96.2(2), ∠[Cl–Pd–Cl] = 91.1(2).
O
H
P
MeOH, Δ
N
+
N
1
(– H2O)
CHO
P(t-Bu)2
2b
L*2 (26%)
The enantio-inducing ability of the P,N-chelating tetra-
hydro-1H-imidazo[1,5-a]indolephosphine ligands was pre-
liminarily examined for Suzuki–Miyaura biaryl coupling of
6a and 7A under homogeneous conditions.7 The cross-cou-
pling8 of aryl halides and aryl boronic acids, the so-called
Suzuki–Miyaura coupling, is one of the most versatile and
successful synthetic tools for carbon–carbon bond forma-
tion. However, although axially chiral biaryls are highly ac-
cessible via this coupling only scattered attention has been
paid to the asymmetric Suzuki–Miyaura biaryl coupling.9
Representative results on the asymmetric coupling of 6a
and 7A are shown in Table 1. Thus, the reaction of 1-iodo-2-
methylnaphthalene (6a-I) and 2-methyl-1-naphthalenebo-
ronic acid (7A) (5 equiv) was carried out in toluene in the
presence of 10 mol% of Pd(OAc)2 and imidazoindole-di-
phenylphosphine L1 (Pd/P = 1:1) and K3PO4 (10 mol equiv)
at 100 °C for 5 hours to give a quantitative yield of 2,2′-di-
methyl-1,1′-binaphthyl (8aA). The enantiomeric purity and
absolute configuration of 8aA were determined by HPLC
O
H
N
P
MeOH, Δ
N
+
1
(– H2O)
CHO
2c
P(c-Hex)2
L*3 (32%)
Scheme 2 Preparation of L*2 and L*3
The coordination manner of the imidazoindolephos-
phine ligand to a transition metal was studied by X-ray
crystal structure analysis of the parent palladium complex
L*1-PdCl2 (Scheme 3,Figure 2 A). The complex L*1-PdCl2
was prepared by mixing L*1 with palladium dichloride
(L/Pd = 1.0:1.0) in refluxing dichloroethane and single crys-
tals were obtained as yellow prisms by recrystallization
from dichloromethane. The molecular structure is shown in
Figure 2 A. The complex L*1-PdCl2 adopts square planar ge-
ometry with a phosphorus atom, a nitrogen atom of indole
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
Y. Uozumi et al.
Paper
Synthesis
analysis using a chiral stationary phase column and mea-
surement of the specific rotation to be 90% ee (S) (Table 1,
entry 1). Bromo- and chloronaphthalene 6a-Br and 6a-Cl
exhibited lower reactivity (entries 2 and 3). The chemical
yield and the enantiomeric purity of 8aA were lowered
with the imidazoindole-di(tert-butyl)phosphine L2 to 78%
yield and 86% ee, respectively (entry 4). Imidazoindole-
di(cyclohexyl)phosphine L3 was identified as the best li-
gand. Thus, starting with iodide 6a-I, the chemical yield
and the enantiomeric purity of binaphthyl 8aA were 98%
and 92% ee under similar conditions (entry 7). The palladi-
um catalyst of L3 was so catalytically active that the cou-
pling took place at 60 °C to give 94% ee of 8 (24 h, 70% yield,
entry 9). It is noteworthy that 1-chloro-2-methylnaphtha-
lene (6a-Cl) also underwent the coupling with 7A using the
palladium-L3 catalyst at 60 °C to afford 91% ee of 8aA,
though the chemical yield was modest (48%, entry 10).
group were prepared by condensation of indoline carbox-
anilide 3 with 2-phosphinobenzaldehydes 2a–c in 69%, 48%,
and 32% yield, respectively, according to the procedures for
the preparation of L* (Scheme 4). After alkaline hydrolysis
of the ester groups of 4a,b, and c (89%, 73%, and 85%, re-
spectively), the resulting carboxylic acids 5a–c were an-
chored onto PS-PEG amino resin by 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (EDCI·HCl) and
1-hydroxybenzotriazole (HOBt) in DMF. Negative Kaiser
tests indicated that the condensation with 5a–c were com-
pleted to form the corresponding PS-PEG resin-supported
imidazoindolephosphine ligands, PS-PEG-L*1, PS-PEG-L*2,
and PS-PEG-L*3, quantitatively. The gel-phase 31P{1H} NMR
study of resin-supported phosphines were performed with
MAS-NMR probe by use of the standard solution-phase pa-
rameters. A narrow singlet at δ = –19.7 was observed for the
spectrum of PS-PEG-L*1 in CDCl3. The 31P resonances of PS-
PEG-L*2 and PS-PEG-L*3 were observed as narrow singlets
at +12.5 ppm and –19.0 ppm, respectively.
Table 1 Palladium-Catalyzed Asymmetric Binaphthyl Coupling with
Imidazoindolephosphinesa
O
H
MeOH, Δ
B(OH)2
N
H
MeO2C(CH2)3
+
2a–c
N
H
Me
(– H2O)
Me
Pd-L*
+
3
Me
Me
O
H
X
4a (R = Ph): 69%
4b (R = t-Bu): 48%
4c (R = c-Hex): 32%
6a
7A
(S)-8aA
N
MeO2C(CH2)3
N
X = I, Br, Cl
Yield (%)b
ee (%)c
PR2
Entry
Ligand
Halide
O
H
1
2
L1
L1
L1
L2
L2
L2
L3
L3
L3
L3
6a-I
98
71
<2
78
52
39
98
57
70
48
90
90
N/A
86
87
72
92
88
94
91
OH–
6a-Br
6a-Cl
6a-I
N
HO2C(CH2)3
N
3
5a (R = Ph): 89%
5b (R = t-Bu): 73%
5c (R = c-Hex): 85%
PR2
4
5
6a-Br
6a-Cl
6a-I
6
7
PS
O
NH2
O
n
PS-PEG-L*1 (R = Ph)
PS-PEG-L*2 (R = t-Bu)
PS-PEG-L*3 (R = c-Hex)
8
6a-Cl
6a-I
9d
10d
EDCI, HOBt, DMF
quantitative
6a-Cl
Scheme 4 Preparation of PS-PEG resin-supported imidazoindolephos-
phines
a Conditions: 6 (1.0 mmol), 7 (5.0 mmol), Pd(OAc)2 (0.1 mmol), L* (0.1
mmol), K3PO4 (5.0 mmol), toluene (2 mL), 100 °C, 5 h, unless otherwise
noted.
b Isolated yield.
The asymmetric catalysis in water with a recyclable het-
erogeneous catalyst would approach what may be consid-
ered an ideal organic chemical process. Over the past ten
years, we have demonstrated that a wide variety of non-
asymmetric as well as asymmetric catalytic organic trans-
formations can be performed in water by use of amphiphil-
ic polystyrene-poly(ethylene glycol) copolymer (PS-PEG)
resin-supported transition metal complexes and nanoparti-
cles. Along the same line, the asymmetric Suzuki–Miyaura
biaryl coupling was examined in water using amphiphilic
resin-supported PS-PEG-L*. We were pleased to find that
the asymmetric Suzuki–Miyaura biaryl coupling took place
c Determined by HPLC analysis using Chiralpack OD-H. [α]D20 +32.5 (c 0.8
CHCl3) for S of 94% ee. N/A: Not available.
d Carried out at 60 °C for 24 h.
With the encouraging results on the asymmetric biaryl
coupling under homogeneous conditions in hand, we next
examined the heterogeneous- and the aqueous-switching
of the asymmetric coupling reaction. Thus, the imidazoin-
dole phosphines were immobilized onto the amphiphilic
polystyrene-poly(ethylene glycol) copolymer (PS-PEG)10
resin by a butyryl amide tether. The imidazoindole ligands
4a–c having an N-[4-(methoxycarbonylpropyl)phenyl]
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
Y. Uozumi et al.
Paper
Synthesis
smoothly in water to provide good to excellent stereoselec-
tivity with a wide substrate tolerance when a palladium
complex of PS-PEG-L* was used in the presence of TBAF.
Representative results are summarized in Table 2. Thus, the
reaction of 6a-I and 7A was catalyzed with the amphiphilic
polymeric PS-PEG-L*3-Pd to give a 95% yield of 8aA with
94% ee (S), which was isolated via scCO2 extraction from the
catalyst resin beads followed by chromatographic purifica-
tion (Table 2, entry 3). The coupling with PS-PEG-L*1 and
-L*2 gave (S)-8aA with 90% and 86% ees, respectively, under
otherwise the same conditions (entries 1 and 2). Coupling
of naphthyl bromide 6a-Br also proceeded smoothly with
PS-PEG-L*1-3 to give (S)-8aA in 71% (87% ee), 64% (88% ee),
and 90% (88% ee) yield, respectively (entries 4–6). Recycle
Table 2 Palladium-Catalyzed Asymmetric Biaryl Coupling in Water with Supported Imidazoindolephosphinesa
R3
R3
B(OH)2
R4
R2
R4
R1
R4
Pd-L*
or
+
or
R1
in H2O
R2
X
Br
6
9
7
8
10
a: R1 = Me
b: R1 = OMe
c: R1 = OEt
a: R2 = Me, R3 = H
A: R4 = Me
B: R4 = OMe
C: R4 = OEt
b: R2 = Me, R3 = CN
c: R2 = Me, R3 = CO2Me
d: R2 = NO2, R3 = H
d: R1 = CO2Me
X = Cl, Br, I
Entry
6 or 9
7
Product
8aA
Ligand
Yield (%)b
ee (%)c
1
2
6a-I
7A
7A
7A
7A
7A
7A
7A
7A
7A
7A
7A
7A
7A
7A
7A
7C
7A
7C
7B
7A
7A
7A
7A
7A
PS-PEG-L*1
PS-PEG-L*2
PS-PEG-L*3
PS-PEG-L*1
PS-PEG-L*2
PS-PEG-L*3
(1st recycle)
(2nd recycle)
(3rd recycle)
(4th recycle)
PS-PEG-L*1
PS-PEG-L*2
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
PS-PEG-L*3
99
85
95
71
64
90
88
86
89
89
<2
40
55
85
86
93
90
90
77
61
96
89
93
96
90 (S)
86 (S)
85 (S)
87 (S)
88 (S)
88 (S)
88 (S)
88 (S)
87 (S)
88 (S)
N/A
6a-I
3
6a-I
4
6a-Br
6a-Br
6a-Br
6a-Br
6a-Br
6a-Br
6a-Br
6a-Cl
6a-Cl
6a-Cl
6b-I
6b-Cl
6a-I
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
80 (S)
89 (S)
92 (R)
88 (R)
92 (R)
92 (R)
92 (S)
92 (S)
88 (R)
92
8bA
8bA
8aC
6c-I
8cA
6b-I
6c-I
8bC
8cB
6d-Br
9a
8dA
10aA
10bA
10cA
10dA
9b
92
9c
94
9d
92 (R)
a All reactions were carried out in water at 80 °C for 24 h. Ratio of 6 (mol)/7 (mol)/TBAF (mol)/Pd(OAc)2 [or PdCl2(MeCN)2] (mol)/PS-PEG-L* (mol of P)/H2O
(L) = 1.0:5.0:10:0.1:0.1:20.
b Isolated yield.
c Determined by HPLC (Chiralpak OD-H or AD-H). The absolute configuration is shown in parentheses. N/A: Not available.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
Y. Uozumi et al.
Paper
Synthesis
experiments of the supported catalyst PS-PEG-L*3-Pd were
performed with 6a-Br. The catalyst PS-PEG-L*3-Pd was
readily recovered and reused 4 times without any reactiva-
tion of the recovered resin catalyst beads to give 8aA in 88%
average yield with an average stereoselectivity of 88% ee
where no significant loss of catalytic activity or stereoselec-
tivity was observed (entries 7–10). Coupling of naphthyl
chloride 6a-Cl took place with PS-PEG-L*3-Pd under simi-
lar conditions to give 89% ee of 8aA (entry 13), whereas the
reaction hardly proceeded with PS-PEG-L*1 bearing a P-
phenyl coordinating group (entry 11).
MOP ligands, in 70% isolated yield as a white precipitate.
The enantiomeric purity of 12 was estimated to be ca. 94%
ee before purification (as a crude residue), and was in-
creased through purification to 99% ee (S) (Scheme 5).
Pd(OAc)2 (10 mol%)
PS-PEG-L*3 (10 mol% P)
+ 7B
P(O)(OEt)2
n-Bu4NF
in H2O, 80 °C, 24 h
Br
11
A series of unsymmetric binaphthyls were obtained in
their enantioenriched forms via the asymmetric cross-
coupling of various naphthyl halides 6 and naphthylboronic
acids 7 having different 2-substitutents. Thus, the unsym-
metric 2-methoxy-2′-methyl-1,1′-binaphthyl (8bA) was ob-
tained with 92% ee and 88% ee from 6b-I and 6b-Cl,
respectively (Table 2, entries 14 and 15). The coupling reac-
tion of 6a-I and 7C, and that of the reverse combination (6c-
I and 7A) gave essentially the same results where both 92%
ee of 8aC (= 8cA) was obtained in 93% and 90% isolated
yield, respectively (entries 16 and 17). The asymmetric cou-
pling of 1-iodo-2-methoxynaphthalene (6b-I) and 2-
ethoxynaphthalene boronic acid (7C) gave an unsymmetric
ether of binaphthol, 2-ethoxy-2′-methoxy-1,1′-binaphthyl
(8bC) of 92% ee (entry 18). The reverse combination (6c-I
and 7B) also gave 92% ee of 8cB (= 8bC) (entry 19), where
the chemical yield (77%) was slightly lower than that ob-
tained from sterically less hindered 2-methoxynaphthyl 6b
(vs entry 18). Because of wide functional group tolerance of
the Suzuki–Miyaura coupling, the asymmetric formation of
biaryls bearing electrophilic groups was achieved under
similar conditions. Thus, the reaction of 2-methoxycarbon-
yl-1-bromonaphthalene (6d-Br) with 7A gave 2-methoxy-
carbonyl-2′-methyl-1,1′-binaphthyl (8dA) in 61% yield with
88% ee (entry 20). Bromobenzene 9 having appropriate
ortho-substituents delivered the axially chiral phenylnaph-
thalene derivatives 10. Thus, 2-bromotoluene (9a), 4-bro-
mo-3-methylbenzonitrile (9b), methyl 4-bromo-3-methyl-
benzoate (9c), and 2-bromonitrobenzene (9d) underwent
asymmetric coupling with 7A in water to afford 89–96%
yield of 1-(substituted aryl)-2-methylnaphthalenes 10aA,
10bA, 10cA, and 10dA with 92%, 92%, 94%, and 92% enan-
tiomeric excess, respectively (entries 21–24), where the
electrophilic substituents (e.g. CN, CO2Me, NO2) on the ben-
zene rings of 9 were retained.
P(O)(OEt)2
PPh2
OMe
OMe
12
MOP
94% ee (crude mixture)
>99% ee (white precipitate)
crystallization
Scheme 5 Application to MOP synthesis
In summary, a series of optically active P,N-chelating li-
gands bearing tetrahydro-1H-imidazo[1,5-a]indole back-
bone, were designed, prepared, and readily immobilized
onto an amphiphilic polystyrene-poly(ethylene glycol) co-
polymer (PS-PEG) resin to afford PS-PEG resin-supported
chiral phosphine ligands. Palladium complexes of the poly-
meric ligands exhibited good catalytic activity and enantio-
selectivity for a given reaction (e.g., Suzuki–Miyaura biaryl
coupling) in water under heterogeneous conditions, where
the fine tuning of the catalytic as well as enantioselective
ability was realized by the introduction of several types of
P-alkyl substituents. X-ray crystal structure analysis of the
palladium complex L*1-PdCl2 revealed that the imidazoin-
dolephosphine coordinates to palladium(II) in a P,N-chelat-
ing fashion to construct the effective chiral environment.
All manipulations were performed under a N2 atmosphere. H2O was
deionized with a Millipore system as a Milli-Q grade and was de-
gassed by the freeze–pump–thaw method prior to use. NMR spectra
were recorded at 25 °C on a JEOL JNM-A500 spectrometer (500 MHz
for 1H, 125 MHz for 13C, 202 MHz for 31P) or a JEOL JNM-AL400 spec-
trometer (400 MHz for 1H, 100 MHz for 13C, 162 MHz for 31P). ICP-AES
analyses were performed on Leeman Labs Inc. Profile Plus using Pd
standard solution (Kanto Chemical) as a standard. Melting points
were determined using a Yanaco micro melting point apparatus MP-
J3 and are uncorrected. ESI mass spectra were recorded on a JEOL
JMS-T100LC spectrometer. The GC-MS was measured by an Agilent
6890 GC/5973N MS detector. IR spectra were obtained using a JASCO
FT/IR-460 plus spectrophotometer in ATR mode. Optical rotations
were recorded on a JASCO P-1020 polarimeter. PS-PEG amino-resin
was purchased from RAPP POLYMERETM (TentaGel®S NH2, average
diameter 0.90 mm, 1% divinylbenzene crosslinked, loading value of
amino residue 0.2–0.3 mmol·g–1).
The stereoselective asymmetric biaryl coupling system
was applied to the preparation of MOP ligand, which has
previously been developed by Uozumi and Hayashi as an
optically active monophosphine ligand. The reaction of
phosphonate 11 and 7B afforded diethyl 2′-methoxy-1,1′-
binaphth-2-yl phosphonate (S)-12, a synthetic precursor of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
Y. Uozumi et al.
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Synthesis
Chiral Imidazoindolephosphines; (3R,9aS)-2-Phenyl-3-[2-(diphen-
ylphosphino)phenyl]tetrahydro-1H-imidazo[1,5-a]indole-1-one
(L*1); Typical Procedure
JC,P = 7.3 Hz), 27.1 (d, JC,P = 20.7 Hz), 27.0 (d, JC,P = 18.6 Hz), 26.9 (d,
JC,P = 3.0 Hz).
31P{1H} NMR (202 MHz, CDCl3): δ = –21.2.
(S)-N-Phenylindoline-2-carboxamide (1; 338 mg, 1.0 mmol) and 2-
(diphenylphosphino)benzaldehyde (2a; 580 mg, 2 mmol) were dis-
solved in MeOH (5 mL). The reaction mixture was heated to 80 °C in a
sealed tube for 3 h. After cooling down to r.t., the mixture was ex-
tracted with EtOAc and concentrated. The resulting residue was chro-
matographed on silica gel (eluent: acetone/hexane = 1:5) to give a
white solid; yield: 245 mg (48%).
Anal. Calcd for C34H39N2OP: C, 78.13; H, 7.52; N, 5.36. Found: C, 78.18;
H, 7.56; N, 5.40.
4-Methoxycarbonylpropyl Chiral Imidazoindolephosphines 4;
(3R,9aS)-2-{[4-(Methoxycarbonylpropyl)phenyl]-3-(2-diphenyl-
phosphino)phenyl}tetrahydro-1H-imidazo[1,5-a]indole-1-one
(4a); Typical Procedure
[CAS Reg. No.: 375810-10-9]
Mp 94–96 °C; [α]D19 +127 (c 0.7, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.68 (d, J = 8.0 Hz, 1 H), 7.41–7.32 (m,
15 H), 7.20–7.10 (m, 6 H), 7.03–6.93 (m, 2 H), 4.40 (d, J = 9.5 Hz, 1 H),
3.56 (d, J = 16.0 Hz, 1 H), 3.15 (dd, J = 9.5, 16.0 Hz, 1 H), 1.37 (d,
J = 12.2 Hz, 9 H), 1.29 (d, J = 12.2 Hz, 9 H).
(S)-2-{[4-(Methoxycarbonylpropyl]phenyl)aminocarbonyl}indoline
(3; 676 mg, 2 mmol) and 2-(diphenylphosphino)benzaldehyde (2a;
1.16 g, 4 mmol) were dissolved in MeOH (5 mL). The reaction mixture
was heated to 80 °C in a sealed tube for 48 h. After cooling to r.t., the
mixture was extracted with EtOAc and concentrated. The resulting
residue
was
chromatographed
on
silica
gel
(eluent:
acetone/hexane = 1:2) to give colorless fine prisms; yield: 840 (69%);
13C NMR (126 MHz, CDCl3): δ = 174.3, 142.3–113.8 (Carom, overlapped),
81.4 (d, JC,P = 24.9 Hz), 64.2, 31.5.
31P{1H} NMR (202 MHz, CDCl3): δ = –19.6.
MS (ESI-TOF): m/z = 533 [M + Na]+.
mp 115–117 °C; [α]D21 –169 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.71 (d, J = 6.5 Hz, 1 H), 7.43–7.13 (m,
18 H), 6.97–6.91 (m, 3 H), 4.37 (d, J = 8.5 Hz, 1 H), 3.64 (s, 3 H), 3.53 (d,
J = 16.5 Hz, 1 H), 3.09 (dd, J = 8.5, 16.5 Hz, 1 H), 2.52 (t, J = 7.5 Hz, 2 H),
2.26 (t, J = 7.5 Hz, 2 H), 1.85 (quin, J = 7.5 Hz, 2 H).
(3R,9aS)-2-Phenyl-3-{2-[di(tert-butyl)phosphino]phenyl}tetrahy-
dro-1H-imidazo[1,5-a]indole-1-one (L*2)
White solid; yield: 123 mg (26%); mp 102–104 °C; [α]D21 +27.3 (c 0.7,
13C NMR (126 MHz, CDCl3): δ = 174.1, 173.6, 142.3–113.5 (Carom, over-
lapped), 81.4 (d, JC,P = 25.9 Hz), 64.1, 51.3, 34.3, 33.1, 31.4, 26.1.
31P{1H} NMR (202 MHz, CDCl3): δ = –18.9 (s).
MS (ESI-TOF): m/z = 633 [M + Na]+.
CHCl3).
IR (ATR): 2962, 2899, 1720, 1511, 1201 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 12.0 Hz, 1 H), 7.94 (d, J = 8.0
Hz, 1 H), 7.49–7.47 (m, 1 H), 7.36–7.35 (m, 1 H), 7.26–7.17 (m, 4 H),
7.12–7.07 (m, 2 H), 6.96–6.93 (m, 1 H), 6.80 (dd, J = 7.5 Hz, 1 H), 6.63
(dd, J = 7.5 Hz, 1 H), 4.85 (d, J = 8.0 Hz, 1 H), 4.65 (dd, J = 2.5, 12.0 Hz, 1
H), 3.74 (dd, J = 2.5, 16.5 Hz, 1 H), 3.87–3.32 (m, 1 H), 1.37 (d, J = 12.2
Hz, 9 H), 1.29 (d, J = 12.2 Hz, 9 H).
13C NMR (126 MHz, CDCl3): δ = 175.8, 147.4, 138.9, 138.8, 138.6,
137.1, 135.5 (d, JC,P = 3.1 Hz), 131.8 (d, JC,P = 5.2 Hz), 130.3, 129.0 (d,
JC,P = 21.7 Hz), 128.5, 128.2, 128.0, 126.2, 125.7 (d, JC,P = 2.0 Hz), 124.8,
124.6, 121.1, 121.0, 116.6, 77.5, 65.5, 33.1 (d, JC,P = 22.7 Hz), 32.6, d,
JC,P = 19.6 Hz), 31.0 (d, JC,P = 15.5 Hz, 3 C), 30.8 (d, JC,P = 14.4 Hz, 3 C).
(3R,9aS)-2-[4-(Methoxycarbonylpropyl)phenyl]-3-({2-[di(tert-bu-
tyl)phosphino]phosphino}phenyl)tetrahydro-1H-imidazo[1,5-
a]indole-1-one (4b)
White solid; yield: 547 mg (48%); mp 125–127 °C; [α]D21 +26.8 (c 1.0,
CHCl3).
IR (ATR): 2957, 2919, 1730, 1588, 1490 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.15–8.13 (m, 1 H), 7.93 (d, J = 7.0 Hz, 1
H), 7.61 (d, J = 7.5 Hz, 1 H), 7.38–7.30 (m, 4 H), 7.25–7.16 (m, 3 H),
7.01–6.93 (m, 3 H), 4.35 (dd, J = 1.5, 9.5 Hz, 1 H), 3.62 (s, 3 H), 3.58 (d,
J = 15.5 Hz, 1 H), 3.19 (dd, J = 10.0, 16.0 Hz, 1 H), 2.52 (t, J = 7.5 Hz, 2
H), 2.24 (t, J = 7.5 Hz, 2 H), 1.83 (quin, J = 7.5 Hz, 2 H), 1.25 (dd,
J = 12.5, 17.5 Hz, 18 H).
13C NMR (126 MHz, CDCl3): δ = 174.9, 173.8, 152.0, 144.6, 144.4,
138.1, 136.3, 135.3, 129.7, 129.0, 128.7, 127.5, 127.4, 125.3, 125.2,
124.9, 122.3, 121.2, 114.4, 114.2, 82.1 (d, JC,P = 35.2 Hz), 63.7, 51.4,
34.4, 33.2, 33.0 (d, JC,P = 7.3 Hz), 32.9, d, JC,P = 13.4 Hz), 31.3, 30.7 (d,
JC,P = 14.4 Hz, 3 C), 30.6 (d, JC,P = 14.4 Hz, 3 C), 26.3.
31P{1H} NMR (202 MHz, CDCl3): δ = 12.8.
Anal. Calcd for C30H35N2OP: C, 76.57; H, 7.50; N, 5.95. Found: C, 76.77;
H, 7.29; N, 5.96
(3R,9aS)-2-Phenyl-3-[2-(dicyclohexylphosphino)phenyl]tetrahy-
dro-1H-imidazo[1,5-a]indole-1-one (L*3)
21
White solid; yield: 169 mg (32%); mp 95–98 °C; [α]D +49.2 (c 1.0,
31P{1H} NMR (202 MHz, CDCl3): δ = 7.4 (s).
CHCl3).
Anal. Calcd for C35H43N2O3P: C, 73.66; H, 7.59; N, 4.91. Found: C,
74.00; H, 7.49; N, 4.96.
IR (ATR): 2928, 2881, 1690, 1258 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.00 (dd, J = 2.5, 6.1 Hz, 1 H), 7.67–7.65
(m, 1 H), 7.59 (d, J = 7.0 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H), 7.38–7.30 (m,
3 H ), 7.26–7.14 (m, 3 H), 7.04–7.01 (m, 1 H), 6.95 (t, J = 7.5 Hz, 1 H),
4.44 (d, J = 10.0 Hz, 1 H), 3.59 (d, J = 16.0 Hz, 1 H), 3.59 (d, J = 16.0 Hz,
1 H), 3.23 (dd, J = 10.0, 16.0 Hz, 1 H), 2.07–2.01 (m, 4 H), 1.82–1.59
(m, 8 H), 1.43–1.13 (m, 10 H).
13C NMR (126 MHz, CDCl3): δ = 174.5, 152.0, 144.5 ( d, JC,P = 20.6 Hz),
138.1, 135.3, 134.1, 134.0, 129.7, 128.9, 128.7, 128.2, 127.8, 125.3,
125.2, 124.9, 122.4, 120.4, 114.4, 114.2, 81.4 (d, JC,P = 31.0 Hz), 64.1,
51.4, 35.8 (d, JC,P = 9.3 Hz), 35.2 (d, JC,P = 9.3 Hz), 34.4, 33.2, 31.5, 30.8
(d, JC,P = 17.6 Hz), 30.6 (d, JC,P = 15.5 Hz), 29.7 (d, JC,P = 9.3 Hz), 29.6 (d,
(3R,9aS)-2-(4-(Methoxycarbonylpropyl)phenyl)-3-(2-(cyclohex-
yl)phosphino)phosphino)phenyl)tetrahydro-1H-imidazo[1,5-
a]indole-1-one (4c)
White solid; yield: 400 mg (32%); mp 118-120 °C; [α]D21 +56.8 (c 1.1,
CHCl3).
IR (ATR): 3065, 2905, 1696, 1461 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.00 (d, J = 6.1 Hz, 1 H), 7.66 (m, 1 H),
7.56 (d, J = 7.2 Hz, 1 H), 7.39–7.29 (m, 4 H), 7.25–7.22 (m, 3 H), 7.16–
6.93 (m, 2 H), 4.42 (d, J = 10.0 Hz, 1 H), 3.62 (s, 3 H), 3.58 (d, J = 15.9
Hz, 1 H), 3.22 (dd, J = 10.0, 15.9 Hz, 1 H), 2.52 (t, J = 7.3 Hz, 2 H), 2.07–
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
Y. Uozumi et al.
Paper
Synthesis
1.86 (m, 2 H), 2.24 (t, J = 7.3 Hz, 2 H), 2.07–1.99 (m, 3 H), 1.83 (quin,
J = 7.3 Hz, 2 H), 1.73–1.71 (m, 2 H), 1.69–1.59 (m, 2 H), 1.41–1.11 (m,
14 H).
(3R,9aS)-2-[4-(Hydroxycarbonylpropyl)phenyl]-3-[2-(dicyclohex-
ylphosphino)phenyl]tetrahydro-1H-imidazo[1,5-a]indol-1-one
(5c)
13C NMR (126 MHz, CDCl3): δ = 174.5, 173.8, 152.0, 144.5 (d, JC,P = 20.7
Hz), 138.1, 135.3, 134.1, 134.0, 129.7, 128.9, 128.7, 128.2, 127.8,
125.3, 125.2, 124.9, 122.4, 120.4, 114.4, 114.2, 81.4 (d, JC,P = 31.0 Hz),
64.1, 51.4, 35.8 (d, JC,P = 9.3 Hz), 35.2 (d, JC,P = 9.3 Hz), 34.4, 33.2, 31.5,
30.8 (d, JC,P = 17.6 Hz), 30.6 (d, JC,P = 15.5 Hz), 29.7 (d, JC,P = 9.3 Hz),
29.6 (d, JC,P = 7.3 Hz), 27.2, 27.1 (d, JC,P = 20.7 Hz), 27.0 (d, JC,P = 18.6
Hz), 26.9 (d, JC,P = 3.0 Hz), 26.3, 26.2, 22.6.
Starting from 4c (311 mg, 0.5 mmol), 5c was obtained as a white sol-
id; yield: 258 mg (85%); mp 121–123 °C; [α]D21 +43.2 (c 0.9, CHCl3).
IR (ATR): 3110, 2921, 1720 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.97 (d, J = 7.3 Hz, 1 H), 7.65 (m, 1 H),
7.54 (d, J = 7.2 Hz, 1 H), 7.35–7.31 (m, 4 H), 7.25–7.17 (m, 3 H), 7.00–
6.95 (m, 2 H), 4.46 (d, J = 10.0 Hz, 1 H), 3.58 (d, J = 14.7 Hz, 1 H), 3.23
(dd, J = 10.0, 14.7 Hz, 1 H), 2.52 (t, J = 6.7 Hz, 2 H), 2.26 (t, J = 7.4 Hz, 2
H), 2.16–2.01 (m, 4 H), 1.83 (quin, J = 7.4 Hz, 2 H), 1.73–1.39 (m, 8 H),
1.34–1.10 (m, 12 H).
13C NMR (126 MHz, CDCl3): δ = 178.8, 174.6, 152.1, 144.4 (d, JC,P = 21.7
Hz), 138.0, 135.2, 134.0, 129.5, 128.9, 128.7, 128.2, 127.7, 125.1,
125.0, 124.9, 122.3 121.0, 114.3, 114.2, 81.6 (d, JC,P = 31.0 Hz), 64.1,
35.8 (d, JC,P = 9.3 Hz), 35.3 (d, JC,P = 9.3 Hz), 34.3, 33.1, 31.5, 31.4, 30.9
(d, JC,P = 15.5 Hz), 29.7 (d, JC,P = 9.3 Hz), 29.6 (d, JC,P = 7.3 Hz), 27.2, 27.1
(d, JC,P = 20.7 Hz), 27.1 (d, JC,P = 18.3 Hz), 26.9 (d, JC,P = 3.0 Hz), 26.3,
26.1, 26.0, 22.6.
31P{1H} NMR (202 MHz, CDCl3): δ = –21.2 (s).
Anal. Calcd for C39H47N2O3P: C, 75.21; H, 7.61; N, 4.50. Found: C,
75.18; H, 7.59; N, 4.53.
4-Hydroxycarbonylpropyl Chiral Imidazoindolephosphines 5;
(3R,9aS)-2-{[4-(Hydroxycarbonylpropyl)phenyl]-3-(2-diphenyl-
phosphino)phenyl}tetrahydro-1H-imidazo[1,5-a]indol-1-one
(5a); Typical Procedure
To a solution of 4a (421 mg, 0.7 mmol) in 1,4-dioxane (20 mL) was
added aq 1 N NaOH (8 mL) at 0 °C. The reaction mixture was stirred at
25 °C for 10 h. The residual material was acidified with aq 5% HCl and
extracted with Et2O (3 ×). The combined extracts were dried (Na2SO4)
and concentrated in vacuo. The resulting residue was chromato-
graphed on silica gel (eluent: acetone/hexane = 1:2) to give colorless
fine prisms; yield: 365 mg (89%).
31P{1H} NMR (202 MHz, CDCl3): δ = –21.1 (s).
Anal. Calcd for C38H45N2O3P: C, 74.97; H, 7.45; N, 4.60. Found: C,
75.12; H, 7.40; N, 4.58.
PS-PEG Resin-Supported Chiral Imidazoindolephosphines (PS-
PEG-L*); General Procedure
[CAS Reg. No.: 338463-32-4]
Mp 112–115 °C; [α]D21 –198.6 (c 1.0, CHCl3).
A Merrifield vessel was charged with PS-PEG-NH2 [1.50 g, 0.40 mmol
(total loading of amino residue)], 5 (0.80 mmol), EDCI·HCl (319 mg,
1.67 mmol), HOBt (300 mg, 2.20 mmol), and DMF (20.0 mL), and the
reaction mixture was shaken on a wrist-action shaker at 25 °C for 24
h. Complete consumption of the primary amino residue of the resin
was monitored by Kaiser test. The mixture was filtered and the resin
was washed with DMF (5 × 20 mL) and EtOAc (5 × 20 mL). The resin
was dried under reduced pressure to give PS-PEG-L*.
1H NMR (500 MHz, CDCl3): δ = 7.7 (d, J = 7.9 Hz, 1 H), 7.36–7.15 (m, 20
H), 6.88–6.78 (m, 3 H), 4.34 (dd, J = 1.2, 9.8 Hz, 1 H), 3.48 (d, J = 16.5
Hz, 1 H), 3.23 (dd, J = 9.8, 16.5 Hz, 1 H), 2.46 (t, J = 7.2 Hz, 2 H), 2.23 (t,
J = 7.2 Hz, 2 H), 1.78 (quin, J = 7.2 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 178.5, 174.2, 151.2–113.8 (Carom, over-
lapped), 81.5 (d, JC,P = 25.8 Hz), 64.2, 34.3, 33.0, 31.6, 26.0.
31P{1H} NMR (202 MHz, CDCl3): δ = –19.6 (s).
MS (ESI-TOF): m/z = 619 [M + Na]+.
PS-PEG-L*1
Yield: 1.72 g (99%); pale yellow resin.
31P{1H} NMR (SR-MAS NMR, 162 MHz): δ = –19.7.
PS-PEG-L*2
(3R,9aS)-2-[4-(Hydroxycarbonylpropyl)phenyl]-3-{2-[di(tert-bu-
tyl)phosphino]phenyl}tetrahydro-1H-imidazo[1,5-a]indol-1-one
(5b)
Yield: 1.68 g (98%); pale yellow resin.
31P{1H} NMR (SR-MAS NMR, 162 MHz) δ = 12.5.
Starting from 4b (285 mg, 0.5 mmol), 5b was obtained as a white sol-
id; yield: 202 mg (73%); mp 125–127 °C; [α]D21 +28.8 (c 1.0, CHCl3).
IR (ATR): 2962, 2360, 2341, 1735, 1510, 1365, 1232 cm–1
.
PS-PEG-L*3
1H NMR (500 MHz, CDCl3): δ = 8.34 (m, 1 H), 7.87 (m, 1 H), 7.66–7.47
(m, 6 H), 7.35–7.32 (m, 1 H), 7.17–6.96 (m, 3 H), 4.26 (dd, J = 1.0, 10.0
Hz, 1 H), 3.56 (d, J = 16.0 Hz, 1 H), 3.15 (dd, J = 10.0, 16.0 Hz, 1 H), 2.50
(t, J = 7.5 Hz, 2 H), 2.21 (t, J = 7.5 Hz, 2 H), 1.83 (quin, J = 7.5 Hz, 2 H),
1.44 (dd, J = 12.5, 17.5 Hz, 18 H).
13C NMR (126 MHz, CDCl3): δ = 174.9, 173.8, 152.0, 144.6, 144.5,
138.2, 136.3, 135.4, 129.7, 129.0, 128.7, 127.6, 127.4, 125.3, 125.2,
124.9, 122.3, 121.2, 114.4, 114.2, 82.2 (d, JC,P = 35.0 Hz), 63.8 34.4,
33.2, 33.1 (d, JC,P = 7.3 Hz), 32.9, d, JC,P = 13.3 Hz), 31.3, 30.7 (d,
JC,P = 14.4 Hz, 3 C), 30.6 (d, JC,P = 14.4 Hz, 3 C), 26.3.
Yield: 1.70 g (98%); pale yellow resin.
31P{1H} NMR (MAS NMR, 162 MHz): δ = –19.0 (s).
Asymmetric Cross Coupling in Water; (S)-2,2′-Dimethyl-1,1′-
binaphthyl (8aA); Typical Procedure
1-Iodo-2-methylnaphthalene (6a; 268 mg, 1 mmol), 1-(2-methyl-
naphthyl)boronic acid 7A (930 mg, 5 mmol), PS-PEG-L*1 (430 mg, 0.1
mmol P), PdCl2(MeCN)2 (34 mg, 0.1 mmol), and TBAF (260 mg, 10
mmol) were suspended in H2O (20 mL), and the reaction mixture was
stirred at 80 °C for 24 h under N2. After cooling down to r.t., the mix-
ture was filtered and the resin beads were washed with H2O (3 × 20
mL). The resin beads were eluted with supercritical CO2 until com-
plete extraction of soluble organic materials. The crude residue was
chromatographed on silica gel to give 8aA as a colorless hard oil. The
ee value of the product was determined by HPLC using a chiral sta-
31P{1H} NMR (202 MHz, CDCl3): δ = 7.4 (s).
Anal. Calcd for C34H41N2O3P: C, 73.36; H, 7.42; N, 5.03. Found: C,
73.66; H, 7.64; N, 4.96.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
Y. Uozumi et al.
Paper
Synthesis
tionary phase column (Chiralpak OD-H); yield: 280 mg (99%; Table 2,
entry 1).
1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 9.3 Hz, 1 H), 7.87–7.83 (m, 3
H), 7.48 (d, J = 8.3 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.36 (t, J = 7.3 Hz, 1
H), 7.31 (t, J = 7.6 Hz, 1 H), 7.19–7.16 (m, 2 H), 7.13 (d, J = 8.3 Hz, 1 H),
7.00 (d, J = 8.3 Hz, 1 H), 4.36 (q, J = 5.9 Hz, 2 H), 2.11 (s, 3 H), 0.90 (d,
J = 5.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 153.2, 135.0, 133.9, 133.3, 132.6,
132.0, 129.3, 129.0, 128.6, 127.8, 127.7, 127.2, 126.3, 126.1, 125.6,
125.3, 124.5, 124.1, 123.7, 117.7, 71.7, 22.4, 22.3, 20.3.
[CAS Reg. No.: 32587-64-7]
Colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.89 (d, J = 7.9 Hz, 2 H), 7.88 (d, J = 7.9
Hz, 2 H), 7.51 (d, J = 8.5 Hz, 2 H), 7.38–7.41 (m, 2 H), 7.19–7.23 (m, 2
H), 7.04 (d, J = 8.5 Hz, 2 H), 2.03 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 135.1 (2 C), 134.3 (2 C), 132.8 (2 C),
132.2 (2 C), 128.7 (2 C), 127.9 (2 C), 127.4 (2 C), 126.1 (2 C), 125.6 (2
C), 124.9 (2 C), 20.2 (2 C).
MS (EI+): m/z = 328 (M+).
[α]D20 +50.1 (c 0.9, CHCl3) for 90% ee. The absolute configuration was
determined by the sign of the specific rotation.13
MS (EI+): m/z = 282 (M+), 267 (M+ – CH3), 252 (M+ – C2H6).
Optical property was measured with a sample of 94% ee (Table 1, en-
try 9); [α]D20 +32.5 (c 0.8, CHCl3) for (S) of 94% ee.11 The enantiomeric
excess was determined by HPLC analysis using a chiral stationary
phase column [chiralcel OD-H (250 mm), eluent; n-hexane, flow rate;
0.5 mL/min, tR (major) = 20.0 min; tR (minor) = 24.2 min] to be 94% ee.
Methyl (R)-2′-Methyl-1,1′-binaphthyl-2-carboxylate (8dA)
[CAS Reg. No.: 113567-20-7]
Colorless prisms; yield: 200 mg (61%); mp 197–198 °C.
1H NMR (500 MHz, CDCl3): δ = 8.00–7.86 (m, 4 H), 7.50 (d, J = 9.3 Hz, 1
H), 7.45 (d, J = 7.3 Hz, 1 H), 7.38–6.10 (m, 6 H), 3.73 (s, 3 H), 2.09 (s, 3
H).
(R)-2-Methoxy-2′-methyl-1,1′-binaphthyl (8bA)
White solid; yield: 253 mg (85%); mp 119–120 °C.
13C NMR (125 MHz, CDCl3): δ = 168.3, 154.4, 134.9, 133.6, 133.2,
132.3, 132.1, 129.3, 129.2, 128.6, 128.5, 127.9, 127.5, 127.4, 126.5,
125.8, 125.0, 124.7, 123.6, 122.0, 113.8, 56.6, 20.3.
1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.5 Hz, 1 H), 7.88–7.86 (m, 3
H), 7.50 (d, J = 7.9 Hz, 1 H), 7.45 (d, J = 9.2 Hz, 1 H), 7.38–7.35 (m, 1 H),
7.33–7.30 (m, 1 H), 7.21–7.18 (m, 2 H), 7.12 (d, J = 7.9 Hz, 1 H), 6.98
(d, J = 8.5 Hz, 1 H), 3.75 (s, 3 H), 2.09 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.4, 135.0, 133.6, 133.2, 132.3,
132.1, 129.3, 129.2, 128.6, 128.0, 127.9, 127.8, 127.5, 126.5, 125.8,
125.7, 125.1, 124.7, 123.6, 113.8, 56.6, 20.3.
MS (EI+): m/z = 326 (M+).
[α]D20 –53.2 (c 0.902, CHCl3) for 88% ee. The enantiomeric excess was
determined by HPLC analysis using a chiral stationary phase column
[chiralpac AD-H (500 mm), eluent; n-hexane/i-PrOH = 95:5, flow
rate; 0.5 mL/min, tR (major) = 70.9 min; tR (minor) = 77.9 min] to be
88% ee. The absolute configuration was determined by the sign of the
specific rotation.14
MS (EI+): m/z = 298 (M+), 268 (M+ – CH2O).
20
[α]D +22.3 (c 1.3, CHCl3). The enantiomeric excess was determined
by HPLC analysis using a chiral stationary phase column [chiralpac
AD-H (500 mm), eluent; n-hexane/i-PrOH = 100:1, flow rate; 0.5
mL/min, tR (major) = 65.4 min; tR (minor) = 89.8 min] to be 92% ee.
The absolute configuration was determined by the sign of the specific
rotation.12
2-Methyl-1-o-tolylnaphthalene (10aA)
[CAS Reg. No.: 93870-58-7]
Colorless oil; yield: 223 mg (96%).
1H NMR (500 MHz, CDCl3): δ = 7.83 (d, J = 8.5 Hz, 1 H), 7.77 (d, J = 8.5
Hz, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 7.39–7.22 (m, 6 H), 7.11 (d, J = 8.5 Hz,
1 H), 2.16 (s, 3 H), 1.91 (s, 3 H).
(R)-2-Ethoxy-2′-methyl-1,1′-binaphthyl (8aC)
Colorless needles; yield: 290 mg (93%); mp 71–72 °C.
13C NMR (125 MHz, CDCl3): δ = 139.2, 137.5, 136.8, 133.1, 132.5,
132.0, 130.0, 129.9, 128.6, 127.8, 127.4, 127.1, 125.9, 125.8, 125.7,
124.7, 20.3, 19.5.
1H NMR (500 MHz, CDCl3): δ = 7.94 (d, J = 9.2 Hz, 1 H), 7.87–7.84 (m, 3
H), 7.49 (d, J = 7.9 Hz, 1 H), 7.42 (d, J = 9.2 Hz, 1 H), 7.38–7.35 (m, 1 H),
7.33–7.30 (m, 1 H), 7.20–7.17 (m, 2 H), 7.13 (d, J = 8.5 Hz, 1 H), 6.99
(d, J = 8.5 Hz, 1 H), 4.10–3.99 (m, 2 H), 2.10 (s, 3 H), 1.05 (t, J = 7.0 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 153.8, 134.9, 133.8, 133.3, 132.5,
132.1, 129.2, 129.1, 128.6, 127.9, 127.8, 127.3, 126.4, 126.0, 125.7,
125.2, 124.6, 123.6, 122.9, 115.6, 64.9, 20.3, 15.0.
MS (EI+): m/z = 232 (M+).
[α]D20 –92.7 (c 1.3, CHCl3) for 92% ee. The enantiomeric excess was de-
termined by HPLC analysis using a chiral stationary phase column
[chiralcel OD-H (250 mm), eluent; n-hexane, flow rate; 0.5 mL/min, tR
(major) = 25.4 min; tR (minor) = 28.1 min] to be 92% ee.
MS (EI+): m/z = 312 (M+), 268 (M+ – C2H4O).
3-Methyl-4-(2-methylnaphthalen-1-yl)benzonitrile (10bA)
[α]D20 –5.4 (c 1.63, CHCl3) for 92% ee. The enantiomeric excess was de-
termined by HPLC analysis using a chiral stationary phase column
[chiralpac AD-H (500 mm), eluent; n-hexane/i-PrOH = 95:5, flow
rate; 0.5 mL/min, tR (major) = 42.3 min; tR (minor) = 54.9 min] to be
92% ee. The absolute configuration was determined by the sign of the
specific rotation.
Colorless oil; yield: 229 mg (89%).
IR (ATR): 3122, 2965, 1511, 1220 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J = 8.5 Hz, 1 H), 7.82 (d, J = 8.5
Hz, 1 H), 7.67 (s, 1 H), 7.61 (m, 1 H), 7.44–7.41 (m, 2 H), 7.35–7.32 (m,
1 H), 7.24 (d, J = 8.5 Hz, 1 H), 7.09 (m, 1 H), 2.13 (s, 3 H), 1.95 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 144.7, 138.7, 135.4, 133.5, 132.7,
132.0, 131.7, 131.0, 129.8, 128.5, 128.1, 128.0, 126.4, 125.1, 124.9,
119.1, 111.4, 20.2, 19.3.
(S)-2-Ethoxy-2′-methoxy-1,1′-binaphthyl (8bC)
Colorless oil; yield: 294 mg (90%).
MS (EI+): m/z = 257 (M+).
HRMS (EI+): m/z [M]+ calcd for C19H15N: 257.1205; found: 257.1196.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
Y. Uozumi et al.
Paper
Synthesis
[α]D20 –52.3 (c 0.8, CHCl3) for 92% ee. The enantiomeric excess was de-
termined by HPLC analysis using a chiral stationary phase column
[chiralcel OD-H (250 mm), eluent; n-hexane/i-PrOH = 98:2, flow rate;
0.5 mL/min, tR (major) = 19.6 min; tR (minor) = 24.4 min] to be 92% ee.
Acknowledgment
This work was supported by the CREST and ACCEL programs, spon-
sored by the JST. We thank the JSPS and the MEXT for partial financial
support of this work. We also thank Prof. Haifeng Zhou at China Three
Gorges University for suggestions.
Methyl 3-Methyl-4-(2-methylnaphthalen-1-yl)benzoate (10cA)
White solid; yield: 363 mg (93%); mp 121–122 °C.
IR (ATR): 2931, 2977, 1691, 1511, 1420 cm–1
.
Supporting Information
1H NMR (500 MHz, CDCl3): δ = 7.94–7.84 (m, 3 H), 7.56 (d, J = 8.5 Hz, 1
H), 7.40 (d, J = 9.2 Hz, 1 H), 7.35–7.30 (m, 2 H), 7.22–7.13 (m, 2 H),
4.02 (s, 3 H), 2.19 (s, 3 H), 1.54 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.3, 153.7, 152.8, 134.3, 129.9,
129.4, 129.0, 127.8, 126.1, 125.8, 125.5, 123.9, 123.7, 121.9, 121.7,
118.1, 117.4, 55.8, 22.4, 20.3.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1589407. Included are NMR charts,
HPLC data, and the CIF file of L*1-PdCl2.
S
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References
MS (EI+): m/z = 290 (M+).
(1) For reviews, see: (a) Uozumi, Y. Top. Curr. Chem. 2004, 242, 77.
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(R)-2-Methyl-1-(2-nitrophenyl)naphthalene (10dA)
White solid; yield: 252 mg (96%); mp 131–132 °C.
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7.80 (d, J = 7.9 Hz, 1 H), 7.74–7.71 (m, 1 H), 7.69–7.61 (m, 1 H), 7.41–
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[α]D20 –101.0 (c 0.8, CHCl3) for (R) of 92% ee {Lit.15 [α]D25 –95.0 (c 1.0,
THF) for (R)}. The enantiomeric excess was determined by HPLC anal-
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eluent; n-hexane, flow rate; 0.5 mL/min, tR (major) = 35.9 min; tR (mi-
nor) = 42.7 min] to be 92% ee. The absolute configuration was deter-
mined by the sign of the specific rotation.
Diethyl (S)-2′-Methoxy-1,1′-binaphthyl-2-ylphosphonate (12)
[CAS Reg. No.: 919491-25-1]
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Colorless needles; yield: 295 mg (70%); mp 124–125 °C.
1H NMR (500 MHz, CDCl3): δ = 8.22 (m, 1 H), 8.01 (m, 2 H), 7.99 (d,
J = 8.0 Hz, 1 H), 7.85 (d, J = 8.1 Hz, 1 H), 7.52 (m, 1 H), 7.45 (d, J = 9.0
Hz, 1 H), 7.28 (m, 3 H), 7.16 (m, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 3.77 (s, 3
H), 3.68 (m, 2 H), 3.56 (m, 2 H), 0.98 (t, J = 7.1 Hz, 3 H), 0.77 (t, J = 7.1
Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 155.0, 140.5 (d, JC,P = 9.0 Hz), 134.8 (d,
JC,P = 2.6 Hz), 133.8, 132.9 (d, JC,P = 16.3 Hz), 129.9, 128.9 (d, JC,P = 9.8
Hz), 128.6, 128.2, 128.0, 127.9, 127.6 (d, JC,P = 14.4 Hz), 127.3, 127.0
(d, JC,P = 18.1 Hz), 126.9, 126.4, 126.0, 123.5, 121.1 (d, JC,P = 5.5 Hz),
113.0, 61.8 (d, JC,P = 5.7 Hz), 61.7 (d, JC,P = 6.0 Hz), 56.2, 15.9 (d,
JC,P = 6.5 Hz), 15.5 (d, JC,P = 6.9 Hz).
31P{1H} NMR = 17.0.
[α]D20 –19.5 (c 1.15, CHCl3) for 86% ee (Lit.16 [α]D+21.2 (c 1.015, CHCl3)
for (R) of >99% ee). The absolute configuration was determined by the
sign of the specific rotation.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J