A chiral picolinic acid ligand, Cl-NAPH-PyCOOH, for CPRU-catalyzed dehydrative allylation: Design, synthesis, and properties

Article abstract of DOI:10.1246/bcsj.20190134

A CpRu/Br?nsted acid-combined catalyst, CpRu(II)/pico-linic acid (PyCOOH), acts as an efficient catalyst for the allyl protection/deprotection of alcohols. This discovery has resulted in the development of a new axially chiral ligand, Cl-Naph-PyCOOH (2a;

Full text of DOI:10.1246/bcsj.20190134

Advance Publication Cover Page
A Chiral Picolinic Acid Ligand, Cl-Naph-PyCOOH, for CpRu-catalyzed
Dehydrative Allylation: Design, Synthesis, and Properties
Shinji Tanaka, Yusuke Suzuki, Takahiro Kimura, and Masato Kitamura*
Advance Publication on the web June 20, 2019
doi:10.1246/bcsj.20190134
© 2019 The Chemical Society of Japan
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Publication manuscripts.

A Chiral Picolinic Acid Ligand, Cl-Naph-PyCOOH, for CpRu-catalyzed
Dehydrative Allylation: Design, Synthesis, and Properties
Shinji Tanaka, Yusuke Suzuki, Takahiro Kimura, and Masato Kitamura*
Graduate School of Pharmaceutical Sciences and Research Center for Materials Science, Nagoya University, Chikusa, Nagoya 464-8601
E-mail: kitamura@ps.nagoya-u.ac.jp
Masato Kitamura
Masato Kitamura received his Doctor of Agriculture at Nagoya University (NU) (Professors T. Goto and M. Isobe) in
1983. After postdoctoral work with Professor G. Stork (Columbia University), he joined the Noyori group at Faculty of
Science in NU as Assistant Professor (1983), and was promoted to Associate Professor (1990). In 1998, he moved to
Research Center for Materials Science in NU as Full Professor. Currently, he is studying at Graduate School of
Pharmaceutical Sciences in NU from 2012. He is a recipient of The CSJ Award for Young Chemists (1989) and
Synthetic Organic Chemistry Award, Japan (2012).
Abstract
during the four decades since 1979 when Mares found the
utility of tungsten peroxo picolinate for the catalytic oxidation
of alcohols.4 The main use is in oxidation4, 5 but also for
carbon-carbon bond formation6 and functional group
transformation.7 The asymmetric version is limited to the
epoxidation of alkenes.8 All applications utilize PyCOOH as
an achiral supporting ligand, and the chirality of the metal
complexes is introduced by highly sophisticated chiral NNN
A
CpRu/Brønsted
acid-combined
catalyst,
CpRu(II)/picolinic acid (PyCOOH), acts as an efficient catalyst
for the allyl protection/deprotection of alcohols. This
discovery has resulted in the development of a new axially
chiral ligand, Cl-Naph-PyCOOH (2a;
6-(2-chloronaphthalen-1-yl)-5-methylpyridine-2-carboxylic
acid) through an investigation on the ligand structure-reactivity
relationship in the CpRu-catalyzed dehydrative cyclization of
(E)-hept-2-ene-1,7-diol (5) to 2-vinyltetrahydro-2H-pyran (6).
A large-scale synthetic procedure for 2a and the allyl esters 2b
has been established. The activation energy ΔG‡ of the
stereoinversion and the half-life time of (R)-2b racemization
have been determined to be 33.7 kcal/mol and 16,000 years at
25 °C, respectively. The CpRu(II)/(R)-Cl-Naph-PyCOOH
catalyst exists as a 1:1 diastereomeric mixture of (R,RRu)-3 (AR)
and (R,SRu)-3 (AS) because of the axial chirality of 2a and the
Ru stereogenic center. The epimerization rate of the Ru
center is 19.5/sec at 30 °C with an energy barrier ΔG‡ of 16.0
kcal/mol. Both AR and AS have their own reactivity and
enantioselectivity. Nevertheless, an enantiomer ratio of up to
>99:1 can be realized in the allylative cyclization of E-allylic
alcohols possessing a protic nucleophile, OH, NHCOR,
NHSO2R, or COOH, at the terminal position. Questions
about the mechanism have been raised as progress is being
made towards a mechanistic investigation.
ligands.
There are no reports on catalytic asymmetric
reactions using metal complexes of chirally modified PyCOOH
ligands.
In the course of developing
a catalyst for allyl
protection/deprotection through an automated combinatorial
screening of metal precursors and ligands, we found that the
combination of [RuCp(CH3CN)3]PF6 (1) with PyCOOH shows
a high reactivity in the allylation of alcohols using allyl alcohol
(AllOH). Further structural optimization of the PyCOOH
ligand has led to quinaldic acid (QAH), which shows a
one-order higher reactivity in combination with 1.9 As shown
in Figure 1a, the CpRu(II)/QAH catalyzes either dehydrative
installation of an allyl group into alcohols using AllOH in
aprotic solvents such as CH2Cl2 or removal of an allyl group
from allyl ethers (AllOR) in protic solvents such as CH3OH.10
The CpRu(II)/QAH chemistry has contributed not only to the
allyl protection/deprotection of alcohols but also to selective
S-allylation of oligo peptides in aqueous media,11 deprotection
of amines and carboxylic acids,12 and the synthesis of various
important compounds.13 Figure 1b illustrates our leading
concept used for the combinatorial screening, which is named
Keywords: Axially chiral ligand, Ruthenium,
Asymmetric dehydrative allylation
the
Intramolecular
Redox-mediated
Donor-Acceptor
Bifunctional Catalyst (Intramol-RDACat)14 or transition
metal/Brønsted acid-combined catalyst.15 In the conceptual
catalyst, M(n)Cp(Ls–LhH), M(n) represents a low valence
transition metal, and Ls and Lh are a soft ligating atom such as
sp3P, sp2N, and sp3S and a hard ligating atom such as sp3O and
1. Introduction
Picolinic acid (PyCOOH) is a simple molecule packed
with significant functional groups to capture various metals.
The σ donative and π acceptive sp2N of the pyridine cooperates
with the carboxylic acid moiety located at the C(2) position in
capturing typical metals and transition metals with either high
or low valences. The strong chelating ability plays an
important role in our human body for absorbing trace elements
such as Cr, Mo, Mg, Fe, Cu, and Zn to express various
physiological activities.1 An enormous number of reports on
the metal complexes have been published2 since the first
discovery of metal picolinate by Webster in 1936.3 As a
result, a number of catalytic reactions have been reported
sp3N, respectively.
The monoanionic and highly
electron-donative cyclopentadienyl (Cp) ligand enhances the
electron density of M(n) to facilitate its oxidation to M(n+2).
In addition, the η5 Cp and bidentate Ls–LhH ligands increase
the degree of coordinative saturation to suppress
self-aggregation that sometimes causes catalyst deactivation.
Complex M(n)Cp(Ls–LhH) captures AllOH via a coordination
of the soft C=C bond to the soft M(n) and via an interaction of
the hard OH oxygen atom with the hard H+. The resulting
δ+-δ–-δ+-δ–-δ+-δ– charge-alternation including M(n) oxidation

stabilizes the transition state to facilitate the formation of
M(n+2)Cp(π-allyl)(Ls–Lh) by liberation of H2O. The
ester 2b and propose a possible mechanism under the premise
that the reaction proceeds via π-allyl Ru intermediates in a
similar way to the CpRu/PyCOOH-catalyzed dehydrative
allylation.10
subsequent reductive nucleophilic attack of ROH on the
electron deficient π-allyl carbon gives AllOR. In CH3OH, the
allyloxy bond of AllOR is reversibly cleaved according to the
same Intramol-RDACat mechanism to move the equilibrium to
the AllOMe/ROH side.
2. Results and Discussion
2.1. Ligand Structure–reactivity Relationship. To
design a chiral PyCOOH-type ligand for the asymmetric
a
dehydrative
allylative
cyclization,
the
ligand
HO
H2O
structure-reactivity relationship was investigated in the reaction
of (E)-hex-2-ene-1,6-diol (5) to 2-vinyltetrahydro-2H-pyran (6)
using [RuCp(CH3CN)3]PF6 (1) and modified PyCOOH ligand
L under the conditions of [5] = 100 mM, [1] = [L] = 1 mM (1
mol%), DMA, and a 100 °C-oil bath temperature. The
reaction time was set to 10 min for clarifying the reactivity
difference. The yields were determined by GC analysis
(column, J&W Scientific DB-5 (0.25 mm x 0.25 µm x 30 m);
50 °C for 10 min –> 10 °C increase/min –> 200 °C; 140 kPa;
100:1 split ratio; tR of 6, 6.9 min; tR of 5, 18.7 min). The
results are shown in Figure 3. Quinaldic acid (QAH; L1), its
allyl ester L2, and PyCOOH (L4) quantitatively afforded
allylation
O
–
+ PF6
– H+
N
O
II
Ru
RO
ROH
CpRuQAH
deallylation
CH3O
CH3OH
b
–
δ
–
δ
Ls
Lh
Ls
Lh
+
δ
+
δ
+
6-exo-trig-cyclized product 6.
No 8-endo-trig-cyclized
H δ
–
+
Mn
δ
δ
–
δ
H2O
Mn+2
O
product was generated. Introduction of a methyl group at
C(8) of QAH or a tert-butyl group at C(6) of PyCOOH led to
no reaction (L3 and L5). The reactivity was recovered by
10% by replacement of a tert-butyl group at C(6) with a
sterically more flexible phenyl group (L6). Full recovery of
the reactivity was attained by use of o-Cl-Ph- or
o-Br-Ph-substituted PyCOOH (L7 and L8). Introduction of
H
Figure 1. (a) Dehydrative allylation and deallylation catalyst,
CpRu/quinaldic acid (QAH). (b) Intramolecular
Redox-mediated Donor-Acceptor bifunctional Catalyst
(Intramol-RDACat) concept for combinatorial screening of
catalyst
1 mol%
ligand
[RuCp(CH3CN)3]PF6
The discovery of a CpRu(II)/PyCOOH-combined catalyst
represents a step towards the development of the first
OH
+
H2O
O
DMA, 100 °C, 10 min
OH
high-performance
asymmetric
dehydrative
allylative
5
6
cyclization.16 As shown in Figure 2, introduction of chirality
into PyCOOH as (R)- or (S)-Cl-Naph-PyCOOH (2a; (R)- and
(S)-6-(2-chloronaphthalen-1-yl)-5-methylpyridine-2-carboxylic
acid) has led to the new chiral CpRu complexes,
100 mM
ligand
COOH
N
COOAll
N
COOH
N
COOH
N
COOH
N
[RuCp((R)-Cl-Naph-PyCOOH)]PF6
((R)-3)
and
[RuCp(π-C3H5)((R)-Cl-Naph-PyCOO)]PF6 ((R)-4).
These
L1
99% yield
L2
99
L3
<1
L4
98
L5
<1
complexes efficiently catalyze the asymmetric dehydrative
cyclization of E-allylic alcohols 5 tethered with protonic
nucleophiles such as OH, NHCOR, NHSO2R, and COOH,
furnishing the corresponding saturated heterocycles (S)-6 with
up to >99:1 S/R enantiomer ratio (er).17
(2)a
COOH
N
Cl
Br
L6
11
L7
99
(15)a
L8
99
(4)a
R
Cl
CF3
F
OCH3
O
Cl
L9
37
L10
3b
L11
6b
L12
10b
N
R
OR’
(R)-2a: R = Cl, R’ = H
(R)-2b: R = Cl, R’ = CH2CH=CH2
Cl
PF6
PF6
O
O
–
Cl
L15
9b
OH+
L13
5b
L14
6b
N
O
RuIV
N
R
R
RuII
Cl
Cl
PyCOOH => 5-CH3-PyCOOH
Cl-Ph => Cl-Naph
(R)-4
(R)-3
axially chiral Cl-Naph-PyCOOH
O
OH
O
1–0.03 mol%
HO
OH
(R)-3 or (R)-4
+
DMA, 100 °C
1–3 h
N
NuH
Nu
(S)-6
up to quant
up to > 99:1 S/R er
N
Nu
Cl
Cl
(R)-6
5
R
S
NuH = OH, NCOR, NHSO2R, COOH
(CH2)n (n = 0–2) or 1,2-phenylene
:
Figure 2. Asymmetric dehydrative intramolecular allylation
Figure 3. Ligand structure-reactivity relationship in the
CpRu-catalyzed dehydrative cyclization of 5 to 6 toward the
design of an axially chiral picolinic acid ligand. a 0.1 mol%.
b Allyl ester was used
using CpRu/Cl-Naph-PyCOOH
In this paper, we would like to report the details for the
design and synthesis of Cl-Naph-PyCOOH (2a) and its allyl

two ortho Cl groups led to one-fifth of the reactivity of
o-Cl-Ph-PyCOOH (L9 vs L7). More electron-withdrawing
CF3 or F groups decreased the reactivity (L10 and L11), and
electron-donating CH3O or CH3 groups were also not effective
(L12 and L13). Movement of the Cl substituent from the
ortho to meta or para position eradicated the reactivity (L14
and L15). Taking into consideration the ligand-structure
effect on the reactivity and the higher stability of Cl-Ph toward
a low valence transition metal than Br-Ph, the axially chiral
Cl-Naph-PyCOOH (2a) ligand was designed; here, the basic
skeleton of o-Cl-Ph-PyCOOH was modified by introducing a
methyl group at C(5) of the Py moiety and by replacing the
Cl-Ph group with a C(2’)-Cl-naphthyl (Cl-Naph) group to
suppress stereoinversion.
which was separated by silica-gel chromatography to give
(Ra,1S)-11 in 47% yield and (Sa,1S)-11 in 45% yield.
21
Hydrolysis of each diastereomer gave (R)-2a ([α]D 136 (c
22
1.02, CHCl3)) or (S)-2a ([α]D –143 (c 1.06, CHCl3)). Acid
chlorination followed by allyl esterification afforded
21
(R)-Cl-Naph-PyCOOAll ((R)-2b; [α]D 122 (c 1.10, CHCl3))
20
and (S)-2b ([α]D –121 (c 0.53, CHCl3)) in 93% yield from
11.20
2.3. Stereochemical Stability. Possible racemization
processes of 2 are illustrated in Figure 5a. The atropisomeric
biaryl compound 2 undergoes stereochemical inversion by
clockwise or anticlockwise rotation through the C(6)–C(1')
bond joining the two aryl rings. The rotation proceeds via two
possible transition states, TS180 and TS0 with the
C(2')=C(1')–C(6)=N(1) dihedral angle f of 180 deg and 0 deg,
respectively. The energy barrier for the stereoinversion is
determined mainly by the relative steric demand between N(1)
(smaller: S) and C(5)Me (larger: L) in the Py part and between
C(2')Cl (smaller: S') and C(8')H (larger: L') in another aryl
partner and also by electronic effects. In TS0, the larger
substituents L and L' are located in the overcrowded fjords
region21 while the smaller S and larger L' combination in TS180
decreases the degree of the penetration across the fjords.
Furthermore, TS180 is electronically favored in terms of
electron flow from the Cl lone pair to N(1) in the
s-trans-arranged Cl–C(2')=C(1')–C(6)=N(1) conjugated system,
and electronic repulsion between the lone pairs of sp2N(1) and
the Cl atom destabilizes the s-cis-arranged TS0. The van der
Waals radius of Cl is close to that of Me (effective van der
Waals radius (ER): Cl 1.73 vs Me 1.80); therefore, the energy
2.2. Ligand Synthesis.
As shown in Figure 4a,
(±)-Cl-Naph-PyCOOH ((±)-2a) was retrosynthesized to
commercially available 2-bromo-3-methylpyridine (7) and
naphthalen-1-ylboronic acid (8) via a Suzuki-Miyaura coupling
between C(1’) and C(6), introduction of C(2’)-Cl by
Py-sp2N-promoted silylation followed by Si/Cl exchange, and
introduction of a 2-CN group by a Reissert-Henze reaction
followed by hydrolysis to COOH. Figure 4b shows the
synthetic route. The Pd-catalyzed coupling of 7 with 8 on a
50-g scale efficiently proceeded at 100 °C in a 5:1 DME–H2O
mixed solvent containing K2CO3. The crude coupling product
was subjected to the Murai reaction using (C2H5)3SiH and
norbornene under the influence of Ru3(CO)12 in toluene,18
giving C(2’)-silylated product 9 in 93% yield in two steps.
The (C2H5)3Si group of 9 was converted to a C(2’)-Cl group by
treatment with BCl3 in CH2Cl2 followed by CuCl2 in a 1:1
CH3OH–H2O mixed solvent to give 10 in 95% yield.19
Oxidation of the Py-sp2N atom of 10 by H2O2 in AcOH
followed by reaction of the N-oxide product with (CH3)3SiCN
and dimethylcarbamoyl chloride introduced a CN group at C(2),
which was hydrolyzed to give (±)-2a in 82% yield in three
steps from 10. (S)-Camphorsultam was introduced to (±)-2a
and afforded the corresponding 1:1 diastereomeric mixture,
TS0
ϕ(N=C–C=CCl): 0°
a
TS180
ϕ(N=C–C=CCl): 180°
X
L
S
N
fjord cove
X
S
L
X
Cl
S'
X
N
fjord cove
X
L'
5
N
N
N
Cl
S'
L'
6
ϕ = 0°
S
S
R
8'
1'
Cl
Cl
Cl
2'
ΔG‡
(R)-2b
ΔG‡
a
Reissert Henze
nitrilation of pyridine N-oxide
followed by hydrolysis
180°
0°
O
Suzuki-Miyaura
coupling
b
N
R
5
2
Br
7
N
OH
6
1’
2’
B(OH)2
Cl
S
>99.9:0.1
99.4:0.6
0
Si/Cl exchange
Py sp2N-promoted
Murai silylation
1
90.2:9.8
81.9:18.1
75.8:24.2
73.1:26.9
12
8
(±)-2a
25
37
b
0.5 mol% Ru2(CO)12
2 mol amt (C2H5 3SiH
2 mol amt norbornene
toluene
reflux, 36 h
43
0.5 mol% Pd(P(C6H5
1.4 mol amt K2CO3
) )
3 4
)
10
12
16
8
t, min
5:1 DME–H2
100 °C, 42 h
O
N
7
+ 8
c
5
Si(C2H5)3
9
93% yield in 2 steps
4.5
-0.0003t + 4.6269 (r = 0.99933)
a) 1.2 mol amt BCl3
CH2Cl2
–78 °C –> rt, 1.5 h
4
a) 3 mol amt H2O2 (30 w%)
AcOH, reflux, 18 h
N
3.5
3
b) 3 mol amt CuCl2
1:1 CH3OH–H2
reflux, 96 h
b) 1.2 mol amt (CH3
1.7 mol amt (CH3
CH2Cl2, reflux, 42 h
)
3SiCN
O
Cl
)
2NCOCl
10
95% yield
c) 12 M aq HCl, relfux, 24 h
2.5
2
O
O
a) SOCl2
50 °C, 3 h
0
1000 2000 3000 4000 5000 6000 7000
time, min
N
OH
N
O
N
S
b) Na salt of
1 mol amt
S
1
(S)-camphorsultam
toluene, 28 °C, 24 h
c) SiO2 separation
Cl
Cl
O
Figure 5. Possible racemization process of (R)-Cl-Naph-PyX
(X = COOCH2CH=CH2, (R)-2b) and determination of the t1/2
values. (a) Energy diagram in the C(6)-C(1') bond rotation of
(R)-2b. (b) The R/S er change of (R)-2b in DMA at 130 °C as
determined by HPLC analysis (CHIRALCEL OD-H (4.6 mm φ
x 250 mm); 1:5 2-PrOH–hexane eluent; 1.0 mL/min flow rate;
254-nm detection; 25 °C). (c) Logarithmic plots of the ers
over time
(±)-2a
(Ra,1S)-11: 47% yield
(Sa,1S)-11: 45% yield
82% yield from 10
a) 1.5 mol amt LiOH•H2
O
O
10:1 THF–H2
28 °C, 14 h
a) SOCl2
50 °C, 3 h
(R)-2a
(S)-2a
(R)-2b
(S)-2b
b) MTBE/H2O/AcOH
partition
b) allyl alcohol
28 °C, 24 h
93% yield in 3 steps
er >99:1
quant
er >99:1
Figure 4. (a) Retrosynthetic analysis of (±)-2a. (b)
Syntheses of (R)- and (S)-Cl-Naph-PyCOOH (2a) and the allyl
ester 2b

W: 4.82 Hz
a
barrier toward TS180 would also be high but would be lower
than that toward TS0. To understand the racemization profile
of optically pure 2 quantitatively, the time-course change in the
er of (R)-2b (10 mM) in DMA at 130 °C was measured by
chiral HPLC analysis (Figure 5b). The ers decreased from
>99.9:0.1 to 99.4:0.6 (1 h), 90.2:9.8 (12 h), 81.9:18.1 (25 h),
75.8:24.2 (37 h), and 73.1:26.9 (43 h). The logarithmic plots
of ers versus time gave a linear relationship with a correlation
coefficient of 0.99933 (ln(R/S) = –3.00 x 10–4t + 4.63),
determining the rate of racemization krac to be 5.01 x 10–6 s–1.
The activation energy barrier ΔG‡ at 25 °C and the half-life
time (t1/2) of (R)-2b racemization were calculated to be 141
PF6
O
–
PF6
O
–
S
S
Cl
N
OH+
H
+O
N
R
R
RuRII
RuSII
Cl
Cp
18 °C
AR
AS
6.0
5.0
4.0
3.0
ppm
30 °C
k30 = π x ΔW = 19.5 s–1
W:11.02 Hz
Cp
6.0
5.0
4.0
3.0
ppm
kJ/mol (33.7 kcal/mol) using the Eyring equation (ΔG‡
8.314T ln (2.084 x 1010 T/krac)) and 16,000 years at 25 °C using
t1/2 ln2/krac respectively. In comparison to
=
40 °C
k40 = π x ΔW = 84.3 s–1
W:31.67 Hz
=
,
Cp
Me-Naph-PyCOOAll with the same level of ER as Cl, the
half-life time is shortened by two orders of magnitude
(1,500,000 years vs 16,000 years).22 The electronically
stabilized TS180 would be ascribed to the shorter half-life time
of Cl-Naph-PyCOOAll in comparison to Me-Naph-PyCOOAll.
In the reaction of 5 using (R)-3 or (R)-4, the cyclized
product 6 with a 96:4 S/R er was quantitatively obtained under
the conditions of [5] = 1000 mM, [1] = [(R)-2b] = 1 mM (0.1
mol%), DMA, 100 °C; 1 h. A decrease in the substrate
concentration from 1000 mM to 100 mM slightly increases the
er to 97:3.16 Generation of the minor (R)-6 is not due to the
racemization of the chiral ligand during the course of the
reaction at 100 °C, as confirmed by the recovery of the ligand
without any er deterioration (Figure 6). The stereochemical
stability of the ligand should be significantly enhanced after
formation of the CpRu complex because the N(1)–RuCp part
becomes the largest. The complexation of (R)-2a or (R)-2b
with 1 is also thought to contribute to the stereochemical
stability.
6.0
5.0
4.0
3.0
ppm
Et3NHPF6
Et3NHPF6
b
O
O
O
S
S
Cl
N
O
N
R
R
RuRII
RuSII
Cl
n
n
AR
AS
W: 2.75 Hz
–40 °C
7.35
7.25
7.15
6.0
5.0
4.0
3.0
ppm
–20 °C
k–20 = π x ΔW = 15.1 s–1
W:7.57 Hz
7.35
7.25
7.15
a)
b)
SOCl2
50 °C, 30 min
10 mM (R)-4
(>99:1 er)
6.0
5.0
4.0
3.0
ppm
OH
(R)-2b
(>99:1 er)
residue
removal of
DMA,
100 °C, 1 h
AllOH
rt, 18 h
0 °C
OH
5
W:41.31 Hz
all of volatiles
at 0.02 mbar and
40 °C
k0 = π x ΔW = 121.1 s–1
1 M
O
7.35
7.25
7.15
(S)-6
96:4 er
6.0
5.0
4.0
3.0
ppm
Figure 6. The process of recovering (R)-2b after the reaction
of 5 at 100 °C for 1 h
Figure 7. 1H-NMR spectra of the Cp and Cl-Naph regions of
(R)-3 in acetone-d6 at different temperatures. (a) In the
absence of Et3N at 18 °C, 30 °C, and 40 °C. (b) In the
presence of one mol amount of Et3N at –40 °C, –20 °C, and
0 °C. S: CH3CN or acetone-d6
2.4. Characteristics of Cl-Naph-PyCOOH/CpRu
Complex. Figure 7 shows the Cp and Cl-Naph signal
regions of the 1H-NMR spectra of
a 1:1 mixture of
(R)-Cl-Naph-PyCOOH ((R)-2a) and [RuCp(CH3CN)3]PF6 (1)
in acetone-d6 in the absence and presence of one mol amount of
Et3N.
DMA-d9 liberated black precipitates probably due to
disproportionation of Ru(II) to Ru(0). The chemical shift
difference (0.23 ppm) of the two Cp signals are too large to
coalesce at a temperature lower than 100 °C. There were no
other signals that were clearly merged in the temperature range
from –40 °C to 50 °C.
In the presence of Et3N (Figure 7b), the two Cp signals
appeared at δ 3.10 ppm (W = 2.75 Hz) and δ 3.35 ppm in a ca.
1:1 ratio at –40 °C (acetone-d6). The W value of the signal at
a higher field was increased to 7.57 Hz at –20 °C and to 41.31
Hz at 0 °C, determining the flipping rate to be 15.1/sec
(–20 °C) and 121/sec (0 °C) with ΔG‡ = 13.4 kcal/mol and 13.3
kcal/mol, respectively. The corresponding neutral complexes
In the absence of Et3N (Figure 7a), the Cp signals
resonated at δ 3.29 ppm and δ 3.52 ppm at 18 °C. These were
assignable to the two diastereomeric CpRu complexes,
(R,RRu)-3 (AR) and (R,SRu)-3 (AS), which are in a rapid
equilibrium as shown in Figure 8. The 1:1 ratio indicated that
the equilibrium constant K is nearly 1. The two signals were
broadened by raising the temperature, e.g., the half-width (W)
of the signal at δ 3.29 ppm was widened from 4.82 Hz (18 °C)
to 11.02 Hz (30 °C) and 31.67 Hz (40 °C), determining the Cp
flipping rate to be 19.5/sec (k30 = πΔW = π(11.02 – 4.82)) at
30 °C with ΔG‡ = 16.0 kcal/mol and 84.3/sec (k40 = π(31.67 –
4.82)) at 40 °C with ΔG‡ = 15.6 kcal/mol. The complex 3 was
not stable at a high temperature in the absence of the allylic
alcohol substrate; an increase in temperature to 100 °C in
n
n
AR and AS are thought to be generated by liberation of a
HPF6/Et3N salt. In this case, the 1H signals at δ 7.21 ppm and
δ 7.27 ppm (–40 °C) were merged at 0 °C. With the chemical
shift difference of the two signals in Hz (0.06 ppm = 8.26 Hz)

and the coalescence temperature (0 °C = 273 K), the
interconversion rate between ARn and ASn was determined to be
91.7/sec at 0 °C with ΔG‡ = 13.5 kcal/mol, which qualitatively
agree with the result obtained by the above half-width analysis
of the Cp signal at δ 3.10 ppm.
reasons that are presently unclear.
Among many possibilities, two simplified pathways via
π-allyl intermediates23 are shown in Figure 9: i)
π-σ-π-isomerization-involved pathways giving major (S)-6
from AR and minor (R)-6 from AS and ii)
π-σ-π-isomerization-non-involved pathways giving minor (R)-6
from AR and major (S)-6 from AS. Complexes AR and AS
interact with 5 to generate catalyst/substrate complexes,
BR-saRe, BR-ssSi, BS-saSi, and BS-ssRe, with equilibrium
Figure 8 illustrated the possible preequilibria of the
CpRu/(R)-Cl-Naph-PyCOOH catalyst (R)-3.
In the
monocationic AR and AS complexes existing as a 1:1 mixture,
coordination of the carboxylic acid oxygen atom of
Cl-Naph-PyCOOH to the cationic Ru(II) center would enhance
the acidity of the COOH to liberate HPF6 by the formation of
1
2
1
2
constants, KR , KR , KS , and KS , respectively. Here, "saRe"
indicates that the C(3) substituent of 5 is syn to C(2)H and anti
to the Ru carboxylato moiety and that the Re face of C(3) is
directed to the Ru side. In terms of stereo-complementarity,
inequalities KR1 < KR2 and KS1 < KS2 would be established. In
the π-σ-π-isomerization-involved pathways (Figure 9, right),
BR-saRe releases H2O to the Ru side or inside (H2Oin) to move
to π-CR-saRe, which isomerizes to the sterically favored
π-CR-ssSi via a Ru-C(1) bond rotation, eliminating the steric
repulsion in the 2nd quadrant. Reductive nucleophilic attack
of the terminal NuH to π-allyl C(3) from the Ru side (NuHin)
gives (S)-6 as the major isomer. In a similar way to this
process, the BS-saSi => H2Oin => π-CS-saSi => Ru-C(1) =>
n
n 10e
the corresponding neutral complexes, AR and AS .
The
monocationic complex can supply H+ for allylic alcohol
substrate 5 in an intramolecular manner, whereas liberation of
HPF6 can make it possible to activate 5 intermolecularly. The
two modes increase the number of the possible reaction
pathways from 5 possessing a protonic nucleophile NuH at the
terminus (NuH: OH, NHCOR, NHSO2R, or COOH) to the
major (S)-6 and minor (R)-6. The coordinative regions of the
chiral Brønsted acid/CpRu(II)-combined catalyst (R)-3 were
schematically shown by the 1st to 4th quadrants made by
horizontal and vertical lines crossing the central Ru. Black
and grey regions are sterically congested because of the
Cl-Naph moiety. Complex AR is characterized by the Ph
moiety of Cl-Naph standing up in the 2nd quadrant, whereas AS
is characterized by the existence of a Cl atom in the 1st
quadrant. The difference is supposed to realize a significant
difference between the reactivities of AR andAS for some
π-CS-ssRe => NuHin process produces (R)-6.
In this
1
1
1
1
combination, KR kR must be larger than KS kS for the
predominant generation of (S)-6. The H2Oin and NuHin mode
is supposed to be facilitated by an intramolecular H+ assistance
from Cl-Naph-PyCOOH coordinated to Ru(II) and by an
intramolecular hydrogen bond of NuH with the basic Ru
carboxylato oxygen atom, respectively. π-σ-π-isomerization
non-involved pathways start from the sterically favored BR-ssSi
and BS-ssRe (Figure 9, left): BR-ssSi => H2Oout => π-CR-ssSi
=> NuHout pathway and BS-ssRe => H2Oout => π-CS-ssRe =>
NuHout pathway to generate the minor (R)-6 and major (S)-6,
respectively, without any intramolecular H+ assistance or
hydrogen bond assistance. In this combination, an inequality,
2
3
1
4
2
3
1
4
electron
rich and σ-hole
region
standing up
PF6
PF6
O
–
Cl
O
–
H+O
Cl
OH+
RuRII
N
K
N
O
H
N
O
H
RuSII
N
RuRII
RuSII
Cl
Cl
2
2
2
2
sterically
most crowded
sterically
most crowded
KS kS > KR kR , should be established for making the (S)-6
major. The 3rd quadrant of BR-ssSi and the 4th quadrant of
BS-ssRe are sterically congested, making the H2O liberation to
the inside impossible. These H2Oout/NuHout processes can be
realized through an activation of 5 in BS-ssRe or BR-ssSi from
the outside by the highly acidic HPF6 which is generated from
AR and AS by formation of the corresponding neutral
complexes. Activation of 5 by another AR or AS is also
possible.
(R,SRu)-3 (AS
)
(R,RRu)-3 (AR
)
H+
H+
HPF6
HPF6
O
O
RuRII
Cl
O
O
Cl
N
N
O
N
O
RuSII
N
RuRII
RuSII
Cl
AR
Cl
n
n
AS
Figure 8. Diastereomeric mixture of the
(R)-Cl-Naph-PyCOOH/CpRu complex and the neutral
complexes. PF6 or PF6– is omitted in the schematic view
2
3
1
OH
HNu
sub:
H
H
NuH: OH, NHCOR, NHSO2R, and COOH
:
(CH2)n (n = 0–2)
NuH
NuH
NuH
NuH
+ sub
H
HO
H
2
2
2
2
+ sub
1
2
1
3
1
1
3
3
1
3
II
H
1
3
– AR
2
KR
KR
O
O
O
H
N
N
O
N
N
N
O
O
IV
RuRII
RuR
Nu
(S)-6
IV
H
H
H
RuRIV
Nu
RuR
RuR
AR
Ru-C(1)
NuHout
H2Oout
H2Oin
NuHin
(R)-6
minor
– sub
– sub
NuH
Cl
Cl
π-CR-saRe
Cl
Cl
Cl
major
2
3
1
4
2
3
1
4
π-CR-ssSi
BR-ssSi
BR-saRe
π-CR-ssSi
1
2
kR
kR
K
2
1
kS
kS
HNu
HNu
HNu
HNu
H
OH
2
3
2
+ sub
2
+ sub
1
H
2
Cl
Cl
Cl
2
Cl
2
Cl
1
3
1
3
1
1
3
3
1
– AS
KS
KS
H
HO
N
N
N
N
N
IV
O
O
O
O
O
RuSII
RuSII
RuSII
H
H
IV
RuS
AS
RuS
Nu
Nu
H
Ru-C(1)
NuHout
H2Oout
H2Oin
NuHin
– sub
– sub
(R)-6
minor
(S)-6
major
NuH
π-CS-ssRe
2
3
1
4
2
3
1
4
π-CS-ssRe
BS-ssRe
BS-saSi
π-CS-saSi
non-isomerization route
H2O liberation outside from Ru side (H2Oout
π-σ-π isomerization route
H2O liberation to Ru side (H2Oin)
)
PF6: omitted.
NuH attack outside from Ru side (NuHout
)
NuH attack from Ru side (NuHin
)
Figure 9. Reaction pathways via intramolecular and intermolecular activations of the allylic alcohol substrate 5

The number of reaction pathways reaches 32 by 4
parameters including ss/sa and outside/inside modes both in the
H2O liberation step and in the NuH nucleophilic attack step;
this is the case even with the assumptions that an endo-CpRu
complex is formed,24 the Ru-C(1) rotation is involved in the
π-CR-saRe isomerization to π-CR-ssSi, and the sterically
favored syn,syn-complex is not isomerized to the disfavored
syn,anti-complex. The reaction pathways shown in Figure 9
under investigation to determine the pathway from 5 to the
major (S)-6.
4. Experimental
4.1. General.
4.1.1. Instrumentation. Nuclear magnetic resonance
(NMR) spectra were recorded on JEOL JNM-ECA-600 (600
1
MHz for H, 152 MHz for 13C), and the chemical shifts are
raise many questions about the mechanism:
i) Is a
expressed in parts per million (ppm) downfield from Si(CH3)4
"Redox-mediated Donor-Acceptor bifunctional Catalyst
mechanism" really operating?; ii) In the case of the
H2Oin/NuHin process, why does the reaction start from the
sterically disfavored substrate/catalyst complexes?; iii) Why
does AR more quickly turnover than AS in the H2Oin/NuHin
pathway?; iv) Why does AS more quickly turnover than AR in
the H2Oout/NuHout pathway?; v) Is a π-allyl Ru intermediate
really operating, and is there any possibility for the operation of
σ-allyl Ru intermediate?; and vi) What is the role of the
chlorine atom, and is there any possibility for involvement of a
1
or in ppm relative to CHCl3 (δ 7.26 in H NMR and δ 77.0 in
1
13C NMR). The signal coupling patterns of H and 13C NMR
are indicated as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; and br, broad signal. The resolutions of
1H- and 13C-NMR spectra were 0.689 Hz and 1.44 Hz
respectively. X-ray crystallographic analyses were conducted
on a Rigaku Saturn 70 CCD system and the structures were
solved by direct methods using "Crystal Structure"
crystallographic software.
High-resolution mass spectra
hydrogen bond25 or halogen bond26?
To answer these
(HRMS) were measured by ESI ionization method on a Bruker
Daltonics micrOTOF-QII system. Shimadzu 17A and 2014
systems were used for gas chromatography (GC) analyses.
High performance liquid chromatography (HPLC) analyses
were performed on a Shimadzu LC-10A system. Optical
rotations were measured on a JASCO P-1010-GT system.
Melting points (mp) were determined on a Yanaco Micro
Melting Point Apparatus.
questions, we are now trying to elucidate the mechanism via
D-labeling experiments, kinetic studies, NMR studies, isolation
of Ru complexes related to the present reaction and structural
elucidation by X-ray diffraction, and theoretical calculations.
3. Conclusion
Discovery of the CpRu(II)/PyCOOH combined catalyst
for the allyl protection/deprotection of alcohols9,10 motivated
further work on the development of an asymmetric version;
2-Cl-Ph-PyCOOH (L7) came up through investigation on the
ligand structure-reactivity relationship in the dehydrative
intramolecular allylation of ω-hydroxy allylic alcohol 5 to the
corresponding cyclic ether 6. Endowment of chirality with the
4.1.2. Manipulation. A Teflon-coated magnetic bar was
used for stirring of a reaction mixture. Room temperature (rt)
was in the range of 28 °C from 25 °C. Reactions at higher
temperature than rt were carried out by use of oil bath.
Reactions at 0 °C and at –78 °C were carried out by use of an
ice bath and of a dry ice/CH3OH bath, respectively. Solvents
after general workup process were removed by means of a
rotary evaporator. Concentration of a reaction mixture in a
Schlenk tube was performed by connecting to a vacuum-Ar line
via a cold trap cooled by liquid N2. Organic extract obtained
by a general partition-based workup was dried over anhydrous
Na2SO4 for ca. 30 min. "Aqueous" and "saturated" were
abbreviated as "aq" and "sat," respectively. Brine means sat
aq NaCl. All of metal-catalyzed reactions were carried out
under Ar atmosphere by use of a general Schlenk technique
unless otherwise specified. A Schlenk with Teflon J. Young
valve was specified by "Young-type Schlenk." Schlenks were
dried, before use, at ca. 250 °C by use of a heat gun under a
reduced pressure, and silicon grease was used for connecting to
a cold finger, a reflux condenser, and a glass stopper. Liquid
reagents were introduced by use of a syringe via a septum
rubber. After introduction, the septum was replaced with a
glass stopper or with a Young valve. Heating in a closed
system was carried out after reducing the pressure of the whole
system or after raising the temperature followed by closing the
system. Degassed solvents and degassed solutions of reagents,
catalysts, and substrates were transferred to another Schenk by
use of a gas-tight syringe or cannulation method. Cannulation
was performed by use of a stainless tube through a septum
basic skeleton has established
a
new axially chiral
Cl-Naph-PyCOOH. Use of CpRu(II)/(R)-Cl-Naph-PyCOOH
complex ((R)-3) has enabled the asymmetric construction of
α-alkenyl-substituted heterocycles in quantitative yields with
up to >99:1 er under the influence of even 0.01 mol% of
(R)-3.16,17
The breakaway from the traditional
"salt-liberation-type" Tsuji-Trost asymmetric reaction to the
new "dehydrative" process should extend a synthetic possibility
for complex chiral natural and unnatural products.
Establishment of
a large-scale synthetic procedure for
Cl-Naph-PyCOOH (2a) and the allyl esters 2b has realized a
reliable supply of the chiral ligands. The half-life time of
(R)-2b racemization is 16,000 years at 25 °C with the activation
energy barrier ΔG‡ of 33.7 kcal/mol. The stereochemical
stability is further enhanced by the formation of the
corresponding Ru complexes.
The monocationic
CpRu(II)/(R)-Cl-Naph-PyCOOH complex 3 fluctuates between
many species including the diastereomers, (R,RRu)-3 and
(R,SRu)-3 and the neutral complex/HPF6; therefore, there are
many possible reaction pathways for generation of the major
(S)-6 and minor (R)-6. The number of reaction pathways
reaches 32 by 4 parameters including ss/sa and outside/inside
modes both in the H2O liberation step and in the NuH
nucleophilic attack step; this is the case even with the
assumptions that an endo-CpRu π-allyl complex is formed,24
the Ru-C(1) rotation is involved in the π-CR-saRe isomerization
to π-CR-ssSi, and the sterically favored syn,syn-complex is not
isomerized to the disfavored syn,anti-complex. Among these
possible pathways, the two most probable are proposed to occur
via π-allyl intermediates, although there is no proof at the
rubber under a slightly positive pressure of Ar.
One
freeze-thaw cycle consists of i) freezing a liquid mixture, ii)
evacuation of the system at the freezing stage, iii) closing the
system, iv) thawing the frozen liquid, and v) releasing the
negative pressure to atmospheric pressure by filling Ar gas.
For the general synthesis of substrates under Ar atmosphere,
non-degassed solvents were used.
4.2. Materials.
present stage.
D-Labeling experiments, NMR studies,
4.2.1. Solvents. Solvents for the the catalytic reaction
and the complex preparation were dried and degassed at the
isolation and structural elucidation of the related CpRu
complexes, kinetic studies, and theoretical calculations are now

reflux temperature in the presence of appropriate drying agents
(2.5 g/L) under Ar stream for 6 h and distilled into Schlenk
flasks: Acetone-d6 from molecular sieves 4A (MS 4A).
1,2-Dimethoxyethane (DME), N,N-dimethylacetamide (DMA),
and dichloromethane (CH2Cl2) from CaH2. Toluene from
Na/benzophenone ketyl. Distilled water (H2O) was purchased
from Fujifilm Wako Pure Chemical and used without further
purification. These were degassed by three freeze-thaw cycles
before use. 2-Propanol (2-PrOH) for HPLC analyses, extra
grade solvent was used. For the preparation of substrates,
extraction, and column chromatography, first grade solvents
were used without purification: dichloromethane (CH2Cl2),
1,4-dioxane, ethyl acetate (EtOAc), diethyl ether (Et2O),
hexane, methanol (CH3OH), tert-butyl methyl ether (TBME),
and N,N-dimethylformamide (DMF).
and 13C-NMR spectra, molecular structures of (Ra,1S)-11 and
(Sa,1S)-11, and the crystallographic data were listed in
supporting information.
4.3.
Ligand
Structure-reactivity
Relationship.
General procedure: All manipulations were carried out under
Ar by use of a general Schlenk technique, and all of solvents
and solutions were degassed by three freeze-thaw cycles just
before use. A 10 mM-solution of [RuCp(CH3CN)3]PF6 (1) in
CH2Cl2 (200 µL, 2.00 µmol) was charged in a dried and
Ar-filled 10-mL Young Schlenk. To this was added a solution
of ligand (10.0 mM in CH2Cl2, 200 µL, 2.00 µmol) by use of
gas-tight syringes. The solution was carefully concentrated in
vacuo. To this was added (E)-5 (100 mM in DMA, 2.00 mL,
200 µmol) at rt. Heating to 100 °C and sealing the tube, the
mixture was stirred at the temperature for 10 min. The
reaction mixture was cooled to 0 °C, and 1-µL portion of the
reaction mixture was subjected to GC analysis (column, J&W
Scientific DB-5 (0.25 mm φ x 0.25 mm x 30 m); temp, 50 °C
for 10 min –> 10 °C increase/min –> 200 °C; 140 kPa;
splitless; tR of 6, 6.9 min; tR of (E)-5, 18.7 min), and
conversions were determined by comparison of the signal
intensities. All of the reactions were carried on the same
reaction scale. Ligand and conversion are listed below.
QAH (L1) and 99%. QAAll (L2) and 99%. 8-CH3-QAH
(L3) and <1%. PyCOOH (L4) and 98%. t-Bu-PyCOOH
4.2.2. Silica gels and Celite. Analytical thin-layer
chromatography (TLC) was performed using Merck 5715
plates precoated with silica gel 60 F254 (layer thickness, 0.25
mm). The product spots were visualized with a solution of
phosphomolybdic acid (PMA), p-anisaldehyde, iodine (I2), or
cerium ammonium molybdate (CAM).
column chromatography (SiO2-chromatography)
Flash silica-gel
was
performed using Daiko AP 300. Molecular sieves 4A (MS
4A) was purchased from Nacalai Tesque, and was activated at
250 °C under vacuum before use.
4.2.3. Reagents, chemicals, and ligands.
reagents which were purchased from companies were used
without further purification. These are listed below in the
All of
(L5) and <1%.
2-Cl-Ph-PyCOOH (L7) and 99%. 2-Br-Ph-PyCOOH (L8)
and 99%. 2,6-Cl2-Ph-PyCOOH (L9) and 37%.
2-CF3-Ph-PyCOOAll (L10) and 3%. 2-F-Ph-PyCOOAll
Ph-PyCOOH (L6) and 11%.
alphabetical order neglecting number suffix.
Aldrich:
trichloroborane (BCl3) 1.0 M solution in heptane, copper(II)
chloride (CuCl2), 2-(trifluoromethyl)phenylboronic acid, and
(L11) and 6%. 2-CH3O-Ph-PyCOOAll (L12) and 10%.
2-CH3-Ph-PyCOOAll (L13) and 5%. 3-Cl-Ph-PyCOOAll
(L14) and 6%. 4-Cl-Ph-PyCOOAll (L15) and 9%.
2-fluorophenylboronic
acid.
Furuya
metal:
dodecacarbonyltriruthenium(0) (Ru3(CO)12). Kanto chemical:
naphthalene-1-boronic acid. Kishida Chemical: 12 M aq
HCl. Nacalai tesque: acetic acid (AcOH), 30% aq hydrogen
peroxide (H2O2), lithium hydroxide monohydrate (LiOH·H2O),
sodium bicarbonate (NaHCO3), and 60 wt% sodium hydride
4.4. Synthesis of PyCOOH-related Compounds.
4.4.1. Cl-Naph-PyCOOH (2a) and Cl-Naph-PyCOOAll
(2b). The small-scale synthetic procedures to (±)-2 without
optimization of the reaction conditions have been already
reported in supporting information of ref 16. In this full paper,
the large-scale and optimized procedures are reported. All of
(NaH).
6-bromopyridine-2-carboxylic acid, 3-chlorophenylboronic
acid, lithium aluminum hydride (LiAlH4),
2-methoxyphenylboronic acid, N,N-dimethylcarbamoyl
chloride, 2-methylphenylboronic acid, trimethylsilyl cyanide
((CH3)3SiCN), tetrakis(triphenylphosphine)palladium(0)
Tokyo
Chemical
Industry
(TCI):
the H- and 13C-NMR spectra of the synthetic intermediates
1
were consistent with those reported in ref 16.
Process (i): A dry 1-L Schlenk tube was charged with
naphthalene-2-boronic acid (8) (50.0 g, 291 mmol),
2-bromo-3-methylpyridine (7) (47.6 g, 378 mmol), DME (250
mL), K2CO3 (57.4 g, 415 mmol), and H2O (50 mL). The
solution was degassed by three freeze-thaw cycles, and
Pd(PPh3)4 (1.60 g, 1.38 mmol) was added. Equipping a spiral
condenser, the mixture was refluxed for 24 h. After being
cooled to rt, all of volatiles were removed in vacuo. The
residue was partitioned between EtOAc (200 mL) and H2O
(200 mL). The aq layer was extracted by three 50-mL
portions of EtOAc, and the combined organic layers were
washed with H2O (200 mL) and brine (200 mL). Drying over
Na2SO4 (10 g)/filtration/evaporation process afforded a crude
(Pd(PPh3)4), pyridine-2-carboxylic acid (PyCOOH, L4),
quinone-2-carboxylic acid (L1), and thionyl chloride (SOCl2).
Fujifilm
Wako
Pure
Chemical:
allyl
alcohol,
2-bromo-3-methylpyridine, 70 wt% m-chlorobenzoyl peroxide
(mCPBA), triethylsilane ((C2H5)3SiH), and potassium
carbonate
(K2CO3).
Strem:
tris(acetonitrile)cyclopentadienylruthenium
hexafluorophosphate ([RuCp(CH3CN)3]PF6).
The next compounds were prepared according to the
procedures
reported:
(1S)-camphorsultam,27
2-chlorophenylpyridine,28
2-(2,6-dichlorophenyl)pyridine,28
product (63 g).
EtOAc–hexane (300 mL) to give
The solid was washed with 1:2
nearly pure
6-tert-butylpyridine-2-carboxylic acid (t-Bu-PyCOOH, L5),29
2-(2-bromophenyl)pyridine,28 (E)-hept-2-ene-1,7-diol (5),16
8-methylquinoline-2-carboxylic acid (8-CH3-QAH, L3),30 allyl
6-phenylpyridine-2-carboxylate (Ph-PyCOOAll, L6),31 allyl
quinoline-2-carboxylate (QAAll, L2).32 Cl-Naph-PyCOOH
(2a), Cl-Naph-PyCOOAll (2b), 2-Cl-Ph-PyCOOH (L7),
a
3-methyl-2-naphthalen-1-ylpyridine (57.7 g, 95% yield). This
was used for the next reaction without further purification. 1H
NMR (CDCl3) δ 2.07 (s, 3H, CH3), 7.26 (dd, J = 7.57, 4.82 Hz,
1H, ArH), 7.37–7.57 (m, 5H, ArH), 7.64 (d, J = 7.57 Hz, 1H,
ArH), 7.88–7.91 (m, 2H, ArH), 8.59 (d, J = 7.57 Hz, 1H, ArH).
Process (ii): A dry 1-L Schlenk tube was charged with
3-methyl-2-naphthalen-1-ylpyridine (40.0 g, 182 mmol),
(C2H5)3SiH (60.0 mL, 379 mmol), norbornene (34.4 g, 365
mmol), and toluene (160 mL). The solution was degassed by
three freeze-thaw cycles, and Ru3(CO)12 (583 mg, 0.912 mmol)
was added. Equipping a spiral condenser, the mixture was
2-Br-Ph-PyCOOH
(6-(2,6-dichlorophenyl)picolinic
(L8),
2,6-Cl2-Ph-PyCOOH
acid (L9)),
2-CF3-Ph-PyCOOAll (L10), 2-F-Ph-PyCOOAll (L11),
2-CH3O-Ph-PyCOOAll (L12), 2-CH3-Ph-PyCOOAll (L13),
3-Cl-Ph-PyCOOAll (L14), and 4-Cl-Ph-PyCOOAll (L15) were
synthesized. For the procedures, see section 4.4. The 1H-

refluxed for 36 h. After being cooled to rt, all of volatiles
were removed in vacuo to give a crude product (77 g). This
was purified by SiO2-chromatogtaphy (150 g, hexane eluent
added AcOH (30 mL), and this was extracted by CH2Cl2 (150
mL x 3). The combined organic layers were washed with
brine (200 mL) and dried over Na2SO4 (20 g). Filtration
followed by evaporation gave a nearly pure (±)-2a (40.8 g,
82%) as a white solid. 1H NMR (CDCl3) δ 2.16 (s, 3H, CH3),
7.05 (d, J = 8.26 Hz, 1H, ArH), 7.43 (dd, J = 8.26, 6.89 Hz, 1H,
ArH), 7.53 (dd, J = 8.26, 6.89 Hz, 1H, ArH), 7.60 (d, J = 8.26
Hz, 1H, ArH), 7.94 (d, J = 8.26 Hz, 2H, ArH), 7.97 (d, J = 7.57
Hz, 1H, ArH), 8.27 (d, J = 7.57 Hz, 1H, ArH).
Process (vi): A dry 500-mL Schlenk tube was charged
with (S)-camphorsultam (8.68 g, 40.3 mmol), 60 wt% NaH
(3.22 g, 80.6 mmol), and toluene (80 mL), and the mixture was
stirred for 1 h at rt. Another dry 150-mL Schlenk tube was
charged with (±)-2a (12.0 g, 40.3 mmol) and SOCl2 (30 mL)
under Ar stream. The mixture was stirred at 50 °C for 3 h in a
closed system, and then concentrated in vacuo. The residue
was dissolved in THF (30 mL). The THF solution of (±)-2a
was transferred to the toluene solution of (S)-camphorsultam,
and the Schlenk of (±)-2a was washed with THF (30 mL x 2).
The whole solution was stirred at rt for 24 h. The solution
was evaporated, and the residue was partitioned between Et2O
(100 mL) and H2O (80 mL). The aq layer was extracted with
Et2O (100-mL x 2). The combined organic layers were
washed with brine (200 mL), and dried over Na2SO4 (20 g).
Filtration followed by evaporation gave a crude product (23 g)
then
1:10
EtOAc–hexane
eluent)
to
give
2-(2-(triethylsilyl)naphthalen-1-yl)-3-methylpyridine (9) (59.6
g, 98% yield) as a brown solid. 1H NMR (CDCl3) δ 0.35–0.45
(m, 6H, CH2CH3), 0.70 (t, J = 7.76 Hz, 9H, CH2CH3), 1.95 (s,
3H, CH3), 7.00 (d, J = 7.57 Hz, 1H, ArH), 7.19–7.32 (m, 4H,
ArH), 7.60 (dd, J = 7.57, 1.1 Hz, 1H, ArH), 7.70 (d, J = 7.57
Hz, 1H, ArH), 7.75 (d, J = 7.57 Hz, 1H, ArH), 8.58 (dd, J =
4.92, 0.8 Hz, 1H, ArH).
Process (iii): A dry 2-L Schlenk tube was charged with 9
(59.0 g, 177 mmol) and CH2Cl2 (360 mL) and cooled to –78 °C.
To this was added BCl3 (1 M in heptane, 212 mL, 212 mmol).
After 1.5-h stirring at the same temperature in a closed system,
all volatiles were removed in vacuo. The Schlenk tube
containing a yellowish brown residue was then charged with
CH3OH (180 mL), H2O (180 mL), and CuCl2 (71.4 g, 531
mmol). The tube was sealed with a cold finger, and the
mixture was heated to reflux for 96 h. Cooling to rt, the
whole mixture was partitioned between CH2Cl2 (200 mL) and 5
M aq NH3 (200 mL). The aq layer was extracted by three
200-mL portions of CH2Cl2, and the combined organic layers
were washed with 5 M aq NH3 (200 mL) and brine (200 mL).
Drying over Na2SO4 (20 g)/filtration/evaporation process
afforded a light-green oil (53 g), which was purified by
SiO2-chromatography (250 g; 1:8 EtOAc–hexane) to give
2-(2-chloronaphthalen-1-yl)-3-methylpyridine (10) as a white
solid (42.6 g, 95%). 1H NMR (CDCl3) δ 2.05 (s, 3H, CH3),
7.15 (d, J = 8.94 Hz, 1H, ArH), 7.32 (dd, J = 7.56, 4.81 Hz, 1H,
ArH), 7.38 (t, J = 7.56 Hz, 1H, ArH), 7.46 (t, J = 8.25 Hz, 1H,
ArH), 7.55 (d, J = 8.94 Hz, 1H, ArH), 7.68 (d, J = 7.56 Hz, 1H,
ArH), 7.84 (d, J = 8.25 Hz, 1H, ArH), 7.87 (d, J = 8.25 Hz, 1H,
ArH), 8.64 (d, J = 4.81 Hz, 1H, ArH).
Process (iv): A dry 1-L Schlenk tube was charged with
(±)-10 (42.6 g, 168 mmol), AcOH (110 mL), and aq H2O2 (52.3
mL, 512 mmol). Equipping a spiral condenser, the mixture
was refluxed for 18 h. After all volatiles were removed in
vacuo, the residue was partitioned between CH2Cl2 (200 mL)
and sat aq NaHCO3 (300 mL). The aq layer was extracted by
two-200 mL portions of CH2Cl2. The combined organic
layers were washed with brine (200 mL), and then dried over
Na2SO4 (20 g). Filtration followed by evaporation gave
nearly pure (±)-2-(2-chloronaphthalen-1-yl)-3-methylpyridine-
N-oxide (41 g) as a brown solid. A dry 1-L three-necked flask
was charged with the N-oxide compound (41 g), CH2Cl2 (300
mL), N,N-dimethylcarbamoyl chloride (18.1 mL, 197 mmol),
and (CH3)3SiCN (36.1 mL, 287 mmol). The flask was
equipped with a reflux condenser, and then the mixture was
stirred at 60 °C for 42 h. After cooled to rt, the mixture was
evaporated in vacuo. The residue was partitioned between
CH2Cl2 (150 mL) and sat aq NaHCO3 (150 mL). The aq layer
was extracted with two 150-mL portions of CH2Cl2. The
combined organic layers were washed with brine (200 mL), and
dried over Na2SO4 (15 g). Filtration followed by evaporation
as brown solid.
This was purified two times by
SiO2-chromatography (400 g, 1:4 EtOAc–hexane eluent) to
give
(R)-6-(2-chloronaphthalen-1-yl)-5-
(S)-camphorsultam imide
methylpyridine-2-carbonyl
((Ra,1S)-11) (9.34 g, 47% yield) as a white solid and
(S)-6-(2-chloronaphthalen-1-yl)-5-methylpyridine-2-carbonyl
(S)-camphorsultam imide ((Sa,1S)-11) (9.04 g, 45% yield) as a
white solid, respectively. (Ra,1S)-11: 1H NMR (CDCl3) δ
0.91 (s, 3H, CH3), 1.00–1.05 (m, 1H, CH2CCHCH2), 1.20 (s,
3H, CH3), 1.26 (dt, J = 10.3, 2.75 Hz, 1H, CHCHHCH),
1.71–1.77 (m, 2H, CH2CH2), 1.80–1.88 (m, 2H, CH2CH2),
1.93–1.98 (m, 1H, CHCHHCH), 2.07 (s, 3H, CH3), 3.33 (d, J =
13.8 Hz, 1H, SCHH), 3.43 (d, J = 13.8 Hz, 1H, SCHH), 4.28
(m, 1H, NCH), 7.29 (d, J = 8.26 Hz, 1H, ArH), 7.40 (dt, J =
7.57, 1.38 Hz, 1H, ArH), 7.49 (dt, J = 7.57, 1.38 Hz, 1H, ArH),
7.54 (d, J = 8.26 Hz, 1H, ArH), 7.80 (d, J = 7.57 Hz, 1H, ArH),
7.84–7.89 (m, 3H, ArH); 13C NMR (CDCl3) δ 18.8, 20.1, 21.8,
26.3, 33.3, 39.7, 45.5, 47.8, 48.9, 53.0, 66.1, 124.0, 125.7,
126.3, 127.1, 127.3, 128.3, 129.9, 131.0, 132.2, 132.5, 134.9,
136.8, 138.6, 149.4, 155.1, 166.6; HRMS (ESI) calcd for
19.7
C27H28ClN2O3S [M+H]+ 495.1504, found 495.1501; [α]D
+42.5 (c 1.00, CHCl3); mp. 190 °C. (Sa,1S)-11: 1H NMR
(CDCl3) δ 0.94 (s, 3H, CH3), 1.12–1.17 (m, 1H, CH2CCHCH2),
1.21 (s, 3H, CH3), 1.21–1.33 (m, 2H, CHCH2CH), 1.73–1.87
(m, 4H, CH2CH2), 2.09 (s, 3H, CH3), 3.32 (d, J = 13.8 Hz, 1H,
SCHH), 3.43 (d, J = 13.8 Hz, 1H, SCHH), 4.41 (m, 1H, NCH),
7.00 (d, J = 8.25 Hz, 1H, ArH), 7.39 (dt, J = 7.57, 1.37, Hz, 1H,
ArH), 7.49 (ddd, J = 8.25, 7.57, 1.37 Hz, 1H, ArH), 7.56 (d, J =
8.94 Hz, 1H, ArH), 7.82 (d, J = 8.25 Hz, 1H, ArH), 7.87–7.89
(m, 3H, ArH); 13C NMR (CDCl3) δ 18.8, 20.2, 26.3, 33.2, 39.8,
45.7, 47.9, 49.4, 52.7, 65.9, 124.2, 125.5, 126.6, 127.0, 127.8,
128.3, 130.2, 130.2, 132.3, 132.9, 134.8, 136.9, 138.9, 149.6,
155.3, 165.6; HRMS (ESI) calcd for C27H28ClN2O3S [M+H]+
495.1504, found 495.1496; [α]D20.5 –204.3 (c 1.00, CHCl3); mp.
161 °C. Compound (Ra,1S)-11 (10 mg) was charged into a
test tube (5 mm φ x 3 cm) and to this was added EtOAc (0.5
mL). The mixture was heated to be a clear solution, and this
was kept at rt for 24 h to give a colorless plate crystal (7.3 mg).
This was subjected to X-ray crystallographic analysis to
determine the absolute stereochemistry. The Sa,1S isomer was
also recrystallized in a similar way ((Sa,1S)-11 (9.8 mg), EtOAc
gave
a
nearly-pure
(±)-6-(2-chloronaphthalen-1-yl)-5-
methylpyridine-2-carbonitrile (42 g). This was used for the
next reaction without further purification.
Process (v): A 300-mL round-bottom flask was charged
with the product obtained process (iv) (42 g) and 12 M aq HCl
(90 mL). A spiral condenser was connected to the flask and
the mixture was refluxed for 24 h in an open system. After
cooled to rt, all of the volatiles were removed in vacuo to give a
yellow solid. This was partitioned between CH2Cl2 (200 mL)
and 2 M aq NaOH (150 mL). The organic layer was extracted
by 2 M aq NaOH (100 mL). To the combined aq layers were

(0.5 mL), colorless block crystal (8.2 mg)) and determined the
absolute stereochemistry by X-ray crystallographic analysis.
Process (vii): A 1-L round-bottom flask was charged
with (Ra,1S)-11 (13.0 g, 26.3 mmol), LiOH·H2O (1.65 g, 39.3
mmol), THF (260 mL), and H2O (26.0 mL). The mixture was
stirred at rt for 24 h. All of volatiles were removed in vacuo,
and the residue was partitioned between TBME (200 mL) and
H2O (300 mL). The aq layer was washed by three 200-mL
portions of TBME. To the aq layer was added AcOH (30 mL),
and the mixture was extracted with CH2Cl2 (200 mL x 4).
The combined organic layers were washed by brine (300 mL),
and dried over Na2SO4 (20 g). Filtration followed by
evaporation afforded a crude product (R)-2a. The product was
transferred to 250-mL Schlenk tube. To this was added SOCl2
(26.0 mL). After heating at 50 °C for 3 h followed by
concentration in vacuo, allyl alcohol (50 mL) was introduced.
The solution was stirred at rt for 24 h, and the mixture was
evaporated. The residue was partitioned between CH2Cl2
(150 mL) and sat aq NaHCO3 (150 mL). The aq layer was
extracted with CH2Cl2 (150 mL x 2). The combined organic
layers were washed by brine (200 mL) and dried over Na2SO4
(20 g). Filtration followed by evaporation afforded a crude
product (14 g) as yellow oil, which was purified by
SiO2-chromatography (200 g; 1:6 EtOAc–hexane eluent) to
give (R)-allyl 6-(2-chloronaphthalen-1-yl)-5-methylpyridine-
2-carboxylate ((R)-2b) (8.21 g, 93% yield). 1H NMR (CDCl3)
δ 2.08 (s, 3H, CH3), 4.89 (d, J = 5.51 Hz, 2H, OCH2), 5.26 (dd,
J = 10.3, 1.38 Hz, 1H, CH=CHH), 5.38 (dd, J = 17.2, 1.38 Hz,
1H, CH=CHH), 6.00–6.08 (m, 1H, CH=CH2), 7.09 (d, J = 8.26
Hz, 1H, ArH), 7.36 (dd, J = 8.26, 6.89 Hz, 1H, ArH), 7.46 (t, J
= 7.57 Hz, 1H, ArH), 7.52 (d, J = 8.95 Hz, 1H, ArH),
7.80–7.87 (m, 3H, ArH), 8.17 (d, J = 7.57 Hz, 1H, ArH).
Process (viii): A 50-mL round-bottom flask was charged
with (R)-2b (700 mg, 2.07 mmol), LiOH·H2O (123 mg, 2.93
mmol), dioxane (18.0 mL), and H2O (2.00 mL). The mixture
was stirred at rt for 10 h. All of volatiles were removed in
vacuo, and the residue was partitioned between EtOAc (50 mL)
and H2O (100 mL). The aq layer was washed with EtOAc (50
mL). To the aq layer was added AcOH (10 mL). The
mixture was extracted with CH2Cl2 (50 mL x 3). The
combined organic layers were washed with brine (100 mL) and
dried over Na2SO4 (10 g). Filtration followed by evaporation
afforded (R)-2a (570 mg, 92% yield). 1H NMR (CDCl3) δ
2.16 (s, 3H, CH3), 7.05 (d, J = 8.26 Hz, 1H, ArH), 7.43 (dt, J =
8.26, 1.38 Hz, 1H, ArH), 7.54 (dt, J = 6.89, 1.38 Hz, 1H, ArH),
7.60 (d, J = 8.26 Hz, 1H, ArH), 7.94 (d, J = 9.64 Hz, 2H, ArH),
7.96 (d, J = 7.57 Hz, 1H, ArH), 8.27 (d, J = 7.57 Hz, 1H, ArH).
All of the physical properties were consistent with those
obtained on a small scale.16
and mCPBA (1.64 g, 9.50 mmol) was added slowly. The
temperature was gradually raised to rt, and the colorless
solution was stirred for 6 h. Cooling again to 0 °C, 1 M aq
NaOH (10 mL) was slowly added. The organic layer was
washed with 1 M aq NaOH (10 mL) and brine (10 mL), and
then dried over Na2SO4 (10 g). Filtration followed by
evaporation
gave
nearly
pure
2-(2-chlorophenyl)-pyridine-N-oxide (1.28 g) as a yellow oil.
This was used for the next reaction without further purification.
Process (ii) A dry 50-mL Schlenk tube was charged with
the N-oxide compound (750 mg, 3.65 mmol), CH2Cl2 (10 mL),
and N,N-dimethylcarbamoyl chloride (587 mg, 5.46 mmol) in
this order. After 30 min at rt, (CH3)3SiCN (542 mg, 5.46
mmol) in CH2Cl2 (5 mL) was added. The Schlenk tube was
equipped with a reflux condenser, and then the mixture was
stirred at 50 °C for 12 h. After being cooled to rt, the mixture
was added to 10 wt% aq K2CO3 (10 mL) and stirred for 1 h.
The mixture was extracted with CH2Cl2 (10 mL), and the
organic layer was washed with H2O (10 mL), sat aq NaHCO3
(10 mL), and brine (10 mL), and dried over Na2SO4 (10 g).
Filtration followed by evaporation gave a yellow oil, which was
purified by SiO2-chromatography (30 g; eluent, 1:19
EtOAc–hexane)
to
give
6-(2-chlorophenyl)pyridine-2-carbonitrile (720 mg, 92% yield).
1H NMR (CDCl3) δ 7.38–7.42 (m, 2H, ArH), 7.49–7.51 (m, 1H,
ArH), 7.62–7.64 (m, 1H, ArH), 7.71 (dd, J = 6.87, 1.37 Hz, 1H,
ArH), 7.90–7.94 (m, 2H, ArH).
Process (iii) A dry 50-mL Schlenk tube was charged
with 6-(2-chlorophenyl)pyridine-2-carbonitrile (1.00 g, 4.66
mmol) and 6 M aq HCl (15.5 mL). A spiral condenser was
connected to the tube and the mixture was refluxed for 15 h in
an open system. After being cooled to rt, all of the volatiles
were
removed
in
vacuo
to
give
acid
6-(2-chlorophenyl)pyridine-2-carboxylic
(2-Cl-Ph-PyCOOH, L7) (1.05 g, 97% yield) as a white solid.
1H NMR (CDCl3) δ 7.41–7.44 (m, 2H, ArH), 7.52–7.55 (m, 1H,
ArH), 7.57–7.60 (m, 1H, ArH), 7.94 (d, J = 7.56 Hz, 1H, ArH),
8.05 (t, J = 7.56 Hz, 1H, ArH), 8.25 (d, J = 7.56 Hz, 1H, ArH);
13C NMR (CDCl3) δ 122.3, 127.2, 129.0, 130.5, 130.6, 131.4,
132.3, 137.0, 138.5, 145.7, 155.7, 163.9; HRMS (ESI) calcd for
C12H7ClNO2 [M–H]– 232.0171, found 232.0187; mp. 165 °C.
4.4.2. 2-Br-Ph-PyCOOH (L8). The procedures were
the same as those for L7. The organic synthetic parameters
were listed below. (i) 2-(2-Bromophenyl)pyridine (271 mg,
1.16 mmol), CH2Cl2 (10 mL), mCPBA (686 mg, 2.78 mmol),
0 °C –> rt, 3 h. Workup: addition of 1 M aq NaOH (10 mL)
at 0 °C; washing of organic layer with 1 M aq NaOH (10 mL)
and brine (10 mL); dryness over Na2SO4 (10 g);
filtration/evaporation. Crude 2-(2-bromophenyl)pyridine-N-
oxide (280 mg, yellow oil). (ii) The N-oxide compound (280
mg), CH2Cl2 (2.30 mL), N,N-dimethylcarbamoyl chloride (130
µL, 1.39 mmol), 30 min, rt, (CH3)3SiCN (290 µL, 2.32 mmol)
in CH2Cl2 (2 mL), reflux, 12 h. Workup: addition of 10 wt%
aq K2CO3 (10 mL) at rt; extraction with CH2Cl2 (10 mL);
washing of organic layer with H2O (10 mL), sat aq NaHCO3
(10 mL), and brine (10 mL); dryness over Na2SO4 (10 g);
(S)-Allyl 6-(2-chloronaphthalen-1-yl)-5-methylpyridine-
2-carboxylate ((S)-2b) and (S)-6-(2-chloronaphthalen-1-yl)-5-
methylpyridine-2-carboxylic acid ((S)-2a) were also prepared
from (Sa,1S)-11 (1.00 g, 2.02 mmol) in the same way as the R
case. Conditions for (S)-2b synthesis: LiOH·H2O (127 mg,
3.03 mmol), THF (18.0 mL), H2O (2.00 mL), rt, 14 h. SOCl2
(1.50 mL), 50 °C, 3 h. Allyl alcohol (2.80 mL), rt, 24 h.
(S)-2b (598 mg, 91% yield). Conditions for (S)-2a synthesis:
(S)-2b (300 mg, 890 mmol), LiOH·H2O (52.4 mg, 1.25 mmol),
dioxane (9.00 mL), H2O (1.00 mL), rt, 14 h. (S)-2a (247 mg,
93% yield). All of the physical properties were consistent
with those obtained on a small scale.16
filtration/evaporation.
Crude 6-(2-bromophenyl)pyridine-2-
1
carbonitrile (620 mg, yellow oil): H NMR (600 MHz, CDCl3)
δ 7.32 (ddd, J = 7.57, 7.57, 1.38 Hz, 1H, Ar), 7.45 (dd, J =
8.26, 7.57 Hz, 1H, Ar), 7.56 (dd, J = 7.57, 2.07 Hz, 1H, Ar),
7.70 (dd, J = 8.26, 1.38 Hz, 1H, Ar), 7.72 (dd, J = 7.57, 1.38
Hz, 1H, Ar), 7.90 (m, 2H, Ar). (iii) The crude carbonitrile
(620 mg), 12 M aq HCl (3.0 mL), reflux, 24 h. Workup:
evaporation in vacuo; partition between CH2Cl2 (10 mL) and aq
NaHCO3–AcOH (10 mL); adjustment of pH of the aq layer to 4
by AcOH; extraction of the aq layer with CH2Cl2 (10 mL x 2);
4.4.2. 2-Cl-Ph-PyCOOH (L7).
50-mL-two-necked round bottom flask equipped with a glass
stopper and three-way stopcock was charged with
Process (i) A dry
a
2-(2-chlorophenyl)pyridine (1.20 g, 6.32 mmol) and CH2Cl2
(10 mL). The resulting colorless solution was cooled to 0 °C,

dryness of the organic layers over Na2SO3 (10 g);
eluent,
1:3
EtOAc–hexane)
to
give
allyl
filtration/evaporation. Crude L8 (350 mg). Purification:
6-(2-trifluoromethylphenyl)pyridine-2-carboxylate (L10) (606
mg, 81% yield) as a colorless oil. 1H NMR (CDCl3) δ 4.91 (dt,
J = 5.51, 1.38 Hz, 2H, CH2CH=CH2), 5.28 (dd, J = 10.3, 1.38
Hz, 1H, CH2CH=CHH), 5.42 (dd, J = 17.2, 1.38 Hz, 1H,
CH2CH=CHH), 6.02–6.08 (m, 1H, CH2CH=CH2), 7.52 (t, J =
8.26 Hz, 1H, ArH), 7.53 (d, J = 8.26 Hz, 1H, ArH), 7.60 (d, J =
7.57 Hz, 1H, ArH), 7.61 (t, J = 7.57 Hz, 1H, ArH), 7.75 (d, J =
7.57 Hz, 1H, ArH), 7.89 (t, J = 8.26 Hz, 1H, ArH), 8.15 (d, J =
7.57 Hz, 1H, ArH); 13C NMR (CDCl3) δ 66.4, 118.7,
123.9,124.9, 126.4, 127.2, 128.6, 131.6, 131.75, 131.81, 136.9,
139.1, 147.7, 158.0, 164.7; HRMS (ESI) calcd for
C16H12F3NNaO2 [M+Na]+ 330.0712, found 330.0717.
4.4.5. 2-F-Ph-PyCOOAll (L11). The procedures were
the same as those for L10. (i) 2-Fluorophenylboronic acid
(347 mg, 2.48 mmol), DME (13 mL), 2 M aq K2CO3 (6.6 mL),
6-bromopyridine-2-carboxylic acid (500 mg, 2.48 mmol),
Pd(PPh3)4 (143 mg, 124 µmol), reflux, 12 h. Workup:
addition of CH2Cl2 (10 mL); extraction of the aq layer with
recrystallization
from
1:1:0.5
Et2O–2-PrOH–CH2Cl2.
6-(2-Bromophenyl)pyridine-2-carboxylic acid (L8) (290 mg,
90% yield, white solid): 1H NMR (CDCl3) δ 7.34 (dt, J = 7.57,
1.38 Hz, 1H, ArH), 7.47 (t, J = 7.57 Hz, 1H, ArH), 7.53 (dd, J
= 7.57, 1.38 Hz, 1H, ArH), 7.74 (d, J = 7.57 Hz, 1H, ArH),
7.89 (d, J = 7.57 Hz, 1H, ArH), 8.05 (t, J = 7.57 Hz, 1H, ArH),
8.25 (d, J = 7.57 Hz, 1H, ArH); 13C NMR (CDCl3) δ 121.7,
122.4, 127.8, 128.9, 130.7, 131.3, 133.7, 138.5, 138.9, 145.6,
157.1, 164.0; HRMS (ESI) calcd for C12H7BrNO2 [M–H]–
275.9666, found 275.9676; mp. 154 °C.
4.4.3. 2,6-Cl2-Ph-PyCOOH (L9). The procedures were
the same as those for L7. (i) 2-(2,6-Dichlorophenyl)pyridine
(1.10 g, 4.91 mmol), CH2Cl2 (15 mL), mCPBA (1.69 g, 9.79
mmol), 0 °C –> rt, 6 h. Workup: addition of 1 M aq NaOH
(10 mL) at 0 °C; washing of organic layer with 1 M aq NaOH
(10 mL) and brine (10 mL); dryness over Na2SO4 (3 g);
filtration/evaporation. Nearly pure 2-(2,6-dichlorophenyl)-
pyridine-N-oxide (1.2 g, yellow oil).
(ii) The N-oxide
CH2Cl2 (10 mL x 3); dryness over Na2SO4 (10 g);
compound (1.2 g), CH2Cl2 (15 mL), N,N-dimethylcarbamoyl
chloride (676 µL, 7.35 mmol), 30 min, rt, (CH3)3SiCN (923 µL,
7.35 mmol) in CH2Cl2 (5 mL), 50 °C, 12 h. Workup:
addition of 10 wt% aq K2CO3 (10 mL) at rt followed by 1-h
stirring; extraction with CH2Cl2 (20 mL); washing of the
organic layer with H2O (20 mL) and brine (20 mL); dryness
filtration/evaporation process. Crude product (ca. 0.5 g,
yellow solid). (ii) The carboxylic acid compound (ca. 0.5 g),
SOCl2 (3.60 mL), 50 °C, 1 h; concentration in vacuo; allyl
alcohol (3.40 mL), 8 h, rt. Workup: concentration in vacuo;
dissolving in CH2Cl2 (10 mL); washing with sat aq NaHCO3 (5
mL); dryness over Na2SO4 (5 g); filtration/evaporation. Crude
product (ca. 600 mg). Purification: SiO2-chromatography (25
over Na2SO4 (6 g); filtration/evaporation.
Purification:
SiO2-chromatography (50 g; eluent, 1:7 EtOAc–hexane).
6-(2,6-Dichlorophenyl)pyridine-2-carbonitrile (1.15 g, 94%
yield): H NMR (CDCl3) δ 7.33 (dd, J = 8.25, 1.37 Hz, 1H,
ArH), 7.42 (d, J = 8.25 Hz, 2H, ArH), 7.57 (d, J = 8.25, 1H,
ArH), 7.76 (d, J = 8.25 Hz, 1H, ArH), 7.98 (t, J = 7.56 Hz, 1H,
ArH). (iii) The carbonitrile compound (1.08 g, 4.33 mmol), 6
M aq HCl (8 mL), reflux, 15 h. Workup: evaporation in
g;
eluent,
1:3
EtOAc–hexane).
Allyl
6-(2-fluorophenyl)pyridine-2-carboxylate (L11) (457 mg, 72%
yield) as a colorless oil: 1H NMR (CDCl3) δ 4.92 (dd, J = 6.20,
1.38 Hz, 1H, CH2CH=CH2), 5.31 (d, J = 10.3 Hz, 1H,
1
CH2CH=CHH), 5.46 (dd,
J
=
17.2, 1.38 Hz, 1H,
CH2CH=CHH), 6.06–6.12 (m, 1H, CH2CH=CH2), 7.14 (t, J =
8.95 Hz, 1H, ArH), 7.27 (t, J = 7.57 Hz, 1H, ArH), 7.38 (dd, J
= 8.26, 7.57 Hz, 1H, ArH), 7.87 (dd, J = 7.57, 2.07 Hz, 1H,
ArH), 7.97 (d, J = 6.89 Hz, 1H, ArH), 8.07 (d, J = 8.26 Hz, 1H,
ArH), 8.11 (dd, J = 7.57, 2.07 Hz, 1H, ArH); 13C NMR
(CDCl3) δ 66.4, 116.2, 118.8, 123.7, 124.7, 126.6, 127.7,
130.90, 131.5, 137.3, 148.2, 153.6, 159.8, 161.5, 164.9; HRMS
(ESI) calcd for C15H12FNNaO2 [M+Na]+ 280.0744, found
280.0749.
4.4.6. 2-CH3O-Ph-PyCOOAll (L12). The procedures
were the same as those for L10. (i) 2-Methoxyphenylboronic
acid (377 mg, 2.48 mmol), DME (13 mL), 2 M aq K2CO3 (6.6
mL), 6-bromopyridine-2-carboxylic acid (500 mg, 2.48 mmol),
Pd(PPh3)4 (143 mg, 124 µmol), reflux, 12 h. Workup:
addition of CH2Cl2 (10 mL); extraction of the aq layer with
vacuo
to
liberate
a
white
solid
product.
6-(2,6-Dichlorophenyl)pyridine-2-carboxylic acid (L9) (1.05 g,
91% yield): 1H NMR (CDCl3) δ 7.36 (t, J = 8.26 Hz, 1H, ArH),
7.46 (d, J = 8.26 Hz, 2H, ArH), 7.65 (d, J = 7.57 Hz, 1H, ArH),
8.09 (t, J = 7.57 Hz, 1H, ArH), 8.29 (d, J = 7.57 Hz, 1H, ArH);
13C NMR (CDCl3) δ 123.0, 128.4, 129.6, 130.6, 134.5, 136.4,
138.9, 145.9, 154.1, 163.8; HRMS (ESI) calcd for
C12H6Cl2NO2 [M–H]– 265.9781, found 265.9781; mp. 180 °C.
4.4.4. 2-CF3-Ph-PyCOOAll (L10). Process (i): A dry
50-mL
2-(trifluoromethyl)phenylboronic acid (522 mg, 2.75 mmol),
DME (13 mL), aq K2CO3 (6.6 mL), and
Schlenk
tube
was
charged
with
2
M
6-bromopyridine-2-carboxylic acid (505 mg, 2.50 mmol).
The solution was degassed by three freeze-thaw cycles, and
Pd(PPh3)4 (143 mg, 124 µmol) was added. Equipping a spiral
condenser, the mixture was refluxed for 12 h. After being
cooled to rt, the reaction mixture was extracted with CH2Cl2
(10 mL). The aq layer was extracted by three 10-mL portions
of CH2Cl2, and the combined organic layers were dried over
Na2SO4 (10 g). Filtration/evaporation process afforded a
yellow solid (ca. 1 g). This was used for the next reaction
without further purification.
CH2Cl2 (10 mL
x 3); dryness over Na2SO4 (10 g);
filtration/evaporation. Crude product (ca. 0.5 g, yellow solid).
(ii) The carboxylic acid compound (ca. 0.5 g), SOCl2 (3.60 mL),
50 °C, 1 h; concentration in vacuo; allyl alcohol (3.40 mL), 8 h,
rt. Workup: concentration in vacuo; dissolving in CH2Cl2 (10
mL); washing with sat aq NaHCO3 (5 mL); dryness over
Na2SO4 (5 g); filtration/evaporation. Crude product (ca. 0.5 g,
white solid). Purification: SiO2-chromatography (25 g; eluent,
1:3 EtOAc–hexane).
Allyl 6-(2-methoxyphenyl)pyridine-
Process (ii): A dry 50-mL Schlenk tube was charged
with 6-(2-trifluoromethylphenyl)pyridine-2-carboxylic acid (ca.
1 g) and to this was added SOCl2 (3.60 mL) under Ar stream.
The mixture was stirred at 50 °C for 1 h in a closed system, and
then concentrated in vacuo. To this was added allyl alcohol
(3.40 mL). After 6-h stirring at rt followed by concentration,
the resulting residue was dissolved in CH2Cl2 (10 mL). This
was washed with sat aq NaHCO3 (5 mL) and dried over
Na2SO4 (5 g). Filtration/evaporation process afforded a white
solid, which was purified by SiO2-chromatography (25 g;
2-carboxylate (L12) (425 mg, 64% yield) as a colorless oil:
1H NMR (CDCl3) δ 3.84 (s, 3H, OCH3), 4.91 (d, J = 5.51 Hz,
2H, CH2CH=CH2), 5.30 (d, J = 11.0 Hz, 1H, CH2CH=CHH),
5.45 (dd, J = 17.2, 1.38 Hz, 1H, CH2CH=CHH), 6.05–6.11 (m,
1H, CH2CH=CH2), 6.98 (d, J = 8.26 Hz, 1H, ArH), 7.09 (t, J =
7.57 Hz, 1H, ArH), 7.37 (t, J = 8.26 Hz, 1H, ArH), 7.81 (t, J =
7.57 Hz, 1H, ArH), 7.91 (dd, J = 7.57, 1.38 Hz, 1H, ArH), 8.03
(d, J = 8.26 Hz, 1H, ArH), 8.04 (d, J = 8.26 Hz, 1H, ArH); 13
C
NMR (CDCl3) δ 55.5, 66.1, 111.3, 118.5, 121.2, 122.9, 128.2,
128.4, 130.3, 131.5, 132.0, 136.3, 147.8, 156.2, 157.0, 165.2;

HRMS (ESI) calcd for C16H15NNaO3 [M+Na]+ 292.0944,
found 292.0963.
Purification: recrystallization from 2:2:1 Et2O–CH2Cl2–hexane
(ca 1 mL). 6-(4-Chlorophenyl)pyridine-2-carboxylic acid
4.4.7. 2-CH3-Ph-PyCOOAll (L13). The procedures
were the same as those for L10. (i) 2-Methylphenylboronic
acid (405 mg, 2.98 mmol), DME (13 mL), 2 M aq K2CO3 (6.6
mL), 6-bromopyridine-2-carboxylic acid (500 mg, 2.48 mmol),
Pd(PPh3)4 (143 mg, 124 µmol), reflux, 12 h. Workup:
addition of CH2Cl2 (10 mL); extraction of the aq layer with
(419 mg, 72% yield) as a colorless solid: 1H NMR (CDCl3) δ
7.51 (d, J = 8.26 Hz, 2H, ArH), 7.94 (d, J = 8.26 Hz, 2H, ArH),
7.98 (d, J = 8.95 Hz, 1H, ArH), 8.05 (t, J = 8.26 Hz, 1H, ArH),
8.21 (d, J = 7.57 Hz, 1H, ArH). (ii) The carboxylic acid
compound (110 mg, 471 µmol), SOCl2 (170 µL), 50 °C, 1 h;
concentration in vacuo; allyl alcohol (160 µL); 6 h, rt.
Workup: concentration in vacuo; dissolving in CH2Cl2 (10
mL); washing with sat aq NaHCO3 (5 mL); dryness over
Na2SO4 (5 g); filtration/evaporation. Crude product (ca. 0.5 g,
white solid). Purification: SiO2-chromatography (25 g;
CH2Cl2 (10 mL
x 3); dryness over Na2SO4 (10 g);
filtration/evaporation. Crude product (ca. 0.5 g, yellow solid).
(ii) The carboxylic acid compound (ca. 0.5 g), SOCl2 (3.60 mL),
50 °C, 1 h; concentration in vacuo; allyl alcohol (3.40 mL), 8 h,
rt. Workup: concentration in vacuo; dissolving in CH2Cl2
(10 mL); washing with sat aq NaHCO3 (5 mL); dryness over
Na2SO4 (5 g); filtration/evaporation. Crude product (ca. 0.5 g,
white solid). Purification: SiO2-chromatography (25 g; eluent,
eluent,
1:3
EtOAc–hexane).
Allyl
6-(2-trifluoromethylphenyl)pyridine-2-carboxylate (L15) (125
mg, 97% yield) as a colorless oil: 1H NMR (CDCl3) δ 4.93 (d, J
= 5.51 Hz, 2H, CH2CH=CH2), 5.34 (d, J = 10.3 Hz,
1:3
EtOAc–hexane).
Allyl
CH2CH=CHH), 5.48 (d, J = 17.2 Hz, CH2CH=CHH),
6-(2-methylphenyl)pyridine-2-carboxylate (L13) (363 mg, 58%
yield) as a colorless oil: 1H NMR (CDCl3) δ 2.40 (s, 3H, CH3),
4.92 (dt, J = 5.51, 1.38 Hz, 2H, CH2CH=CH2), 5.30 (dd, J =
10.3, 1.38 Hz, 1H, CH2CH=CHH), 5.45 (d, J = 17.2, 1.38 Hz,
1H, CH2CH=CHH), 6.04–6.11 (m, 1H, CH2CH=CH2),
7.28–7.33 (m, 2H, ArH), 7.43 (d, J = 7.57 Hz, 1H, ArH), 7.59
(dd, J = 7.57, 1.38 Hz, 1H, ArH), 7.89 (t, J = 7.57 Hz, 1H,
ArH), 8.09 (d, J = 7.57 Hz, 1H, ArH); 13C NMR (CDCl3) δ
20.4, 66.2, 118.6, 123.0, 125.9, 127.2, 128.6, 129.8, 130.9,
131.9, 136.1, 137.0, 139.5, 147.6, 160.3, 165.1; HRMS (ESI)
calcd for C16H15NNaO2 [M+Na]+ 276.0995, found 276.1024.
4.4.8. 3-Cl-Ph-PyCOOAll (L14). The procedures were
the same as those for L10. (i) 3-Chlorophenylboronic acid
(465 mg, 2.98 mmol), DME (13 mL), 2 M aq K2CO3 (6.6 mL),
6-bromopyridine-2-carboxylic acid (500 mg, 2.48 mmol),
Pd(PPh3)4 (143 mg, 124 µmol), reflux, 24 h. Workup:
addition of CH2Cl2 (10 mL); extraction of the aq layer with
6.07–6.13 (m, 1H, CH2CH=CH2), 7.46 (d, J = 8.26 Hz, 2H,
ArH), 7.88–7.92 (m, 2H, ArH), 8.03 (d, J = 8.26 Hz, 1H, ArH),
8.07 (d, J = 6.89 Hz, 1H, ArH); 13C NMR (CDCl3) δ 66.4,
118.8, 123.2, 123.6, 128.4, 129.0, 131.9, 135.7, 136.8, 137.8,
148.1, 156.4, 164.9; HRMS (ESI) calcd for C15H12ClNNaO2
[M+Na]+ 296.0449, found 296.0427; mp. 43 °C.
4.5. Determination of the Half Life Time of
(R)-Cl-Naph-PyCOOAll.
A 20-mL Young-type Schlenk
flask was charged with (R)-2b (2.98 mg, 10.0 µmol) and DMA
(1.00 mL). After degassing the system by three-freeze/thaw
cycles, the mixture was heated at 130 °C by use of a Riko
MH-5D oil bath, which was adjusted so that the measurement
temperature was kept the same throughout the whole process.
After 1 h, the Schlenk flask was moved to an ice bath, and an
aliquot of the mixture (ca. 0.1 mL) was sampled under Ar.
Immediately after sampling (ca. 5 min), the Schlenk flask was
inserted into the 130 °C-oil bath. The sample was partitioned
between Et2O (1 mL) and H2O (1 mL). The organic layer was
washed with H2O (1 mL x 2) and concentrated in vacuo. This
was subjected to er analysis by HPLC (column, CHIRALCEL
OD-H (0.46 cm φ x 25 cm); eluent, 1:5 2-PrOH–hexane; flow
rate, 1 mL min–1; detection, 254-nm light; tR, 8.9 min ((R)-2b)
and 12.2 min ((S)-2b)), determining the er to be 99.4:0.6. In
the same way, the ers were measured at 12 h, 25 h, 37 h, and 43
CH2Cl2 (10 mL
x 3); dryness over Na2SO4 (10 g);
filtration/evaporation. Crude product (ca. 0.5 g, yellow solid).
Purification: recrystallization from 2:2:1 Et2O–CH2Cl2–hexane
(ca 1 mL).
6-(3-Chlorophenyl)pyridine-2-carboxylic acid
(L14) (403 mg, 70% yield) as a colorless solid: 1H NMR
(CDCl3) δ 7.48 (br, 2H, ArH), 7.86–7.87 (m, 1H, ArH), 7.99 (d,
J = 7.57 Hz, 2H, ArH), 8.05 (t, J = 7.57 Hz, 1H, ArH), 8.23 (d,
J = 7.57 Hz, 1H, ArH). (ii) The carboxylic acid compound
(100 mg, 428 µmol), SOCl2 (160 µL), 50 °C, 1 h; concentration
h
to be 90.2:9.8, 81.9:18.1, 75.8:24.2, and 73.1:26.9,
respectively. The logarithmic plot of ln(ee) versus time
determined the racemization rate krac to be 5.01 x 10–6 s–1. (ee
= enantiomeric excess, ee = (100 x |[R isomer] – [S
isomer]|)/([R isomer] + [S isomer])). By use of the Eyring
equation (ΔG‡ = 8.314T ln(2.084 x 1010 T/krac)), the rotational
energy barrier ΔG‡ was determined to be 140.6 kJ mol–1 at 403
K. The half-life time was calculated to be 16,000 year at
25 °C (t1/2 = ln2/krac).
in vacuo; allyl alcohol (150 µL),
6
h, rt.
Workup:
concentration in vacuo; dissolving in CH2Cl2 (10 mL); washing
with sat aq NaHCO3 (5 mL); dryness over Na2SO4 (5 g);
filtration/evaporation. Crude product (ca. 0.5 g, white solid).
Purification:
EtOAc–hexane).
SiO2-chromatography (25 g; eluent, 1:3
Allyl 6-(3-chlorophenyl)pyridine-2-
1
carboxylate (L14) (93.1 mg, 80% yield) as a colorless oil: H
NMR (CDCl3) δ 4.92 (d, J = 6.20 Hz, 2H, CH2CH=CH2), 5.33
(d, J = 10.3 Hz, CH2CH=CHH), 5.48 (dd, J = 17.2, 1.38 Hz,
1H, CH2CH=CHH), 6.06–6.13 (m, 1H, CH2CH=CH2),
7.38–7.42 (m, 2H, ArH), 7.86–7.93 (m, 3H, ArH), 8.06 (s, 1H,
ArH), 8.07 (d, J = 6.89 Hz, 1H, ArH); 13C NMR (CDCl3) δ
66.4, 118.8, 123.5, 123.8, 125.2, 127.3, 129.4, 130.0, 131.8,
134.9, 137.8, 140.1, 148.1, 156.1, 164.8; HRMS (ESI) calcd for
C15H12NNaO2 [M+Na]+ 296.0449, found 296.0469; mp. 46 °C.
4.4.9. 4-Cl-Ph-PyCOOAll (L15). The procedures were
the same as those for L10. (i) 4-Chlorophenylboronic acid
(466 mg, 2.98 mmol), DME (13 mL), 2 M aq K2CO3 (6.6 mL),
6-bromopyridine-2-carboxylic acid (500 mg, 2.48 mmol),
Pd(PPh3)4 (143 mg, 124 µmol), reflux, 24 h. Workup:
addition of CH2Cl2 (10 mL); extraction of the aq layer with
1
4.6. H-NMR Experiments. A Young type NMR tube
was charged with (R)-Cl-Naph-PyCOOH ((R)-2a) (2.98 mg,
10.0 µmol), [RuCp(CH3CN)3]PF6 (1) (4.34 mg, 10.0 µmol),
and acetone-d6 (900 mL). The resulting reddish solution was
subjected to 1H-NMR analysis at 18 °C, 30 °C, and 40 °C
(Figure 7a). A solution of Et3N (100 mM in acetoen-d6, 100
µL, 10 µmol) was added to another (R)-2a/1 solution prepared
in the same way. After 30 min at 27 °C, this was subjected to
1H-NMR analysis at –40 °C, –20 °C, and 0 °C (Figure 7b).
Acknowledgement
This work was aided by a Grant-in-Aid for Scientific
Research (JP25410112, JP22750088, JP16F16339) from the
Ministry of Education, Culture, Sports, Science and
Technology (Japan).
CH2Cl2 (10 mL
x 3); dryness over Na2SO4 (10 g);
filtration/evaporation. Crude product (ca. 0.5 g, yellow solid).

Kitamura, Tetrahedron 2015, 71, 6559.
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