New efficient method for the synthesis of chiral 2,2′-bipyridyl ligands

Article abstract of DOI:10.1055/s-2005-869983

An efficient preparation of chiral 2,2′-bipyridines was developed. Compound 1 was synthesized in 54% yield for three steps starting from 2,6-dibromopyridine. In this synthesis, only catalytic amounts of metals were used in the asymmetric reduction and homo-coupling reaction steps. The total yield and simplicity of experimental procedures were much improved compared with those of the previous report. Other chiral 2,2′-bipyridines were similarly synthesized with high efficiency. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869983

2176
PAPER
New Efficient Method for the Synthesis of Chiral 2,2¢-Bipyridyl Ligands
C
hira
l
2,2
¢
-Bip
h
yridyl
L
igan
u
ds npei Ishikawa, Tomoaki Hamada, Kei Manabe, Shu Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku Tokyo 113-0033, Japan
Fax +81(3)56840634; E-mail: skobayas@mol.f.u-tokyo.ac.jp
Received 31 January 2005; revised 14 March 2005
Abstract: An efficient preparation of chiral 2,2¢-bipyridines was
developed. Compound 1 was synthesized in 54% yield for three
N
N
steps starting from 2,6-dibromopyridine. In this synthesis, only cat-
alytic amounts of metals were used in the asymmetric reduction and
homo-coupling reaction steps. The total yield and simplicity of ex-
perimental procedures were much improved compared with those
of the previous report. Other chiral 2,2¢-bipyridines were similarly
synthesized with high efficiency.
OH
HO
1
Figure 1 Chiral 2,2¢-bipyridine 1
rane (Ipc2BCl)7 was used in the asymmetric reduction of
1-(6-bromopyridin-2-yl)-2,2-dimethylpropanone 2. In
this procedure, byproducts, such as a chloro-substituted
pyridyl alcohol as mentioned in the previous report and
other compounds presumably derived from Ipc2BCl were
found, which we were unable to remove at this stage.
Therefore, subsequent homo-coupling reaction had to be
performed using a mixture of the desired compound and
such byproducts. In the homo-coupling reaction, stoichio-
metric amounts of reagents (NiCl2, PPh3, and Zn) were
used again, and the reaction proceeded in moderate yield.
Although this nickel(0)/triphenylphosphine-mediated re-
action is known as the usual method to synthesize various
kinds of bipyridines,1,8 the yields are usually moderate due
to dehalogenation of the starting materials. Moreover, in
the homo-coupling reaction of 3, since 3 contains a small
amount of the opposite enantiomer, 1 was obtained with
contamination of the meso isomer, removal of which was
found to be difficult.
Key words: chiral ligand, chiral 2,2¢-bipyridine, catalyst, asym-
metric reduction, homo-coupling
Recently, much attention has been paid to 2,2¢-bipyridyl
ligands in the field of catalysis, photochemistry, electro-
chemistry, supramolecular chemistry, etc. In particular,
over the past two decades, chiral 2,2¢-bipyridyl ligands
have been often used in asymmetric reactions1 due to their
stability and excellent coordinating ability with a wide
range of metal ions. 2
Chiral 2,2¢-bipyridine 1 (Figure 1) and the corresponding
methyl ether, first synthesized by Bolm et al.,3 were em-
ployed in enantioselective reactions4 such as alkylation of
aldehydes, conjugate addition to enones, cyclopropana-
tion, and allylation of aldehydes. Among our recent stud-
ies on catalytic asymmetric hydroxymethylation of silicon
enolates, a chiral bipyridine 1-Sc(III) complex was found
to be an efficient catalyst to afford the desired compounds
with high enantioselectivity in aqueous media.5 More-
over, enantioselective addition of alcohols and amines to
meso-epoxides proceeded smoothly using a similar cata-
lyst in an organic solvent.6 These reports suggest that this
chiral ligand can be a candidate of choice for different
types of asymmetric transformations. In order to extend
the utility of this chiral ligand, it is required to establish an
efficient method of preparation that satisfies the increas-
ing demands for its supply in large amount. However, no
alternative synthetic method has appeared since the report
by Bolm et al. In this paper, we describe a new method for
the synthesis of 1 using a Ru-catalyzed asymmetric reduc-
tion and a Pd-catalyzed coupling reaction.
Br
N
Br
Br
N
O
2
asymmetric
reduction
homo-coupling
1
Br
N
OH
3
Scheme 1
To establish a more efficient preparation method, we first
In the reported method,3b the desired product 1 is accessed investigated the catalytic asymmetric reduction of ketone
in three steps starting from commercially available 2,6-di- 2. The reported method using Ipc2BCl gave the alcohol 3
bromopyridine (Scheme 1). We carried out the synthesis in 59% yield with 90% ee.3b After several trials of the
and encountered some difficulties. First, a stoichiometric asymmetric reduction, a system of RuCl[(S,S)-Tsdpen](p-
amount of optically active B-chlorodiisopinocampheylbo- cymene) with HCO2H/Et3N as a hydrogen source9 was
found to be very efficient, and the desired alcohol 3 was
obtained in 95% yield with 91% ee (Scheme 2). This re-
sult was unexpected, because structurally related piv-
alophenone is known as one of the most difficult
SYNTHESIS 2005, No. 13, pp 2176–2182
x
x.
x
x
.
2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-869983; Art ID: F02405SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chiral 2,2¢-Bipyridyl Ligands
2177
R1
R1
substrates for obtaining high yield with high selectivity in
the Ru-catalyzed asymmetric reduction.10 Fortunately, al-
cohol 3 was crystallized, and the opposite enantiomer was
completely separated by recrystallization at this stage.
Next, we investigated homo-coupling of 3. After several
trials, 1 was obtained in 93% yield using a catalytic
amount of PdCl2(PhCN)2 and tetrakis(dimethylami-
no)ethylene (TDAE) as a reductant.11 The reaction pro-
ceeded smoothly and no epimerization of the chiral
centers was observed. It should be noted that protection of
the hydroxy groups was not needed in this transformation.
After purification by column chromatography on silica
gel, single diastereomer 1 was obtained in excellent yield.
According to these procedures, 1 was synthesized in a
gram scale.
RuCl[(S,S)-Tsdpen](p-cymene)
(0.010 equiv)
R2
R2
*
HCOOH (4.3 equiv)
Br
NEt3 (2.5 equiv)
Br
N
N
O
OH
r.t.
Scheme 3
The homo-coupling conditions for alcohol 3 to afford 1
were also applied to alcohols 8–11 (Scheme 4, Table 2). It
is noted that no epimerization was observed at all in all
cases. In the reaction of 10, the yield was relatively low
because of high polarity of the product, and the product
was lost during purification. In the homo-coupling of 11
having a methoxy group at the 4 position of the pyridine
ring, the reaction was retarded dramatically, probably be-
cause catalytic activity of palladium was decreased by the
electron-donation of the nitrogen enhanced by the substit-
uent. Although the yield of the desired product 15 was
low, almost all of the starting material 11 was recovered
without racemization. Thus, this method is superior to the
conventional method using a stoichiometric amount of a
nickel complex, where dehalogenation of the starting ma-
terial is usually observed.
a
b
1
Br
N
Br
N
O
OH
2
3
Scheme 2 Reagents and conditions: (a) RuCl[(S,S)-Tsdpen](p-cy-
mene) (0.010 equiv), HCO2H (4.3 equiv), Et3N (2.5 equiv), r.t., 14 h
[95%, 91% ee, S; after recrystallization from hexane 71%, >99.5% ee,
S]; (b) PdCl2(PhCN)2 (0.050 equiv), TDAE (2.0 equiv), DMF, 50 °C,
10 h [93%, >99.5% de, >99.5% ee, S,S].
R1
The above-mentioned synthetic procedure for 1 was then
applied to the synthesis of other chiral 2,2¢-bipyridine de-
rivatives. The asymmetric reduction mentioned above
could be applied to other substrates (Scheme 3, Table 1).
In the reduction of 4 having a methyl group in place of the
tert-butyl group, high yield and high selectivity were ob-
tained (entry 1). The absolute configuration of the product
was determined to be S,3b which is the same as that of 1.
On the other hand, in the case of 5 having an isopropyl
group, the enantioselectivity obtained was, unfortunately,
very poor (entry 2).12 When the reduction of 6 having a
phenyl group was conducted, high yield was obtained al-
though the selectivity was moderate (entry 3). It is inter-
esting that the absolute configuration of the major product
was R, which is opposite to that of the product having a
methyl or tert-butyl group. The electron-donating substit-
uent at the 4 position of the pyridine ring did not affect the
yield and selectivity (entry 4). Optically pure pyridyl alco-
hols 8–11 were obtained by recrystallization or column
chromatography of the corresponding camphanates and
subsequent hydrolysis (see Experimental).
PdCl2(PhCN)2 (0.050 equiv)
TDAE (2.0 equiv)
R2
*
Br
N
DMF, 50 °C
R1
OH
R1
N
N
*
*
R2
R2
OH
HO
Scheme 4
In summary, we have established a convenient method for
the preparation of various kinds of chiral 2,2¢-bipyridines.
In this method, only catalytic amounts of metals were
needed both in the asymmetric reduction and the homo-
coupling reaction. Purification of the products was per-
formed easily. By following these procedures, the total
yields and easiness of experimental procedures were
much improved compared to those of the previous report.
This study will contribute not only to the development of
Table 1 Asymmetric Reductions (Scheme 3)
Entry
R1
H
R2
Substrate
Time (h)
Product
Yield (%)
ee (%)
87 (S)
18 (R)
47 (R)
90 (S)
1
2
3
4
Me
i-Pr
Ph
4
5
6
7
3.5
8
8
9
97
93
99
94
H
H
6
10
11
MeO
t-Bu
46
Synthesis 2005, No. 13, 2176–2182 © Thieme Stuttgart · New York

2178
S. Ishikawa et al.
PAPER
Table 2 Homo-Coupling Reactions (Scheme 4)
Entry
R1
H
R2
Substrate
8 (S)
Time (h)
11
Product
12 (S,S)
13 (R,R)
14 (R,R)
15 (S,S)
Yield (%)
1
2
3
4
Me
i-Pr
Ph
79
84
58
36
H
9 (R)
4.5
H
10 (R)
11 (S)
29
MeO
t-Bu
68
Anal. Calcd for C10H14BrNO: C, 49.20; H, 5.78; N, 5.74. Found: C,
49.13; H, 5.73; N, 5.67.
asymmetric catalysts but also to progress in any research
fields using chiral 2,2¢-bipyridine compounds.
(S,S)-6,6¢-Bis(1-hydroxy-2,2-dimethylpropyl)-2,2¢-bipyridine
(1)3b
Melting points are uncorrected. CDCl3 was used as a solvent for 1H
and 13C NMR spectra unless otherwise noted. TMS served as an in-
ternal standard (d = 0) for 1H NMR and CDCl3 as an internal stan-
dard (d = 77.0) for 13C NMR. Preparative TLC (PTLC) was carried
out using Wakogel B-5F. Column chromatography was carried out
on silica gel 60 (70–230 mesh). All reactions were performed under
an argon atmosphere. Tetrakis(dimethylamino)ethylene was pre-
pared according to the procedure described in the literature.13
To a solution of PdCl2(PhCN)2 (471 mg, 1.23 mmol) in DMF (121
mL) were added 3 (6.01 g, 24.6 mmol, >99.5% ee) and tetrakis(di-
methylamino)ethylene (TDAE) (11.4 mL, 49.2 mmol) at r.t. After
stirring at 50 °C for 10 h, the solution was cooled to r.t., and H2O
(500 mL) was added. The aqueous layer was extracted with Et2O
(3 × 250 mL). The combined organic layers were washed with brine
(1 × 200 mL), and dried (Na2SO4). The solvent was removed under
reduced pressure, and the residue was purified by column chroma-
tography (SiO2, hexane–EtOAc, 4:1). Compound 1 was obtained as
1-(6-Bromopyridin-2-yl)-2,2-dimethylpropanone (2)
Compound 2 was prepared using a protocol described in the litera-
ture.3b
20
a white solid (93% yield, >99.5% ee); [a]D +33.8 (c = 1.70,
CH2Cl2); for S,S >99.5% ee, >99.5% de (Lit.3b [a]Dr.t. –37.4 (c = 1.7,
CH2Cl2); for R,R >99% ee, >99% de).
1H NMR (300 MHz, CDCl3): d = 1.45 (s, 9 H), 7.58 (dd, 1 H,
J = 1.1, 7.9 Hz), 7.67 (dd, 1 H, J = 7.5, 7.9 Hz), 7.87 (dd, 1 H,
J = 1.1, 7.5 Hz).
1H NMR (300 MHz, CDCl3): d = 0.97 (s, 18 H), 4.43 (s, 2 H), 7.23
(d, 2 H, J = 7.7 Hz), 7.78 (dd, 2 H, J = 7.7, 7.8 Hz), 8.31 (d, 1 H,
J = 7.8 Hz).
13C NMR (75 MHz, CDCl3): d = 27.3, 44.2, 122.5, 130.5, 139.0,
139.6, 154.7, 204.8.
13C NMR (75 MHz, CDCl3): d = 25.9, 36.3, 80.2, 119.5, 123.0,
136.6, 153.8, 159.3.
(S)-1-(6-Bromopyridin-2-yl)-2,2-dimethylpropanol (3)
HPLC [racemate, Daicel Chiralcel OD, hexane–i-PrOH (19:1),
flow rate 1.0 mL/min]: dl isomer: tR 40.2 min (R,R), tR 48.7 min
(S,S); meso isomer: tR 19.9 min.
A mixture of Et3N (26.9 mL, 193 mmol) and formic acid (12.5 mL,
332 mmol) was added to ketone 2 and RuCl[(1S,2S)-N-p-toluene-
sulfonyl-1,2-diphenylethanediamine](p-cymene) (491 mg, 0.772
mmol). The mixture was stirred at r.t. for 14 h, and then H2O (200
mL) was added. The aqueous layer was extracted with EtOAc (2 ×
200 mL). The combined organic layers were washed once with sat.
aq solution of NaHCO3 (1 × 100 mL) and brine (1 × 100 mL), and
dried (Na2SO4). The solvent was removed under reduced pressure,
and the residue was purified by column chromatography (SiO2, hex-
ane–EtOAc, 6:1). Compound 3 was obtained as a white solid (95%
yield, 18.0 g, 91% ee). The enantiomerically pure form was ob-
tained by recrystallization from hexane (70 mL) (71% yield, 13.5 g,
1-(6-Bromopyridin-2-yl)ethanone (4)
Compound 4 was prepared using a protocol described in the litera-
ture.3b
1H NMR (400 MHz, CDCl3): d = 2.71 (s, 3 H), 7.65–7.73 (m, 2 H),
7.98–8.00 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 25.7, 120.4, 131.7, 139.1, 141.3,
154.2, 198.5.
22
>99.5% ee); mp 76–78 °C; [a]D +23.3 (c = 1.00, CHCl3); for S
1-(6-Bromopyridin-2-yl)-2-methylpropanone (5)
>99.5% ee. The absolute configuration of the major product was de-
termined to be S by comparison of the optical rotation of homo-cou-
pling product 1, which was synthesized as described below, with the
reported one.3b
A suspension of 2,6-dibromopyridine (200 mg, 0.844 mmol) in
Et2O (4.2 mL) was cooled to –78 °C and n-BuLi (0.59 mL, 1.58 M
n-hexane solution, 0.928 mmol) was slowly added over a period of
5 min. The suspension became a clear yellow solution. After stirring
for 30 min at this temperature, a solution of N-methoxy-N-methyl-
isobutyramide (111 mg, 0.844 mmol), which was prepared accord-
ing to the literature,14 in Et2O (1.0 mL) was added, and the reaction
mixture was allowed to warm to r.t. After stirring for 3.5 h, a sat. aq
solution of NH4Cl was added. The layers were separated, and the
aqueous layer was extracted once with Et2O. The combined organic
layers were dried (MgSO4). The solvent was removed under re-
duced pressure, and the residue was purified by PTLC (SiO2, hex-
ane–EtOAc, 6:1). Compound 5 was obtained as a colorless oil (67%
yield).
IR (KBr): 3413, 2973, 2955, 1581, 1551, 1436, 1405, 1122, 767,
709 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.91 (s, 9 H), 3.71 (br s), 4.33 (s,
1 H), 7.19 (d, 1 H, J = 7.6 Hz), 7.37 (d, 1 H, J = 7.8 Hz), 7.50 (dd,
1 H, J = 7.6, 7.8 Hz).
13C NMR (100 MHz, CDCl3): d = 25.7, 36.1, 80.3, 121.4, 126.6,
137.9, 140.5, 161.9.
MS (ESI-TOF): m/z = 268, 266 [M + Na]+, 246, 244 [M + H]+, 228,
226.
IR (neat): 2972, 1700, 1555, 1429, 1124, 994 cm–1.
HPLC [racemate, Daicel Chiralcel OJ, hexane–i-PrOH (100:1),
flow rate 0.5 mL/min]: tR 19.2 min (R), tR 22.4 min (S).
Synthesis 2005, No. 13, 2176–2182 © Thieme Stuttgart · New York

PAPER
Chiral 2,2¢-Bipyridyl Ligands
2179
1H NMR (400 MHz, CDCl3): d = 1.20 (d, 6 H, J = 6.8 Hz), 4.04
(sept, 1 H, J = 6.8 Hz), 7.64–7.67 (m, 1 H), 7.70–7.73 (m, 1 H),
7.98–8.00 (m, 1 H).
1H NMR (300 MHz, CDCl3): d = 1.43 (s, 9 H), 3.88 (s, 3 H), 7.08
(d, 1 H, J = 2.0 Hz), 7.39 (d, 1 H, J = 2.0 Hz).
13C NMR (75 MHz, CDCl3): d = 27.4, 44.3, 55.8, 109.4, 115.9,
140.6, 155.7, 167.4, 205.0.
13C NMR (100 MHz, CDCl3): d = 18.5, 34.2, 121.2, 131.4, 139.1,
141.2, 153.6, 204.1.
HRMS-ESI-TOF: m/z calcd for C11H15BrNO2 [M + H]+: 272.0286;
found: 272.0281; m/z calcd for C11H14BrNO2Na [M + Na]+:
294.0106; found: 294.0101.
MS: m/z = 229, 227 [M+], 186, 184, 159, 157.
Anal. Calcd for C9H10BrNO: C, 47.39; H, 4.42; N, 6.14. Found: C,
47.56; H, 4.63; N, 6.10.
Anal. Calcd for C11H14BrNO2: C, 48.55; H, 5.19; N, 5.15. Found: C,
48.68; H, 5.04; N, 5.16.
(6-Bromopyridin-2-yl)(phenyl)methanone (6)
Compound 6 was prepared using a slightly modified experimental
protocol described in the literature.15 To a suspension of 2,6-dibro-
mopyridine (200 mg, 0.844 mmol) in Et2O (4.2 mL) cooled at
–78 °C, was slowly added n-BuLi (0.58 mL, 1.59 M n-hexane solu-
tion, 0.928 mmol) over a period of 5 min. The suspension became a
clear yellow solution. After stirring for 1 h at this temperature, ben-
zonitrile (96 mL, 0.928 mmol) was added, and the solution was al-
lowed to warm to r.t. After stirring for 2 h, an ice cold 3 N aq
solution of HCl (5 mL) was added at 0 °C. The mixture was stirred
at r.t. for 20 min. The layers were separated, and the aqueous layer
was treated with a 3 N aq solution of NaOH until the solution be-
came slightly basic. The aqueous layer was extracted with Et2O
(3 ×). The combined organic layers were dried (MgSO4). The sol-
vent was removed under reduced pressure, and the residue was pu-
rified by PTLC (SiO2, hexane–EtOAc, 4:1). Compound 6 was
obtained as a yellow solid (58% yield). In a large scale synthesis, 6
was purified by recrystallization from EtOH; mp 63–64 °C.
(S)-(6-Bromopyridin-2-yl)ethanol (8)
Compound 8 was prepared by asymmetric reduction of 4 using the
procedure described for 3. The desired product was purified by col-
umn chromatography (SiO2, hexane–EtOAc, 1:1) and obtained as a
colorless oil (97% yield, 87% ee). To remove the minor enantiomer,
the corresponding camphanate ester was prepared according to the
literature.3b The camphanate was obtained as a white solid (98%
yield, 8.57 g, 90% de). The diastereomerically pure form was ob-
tained by recrystallization from hexane–CHCl3 (100/10 mL) (71%
18
yield, 6.22 g, >99.5% de); [a]D –45.3 (c = 0.49, EtOH); >99.5%
de.
Camphanate Ester of 8
1H NMR (300 MHz, CDCl3): d = 0.97 (s, 3 H), 1.11 (s, 3 H), 1.13
(s, 3 H), 1.64 (d, 3 H, J = 6.6 Hz), 1.64–1.74 (m, 1 H), 1.90–2.10
(m, 2 H), 2.43–2.53 (m, 1 H), 5.99 (q, 1 H, J = 6.6 Hz), 7.37–7.42
(m, 2 H), 7.54–7.60 (m, 1 H).
IR (KBr): 3055, 1675, 1552, 1426, 1320, 1245, 1148, 1117, 950,
783, 737, 703, 693, 670, 635 cm–1.
13C NMR (75 MHz, CDCl3): d = 9.7, 16.6, 16.6, 20.8, 28.9, 30.5,
54.4, 54.8, 73.5, 90.9, 119.1, 127.3, 139.2, 141.5, 160.9, 166.6,
178.2.
1H NMR (400 MHz, CDCl3): d = 7.48–7.52 (m, 2 H), 7.59–7.63 (m,
1 H), 7.67–7.69 (m, 1 H), 7.74–7.78 (m, 1 H), 7.97–8.00 (m, 1 H),
8.09–8.12 (m, 2 H).
The camphanate was hydrolyzed by the following procedure. To a
solution of the corresponding camphanate (5.93 g, 15.5 mmol,
>99.5% de) in 1,4-dioxane (70.0 mL) was added a 10 N aq solution
of KOH (7.75 mL, 77.5 mmol) at r.t. After stirring for 13 h at this
temperature, H2O was added. The aqueous layer was extracted with
Et2O (3 ×). The combined organic layers were washed once with
brine, and dried (Na2SO4). The solvents were removed under re-
duced pressure, and the residue was purified by column chromatog-
raphy (SiO2, CHCl3–MeOH, 19:1). Compound 8 was obtained as a
colorless oil (quant., >99.5% ee).
13C NMR (100 MHz, CDCl3): d = 123,4, 128.2, 130.8, 131.1, 133.2,
135.4, 139.3, 140.7, 155.6, 191.6.
HRMS-ESI-TOF: m/z calcd for C12H9BrNO [M + H]+: 261.9868;
found: 261.9860; m/z calcd for C12H8BrNONa [M + Na]+:
283.9687; found: 283.9678.
Anal. Calcd for C12H8BrNO: C, 54.99; H, 3.08; N, 5.34. Found: C,
55.01; H, 3.26; N, 5.23.
8
1-(6-Bromo-4-methoxypyridin-2-yl)-2,2-dimethylpropan-1-one
(7)
[a]D27 –8.1 (c = 2.75, CHCl3); for S >99.5% ee [Lit.3b [a]Dr.t. +10.8
(c = 2.75, CHCl3); for R 68% ee].
Compound 7 was prepared using a slightly modified experimental
protocol described in the literature.3b A suspension of 2,6-dibromo-
4-methoxypyridine (1.33 g, 5.00 mmol), which was prepared ac-
cording to the literature16 from 2,6-dibromopyridine in 5 steps, in
Et2O (20.0 mL) was cooled to –78 °C, and n-BuLi (3.43 mL, 1.60
M n-hexane solution, 5.50 mmol) was slowly added over a period
of 5 min. The suspension became a clear yellow solution. After stir-
ring for 1 h at this temperature, pivalonitrile (0.66 mL, 6.00 mmol)
was added. The solution turned orange in color. After stirring at
–78 °C for 1 h, the solution was allowed to warm to r.t., and a 2 N
aq solution of H2SO4 (18 mL) was added. The mixture was refluxed
for 2 h, and then cooled to r.t. The layers were separated, and the
aqueous layer was extracted with Et2O (2 ×) The combined organic
layers were washed once with sat. aq solution of Na2CO3, and dried
(Na2SO4). The solvent was removed under reduced pressure, and
the residue was purified by column chromatography (SiO2, hexane–
EtOAc, 6:1). Compound 7 was obtained as a white solid (86%
yield); mp 58–60 °C.
1H NMR (400 MHz, CDCl3): d = 1.51 (d, 3 H, J = 6.6 Hz), 3.52 (br
s), 4.88 (q, 1 H, J = 6.6 Hz), 7.30 (d, 1 H, J = 7.6 Hz), 7.38 (d, 1 H,
J = 7.8 Hz), 7.55 (dd, 1 H, J = 7.6, 7.8 Hz).
13C NMR (100 MHz, CDCl3): d = 24.0, 69.1, 118.5, 126.5, 139.1,
141.1, 165.2.
HPLC [racemate, Daicel Chiralcel OB-H, hexane–i-PrOH (100:1),
flow rate 1.0 mL/min]: tR 28.5 min (R), tR 32.7 min (S).
(R)-1-(6-Bromopyridin-2-yl)-2-methylpropanol (9)
Compound 9 was also obtained by asymmetric reduction of 5 using
the described procedure for 3. The desired product was purified by
column chromatography (SiO2, hexane–EtOAc, 6:1), and obtained
as a colorless oil (93% yield, 18% ee). The absolute configuration
of the major product by this method was revealed to be R. Since this
asymmetric reduction resulted in low enantioselectivity, enantio-
merically pure 9 was obtained as described below.
IR (KBr): 2979, 2953, 1688, 1590, 1543, 1482, 1463, 1416, 1302,
1129, 991, 875, 751 cm–1.
To a solution of ketone 5 (3.79 g, 16.6 mmol) in EtOH (100 mL)
was added NaBH4 (0.88 g, 23.3 mmol) at r.t. After stirring for 20
min at this temperature, a sat. aq solution of NaHCO3 was added,
and the mixture was refluxed for 1 h. The mixture was filtered
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2180
S. Ishikawa et al.
PAPER
through Celite, and the aqueous layer was extracted with EtOAc
(3 ×). The combined organic layers were washed with brine (2 ×),
and dried (Na2SO4). The solvents were removed under reduced
pressure, and racemic 9 was obtained without further purification
(98% yield).
(R)-2-Methyl-1-(pyridin-2-yl)propanol
This compound was prepared using a protocol described in the lit-
erature.3b To a solution of 9 (69.6 mg, 0.302 mmol, >99.5% ee) in
toluene (3.0 mL) were added Bu3SnH (0.16 mL, 0.605 mmol) and
azobisisobutyronitrile (AIBN) (19.8 mg, 0.121 mmol) at r.t. The
mixture was stirred at 100 °C for 1.5 h. The solvent was removed
under reduced pressure, and the residue was purified by PTLC
(SiO2, CHCl3–MeOH, 19:1). The desired product was obtained as a
colorless oil (76% yield). The absolute configuration of the product
Each enantiomer was separated by column chromatography of its
camphanate ester as described below. To the racemic mixture of 9
(3.55 g, 15.4 mmol) and (–)-camphanic chloride (3.68 g, 17.0
mmol) was added pyridine (12.5 mL, 154 mmol) at r.t. After stirring
for 11 h at this temperature, H2O was added. The aqueous layer was
extracted with EtOAc (2 ×). The combined organic layers were
washed with a 1 N aq solution of HCl (3 ×), H2O (2 ×) and brine
(1 ×), and dried (Na2SO4). The solvents were removed under re-
duced pressure to give the crude mixture (ca. 99% yield). The dia-
stereomers were separated by column chromatography (SiO2,
benzene–Et2O, 30:1) to afford four fractions. 1H NMR analysis of
these fractions revealed the following: First fraction: diastereomer-
ically pure, 18% yield, >99.5% de; second: 34% yield, 28% de;
third: 25% yield, 58% de (opposite diastereomer); fourth: 17%
yield, 82% de (opposite diastereomer).
24
was determined to be R by comparison of the optical rotation; [a]D
+24.6 (c = 1.36, CHCl3), for R [Lit.12 [a]D17 –25.2 (c = 0.96, CHCl3),
for S].
1H NMR (400 MHz, CDCl3): d = 0.79 (d, 3 H, J = 6.8 Hz), 1.01 (d,
3 H, J = 6.8 Hz), 2.03 (dqq, 1 H, J = 4.6, 6.8, 6.8 Hz), 4.25 (br s),
4.55 (d, 1 H, J = 4.6 Hz), 7.18–7.24 (m, 2 H), 7.65–7.69 (m, 1 H),
8.53–8.54 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 16.0, 19.4, 35.1, 77.2, 121.0,
122.2, 136.3, 147.9, 161.2.
(R)-(6-Bromopyridin-2-yl)(phenyl)methanol (10)
Compound 10 was prepared by asymmetric reduction of 6 using the
procedure described for 3. The desired product was purified by col-
umn chromatography (SiO2, hexane–EtOAc, 2:1), and obtained as
a clear oil (99% yield, 47% ee). The absolute configuration of the
major enantiomer was determined to be R by X-ray analysis of its
camphanate which was obtained as below. To remove the minor
enantiomer, the corresponding camphanate was prepared using the
procedure described for the camphanate derived from 9. The crude
product was obtained as a white solid (quant., 8.32 g, 47% de). The
diastereomerically pure form was obtained as colorless plates by re-
crystallization from hexane–CHCl3 (70/35 mL) (55% yield, 4.59 g,
>99.5% de). For X-ray crystal structure analysis, see Ref.17
First Fraction, Camphanate Ester of 9
Mp 97–99 °C; [a]D21 +22.0 (c = 1.25, EtOH); >99.5% de.
IR (KBr): 2970, 2935, 2879, 1790, 1743, 1579, 1556, 1444, 1304,
1263, 1169, 1103, 1061, 989 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.94 (d, 3 H, J = 6.8 Hz), 0.96 (d,
3 H, J = 6.8 Hz), 1.00 (s, 3 H), 1.08 (s, 3 H), 1.13 (s, 3 H), 1.68–1.75
(m, 1 H), 1.91–1.98 (m, 1 H), 2.05–2.12 (m, 1 H), 2.37 (dqq, 1 H,
J = 5.4, 6.8, 6.8 Hz), 2.31–2.42 (m, 1 H), 5.72 (d, 1 H, J = 5.4 Hz),
7.24–7.26 (m, 1 H), 7.38–7.40 (m, 1 H), 7.52–7.55 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 9.6, 16.7, 16.7, 17.0, 18.9, 28.8,
30.9, 32.5, 54.2, 54.8, 81.2, 91.1, 119.9, 127.1, 138.6, 141.5, 159.7,
166.9, 178.3.
Camphanate Ester of 10
Mp 150–151 °C; [a]D23 –20.0 (c = 1.00, CHCl3); for R 99.5% de.
MS (FAB): m/z = 412, 410 [M + H]+, 366, 332, 214, 212.
IR (KBr): 2964, 1781, 1735, 1581, 1555, 1436, 1399, 1354, 1311,
1261, 1163, 1120, 1098, 1061, 971, 927, 780, 742, 705 cm–1.
Anal. Calcd for C19H24BrNO4: C, 55.62; H, 5.90; N, 3.41. Found: C,
55.91; H, 6.08; N, 3.43.
1H NMR (400 MHz, CDCl3): d = 1.00 (s, 3 H), 1.06 (s, 3 H), 1.12
(s, 3 H), 1.70 (ddd, 1 H, J = 4.1, 9.2, 13.3 Hz), 1.93 (ddd, 1 H,
J = 4.6, 11.0, 13.3 Hz), 2.08 (ddd, 1 H, J = 4.6, 9.2, 13.8 Hz), 2.49
(ddd, 1 H, J = 4.1, 11.0, 13.8 Hz), 6.91 (s, 1 H), 7.31–7.38 (m, 5 H),
7.44–7.47 (m, 2 H), 7.50–7.54 (m, 1 H).
The camphanate (>99.5% de) was hydrolyzed using the procedure
described for 8. The desired product 9 was purified by column chro-
matography (SiO2, hexane–EtOAc, 2:1), and obtained as a colorless
oil (94% yield, >99.5% ee).
13C NMR (100 MHz, CDCl3): d = 9.8, 16.7, 16.7, 28.9, 30.8, 54.5,
54.9, 78.1, 91.0, 119.7, 127.3, 127.4, 128.7, 128.8, 137.5, 139.1,
141.6, 159.7, 166.4, 178.3.
9
[a]D24 +49.0 (c = 2.88, EtOH); for R >99.5% ee.
IR (neat): 3421, 2961, 1582, 1555, 1437, 1408, 1158, 779, 701 cm–1.
MS (FAB): m/z = 446, 444 [M + H]+, 366, 248, 246.
1H NMR (400 MHz, CDCl3): d = 0.84 (d, 3 H, J = 6.8 Hz), 0.97 (d,
3 H, J = 6.8 Hz), 2.04 (dqq, 1 H, J = 4.9, 6.8, 6.8 Hz), 3.45 (br s),
4.49 (d, 1 H, J = 4.9 Hz), 7.23 (d, 1 H, J = 7.6 Hz), 7.37 (d, 1 H,
J = 7.8 Hz), 7.53 (dd, 1 H, J = 7.6, 7.8 Hz).
Anal. Calcd for C22H22BrNO4: C, 59.47; H, 4.99; N, 3.15. Found: C,
59.29; H, 4.94; N, 3.11.
The camphanate was hydrolyzed using the procedure described for
8. The desired product 10 was purified by column chromatography
(SiO2, hexane–EtOAc, 2:1) and recrystallization from hexane–
CHCl3, and obtained as colorless needles (84% yield, >99.5% ee).
13C NMR (100 MHz, CDCl3): d = 14.5, 42.9, 64.5, 128.4, 128.7,
133.3, 136.1, 204.4.
MS: m/z = 231, 229 [M+], 188, 186.
Anal. Calcd for C9H12BrNO: C, 46.98; H, 5.26; N, 6.09. Found: C,
46.85; H, 5.26; N, 6.07.
10
Mp 105–107 °C; [a]D23 –201.2 (c = 1.00, CHCl3); for R >99.5% ee.
HPLC [racemate, Daicel Chiralcel OD, hexane–i-PrOH (100:1),
flow rate 0.5 mL/min]: tR 31.4 min (R), tR 34.1 min (S).
IR (KBr): 3289, 1586, 1556, 1442, 1404, 1128, 788, 739, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.41 (br s), 5.65 (s, 1 H), 7.03–
7.06 (m, 1 H), 7.16–7.30 (m, 6 H), 7.34–7.39 (m, 1 H).
The absolute configuration of the product was determined to be R
by comparison of the optical rotation of the debrominated com-
pound 2-methyl-1-(pyridin-2-yl)propanol with that of the litera-
ture.12 The preparation of 2-methyl-1-(pyridin-2-yl)propanol is
described below.
13C NMR (100 MHz, CDCl3): d = 74.9, 119.9, 126.7, 126.9, 128.0,
128.6, 139.1, 140.7, 142.1, 162.9.
HRMS-ESI-TOF: m/z calcd for C12H11BrNO [M + H]+: 264.0024;
found: 264.0020; m/z calcd for C12H10BrNONa [M + Na]+:
285.9843; found: 285.9843.
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PAPER
Chiral 2,2¢-Bipyridyl Ligands
2181
Anal. Calcd for C12H10BrNO: C, 54.57; H, 3.82; N, 5.30. Found: C,
54.46; H, 3.94; N, 5.24.
1H NMR (400 MHz, CDCl3): d = 1.56 (d, 6 H, J = 6.6 Hz), 4.66 (br
s), 4.96 (q, 2 H, J = 6.6 Hz), 7.30 (d, 2 H, J = 7.8 Hz), 7.81 (dd, 2 H,
J = 7.8, 7.8 Hz), 8.31 (d, 2 H, J = 7.8 Hz).
HPLC [racemate, Daicel Chiralpak AD, hexane–i-PrOH (19:1),
flow rate = 1.0 mL/min]: tR 16.0 min (R), tR 18.2 min (S).
13C NMR (100 MHz, CDCl3): d = 24.2, 68.6, 119.4, 119.9, 137.7,
153.8, 162.3.
(S)-1-(6-Bromo-4-methoxypyridin-2-yl)-2,2-dimethylpropan-1-
ol (11)
(R,R)-6,6¢-Bis(1-hydroxy-2-methylpropyl)-2,2¢-bipyridine (13)
Compound 13 was obtained using the procedure described for 1.
The desired product was obtained as a white solid (84% yield,
>99.5% ee, >99% de); mp 78–79 °C; [a]D21 +68.8 (c = 1.05, EtOH);
for R,R >99.5% ee, >99% de.
Compound 11 was prepared by asymmetric reduction of 7 using the
procedure described for 3. The desired product was purified by col-
umn chromatography (SiO2, hexane–EtOAc, 6:1) and obtained as a
white solid (94% yield, 90% ee). The absolute configuration of the
major enantiomer was determined to be S by X-ray analysis of its
camphanate which was obtained as below. To remove the minor
enantiomer, the corresponding camphanate was prepared using the
procedure described for camphanate derived from 9. The crude
product was obtained as a white solid (quant., 2.36 g, 90% de). The
diastereomerically pure form was obtained as colorless cubes by re-
crystallization from hexane (48 mL) (75% yield, 1.73 g, >99.5%
de). For X-ray crystal structure analysis, see ref.17
IR (KBr): 3406, 2956, 2870, 1574, 1441, 1041, 794, 665 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.83 (d, 6 H, J = 6.6 Hz), 1.06 (d,
6 H, J = 6.8 Hz), 2.10 (dqq, 2 H, J = 3.2, 6.6, 6.8 Hz), 4.49 (br s),
4.63 (d, 2 H, J = 3.2 Hz), 7.25 (d, 2 H, J = 7.6 Hz), 7.81 (dd, 2 H,
J = 7.6, 7.8 Hz), 8.32 (d, 1 H, J = 7.8 Hz).
13C NMR (100 MHz, CDCl3): d = 16.0, 19.4, 35.1, 76.9, 119.5,
121.2, 137.4, 153.8, 160.6.
MS: m/z = 300 [M+], 283, 257.
Camphanate Ester of 11
Mp 114–115 °C; [a]D23 –20.8 (c = 0.50, CHCl3); for S >99.5% de.
Anal. Calcd for C18H24N2O2: C, 71.97; H, 8.05; N, 9.33. Found: C,
71.73; H, 8.24; N, 9.03.
IR (KBr): 2974, 1788, 1739, 1594, 1550, 1271, 1171, 1102, 1066,
855 cm–1.
HPLC [racemate, Daicel Chiralpak AD, hexane–i-PrOH (19:1),
flow rate 1.0 mL/min]: dl isomer: tR 26.9 min (R,R), tR 30.7 min
(S,S), meso isomer: tR 47.8 min.
1H NMR (400 MHz, CDCl3): d = 0.96 (s, 3 H), 1.00 (s, 9 H), 1.13
(s, 3 H), 1.22 (s, 3 H), 1.67–1.74 (m, 1 H), 1.93–2.00 (m, 1 H), 2.01–
2.08 (m, 1 H), 2.44–2.51 (m, 1 H), 3.84 (s, 3 H), 5.42 (s, 1 H), 6.77
(d, 1 H, J = 1.2 Hz), 6.90 (d, 1 H, J = 1.2 Hz).
(R,R)-6,6¢-Bis(1-hydroxy-1-phenylmethyl)-2,2¢-bipyridine (14)
Compound 14 was obtained using the procedure described for 1.
The desired product was obtained as a white solid (58% yield,
>99.5% ee, >99.5% de); mp 40–42 °C; [a]D –532.7 (c = 0.76,
CHCl3); for R,R >99.5% ee, >99.5% de.
13C NMR (100 MHz, CDCl3): d = 9.7, 16.5, 16.6, 26.1, 29.0, 30.7,
34.9, 54.5, 54.9, 55.6, 84.0, 91.2, 109.2, 112.0, 141.7, 159.0, 166.7,
178.3.
22
MS (FAB): m/z = 456, 454 [M + H]+, 376, 258, 256.
IR (KBr): 3387, 3061, 3029, 2882, 1569, 1493, 1437, 1399, 1050,
792, 747, 698 cm–1.
Anal. Calcd for C21H28BrNO5: C, 55.51; H, 6.21; N, 3.08. Found: C,
55.34; H, 6.11; N, 3.00.
1H NMR (400 MHz, CDCl3): d = 5.50 (br s), 5.82 (s, 2 H), 7.16 (d,
2 H, J = 7.8 Hz), 7.26–7.30 (m, 2 H), 7.33–7.36 (m, 4 H), 7.40–7.42
(m, 4 H), 7.78 (dd, 2 H, J = 7.8, 7.8 Hz), 8.39 (d, 2 H, J = 7.8 Hz).
The camphanate was hydrolyzed using the procedure described for
8. The desired product 11 was obtained as a white solid (quant.,
>99.5% ee).
13C NMR (100 MHz, CDCl3): d = 74.8, 119.8, 121.8, 127.2, 127.9,
128.6, 138.0, 143.0, 153.3, 160.3.
11
Mp 80–81 °C; [a]D23 +9.1 (c = 1.00, CHCl3); for S >99.5% ee.
HRMS-ESI-TOF: m/z calcd for C24H20N2O2Na [M + Na]+:
391.1422; found: 391.1417.
IR (KBr): 3351, 2976, 1600, 1546, 1291, 1122, 1051, 879, 829
cm–1.
HPLC [racemate, Daicel Chiralpak AD, hexane–i-PrOH (19:1),
flow rate 1.0 mL/min]: dl isomer: tR 39.8 min (R,R), tR 54.1 min
(S,S), meso isomer: tR 72.8 min.
1H NMR (400 MHz, CDCl3): d = 0.92 (s, 9 H), 3.85 (s, 3 H), 4.26
(s, 1 H), 6.69 (d, 1 H, J = 2.2 Hz), 6.91 (d, 1 H, J = 2.2 Hz).
13C NMR (100 MHz, CDCl3): d = 25.9, 36.2, 55.7, 80.5, 108.9,
111.8, 141.2, 162.5, 166.5.
(S,S)-6,6¢-Bis(1-hydroxy-2,2-dimethylpropyl)-4,4¢-dimethoxy-
2,2¢-bipyridine (15)
Compound 15 was obtained using the procedure described for 1.
The desired product was obtained as a white solid (36% yield,
22
99.5% ee, >99.5% de); mp 186–188 °C; [a]D +21.1 (c = 1.00,
CHCl3); for S,S >99.5% ee, >99.5% de.
HRMS-ESI-TOF: m/z calcd for C11H17BrNO2 [M + H]+: 274.0443;
found: 274.0444; m/z calcd for C11H16BrNO2Na [M + Na]+:
296.0262; found: 296.0255.
Anal. Calcd for C11H16BrNO2: C, 48.19; H, 5.88; N, 5.11. Found: C,
48.26; H, 5.87; N, 5.15.
IR (KBr): 3464, 2960, 1580, 1464, 1321, 1044, 1017 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.97 (s, 18 H), 3.94 (s, 6 H), 4.34–
4.41 (m, 4 H), 6.73 (d, 2 H, J = 2.3 Hz), 7.85 (d, 2 H, J = 7.8 Hz).
HPLC [racemate, Daicel Chiralpak AD, hexane–i-PrOH (19:1),
flow rate, 1.0 mL/min]: tR 10.2 min (S), tR 15.0 min (R).
13C NMR (100 MHz, CDCl3): d = 26.0, 36.2, 55.3, 80.3, 105.7,
109.1, 155.3, 160.9, 166.4.
(S,S)-6,6¢-Bis(1-hydroxyethyl)-2,2¢-bipyridine (12)3b
MS (ESI-TOF): m/z = 389 [M + H]+
Compound 12 was obtained using the procedure described for 1.
The desired product was obtained as a white solid (79% yield,
27
>99.5% ee, >99.5% de); [a]D +31.1 (c = 1.68, CHCl3); for S,S
>99.5% ee, >99.5% de.
Anal. Calcd for C22H32N2O4: C, 68.01; H, 8.30; N, 7.21. Found: C,
67.76; H, 8.21; N, 7.18.
HPLC [racemate, Daicel Chiralcel OD, hexane–i-PrOH (19:1),
flow rate 1.0 mL/min] dl isomer: tR 67.7 min (S,S), tR 70.2 min
(R,R), meso isomer: tR 51.4 min.
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2182
S. Ishikawa et al.
PAPER
(7) (a) Chandrasekharan, J.; Ramachandran, P. V.; Brown, H. C.
J. Org. Chem. 1985, 50, 5446. (b) Brown, H. C.;
Chandrasekharan, J.; Ramachandran, P. V. J. Org. Chem.
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(8) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.;
Montanucci, M. Synthesis 1984, 736.
Acknowledgment
This work was partially supported by CREST, SORST, and ERA-
TO, Japan Science and Technology Agency (JST) and a Grant-in-
Aid for Scientific Research from Japan Society of the Promotion of
Science. T. H. thanks the JSPS for a fellowship for Japanese Junior
Scientists.
(9) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
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40.
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Synthesis 2005, No. 13, 2176–2182 © Thieme Stuttgart · New York