Preparation of new chiral pyridine-phosphine ligands and their Pd-catalyzed asymmetric allylic alkylations

Article abstract of DOI:10.1016/S0957-4166(01)00535-3

Enantiomerically pure 2-(diphenylphosphino)methyl-N-[1-(2-pyridinyl)ethyl] 1 and 2 have been prepared by the stereospecific substitution of enantiomerically pure 1-(2-pyridinyl)ethyl methanesulfonate 6 eith enantiomerically pure 2-(diphenylphosphino)methylpyrrolidine. Asymmetric allylic akylation of 1,3-diphenyl-2-propenyl acatate 11 with dimethyl malonate sodium salt using the (S,S)-ligand 1 affords the (R)-product 12 with up to 86% e.e. in good yield.

Full text of DOI:10.1016/S0957-4166(01)00535-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2999–3006
Preparation of new chiral pyridine–phosphine ligands and their
Pd-catalyzed asymmetric allylic alkylations
Jun’ichi Uenishi* and Masahiro Hamada
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
Received 24 October 2001; accepted 22 November 2001
Abstract—Enantiomerically pure 2-(diphenylphosphino)methyl-N-[1-(2-pyridinyl)ethyl]pyrrolidines 1 and 2 have been prepared by
the stereospecific substitution of enantiomerically pure 1-(2-pyridinyl)ethyl methanesulfonate 6 with enantiomerically pure
2-(diphenylphosphino)methylpyrrolidine. Asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate 11 with dimethyl
malonate sodium salt using the (S,S)-ligand 1 affords the (R)-product 12 with up to 86% e.e. in good yield. © 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
philes,7 which takes place stereospecifically with com-
plete inversion of the configuration, allowing the syn-
thesis of new homochiral pyridines bearing a variety of
functionalities, including amino, alkylamino, cyclic-
amino, azido, alkylsulfenyl, aryloxy, acyloxy and
acylthio groups at the stereogenic carbon.7,8 An exam-
ple for the coupling of chiral pyridine with pyrrolidine
is shown in Scheme 1. The enantiomerically pure (R)-1-
(2-pyridinyl)ethanol prepared by lipase-catalyzed
kinetic acetylation with vinyl acetate9 was mesylated
and reacted with pyrrolidine in DMSO at 60°C.
Chiral ligands are widely used for asymmetric reaction
in organic synthesis.1 To date, a large number of chiral
ligands have been prepared, and their usefulness for
asymmetric reactions has been investigated.2 Neverthe-
less, the search for new chiral ligands and catalysts is
continually increasing, since there is high demand for
new and efficient chiral ligands for application in tran-
sition metal-catalyzed asymmetric synthesis.3 A consid-
erable number of P,N-ligands having phosphine and
nitrogen functional moieties have been reported in the
past few years4–6 and, in connection with this, phos-
phine ligands bearing a pyridine ring are of particular
interest to us.6 We have developed a synthetic method
for chiral pyridine derivatives, and both enantiomeric
isomers for various pyridine derivatives are now avail-
able.7–9 We have extended our chiral pyridine synthesis
to phosphine-containing 1-(2-pyridinyl)ethylamine
derivatives. Herein, we describe the synthesis of new
chiral pyridine–phosphine ligands 1 and 2 (Fig. 1) and
their applications in asymmetric catalysis.
X
N
N
N
N
Y
Ph2P
1
1a'
a : X = H, Y=PPh2
b : X = Ph, Y=PPh2
c : X = 3,5-dimethylphenyl, Y=PPh2
d : X = 2,6-dimethylphenyl, Y=PPh2
e : X = H, Y=OCH3
2. Results and discussion
2.1. Preparation of P,N-ligands 1–3
N
N
N
We have reported the substitution reaction of chiral
1-(2-pyridinyl)ethyl methanesulfonate with nucleo-
Ph2P
Ph2P
3
2
* Corresponding author. Fax: +81-75-595-4763; e-mail: juenishi@
mb.kyoto-phu.ac.jp
Figure 1.
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00535-3

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J. Uenishi, M. Hamada / Tetrahedron: Asymmetry 12 (2001) 2999–3006
propylethylamine at 60°C, the reaction took 17 h to
i) MsCl, DMAP
CH2Cl2, rt
obtain the desired 1a in satisfactory yield. Since the
diastereoisomeric (2S,1%R)-isomer could not be detected
in the NMR spectrum of the crude products, it was
concluded that no isomerization occurred under the
reaction conditions (Scheme 4).
N
N
N
ii) pyrrolidine
DMSO, 60°C
OH
(ref. 7)
H
N
i-Pr2NEt
1a-e
+
Scheme 1.
6a-d
Y
MeCN
60 °C
For the synthesis of ligands 1–3 using the above reac-
tion, chiral pyridine and (diphenylphosphino)-
methylpyrrolidine fragments are required. According to
this synthetic analysis, mesylates 6a–d, which can be
derived from 1-(2-pyridinyl)ethanol 5a–d, will be used
as the chiral pyridine fragment. Therefore, we first
planned to prepare enantiomerically pure 5b–d. Suzuki
cross-coupling reaction of (R)-1-[2-(6-bromopyri-
dinyl)]ethanol (R)-49a with phenylboronic acid using
Pd(PPh3)4 as a catalyst in the presence of aq. Na2CO3
gave (R)-1-[2-(6-phenylpyridinyl)]ethanol 5b in 77%
yield. Similarly, 5c and 5d were produced from 3,5-
dimethylphenylboronic acid and 2,6-dimethylphenyl-
boronic acid in 69 and 97% yields, respectively.
Mesylation of 5a–d with methanesulfonyl chloride in
the presence of DMAP in CH2Cl2 gave the correspond-
ing mesylate 6a7 in 97%, 6b in 98%, 6c in 69% and 6d
in 97% yields, respectively (Schemes 2 and 3).
(S)-7 : Y = PPh2
8 : Y = OCH3
H
N
i-Pr2NEt
+
1a'
6a
Ph2P
MeCN
60 °C
(R)-7
Scheme 4.
In the same manner, the reaction of 6b–d with (S)-7
gave 1b–d proceeded in 91, 78 and 86% yields, respec-
tively. No diastereoisomeric products were observed in
these reactions. Methoxymethyl derivative 1e was
obtained by the coupling of 6a and (S)-prolinol methyl
ether 811 in 96% yield under the same reaction condi-
tions. Since no isomerization occurred during the sub-
stitution, all the ligands were assumed to be
enantiomerically pure.
ArB(OH)2
Pd(PPh3)4
Na2CO3
THF
Br
N
X
N
OH
(R)-4
OH
The diastereomer 1a% was independently prepared in
70% yield by the coupling of 6a with (R)-7, N-(2-
pyridinylmethyl)pyrrolidine 2 was also obtained in 68%
yield. Phenethyl ligands 3 and 3%, in which the pyridine
ring in 1a and its diastereoisomer was replaced with a
phenyl ring, were also synthesized (Scheme 5). Racemic
a-phenethylchloride was treated with (S)-7 in acetoni-
trile to give 3 in 37% yield and 3% in 34% yield after
5b-c
b : X = phenyl
c : X = 3,5-dimethylphenyl
d : X = 2,6-dimethylphenyl
Scheme 2.
MsCl
DMAP
5a-d
X
N
CH2Cl2
7S
OMs
i-Pr2NEt
6a-d
Cl
N
N
a : X = H
b : X = phenyl
c : X = 3,5-dimethylphenyl
d : X = 2,6-dimethylphenyl
N
MeCN
60 °C
Ph2P
9
2
Scheme 3.
7S
+
i-Pr2NEt
Initially, we conducted the coupling reaction of 6a with
(S)-2-(diphenylphosphino)methylpyrrolidine (S)-710 in
DMSO. Although the reaction was completed smoothly
over 6 h to give 1a (2S,1%S-isomer), isolation of 1a from
DMSO was troublesome. Cationic resin was required
for the purification. However, when acetonitrile was
employed for the reaction in the presence of N,N-diiso-
N
N
MeCN
rt
Br
Ph2P
Ph2P
10
3
3'
Scheme 5.

J. Uenishi, M. Hamada / Tetrahedron: Asymmetry 12 (2001) 2999–3006
3001
separation by HPLC. The relative stereochemistries of
3 and 3% are comparable to those for 1 possessing
(S,S)-configuration and 1a% possessing (S,R)-configura-
tion. Since the stereogenic center on the pyrrolidine ring
derived from (S)-7 intrinsically possesses (S)-configura-
tion, the absolute stereochemistries of 3 and 3% were
assigned as (S,S) and (R,S). In the proton NMR
spectra, both methyl and methine protons of
pyridinylethyl and phenethyl groups in the more polar
isomers 1a and 3 appear at lower field than those in the
less polar isomers 1a% and 3%. Thus, the methyl and
methine protons are observed at 1.33 and 3.98 ppm in
1a and 1.39 and 3.78 ppm in 3, respectively, whilst the
corresponding protons for 1a% and 3% resonate at higher
field (1.27 and 3.91 ppm for 1a% and 1.22 and 3.68 ppm
for 3%).
but poor selectivity (entry 6). Since this type of ligand
showed excellent chemical reactivity, the reaction was
carried out at low temperature. In fact, the reaction was
able to be conducted at −40°C for ligands 1b, 1c and
1d, giving (R)-products in good yields and increasing
the selectivity up to 84–86% e.e. (entries 7–9). Unex-
pectedly, phenethyl ligands 3, and 3% also showed good
selectivity. This result indicated that the pyridine ring
nitrogen is unnecessary for high selectivity (entries 11
and 12). Since a simple N-benzyl substituted 2-
(diphenylphosphino)methylpyrrolidine also worked well
in this asymmetric reaction,14 we concluded that an
N-substituent on the 1-(2-pyridinyl)ethyl group and a
1-arylethyl group on the pyrrolidine ring are important
for the asymmetric induction (Scheme 6).
2.3. Mechanistic considerations
2.2. Asymmetric allylic alkylation
The ligands 1a and 1a% possess three possible electron-
donor atoms for coordination with palladium. Initially,
we expected that the nitrogen atom of the pyridine ring
and the phosphorus atom of the phosphine unit would
be employed as electron-donors for the bidentate ligand
during the formation of the Pd complex (A in Fig. 2),
where the chiral pyrrolidine moiety might not only play
a role as a tether for connecting the pyridinyl and
phosphinyl units but also control the conformation of
the complex in cooperation with another stereogenic
center present in the pyridinylethyl unit. In fact, the
complex was well arranged to have a favorable confor-
mation for high asymmetric induction at least in the
molecular model. However, the fact that the nitrogen of
the pyridine ring is not essential for increasing the
enantioselectivity indicates that the pyrrolidine group is
more important, and also suggests that the Pd complex
Pd-catalyzed asymmetric allylic alkylation of 1,3-
diphenyl-2-propenyl acetate and a dialkyl malonate
sodium salt is an established and popular method for
testing the asymmetric induction ability of a chiral
ligand.12 Ligands 1–3 were applied in the Pd-catalyzed
asymmetric allylic alkylation, the results of which are
shown in Table 1. All of the ligands showed excellent
reactivity at 0°C. In comparison with the results for 1a
and 1a% (entries 1 and 2), the stereogenic center of the
pyridinylethyl group influenced the enantioselectivity.
(S,S)-Ligand 1a gave the (R)-isomer in 58% e.e., while
(R,S)-ligand 1a% gave the (S)-isomer with 26% e.e.13 It
is interesting that ligand 2 lacking a methyl group also
produces the (R)-isomer with similar e.e. (51%, entry
10) to that for 1a. This result indicated that the abso-
lute configuration of the product was controlled by the
chirality of the pyrrolidine moiety. The introduction of
an aryl group at C(6) of the pyridine ring increased the
selectivity up to 75–77% (entries 3–5). However, the
presence of methyl substituents on the aryl ring did not
influence the selectivity. The diphenylphosphine moiety
was found to be essential; ligand 1e, in which the
diphenylphosphinomethyl group was replaced with a
methoxymethyl group, gave the highest chemical yield
[PdCl(π-C3H5)]2
MeO2C
Ph
CO2Me
Ph
OAc
Ph
NaCH(CO2Me)2
Ph
Ligand, THF
11
12
Scheme 6.
Table 1. Pd-catalyzed asymmetric allylic alkylation
Entry
Ligand
Temp. (°C)
Time (h)
Yielda (%)
E.e.b (%)
Configurationc
1
2
3
4
5
6
7
8
1a
1a%
1b
1c
1d
1e
1b
1c
1d
2
0
0
0
0
0
3
3
3
3
3
18
40
40
40
3
81
85
68
72
79
94
79
72
74
93
75
58
58
26
76
77
75
6
84
84
86
51
73
60
R
S
R
R
R
S
R
R
R
R
R
R
0–rt
−40
−40
−40
0
9
10
11
12
3
3%
0
0
3
3
a Isolated yields.
b Determined by HPLC using a chiral column.
c Determined by optical rotation.

3002
J. Uenishi, M. Hamada / Tetrahedron: Asymmetry 12 (2001) 2999–3006
pyridinyl and methyl groups can take positions with no
severe steric congestion. On the other hand, when the
corresponding hydrogen of the (R)-stereogenic center
derived from 1a% occupies the same front side, steric
interactions between the methyl groups and the methyl-
ene hydrogens at C(2) of the pyrrolidine ring are
inevitable. The electron donating property of a nitrogen
atom on the pyridine ring may weakly influence the Pd
center or p-allyl acceptor but surely destabilizes the
intermediate. This undesirable effect at the pyridine
ring leads to decreased enantioselectivity. The aryl
group with or without methyl substituents, located at
the 6-position on the pyridine ring, might interfere with
the nitrogen atom of the pyridine ring close to the Pd
center or p-allyl acceptor.
Me
*
N
N
*
Me
Pd
N
Pd
P
N
*
P
*
A
B
Figure 2.
shown as B in Fig. 2 is formed with bonding via the
nitrogen atom of the pyrrolidine and not the pyridine
ring nitrogen.
3. Conclusion
Based on the experimental results, we considered the
reaction mechanism of the Pd-catalyzed allylic alkyla-
tion. Plausible transition-state structures of the P,N-lig-
and–Pd–p-allyl complexes are shown in Fig. 3 (1a and
1a% are used for the ligand). Each intermediate is able to
adopt two preferred conformations, showing as ‘M-ori-
entation’ in M-form and ‘W-orientation’ in W-form of
the p-allyl groups. Since the W-form is assumed to have
greater steric interference between the phenyl group
and C(5) methylene group on the pyrrolidine ring, the
M-form would be preferred. In addition, nucleophiles
usually have favored attacking on the terminal p-allylic
carbon located trans to the phosphorous donor,
because it is a better p-acceptor carbon in the case of
the P,N-ligand.15 Therefore, when 1a was used, an
(R)-product would be expected to be formed through
the M-form intermediate I by nucleophilic attack of
malonate at the position indicated by the arrow. In
fact, the (R)-isomer was produced selectively. When a
hydrogen of the (S)-stereogenic center in the pyridinyl-
ethyl unit is placed on the front side of I, both the
Several homochiral P,N-ligands 1 having chiral (2-
pyridinyl)ethyl
and
2-(diphenylphosphino)methyl-
pyrrolidinyl moieties have been newly synthesized in
enantiomerically pure form in good yields. Pd-catalyzed
asymmetric allylic alkylation using ligands 1 proceeded
even at low temperature (where the level of asymmetric
induction increases) to give the allylated products with
up to 86% e.e.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a JEOL
LA-300 apparatus at 300 and 75.5 MHz, respectively.
Mass spectra were obtained on a JEOL-SX 102A
instrument. IR spectra were recorded on a JASCO
FT/IR-410 spectrometer. Optical rotations were mea-
S
S
P
Me
S
N
P
N
Pd
N
Pd
H
H
R
H
H
N
Ph
Me
Ph
Ph
Ph
R
R
I ; M-form (derived from 1a)
II ; M-form (derived from 1a')
S
S
P
Ph
N
P
Me
N
Ph
N
Pd
Pd
H
Ph
H
R
S
Ph
H
H
Me
N
S
S
I' ; W-form (derived from 1a)
II' ; W-form (derived from 1a')
Figure 3.

J. Uenishi, M. Hamada / Tetrahedron: Asymmetry 12 (2001) 2999–3006
3003
sured on a JASCO DIP-360 instrument. Thin-layer
chromatography (TLC) was performed by using Merck
60F254 precoated with silica gel on glass plate. Silica gel
(Merck 60F254 230–400 mesh) was used for flash
chromatography.
4.2.3.
(2S)-N-[(1S)-1-[2-[6-(3,5-Dimethylphenyl)pyri-
dinyl]]ethyl]-2-(diphenylphosphino)methylpyrrolidine 1c.
Reaction time 30 h; solvent for chromatography, 30%
EtOAc in hexane. Yield 78%; oil; Rf=0.15 (30% EtOAc
in hexane); [h]D24=−153 (c 0.9, CHCl3); IR (neat) wmax
:
3055, 3014, 2958, 2927, 1446 cm−1; 1H NMR (300
MHz): l 1.45 (d, J=7.0 Hz, 3H), 1.53–1.89 (m, 5H),
2.36 (s, 6H), 2.68–2.88 (m, 3H), 2.93–3.00 (m, 1H), 4.12
(q, J=7.0 Hz, 1H), 6.90 (quint, J=4.4 Hz, 1H), 7.02 (s,
1H), 7.11–7.32 (m, 8H), 7.42 (td, J=7.3 and 2.2 Hz,
2H), 7.52 (d, J=1.1 Hz, 1H), 7.53 (s, 1H), 7.60 (s, 2H);
13C NMR (75 MHz): l 20.6 (CH3), 21.4 (2C, Ar-CH3),
22.5 (C-4), 31.3 (d, J=10.0 Hz, C-3), 32.6 (d, J=13.7
Hz, C-6), 47.9 (C-5), 57.4 (d, J=17.4 Hz, C-2), 60.0
(CH), 118.5, 120.6, 124.8 (2C), 128.3 (d, J=6.2 Hz,
4C), 128.3, 128.5, 130.4 (2C), 132.6 (d, J=18.7 Hz, 2C),
133.1 (d, J=18.7 Hz, 2C), 136.4, 138.1, 138.4 (d, J=
13.7 Hz), 139.6, 139.7 (d, J=11.2 Hz), 156.4, 162.0; MS
(EI) m/z 478 (M+); HRMS (EI) m/z calcd for
C32H35N2P 478.2538, found 478.2540 (M+).
4.2. General method for the substitution reaction of
mesylate 6 with pyrrolidines
A carefully degassed mixture of mesylate 6a–d (0.5
mmol), pyrrolidine 7 or 8 (0.5–1.0 mmol, depending on
the economic value of the mesylate and pyrrolidine)
and N,N-diisopropylethylamine (2 mmol) in acetoni-
trile (2 ml) was heated at 60°C under an argon atmo-
sphere. After the reaction completed, the heating bath
was removed and the solvent was evaporated under
reduced pressure. Chloroform was added and the mix-
ture was washed with water and brine. The organic
layer was dried over MgSO4 and condensed. The resid-
ual oil was purified by flash column chromatography
on silica gel to give 1a–e and 1%a. Yields, physical and
spectroscopic data together with reaction time and sol-
vents used for column chromatography follow.
4.2.4.
(2S)-N-[(1S)-1-[2-[6-(2,6-Dimethylphenyl)pyri-
4.2.1. (2S)-2-(Diphenylphosphino)methyl-N-[(1S)-1-(2-
pyridinyl)ethyl]pyrrolidine 1a. Reaction time 17 h; sol-
vent for chromatography, 50% EtOAc in hexane. Yield
67%; oil; Rf=0.45 (2% Et3N in EtOAc); [h]2D4=−175 (c
2.1, CHCl3); IR (neat): wmax 3053, 2968, 2871, 1433
dinyl]]ethyl]-2-(diphenylphosphino)methylpyrrolidine 1d.
Reaction time 20 h; solvent for chromatography, 30%
EtOAc in hexane. Yield 86%; oil; Rf=0.15 (30% EtOAc
in hexane); [h]D24=−156 (c 1.9, CHCl3); IR (neat) wmax
:
3055, 3014, 2958, 2927, 1454 cm−1; 1H NMR (300
MHz): l 1.38 (d, J=7.0 Hz, 3H), 1.51–1.93 (m, 4H),
1.97 (s, 6H), 2.00–2.19 (m, 1H), 2.54 (dt, J=13.2 and
3.7 Hz, 1H), 2.74–2.84 (m, 1H), 2.85–2.97 (m, 2H), 4.01
(q, J=7.0 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H), 7.02 (d,
J=7.7 Hz, 1H), 7.06 (d, J=7.3 Hz, 2H), 7.13–7.38 (m,
9H), 7.39–7.44 (m, 2H), 7.57 (t, J=7.7 Hz, 1H); 13C
NMR (75 MHz): l 20.2 (2C, Ar-CH3), 21.1 (CH3), 22.8
(C-4), 31.4 (d, J=10.0 Hz, C-3), 33.5 (d, J=13.7 Hz,
C-6), 49.0 (C-5), 57.7 (d, J=18.7 Hz, C-2), 61.0 (CH),
120.1, 122.4, 127.4 (2C), 127.6, 128.2 (4C), 128.3, 128.5,
132.5 (d, J=17.4 Hz, 2C), 133.1 (d, J=18.7 Hz, 2C),
135.7, 136.2 (2C), 138.6 (d, J=13.7 Hz), 139.4 (d,
J=12.5 Hz), 140.8, 158.9, 162.6; MS (EI) m/z 478
(M+); HRMS (EI) m/z calcd for C32H35N2P 478.2538,
found 478.2531 (M+).
1
cm−1; H NMR (300 MHz): l 1.39 (d, J=6.6 Hz, 3H),
1.55–1.66 (m, 1H), 1.70–1.95 (m, 4H), 2.58–2.76 (m,
3H), 2.90–3.00 (br, 1H), 4.00 (q, J=6.6 Hz, 1H), 6.96
(d, J=7.7 Hz, 1H), 7.09 (ddd, J=7.3, 4.8 and 1.1 Hz,
1H), 7.23–7.40 (m, 10H), 7.48 (td, J=7.7 and 1.8 Hz,
1H), 8.50 (ddd, 4.8, 1.8 and 1.1 Hz, 1H); 13C NMR (75
MHz): l 20.3 (CH3), 22.5 (C-4), 31.2 (d, J=8.6 Hz,
C-3), 32.6 (br d, C-6), 48.5 (C-5), 57.5 (d, J=18.5 Hz,
C-2), 60.3 (CH), 121.9, 122.6, 128.3 (4C), 128.4, 128.7,
132.4 (d, J=17.3 Hz, 2C), 133.3, (d, J=19.8 Hz, 2C),
136.0, 138.1 (d, J=16.1 Hz), 139.4, 148.9, 163.2; MS
(EI) m/z 374 (M+); HRMS (EI) m/z calcd for
C24H27N2P 374.1912, found 374.1918 (M+).
4.2.2. (2S)-2-(Diphenylphosphino)methyl-N-[(1S)-1-[2-
(6-phenylpyridinyl)]ethyl]pyrrolidine 1b. Reaction time
24 h; solvent for chromatography, 30% EtOAc in hex-
ane. Yield 91%; oil; Rf=0.26 (40% EtOAc in hexane);
[h]2D4=−178 (c 2.0, CHCl3); IR (neat) wmax: 3057, 3012,
4.2.5.
(2S)-2-Methoxymethyl-N-[(1S)-1-(2-pyridinyl)-
1
2970, 2873, 1444 cm−1; H NMR (300 MHz): l 1.46 (d,
ethyl]pyrrolidine 1e. Reaction time 10 h; solvent for
chromatography, 80% EtOAc in hexane. Yield 96%;
oil; Rf=0.17 (2% Et3N in EtOAc); [h]2D5=−85 (c 1.3,
CHCl3); IR (neat) wmax: 2970, 2873, 1589, 1471 cm−1; 1H
NMR (300 MHz): l 1.48 (d, J=6.8 Hz, 3H), 1.55–1.85
(m, 4H), 2.45–2.55 (m, 1H), 2.82–2.90 (m, 1H), 2.97–
3.03 (m, 1H), 3.23 (dd, J=9.4 and 7.9 Hz, 1H), 3.34 (s,
3H), 3.39 (dd, J=9.4 and 4.2 Hz, 1H), 3.98 (q, J=6.8
Hz, 1H), 7.13 (ddd, J=7.5, 4.8 and, 1.1 Hz, 1H), 7.32
(d, J=7.7 Hz, 1H), 7.63 (td, J=7.7 and 1.8 Hz, 1H),
8.55 (dt, J=4.8 and 1.8 Hz, 1H); 13C NMR (75 MHz):
l 20.8 (CH3), 23.4 (C-4), 28.8 (C-3), 51.2 (C-5), 59.0
(-OCH3), 59.0 (C-6), 63.2 (CH), 76.8 (C-2), 121.8,
122.4, 136.0, 148.9, 163.3; MS (FAB) m/z 221 (M++H);
HRMS (FAB) m/z calcd for C13H21N2O 221.1654,
found 221.1662 (M++H).
J=7.0 Hz, 3H), 1.52–1.66 (m, 1H), 1.66–1.88 (m, 3H),
2.04 (td, J=12.5 and 2.6 Hz, 1H), 2.72 (dq, J=11.0
and 3.3 Hz, 2H), 2.80–2.90 (m, 1H), 2.95–3.05 (m, 1H),
4.13 (q, J=7.0 Hz, 1H), 6.87 (dd, J=7.6 and 1.8 Hz,
1H), 7.10–7.25 (m, 3H), 7.27–7.35 (m, 5H), 7.36–7.50
(m, 5H), 7.51–7.60 (m, 2H), 8.00 (dd, 8.1 and 1.5 Hz,
2H); 13C NMR (75 MHz): l 20.3 (CH3), 22.4 (C-4),
31.3 (d, J=8.7 Hz, C-3), 32.7 (d, J=13.7 Hz, C-6), 47.7
(C-5), 57.4 (d, J=18.7 Hz, C-2), 59.6 (CH), 118.2,
120.8, 126.8, 128.3 (d, J=6.2 Hz, 4C), 128.5, 128.6
(4C), 128.7, 132.5 (d, J=18.7 Hz, 2C), 133.1 (d, J=19.9
Hz, 2C), 136.5, 138.5 (d, J=13.7 Hz), 139.5, 139.6 (d,
J=12.5 Hz), 155.9, 161.8; MS (EI) m/z 450 (M+);
HRMS (EI) m/z calcd for C30H31N2P 450.2225, found
450.2231 (M+).

3004
J. Uenishi, M. Hamada / Tetrahedron: Asymmetry 12 (2001) 2999–3006
4.2.6. (2R)-2-(Diphenylphosphino)methyl-N-[(1S)-1-(2-
pyridinyl)ethyl]pyrrolidine 1a%. Reaction time 8 h; sol-
vent for chromatography, 60% EtOAc in hexane. Yield
70%; oil; Rf=0.47 (2% Et3N in EtOAc); [h]2D6=+66 (c
1.3, CHCl3); IR (neat) wmax: 3051, 2966, 2871, 1433
Hz, 1H), 4.94 (qd, J=6.3 and 4.6 Hz, 1H), 7.11–7.15
(m, 3H), 7.20 (d, J=6.6 Hz, 1H), 7.23 (d, J=6.6 Hz,
1H), 7.76 (t, J=7.8 Hz, 1H); 13C NMR (75 MHz): l
20.2 (2C, Ar-CH3), 24.5 (CH3), 68.8 (CH), 117.6,
123.0, 127.6 (2C), 128.0, 135.8, 137.0 (2C), 140.2, 158.2,
162.9; MS (EI) m/z 227 (M+); HRMS (EI) m/z calcd
for C15H17NO 227.1310, found 227.1305 (M+).
1
cm−1; H NMR (300 MHz): l 1.27 (d, J=6.6 Hz, 3H),
1.60–1.83 (m, 3H), 1.85–2.00 (m, 2H), 2.24 (dt, J=9.2
and 4.0 Hz, 1H), 2.53 (q, J=7.7 Hz, 1H) 2.75–3.00 (br,
2H), 3.91 (q, J=6.6 Hz, 1H), 7.09 (ddd, J=7.3, 5.1 and
1.1 Hz, 1H), 7.24–7.40 (m, 11H), 7.56 (td, J=7.7 and
1.8 Hz, 1H), 8.50 (ddd, 4.8, 1.8 and 1.1 Hz, 1H); 13C
NMR (75 MHz): l 16.5 (CH3), 22.9 (C-4), 31.2 (d,
J=8.7 Hz, C-3), 33.5 (d, J=13.7 Hz, C-6), 49.2 (C-5),
58.9 (d, J=15.9 Hz, C-2), 61.6 (CH), 121.8, 122.3,
128.3 (4C), 128.4, 128.6, 132.4 (d, J=18.6 Hz, 2C),
133.1 (d, J=18.5 Hz, 2C), 136.2, 138.4 (d, J=13.6 Hz),
139.3 (d, J=12.4 Hz), 148.8, 164.2; MS (EI) m/z 374
(M+); HRMS (EI) m/z calcd for C24H27N2P 374.1912,
found 374.1915 (M+).
4.4. Mesylation of 5
To a solution of 1-(2-pyridinyl)ethanol 5 (0.50 mmol),
Et3N (4.0 mmol) and DMAP (0.15 mmol) in CH2Cl2 (5
ml) was added MsCl (1.5 mmol) at 0°C. The mixture
was stirred for 30 min at the same temperature. Then,
water and EtOAc were added. The organic layer was
separated and washed with water and brine and dried
over MgSO4. After the solvent was removed, the
residue was purified by flash column chromatography
on silica gel to give 6b–d. Yields, physical and spectro-
scopic data together with solvents used for column
chromatography follow.
4.3. Preparation of 6-aryl substituted 1-(2-pyridinyl)-
ethanol 5b–d
4.4.1. (R)-1-[2-(6-Phenylpyridinyl)]ethyl methanesul-
fonate 6b. Solvent for chromatography 15% EtOAc in
hexane. Yield 98%; oil; Rf=0.49 (20% EtOAc in hex-
ane); [h]2D4=+62 (c 1.8, CHCl3); IR (neat) wmax: 2987,
To a mixture of 1-[2-(6-bromopyridinyl)]ethanol 4R
(0.5 mmol), arylboronic acid (2.0 mmol) in THF (20
ml), were added Pd(PPh3)4 (0.025 mmol) and Na2CO3
(2.5 ml, 2.0 M aq. solution). The mixture was degassed
and heated under reflux for 8 h for phenylboronic acid,
24 h for 3,5-dimethylphenylboronic acid and 50 h for
2,6-dimethylphenylboronic acid. After cooling, the sol-
vent was evaporated. EtOAc was added and washed
with aq. NaHCO3, water, brine and dried over MgSO4.
Solvent was removed and the residue was purified by
flash column chromatography on silica gel. Yields,
physical and spectroscopic data together with reaction
time and solvents used for column chromatography
follow.
1
2937, 1972, 1733 cm−1; H NMR (300 MHz): l 1.84 (d,
J=6.6 Hz, 3H), 2.95 (s, 3H), 5.87 (q, J=6.6 Hz, 1H),
7.40–7.51 (m, 4H), 7.72 (d, J=7.7 Hz, 1H), 7.81 (t,
J=7.7 Hz, 1H) 8.01–8.05 (m, 2H); 13C NMR (75
MHz): l 21.7 (CH3), 38.8 (SO2-CH3), 81.1 (CH), 118.9,
120.0, 126.9 (2C), 128.8 (2C), 129.3, 137.9, 138.6, 156.9,
158.0; MS (EI) m/z 277 (M+); HRMS (EI) m/z calcd
for C14H15NO3S 277.0772, found 277.0773 (M+).
4.4.2.
(R)-1-[2-[6-(3,5-Dimethylphenyl)pyridinyl]]ethyl
methanesulfonate 6c. Solvent for chromatography 5%
Et2O in benzene. Yield 91%; oil; Rf=0.49 (10% Et2O in
4.3.1. (R)-1-[2-(6-Phenylpyridinyl)]ethanol 5b. Reaction
time 8 h; solvent for chromatography, 10% Et2O in
benzene. Yield 84%. Physical and spectroscopic data
was reported.9a
benzene); [h]D24=+25 (c 1.9, CHCl3); IR (neat) wmax
:
2985, 2937, 1734 cm−1; H NMR (300 MHz): l 1.83 (d,
J=6.6 Hz, 3H), 2.40 (s, 6H), 2.94 (s, 3H), 5.86 (q,
J=6.6 Hz, 1H), 7.07 (s, 1H), 7.39 (dd, J=7.3 and 1.1
Hz, 1H), 7.61 (s, 2H), 7.68 (dd, J=7.3 and 1.1 Hz, 1H),
7.79 (t, J=7.7 Hz, 1H); 13C NMR (75 MHz): l 21.4
(CH3), 21.8 (2C, Ar-CH3), 38.7 (SO2-CH3), 81.3 (CH),
118.7, 120.2, 124.8 (2C), 130.9 (2C), 137.7, 138.3, 138.7,
157.3, 158.0; MS (EI) m/z 305 (M+); HRMS (EI) m/z
calcd for C16H19NO3S 305.1085, found 305.1081 (M+).
1
4.3.2. (R)-1-[2-[6-(3,5-Dimethylphenyl)pyridinyl]]ethanol
5c. Reaction time 24 h; solvent for chromatography
15% EtOAc in hexane. Yield 69%; oil; Rf=0.27 (20%
EtOAc in hexane); [h]D24=−21 (c 2.2, CHCl3); IR (neat)
1
wmax: 3400, 2974, 2920 cm−1; H NMR (300 MHz): l
1.55 (d, J=6.2 Hz, 3H), 2.40 (s, 6H), 4.85 (br, 1H), 4.94
(br q, J=6.2 Hz, 1H), 7.07 (br s, 1H), 7.17 (d, J=7.3
Hz, 1H), 7.61 (d, J=7.3 Hz, 1H), 7.62 (s, 2H), 7.73 (t,
J=7.7 Hz, 1H); 13C NMR (75 MHz): l 21.4 (CH3),
24.4 (2C, Ar-CH3), 68.5 (CH), 118.0, 119.0, 124.8 (2C),
130.8 (2C), 137.5, 138.3, 138.7, 155.9, 162.3; MS (EI)
m/z 227 (M+); HRMS (EI) m/z calcd for C15H17NO
227.1310, found 227.1307 (M+).
4.4.3.
(R)-1-[2-[6-(2,6-Dimethylphenyl)pyridinyl]]ethyl
methanesulfonate 6d. Solvent for chromatography 10%
Et2O in benzene. Yield 92%; oil; Rf=0.44 (10% Et2O in
benzene); [h]D25=+53 (c 1.1, CHCl3); IR (neat) wmax
:
3026, 2983, 1587 cm−1; H NMR (300 MHz): l 1.78 (d,
J=6.6 Hz, 3H), 2.03 (s, 6H), 2.96 (s, 3H), 5.84 (q,
J=6.6 Hz, 1H), 7.11 (d, J=7.3 Hz, 2H), 7.12–7.23 (m,
2H), 7.45 (d, J=7.6 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H);
13C NMR (75 MHz): l 20.2 (2C, Ar-CH3), 22.0 (CH3),
38.6 (SO2-CH3), 80.8 (CH), 118.4, 124.3, 127.7 (2C),
128.1, 135.6, 137.4 (2C), 139.9, 158.4, 159.6; MS (EI)
m/z 305 (M+); HRMS (EI) m/z calcd for C16H19NO3S
305.1085, found 305.1088 (M+).
1
4.3.3. (R)-1-[2-[6-(2,6-Dimethylphenyl)pyridinyl]]ethanol
5d. Reaction time 50 h; solvent for chromatography
20% EtOAc in hexane. Yield 97%; oil; Rf=0.10 (10%
Et2O in benzene); [h]D24=−5 (c 0.9, CHCl3); IR (neat)
1
wmax: 3388, 2972, 2924 cm−1; H NMR (300 MHz): l
1.53 (d, J=6.3 Hz, 3H), 2.05 (s, 6H), 4.36 (d, J=4.6

J. Uenishi, M. Hamada / Tetrahedron: Asymmetry 12 (2001) 2999–3006
3005
4.5. (S)-2-(Diphenylphosphino)methyl-N-(2-pyridinyl)-
C-3), 33.9 (d, J=13.7 Hz, C-6), 50.0 (C-5), 58.9 (d,
J=18.7 Hz, C-2), 60.6 (CH), 126.7, 127.7 (2C), 128.2
(4C), 128.3 (2C), 128.4, 128.5, 132.4 (d, J=18.7 Hz,
2C), 133.1 (d, J=18.7 Hz, 2C), 138.3 (d, J=13.7 Hz),
139.4 (d, J=12.5 Hz), 145.3; MS (EI) m/z 373 (M+);
HRMS (EI) m/z calcd for C25H28NP 373.1959, found
373.1954 (M+).
methylpyrrolidine 2
A solution of 2-pyridinylmethyl chloride hydrochloride
9 (61 mg, 0.37 mmol) and (S)-7 (50 mg, 0.18 mmol) in
i
a mixture of Pr2NEt and acetonitrile (1:2, 1.2 ml) was
degassed and heated at 60°C for 6 h under an Ar
atmosphere. After cooling, the mixture was concen-
trated, and CHCl3 was added. The resulting solution
was washed with water and brine, dried over Na2SO4.
The solvent was removed and the residue was purified
by flash column chromatography on silica gel eluted
with EtOAc to give 2 (44 mg, 68%). Oil; Rf=0.51 (5%
Et3N in EtOAc); [h]2D4=−115 (c 1.65, CHCl3); IR (neat)
wmax: 3055, 2962, 2873, 1435 cm−1; 1H NMR (300
MHz): l 1.60–1.85 (m, 3H), 1.95–2.26 (m, 3H), 2.50–
2.65 (m, 2H), 2.97 (br t, J=7.7 Hz, 1H), 3.37 (d,
J=13.6 Hz, 1H), 4.14 (d, J=13.6 Hz, 1H), 7.11 (dd,
J=7.3 and 5.1 Hz, 1H), 7.25–7.35 (m, 7H), 7.36–7.50
(m, 4H), 7.57 (td, J=7.7 and 1.8 Hz, 1H), 8.51 (ddm,
J=4.0 and 0.7 Hz, 1H); 13C NMR (75 MHz): l 22.2
(C-4), 31.6 (d, J=7.5 Hz, C-3), 33.7 (d, J=13.7 Hz,
C-6), 54.0 (C-5), 59.9 (CH2), 62.0 (d, J=18.7 Hz, C-2),
121.7, 123.0, 128.3 (d, J=7.5 Hz, 4C), 128.4, 128.7,
132.5 (d, J=18.7 Hz, 2C), 133.0 (d, J=19.9 Hz, 2C),
136.2, 138.4 (d, J=13.7 Hz), 139.3 (d, J=12.5 Hz),
149.0, 159.5; MS (EI) m/z 360 (M+); HRMS (EI) m/z
calcd for C23H25N2P 360.1755, found 360.1759 (M+).
4.7. Palladium-catalyzed allylic alkylation
A mixture of ligand 1, 2, or 3 (0.06 mmol) and [PdCl(p-
C3H5)]2 (10.0 mg, 0.02 mmol) was stirred in THF (1 ml)
for 15 min at room temperature. Then, 1,3-diphenyl-2-
propenyl acetate 11 (134 mg, 0.54 mmol) in THF (1 ml)
was added to the mixture, and stirred for 30 min. The
mixture was added to a solution of dimethyl malonate
sodium salt (0.25 M in THF, 1.08 mmol) in THF (4
ml). After the starting material was consumed by tlc
analysis, benzene and 10% aq. HCl were added, and the
mixture was heated under reflux for 1 h. The aqueous
layer was re-extracted with Et2O. All the organic
extracts were combined, washed with saturated aq.
NaHCO3, water and brine and dried over Na2SO4.
After the solvent was removed, the residue was purified
by flash column chromatography on silica gel eluted
with 10% EtOAc in hexane to give 12 as an oil. The
absolute configuration of 12 was determined by com-
parison of its chiroptical value with that of the reported
data.13 The e.e. value was determined by HPLC analy-
sis attached with an optically active column (Daicel
OJ).
4.6. (2S)-2-(Diphenylphosphino)methyl-N-[(1S)-1-
phenylethyl]pyrrolidine 3 and its diastereoisomer 3%
A solution of 1-(phenyl)ethyl bromide 10 (100 mg, 0.37
mmol) and (S)-7 (137 mg, 0.74 mmol) in a mixture of
iPr2NEt and acetonitrile (1:3, 1.2 ml) was degassed and
stirred for 6 h at room temperature. After the same
work up as described for 2, a mixture of 3 and 3% (116
mg) was obtained in 84% yield. The mixture was sepa-
rated by HPLC. Polar diastereomer 3; (51 mg, 37%);
oil; Rf=0.23 (30% EtOAc in hexane); [h]2D5=−173 (c
0.9, CHCl3); IR (neat) wmax: 3055, 2966, 2873, 1585
Acknowledgements
The authors are grateful to Professor Y. Ito for his
encouragement and valuable discussions. This work
was financially supported by the Grant-in-Aid for Sci-
entific Research on Priority Areas (A) from the Min-
istry of Education, Science, Sports and Culture, Japan,
and a Special Grant for Cooperative Research adminis-
tered by the Japan Private School Promotion
Foundation.
1
cm−1; H NMR (300 MHz): l 1.33 (d, J=6.8 Hz, 3H),
1.53–1.63 (m, 1H), 1.70–1.90 (m, 3H), 1.94–2.05 (m,
1H), 2.36–2.46 (m, 1H), 2.54 (ddd, J=13.0, 4.8 and 2.9
Hz, 1H), 2.60–2.70 (m, 1H), 2.80–2.90 (m, 1H), 3.78 (q,
J=6.8 Hz, 1H), 7.00 (dd, J=6.6 and 2.4 Hz, 2H),
7.17–7.21 (m, 3H), 7.23–7.38 (m, 8H), 7.39–7.44 (m,
2H); 13C NMR (75 MHz): l 21.6 (CH3), 22.5 (C-4),
31.2 (d, J=8.7 Hz, C-3), 33.5 (d, J=13.7 Hz, C-6), 48.4
(C-5), 57.0 (d, J=19.8 Hz, C-2), 58.8 (CH), 126.8,
128.1 (d, J=8.7 Hz, 2C), 128.2 (d, J=10.0 Hz, 2C),
128.3, 128.4 (2C), 128.5, 128.7 (2C), 132.4 (d, J=17.4
Hz, 2C), 133.4 (d, J=19.9 Hz, 2C), 138.4 (d, J=14.9
Hz), 139.5 (d, J=13.1 Hz), 141.6; MS (EI) m/z 373
(M+); HRMS (EI) m/z calcd for C25H28NP 373.1959,
found 373.1958 (M+). Less polar diastereomer 3%; (47
mg, 34%); oil; Rf=0.23 (30% EtOAc in hexane); [h]2D5=
−81 (c 0.8, CHCl3); IR (neat) wmax: 3055, 2966, 2873,
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