Regioselective introduction of electrophiles into piperidine derivatives at the 4-position

Article abstract of DOI:10.3987/COM-08-S(N)26

Regioselective introduction of various electrophiles (aldehydes, ketones, and imines) into piperidine skeleton at the 4-position was achieved with a catalytic amount of Pd(OAc)₂/PPh₃ in the presence of excess Et₂Zn. In add

Full text of DOI:10.3987/COM-08-S(N)26

HETEROCYCLES, Vol. 76, No. 1, 2008
177
HETEROCYCLES, Vol. 76, No. 1, 2008, pp. 177 - 182. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd March, 2008, Accepted, 14th April, 2008, Published online,17th April, 2008. COM-08-S(N)26
REGIOSELECTIVE INTRODUCTION OF ELECTROPHILES INTO
PIPERIDINE DERIVATIVES AT THE 4-POSITION†
Osamu Onomura,* Noriyuki Fujimura, Takahisa Oda, Yoshihiro
Matsumura, and Yosuke Demizu
Department of Pharmaceutical Sciences, Graduate School of Biomedical
Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
Abstract – Regioselective introduction of various electrophiles (aldehydes,
ketones, and imines) into piperidine skeleton at the 4-position was achieved with
a catalytic amount of Pd(OAc)2/PPh3 in the presence of excess Et2Zn. In addition,
enantioselective introduction of benzaldehyde into piperidine derivatives was
accomplished by using chiral phosphine ligand with moderate enantioselectivity.
Piperidines possessing substituents at the 4-position are useful synthetic intermediates for a variety of
natural products and drug candidates.1 Accordingly, it is worthwhile to develop convenient methods for
introduction of substituents at the 4-position of piperidine skeleton. Although some methods for the
nucleophilic substitution are known,2 the electrophilic substitution has not been reported to date. We wish
to report herein regioselective introduction of various electrophiles (aldehydes, ketones, and imines) into
piperidine derivatives at the 4-position. Our strategy for generation of nucleophilic species from
piperidine derivatives is shown in Scheme 1. First, electrochemical preparation of
N-protected 2,3-didehydro-4-acetoxypiperidine 2, followed by generation of π-allyl palladium 3 from 2
by Pd(OAc)2/PPh3 and then, successive umpolung of 3 mediated by Et2Zn.3
Scheme 1
OAc
El
Pd
OAc
-2e
Pd(0)
Et2Zn
El
N
N
N
N
PG
PG
PG
PG
4
1
2
3

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HETEROCYCLES, Vol. 76, No. 1, 2008
Compounds 2 were prepared as follows (Eq. 1). Electrochemical oxidation of N-protected piperidines 1
afforded 2-methoxypiperidines 5. Subsequent removal of methanol from 5, followed by
bromomethoxylation and dehydrobromination gave N-protected 2-methoxy-3,4-didehydropiperidines 6,4
which were treated with AcOH to afford compounds 2 quantitatively.
OAc
-2e
1) NH4Cl, ∆
AcOH
(1)
N
N
OMe
N
OMe
N
in MeOH
2) Br2, NaOMe
3) DBU, DMF
PG
1
PG
5
PG
6
PG
2
With N-benzoyl-2,3-didehydro-4-acetoxypiperidine (2a)5 in hand, we first examined the reaction of 2a
with benzaldehyde using a catalytic amount of Pd(OAc)2/PPh3 in the presence of excess Et2Zn in toluene
(Eq. 2).6 The reaction proceeded smoothly within 2 h to afford 4-substituted piperidine 4a as a major
product in 81% and 2-substituted 7a as a minor product in 11% yields.
HO
Ph
OAc
N
PhCHO (1.5 equiv)
Pd(OAc)2 (0.05 equiv)
PPh3 (0.05 equiv)
Et2Zn (4.0 equiv)
Ph
OH
N
+
N
(2)
O
O
O
4a, 81%
toluene
rt, 2 h
7a, 11%
2a
In order to improve the regioselectivity, we screened a variety of N-protecting groups of 2 shown in Table
1 (Eq. 3). p-Chlorobenzoylated piperidine 2b or p-trifluoromethylbenzoylated 2c mainly afforded
4-substituted piperidine 4b or 4c along with some amount of 2-substituted 7b or 7c, respectively (entries
1 and 2). However the reaction of p-nitrobenzoylated one (2d) with benzaldehyde did not proceed at all
(entry 3). On the other hand, compound 2e protected with p-methoxybenzoyl group gave exclusively
4-substituted piperidine 4e in excellent yield (entry 4), and 2f protected with methoxycarbonyl group also
gave 4-substituted 4f in moderate yield (entry 5).
HO
Ph
OAc
PhCHO (1.5 equiv)
Pd(OAc)2 (0.05 equiv)
PPh3 (0.05 equiv)
Et2Zn (4.0 equiv)
Ph
OH
N
+
N
R
N
(3)
O
R
toluene
rt, 2 h
O
O
R
2b-f
4b-f
7b-f

HETEROCYCLES, Vol. 76, No. 1, 2008
179
Table 1. Effect of N-protecting group on regioselectivity
entry
(yield: %)
4-acetate
R
product
2b
2c
2d
2e
2f
4b
4c
4d
4e
4f
7b
7c
7d
7e
7f
1
2
3
4
5
p-ClC6H4
p-CF3C6H4
p-NO2C6H4
p-MeOC6H4
OMe
(71)
(66)
( 0)
(93)
(54)
( 8)
(13)
( 0)
( 0)
( 0)
Next, the electrophilic substitution of 2e with various electrophiles was examined (Eq. 4). These results
are summarized in Table 2. Some aromatic (entries 1-3) and aliphatic aldehydes (entry 4) gave the
corresponding coupling products 8e-11e in good yields. Styrene oxide, which was transformed into
phenylacetaldehyde under the reaction conditions, afforded 12e in 80% yield (entry 5). Moreover, acyclic
(entries 6-8) and cyclic ketones (entry 9) gave 4-substituted products 13e-16e in good to high yields,
while benzylideneaniline gave amine 17e in high yield (entry 10).
OAc
N
El
N
electrophile (1.5 equiv)
Pd(OAc)2 (0.05 equiv)
PPh3 (0.05 equiv)
Et2Zn (4.0 equiv)
(4)
O
O
toluene
rt, 2 h
OMe
OMe
2e
8e-17e
Table 2. Introduction of various electrophiles into 2e
product
product
(yield: %)
El
entry
electrophile
entry
electrophile
(yield: %)
El
OH
O
Me
OH
(70)
(86)
(78)
p-MeC6H4CHO
p-ClC6H4CHO
13e
14e
8e
1
2
6
7
C6H4p-Me
OH
Me
Ph
Me
Me
Me
O
Ph
OH
Me
(67)
9e
C6H4p-Cl
O
Ph
OH
OH
(70)
(65)
2-furyl-CHO
10e
15e
3
8
O
Ph
iPr
iPr
O
OH
OH
(69)
(64)
(81)
4
5
i-Pr-CHO
9
16e
17e
11e
i-Pr
OH
Ph
styrene oxide
(80)
10
12e
Ph
Ph
Ph
N
Bn
N
H

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HETEROCYCLES, Vol. 76, No. 1, 2008
The reaction of pipecolinic acid derivative 18 with acetone proceeded regio- and stereo-selectively to
afford cis-2,4-disubstituted product 19 in high yield (Eq. 5).7 The relative stereoconfiguration of 19 was
deduced by NOE correlation.8
OH
Me
Me
acetone (1.5 equiv)
Pd(OAc)2 (0.05 equiv)
PPh3 (0.05 equiv)
Et2Zn (4.0 equiv)
OAc
(5)
MeO2C
N
MeO2C
N
toluene
rt, 2 h
CO2Me
18
CO2Me
19, 86%
Chiral phosphine ligand A9 was used to introduce chirality in product 4e.10 Use of toluene as a solvent
gave diastereomer mixture of 4e in low enantioselectivities, while CH2Cl2 led to moderate improvement
in enantioselectivities of 4e (Eq. 6).12
HO
Ph
PhCHO (1.5 equiv)
Pd(OAc)2 (0.05 equiv)
Et2Zn (4.0 equiv)
*
PPh2
*
N
N
chiral ligand A (0.05 equiv)
(6)
O
2e
solvent
rt, 6 h
O
N
chiral ligand A
OMe
4e
yield
diastereomer ratio and ee
75 (11% ee) : 25 ( 20% ee)
80 (44% ee) : 20 ( 36% ee)
solvent
toluene
CH2Cl2
70%
62%
In summary, efficient regioselective introduction of various electrophiles into piperidine skeleton at the
4-position was achieved with a catalytic amount of Pd(OAc)2/PPh3 in the presence of excess Et2Zn. In
addition, enantioselective introduction of benzaldehyde into 2e at the 4-position was accomplished by use
of chiral phosphine ligand A with moderate enantioselectivity. Further improvement of diastereo- and
enantio-selectivity is underway.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific Research (C) (19550109) from Japan Society
for the Promotion of Science and a Grant-in-Aid for Young Scientists (B) (19790017) from the Ministry
of Education, Science, Sports and Culture, Japan, respectively.

HETEROCYCLES, Vol. 76, No. 1, 2008
181
REFERENCES AND NOTES
† Dedicated to Professor Ryoji Noyori on the occasion of his 70th birthday.
1. For recent examples, see: C. De Risi, G. Fanton, G. P. Pollini, C. Trapella, F. Valente, and V.
Zanirato, Tetrahedron: Asymmetry, 2008, 19, 131; G. S. Kauffman, P. S. Watson, and W. A. Nugent,
J. Org. Chem., 2006, 71, 8975; L. F. Solares, I. Lavandera, V. Gotor-Fernández, R. Brieva, and V.
Gotor, Tetrahedron, 2006, 66, 3284; Y. Mi and E. J. Corey, Tetrahedron Lett., 2006, 47, 2515; K.
Tanaka, T. Kobayashi, H. Mori, and S. Katsumura, J. Org. Chem., 2004, 69, 5906; I. T. Raheem, S.
N. Goodman, and E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 706.
2. D. Minato, M. Imai, Y. Kanda, O. Onomura, and Y. Matsumura, Tetrahedron Lett., 2006, 47, 5485;
M. Ecija, A. Diez, M. Rubiralta, N. Casamitjana, M. J. Kogan, and E. Giralt, J. Org. Chem., 2003,
68, 9541; K. S. K. Murthy, A. W. Rey, and M. Tjepkema, Tetrahedron Lett., 2003, 44, 5355; T.
Senda, M. Ogasawara, and T. Hayashi, J. Org. Chem., 2001, 66, 6852; Y. Yoshimoto, C. Horikawa,
T. Maki, and M. Watanabe, Tetrahedron Lett., 1996, 37, 5715; T. Shono, J. Terauchi, Y. Ohki, and
Y. Matsumura, Tetrahedron Lett., 1990, 31, 6385.
3. Y. Tamaru, Eur. J. Org. Chem., 2005, 2647; M. Kimura, M. Shimizu, S. Tanaka, and Y. Tamaru,
Tetrahedron, 2005, 61, 3709; M. Kimura, M. Shimizu, K. Shibata, M. Tazoe, and Y. Tamaru, Angew.
Chem., Int. Ed., 2003, 42, 3392.
4. Y. Matsumura, D. Minato, and O. Onomura, J. Organomet. Chem., 2007, 692, 654; O. Onomura, Y.
Kanda, M. Imai, and Y. Matsumura, Electrochim. Acta, 2005, 50, 4926; T. Shono, Y. Matsumura, O.
Onomura, and Y. Yamada, Tetrahedron Lett., 1987, 28, 4073.
1
5. Characterization data of 2a: Colorless oil. IR (neat): 3447, 2937, 1738, 1645, 1578 cm-1. H NMR
(300 MHz, CDCl3) δ 1.92-2.21 (m, 5H), 3.41-3.53 (m, 1H), 4.28 (br s, 1H), 5.00 (br s, 1H),
5.20-5.29 (m, 1H), 6.68 (br s, 1H), 7.29-7.57 (m, 5H). MS [HR-FAB(+)]: m/z calcd for C14H16NO3
246.1130 [M+H]+ found 246.1108.
6. A typical experimental procedure: A solution of piperidine derivative 2a (0.3 mmol, 73.5 mg),
Pd(OAc)2 (0.015 mmol, 3.4 mg), PPh3 (0.015 mmol, 3.4 mg), 1M Et2Zn in hexane (1.2 mmol, 1.2
mL), and benzaldehyde (0.45 mmol, 48 mg) in toluene (2.0 mL) was stirred for 2 h under a nitrogen
atmosphere. The resulting mixture was poured into saturated aqueous NH4Cl and extracted with
AcOEt (10 mL x 3). The combined organic layer was dried over MgSO4 and concentrated in vacuo,
the residue was chromatographed on silica gel (hexane/AcOEt = 3/1) to afford 4a in 81% and 7a in
1
11% yield as colorless oil, respectively. 4a: IR (neat): 3450, 2920, 1655, 1490 cm-1. H NMR (300
MHz, CDCl3) δ 1.92-2.10 (m, 2H), 2.52-2.65 (m, 1H), 3.31-3.42 (m, 1H), 3.50-3.63 (m, 1H),
3.95-4.13 (m, 1H), 4.45-4.51 (m, 1H), 5.08-5.15 (m, 1H), 6.45-6.55 (m, 1H), 7.20-7.61 (m, 10H).
MS [HR-FAB(+)]: m/z calcd for C19H20NO2 294.1494 [M+H]+ found 294.1493. 7a: IR (neat): 3420,

182
HETEROCYCLES, Vol. 76, No. 1, 2008
1
2931, 1716, 1645 cm-1. H NMR (300 MHz, CDCl3) δ 1.43-1.73 (m, 1H), 2.16-2.27 (m, 1H),
3.13-3.25 (m, 1H), 3.25-3.47 (m, 2H), 4.39-4.53 (m, 1H), 4.81-4.92 (m, 2H), 5.82-5.88 (m, 1H),
7.20-7.61 (m, 10H).
1
7. Characterization data of 19. Colorless oil. IR (neat): 3504, 2959, 1716, 1655, 1448 cm-1. H NMR
(300 MHz, CDCl3) δ 1.19 (s, 3H), 1.22 (s, 1.2H), 1.23 (s, 1.8H), 1.45 (br s, 1H), 1.72-1.84 (m, 1H),
2.08-2.14 (m, 1H), 2.39-2.47 (m, 1H), 3.75 (s, 3H), 3.76 (s, 1.2H), 3.80 (s, 1.8H), 4.82-4.85 (m,
0.4H), 4.90 (d, J=8.5 Hz, 0.6H), 4.97-5.00 (m, 1H), 6.87 (d, J=8.5 Hz, 0.6H), 7.00 (d, J=8.5 Hz,
0.4H). MS [HR-FAB(+)]: m/z calcd for C12H20NO5 258.1341 [M+H]+ found 258.1339.
8. NOE correlation was observed between H2 and H4.
OH
Me
H4
Me
NOE
H2
MeO2C
N
CO2Me
9. K. Hiroi, Y. Suzuki, and I. Abe, Tetrahedron: Asymmetry, 1999, 10, 1173.
10. It was proposed in ref 11 that a plausible intermediate in the asymmetric reaction of cyclohexenyl
acetate with benzaldehyde might be η1-allylpalladium species 21 generated from η3-allylpalladium
species 20 with Et2Zn.
Et2Zn
PdX2L*2
L*
Pd
L*
Et
20
21
11. G. P. Howell, A. J. Minnaard, and B. L. Feringa, Org. Biomol. Chem., 2006, 4, 1278.
12. Characterization data of 4e obtained in CH2Cl2 (The absolute stereoconfiguration is not determined).
1
Colorless oil. [α]19D −9.1 (c 1.07, CHCl3). IR (neat): 3420, 2934, 1732, 1651 cm-1. H NMR (300
MHz, CDCl3) δ 1.70 (br s, 1H), 1.99 (br s, 2H), 2.59-2.64 (m, 1H), 3.52-3.61 (m, 1H), 3.84 (s, 3H),
3.99-4.04 (m, 1H), 4.43-4.58 (m, 1H), 5.05-5.19 (br s, 1H), 6.60 (br s, 1H), 6.90 (d, J=8.7 Hz, 2H),
7.22-7.40 (m, 5H), 7.45 (d, J=8.7 Hz, 2H). MS [HR-FAB(+)]: m/z calcd for C20H22NO3 324.1600
[M+H]+ found 324.1598. The diastereoselectivity and optical purity of 4e were determined by chiral
HPLC: Daicel Chiralcel OJ-H column (4.6 mmφ, 250 mm), n-hexane : i-PrOH = 3 : 1, wavelength:
254 nm, flow rate: 1.0 mL/min, retention time: Major diastereomer 12.9 min (rich), 22.9 min and
minor diastereomer 27.5 min (rich), 38.5 min.