Concise synthesis of trans- and cis-3,4-disubstituted piperidines based on regio- and stereoselective allylation of cyclopentenyl esters

Article abstract of DOI:10.1016/j.tetlet.2004.08.174

3,4-Disubstituted piperidines were synthesized through anti S _N2′ allylation of 4-substituted 2-cyclopentenyl esters with reagents based on RMgX and CuX, thus allowing equal access to both trans- and cis-isomers. As an application, the paroxeti

Full text of DOI:10.1016/j.tetlet.2004.08.174

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8065–8068
Concise synthesis of trans- and cis-3,4-disubstituted
piperidines based on regio- and stereoselective
allylation of cyclopentenyl esters
Junji Igarashi, Hiroyuki Ishiwata and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259-B-52 Nagatsuta-cho,
Midori-ku, Yokohama 226-8501, Japan
Received 9 July 2004; revised 25 August 2004; accepted 27 August 2004
Available online 21 September 2004
Abstract—3,4-Disubstituted piperidines were synthesized through anti SN20 allylation of 4-substituted 2-cyclopentenyl esters with
reagents based on RMgX and CuX, thus allowing equal access to both trans- and cis-isomers. As an application, the paroxetine
intermediate was synthesized efficiently. During the investigation, the MeOCH2CO2 group was found to show high reactivity in
the pivotal anti SN20 type reaction using the reagent derived from (i-PrO)Me2SiCH2MgCl and CuCN.
Ó 2004 Elsevier Ltd. All rights reserved.
The 3,4-disubstituted piperidine framework is frequently
seen in an important class of nitrogen-containing com-
pounds such as those delineated in Figure 1. Due to
their unique biological properties, the piperidines have
been target molecules in organic synthesis.1 A crucial
step in most of the previous syntheses2 is installation
of the second substituent, and the step has been accomp-
lished stereoselectively by taking advantage of the ther-
modynamic stability of the disubstituted product or of
the kinetic approach of the reagent from a less hindered
side of the monosubstituted piperidine. Consequently,
these syntheses produce trans substituted piperidines
efficiently, and application to cis-isomer synthesis suffers
from low efficiency and/or lengthy sequence. Recently,
new approaches to trans as well as cis disubstituted pip-
eridines have been published by Beak and co-workers3
and Amat et al.4 Herein, we report another approach
to these piperidines, which relies on allylic substitution
reaction, for the first time.
F
HN
O
O
NMe
O
O
MeO
(–)-Paroxetine
(+)-Femoxetine
Recently, we have reported several reagents for the SN2
or SN20 reaction of carbon nucleophiles to 4-cyclopen-
tene-1,3-diol monoacetate (1)5 and their application to
cyclopentanoids synthesis.6 The reagents and the solvent
indicated in step 1 of Scheme 1 afford the SN2 products 2
with trans stereochemistry. We also reported SN2 or anti
SN20 butylation of cis and trans acetates derived from 2.7
The anti SN20 butylation (step 2 of Scheme 1, R2 = n-Bu)
proceeds with reagents derived from BuMgX and CuCN
in ratio of 1:1 or 2:1 in Et2O. Although examination of
other RMgX for step 2 was probably the next step of
investigation before application, we started the investi-
gation presented in Scheme 2 in expectation that the
transformation would furnish trans- and cis-3,4-disub-
stituted piperidines in a stereoselective manner. This
approach was indeed successful in several cases as
OMe
N
N
H
H
HN
N
MeO
CO2Me
(–)-Corynantheidine
Quinine intermediate
Figure 1. 3,4-Disubstituted piperidines.
Keywords: 3,4-Disubstituted piperidine; SN2 type reaction; Anti SN20
type reaction; Cyclopenten-1,3-diol monoacetate; Paroxetine.
*
Corresponding author. Tel.: +81 45 924 5789; fax: +81 45 924
5789; e-mail: ykobayas@bio.titech.ac.jp
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.174

8066
J. Igarashi et al. / Tetrahedron Letters 45 (2004) 8065–8068
R1
R2
(i-PrO)Me2SiCH2MgCl
Ph
R2–m
Ph
(3 equiv)
RCOO
step 2
CuX (3.6 equiv)
Me
Me
Si OPr-i
OAc
R1
trans-3
R1–m
11a–f
see Text and Table 1
HO
HO
trans-3b
step 1
R1
R2
R2–m
1
2
Ph
Ph
OTBS
a,b,c,d
e,f
step 2
N
OTBS
cis-3
49%
57%
Bn
13
14
Scheme 1. Method for synthesis of trans- and cis-3: step 1, Li+ [R1-
borate]ꢀ/NiCl2 (PPh3)2 (cat.) in THF or R1MgCl/CuX (cat.) (X = CN,
I) in THF; step 2, see the text. For the present study, the following
compounds were synthesized from 2a (R1 = Ph) and 2b (R1 = p-F–
C6H4): trans- and cis-3a, R1 = Ph, R2 = Bu; trans- and cis-3b, R1 = Ph,
R2 = CH2SiMe2 (OPr-i); trans-3c, R1 = p-F–C6H4, R2 = CH2SiMe2
(OPr-i); trans-3d, R1 = p-F–C6H4, R2 = Bu.
Scheme 4. (a)–(d): See steps (a)–(d) in Scheme 3; (e) H2O2, KF,
KHCO3, 60–65°C; (f) TBSCl, imidazole.
91%) followed by reaction with BuCu(CN)(MgBr) in
Et2O(91%). Transformation of cis-3a proceeded with
similar efficiency to that of trans-3a, thus providing cis
piperidine 10 in 58% overall yield.
R1
R2
R1
R2
X
R1
R2
*
*
*
*
*
*
R3–NH2
N
X
Synthesis of piperidine with a CH2OR group at the
3-position was next studied by using (i-PrO)Me2Si-
CH2MgCl as a source of the CH2OR group,8 which is
a part of paroxetine and femoxetine9 (Scheme 4). As
mentioned above, butylation of acetate 11a (R = Me)
to trans-3a was best accomplished in Et2O with the cop-
per reagents derived from BuMgX (X = Br, Cl) and
CuCN.10 In the present case, THF was unfortunately
the solvent for preparation of (i-PrO)Me2SiCH2MgCl.
As expected from the butylation, 11a with (i-PrO)Me2-
SiCH2Cu(CN)MgCl (12a) in THF proceeded little,
and most of 11a was recovered after the reaction.
R3
4
5
3
Scheme 2. An approach to 3,4-disubstituted piperidines.
mentioned below. Moreover, we found a new leaving
group to achieve step 2 of Scheme 1 efficiently.
Results of the preliminary study are summarized in
Scheme 3, in which the starting cyclopentene, trans-3a,
was prepared from monoacetate 1 by a sequence of reac-
tions: (1) PhMgCl/CuCN (cat.) to produce 2a (R1 = Ph),
87%; (2) AcOH, DIAD, PPh3, 90%; (3) BuCu(CN)MgBr
in Et2O, 90%. Ozonolysis proceeded well in n-PrOH to
afford diol 7 in 85% yield after reductive workup with
NaBH4. Subsequently, diol 7 was converted into iodide
8. Finally, reaction of 8 with BnNH2 at 115°C for 2h in
dioxane produced trans piperidine 9 in 54% overall yield
from trans-3a. The corresponding tosylate derived from
diol 7 was less reactive than iodide 8 for the piperidine
ring formation.
We explored copper salts and leaving groups other than
the AcO group. The reaction of 11a (R = Me) with
(i-PrO)Me2SiCH2CuÆMgICl (12b) prepared from (i-
PrO)Me2 SiCH2MgCl and CuI in place of CuCN
proceeded at 15–20°C regioselectively, but slowly, to
provide trans-3b in 24% yield after 15h (Table 1, entry
1). Due to the slow reaction, decomposition of 12b
and a nucleophilic reaction at the acetyl carbon com-
peted with the desired reaction. We then investigated
potency of an RCO2 group as a leaving group of 11.
The above transformation was applied to cis-3a, which
was prepared from 2a by acetylation (Ac2O, pyridine,
Table 1. Reaction of 11a with reagents 12ab and 12bb derived from (i-
PrO)Me2SiCH2MgCl (3.0equiv) and CuX (3.6equiv)c
Entry
Substrate 11
Reagent
Results (% obtained)d
Ph
Bu
Ph
Bu
X
Ph
Bu
a,b
d
No
R
trans-3b
Alcohole 11
N
X
85%
88%
Bn
1
2
3
4
5
6
7
11a Me
11b t-Bu
12b
12b
2413
63
<1
9
trans-3a
7, X = OH
8, X = I
<1
99
c
Mixturef
76 (62)
67 (55)
99 (97)
88
54% from
11c p-NO2C6H4 12b
72%
trans-3a
11d CH2Cl
11e CHCl2
12b
12b
12b
12a
24<1
33
<1
<1
<1
<1
a,b,c,d
11f CH2OMe
11f CH2OMe
Ph
Bu
Ph
Bu
12
N
a Prepared by Mitsunobu inversion of 2a with RCO2H in good yields.
b 12a: (i-PrO)Me2SiCH2Cu(CN)MgCl; 12b: (i-PrO)Me2SiCH2CuÆMgICl.
c Reaction was carried out between 0 and 20°C in THF for 2–15h.
d Yields in parentheses are those isolated by chromatography.
e Produced by nucleophilic attack at the ester carbon of 11.
f A mixture of unidentified products.
Bn
58%
10
cis-3a
Scheme 3. A simple case of the transformation: (a) O3, ꢀ70°C then
Me2S; (b) NaBH4, 0°C; (c) I2, imidazole, PPh3; (d) BnNH2, dioxane,
115°C.

J. Igarashi et al. / Tetrahedron Letters 45 (2004) 8065–8068
8067
Among the RCO2 groups indicated in entries 2–7 of
Table 1, ClCH2CO2, Cl2CHCO2, and MeOCH2CO2
groups provided better yields of trans-3b. Inter alia,
the MeOCH2CO2 group produced trans-3b as the sole
product in 97% isolated yield without formation of the
corresponding alcohol (entry 6).11,12 In entry 7, the rea-
gent based on CuCN (i.e., 12a) was also examined to
provide trans-3b in 10% lower yield and the alcohol in
12% yield, thus ensuring the excellent result of entry 6
with CuI-based reagent 12b.
vide sufficient reactivity in reaction with (i-PrO)Me2-
SiCH2CuÆMgICl (12b). The generality of the ester
group as a leaving group in allylation reaction is under
investigation.13
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
The product synthesized above (trans-3b) was converted
into 13 by the Tamao reaction8 (56%) followed by silyl-
ation of the resulting alcohol (87%). The transformation
established for trans-3a (Scheme 3) was applied to 13 to
produce piperidine 14 (5 in Scheme 2 with R1 = Ph,
R2 = CH2OTBS, and R3 = Bn) in 57% yield from 13.
References and notes
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C6H4MgCl (3equiv) in the presence of CuI (30mol%)
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In summary, an approach to 3,4-disubstituted piperi-
dines was established. An advantage of the approach
is the equal access to trans as well as cis piperidines.
Moreover, the MeOCH2CO2 group was found to pro-
F
OAc
e,f
g,h,i
58%
HO
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RCO2
63%
1
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´
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Bn
16
17, R = TBS
18, R = H
j
76%
Scheme 5. (a)–(d): See steps (a)–(d) in Scheme 3; (e) p-F–C6H4MgCl
(3equiv), CuI (0.3equiv), THF; (f) MeOCH2CO2H, DIAD, PPh3,
ꢀ78°C; (g) 12b (3equiv), THF, 2h; (h) H2O2, KF, KHCO3, 60–65°C;
(i) TBSCl, imidazole; (j) Bu4NF.

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J. Igarashi et al. / Tetrahedron Letters 45 (2004) 8065–8068
´
´
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were less reactive or less selective, providing ca. 30% yield
of the butylation product or ca. 2:1 regioselection.
11. To an ice-cold mixture of CuI (224mg, 1.18mmol) and
THF (1mL) was added (i-PrO)Me2SiCH2MgCl (1.4mL,
0.70M in THF, 0.98mmol) slowly. After 20min of
stirring at 0°C, compound 11f (76mg, 0.327mmol) in
THF (0.7mL) was added dropwise. The reaction was
carried out at 15–20°C for 2h, and quenched by
addition of saturated NH4Cl and 28% NH4OH to afford
trans-3b (87mg) in 97% yield after chromatography on
silica gel.
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12. Although results of entries 4and 6 suggested use of the
FCH2CO2 group, we did not examine it for reasons of
toxicity.
13. Butylation of 15 afforded trans-3d (see Scheme 1 for the
structure), which produced the corresponding piperidine
as well.