A novel method for synthesizing 3-arylpyrrolidine and 4-arylpiperidine derivatives through an acid-promoted skeletal rearrangement

Article abstract of DOI:10.1016/j.tetlet.2013.01.034

A novel method for synthesizing 3-arylpyrrolidine and 4-arylpiperidine derivatives through an acid-promoted skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso-Friedel-Crafts-type addition of phenols to allyl cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and an intramolecular aza-Prins reaction, proceeded sequentially to afford 3-arylpyrrolidine and 4-arylpiperidine derivatives in good yield with high diastereoselectivity.

Full text of DOI:10.1016/j.tetlet.2013.01.034

Tetrahedron Letters 54 (2013) 1562–1565
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel method for synthesizing 3-arylpyrrolidine and 4-arylpiperidine
derivatives through an acid-promoted skeletal rearrangement
⇑
Takuya Yokosaka, Tetsuhiro Nemoto, Yasumasa Hamada
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method for synthesizing 3-arylpyrrolidine and 4-arylpiperidine derivatives through an acid-pro-
moted skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramo-
lecular ipso-Friedel–Crafts-type addition of phenols to allyl cations, formation of iminium cations through
rearomatization of the spirocyclohexadienone units, and an intramolecular aza-Prins reaction, proceeded
sequentially to afford 3-arylpyrrolidine and 4-arylpiperidine derivatives in good yield with high
diastereoselectivity.
Received 3 December 2012
Revised 7 January 2013
Accepted 9 January 2013
Available online 16 January 2013
Keywords:
Pyrrolidine
Ó 2013 Elsevier Ltd. All rights reserved.
Piperidine
ipso-Friedel–Crafts reaction
Aza-Prins reaction
Skeletal rearrangement
Pyrrolidine and piperidine rings are ubiquitous structures in a
wide variety of alkaloids. Alkaloids bearing these heterocyclic
frameworks often exhibit diverse biological activities and are
attractive synthetic targets in medicinal chemistry.1 Therefore,
considerable efforts have been directed toward the development
of an efficient synthetic method for functionalized pyrrolidine
and piperidine derivatives.2 Among them, 3-arylpyrrolidines and
4-arylpiperidines are the most important classes of compounds.
These structural motifs are found in various pharmaceuticals and
F
F
O
HO
Ph
N
O
O
F
O
N
N
H
MC4 receptor agonist
Paroxetine
5a
drug candidates, such as Paroxetine,3,4 MC4 receptor agonists,
F
CCR5 antagonists,5b and hNK1 antagonists5c (Fig. 1).
O
N
F3C
F
As part of our ongoing studies aimed at developing efficient
synthetic methods for functionalized heterocycles, we recently re-
ported a novel synthetic method for tricyclic indole derivatives
through an acid-promoted skeletal rearrangement (Scheme 1a).6
The method is based on a three-step reaction sequence: (1) intra-
molecular ipso-Friedel–Crafts-type addition of phenol derivatives
to 3-alkylidene indolenium cations, (2) formation of iminium cat-
ions through rearomatization of spirocyclohexadienone units,
and (3) an intramolecular Pictet–Spengler reaction. We hypothe-
sized that, after the generation of an iminium cation via the intra-
molecular ipso-Friedel–Crafts-type addition of a phenol derivative7
to an allyl cation and subsequent rearomatization, entrapment of
the iminium cation by an intramolecular aza-Prins reaction8 would
produce functionalized 3-arylpyrrolidine derivatives (n = 1) or 4-
arylpiperidine derivatives (n = 2) that are of potential interest as
N
N
N
N
CF3
N
N
CO2H
O
N
O
CCR5 antagonist
hNK1 antagonist
Figure 1. Examples of drugs and pharmaceutical leads containing 3-arylpyrrolidine
or 4-arylpiperidine unit.
drug design scaffolds (Scheme 1b). Herein, we report a novel meth-
od for synthesizing 3-arylpyrrolidine and 4-arylpiperidine deriva-
tives possessing three contiguous chiral centers through an acid-
promoted skeletal rearrangement.
Our studies began with model substrate 1a (Table 1). Treatment
of 1a with trifluoroacetic acid (TFA) in CH2Cl2 at 0 °C led to the
⇑
Corresponding author. Tel./fax: +81 43 226 2920.
E-mail address: hamada@p.chiba-u.ac.jp (Y. Hamada).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.034

T. Yokosaka et al. / Tetrahedron Letters 54 (2013) 1562–1565
1563
(a) Our previous work
R4
N
n
OR1
R3
R4
R4
R1O
N
N
n
H+
R4
R1O
OH
N
R3
n
n
+
R1O
R3
-H2O
R3
-H+
N
N
N
N
R2
R2
R2
R2
(b) This work
R5O
R5O
Ts
Ts
N
N
R6
R7
HO
H+
-H2O
Ts
N
n
R5O
n
OH
R6
n
R5O
R7
R7
R6
n
R7
N
R6
Ts
intramolecular
aza-Prins reaction
acid-promoted
spirocyclization
rearomatization
Scheme 1. Backgrounds and plan of this work.
Table 1
Optimization of the reaction conditions
OMe
OMe
Ts
1) Acid (equiv.)
Solvent (0.1 M)
temp., time
N
O
2) aq sat-NaHCO3
CH3CN, rt
OH
O
H
CF3
MeO
H
H
Ph
Ph
H
N
Ts
N
HO Ph
1a
Ts
2a'
2a
Entry
Acid (equiv)
Solvent
Temp.
Time (h)
Yielda (%)
drb
1
2
3
4
5
6
7
8
9
10
11
12
13
TFA (1)
TFA (2)
TFA (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
rt
24
24
24
9
1
1
0
10
55
75
82
82
14
78
Messy
Messy
Trace
22
—
—
14:1
18:1
18:1
18:1
13:1
17:1
—
—
—
16:1
17:1
TFA (10)
TFA (15)
TFA (20)
TFA (15)
TFA (15)
TfOH (1)
Tf2NH (1)
TsOH H2O (1)
Sc(OTf)3 (0.2)
In(OTf)3 (0.2)
3
1
0.2
0.2
24
24
24
rt
39
a
Isolated yield.
b
Determined by 1H NMR analysis.
gradual consumption of 1a and the formation of trifluoroacetate
adduct 2a0 as the initial adduct. Due to susceptibility of 2a0 to
hydrolysis during silica gel column chromatography, the reaction
was purified after converting 2a0 into 2a by aqueous basic treat-
ment of the concentrated reaction mixture. Reactivity was gradu-
ally improved by increasing the amount of TFA (entries 1–6).
When the reaction was performed using 15 equiv of TFA, 4-arylpi-
peridine derivative 2a was obtained in 82% yield with high diaste-
reoselectivity (diastereomeric ratio = 18:1) (entry 5).9 The yield
decreased when the reaction was performed in CH3CN or CH3NO2
instead of CH2Cl2 (entries 7 and 8). The use of more acidic promot-
ers resulted in a messy reaction (entries 9–11). The same reaction
was also examined using several Lewis acid catalysts. With
20 mol % of Sc(OTf)3 or In(OTf)3 as an acid promoter, the reaction
proceeded slowly at room temperature to provide 2a in 22% and
39% yields, respectively, (entries 12 and 13). Thus, we selected
the reaction conditions in entry 5 as optimum for this process.
We next examined the scope and limitations of different sub-
strates under the optimized reaction conditions (Table 2). In addi-
tion to para-substituted O-methyl ether derivative 1a (entry 1),
phenol derivative 1b, O-benzyl ether derivative 1c, and O-t-butyl-
dimethylsilyl (TBS) ether derivative 1d were applicable to this
reaction, and the corresponding 4-arylpiperidine derivatives 2b,
2c, and 2d were obtained in 68%, 91% and 95% yields, respectively
(entries 2–4). Substrates 1e–i, bearing a tolyl group or a naphthyl
group on the R3 position, also reacted smoothly to give the corre-
sponding products 2e–i in excellent yield with high diastereoselec-
tivity (entries 5–9). Moreover, ortho-substituted O-TBS ether
derivative 1j was suitable substrates for this reaction, affording
the corresponding product 2j in good yield (entry 10). This reaction
system was also effective for tert-allyl alcohol derivatives with
dialkyl substituents 1k (R3 = R4 = Me), demonstrating that sub-
strates applicable to this reaction are not limited to benzyl alcohol
derivatives (entry 11). Furthermore, when substrate 1l, bearing a
CH2 unit-shorter tether than 1a, was treated with 15 equiv of
TFA under diluted conditions, the reaction proceeded smoothly
to give 3-arylpyrrolidine derivative 2l in 88% yield (entry 12).
A plausible reaction pathway is shown in Scheme 2. Initially, al-
lyl cation A is formed by the acid-promoted dehydration of 1a.
Subsequently, an intramolecular ipso-Friedel–Crafts-type addition
of the phenol derivative to the allyl cation proceeds to give dearo-
matized cationic species B. Sequential rearomatization of the spi-
rocyclohexadienone moiety accompanying the C–C bond cleavage
results in the formation of iminium cation C. An intramolecular
aza-Prins reaction of intermediate C occurs subsequently in a dia-
stereoselective manner, resulting in the formation of piperidine
derivative D, bearing a carbocation on the exocyclic benzylic posi-
tion. Finally, this benzylic cation is captured by a trifluoroacetate

1564
T. Yokosaka et al. / Tetrahedron Letters 54 (2013) 1562–1565
Table 2
Substrate scope
R1
R2
Ts
N
1) TFA (15 equiv.), CH2Cl2 (0.1 M)
0 °C, time
R2
OH
R4
R3
R1
H
n
2) aq sat-NaHCO3 /CH3CN
rt
H
R4
n
N
Ts
HO R3
Entry
Substratea
R1
R2
R3
R4
n
Product
Time (h)
Yieldb (%)
drc
1
2
3
4d
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
OMe
OH
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
Me
H
1
1
1
1
1
1
1
1
1
1
1
0
2a
2b
2c
2d
2e
2f
2g
2h
2i
1
22
2
3
2
2
2
2
2
82
68
91
95
99
92
98
91
95
83
55
88
18:1
13:1
OBn
OTBS
OMe
OMe
OMe
OMe
OMe
H
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4-Tolyl
3-Tolyl
2-Tolyl
1-Naphthyl
2-Naphthyl
Ph
d
10
1j
1k
1l
OTBS
H
H
2j
2k
2l
1
4
7
11
OMe
OMe
Me
Ph
12d
a
Pure E isomers were used as substrates.
Isolated yield.
b
c
Determined by 1H NMR analysis.
d
The reaction was performed in CH2Cl2 (0.025 M).
Ts
N
CF3COO Ts
N
Ts
N
Ts
N
CF3COOH
-H2O
MeO
MeO
MeO
MeO
CF3COO
HO Ph
Ph
CF3COO
Ph
1a
C
Ph
B
A
OMe
OMe
OMe
OMe
O
OH
Ph
O
CF3
Ph
H
OH
-CF3COO
H
H
H
Ph
Ph
H
H
H
N
Ts
N
Ts
N
Ts
N
Ts
CF3COO
CF3COO
C
2a
D
2a'
Scheme 2. Proposed reaction pathway.
nucleophile. A trifluoroacetate anion selectively attacks from an-
other accessible face and the product with three contiguous chiral
centers is obtained with high diastereoselectivity.10
In conclusion, we developed an innovative method for synthe-
sizing 3-arylpyrrolidine and 4-arylpiperidine derivatives through
an acid-promoted skeletal rearrangement. Structurally diverse pyr-
rolidine and piperidine derivatives were obtained in good yield
with high diastereoselectivity under mild and simple reaction con-
ditions. Further studies are in progress to investigate the pharma-
cological activity of these derivatives.
(a) from C to D
D
2a'
(b) from to
H
H
H
H
H
H
R
Ph
TsN
OMe
H
N
H
CF3COO
Ts
R = para-methoxyphenyl
Figure 2. Rationale for the high diastereoselectivity.
anion to give 2a0, which is converted into 2a by base-promoted
hydrolysis.
Acknowledgements
The high diastereoselectivity observed in the 4-arylpiperidine
synthesis can be explained by the transition state models shown
in Figure 2. From C to D: Intramolecular C–C bond formation pro-
ceeds through a transition state with minimum allylic strain
(Fig. 2a). The 3,4-trans configuration is constructed during this pro-
cess. From D to 2a0: Allylic strain should also play an important role
in determining the conformational preference of the transition
state structure, because the C–C bond between the phenyl group
and the cationic benzylic carbon bond has partial double bond
characters. As shown in Figure 2b, the para-methoxylphenyl group
effectively shields the one face of the benzylic cation from the
This work was supported by a Grant-in Aid for Scientific Re-
search from the JSPS, Japan, the Research Foundation for Pharma-
ceutical Sciences, Chiba University, and the Inohana Foundation.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tetlet.
2013.01.034.

T. Yokosaka et al. / Tetrahedron Letters 54 (2013) 1562–1565
1565
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9. Among the four possible diastereomers, only two isomers were observed in 1
H
NMR analysis of the crude reaction mixture. Diastereomeric ratio represents
the ratio of these isomers. For determination of the relative configuration of the
reaction adducts, see the Supplementary data.
A p–electron interaction between the phenol derivative moiety (electron-rich
aromatic ring) and the benzylic cation moiety (electron-deficient aromatic
ring) might be participated in the stabilization of the transition state.
10.