Novel synthesis of substituted pyrrolidines and piperidines via radical addition-ionic cyclization reaction of oxime ethers

Article abstract of DOI:10.1016/j.tet.2007.11.081

We have developed a novel synthetic route to nitrogen-containing heterocycles via radical addition-ionic cyclization reaction. Treatment of oxime ethers carrying the tosyloxy group with Et₃B and alkyl iodide in the presence of Lewis acid gave the substituted pyrrolidines and piperidines. The reaction of oxime ethers carrying the methoxycarbonyl group proceeded under the same conditions to give the amino esters, which were easily converted into the corresponding lactams by the treatment with concd HCl. On the other hand, the oxime ether bearing the phenoxycarbonyl group afforded directly alkylated lactams under the radical reaction conditions. The utility of this domino reaction was demonstrated by the synthesis of (±)-bgugaine and the formal synthesis of 5,8-disubstituted indolizidine alkaloids.

Full text of DOI:10.1016/j.tet.2007.11.081

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1270e1284
www.elsevier.com/locate/tet
Novel synthesis of substituted pyrrolidines and piperidines via radical
additioneionic cyclization reaction of oxime ethers
*
Okiko Miyata, Shinya Takahashi, Akira Tamura, Masafumi Ueda, Takeaki Naito
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Received 1 October 2007; received in revised form 21 November 2007; accepted 21 November 2007
Abstract
We have developed a novel synthetic route to nitrogen-containing heterocycles via radical additioneionic cyclization reaction. Treatment of
oxime ethers carrying the tosyloxy group with Et3B and alkyl iodide in the presence of Lewis acid gave the substituted pyrrolidines and piperi-
dines. The reaction of oxime ethers carrying the methoxycarbonyl group proceeded under the same conditions to give the amino esters, which
were easily converted into the corresponding lactams by the treatment with concd HCl. On the other hand, the oxime ether bearing the phenoxy-
carbonyl group afforded directly alkylated lactams under the radical reaction conditions. The utility of this domino reaction was demonstrated by
the synthesis of (ꢀ)-bgugaine and the formal synthesis of 5,8-disubstituted indolizidine alkaloids.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Radical reaction; Pyrrolidine; Piperidine; Oxime ether; Indolizidine
1. Introduction
radical additionenucleophilic substitution by using the oxime
ether group as a nucleophile. Addition reactions2b,c,3 of carbon
fragments to C]N bonds of imines and related compounds
are one of the typical techniques for the construction of diver-
gently substituted heterocycles. Among the different types of
imines, the oxime ethers are well-known2b,c,3 to be excellent
radical acceptors. We have also reported3 that the intermole-
cular radical addition reactions to aldoximes proceeded
smoothly. Additionally, we have recently found the tandem
radical additionealdol type reaction of a,b-unsaturated oxime
ethers.4
We designed radical additionecyclization reaction of the
oxime ethers aiming at development of new strategy for the
construction of heterocycles. We chose the oxime ethers 1
bearing leaving group at u-position as the substrates. The
Et3B induced radical addition to oxime ethers 1 would proceed
in the presence of various types of alkyl iodides to form the
borylamines B, which are subjected to intramolecular nucleo-
philic substitution to give nitrogen-containing heterocycles.
Since oxime ethers 1 have two electrophilic sites, the ionic
reaction of substrate 1 with nucleophile could occur on not
only imino group but also the tosyloxymethyl and the
The nitrogen-containing heterocycles are common sub-
structures found widely in biologically active materials and
hence attract broad interest, particularly in the areas of syn-
thetic methodology, bioorganic and medicinal chemistry, and
natural product synthesis.1
Domino types of reactions2a are one-pot multi-step pro-
cesses and hence very powerful for the rapid construction of
complex organic molecules efficiently and elegantly in a con-
vergent and eco-friendly manner with minimum waste gener-
ation. The biological importance of the nitrogen heterocycles
and our continued interest in the synthesis of novel organic
molecules employing tandem sequences prompted us to inves-
tigate the radical reactions of several oxime ethers bearing
leaving group at the terminal position.
We have now developed a new methodology for the con-
struction of substituted pyrrolidines and piperidines via the
* Corresponding author. Tel.: þ81 78 441 7554; fax: þ81 78 441 7556.
E-mail address: taknaito@kobepharma-u.ac.jp (T. Naito).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.081

O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1271
Table 1
Radical additioneionic cyclization of oxime ether 3
alkoxycarbonyl groups to form complex mixture, which is
a drawback of normal ionic reactions (Scheme 1).
OBn
N
OBn
N
Et3B
Lewis acid
Et
electrophilic site
TsO
CH2Cl2
OBn
N
Et3B
Y
OBn
N
3
R-I
6a
R
Et3B
Y
Entry
Lewis acid
Temperature (ꢁC)
Time (h)
Yield (%)
Radical
addition
n
n
1
2
3
4
5
6
7
8
9
None
None
rt
24
7
nr
n = 1, 2
1
20 (24)a
75
45
A
40
rt
C
C
Y
: CH2OTs
BF3$OEt2 (2 equiv)
BF3$OEt2 (2 equiv)
Cu(OTf)2 (2 equiv)
Mg(ClO4)2 (2 equiv)
Sc(OTf)3 (1 equiv)
TMSOTf (1 equiv)
Hf(OTf)4 (1 equiv)
3.5
2
Y: COOR
40
rt
4
27 (25)a
43
45 (20)a
62
66
OBn
N
Et2B
OBn
N
rt
7
X
R
R
rt
3.5
3.5
3.5
Y
Cyclization
rt
n
n
rt
2
B
nr: no reaction.
a
Yields in parentheses are for recovered starting material.
X = H2
X = O
Scheme 1.
as a Lewis acid at room temperature to give the desired prod-
uct 6a in good yield (entry 3), while the yield of 6a was
decreased at the elevated temperature (entry 4). When the
various types of Lewis acids were used in the place of
BF3$Et2O, 6a was obtained only in moderate yields (entries
5e9).
On the other hand, the alkyl radical would prefer addition
reaction rather than substitution reaction. Therefore, the reac-
tion of substrate with alkyl radical would chemoselectively
proceed in the first step to form the borylamines B.
We next examined the reaction of oxime ether 3 in the pres-
ence of various types of alkyl iodides as radical precursors
(Table 2). Et3B and BF3$OEt2 were further added when the
radical reaction proceeded slowly (entries 1e8). The treatment
of 3 with 10 equiv of i-PrI gave a mixture of 6b and 6a in 38
and 18% yields, respectively (entry 1). When 20 equiv of i-PrI
was employed, the yield of 6b was increased (entry 2).
In the presence of other secondary alkyl iodides as radical
precursors, the reactions also proceeded smoothly to give alkyl-
ated pyrrolidines 6d, 6f, and 6g (entries 4, 6, and 7). In the
cases using sterically hindered tertiary alkyl iodides, only
2. Results and discussion
2.1. Preparation and radical additioneionic cyclization
reaction of oxime ethers 3, 9, and 14 carrying a tosyloxy
group
We first picked up oxime ether 3 carrying the tosyloxy
group as a substrate, which was prepared from 2,3-dihydro-
furan (4) by the treatment with benzyloxyamine5 followed
by tosylation (Scheme 2).
Table 2
Radical reaction of 3 with various types of alkyl iodides
OBn
N
O
·
HCl
BnONH2
Et3B
HO
H2O
OBn
N
BF3·OEt2
OBn
N
R-I (20 eq.)
4
R
5
TsO
CH2Cl2
rt
TsCl
Et3N
CH2Cl2
3
6a (R = Et)
b R = i-Pr)
d (R = s-Bu)
e (R = i-Bu)
f (R = c-Pentyl)
g (R = c-Hexyl)
OBn
N
TsO
3
Entry
ReI (equiv)
Et3B
(equiv)
BF3$OEt2
(equiv)
Time
(h)
Yield (%)
80% (2 steps)
E/Z= 3/2
6beh
6a
Scheme 2.
1
2
3
4
5
6
7
8
i-PreI (10)
i-PreI (20)
t-BueI (20)
s-BueI (20)
i-BueI (20)
6
6
9
6
6
6
6
6
4
4
6
4
4
4
4
4
23
3
38
51
nr
18
13
23
22
23
3
The domino reaction of oxime ether 3 was examined under
various reaction conditions (Table 1). When the oxime ether 3
was treated with Et3B at room temperature, only recovered
starting material was obtained (entry 1). The pyrrolidine 6a
was obtained in 20% yield by heating at 40 ꢁC (entry 2).
The reaction was carried out in the presence of BF3$Et2O3
80
13
68
64
nr
19
44
26
32
c-PentyleI (20)
c-HexyleI (20)
AdamantyleI (20)
4
23
nr: no reaction.

1272
O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
R
OBn
N
F3B
TsO
Iodine atom-transfer
process
EtI
3
OBn
N
F3B
TsO
O2
Radical initiator
R
RI
Et
Et3B
C
OBn
BF3
OBn
Radical terminator
N
R
Et2B
TsO
Et3B
N
R
Cyclization
6
D
Scheme 3.
1
the starting oxime ether was recovered (entries 3 and 8). The
reaction of 3 with primary alkyl iodide, that is, i-BuI gave 6a
as a major product along with 6e (entry 5).
We propose possible reaction pathway for this reaction
according to the reaction mechanism postulated in our previ-
ous reports2c,3 (Scheme 3).
In this case, H NMR spectrum of the crude reaction mix-
ture did not show the existence of piperidines 11a,b,deg, but
acyclic products 10a,b,deg, which easily cyclized during
purification by silica gel chromatography to afford alkylated
piperidines 11a,b,deg (Table 3). The radical reaction of 9
with various types of alkyl iodides showed a tendency similar
to that of 3. The tertiary alkyl radical did not work well (en-
tries 3 and 8) and primary alkyl radical gave the corresponding
product 11e in low yield (entry 5). Et3B and BF3$OEt2 were
further added when the radical reaction proceeded slowly
(entries 3e8).
The ethyl radical is generated from Et3B in the presence of
O2. In the presence of RI, the iodine atom-transfer reaction
proceeds to form R radical, which adds intermolecularly to
the BF3$Et2O-activated oxime ether 3. The aminyl radical C
formed is then trapped by Et3B to form the complex D. The
desired product 6 is obtained as a result of the intramolecular
cyclization of D.
In the case of primary alkyl iodide (i-BuI), the ethylated
product 6a was obtained as a major product. This result sug-
gests that the iodine atom-transfer proceeds slowly because
isobutyl radical formed is unstable. On the other hands, the io-
dine atom-transfer proceeds smoothly in the reaction using
tert-butyl iodide and adamantyl iodide because the stable ter-
tiary alkyl radicals are formed. However, the desired products
6 were not obtained because the radical addition reaction of
stable alkyl radical to less reactive oxime ether 3 would pro-
ceed hardly.
We then investigated the domino reaction using glyoxylic
oxime ether 14 as a substrate expecting that more electrophilic
oxime ethers may undergo the radical addition even in the ab-
sence of Lewis acid.2c,3 The oxime ether 14 was prepared by
the condensation of carboxylic acid 136 with the alcohol 127
(Scheme 5).
Table 3
Radical additioneionic cyclization of oxime ether 9
Et3B
OBn
N
OBn
N
OBn
TsO HN
BF3·OEt2
R-I (20 eq.)
R
TsO
R
SiO2
CH2Cl2
rt
The radical reaction was extended to the homologous sys-
tem 9, prepared from dihydropyran 75 (Scheme 4).
10a (R = Et)
b (R = i-Pr)
d (R = s-Bu)
e (R = i-Bu)
11a (R = Et)
b (R = i-Pr)
9
d (R = s-Bu)
e (R = i-Bu)
f (R = c-Pentyl)
g (R = c-Hexyl)
f (R = c-Pentyl)
g (R = c-Hexyl)
OBn
N
O
HO
BnONH2 •HCl
H2O
Entry
ReI
Et3B
(equiv)
BF3$OEt2
(equiv)
Time
(h)
yield (%)
8
7
11beh
11a
TsCl
Et3N
1
2
3
4
5
6
7
8
d
i-PreI
3
3
9
6
6
6
6
9
2
2
6
4
4
4
4
6
4
6
d
38
0
51
9
CH2Cl2
OBn
t-BueI
s-BueI
i-BueI
23
16
23
5
16
16
16
15
16
30
16
57
54
nr
TsO
N
c-PentyleI
c-HexyleI
AdamantyleI
9
E/Z= 4/3
4
23
67% (2 steps)
Scheme 4.
nr: no reaction.

O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1273
O
OBn
HN
R
TsO
H
R
O
•H2O
O
HO
TsO
NHOBn
OH
HO
O
O
O
BnONH2•HCl
AcONa
TsCl
E
MeOH
88%
F
pyridine
70%
Scheme 6.
O
OH
NOBn
2.2. Preparation and radical additioneionic cyclization
reaction of oxime ethers 23, 24, 31, and 32 carrying an
ester group
TsO
HO
13
12
DCC
DMAP
CH2Cl2
86%
In our second approach, we picked up oxime ethers 23 and
24, which carry the ester group as a functional group (Table 5).
The hydroxyl esters 199 and 209 that have different length
carbon chains were prepared from lactones 17 and 18, respec-
tively. The hydroxyl esters 19 and 20 were converted into the
requisite oxime ethers 2310 and 24 via oxidation and subse-
quent condensation with benzyloxyamine (Scheme 7).
In the presence of Lewis acid, two substrates 23 and 24
underwent alkyl radical addition in all cases to give adducts
25 and 26 (Table 5). Et3B and BF3$OEt2 were further added
when the radical reaction proceeded slowly (entries 3, 5, 8,
11, 13, and 16). However, the products 25 and 26 did not cy-
clize under the radical conditions. On treatment with hydro-
chloric acid, these adducts 25 and 26 afforded the cyclized
lactams 27 and 28 in good yields, except for the cyclization
of 26h.
OBn
N
TsO
O
O
14
Scheme 5.
As expected, radical addition reaction of 14 proceeded very
smoothly to give adducts 15aeh (Table 4) but intramolecular
cyclization did not occur even when 15aeh were subjected to
acidic conditions. Et3B and BF3$OEt2 were further added
when the radical reaction proceeded slowly (entries 3 and
8). Interestingly, we obtained tertiary alkyl radical addition
products 15c,h in excellent yields (entries 3 and 8). The
even stable tertiary alkyl radical adds easily to 14 because of
high reactivity of oxime ether 14 as a radical acceptor.
Wiberg8 has reported that Z-rotamer of methyl formate is
more stable than E-rotamer because of small dipole moment
of Z-rotamer.
According to Landais’s recent report,11 we next employed
the phenyl esters 31 and 32, prepared from the corresponding
methyl esters 23 and 24, because the phenoxy group is a better
leaving group than the methoxy group. Under the standard
radical conditions, 31 and 32 gave the expectedly cyclized
lactams 27 and 28 in good yields (Scheme 8, Table 6).
As described above, no cyclization of 15 was observed due
to the stable zig-zag conformation E that makes it unsuitable
for cyclization (Scheme 6).
2.3. Synthesis of (ꢀ)-bgugaine and formal synthesis
of 5,8-disubstituted indolizidine alkaloid
Table 4
Radical additioneionic cyclization of oxime ether 14
OBn
OBn
Et3B
Based on these results, we then applied our method to the
synthesis of a few alkaloids from common oxime ether 3 in
order to evaluate the potentiality of our method. Most simple
application is the synthesis of an alkaloid, bgugaine (36)
(Scheme 9). (ꢂ)-Bgugaine is a 2-alkylpyrrolidine isolated
from the tubers of Arisarum vulgare,12,13 a toxic Araceae
responsible for human and animal poisonings in Morocco.
This alkaloid shows antibacterial activity against Gram posi-
tive bacteria and antimycotic activity against some Candida
and Cryptococcus strains.12e14
TsO
N
TsO
HN
R
O
R-I (20 eq.)
CH2Cl2
rt
O
O
O
14
15a (R = Et)
b (R = i-Pr)
c (R = t-Bu)
d (R = s-Bu)
e (R = i-Bu)
OBn
N
R
f (R = c-Pentyl)
g (R = c-Hexyl)
h (R = Adamantyl)
O
16
O
Radical reaction of oxime ether 3 with longer alkyl chain
iodide 34 gave the alkylated and cyclized product 33 in mod-
erate yield. The improvement of yield was difficult because of
less effective iodine atom-transfer reaction of primary alkyl
iodide 34. Transformation of the functional groups involving
reductive debenzyloxylation and reductive methylation af-
forded simple alkaloid, (ꢀ)-bgugaine (36). The physical and
spectral properties of our prepared pyrrolidine 36 were identi-
cal with those of an authentic sample reported in the
literature.14
Entry
ReI
Et3B
(equiv)
Time
(h)
Yield (%)
15beh
15a
1
2
3
4
5
6
7
8
d
i-PreI
3
3
6
3
3
3
3
6
2.5
2
d
81
86
71
22
75
70
94
79
10
0
t-BueI
s-BueI
i-BueI
2.3
5
26
61
10
24
3
3
c-PentyleI
c-HexyleI
AdamantyleI
4.5
4
6

1274
O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
Table 5
Intermolecular radical additioneionic cyclization reaction of oxime ethers 23 and 24
Et3B
a: R = Et
OBn
N
OBn
HN
OBn
N
BF3·OEt2
R-I
b: R = i-Pr
MeO
O
MeO
O
R
O
R
c. HCl
THF
c: R = t-Bu
d: R = s-Bu
e: R = i-Bu
f: R = c-Pentyl
g: R = c-Hexyl
h: R = Adamantyl
CH2Cl2
rt
n
n
n
23: n=1
24: n=2
25: n=1
26: n=2
27: n=1
28: n=2
Entry
Substrate
ReI
Et3B
(equiv)
BF3$OEt2
(equiv)
Time
(h)
Yield (%)
25, 26
27, 28
1
2
3
4
5
6
7
8
23
23
23
23
23
23
23
23
d
3
3
9
3
9
3
3
3
2
2
6
2
6
2
2
6
2
2
25a (79)
25b (78)a
25c (39)
25d (83)a
25e (26)a
25f (63)a
25g (53)a
25h (48)
27a (78)
27b (79)
27c (65)
27d (95)
27e (85)
27f (81)
27g (85)
27h (70)
i-PreI
t-BueI
s-BueI
i-BueI
23
5
24
2
c-PentyleI
c-HexyleI
AdamantyleI
2
24
9
24
24
24
24
24
24
24
24
d
i-PreI
t-BueI
s-BueI
i-BueI
3
3
9
3
9
3
3
3
2
2
6
2
6
2
2
6
2
2
26a (70)
26b (67)b
26c (24)
26d (55)b
26e (11)b
26f (62)b
26g (61)b
26h (50)b
28a (85)
28b (78)
28c (70)
28d (77)
28e (83)
28f (81)
28g (70)
d
10
11
12
13
14
15
16
a
23
5
24
2
c-PentyeI
c-HexyleI
AdamantyleI
2
24
The ethylated product 25a was also obtained in 14e34% yield.
The ethylated product 26a was obtained in 13e44% yield.
b
Table 6
Intermolecular radical additioneionic cyclization reaction of oxime ethers 31
and 32
DMSO
Et3N
MeOH
OH
n=1:
P2O5
Et3N
O
MeO
O
O
n=2: H2SO4
MeOH
Et3B (3 eq.)
BF3·OEt2 (2 eq.)
R-I (20 eq.)
n
OBn
N
n
OBn
N
PhO
O
17: n=1
18: n=2
19: n=1
20: n=2
O
R
CH2Cl2
rt
n
n
31: n=1
32: n=2
OBn
27a: R =Et, n=1
27b: R =i-Pr, n=1
28a: R =Et, n=2
28b: R =i-Pr, n=2
BnONH2·HCl
MeO
O
MeO
O
AcONa
N
CHO
MeOH
n
n
23: n=1 (E/Z= 2/1) 46%
24: n=2 (E/Z= 3/2) 88%
21: n=1
73% (2steps)
22: n=2
Entry
Substrate
ReI
Time (h)
Yield (%)
27b, 28b
27a, 28a
65% (2steps)
1
2
3
4
31
31
32
32
d
5
4
3
5
d
68
d
63
72
Scheme 7.
i-PreI
d
i-PreI
Trace
70
Trace
Another application is the formal synthesis of 5,8-disubsti-
tuted indolizidine alkaloids 37,15 which have been isolated
from the skin of poison frogs of Dendrobatidae family
(Scheme 10). Due to the extreme scarcity of these alkaloids
from natural sources and their potent biological activities in
neuroscience, considerable attention has been paid to the
chemical synthesis of these alkaloids. The addition of second-
ary alkyl radical generated from 3816 to oxime ether 3 pro-
ceeded effectively to form the cyclized product 39, which
was a 1:1 mixture of two diastereomers 39a and 39b. After
Phenol
OBn
OBn
N
OBn
N
DCC
PhO
N
MeO
O
HO
O
NaOH
THF
H2O
DMAP
O
CH2Cl2
n
n
n
23: n=1
24: n=2
31: n=1 (E/Z= 2/1) 39% (2 steps)
32: n=2 (E/Z= 3/2) 66% (2 steps)
29: n=1
30: n=2
Scheme 8.

O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1275
n-C14H29-I 34
(20 eq.)
was applied to the synthesis of (ꢀ)-bgugaine and the formal
OBn
N
OBn
N
synthesis of 5,8-disubstituted indolizidine alkaloids.
Et3B (6 eq.)
n-C14H29
BF3·OEt 2 (4 eq.)
Zn
TsO
CH2Cl2
rt
30%
4. Experimental
AcOH
67%
33
3
4.1. General
H
1
Melting points are uncorrected. H and 13C NMR spectra
Me
N
HCHO
N
n-C14H29
NaBH4
n-C14H29
were recorded at 200, 300, or 500 MHz and at 50, 75, or
125 MHz for solution in deuteriochloroform (with tetrame-
thylsilane as an internal reference), respectively. IR spectra
were recorded using FTIR apparatus for solutions in chloro-
form except for KBr pellet. Mass spectra were obtained by
EI method. Flash column chromatography (FCC) was
preformed using E. Merck Kieselgel 60 (230e400 mesh). Me-
dium-pressure column chromatography (MCC) was performed
MeOH
rt
76%
35
Bgugaine (36)
Scheme 9.
R1
H
N
R2
using Lober Große B (E. Merck 310-25, Lichroprep Si60).
¨
Preparative TLC (PTLC) separations were carried out on
precoated silica gel plates (E. Merck 60F254).
Indolizidine alkaloids (37)
O
4.2. (E/Z)-4-[[(4-Methylphenyl)sulfonyl]oxy]butanal
O-(phenylmethyl)oxime (3)
OEt
O
OEt
38
I
OBn
Et3B (6 eq.)
BF3·OEt 2 (4 eq.)
N
To a solution of BnONH2$HCl (16 g, 100 mmol) in H2O
(80 mL) was added slowly 2,3-dihydrofuran (4) (7.6 mL,
100 mmol) under a nitrogen atmosphere at room temperature.
After being stirred for 3.5 h, the reaction mixture was neutral-
ized with NaHCO3 and saturated with NaCl. The reaction mix-
ture was diluted with H2O and then extracted with Et2O. The
organic phase was washed with brine, dried over MgSO4, and
NOBn
TsO
CH2Cl2
rt
39 dr=1:1
3
82%
separation
1
then concentrated at reduced pressure. H NMR spectrum of
the residue proved the formation of desired oxime ether, which
without further purification was subjected to the following
reaction. To a solution of oxime ethers 55 (2 g, 10 mmol) in
CH2Cl2 (30 mL) were added Et3N (1.9 mL, 13 mmol) and
TsCl (2.4 g, 12 mmol) under a nitrogen atmosphere at 0 ꢁC.
The reaction mixture was allowed to reach room temperature.
After being stirred at room temperature overnight, the reaction
mixture was diluted with H2O and then extracted with CHCl3.
The organic phase was washed with brine, dried over MgSO4,
and then concentrated at reduced pressure. The crude product
was purified by FCC (n-hexane/AcOEt¼1:1) to afford 3
(2.9 g, 80%) as a colorless oil and a 3:2 mixture of E- and
Z-isomers; 1H NMR (200 MHz, CDCl3) d 7.77 (2H, br d,
J¼8.5 Hz), 7.39e7.25 (7Hþ3/5H, m), 6.61 (2/5H, br t, J¼
6.0 Hz), 5.07 (4/5H, s), 5.00 (6/5H, s), 4.05 (6/5H, t,
J¼6.0 Hz), 4.02 (4/5H, t, J¼6.0 Hz), 2.43 (3H, s), 2.41e2.17
(2H, m), 1.92e1.75 (2H, m); 13C NMR (75 MHz, CDCl3)
d 149.9, 149.1, 144.7, 137.8, 137.5, 132.9, 132.9, 129.8,
128.3, 127.9, 127.8, 77.2, 75.8, 75.6, 69.5, 69.3, 25.6, 25.6,
22.1, 21.6; HRMS (EI, m/z) calcd for C18H21NO4S (Mþ)
347.1190, found 347.1191.
CO2Et
NOBn
CO2E
NOBn
39b
39a
less polar
more polar
Zn
AcOH
Zn
55%
98%
AcOH
Me
H
Me
H
8
N
O
N
O
40b
40a
Scheme 10.
separation of the isomers, each compound was converted into
respective bicyclic lactams 40a and 40b, of which lactam 40a
is known as a synthetic key intermediate17 of poison frog
alkaloids.
3. Conclusion
4.2.1. 2-Ethyl-1-(phenylmethoxy)pyrrolidine (6a) (Table 1,
entry 3)
To a solution of 3 (50 mg, 0.14 mmol) in CH2Cl2 (4.0 mL)
were added BF3$OEt2 (0.04 mL, 0.28 mmol) and Et3B (l mol/L
We have succeeded in the development of radical additione
ionic cyclization method for the preparation of substituted pyr-
rolidines and piperidines. Additionally, this domino reaction

1276
O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
in n-hexane) (0.42 mL, 0.42 mmol) under a nitrogen atmo-
sphere at room temperature. After being stirred for 3.5 h, the
reaction mixture was neutralized with K2CO3 and diluted
with H2O and then extracted with CHCl3. The organic phase
was washed with brine, dried over MgSO4, and then concen-
trated at reduced pressure. The crude product was purified
by MCC (n-hexane/AcOEt¼3:1) to afford 6a (22 mg, 75%)
ddd, J¼12.0, 7.0, 5.5 Hz), 2.98 (1H, m), 2.86e2.77 (1H, m),
1.99e1.26 (7H, m), 0.93 (3H, d, J¼6.5 Hz), 0.89 (3H, d,
J¼6.5 Hz); 13C NMR (125 MHz, CDCl3) d 138.1, 128.5,
128.3, 127.7, 75.6, 66.4, 55.6, 29.7, 27.9, 26.0, 23.5, 22.6, 20.8;
HRMS (EI, m/z) calcd for C15H23NO (Mþ) 233.1778, found
233.1775.
1
as a colorless oil; H NMR (500 MHz, CDCl3) d 7.37e7.25
4.2.6. 2-Cyclopentyl-1-(phenylmethoxy)pyrrolidine (6f)
(24 mg, 68%)
(5H, m), 4.75 and 4.73 (2H, AB q, J¼11.0 Hz), 3.23 (1H,
ddd, J¼12.0, 8.5, 4.5 Hz), 2.80 (2H, m), 1.95e1.88 (1H, m),
1.81e1.68 (3H, m), 1.41e1.33 (2H, m), 0.93 (3H, t, J¼
7.5 Hz); 13C NMR (125 MHz, CDCl3) d 138.1, 128.6, 128.3,
127.7, 75.7, 69.4, 55.7, 26.9, 26.3, 20.3, 11.1; HRMS (EI,
m/z) calcd for C13H19NO (Mþ) 205.1466, found 205.1444.
1
A colorless oil; H NMR (300 MHz, CDCl3) d 7.41e7.24
(5H, m), 4.73 (2H, s), 3.19 (1H, ddd, J¼12.0, 7.0, 5.0 Hz),
2.91e2.80 (2H, m), 2.04e1.15 (13H, m); 13C NMR (75 MHz,
CDCl3) d 138.1, 128.5, 128.2, 127.6, 75.1, 72.7, 56.2, 43.2,
31.0, 29.7, 26.7, 25.6, 25.3, 21.3; HRMS(RI, m/z) calcd for
C16H23NO (Mþ) 245.1779, found 245.1806.
4.2.2. General procedure for alkyl radical additioneionic
cyclization reaction of oxime ether 3
4.2.7. 2-Cyclohexyl-1-(phenylmethoxy)pyrrolidine (6g)
(24 mg, 64%)
To a solution of3(50 mg,0.14 mmol)in CH2Cl2 (4.0 mL)were
added alkyl iodide (2.8 mmol), BF3$OEt2 (0.03 mL, 0.28 mmol),
and Et3B (l mol/L in n-hexane) (0.42 mL, 0.42 mmol) under
a nitrogen atmosphere at room temperature. After being stirred
for 1.5 h, additional BF3$OEt2 (0.03 mL, 0.28 mmol) and Et3B
(l mol/L in n-hexane) (0.42 mL, 0.42 mmol) were added to
the solution. After being stirred for 1.5e21.5 h, the reaction
mixture was neutralized with K2CO3, diluted with H2O,
and then extracted with CHCl3. The organic phase was
washed with brine, dried over MgSO4, and then concentrated
at reduced pressure. The crude product was purified by MCC
(n-hexane/AcOEt¼20:1) to afford pyrrolidines 6 as shown in
Table 2.
1
A colorless oil; H NMR (300 MHz, CDCl3) d 7.35e7.26
(5H, m), 4.72 (2H, s), 3.18 (1H, m), 2.86e2.75 (2H, m),
1.89e0.86 (15H, m); 13C NMR (50 MHz, CDCl3) d 138.2,
128.6, 128.3, 127.6, 75.0, 73.2, 56.2, 40.1, 31.3, 29.0, 26.8, 26.5,
26.4, 24.9, 21.4; HRMS (EI, m/z) calcd for C17H25NO (Mþ)
259.1925, found 259.1935.
4.3. (E/Z)-5-[[(4-Methylphenyl)sulfonyl]oxy]pentanal
O-(phenylmethyl)oxime (9)
According to the procedure given for the preparation of ox-
ime ether 3, the treatment of 3,4-dihydropyran 7 (4.3 mL,
48 mmol) with BnONH2$HCl (4.0 g, 48 mmol) followed by to-
sylation of resulting alcohol 85 (4.0 g, 19 mmol) with TsCl
(4.5 g, 23 mmol) in the presence of Et3N (3.5 mL, 25 mmol)
gave 9 (4.7 g, 67%) as a colorless oil and a 4:3 mixture of E-
4.2.3. 2-(1-Methylethyl)-1-(phenylmethoxy)pyrrolidine (6b)
(16 mg, 51%)
Acolorlessoil;1HNMR(500 MHz,CDCl3)d7.36e7.26(5H,
m),4.74and4.71(2H,ABq,J¼11.0 Hz),3.19(1H,ddd,J¼11.0,
8.0, 4.5 Hz), 2.80 (1H, m), 2.74 (1H, br q, J¼7.0 Hz), 1.85 (1H,
m), 1.81e1.72 (2H, m), 1.69e1.64 (1H, m), 1.44 (1H, m), 0.97
(3H, d, J¼7.0 Hz), 0.90(3H, d, J¼7.0 Hz);13CNMR(125 MHz,
CDCl3) d 137.8, 128.3, 127.9, 127.3, 74.8, 73.4, 55.8, 29.4, 23.6,
20.7, 20.3, 17.6; HRMS (EI, m/z) calcd for C14H21NO (Mþ)
219.1622, found 219.1648.
1
and Z-isomers; H NMR (300 MHz, CDCl3) d 7.78 (2H, br d,
J¼8.0 Hz), 7.39e7.26 (7Hþ4/7H, m), 6.61 (3/7H, br t, J¼
6.0 Hz), 5.08 (6/7H, s), 5.03 (8/7H, s), 4.02 (2H, t, J¼
6.0 Hz), 2.45 (3H, s), 2.32 (6/7H, br q, J¼6.0 Hz), 2.15 (8/7H,
br q, J¼6.0 Hz), 1.71e1.50 (4H, m); 13C NMR (75 MHz,
CDCl3) d 151.0, 150.2, 144.6, 137.8, 137.5, 132.9, 129.7,
128.2, 128.0, 127.8, 127.7, 127.6, 75.6, 75.4, 69.8, 69.8, 28.6,
28.2, 27.9, 25.5, 25.5, 24.8, 22.2, 21.9, 21.4; HRMS (EI, m/z)
calcd for C19H23NO4S (Mþ) 361.1346, found 361.1353.
4.2.4. 2-(1-Methylpropyl)-1-(phenylmethoxy)pyrrolidine
(6d) (27 mg, 80%)
A colorless oil as a 1:1 mixture of diastereomers; 1H NMR
(300 MHz, CDCl3) d 7.34e7.26 (5H, m), 4.73 (1H, s), 4.71
(1H, s), 3.18 (1H, m), 2.86e2.72 (2H, m), 1.83e1.01 (7H,
m), 0.97e0.87 (6H, m); 13C NMR (50 MHz, CDCl3) d 138.2,
128.6, 128.2, 127.6, 75.3, 75.1, 73.0, 72.0, 56.1, 55.9, 36.6, 35.8,
29.7, 27.4, 24.9, 24.5, 23.0, 21.2, 20.7, 19.4, 16.8, 16.7, 14.1,
11.9, 11.7; HRMS (EI, m/z) calcd for C15H23NO (Mþ)
233.1778, found 233.1798.
4.3.1. 2-Ethyl-1-(phenylmethoxy)piperidine (11a) (Table 3,
entry 1)
According to the procedure given for the preparation of pyr-
rolidine 6a, the treatment of 9 (50 mg, 0.14 mmol) with Et3B
(l mol/L in n-hexane) (0.42 mL, 0.42 mmol) in the presence
of BF3$OEt2 (0.04 mL, 0.28 mmol) followed by the purifica-
tion by MCC (n-hexane/AcOEt¼20:1) gave 11a (16 mg,
1
51%) as a colorless oil; H NMR (500 MHz, CDCl3) d 7.37e
7.26 (5H, m), 4.73 and 4.69 (2H, AB q, J¼10.0 Hz), 3.40
(1H, br d, J¼10.5 Hz), 2.46 (1H, br t, J¼10.5 Hz), 2.31 (1H,
m), 2.00 (1H, m), 1.82 (1H, br d, J¼10.5 Hz), 1.71 (1H, br d,
J¼10.5 Hz), 1.63 (1H, br d, J¼10.5 Hz), 1.59e1.52 (1H, m),
1.43 (1H, m), 1.23 (2H, m), 0.91 (3H, t, J¼7.5 Hz);
4.2.5. 2-(2-Methylpropyl)-1-(phenylmethoxy)pyrrolidine
(6e) (4.2 mg, 13%)
1
A colorless oil; H NMR (300 MHz, CDCl3) d 7.37e7.26
(5H, m), 4.75 and 4.71 (2H, AB q, J¼11.0 Hz), 3.21 (1H,

O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1277
13C NMR (125 MHz, CDCl3) d 137.5, 128.7, 128.3, 127.8,
75.2, 68.3, 56.8, 30.2, 25.9, 25.6, 23.9, 9.8; HRMS (EI, m/z)
calcd for C14H21NO (Mþ) 219.1622, found 219.1629.
4.3.7. 2-Cyclohexyl-1-(phenylmethoxy)piperidine (11g)
(20 mg, 54%)
1
A colorless oil; H NMR (300 MHz, CDCl3) d 7.38e7.26
(5H, m), 4.72 and 4.66 (2H, AB q, J¼10.5 Hz), 3.43 (1H, br
d, J¼9.5 Hz), 2.46 (1H, br t, J¼10.5 Hz), 2.27 (1H, dt,
J¼10.5, 3.0 Hz), 2.09e1.03 (17H, m); 13C NMR (75 MHz,
CDCl3) d 137.6, 128.9, 128.3, 127.8, 74.8, 72.0, 57.2, 38.2,
30.4, 27.1, 26.8, 25.9, 25.7, 24.1; HRMS (EI, m/z) calcd for
C18H27NO (Mþ) 273.2091, found 273.2104.
4.3.2. General procedure for alkyl radical additioneionic
cyclization reaction of oxime ether 9
According to the procedure given for the preparation of pyrro-
lidine 6b, the treatment of 9 (50 mg, 0.14 mmol) with Et3B (l mol/
L in n-hexane) (0.42 or 0.84 mL, 0.42 or 0.84 mmol) in the
presence of BF3$OEt2 (0.04 or 0.08 mL, 0.28 or 0.56 mmol)
and alkyl iodide (2.8 mmol) gave 11 as shown in Table 3.
4.4. 2-[[(4-Methylphenyl)sulfonyl]oxy]ethyl (E)-[(phenyl-
methoxy)imino]acetate (14)
To a solution of 127 (830 mg, 3.84 mmol) and 136
(229 mmol, 1.28 mmol) in CH2Cl2 (4 mL) were added
DMAP (125 mg, 1.02 mmol) and DCC (291 mg, 1.41 mmol)
under a nitrogen atmosphere at 0 ꢁC. The mixture was allowed
to reach room temperature. After being stirred for 5 h, the re-
action mixture was filtered and the filtrate was diluted with
0.5 M HCl and then extracted with CHCl3. The organic phase
was diluted with satd aq NaHCO3 and then extracted with
CHCl3. The organic phase was washed with brine, dried
over MgSO4, and then concentrated at reduced pressure. The
crude product was purified by FCC (hexane/AcOEt¼1:1) to
afford 14 (414 mg, 86%) as a colorless oil; IR (CHCl3)
4.3.3. 2-(1-Methylethyl)-1-(phenylmethoxy)piperidine (11b)
(12 mg, 38%)
1
A colorless oil; H NMR (500 MHz, CDCl3) d 7.36e7.27
(5H, m), 4.74 and 4.69 (2H, AB q, J¼10.5 Hz), 3.43 (1H,
m), 2.46 (2H, m), 2.28 (1H, br d, J¼11.0 Hz), 1.67e1.51 (4H,
m), 1.29e1.15 (2H, m), 0.95 (3H, d, J¼7.0 Hz), 0.89 (3H, d,
J¼7.0 Hz); 13C NMR (125 MHz, CDCl3) d 137.6, 128.7,
128.3, 127.8, 74.7, 71.9, 57.2, 29.7, 26.8, 25.9, 24.0, 19.6,
16.1; HRMS (EI, m/z) calcd for C15H23NO (Mþ) 233.1778,
found 233.1798.
1
1742 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.79 (2H, br d,
4.3.4. 2-(1-Methylpropyl)-1-(phenylmethoxy)piperidine
(11d) (10 mg, 30%)
J¼8.5 Hz), 7.42 (1H, s), 7.38e7.30 (7H, m), 5.30 (2H, s),
4.42e4.27 (4H, m), 2.43 (3H, s); 13C NMR (75 MHz, CDCl3)
d 161.3, 145.1, 140.2, 135.8, 132.7, 129.9, 128.6, 128.0, 78.3,
67.1, 62.5, 21.6; HRMS (EI, m/z) calcd for C18H19NO6S (Mþ)
377.0932, found 377.0943.
A colorless oil as a 1:1 mixture of diastereomers; 1H NMR
(300 MHz, CDCl3) d 7.35e7.28 (5H, m), 4.73 and 4.69 (1H,
AB q, J¼10.5 Hz), 4.71 and 4.63 (1H, AB, J¼10.5 Hz),
3.42 (1H, br d, J¼10.5 Hz), 2.46 (1H, br t, J¼10.5 Hz), 2.34
(1H, m), 2.14e1.22 (9H, m), 0.96e0.87 (6H, m); 13C NMR
(75 MHz, CDCl3) d 137.7, 128.8, 128.7, 128.3, 127.8, 127.7,
74.7, 72.5, 70.8, 57.2, 34.4, 34.0, 27.0, 25.9, 24.7, 24.3, 24.1,
24.0, 23.2, 16.2, 13.7, 12.8, 12.5; HRMS (EI, m/z) calcd for
C16H25NO (Mþ) 247.1935, found 247.1922.
4.4.1. 2-[[(4-Methylphenyl)sulfonyl]oxy]ethyl 2-[(Phenyl-
methoxy)amino]butanoate (15a) (Table 4, entry 1)
To a solution of 14 (50 mg, 0.13 mmol) in CH2Cl2 (3.7 mL)
was added Et3B (l mol/L in n-hexane) (0.40 mL, 0.40 mmol)
under a nitrogen atmosphere at room temperature. After being
stirred for 2 h, the reaction mixture was neutralized with
K2CO3, diluted with H2O, and then extracted with CHCl3.
The organic phase was washed with brine, dried over
MgSO4, and then concentrated at reduced pressure. The crude
product was purified by MCC (n-hexane/AcOEt¼20:1) to
afford 15a (41 mg, 79%) as a colorless oil; IR (CHCl3)
4.3.5. 2-(2-Methylpropyl)-1-(phenylmethoxy)piperidine
(11e) (5.6 mg, 16%)
1
A colorless oil; H NMR (300 MHz, CDCl3) d 7.35e7.26
(5H, m), 4.71 (2H, s), 3.42 (1H, m), 2.50e2.30 (2H, m),
2.01e1.19 (9H, m), 0.93 (3H, d, J¼7.5 Hz), 0.91 (3H, d,
J¼7.5 Hz); 13C NMR (75 MHz, CDCl3) d 138.0, 128.8,
128.3, 127.7, 75.2, 68.2, 56.8, 38.7, 30.4, 28.9, 25.9, 23.9, 23.7,
23.0; HRMS (EI, m/z) calcd for C16H25NO (Mþ) 247.1935,
found 247.1943.
1
3275, 1742 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.78 (2H,
br d, J¼8.0 Hz), 7.33e7.26 (7H, m), 5.87 (1H, br s), 4.66
(2H, s), 4.39e4.18 (4H, m), 3.48 (1H, t, J¼7.0 Hz), 2.43 (3H,
s), 1.60e1.40 (2H, m), 0.88 (3H, t, J¼7.5 Hz); 13C NMR
(75 MHz, CDCl3) d 173.6, 145.0, 137.7, 132.7, 129.9, 128.4,
128.3, 127.9, 127.8, 76.1, 67.4, 64.9, 61.8, 22.7, 21.6, 10.4;
HRMS (EI, m/z) calcd for C20H25NO6S (Mþ) 407.1401, found
407.1416.
4.3.6. 2-Cyclopentyl-1-(phenylmethoxy)piperidine (11f)
(21 mg, 57%)
1
A colorless oil; H NMR (300 MHz, CDCl3) d 7.41e7.26
(5H, m), 4.70 (2H, s), 3.40 (1H, m), 2.49e1.26 (17H, m);
13C NMR (75 MHz, CDCl3) d 137.6, 128.6, 128.3, 127.7,
74.6, 69.4, 56.7, 53.7, 42.6, 40.2, 29.5, 27.3, 26.0, 25.6, 23.8;
HRMS (EI, m/z) calcd for C17H25NO (Mþ) 259.1935, found
259.1947.
4.4.2. General procedure for primary or secondary alkyl
radical addition reaction of oxime ether 14
To a solution of 14 (50 mg, 0.13 mmol) in CH2Cl2 (3.7 mL)
were added alkyl iodide (2.7 mmol) and Et3B (l mol/L in
n-hexane) (0.40 mL, 0.40 mmol) under a nitrogen atmosphere

1278
O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
at room temperature. After being stirred for 2e6 h, the reac-
tion mixture was neutralized with K2CO3, diluted with H2O
and then extracted with CHCl3. The organic phase was washed
with brine, dried over MgSO4, and then concentrated at
reduced pressure. The crude product was purified by
MCC (n-hexane/AcOEt¼20:1) to afford 15 as shown in
Table 4.
4.4.7. 2-[[(4-Methylphenyl)sulfonyl]oxy]ethyl 2-[(Phenyl-
methoxy)amino]cyclohexaneacetate (15g) (43 mg, 70%)
1
A colorless oil; IR (CHCl3) 3269, 1734 cmꢂ1; H NMR
(300 MHz, CDCl3) d 7.79 (2H, br d, J¼8.0 Hz), 7.36e7.25
(7H, m), 5.89 (1H, br s), 4.63 (2H, s), 4.43e4.23 (4H, m),
3.36 (1H, d, J¼7.0 Hz), 2.44 (3H, s), 1.76e0.90 (11H, m);
13C NMR (75 MHz, CDCl3) d 173.6, 145.0, 137.8, 132.8,
129.9, 128.6, 128.2, 127.9, 127.8, 75.9, 68.9, 67.4, 61.7,
38.4, 29.7, 29.5, 26.0, 25.9, 21.6; HRMS (EI, m/z) calcd for
C24H31NO6S (Mþ) 461.1870, found 461.1891.
4.4.3. N-(Phenylmethoxy)valine 2-[[(4-methylphenyl)-
sulfonyl]oxy]ethyl ester (15b) (43 mg, 81%)
A colorless oil; IR (neat) 3269, 1742 cmꢂ1 1H NMR
;
4.4.8. General procedure for tertiary alkyl radical addition
reaction of oxime ether 14 (Table 4, entries 3 and 8)
(300 MHz, CDCl3) d 7.78 (2H, br d, J¼7.0 Hz), 7.33e7.25
(7H, m), 5.90 (1H, br s), 4.64 (2H, s), 4.40e4.21 (4H, m),
3.31 (1H, d, J¼7.0 Hz), 2.43 (3H, s), 1.78e1.61 (1H, m), 0.87
(3H, d, J¼7.0 Hz), 0.84 (3H, d, J¼7.0 Hz); 13C NMR
(75 MHz, CDCl3) d 173.5, 145.0, 137.7, 132.7, 129.9, 128.6,
128.2, 127.9, 127.8, 75.9, 69.4, 67.4, 61.7, 29.0, 21.6, 19.2,
19.2; HRMS (EI, m/z) calcd for C21H27NO6S (Mþ)
421.1558, found 421.1555.
To a solution of 14 (50 mg, 0.13 mmol) in CH2Cl2 (3.7 mL)
were added alkyl iodide (2.65 mmol) and Et3B (l mol/L in
n-hexane) (0.40 mL, 0.40 mmol) under a nitrogen atmosphere
at room temperature. After being stirred for 1.5 h, an addi-
tional Et3B (l mol/L in n-hexane) (0.40 mL, 0.40 mmol) was
added to the solution. After being stirred for 1e4.5 h, the re-
action mixture was neutralized with K2CO3, diluted with
H2O, and then extracted with CHCl3. The organic phase was
washed with brine, dried over MgSO4, and then concentrated
at reduced pressure. The crude product was purified by MCC
to afford 15c,h as shown in Table 4.
4.4.4. N-(Phenylmethoxy)isoleucine 2-[[(4-methylphenyl)-
sulfonyl]oxy]ethyl ester (15d) (41 mg, 71%)
A colorless oil as a 1:1 mixture of diastereomers; IR (neat)
1
3269, 1739 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.78 (2H,
br d, J¼8.5 Hz), 7.36e7.25 (7H, m), 5.91 (1H, br s), 4.64
(1H, s), 4.64 (1H, s), 4.40e4.21 (4H, m), 3.44 (1H, m),
2.44 (3H, s), 1.58e1.03 (3H, m), 0.85e0.78 (6H, m); 13C
NMR (75 MHz, CDCl3) d 173.5, 145.0, 137.8, 132.8, 129.9,
128.6, 128.6, 128.3, 127.9, 127.8, 76.0, 68.0, 67.4, 61.8,
35.7, 35.3, 26.3, 25.9, 21.6, 15.5, 15.2, 11.3, 11.0; HRMS
(EI, m/z) calcd for C22H29NO6S (Mþ) 435.1714, found
435.1712.
4.4.9. 3-Methyl-N-(phenylmethoxy)valine 2-[[(4-
methylphenyl)sulfonyl]oxy]ethyl ester (15c) (50 mg, 86%)
A colorless oil; IR (CHCl3) 3285, 1736 cmꢂ1; H NMR
1
(300 MHz, CDCl3) d 7.77 (2H, br d, J¼8.0 Hz), 7.33e7.25
(7H, m), 5.99 (1H, br s), 4.62 (2H, s), 4.32e4.20 (4H, m),
3.26 (1H, s), 2.43 (3H, s), 0.86 (9H, s); 13C NMR (50 MHz,
CDCl3) d 173.5, 145.0, 137.8, 132.7, 129.9, 128.7, 128.2,
127.9, 127.7, 75.7, 71.9, 67.4, 61.6, 33.0, 26.9, 21.6; HRMS
(EI, m/z) calcd for C22H29NO6S (Mþ) 435.1713, found
435.1727.
4.4.5. N-(Phenylmethoxy)leucine 2-[[(4-methylphenyl)-
sulfonyl]oxy]ethyl ester (15e) (13 mg, 22%)
4.4.10. 2-[[(4-Methylphenyl)sulfonyl]oxy]ethyl 2-[(phenyl-
methoxy)amino]tricycle[3.3.1.13,7]-decane-1-acetate (15h)
(63 mg, 94%)
1
A colorless oil; IR (CHCl3) 3269, 1742 cmꢂ1; H NMR
(300 MHz, CDCl3) d 7.78 (2H, br d, J¼8.5 Hz), 7.37e7.29
(7H, m), 5.91 (1H, br s), 4.68 (1H, s), 4.35e4.21 (4H, m),
3.61 (1H, t, J¼7.0 Hz), 2.44 (3H, s), 1.62 (1H, m), 1.29
(2H, m), 0.87 (3H, d, J¼7.0 Hz, Me), 0.84 (3H, d, J¼7.0 Hz,
Me); 13C NMR (75 MHz, CDCl3) d 174.2, 145.1, 137.8, 132.8,
130.0, 128.5, 128.3, 128.0, 127.8, 76.1, 67.4, 62.1, 61.9, 38.3,
25.0, 22.6, 22.1, 21.6; HRMS (EI, m/z) calcd for C22H29NO6S
(Mþ) 435.1714, found 435.1717.
Colorless crystals; mp 123e125 ꢁC (hexane/AcOEt); IR
(CHCl3) 3280, 1731 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d 7.78 (2H, br d, J¼8.5 Hz), 7.36e7.29 (7H, m), 6.04 (1H,
br s), 4.61 (2H, s), 4.39e4.23 (4H, m), 3.20 (1H, s), 2.44
(3H, s), 1.91e1.26 (15H, m). 13C NMR (75 MHz, CDCl3)
d 173.0, 145.0, 137.8, 132.8, 129.9, 128.6, 128.2, 127.9, 127.7,
75.7, 72.9, 67.4, 61.6, 40.4, 39.1, 36.7, 35.1, 28.2, 21.6;
HRMS (EI, m/z) calcd for C28H35NO6S (Mþ) 513.2183, found
513.2174.
4.4.6. 2-[[(4-Methylphenyl)sulfonyl]oxy]ethyl 2-[(Phenyl-
methoxy)amino]cyclopentaneacetate (15f) (44 mg, 75%)
1
A colorless oil; IR (CHCl3) 3275, 1737 cmꢂ1; H NMR
4.5. Methyl 4-oxobutanoate (21)
(300 MHz, CDCl3) d 7.78 (2H, br d, J¼8.5 Hz), 7.33e7.25
(7H, m), 5.86 (1H, br s), 4.64 (2H, s), 4.39e4.21 (4H, m),
3.34 (1H, m), 2.43 (3H, s), 1.83e1.21 (9H, m); 13C NMR
(75 MHz, CDCl3) d 173.7, 145.0, 137.7, 132.7, 129.9, 128.6,
128.2, 127.9, 127.8, 76.0, 68.2, 67.4, 61.7, 39.7, 30.0, 29.0,
24.9, 24.9, 21.6; HRMS (EI, m/z) calcd for C23H29NO6S (Mþ)
447.1714, found 447.1715.
To a solution of 199 (2.7 g, 23 mmol) in CH2Cl2 (116 mL)
were added DMSO (3.3 mL, 46 mmol) and P2O5 (6.6 g,
46 mmol) under a nitrogen atmosphere at room temperature.
After being stirred for 2 h, the mixture was cooled to 0 ꢁC
and then Et3N (11 mL, 81 mmol) was added. After being stirred
for 1.5 h, the reaction mixture was diluted with 10% HCl and

O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1279
then extracted with CHCl3. The organic phase was washed with
brine, dried over MgSO4, and then concentrated at reduced
pressure. The crude product was purified by FCC (hexane/
AcOEt¼1:1) to afford 21 (2.0 g, 73%) as a colorless oil.
The spectral data were identical with those reported in
literature.9
presence of BF3$OEt2 (0.06 mL, 0.45 mmol) gave 25a
(45 mg, 79%) as colorless oil; IR (CHCl3) 3264,
a
1732 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.35e7.26 (5H,
m), 4.67 (2H, s), 3.65 (3H, s), 2.77 (1H, br quint,
J¼6.0 Hz), 2.39 (2H, t, J¼7.5 Hz), 1.86e1.68 (4H, m, 0.91
(3H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3) d 174.3,
138.0, 128.4, 128.3, 127.7, 76.4, 61.2, 51.5, 30.6, 26.7, 24.5,
10.1; HRMS (EI, m/z) calcd for C14H21NO3 (Mþ) 251.1520,
found 251.1546.
1
4.5.1. Methyl 5-oxopentanoate (22)
According to the procedure given for the preparation of 21,
the treatment of hydroxyl ester 209 (2.6 g, 20 mmol) with
DMSO (2.8 mL, 40 mmol) in the presence of P2O5 (5.7 g,
40 mmol) gave 22 (1.7 g, 65%) as a colorless oil.
The spectral data were identical with those reported in
literature.9
4.5.5. General procedure for alkyl radical addition reaction
of oxime ether 23
According to the procedure given for the preparation of
pyrrolidine 6b, the treatment of 23 (50 mg, 0.23 mmol) with
Et3B (l mol/L in n-hexane) (0.68 or 2.04 mL, 0.68 or
2.04 mmol) in the presence of BF3$OEt2 (0.06 or 0.18 mL,
0.45 or 1.35 mmol) and alkyl iodide (4.5 mmol) gave 25 as
shown in Table 5.
4.5.2. Methyl (E/Z)-4-[(phenylmethoxy)imino]butanoate
(23)
To a solution of 21 (0.75 g, 6.5 mmol) in MeOH (30 mL)
were added BnONH2$HCl (1.6 g, 9.7 mmol) and AcONa
(1.1 g, 13 mmol) under a nitrogen atmosphere at room temper-
ature. After the reaction mixture was stirred overnight, the
reaction mixture was concentrated at reduced pressure and neu-
tralized with NaHCO3. Then the reaction mixture was diluted
with H2O and then extracted with CHCl3. The organic phase
was washed with brine, dried over MgSO4, and then concen-
trated at reduced pressure. The crude product was purified by
FCC (hexane/AcOEt¼5:1) to afford 2310 (0.66 g, 46%) as a col-
orless oil and a 2:1 mixture of E- and Z-isomers; IR (neat)
4.5.6. Methyl 5-methyl-4-[(phenylmethoxy)amino]-
hexanoate (25b) (47 mg, 78%)
A colorless oil; IR (neat) 3280, 1739 cmꢂ1 1H NMR
;
(200 Hz, CDCl3) d 7.36e7.26 (5H, m), 5.54 (1H, br s), 4.66
(2H, s), 3.65 (3H, s), 2.60 (1H, ddd, J¼9.0, 5.5, 4.0 Hz),
2.51e2.28 (2H, m), 2.01e1.73 (2H, m), 1.67e1.48 (1H, m),
0.92 (3H, d, J¼7.0 Hz), 0.89 (3H, d, J¼7.0 Hz); 13C NMR
(75 MHz, CDCl3) d 174.4, 138.0, 128.4, 128.3, 127.7, 76.2,
65.3, 51.5, 31.5, 28.9, 23.7, 19.1, 18.0; HRMS (EI, m/z) calcd
for C15H23NO3 (Mþ) 265.1677, found 251.1687.
1
1737 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.50 (2/3H, br t,
J¼5.0 Hz), 7.37e7.28 (5H, m), 6.74 (1/3H, br t, J¼5.0 Hz),
5.11 (2/3H, s), 5.04 (4/3H, s), 3.68 (3/3H, s), 3.66 (6/3H, s),
2.67e2.47 (4H, m); 13C NMR (75 MHz, CDCl3) d 172.5,
149.8, 148.9, 137.7, 137.5, 128.2, 128.1, 127.8, 127.7, 75.7,
75.5, 51.5, 30.4, 30.3, 24.8, 21.2; HRMS (EI, m/z) calcd for
C12H15NO3 (Mþ) 221.1051, found 221.1066.
4.5.7. Methyl 5,5-dimethyl-4-[(phenylmethoxy)amino]-
hexanoate (25c) (25 mg, 39%)
A colorless oil; IR (neat) 3286, 1739 cmꢂ1 1H NMR
;
(200 Hz, CDCl3) d 7.34e7.26 (5H, m), 5.58 (1H, br s), 4.64
(2H, s), 3.65 (3H, s), 2.67e2.35 (3H, m), 1.98e1.54 (2H,
m), 0.95 (9H, s); 13C NMR (50 MHz, CDCl3) d 174.6, 138.1,
128.3, 128.3, 127.6, 77.2, 75.9, 68.7, 51.4, 34.4, 32.6, 27.3,
24.2; HRMS (CI, m/z) calcd for C16H26NO3 (MþHþ)
280.1911, found 280.1927.
4.5.3. Methyl (E/Z)-5-[(phenylmethoxy)imino]pentanoate
(24)
According to the procedure given for the preparation of
oxime ether 23, the treatment of aldehyde 22 (1.7 g,
13 mmol) with BnONH2$HCl (3.1 g, 19 mmol) in the presence
of AcONa (2.1 g, 26 mmol) gave 24 (2.7 g, 88%) as a colorless
oil and a 3:2 mixture of E- and Z-isomers; IR (CHCl3)
4.5.8. Methyl 5-methyl-4-[(phenylmethoxy)amino]-
heptanoate (25d) (52 mg, 83%)
A colorless oil as a 1:1 mixture of diastereomers; IR (neat)
1
1
1736 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.43 (3/5H, br t,
3264, 1739 cmꢂ1; H NMR (300 Hz) d 7.34e7.26 (5H, m),
J¼6.0 Hz), 7.37e7.26 (5H, m), 6.68 (2/5H, br t, J¼6.0 Hz),
5.09 (4/5H, s), 5.05 (6/5H, s), 3.67 (3H, s), 2.47e2.19 (4H,
m), 1.90e1.76 (2H, m); 13C NMR (75 MHz, CDCl3) d 173.3,
173.2, 150.9, 150.0, 137.8, 137.5, 128.2, 128.1, 127.8, 127.7,
127.6, 77.2, 76.6, 75.6, 75.5, 51.4, 33.3, 32.9, 28.7, 25.1, 21.6,
21.4; HRMS (EI, m/z) calcd for C13H17NO3 (Mþ) 235.1207,
found 235.1202.
5.51 (1H, br s), 4.65 (2H, s), 3.65 (3H, s), 2.78e2.69 (1H,
m), 2.51e2.30 (2H, m), 1.84e1.03 (5H, m), 0.92e0.82 (6H,
m); 13C NMR (75 MHz, CDCl3) d 174.3, 138.1, 138.1, 128.4,
128.4, 128.3, 127.7, 76.2, 76.2, 64.0, 63.7, 51.4, 36.0, 35.4,
31.7, 31.6, 26.1, 25.1, 24.5, 23.0, 15.1, 13.9, 11.9, 11.9; HRMS
(EI, m/z) calcd for C16H25NO3 (Mþ) 279.1833, found
279.1845.
4.5.4. Methyl 4-[(phenylmethoxy)amino]hexanoate (25a)
(Table 5, entry 1)
According to the procedure given for the preparation of
pyrrolidine 6a, the treatment of 23 (50 mg, 0.23 mmol) with
Et3B (l mol/L in n-hexane) (0.68 mL, 0.68 mmol) in the
4.5.9. Methyl 6-methyl-4-(phenylmethoxy)amino]-
heptanoate (25e) (16 mg, 26%)
A colorless oil; IR (neat) 3264, 1737 cmꢂ1 1H NMR
;
(300 Hz, CDCl3) d 7.35e7.26 (5H, m), 5.40 (1H, br s), 4.67
(2H, s), 3.66 (3H, s), 2.92 (1H, m), 2.39 (2H, t, J¼7.5 Hz),

1280
O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1.83e1.09 (5H, m), 0.88 (6H, d, J¼7.5 Hz); 13C NMR
(75 MHz, CDCl3) d 174.3, 138.0, 128.4, 128.3, 127.7, 76.5,
57.7, 51.5, 41.2, 30.4, 27.6, 24.9, 22.9, 22.7; HRMS (EI,
m/z) calcd for C16H25NO3 (Mþ) 279.1833, found 279.1819.
4.5.15. 5-(1-Methylethyl)-1-(phenylmethoxy)-2-
pyrrolidinone (27b)
1
A colorless oil; IR (neat) 1698 cmꢂ1; H NMR (300 Hz,
CDCl3) d 7.46e7.34 (5H, m), 5.04 and 4.96 (2H, AB q,
J¼10.5 Hz), 3.37 (1H, ddd, J¼8.5, 5.5, 3.5 Hz), 2.31 (1H,
ddd, J¼17.0, 9.5, 6.5 Hz), 2.25 (1H, m), 2.15 (1H, m),
1.92e1.64 (2H, m), 0.87 (3H, d, J¼7.0 Hz), 0.84 (3H, d, J¼
7.0 Hz); 13C NMR (50 MHz, CDCl3) d 171.0, 135.3, 129.4,
128.7, 128.5, 77.2, 62.3, 28.6, 27.2, 18.1, 16.4, 15.5; HRMS
(EI, m/z) calcd for C14H20NO2 (Mþ) 234.1493, found
234.1500.
4.5.10. Methyl 4-[(phenylmethoxy)amino]cyclopentane-
butanoate (25f) (41 mg, 63%)
A colorless oil; IR (neat) 3280, 1731 cmꢂ1 1H NMR
;
(300 Hz, CDCl3) d 7.35e7.26 (5H, m), 5.57 (1H, br s), 4.68
(2H, s), 3.66 (3H, s), 2.62 (1H, td, J¼8.5, 3.5 Hz), 2.45 (2H,
t, J¼7.5 Hz), 2.01e1.87 (2H, m), 1.83e1.14 (9H, m); 13C
NMR (75 MHz, CDCl3) d 174.6, 138.0, 128.4, 128.3, 127.7,
76.4, 64.8, 51.5, 41.6, 30.6, 30.0, 29.7, 26.0, 25.3, 25.3;
HRMS (EI, m/z) calcd for C17H25NO3 (Mþ) 291.1833, found
291.1854.
4.5.16. 5-(1,1-Dimethylethyl)-1-(phenylmethoxy)-
2-pyrrolidinone (27c)
1
A colorless oil; IR (neat) 1706 cmꢂ1; H NMR (300 Hz,
CDCl3) d 7.46e7.33 (5H, m), 5.04 and 4.95 (2H, AB q,
J¼10.5 Hz), 3.25 (1H, dd, J¼8.0, 5.0 Hz), 2.33 (1H, ddd,
J¼17.0, 9.5, 6.0 Hz), 2.22 (1H, ddd, J¼17.0, 9.5, 6.0 Hz),
1.97e1.72 (2H, m), 0.96 (9H, s); 13C NMR (75 MHz, CDCl3)
d 170.9, 134.9, 129.7, 128.8, 128.5, 77.2, 75.1, 65.8, 34.8,
27.1, 26.3, 18.7; HRMS (EI, m/z) calcd for C15H22NO2
(MþHþ) 248.1649, found 248.1657.
4.5.11. Methyl 4-[(phenylmethoxy)amino]cyclohexane-
butanoate (25g) (37 mg, 53%)
A colorless oil; IR (neat) 3274, 1734 cmꢂ1 1H NMR
;
(200 Hz, CDCl3) d 7.40e7.26 (5H, m), 5.57 (1H, br s), 4.65
(2H, s), 3.65 (3H, s), 2.59 (1H, ddd, J¼9.0, 5.5, 3.5 Hz),
2.46e2.36 (2H, m), 1.92e0.91 (13H, m); 13C NMR (75 MHz,
CDCl3) d 174.4, 138.1, 128.4, 128.3, 127.7, 76.2, 64.8, 51.5,
39.0, 31.5, 29.5, 28.7, 26.6, 26.4, 24.2; HRMS (EI, m/z) calcd
for C18H27NO3 (Mþ) 305.1990, found 305.2013.
4.5.17. 5-(1-Methylpropyl)-1-(phenylmethoxy)-
2-pyrrolidinone (27d)
A colorless oil as a 1:1 mixture of diastereomers; IR (neat)
4.5.12. Methyl 4-[(phenylmethoxy)amino]tricyclo-
1
[3.3.1.13,7]decane-1-butanoate (25h) (39 mg, 48%)
1709 cmꢂ1; H NMR (300 Hz, CDCl3) d 7.45e7.33 (5H, m),
A colorless oil; IR (neat) 3264, 1734 cmꢂ1
;
1H NMR
5.05 and 4.97 (1H, AB q, J¼10.5 Hz), 5.05 and 4.93 (1H, AB
q, J¼10.5 Hz), 3.43 (1H, m), 2.31e2.25 (2H, m), 1.96e0.96
(5H, m), 0.93e0.79 (6H, m), 13C NMR (75 MHz, CDCl3)
d 171.1, 171.0, 135.4, 135.3, 129.4, 128.8, 128.5, 76.5, 76.4,
62.2, 61.1, 36.1, 34.8, 27.2, 25.5, 22.8, 17.3, 16.0, 14.6, 12.5,
12.0, 11.9; HRMS (EI, m/z) calcd for C15H21NO2 (Mþ)
247.1571, found 247.1566.
(300 Hz, CDCl3) d 7.36e7.27 (5H, m), 5.70 (1H, br s), 4.64
(2H, s), 3.65 (3H, s), 2.58 (1H, ddd, J¼16.0, 9.0, 6.5 Hz),
2.41 (1H, ddd, J¼16.0, 9.0, 6.5 Hz), 2.26 (1H, dd, J¼10.5,
3.0 Hz), 1.97e1.55 (17H, m); 13C NMR (75 MHz, CDCl3)
d 174.6, 138.2, 128.3, 128.2, 127.6, 77.2, 75.9, 69.4, 51.4,
39.3, 37.1, 36.4, 32.6, 29.2, 28.5, 22.7; HRMS (EI, m/z) calcd
for C22H31NO3 (Mþ) 357.2302, found 357.2309.
4.5.18. 5-(2-Methylpropyl)-1-(phenylmethoxy)-
2-pyrrolidinone (27e)
4.5.13. General procedure for cyclization reaction of amino
ester 25
A colorless oil; IR (CHCl3) 1698 cmꢂ1; 1H NMR (300 Hz,
CDCl3) d 7.46e7.36 (5H, m), 5.06 and 4.94 (2H, AB q,
J¼10.5 Hz), 3.49e3.38 (1H, m), 2.41e2.20 (2H, m), 2.11e
1.12 (5H, m), 0.90 (3H, d, J¼6.5 Hz), 0.81 (3H, d, J¼
6.5 Hz); 13C NMR (75 MHz, CDCl3) d 171.3, 135.4, 129.5,
128.8, 128.5, 77.2, 56.8, 41.9, 27.1, 24.6, 23.6, 22.5, 21.8;
HRMS (EI, m/z) calcd for C15H21NO2 (Mþ) 247.1571, found
247.1556.
To a solution of 25 (8.2e53 mg, 0.03e0.20 mmol) in THF
(1.4e11 mL) was added concd HCl (2 drops by a syringe)
under a nitrogen atmosphere at reflux. After being stirred for
1.5e5 h, the mixture was concentrated at reduced pressure.
The resulting residue was purified by PTLC (n-hexane/
AcOEt¼1:1) to afford 27aeh as shown in Table 5.
4.5.14. 5-Ethyl-1-(phenylmethoxy)-2-pyrrolidinone (27a)
A colorless oil; IR (CHCl3) 1698 cmꢂ1; 1H NMR (300 Hz,
CDCl3) d 7.47e7.34 (5H, m), 5.06 and 4.94 (2H, AB q,
J¼10.0 Hz), 3.38 (1H, m), 2.35 (1H, ddd, J¼17.0, 9.5,
6.0 Hz), 2.27 (1H, ddd, J¼17.0, 9.5, 7.0 Hz), 2.05 (1H, dddd,
J¼13.0, 9.5, 7.0, 5.5 Hz), 1.82 (1H, br dqd, J¼14.0, 7.0,
4.0 Hz), 1.61 (1H, m), 1.39 (1H, br dquint, J¼14.0, 7.0, Hz),
0.87 (3H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3) d 171.3,
135.2, 129.3, 128.6, 128.4, 76.9, 59.1, 27.0, 25.5, 21.1, 8.7;
HRMS (EI, m/z) calcd for C13H17NO2 (Mþ) 219.1258, found
219.1265.
4.5.19. 5-Cyclopentyl-1-(phenylmethoxy)-2-pyrrolidinone
(27f)
A colorless oil; IR (CHCl3) 1691 cmꢂ1; 1H NMR (300 Hz,
CDCl3) d 7.50e7.29 (5H, m), 5.06 and 4.93 (2H, AB q,
J¼10.5 Hz), 3.44 (1H, br q, J¼6.5 Hz), 2.40e2.25 (2H, m),
2.23e1.15 (11H, m); 13C NMR (75 MHz, CDCl3) d 171.2,
135.1, 129.4, 128.7, 128.4, 76.5, 61.2, 42.8, 29.5, 27.8, 27.2,
25.7, 25.0, 19.9; HRMS (CI, m/z) calcd for C16H22NO2
(MþHþ) 260.1649, found 260.1641.

O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1281
4.5.20. 5-Cyclohexyl-1-(phenylmethoxy)-2-pyrrolidinone
(27g)
4.5.25. Methyl 6,6-dimethyl-5-[(phenylmethoxy)amino]-
heptanoate (26c) (15 mg, 24%)
A colorless oil; IR (neat) 1703 cmꢂ1; H NMR (300 Hz,
CDCl3) d 7.46e7.33 (5H, m), 5.05 and 4.96 (2H, AB q,
J¼10.5 Hz), 3.32 (1H, m), 2.36e2.18 (2H, m), 1.93e0.92
(13H, m); 13C NMR (75 MHz, CDCl3) d 171.0, 135.4,
129.4, 128.7, 128.5, 76.4, 62.2, 39.1, 28.8, 27.3, 26.4, 26.3, 26.3,
25.9, 17.6; HRMS (EI, m/z) calcd for C17H23NO2 (Mþ)
273.1727, found 273.1711.
A colorless oil; IR (neat) 3274, 1737 cmꢂ1 1H NMR
;
1
(200 MHz, CDCl3) d 7.41e7.25 (5H, m), 5.57 (1H, br s),
4.66 (2H, s), 3.66 (3H, s), 2.44 (1H, dd, J¼9.0, 3.0 Hz), 2.32
(2H, m), 1.97e1.30 (4H, m), 0.92 (9H, s); 13C NMR (75 MHz,
CDCl3) d 174.1, 138.2, 128.3, 128.3, 127.6, 75.8, 69.2, 51.4,
34.3, 34.2, 28.3, 27.3, 26.8, 23.6; HRMS (CI, m/z) calcd for
C17H28NO3 (MþHþ) 294.2067, found 294.2043.
4.5.26. Methyl 6-methyl-5-[(phenylmethoxy)amino]-
octanoate (26d) (34 mg, 55%)
A colorless oil as a 1:1 mixture of diastereomers; IR
4.5.21. 5-Tricyclo[3.3.1.13,7]dec-1-yl-1-(phenylmethoxy)-
2-pyrrolidinone (27h)
Colorless crystals; mp 81e83 ꢁC (hexane/AcOEt); IR
(CHCl3) 3264, 1734 cmꢂ1
;
1H NMR (300 Hz, CDCl3)
1
(CHCl3) 1690 cmꢂ1; H NMR (300 Hz, CDCl3) d 7.46e7.36
d 7.35e7.26 (5H, m), 5.51 (1H, br s), 4.68 (1H, s), 4.66 (1H,
s), 3.66 (3H, s), 2.76 (1H, m), 2.30 (2H, m), 1.78e1.02 (7H,
m), 0.92e0.82 (6H, m); 13C NMR (75 MHz, CDCl3) d 174.0,
138.1, 138.1, 128.4, 128.4, 128.3, 127.7, 76.3, 64.2, 64.1, 51.4,
35.8, 35.4, 34.2, 28.4, 27.0, 26.0, 25.2, 22.4, 22.3, 14.9, 14.1,
12.0, 12.0; HRMS (EI, m/z) calcd for C17H27NO3 (Mþ)
293.1989, found 293.2003.
(5H, m), 5.03 and 4.94 (2H, AB q, J¼10.5 Hz), 3.05 (1H,
dd, J¼8.5, 4.0 Hz), 2.37e2.13 (2H, m), 1.98e1.50 (17H,
m); 13C NMR (75 MHz, CDCl3) d 170.7, 135.0, 129.7,
128.8, 128.5, 75.2, 66.3, 38.4, 36.9, 36.9, 28.1, 27.4, 17.4;
HRMS (CI, m/z) calcd for C21H28NO2 (MþHþ) 326.2095,
found 326.2107.
4.5.27. Methyl 7-methyl-5-[(phenylmethoxy)amino]-
octanoate (26e) (7 mg, 11%)
4.5.22. Methyl 5-[(phenylmethoxy)amino]heptanoate (26a)
According to the procedure given for the preparation of
pyrrolidine 6a, the treatment of 24 (50 mg, 0.21 mmol) with
Et3B (l mol/L in n-hexane) (0.64 mL, 0.64 mmol) in the pres-
ence of BF3$OEt2 (0.05 mL, 0.43 mmol) gave 26a (39 mg,
A colorless oil; IR (neat) 3285, 1745 cmꢂ1 1H NMR
;
(300 MHz, CDCl3) d 7.35e7.26 (5H, m), 5.44 (1H, br s),
4.68 (2H, s), 3.67 (3H, s), 2.90 (1H, br quint, J¼6.0 Hz),
2.31 (2H, t, J¼7.5 Hz), 1.72e1.11 (7H, m), 0.88 (3H, d, J¼
6.5 Hz), 0.87 (3H, t, J¼6.5 Hz); 13C NMR (75 MHz, CDCl3)
d 173.5, 137.6, 128.4, 128.2, 127.8, 75.6, 58.2, 41.2, 34.2,
32.1, 24.9, 23.1, 22.6, 21.8, 21.1; HRMS (EI, m/z) calcd for
C17H27NO3 (Mþ) 293.1991, found 293.1993.
1
70%) as a colorless oil; IR (CHCl3) 3258, 1731 cmꢂ1; H
NMR (300 MHz, CDCl3) d 7.36e7.26 (5H, m), 5.49 (1H, br
s), 4.69 (2H, s), 3.66 (3H, s), 2.78 (1H, br quint, J¼6.0 Hz),
2.30 (2H, t, J¼7.5 Hz), 1.75e1.35 (6H, m), 0.90 (3H, t,
J¼7.5 Hz); 13C NMR (75 MHz, CDCl3) d 174.0, 138.1,
128.4, 128.3, 127.7, 76.5, 61.5, 51.5, 34.2, 30.9, 24.4, 21.3,
10.0; HRMS (EI, m/z) calcd for C15H23NO3 (Mþ) 265.1677,
found 265.1685.
4.5.28. Methyl 5-[(phenylmethoxy)amino]-
cyclopentanepentanoate (26f) (40 mg, 62%)
A colorless oil; IR (CHCl3) 3280, 1728 cmꢂ1; H NMR
1
(300 MHz, CDCl3) d 7.36e7.26 (5H, m), 4.69 (2H, s), 3.66
(3H, s), 2.67e2.58 (1H, m), 2.30 (2H, t, J¼7.5 Hz),
2.01e1.10 (14H, m); 13C NMR (75 MHz, CDCl3) d 174.1,
138.1, 128.3, 128.3, 127.7, 76.3, 65.1, 51.4, 41.6, 34.3, 30.1,
30.0, 29.7, 25.3, 25.3, 21.2; HRMS (EI, m/z) calcd for
C18H27NO3 (Mþ) 305.1990, found 305.1993.
4.5.23. General procedure for alkyl radical addition
reaction of oxime ether 24
According to the procedure given for the preparation of
pyrrolidine 6b, the treatment of 24 (50 mg, 0.21 mmol) with
Et3B (l mol/L in n-hexane) (0.64 or 1.9 mL, 0.64 or 1.9 mmol)
in the presence of BF3$OEt2 (0.05 or 0.15 mL, 0.43 or
1.3 mmol) and alkyl iodide (2.8 mmol) gave 26 as shown in
Table 5.
4.5.29. Methyl 5-[(phenylmethoxy)amino]-
cyclohexanepentanoate (26g) (41 mg, 61%)
1
A colorless oil; IR (CHCl3) 3280, 1728 cmꢂ1; H NMR
(300 MHz, CDCl3) d 7.36e7.26 (5H, m), 4.69 (2H, s), 3.66
(3H, s), 2.67e2.58 (1H, m), 2.30 (2H, t, J¼7.5 Hz, 2-H2),
2.01e1.10 (14H, m); 13C NMR (75 MHz, CDCl3) d 174.0,
138.1, 128.4, 128.3, 127.7, 76.2, 65.0, 51.4, 39.0, 34.2, 29.4,
28.8, 28.2, 26.7, 26.5, 26.5, 22.1; HRMS (EI, m/z) calcd for
C19H29NO3 (Mþ) 319.2145, found 319.2145.
4.5.24. Methyl 6-methyl-5-[(phenylmethoxy)amino]-
heptanoate (26b) (40 mg, 67%)
1
A colorless oil; IR (CHCl3) 3269, 1734 cmꢂ1; H NMR
(200 MHz, CDCl3) d 7.37e7.26 (5H, m), 5.59 (1H, br s), 4.69
(2H, s), 3.66 (3H, s), 2.64 (1H, dt, J¼6.0, 4.5 Hz), 2.30 (2H, t,
J¼7.5 Hz), 2.02e1.26 (5H, m), 0.90 (3H, d, J¼7.0 Hz), 0.89
(3H, d, J¼7.0 Hz); 13C NMR (75 MHz, CDCl3) d 174.1,
138.1, 128.4, 128.3, 127.7, 76.3, 65.5, 51.5, 34.2, 28.7, 27.7,
22.2, 18.9, 18.0; HRMS (EI, m/z) calcd for C16H25NO3 (Mþ)
279.1833, found 279.1833.
4.5.30. Methyl 5-[(phenylmethoxy)amino]tricyclo-
[3.3.1.13,7]decane-1-pentanoate (26h) (40 mg, 50%)
A colorless oil; IR (neat) 3275, 1737 cmꢂ1 1H NMR
;
(300 Hz) d 7.41e7.25 (5H, m), 5.66 (1H, br s), 4.66 (2H, s),

1282
O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
3.66 (3H, s), 2.32 (1H, m), 2.25 (2H, dd, J¼9.5, 3.0 Hz),
2.09e1.23 (19H, m); 13C NMR (75 MHz, CDCl3) d 174.2,
138.2, 128.3, 128.2, 127.6, 75.8, 51.4, 39.3, 37.2, 36.2, 34.2,
28.5, 26.7, 23.6; HRMS (EI, m/z) calcd for C23H33NO3
(Mþ) 371.2458, found 371.2460.
4.5.36. 6-(2-Methylpropyl)-1-(phenylmethoxy)-
2-piperidinone (28e)
1
A colorless oil; IR (neat) 1663 cmꢂ1; H NMR (300 H,
CDCl3) d 7.43e7.29 (5H, m), 4.99 and 4.92 (2H, AB q,
J¼10.5 Hz), 3.42 (1H, br quint, J¼5.0 Hz), 2.46e2.32 (2H,
m), 1.84e1.33 (7H, m), 0.90 (3H, d, J¼6.5 Hz), 0.82 (3H,
d, J¼6.5 Hz); 13C NMR (75 MHz, CDCl3) d 167.4, 135.6,
129.5, 128.6, 128.4, 75.9, 58.9, 41.3, 33.2, 28.1, 24.9, 23.7,
21.4, 17.8; HRMS (EI, m/z) calcd for C16H23NO2 (Mþ)
261.1728, found 261.1721.
4.5.31. General procedure for cyclization reaction of amino
ester 26
To a solution of 26 (8.2e53 mg, 0.03e0.20 mmol) in THF
(1.4e11 mL) were added concd HCl (2 drops by a syringe)
under a nitrogen atmosphere at reflux. After being stirred for
1.5e5 h, the mixture was concentrated at reduced pressure.
The resulting residue was purified by PTLC (n-hexane/
AcOEt¼1:1) to afford 28 as shown in Table 5.
4.5.37. 6-Cyclopentyl-1-(phenylmethoxy)-2-piperidinone
(28f)
1
A colorless oil; IR (neat) 1662 cmꢂ1; H NMR (300 Hz,
CDCl3) d 7.46e7.34 (5H, m), 5.00 and 4.92 (2H, AB q,
J¼10.0 Hz), 3.36 (1H, br q, J¼6.0 Hz), 2.45 (2H, m),
2.27e1.13 (13H, m); 13C NMR (75 MHz, CDCl3) d 167.4,
135.5, 129.5, 128.5, 128.4, 75.3, 63.8, 43.1, 33.2, 30.5, 28.5,
26.8, 25.6, 24.7, 18.2; HRMS (EI, m/z) calcd for C17H23NO2
(Mþ) 273.1727, found 273.1726.
4.5.32. 6-Ethyl-1-(phenylmethoxy)-2-piperidinone (28a)
1
A colorless oil; IR (neat) 1663 cmꢂ1; H NMR (200 Hz,
CDCl3) d 7.46e7.26 (5H, m), 5.02 and 4.91 (2H, AB q,
J¼10.0 Hz), 3.37 (1H, m), 2.44 (2H, m), 2.03e1.41 (6H,
m), 0.88 (3H, t, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 167.7, 135.5, 129.4, 128.5, 128.4, 75.9, 61.9, 33.4, 27.5,
25.0, 18.3, 9.7; HRMS (EI, m/z) calcd for C14H19NO2 (Mþ)
233.1415, found 233.1416.
4.5.38. 6-Cyclohexyl-1-(phenylmethoxy)-2-piperidinone
(28g)
1
A colorless oil; IR (neat) 1667 cmꢂ1; H NMR (200 Hz,
CDCl3) d 7.48e7.34 (5H, m), 5.03 and 4.88 (2H, AB q,
J¼10.5 Hz), 3.32 (1H, m), 2.60e2.30 (2H, m), 2.10e0.94
(15H, m); 13C NMR (75 MHz) d 168.2, 135.5, 129.5, 128.6,
128.4, 75.4, 64.9, 39.3, 33.5, 29.5, 26.9, 26.7, 26.6, 26.2,
24.9, 19.3; HRMS (CI, m/z) calcd for C18H26NO2 (MþHþ)
288.1962, found 288.1968.
4.5.33. 6-(1-Methylethyl)-1-(phenylmethoxy)-2-piperidinone
(28b)
1
A colorless oil; IR (neat) 1663 cmꢂ1; H NMR (300 Hz,
CDCl3) d 7.47e7.33 (5H, m), 5.01 and 4.91 (2H, AB q,
J¼10.0 Hz), 3.37 (1H, m), 2.54e2.31 (3H, m), 1.89e1.46
(4H, m), 0.88 (3H, d, J¼7.0 Hz), 0.87 (3H, d, J¼7.0 Hz); 13C
NMR (75 MHz, CDCl3) d 168.2, 135.4, 129.5, 128.6, 128.4,
75.3, 65.1, 33.6, 28.3, 23.4, 19.2, 18.6, 15.8; HRMS (EI, m/z)
calcd for C15H22NO2 (MþHþ) 248.1649, found 248.1635.
4.6. Phenyl (E/Z)-4-[(phenylmethoxy)imino]butanoate
(31)
To a solution of NaOH (99 mg, 2.5 mmol) in THFeH2O
(12e6 mL) was added 23 (500 mg, 2.3 mmol) under a nitrogen
atmosphere at 0 ꢁC. After being stirred at the same tempera-
ture for 3.5 h, the reaction mixture was acidified with 10%
HCl and then extracted with CHCl3. The organic phase was
washed with brine, dried over MgSO4, and then concentrated
4.5.34. 6-(1,1-Dimethylethyl)-1-(phenylmethoxy)-
2-piperidinone (28c)
A colorless oil; IR (CHCl3) 1646 cmꢂ1; 1H NMR (300 Hz,
CDCl3) d 7.44e7.31 (5H, m), 4.92 and 4.88 (2H, AB q,
J¼10.5 Hz), 3.30 (1H, m), 2.53e2.27 (3H, m), 1.85e1.19
(4H, m), 0.99 (9H, s); 13C NMR (75 MHz, CDCl3) d 167.7,
135.2, 130.0, 128.6, 128.4, 74.2, 67.3, 36.3, 33.5, 28.4, 26.7,
19.2; HRMS (EI, m/z) calcd for C16H23NO2 (Mþ) 261.1728,
found 261.1713.
1
at reduced pressure. H NMR spectrum of the residue proved
the formation of desired carboxylic acid 29, which without
further purification was subjected to the following reaction.
To a solution of crude carboxylic acid 29 and phenol
(101 mg, 1.1 mmol) in CH2Cl2 (1.1 mL) were added DMAP
(105 mg, 0.9 mmol) and DCC (243 mg, 1.2 mmol) under a ni-
trogen atmosphere at 0 ꢁC. After being stirred for 7 h at the
same temperature, the reaction mixture was filtered and the fil-
trate was acidified with 0.5 M HCl and then extracted with
CHCl3. The organic phase was washed with satd aq NaHCO3
and then extracted with CHCl3. The organic phase was washed
with brine, dried over MgSO4, and then concentrated at
reduced pressure. The crude product was purified by MCC
(hexane/AcOEt¼3:1) to afford 31 (254 mg, 39%) as a colorless
oil and a 2:1 mixture of E- and Z-isomers; IR (neat)
4.5.35. 6-(1-Methylpropyl)-1-(phenylmethoxy)-
2-piperidinone (28d)
A colorless oil as a 1:1 mixture of diastereomers; IR (neat)
1
1664 cmꢂ1; H NMR (300 Hz, CDCl3) d 7.47e7.31 (5H, m),
5.03 and 4.91 (1H, AB q, J¼10.0 Hz), 5.01 and 4.86 (1H, AB
q, J¼10.0 Hz), 3.47 (1H, m), 2.52e2.30 (2H, m), 2.23e0.99
(7H, m), 0.93 (6H, m); 13C NMR (75 MHz, CDCl3) d 168.4,
168.3, 135.5, 135.4, 129.6, 129.5, 128.6, 128.4, 75.4, 75.3,
65.4, 63.8, 35.7, 34.9, 33.6, 33.6, 25.9, 24.4, 23.3, 19.4, 19.3,
15.3, 13.1, 12.2, 12.2; HRMS (EI, m/z) calcd for C16H23NO2
(Mþ) 261.1728, found 261.1720.
1
1761 cmꢂ1; H NMR (300 MHz, CDCl3) d 7.57 (2/3H, br t,
J¼5.0 Hz), 7.35e6.81 (10Hþ1/3H, m), 5.14 (2/3H, s), 5.07

O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
1283
(4/3H, s), 2.82e2.77 (2H, m), 2.63 (2H, br q, J¼6.5 Hz); 13C
4.7. 1-Iodotetradecane (34)
NMR (75 MHz, CDCl3) d 170.9, 150.6, 149.6, 148.7, 137.6,
129.4, 129.4, 128.4, 128.3, 128.0, 127.9, 125.8, 121.5, 76.0,
75.8, 30.8, 25.0, 21.4; HRMS (CI, m/z) calcd for C17H18NO3
(MþHþ) 284.1286, found 284.1281.
To a solution of 1-bromotetradecane (2.0 mL, 6.85 mmol)
in acetone (4.0 mL) was added NaI (2.6 g, 17 mmol) under
a nitrogen atmosphere. After being refluxed for 27 h, the
reaction mixture was filtered. The filtrate was concentrated
at reduced pressure, diluted with satd aq Na2S2O3, and then
extracted with Et2O. The organic phase was washed with
brine, dried over MgSO4, and then concentrated at reduced
pressure to afford 34 (2.2 g, 99%) as a colorless oil. The spec-
tral data were identical with those reported in literature.18
4.6.1. Phenyl (E/Z)-5-[(phenylmethoxy)imino]pentanoate
(32)
According to the procedure given for the preparation of ox-
ime ether 31, the treatment of 24 (500 mg, 2.1 mmol) with
NaOH (94 mg, 2.3 mmol) followed by esterification of result-
ing carboxylic acid 30 with phenol (200 mg, 2.1 mmol) in the
presence of DCC (482 mg, 2.3 mmol) and DMAP (207 mg,
1.7 mmol) gave 32 (418 mg, 66%) as a colorless oil and a 3:2
4.7.1. 2-Tetradecyl-1-(phenylmethoxy)pyrrolidine (33)
According to the procedure given for the preparation of
pyrrolidine 6e, the treatment of 3 (96 mg, 0.28 mmol) with
Et3B (l mol/L in n-hexane) (0.83 mL, 0.83 mmol) in the pres-
ence of BF3$OEt2 (0.07, 0.55 mmol) and n-C14H29I (1.8 g,
5.6 mmol) gave 33 (31 mg, 30%) as a colorless oil; 1H
NMR (200 MHz, CDCl3) d 7.35e7.26 (5H, m), 4.74 (2H, s),
3.23 (1H, m), 2.87e2.73 (2H, m), 1.74e1.26 (30H, m), 0.88
(3H, t, J¼6.5 Hz); 13C NMR (75 MHz, CDCl3) d 138.1, 128.6,
128.2, 127.7, 77.2, 75.6, 68.1, 55.6, 33.6, 31.9, 29.9, 29.7,
29.7, 29.4, 27.4, 26.9, 22.7, 20.5, 14.1; HRMS (EI, m/z) calcd
for C25H43NO (Mþ) 373.3343, found 373.3341.
1
mixture of E- and Z-isomers; IR (neat) 1758 cmꢂ1; H NMR
(300 MHz, CDCl3) d 7.47 (3/5H, t, J¼6.0 Hz), 7.38e6.71
(10Hþ2/5H, m), 5.12 (4/5H, s), 5.07 (6/5H, s), 2.58 (2H, t,
J¼7.5 Hz), 2.50 (4/5H, br q, J¼7.5 Hz), 2.32 (6/5H, br q,
J¼7.5 Hz), 1.94 (2H, m); 13C NMR (75 MHz, CDCl3) d 171.5,
150.8, 150.5, 150.0, 137.8, 137.5, 129.4, 129.3, 128.3, 128.2,
127.9, 127.8, 127.7, 125.7, 121.4, 115.2, 77.2, 75.7, 75.5, 33.6,
33.2, 28.7, 25.0, 21.5, 21.4; HRMS (EI, m/z) calcd for
C18H19NO3 (Mþ) 297.1364, found 297.1381.
4.6.2. Ethyl radical additioneionic cyclization reaction
of oxime ether 31
4.7.2. 2-Tetradecylpyrrolidine (35)
To a solution of 33 (25 mg, 0.09 mmol) in AcOH (1.2 mL)
was added zinc dust (49 mg, 0.75 mmol) under a nitrogen
atmosphere at 65 ꢁC. After being stirred at the same tempera-
ture for 3 h, the reaction mixture was filtrated. The filtrate was
concentrated at reduced pressure and was neutralized with
K2CO3. The mixture was diluted with H2O and then extracted
with CHCl3. The organic phase was washed with brine, dried
over MgSO4, and then concentrated at reduced pressure. The
crude product was purified by FCC (CHCl3eMeOH¼20:1)
to afford 35 (6.7 mg, 67%) as a colorless oil.
According to the procedure given for the preparation of
pyrrolidine 6a, the treatment of 31 (50 mg, 0.18 mmol) with
Et3B (l mol/L in n-hexane) (0.53 mL, 0.53 mmol) in the pres-
ence of BF3$OEt2 (0.04 mL, 0.35 mmol) gave 27a (28 mg,
72%) as a colorless oil.
4.6.3. Isopropyl radical additioneionic cyclization reaction
of oxime ether 31
According to the procedure given for the preparation of pyr-
rolidine 6b, the treatment of 31 (50 mg, 0.18 mmol) with Et3B
(l mol/L in n-hexane) (0.53 mL, 0.53 mmol) in the presence
of BF3$OEt2 (0.04 mL, 0.35 mmol) and i-PrI (0.35 mmol,
3.5 mmol) gave 27b (28 mg, 68%) as a colorless oil.
4.7.3. (ꢀ)-N-Methyl-2-tetradecylpyrrolidine ((ꢀ)-bgugaine)
(36)
According to the reported procedure,14c the treatment of 35
(15 mg, 0.06 mmol) with 37% aq HCHO (0.12 mL) and NaBH4
in MeOH (0.4 mL) gave 36 (12 mg, 76%) as a colorless oil; 1H
NMR (500 MHz, CDCl3) d 3.49 (1H, m), 2.57 (3H, s), 2.11e
2.01 (2H m), 1.82e1.60 (6H, m), 1.26 (24H, m), 0.88 (3H, t,
J¼7.0 Hz); HRMS (EI, m/z) calcd for C19H39NO (Mþ)
281.3081, found 281.3070.
4.6.4. Ethyl radical additioneionic cyclization reaction
of oxime ether 32
According to the procedure given for the preparation of
pyrrolidine 6a, the treatment of 32 (50 mg, 0.17 mmol) with
Et3B (l mol/L in n-hexane) (0.50 mL, 0.50 mmol) in the pres-
ence of BF3$OEt2 (0.04 mL, 0.34 mmol) gave 28a (28 mg,
70%) as a colorless oil.
The spectral data were identical with those reported in
literature.14
4.7.4. Alkyl radical additionecyclization reaction of oxime
ether 3
4.6.5. Isopropyl radical additioneionic cyclization reaction
of oxime ether 32
According to the procedure given for the preparation of pyr-
rolidine 6d, the treatment of 3 (200 mg, 0.58 mmol) with Et3B
(l mol/L in n-hexane) (1.7 mL, 1.7 mmol) in the presence of
BF3$OEt2 (0.14 mL, 1.2 mmol) and g-iodovalerate 3816 (1.5 g,
5.8 mmol) gave polar isomer 39a (62 mg, 41%) as a colorless
oil and less polar isomer 39b (62 mg, 41%) as a colorless oil.
According to the procedure given for the preparation of pyr-
rolidine 6b, the treatment of 32 (50 mg, 0.17 mmol) with Et3B
(l mol/L in n-hexane) (0.50 mL, 0.50 mmol) in the presence of
BF3$OEt2 (0.04 mL, 0.34 mmol) and i-PrI (0.33 mmol,
3.4 mmol) gave 28b (26 mg, 63%) as a colorless oil.

1284
O. Miyata et al. / Tetrahedron 64 (2008) 1270e1284
Ethyl (R*,S*)-4-[2-[1-(phenylmethoxy)]pyrrolidinyl]penta-
;
noate (39a). IR (neat) 1734 cmꢂ1 1H NMR (300 MHz,
Acknowledgements
CDCl3) d 7.34e7.26 (5H, m), 4.71 (2H, s), 4.12 (2H, q,
J¼7.5 Hz), 3.18 (1H, m), 2.80 (2H, m), 2.44e2.17 (2H, m),
1.85e1.38 (7H, m), 1.24 (3H, t, J¼7.5 Hz), 0.89 (3H, d, J¼
7.5 Hz); 13C NMR (75 MHz) d 173.9, 138.0, 128.6, 128.2,
127.6, 75.2, 71.8, 60.2, 55.8, 34.0, 32.4, 29.8, 23.2, 20.8, 14.4,
14.2; HRMS(EI, m/z) calcd for C18H27NO3 (Mþ) 305.1990,
found 305.1982.
We are grateful to acknowledge the research Grants-in-Aid
for Scientific Research (B) (T.N.) and Scientific Research (C)
(O.M.) from Japan Society for the Promotion of Science,
Scientific Research on Priority Areas (A) (T.N.) from the
Ministry of Education, Culture, Sports, and Technology. This
work was supported in part by the Second Project for
Advanced Research and Technology by Kobe Pharmaceutical
University.
Ethyl (R*,R*)-4-[2-[1-(Phenylmethoxy)]pyrrolidinyl]penta-
;
noate (39b). IR (neat) 1734 cmꢂ1 1H NMR (300 MHz,
CDCl3) d 7.36e7.26 (5H, m), 4.71 (2H, s), 4.13 (2H, q, J¼
7.0 Hz), 3.18 (1H, m), 2.80 (2H, m), 2.43e2.17 (2H, m),
2.00e1.31 (7H, m), 1.26 (3H, t, J¼7.0 Hz), 0.94 (3H, d, J¼
7.0 Hz); 13C NMR (75 MHz, CDCl3) d 174.0, 138.0, 128.7,
128.2, 127.7, 75.1, 72.4, 60.2, 56.0, 34.3, 32.5, 27.3, 24.0,
21.0, 16.9, 14.3; HRMS (EI, m/z) calcd for C18H27NO3 (Mþ)
305.1990, found 305.1990.
References and notes
1. (a) Gribble, G. W. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 2, p 207; (b) Balasubramanian, M.; Keay, J. G. Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5, p 245.
2. (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Tietze, L. F., Brasche, G., Gericke, K. M., Eds.;
Wiley-VCH: Weinheim, 2006; p 219; (b) Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vols. 1 and
2; (c) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140.
3. (a) Miyabe, H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett. 2000, 2, 4071; (b)
Miyabe, H.; Fujii, K.; Tanaka, H.; Naito, T. Chem. Commun. 2001, 831;
(c) Miyabe, H.; Ueda, M.; Fujii, K.; Nishimura, A.; Naito, T. J. Org.
Chem. 2003, 68, 5618; (d) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito,
T. Tetrahedron Lett. 1998, 39, 631; (e) Miyabe, H.; Shibata, R.; Sangawa,
M.; Ushiro, C.; Naito, T. Tetrahedron 1998, 54, 11431; (f) Miyabe, H.;
Yamakawa, K.; Yoshioka, N.; Naito, T. Tetrahedron 1999, 55, 11209;
(g) Miyabe, H.; Fujii, K.; Naito, T. Org. Biomol. Chem. 2003, 1, 381.
4. Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew. Chem.,
Int. Ed. 2005, 44, 6190.
4.7.5. cis-Hexahydro-8-methyl-5(1H)-indolizinone (40a)
To a solution of 39a (25 mg, 0.08 mmol) in AcOH (1.1 mL)
was added zinc dust (43 mg, 0.65 mmol) under a nitrogen
atmosphere at room temperature. After being stirred at room
temperature for 27 h, additional zinc dust (43 mg, 0.65 mmol)
and AcOH (1.1 mL) were added to the solution. After being
stirred at room temperature for 21 h, the reaction mixture was
filtrated. The filtrate was concentrated at reduced pressure
and was neutralized with K2CO3. The reaction mixture was
diluted with H2O and then extracted with CHCl3. The organic
phase was washed with brine, dried over MgSO4, and then con-
centrated at reduced pressure. The crude product was purified
by FCC (CHCl3eMeOH¼10:1) to afford 40a (12.3 mg, 98%)
5. Martin, D. J. Prakt. Chem. 1995, 337, 599.
6. Kolasa, T.; Sharma, S. K.; Miller, M. J. Tetrahedron 1988, 44, 5431.
7. Bradshaw, J. S.; Krakowiak, K. E.; Lindh, G. C.; Izatt, R. M. Tetrahedron
1987, 43, 4271.
1
as a colorless oil; IR (neat) 1632 cmꢂ1; H NMR (300 MHz,
8. Wiberg, K. B.; Laidig, K. E. J. Am. Chem. Soc. 1987, 109, 5935.
9. Gannett, P. M.; Nagel, D. L.; Reilly, P. J.; Lawson, T.; Sharpe, J.; Toth, B.
J. Org. Chem. 1988, 53, 1064.
CDCl3) d 3.64e3.00 (3H, m), 2.52e2.29 (2H, m), 2.20e
1.32 (7H, m), 1.03 (3H, d, J¼7.5 Hz); 13C NMR (75 MHz,
CDCl3) d 169.2, 65.1, 45.2, 35.3, 32.2, 31.4, 29.9, 22.1, 18.1;
HRMS (EI, m/z) calcd for C9H15NO (Mþ) 153.1153, found
153.1147.
10. Kim, S.; Song, H.; Choi, T.; Yoon, J. Angew. Chem., Int. Ed. 2001, 40,
2524.
11. Godineau, E.; Schafer, C.; Landais, Y. Org. Lett. 2006, 8, 4871.
¨
12. Melhaoui, A.; Jossang, A.; Bodo, B. J. Nat. Prod. 1992, 55, 950.
13. Melhaoui, A.; Mallea, M.; Jossang, A.; Bodo, B. Nat. Prod. Lett. 1993, 2,
237.
The spectroscopic data of 40a were identical with those
previously reported.17
14. The synthesis of bgugaine. (a) Enders, D.; Thiebes, C. Pure Appl. Chem.
2001, 73, 573; (b) Takahata, H.; Ihara, K.; Kubota, M.; Momose, T.
Heterocycles 1997, 46, 349; (c) Jossang, A.; Melhaoui, A.; Bodo, B.
Heterocycles 1996, 43, 755; (d) Enders, D.; Thiebes, C. J. Indian Chem.
Soc. 1999, 76, 561.
4.7.6. trans-Hexahydro-8-methyl-5(1H)-indolizinone (40b)
According to the procedure given for the preparation of
indolizidine 40a, the treatment of 39b (30 mg, 0.10 mmol)
with zinc dust (51 mg, 0.79 mmol) and AcOH (1.3 mL) gave
15. (a) Flitsch, W. Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 8,
p 237; (b) Momose, T.; Toyooka, N. J. Org. Chem. 1994, 59, 943.
16. Kolb, M.; Barth, J. Synth. Commun. 1981, 11, 763.
40b (8.2 mg, 55%) as a colorless oil; IR 1619 (neat) cmꢂ1
;
1H NMR (300 MHz, CDCl3) d 3.65e3.43 (3H, m), 2.34
(2H, m), 2.23e1.35 (7H, m), 0.89 (3H, d, J¼7.5 Hz); 13C
NMR (75 MHz, CDCl3) d 168.9, 61.9, 45.2, 29.2, 28.3, 28.1,
27.1, 22.2, 11.2; HRMS (EI, m/z) calcd for C9H15NO (Mþ)
153.1153, found 153.1151.
17. (a) Song, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 2002, 43, 8635; (b)
´
Aube, J.; Rafferty, P. S.; Milligan, G. L. Heterocycles 1993, 35, 1141; (c)
Satake, A.; Shimizu, I. Tetrahedron: Asymmetry 1993, 4, 1405.
18. Nakajima, R.; Morita, K.; Hara, T. Bull. Chem. Soc. Jpn. 1981, 54, 3599.