Distannane mediated reaction of N-acyliminium ion pools with alkyl halides. A chain mechanism involving radical addition followed by electron transfer

Article abstract of DOI:10.1016/j.tet.2006.03.114

Hexabutyldistannane was found to be an effective mediator allowing the reaction of N-acyliminium ion pools with alkyl halides. A chain mechanism involving the addition of an alkyl radical generated from an alkyl halide to an N-acyliminium ion followed by the one-electron reduction of the resulting radical-cation by distannane was proposed.

Full text of DOI:10.1016/j.tet.2006.03.114

Tetrahedron 62 (2006) 6519–6525
Distannane mediated reaction of N-acyliminium ion pools
with alkyl halides. A chain mechanism involving radical
addition followed by electron transfer
*
Tomokazu Maruyama, Seiji Suga and Jun-ichi Yoshida
*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 615-8510, Japan
Received 18 January 2006; accepted 23 March 2006
Available online 6 May 2006
Abstract—Hexabutyldistannane was found to be an effective mediator allowing the reaction of N-acyliminium ion pools with alkyl halides.
A chain mechanism involving the addition of an alkyl radical generated from an alkyl halide to an N-acyliminium ion followed by the one-
electron reduction of the resulting radical-cation by distannane was proposed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
benzyl, and phenyl radicals, to protonated heteroaromatic
6
,7
rings, serves as an example of the process. In this reaction,
the rates of the addition to protonated heteroaromatic com-
pounds are much higher than that of the addition to the
unprotonated compounds. For example, the addition of an
n-butyl radical to the protonated picoline is 100 times faster
than that to neutral picoline, indicating significant polar
Radical-cations serve as key intermediates in a variety of
electron transfer driven transformations in organic synthesis.
For example, one-electron oxidation of organic compounds
gives radical-cations, which undergo follow-up reactions.
Fragmentation of radical-cations to give either a carbocation
or a neutral carbon radical as shown in Scheme 1 is one of the
most feasible pathways. Extensive studies have been carried
out on fragmentation reactions of radical-cations, which are
7
effects in the transition state (Scheme 3).
1
2
Much less information upon the
generated in chemical, electrochemical, and photochemi-
C
+
X
C
X
3
4
reaction of a radical and a cation
to form a radical-cation
cal electron transfer. Schmittel’s classification of reactivity
patterns of radical-cations is very useful to understand elec-
tron transfer driven reactions.
X = carbon or heteroatom
5
Scheme 2.
CH3
CH3
C
C
+
+
X
X
k = 1.3 x 103
-
e
much information upon
radical-cation fragmentation
C X
C X
+
n-Bu
n-Bu
N
N
Bu-n
Bu-n
key step of
X = carbon or heteroatom
Scheme 1.
:
Minisci reaction
CH3
CH3
k = 1.1 x 105
+
accelerated
N
H
Much less information, by contrast, is available for the
reverse process: the reaction of a radical and a cation to form
a radical-cation (Scheme 2). The Minisci reaction, which
involves the addition of nucleophilic radicals, such as alkyl,
N
H
Scheme 3.
In the arylative amination of aldehydes promoted by tita-
nium trichloride, a mechanism involving the addition of an
aryl radical to the cationic carbon of the protonated imine
*
0
Corresponding authors. Tel.: +81 75 383 2726; fax: +81 75 383 2727;
e-mail: yoshida@sbchem.kyoto-u.ac.jp
8
intermediate has been suggested (Scheme 4).
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.114

6520
T. Maruyama et al. / Tetrahedron 62 (2006) 6519–6525
Y
pools. N-Acyliminium ion 2, generated from N-methoxy-
Ti (III)
carbonyl-2-trimethylsilylpyrrolidine 1 by low temperature
electrochemical oxidation and accumulated in a solution
(cation pool), was utilized as a carbocation component
N
Y
2
+
O
+
H
HN
+
H
+
R
N
R
X
H N
2
(
Scheme 7).
X
Y
key step
Y
HN
H
H
N
SiMe3
CO2Me
R
X
R
1
X
+
-
2e, -"Me Si " -78 °C
3
Scheme 4.
N
R
It has also been reported that alkyl radical addition to C]N
bond is remarkably accelerated by the Lewis acid such as
N
R
CO2Me
2
CO Me
2
9
BF $OEt (Scheme 5). Lewis acid was suggested to lower
3
2
N-acyliminium
ion pool
the LUMO energy of the radical acceptor and decrease the
electron density at the iminyl carbon atom. Similar reactions
are possible using imines having an electron-deficient
substituent.
Scheme 7.
1
2
The triethylborane/O system, which could be widely
2
utilized to generate alkyl radicals from alkyl halides at low
temperatures, was unsuccessful; however, we found that
the hexabutyldistannane (Bu SnSnBu )/hn system was quite
BF -OEt
R I, Bu3SnH, Et3B
3
2
2
1
R
NOHBn
1
R
NOBn
2
3
3
R
successful. Thus, heptyl iodide reacted with 2 in the pres-
ꢁ
key step
BF3
NOBn
ence of Bu SnSnBu under UV irradiation at ꢀ20 C to
3
3
1
1
BF3
NOBn
R
afford the corresponding heptylated compound 3 (Table 1,
entries 1 and 2). It was surprising that the reaction proceeded
even in the dark (entries 3–15), although photo irradiation
was well-known to enhance the homolytic cleavage of
1
R
2
R
2
+
R
BF3
NOBn
BF3
NOBn
1
R
R
13
Sn–Sn bond. A stoichiometric amount of Bu SnSnBu was
3
3
2
R
necessary to complete the reaction, because the reactions
using 0.5 and 0.1 equiv of Bu SnSnBu led to the formation
of 3 in 50 and 10% yields, respectively (entries 8 and 9).
3
3
Scheme 5.
The reaction rates strongly depended on temperature.
ꢁ
These observations in the literature indicate the importance
of electrophilic character of radical acceptors in radical
addition and prompted us to investigate the radical addition
to N-acyliminium ions, which are generated and accumu-
The reaction almost completed around 60 min at ꢀ20 C
Table 1. The addition of heptyl radical to the N-acyliminium ion 2
1
0
lated by the ‘cation pools’ method (Scheme 6). In a prelim-
inary communication we have reported that the reaction does
C H I (5.0 eq)
7
15
(Bu Sn)
3
2
1
1
N
C H
7 15
take place in the presence of distannane. A chain mecha-
nism involving the addition of an alkyl radical generated
from an alkyl iodide to an N-acyliminium ion followed by
the one-electron reduction of the resulting radical-cation
by distannane has been proposed. In this paper we report
full details of this study.
N
CH Cl
2
CO2Me
2
CO Me
3
2
2
Entry
Temperature
ꢁ
Time
(min)
Condition
(Bu
(equiv)
3
Sn)
2
Yield
(%)
(
C)
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
60
60
60
60
60
60
60
180
180
5
30
60
60
60
60
hn
hn
5.0
2.5
2.5
1.5
1.5
1.0
0.5
0.5
0.1
1.5
1.5
1.5
1.5
1.5
1.5
64
66
77
77
a
Dark
Dark
Dark
Dark
Dark
Dark
Dark
Dark
Dark
Dark
Dark
Dark
Dark
C M M = H, Si
b
86
+
-
2e -M
C
72
37
50
10
16
45
82
9c
+
R
C R
0
1
2
3
4
5
cation pool
Scheme 6.
ꢀ78
ꢀ20
ꢀ20
82
8
d
2
. Result and discussion
a
b
c
d
Isolated yield.
Slow addition of distannane.
,2,6,6-Tetramethyl-1-piperidinyloxyl (TEMPO) (0.1 equiv) was added.
TEMPO (1.0 equiv) was added.
We began our study with surveying appropriate conditions to
generate alkyl radicals, which could react with the cation
2

T. Maruyama et al. / Tetrahedron 62 (2006) 6519–6525
6521
(
ꢀ
entries 4, 10, and 11), but only 9% of 3 was obtained at
ꢁ
electron
transfer
initiation
step
(Bu Sn)
3
+
(Bu3Sn)2
2
+
78 C (entry 13).
N
N
CO Me
CO Me
2
2
To obtain a deeper insight into the mechanism, the reaction
of 2 with Bu SnSnBu in the absence of alkyl halides was
examined at ꢀ20 C. The dimeric product 4 was obtained
in 81% yield (a mixture of dl and meso) probably via
one-electron reduction of 2 by Bu SnSnBu to form radical
intermediate 5 (Scheme 8). The radical-cation of
Bu SnSnBu thus formed may undergo Sn–Sn bond cleav-
age to give a tributylstannyl radical.
Bu3SnF
Bu3Sn
RI
3
3
BF4-
ꢁ
+
Bu Sn
3
BF3
Bu SnI
3
3
4,15
3
1
(
Bu Sn)
R
3
2
3
3
R
N
CO Me
N
2
CO Me
2
reduction
Bu3Sn)2
R
N
radical
(
CO Me
addition
N
N
N
N
2
CO Me
2
CO Me
2
CO Me CO Me
2
2
2
Scheme 10.
5
4, 81%
-
20 °C
2
+
CH Cl
+
2
N-acyliminium ion 2 to generate the radical-cation, which
undergoes the electron transfer reaction with Bu SnSnBu
Bu SnSnBu
3
Bu SnSnBu
3
Bu Sn
+
SnBu
3
3
3
3
3
3
to give the final product together with the radical-cation of
Bu SnSnBu . This electron transfer regenerates the radi-
cal-cation of Bu SnSnBu . It is important to note that the re-
Scheme 8.
3
3
The reaction with cyclopropylmethyl iodide 6 was also
examined, because the ring opening of cyclopropylmethyl
3
3
duction of the radical-cation by Bu SnSnBu is faster than
3
3
1
6
the reduction of cation 2 by Bu SnSnBu . This consideration
3
radical is often used as a radical clock (Scheme 9). The
product having the cyclopropyl ring (8) was obtained
together with the ring-opened product (7). Formation of the
product containing cyclopropyl ring indicated that the rate
of radical addition to N-acyliminium ion 2 is comparable
to that of ring opening. It is also worth mentioning that
the product ratio depends upon the concentration of 2. At
lower concentration of 2, the relative rate of the isomeriza-
tion compared to the addition increases, and therefore, the
amount of 7 increased with the expense of 8.
3
1
8
is supported by the DFT calculations. The DFT calcula-
tions using N-(methoxycarbonyl)dimethylamine as a model
compound indicate that the ionization energy of the radical
to cation is ca. 6 eV, whereas the ionization of the neutral
molecule to radical-cation is 8.44 eV (Fig. 1). It is also note-
1
7
worthy that the slow addition of Bu SnSnBu increased the
3
3
yield of the product (Table 1, entry 5). Moreover, the addi-
tion of a catalytic amount of TEMPO (0.1 equiv) as a radical
inhibitor did not affect the yield of 3, but the addition of
a stoichiometric amount of TEMPO (1.0 equiv) decreased
the yield significantly (8%) (Table 1, entries 14 and 15).
These results suggested the participation of Bu SnSnBu
(
5.0 eq)
3
3
I
6
in the initiation step of the reaction, and the radical initiation
process took place spontaneously in situ.
(
Bu Sn) (1.5 eq)
3 2
+
N
dropwise
+
N
N
CO Me
-20 °C, 2 h
2
CO Me 7
CO Me 8
Next, we investigated the scope of the present method
using other organic halides and cation pools (Table 2).
The reaction with an alkyl bromide was rather slow, and
2
2
2
conc. of 2
ratio
0
0
0
.05 M
20%
16%
12%
27:73
34:66
44:56
54%
30%
15%
.025 M
.01 M
N
+
intermolecular reaction
addition:
vs
+
N
(favorable in high concentration)
O
O
CO Me
N
2
O
isomerization:
intramolecular reaction
O
(
favorable in low concentration)
cation (transoid)
.04 eV
0
Scheme 9.
N
cation (cisoid)
radical (cisoid)
-6.06 eV
0
.00 eV
O
O
On the basis of the above observations, we propose a mecha-
nism described in Scheme 10. The reaction is initiated by
one-electron transfer from Bu SnSnBu to N-acyliminium
radical (transoid)
-6.07 eV
N
N
3
3
radical-cation
0.00 eV
O
O
O
O
ion 2 to generate the radical-cation of Bu SnSnBu .
3
3
N
Cleavage of the Sn–Sn bond leads to the formation of a tri-
butylstannyl radical, together with a tributylstannyl cation,
which may react with tetrafluoroborate (electrolyte in elec-
trolysis, see Section 4) to give tributylstannyl fluoride. The
tributylstannyl radical abstracts iodine atom from an alkyl
iodide to give an alkyl radical. The alkyl radical adds to
O
O
neutral
8.44 eV
-
Figure 1. DFT calculations of the radical-cation, neutral molecule, cation,
and radical of a model compound.

6522
T. Maruyama et al. / Tetrahedron 62 (2006) 6519–6525
1
13
Table 2. Reactions of organic halides with N-acyliminium ion pools in the
presence of Bu SnSnBu
( H 500 MHz and C 125 MHz), and JEOL ECA-600
H 600 MHz and C 150 MHz) spectrometers in CDCl3.
1
13
3
3
(
RX (5.0 eq)
R
EI and CI mass spectra were recorded on JMS-SX102A
spectrometer. FAB mass spectra were recorded on JMS-
HX110A spectrometer. IR spectra were measured with a
SHIMADZU FTIR 1600 spectrometer. GC analysis was
performed on a gas chromatograph (SHIMADZU GC-14B)
equipped with a flame ionization detector using a fused silica
capillary. Gel permeation chromatography (GPC) was carried
out by Japan Analytical Industry’s LC-908 equipped with
1
R2
CO2Me
(Bu3Sn)2 (1.5 eq)
R
N
1
1
N
R
R
-20 °C, 1 h
CO2Me
CH Cl
2
2
1
2
RX
Yield (%)
R
N
R
CO Me
Normal
addition
Slow
addition
2
JAIGEL-1H and 2H using CHCl as an eluent. Thin-layer
3
chromatography (TLC) was carried out by using Merck
precoated silica gel F254 plates (thickness 0.25 mm).
C
7
H
15
I
77
20
1
86
39
C
7
H
15Br
15Cl
N
7
C H
CO2Me
ClC
c-C
iso-C
tert-C H I
4 9
PhCH Br
2
7
H
14
I
I
81
74
73
6
H
11
60
43
19
69
3
4
.2. Materials
3 7
H I
77
Dichloromethane was washed with water and distilled from
P O , then removal of a trace amount of acid was carried out
by distillation from dried K CO , and distillate was stored
I
2
5
2
3
4
Br
˚
over 4 A molecular sieves. Trifluoromethanesulfonic acid
TfOH) was purchased from Nacalai and was used with-
(
Ph
Ph
Br
Cl
Complex
mixture
Complex
mixture
out purification. Tetrabutylammonium tetrafluoroborate
(Bu NBF ) was purchased from TCI and dried with P O
2 5
4
4
under vacuum. All reactions were carried out under Ar atmo-
sphere unless otherwise noted.
N
C H15I
7
35
57
CO Me
4.3. Reactions
2
N
4.3.1. Generation of N-acyliminium ion pool (2). The
anodic oxidation was carried out in an H-type divided cell
C
7
H
15
I
31
CO Me
2
(4G glass filter) equipped with a carbon felt anode (Nippon
Carbon JF-20-P7, ca. 320 mg, dried at 250 C/1 mmHg for
ꢁ
1
h before use) and a platinum plate cathode (40ꢂ20 mm).
In the anodic chamber was placed a solution of 1
563.8 mg, 2.8 mmol) in 0.3 M Bu NBF /CH Cl (56 mL).
the reaction with an alkyl chloride was unsuccessful. The re-
action with 1-chloro-6-iodoheptane gave rise to the forma-
tion of the corresponding chloroheptylated compound in
(
4
4
2
2
In the cathodic chamber were placed 0.3 M Bu NBF /
4
CH Cl (56 mL) and trifluoromethanesulfonic acid (0.62 mL,
2
4
8
1% yield. The slow addition of the distannane was quite ef-
2
fective for the improvement in the yields of the product in the
reaction with secondary and tertiary alkyl iodides. Benzyl
bromide smoothly reacted with the cation, whereas the reac-
tions using allylic halides were ineffective. The reaction also
works for other cyclic and acyclic N-acyliminium ions.
7
.0 mmol). The constant current electrolysis (20 mA) was
ꢁ
F/mol of electricity was consumed.
carried out at ꢀ78 C with magnetic stirring until 2.5
4
.3.2. Methyl 2-heptylpyrrolidinecarboxylate (3).
Typical procedure. The electrolysis of 1 was carried out
as described above. To the cation pool 2 generated from 1
3. Conclusion
(56.4 mg, 0.28 mmol) was added 1-iodoheptane (0.20 mL,
1
.25 mmol), and hexabutyldistannane (0.19 mL, 0.375 mmol)
ꢁ
In summary, we found that Bu SnSnBu markedly promoted
3
3
at ꢀ20 C, and the reaction mixture was stirred for 1 h.
the reactions of alkyl halides with N-acyliminium ions. A
chain mechanism involving the addition of an alkyl radical
to an N-acyliminium ion followed by electron transfer re-
duction of thus formed radical-cation has been suggested.
The present observations shed light on a new aspect of the
chemistry of radical-cations. It is also noteworthy that the
present reaction opens a new possibility for radical-cation
ꢁ
Triethylamine were added to the solution at ꢀ20 C, and
the resulting mixture was warmed up to room temperature.
Solvent was removed under reduced pressure. DBU
(1.2 mL, 0.90 mmol) and diethyl ether (10 mL) were added
to the residue, and thus obtained solution was quickly filtered
through a short column (10 cm) of silica gel. The silica gel
was washed with ether (150 mL). The combined solu-
tion was concentrated by rotary evaporator, and the crude
product thus obtained was purified using flash chromato-
graphy (hexane/EtOAc 9:1) and GPC to obtain the title
1
9
crossover-mediated carbon–carbon bond formation.
4. Experimental
1
compound (49 mg, 77% by GC analysis): H NMR
(400 MHz, CDCl ) d 0.88 (t, J¼6.8 Hz, 3H), 1.20–1.36 (m,
13
4
.1. General remarks
3
1
(m, 2H), 3.67 (s, 3H), 3.73–3.86 (m, 1H); C NMR
1H), 1.63–1.71 (m, 2H), 1.76–1.97 (m, 3H), 3.30–3.49
1
13
H and C NMR spectra were recorded on Varian GEMINI-
2000 ( H 300 MHz and C 75 MHz), Varian MERCURY-
plus-400 ( H 400 MHz and C 100 MHz), JEOL A-500
1
13
(100 MHz, CDCl ) d 14.2, 22.8, 23.6, 26.3, 29.4, 29.7,
3
30.2, 31.9, 34.2, 46.4, 52.1, 57.7, 155.4; IR (neat) 2926.4,
1
13

T. Maruyama et al. / Tetrahedron 62 (2006) 6519–6525
6523
ꢀ
1
+
1705.3 cm ; LRMS (CI) m/e 228 (M +H); HRMS (CI)
calcd for C H NO (M +H): 228.1964, found: 228.1965.
bromide (0.15 mL, 1.25 mmol), and then purified by flash
chromatography (hexane/EtOAc 9:1) and GPC to obtain
the title compound (42.4 mg, 0.190 mmol, 69% yield): H
+
1
3
26
2
1
4
.3.3. Methyl 2-cyclohexylpyrrolidinecarboxylate.
NMR (400 MHz, CDCl ) d 1.69–1.89 (m, 4H), 2.58 (dd,
3
Typical procedure for slow addition of hexabutyldistan-
nane. The electrolysis of 1 was carried out as described
above. To the cation pool 2 generated from 1 (56.4 mg,
J¼13.2, 9.6 Hz, 1H), 2.96–3.09 (m, 0.5H), 3.16–3.26 (m,
0.5H), 3.31–3.50 (m, 2H), 3.732 (s, 3H), 3.99–4.14 (m,
1
3
1H), 7.12–7.30 (m, 5H); C NMR (100 MHz, CDCl3)
d 22.8 and 23.6, 29.0 and 29.9, 39.6 and 40.6, 46.6, 52.2,
58.6 and 59.3, 126.0, 128.2, 129.3, 138.8, 155.4; IR (neat)
0
.28 mmol) was added 1-iodocyclohexane (0.16 mL, 1.25
ꢁ
.375 mmol) was added dropwise over a period of 30 min
mmol) at ꢀ20 C. Then, hexabutyldistannane (0.19 mL,
ꢀ
1
+
0
at the same temperature. Then the reaction mixture was
2953.4, 1699.5, 702.2 cm ; LRMS (CI) m/e 220 (M +H);
HRMS (CI) calcd for C H NO (M +H): 220.1338, found:
220.1337.
+
1
3
18
2
ꢁ
stirred for 1.0 h at ꢀ20 C. Triethylamine was added to the
ꢁ
solution at ꢀ20 C, and the resulting mixture was warmed
up to room temperature. Solvent was removed under reduced
pressure. DBU (1.2 mL, 0.90 mmol) and diethyl ether
4.3.7. Methyl ethyl(1-methyloctyl)aminecarboxylate.
The electrolysis of diethylamine carboxylate (52.5 mg,
0.40 mmol) was carried out as described above. To the cation
pool 2 thus generated in the anodic chamber, were added
1-iodoheptane (0.33 mL, 2.0 mmol) and hexabutyldistan-
(
10 mL) were added to the residue, and thus obtained solu-
tion was quickly filtered through a short column (10 cm) of
silica gel. The silica gel was washed with ether (150 mL).
The combined solution was concentrated by rotary evapora-
tor, and the crude product thus obtained was purified by flash
chromatography (hexane/EtOAc 9:1) and GPC to obtain the
ꢁ
nane (0.30 mL, 0.60 mmol) at ꢀ20 C and the reaction mix-
ture was stirred for 1 h. Triethylamine was added to the
ꢁ
stirred solution at ꢀ20 C. Then the mixture was warmed
1
title compound (33.6 mg, 0.159 mmol, 60% yield): H NMR
(
up to room temperature. Solvent was removed under reduced
pressure and the residue was quickly filtered through a short
column (10 cm) of silica gel to remove Bu NBF . The silica
400 MHz, CDCl ) d 0.87–1.09 (m, 2H), 1.09–1.30 (m, 3H),
3
1
3
.54–1.70 (m, 4H), 1.70–1.90 (m, 6H), 3.21–3.31 (m, 1H)
.40–3.83 (m, 2H) 3.69 (s, 3H); C NMR (100 MHz,
4
4
1
3
gel was washed with ether (150 mL). Then, the crude prod-
uct thus obtained was purified using flash chromatography
(hexane/EtOAc 9:1) and GPC to obtain the title compound
CDCl ) d 23.6 and 24.4, 26.2, 26.4, 26.6, 27.3 and 27.7,
3
3
0.0, 40.6 and 41.3, 46.7, 52.1, 61.8 and 62.4, 156.0; IR
neat) 2926.4, 1703.4 cm ; LRMS (CI) m/e 212 (M +H);
ꢀ
1
+
1
(
HRMS (CI) calcd for C H NO (M +H): 212.1651, found:
(28.6 mg, 0.125 mmol, 31% yield): H NMR (400 MHz,
CDCl ) d 0.87 (t, J¼6.8 Hz, 3H), 1.00–1.19 (m, 6H),
+
1
2
22
2
3
2
12.1656.
1.19–1.57 (m, 13H), 3.00–3.29 (m, 2H), 3.69 (s, 3H),
3.91–4.21 (m, 1H); C NMR (100 MHz, CDCl ) d 14.5,
1
3
3
4
.3.4. Methyl 2-(4-chlorobutyl)pyrrolidinecarboxylate.
15.4 and 16.1, 19.6 and 20.0, 23.1, 27.1, 29.6, 30.0, 32.2,
35.3, 37.4 and 38.2, 52.3, 52.5, 156.9; IR (neat) 2928.3,
1703.4 cm ; LRMS (CI) m/e 230 (M +H); HRMS (CI)
Prepared from cation pool 2 generated from 1 (50.3 mg,
.25 mmol), hexabutyldistannane (0.19 mL, 0.375 mmol),
ꢀ
1
+
0
+
and 1-chloro-4-iodobutane (0.15 mL, 1.25 mmol), and then
purified by flash chromatography (hexane/EtOAc 9:1) to
obtain the title compound (44.6 mg, 0.203 mmol, 81%
calcd for C H NO (M +H): 230.2120, found: 230.2119.
1
3
28
2
4.3.8. Methyl 2-(3-butenyl)pyrrolidinecarboxylate (7).
Prepared from cation pool 2 generated from 1 (56.4 mg,
0.28 mmol), hexabutyldistannane (0.19 mL, 0.375 mmol),
and cyclopropylmethyl iodide (227.5 mg, 1.25 mmol), and
then purified by flash chromatography (hexane/EtOAc 9:1)
and GPC to obtain the title compound (5.5 mg,
1
yield): H NMR (400 MHz, CDCl ) d 1.13–2.03 (m, 10H),
3
3
.21–3.50 (m, 2H), 3.53 (t, J¼6.4 Hz, 2H), 3.66 (s, 3H),
1
3
3
and 24.0, 23.5, 30.0 and 30.6, 32.5, 33.2 and 33.8, 45.0,
.71–3.89 (m, 1H); C NMR (100 MHz, CDCl ) d 23.1
3
4
2
6.3 and 46.6, 52.1, 57.0 and 57.7, 155.4; IR (neat)
955.4, 2872.4, 1701.4 cm ; LRMS (CI) m/e 220
ꢀ1
1
0.030 mmol, 11% yield): H NMR (400 MHz, CDCl3)
d 1.30–2.11 (m, 8H), 3.28–3.47 (m, 2H), 3.74–3.88 (m,
+
+
(
M +H); HRMS (CI) calcd for C H ClNO (M +H):
0
1
18
2
1
3
2
20.1104, found: 220.1100.
1H), 4.88–5.11 (m, 2H), 5.72–5.88 (m, 1H); C NMR
100 MHz, CDCl ) d 22.9 and 23.8, 29.8 and 30.4, 33.0
and 33.5, 46.2, 52.0, 56.8 and 57.4, 114.5, 138.2, 155.6;
(
3
4
.3.5. Methyl 2-isopropylpyrrolidinecarboxylate.
ꢀ
1
Prepared from cation pool 2 generated from 1 (56.4 mg,
.28 mmol), hexabutyldistannane (0.19 mL, 0.375 mmol),
and iso-propyl iodide (0.12 mL, 1.25 mmol), and then puri-
IR (neat) 2953.9, 1701.4, 733.0 cm ; LRMS (EI) m/e 183
(M ); HRMS (EI) calcd for C H NO (M ): 183.1259,
10 17 2
+
+
0
found: 183.1256.
fied by flash chromatography (hexane/EtOAc 9:1) and GPC
to obtain the title compound (20.6 mg, 0.120 mmol, 43%
yield): H NMR (400 MHz, CDCl ) d 0.77–0.94 (m, 6H),
3
4.3.9. Methyl 2-(cyclopropylmethyl)pyrrolidine-
carboxylate (8). Prepared from cation pool 2 generated from
1 (56.4 mg, 0.28 mmol), hexabutyldistannane (0.19 mL,
0.375 mmol), and cyclopropylmethyl iodide (227.5 mg,
1.25 mmol), and then purified by flash chromatography
(hexane/EtOAc 9:1) and GPC to obtain the title compound
1
1
3
.69–1.94 (m, 4H), 2.00–2.30 (m, 1H), 3.20–3.30 (m, 1H),
.54–3.80 (m, 2H), 3.64 (s, 3H); C NMR (100 MHz,
1
3
CDCl ) d 17.2, 19.9, 24.8, 26.0, 30.4, 47.4, 52.4, 63.3,
3
ꢀ
1
1
(
56.2; IR (neat) 2961.1, 1703.4 cm ; LRMS (CI) m/e 172
M +H); HRMS (CI) calcd for C H NO (M +H):
+
+
1
(22.0 mg, 0.12 mmol, 42% yield). H NMR (400 MHz,
CDCl ) d 0.01–0.16 (m, 2H), 0.37–0.50 (m, 2H), 0.54–
9
18
2
1
72.1338, found: 172.1337.
3
0.67 (m, 1H), 1.33–1.46 and 1.49–1.59 (m, 2H), 1.77–2.03
(m, 4H), 3.29–3.51 (m, 2H), 3.67 (s, 3H), 3.80–3.99 (m,
1H); C NMR (100 MHz, CDCl ) d 4.3, 5.2, 8.3, 23.5 and
3
4.3.6. Methyl 2-benzylpyrrolidinecarboxylate. Prepared
from cation pool 2 generated from 1 (56.4 mg, 0.28 mmol),
hexabutyldistannane (0.19 mL, 0.375 mmol), and benzyl
1
3
24.3, 30.2 and 30.9, 38.7 and 39.6, 46.6, 52.4, 58.0 and

6524
T. Maruyama et al. / Tetrahedron 62 (2006) 6519–6525
ꢀ
1
5
1
1
8.5, 155.8; IR (neat) 2955.3, 1703.4 cm ; LRMS (CI) m/e
84 (M +H); HRMS (CI) calcd for C H NO (M +H):
84.1338, found: 184.1339.
3. (a) Brumfield, M. A.; Quillen, S. L.; Yoon, U. C.; Mariano, P. S.
J. Am. Chem. Soc. 1984, 106, 6855; (b) Pandey, G.;
Kumaraswamy, G.; Bhalerao, U. T. Tetrahedron Lett. 1989,
+
+
1
0
18
2
3
0, 6059; (c) Popielarz, R.; Arnold, D. R. J. Am. Chem. Soc.
4
.3.10. Methyl 2-heptylpiperidinecarboxylate. Prepared
1990, 112, 3068; (d) Mikami, T.; Harada, M.; Narasaka, K.
Chem. Lett. 1999, 425; (e) Jonas, M.; Blechert, S.; Steckhan,
E. J. Org. Chem. 2001, 66, 6896; (f) Seiders, J. R., II; Wang,
L.; Floreancig, P. E. J. Am. Chem. Soc. 2003, 125, 2406; (g)
Liu, H.; Shuangyi Wan, S.; Floreancig, P. E. J. Org. Chem.
2005, 70, 3814 and references cited therein.
from cation pool generated from methyl piperidinecar-
boxylate (60.3 mg, 0.28 mmol), 1-iodoheptane (0.20 mL,
1
mmol), and then purified by flash chromatography (hex-
.25 mmol), and hexabutyldistannane (0.19 mL, 0.375
ane/EtOAc 9:1) and GPC to obtain the title compound
23.7 mg, 0.098 mmol, 35% yield): H NMR (400 MHz,
1
(
4. Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. 1997, 36,
2550; See also: Baciocchi, E.; Bietti, M.; Lanzalunga, O.
Acc. Chem. Res. 2000, 33, 243.
CDCl ) d 0.88 (t, J¼6.8 Hz, 3H), 1.14–1.33 (m, 10H),
3
1
4
.33–1.71 (m, 8H), 2.74–2.87 (m, 1H), 3.67 (s, 3H), 3.90–
.06 (m, 1H), 4.14–4.27 (m, 1H); C NMR (120 MHz,
1
3
5. For mechanistic studies of radical-cation fragmentation reac-
tions see: (a) Hammerum, S.; Audier, H. E. J. Chem. Soc.,
Chem. Commun. 1988, 860; (b) Arnold, D. R.; Lamont, L. J.
Can. J. Chem. 1989, 67, 2119; (c) Horner, J. H.; Martinez,
F. N.; Musa, O. M.; Newcomb, M.; Shahin, H. E. J. Am.
Chem. Soc. 1995, 117, 11124; (d) Burton, R. D.; Bartberger,
M. D.; Zhang, Y.; Eyler, J. R.; Schanze, K. S. J. Am. Chem.
Soc. 1996, 118, 5655; (e) Baciocchi, E.; Bietti, M.; Putignani,
L.; Steenken, S. J. Am. Chem. Soc. 1996, 118, 5952; (f) Su,
Z.; Mariano, P. S.; Falvey, D. E.; Yoon, U. C.; Oh, S. W.
J. Am. Chem. Soc. 1998, 120, 10676; (g) Gould, I. R.;
Lenhard, J. R.; Muenter, A. A.; Godleski, S. A.; Farid, S.
J. Am. Chem. Soc. 2000, 122, 11934.
6. (a) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.;
Perchinummo, M. Tetrahedron 1971, 27, 3575; (b) Minisci, F.
Synthesis 1973, 1; (c) Minisci, F.; Fontana, F.; Pianese, G.;
Yan, Y. M. J. Org. Chem. 1993, 58, 4207; (d) Minisci, F.;
Vismara, E.; Fontana, F.; Morini, G.; Serravalle, M. J. Org.
Chem. 1986, 51, 4411 and references cited therein.
CDCl ) d 14.1, 18.9, 22.6, 25.6, 26.2, 28.3, 29.3, 29.5,
3
2
2
9.5, 31.8, 40.0, 50.7, 52.3, 156.3; IR (neat) 2930.2,
856.9, 1701.4 cm ; LRMS (CI) m/e 242 (M +H);
ꢀ1
+
+
HRMS (CI) calcd for C H NO (M +H): 242.2115, found:
1
2
4
28
2
42.2120.
0
0
4
.3.11. N,N -Dimethoxycarbonyl-2,2 -bipyrrolidine (4).
This compound was obtained by the reaction of 2 and
Bu SnSnBu in the absence of an alkyl halide. The electrol-
3
3
ysis of 1 was carried out as described above. To the cation
pool 2 (0.056 M, 5.0 mL, 0.28 mmol) was added hexabutyl-
ꢁ
tion mixture was stirred for 5 h at the same temperature.
distannane (0.19 mL, 0.375 mmol) at ꢀ20 C and the reac-
Triethylamine (0.25 mL) was added to stirred solution at
ꢁ
ꢀ
20 C and the resulting mixture was warmed to room tem-
perature. Solvent was removed under reduced pressure and
the residue was quickly filtered through a short column
(
10 cm) of silica gel to remove Bu NBF . The silica gel
4 4
was washed with ether (150 mL). Then, the crude product
thus obtained was purified using flash chromatography (hex-
ane/EtOAc 9:1) and GPC to obtain the title compound
7. Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489.
8. (a) Clerici, A.; Porta, O. Tetrahedron Lett. 1990, 31, 2069; (b)
Clerici, A.; Porta, O. Gazz. Chim. Ital. 1992, 122, 165; (c)
Cannella, R.; Clerici, A.; Pastori, N.; Regolini, E.; Porta, O.
Org. Lett. 2005, 7, 645.
(29.3 mg, 0.114 mmol, 82% yield), which was identified
by comparison of its H NMR spectrum with that of an
authentic sample reported previously.
1
1
4
9. (a) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett.
002, 4, 131; (b) Miyabe, H.; Ueda, M.; Naito, T. Synlett
2
4
.3.12. DFT calculations. The DFT calculations were
2004, 1140; (c) Miyabe, H.; Yamaoka, Y.; Takemoto, Y.
J. Org. Chem. 2005, 70, 3324.
carried out with model compounds (methyl dimethylamine
carboxylate, the radical-cation, radical, and cation derived
from it at B3LYP/6-31G(d) level using the Gaussian 98W
and 2003W. Geometries were fully optimized. All the
optimized geometries were local minima according to the
vibration analysis.
10. (a) Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto,
A.; Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546; (b) Suga,
S.; Suzuki, S.; Yamamoto, A.; Yoshida, J. J. Am. Chem. Soc.
2000, 122, 10244; (c) Suga, S.; Okajima, M.; Yoshida, J.
Tetrahedron Lett. 2001, 42, 2173; (d) Suga, S.; Okajima, M.;
Fujiwara, K.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 7941;
1
8
(
e) Yoshida, J.; Suga, S. Chem.—Eur. J. 2002, 8, 2650; (f)
Suga, S.; Watanabe, M.; Yoshida, J. J. Am. Chem. Soc. 2002,
24, 14824; (g) Suga, S.; Nagaki, A.; Yoshida, J. Chem.
Acknowledgements
1
This work was partially supported by the Grant-in-Aid
for Scientific Research, Japan. We also thank Professor
MichaelSchmittelofSiegenUniversityforhelpfuldiscussion.
Commun. 2003, 354; (h) Suga, S.; Nagaki, A.; Tsutsui, Y.;
Yoshida, J. Org. Lett. 2003, 5, 945; (i) Suga, S.; Kageyama,
Y.; Babu, G.; Itami, K.; Yoshida, J. Org. Lett. 2004, 6, 2709;
(
j) Suzuki, S.; Matsumoto, K.; Kawamura, K.; Suga, S.;
Yoshida, J. Org. Lett. 2004, 6, 3755; (k) Suga, S.; Nishida,
T.; Yamada, D.; Nagaki, A.; Yoshida, J. J. Am. Chem. Soc.
References and notes
2
004, 126, 14338; (l) Nagaki, A.; Kawamura, K.; Suga, S.;
1
2
. (a) Narasaka, K.; Okauchi, T.; Arai, N. Chem. Lett. 1992, 1229;
b) Chen, C.; Mariano, P. S. J. Org. Chem. 2000, 65, 3252; (c)
Saitoh, T.; Ichikawa, J. J. Am. Chem. Soc. 2005, 127, 9696.
. (a) Yoshida, J.; Nishiwaki, K. J. Chem. Soc., Dalton Trans.
1998, 2589; (b) Moeller, K. D. Tetrahedron 2000, 56, 9527
and references cited therein.
Ando, T.; Sawamoto, M.; Yoshida, J. J. Am. Chem. Soc.
2004, 126, 14702; (m) Okajima, M.; Suga, S.; Itami, K.;
Yoshida, J. J. Am. Chem. Soc. 2005, 127, 6930; (n) Suga, S.;
Tsutsui, Y.; Nagaki, A.; Yoshida, J. Bull. Chem. Soc. Jpn.
2005, 78, 1206; (o) Nagaki, A.; Togai, M.; Suga, S.; Aoki,
N.; Mae, K.; Yoshida, J. J. Am. Chem. Soc. 2005, 127, 11666.
(

T. Maruyama et al. / Tetrahedron 62 (2006) 6519–6525
6525
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1. Maruyama, T.; Suga, S.; Yoshida, J. J. Am. Chem. Soc. 2005,
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2. Nozaki, K.; Oshima, K.; Utimoto, K. J. Am. Chem. Soc. 1987,
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Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski,
J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,
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J. A. Gaussian 03, Revision B.05; Gaussian: Pittsburgh, PA,
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1
1
1
1
Bull. Chem. Soc. Jpn. 2004, 77, 1545.
1
5. It has been reported that 10-methylacridinium ion reacts with
distannane via electron transfer mediated radical chain mecha-
nism to yield the dimeric product. Fukuzumi, S.; Kitano, T.;
Mochida, K. J. Am. Chem. Soc. 1990, 112, 3246; See also:
Krusic, P. J.; Stoklosa, H.; Manzer, L. E.; Meakin, P. J. Am.
Chem. Soc. 1975, 97, 667.
1
6. The rate constant of the ring opening is reported to be
ꢀ1
8
1
Chem. Soc. 1976, 98, 7024.
.3ꢂ10 s : Maillard, B.; Forrest, D.; Ingold, K. U. J. Am.
1
7. The rate constant of the addition of a primary alkyl radical
4
to protonated pyridine derivatives is reported to be 10 –
19. For example: (a) Crich, D.; Ranganathan, K.; Neelamkavil, S.;
Huang, X. J. Am. Chem. Soc. 2003, 125, 7942; (b) Crich, D.;
Ranganathan, K. J. Am. Chem. Soc. 2002, 124, 12422; (c)
Newcomb, M.; Miranda, N.; Sannigrahi, M.; Huang, X.;
Crich, D. J. Am. Chem. Soc. 2001, 123, 6445.
6
0 M
ꢀ1 ꢀ1
1 s . See: Citterio, A.; Minisci, F.; Franchi, V.
J. Org. Chem. 1980, 45, 4752. See also Ref. 7.
1
8. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;