Efficient synthesis of pyrrolizidine by Pd-catalyzed consecutive double amphiphilic allylation of nitrile

Article abstract of DOI:10.1016/j.tet.2015.04.110

Abstract The combination of a Pd catalyst and triethylborane promotes double amphiphilic allylation of nitriles with 2-methylenepropane-1,3-diol to serve as a 1,3-dipolar equivalent, providing pyrrolizidine derivatives. The resulting bicyclic compounds ca

Full text of DOI:10.1016/j.tet.2015.04.110

Accepted Manuscript
Efficient Synthesis of Pyrrolizidine by Pd-Catalyzed Consecutive Double Amphiphilic
Allylation of Nitrile
Naoshi Yamada, Goki Hitara, Gen Onodera, Masanari Kimura
PII:
S0040-4020(15)00637-7
10.1016/j.tet.2015.04.110
TET 26713
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 March 2015
Revised Date: 28 April 2015
Accepted Date: 29 April 2015
Please cite this article as: Yamada N, Hitara G, Onodera G, Kimura M, Efficient Synthesis of
Pyrrolizidine by Pd-Catalyzed Consecutive Double Amphiphilic Allylation of Nitrile, Tetrahedron (2015),
doi: 10.1016/j.tet.2015.04.110.
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Efficient Synthesis of Pyrrolizidine by Pd-
Catalyzed Consecutive Double Amphiphilic
Allylation of Nitrile
Leave this area blank for abstract info.
Naoshi Yamada, Goki Hitara, Gen Onodera, and Masanari Kimura*
Graduate School of Engineering, Nagasaki University, Bunkyo-machi 1-14, Nagasaki 852-8521, Japan

1
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Tetrahedron
journal homepage: www.elsevier.com
Efficient Synthesis of Pyrrolizidine by Pd-Catalyzed Consecutive Double Amphiphilic
Allylation of Nitrile
Naoshi Yamada, Goki Hitara, Gen Onodera, and Masanari Kimura∗
Graduate School of Engineering, Nagasaki University, Bunkyo-machi 1-14, Nagasaki 852-8521, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The combination of a Pd catalyst and triethylborane promotes double amphiphilic allylation of
nitriles with 2-methylenepropane-1,3-diol to serve as a 1,3-dipolar equivalent, providing
pyrrolizidine derivatives. The resulting bicyclic compounds can be used for efficient synthesis
of important pyrrolizidine alkaloids.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
palladium
allylation
amphiphilic
nitrile
pyrrolizidine
—
——
∗
Corresponding author. Tel.: +81-95-819-2677; fax: +81-95-819-2677; e-mail: masanari@nagasaki-u.ac.jp

2
Tetrahedron
1
. Introduction
efficient and innovative methods for the synthesis of pyrrolidines
ACCEPTED MANUSCRIPT
in a formal [3+2] cycloaddition manner involving a 1,3-dipolar
equivalent with aldimines.
Since the discovery of the reaction of π-allylpalladium chloride
with ethyl malonate and acetoacetate by Tsuji, π-allylpalladium
complexes have been one of the most important key
intermediates for efficient C-C bond transformation reactions in
modern organic chemistry. Recently, we developed a method
1
Scheme 3. Pd-catalyzed amphiphilic allylation of aldimine with 2-
2
for direct formation of π-allylpalladium from allylic alcohols,
promoted by a Pd catalyst and triethylborane. An example is the
activation of allylic alcohols promoted by triethylborane as a
Lewis acid, which facilitates oxidative addition toward the Pd(0)
catalyst to form a π-allylpalladium species serving as an allylic
3
cation equivalent (Scheme 1).
methylenepropane-1,3-diol
Synthetic strategies for six-membered nitrogen-containing
heterocyclic compounds are highly significant. For instance,
piperidine rings are widely distributed in nature and are useful as
important building blocks for physiologically active molecules,
and piperidine alkaloids are representative of a class with potent
Scheme 1. Umpolung of π-allylpalladium with Et B
3
7
biological activity. Recently, we developed novel and efficient
Under the reaction system involving a Pd catalyst and
triethylborane, soft nucleophiles, such as malonates, amines, and
indoles undergo electrophilic allylations with allylic alcohols,
giving rise to allylation products by direct Tsuji-Trost allylation.
Interestingly, moreover, in the presence of electrophiles, a similar
catalytic system consisting of a Pd catalyst and triethylborane
also promoted nucleophilic allylation of carbonyl groups, such as
synthetic methods for the formation of a piperidine ring promoted
by a π-allylpalladium (Scheme 4). This is the first example of
Pd-catalyzed amphiphilic allylation of aldimines with bis-allylic
moieties via a formal [4+2] cycloaddition reaction, followed by
oxidation with DDQ to construct isoquinoline analogues from
2,3-bismethylene-butane-1,4-diol.
8
Scheme 4. Pd-catalyzed amphiphilic allylation of aldimine with 2,3-
aldehydes and aldimines to afford homoallylic alcohols and
4
homoallylamines, respectively (Scheme 2).
In these cases,
umpolung of π-allylpalladium with triethylborane proceeded to
afford an allyldiethylborane as an allyl anion equivalent for
nucleophilic allylation of electrophiles involving an allyl-ethyl
exchange reaction.
dimethylenebutane-1,4-diol derivative
Among
nitrogen-containing
heterocyclic
compounds,
pyrrolizidine alkaloids are one of the most important natural
occurring molecules as necine bases; various species have been
shown to exhibit hepatotoxicity, antitumor activity, and
9
carcinogenicity.
Efficient construction of the pyrrolizidine
significant contribution to the
development of total syntheses of natural products such as
framework represents
a
10
pyrrolizidine alkaloids. In the course of our studies involving
amphiphilic allylation, we developed amphiphilic allylation
reactions of nitriles. We reveal here that a similar reaction
system consisting of a Pd catalyst and triethylborane effectively
promotes the consecutive double amphiphilic allylation of nitriles
with 2-methylenepropane-1,3-diol to form a pyrrolizidine ring in
a single manipulation (Scheme 5).
Scheme 2. Pd/Et B promoted amphiphilic allylation of allyl
alcohols with various electrophiles and nucleophiles
3
1
,3-Dipolar cycloaddition reactions provide an efficient and
convenient method for construction of five-membered
cycloalkanes and heterocycles. We have developed
a
straightforward and convenient method for [3+2] cycloaddition
of aldimine with commercially available 2-methylenepropane-
1
,3-diol through a formal 1,3-zwitterion species under a Pd
catalyst/triethylborane system. One of the allyl alcohol moieties
of the symmetrical bis-allyl alcohol undergoes nucleophilic
allylation with the iminium carbon atom of the aldimine to form
3
-hydroxylmethyl-3-butenylamine, while the remaining allyl
alcohol moiety selectively reacts intramolecularly as an allyl
cation equivalent with the homoallylamine moiety to furnish 3-
5
methylenepyrrolidines (Scheme 3).
The regio- and
Scheme 5. Pd-catalyzed consecutive double amphiphilic allylation
of nitrile with 2-methylenepropane-1,3-diol
stereoselectivities of the reaction using substituted 2-
methylenepropane-1,3-diols were in contrast with the results of6
trimethylenemethane (TMM) chemistry reported by B. M. Trost.
Thus, amphiphilic allylation was concluded to be among the most

3
2
. Results and discussion
decomposition of 1a directly, but rather through other
amphiphilic allylation prosesses.
ACCEPTED MANUSCRIPT
First, we investigated Pd-catalyzed amphiphilic allylation of
benzonitrile with 2-methylenepropane-1,3-diol in the presence of
triethylborane. The VPC (vapor phase chromatography) results
are summarized in Table 1. 2-Methylenepropane-1,3-diol reacted
with benzonitrile to form a pyrrolizidine 1a in the presence of
triethylborane, 20 mol% Pd(OAc)2 and various phosphine
ligands. In some cases, the monocyclized product 2a and the bis-
homoallylamine 3a were detected as by-products along with the
desired product 1a by VPC analysis. The reaction features and
the yields were dependent on the type of ligand used. In accord
with the previous best result using tri-n-butylphosphine for
amphiphilic allylation of aldimine with 2-methylenepropane-1,3-
Table 1. Reaction of 2-methylenepropane-1,3-diol with
benzonitrile
a
5
diol to form a pyrrolidine ring, tri-n-butylphosphine turned out
to be the most efficient ligand for double amphiphilic allylations
of benzonitrile with bis-allylic alcohol, affording 1a in 59% yield
b
VPC Yield %
Entry Ligand
Solvent
1a
2a
3a
total
in THF (entry 3, Table 1).
expected product 1a in modest yield (entry 1, Table 1).
Tricyclohexylphosphine was not effective at all (entry 2, Table
Triphenylphosphine gave the
1
2
3
4
5
6
7
8
9
1
PPh
PCy
P Bu
Xphos
Sphos
Johnphos
Xantphos
DPEphos
3
THF
THF
THF
THF
THF
THF
THF
THF
THF
8
0
4
1
20
10
5
6
8
0
0
18
(11)
18
12
19
0
1
6
7
7
34
12
12
8
21
8
8
0
0
5
(5)
8
14
13
0
23
22
12
15
0
46
13
91
73
39
28
37
0
3
n
3
59
55
13
14
21
0
1
(
).
XPhos) provided the desired product 1a with the second best
yield in THF solvent (entry 4, Table 1). In contrast, Buchwald’s
ligands, such as 2-dicyclohexylphosphino-2',6'-
dimethoxybiphenyl (SPhos) and 2-(di-tert-
2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
DPPE
0
76
0
butylphosphino)biphenyl (JohnPhos), were far less efficient than
XPhos (entries 5 and 6, Table 1). The use of diphosphine ligands
tended to inhibit the amphiphilic allylation (entries 7-9, Table 1).
c
n
0
P Bu
3
dioxane
99
(83)
89
57
75
0
51
100
82
80
0
(67)
n
d
11
P Bu
3
3
3
3
DCE
63
31
n
1
1
1
1
16
1
1
2
3
4
5
P Bu
benzene
n-hexane 43
DMF
Next, we screened the several solvents for the reaction using
tri-n-butylphosphine and XPhos. When tri-n-butylphosphine was
used, the reactions carried out in 1,4-dioxane and 1,2-
dichloroethane (DCE) gave the product 1a in 76% and 63% yield
n
P Bu
n
P Bu
0
Xphos
Xphos
Xphos
Xphos
Xphos
dioxane
27
72
63
d
DCE
7
8
9
benzene
n-hexane 58
DMF
(entries 10 and 11, Table 1), while the use of benzene and hexane
gave the lower yields (entries 12 and 13, Table 1). In fact, under
the reaction conditions using tri-n-butylphosphine in 1,4-dioxane,
1
0
0
a
A
mixture of 2-methylenepropane-1,3-diol (1.2 mmol),
(0.1 mmol), ligand
monophosphine 0.4 mmol, bidentatephosphine 0.2 mmol), and
triethylborane (5.0 mmol) was stirred at 50 ˚C in solvent (1 mL) for
1
a, 2a and 3a could be separated by recycling preparative HPLC
benzonitrile (0.5 mmol),
Pd(OAc)2
1 13
and were characterized by H- and C-NMR spectroscopy (entry
1
(
11
0, Table 1).
N,N-Dimethylformamide (DMF) was an
ineffective solvent for the reaction owing to the deactivation of
triethylborane as a Lewis acid. When XPhos was used as a
ligand in 1,4-dioxane, pyrrolizidine 1a was obtained in lower
yield, in contrast with the result using tri-n-butylphosphine (entry
b
c
2
4 h under N2. Yields are determined by VPC analysis. Isolated
yield is shown in parentheses. DCE: 1,2-dichloroethane
d
1
5, Table 1). The reaction in 1,2-dichloroethane yielded the
Next, we investigated amphiphilic allylation of various nitriles
with 2-methylenepropane-1,3-diol to form pyrrolizidine
derivatives (1) under the optimized conditions described above.
The isolated yields of the resulting pyrrolizidines 1b-1m are
shown in Table 2. The reaction of 4-methylbenzonitrile with 2-
methylenepropane-1,3-diol led to formation of the corresponding
product 1a in 72% yield (entry 16, Table 1). The use of benzene
and hexane gave 1a in moderate yields, although DMF was
ineffective under the same conditions (entries 17-19, Table 1).
We concluded that the appropriate conditions for amphiphilic
allylation were the use of tri-n-butylphosphine in 1,4-dioxane and
XPhos in DCE.
12
pyrrolizidine 1b in 72% yield (entry 1, Table 2).
Methoxybenzonitrile was converted to 1c in moderate yield
entry 2, Table 2). Halobenzonitriles such as 4-fluorobenzonitrile
4-
In order to shed more light on the reaction mechanism for
double amphiphilic allylation of nitrile, the time course of the
reaction under the conditions shown in entry 3 of Table 1 was
investigated by VPC analysis. The resulting data are shown in
Figure 1. The desired product 1a was formed in extremely high
ratio among all of products, and both pyrrolidine 2a and bis-
homoallylamine 3a had already been formed even at the initial
stage of the reaction. After 24 hours, most of bis-allyl alcohol
had been consumed quantitatively, converting to almost the total
amount of the products 1a, 2a, and 3a. Pyrrolizidine 1a did not
decompose with extension of the reaction time over 24 hours.
Furthermore, the independently isolated products 1a, 2a, and 3a
were intact and were recovered quantitatively even after being
exposed to similar reaction conditions. Although some aspects of
the product distribution could not be clarified, these results seem
to suggest that the products 2a and 3a were formed not by
(
and 4-chlorobenzonitrile tolerated amphiphilic allylation with 2-
methylenepropane-1,3-diol to afford 1d and 1e in 52% and 57%
yield (entries 3 and 4, Table 2). When 4-phenylbenzonitrile was
employed
to
react with
2-methylenepropane-1,3-diol,
pyrrolizidine 1f was obtained in 41% yield (entry 5, Table 2).
The 3-substituted benzonitriles, 3-methylbenzonitrile and 3-
chlorobenzonitrile gave the cyclized products 1g and 1h in lower
yields than that 4-substituted benzonitriles (entries 6 and 7, Table
2
). In the case of an α β-unsaturated nitrile, the use of XPhos as
a ligand gave a better result than the use of tri-n-butylphosphine
entry 8, Table 2). Aliphatic nitriles participated in the formation
(
of the desired amphiphilic allylation products. Alkyl nitriles such
as β-phenethyl-, cyclopropyl-, and n-butyl-substituted nitriles
underwent similar amphiphilic allylation reactions, with isolated
yields hovering around 30% (entries 10-12, Table 2).

4
Tetrahedron
TEyie
Pyrrolizidine 1j was obtained as a single pro
A
du
C
ct
C
in
E
72
P
%
D
ld MAof
N
i
U
nte
S
rm
C
e
R
dia
I
t
P
e III undergoes further electrophilic allylation
T
by the use of phenylacetonitrile (entry 9, Table 2).
intramolecularly to form the final product, pyrrolizidine ring 1.
Monocyclized pyrrolidine (2) and symmetrical homoallylamines
(
3) may be produced via dehydrative reduction as side reactions
from intermediate III and intermediate II, respectively, under
similar catalytic systems. Thus, it is likely that 2-
methylenepropane-1,3-diol can serve as a 1,3-zwitterionic
species, undergoing the consecutive double amphiphilic
allylation with nitrile to form a pyrrolizidine ring as a single
manipulation.
1
00"
total
1a
9
8
7
6
5
4
3
2
1
0"
0"
0"
0"
0"
0"
0"
0"
0"
2a
3a
0
"
0
"
4"
8" 12" 16" 20" 24" 28" 32" 36" 40" 44" 48"
time (h)
Figure 1. Time course of the products 1a, 2a, and 3a under the
Pd/Et B system
3
Table 2. Reactions of 2-methylenepropane-1,3-diol with various
a
nitriles
Entry
Nitrile
4-MeC
Isolated yield % of 1
1
2
3
4
5
6
H
4
1b: 72
1c: 49
1d: 52
1e: 57
1f: 41
1g: 31
1h: 39
1i: 30
1j: 72
1k: 36
1l: 24
1m: 24
4-MeOC
4-FC
6
H
4
6
H
4
4-ClC
6 4
H
4-PhC H
6 4
3-MeC
6 4
3-ClC H
cinnamyl
Bn
phenethyl
6
6 4
H
Scheme 6. A plausible reaction mechanism for Pd/Et B promoted
3
7b
amphiphilic allylation of nitrile
8
9
1
1
0
1
cyclopropyl
3. Conclusion
n
1
2
Bu
a
A mixture of 2-methylenepropane-1,3-diol (1.2 mmol), nitrile (0.5 mmol),
Pd(OAc) (0.1 mmol), P(n-Bu) (0.4 mmol), and triethylborane (5.0 mmol)
was stirred at 50 ˚C in 1,4-dioxane (0.5 mL) for 24 h under N
of 2-methylenepropane-1,3-diol (1.2 mmol), nitrile (0.5 mmol), Pd(OAc)
0.1 mmol), Xphos (0.2 mmol), and triethylborane (5.0 mmol) was stirred in
DCE (0.5 mL) for 24 h under N
In conclusion, we demonstrated that a combination of
Pd(OAc)2 and triethylborane promoted consecutive double
amphiphilic allylation of nitriles with 2-methylenepropane-1,3-
diol and succeeded in producing pyrrolizidine derivatives. The
resulting 2,6-bismethylenepyrrolizidines are an important
building block for efficient synthesis of pyrrolizidine alkaloids.
The application and extension of this strategy in medicinal
chemistry are under current investigation.
2
3
b
2
. A mixture
2
(
2
.
A plausible reaction pathway for consecutive double amphiphilic
13
allylation is shown in Scheme 6.
The allyl alcohol moiety
reacts with the Pd(0) catalyst to form a π-allylpalladium
intermediate via oxidative addition promoted by triethylborane as
a Lewis acid. Transmetallation of π-allylpalladium with an ethyl
group of triethylborane generates an allyl anion equivalent, which
subsequently reacts with nitrile to form aldimine intermediate I.
Aldimine I undergoes nucleophilic allylation with a further allyl
anion species to form the symmetrical bis-homoallylamine
4
4
. Experimental section
.1. General
Reactions employed oven-dried glassware unless otherwise
noted. Thin layer chromatography (TLC) employed glass 0.25
mm silica gel plates with UV indicator (Merck, Silica gel 60F254).
Flash chromatography columns were packed with silica gel as a
slurry in hexane. Gradient flash chromatography was conducted
eluting with a continuous gradient from hexane to the indicated
intermediate II.
Eventually, II undergoes intramolecular
electrophilic allylation to construct the pyrrolidine ring III in the
presence of Pd(0) and triethylborane. The allyl alcohol fragment

5
1
3
solvent. Proton and carbonte Nt r aMm Re t hd ya lt sa il wa ne er Ae o
C
bt
C
ain
E
e
P
d
T
w
E
ith
D
a
MA2H
N
);US
C
C
N
R
MRIP(C
T
DCl3, 100 MH
) 20.9, 44.8, 59.0, 76.1, 105.9,
Z
JEOL JNM-AL400 with
as an internal
125.6, 129.0, 135.8, 143.7, 149.1; High-resolution MS(EI) calcd
+
standard. Chemical shift values were given in ppm downfield
from the internal standard. Infrared spectra were recorded with a
JASCO A-100 FT-IR spectrophotometer. High resolution mass
spectra (HRMS) were measured with a JEOL JMS-700N.
Analytical vapor-phase chromatography (VPC) was carried out
on a Shimadzu GC-2014 gas chromatograph equipped with a
Stabilwax®-DA column (30 m x 0.25 mm ID x 0.25 ꢀm df) and
FID detector (injection: 250°C, 2.0 ꢀl, 50:1 split, oven: 100 °C
for C16H19N: 225.1517, Found m/z: 225.1517 (M ).
5-(4-Methoxyphenyl)-3,7-dimethylenepyrrolizidine (1c)
1
H NMR( CDCl 400 MH ) δ 2.73-2.75 (m, 4H), 3.30 (dm, J =
15.4 H , 2H), 3.71 (dm, J = 15.4 H , 2H), 3.76 (s, 3H), 4.86
(dquintet, J = 0.48, 1.72 H , 2H) , 4.91 (dquintet, J = 0.48, 1.72
3,
Z
Z
Z
Z
1
3
H , 2H), 6.82 (d, J = 8.80 H , 2H), 7.36 (d, J = 8.80 H , 2H);
NMR(CDCl3, 100 MH
C
Z
Z
Z
) 44.7, 55.1, 58.9, 75.8, 105.9, 113.5,
Z
(
15 min), 10 °C/min to 250 °C, carrier gas: helium 30 cm/sec,
126.8, 138.7, 149.1, 158.1; High-resolution MS(EI) calcd for
+
constant, FID temperature: 280 °C).
C
16
H
19NO: 241.1467, Found m/z: 241.1464 (M ).
5-(4-Fluorophenyl)-3,7-dimethylenepyrrolizidine (1d)
1
4
.2. General procedure for synthesis of 5-phenyl-3,7-
dimethylenepyrrolizidine (1a) (entry 10, Table 1)
H NMR( CDCl 400 MH ) δ 2.70-2.81 (m, 4H), 3.32 (dm, J =
3,
Z
A flask was charged with Pd(OAc) (22.5 mg, 0.1 mmol). The
flask was evacuated and filled with nitrogen. To the flask were
15.2 H
Z
, 2H), 3.72 (dm, J = 15.2 H
Z
, 2H), 4.86-4.89 (m, 2H),
2
13
4.91-4.94 (m, 2H), 6.95-6.99 (m, 2H), 7.39-7.44 (m, 2H);
C
=
2
added 1,4-dioxane (1.0 mL), n-Bu P (50 ꢀL, 0.2 mmol), 2-
NMR(CDCl3, 100 MH ) 44.9, 59.0, 75.8, 106.1, 114.9 (d, JCF
Z
3 4
3
methylenepropane-1,3-diol (106.2 mg, 1.2 mmol), and
20.6), 127.4 (d, JCF = 7.41), 142.4 (d, JCF = 3.29), 148.8, 161.6
1
benzonitrile (51.5 mg, 0.5 mmol). Et B (5.0 mmol) was added
(d, JCF = 242.9); High-resolution MS(EI) calcd for C15
H16FN:
3
+
to the reaction mixture. The mixture was stirred at 50 °C for 24
h. The progress of the reaction was monitored by TLC. After
229.1267, Found m/z: 229.1246 (M ).
the reaction was complete, saturated aqueous NaHCO was added,
and the mixture was extracted with AcOEt for 3 times. The
5-(4-Chlorophenyl)-3,7-dimethylenepyrrolizidine (1e)
3
1
H NMR( CDCl3, 400 MH ) δ 2.71 (d, J = 16.1 H , 2H), 2.79 (d,
Z
Z
combined organic layers were dried with MgSO , then the
J = 16.1 H , 2H), 3.32 (d, J = 15.1 H , 2H), 3.72 (d, J = 15.1 H ,
Z Z Z
4
solvent was evaporated in vacuo. The residue was subjected to
column chromatography over silica gel to give 1a (n-
hexane/AcOEt = 50/1, 68.5 mg, 0.32 mmol, 67% yield). By-
products, 2a and 3a were separted by recycling preparative
HPLC instrument (KC9100, Japan Analytical Industry, CO., Ltd).
2H), 4.87-4.89 (m, 2H), 4.91-4.93 (m, 2H), 7.26 (d, J = 8.56 HZ,
13
2H), 7.40 (d, J = 8.56 Hz, 2H); C NMR(CDCl 100 MHz) 44.8,
3,
59.0, 75.8, 106.2, 127.2, 128.3, 132.0, 145.4, 148.6; High-
35
resolution MS(EI) calcd for C H ClN: 245.0971, Found m/z:
245.0959 (M ).
15
16
+
5
-Phenyl-3,7-dimethylenepyrrolizidine (1a)
1
H NMR(CDCl 400 MH ) δ 2.78-2.80 (m, 4H), 3.33 (d, J =
5-Biphenyl-3,7-dimethylenepyrrolizidine (1f)
3,
Z
1
1
4
7
1
5.1 H , 2H), 3.75 (d, J = 15.1 H , 2H), 4.86-4.88 (m, 2H) , 4.90-
H NMR( CDCl3, 400MH
) δ 2.83-2.85 (m, 4H), 3.37 (dm, J =
Z
Z
Z
.93 (m, 2H), 7.17 (tt, J = 0.61, 7.42 H , 1H), 7.27-7.31 (m, 2H),
15.2 H , 2H), 3.81 (dm, J = 15.2 H , 2H), 4.91-4.93 (m, 2H),
Z
Z
Z
13
.43-7.47 (m, 2H); C NMR(CDCl 100 MH ) 45.0, 59.2, 76.3,
4.96-4.98 (m, 2H), 7.32 (tt, J = 1.34, 7.33 H , 1H), 7.40-7.44 (m,
Z
13
3,
Z
05.8, 125.7, 126.3, 128.2, 146.8, 149.0; IR(neat) 3072 (m), 3024
2H), 7.54-7.55 (m, 4H), 7.57-7.60 (m, 2H); C NMR(CDCl 100
3,
(m), 2855 (w), 2808 (w), 2349 (m), 1665 (m), 1601 (m), 1431
MH ) 44.9, 59.1, 76.3, 106.1, 126.2, 126.9, 127.0, 127.1, 127.2,
Z
(
m), 988 (w), 881 (s), 766 (m),702 (s), 623 (m); High-resolution
127.3, 128.7, 139.2, 140.9; High-resolution MS(EI) calcd for
C H N: 287.1674, Found m/z: 287.1658 (M ).
21 21
+
+
MS(EI) calcd for C H N: 211.1361, Found m/z: 211.1360 (M ).
15
17
5
-(2-Methyl-2-propene)-5-phenyl-3-methylenepyrrolidine
(
2a)
5-(3-Methylphenyl)-3,7-dimethylenepyrrolizidine (1g)
1
1
H NMR(CDCl 400 MH ) δ 1.24 (s, 3H), 1.92-2.02 (br, 2H),
H NMR( CDCl 400 MH ) δ 2.36 (s, 3H), 2.81 (m, 4H), 3.35
3,
Z
3,
Z
2
1
1
7
.48 (s, 1H), 2.49 (s, 1H), 2.76 (s, 2H), 3.60 (dm, J = 1.55 HZ,
(dm, J = 15.2 H , 2H), 3.78 (dm, J = 15.2 H , 2H), 4.89-4.91 (m,
Z
Z
H), 3.68 (dm, J = 1.55 H , 1H), 4.54-4.56 (m, 1H), 4.77-4.79 (m,
2H), 4.94-4.96 (m, 2H), 7.02-7.04 (m, 1H), 7.20-7.27 (m, 2H),
13
Z
H), 4.89 (m, 1H), 4.98 (m, 1H), 7.20 (tt, J = 1.48, 7.20 H , 1H),
7.31 (s, 1H); C NMR(CDCl 100 MH ) 21.5, 44.8, 59.0, 76.2,
3, Z
Z
13
.28-7.32 (m, 2H), 7.37-7.40 (m, 2H); C NMR(CDCl3, 100
105.9, 122.8, 126.3, 127.1, 128.1, 137.8, 146.6, 149.0; High-
MH ) 24.0, 46.4, 48.6, 49.8, 67.1, 105.3, 114.5, 126.1, 126.4,
resolution MS(EI) calcd for C H N: 225.1517, Found m/z:
225.1513 (M ).
Z
16 19
+
1
(
1
28.1, 142.8, 146.3, 149.6; IR(neat) 3333 (br), 3072 (m), 3026
w), 2922 (m), 2852 (w), 1641 (s), 1447 (s), 1375 (m), 1065(m),
030 (w), 883 (s), 733 (s),700 (s), 625 (w); High-resolution
5-(3-Chlorophenyl)-3,7-dimethylenepyrrolizidine (1h)
+
1
MS(EI) calcd for C H N: 213.1517, Found m/z: 213.1521 (M ).
H NMR( CDCl 400 MH ) δ 2.73 (d, J = 16.2 H , 2H), 2.80 (d,
15
19
3,
Z
Z
2
,6-Dimethyl-4-phenyl-1,6-heptadiene-4-amine (3a)
J = 16.2 H , 2H), 3.33 (d, J = 14.9 H , 2H) 3.74 (d, J = 14.9 H ,
Z
Z
Z
1
H NMR(CDCl 400 MH ) δ 1.25 (s, 6H), 1.60-1.82 (br, 2H),
2H), 4.89 (s, 2H), 4.93 (s, 2H), 7.17 (d, J = 7.82 H , 1H), 7.23 (t,
Z
13
3,
Z
2
2
7
2
.44 (d, J = 13.2 H , 2H), 2.69 (d, J = 13.2 H , 2H), 4.67-4.68 (m,
J = 7.82 H , 1H), 7.32 (d, J = 7.82 H , 1H), 7.49 (s, 1H);
C
Z
Z
Z
Z
H), 4.79-4.80 (m, 2H), 7.20 (tt, J = 1.24, 7.32 H , 1H), 7.43-
NMR(CDCl3, 100 MH ) 44.9, 59.1, 76.0, 106.2, 124.0, 126.1,
Z
Z
13
.47 (m, 2H), 7.18-7.33 (m, 2H); C NMR(CDCl3, 100 MHZ)
4.4, 52.7, 56.6, 115.3, 126.1, 126.1, 128.0, 142.5, 147.1;
126.5, 129.6, 134.3, 148.5, 149.3; High-resolution MS(EI) calcd
+
for C H ClN: 245.0971, Found m/z: 245.0930 (M ).
15
16
IR(neat) 3379 (br), 3072 (m), 2926 (m), 2855 (w), 1643 (m),
582 (w), 1447 (s), 1375 (m), 1263 (w), 1030 (w), 893 (s), 700
1
5-(2-Phenylethylene)-3,7-dimethylenepyrrolizidine (1i)
1
(
s), 635 (w); High-resolution MS(EI) calcd for C H N:
H NMR(CDCl 400 MH ) δ 2.58 (d, J = 16.4 H , 2H), 2.69 (d,
15
21
3,
Z
Z
+
2
15.1674, Found m/z: 215.1677 (M ).
J = 16.4 H , 2H), 3.27 (d, J = 16.4 H , 2H), 3.74 (d, J = 16.4 H ,
Z Z Z
2
H), 4.93 (s, 2H), 5.00 (s, 2H), 6.23 (d, J = 16.1 H , 1H), 6.52 (d,
Z
5
-(4-Methylphenyl)-3,7-dimetylenepyrrolizidine (1b)
J = 16.1 H , 1H), 7.20 (t, J = 7.32 H , 1H), 7.29 (t, J = 7.32 H ,
Z Z Z
13
1
H NMR(CDCl 400 MH ) δ 2.32 (s, 3H), 2.78 (s, 4H), 3.32 (d,
2H), 7.38 (d, J = 7.32 H , 2H); C NMR(CDCl 100 MH ) 41.8,
Z 3, Z
3,
Z
J = 15.4 H , 2H), 3.73 (d, J = 15.4 H , 2H), 4.87-4.87 (m, 2H),
58.5, 74.1, 106.3, 126.4, 127.4, 128.2, 128.5, 134.7, 137.2, 148.9;
Z
Z
4
.92-4.95 (m, 2H), 7.13 (d J = 8.32 H , 2H), 7.36 (d J = 8.32 H ,
Z
Z

6
Tetrahedron
19 ACCEPTED MANUSCRIPT
High-resolution MS(EI) calcd for C H N: 237.1517, Found
M.; Tamaru, Y. Heterocycles 2006, 67, 535-542. (h) Kimura, M.;
Fukasaka, M.; Tamaru, Y. Synthesis 2006, 3611-3616. (i) Kimura,
17
+
m/z: 223.1499 (M ).
M.; Mukai, R.; Tamaki, T.; Horino, Y.; Tamaru, Y. J. Am. Chem.
Soc. 2007, 129, 4122-4123. (j) Kimura, M.; Kohno, T.; Toyoda,
K.; Mori, T. Heterocycles 2010, 82, 281-287. (k) Fukushima, M.;
Takushima, D.; Satomura, H.; Onodera, G.; Kimura, M. Chem.
Eur. J. 2012, 18, 8019-8023. (l) Takushima, D.; Fukushima, M.;
Satomura, H.; Onodera, G.; Kimura, M. Heterocycles 2012, 86,
171-180.
(a) Kimura, M.; Tomizawa, T.; Horino, Y.; Tanaka, S. Tamaru Y.
Tetrahedron Lett. 2000, 41, 3627-3629. (b) Kimura, M.; Shimizu,
M.; Shibata, K.; Tazoe, M. Tamaru, Y. Angew. Chem. Int. Ed.
Engl. 2003, 42, 3392-3395. (c) Shimizu, M.; Kimura, M.; Y.
Tamaru, Chem. Eur. J. 2005, 11, 6629-6642. (d) Shimizu, M.;
Kimura, M.; Watanabe, T.; Tamaru, Y. Org. Lett. 2005, 7, 637-
5
-Benzyl-3,7-dimethylenepyrrolizidine (1j)
1
H NMR( CDCl 400 MH ) δ 2.26 (d, J = 15.9 H , 2H), 2.57 (d,
3,
Z
Z
J = 15.9 H , 2H), 2.72 (s, 2H), 3.25 (d, J = 15.4 H , 2H), 3.79 (d,
J = 15.4 H , 2H), 4.92 (s, 2H), 4.96 (s, 2H), 7.18-7.24 (m, 3H),
Z
Z
Z
13
7
7
.26-7.30 (m, 2H); C NMR(CDCl 100 MH ) 40.5, 44.6, 59.0,
4.3, 106.2, 126.2, 128.1, 130.2, 138.8, 149.1; High-resolution
3, Z
4
.
+
MS(EI) calcd for C H N: 225.1517, Found m/z: 225.1495 (M ).
16
19
5
-Phenylethyl-3,7-dimethylenepyrrolizidine (1k)
1
H NMR(CDCl3, 400 MH ) δ 1.71-1.77 (m, 2H), 2.50 (d, J =
Z
6
40. (e) Kimura, M.; Shimizu, M.; Tanaka, S.; Tamaru, Y.
1
6.4 H , 2H), 2.54 (d, J = 16.4 H , 2H), 2.61-2.64 (m, 2H), 3.24
Z
Z
Tetrahedron 2005, 61, 3709-3718. (f) Yamaguchi, Y.; Hashimoto,
M.; Tohyama, K.; Kimura, M. Tetrahedron Lett. 2011, 52, 913-
915. (g) Hirata, G.; Onodera, G.; Kimura, M. Synlett 2014, 16,
(
d, J = 15.1 H , 2H), 3.71 (d, J = 15.1 H , 2H), 4.93 (s, 2H), 4.98
Z Z
13
(s, 2H), 7.17-7.19 (m, 3H), 7.25-7.29 (m, 2H); C NMR(CDCl3,
2
306-2310.
1
1
2
00 MH ) 31.3, 40.6, 40.9, 58.9, 73.5, 106.3, 125.7, 128.3, 128.4,
42.6, 149.1; High-resolution MS(EI) calcd for C H N:
39.1674, Found m/z: 239.1668 (M ).
Z
5
6
.
.
Kimura, M.; Tamaki, T.; Nakata, M.; Tohyama, K.; Tamaru, Y.
Angew. Chem. Int. Ed. 2008, 47, 5803-5805.
(a) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc. 1979, 101,
17
21
+
6
429-6432. (b) Trost, B. M.; Chan, D. M. T. J. Am. Chem. Soc.
5
-Cyclopropyl-3,7-dimethylenepyrrolizidine (1l)
1979, 101, 6432-6433 (c) Trost, B. M.; Cramer, N.; Silverman, S.
M. J. Am. Chem. Soc. 2007, 129, 12396-12397. (d) Trost, B. M.;
Silverman, S. M.; Stambuli, J. P. J. Am. Chem. Soc. 2007, 129,
1
H NMR(CDCl 400 MH ) δ 0.19-0.23 (m, 2H), 0.35-0.40 (m,
3,
Z
2
1
2
1
1
H), 0.91 (tt, J = 5.60, 8.28 H , 1H), 2.30 (s, 4H), 3.19 (d, J =
Z
1
2398-12399.
5.1 H , 2H), 3.74 (d, J = 15.1 H , 2H), 4.89 (s, 2H), 4.93 (s,
Z
Z
7. (a) Fuhshuku, K.; Mori, K. Tetrahedron: Asymmetry 2007, 18,
2104-2107. (b) Felpin, F.-X.; Boubekeur, K.; Lebreton, J. Eur. J.
Org. Chem. 2007, 4888-4894. (c) Srivastava, A. K.; Das, S. K.;
Panda, G. Tetrahedron 2009, 65, 5322-5327. (d) Chiou, W.-H.;
Lin, G.-H. Liang, C.-W. J. Org. Chem. 2010, 75, 1748-1751 . (e)
Bera, S.; Mondal, D.; Singh, M.; Kale, R. K. Tetrahedron 2013,
13
H); C NMR(CDCl3, 100 MH ) 0.9, 18.7, 40.5, 59.6, 73.5,
Z
05.8, 149.6; High-resolution MS(EI) calcd for C H N:
12
17
+
75.1361, Found m/z: 175.1360 (M ).
5
-Propyl-3,7-dimethylenepyrrolizidine (1m)
6
9, 969-1011.
1
H NMR(CDCl 400 MH ) 0.90-0.94 (m, 5H), 1.83 (d, J = 10.2
3,
Z
8. Hirata, G.; Yamada, N.; Sanada, S.; Onodera, G.; Kimura. M.
H , 2H), 2.36 (d, J = 15.4 H , 2H), 2.44 (d, J = 15.4 H , 2H),
Org. Lett. 2015, 17, 600-603.
Z
Z
Z
9
.
(a) Niwa, H.; Ogawa, T.; Okamoto, O.; Yamada, K. Tetrahedron
1992, 48, 10531–10548. (b) Correia, C. R. D.; de Faria, A. R.;
Carvalho, E. S. Tetrahedron Lett. 1995, 36, 5109–5112. (c) White,
J. D.; Hrnciar, P.; Yokoichi, A. F. T. J. Am. Chem. Soc. 1998, 120,
7359-7360. (d) Tang, X.-Q.; Montgomery, J. J. Am. Chem. Soc.
3
4
5
.21 (d, J = 15.4 H , 2H), 3.69 (d, J = 15.4 H , 2H), 4.91 (s, 2H),
Z Z
13
.96 (s, 2H); C NMR(CDCl 100 MH ) 14.7, 18.4, 40.8, 41.5,
3,
Z
8.8, 73.7, 106.1, 149.4; High-resolution MS(EI) calcd for
+
C H N: 177.1517, Found m/z: 177.1502 (M ).
12
19
2
000, 122, 6950-6954. (e) Gallos, J. K.; Sarli, V. C.; Koftis, T. V.;
Coutouli-Argyropoulou, E. Tetrahedron Lett. 2000, 41, 4819–
Acknowledgments
4
2
822. (f) Dieter, R. K.; Chen, N.; Watson, R. T. Tetrahedron
005, 61, 3221–3230. (g) Nicolai, S.; Piemontesi, C.; Waser, J.
This work was supported by Grants-in Aid for Scientific
Research (B) (26288052) from the Ministry of Education,
Culture, Sports and Technology (MEXT), Japan.
Angew. Chem. Int. Ed. 2011, 50, 4680-4683. (h) Rehák, J.; Fisera,
L.; Kozísek, J.; Bellovicová, L. Tetrahedron 2011, 67, 5762–5769.
(i) de Miguel, F.; Velado, M.; Herradón, B.; Mann, Enrique, Eur.
J. Org. Chem. 2012, 4347-4357. (j) Kondo, Y.; Suzuki, N.;
Takahashi, M.; Kumamoto, T.; Masu, H.; Ishikawa, T. J. Org.
Chem. 2012, 77, 7988-7999. (k) Rajarathinam, B.; Vasuki, G.
Org. Lett. 2012, 14, 5204-5206. (l) Xing, D.; Yang, D. Org. Lett.
2013, 15, 4370-4373. (m) Reddy, P. V.; Smith, J.; Kamath, A.;
Jamet, H.; Veyron, A.; Koos, P.; Philouze, C.; Greene, A. E.;
Delair, P. J. Org. Chem. 2013, 78, 4840-4849.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/
1
0. (a) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773-781. (b)
Majumdar, K. C.; Sinha, B. Synthesis 2013, 45, 1271-1299. (c)
Robertson, J.; Stevens, K. Nat. Prod. Rep. 2014, 31, 1721-1788.
References and notes
1
2
3
.
.
.
Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6,
387–4388.
Tsuji, J. Palladium Reagents and Catalysts – New Perspectives for
the 21th Century, John Wiley & Sons: Chichester, 2004.
(a) Horino, Y.; Naito, M.: Kimura, M.; Tanaka, S.; Tamaru, Y.
Tetrahedron Lett. 2001, 42, 3113-3118. (b) Kimura, M.; Horino,
Y.; Mukai, R.; Tanaka, S.; Tamaru, Y. J. Am. Chem. Soc. 2001,
11. See supporting information.
12. Although the corresponding pyrrolidines 2 and symmetrical
4
homoallylamines
3
tend to be formed as by-products,
unfortunately, these could not be completely separated by means
of by recycling preparative HPLC. Therefore, isolated yields of 1
are shown in Table 2.
13. Intermediates I-III in Scheme 6 were not detected during the
reactions. Reduced products 1a and 2a might be derived from the
intermediates II and III, respectively. As the intermediate I is
more reactive than nitrile as an electrophile, the intermediate I
would readily consume to undergo the nucleophilic allylation.
1
23, 10401-10402. (c) Kimura, M.; Futamata, M.; Shibata, K.;
Tamaru, Y. Chem. Commun. 2003, 39, 234-235. (d) Kimura, M.;
Mukai, R.; Tanigawa, N.; Tanaka, S.; Tamaru, Y. Tetrahedron
2
003, 59, 7767-7777. (e) Mukai, R.; Horino, Y.; Tanaka, S.;
Tamaru, Y. Kimura, M. J. Am. Chem. Soc. 2004, 126, 11138-
1139. (f) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J.
Am. Chem. Soc. 2005, 127, 4592-4593. (g) Kimura, M.; Fukasaka,
1

ACCEPTED MANUSCRIPT
Supporting Information
Efficient Synthesis of Pyrrolizidine by Pd-Catalyzed Consecutive Double Amphiphilic
Allylation of Nitrile
Naoshi Yamada, Goki Hirata, Gen Onodera, and Masanari Kimura*
Graduate School of Science and Technology, Nagasaki University
Department of Applied Chemistry, Faculty of Engineering, Nagasaki University
Bunkyo-machi, Nagasaki 852-8521, Japan
E-mail: masanari@nagasaki-u.ac.jp
Experimental Section
Reactions employed oven-dried glassware unless otherwise noted.
Thin layer
chromatography (TLC) employed glass 0.25 mm silica gel plates with UV indicator
(
Merck, Silica gel 60F254).
Flash chromatography columns were packed with silica
Gradient flash chromatography was conducted eluting with
gel as a slurry in hexane.
a continuous gradient from hexane to the indicated solvent. Proton and carbon NMR
data were obtained with a JEOL JNM-AL400 with tetramethylsilane as an internal
standard.
standard.
Chemical shift values were given in ppm downfield from the internal
Infrared spectra were recorded with a JASCO A-100 FT-IR
spectrophotometer.
Analytical vapor-phase chromatography (VPC) was carried out
on a Shimadzu GC-2014 gas chromatograph equipped with a Stabilwax®-DA column
S 1

ACCEPTED MANUSCRIPT
(30 m x 0.25 mm ID x 0.25 µm df) and FID detector (injection: 250°C, 2.0 µl, 50:1 split,
oven: 100 °C (15 min), 10 °C/min to 250 °C, carrier gas: helium 30 cm/sec, constant,
FID temperature: 280 °C).
with a JEOL JMS-700N.
High resolution mass spectra (HRMS) were measured
Solvents and Reagents
1
,4-Dioxane was dried and distilled from benzophenone and sodium immediately prior
to use under nitrogen atmosphere.
Pd(OAc) , n-Bu P, Et B (1.0 M hexane solution),
2 3 3
2
-methylenepropane-1,3-diol,
-fluorobenzonitrile, 4-chlorobenzonitrile, and 4-phenylbenzonitrile were purchased
Benzonitrile, 3-methylbenzonitrile,
-chlorobenzonitrile, phenylacetonitrile, cinnamonitrile, cyclopropionitrile, and
4-methylbenzonitrile,
4-methoxybenzonitrile,
4
and used without further purification.
3
butyronitrile were purchased and distilled prior to use by Kugelrohr apparatus.
General procedure for synthesis of 5-phenyl-3,7-dimethylenepyrrolizidine (1a)
(entry 10, Table 1)
A flask was charged with Pd(OAc) (22.5 mg, 0.1 mmol).
The flask was evacuated
To the flask were added 1,4-dioxane (1.0 ml), n-Bu P (50 μl,
2
and filled with nitrogen.
.2 mmol), 2-methylenepropane-1,3-diol (106.2 mg, 1.2 mmol), and benzonitrile (51.5
mg, 0.5 mmol). Et B (5.0 mmol) was added to the reaction mixture. The mixture
3
0
3
was stirred at 50 °C for 24 h. The progress of the reaction was monitored by TLC.
After the reaction was complete, saturated aqueous NaHCO was added, and the mixture
3
was extracted with AcOEt for 3 times.
The combined organic layers were dried with
MgSO , then the solvent was evaporated in vacuo.
The residue was subjected to
4
S 2

ACCEPTED MANUSCRIPT
column chromatography over silica gel to give 1a (n-hexane/AcOEt = 50/1, 68.5 mg,
0
.32 mmol, 67% yield).
By-products, 2a and 3a were separted by recycling
preparative HPLC instrument (eluent: CHCl , KC9100, Japan Analytical Industry, CO.,
3
Ltd)
5
-Phenyl-3,7-dimethylenepyrrolizidine (1a) (n-hexane/AcOEt = 50/1, 68.5 mg, 0.32
1
mmol, 67% yield).
5.1 H
J = 0.61, 7.42 H
MH ) 45.0, 59.2, 76.3, 105.8, 125.7, 126.3, 128.2, 146.8, 149.0; IR(neat) 3072 (m),
024 (m), 2855 (w), 2808 (w), 2349 (m), 1665 (m), 1601 (m), 1431 (m), 988 (w), 881
s), 766 (m),702 (s), 623 (m); High-resolution MS(EI) calcd for C15 17N: 211.1361,
H NMR(CDCl3, 400 MH
Z
) δ 2.78-2.80 (m, 4H), 3.33 (d, J =
1
Z
, 2H), 3.75 (d, J = 15.1 H
Z
, 2H), 4.86-4.88 (m, 2H) , 4.90-4.93 (m, 2H), 7.17 (tt,
1
3
Z
, 1H), 7.27-7.31 (m, 2H), 7.43-7.47 (m, 2H); C NMR(CDCl3, 100
Z
3
(
H
+
Found m/z: 211.1360 (M ).
5
-(2-Methyl-2-propene)-5-phenyl-3-methylenepyrrolidine (2a)
1
H NMR(CDCl3, 400 MH
H), 2.76 (s, 2H), 3.60 (dm, J = 1.55 H
H), 4.77-4.79 (m, 1H), 4.89 (m, 1H), 4.98 (m, 1H), 7.20 (tt, J = 1.48, 7.20 H
Z
) δ 1.24 (s, 3H), 1.92-2.02 (br, 2H), 2.48 (s, 1H), 2.49 (s,
, 1H), 3.68 (dm, J = 1.55 H , 1H), 4.54-4.56 (m,
, 1H),
) 24.0, 46.4, 48.6,
1
1
7
4
3
Z
Z
Z
1
3
.28-7.32 (m, 2H), 7.37-7.40 (m, 2H); C NMR(CDCl3, 100 MH
Z
9.8, 67.1, 105.3, 114.5, 126.1, 126.4, 128.1, 142.8, 146.3, 149.6; IR(neat) 3333 (br),
072 (m), 3026 (w), 2922 (m), 2852 (w), 1641 (s), 1447 (s), 1375 (m), 1065(m), 1030
(w), 883 (s), 733 (s),700 (s), 625 (w); High-resolution MS(EI) calcd for C15H19N:
+
2
13.1517, Found m/z: 213.1521 (M ).
2
,6-Dimethyl-4-phenyl-1,6-heptadiene-4-amine (3a)
1
Z Z
H NMR(CDCl3, 400 MH ) δ 1.25 (s, 6H), 1.60-1.82 (br, 2H), 2.44 (d, J = 13.2 H ,
2
H), 2.69 (d, J = 13.2 H
Z
, 2H), 4.67-4.68 (m, 2H), 4.79-4.80 (m, 2H), 7.20 (tt, J = 1.24,
S 3

ACCEPTED MANUSCRIPT
1
3
7
.32 H
Z Z
, 1H), 7.43-7.47 (m, 2H), 7.18-7.33 (m, 2H); C NMR(CDCl3, 100 MH ) 24.4,
5
2.7, 56.6, 115.3, 126.1, 126.1, 128.0, 142.5, 147.1; IR(neat) 3379 (br), 3072 (m), 2926
(m), 2855 (w), 1643 (m), 1582 (w), 1447 (s), 1375 (m), 1263 (w), 1030 (w), 893 (s),
7
00 (s), 635 (w); High-resolution MS(EI) calcd for C15H21N: 215.1674, Found m/z:
+
2
15.1677 (M ).
Time Course of the Reaction of Benzonitirile with 2-Methylenepropane-1,3-diol
Figure 1): A flask was charged with Pd(OAc) (33.8 mg, 0.15 mmol). The flask
was evacuated and filled with nitrogen. To the flask were added THF (0.75 ml),
n-Bu P (75 µl, 0.3 mmol), 2-methylenepropane-1,3-diol (158.6 mg, 1.8 mmol), and
benzonitrile (77.3 mg, 0.75 mmol). Et B (7.5 mmol) was added to the reaction
mixture. The mixture was stirred at 50 °C. The reaction was monitored by VPC
using cyclododecane as an internal standard [retention time: 5.11 min (cyclododecane),
(
2
3
3
1
0.79 min (3a), 11.96 min (2a), 12.24 min (1a)].
5
-(4-Methylphenyl)-3,7-dimethylenepyrrolizidine (1b)
1
H NMR (CDCl3, 400 MH
Z
) δ 2.32 (s, 3H), 2.78 (s, 4H), 3.32 (d, J = 15.4 H
Z
, 2H), 3.73
, 2H),
Z Z
.36 (d J = 8.32 H , 2H); C NMR(CDCl3, 100 MH ) 20.9, 44.8, 59.0, 76.1, 105.9,
(
d, J = 15.4 H , 2H), 4.87-4.87 (m, 2H), 4.92-4.95 (m, 2H), 7.13 (d J = 8.32 H
Z
Z
1
3
7
1
25.6, 129.0, 135.8, 143.7, 149.1; High-resolution MS(EI) calcd for C16H19N: 225.1517,
+
Found m/z: 225.1517 (M ).
5
-(4-Methoxyphenyl)-3,7-dimethylenepyrrolizidine (1c)
1
H NMR (CDCl3, 400 MH
Z
) δ 2.73-2.75 (m, 4H), 3.30 (dm, J = 15.4 H
Z
, 2H), 3.71 (dm,
J = 15.4 H
Z
, 2H), 3.76 (s, 3H), 4.86 (dquintet, J = 0.48, 1.72 H , 2H) , 4.91 (dquintet, J
Z
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3
=
0.48, 1.72 H
Z
, 2H), 6.82 (d, J = 8.80 H
Z
, 2H), 7.36 (d, J = 8.80 H
Z
, 2H);
C
NMR(CDCl3, 100 MH
Z
) 44.7, 55.1, 58.9, 75.8, 105.9, 113.5, 126.8, 138.7, 149.1, 158.1;
+
High-resolution MS(EI) calcd for C16
H
19NO: 241.1467, Found m/z: 241.1464 (M ).
5
-(4-Fluorophenyl)-3,7-dimethylenepyrrolizidine (1d)
1
Z Z
H NMR (CDCl3, 400 MH ) δ 2.70-2.81 (m, 4H), 3.32 (dm, J = 15.2 H , 2H), 3.72 (dm,
J = 15.2 H
Z
, 2H), 4.86-4.89 (m, 2H), 4.91-4.94 (m, 2H), 6.95-6.99 (m, 2H), 7.39-7.44
1
3
2
(
m, 2H); C NMR(CDCl3, 100 MH
Z
) 44.9, 59.0, 75.8, 106.1, 114.9 (d, JCF = 20.6),
3
4
1
1
27.4 (d, JCF = 7.41), 142.4 (d, JCF = 3.29), 148.8, 161.6 (d, JCF = 242.9);
+
High-resolution MS(EI) calcd for C15H16FN: 229.1267, Found m/z: 229.1246 (M ).
5
-(4-Chlorophenyl)-3,7-dimethylenepyrrolizidine (1e)
1
H NMR (CDCl3, 400 MH
d, J = 15.1 H , 2H), 3.72 (d, J = 15.1 H
.26 (d, J = 8.56 HZ, 2H), 7.40 (d, J = 8.56 Hz, 2H); C NMR(CDCl3, 100 MHz) 44.8,
9.0, 75.8, 106.2, 127.2, 128.3, 132.0, 145.4, 148.6; High-resolution MS(EI) calcd for
Z
) δ 2.71 (d, J = 16.1 H
Z Z
, 2H), 2.79 (d, J = 16.1 H , 2H), 3.32
(
Z
Z
, 2H), 4.87-4.89 (m, 2H), 4.91-4.93 (m, 2H),
1
3
7
5
3
5
+
C
15
H16 ClN: 245.0971, Found m/z: 245.0959 (M ).
5
-Biphenyl-3,7-dimethylenepyrrolizidine (1f)
1
H NMR (CDCl3, 400MH
Z
) δ 2.83-2.85 (m, 4H), 3.37 (dm, J = 15.2 H
Z
, 2H), 3.81 (dm,
, 1H),
Z
.40-7.44 (m, 2H), 7.54-7.55 (m, 4H), 7.57-7.60 (m, 2H); C NMR(CDCl3, 100 MH )
J = 15.2 H
Z
, 2H), 4.91-4.93 (m, 2H), 4.96-4.98 (m, 2H), 7.32 (tt, J = 1.34, 7.33 H
Z
1
3
7
4
4.9, 59.1, 76.3, 106.1, 126.2, 126.9, 127.0, 127.1, 127.2, 127.3, 128.7, 139.2, 140.9;
+
High-resolution MS(EI) calcd for C21
H
21N: 287.1674, Found m/z: 287.1658 (M ).
5
-(3-Methylphenyl)-3,7-dimethylenepyrrolizidine (1g)
1
Z Z
H NMR (CDCl3, 400 MH ) δ 2.36 (s, 3H), 2.81 (m, 4H), 3.35 (dm, J = 15.2 H , 2H),
3
.78 (dm, J = 15.2 H
Z
, 2H), 4.89-4.91 (m, 2H), 4.94-4.96 (m, 2H), 7.02-7.04 (m, 1H),
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7
Z
.20-7.27 (m, 2H), 7.31 (s, 1H); C NMR(CDCl3, 100 MH ) 21.5, 44.8, 59.0, 76.2,
1
05.9, 122.8, 126.3, 127.1, 128.1, 137.8, 146.6, 149.0; High-resolution MS(EI) calcd
+
for C16
H
19N: 225.1517, Found m/z: 225.1513 (M ).
5
-(3-Chlorophenyl)-3,7-dimethylenepyrrolizidine (1h)
1
H NMR (CDCl3, 400 MH
d, J = 14.9 H , 2H) 3.74 (d, J = 14.9 H
.82 H , 1H), 7.23 (t, J = 7.82 H
NMR(CDCl3, 100 MH
Z
) δ 2.73 (d, J = 16.2 H
Z
, 2H), 2.80 (d, J = 16.2 H
Z
, 2H), 3.33
(
Z
Z
, 2H), 4.89 (s, 2H), 4.93 (s, 2H), 7.17 (d, J =
1
3
7
Z
Z
Z
, 1H), 7.32 (d, J = 7.82 H , 1H), 7.49 (s, 1H); C
Z
) 44.9, 59.1, 76.0, 106.2, 124.0, 126.1, 126.5, 129.6, 134.3,
1
2
48.5, 149.3; High-resolution MS(EI) calcd for C15 16ClN: 245.0971, Found m/z:
H
+
45.0930 (M ).
-(2-Phenylethylene)-3,7-dimethylenepyrrolizidine (1i)
5
1
H NMR (CDCl3, 400 MH
Z
Z Z
) δ 2.58 (d, J = 16.4 H , 2H), 2.69 (d, J = 16.4 H , 2H), 3.27
(
d, J = 16.4 H , 2H), 3.74 (d, J = 16.4 H
Z
Z
, 2H), 4.93 (s, 2H), 5.00 (s, 2H), 6.23 (d, J =
1
2
1
6.1 H
Z
, 1H), 6.52 (d, J = 16.1 H
Z
, 1H), 7.20 (t, J = 7.32 H
Z
, 1H), 7.29 (t, J = 7.32 H
Z
,
1
3
H), 7.38 (d, J = 7.32 H
Z
, 2H); C NMR(CDCl3, 100 MH
Z
) 41.8, 58.5, 74.1, 106.3,
26.4, 127.4, 128.2, 128.5, 134.7, 137.2, 148.9; High-resolution MS(EI) calcd for
+
C
17
H
19N: 237.1517, Found m/z: 223.1499 (M ).
5
-Benzyl-3,7-dimethylenepyrrolizidine (1j)
1
H NMR (CDCl3, 400 MH
Z
) δ 2.26 (d, J = 15.9 H
Z
, 2H), 2.57 (d, J = 15.9 H
, 2H), 4.92 (s, 2H), 4.96 (s, 2H),
.18-7.24 (m, 3H), 7.26-7.30 (m, 2H); C NMR(CDCl3, 100 MH ) 40.5, 44.6, 59.0,
Z
, 2H), 2.72
(
s, 2H), 3.25 (d, J = 15.4 H
Z
, 2H), 3.79 (d, J = 15.4 H
Z
1
3
7
7
Z
4.3, 106.2, 126.2, 128.1, 130.2, 138.8, 149.1; High-resolution MS(EI) calcd for
+
C
16
H
19N: 225.1517, Found m/z: 225.1495 (M ).
5
-Phenylethyl-3,7-dimethylenepyrrolizidine (1k)
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H NMR (CDCl3, 400 MH
16.4 H , 2H), 2.61-2.64 (m, 2H), 3.24 (d, J = 15.1 H
.93 (s, 2H), 4.98 (s, 2H), 7.17-7.19 (m, 3H), 7.25-7.29 (m, 2H); C NMR(CDCl3, 100
Z
) δ 1.71-1.77 (m, 2H), 2.50 (d, J = 16.4 H
Z
, 2H), 2.54 (d, J
=
Z
Z
, 2H), 3.71 (d, J = 15.1 H
Z
, 2H),
1
3
4
MH
Z
) 31.3, 40.6, 40.9, 58.9, 73.5, 106.3, 125.7, 128.3, 128.4, 142.6, 149.1;
+
High-resolution MS(EI) calcd for C17
H
21N: 239.1674, Found m/z: 239.1668 (M ).
5
-Cyclopropyl-3,7-dimethylenepyrrolizidine (1l)
1
H NMR (CDCl3, 400 MH
Z
) δ 0.19-0.23 (m, 2H), 0.35-0.40 (m, 2H), 0.91 (tt, J = 5.60,
8
.28 H
Z
, 1H), 2.30 (s, 4H), 3.19 (d, J = 15.1 H , 2H), 3.74 (d, J = 15.1 H , 2H), 4.89 (s,
Z
Z
1
3
2
H), 4.93 (s, 2H); C NMR(CDCl3, 100 MH
Z
) 0.9, 18.7, 40.5, 59.6, 73.5, 105.8, 149.6;
+
High-resolution MS(EI) calcd for C12
H
17N: 175.1361, Found m/z: 175.1360 (M ).
5
-Propyl-3,7-dimethylenepyrrolizidine (1m)
1
H NMR (CDCl3, 400 MH
5.4 H , 2H), 2.44 (d, J = 15.4 H
H), 4.91 (s, 2H), 4.96 (s, 2H); C NMR(CDCl3, 100 MH
Z
) 0.90-0.94 (m, 5H), 1.83 (d, J = 10.2 H
, 2H), 3.21 (d, J = 15.4 H , 2H), 3.69 (d, J = 15.4 H
) 14.7, 18.4, 40.8, 41.5, 58.8,
19N: 177.1517, Found m/z:
Z
, 2H), 2.36 (d, J =
1
2
7
1
Z
Z
Z
Z
,
1
3
Z
3.7, 106.1, 149.4; High-resolution MS(EI) calcd for C12
H
+
77.1502 (M ).
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