Elemental-Sulfur-Incorporated Cyclizations of Pyrrolidines Leading to Thienopyrroles

Article abstract of DOI:10.1021/acs.joc.0c01363

We report, herein, the synthesis of thieno[3,2-b]pyrroles from the direct oxidative [4 + 1] cyclization of 2-alkynyl pyrrolidines with elemental sulfur. This transformation likely originates from electrophilic attack at the β-position of pyrrolidine follo

Full text of DOI:10.1021/acs.joc.0c01363

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Article
Elemental Sulfur-Incorporated Cyclizations
of Pyrrolidines Leading to Thienopyrroles
Yuanyuan Yue, Huibin Shao, Zhixian Wang, Ke Wang, Le Wang, Kelei Zhuo, and Jianming Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01363 • Publication Date (Web): 23 Jul 2020
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Elemental Sulfur-Incorporated Cyclizations of Pyrrolidines Leading to
Thienopyrroles
Yuanyuan Yue *, Huibin Shao, Zhixian Wang, Ke Wang, Le Wang, Kelei Zhuo and
Jianming Liu*
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Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key
Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and
Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China.
E-mail address: yuanyuanyue@htu.cn and jmliu@htu.cn.
S
R1
1
,4-dioxane
+
S8
N
R
R1
120 oC, 24 h
N
R
Highly chemoselective
More than 40 examples
Available starting materials
Gram-scale synthesis
Utilization of pyrrolidine
Thienannulation reaction
Abstract: We report, herein, the synthesis of thieno[3,2-b]pyrroles from the direct
oxidative [4+1] cyclization of 2-alkynyl pyrrolidines with elemental sulfur. This
transformation likely originates from electrophilic attack at the β-position of
pyrrolidine followed by an intramolecular thienannulation to deliver the desired
product. Mechanistic investigation suggests that the present reaction involves the
formation of dihydrothieno[3,2-b]pyrrole as an intermediate.
Keywords: thieno[3,2-b]pyrrole, elemental sulfur, oxidative annulation,
thienannulation reaction.
INTRODUCTION
Thienopyrroles are molecules that contain thiophene and pyrrole rings and are used as
structural cores for important components of natural products, organic optoelectronic
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materials, agrochemicals and pharmaceuticals.1 Of particular interest are
thieno[3,2-b]pyrrole-based anti-inflammatory agents, immunomodulators, and
bioisosteric analogues of hallucinogens, due to their inhibitory effects on MCP-1.
Hence, there has been great interest in developing new strategies for the synthesis of
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thieno[3,2-b]pyrrole in the past few decades. In particular, research has been focused
on synthesizing thieno[3,2-b]pyrroles via the direct functionalization of the thiophene
ring (Scheme 1a).3-6 Despite considerable advances, this approach has suffered from
harsh reaction conditions and low yields for the desired product. Furthermore, it
requires the utilization of a multistep process and the construction of a special
substrate. An alternative route is the elemental sulfur-incorporated annulate
functionalization of the pyrrole ring (Scheme 1b). However, the synthesis of
thieno[3,2-b]pyrrole via the latter route remains to be explored. Direct
functionalization of pyrrole rings for thieno[3,2-b]pyrrole synthesis is challenging
since the electron-rich and relatively low-aromatic pyrrole rings can lead to multiple
side reactions and increase the reaction complexity under oxidative conditions.
Consequently, the development of effective methods to synthesize
thieno[3,2-b]pyrroles remains highly demanding.
We hypothesize that the utilization of pyrrolidine as an initial skeleton can be used
to overcome the above limitation (Scheme 1c). Recent work has shown that α-alkyne
functionalized pyrrolidines can be easily obtained from widely accessible proline.7
Furthermore, elemental sulfur is a promising oxidant and electrophile owing to its
8
numerous oxidation states. Motivated by these promising advancements in the
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synthesis of S-containing compounds,9-18 we explored the possibility of synthesizing
thieno[3,2-b]pyrroles by incorporating elemental sulfur and pyrrolidine. The first step
involved the synthesis of thiophene via oxidative annulation using elemental sulfur as
the oxidant. After the thienannulation reaction, further dehydrogenative aromatization
delivers the final product. In this route, elemental sulfur not only serves as an
electrophile but also functions as an oxidant.
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Scheme 1. The Different Strategies Used for the Synthesis of Thieno[3,2-b]pyrroles.
a) Synthesis of thieno[3, 2-b]pyrrole from thiophene
S
R1
R2
R1
X
Catalyst
Cyclization
N
R
R2
Y
S
b) Synthesis of thieno[3, 2-b]pyrrole from pyrrole
X
S
S
R1
R2
Catalyst
Cyclization
Y
N
R
N
R
c) Our strategy:
R1
Metal-free
+
S8
N
R
R1
N
R
S
R1
S8
N
R
R1
N
R
RESULTS AND DISCUSSION
To verify our hypothesis, we first focused on the synthesis of thieno[3,2-b]pyrrole
from 1-benzyl-2-(phenylethynyl)-pyrrolidine (1a) and elemental sulfur. After
considerable efforts, the cyclization was achieved by heating the mixture of 1a and S8
in 1,4-dioxane at 120 C for 24 hours. The desired product 2a was obtained in 74%
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yield (Table 1, entry 1). When the base was added, a lower yield for the product was
observed (Table 1, entry 2). No other additives were required. Both the reaction
temperature and reaction time were found to have a crucial effect on the formation of
2a (Table 1, entries 3-4). Increasing the reaction time and temperature led to the
positive results. Thus, decreasing the amount of elemental sulfur in 1,4-dioxane (2
mL) resulted in dramatically decreased yield for 2a (Table 1, entry 5). However,
using a lower amount of dioxane and elemental sulfur, the final product was obtained
in 62%-78% yields (Table 1, entries 6 and 7). In addition, using nonpolar solvents
under similar conditions resulted in trace to moderate yields (Table 1, entries 8 and 9).
Meanwhile, relatively lower yields were observed in DMF, pyridine, and
N-methylpiperidine (Table 1, entry 10). Interestingly, when N-methylmorpholine was
used instead of 1, 4-dioxane, the reaction proceeded smoothly to afford the desired
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product
1-benzyl-2-(phenylethynyl)-pyrrolidine (1a) was exposed to air, the corresponding
product 2a resulted in moderate yield (Table 1, entry 12) as
2a
in
85%
yield
(Table
1,
entry
11).
When
a
1-benzyl-2-(phenylethynyl)-pyrrolidine (1a) was easy to decompose in air. The
optimized condition can be summarized as follows: 1a (0.30 mmol), S (0.45 mmol),
8
N-methylmorpholine (2.0 mL), 120 °C, 24 h under N atmosphere.
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Table 1. Optimization of the Reaction Conditions.a
"
Standard Condition"
S
S (1.5 equiv)
8
N
1
,4-dioxane (2.0 mL)
Bn
N
o
120 C, 24 h
Bn
2
a
1a
1
1
1
1
1
1
1
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0
entry
variation from the standard condition
none
yield (%)
1
2
74
0, 7
t
K CO , NaO Bu were added
2
3
o
o
o
3
4
100 C,110 C instead of 120 C
17, 30
64, 64, 63
41, 43
o
o
o
3
6 h at 100 C, 110 C, 120 C
5
6
7
S8 (0.50, 1.0 equiv) in 1,4-dioxane (2.0 mL)
S (0.75 equiv) in 1,4-dioxane (1.0, 1.5 mL)
8
62, 78
73
S (1.0 equiv) in 1,4-dioxane (1.0 mL)
8
8
9
THF, Toluene, DME and Anisole instead
of 1,4-dioxane
55, 37, 57, trace
trace, trace
tert-Butyl methyl ether, tetraethylene glycol
dimethyl ether instead of 1,4-dioxane
10
DMF, Pyridine, N-methylpiperidine and
instead of 1,4-dioxane
53, trace, trace
11
N-methylmorpholine instead of 1,4-dioxane
in air
85
48
12
a
Standard conditions: 1a (0.30 mmol), S (1.5 equiv), 1,4-dioxane (2.0 mL), N , 120 C, 24 h.
8
2
With the optimum conditions identified, we investigated the substrate scope for this
oxidative cyclization by elemental sulfur to construct thieno[3,2-b]pyrrole derivatives
(Scheme 2). During the process of condition optimization, we have found that
N-methylmorpholine was the best solvent for the elemental sulfur incorporated
cyclization
of
1-benzyl-2-(phenylethynyl)pyrrolidine
(1g)
(1a),
1
1
-benzyl-2-((4-methoxyphenyl)ethynyl)pyrrolidine
and
-benzyl-2-((4-ethoxyphenyl)ethynyl)pyrrolidine (1h). Then, 1,4-dioxane was found
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to be more efficient than N-methylmorpholine in the synthesis of other thienopyrroles.
A series of electron-donating pyrrolidines in the 4-position of the benzene ring were
found to be compatible with oxidative cyclization, providing the corresponding
products in 54-82% yields (2a-2h). The structures of 2b and 2h were unambiguously
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confirmed by single-crystal X-ray diffraction analysis. Substitution on the 4-position
of the benzene ring, such as fluoro, chloro, bromo, and trifluoromethyl groups, under
the optimum conditions identified above led to the generation of the final products in
good yields (2i-2l). When an ortho substituent was introduced to the elemental sulfur
incorporating the pyrrolidine ring, the reaction proceeded smoothly to afford the
desired product in 55% yield (2m). Excitingly, when 1n was subjected to optimized
conditions, 4-benzyl-2-(3-bromophenyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole (2n)
was obtained in 63% yield. Other meta substituents were found to completely convert
to the desired thieno[3,2-b]pyrroles (2o and 2p). Additionally, thiophene-substituted
substrates could be installed without decreasing the final product yield (2q and 2r).
Furthermore, a biphenyl-substituted substrate was also found to be amenable to this
transformation,
which
resulted
in
a
66%
yield
(2s).
Finally,
1
-benzyl-2-(dec-1-yn-1-yl)pyrrolidine was evaluated under the optimized condition,
providing the desired products in 21% yield (2t). Overall, little adjustments to the
reaction conditions were necessary to deliver the desired thieno[3,2-b]pyrroles in
good yields.
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Scheme 2. Scope for 1-Benzyl-2-(phenylethynyl)pyrrolidine Derivatives.a
S (1.5 equiv)
,4-dioxane (2.0 mL)
8
S
Ar
1
N
o
Ar
120 C, 24 h
N
Bn
Bn
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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2
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2
R
R
R
S
S
S
N
N
N
Bn
Bn
Bn
2
a, R = H, 85%b
2b, R = Me, 58%a
2c, R = Et, 65%b
2f, R = t-Bu, 59%a
2d, R = n-Pr, 61%b
2e, R = n-Bu, 62%b
2
2
g, R = OMe, 60%b
h, R = OEt, 60%b
R
CF3
S
S
S
N
N
F
N
Bn
Bn
Bn
2
2
i, R = F, 60%c
j, R = Cl, 58%c
2l, 58%d
2m, 55%c
2k, R = Br, 54%c
S
S
S
Br
OMe
Cl
N
N
N
Bn
Bn
Bn
n, 63%a
2o, 56%d
2p, 62%a
2
S
S
S
S
S
N
N
N
Bn
Bn
Bn
2q, 64%a
2r, 62%a
2s, 66%e
S
N
Bn
2
t, 21%a
a
b
c
Reaction conditions: 1 (0.30 mmol), S (1.5 equiv), 1,4-dioxane (2.0 mL), N , 120 C, 24 h.
8
2
S8 (1.5 equiv), N-methylmorpholine (2.0 mL).
S8 (1.0 equiv), 1,4-dioxane (1.0 mL).
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d
e
1
15 C, 24 h.
1
20 C, 36 h.
After synthesizing thieno[3,2-b]pyrroles, we turned our efforts towards exploring
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the effect of an N-substituent at the benzene ring (Scheme 3). Pyrrolidines with either
electron-donating groups (4-Me and 4-OMe) or electron-withdrawing groups (4-F,
4-Cl, 4-Br and 4-CN) were found to react smoothly with elemental sulfur to deliver
the corresponding thieno[3,2-b]pyrroles in 43-70% yields (4a-4f). Notably,
N-substituents at the 3-position of the benzene ring were found to be suitable for
oxidative cyclization, affording the final products in 70% and 57% yields,
respectively (4g and 4h). Meanwhile, a range of N-benzyl pyrrolidines bearing
different substituents at the meta-position of the phenyl ring were well tolerated,
which provided various products in good yields (4i-4k). In addition, this oxidative
cyclization was also found to proceed successfully with a pyrrolidine bearing
naphthalene group, leading to the desired product in 60% yield (4l).
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Scheme 3. Scope for 1-Benzyl-2-(phenylethynyl)pyrrolidine Derivatives.a
S
Ph
S (1.5 equiv)
8
N
1,4-dioxane (2.0 mL)
Ph
N
o
1
20 C, 24 h
Ar
Ar
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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4
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4
4
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1
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1
2
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0
3
4
S
S
S
N
N
N
R
R
R
4
4
a, R = Me, 70%a
b, R = OMe, 43%a
4c, R = Cl, 67%a
4d, R = Br, 62%a
4e, R = F, 58%a
4f, R = CN, 69%a
S
S
S
N
N
R
N
R
4i, R = Me, 58%b
4
4
g, R = Me, 70%a
h, R = Cl, 57%a
j, R = Cl, 52%c
4l, 60%c
4
4
k, R = CN, 54%c
a
b
c
Reaction conditions: 3 (0.30 mmol), S (1.5 equiv), 1,4-dioxane (2.0 mL), N , 120 C, 24 h.
8
2
S8 (1.5 equiv), N-methylmorpholine (2.0 mL).
S8 (1.0 equiv), 1,4-dioxane (1.0 mL).
Encouraged by these results, we next aimed to expand the scope for N-substituent
pyrrolidines bearing an ethyl acetate group (Scheme 4). A variety of N-substituent
pyrrolidines bearing an ethyl acetate group were successfully utilized to perform the
oxidative cyclization of aliphatic amine, forming the corresponding products in good
yields
(6a-6d).
Furthermore,
the
reaction
with
ethyl
2-(2-phenyl-4H-thieno[3,2-b]pyrrol-4-yl)propanoates bearing electron-donating and
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
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5
5
6
electron-withdrawing groups proceeded smoothly to generate the targeted products in
5
6%-65% yields (6e-6i).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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0
1
2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Scope for 1-Benzyl-2-(phenylethynyl)pyrrolidine Derivatives.a
S (1.5 equiv)
8
S
Ar
1
,4-dioxane (2.0 mL)
N
o
Ar
120 C, 24 h
N
R
R
5
6
Cl
OMe
S
S
S
N
N
N
O
O
O
OEt
OEt
6b, 52%b
OEt
6c, 55%b
a, 59%a
6
OMe
Ph
S
S
S
N
N
N
O
O
O
OEt
OEt
OEt
d, 52%b
6e, 60%a
6f, 63%a
6
Cl
Ph
S
S
S
N
N
N
O
O
O
OEt
6g, 65%a
OEt
6h, 60%a
OEt
6i, 56%
a
a
b
o
Reaction conditions: 5 (0.30 mmol), S (1.0 equiv), 1,4-dioxane (1.0 mL), N , 120 C, 24 h.
8
2
S8 (1.5 equiv), N-methylmorpholine (2.0 mL).
To explore the practicality of this strategy, a gram-scale experiment was carried out
(Scheme 5). The desired product was obtained in 55% yield, which demonstrated that
this protocol was also readily scalable and practical.
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Scheme 5. Gram-Scale Experiment.
S
Ph
1
,4-dioxane (40 mL)
N
+
S8
Ph
o
N 120 C, 24 h
2
,
Bn
N
Bn
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
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3
4
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4
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5
5
5
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0
1
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9
0
1
2
3
4
5
6
7
8
9
0
1a, 8.0 mmol
12 mmol
2a, 1.27g, 55% yield
To better understand the mechanism for the functionalization of pyrrolidine, some
control experiments were performed (Scheme 6). An EPR experiment for the
thienannulation reaction was conducted under the optimized condition, with no EPR
signal observed (see SI for more details). This result indicated that a free radical
process may not be involved in the present thienannulation reaction of aliphatic
amine. When the thienannulation reaction of 1-benzyl-2-(phenylethynyl)pyrrolidine
(1a)
was
carried
out
at
110
°C
for
24 h,
4-benzyl-2-phenyl-5,6-dihydro-4H-thieno[3,2-b]pyrrole (2a’) was unexpectedly
observed in 39% yield (Scheme 6a). Then, 2a’ was subjected to the standard
condition, and the targeted product was obtained in 85% yield (Scheme 6b). This
result demonstrated that 2a’ was most likely the intermediate of this transformation.
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4
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4
4
4
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5
5
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5
5
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5
5
6
Scheme 6. Control Experiments.
a)
S
S
Ph
Ph
S (1.5 equiv)
8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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8
9
0
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5
6
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9
0
1
2
3
4
5
6
7
8
9
0
1
,4-dioxane (2.0 mL)
N
+
Ph
N
N
o
N , 100 C, 24 h
Bn
2
Bn
Bn
1a
2a' 39%
2a, 17%
b)
S
S (1.5 equiv)
,4-dioxane (2.0 mL)
S
Ph
8
Ph
1
o
N
N , 120 C, 24 h
2
N
Bn
a'
Bn
2
2a, 85%
Based on the results of this work, a plausible pathway is proposed (Scheme 7).
Initially, 1a undergoes oxidation to form the intermediate I, followed by the loss of
+
H to give the intermediate II. Electrophilic sulfuration of intermediate II generated
intermediate III. The cation at the β-position of pyrrolidine is easily stabilized by the
conjugation of the propargylic group. Subsequently, intermediate III undergoes H+
elimination to afford the common intermediate IV. A nucleophilic attack of the sulfur
anion on the alkynyl group easily occurs, leading to intermediate V, furnished by the
elimination of elemental sulfur (S ). After the protonation and aromatization, the
n-1
final product 2a is released.
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Scheme 7. Possible Reaction Mechanism.
Sn
S8
H S
2
H+
N
N+
Ph
N
Ph
Ph
Bn
Bn
Bn
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1a
I
II
Sn-1
S
H S
H+
Sn-1
S
Ph
-
Sn-1
N
Ph
N
N
Ph
Bn
Bn
Bn
III
IV
V
S
+
Ph
[
H ]
S
[O]
Ph
N
N
Bn
Bn
2a'
2a
CONCLUSION
In summary, we have reported a new strategy for the synthesis of
thieno[3,2-b]pyrroles via elemental sulfur incorporated pyrrolidine rings. The reaction
occurs at the β-position of pyrrolidine to deliver the desired product, which is
furnished by the electrophilic attack of elemental sulfur and an intramolecular
cyclization reaction. We also demonstrated that this transformation can be extended to
explore the functionalization of pyrrolidine with various substrates and shows good
reaction efficiency on the gram scale. Notably, the utilization of elemental-promoted
oxidative cyclization of pyrrolidine can provide valuable information for the further
design of S-containing compounds.
EXPERIMENTAL SECTION
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6
General Information. All the solvents and other reagents were purchased from
commercial suppliers without further purification. All reactions were performed in N2
atmosphere. The substituted pyrrolidines 1, 3 and 5 were prepared in accordance with
0
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0
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1
13
1
the reported literature. H and C{ H} NMR spectra were recorded using a Bruker
1
13
1
1
Avance/600 ( H: 600 MHz, C{ H}: 150 MHz at 25 ºC) or Bruker Avance/400 ( H:
1
3
1
1
19
400 MHz, C{ H}: 100 MHz at 25 ºC) and TMS as internal standard. H and F
NMR multiplicities are reported as follows: singlet (s), doublet (d), doublet of
doublets (dd), quartet (q), multiplet (m), and broad resonance (br). All high-resolution
mass spectra (HRMS) were measured with a mass spectrometer by using electrospray
ionization (ESI-oa-TOF). Melting points were measured by a melting point apparatus
equipped with a thermometer and used uncorrected. All reactions were monitored by
thin-layer chromatography (TLC) through GF254 silica gel-coated plates. Flash
chromatography was conducted on silica gel (200-300 mesh, purchased from
Sinopharm Chemical Reagent Co., Ltd). Di-tert-butyl peroxide (97%) was purchased
from Sinopharm Chemical Reagent Co., Ltd.
General procedure for the synthesis of substituted pyrrolidines (1, 3 and 5):
7
a
General procedure (A): CuBr (0.045 mmol, 6.5 mg) was added to a solution of
N,N,N',N'-tetramethylethylenediamine (13.5 μL, 0.09 mmol) in toluene (2.0 mL). The
mixture was then stirred for 10 min under N atmosphere. Next, benzylproline (61.6
2
mg, 0.30 mmol), ethynylbenzene (49.4 μL, 0.45 mmol) and tert-butyl peroxide (77.2
μL, 0.42 mmol) were injected into a Schlenk tube with a syringe under N2
atmosphere. The contents of the Schlenk tube were then allowed to stir at 110 C by
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using a heating mantle for 12 h followed by cooling to room temperature. The
reaction mixture was diluted with ethyl acetate and filtered through a short florisil
column eluting with ethyl acetate. The residue was concentrated under vacuum,
purified by chromatography on silica gel and then eluted with petroleum ether/ethyl
acetate as an eluent to obtain the desired product 1a.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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5
5
5
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5
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0
1
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0
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1
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3
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8
9
0
1
2
3
4
5
6
7
8
9
0
General procedure (B):7b (4-methylbenzyl)proline (65.8 mg, 0.30 mmol),
ethynylbenzene (65.9 μL, 0.60 mmol) and Cu (OH) CO (6.6 mg, 0.03 mmol) were
2
2
3
mixed in a 25 mL flame-dried Schlenk tube equipped with a stir bar and then the tube
was sealed. Next, the Schlenk tube was purged three times with N . Then, toluene (2.0
2
mL) and DBU (134.5 μL, 0.90 mmol) was injected into the Schlenk tube with a
syringe under N atmosphere. The contents of the Schlenk tube were then allowed to
2
stir at 110 C with a heating mantle for 24 h followed by cooling to room temperature.
The reaction mixture was then diluted with ethyl acetate and filtered through a short
florisil column eluting with ethyl acetate. Next, the residue was concentrated under
vacuum, purified by chromatography on silica gel and then eluted with petroleum
ether/ethyl acetate as an eluent to obtain the desired product 3a.
7
c
General procedure (C): L-proline (51.8 mg, 0.45 mmol), and CuBr (6.5 mg, 0.045
mmol) were mixed in a 25 mL flame-dried Schlenk tube equipped with a stir bar and
then the tube was sealed. Next, the Schlenk tube was purged three times with N2.
Then, ethyl glyoxalate (41.6 μL, 0.42 mmol), N,N-diisopropylethylamine (14.9 μL,
0.09 mmol) ethynylbenzene (33.0 μL, 0.30 mmol) and toluene (1.5 mL) were injected
into the Schlenk tube with a syringe under N atmosphere. The contents of the
2
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6
Schlenk tube were then allowed to stir at 110 C by using a heating mantle for 12 h
followed by cooling to room temperature. Next, the reaction mixture was diluted with
ethyl acetate and filtered through a short florisil column eluting with ethyl acetate.
The residue was concentrated under vacuum, purified by chromatography on silica gel
and then eluted with petroleum ether/ethyl acetate as an eluent to obtain the desired
product 5a.
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1
-Benzyl-2-(phenylethynyl)pyrrolidine (1a). The title compound was prepared
according to the general procedure (A) and purified by flash column chromatography
1
to give a yellow liquid, 54.8 mg, 70% yield. H NMR (400 MHz, CDCl ) δ 7.46 (q, J
3
=
4.0 Hz, 2H), 7.39 (dd, J = 8.0, 1.2 Hz, 2H), 7.33-7.28 (m, 5H), 7.26-7.22 (m, 1H),
4.06 (d, J = 16.0 Hz, 1H), 3.63-3.58 (m, 2H), 2.81-2.75 (m, 1H), 2.57-2.51 (m, 1H),
2
.21-2.12 (m, 1H), 2.07-1.76 (m, 3H). ESI-MS (M): 261.
1
-Benzyl-2-(p-tolylethynyl)pyrrolidine (1b). The title compound was prepared
according to the general procedure (A) and purified by flash column chromatography
1
to give a yellow liquid, 51.9 mg, 63% yield. H NMR (400 MHz, CDCl ) δ 7.39 (dd, J
3
= 8.0, 1.4 Hz 2H), 7.36-7.29 (m, 4H), 7.26-7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 2H),
4
2
.07 (d, J = 12.0 Hz, 1H), 3.63-3.58 (m, 2H), 2.81-2.75 (m, 1H), 2.58-2.52 (m, 1H),
.34 (s, 3H), 2.19-2.12 (m, 1H), 2.05-1.88 (m, 2H), 1.83-1.76 (m, 1H). ESI-MS (M):
275.
1
-Benzyl-2-((4-ethylphenyl)ethynyl)pyrrolidine (1c). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 50.3 mg, 58% yield. H NMR (400 MHz,
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CDCl ) δ 7.41-7.38 (m, 4H), 7.33 (td, J = 8.0, 4.0 Hz, 2H), 7.27 (t, J = 2.0 Hz, 1H),
3
7
.15 (dd, J = 8.0, 4.0 Hz, 2H), 4.08 (d, J = 12.0 Hz, 1H), 3.63-3.58 (m, 2H), 2.82-2.76
(m, 1H), 2.66 (q, J = 8.0 Hz, 2H), 2.58-2.52 (m, 1H), 2.20-2.13 (m, 1H), 2.08-1.89
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
(m, 2H), 1.86-1.77 (m, 1H), 1.24 (t, J = 6.0 Hz, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 144.3, 138.8, 131.7, 129.3, 128.2, 127.8, 127.0, 120.6, 87.9, 85.1, 57.2,
3
+
54.5, 51.5, 31.7, 28.8, 22.0, 15.4. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N
2
1
24
+
(
M+H ): 290.1903; found 290.1903.
1
-Benzyl-2-((4-propylphenyl)ethynyl)pyrrolidine (1d). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 50.0 mg, 55% yield. H NMR (400 MHz,
CDCl ) δ 7.42-7.37 (m, 3H), 7.33 (td, J = 8.0, 4.0 Hz, 2H), 7.28-7.23 (m, 2H), 7.13
3
(d, J = 8.0 Hz, 2H), 4.08 (d, J = 12.0 Hz, 1H), 3.63 (q, J = 6.7 Hz, 2H), 2.82-2.76 (m,
1
H), 2.59 (td, J = 8.0, 2.0 Hz, 3H), 2.20-2.13 (m, 1H), 2.06-1.91 (m, 2H), 1.85-1.78
1
3
1
(m, 1H), 1.64 (q, J = 5.3 Hz, 2H), 0.94 (t, J = 8.0 Hz, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 142.8, 138.9, 131.7, 129.3, 128.5, 128.2, 127.0, 120.6, 88.0, 85.1, 57.2,
3
+
54.5, 51.5, 38.0, 31.7, 24.4, 22.1, 13.8. HRMS (ESI-TOF) m/z: [M+H] Calcd for
+
C H N (M+H ): 304.2060; found 304.2060.
2
2
26
1
-Benzyl-2-((4-butylphenyl)ethynyl)pyrrolidine (1e). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 50.4 mg, 53% yield. H NMR (400 MHz,
CDCl ) δ 7.28 (td, J = 8.0, 4.0 Hz, 4H), 7.21 (td, J = 8.0, 4.0 Hz, 2H), 7.13 (t, J = 8.0
3
Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 3.96 (d, J = 12.0 Hz, 1H), 3.52-3.47 (m, 2H),
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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2.70-2.64 (m, 1H), 2.51-2.40 (m, 3H), 2.08-2.00 (m, 1H), 1.96-1.77 (m, 2H),
1
.72-1.65 (m, 1H), 1.50-1.44 (m, 2H), 1.27-1.21 (m, 2H), 0.82 (t, J = 8.0 Hz, 3H);
13
1
C{ H} NMR (101 MHz, CDCl ) δ 141.9, 137.8, 130.6, 128.2, 127.3, 127.1, 125.9,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
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1
2
3
4
5
6
7
8
9
0
119.5, 86.9, 84.1, 56.1, 53.4, 50.4, 34.5, 32.4, 30.6, 21.3, 21.0, 12.9. HRMS
+
+
(
ESI-TOF) m/z: [M+H] Calcd for C H N (M+H ): 318.2216; found 318.2213.
23 28
1-Benzyl-2-((4-(tert-butyl)phenyl)ethynyl)pyrrolidine (1f). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 52.3 mg, 55% yield. H NMR (400 MHz,
CDCl ) δ 7.41-7.37 (m, 4H), 7.34-7.29 (m, 4H), 7.25-7.22 (m, 1H), 4.06 (d, J = 12.0
3
Hz, 1H), 3.62-3.57 (m, 2H), 2.80-2.74 (m, 1H), 2.57-2.51 (m, 1H), 2.20-2.11 (m, 1H),
1
3
1
2.06-1.88 (m, 2H), 1.84-1.75 (m, 1H), 1.31 (s, 9H); C{ H} NMR (101 MHz, CDCl )
3
δ 151.2, 138.8, 131.5, 129.3, 128.2, 127.0, 125.3, 120.4, 88.0, 85.1, 57.2, 54.5, 51.5,
+
+
3
4.8, 31.7, 31.2, 22.1. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N (M+H ):
23 28
318.2216; found 318.2217.
1
-Benzyl-2-((4-methoxyphenyl)ethynyl)pyrrolidine (1g). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 52.4 mg, 60% yield. H NMR (400 MHz,
CDCl ) δ 7.39 (dd, J = 8.0, 4.0 Hz, 4H), 7.31 (td, J = 6.0, 4.0 Hz, 2H), 7.24-7.22 (m,
3
1H), 6.83 (dd, J = 4.0, 4.0 Hz, 2H), 4.07 (d, J = 12.0 Hz, 1H), 3.80 (s, 3H), 3.58 (q, J
=
9.3 Hz, 2H), 2.81-2.75 (m, 1H), 2.54-2.48 (m, 1H), 2.20-2.11 (m, 1H), 2.06-1.86
(m, 2H), 1.83-1.73 (m, 1H). ESI-MS (M): 291.
-Benzyl-2-((4-ethoxyphenyl)ethynyl)pyrrolidine (1h). The title compound was
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prepared according to the general procedure (A) and purified by flash column
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chromatography to give a yellow liquid, 53.1 mg, 58% yield. H NMR (600 MHz,
CDCl ) δ 7.45-7.38 (m, 4H), 7.32 (t, J = 6.0 Hz, 2H), 7.25 (t, J = 6.0 Hz, 1H), 6.83
3
1
1
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(dd, J = 6.0, 6.0 Hz, 2H), 4.08-4.01 (m, 3H), 3.61-3.56 (m, 2H), 2.80-2.76 (m, 1H),
2
.54-2.50 (m, 1H), 2.19-2.13 (m, 1H), 2.05-1.99 (m, 1H), 1.95-1.89 (m, 1H),
1
3
1
1.83-1.77 (m, 1H), 1.41 (t, J = 9.0 Hz, 3H); C{ H} NMR (151 MHz, CDCl ) δ
3
1
58.8, 134.1, 133.1, 129.3, 128.2, 127.0, 115.4, 114.4, 87.1, 84.9, 63.5, 57.2, 54.6,
+
+
5
1.5, 31.7, 22.0, 14.8. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H NO (M+H ):
21 24
306.1852; found 306.1851.
1
-Benzyl-2-((4-fluorophenyl)ethynyl)pyrrolidine (1i). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 54.4 mg, 65% yield. H NMR (600 MHz,
CDCl ) δ 7.42 (t, J = 6.0 Hz, 2H), 7.38 (d, J = 12.0 Hz, 2H), 7.32 (t, J = 6.0 Hz, 2H),
3
7.25 (d, J = 6.0 Hz, 1H), 7.00 (t, J = 9.0 Hz, 2H), 4.05 (d, J = 12.0 Hz, 1H), 3.61-3.56
(
m, 2H), 2.80-2.76 (m, 1H), 2.55-2.51 (m, 1H), 2.18-2.13 (m, 1H), 2.05-1.99 (m, 1H),
1.94-1.89 (m, 1H), 1.83-1.77 (m, 1H). ESI-MS (M): 279.
-Benzyl-2-((4-chlorophenyl)ethynyl)pyrrolidine (1j). The title compound was
1
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 53.1 mg, 60% yield. H NMR (400 MHz,
DMSO-d ) δ 7.47-7.42 (m, 4H), 7.35-7.30 (m, 4H), 7.26-7.22 (m, 1H), 3.94 (d, J =
6
16.0 Hz, 1H), 3.62-3.54 (m, 2H), 2.66-2.60 (m, 1H), 2.50-2.46 (m, 1H), 2.16-2.07 (m,
1
3
1
1
H), 1.92-1.71 (m, 3H); C{ H} NMR (101 MHz, DMSO-d ) δ 139.3, 133.6, 133.5,
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129.2, 129.1, 128.6, 127.3, 121.9, 90.8, 83.9, 56.9, 54.3, 51.5, 31.7, 22.2. HRMS
+
+
(
ESI-TOF) m/z: [M+H] Calcd for C H ClN (M+H ): 296.1201; found 296.1205.
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1
-Benzyl-2-((4-bromophenyl)ethynyl)pyrrolidine (1k). The title compound was
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prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 59.0 mg, 58% yield. H NMR (400 MHz,
DMSO-d ) δ 7.54 (dt, J = 12.0, 2.0 Hz, 2H), 7.36 (dd, J = 4.0, 4.0 Hz, 2H), 7.32-7.28
6
(m, 4H), 7.25-7.21 (m, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.59-3.52 (m, 2H), 2.65-2.59
(m, 1H), 2.49-2.43 (m, 1H), 2.14-2.05 (m, 1H), 1.92-1.82 (m, 1H), 1.81-1.68 (m, 2H);
1
3
1
C{ H} NMR (101 MHz, DMSO-d ) δ 139.3, 133.8, 132.1, 129.1, 128.6, 127.3,
6
1
22.3, 122.1, 90.9, 84.0, 56.9, 54.3, 51.5, 31.7, 22.2. HRMS (ESI-TOF) m/z: [M+H]+
+
Calcd for C H BrN (M+H ): 340.0695; found 340.0690.
1
9
19
1
-Benzyl-2-((4-(trifluoromethyl)phenyl)ethynyl)pyrrolidine (1l). The title compound
was prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 54.3 mg, 55% yield. H NMR (400 MHz,
CDCl ) δ 7.56-7.51 (m, 4H), 7.37 (d, J = 8.0 Hz, 2H), 7.31 (td, J = 8.0, 4.0 Hz, 2H),
3
7.24 (d, J = 4.0 Hz, 1H), 4.04 (d, J = 12.0 Hz, 1H), 3.62-3.58 (m, 2H), 2.81-2.75 (m,
1
3
1
1
H), 2.58-2.52 (m, 1H), 2.23-2.13 (m, 1H), 2.07-1.77 (m, 3H); C{ H} NMR (101
MHz, CDCl ) δ 138.7, 132.0, 129.2, 128.3, 127.2 (d, J = 17.2 Hz), 125.2 (q, J = 4.0
3
+
Hz), 91.7, 83.7, 57.3, 54.4, 51.7, 31.6, 22.1. HRMS (ESI-TOF) m/z: [M+H] Calcd
+
for C H F N (M+H ): 330.1464; found 330.1463.
2
0
19 3
1-Benzyl-2-((2-fluorophenyl)ethynyl)pyrrolidine (1m). The title compound was
prepared according to the general procedure (A) and purified by flash column
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chromatography to give a yellow liquid, 44.4 mg, 53% yield. H NMR (400 MHz,
CDCl ) δ 7.47-7.40 (m, 3H), 7.35-7.27 (m, 4H), 7.12-7.06 (m, 2H), 4.06 (d, J = 12.0
3
Hz, 1H), 3.69-3.65 (m, 2H), 2.82-2.75 (m, 1H), 2.65-2.59 (m, 1H), 2.23-2.14 (m, 1H),
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7
8
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0
1
3
1
2.10-1.91 (m, 2H), 1.87-1.79 (m, 1H); C{ H} NMR (101 MHz, CDCl ) δ 162.9 (J =
3
2
53 Hz), 138.8, 133.6, 129.6 (J = 8.1 Hz), 129.3, 128.2, 127.0, 123.9 (J = 3.0 Hz),
115.5 (J = 21.2 Hz), 112.0 (J = 15.2 Hz), 94.2, 78.4, 57.0, 54.4, 51.4, 31.6, 22.0.
+
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H FN (M+H ): 280.1496; found
1
9
19
2
80.1495.
1-Benzyl-2-((3-bromophenyl)ethynyl)pyrrolidine (1n). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 52.9 mg, 52% yield. H NMR (400 MHz,
CDCl ) δ 7.59 (t, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.0, 4.0 Hz, 1H), 7.36 (td, J = 8.0, 4.0
3
Hz, 3H), 7.31 (td, J = 8.0, 4.0 Hz, 2H), 7.25-7.22 (m, 1H), 7.16 (t, J = 6.0 Hz, 1H),
4.02 (d, J = 12.0 Hz, 1H), 3.59 (q, J = 6.7 Hz, 2H), 2.79-2.73 (m, 1H), 2.58-2.52 (m,
1
1
H), 2.20-2.11 (m, 1H), 2.05-1.76 (m, 3H); 13C{ H} NMR (101 MHz, CDCl ) δ
3
138.7, 134.5, 131.1, 130.3, 129.7, 129.2, 128.3, 127.1, 125.4, 122.1, 90.4, 83.6, 57.3,
+
+
5
3
4.4, 51.6, 31.6, 22.1. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H BrN (M+H ):
19 19
40.0695; found 340.0694.
1-Benzyl-2-((3-methoxyphenyl)ethynyl)pyrrolidine (1o). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 41.9 mg, 48% yield. H NMR (400 MHz,
CDCl ) δ 7.41 (dd, J = 8.0, 4.0 Hz, 2H), 7.33 (td, J = 6.0, 4.0 Hz, 2H), 7.28-7.27 (m,
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1H), 7.25-7.21 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 4.0 Hz, 1H), 6.89-6.86
(m, 1H), 4.08 (d, J = 12.0 Hz, 1H), 3.82 (s, 3H), 3.64-3.59 (m, 2H), 2.83-2.77 (m,
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C{ H} NMR (101 MHz, CDCl ) δ 159.3, 138.8, 129.3, 129.2, 128.2, 127.0, 124.4,
3
1
24.3, 116.7, 114.5, 88.7, 84.9, 57.3, 55.3, 54.5, 51.6, 31.6, 22.1. HRMS (ESI-TOF)
+
+
m/z: [M+H] Calcd for C H NO (M+H ): 292.1696; found 292.1696.
2
0
22
1
-Benzyl-2-((3-chlorophenyl)ethynyl)pyrrolidine (1p). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 44.3 mg, 50% yield. H NMR (400 MHz,
CDCl ) δ 7.43 (d, J = 4.0 Hz, 1H), 7.38 (dd, J = 8.0, 4.0 Hz, 2H), 7.33-7.29 (m, 3H),
3
7.28-7.19 (m, 3H), 4.03 (d, J = 12.0 Hz, 1H), 3.62-3.57 (m, 2H), 2.79-2.74 (m, 1H),
1
3
1
2
.58-2.52 (m, 1H), 2.20-2.11 (m, 1H), 2.05-1.74 (m, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 138.7, 134.1, 131.7, 129.9, 129.5, 129.2, 128.3, 127.1, 125.2, 90.3, 83.7,
3
+
57.3, 54.4, 51.6, 31.7, 22.1. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H ClN
1
9
19
+
(
M+H ): 296.1201; found 296.1196.
1-Benzyl-2-(thiophen-2-ylethynyl)pyrrolidine (1q). The title compound was prepared
according to the general procedure (A) and purified by flash column chromatography
1
to give a yellow liquid, 41.7 mg, 52% yield. H NMR (400 MHz, CDCl ) δ 7.36 (dd, J
3
= 8.0, 4.0 Hz, 2H), 7.28 (td, J = 8.0, 4.0 Hz, 2H), 7.23-7.18 (m, 1H), 7.16-7.13 (m,
2
H), 6.90 (q, J = 4.0 Hz, 1H), 4.01 (d, J = 12.0 Hz, 1H), 3.59-3.54 (m, 2H), 2.75-2.70
(m, 1H), 2.53-2.47 (m, 1H), 2.16-2.07 (m, 1H), 2.03-1.95 (m, 1H), 1.93-1.69 (m, 2H);
1
3
1
C{ H} NMR (101 MHz, CDCl ) δ 138.9, 131.7, 129.3, 128.4, 127.1, 127.0, 126.7,
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123.5, 93.0, 78.2, 57.4, 54.7, 51.7, 31.7, 22.2. HRMS (ESI-TOF) m/z: [M+H] Calcd
+
for C H NS (M+H ): 268.1154; found 268.1149.
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-Benzyl-2-(thiophen-3-ylethynyl)pyrrolidine (1r). The title compound was prepared
1
1
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9
0
according to the general procedure (A) and purified by flash column chromatography
1
to give a yellow liquid, 44.1 mg, 55% yield. H NMR (400 MHz, CDCl ) δ 7.42-7.37
3
(m, 3H), 7.31 (td, J = 6.0, 2.0 Hz, 2H), 7.27-7.22 (m, 2H), 7.12 (d, J = 4.0 Hz, 1H),
4
2
.06 (d, J = 12.0 Hz, 1H), 3.62-3.57 (m, 2H), 2.81-2.75 (m, 1H), 2.57-2.51 (m, 1H),
13
1
.20-2.11 (m, 1H), 2.06-1.97 (m, 1H), 1.95-1.86 (m, 1H), 1.84-1.74 (m, 1H); C{ H}
NMR (101 MHz, CDCl ) δ 138.6, 130.1, 129.3, 128.3, 128.3, 127.1, 125.2, 122.4,
3
+
8
8.2, 80.1, 57.2, 54.5, 51.5, 31.6, 22.1. HRMS (ESI-TOF) m/z: [M+H] Calcd for
+
C H NS (M+H ): 268.1154; found 268.1157.
1
7
18
2
-([1,1'-Biphenyl]-4-ylethynyl)-1-benzylpyrrolidine (1s). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 70.8 mg, 70% yield. H NMR (400 MHz,
CDCl ) δ 7.63 (dd, J = 8.0, 4.0 Hz, 2H), 7.60-7.55 (m, 4H), 7.49-7.43 (m, 4H),
3
7.40-7.34 (m, 3H), 7.31-7.27 (m, 1H), 4.12 (d, J = 12.0 Hz, 1H), 3.66 (q, J = 6.7 Hz,
2
2
H), 2.86-2.81 (m, 1H), 2.62-2.56 (m, 1H), 2.25-2.17 (m, 1H), 2.13-2.04 (m, 1H),
.01-1.94 (m, 1H), 1.90-1.81 (m, 1H). ESI-MS (M): 337.
1-Benzyl-2-(dec-1-yn-1-yl)pyrrolidine (1t). The title compound was prepared
according to the general procedure (A) and purified by flash column chromatography
1
to give a yellow liquid, 40.1 mg, 45% yield. H NMR (400 MHz, CDCl ) δ 7.37-7.27
3
(
m, 4H), 7.25-7.21 (m, 1H), 4.02 (d, J = 12.0 Hz, 1H), 3.48 (d, J = 16.0 Hz, 1H),
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3.32-3.28 (m, 1H), 2.74-2.69 (m, 1H), 2.44-2.38 (m, 1H), 2.23 (td, J = 7.2, 2.0 Hz,
2
1
H), 2.10-2.00 (m, 1H), 1.92-1.67 (m, 3H), 1.57-1.50 (m, 2H), 1.45-1.38 (m, 2H),
.32-1.19 (m, 10H), 0.87 (t, J = 6.0 Hz, 3H). ESI-MS (M): 297.
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1-(4-Methylbenzyl)-2-(phenylethynyl)pyrrolidine (3a). The title compound was
prepared according to the general procedure (B) and purified by flash column
1
chromatography to give a yellow liquid, 53.6 mg, 65% yield. H NMR (400 MHz,
CDCl ) δ 7.52-7.49 (m, 2H), 7.36-7.31 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 4.07 (dd, J
3
=
12.0, 4.0 Hz, 1H), 3.65-3.61 (m, 2H), 2.85-2.79 (m, 1H), 2.61-2.55 (m, 1H), 2.38 (s,
3H), 2.25-2.15 (m, 1H), 2.12-1.91 (m, 2H), 1.88-1.79 (m, 1H). ESI-MS (M): 275.
-(4-Methoxybenzyl)-2-(phenylethynyl)pyrrolidine (3b). The title compound was
1
prepared according to the general procedure (C) and purified by flash column
1
chromatography to give a yellow liquid, 24.4 mg, 28% yield. H NMR (600 MHz,
CDCl ) δ 7.46 (d, J = 6.0 Hz, 2H), 7.33-7.31 (m, 5H), 6.87 (d, J = 6.0 Hz, 2H), 4.00
3
(d, J = 12.0 Hz, 1H), 3.80 (s, 3H), 3.59-3.56 (m, 2H), 2.80-2.76 (m, 1H), 2.56-2.52
(
m, 1H), 2.19-2.13 (m, 1H), 2.06-2.01 (m, 1H), 1.96-1.89 (m, 1H), 1.84-1.77 (m, 1H).
ESI-MS (M): 291.
-(4-Chlorobenzyl)-2-(phenylethynyl)pyrrolidine (3c). The title compound was
1
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 53.1 mg, 60% yield. H NMR (400 MHz,
CDCl ) δ 7.38-7.35 (m, 2H), 7.24-7.21 (m, 6H), 7.17 (d, J = 12.0 Hz, 1H), 3.93 (d, J
3
= 12.0 Hz, 1H), 3.53-3.50 (m, 2H), 2.71-2.65 (m, 1H), 2.50-2.45 (m, 1H), 2.14-2.05
1
3
1
(
m, 1H), 1.99-1.81 (m, 2H), 1.78-1.69 (m, 1H); C{ H} NMR (101 MHz, CDCl ) δ
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136.2, 131.7, 130.7, 129.5, 127.3, 127.2, 127.0, 122.2, 87.3, 84.2, 55.4, 53.4, 50.5,
+
+
3
0.6, 21.0. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H ClN (M+H ): 296.1201;
19 19
found 296.1204.
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1-(4-Bromobenzyl)-2-(phenylethynyl)pyrrolidine (3d). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 62.2 mg, 61% yield. H NMR (400 MHz,
CDCl ) δ 7.45-7.32 (m, 4H), 7.32-7.25 (m, 5H), 3.99 (d, J = 16.0 Hz, 1H), 3.63-3.58
3
(
m, 2H), 2.79-2.74 (m, 1H), 2.61-2.55 (m, 1H), 2.22-2.12 (m, 1H), 2.07-1.90 (m, 2H),
1.88-1.77 (m, 1H). ESI-MS (M): 340.
-(4-Fluorobenzyl)-2-(phenylethynyl)pyrrolidine (3e). The title compound was
1
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 54.4 mg, 65% yield. H NMR (400 MHz,
CDCl ) δ 7.48 (q, J = 4.0 Hz, 2H), 7.39-7.36 (m, 2H), 7.34-7.31 (m, 3H), 7.04-7.00
3
(m, 2H), 4.04 (d, J = 12.0 Hz, 1H), 3.61 (td, J = 6.0, 4.0 Hz, 2H), 2.81-2.76 (m, 1H),
2
.59-2.53 (m, 1H), 2.24-2.15 (m, 1H), 2.10-1.90 (m, 2H), 1.88-1.78 (m, 1H). ESI-MS
(M): 279.
-((2-(Phenylethynyl)pyrrolidin-1-yl)methyl)benzonitrile (3f). The title compound
4
was prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 48.9 mg, 57% yield. H NMR (400 MHz,
CDCl ) δ 7.60 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.44-7.42 (m, 2H), 7.31
3
(t, J = 4.0 Hz, 3H), 4.08 (d, J = 12.0 Hz, 1H), 3.69-3.61 (m, 2H), 2.80-2.74 (m, 1H),
1
3
1
2
.60-2.54 (m, 1H), 2.23-2.14 (m, 1H), 2.08-1.91 (m, 2H), 1.88-1.79 (m, 1H); C{ H}
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NMR (101 MHz, CDCl ) δ 144.8, 132.1, 131.7, 129.6, 128.3, 128.2, 123.1, 119.0,
3
+
1
10.8, 88.1, 85.4, 56.9, 54.6, 51.7, 31.7, 22.2. HRMS (ESI-TOF) m/z: [M+H] Calcd
+
for C H N (M+H ): 287.1543; found 287.1549.
2
0
19
2
0
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1-(2-Methylbenzyl)-2-(phenylethynyl)pyrrolidine (3g). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 52.0 mg, 63% yield. H NMR (400 MHz,
CDCl ) δ 7.49 (dd, J = 8.0, 4.0 Hz, 2H), 7.38 (td, J = 4.0, 4.0 Hz, 1H), 7.36-7.32 (m,
3
3
H), 7.19 (t, J = 4.0 Hz, 3H), 4.13 (d, J = 12.0 Hz, 1H), 3.64 (t, J = 6.0 Hz, 1H), 3.57
(d, J = 12.0 Hz, 1H), 2.86-2.80 (m, 1H), 2.58-2.53 (m, 1H), 2.47 (s, 3H), 2.25-2.16
1
3
1
(
m, 1H), 2.09-2.01 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.79 (m, 1H); C{ H} NMR
(101 MHz, CDCl ) δ 137.4, 137.3, 131.7, 130.2, 129.6, 128.3, 127.9, 127.0, 125.6,
3
1
23.5, 89.2, 84.7, 55.2, 55.0, 51.8, 31.8, 22.2, 19.3. HRMS (ESI-TOF) m/z: [M+H]+
+
Calcd for C H N (M+H ): 276.1747; found 276.1744.
2
0
22
1-(2-Chlorobenzyl)-2-(phenylethynyl)pyrrolidine (3h). The title compound was
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 48.7 mg, 55% yield. H NMR (400 MHz,
CDCl ) δ 7.54-7.50 (m, 1H), 7.45-7.42 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 7.30-7.25
3
(
m, 3H), 7.23-7.18 (m, 1H), 7.15 (td, J = 8.0, 4.0 Hz, 1H), 4.13 (dd, J = 14.0, 4.0 Hz,
1H), 3.82 (dd, J = 16.0, 4.0 Hz, 1H), 3.68 (td, J = 6.0, 4.0 Hz, 1H), 2.88-2.82 (m, 1H),
.60-2.53 (m, 1H), 2.22-2.13 (m, 1H), 2.08-1.97 (m, 1H), 1.96-1.87 (m, 1H),
2
1
3
1
1.84-1.74 (m, 1H); C{ H} NMR (101 MHz, CDCl ) δ 136.8, 134.2, 131.8, 130.9,
3
1
29.5, 128.3, 128.1, 128.0, 126.7, 123.5, 88.9, 85.0, 55.0, 54.0, 51.8, 31.8, 22.3.
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+
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H ClN (M+H ): 296.1201; found
1
9
19
2
96.1208.
-(3-Methylbenzyl)-2-(phenylethynyl)pyrrolidine (3i). The title compound was
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prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 41.3 mg, 50% yield. H NMR (400 MHz,
CDCl ) δ 7.44-7.40 (m, 2H), 7.27-7.25 (m, 3H), 7.19-7.15 (m, 3H), 7.03 (dd, J = 4.0,
3
4
.0 Hz, 1H), 4.01 (dt, J = 12.0, 2.0 Hz 1H), 3.59-3.52 (m, 2H), 2.79-2.72 (m, 1H),
.56-2.49 (m, 1H), 2.30 (d, J = 2.4 Hz, 3H), 2.19-2.09 (m, 1H), 2.05-1.83 (m, 2H),
2
1
3
1
1.82-1.73 (m, 1H); C{ H} NMR (101 MHz, CDCl ) δ 138.5, 137.8, 131.8, 130.1,
3
1
28.3, 128.1, 128.0, 127.8, 126.4, 123.4, 88.7, 85.1, 57.2, 54.6, 51.6, 31.6, 22.0, 21.4.
+
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N (M+H ): 276.1747; found
2
0
22
2
76.1748.
-(3-Chlorobenzyl)-2-(phenylethynyl)pyrrolidine (3j). The title compound was
1
prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 59.5 mg, 67% yield. H NMR (400 MHz,
CDCl ) δ 7.46-7.42 (m, 2H), 7.40 (t, J = 4.0 Hz, 1H), 7.31-7.27 (m, 3H), 7.25 (dd, J =
3
4
.0, 4.0 Hz, 1H), 7.23-7.20 (m, 2H), 4.01 (d, J = 12.0 Hz, 1H), 3.61-3.56 (m, 2H),
2
.79-2.73 (m, 1H), 2.56-2.50 (m, 1H), 2.21-2.12 (m, 1H), 2.07-1.87 (m, 2H),
1.85-1.75 (m, 1H). ESI-MS (M): 296.
-((2-(Phenylethynyl)pyrrolidin-1-yl)methyl)benzonitrile (3k). The title compound
3
was prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 51.5 mg, 60% yield. H NMR (400 MHz,
2
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CDCl ) δ 7.72 (t, J = 2.0 Hz, 1H), 7.64 (dt, J = 8.0, 2.0 Hz, 1H), 7.54 (dt, J = 8.0, 2.0
3
Hz, 1H), 7.45-7.39 (m, 3H), 7.33-7.30 (m, 3H), 4.06 (d, J = 12.0 Hz, 1H), 3.68-3.62
(m, 2H), 2.80-2.74 (m, 1H), 2.61-2.55 (m, 1H), 2.24-2.15 (m, 1H), 2.09-1.92 (m, 2H),
0
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0
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3
1
1.90-1.79 (m, 1H); C{ H} NMR (101 MHz, CDCl ) δ 139.5, 132.4, 131.5, 130.7,
3
1
29.7, 128.0, 127.3, 127.1, 122.0, 118.0, 111.3, 87.0, 84.4, 84.4, 55.4, 53.5, 50.6,
+
+
30.6, 21.1. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H N (M+H ): 287.1543;
2
0
19
2
found 287.1538.
-(Naphthalen-1-ylmethyl)-2-(phenylethynyl)pyrrolidine (3l). The title compound
1
was prepared according to the general procedure (A) and purified by flash column
1
chromatography to give a yellow liquid, 56.9 mg, 61% yield. H NMR (400 MHz,
CDCl ) δ 8.53 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.0, 4.0 Hz, 1H), 7.83 (d, J = 8.0 Hz,
3
1
H), 7.60-7.51 (m, 5H), 7.49-7.45 (m, 1H), 7.42-7.35 (m, 3H), 4.71 (dd, J = 12.0, 4.0
Hz, 1H), 3.93 (dd, J = 14.0, 4.0 Hz, 1H), 3.70 (td, J = 8.0, 4.0 Hz, 1H), 2.91-2.85 (m,
1H), 2.65-2.58 (m, 1H), 2.28-2.19 (m, 1H), 2.15-2.06 (m, 1H), 2.01-1.81 (m, 2H).
ESI-MS (M): 311.
Ethyl 2-(2-(phenylethynyl)pyrrolidin-1-yl)acetate (5a). The title compound was
prepared according to the general procedure (C) and purified by flash column
1
chromatography to give a yellow liquid, 43.9 mg, 57% yield. H NMR (400 MHz,
DMSO-d ) δ 7.43-7.39 (m, 2H), 7.38-7.35 (m, 3H), 4.09 (q, J = 8.0 Hz, 2H), 3.87 (q,
6
J = 4.0 Hz, 1H), 3.54 (d, J = 16.0 Hz, 1H), 3.39 (d, J = 16.0 Hz, 1H), 2.82-2.76 (m,
1H), 2.71-2.66 (m, 1H), 2.17-2.08 (m, 1H), 1.90-1.71 (m, 3H), 1.19 (t, J = 6.0 Hz,
3
H). ESI-MS (M): 257.
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Ethyl 2-(2-((4-methoxyphenyl)ethynyl)pyrrolidin-1-yl)acetate (5b). The title
compound was prepared according to the general procedure (C) and purified by flash
1
column chromatography to give a yellow liquid, 55.1 mg, 64% yield. H NMR (400
1
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MHz, CDCl ) δ 7.34 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 4.21-4.15 (m, 2H),
3
3
.90 (q, J = 4.0 Hz, 1H), 3.79 (s, 3H), 3.63 (d, J = 20.0 Hz, 1H), 3.46 (d, J = 16.0 Hz,
1H), 2.95-2.89 (m, 1H), 2.80-2.75 (m, 1H), 2.26-2.18 (m, 1H), 2.04-1.95 (m, 2H),
.90-1.82 (m, 1H), 1.27 (t, J = 6.0 Hz, 3H). ESI-MS (M): 287.
1
Ethyl 2-(2-((4-chlorophenyl)ethynyl)pyrrolidin-1-yl)acetate (5c). The title compound
was prepared according to the general procedure (C) and purified by flash column
1
chromatography to give a yellow liquid, 52.4 mg, 60% yield. H NMR (400 MHz,
CDCl ) δ 7.25 (dd, J = 8.0, 4.0 Hz, 2H), 7.17 (dd, J = 8.0, 4.0 Hz, 2H), 4.14-4.07 (m,
3
2
H), 3.83 (td, J = 6.0, 2.0 Hz, 1H), 3.55 (dd, J = 20.0, 4.0 Hz, 1H), 3.38 (dd, J = 16.0,
4
.0 Hz, 1H), 2.86-2.81 (m, 1H), 2.74-2.67 (m, 1H), 2.19-2.10 (m, 1H), 1.98-1.84 (m,
1
3
1
2H), 1.82-1.75 (m, 1H), 1.19 (td, J = 8.0, 2.0 Hz, 3H); C{ H} NMR (101 MHz,
CDCl ) δ 170.7, 134.0, 132.9, 128.5, 121.6, 89.1, 83.9, 60.6, 54.3, 53.6, 51.7, 31.8,
3
+
+
22.4, 14.2. HRMS (ESI-TOF) m/z: [M+H] Calcd for C H ClNO (M+H ):
1
6
19
2
2
92.1099; found 292.1097.
Ethyl 2-(2-([1,1'-biphenyl]-4-ylethynyl)pyrrolidin-1-yl)acetate (5d). The title
compound was prepared according to the general procedure (C) and purified by flash
1
column chromatography to give a yellow liquid, 53.9 mg, 54% yield. H NMR (400
MHz, CDCl ) δ 7.58 (dt, J = 4.0, 2.0 Hz, 2H), 7.55-7.48 (m, 4H), 7.44 (td, J = 8.0, 4.0
3
Hz, 2H), 7.37-7.33 (m, 1H), 4.24-4.18 (m, 2H), 3.97 (q, J = 4.0 Hz, 1H), 3.67 (d, J =
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