Synthesis of functionalized indolizines: Via gold(i)-catalyzed intramolecular hydroarylation/aromatization of pyrrole-ynes

Article abstract of DOI:10.1039/c7ob02102j

A gold-catalyzed intramolecular hydroarylation/aromatization of pyrrole-ynes has been developed. This method provides a concise and straightforward route to functionalized indolizines through the construction of the pyridine ring of indolizines and also allows elaboration of its pyrrole moiety with or without functional groups. In addition, a wide variety of functional groups, such as aryl, alkenyl, alkynyl, pyridyl or thienyl groups, can be easily incorporated into the pyridine unit of the indolizine products under mild conditions. The utility of the indolizine products was demonstrated by their efficient transformations into various C3-functionalized indolizine derivatives.

Full text of DOI:10.1039/c7ob02102j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Synthesis of Functionalized Indolizines via Gold(I)-Catalyzed Intramolecular
Hydroarylation/aromatization of Pyrrole-Ynes
Xiangdong Li, Jidong Zhao, Xin Xie and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
People’s Republic of China
Fax: (+86) 21-64166128, E-mail: yhliu@sioc.ac.cn
R3
R3
cat. LAu+
N
R1
HO
DCM, rt
N
R2
R2
R1
R4
R4
2
R = H, alkyl, aryl, EWG 20 examples with up to 98% yield
pyridine ring construction
mild reaction conditions
wide functional group compatibility high efficiency
Abstract: A gold-catalyzed intramolecular hydroarylation/aromatization of pyrrole-ynes
has been developed. The method provides a concise and straightforward route to
functionalized indolizines through the construction of the pyridine ring of indolizines, and
also allows elaboration of its pyrrole moiety with or without functional groups. In addition,
a wide variety of the functional groups, such as aryl, alkenyl, alkynyl, pyridyl or thienyl
groups can be easily incorporated into the pyridine unit of the indolizine products under
mild conditions. The utility of the indolizine products was demonstrated by their efficient
transformations into various C3-functionalized indolizine derivatives.
1

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INTRODUCTION
Indolizines are important N-fused aromatic heterocycles, which have attracted a lot of
attention due to their pharmacological potential and unique photophysical properties. Many
1
of the synthetic indolizines have displayed important biological activities, such as
1
b
1c
1d
antibacterial, antiproliferative activity, 15-lipoxygenase inhibitor, and H receptor
3
1
e
2
antagonist etc (Figure 1). They have also found utilities in the field of materials science
Br
HO
N
CN
Ph
Ph
NC
N
Me
Ph
Antibacterial activity
O
Antiproliferative activity
OMe
O O
S
O
N
3
NC
O
N
Ph
N
OMe
Me
Ph
5-Lipoxygenase inhibitor
1
H receptor antagonist
3
Figure 1. Representative biologically active indolizine derivatives
2
a
2b
such as organic light emitting devices (OLEDs), fluorescent probes, and biological
2
c
markers. Therefore, the development of efficient methods for the construction of
3
functionalized indolizines has gained much attention. Documented approaches to
4
5
indolizines mainly involve Scholtz reaction, Tschitschibabin reaction, dipolar
6
cycloadditions of pyridinium ylides with electron-deficient alkynes or alkenes,
2

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transition-metal-catalyzed cycloisomerizations of alkynylpyridine or propargyl pyridine
7
derivatives, etc. These reactions generally focused on the construction of the pyrrole ring
from pyridine derivatives. In contrast, few methods have allowed the formation of the
8
,9
pyridine ring from pyrrole derivatives, and most of them limited to the synthesis of
8
e-g
8h
benzofused derivatives,
or restricted to activated substrates (Scheme 1a). In line with
the latter strategy, we recently developed an efficient route to highly substituted indolizines
1
0
via
gold-catalyzed
intermolecular
hydroarylation/cycloaromatization
of
9

-(N-pyrrolyl)ketones with alkynes (Scheme 1b). However, in this method, the substrates
bearing one or more substituents on the pyrrole ring were required in order to improve the
regioselectivity of the intermolecular hydroarylation, leading to indolizines with limited
substitution pattern on the pyrrole ring. For example, indolizines with a non-substituted
1
1
pyrrole ring could not be constructed efficiently by this method. To solve this problem,
we envisioned that a gold-catalyzed intramolecular hydroarylation/aromatization of
pyrrole-ynes might be utilized for the synthesis of indolizines with a wider diversity,
especially, on their pyrrole rings (Scheme 1c). In this strtagy, both of the pyrrole-ynes with
or without substituents on the pyrrole ring might be feasible due to the enhanced
1
2
regioselectivity of the intramolecular hydroarylation
compared with that of
intermolecular hydroarylation reactions, in which hydroarylation would occur
predominantly at the C-2 position of the pyrrole moiety. Furthermore, the method would
also allow for installing the C-5, C-6, and C-8 substituents on the resulting indolizines,
which are not easily accessible with the existing methods. Herein, we report the facile
synthesis of functionalized indolizines based on the above strategy.
3

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Scheme 1. Synthesis of Indolizines
a. Two complementary pathways towards the indolizine scaffold
pyrrole ring
formation
8
pyridine ring
formation
1
8
a
7
6
2
N
N
N
well studied
less studied
4
3
R
5
b. Intermolecular hydroarylation/cycloaromatization to indolizines (our previous work)
R5
R4
R4
R6
cat. LAu+
O
R3 + R5
R6
R3
N
o
R1
toluene, 80 C
N
R1
R2
R2
one or more substituents on the pyrrole ring are required
c. Intramolecular hydroarylation/aromatization to indolizines (this work)
R3
R3
cat. LAu+
N
R1
HO
R2
N
R2
DCM, rt
R  H, alkyl, aryl, EWG
R1
R4
2
R4
with or without substituents on the pyrrole ring
RESULTS AND DISCUSSION
Pyrrole-ynes 2 employed in the present study could be prepared through addition of
alkynylithium reagent to -(N-pyrrolyl)ketones 1. -(N-pyrrolyl)ketones 1 are usually
prepared by the reaction of N-H pyrrole with alkylating reagents in the presence of a
1
3
base. However, when free pyrrole was employed as the substrate, we failed to achieve
satisfactory yields of the target products using -bromoketones such as
2
-bromo-1-phenylethanone as the alkylating reagent. After some trails, it was found that
N-alkylation of pyrrole proceeded cleanly using 1-bromo-but-3-yn-2-ols as the alkylating
1
4
reagent, which also functioned as a synthetic equivalent of α-bromoketone through
elimination of an alkynyl group in this reaction. Addition of alkynylithium reagent to the
4

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resulting N-substituted pyrroles 1 provided the substrate 2 (Scheme 2). The method allows
for the convenient incorporation of various functional groups on either alkyne or pyrrole
moiety in 2, and was used for the synthesis of the most of the substrates.
Scheme 2. Synthesis of Pyrrole-ynes 2
R3
Ph
2
R3
R KOH, DMSO, rt
O
Li
+
N
Br
R1
N
N
R2
R1
R1
in THF
R2
H
OH
Ph
OH
1
2
masked -bromoketones
For our initial experiments, we focused on the optimization of the gold-catalyzed
cyclization of 2a (Table 1). To our delight, the expected indolizine 3a was obtained in 92%
yield in the presence of 5 mol% Johnphos(MeCN)AuSbF (catalyst A) in DCE at room
6
temperature for 9 h (Table 1, entry 1). The reaction could also proceed in various solvents
such as DCM, toluene, CH CN or THF, leading to 3a in 93-94% yields (Table 1, entries
3
2
-5). Further optimization indicated that N-heterocyclic carbene gold(I) complex of
IPrAuCl/AgSbF (IPr = 2,6-bis(diisopropylphenyl)imidazol-2-ylidene) displayed more
6
efficient catalytic activity by shortening the reaction time dramatically to 2 h (Table 1,
entry 6). However, the use of more electrophilic PPh AuCl/AgSbF led to 91% yield of 3a
3
6
with a prolonged reaction time (Table 1, entry 7). With IPrAuCl as the gold catalyst, the
-
-
-
effects of counter anions such as OTs , BF or PF were also examined (Table 1, entries
4
6
-
8
-10). Gratifyingly, it was found that PF was highly efficient for this transformation,
6
leading to 3a in 96% yield within 3 min, possibly due to the more weakly coordinating
5

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ability of this anion with gold (Table 1, entry 10). When the catalyst loading was lowered
to 1-2 mol%, good results could also be obtained with a slightly prolonged reaction time
(
Table 1, entries 11-12). The use of AgPF alone only provided little amounts of the desired
6
product (Table 1, entry 13). Brønsted acid such as HNTf or Lewis acid such as Sc(OTf)
2
3
failed to catalyze the reaction (Table 1, entries 14-15).
Table 1. Optimization of the Catalytic System
Ph
tBu
Ph
+
-
tBu
SbF6
catalyst
P Au NCMe
N
N
solvent, rt
Ph
Ph
OH
2a
3a
catalyst A
yield (%)a
entry
catalyst (mol%)
solvent
time
1
2
3
4
5
6
7
8
9
catalyst A (5)
catalyst A (5)
catalyst A (5)
catalyst A (5)
catalyst A (5)
DCE
9 h
92
94
93
93
93
94
91
96
95
96
97
96
7b
DCM
8 h
toluene
8 h
CH CN
32 h
19 h
2 h
3
THF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
c
IPrAuCl/AgSbF (5)
6
PPh AuCl/AgSbF (5)
36 h
15 min
0.5 h
3 min
10 min
1 h
3
6
IPrAuCl/AgOTs (5)
IPrAuCl/AgBF (5)
4
1
1
1
1
1
1
0
1
2
3
4
5
IPrAuCl/AgPF (5)
6
IPrAuCl/AgPF (2)
6
IPrAuCl/AgPF (1)
6
AgPF (5)
42 h
24 h
24 h
6
HNTf (10)
0c
2
Sc(OTf) (5)
0d
3
a
b
d
Isolated yields. 2a was recovered in 82% yield. 2a was recovered in 67% yield. 2a was
recovered in 93% yield.
6

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With an optimized set of conditions in hand (Table 1, entry 11), we focused our
attention on the preparative scope of the reaction. Gratifyingly, this reaction proved to be
quite general with respect to the substitution pattern on the pyrrole ring and the alkyne
terminus. In most cases, the desired indolizine products were obtained in high to excellent
yields (Table 2). We first investigated the effect of substituents on the alkyne terminus. In
the cases of aryl-substituted alkynes, various functional groups on the aryl ring are
compatible. For example, both electron-rich (p-OMe, p-NH ) aryl alkynes and electron
2
deficient (p-CF ) underwent the reaction smoothly, providing the corresponding products
3
3
b-3d in high yields of 86-94%. 2-Pyridyl and 2-thienyl groups were also tolerated well in
the reaction and afforded 3e-3f in 85-97% yields. In the case of pyridine-substituted
o
substrate, higher reaction temperature of 80 C was required in order to achieve a better
yield. Reaction of the cyclohexenyl-substituted 2g gave 3g in high yield of 94%.
Interestingly, substrate bearing an alkynyl substituent on the alkyne terminus proved to be
also suitable for the reaction, providing alkynyl indolizine 3h in 54% yield. The reactions
of alkyl-substituted alkynes such as n-butyl-, tert-butyl, or cyclopropyl-substituted ones
were also satisfactory, leading to 3i-3k in 80-96% yields. Terminal alkyne also worked but
with a prolonged time, and the desired product 3l was isolated in high yield of 90%.
Silyl-substituted substrates, such as TMS-substituted one transformed to 3m successfully
1
in 84% yield. The substrate bearing a methyl substituent as R gave 6-methylindolizine 3n
4
in 91% yield. The substrates bearing a methyl or a benzyl substituent as R gave 5, 6,
8
-tri-substituted indolizines 3o and 3p in 98% and 95% yields, respectively. Next, we
7

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anticipated that the use of substrates derived from functionalized pyrroles would enable the
incorporation of substituents on the pyrrole ring of indolizine scaffold. As for the pyrrole
moiety in pyrrole-yne 2, substrates derived from 2,4-dimethyl pyrrole and 2,3-diphenyl
pyrrole worked well to provide 3q-3r in 66-97% yields. Substrate bearing an
electron-withdrawing group such as a cyano group on the pyrrole moiety was also tolerated,
and the corresponding product of 3s was obtained in 93% yield. The reaction could also be
extended efficiently to a substrate derived from indole, in which pyrido[1,2-a]indole 3t
was obtained in 55% yield.
a
Table 2. Substrate Scope of the Gold-Catalyzed Indolizine Synthesis
8

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R3
DOI: 10.1039/C7OB02102J
R3
2
mol% IPrAuCl/AgPF6
DCM, rt
N
R2
N
R1
R1
HO
R2
R4
R4
2
3
OMe
NH2
CF3
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
3a, 10 min, 97%
3b, 10 min, 94%
3c, 30 min, 91%
3d, 10 min, 86%
3e, 1 h, 85%b
Ph
S
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
3f, 10 min, 97%
3g, 2 h, 94%
3h, 1 h, 54%
3i, 10 min, 90%
3j, 24 h, 80%
H
SiMe3
Ph
Ph
N
N
N
N
N
Ph
Ph
Ph
Ph
Me
3m, 24 h, 84%c
3n, 0.5 h, 91%b
3k, 10 min, 96%
3l, 36 h, 90%
3o, 1 h, 98%
Ph
Ph
Ph
Ph
Ph
N
Ph
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
CN
Ph
3s, 48 h, 93%d
3t, 5 h, 55%b
3p, 16 h, 95%
3q, 10 min, 66%
3r, 30 min, 97%
a
b
o
c
d
Isolated yields. 5 mol% IPrAuCl/AgPF , DCE, 80 C. 5 mol% IPrAuCl/AgSbF . 5
6
6
o
mol% IPrAuCl/AgPF , 40 C.
6
To explore the potential synthetic utility of the methodology, further derivatization of
indolizine products 3 were carried out (Scheme 3). For examples, 3a could be alkenylated
1
5
at its C3-position regioselectively via gold-catalyzed hydroarylation of alkyne to produce
1
6
4
in 65% yield. CuI-catalyzed C3 thioetherfication of 3a using 1,2-diphenyldisulfane as
the reactant afforded 5 in 72% yield. Gold(I)-catalyzed alkynylation of 3a with an alkynyl
9

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1
7
DOI: 10.1039/C7OB02102J
hypervalent iodine reagent provided C3-alkynylated indolizine 6 in 78% yield. In
1
8
addition, palladium-catalyzed alkynylation of 3a with alkynyl bromide afforded
3
-alkynyl substituted indolizine 7a and 7b in 48-56% yields. The structure of 7b was
1
9
unambiguously confirmed by X-ray crystallographic analysis.
Scheme 3. Functionalization of Indolizine 3a
Ph
Ph
1.2 equiv Ar
PhS SPh
5
mol% PPh AuNTf
10 mol% CuI, DMSO
3
2
N
o
o
N
toluene, 80 C, 2 h
Ar = 4-MeOC6H4
110 C, 12 h
Ph
Ph
Ph
SPh
Ar
4, 65%
5, 72%
N
i
Pr Si
3
I
O
Ph
1
.5 equiv Ar
Br
3a
Ph
Ph
N
O
5
3 2
mol% Pd(PPh ) Cl2
(
1.2 equiv)
2
equiv KOAc
N
o
toluene, 80 C
Ph
5 mol% AuCl, Et2O, rt, 2 h
Ph
6, 78%
7a, Ar = 4-MeOC6H4, 15 h, 56%
7b, Ar = 3,4,5-(MeO) C H , 18 h, 48%
i
SiPr
Ar
3
3
6 2
2
0
A possible reaction mechanism for the present Au(I)-catalyzed indolizine synthesis is
illustrated in Scheme 4. Initially, the propargylic alcohol was activated by gold catalyst
through coordination, this is followed by regioselective intramolecular hydroarylation of
the alkyne with the pyrrole moiety to afford the vinylgold intermediate 9. Protodeauration
2
1
of 9 followed by elimination of water leads to the final product 3.
Scheme 4. Proposed Reaction Mechanism
1
0

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R3
R3
LAu+
N
N
R1
HO
R1
R4
R4
2
+ H O
2
3
R3
R3
H
N
LAu
R1
LAu+
+
N
R1
HO
HO
R4
R4
9
8
CONCLUSION
In summary, we have developed an efficient method for the synthesis of
multi-substituted indolizines based on gold-catalyzed intramolecular
hydroarylation/aromatization of pyrrole-ynes. The method allows for accessing indolizines
with or without functional groups on its pyrrole ring. In addition, a wide variety of the
functional groups, such as aryl, alkenyl, alkynyl, pyridyl or thienyl groups can also be
easily incorporated into the pyridine unit of the indolizine products. The utility of
indolizine products was demonstrated by their efficient transformations into various
3
-functionalized indolizine derivatives.
EXPERIMENTAL SECTION
General Methods. All reactions were carried out using standard Schlenk technique under
Argon unless noted. DCM and DCE were distilled from CaH . Toluene and THF were
2
distilled from sodium and benzophenone. MeCN and THF (for the synthesis of starting
materials) were dried using Innovative Technology Solvent Purifier. Unless noted, all
11

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2
DOI: 10.1039/C7OB02102J
commercial reagents were used without further purification. Ph PAuCl was prepared
3
according
Acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoroantimonate (catalyst
A), 1,3-Bis(2,6-di-isopropylphenyl)-imidazole-2-ylidenegold(I) chloride and AgSbF were
to
the
published
method.
(
6
1
13
purchased from Chemical Company. H and C NMR spectra were recorded on 400 MHz
1
NMR spectrometer. H NMR spectra was recorded with tetramethylsilane (δ = 0.00 ppm)
1
3
as an internal reference; C NMR spectra was recorded with CDCl (δ = 77.00 ppm) or
3
C D (δ = 128.06 ppm) as an internal reference. High-resolution mass spectra was
6
6
performed on a mass spectrometer with a TOF analyzer. Melting points were measured
using a SGW-4 microscopic melting point apparatus.
Synthesis of -(N-pyrrolyl)ketones 1a-1d.
Typical procedure for the synthesis of 1-phenyl-2-(1H-pyrrol-1-yl)ethan-1-one (1a).
Under argon, to a Schlenk tube were added DMSO (60 mL), pyrrole (4.04 mL, 58.2 mmol)
and KOH (4.35 g, 77.6 mmol). The resulting mixture was stirred at room temperature for 1
h. Then, 1-bromo-2,4-diphenylbut-3-yn-2-ol (5.84 g, 19.4 mmol) in DMSO (10 mL) was
added dropwise. The reaction mixture was stirred at room temperature for another 10 h.
Then the mixture was quenched with water, extracted with ethyl acetate, washed with brine
and dried over anhydrous Na SO . The solvent was evaporated under the reduced pressure
2
4
and the residue was purified by column chromatography on silica gel (eluent: petroleum
1
ether: dichloromethane = 2:1) to afford 1a (3.11 g, 87% yield) as a light yellow solid. H
NMR (400 MHz, CDCl ) δ 7.96-7.93 (m, 2H), 7.64-7.59 (m, 1H), 7.51-7.47 (m, 2H), 6.66
3
1
2

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DOI: 10.1039/C7OB02102J
(
t, J = 2.4 Hz, 2H), 6.24 (t, J = 2.4 Hz, 2H), 5.29 (s, 2H); C NMR (100 MHz, CDCl ) δ
3
1
93.3, 134.6, 133.9, 128.9, 127.9, 121.9, 109.0, 55.3. The spectroscopic data is in
1
2a
agreement with that previously reported. In another experiment, phenylacetylene was
detected as a by-product through analyzing the crude reaction mixture by NMR, which
revealed that the alkynyl group was eliminated to furnish a ketone functionality in the
reaction.
2
-(2,4-Dimethyl-1H-pyrrol-1-yl)-1-phenylethan-1-one (1b). 8 mmol scale. 3.0 equiv of
,4-dimethyl-1H-pyrrole (24.0 mmol, 2.28 g) and 4.0 equiv of KOH were used. Column
2
chromatography on silica gel (eluent: petroleum ether: ethyl acetate: dichloromethane =
1
3
0:1:3) afforded the title product in 65% yield (1.11 g) as a light yellow solid. H NMR
(
400 MHz, CDCl ) δ 7.96-7.94 (m, 2H), 7.63-7.59 (m, 1H), 7.51-7.47 (m, 2H), 6.31 (s,
3
1
3
1
1
H), 5.82 (s, 1H), 5.14 (s, 2H), 2.08 (s, 6H); C NMR (100 MHz, CDCl ) δ 193.7, 134.6,
3
33.8, 128.9, 128.8, 127.8, 118.7, 118.1, 109.0, 52.6, 11.8, 11.7. The spectroscopic data is
9
in agreement with that previously reported.
2
-(2,3-Diphenyl-1H-pyrrol-1-yl)-1-phenylethan-1-one (1c). 6 mmol scale. 1.5 equiv of
of 2,3-diphenyl-1H-pyrrole and 2 equiv of KOH (12 mmol, 673 mg) were used. Column
chromatography on silica gel (eluent: petroleum ether: dichloromethane = 4:1 to 3:1)
1
afforded the title product in 81% yield (1.64 g) as a white solid. H NMR (400 MHz,
CDCl ) δ 7.78-7.76 (m, 2H), 7.55-7.51 (m, 1H), 7.40-7.37 (m, 2H), 7.27-7.17 (m, 7H),
3
7
.15-7.12 (m, 2H), 7.07-7.03 (m, 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H),
1
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3
DOI: 10.1039/C7OB02102J
5
1
.14 (s, 2H); C NMR (100 MHz, CDCl ) δ 193.9, 136.3, 134.5, 133.7, 132.3, 130.9,
3
30.8, 128.7, 128.6, 127.9, 127.81, 127.77, 127.6, 125.0, 122.8, 122.3, 108.9, 53.1. The
9
spectroscopic data is in agreement with that previously reported.
2
-(1H-Indol-1-yl)-1-phenylethan-1-one (1d). 8 mmol scale. 1.0 equiv of indole and 2
equiv of KOH were used. Column chromatography on silica gel (eluent: petroleum ether:
ethyl acetate: dichloromethane = 30:1:10) afforded the title product in 78% yield (1.47 g)
o
1
as a white solid. M.p. 124-125 C. H NMR (400 MHz, CDCl ) δ 7.88-7.86 (m, 2H),
3
7
3
1
.65-7.62 (m, 1H), 7.57-7.53 (m, 1H), 7.43-7.39 (m, 2H), 7.16-7.07 (m, 3H), 6.97 (d, J =
1
3
.2 Hz, 1H), 6.56 (d, J = 3.2 Hz, 1H), 5.27 (s, 2H); C NMR (100 MHz, CDCl ) δ 193.1,
3
36.5, 134.5, 133.8, 128.8, 128.7, 128.5, 127.9, 121.8, 121.0, 119.6, 108.9, 102.2, 52.0; IR
(neat): 3048, 2920, 1692, 1512, 1483, 1464, 1449, 1324, 1224, 1002, 983, 755, 740, 724,
-1
+
6
88, 660 cm ; HRMS (ESI) calcd for C H NO [M+H] : 236.1070, found 236.1069.
16 14
Synthesis of α-(N-pyrrolyl)ketones 1e and 1f.
Typical procedure for the synthesis of 1-phenyl-2-(1H-pyrrol-1-yl)propan-1-one (1e).
o
Under argon, 1a (1.11 g, 6.0 mmol) was added to a stirred and cooled (0 C) suspension of
sodium hydride (60% w/w in mineral oil, 360 mg, 9.0 mmol) in THF (25 mL). After 30
min, the iodomethane (560 μL, 9.0 mmol) was added slowly and the reaction mixture was
o
kept at 0 C for 1 h. Thereafter, the reaction mixture was quenched with saturated NH Cl
4
aqueous solution. The product was extracted with ethyl acetate, washed with brine, dried
over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
2
4
1
4

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residue was purified by column chromatography on silica gel (eluent: petroleum ether:
1
ethyl acetate = 30:1) to afford 1e in 77% yield (0.918 g) as a light yellow liquid. H NMR
(
400 MHz, CDCl ) δ 7.90-7.88 (m, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H),
3
6
.75 (t, J = 2.0 Hz, 2H), 6.18 (t, J = 2.0 Hz, 2H), 5.64 (q, J = 6.8 Hz, 1H), 1.73 (d, J = 7.2
1
3
Hz, 3H); C NMR (100 MHz, CDCl ) δ 196.1, 134.9, 133.5, 128.8, 128.4, 119.7, 108.9,
3
5
1
9
2
8.2, 18.6; IR (neat): 3099, 3064, 2989, 2935, 1678, 1595, 1490, 1446, 1391, 1374, 1341,
306, 1293, 1272, 1240, 1214, 1183, 1159, 1114, 1096, 1069, 1050, 1014, 1001, 983, 963,
-1
+
34, 809, 760, 723, 683, 659, 626 cm ; HRMS (ESI) calcd for C H NO [M+H] :
1
3
14
00.1070, found 200.1071.
1
,3-Diphenyl-2-(1H-pyrrol-1-yl)propan-1-one (1f). 6 mmol scale. Benzyl bromide was
used. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 40:1)
1
afforded the title product in 87% yield (1.43 g) as a colorless oil. H NMR (400 MHz,
CDCl ) δ 7.85-7.83 (m, 2H), 7.48-7.44 (m, 1H), 7.36-7.32 (m, 2H), 7.21-7.13 (m, 3H),
3
6
1
1
2
.98-6.95 (m, 2H), 6.65-6.63 (m, 2H), 6.11-6.09 (m, 2H), 5.57-5.54 (m, 1H), 3.46-3.41 (m,
1
3
H), 3.29-3.23 (m, 1H); C NMR (100 MHz, CDCl ) δ 194.9, 137.1, 135.2, 133.5, 128.9,
3
28.6, 128.4, 128.3, 126.7, 119.8, 109.0, 64.0, 39.0; IR (neat): 3082, 3062, 3026, 2961,
927, 1681, 1597, 1580, 1538, 1486, 1450, 1402, 1349, 1304, 1288, 1274, 1256, 1203,
1173, 1094, 1069, 1029, 1003, 989, 969, 930, 869, 801, 769, 756, 715, 696, 683, 665, 627
-1
+
cm ; HRMS (ESI) calcd for C H NO [M+H] : 276.1383, found 276.1384.
1
9
18
Synthesis of 1-(2-oxo-2-phenylethyl)-1H-pyrrole-2-carbonitrile (1g). Under argon, to a
1
5

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Schlenk tube were added 1H-pyrrole-2-carbonitrile (461 mg,
5
mmol),
2
-bromo-1-phenylethan-1-one (1.19 g, 6 mmol), K CO (1.04 g, 7.5 mmol) and CH CN
2 3 3
(25 mL) sequentially. The resulting mixture was stirred at room temperature for 20.5 h.
Then, the mixture was filtered through a pad of celite, concentrated under reduced pressure,
diluted with ethyl acetate, washed with brine and dried over anhydrous Na SO . The
2
4
solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: dichloromethane = 3:2) to afford 1g
o
1
(
0.933 g, 89% yield) as a yellow solid. M.p. 97-98 C. H NMR (400 MHz, CDCl ) δ 7.95
3
(d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 3.2 Hz,
1
3
2
1
2
H), 6.26 (t, J = 3.2 Hz, 1H), 5.46 (s, 2H); C NMR (100 MHz, CDCl ) δ 191.4, 134.3,
3
33.8, 128.9, 128.0, 127.9, 120.3, 113.4, 110.0, 104.7, 54.0; IR (neat): 3132, 3119, 2928,
853, 2216, 2163, 1698, 1595, 1581, 1528, 1468, 1448, 1433, 1406, 1352, 1322, 1224,
-1
1
155, 1077, 1024, 994, 923, 881, 833, 812, 755, 731, 688, 655, 631 cm ; HRMS (ESI)
+
calcd for C H N O [M+H] : 211.0866, found 211.0866.
1
3
11
2
Synthesis of pyrrole-ynes 2a-2b, 2g, 2i-2k, 2m and 2o-2t.
Typical procedure for the synthesis of 2,4-diphenyl-1-(1H-pyrrol-1-yl)but-3-yn-2-ol
(2a). Under argon, to a solution of phenylacetylene (1.81 mL, 16.5 mmol) in THF (30 mL)
o
was added n-BuLi (6 mL, 15 mmol, 2.5 M in hexane) at 0 C. After stirring at the same
temperature for 1 h, 1a (926 mg, 5 mmol) was added, and the reaction mixture was
warmed up to room temperature and stirred for 1 h. Then, the resulting mixture was
quenched with saturated NH Cl solution, extracted with ethyl acetate, washed with brine,
4
1
6

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and dried over anhydrous Na SO . The solvent was evaporated under the reduced pressure
2
4
and the residue was purified by column chromatography on silica gel (eluent: petroleum
ether: dichloromethane= 4:1 to 1:1) to afford 2a in 81% isolated yield (1.16 g) as a light
1
yellow oil. H NMR (400 MHz, CDCl ) δ 7.65-7.62 (m, 2H), 7.46-7.43 (m, 2H), 7.40-7.28
3
(m, 6H), 6.71 (t, J = 2.0 Hz, 2H), 6.14 (t, J = 2.0 Hz, 2H), 4.24-4.15 (m, 2H), 2.76 (s, 1H);
1
3
C NMR (100 MHz, CDCl ) δ 141.3, 131.7, 128.8, 128.4, 128.32, 128.31, 125.6, 122.4,
3
1
1
7
21.9, 108.1, 89.2, 87.4, 73.4, 61.9; IR (neat): 3534, 3451, 3060, 2940, 2230, 1956, 1683,
598, 1573, 1491, 1448, 1396, 1287, 1265, 1172, 1090, 1072, 1027, 998, 971, 916, 815,
-1
+
56, 723, 689 cm ; HRMS (ESI) calcd for C H NO [M+H] : 288.1383, found 288.1381.
2
0
18
4
-(4-Methoxyphenyl)-2-phenyl-1-(1H-pyrrol-1-yl)but-3-yn-2-ol (2b). 4 mmol scale.
Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 30:1 to 10:1)
1
afforded the title product in 93% yield (1.18 g) as a light yellow oil. H NMR (400 MHz,
CDCl ) δ 7.65 (d, J = 6.8 Hz, 2 H), 7.40-7.34 (m, 5 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.72 (t, J
3
=
2.0 Hz, 2 H), 6.14 (t, J = 2.0 Hz, 2 H), 4.24-4.16 (m, 2 H), 3.80 (s, 3 H), 2.77 (s, 1 H);
1
3
C NMR (100 MHz, CDCl ) δ 159.9, 141.5, 133.2, 128.3, 128.2, 125.7, 122.4, 114.0,
3
113.9, 108.0, 87.9, 87.4, 73.5, 62.0, 55.3; IR (neat): 3458, 2937, 2837, 2227, 1605, 1570,
1
7
508, 1495, 1448, 1288, 1246, 1172, 1107, 1090, 1072, 1057, 1027, 972, 917, 831, 773,
-1
+
23, 697 cm ; HRMS (ESI) calcd for C H NO [M+H] : 318.1489, found 318.1487.
2
1
20
2
4
-(Cyclohex-1-en-1-yl)-2-phenyl-1-(1H-pyrrol-1-yl)but-3-yn-2-ol (2g). 4 mmol scale.
Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1)
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7

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1
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afforded the title product in 91% yield (1.06 g) as a light yellow oil. H NMR (400 MHz,
CDCl ) δ 7.57-7.55 (m, 2H), 7.37-7.28 (m, 3H), 6.64 (t, J = 2.4 Hz, 2H), 6.16-6.14 (m, 1H),
3
6
4
8
2
1
.10 (t, J = 2.4 Hz, 2H), 4.15-4.07 (m, 2H), 2.61 (s, 1H), 2.14-2.08 (m, 4H), 1.66-1.56 (m,
1
3
H); C NMR (100 MHz, CDCl ) δ 141.6, 136.1, 128.2, 128.1, 125.6, 122.4, 119.7, 107.8,
3
9.3, 86.5, 73.3, 62.0, 28.8, 25.6, 22.1, 21.3; IR (neat): 3454, 3060, 3028, 2929, 2858,
832, 2217, 1678, 1601, 1547, 1494, 1448, 1435, 1397, 1346, 1288, 1240, 1172, 1137,
-1
090, 1072, 1057, 1016, 971, 918, 842, 800, 786, 766, 722, 697, 643, 631, 614 cm ;
+
HRMS (ESI) calcd for C H NO [M+H] : 292.1696, found 292.1697.
2
0
22
2
-Phenyl-1-(1H-pyrrol-1-yl)oct-3-yn-2-ol (2i). 4 mmol scale. Column chromatography
on silica gel (eluent: petroleum ether: ethyl acetate = 25:1) afforded the title product in
1
9
7
2
1% yield (0.972 g) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.57-7.55 (m, 2H),
3
.37-7.30 (m, 3H), 6.63 (t, J = 2.4 Hz, 2H), 6.10 (t, J = 2.4 Hz, 2H), 4.13-4.05 (m, 2H),
.54 (s, 1H), 2.26 (t, J = 6.8 Hz, 2H), 1.55-1.49 (m, 2H), 1.44-1.38 (m, 2H), 0.92 (t, J = 7.2
13
Hz, 3H); C NMR (100 MHz, CDCl ) δ 141.9, 128.2, 128.1, 125.6, 122.3, 107.8, 88.5,
3
8
1
1
0.5, 73.0, 62.0, 30.4, 22.0, 18.4, 13.5; IR (neat): 3459, 3061, 2957, 2932, 2861, 2237,
683, 1601, 1548, 1495, 1449, 1430, 1379, 1327, 1288, 1235, 1173, 1142, 1090, 1071,
-1
050, 1031, 1003, 971, 927, 887, 820, 769, 722, 698, 671 cm ; HRMS (ESI) calcd for
+
C H NO [M+H] : 268.1696, found 268.1695.
18
22
5
,5-Dimethyl-2-phenyl-1-(1H-pyrrol-1-yl)hex-3-yn-2-ol (2j). 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) afforded the
1
8

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1
DOI: 10.1039/C7OB02102J
title product in 88% yield (0.941 g) as a colorless oil. H NMR (400 MHz, CDCl ) δ
3
7
4
1
2
1
.57-7.54 (m, 2H), 7.37-7.30 (m, 3H), 6.63 (t, J = 2.0 Hz, 2H), 6.09 (t, J = 2.0 Hz, 2H),
1
3
.06 (s, 2H), 2.53 (s, 1H), 1.25 (s, 9H); C NMR (100 MHz, CDCl ) δ 141.9, 128.2, 128.0,
3
25.7, 122.4, 107.7, 96.4, 79.1, 72.9, 62.1, 30.7, 27.4; IR (neat): 3464, 3062, 2968, 2867,
247, 1686, 1602, 1548, 1495, 1475, 1448, 1393, 1362, 1288, 1265, 1205, 1172, 1118,
-1
090, 1070, 1030, 1003, 973, 923, 873, 840, 778, 721, 697 cm ; HRMS (ESI) calcd for
+
C H NO [M+H] : 268.1696, found 268.1699.
18
22
4
-Cyclopropyl-2-phenyl-1-(1H-pyrrol-1-yl)but-3-yn-2-ol (2k). 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: dichloromethane = 3:1 to 1:1)
1
afforded the title product in 92% yield (0.923 g) as a colorless oil. H NMR (400 MHz,
CDCl ) δ 7.57-7.54 (m, 2H), 7.38-7.29 (m, 3H), 6.63 (t, J = 2.0 Hz, 2H), 6.12-6.11 (m, 2H),
3
4
.12-4.04 (m, 2H), 2.49 (s, 1H), 1.33-1.26 (m, 1H), 0.84-0.77 (m, 2H), 0.77-0.68 (m, 2H);
1
3
C NMR (100 MHz, CDCl ) δ 141.8, 128.2, 128.1, 125.6, 122.3, 107.9, 91.5, 75.6, 73.0,
3
6
1
9
2
2.1, 8.22, 8.19, -0.6; IR (neat): 3455, 3089, 3010, 2939, 2239, 1955, 1891, 1810, 1682,
601, 1546, 1495, 1449, 1429, 1397, 1361, 1287, 1174, 1090, 1072, 1056, 1029, 1003, 968,
-1
+
30, 890, 868, 813, 768, 723, 697, 665 cm ; HRMS (ESI) calcd for C H NO [M+H] :
1
7
18
52.1383, found 252.1383.
2
-Phenyl-1-(1H-pyrrol-1-yl)-4-(trimethylsilyl)but-3-yn-2-ol (2m). 4 mmol scale.
Column chromatography on silica gel (eluent: petroleum ether: dichloromethane = 40:1 to
1
2
0:1) afforded the title product in 89% yield (1.01 g) as a colorless oil. H NMR (400 MHz,
1
9

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CDCl ) δ 7.57-7.54 (m, 2H), 7.39-7.32 (m, 3H), 6.64 (t, J = 2.0 Hz, 2H), 6.10 (t, J = 2.0 Hz,
3
1
3
2
H), 4.16-4.06 (m, 2H), 2.57 (s, 1H), 0.21 (s, 9H); C NMR (100 MHz, CDCl ) δ 141.0,
3
1
28.32, 128.28, 125.6, 122.4, 108.0, 105.4, 92.7, 73.2, 61.9, -0.3; IR (neat): 3450, 2959,
899, 2169, 1495, 1449, 1288, 1250, 1174, 1090, 1073, 1028, 973, 918, 902, 840, 789, 760,
2
-1
+
7
20, 697, 645, 632, 612 cm ; HRMS (ESI) calcd for C H NOSi [M+H] : 284.1465,
17 22
found 284.1467.
1
,3-Diphenyl-4-(1H-pyrrol-1-yl)pent-1-yn-3-ol (2o). 4.605 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 30:1) afforded the
title product in 95% yield (1.32 g) as a mixture of two diastereoisomers in a ratio of 3.9:1
1
as a light yellow oil. H NMR (400 MHz, CDCl ) two isomers: δ 7.66-7.63 (m), 7.50-7.46
3
(
m), 7.43-7.40 (m), 7.34-7.22 (m), 6.84 (t, J = 2.0 Hz, major isomer), 6.56 (t, J = 2.0 Hz,
minor isomer), 6.14 (t, J = 2.0 Hz, major isomer), 6.01 (t, J = 2.0 Hz, minor isomer),
.28-4.22 (m), 2.78 (s, major isomer), 2.73 (s, minor isomer), 1.55 (d, J = 6.8 Hz, minor
4
1
3
isomer), 1.44 (d, J = 6.8 Hz, major isomer); C NMR (100 MHz, CDCl ) two isomers: δ
3
1
1
1
1
41.6, 141.1, 131.59, 131.56, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 127.8, 126.2, 125.7,
21.98, 121.96, 120.7, 120.3, 107.6, 107.0, 89.5, 88.33, 88.28, 87.2, 76.8, 76.2, 65.1, 64.3,
6.5, 15.8; IR (neat): 3543, 3451, 3060, 3031, 2985, 2940, 2225, 1598, 1487, 1447, 1408,
376, 1341, 1302, 1272, 1174, 1092, 1070, 1028, 971, 944, 927, 756, 722, 690, 647, 627
-1
+
cm ; HRMS (ESI) calcd for C H NO [M+H] : 302.1539, found 302.1540.
2
1
20
1
,3,5-Triphenyl-4-(1H-pyrrol-1-yl)pent-1-yn-3-ol (2p). 4.82 mmol scale. Column
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0

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chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 30:1) afforded the
title product in 94% yield (1.71 g) as a mixture of two diastereoisomers in a ratio of 10:1 as
1
a yellow oil. Major isomer: H NMR (400 MHz, CDCl ): δ 7.72-7.70 (m, 2H), 7.57-7.52
3
(m, 2H), 7.37-7.28 (m, 6H), 7.09-7.04 (m, 3H), 6.78 (t, J = 2.0 Hz, 2H), 6.75-6.72 (m, 2H),
6
1
1
.07 (t, J = 2.0 Hz, 2H), 4.28-4.24 (m, 1H), 3.34-3.28 (m, 1H), 3.16-3.12 (m, 1H), 2.81 (s,
1
3
H); C NMR (100 MHz, CDCl ): δ 141.2, 138.0, 131.65, 128.9, 128.4, 128.3, 128.25,
3
28.18, 128.1, 126.31, 126.26, 121.9, 121.1, 108.0, 88.8, 88.7, 76.4, 72.3, 36.7; Minor
1
isomer: H NMR (400 MHz, CDCl ): δ 7.51-7.49 (m, 2H), 7.46-7.44 (m, 2H), 7.25-7.23
3
(m, 3H), 6.88-6.86 (m, 2H), 6.55 (t, J = 2.0 Hz, 2H), 5.95 (t, J = 2.0 Hz, 2H), 4.23-4.20 (m,
1
H), 3.46-3.41 (m, 1H), 2.85 (s, 3H), other peaks are overlapped with the signals of the
1
3
major isomer; C NMR (100 MHz, CDCl ): δ 141.9, 138.4, 131.71, 128.8, 128.5, 128.0,
3
1
27.9, 126.2, 125.6, 120.5, 107.4, 89.3, 87.6, 76.1, 71.5, 36.1, other peaks are overlapped
with the signals of the major isomer; IR (neat), two isomers: 3541, 3442, 3061, 3028, 2936,
2
227, 1952, 1885, 1806, 1600, 1487, 1448, 1409, 1306, 1278, 1173, 1091, 1070, 1030, 920,
-1
+
8
46, 754, 724, 690, 648, 628 cm ; HRMS (ESI) calcd for C H NO [M+H] : 378.1852,
27 24
found 378.1852.
1
-(2,4-Dimethyl-1H-pyrrol-1-yl)-2,4-diphenylbut-3-yn-2-ol (2q). 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) afforded the
1
title product in 88% yield (1.11 g) as a light yellow oil. H NMR (400 MHz, CDCl ) δ
3
7
4
.66-7.64 (m, 2H), 7.47-7.44 (m, 2H), 7.41-7.29 (m, 6H), 6.57 (s, 1H), 5.71 (s, 1H),
1
3
.13-4.02 (m, 2H), 2.82 (s, 1H), 2.06 (s, 6H); C NMR (100 MHz, CDCl ) δ 141.7, 131.7,
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1
5
1
7
29.7, 128.8, 128.4, 128.33, 128.27, 125.7, 122.1, 119.3, 117.6, 108.5, 89.8, 87.3, 73.7,
8.0, 12.0, 11.9; IR (neat): 3414, 3060, 3031, 2933, 2861, 2230, 1683, 1598, 1517, 1490,
446, 1410, 1386, 1337, 1277, 1202, 1176, 1145, 1092, 1061, 1026, 1000, 917, 846, 821,
-1
+
55, 690, 627 cm ; HRMS (ESI) calcd for C H NO [M+H] : 316.1696, found 316.1698.
2
2
22
1
-(2,3-Diphenyl-1H-pyrrol-1-yl)-2,4-diphenylbut-3-yn-2-ol (2r). 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) afforded the
1
title product in 75% yield (1.32 g) as a light yellow oil. H NMR (400 MHz, CDCl ) δ
3
7
2
1
1
2
1
.44-7.40 (m, 4H), 7.33-7.17 (m, 10H), 7.12-7.09 (m, 4H), 7.06-7.00 (m, 3H), 6.48 (d, J =
1
3
.8 Hz, 1H), 4.26-4.17 (m, 2H), 2.70 (s, 1H); C NMR (100 MHz, CDCl ) δ 141.6, 136.5,
3
32.4, 131.8, 131.6, 131.5, 128.8, 128.3, 128.24, 128.22, 127.9, 127.7, 127.4, 125.6, 124.9,
22.5, 122.3, 121.9, 108.3, 89.7, 87.5, 73.7, 57.5; IR (neat): 3527, 3453, 3057, 3030, 2932,
226, 1885, 1810, 1677, 1600, 1574, 1503, 1490, 1472, 1446, 1421, 1390, 1344, 1270,
-1
206, 1176, 1094, 1068, 1025, 916, 843, 782, 756, 731, 690, 640 cm ; HRMS (ESI) calcd
+
for C H NO [M+H] : 440.2009, found 440.2009.
3
2
26
1
-(2-Hydroxy-2,4-diphenylbut-3-yn-1-yl)-1H-pyrrole-2-carbonitrile (2s). 4 mmol scale.
Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1)
1
afforded the title product in 81% yield (1.01 g) as a light yellow oil. H NMR (400 MHz,
CDCl ) δ 7.67-7.64 (m, 2H), 7.50-7.47 (m, 2H), 7.43-7.31 (m, 6H), 6.96-6.95 (m, 1H),
3
1
3
6
.77-6.76 (m, 1H), 6.17-6.16 (m, 1H), 4.42-4.33 (m, 2H), 2.76 (s, 1H); C NMR (100
MHz, CDCl ) δ 140.8, 131.8, 129.0, 128.8, 128.6, 128.4, 128.0, 125.7, 121.5, 119.7, 113.8,
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1
1
1
09.3, 105.6, 88.2, 88.0, 73.4, 59.9; IR (neat): 3375, 3051, 3032, 2953, 2227, 1599, 1528,
489, 1464, 1442, 1406, 1332, 1308, 1263, 1244, 1218, 1190, 1147, 1098, 1072, 1062,
-1
041, 1004, 917, 896, 885, 813, 799, 756, 732, 706, 690, 665, 642, 613 cm ; HRMS (ESI)
+
calcd for C H N O [M+NH ] : 330.1601, found 330.1602.
2
1
20
3
4
1
-(1H-Indol-1-yl)-2,4-diphenylbut-3-yn-2-ol
(2t).
4
mmol
scale.
Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 50:1 to 30:1)
1
afforded the title product in 82% yield (1.11 g) as a light yellow oil. H NMR (400 MHz,
CDCl ) δ 7.69-7.66 (m, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.42-7.21 (m, 9H), 7.17-7.05 (m,
3
1
3
3
1
1
2
1
6
H), 6.49 (d, J = 3.6 Hz, 1H), 4.45 (s, 2H), 2.72 (s, 1H); C NMR (100 MHz, CDCl ) δ
3
41.5, 137.2, 131.7, 129.4, 128.8, 128.44, 128.40, 128.23, 128.21, 125.7, 121.8, 121.5,
20.6, 119.4, 110.2, 101.7, 89.3, 87.6, 74.2, 58.5; IR (neat): 3520, 3055, 3031, 2935, 2230,
199, 1953, 1885, 1674, 1611, 1598, 1514, 1488, 1461, 1447, 1397, 1335, 1313, 1254,
205, 1173, 1128, 1100, 1088, 1068, 1012, 917, 882, 844, 818, 756, 737, 690, 658, 637,
-1
+
18 cm ; HRMS (ESI) calcd for C H NO [M+H] : 338.1539, found 338.1540.
2
4
20
Synthesis of 2-phenyl-1-(1H-pyrrol-1-yl)but-3-yn-2-ol (2l). Under argon, to a solution of
ethynyltrimethylsilane (4.66 mL, 33 mmol) in THF (30 mL) was added n-BuLi (12 mL, 30
o
mmol, 2.5 M in hexane) at 0 C. After stirring at the same temperature for 1 h, 1a (1.85 g,
1
0 mmol) was added, and the reaction mixture was warmed up to room temperature and
stirred for 1 h. Then, the resulting mixture was quenched with saturated NH Cl solution,
4
extracted with ethyl acetate, washed with brine, and dried over anhydrous Na SO . The
2
4
2
3

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solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1) to afford 2m as
a crude product.
Under air, to a solution of the above crude 2m in MeOH (30 mL) was added K CO
2
3
(829 mg, 6 mmol). The resulting suspension was stirred under room temperature for 11 h.
Then, the mixture was quenched with saturated NH Cl solution, extracted with ethyl
4
acetate, washed with brine and dried over anhydrous Na SO . The solvent was evaporated
2
4
under the reduced pressure and the residue was purified by column chromatography on
silica gel (eluent: petroleum ether: ethyl acetate = 20:1 to 10:1) to afford 2l (1.825 g, 86%
1
yield) as a colorless oil. H NMR (400 MHz, CDCl ) δ 7.56-7.52 (m, 2H), 7.37-7.29 (m,
3
3
H), 6.62 (t, J = 2.0 Hz, 2H), 6.09 (t, J = 2.0 Hz, 2H), 4.16-4.06 (m, 2H), 2.70 (s, 1H), 2.67
13
(
s, 1H); C NMR (100 MHz, CDCl ) δ 140.7, 128.4, 128.3, 125.5, 122.4, 108.1, 84.1, 75.9,
3
7
1
2.8, 61.5; IR (neat): 3305, 3267, 2114, 1499, 1439, 1387, 1345, 1288, 1250, 1178, 1098,
-1
076, 1017, 973, 916, 873, 774, 752, 730, 704, 694, 665, 631 cm ; HRMS (EI) calcd for
+
C H NO [M] : 211.0997, found 211.1006.
14
13
Synthesis of pyrrole-ynes 2c-2f.
Typical procedure
-(4-aminophenyl)-2-phenyl-1-(1H-pyrrol-1-yl)but-3-yn-2-ol (2c). Under argon, to a
for
the
synthesis
of
4
solution of 2l (845 mg, 4 mmol) and 4-iodoaniline (1.05 g, 4.8 mmol) in triethylamine (20
mL) were added CuI (38.1 mg, 0.2 mmol) and Pd(PPh ) Cl (56.2 mg, 0.08 mmol). The
3
2
2
o
resulting suspension was stirred under 50 C for 3 h. Then, the mixture was filtered through
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4

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a pad of celite, diluted with ethyl acetate, washed with brine, and dried over anhydrous
Na SO . The solvent was evaporated under the reduced pressure and the residue was
2
4
purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =
1
3
:1 to 2:1) to afford 2c (0.898 g, 74% yield) as a light yellow solid. H NMR (400 MHz,
CDCl ) δ 7.63 (d, J = 7.6 Hz, 2H), 7.38-7.30 (m, 3H), 7.16 (d, J = 8.4 Hz, 2H), 6.73 (s,
3
1
3
2
H), 6.52 (d, J = 8.4 Hz, 2H), 6.14 (s, 2H), 4.21-4.11 (m, 2H), 3.56 (bs, 3H); C NMR
(
100 MHz, CDCl ) δ 146.8, 141.8, 133.0, 128.3, 128.1, 125.7, 122.5, 114.9, 111.4, 107.9,
3
8
1
9
8.0, 87.2, 73.3, 62.1; IR (neat): 3462, 3372, 3216, 3059, 3033, 2940, 2222, 1891, 1619,
606, 1513, 1494, 1448, 1431, 1397, 1286, 1215, 1175, 1128, 1090, 1072, 1057, 1027, 972,
-1
38, 912, 829, 768, 723, 697, 657, 642, 628, 609 cm ; HRMS (ESI) calcd for C H N O
2
0
19
2
+
[
M+H] : 303.1492, found 303.1494.
2
-Phenyl-1-(1H-pyrrol-1-yl)-4-(4-(trifluoromethyl)phenyl)but-3-yn-2-ol (2d). 4 mmol
scale. Column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1)
1
afforded the title product in 92% yield (1.31 g) as a colorless oil. H NMR (400 MHz,
CDCl ) δ 7.62-7.59 (m, 2H), 7.55-7.48 (m, 4H), 7.39-7.31 (m, 3H), 6.68 (t, J = 2.0 Hz, 2H),
3
1
3
6
1
1
.13 (t, J = 2.0 Hz, 2H), 4.22-4.13 (m, 2H), 2.94 (s, 1H); C NMR (100 MHz, CDCl ) δ
3
2
5
40.8, 131.9, 130.4 (q, J = 32.1 Hz), 128.5, 128.4, 125.7 (q, J = 1.5 Hz), 125.5,
C-F
C-F
3
1
25.2 (q, J = 3.8 Hz), 123.7 (q, J = 271.6 Hz), 122.4, 108.2, 91.6, 86.0, 73.5, 61.8;
C-F
C-F
IR (neat): 3443, 3062, 2941, 1614, 1494, 1450, 1404, 1320, 1288, 1166, 1124, 1105, 1090,
-1
1
066, 1015, 972, 917, 842, 771, 724, 697, 644, 630, 613 cm ; HRMS (ESI) calcd for
+
C H F NO [M+H] : 356.1257, found 356.1257.
21
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2
-Phenyl-4-(pyridin-2-yl)-1-(1H-pyrrol-1-yl)but-3-yn-2-ol (2e). 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: dichloromethane: ethyl acetate =
:4:1 to dichloromethane: ethyl acetate = 4:1) afforded the title product in 93% yield (1.07
1
o
1
g) as a white solid. M.p. 145-146 C. H NMR (400 MHz, CDCl ) δ 8.41 (d, J = 4.4 Hz,
3
1
6
1
6
1
H), 7.64-7.57 (m, 3H), 7.36-7.28 (m, 4H), 7.20-7.16 (m, 1H), 6.64 (t, J = 2.0 Hz, 2H),
1
3
.06 (t, J = 2.0 Hz, 2H), 4.89 (bs, 1H), 4.31-4.23 (m, 2H); C NMR (100 MHz, CDCl ) δ
3
49.7, 142.1, 141.2, 136.3, 128.3, 128.2, 127.4, 125.7, 123.3, 122.4, 107.9, 90.2, 85.9, 73.1,
1.7; IR (neat): 3063, 2940, 2774, 2232, 1703, 1679, 1586, 1562, 1494, 1467, 1431, 1341,
-1
289, 1195, 1155, 1095, 1070, 999, 972, 942, 916, 828, 778, 735, 696, 646, 610 cm ;
+
HRMS (ESI) calcd for C H N O [M+H] : 289.1335, found 289.1337.
1
9
17
2
2
-Phenyl-1-(1H-pyrrol-1-yl)-4-(thiophen-2-yl)but-3-yn-2-ol (2f). 4 mmol scale. Column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1) afforded the
1
title product in 90% yield (1.052 g) as a light yellow oil. H NMR (400 MHz, CDCl ) δ
3
7
1
.63-7.60 (m, 2H), 7.41-7.33 (m, 3H), 7.29-7.27 (m, 1H), 7.24-7.23 (m, 1H), 6.99-6.97 (m,
1
3
H), 6.71 (t, J = 2.4 Hz, 2H), 6.14 (t, J = 2.4 Hz, 2H), 4.26-4.16 (m, 2H), 2.69 (s, 1H); C
NMR (100 MHz, CDCl ) δ 140.9, 132.7, 128.44, 128.41, 127.8, 127.0, 125.6, 122.4, 121.7,
3
1
1
6
08.2, 93.0, 81.0, 73.7, 61.9; IR (neat): 3441, 3101, 3061, 3029, 2939, 2220, 1493, 1448,
426, 1287, 1221, 1181, 1090, 1072, 1035, 971, 916, 851, 833, 775, 721, 695, 659, 643,
-1
+
28, 611 cm ; HRMS (ESI) calcd for C H NOS [M+H] : 294.0947, found 294.0949.
1
8
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6

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Synthesis of 2,6-diphenyl-1-(1H-pyrrol-1-yl)hexa-3,5-diyn-2-ol (2h). Under argon, to a
solution of 2l (845 mg, 4 mmol), CuCl (59.4 mg, 0.6 mmol) and hydroxylamine
hydrochloride (83.4 mg, 1.2 mmol) in toluene (25 mL) were added (bromoethynyl)benzene
o
(
941 mg, 5.2 mmol) and butan-1-amine (439 mg, 6.0 mmol) at 0 C. The resulting
suspension was stirred under room temperature for 12 h. Then, the mixture was quenched
with saturated NH Cl solution, extracted with ethyl acetate, washed with brine and dried
4
over anhydrous Na SO . The solvent was evaporated under the reduced pressure and the
2
4
residue was purified by column chromatography on silica gel (eluent: petroleum ether:
1
ethyl acetate = 50:1 to 40:1) to afford 2h (1.06 g, 85% yield) as a light yellow oil. H NMR
(
400 MHz, CDCl ) δ 7.57-7.55 (m, 2H), 7.51-7.49 (m, 2H), 7.40-7.30 (m, 6H), 6.67 (t, J =
3
1
3
2
.0 Hz, 2H), 6.14 (t, J = 2.0 Hz, 2H), 4.25-4.12 (m, 2H), 2.73 (s, 1H); C NMR (100 MHz,
CDCl ) δ 140.5, 132.6, 129.5, 128.54, 128.47, 128.4, 125.5, 122.4, 121.1, 108.4, 82.1, 79.7,
3
7
1
8
3
3.6, 72.9, 72.1, 61.6; IR (neat): 3436, 3060, 3031, 2940, 2338, 2233, 1678, 1599, 1570,
493, 1443, 1396, 1324, 1288, 1235, 1177, 1121, 1090, 1071, 1055, 1027, 1001, 970, 917,
-1
+
85, 841, 755, 722, 697, 687, 642, 628 cm ; HRMS (ESI) calcd for C H NO [M+H] :
2
2
18
12.1383, found 312.1383.
Synthesis of 2-methyl-4-phenyl-1-(1H-pyrrol-1-yl)but-3-yn-2-ol (2n).
1
) Synthesis of the precursor of 1-bromo-2-methyl-4-phenylbut-3-yn-2-ol.
To a solution of N-bromosuccinimide (4.27 g, 24 mmol) and p-TsOH·H O (0.380 g, 2.0
2
mmol) in dichloromethane (32 mL) was added a solution of acetone (1.16 g, 20 mmol) in
o
o
dichloromethane (8 mL) at 0 C. The resulting mixture was refluxed under 60 C for 5 h.
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7

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Then, the mixture was quenched with water, extracted with dichloromethane, washed with
saturated NaHCO solution and brine, dried over anhydrous Na SO , and reduced to afford
3
2
4
crude product of 1-bromopropan-2-one which was used without further purification.
Under argon, to a solution of phenylacetylene (2.86 mL, 26 mmol) in THF (40 mL)
was added ethylmagnesium bromide (8 mL, 24 mmol, 3.0 M in diethyl ether) dropwise at 0
o
C. Then the resulting mixture was stirred at the same temperature for 1 h. Then, the above
o
crude product of 1-bromopropan-2-one was added. The reaction mixture was stirred at 0 C
for another 0.5 h. Then, the reaction was quenched with saturated NH Cl solution,
4
extracted with ethyl acetate, washed with brine and dried over anhydrous Na SO . The
2
4
solvent was evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 30:1) to afford
1
1
-bromo-2-methyl-4-phenylbut-3-yn-2-ol (3.07 g, 64% yield) as a colorless liquid. H
NMR (400 MHz, CDCl ) δ 7.45-7.42 (m, 2H), 7.33-7.26 (m, 3H), 3.69-3.58 (m, 2H), 3.01
3
1
3
(
s, 1H), 1.70 (s, 3H); C NMR (100 MHz, CDCl ) δ 131.7, 128.6, 128.2, 121.9, 89.6, 84.3,
3
6
1
7.2, 43.9, 27.4; IR (neat): 3533, 3384, 3056, 2986, 2231, 1598, 1489, 1444, 1416, 1371,
-1
331, 1281, 1235, 1203, 1159, 1107, 1049, 950, 930, 864, 812, 755, 689, 661 cm ; HRMS
+
(
EI) calcd for C H OBr [M] : 237.9993, found 237.9986.
1
1
11
2
) Synthesis of 2n.
Under argon, to a Schlenk tube were added KOH (1.34 g, 23.8 mmol), DMSO (30 mL)
and pyrrole (1.20 g, 17.85 mmol). The resulting mixture was stirred at room temperature
for 1 h. Then, 1-bromo-2-methyl-4-phenylbut-3-yn-2-ol (2.85 g, 11.9 mmol) in DMSO (10
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8

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mL) was added dropwise. The reaction mixture was stirred at room temperature for another
3
h. Then the mixture was quenched with water, extracted with ethyl acetate, washed with
brine and dried over anhydrous Na SO . The solvent was evaporated under the reduced
2
4
pressure and the residue was purified by column chromatography on silica gel (eluent:
petroleum ether: ethyl acetate = 10:1) to afford an inseparable mixture of 2n and
1
-(1H-pyrrol-1-yl)propan-2-one as a light yellow oil.
In order to obtain the pure 2n, further reduction reaction was performed. Under air, to
a solution of the above mixture in MeOH (20 mL) was added NaBH (151 mg, 4 mmol).
4
The resulting suspension was stirred under room temperature for 1 h. Then, the mixture
was quenched with water, extracted with ethyl acetate, washed with brine and dried over
anhydrous Na SO . The solvent was evaporated under the reduced pressure and the residue
2
4
was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl
1
acetate = 10:1) to afford 2n (0.824 g, 31% yield) as a colorless oil. H NMR (400 MHz,
CDCl ) δ 7.40-7.38 (m, 2H), 7.31-7.27 (m, 3H), 6.81 (t, J = 2.0 Hz, 2H), 6.18 (t, J = 2.0 Hz,
3
1
3
2
1
2
9
2
H), 4.14-3.98 (m, 2H), 2.45 (bs, 1H), 1.55 (s, 3H); C NMR (100 MHz, CDCl ) δ 131.6,
3
28.6, 128.3, 122.3, 122.1, 108.3, 90.4, 85.0, 68.3, 60.3, 26.9; IR (neat): 3447, 2982, 2933,
232, 1679, 1598, 1573, 1494, 1443, 1374, 1317, 1287, 1215, 1121, 1087, 1067, 1027, 969,
-1
+
44, 925, 899, 816, 755, 723, 690, 616 cm ; HRMS (ESI) calcd for C H NO [M+H] :
1
5
16
26.1226, found 226.1228.
Synthesis of indolizines 3.
Typical procedure for the synthesis of 6,8-diphenylindolizine (3a). A Schlenk tube
2
9