Tandem Copper-Catalyzed Propargylation/Alkyne Azacyclization/Isomerization Reaction under Microwave Irradiation: Synthesis of Fully Substituted Pyrroles

Article abstract of DOI:10.1021/acs.joc.5b02429

A copper-catalyzed and microwave-assisted synthesis of fully substituted pyrroles has been developed. A series of pentasubstituted pyrroles, especially α-arylpyrroles, could be obtained in moderate to good yields (up to 93%) through a tandem propargylation/alkyne azacyclization/isomerization sequence from readily available β-enamino compounds and propargyl acetates.

Full text of DOI:10.1021/acs.joc.5b02429

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Article
Tandem Copper-Catalyzed Propargylation/Alkyne Azacyclization/Isomerization
Reaction Under Microwave Irradiation: Synthesis of Fully Substituted Pyrroles
Xiao-Yan Zhang, Zhi-Wei Yang, Zhongzhu Chen, Jun Wang, Dong-
Lin Yang, Ze Shen, Li-Li Hu, Jian-Wu Xie, Jin Zhang, and Hai-Lei Cui
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02429 • Publication Date (Web): 12 Feb 2016
Downloaded from http://pubs.acs.org on February 14, 2016
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Tandem CopperꢀCatalyzed Propargylation/Alkyne Azacyclization/Isomerization
Reaction Under Microwave Irradiation: Synthesis of Fully Substituted Pyrroles
a,b
a
a
a
a
a
a
b
a
XiaoꢀYan Zhang, ZhiꢀWei Yang, Zhongzhu Chen, Jun Wang, DongꢀLin Yang, Ze Shen, LiꢀLi Hu, JianꢀWu Xie, Jin Zhang,* HaiꢀLei
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a
Cui*
a
International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan,
Chongqing 402160, P.R. China; E-mail: hxxzj2282@163.com; cuihailei616@163.com
b
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry and Life Science, Zhejiang Normal
University, Jinhua 321004, P. R. China
Abstract A copperꢀcatalyzed and microwave assisted synthesis of fully substituted pyrroles has been developed. A series of
pentasubstituted pyrroles, especially αꢀarylpyrroles, could be obtained in moderate to good yields (up to 93%) through a tandem
propargylation/alkyne azacyclization/isomerization sequence from readily available βꢀenamino compounds and propargyl acetates.
O
R4
R1
OAc
R3
R5
NH
O
Cu(OTf) , MW
2
+
R4
N
R2
R3
R
2
R5
R1
27 examples
up to 93% yield
Keywords: Copper, Microwave, βꢀKetoesters, Propargyl Acetate, Pyrrole
INTRODUCTION
Fully substituted pyrroles are important bioactive motifs, widely presented in many biologically active compounds and natural
1
1c
products (Figure 1), including permethyl Storniamide A acting as inhibitors of multidrug resistance (MDR) phenomenon,
1
e,1f
1d
1h
Atorvastatin
for the treatment of dyslipidemia, Bclꢀ2/BclꢀxL inhibitor and CB1 antagonist . The great importance and potent
bioactivity suggest the need for simple and efficient methods to construct these molecules, especially the convenient oneꢀstep
2
,3
synthesis of fully substituted pyrroles.
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MeO
OMe
OMe
HN
MeO
MeO
O
OMe
HN
H
N
N
N
O
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O
F
MeO
OH
OH
OMe
Permethyl Storniamide A
O
HO
Atorvastatin (Lipitor)
HO
O
N
O
N
O
H N
2
S
O
N
S
N
H
N
N
Cl
H
N
O N
2
Cl
Bcl-2/Bcl-xL inhibitor
CB1 antagonist
Figure 1. Natural Product and Pharmaceuticals Bearing Fully Substituted Pyrrole
Recently, the activation of propargyl alcohols and their derivatives by transition metal catalysts or organocatalysts has emerged
4
ꢀ9
as a powerful tool for the easy assembly of multisubstituted pyrroles and other heterocycles with potent activity. The
multicomponent reaction of propargyl alcohols, amines and 1,3ꢀdicarbonyl compounds is an elegant and general route for the
5
synthesis of fully substituted pyrroles. Cadierno and Gimeno developed a oneꢀpot threeꢀcomponent synthesis of fully substituted
pyrroles from propargylic alcohols, 1,3ꢀdicarbonyl compounds and primary amines under the catalysis of combination of
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Ruthenium
and
trifluoroacetic
acid.
Zhan
and
coꢀworkers
disclosed
an
Indium
Chlorideꢀpromoted
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propargylation/amination/isomerization tandem reaction affording highly substituted pyrroles in good yields. Roy and coꢀworkers
used IrꢀSn bimetallic catalyst to synthesize fully decorated furan and pyrroles through alkylation of 1,3ꢀdicarbonyl compounds with
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benzylic and propargylic alcohols. Zheng and coꢀworkers demonstrated a silverꢀcatalyzed synthesis of fully substituted pyrroles.
The use of simple materials with high efficiency shows the unique advantages of these methodologies on the synthesis of fully
substituted pyrroles. However, these methods suffered from the employment of expensive metal catalyst or a special substrate scope.
As far as we know, acetoacetates and 1,3ꢀdiketones were employed to afford pyrroles in most cases, whereas the application of
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aromatic βꢀketoesters has never been reported in the synthesis of substituted pyrroles via activation of propargyl alcohols and their
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derivatives until now, probably due to their relatively poor reactivities. Given the importance of corresponding αꢀarylꢀsubstituted
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pyrroles that form a set of molecules exhibiting a broad range of bioactivities and pharmacological activities, the development of a
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rapid and easy construction of pentasubstituted αꢀarylpyrroles derived from simple aromatic βꢀketoesters derivatives is extremely
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desirable. We felt that preformed βꢀenamino compounds from aromatic βꢀketoesters may be used instead of βꢀketoesters and
12,13
amines in the multicomponent reactions to improve the reaction activities and avoid the formation of byproducts.
Thus, as
hypothesized, the desired αꢀarylꢀpentasubstituted pyrroles could be obtained through
a domino copperꢀcatalyzed
propargylation/alkyne azacyclization/isomerization sequence of propargyl acetates with preformed βꢀenamino compounds from
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aromatic βꢀketoesters (Scheme 1).
Herein, we report our development of an efficient copperꢀcatalyzed synthesis of fully
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substituted αꢀarylpyrroles from βꢀenamino compounds and propargyl acetates under microwave irradiation.
Multicomponent reactions involving the use of β−ketoesters:
R3
[
Ru]/TFA, or [In]
or [Ir]/[Sn], or [Ag]
2
O
O
OH
R OOC
R
4
1
R NH
+
2
+
R3
OR2
N
R1
R4
Me
This work:
R1
R3
2
OAc
R OOC
R4
NH
O
[
Cu]
+
R3
Ar
OR2
MW
N
R1
R4
Ar
Scheme 1. Design for the Synthesis of αꢀArylsubstituted Pyrroles
RESULTS AND DISCUSSION
We chose βꢀenamino ester 1a and secondary propargyl acetate 2a as model substrates to react with each other in toluene in the
o
presence of 10 mol% of CuBr as catalyst at 150 C under microwave irradiation. The reaction proceeded smoothly to give the
1
desired pentasubstituted pyrrole 3a with a pleasing 91% yield (by H NMR), while only 8% yield was observed without the
employment of catalyst (Table 1, entry 1 versus entry 2). To improve the yield, other copper salts were screened (entries 3ꢀ7).
Among these copper salts, Cu(OTf)
2
3
showed the best catalytic ability giving 95% NMR yield. Other salts such as AgOTf, Yb(OTf) ,
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Ni(OTf)
3
and Sc(OTf)
3
2 .
were less effective compared with Cu(OTf) (entries 8ꢀ11) Without microwave irradiation, 74% yield was
o
attained by heating at 150 C for 100 mintues (entry 12). Excellent NMR yield (99%) and isolated yield (91%) were achieved by
reducing the catalyst loading to 5 mol% (entry 13). However, the yield was slightly decreased when the reaction was performed at a
higher concentration (entries 14 and 15). It should be noted that all the reactions were carried out without exclusion of moisture or
air from the reaction system.
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Table 1: Reaction Development.
OMe
Ph
OAc
Catalyst, toluene
MW, 150 oC, 20 min
NH
EtOOC
Ph
+
COOEt
Me
Ph
Ph
MeO
N
1a
2a
3
a
b
Entry
Catalyst
CuBr
-
Yield [%]
1
2
3
4
5
6
7
8
9
91
8
CuI
73
78
95
5
CuCl
Cu(OTf)
2
Cu(OAc)
2
CuBr
2
66
61
58
16
35
74
99 (91)
98
64
AgOTf
Yb(OTf)
3
10
11
12
13
14
15
Ni(OTf)
3
Sc(OTf)
3
c
Cu(OTf)
Cu(OTf)
Cu(OTf)
Cu(OTf)
2
d
e
2
2
2
d,f
f
a
Unless otherwise noted, reaction was performed with 0.2 mmol of 1a, 0.24 mmol of 2a and 10 mol% of catalyst in 1.0 mL of toluene irradiated by microwave for
b
1
c
o
d
2
2 2
0 minutes. Yield determined by H NMR with CH Br as internal standard. Heated at 150 C for 100 min without microwave irradiation. With 5 mol% of catalyst.
e
f
Isolated yield. At 0.4 M.
The substrate scope was then examined with the optimized reaction condition in hand. As shown in Table 2, variation at N1
position including benzyl, furylmethyl, phenethyl, isopropyl, methoxyethyl, morpholinylethyl, cyclopropyl, cyclohexyl and phenyl
groups was successful, giving moderate to excellent yields ranging from 43% to 91%. Electronꢀdonating and electronꢀwithdrawing
groups on the ring of aromatic βꢀenamino ester could be tolerated delivering the corresponding products in 70% to 80% yields.
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βꢀEnamino ester derived from methyl acetoacetate also worked well in this system yielding the pyrroles 3p and 3q in 93% and 54%
yields respectively. Pleasingly, cyclic βꢀenamino compound could be employed successfully in this system giving 3r in 59% yield.
Next, various secondary propargyl acetates were submitted to this process. Aryl or heteroaryl groups substituted propargyl
acetates with terminal alkyne proceed smoothly to give pyrroles in moderate to good yields (54%ꢀ75%), regardless of
electronꢀdonating and electronꢀwithdrawing groups on the ring. Surprisingly, in the case of alkylated propargyl acetate,
corresponding pyrrole was failed to be obtained and complicated mixture was observed in this reaction probably due to the instable
intermediate. The desired product could be obtained in 57% yield when propargyl acetate with internal alkyne was employed.
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0
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0
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9
0
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2
3
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5
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9
0
1
2
3
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5
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8
9
0
a,b
Table 2: Examination of Substrate Scope.
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O
R4
R1
OAc
Cu(OTf)2 (5 mol%), toluene
MW, 150 oC, 20 min
R5
R3
NH
O
+
R4
R2
R3
R2
N
R1
R5
1
2
3
OMe
OMe
OMe
OMe
Me
3
3
a R1 = H, R2 = H 91%
b R1 = H, R2 = MeO 61%
c R1 = MeO, R2 = MeO 71%
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1
2
3
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9
0
EtOOC
Ph
EtOOC
Ph
EtOOC
Ph
EtOOC
Ph
3
Me
Me
O
Me
Ph
N
N
N
N
R2
3d 63%
3e 54%
3f 76%
R1
OMe
OMe
OMe
OMe
OMe
EtOOC
EtOOC
Ph
EtOOC
Ph
EtOOC
Ph
EtOOC
Ph
Me
O
Me
N
Me
Me
Me
N
N
N
N
N
Ph
Ph
3
g 47%
3i 64%
3j 55%
3k 79%
3
h 43%
O
OMe
OMe
OMe
OMe
3
l R1 = H, R2 = MeO 80%
1
2
3
3
3
m R = MeO, R = MeO 70%
n R1 = H, R2 = Me 74%
o R1 = H, R2 = Br 71%
O
EtOOC
MeOOC
MeOOC
Me
Me
Me
Ph
Me
Me
Ph
N
N
N
N
Me
3p 93%
Ph
Ph
3q 54%
R1
R2
3r 59%c
R3
R2
R1
3
3
3
s R1 = H, R2 = H, R3 = H 71%
O
Ph
t R1 = H, R2 = H, R3 = Me 75%
EtOOC
Me
Ph
Ph
u R1 = H, R2 = H, R3 = Cl 62%
EtOOC
EtOOC
3v R1 = H, R2 = Cl, R3 = Cl 54%d
Me
Ph
N
EtOOC
Ph
3w R1 = H, R2 = MeO, R3 =H 54%e Ph
N
Ph
N
Me
Ph
3
x R1 = F, R2 = H, R3 =H 57%
N
3y 57%f
3a' 57%g
Ph
3z 0%
Ph
a
Unless otherwise noted, reaction was performed with 0.2 mmol of 1, 0.24 mmol of 2 and 5 mol% of Cu(OTf)
2
in 1.0 mL of toluene under microwave irradiation
o
b
c
d
e
f
o
at 150 C for 20 minutes. Isolated yields. Performed with 1.5 equiv of 2. For 25 minutes. For 30 minutes. Performed with 1.5 equiv of 2 at 100 C for 20 minutes.
g
o
2
Performed with 10 mol% of Cu(OTf) at 150 C for 30 minutes.
This process could be easily scaled up for further biomedical research. As shown in Scheme 2, when 1.13 g of compound 1a
was treated in this system, 1.53 g of corresponding product 3a was obtained in 90% yield.
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OMe
Ph
Cu(OTf)2 (5 mol%)
OAc
toluene (10 mL)
NH
MW, 150 oC, 20 min
EtOOC
Ph
+
COOEt
Me
Ph
Ph
MeO
N
1a
2a
3
a
1
.13 g
10
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48
49
50
51
52
53
54
55
56
57
58
59
60
1
.53 g, 90% yield
Scheme 2. Gramꢀscale Reaction
In order to investigate the mechanism of this reaction, control reactions and DꢀH exchange experiments were conducted
Scheme 3). Threeꢀcomponent reactions were performed under the current catalytic system. When methyl acetoacetate was used,
(
the corresponding product 3p can be detected in 40% yield. However, no desired αꢀarylꢀpentasubstituted pyrrole 3a was observed.
The results demonstrate that the use of preformed βꢀenamino compounds from aromatic βꢀketoesters is essential for the synthesis of
1
0
2
αꢀarylꢀpentasubstituted pyrroles. The reactions with enamino esters were then performed in the presence of D O to gain evidence
for mechanism proposal. As shown in Scheme 3, 90% deuterium incorporations in compounds 3a were observed. It indicates that
protonolysis and isomerization occured during this catalytic process.
OMe
OAc
Cu(OTf)2 (20 mol%), toluene
O
MW, 150 oC, 20 min
MeOOC
Me
BnNH2
+
COOMe
+
Me
Ph
Me
MeO
N
2
a
3
p
0% yield (by 1H NMR)
4
OMe
OAc
Cu(OTf)2 (20 mol%), toluene
MW, 150 oC, 20 min
O
BnNH2
+
COOEt
+
complex mixture
EtOOC
Ph
Ph
Me
Ph
MeO
N
2
a
3a
OMe
not observed
Cu(OTf)2 (20 mol%)
Ph
OAc
D O (50 ꢀL), toluene
MW, 150 C, 20 min
2
o
EtOOC
Ph
NH
+
CHD2 90% incorporated
Ph
COOEt
Ph
N
MeO
1a
2a
3
a-D
4
8% yield
Scheme 3. Control Reactions and DꢀH Exchange Experiments
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1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
A mechanistic proposal for this reaction was depicted in Scheme 4 based on results described above and other reported
6
,7,17
studies.
Propargylation of βꢀenamino ester occurs firstly to give a propargylation intermediate. Subsequently, an intramolecular
5
-exo-dig attack to the carbonꢀcarbon triple bond takes place upon the activation of copper catalyst, which was followed by
0
1
2
3
4
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0
1
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0
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9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
protonolysis and isomerization delivering pyrrole.
R1
R2
NH
COOEt
1
R3
nXCu
R1
R4
NH
propargylation
OAc
COOEt
CuXn
R2
R3
R4
2
R3
R4
CuX2
R4
protonolysis
alkyne
azacyclization
R3
R1
CuXn
EtOOC
R3
NH
EtOOC
CuXn
R3
COOEt
R4
R2
R2
N
R1
R4
R2
N
3
a
R1
5-exo-dig
3a
isomerization
R3
EtOOC
R4
R2
N
R1
3
Scheme 4. Proposed Catalytic Cycle
CONCLUSION
In conclusion, we have developed an efficient synthesis of pentasubstituted pyrroles under microwave irradiation. A series of
functionalized pyrroles, especially αꢀarylpyrroles, could be obtained in moderate to good yields (up to 93%) through a tandem
propargylation/alkyne azacyclization/isomerization sequence from βꢀenamino compounds and propargyl acetates. This process
could be scaled up easily for further biomedical research. The extension to the development of other analogous and application in
biomedical research of this strategy is currently ongoing in our laboratory.
EXPERIMENTAL SECTION
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General methods Column chromatography was performed using Merk Silica gel 60 (230ꢀ400 mesh) eluting with EtOAc and
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Hexane. H NMR and C NMR spectra were recorded using a 400 MHz NMR spectrometer. Chemical shifts are reported in ppm
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13
downfield from CDCl (δ = 7.26 ppm) for H NMR and relative to the central CDCl resonance (δ = 77.0 ppm) for C NMR
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spectroscopy. Coupling constants are given in Hz. ESIꢀMS analysis was performed using ion trap mass spectrometer. All
microwave irradiation experiments were carried out in a Biotage® Initiator Classic microwave apparatus with continuous
irradiation power from 0 to 400W with utilization of the standard absorbance level of 250W maximum power. The reaction
mixture temperature is determined by external IR sensor. The reactions were carried out in 10 mL glass tubes, sealed with
microwave cavity. The reaction was irradiated at a required ceiling temperature using maximum power for the stipulated time. Then
o
it was cooled to 50 C with gas jet cooling.
βꢀEnamino compounds were synthesized through microwaveꢀassisted condensation of amines and 1,3ꢀdicarbonyl compounds
1
2
18
developed in our group. Propargyl acetates 2 were prepared according to the literature procedure. All reagents and solvents were
obtained from commercial sources and used without further purification.
1. General Procedure for the Microwave Assisted Synthesis of Enaminoester 1:
A mixture of βꢀketoesters (10 mmol), primary amine (13 mmol), acetic acid (1.0 mmol or 2.0 mmol) and 4Å MS (1g) was diluted
with toluene without exclusion of air (2 mL). The resulting reaction mixture was stirred at rt for 30 seconds, then heated by
o
microwave at 100 C for 30 minutes. The mixture was cooled to rt, filtered and directly purified by a silica gel flash
chromatography (Hexane/EtOAc) to give compound 1 in 27% to 80% yields.
1
9
(
Z)ꢀEthyl 3ꢀ(benzylamino)ꢀ3ꢀphenylacrylate (1a). Known compound; Purified by flash column chromatography
o
1
(
Hexane/EtOAc = 20:1); white solid (mp: 71ꢀ73 C); H NMR (400 MHz, CDCl ) δ 8.91 (brs, 1H), 7.38ꢀ7.15 (m, 10H), 4.67 (s,
3
1
3
1
3
H), 4.25 (d, J = 6.8 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 170.3, 164.7,
1
39.2, 135.9, 129.2, 128.5, 128.3, 127.8, 127.1, 126.8, 86.3, 58.7, 48.3, 14.5 ppm;
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(
Z)ꢀEthyl 3ꢀ((4ꢀmethoxybenzyl)amino)ꢀ3ꢀphenylacrylate (1b). Purified by flash column chromatography (Hexane/EtOAc =
1
2
1
1
C
0:1); yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.84 (brs, 1H), 7.38ꢀ7.33 (m, 5H), 7.10ꢀ7.07 (m, 2H), 6.85ꢀ6.81 (m, 2H), 4.66 (s,
1
3
H), 4.19 (d, J = 6.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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8
9
0
1
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4
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70.3, 164.6, 158.8, 136.0, 131.3, 129.2, 128.3, 128.1, 127.9, 114.0, 86.1, 58.7, 55.2, 47.8, 14.5 ppm; ESIꢀHRMS: calcd. for
+
+
19 3
H21NNaO (M+Na) 334.1414, found 334.1422;
(
Z)ꢀEthyl 3ꢀ((2,4ꢀdimethoxybenzyl)amino)ꢀ3ꢀphenylacrylate (1c). Purified by flash column chromatography
1
(
Hexane/EtOAc = 20:1); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.84 (brs, 1H), 7.39ꢀ7.35 (m, 5H), 6.93 (d, J = 8.0 Hz, 1H),
6
.41ꢀ6.38 (m, 2H), 4.59 (s, 1H), 4.16 (d, J = 6.4 Hz, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.78 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H)
1
3
3
ppm; C NMR (100 MHz, CDCl ) δ 170.2, 164.8, 160.3, 158.2, 136.4, 129.0, 129.0, 128.2, 128.0, 120.0, 103.9, 98.5, 85.5, 58.5,
+
+
5
4
5.3, 55.3, 43.7, 14.6 ppm; ESIꢀHRMS: calcd. for C20H24NO (M+H) 342.1700, found 342.1702;
(
Z)ꢀEthyl 3ꢀ((furanꢀ2ꢀylmethyl)amino)ꢀ3ꢀphenylacrylate (1d). Purified by flash column chromatography (Hexane/EtOAc =
1
2
1
0:1); yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.75 (brs, 1H), 7.43ꢀ7.37 (m, 5H), 7.33 (dd, J = 2.0, 0.8 Hz, 1H), 6.27 (dd, J = 3.2,
1
3
.2 Hz, 1H), 6.10ꢀ6.09 (m, 1H), 4.68 (s, 1H), 4.21 (d, J = 6.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm;
C
3
NMR (100 MHz, CDCl ) δ 170.2, 164.3, 152.3, 142.1, 135.8, 129.3, 128.4, 128.0, 110.2, 106.8, 87.0, 58.8, 41.7, 14.5 ppm;
+
+
3
ESIꢀHRMS: calcd. for C16H18NO (M+H) 272.1281, found 272.1281;
(
Z)ꢀEthyl 3ꢀ(phenethylamino)ꢀ3ꢀphenylacrylate (1e). Purified by flash column chromatography (Hexane/EtOAc = 20:1);
1
colorless oil; H NMR (400 MHz, CDCl
3
) δ 8.60 (brs, 1H), 7.42ꢀ7.28 (m, 3H), 7.26ꢀ7.13 (m, 5H), 7.04 (d, J = 6.8 Hz, 2H), 4.57 (s,
13
1
H), 4.14 (d, J = 7.2 Hz, 2H), 3.27 (dd, J = 14.0, 7.2 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H), 1.35ꢀ1.20 (m, 3H) ppm; C NMR (100 MHz,
3
CDCl ) δ 170.3, 164.7, 138.5, 136.1, 129.0, 128.7, 128.4, 128.2, 127.7, 126.4, 85.6, 58.6, 46.1, 37.8, 14.6 ppm; ESIꢀHRMS: calcd.
+
+
2
for C19H22NO (M+H) 296.1645, found 296.1641;
(Z)ꢀethyl 3ꢀ(isobutylamino)ꢀ3ꢀphenylacrylate (1f). Purified by flash column chromatography (Hexane/EtOAc = 20:1);
1
colorless oil; H NMR (400 MHz, CDCl
3
) δ 8.64 (brs, 1H), 7.43ꢀ7.31 (m, 5H), 4.57 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H), 2.87 (t, J = 6.4
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Hz, 2H), 1.72ꢀ1.66 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H), 0.87ꢀ0.85 (m, 6H) ppm; C NMR (100 MHz, CDCl ) δ 170.4, 165.2, 136.4,
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5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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+
+
1
2
29.0, 128.2, 127.9, 84.9, 58.6, 52.2, 29.8, 19.9, 14.6 ppm; ESIꢀHRMS: calcd. for C15H22NO (M+H) 248.1645, found 248.1650;
(
Z)ꢀethyl 3ꢀ((2ꢀmethoxyethyl)amino)ꢀ3ꢀphenylacrylate (1g). Purified by flash column chromatography (Hexane/EtOAc =
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
1
0:1); pale yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.66 (brs, 1H), 7.40ꢀ7.33 (m, 5H), 4.60 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.40
1
3
(
3
t, J = 5.2 Hz, 2H), 3.34 (s, 3H), 3.22 (dd, J = 11.6, 5.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 170.3,
+
+
1
3
64.5, 136.2, 129.1, 128.3, 127.9, 85.9, 72.1, 58.9, 58.7, 44.3, 14.6 ppm; ESIꢀHRMS: calcd. for C14H20NO (M+H) 250.1438,
found 250.1444;
(
Z)ꢀEthyl 3ꢀ((2ꢀmorpholinoethyl)amino)ꢀ3ꢀphenylacrylate (1h). Purified by flash column chromatography (Hexane/EtOAc
o
1
=
5:1); white solid (mp: 61ꢀ62 C); H NMR (400 MHz, CDCl
3
) δ 8.61 (brs, 1H), 7.39ꢀ7.33 (m, 5H), 4.59 (s, 1H), 4.14 (q, J = 7.2
13
Hz, 2H), 3.75ꢀ3.58 (m, 4H), 3.14 (q, J = 6.4 Hz, 2H), 2.43 (t, J = 6.4 Hz, 2H), 2.40ꢀ2.33 (m, 4H), 1.27 (t, J = 7.2 Hz, 3H) ppm;
C
3
NMR (100 MHz, CDCl ) δ 170.2, 164.4, 136.4, 129.1, 128.3, 127.8, 85.7, 66.9, 58.8, 58.6, 53.5, 41.5, 14.6 ppm; ESIꢀHRMS: calcd.
+
3
+
for C17
H
25
N
2
O
(M+H) 305.1860, found 305.1868;
(
Z)ꢀEthyl 3ꢀ(cyclopropylamino)ꢀ3ꢀphenylacrylate (1i). Purified by flash column chromatography (Hexane/EtOAc = 20:1);
1
pale yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.60 (s, 1H), 7.47ꢀ7.35 (m, 5H), 4.61 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 2.53ꢀ2.45 (m,
1
3
3
1H), 1.26 (t, J = 7.2 Hz, 3H), 0.53ꢀ0.49 (m, 4H) ppm; C NMR (100 MHz, CDCl ) δ 170.4, 165.3, 136.8, 128.9, 128.1, 127.9, 85.3,
+
+
5
2
8.7, 26.8, 14.6, 8.6 ppm; ESIꢀHRMS: calcd. for C14H18NO (M+H) 232.1332, found 232.1342;
(E)ꢀEthyl 3ꢀ(cyclohexylamino)ꢀ3ꢀphenylacrylate (1j). Purified by flash column chromatography (Hexane/EtOAc = 20:1);
1
pale yellow oil; H NMR (400 MHz, CDCl ) δ 8.54 (d, J = 9.2 Hz, 1H), 7.39ꢀ7.33 (m, 5H), 4.55 (s, 1H), 4.14 (q, J = 7.2 Hz, 2H),
3
1
3
3.19ꢀ3.04 (m, 1H), 1.83ꢀ1.71(m, 2H), 1.69ꢀ1.64 (m, 2H), 1.52ꢀ1.42 (m, 1H), 1.36ꢀ1.22 (m, 5H), 1.21ꢀ1.02 (m, 3H) ppm; C NMR
(
100 MHz, CDCl
3
) δ 170.4, 164.3, 136.8, 129.0, 128.3, 127.7, 85.5, 58.6, 52.5, 34.5, 25.3, 24.5, 14.6 ppm; ESIꢀHRMS: calcd. for
+
2
+
C
17
H24NO
(M+H) 274.1802, found 274.1811;
20
(
Z)ꢀethyl 3ꢀphenylꢀ3ꢀ(phenylamino)acrylate (1k). Known compound; Purified by flash column chromatography
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(
(
3
Hexane/EtOAc = 20:1); pale yellow oil; H NMR (400 MHz, CDCl ) δ 10.31 (brs, 1H), 7.37ꢀ7.22 (m, 5H), 7.08ꢀ7.04 (m, 2H), 6.89
1
3
t, J = 7.2 Hz, 1H), 6.66 (d, J = 8.0 Hz, 2H), 5.00 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H) ppm; C NMR (100
MHz, CDCl ) δ 170.0, 159.0, 140.4, 136.0, 129.3, 128.5, 128.3, 128.2, 122.9, 122.1, 91.2, 59.2, 14.5 ppm;
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
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0
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(
Z)ꢀEthyl 3ꢀ(benzylamino)ꢀ3ꢀ(4ꢀmethoxyphenyl)acrylate (1l). Known compound;
Purified by flash column
1
chromatography (Hexane/EtOAc = 20:1); yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.90 (brs, 1H), 7.33ꢀ7.17 (m, 7H), 6.91ꢀ6.84
13
(
m, 2H), 4.67 (s, 1H), 4.30 (d, J = 6.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) ppm; C NMR (100
3
MHz, CDCl ) δ 170.4, 164.7, 160.4, 139.4, 129.3, 128.6, 128.2, 127.1, 126.8, 113.8, 86.1, 58.7, 55.3, 48.4, 14.6 ppm;
(
Z)ꢀEthyl 3ꢀ(benzylamino)ꢀ3ꢀ(2,4ꢀdimethoxyphenyl)acrylate (1m). Purified by flash column chromatography
1
(
Hexane/EtOAc = 10:1); yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.98 (s, 1H), 7.30ꢀ7.24 (m, 2H), 7.23ꢀ7.15 (m, 3H), 7.11 (d, J =
13
7
.6 Hz, 1H), 6.50ꢀ6.43 (m, 2H), 4.54 (s, 1H), 4.25ꢀ4.05 (m, 4H), 3.82 (s, 3H), 3.74 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm; C NMR
(
100 MHz, CDCl
3
) δ 170.6, 162.0, 161.7, 157.4, 139.2, 130.7, 128.4, 127.1, 127.0, 117.8, 104.4, 98.4, 84.7, 58.5, 55.4, 55.4, 48.0,
+
+
1
4
4.6 ppm; ESIꢀHRMS: calcd. for C20H24NO (M+H) 342.1700, found 342.1715;
1
9
(
Z)ꢀEthyl 3ꢀ(benzylamino)ꢀ3ꢀ(pꢀtolyl)acrylate (1n). Known compound; Purified by flash column chromatography
1
(
3
Hexane/EtOAc = 20:1); brown oil; H NMR (400 MHz, CDCl ) δ 8.95 (brs, 1H), 7.38ꢀ7.27 (m, 5H), 7.26ꢀ7.19 (m, 4H), 4.72 (s,
1
3
3
1H), 4.33 (d, J = 6.4 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ
1
70.4, 164.9, 139.3, 139.3, 133.0, 129.0, 128.6, 127.8, 127.1, 126.8, 86.0, 58.7, 48.3, 21.2, 14.6 ppm;
1
9
(Z)ꢀEthyl 3ꢀ(benzylamino)ꢀ3ꢀ(4ꢀbromophenyl)acrylate (1o). Known compound; Purified by flash column chromatography
o
1
(
Hexane/EtOAc = 20:1); white solid (mp: 55ꢀ56 C); H NMR (400 MHz, CDCl ) δ 8.88 (brs, 1H), 7.54ꢀ7.46 (m, 2H), 7.34ꢀ7.27 (m,
3
1
3
2H), 7.26ꢀ7.13 (m, 5H), 4.65 (s, 1H), 4.24 (d, J = 6.4 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H) ppm; C NMR
(
3
100 MHz, CDCl ) δ 170.2, 163.4, 139.0, 134.8, 131.6, 129.5, 128.6, 127.3, 126.7, 123.5, 86.8, 58.9, 48.3, 14.5 ppm;
2
1
(Z)ꢀMethyl 3ꢀ(benzylamino)butꢀ2ꢀenoate (1p). Known compound; Purified by flash column chromatography
1
(
Hexane/EtOAc = 20:1); yellow oil; H NMR (400 MHz, CDCl
3
) δ 8.94 (brs, 1H), 7.37ꢀ7.31 (m, 2H), 7.29ꢀ7.23 (m, 3H), 4.54 (s,
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H), 4.43 (d, J = 6.0 Hz, 2H), 3.63 (s, 3H), 1.91 (s, 3H) ppm; C NMR (100 MHz, CDCl ) δ 170.9, 161.9, 138.7, 128.7, 127.3,
4
5
6
7
8
9
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
26.7, 82.8, 49.9, 46.8, 19.3 ppm;
2
0
(
Z)ꢀMethyl 3ꢀ(phenylamino)butꢀ2ꢀenoate (1q). Known compound; Purified by flash column chromatography
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
o
1
(
(
3
Hexane/EtOAc = 20:1); white solid (mp: 47ꢀ49 C); H NMR (400 MHz, CDCl ) δ 10.35 (brs, 1H), 7.36ꢀ7.29 (m, 2H), 7.20ꢀ7.13
13
3
m, 1H), 7.12ꢀ7.06 (m, 2H), 4.70 (s, 1H), 3.69 (s, 3H), 2.00 (s, 3H) ppm; C NMR (100 MHz, CDCl ) δ 170.7, 159.1, 139.3, 129.1,
1
25.0, 124.5, 85.6, 50.2, 20.3 ppm;
2
2
3
ꢀ(Benzylamino)cyclohexꢀ2ꢀenone (1r). Known compound; Purified by flash column chromatography (Hexane/EtOAc =
o
1
2
5
1
2
:3); yellow solid (mp: 126ꢀ127 C); H NMR (400 MHz, CDCl ) δ 7.42ꢀ7.24 (m, 5H), 5.17 (s, 1H), 5.14ꢀ5.10 (m, 1H), 4.22 (d, J =
3
1
3
3
.2 Hz, 2H), 2.38 (t, J = 6.0 Hz, 2H), 2.34ꢀ2.25 (m, 2H), 2.01ꢀ1.92 (m, 2H) ppm; C NMR (100MHz, CDCl ) δ 197.4, 164.1, 136.8,
28.8, 127.9, 127.7, 97.5, 47.2, 36.4, 29.6, 21.9 ppm;
. General procedure for the microwave assisted synthesis of fully substituted pyrrole 3. A mixture of enamino ester 1 (0.20
2
mmol, 1.0 eq), propargyl acetate 2 (0.24 mmol, 1.2 eq), Cu(OTf) (0.01 mmol, 5 mol%) and toluene (1 mL) was stirred at room
o
temperature for 30 seconds and then heated at 150 C for 20 minutes under microwave irradiation without exclusion of air. The
reaction mixture was then cooled to room temperature and purified directly by a silica gel flash chromatography (Hexane/EtOAc)
giving compound 3.
Ethyl 1ꢀbenzylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3a). Purified by flash column
1
chromatography (Hexane/EtOAc = 20:1); 77.4 mg, 91% yield; yellow gum; H NMR (400 MHz, CDCl
3
) δ 7.32ꢀ7.20 (m, 10H),
13
6
.93ꢀ6.89 (m, 4H), 4.95 (s, 2H), 3.90 (q, J =7.2, 2H), 3.82 (s, 3H), 2.02 (s, 3H), 0.80 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz,
CDCl
3
) δ 165.1, 158.0, 137.9, 137.8, 132.5, 131.5, 130.6, 128.6, 128.2, 128.0, 127.7, 127.2, 127.0, 125.7, 123.0, 113.0, 112.4, 59.0,
+
5
5.2, 47.9, 13.6, 10.6 ppm; ESIꢀHRMS: calcd. for C28
H28NO
3
(M+H) 426.2064, found 426.2051.
Ethyl 1ꢀ(4ꢀmethoxybenzyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3b). Purified by flash
1
column chromatography (Hexane/EtOAc = 5:1); 55.5 mg, 61% yield; pale yellow gum; H NMR (400 MHz, CDCl
3
) δ 7.33ꢀ7.24
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(
m, 7H), 6.93ꢀ6.82 (m, 6H), 4.90 (s, 2H), 3.90 (q, J =7.2, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 2.04 (s, 3H), 0.80 (t, J = 7.2Hz, 3H) ppm;
1
3
C NMR (100MHz, CDCl
3
) δ 165.2, 158.7, 158.0, 137.9, 132.6, 131.5, 130.7, 129.8, 128.3, 128.0, 127.7, 127.0, 126.9, 122.9,
+
1
14.1, 113.0, 112.3, 59.0, 55.2, 47.4, 13.6, 10.6; ESIꢀHRMS: calcd. for C H NO (M+H) 456.2169, found 456.2152.
2
9
30
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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0
Ethyl 1ꢀ(2,4ꢀdimethoxybenzyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3c). Purified by flash
o
1
3
column chromatography (Hexane/EtOAc = 20:1); 68.9 mg, 71% yield; yellow solid (mp: 121ꢀ123 C); H NMR (400 MHz, CDCl )
δ 7.32ꢀ7.28 (m, 7H), 6.94ꢀ6.92 (m, 2H), 6.47ꢀ6.40 (m, 3H), 4.85 (s, 2H), 3.91 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.73 (s,
1
3
3
3
H), 2.03 (s, 3H), 0.82 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 165.3, 160.0, 158.0, 156.7, 138.1, 132.6, 131.5,
1
30.6, 128.5, 127.9, 127.7, 127.2, 126.8, 122.8, 118.6, 113.0, 112.2, 104.1, 98.1, 59.0, 55.3, 55.2, 55.2, 43.0, 13.6, 10.3 ppm;
+
ESIꢀHRMS: calcd. for C30
H32NO
5
(M+H) 486.2275, found 486.2255.
Ethyl 1ꢀ(furanꢀ2ꢀylmethyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3d). Purified by flash
1
column chromatography (Hexane/EtOAc = 10:1); 52.3 mg, 63% yield; pale yellow gum; H NMR (400 MHz, CDCl
3
) δ 7.40ꢀ7.35
(
m, 5H), 7.31 (dd, J = 2.0, 0.8 Hz, 1H), 7.25ꢀ7.22 (m, 2H), 6.93ꢀ6.89 (m, 2H), 6.27 (q, J = 1.6 Hz, 1H), 5.91 (dd, J = 3.2, 0.8 Hz,
1
3
1
H), 4.85 (s, 2H), 3.85 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 2.19 (s, 3H), 0.78 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ
3
1
65.0, 158.0, 150.5, 142.2, 137.7, 132.5, 131.5, 130.9, 128.2, 128.1, 127.8, 127.1, 122.7, 113.0, 112.5, 110.3, 107.6, 59.0, 55.2,
+
41.7, 13.5, 10.5 ppm; ESIꢀHRMS: calcd. for C26
H26NO
4
(M+H) 416.1856, found 416.1840.
Ethyl 4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ1ꢀphenethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3e). Purified by flash column
o
1
3
chromatography (Hexane/EtOAc = 10:1); 47.4 mg, 54% yield; yellow solid (mp: 105ꢀ106 C); H NMR (400 MHz, CDCl ) δ
7
.45ꢀ7.41 (m, 3H), 7.37ꢀ7.34 (m, 2H), 7.25ꢀ7.19 (m, 5H), 6.95ꢀ6.91 (m, 2H), 6.87ꢀ6.85 (m, 2H), 3.94ꢀ3.85 (m, 4H), 3.84 (s, 3H),
1
3
3
2.76 (t, J = 8.0, 2H), 2.09 (s, 3H), 0.79 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 165.1, 158.0, 137.8, 137.2, 133.1,
1
31.5, 130.8, 128.6, 128.6, 128.4, 128.0, 127.9, 126.7, 126.5, 122.5, 113.0, 112.3, 58.9, 55.2, 46.0, 37.3, 13.6, 10.4 ppm;
+
3
ESIꢀHRMS: calcd. for C29H30NO (M+H) 440.2220, found 440.2200.
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Ethyl 1ꢀisobutylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3f). Purified by flash column
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6
7
8
9
1
1
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1
1
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2
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2
2
2
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3
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4
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4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
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chromatography (Hexane/EtOAc = 10:1); 59.6 mg, 76% yield; pale yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.43ꢀ7.34 (m, 5H),
7
.25ꢀ7.23 (m, 2H), 6.93ꢀ6.91 (m, 2H), 3.88ꢀ3.84 (m, 5H), 3.60 (d, J = 7.6 Hz, 2H), 2.18 (s, 3H), 1.85ꢀ1.70 (m, 1H), 0.79 (t, J = 7.2
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
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Hz, 3H), 0.70 (d, J = 6.4 Hz, 6H) ppm; C NMR (100 MHz, CDCl
3
) δ 165.2, 158.0, 137.5, 133.2, 131.5, 131.0, 128.6 127.8, 127.7,
+
1
26.8, 122.5, 113.0, 112.3, 58.9, 55.2, 51.5, 29.3, 19.8, 13.6, 11.0 ppm; ESIꢀHRMS: calcd. for C25
H30NO
3
(M+H) 392.2220, found
3
92.2203.
Ethyl 1ꢀ(2ꢀmethoxyethyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3g). Purified by flash
1
column chromatography (Hexane/EtOAc = 10:1); 37.0 mg, 47% yield; pale yellow oil; H NMR (400 MHz, CDCl ) δ 7.44ꢀ7.36 (m,
3
5
H), 7.27ꢀ7.23 (m, 2H), 6.94ꢀ6.90 (m, 2H), 3.94ꢀ3.83 (m, 7H), 3.39 (t, J = 6.4 Hz, 2H), 3.20 (s, 3H), 2.22 (s, 3H), 0.77 (t, J = 7.2
13
Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
) δ 165.0, 158.0, 137.4, 133.0, 131.5, 130.9, 128.4, 128.1, 127.9, 127.0, 122.4, 113.0,
+
1
12.5, 71.6, 58.9, 58.9, 55.2, 43.8, 13.5, 10.6 ppm; ESIꢀHRMS: calcd. for C24
H28NO
4
(M+H) 394.2013, found 394.1998.
Ethyl 4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ1ꢀ(2ꢀmorpholinoethyl)ꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3h). Purified by flash
1
column chromatography (Hexane/EtOAc = 4:1); 38.5 mg, 43% yield; orange gum; H NMR (400 MHz, CDCl ) δ 7.44ꢀ7.36 (m,
3
5
H), 7.25ꢀ7.21 (m, 2H), 6.93ꢀ6.90 (m, 2H), 3.91ꢀ3.84 (m, 7H), 3.62ꢀ3.60 (m, 4H), 2.46 (t, J = 7.6 Hz, 2H), 2.27 (brs, 4H), 2.21 (s,
1
3
3H), 0.78 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
) δ 165.0, 158.1, 137.2, 132.9, 131.5, 130.8, 128.2, 128.2, 127.9,
+
1
26.5, 122.7, 113.0,112.5, 66.5, 59.0, 58.4, 55.2, 53.5, 41.3, 13.6, 10.6 ppm; ESIꢀHRMS: calcd. for C27
H
33
N
2
O
4
(M+H) 449.2435,
found 449.2415.
Ethyl 1ꢀcyclopropylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3i). Purified by flash column
o
1
3
chromatography (Hexane/EtOAc = 10:1); 48.0 mg, 64% yield; yellow solid (mp: 118ꢀ120 C); H NMR (400 MHz, CDCl ) δ
7
.44ꢀ7.36 (m, 5H), 7.24ꢀ7.22 (m, 2H), 6.93ꢀ6.91 (m, 2H), 3.92 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.08ꢀ3.05 (m, 1H), 2.29 (s, 3H),
1
3
3
0.85 (t, J = 7.2 Hz, 3H), 0.76 (q, J = 5.6 Hz, 2H), 0.58ꢀ0.55 (m, 2H) ppm; C NMR (100 MHz, CDCl ) δ 165.4, 158.0, 137.9,
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33.1, 131.3, 130.6, 129.3, 128.4, 127.4,122.0, 113.0, 112.1, 59.2, 55.2, 27.2, 13.6, 11.3, 9.0 ppm; ESIꢀHRMS: calcd. for
+
C
24
H26NO
3
(M+H) 376.1907, found 376.1894.
Ethyl 1ꢀcyclohexylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3j). Purified by flash column
0
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0
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8
9
0
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8
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7
8
9
0
1
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5
6
7
8
9
0
o
1
3
chromatography (Hexane/EtOAc = 10:1); 45.9 mg, 55% yield; white solid (mp: 138ꢀ140 C); H NMR (400 MHz, CDCl ) δ
7
1
1
.42ꢀ7.38 (m, 3H), 7.36ꢀ7.32 (m, 2H), 7.25ꢀ7.21 (m, 2H), 6.93ꢀ6.90 (m, 2H), 3.85ꢀ3.80 (m, 6H), 2.28 (s, 3H), 1.85ꢀ1.75 (m, 6H),
13
3
.62ꢀ1.57 (m, 1H), 1.18ꢀ1.05 (m, 3H), 0.74 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 165.2, 158.0, 137.6, 134.0,
31.6, 130.9, 128.6, 127.9, 127.7, 126.1, 123.4, 113.0, 112.3, 58.9, 57.7, 55.2, 32.5, 26.3, 25.3, 13.5, 12.6 ppm; ESIꢀHRMS: calcd.
+
for C H NO (M+H) 418.2377, found 418.2360.
2
7
32
3
Ethyl 4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ1,2ꢀdiphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3k). Purified by flash column
o
1
3
chromatography (Hexane/EtOAc = 10:1); 65.0 mg, 79% yield; yellow solid (mp: 140ꢀ142 C); H NMR (400 MHz, CDCl ) δ
7
.35ꢀ7.25 (m, 5H), 7.21ꢀ7.13 (m, 5H), 7.13ꢀ7.09 (m, 2H), 6.96ꢀ6.94 (m, 2H), 3.97ꢀ3.92 (m, 2H), 3.84 (s, 3H), 2.00 (s, 3H), 0.85 (t, J
13
=
7.2 Hz, 3H) ppm; C NMR (100MHz, CDCl
3
) δ 165.4, 158.1, 138.1, 137.4, 132.2, 131.4, 131.0, 128.8, 128.6, 128.1, 128.0,
+
1
4
27.8, 127.3, 127.2, 122.6, 113.1, 59.3, 55.2, 13.6, 11.5 ppm; ESIꢀHRMS: calcd. for C H NO (M+H) 412.1907, found
27 26
3
12.1885.
Ethyl 1ꢀbenzylꢀ2,4ꢀbis(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3l). Purified by flash column
o
1
3
chromatography (Hexane/EtOAc = 10:1); 72.8 mg, 80% yield; yellow solid (mp: 124ꢀ126 C); H NMR (400 MHz, CDCl ) δ
7.30ꢀ7.19 (m, 7H), 6.93ꢀ6.90 (m, 4H), 6.86ꢀ6.83 (m, 2H), 4.96 (s, 2H), 3.92 (q, J =7.2, 2H), 3.83 (s, 3H), 3.79 (s, 3H), 2.02 (s, 3H),
13
0
.85 (t, J = 7.2 Hz, 3H) ppm; C NMR (100MHz, CDCl ) δ 165.3, 159.5, 158.0, 137.9, 137.8, 131.9, 131.5, 128.7, 128.4, 127.1,
3
+
4
126.8, 125.7, 124.6, 122.8, 113.3 113.0, 112.4, 59.0, 55.2, 55.1, 47.8, 13.7, 10.6 ppm; ESIꢀHRMS: calcd. for C29H30NO (M+H)
4
56.2169, found 456.2154.
Ethyl 1ꢀbenzylꢀ2ꢀ(2,4ꢀdimethoxyphenyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3m). Purified by
1
flash column chromatography (Hexane/EtOAc = 5:1); 67.9 mg, 70% yield; yellow gum; H NMR (400 MHz, CDCl
3
) δ 7.29ꢀ7.17
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m, 5H), 7.11ꢀ7.08 (m, 1H), 6.95ꢀ6.89 (m, 4H), 6.46ꢀ6.43 (m, 2H), 4.97 (d, J = 16.8, 1H), 4.87 (d, J = 16.8, 1H), 3.91 (q, J =7.2 Hz,
4
5
6
7
8
9
1
1
1
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1
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1
1
1
1
2
2
2
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3
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3
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3
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1
3
2
1
4
3
H), 3.82 (s, 3H), 3.79 (s, 3H), 3.61 (s, 3H), 0.84 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 165.2, 161.2, 158.9,
57.9, 137.9, 134.4, 133.3, 131.6, 128.6, 128.4, 126.9, 126.8, 126.0, 122.9, 114.1, 112.8, 112.6, 104.0, 98.4, 58.8, 55.2, 55.2, 55.1,
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
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
8.0, 13.7, 10.7 ppm; ESIꢀHRMS: calcd. for C30
H32NO
5
(M+H) 486.2275, found 486.2250.
Ethyl 1ꢀbenzylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀ(pꢀtolyl)ꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3n). Purified by flash column
o
1
3
chromatography (Hexane/EtOAc = 10:1); 65.0 mg, 74% yield; yellow solid (mp: 101ꢀ103 C); H NMR (400 MHz, CDCl ) δ
7
.29ꢀ7.11 (m, 9H), 6.92ꢀ6.90 (m, 4H), 4.96 (s, 2H), 3.91 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.34 (s, 3H), 2.01 (s, 3H), 0.83 (t, J = 7.2
13
Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 165.2, 158.0, 138.1, 137.8, 137.8, 131.5, 130.5, 129.4, 128.6, 128.5, 128.4, 127.1,
3
+
1
26.8, 125.6, 122.8, 112.9, 112.3, 59.0, 55.1, 47.8, 21.2, 13.6, 10.6 ppm; ESIꢀHRMS: calcd. for C29
H30NO
3
(M+H) 440.2220,
found 440.2208.
Ethyl 1ꢀbenzylꢀ2ꢀ(4ꢀbromophenyl)ꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3o). Purified by flash
o
1
column chromatography (Hexane/EtOAc = 10:1); 71.4 mg, 71% yield; pale yellow solid (mp: 121ꢀ124 C); H NMR (400 MHz,
CDCl ) δ 7.45ꢀ7.43 (m, 2H), 7.31ꢀ7.22 (m, 5H), 7.16ꢀ7.14 (m, 2H), 6.93ꢀ6.87 (m, 4H), 4.94 (s, 2H), 3.92 (q, J = 7.2 Hz, 2H), 3.83
3
13
(
s, 3H), 2.03 (s, 3H), 0.85 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl
3
) δ 164.9, 158.1, 137.5, 136.5, 132.3, 131.5, 131.0,
128.8, 128.1, 127.5, 127.3, 125.5, 123.1, 122.5, 113.0, 112.7, 59.2, 55.2, 47.9, 13.6, 10.5 ppm; ESIꢀHRMS: calcd. for C28H27BrNO
3
+
(
M+H) 506.1148, found 506.1143.
Methyl 1ꢀbenzylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ2,5ꢀdimethylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3p). Purified by flash column
1
chromatography (Hexane/EtOAc = 10:1); 64.7 mg, 93% yield; pale yellow oil; H NMR (400 MHz, CDCl ) δ 7.34ꢀ7.24 (m, 3H),
3
7.19ꢀ7.17 (m, 2H), 6.96ꢀ6.89 (m, 4H), 5.10 (s, 2H), 3.82 (d, J = 2.0 Hz, 3H), 3.60 (d, J = 1.6 Hz, 3H), 2.48 (s, 3H), 2.02 (s, 3H)
13
ppm; C NMR (100 MHz, CDCl
3
) δ 166.4, 157.9, 137.0, 134.9, 131.4, 128.9, 128.8, 127.4, 126.1, 125.6, 122.2, 112.9, 110.6, 55.1,
+
50.3, 47.1, 11.6, 10.3 ppm; ESIꢀHRMS: calcd. for C22
H24NO
3
(M+H) 350.1751, found 350.1734.
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Methyl 4ꢀ(4ꢀmethoxyphenyl)ꢀ2,5ꢀdimethylꢀ1ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3q). Known compound; Purified by flash
1
column chromatography (Hexane/EtOAc = 10:1); 36.2 mg, 54% yield; pale yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.57ꢀ7.48
1
3
(
m, 3H), 7.29ꢀ7.28 (m, 4H), 6.97ꢀ6.95 (m, 2H), 3.88 (s, 3H), 3.70 (s, 3H), 2.35 (s, 3H), 1.92 (s, 3H) ppm; C NMR (100 MHz,
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CDCl
3
) δ 166.4, 158.0, 137.9, 135.6, 131.4, 129.4, 128.6, 128.5, 128.3, 126.8, 121.9, 113.0, 110.8, 55.2, 50.4, 12.7, 11.2 ppm;
+
ESIꢀHRMS: calcd. for C21
H22NO
3
(M+H) 336.1594, found 336.1582.
1
ꢀBenzylꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylꢀ6,7ꢀdihydroꢀ1Hꢀindolꢀ4(5H)ꢀone (3r). Purified by flash column chromatography
1
(
Hexane/EtOAc = 5:1); 40.7 mg, 59% yield; brown oil; H NMR (400 MHz, CDCl
3
) δ 7.38ꢀ7.28 (m, 5H), 7.00ꢀ6.98 (m, 2H),
13
6
.93ꢀ6.90 (m, 2H), 5.10 (s, 2H), 3.83 (s, 3H), 2.71 (t, J = 6.4 Hz, 2H), 2.46 (t, J = 6.4 Hz, 2H), 2.15ꢀ2.09 (m, 5H) ppm; C NMR
(
100 MHz, CDCl
3
) δ 193.3, 158.0, 143.1, 136.7, 131.5, 129.0, 127.6, 127.4, 127.2, 125.7, 120.3, 117.6, 113.0, 55.2, 47.3, 38.8,
+
2
3.4, 22.3, 10.1 ppm; ESIꢀHRMS: calcd. for C23
H24NO
2
(M+H) 346.1802, found 346.1790.
Ethyl 1ꢀbenzylꢀ5ꢀmethylꢀ2,4ꢀdiphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3s). Purified by flash column chromatography
1
(
Hexane/EtOAc = 20:1); 56.1 mg, 71% yield; yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.38ꢀ7.20 (m, 13H), 6.91ꢀ6.89 (m, 2H),
13
4
1
.96 (s, 2H), 3.92ꢀ3.86 (m, 2H), 2.03 (s, 3H), 0.78 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 165.2, 138.2, 137.8,
3
36.1, 132.5, 130.6, 130.6, 128.7, 128.2, 127.9, 127.5, 127.3, 127.2, 126.1, 125.7, 123.5, 112.5, 59.2, 48.0, 13.6, 10.7 ppm;
+
ESIꢀHRMS: calcd. for C27
H26NO
2
(M+H) 396.1958, found 396.1943.
Ethyl 1ꢀbenzylꢀ5ꢀmethylꢀ2ꢀphenylꢀ4ꢀ(pꢀtolyl)ꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3t) Purified by flash column chromatography
1
(Hexane/EtOAc = 20:1); 61.4 mg, 75% yield; orange oil; H NMR (400 MHz, CDCl
3
) δ 7.32ꢀ7.16 (m, 12H), 6.90 (d, J =6.8 Hz,
13
2
H), 4.96 (s, 2H), 3.89 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 2.03 (s, 3H), 0.78 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ
3
165.2, 137.9, 137.8, 135.5, 132.9, 132.6, 130.7, 130.3, 128.7, 128.3, 128.1, 127.8, 127.2, 127.0, 125.7, 123.4, 112.5, 59.1, 47.9,
+
2
1.2, 13.5, 10.6 ppm; ESIꢀHRMS: calcd. for C28
H28NO
2
(M+H) 410.2115, found 410.2099.
Ethyl 1ꢀbenzylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3u). Purified by flash column
1
chromatography (Hexane/EtOAc = 20:1); 53.2 mg, 62% yield; orange oil; H NMR (400 MHz, CDCl
3
) δ 7.35ꢀ7.27 (m, 10H),
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.25ꢀ7.23 (m, 2H), 6.90ꢀ6.88 (m, 2H), 4.96 (s, 2H), 3.89 (q, J = 7.2 Hz, 2H), 2.01 (s, 3H), 0.80 (t, J = 7.2 Hz, 3H) ppm; C NMR
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(
100 MHz, CDCl
3
) δ 164.9, 138.4, 137.6, 134.5, 132.3, 132.0, 131.9, 130.7, 128.7, 128.6, 128.2, 127.9, 127.7, 127.3, 125.7, 122.3,
+
1
12.2, 59.2, 48.0, 13.6, 10.6 ppm; ESIꢀHRMS: calcd. for C H ClNO (M+H) 430.1568, found 430.1549.
2
7
25
2
0
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Ethyl 1ꢀbenzylꢀ4ꢀ(3,4ꢀdichlorophenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3v). Purified by flash column
1
chromatography (Hexane/EtOAc = 20:1); 50.0 mg, 54% yield; orange yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.35ꢀ7.28 (m, 2H),
13
7
.25ꢀ7.09 (m, 9H), 6.80 (d, J = 7.2 Hz, 2H), 4.87 (s, 2H), 3.82 (q, J = 7.2 Hz, 2H), 1.94 (s, 3H), 0.74 (t, J = 7.2 Hz, 3H) ppm;
C
NMR (100 MHz, CDCl
3
) δ 164.7, 138.7, 137.4, 136.3, 132.4, 132.1, 131.4, 130.6, 130.1, 129.4, 128.8, 128.3, 127.9, 127.5, 127.4,
+
1
25.6, 121.1, 112.1, 59.3, 48.0, 13.6, 10.6 ppm; ESIꢀHRMS: calcd. for C H Cl NNaO (M+Na) 486.0998, found 486.1021.
2
7
23
2
2
Ethyl 1ꢀbenzylꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3w). Purified by flash column
1
chromatography (Hexane/EtOAc = 10:1); 45.9 mg, 54% yield; yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.34ꢀ7.23 (m, 9H),
1
3
6
.95ꢀ6.93 (m, 4H), 6.91 (m, 1H), 4.97 (s, 2H), 3.91 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 2.05 (s, 3H), 0.81 (t, J = 7.2 Hz, 3H) ppm; C
NMR (100 MHz, CDCl
3
) δ 165.1, 158.9, 138.0, 137.7, 137.4, 132.3, 130.7, 128.7, 128.4, 128.1, 127.8, 127.2, 127.1, 125.7, 123.2,
+
1
23.1, 116.1, 112.5, 111.7, 59.2, 55.2, 47.9, 13.5, 10.6 ppm; ESIꢀHRMS: calcd. For C H NO (M+H) 426.2064, found 426.2060.
28 28
3
Ethyl 1ꢀbenzylꢀ4ꢀ(2ꢀfluorophenyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3x). Purified by flash column
1
chromatography (Hexane/EtOAc = 20:1); 47.1 mg, 57% yield; yellow oil; H NMR (400 MHz, CDCl
3
) δ 7.31ꢀ7.23 (m, 10H),
13
7
.18ꢀ7.07 (m, 2H), 6.90 (d, J = 6.8 Hz, 2H), 4.97 (s, 2H), 3.90 (q, J = 7.2 Hz, 2H), 2.01 (s, 3H), 0.80 (t, J = 7.2 Hz, 3H) ppm;
C
3
NMR (100MHz, CDCl ) δ 164.7, 160.6 (d, JCꢀF = 244.0 Hz), 138.5, 137.7, 132.6 (d, JCꢀF = 4.0 Hz), 132.3, 130.8, 128.7, 128.2 (d,
JCꢀF = 8.0 Hz), 128.1, 127.9, 127.8, 127.2, 125.6, 124.0 (d, JCꢀF = 16.0 Hz), 123.2 (d, JCꢀF = 3.0 Hz), 116.4, 115.0 (d, JCꢀF = 23.0 Hz),
+
112.7, 59.1, 47.9, 13.5, 10.6 ppm; ESIꢀHRMS: calcd. For C27
H25FNO
2
(M+H) 414.1864, found 414.1829.
Ethyl 1ꢀbenzylꢀ4ꢀ(furanꢀ2ꢀyl)ꢀ5ꢀmethylꢀ2ꢀphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3y). Purified by flash column
1
chromatography (Hexane/EtOAc = 20:1); 43.9 mg, 57% yield; red oil; H NMR (400 MHz, CDCl
3
) δ 7.48ꢀ7.47 (m, 1H), 7.34ꢀ7.23
(
m, 8H), 6.89 (d, J = 6.8 Hz, 2H), 6.47ꢀ6.46 (m, 1H), 6.46 (d, J = 1.6 Hz, 1H), 4.95 (s, 2H), 3.98 (q, J = 7.2 Hz, 2H), 2.16 (s, 3H),
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0
3
.90 (t, J = 7.2 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 164.7, 149.1, 141.1, 138.4, 137.4, 132.0, 130.7, 129.4, 128.7, 1283,
+
1
3
27.9, 127.3, 125.7, 112.7, 112.7, 110.6, 108.2, 59.4, 47.9, 13.7, 11.0 ppm; ESIꢀHRMS: calcd. for C25H24NO (M+H) 386.1751,
found 386.1739.
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Ethyl 1,5ꢀdibenzylꢀ2,4ꢀdiphenylꢀ1Hꢀpyrroleꢀ3ꢀcarboxylate (3a’). Purified by flash column chromatography
o
1
(
Hexane/EtOAc = 20:1); 57.1 mg, 57% yield; white solid (mp: 158ꢀ160 C); H NMR (400 MHz, CDCl
3
) δ 7.40ꢀ7.17 (m, 16H),
13
7
.03ꢀ7.01 (m, 2H), 6.80ꢀ6.79 (m, 2H), 4.70 (s, 2H), 3.92 (q, J = 7.2 Hz, 2H), 3.73 (s, 2H), 0.79 (t, J = 7.2 Hz, 3H) ppm; C NMR
(
100 MHz, CDCl
3
) δ 165.1, 139.4, 139.0, 137.8, 135.8, 132.2, 130.7, 130.3, 128.9, 128.7, 128.6, 128.2, 127.8, 127.6, 127.2, 126.4,
+
1
3
26.3, 125.6, 125.6, 112.7, 59.2, 47.9, 30.5, 13.5 ppm; ESIꢀHRMS: calcd. for C H NO (M+H) 472.2271, found 472.2256.
3
3
30
2
. Gramꢀscale reaction in Scheme 2. A mixture of enamino ester 1 (4.0 mmol, 1.0 equiv), propargyl acetate 2 (4.8 mmol, 1.2
2
equiv), Cu(OTf) (0.2 mmol, 5 mol%) and toluene (10 mL) was stirred at room temperature for 30 seconds and then heated at 150
o
C for 20 minutes under microwave irradiation. The reaction mixture was then cooled to room temperature and purified directly by
a silica gel flash chromatography (Hexane/EtOAc) giving compound 3a (1.53 g, 90% yield) as yellow gum.
4. General procedure for control reactions in Scheme 2. A mixture of amine (0.2 mmol, 1.0 equiv), βꢀketoester (0.2 mmol, 1.0
2
equiv), propargyl acetate 2 (0.24 mmol, 1.2 equiv), Cu(OTf) (0.04 mmol, 20 mol%) and toluene (1 mL) was stirred at room
o
temperature for 30 seconds and then heated at 150 C for 20 minutes under microwave irradiation. The reaction mixture was cooled
to room temperature, passed through a short pad of silica gel (eluated with Hexane/EtOAc 2:1) and concentrated by rotary
1
evapration. The yield was then determined by H NMR using CH
2
Br
2
as internal standard.
5
. DꢀH exchange experiment in Scheme 2. A mixture of enamino ester 1 (0.20 mmol, 1.0 equiv), propargyl acetate 2 (0.24 mmol,
2 2
1.2 equiv), Cu(OTf) (0.01 mmol, 5 mol%), D O (50 ꢁL) and toluene (1 mL) was stirred at room temperature for 30 seconds and
o
then heated at 150 C for 20 minutes under microwave irradiation. The reaction mixture was then cooled to room temperature and
purified directly by a silica gel flash chromatography (Hexane/EtOAc) giving compound 3a.
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ACKNOWLEDGMENT We are grateful for the support provided for this study by the National Science Foundation of China
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(
21502013), the Scientific and Technological Research Program of the Chongqing Municipal Education Commission (KJ1501111),
and Chongqing University of Arts and Sciences.
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Supporting Information Available: H NMR and C NMR spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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(
(
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K. J. Org. Chem. 2012, 77, 10441.
(
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Nishibayashi, Y. ChemCatChem. 2009, 1, 342. (c) Detz, R. J.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2009, 6263.
(
d) Nishibayashi, Y. Synthesis 2012, 489. (e) Zhang, D.ꢀY.; Hu, X.ꢀP.; Tetrahedron. Lett. 2015, 56, 283.
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(
5) Hidai and Uemura firstly reported a Ruthenium and Platinumꢀcatalyzed sequential reactions of proparglic alcohols, ketones and
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anilines delivering tetrasubstituted pyrroles. See : Nishibayshi, Y. ; Yoshikawa, M. ; Inada, Y. ; Milton, M. D. ; Hidai, M. ; Uemura,
S. Angew. Chem. Int. Ed. 2003, 42, 2681.
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(
6) Cadierno, V. ; Gimeno, J. ; Nebra, N. Chem.-Eur. J. 2007, 13, 9973.
7) (a) Liu, X.ꢀt. ; Huang, L. ; Zheng, F.ꢀj. ; Zhang, Z.ꢀp. Adv. Synth. Catal. 2008, 350, 2778. (b) Liu, X.ꢀt.; Hao, L. ; Lin, M. ; Chen,
L. ; Zhan, Z.ꢀp. Org. Biomol. Chem., 2010, 8, 3064.
(
(
(
8) Chatterjee, P. N. ; Roy, S. Tetrahedron 2011, 67, 4569.
9) Gujarathi, S. ; Liu, X. ; Song, L. ; Hendrickson, H. ; Zheng, G. Tetrahedron 2014, 70, 5267.
10) Aromatic βꢀketoester is also less active than alkylated βꢀketoesters in the synthesis of furan rings through a
propargylation/alkyne oxacyclization/isomerization cascade strategy. The former type of βꢀketoesters cost a much longer reaction
time and gave a dramatically decreased yield. See: Cadierno, V.; Gimeno, J.; Nebra, N. Adv. Synth. Catal. 2007, 349, 382.
(
11) For reviews on synthesis of αꢀarylꢀsubstituted pyrroles by direct arylation of pyrroles, see: (a) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. Rev. 2007, 36, 1173. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (c) Ackermann, L.; Vicente,
R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48, 9792.
(12) For a microwave assisted synthesis of βꢀenamino esters with βꢀketoester, see experimental section.
(
13) Yoshida and coꢀworker reported a palladiumꢀcatalyzed synthesis of tetrasubstituted pyrroles with propargylic carbonates and
Tosylꢀprotected βꢀenamino esters through the formation of πꢀpropargylpalladium complex. In this study the decomposition of
benzylꢀsubstituted βꢀenamino ester was observed. See: Yoshida, M.; Sugimura, C. Tetrahedron. Lett. 2013, 54, 2082.
(14) For selected examples on the synthesis of multisubstituted pyrroles with βꢀenamino esters, see: (a) Reddy, B. V. S.; Reddy, M.
R.; Rao, Y. G.; Yadav, J. S.; Sridhar, B. Org. Lett. 2013, 15, 464. (b) Ke, J.; He, C.; Liu, H.; Li, M.; Lei, A. Chem. Commun. 2013,
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Chem., 2015, 13, 5867. (e) Abdukader, A.; Xue, Q.; Lin, A.; Zhang, M.; Cheng, Y.; Zhu, C. Tetrahedron Lett 2013, 54, 5898. (f)
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15) Preformed βꢀenamino esters may not be suitable substrates for the synthesis of fully substituted pyrroles in other systems. For
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