A mild and efficient AgSbF6-catalyzed synthesis of fully substituted pyrroles through a sequential propargylation/amination/ cycloisomerization reaction

Article abstract of DOI:10.1016/j.tet.2014.05.073

Development of an efficient synthesis of fully substituted pyrroles via a sequential propargylation/amination/cycloisomerization was accomplished using AgSbF₆ as a catalyst. The one-pot three-component reaction of propargylic alcohols, 1,3-dica

Full text of DOI:10.1016/j.tet.2014.05.073

Accepted Manuscript
A mild and efficient AgSbF -catalyzed synthesis of fully substituted pyrroles through a
6
sequential propargylation/amination/cycloisomerization reaction
Satheesh Gujarathi , Xingui Liu , Lin Song , Howard Hendrickson , Guangrong Zheng
PII:
S0040-4020(14)00767-4
10.1016/j.tet.2014.05.073
TET 25622
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 April 2014
Revised Date: 16 May 2014
Accepted Date: 19 May 2014
Please cite this article as: Gujarathi S, Liu X, Song L, Hendrickson H, Zheng G, A mild and efficient
AgSbF -catalyzed synthesis of fully substituted pyrroles through a sequential propargylation/amination/
6
cycloisomerization reaction, Tetrahedron (2014), doi: 10.1016/j.tet.2014.05.073.
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ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A mild and efficient AgSbF6-catalyzed synthesis of fully substituted pyrroles through
a sequential propargylation/amination/cycloisomerization reaction
Satheesh Gujarathi, Xingui Liu, Lin Song, Howard Hendrickson, Guangrong Zheng
*
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences,
Little Rock, AR 72205, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Development of an efficient synthesis of fully substituted pyrroles via a sequential
propargylation/amination/cycloisomerization was accomplished using AgSbF6 as a catalyst. The
one-pot three-component reaction of propargylic alcohols, 1,3-dicarbonyl compounds, and
primary amines proceeds at a mild temperature, which prevents the formation of furan by-
product. The reaction was also successfully applied to the more basic aliphatic amines with the
addition of 1.1 eq. of acetic acid.
Available online
Keywords:
Propargylation
AgSbF6
2009 Elsevier Ltd. All rights reserved
.
Cycloisomerization
Pyrrole
Heterocycles
Scheme 1). The IrIII-SnIV method only works on aromatic primary
amines.14 The InCl3 method appears to be the most attractive
because of the low cost of catalyst and the wide substrate
compatibility, but a relatively high temperature (reflux in
toluene) is required.13 Therefore, it is still desirable to further
develop mild, highly efficient, and inexpensive reaction systems
for this one-pot transformation.
1. Introduction
There is a great interest in developing efficient synthetic
routes to structurally diverse heterocycles from readily available
simple starting materials, especially in pharmaceutical chemistry
where heterocycles are predominant building blocks.1 Pyrrole,
one of the major heterocycles, is embedded in many biologically
active compounds of both natural and synthetic origin, and is also
present in many organic materials.2,3 Compounds with pyrrole
ring as a key structural motif display an impressive range of
biological properties,3 such as antibacterial,4 antifungal,5 anti-
inflammatory,6 antitubulin,7 anticonvulsant,8 and hypnotic9
activities. Consequently, considerable efforts have been made in
developing methods for construction of the pyrrole ring.10 The
most efficient and versatile strategy for the assembly of pyrroles
is via multicomponent reactions in which three or more starting
materials undergo a series of chemical reactions in a single-pot
without separation and purification of intermediates.3,10a,10h,11 One
prominent example of this strategy is the synthesis of fully
O
O
O
R4
R3
R1
OH
R3
R4
catalyst(s)
R1
2
N
R5
R2
1
R5-NH2
R2
4
3
Cycloisomerization
5-exo-dig
Propargylation
O
R3
O
O
R4
R5
R2
Amination
R4
R3
N
H
R1
R1
R2
5
6
substituted
pyrroles
4
through
a
sequential
propargylation/amination/cycloisomerization
reaction of
propargylic alcohols 1, 1,3-dicarbonyl compounds 2, and primary
amines 3 (Scheme 1).12-14 Three methods have been reported for
this type of one-pot process, including a cooperative [Ru(ŋ3-2-
C3H4Me)(CO)(dppf)][SbF6]/trifluoroacetic acid (TFA) catalytic
system,12 a single metal catalyst InCl3,13 and more recently, a
heterobimetallic catalyst [Ir(COD)(SnCl3)Cl(µ-Cl)]2 (IrIII-SnIV).14
A noticeable limitation of the first method is the high cost of
catalyst and the propargylic alcohols used in the method appear
to be limited to the ones with a terminal alkyne group (R2 = H,
O
H
R4
O
O
R3
R1
Cycloisomerization
5-exo-dig
R3
R4
O
R1
R2
R2
8
7
Scheme 1. One-pot synthesis of fully substituted pyrroles and
the competing furan formation.
Corresponding author. Tel.: +1-501-526-6787; fax: +1-501-526-5945; e-mail: gzheng@uams.edu

A number of Brønsted and Lewis acid catalysts have been
was required with 1,2-DCE as solvent (Table 1, entry 11), while
CH3CN did not promote the formation of 4a and the yield of 4a was
poor when CH3NO3 was used as solvent.
ACCEPTED MANUSCRIPT
reported for the nucleophilic substitution of propargylic alcohols
1 with 1,3-dicarbonyl compounds 2 to form compounds 5
(Scheme 1).15 Some of these catalysts have been shown to
facilitate the subsequent amination/cycloisomerization for the
conversion of 5 to pyrroles 4, although in poor yields.13 In
relation to our recent efforts on the synthetic application of
propargylic alcohols,16 we expanded the list of catalytic systems
for the conversion of 1,3-diphenylpropargylic alcohol 1a and
ethyl acetoacetate 2a to compound 5a (Table 1). Further
exploration of these catalysts on the subsequent
amination/cycloisomerization with aniline 3a led to the discovery
of a novel AgSbF6-catalyzed, efficient and mild one-pot synthesis
of fully substituted pyrroles that we report herein.
The mechanism for the present AgSbF6-catalyzed one pot
pyrrole formation is likely to be similar to previously proposed
InCl3-catalyzed reaction.13
Table 1. Screening of reaction conditions for the formation of
fully substituted pyrroles
2. Results and discussion
Temp Time Temp Time Yield
Entrya Catalyst
Solvent
CH3CN
(°C)b
(h)c
(°C)d
(h)e
(%)f
We selected 1a, 2a, and aniline 3a as the model starting materials
t
o
survey catalysts and reaction conditions for the one-pot
Amberlite
1
reflux
2
reflux 12
0
IR-120Hg
propargylation/amination/cycloisomerization reaction. In addition to
Amberlite IR-120H in acetonitrile (CH3CN) (Table 1, entry 1),16 we
found a number of catalytic systems, including Zn(OTf)2 in toluene,
Sc(OTf)3 in toluene, Yb(OTf)3 in BMIM-PF6, Bi(NO3)3 in toluene,
Bi(OTf)3 in toluene, AgPF6 in toluene, AgBF4 in toluene, and
AgSbF6 in toluene, were also capable of facilitating the nucleophilic
substitution of 1a with 2a to form intermediate 5a under mild heating
(60 °C) (Table 1, entries 2-9). Upon completion of the conversion
from 1a to 5a (0.5-3 hours, monitored by TLC and GC-MS), aniline
3a was added to the reaction mixture to carry out the subsequent
amination/cycloisomerization reaction. We were delighted to find
that the fully substituted pyrrole 4a was formed in the presence of
Zn(OTf)2, Yb(OTf)3, Bi(NO3)3, Bi(OTf)3, AgPF6, AgBF4, and
AgSbF6 (Table 1, entries 2, 5-9), among which AgSbF6 gave the best
results with 82% isolated yield (Table 1, entry 9). With AgSbF6, the
amination/cycloisomerization reaction proceeded smoothly at 60 °C,
no by-products were observed from TLC and GC-MS analysis. The
reaction took place without exclusion of air or moisture from the
reaction mixture. However, when other catalysts were used, reflux
temperature of toluene (110 °C) was required for the conversion of
5a to 4a. Due to the high temperature used in these reactions, a
significant amount of 5a was converted into furan 8a (Scheme 1,
where R1=R2=Ph, R3=OEt, R4=Me), which was partially co-eluted
with 4a on a silica gel column, leading to low yields of 4a and
tedious purification process. The side reaction was somewhat
predictable since several Lewis acids, including InCl3,15e FeCl3,17 and
Cu(OTf)2,15g have previously been shown to efficiently catalyze
furan formation at high temperature (from 1 and 2 to 8 via 5, Scheme
1). Although not explicitly discussed, we suspect that the furan
formation could have occurred in the previously reported InCl3–
catalyzed pyrrole formation reaction due to the high temperature.13,18
Interestingly, we observed that in the absence of catalysts,
intermediate 5a could also be converted into the corresponding furan
in toluene under reflux, albeit in low rate.19 Thus, reaction
temperature played a key role in the formation of furan by-product.
The superior results obtained under AgSbF6 are likely due to its
ability of facilitating the amination/cycloisomerization reaction at a
temperature not high enough for the furan formation.
2
3
Zn(OTf)2
Sc(OTf)3
toluene
toluene
60
60
1
1
reflux 12
reflux 14
37
0
BMIM-
PF6
4
Yb(OTf)3
60
0.5
100
10
0
5
Bi(NO3)3
Bi(OTf)3
AgPF6
toluene
toluene
toluene
toluene
toluene
CH3CN
60
60
60
60
60
Rt
2
reflux 12
reflux 14
reflux 14
reflux 14
35
54
25
18
82
0
6
2
7
2
8
AgBF4
3
9
AgSbF6
AgSbF6
0.5
1
60
6
10
reflux 12
reflux 12
1,2-
DCE
11
12
AgSbF6
AgSbF6
60
0.5
1
76
31
CH3NO2 Rt
60
12
aReaction conditions: 1a/2a/catalyst = 0.5:0.55:0.025 in 2 mL solvent; 3a
(0.55 mmol) added after 1a fully consumed; reaction temperature and time as
indicated.
bReaction temperature for 5a formation.
cReaction time for 5a formation.
dReaction temperature for amination/cycloisomerization.
eReaction time for amination/cycloisomerization.
fIsolated yields of 4a.
g150 mg catalyst was used.
The scope and limitations of this novel AgSbF6-catalyzed one-
pot pyrrole synthesis was then explored under the standard
conditions (Table 1, entry 9). We initially applied the reaction
procedure to 1a and 2a with a series of substituted anilines
(Table 2, entries 2-6). The reactions proceeded smoothly,
yielding the corresponding pyrroles in good isolated yields. It is
interesting to note that every reaction gave a single product peak
on GC-MS and practically identical isolated yields were obtained
with different anilines, although electron-donating group (entry
5, methoxy) substituted aniline appeared to react slightly faster
when compared to electron-withdrawing group (entries 2-4, and
6, halogens and methyl ester) substituted anilines.
The reaction also tested in CH3CN, 1,2-dichloroethane (1,2-
DCE), and nitromethane (CH3NO3) (Table 1, entries 10-12). The
results indicated that the propargylation reaction could tolerate
different solvents; 5a was rapidly formed at 60 °C when 1,2-DCE
was used as solvent or at room temperature when CH3CN or
CH3NO3
was
used
as
solvent.
However,
the
amination/cycloisomerization reaction was remarkably sensitive to
solvents. Toluene was found to be the most effective for the
conversion of 5a to 4a. Compared to toluene, a longer reaction time

ACCEPTED MANUSCRIPT
(entries 8 and 13) substituted and electron-withdrawing group
Table 2. Synthesis of fully substituted pyrroles 4 from
anilines 3a
(entries 7, 9, 10 and 11, halogens) substituted 1,3-diphenyl
propargylic alcohols participated well in the reaction. However,
no propargylation of 2a with 4-cyano substituted 1,3-diphenyl
propargylic alcohol 1f was observed in toluene even at reflux
temperature. This can be explained by the destabilization effect
of the strong electron-withdrawing cyano group on the putative
carbocation intermediate from propargylic alcohol. It appeared
the destabilization effect could be compensated by an increase in
solvent polarity; when toluene was replaced by 1,2-DCE, the
one-pot reaction proceeded smoothly at reflux temperature, and
completed in 16 h to afford 4k in 75% isolated yield (Table 2,
entry 11). Good yields were also obtained when acetylacetone 2b
was used in place of 2a (Table 2, entries14-18). However, when
The scope of the application was then extended to various
benzylic phenyl ring-substituted 1,3-diphenyl propargylic
alcohols (Table 2, entries 7-13). Both electron-donating group
Entry
Propargylic alcohol
Dicarbonyl
compound
Amine
Product
Time (h)b
Isolated yield
1
2
3
4
5
6
7
8
9
1a (R1=Ph)
3a (R6=H)
4a
4b
4c
4d
4e
4f
6
6
8
7
5
8
8
6
6
82%
74%
75%
76%
74%
77%
73%
75%
73%
1a
3b (R6=Cl)
3c (R6=Br)
3d (R6=I)
1a
1a
1a
3e (R6=OMe)
3f (R6=CO2Me)
3a (R6=H)
2a
1a
1b ( R1=4-F-Ph)
1c ( R1=4-MeO-Ph)
1d ( R1=3-Cl-Ph)
2a
2a
2a
4g
4h
4i
3a (R6=H)
3a (R6=H)
10
11
12
13
1e ( R1=4-Cl-Ph)
2a
2a
2a
2a
3b (R6=Cl)
3b (R6=Cl)
3b (R6=Cl)
3b (R6=Cl)
4j
5
74%
75%d
74
O
EtO
R1
1f ( R1=4-CN-Ph)
1b ( R1=4-F-Ph)
4k
4l
16c
10
7
N
Cl
Ph
1g ( R1=3,4-(OCH2O)-Ph)
4m
71%
14
15
16
17
18
1a ( R1=Ph)
3a (R6=H)
4n
4o
4p
4q
4r
8
73%
73%
73%
73%
78%
1c ( R1=4-MeO-Ph)
1h ( R1=3,4,5-(MeO)3Ph)
1h ( R1=3,4,5-(MeO)3Ph)
1h ( R1=3,4,5-(MeO)3Ph)
3a (R6=Cl)
3f (R6=CO2Me)
3b (R6=Cl)
3c (R6=Br)
7
8
2b
10
8
19
20
1a ( R1=Ph)
3a (R6=H)
-
12e
0
2c
2a
1i
1j
3a (R6=H)
3a (R6=H)
4s
4s
6
6
Trace
30%
21
2a
aReaction conditions: AgSbF6 (0.025 mmol), 1 (0.5 mmol), and 2 (0.55 mmol) in 2 mL toluene at 60 °C for 0.5-2 h, 3 (0.55 mmol) then added
and reaction continued at 60 °C for the period of time indicated.
bTime for amination/cycloisomerization.
cReflux in 1,2-DCE.
dIsolated yield from reaction in 1,2-DCE; no reaction was observed in toluene.
eReflux in toluene.

1,3-diphenyl diketone 2c was used, the propargylation of 2c with
neutral or slightly acidic pH. Under this modified method, 1-
ACCEPTED MANUSCRIPT
1a
went
smoothly,
but
no
subsequent
phenylhept-2-yn-1-ol (1k) also worked well with 4-bromo
phenethylamine 3n, yielding the corresponding pyrrole in good
yield (entry 9). Amino alcohols 3i and 3j also gave satisfactory
results with the addition of acetic acid; clean and complete
conversion to the corresponding pyrroles 4w and 4x,
respectively, was observed (entries 4 and 5). In addition, amino
acids as substrates were examined, in which 12-aminododecanoic
acid 3k proceeded smoothly to the corresponding pyrrole 4y in
71% isolated yield (entry 6). However, no desired product was
obtained when glycine 3l was used (entry 7), likely due to the
poor solubility of glycine in toluene. After protection of the
carbonyl acid group of glycine with a t-butyl group, the resulting
compound 3m worked well to afford the corresponding pyrrole
4z in 73% isolated yield (entry 8).
amination/cycloisomerization with aniline occurred after 12 h
reflux in toluene (Table 2, entry 19). We also investigated the
reactivity of 1-phenyl propargylic alcohol 1i under the standard
conditions (Table 2, entry 19). Treatment of 1i with 2a followed
by adding aniline 3a resulted in a complex mixture. Trace
amount of compound 4s was detected by GC-MS, but
purification attempts of by column chromatography on silica gel
were unsuccessful. When the terminal alkyne of 1i was capped
with a trimethylsilyl group, the resulting propargylic alcohol 1j
reacted smoothly with 2a and 3a. Surprisingly, the resulting
pyrrole product turned out to be 4s (Table 2, entry 20). Cleavage
of the trimethylsilyl group occurred during the process.
We extended the scope of the one-pot procedure by employing
aliphatic primary amines (Table 3). Propargylation of 2a with 1a
followed by the addition of benzylamine 3g or phenethylamine
3h afforded the corresponding pyrroles 4t and 4u, respectively.
Unfortunately, the purification process for these products was
tedious. Unlike the reactions involving aniline derivatives which
routinely afforded a single product, reactions using 3g and 3h
resulted in the formation of furan 8 (general structure as in
Scheme 1) by-products as determined by GC-MS. We reasoned
that the higher basicity of aliphatic amines, relative to anilines,
was responsible for promoting the O-cycloisomerization. In fact,
furan formation from propargylated dicarbonyl intermediates
under stoichiometric amount of inorganic bases has been
reported.14,15b Gratifyingly, modification of the reaction by adding
1.1 equiv (relative to amine) of acetic acid to the reaction mixture
completely eliminated the formation of furans; 4t and 4u were
isolated in good yields (Table 3, entries 1 and 2). Thus, the key to
avoiding the furan by-product is to maintain the reaction at near
3. Conclusions
In summary, we have developed a highly efficient method for
the direct nucleophilic substitution of the hydroxyl group of
propargylic alcohols with 1,3-dicarbonyl compounds, and the
sequential formation of fully substituted pyrroles with a wide
range of primary amines in a simple one-pot operation. The
AgSbF6
catalyzed
sequential
propargylation/amination/cycloisomerization reaction proceeds at
a relatively mild temperature (60 °C), which is advantageous in
preventing the formation of furan byproduct. In addition, furan
formation when aliphatic primary amines are used can be
effectively avoided by adding 1.1 equiv. of acetic acid to the
reaction. The method presented here could be a valuable addition
to the available strategies of pyrrole synthesis.

ACCEPTED MANUSCRIPT
Table 3. Synthesis of fully substituted pyrroles 4 from aliphatic primary amines 3
Entrya
Propargylic alcohol
Amine
Product
Time (h)b
Isolated yield
77%
1
1a (R1=Ph, R2=Ph)
6
3g
4t
2
1a
3h
4u
1c
82%
1b (R1=4-F-Ph,
3
4
R2=Ph)
3h
3i
4v
3
6
77%
76%
1a
1a
4w
5
7
76%
3j
4x
4y
6
7
14
71%
0
1a
1a
3k
3l
-
14d
8
9
1a
4z
6
73%
67%
3m
1k (R1=Ph, R2=n-Bu)
3n
4aa
14
aReaction conditions: same as in Table 2 except 1.1 equiv of HOAc was added together with 3.
bReaction time for amination/cycloisomerization.
c50 °C.
dReflux.
spectrometer (GC-MS). Melting points were measured on a
capillary melting point apparatus and are uncorrected. All
reagents and solvents were purchased from commercial sources
and used without further purification. Propargylic alcohols 1b-1h
and 1k were prepared by reacting lithium phenylacetylide (10
mmol, 1M in THF) with an appropriate aldehyde (10 mmol) at -
78 °C.
4. Experimental section
4.1. General
NMR spectra were recorded with 400 MHz spectrometers
for 1H NMR, 100 MHz for 13C NMR. Chemical shifts δ are given
in ppm using tetramethylsilane as an internal standard.
Multiplicities of NMR signals are designated as singlet (s), broad
singlet (br s), doublet (d), doublet of doublets (dd), triplet (t),
quartet (q), and multiplet (m). High resolution mass spectra
(HRMS) were taken with Q-TOF mass spectrometer. Flash
chromatography was performed using silica gel (100-200 mesh)
as the stationary phase. Reaction progress was monitored by thin
layer chromatography (silica-coated glass plates and visualized
under UV light and in iodine) and gas chromatography-mass
4.2. General Procedure for the Synthesis of Fully Substituted
Pyrroles
To a stirred solution of propargylic alcohol (1a-1k, 0.5 mmol)
in toluene (2 mL) was added 1,3-dicarbonyl compound (2a-2c,
0.55 mmol) and AgSbF6 (0.025 mmol, purchased from Sigma-
Aldrich Co.) and the mixture were heated at 60 °C. After
consumption of the starting materials, an appropriate amine (0.55

ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C29H28NO4
mmol) was added and the reaction continAuedCCatEtPheTsEamDe MANUSCRIPT
temperature until completion (GC and TLC analysis). When an
aliphatic amine (3g-3n) was used, 0.55 mmol HOAc was added
prior to the addition of amine. The reaction mixture was diluted
with ethylacetate (10 mL), and then washed with water (5 mL)
and brine (5 mL). The organic layer was dried over anhydrous
MgSO4, filtered, and evaporated under reduced pressure. The
crude product was purified by column chromatography on silica
gel (EtOAc/hexanes) to give desired products.
454.2018; found 454.2031.
4.2.7. Ethyl 1-phenyl-2-methyl-4-(4-fluorophenyl)-5-benzyl-1H-
pyrrole-3-carboxylate (4g). Solid, mp 106-108 °C; H NMR (400
1
MHz, CDCl3): δ 7.36-7.24 (m, 5H), 7.05-6.97 (m, 5H), 6.94-6.85
(m, 2H), 6.62-6.53 (m, 2H), 4.10 (q, J = 7.2 Hz, 2H), 3.64 (s,
2H), 2.27 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3): δ 165.9, 163.0, 160.6, 139.6, 137.4, 136.7, 132.4,
132.3, 132.0, 132.0, 129.6, 129.1, 128.6, 128.6, 128.0, 128.0,
125.8, 123.1, 114.5, 114.3, 111.2, 59.3, 30.7, 29.8, 14.1, 12.6
ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C27H25FNO2
414.1869; found 414.1884.
4.2.1.
Ethyl
1,4-diphenyl-2-methyl-5-benzyl-1H-pyrrole-3-
1
carboxylate (4a).20 Viscous oil; H NMR (400 MHz, CDCl3): δ
7.72-7.39 (m, 8H), 7.00 (t, J = 3.6 Hz, 3H), 6.91 (d, J = 7.2 Hz,
2H), 6.95-6.64 (m, 2H), 4.09 (q, J = 7.2 Hz, 2H), 3.68 (s, 2H),
2.27 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 166.0, 139.7, 137.5, 136.6, 136.4, 130.5, 129.5, 129.0,
128.6, 128.5, 128.1, 127.9, 127.6, 126.2, 125.7, 124.2, 111.2,
59.2, 30.8, 14.0, 12.6 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for
C27H26NO2 396.1964; found 396.1968.
4.2.8. Ethyl 1-phenyl-2-methyl-4-(4-methoxyphenyl)-5-benzyl-
1H-pyrrole-3-carboxylate (4h).20 Viscous oil; 1H NMR (400
MHz, CDCl3): δ 7.33-7.21 (m, 5H), 7.02 (t, J = 4.0 Hz, 3H),
6.97-6.85 (m, 4H), 6.82 (bt, 2H), 4.11 (q, J = 8.0 Hz, 2H), 3.80
(s, 3H), 3.68 (s, 2H), 2.26 (s, 3H), 1.07 (t, J = 8.0 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 166.0, 158.2, 139.8, 137.5,
136.4, 131.5, 129.5, 128.9, 128.7, 128.6, 128.4, 128.1, 127.9,
125.7, 123.8, 113.1, 111.2, 59.2, 55.2, 30.7, 14.2, 12.6 ppm;
HRMS (+ESI) m/z: [M+H]+ Calcd for C28H28NO3 426.2069;
found 426.2063.
4.2.2. Ethyl 1-(4-chlorophenyl)-2-methyl-4-phenyl-5-benzyl-1H-
°
1
pyrrole-3-carboxylate (4b). Solid, mp 76-78 C; H NMR (400
MHz, CDCl3): δ 7.37-7.21 (m, 7H), 7.02-6.06 (m, 3H), 6.83 (d, J
= 8.0 Hz, 2H), 6.66 (t, J = 4.0 Hz, 2H), 4.09 (q, J = 8.0 Hz, 2H),
3.68 (s, 2H), 2.27 (s, 3H), 1.02 (t, J = 8.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 165.8, 139.5, 136.5, 136.2, 136.0, 134.5,
130.4, 129.9, 129.4, 129.5, 128.1, 127.6, 126.4, 125.9, 124.5,
111.6, 59.3, 30.8, 14.0, 12.5 ppm; HRMS (+ESI) m/z: [M+H]+
Calcd for C27H2535ClNO2 430.1575; found 430.1590.
4.2.9. Ethyl 1-phenyl-2-methyl-4-(3-chlorophenyl)-5-benzyl-1H-
pyrrole-3-carboxylate (4i). Viscous oil; 1H NMR (400 MHz,
CDCl3): δ 7.22-7.39 (m, 8H), 7.03 (t, J = 4.0 Hz, 3H), 6.91 (d, J
= 7.6 Hz, 2H), 6.60 (dd, J = 3.6 and 6.8 Hz, 2H), 4.10 (q, J = 7.2
Hz, 2H), 3.67 (s, 2H), 2.27 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 165.7, 139.4, 138.4, 137.3,
137.0, 133.3, 130.8, 129.7, 129.1, 128.8, 128.7, 128.6, 128.6,
128.0, 126.4, 125.9, 122.8, 111.1, 59.3, 30.8, 14.0, 12.6 ppm;
HRMS (+ESI) m/z: [M+H]+ Calcd for C27H2535ClNO2 430.1574;
found 430.1565.
4.2.3. Ethyl 1-(4-bromophenyl)-2-methyl-4-phenyl-5-benzyl-1H-
°
1
pyrrole-3-carboxylate (4c). Solid, mp 95-97 C; H NMR (400
MHz, CDCl3): δ 7.43-7.29 (m, 7H), 7.04 (s, 3H), 6.77 (d, J = 8.0
Hz, 2H), 6.69-6.62 (m, 2H), 4.09 (q, J = 8.0 Hz, 2H), 3.67 (s,
2H), 2.26 (s, 3H), 1.02 (t, J = 8. 0 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3): δ 165.8, 139.5, 136.5, 136.4, 136.1, 132.2, 130.4,
130.2, 129.3, 128.1, 127.6, 126.3, 125.9, 124.5, 122.5, 111.6,
59.3, 30.7, 14.0, 12.5 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for
C27H2579BrNO2 474.1069; found 474.1085.
4.2.10. Ethyl 1-(4-chlorophenyl)-2-methyl-4-(4-chlorophenyl)-5-
°
1
benzyl-1H-pyrrole-3-carboxylate (4j). Solid, mp 105-107 C; H
NMR (400 MHz, CDCl3): δ 7.32-7.22 (m, 6H), 7.08-7.03 (m,
3H), 6.83 (d, J = 8.0 Hz, 2H), 6.64 (t, J = 4.0 Hz, 2H), 4.10 (q, J
= 7.2 Hz, 2H), 3.64 (s, 2H), 2.26 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 165.6, 139.2, 136.7, 135.8,
134.7, 134.7, 132.3, 131.8, 129.8, 129.5, 129.3, 128.2, 128.0,
127.8, 126.0, 123.3, 111.4, 59.4, 30.7, 14.1, 12.6 ppm; HRMS
(+ESI) m/z: [M+H]+ Calcd for C27H2435Cl2NO2 464.1184; found
464.1176.
4.2.4. Ethyl 1-(4-iodophenyl)-2-methyl-4-phenyl-5-benzyl-1H-
°
pyrrole-3-carboxylate (4d). Solid, mp 86-88 C; 1H NMR (400
MHz, CDCl3): δ 7.71 (d, J = 8.0 Hz, 2H), 7.39-7.21 (m, 6H), 7.04
(s, 3H), 6.67-6.61 (m, 4H), 4.08 (q, J = 8.0 Hz, 2H), 3.67 (s, 2H),
2.26 (s, 3H), 1.01 (t, J = 8.0 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 165.8, 139.5, 138.2, 137.2, 136.3, 136.1, 130.4, 129.3,
128.1, 127.6, 126.3, 125.9, 124.5, 111.6, 94.0, 59.3, 30.7, 14.0,
12.5 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C27H25INO2
522.0930; found 522.0920.
4.2.11. Ethyl 1-(4-chlorophenyl)-2-methyl-4-(4-cyanophenyl)-5-
°
1
benzyl-1H-pyrrole-3-carboxylate (4k). Solid, mp 102-104 C; H
NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2H), 7.45 (d, J =
8.0 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.07 (t, J = 4.0 Hz, 3H),
6.85 (d, J = 8.4 Hz, 2H), 6.64 (t, J = 3.2 Hz, 2H), 4.11 (q, J = 7.2
Hz, 2H), 3.64 (s, 2H), 2.27 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 165.3, 141.6, 138.9, 137.3,
135.6, 134.9, 131.5, 131.2, 129.8, 129.4, 128.3, 127.9, 126.3,
123.0, 119.4, 111.2, 110.0, 59.6, 30.7, 14.1, 12.6 ppm; HRMS
(+ESI) m/z: [M+H]+ Calcd for C28H2435ClN2O2 455.1526, found
455.1545.
4.2.5. Ethyl 1-(4-methoxyphenyl)-2-methyl-4-phenyl-5-benzyl-
°
1H-pyrrole-3-carboxylate (4e). Solid, mp 132-134 C; 1H NMR
(400 MHz, CDCl3): δ 7.37-7.16 (m, 5H), 7.05-7.01 (m, 3H), 6.78
(q, J = 8.0 Hz, 4H), 6.69-6.63 (m, 2H), 4.08 (q, J = 8.0 Hz, 2H),
3.78 (s, 3H), 3.68 (s, 2H), 2.26 (s, 3H), 1.01 (t, J = 8.0 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 166.0, 159.4, 139.9, 136.9,
136.5, 130.5, 130.2, 129.7, 129.6, 128.1, 127.9, 127.6, 126.2,
125.7, 124.0, 114.1, 111.0, 59.1, 55.5, 30.8, 14.0, 12.6 ppm;
HRMS (+ESI) m/z: [M+H]+ Calcd for C28H28NO3 426.2069;
found 426.2057.
4.2.12. Ethyl 1-(4-chlorophenyl)-2-methyl-4-(4-fluorophenyl)-5-
°
1
benzyl-1H-pyrrole-3-carboxylate (4l). Solid, mp 102-104 C; H
NMR (400 MHz, CDCl3): δ 7.35-7.20 (m, 4H), 7.08-6.91 (m,
5H), 6.90-6.83 (m, 2H), 6.65 (dd, J = 3.6, 7.2 Hz, 2H), 4.10 (q, J
= 7.2 Hz, 2H), 3.64 (s, 2H), 2.26 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): δ 165.7, 163.0, 160.6, 139.3,
136.6, 135.9, 134.6, 132.1, 132.1, 132.0, 131.9, 129.9, 129.5,
129.3, 128.1, 128.0, 126.0, 123.4, 114.6, 114.4, 111.5, 59.4, 30.7,
14.1, 12.6 ppm; ; HRMS (+ESI) m/z: [M+H]+ Calcd for
C27H2435ClFNO2 448.1479, found 448.1475.
4.2.6. Ethyl 1-(4-methoxycarbonylphenyl)-2-methyl-4-phenyl-5-
benzyl-1H-pyrrole-3-carboxylate (4f). Viscous oil; 1H NMR (400
MHz, CDCl3): δ 7.97 (d, J = 8.0 Hz, 2H), 7.42-7.23 (m, 5H),
7.05-6.95 (m, 5H), 6.63-6.58 (m, 2H), 4.09 (q, J = 8.0 Hz, 2H),
3.92 (s, 3H), 3.69 (s, 2H), 2.27 (s, 3H), 1.02 (t, J = 8.0 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 166.2, 165.8, 141.6, 139.3,
136.3, 136.1, 130.4, 130.3, 130.2, 129.2, 128.7, 128.1, 128.0,
127.6, 126.4, 125.9, 124.7, 111.8, 59.3, 52.4, 30.7, 14.0, 12.5

4.2.13.
methylenedioxidephenyl)-5-benzyl-1H-pyrrole (4m). Solid, mp
(100 MHz, CDCl3): δ 166.1, 137.9, 136.6, 135.8, 130.5, 129.5,
128.6, 128.4 127.5, 126.8, 126.0, 122.4, 111.1, 59.2, 14.0, 12.7,
11.3 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C21H22NO2
320.1651; found 320.1665.
1-(4-Chlorophenyl)-2-methAyl-C3-CacEetyPl-T4-E(3D,4- MANUSCRIPT
°
1
1
121-123 C; H NMR (400 MHz, CDCl3): H NMR (400 MHz,
CDCl3): δ 7.24 (d, J = 8.0 Hz, 2H), 7.07-7.02 (m, 3H), 6.86-6.78
(m, 5H), 6.65 (dd, J = 4.0, 8.0 Hz, 2H), 4.13 (q, J = 8.0 Hz, 2H),
3.67 (s, 3H), 2.24 (s, 3H), 1.11 (t, J = 8.0 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 165.8, 147.0, 146.2, 139.4, 136.3, 136.0, 134.5,
129.9, 129.9, 129.6, 129.2, 128.1, 128.1, 126.0, 124.1, 123.5,
111.6, 111.3, 107.7, 100.8, 59.4, 30.8, 14.2, 12.6 ppm; HRMS
(+ESI) m/z: [M+H]+ Calcd for C28H25ClNO4 474.1472, found
474.1456.
4.2.20. Ethyl 1,5-dibenzyl-2-methyl-4-phenyl-1H-pyrrole-3-
1
carboxylate (4t). Viscous oil; H NMR (400 MHz, CDCl3): δ
7.33-7.12 (m, 11H), 7.01 (d, J = 7.2 Hz, 2H), 6.84 (d, J = 7.2 Hz,
2H), 4.85 (s, 2H), 4.07 (q, J = 7.2 Hz, 2H), 3.75 (s, 2H), 2.47 (s,
3H), 1.00 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
δ 166.0, 139.6, 137.1, 136.5, 136.0, 130.4, 128.9, 128.6, 128.0,
127.9, 127.5, 127.4, 126.3, 126.2, 125.6, 124.9, 111.2, 59.2, 47.2,
30.4, 13.9, 11.6 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for
C28H28NO2 410.2120; found 410.2118.
4.2.14.
1,4-Diphenyl-2-methyl-3-acetyl-5-benzyl-1H-pyrrole
(4n).20 Viscous oil; 1H NMR (400 MHz, CDCl3): δ 7.40-7.24 (m,
8H), 7.01 (t, J = 4.0 Hz, 3H), 6.95-6.91 (m, 2H), 6.62-6.56 (m,
2H), 3.65 (s, 2H), 2.28 (s, 3H), 1.95 (s, 3H) ppm; 13C NMR (100
MHz, CDCl3): δ 197.5, 139.5, 137.3, 136.8, 136.0, 130.7, 129.5,
129.1, 128.6, 128.5, 128.4, 128.1, 128.0, 127.0, 125.8, 123.8,
121.9, 31.1, 30.8, 13.0 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd
for C26H24NO 366.1853, found 366.1837.
4.2.21. Ethyl 1-phenethyl-2-methyl-4-phenyl-5-benzyl-1H-pyrrole
°
1
-3-carboxylate (4u). Solid, mp 85-87 C; H NMR (400 MHz,
CDCl3): δ 7.29-7.14 (m, 11H), 7.06 (d, J = 6.8 Hz, 2H), 6.91 (d, J
= 6.8 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.80 (t, J = 7.2 Hz, 2H),
3.70 (s, 2H), 2.62 (t, J = 8.0 Hz, 2H), 2.55 (s, 3H), 0.98 (t, J = 7.2
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 166.0, 139.9,
137.9, 136.7, 135.4, 130.5, 128.8, 128.7, 128.1, 127.7, 127.5,
126.9, 126.4, 126.1, 124.6, 111.1, 59.1, 46.0, 36.9, 30.5, 14.0,
11.6 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C29H30NO2
424.2276; found 424.2263.
4.2.15.
1-(4-Chlorophenyl)-2-methyl-3-acetyl-4-(4-
1
methoxyphenyl)-5-benzyl-1H-pyrrole (4o). Viscous oil; H NMR
(400 MHz, CDCl3): δ 7.39-7.21 (m, 5H), 7.07-7.02 (m, 3H), 6.92
(d, J = 8.0 Hz, 2H), 6. 83 (d, J = 8.0 Hz, 2H), 6.63 (dd, J = 4.0,
8.0 Hz, 2H), 3.81 (s, 3H), 3.63 (s, 2H), 2.22 (s, 3H), 1.96 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 197.5, 158.8, 139.4, 135.8,
135.7, 134.5, 131.6, 129.8, 129.4, 129.2, 128.5, 128.1, 128.0,
125.9, 123.6, 122.1, 113.9, 55.3, 31.0, 30.8, 13.0 ppm; HRMS
(+ESI) m/z: [M+H]+ Calcd for C27H2535ClNO2 430.1574, found
430.1574.
4.2.22. Ethyl 1-phenethyl-2-methyl-4-(4-fluorophenyl)-5-benzyl-
1
1H-pyrrole-3-carboxylate (4v). Viscous oil; H NMR (400 MHz,
CDCl3): δ 7.31-7.16 (m, 8H), 7.02-6.75 (m, 6H), 4.07 (q, J = 7.2
Hz, 2H), 3.81 (t, J = 8.0 Hz, 2H), 3.66 (s, 2H), 2.63 (t, J = 8.0
Hz, 2H), 2.55 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 165.9, 163.0, 160.5, 139.7, 137.8, 135.5, 132.7,
132.6, 132.0, 131.9, 128.8, 128.8, 128.7, 128.0, 127.9, 126.9,
126.5, 123.5, 114.4, 114.2, 111.1, 59.2, 45.9, 36.9, 30.4, 14.0,
11.7 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C29H29FNO2
442.2182; found 442.2175.
4.2.16. Methyl 4-[2-methyl-3-acetyl-4-(3,4,5-trimethoxyphenyl)-
°
1
5-benzyl-1H-pyrrol-1-yl]benzoate (4p). Solid, mp 99-101 C; H
NMR (400 MHz, CDCl3): δ 7.99 (d, J = 8.0 Hz, 2H), 7.02-7.09
(m, 5H), 6.67-6.71 (m, 2H), 6.56, (s, 2H), 3.93 (s, 3H), 3.87 (s,
3H), 3.77 (s, 6H), 3.70 (s, 2H), 2.25 (s, 3H), 2.05 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 197.4, 166.1, 153.1, 141.2,
139.4, 137.1, 135.4, 131.7, 130.5, 130.3, 129.1, 128.5, 128.1,
127.9, 126.0, 124.2, 122.2, 107.6, 61.0, 56.1, 52.4, 30.9, 30.8,
12.9 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C31H32NO6
514.2229; found 514.2220.
4.2.23. Ethyl 1-(2-hydroxyethyl)-2-methyl-4-phenyl-5-benzyl-1H-
1
pyrrole-3-carboxylate (4w). Viscous oil; H NMR (400 MHz,
CDCl3): δ 7.29-7.15 (m, 8H), 7.04 (d, J = 7.6 Hz, 2H), 4.04 (q, J
= 7.2 Hz, 2H), 3.93 (s, 2H), 3.81 (t, J = 6.0 Hz, 2H), 3.58 (t, J =
6.0 Hz, 2H), 2.56 (s, 3H), 1.56 (br s, 1H), 0.97 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 166.0, 139.7, 136.5, 135.9,
130.4, 128.7, 128.0, 127.5, 126.4, 126.2, 124.8, 111.3, 61.8, 59.2,
46.0, 30.5, 13.9, 11.9 ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for
C23H26NO3 364.1912; found 364.1918.
4.2.17.
1-(4-Chlorophenyl-2-methyl-3-acetyl-4-(3,4,5-
trimethoxyphenyl)-5-benzyl)-1H-pyrrole (4q). Solid, mp 106-108
°C; 1H NMR (400 MHz, CDCl3): δ 7.32-7.21 (m, 2H), 7.09-7.06
(m, 3H), 6.93-6.85 (d, J = 8.8 Hz, 2H), 6.72-6.70 (m, 2H), 6.55
(s, 2H), 3.87 (s, 3H), 3.76 (s, 6H), 3.67 (s, 2H), 2.24 (s, 3H), 2.04
(s, 3H); 13C NMR (100 MHz, CDCl3): δ 197.5, 153.1, 139.6,
137.1, 135.7, 135.6, 134.7, 131.8, 129.7, 29.4, 129.2, 128.2,
128.0, 126.0, 124.0, 122.0, 107.7, 61.0, 56.1, 30.9, 30.8, 12.9
ppm; HRMS (+ESI) m/z: [M+H]+ Calcd for C29H29 35ClNO4
490.1785; found 490.1797.
4.2.24. Ethyl 1-(6-hydroxyhexyl)-2-methyl-4-phenyl-5-benzyl-1H-
pyrrole-3-carboxylate (4x). Viscous oil; 1H NMR (400 MHz,
CDCl3): δ 7.27-7.15 (m, 8H), 7.05 (d, J = 7.6 Hz, 2H), 4.04 (q, J
= 7.2 Hz, 2H), 3.86 (s, 2H), 3.57 (t, J = 7.2 Hz, 2H), 2.53 (s, 3H),
1.63 (br s, 1H), 1.58-1.17 (m, 8H), 0.97 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ 166.1, 139.9, 136.7, 135.3, 130.4,
128.6, 128.0, 127.5, 127.4, 126.3, 126.1, 124.4, 110.8, 62.7, 59.1,
44.2, 32.5, 30.6, 30.5, 26.7, 25.4, 13.9, 11.6 ppm; HRMS (+ESI)
m/z: [M+H]+ Calcd for C27H34NO3 420.2539; found 420.2556.
4.2.18.
1-(4-Bromophenyl-2-methyl-3-acetyl-4-(3,4,5-
trimethoxyphenyl)-5-benzyl)-1H-pyrrole (4r). Viscous oil; 1H
NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.8 Hz, 2H), 7.13-7.05
(m, 3H), 6.85 (d, J = 8.8 Hz, 2H), 6.73-6.69 (m, 2H), 6.55 (s,
2H), 3.86 (s, 3H), 3.75 (s, 6H), 3.68 (s, 2H), 2.24 (s, 3H), 2.04 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 197.4, 153.0, 139.5, 37.1,
136.2, 135.5, 132.4, 131.8, 130.0, 129.2, 128.1, 127.9, 126.0,
124.0, 122.7, 122.0, 107.6, 61.0, 56.1, 30.8, 30.8, 12.9 ppm;
HRMS (+ESI) m/z: [M+H]+ Calcd for C29H2978BrNO4 534.1280;
found 534.1293.
4.2.25. 12-(2-Benzyl-3-phenyl-4-(ethoxycarbonyl)-5-methyl-1H-
pyrrol-1-yl)dodecanoic acid (4y). Viscous oil; 1H NMR (400
MHz, CDCl3): δ 7.21-7.28 (m, 8H), 7.05 (d, J = 7.6 Hz, 2H), 4.04
(q, J = 7.2 Hz, 2H), 3.86 (s, 2H), 3.57 (t, J = 8.0 Hz, 2H), 2.53 (s,
3H), 2.33 (t, J = 7.2 Hz, 2H), 1.72-1.60 (m, 2H), 1.40-1.12 (m,
18H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ
179.9, 166.1, 139.9, 136.8, 135.4, 130.4, 128.5, 127.9, 127.5,
127.4, 126.3, 126.0, 124.4, 110.7, 59.1, 44.3, 34.1, 30.6, 30.5,
29.5, 29.4, 29.4, 29.2, 29.1, 29.1, 26.9, 24.7, 13.9, 11.6 ppm;
HRMS (+ESI) m/z: [M+H]+ Calcd for C33H44NO4 518.3270;
found 518.3271.
4.2.19.
Ethyl
1,4-diphenyl-2,5-dimethyl-1H-pyrrole-3-
1
carboxylate (4s).20 Viscous oil; H NMR (400 MHz, CDCl3): δ
7.56-7.41 (m, 3H), 7.38-7.22 (m, 7H), 4.08 (q, J = 7.2 Hz, 2H),
2.32 (s, 3H), 1.88 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H) ppm; 13C NMR

Punniyamurthy, T. Org. Lett. 2013, 15, 4996-4999; (d)
4.2.26. Ethyl 1-(2-tert-butoxy-2-oxoethyl)-2-methyl-4-phenyl-5-
benzyl-1H-pyrrole-3-carboxylate (4z). Viscous oil; 1H NMR (400
MHz, CDCl3): δ 7.29-7.04 (m, 10H), 4.27 (s, 2H), 4.04 (q, J =
7.2 Hz, 2H), 3.83 (s, 2H), 2.48 (s, 3H), 1.35 (s, 9H), 0.98 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 166.9, 165.8, 139.0,
136.5, 136.2, 130.5, 128.7, 128.0, 127.8, 127.4, 126.4, 126.2,
124.7, 111.3, 82.6, 59.1, 46.3 30.5, 27.9, 13.9, 11.5 ppm; HRMS
(+ESI) m/z: [M+H]+ Calcd for C27H32NO4 434.2331; found
434.2317.
ACCEPTED MANUSCRIPT
Narayan, R.; Frohlich, R.; Wurthwein, E. U. J. Org. Chem.
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(j) Yoshida, M.; Maeyama, Y.; Al-Amin, M.; Shishido, K.
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Mueller, D. S.; Sachwani, R. M.; Kapadia, R.; Londino, H.
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4.2.27. Ethyl 1-(4-bromophenethyl)-2-methyl-4-phenyl-5-pentyl-
1H-pyrrole-3-carboxylate (4aa). Viscous oil; 1H NMR (400
MHz, CDCl3): δ 7.46-7.41 (m, 2H), 7.34-7.16 (m, 5H), 6.98 (d, J
= 8.0 Hz, 2H), 4.04-3.97 (m, 4H), 2.90 (t, J = 8.0 Hz, 2H), 2.52
(s, 3H), 2.29 (t, J = 7.6 Hz, 2H), 1.38-1.34 (m, 2H), 1.18-1.10 (m,
4H), 0.94 (t, J = 7.2 Hz, 3H), 0.79 (t, J = 6.8 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ 166.0, 137.1, 136.9, 134.2, 131.9,
130.5, 130.5, 130.3, 127.4, 125.9, 122.9, 120.9, 111.2, 59.0, 45.1,
36.9, 31.5, 30.5, 24.3, 22.2, 14.0, 13.9, 11.6 ppm; HRMS (+ESI)
m/z: [M+H]+ Calcd for C27H3379BrNO2 482.1695; found
482.1678.
Acknowledements
The authors thank the College of Pharmacy of University of
Arkansas for Medical Sciences and National Institutes of Health
(NIH) Clinical and Translational Science Award (CTSA)
program (UL1TR000039 and KL2TR000063) for financial
support.
Supplementary data
1H and 13C NMR spectra for all compounds are available online.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.xxxxxxx.
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16. Gujarathi, S.; Hendrickson, H. P.; Zheng, G. R.
20. The compound was reported in ref. 13. The NMR data for
Tetrahedron lett. 2013, 54, 3550-3553. ACCEPTED MANUSCRIPT
the compound was in agreement with those reported.
17. Ji, W. H.; Pan, Y. M.; Zhao, S. Y.; Zhan, Z. P. Synlett
2008, 3046-3052.
18. In our hands, significant amount of furan was detected by
GC-MS and TLC when InCl3 was used as a catalyst for the
one-pot pyrrole formation in toluene under reflux.
19. Intermediate 5a was synthesized by either Amberlite IR-
120H- or AgSbF6-catalyzed method. Purification was
carried out by column chromatography on silica gel. Furan
formation was detected by TLC and GC-MS. No
difference in furan formation was observed between these
two different batches of 5a.
Supplementary Material
Copies of all of the 1H and 13C NMR spectra
.

ACCEPTED MANUSCRIPT
3
Graphical Abstract
A mild and efficient AgSbF6-catalyzed synthesis of
fully substituted pyrroles through a sequential
propargylation/amination/cycloisomerization reaction
Leave this area blank for abstract info.
Satheesh Gujarathi, Xingui Liu, Lin Song, Howard Hendrickson, Guangrong Zheng*
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences,
Little Rock, AR 72205, United States

ACCEPTED MANUSCRIPT
A mild and efficient AgSbF6-catalyzed synthesis of fully substituted
pyrroles through a sequential
propargylation/amination/cycloisomerization reaction
Satheesh Gujarathi, Xingui Liu, Lin Song, Howard Hendrickson, Guangrong Zheng*
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas
for Medical Sciences, Little Rock, AR 72205, United States
Supporting Information
Table of Contents
1. Copies of 1H NMR and &13C NMR Spectra of Fully Substituted Pyrroles
S2--------------S28
S1

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4a
13C NMR Spectrum of Compound 4a
S2

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4b
13C NMR Spectrum of Compound 4b
S3

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4c
13C NMR Spectrum of Compound 4c
S4

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4d
13C NMR Spectrum of Compound 4d
S5

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4e
13C NMR Spectrum of Compound 4e
1H NMR Spectrum of Compound 4f
S6

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4f
13C NMR Spectrum of Compound 4f
S7

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4g
13C NMR Spectrum of Compound 4g
S8

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4h
13C NMR Spectrum of Compound 4h
S9

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4i
13C NMR Spectrum of Compound 4i
S10

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4j
13C NMR Spectrum of Compound 4j
S11

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4k
13C NMR Spectrum of Compound 4k
S12

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4l
13C NMR Spectrum of Compound 4l
S13

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4m
13C NMR Spectrum of Compound 4m
S14

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4n
13C NMR Spectrum of Compound 4n
S15

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4o
13C NMR Spectrum of Compound 4o
S16

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4p
13C NMR Spectrum of Compound 4p
S17

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4q
13C NMR Spectrum of Compound 4q
S18

ACCEPTED MANUSCRIPT
1H NMR Spectrum of Compound 4r
13C NMR Spectrum of Compound 4r
S19