Domino Reaction for the Synthesis of Polysubstituted Pyrroles and Lamellarin R

Article abstract of DOI:10.1021/acs.joc.0c01134

A three-component annulation reaction was developed for the synthesis of pyrroles, a class of compounds with various properties valuable to biomedical and polymer industries. Treatment of α-silylaryl triflates, Schiff bases, and alkynes generated polysubs

Full text of DOI:10.1021/acs.joc.0c01134

Subscriber access provided by Curtin University Library
Article
Domino Reaction for the Synthesis of
Polysubstituted Pyrroles and Lamellarin R
Jih Ru Hwu, Animesh Roy, Avijit Panja, Wen-Chieh Huang, Yu-Chen Hu, Kui-
Thong Tan, Chun-Cheng Lin, Kuo Chu Hwang, Ming-Hua Hsu, and Shwu-Chen Tsay
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01134 • Publication Date (Web): 03 Jul 2020
Downloaded from pubs.acs.org on July 3, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 10
The Journal of Organic Chemistry
1
2
3
4
5
Revised 2020630
6
7
Domino Reaction for the Synthesis of Polysubstituted Pyrroles and Lamellarin R
8
9
Jih Ru Hwu,*,†,‡ Animesh Roy,† Avijit Panja,† Wen-Chieh Huang,†,‡ Yu-Chen Hu,‡,§ Kui-Thong Tan,†,‡
Chun-Cheng Lin,†,‡ Kuo-Chu Hwang,†,‡ Ming-Hua Hsu,¶ and Shwu-Chen Tsay†,‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
‡Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu 300,
Taiwan
§Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan
¶Department of Chemistry, National Changhua University of Education, Changhua County, 500, Taiwan
Keywords: domino . aryne . 1,3-dipolar cycloaddition . pyrrole . lamellarin R synthesis
ABSTRACT: A three-component annulation reaction was developed for the synthesis of pyrroles, a class of compounds with various
properties valuable to biomedical and polymer industries. Treatment of a-silylaryl triflates, Schiff bases, and alkynes generated
polysubstituted pyrroles in good yields (61-86%) with regioselectivity. This domino reaction involved completion of five sequential
steps in a single flask, which comprised arynes formation through 1,2-elimination, their alkylation by Schiff bases through 1,2-
addition, 1,4-intramolecular proton transfer, Hüisgen 1,3-dipolar cycloaddition, and dehydrogenative aromatization. It was then suc-
cessfully applied as the key step in the synthesis of the natural product lamellarin R. This new reaction represents an efficient,
sustainable process for the production of chemical materials.
clization by Kostakis and Lykakis,14 Cu-catalyzed cascade pro-
INTRODUCTION
cess involving (3 + 2) cycloaddition of azomethine ylide by Lu
and Wang,15 Li-mediated annulation,16 and phosphonite-medi-
Pyrrole is a five-membered heterocyclic aromatic compound,
ated 1,3-dipolar cycloaddition by Arndtsen.17 Many other es-
which darkens readily upon exposure to air. Although pyrrole
tablished methods for pyrrole generation require the use of ex-
pensive or toxic metal catalysts, some of which produce harm-
ful waste streams.18 20 These concerns inspired us to develop a
novel and efficient approach for the synthesis of pyrroles with
various substituents through a domino reaction.
is not naturally occurring, many of its derivatives are found in
natural products.1 Examples include chlorophylls, porphyrins,
vitamin B12, etc. Pyrrole-containing secondary metabolites in-
clude lamellarin, prodigiosin, rhazinilam, ryanodine, sceptrin,
etc. It is of interest to note that pyrrole is also a constituent of
tobacco smoke.2
Implementation of our newly developed method as the key
step in the synthesis of natural products (e.g., lamellarins)
would affirm its efficiency and applicability. Lamellarins are
pyrrole-derived marine alkaloids with diverse biological prop-
erties.21 This versatility makes lamellarins important subjects
for research. They are often used as a starting point for the de-
sign of anticancer and antiviral compounds.22 In addition, ef-
forts have been devoted to invention of new and improved
methods for lamellarin synthesis.23,24
As a flat and electron-rich ring, pyrrole is susceptible to elec-
trophilic attack and can react with numerous biomolecules.
Thus it becomes an important constituent of well-established
drugs, such as atorvastatin, chlorfenapyr, premazepam, pyrvin-
ium, roseophilin, tolmetin, and zomepirac.3 The pyrrole scaf-
fold is used to construct therapeutic agents with antibacterial,
anticancer, antifungal, anti-inflammatory, antimalarial, antimi-
crobial, antiprotozoal, antipsychotic, antiviral, antitubercular,
and anxiolytic properties among others.4,5 This molecule also
plays an active role as a component of polymers and indigoid
dyes.5 In catalytic reactions, pyrroles are widely used for cor-
rosion inhibition, metallurgy, polymerization, and preserva-
tion.5
Herein we report on a newly developed method for the direct
synthesis of polysubstituted pyrroles from a-silylaryl triflates
1, Schiff bases 2, and alkynes 3. It involves a “single-flask”
reaction. It possesses advantages of a few synthetic steps, a
moderate reaction temperature, and metal-free conditions as
well as provides good regioselectivity and yields. This domino
reaction was applied as the key step in the synthesis of lamel-
larin R, a tetrasubstituted natural pyrrole.
Many methods have been developed for the synthesis of pyr-
roles,6–11 such as the aza-Wittig reaction, the Hantzsch reaction,
the Paal–Knorr condensation reaction, carbenoid insertions, the
Friedel–Crafts acylation, the Heck coupling, hydroarylations,
and the Michael addition. Zard et al.12 provided elegant con-
vergent routes to pyrroles by exploiting unusual radical chem-
istry.
RESULTS AND DISCUSSION
The feasibility of the new method for the synthesis of the pol-
ysubstituted pyrroles in Scheme 1 was investigated. A mixture
of (trimethylsilyl)aryl triflates 1 (1.0 equiv), Schiff bases 2 (1.0
equiv), and alkynes 3 (1.2 equiv) was treated with a fluoride
(2.0 equiv) in acetonitrile at 25 °C. During the optimization of
the new reaction conditions, different combinations of solvents,
Schiff bases have been used in pyrroles synthesis. Examples
include Ag-catalyzed tandem 1,3-dipolar cycloaddition/aroma-
tization by Hu and Wang,13 Cu-catalyzed three-component cy-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 10
1
2
3
4
5
6
7
8
9
fluorides, additive of 18-crown-6, temperatures, and reaction
Table 1. Optimization of Yield for Reaction 1a + 2c + 3b →
4acb by Use of Various Solvents, Fluorides, Temperatures,
and Reaction Times
times were studied for the synthesis of pyrrole 4acb. The data
in Table 1 reveal that the reaction could be conducted in THF
(entries 1–5), acetonitrile (entries 6-8), and toluene (entries 9
and 10). Acetonitrile was the best solvent (entry 8). Among
the three fluorides n-Bu4NF, CsF, and KF, use of CsF without
18-crown-6 produced the highest yields of pyrroles (86% in en-
try 8). This annulation process proceeded well at 25 °C; eleva-
tion of the reaction temperature was unnecessary.
F- source
(2.0 equiv)
additive temperature time yield
entry solvent
(2.0 equiv)
(°C)
25
25
60
60
25
25
60
25
25
80
(h) (%)
10 12
10 20
10 45
4.0 18
8.0 7.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
5
6
7
8
9
THF
THF
CsF
-
KF
18-crown-6
-
Scheme 1. A “Single Flask” Synthesis of Pyrroles 4 from
THF
KF
18-crown-6
a
-Silylaryl Triflates 1, Schiff Bases 2, and Alkynes 3
THF
n-Bu4NF
n-Bu4NF
KF
-
THF
-
CH3CN
CH3CN
CH3CN
toluene
18-crown-6
18-crown-6
-
10
-
-
KF
8.0
CsF
6.0 86
6.0 23
8.0 38
CsF
-
10 toluene
KF
18-crown-6
Various starting materials were used to evaluate the scope of
this new reaction. The methoxy group was allowed to attach to
the benzene nucleus of a-silylaryl triflates 1. The benzene nu-
cleus could be replaced by a pyridine ring (i.e., 1d). Methyl,
methoxy, chloro, and bromo groups could be attached to the
phenyl terminal (R3) in Schiff bases 2. This phenyl group could
also be replaced by a naphthyl, furyl, and thienyl group (i.e., 2f,
2g, and 2h, respectively). The alkyl terminal group of the Schiff
bases 2 must have a methylene unit that was attached to an elec-
tron-withdrawing alkoxycarbonyl group. The two substituents
in alkynes 3 could be hydrogen atoms, alkyl, acetyl, alkoxycar-
bonyl or methoxyphenyl groups. Use of these starting materials
often led to the desired pyrroles in 61–86% yields (Table 2).
The exception involved the use of inactivated alkyne 3g, which
had alkyl groups on both sides of the carbon to carbon triple
bond. As a result, product 4acg was obtained only up to 15%
yield.
To appraise the new reaction processes, we applied the new
annulation reaction as the key step in the synthesis of lamellarin
R (9, Scheme 2). Cesium fluoride (3.0 equiv) in acetonitrile
was added to a solution containing (methoxy)silylphenyl triflate
1b (1.2 equiv), Schiff base 2i (1.0 equiv), and bis(methoxy-
phenyl)acetylene (3h, 1.2 equiv). Reagents 1b and 3h are com-
mercially available; Schiff base 2i is readily available through
the simple condensation of glycine methyl ester hydrochloride
with paraformaldehyde.27 After the annulation reaction pro-
ceeded at 0–10 °C for 6.0 h, the desired pyrroles para-4bih and
its regioisomer meta-4bih were generated in a ratio of 2.3:1.
Finally the isolated pyrrole para-4bih (61%) underwent de-
methylation with BBr3 in methanol at room temperature to pro-
duce lamellarin R (9) in a high yield by use of Jia’s method.23
After 2.0 h of stirring under nitrogen atmosphere followed by
6.0 h of stirring in open air, pyrroles 4aab–dbb were often iso-
lated in 61-86% yields with purity >99.2%. Regarding green
chemistry characteristics, the atom economy25 was calculated to
be 62.8%, whereas the atom efficiency26 was 54.0% for com-
pound 4acb.
ACS Paragon Plus Environment

Page 3 of 10
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 2. Reactants 1
Developed Annulation Reaction along with their Isolated
Yields
3 and Products 4 of the Newly
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aThis Schiff base was generated in situ.
For verification of their configuration conclusively, the mo-
lecular framework of compound 4acb was obtained through
single crystal X-ray diffraction analysis. The data and ORTEP
diagram in the Supporting Information reveal the relative posi-
tions of the four substituents and the vinylic proton of the pyr-
role nucleus.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 10
1
2
3
4
5
Scheme 2. Synthesis of Lamellarin R by Use of an Aryne-
Induced Domino Reaction as the Key Step
CONCLUSIONS
Polysubstituted pyrroles can be synthesized from silylaryl tri-
flates, Schiff bases, and alkynes through an aryne-induced dom-
ino reaction. The overall pathway comprises 1,2-elimination,
1,2-nucleophilic addition, 1,4-proton transfer, (3 + 2) cycload-
dition, and dehydrogenative aromatization. This reaction was
applied successfully as the key step in the synthesis of lamel-
larin R.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Utilization of this new method in chemical synthesis mini-
mizes waste production and reduces the need for extra reagents,
solvents, and labor. Hence this three-component synthetic pro-
tocol is ecologically and environmentally benign for production
of fine chemicals.
EXPERIMENTAL SECTION
Our design and concerns in the development of a single-flask
method for the synthesis of pyrroles 4 from triflates, Schiff ba-
ses, and alkynes is described in Scheme 1. The a-silylaryl tri-
flates 1 first react with cesium fluoride to generate aryne inter-
mediates 5 through 1,2-elimination (Step 1).28 Then Schiff ba-
ses 2 are added to arynes 5 in situ to produce iminium carbani-
ons 6 through 1,2-addition (Step 2). The carbanion center in
betaines 6 may trap an acidic proton nearby to generate azome-
thine ylides 7 through 1,4-intramolecular proton transfer (Step
3).28 Subsequently, the Hüisgen 1,3-dipolar cycloaddition takes
place between ylides 7 and alkynes 3 to give the (3 + 2) cy-
cloadducts 8 (Step 4). Noteworthily, the activated acetylenes 3
as the starting material is expected to be more competitive than
the solvent acetonitrile for reacting with azomethine ylides 7.
Autoxidation in open air29,30 would then lead the 3-pyrrolines 8
to pyrroles 4 as the final products (Step 5). In a control experi-
ment, a compound with a similar framework to intermediates 8
but with a CH2 unit between the CO2R3 group and the pyrroline
ring was produced. It was found inert to the dehydrogenative
aromatization.
General Information. All reactions were carried out in
oven-dried glassware (120 °C) under an atmosphere of nitrogen
unless as indicated otherwise. Acetonitrile, dichloromethane,
ethyl acetate, hexanes, and toluene from Mallinckrodt Chemical
Co. were dried and distilled from CaH2. Tetrahydrofuran (THF)
from Mallinckrodt Chemicals Co. was dried by distillation from
sodium and benzophenone under an atmosphere of nitrogen.
The reagents purchased from Alfa Aesar included 4-bromoben-
zaldehyde, 3-butyn-2-one, 4-chlorobenzaldehyde, diethyl acet-
ylenedicarboxylate, dimethyl acetylenedicarboxylate (DMAD),
ethyl acetylenecarboxylate, glycine ethyl ester hydrochloride,
glycine methyl ester hydrochloride, 4-methoxybenzaldehyde,
methyl acetylenecarboxylate, and 4-methylbenzaldehyde. The
reagents purchased from Sigma–Aldrich included benzalde-
hyde, bis(4-methoxyphenyl)acetylene, furan-2-carboxalde-
hyde, a-naphthaldehyde, 4-octyne, paraformaldehyde, thio-
phene-2-carboxaldehyde, and 3-(trimethylsilyl)pyridin-2-yl tri-
fluoromethanesulfonate. Cesium fluoride (CsF), 18-crown-6,
methyl 2-butynoate, potassium fluoride (KF), tetra-n-bu-
tylammonium fluoride (TBAF), and trimethylamine (Et3N)
were purchased from Acros. The compounds purchased from
Tokyo Chemical Industry Co. included 4,5-dimethoxy-2-(tri-
methylsilyl)phenyl trifluoromethanesulfonate, 4-methoxy-2-
(trimethylsilyl)phenyl trifluoromethanesulfonate, and 2-(trime-
thylsilyl)phenyl trifluoromethanesulfonate.
Results from our trials indicate that the dehydrogenative aro-
matization of pyrrolines 8 indeed proceeded gradually at 25
°C.31 The smooth conversion of 8 ® 4 was facilitated by the
presence of a CO2R3 group attached directly to the C2 position
of 3-pyrrolines 8. Activity of the allylic hydrogen at the a po-
sition to the CO2R3 group increases significantly. Thus pyr-
rolines 8 with such a framework are well suited for dehydro-
genative aromatization.
Analytical thin layer chromatography (TLC) was performed
on precoated plates (silica gel 60 F-254). Purification by grav-
ity column chromatography was carried out by use of Silicycle
ultra-pure silica gel (particle size 40–63 µM, 230–400 mesh).
This approach to pyrrole synthesis accomplishes five steps
sequentially in a single flask. This new domino reaction offers
the following benefits: 1. The reaction generates the desired
products in good-to-high yields at room temperature without
any involvement of harsh conditions or reagents. 2. The entire
“single-flask” reaction can be conducted with ease without iso-
lation of the intermediates.
Infrared spectra (IR) were measured on a Fourier transform
infrared spectrometer (FT-IR). Absorption intensities are rec-
orded by the following abbreviations: s, strong; m, medium;
and w, weak. Proton NMR spectra were obtained on a 400 MHz
spectrometer by use of chloroform-d (CDCl3) as the solvent.
Proton NMR chemical shifts were referenced to the residual
protonated solvent (δ 7.24 ppm for chloroform). Carbon-13
NMR spectra were obtained on a 100 MHz spectrometer by use
of chloroform-d (CDCl3) as the solvent. Carbon-13 chemical
shifts were referenced to the center of the CDCl3 triplet (δ 77.0
ppm). Multiplicities are recorded by the following abbrevia-
tions: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q,
quartet; m, multiplet; and J, coupling constant (hertz). High-
resolution mass spectra (HRMS) were measured on an instru-
ment by use of a time-of-flight mass analyzer (TOF) with elec-
trospray ionization (ESI).
Application of this new reaction as the key step in the synthe-
sis of natural product lamellarin R (9) allowed the establishment
of one pyrrole nucleus, three anisole moieties, and one ester
functionality in its scaffold in a single flask. In the reaction
shown in Scheme 2, a byproduct meta-4bih was isolated in a
26% yield. Its generation was due to two possible 1,2-addi-
tions of Schiff bases 2i to an unsymmetrical benzyne interme-
diate. Thus the addition may occur at both the meta and the
para positions.
ACS Paragon Plus Environment

Page 5 of 10
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
hexanes as the eluent); 1H NMR (CDCl3, 400 MHz) d 7.57 (s,
1H), 7.26-7.24 (m, 3H), 7.07-7.05 (m, 2H), 7.01-6.95 (m, 4H),
4.15 (q, 2H, J = 6.9 Hz), 3.69 (s, 3H), 2.24 (s, 3H), 1.18 (t, 3H,
J = 6.9 Hz); 13C{1H} NMR (CDCl3, 100 MHz) d 163.6, 160.3,
144.4, 138.0, 137.8, 130.5, 128.2, 128.1, 128.1, 127.9, 127.0,
123.3, 119.4, 114.3, 59.9, 51.4, 21.4, 14.2; IR (neat) 2924 (m),
1715 (s, C=O), 1598 (w), 1470 (m), 1201 (s, C-O), 1116 (m),
1039 (m), 758 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C22H21NO4 + H 364.1548, found 364.1551.
Standard Procedure for the Single-Flask Synthesis of
Pyrroles 4. To a stirred solution of 2-silylphenyl triflate 1 (1.0
equiv) in dry CH3CN (2.0-2.5 mL) was added a Schiff base 2
(1.0 equiv), an alkyne 3 (1.2 equiv), and CsF (2.0-2.1 equiv) at
room temperature under nitrogen atmosphere. After the reac-
tion mixture was stirred at 25 °C for 6.0–8.0 h, the reaction mix-
ture was quenched with water (10 mL) and then extracted with
EtOAc (3 × 10 mL). The combined organic layers were dried
over CaSO4 (s), filtered, and concentrated under reduced pres-
sure to afford the products. It was then purified by use of dry
column chromatography on silica gel with a limited amount32
of EtOAc in hexanes as the eluent to give the desired pyrrole 4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(b) The same procedure was followed by use of 2-silylphenyl
triflate 1a (2.60 g, 8.71 mmol, 1.0 equiv), Schiff base 2b34 (1.67
g, 8.71 mmol, 1.0 equiv), ethyl acetylenecarboxylate (3b, 1.02
g, 10.5 mmol, 1.2 equiv), and CsF (2.65 g, 17.4 mmol, 2.0
equiv) in CH3CN (100 mL). The desired pyrrole 4abb (2.59 g,
7.14 mmol) was obtained in 82% yield as a yellow liquid.
4-Ethoxycarbonyl-2-methoxycarbonyl-5-phenyl-N-phe-
nylpyrrole (4aab). The Standard Procedure was followed by
use of 2-silylphenyl triflate 1a (50.2 mg, 0.168 mmol, 1.0
equiv), Schiff base 2a33 (29.8 mg, 0.168 mmol, 1.0 equiv), ethyl
acetylenecarboxylate (3b, 19.8 mg, 0.202 mmol, 1.2 equiv), and
CsF (51.2 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.0 mL).
After the reaction mixture was stirred for 6.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4aab (46.4 mg, 0.134 mmol) in 80% yield
as a yellow liquid: TLC Rf 0.45 (15% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.58 (s, 1H), 7.25-7.23
(m, 3H), 7.22-7.18 (m, 3H), 7.12-7.10 (m, 2H), 7.06-7.04 (m,
2H), 4.13 (q, 2H, J = 7.3 Hz), 3.69 (s, 3H), 1.13 (t, 3H, J = 7.3
Hz); 13C{1H} NMR (CDCl3, 100 MHz) d 163.8, 160.5, 144.5,
137.9, 130.5, 128.8, 128.3, 128.2, 128.1, 127.9, 127.1, 123.4,
119.5, 114.4, 59.9, 51.4, 14.2; IR (neat) 2924 (s), 1714 (s, C=O),
1598 (m), 1470 (m), 1235 (s, C-O), 1122 (m), 1039 (m), 759
(m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H19NO4
+ H 350.1392, found 350.1385.
2-Methoxycarbonyl-4-methylcarbonyl-5-(4-methylphenyl)-
N-phenylpyrrole (4abc). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (50.1 mg, 0.168 mmol, 1.0
equiv), Schiff base 2b34 (32.2 mg, 0.168 mmol, 1.0 equiv), 3-
butyn-2-one (3c, 13.7 mg, 0.201 mmol, 1.2 equiv), and CsF
(51.1 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.2 mL). After
the reaction mixture was stirred for 8.0 h and then worked up,
the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4abc (38.1 mg, 0.114 mmol) in 68% yield
as a yellow liquid: TLC Rf 0.40 (15% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.33 (s, 1H), 7.26-7.23
(m, 3H), 7.07-7.05 (m, 2H), 7.01-6.95 (m, 4H), 3.69 (s, 3H),
2.39 (s, 3H) 2.24 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) d
193.7, 160.3, 144.2, 138.4, 138.1, 130.3, 128.2, 128.1, 128.0,
127.8, 127.3, 123.3, 117.7, 114.2, 51.2, 28.7, 21.3; IR (neat)
2925 (m), 1717 (s, C=O), 1609 (m), 1438 (m), 1247 (s, C-O),
1122 (m), 1032 (s), 749 (w) cm-1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C21H19NO3 + H 334.1443, found 334.1447.
2,4-Dimethoxycarbonyl-5-(4-methylphenyl)-N-phenylpyr-
role (4aba). The Standard Procedure was followed by use of 2-
silylphenyl triflate 1a (50.4 mg, 0.168 mmol, 1.0 equiv), Schiff
base 2b34 (32.1 mg, 0.168 mmol, 1.0 equiv), methyl
acetylenecarboxylate (3a, 16.9 mg, 0.202 mmol, 1.2 equiv), and
CsF (51.6 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.0 mL).
After the reaction mixture was stirred for 6.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4aba (47.3 mg, 0.136 mmol) in 81% yield
as a yellow liquid: TLC Rf 0.45 (15% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.58 (s, 1H), 7.28-7.26
(m, 3H), 7.07-7.06 (m, 2H), 7.02-6.97 (m, 4H), 3.76 (s, 3H),
3.71 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz)
d 160.2, 159.9, 144.3, 137.9, 137.7, 130.3, 128.3, 128.2, 128.1,
127.9, 127.1, 123.5, 119.4, 114.2, 51.3, 51.1, 21.3; IR (neat)
2923 (s), 1713 (s, C=O), 1598 (m), 1470 (s), 1235 (s, C-O),
1116 (s), 1039 (m), 759 (m) cm-1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C21H19NO4 + H 350.1392, found 350.1388.
3,4-Diethoxycarbonyl-2-methoxycarbonyl-5-(4-
methylphenyl)-N-phenylpyrrole (4abf).
The Standard
Procedure was followed by use of 2-silylphenyl triflate 1a (50.5
mg, 0.168 mmol, 1.0 equiv), Schiff base 2b34 (32.2 mg, 0.168
mmol, 1.0 equiv), diethyl acetylenedicarboxylate (3f, 34.5 mg,
0.202 mmol, 1.2 equiv), and CsF (51.3 mg, 0.336 mmol, 2.0
equiv) in CH3CN (2.2 mL). After the reaction mixture was
stirred for 8.0 h and then worked up, the residue was purified
by use of silica gel column chromatography (10% EtOAc in
hexanes as the eluent) to give the desired pyrrole 4abf (52.6 mg,
0.121 mmol) in 72% yield as yellow solids: TLC Rf 0.40 (20%
EtOAc in hexanes as the eluent); mp (recrystallized from EtOH)
144.7–146.9 °C; 1H NMR (CDCl3, 400 MHz) d 7.26-7.24 (m,
3H), 7.09-7.06 (m, 2H), 7.02-6.07 (m, 4H), 4.35 (q, 2H, J =
7.0 Hz), 4.19 (q, 2H, J = 7.2 Hz), 3.75 (s, 3H), 2.24 (s, 3H), 1.34
(t, 3H, J = 7.0 Hz), 1.21 (t, 3H, J = 7.2 Hz); 13C{1H} NMR
(CDCl3, 100 MHz) d 165.2, 164.1, 160.5, 144.6, 138.1, 137.8,
130.6, 129.1, 128.4, 128.2, 128.1, 127.1, 125.5, 119.6, 112.4,
61.3, 60.2, 52.3, 21.3, 14.2, 13.8; IR (neat) 2924 (s), 1714 (s,
C=O), 1599 (w), 1470 (s), 1235 (s, C-O), 1116 (s), 1039 (m),
759 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C25H25NO6 + H 436.1760, found 436.1770.
4-Ethoxycarbonyl-2-methoxycarbonyl-5-(4-methylphenyl)-
N-phenylpyrrole (4abb). (a) The Standard Procedure was
followed by use of 2-silylphenyl triflate 1a (50.3 mg, 0.168
mmol, 1.0 equiv), Schiff base 2b34 (32.3 mg, 0.168 mmol, 1.0
equiv), ethyl acetylenecarboxylate (3b, 19.9 mg, 0.201 mmol,
1.2 equiv), and CsF (51.4 mg, 0.336 mmol, 2.0 equiv) in
CH3CN (2.1 mL). After the reaction mixture was stirred for 6.0
h and then worked up, the residue was purified by use of silica
gel column chromatography (10% EtOAc in hexanes as the
eluent) to give the desired pyrrole 4abb (50.2 mg, 0.139 mmol)
in 83% yield as a yellow liquid: TLC Rf 0.45 (15% EtOAc in
4-Ethoxycarbonyl-2-methoxycarbonyl-5-(4-methoxyphenyl)-
N-phenylpyrrole (4acb). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (301 mg, 1.01 mmol, 1.0
equiv), Schiff base 2c33 (209 mg, 1.01 mmol, 1.0 equiv), ethyl
acetylenecarboxylate (3b, 119 mg, 1.21 mmol, 1.2 equiv), and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 10
1
2
3
4
5
6
7
8
9
CsF (307 mg, 2.02 mmol, 2.0 equiv) in CH3CN (15.0 mL).
CsF (51.6 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.1 mL).
After the reaction mixture was stirred for 8.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4adb (46.7 mg, 0.123 mmol) in 73% yield
as a yellow liquid: TLC Rf 0.45 (20% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.58 (s, 1H), 7.44-7.40
(m, 2H), 7.28-7.25 (m, 2H), 7.23-7.19 (m, 3H), 7.05-7.01 (m,
2H), 4.21 (q, 2H, J = 6.9 Hz), 3.73 (s, 3H), 1.17 (t, 3H, J = 6.9
Hz); 13C{1H} NMR (CDCl3, 100 MHz) d 163.9, 161.0, 144.5,
140.2, 134.7, 130.2, 129.8, 128.5, 128.4, 128.3, 128.2, 124.7,
119.8, 114.6, 59.8, 51.2, 14.1; IR (neat) 2926 (m), 1716 (s,
C=O), 1599 (w), 1490 (m), 1236 (s, C-O), 1092 (m), 1015 (m),
757 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C21H18ClNO4 + H 384.1002, found 384.1007.
After the reaction mixture was stirred for 6.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4acb (328 mg, 0.867 mmol) in 86% yield as
yellow solids: TLC Rf 0.45 (20% EtOAc in hexanes as the
1
eluent); mp (recrystallized from EtOH) 137.6–139.8 °C; H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (CDCl3, 400 MHz) d 7.56 (s, 1H), 7.26-7.23 (m, 3H),
7.06-7.03 (m, 4H), 6.69 (d, 2H, J = 8.8 Hz), 4.15 (q, 2H, J =
7.0 Hz), 3.71 (s, 3H), 3.69 (s, 3H), 1.19 (t, 3H, J = 7.0 Hz);
13C{1H} NMR (CDCl3, 100 MHz) d 163.6, 160.2, 159.2, 144.1,
137.8, 132.0, 128.2, 128.1, 128.0, 123.3, 122.1, 119.5, 114.2,
112.7, 59.9, 55.1, 51.4, 14.3; IR (neat) 2925 (s), 1714 (s, C=O),
1612 (m), 1471 (s), 1250 (s, C-O), 1118 (m), 1041 (m), 759 (m)
cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H21NO5 +
H 380.1498, found 380.1487.
5-(4-Bromophenyl)-4-ethoxycarbonyl-2-methoxycarbonyl-
N-phenylpyrrole (4aeb). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (50.3 mg, 0.168 mmol, 1.0
equiv), Schiff base 2e35 (43.1 mg, 0.168 mmol, 1.0 equiv), ethyl
acetylenecarboxylate (3b, 19.6 mg, 0.201 mmol, 1.2 equiv), and
CsF (51.4 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.3 mL).
After the reaction mixture was stirred for 8.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4aeb (53.1 mg, 0.126 mmol) in 76% yield
as a yellow liquid: TLC Rf 0.45 (20% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.58 (s, 1H), 7.38-7.32
(m, 4H), 7.30 (t, 1H, J = 7.2 Hz), 7.15 (d, 2H, J = 8.0 Hz), 7.03
(d, 2H, J = 8.0 Hz), 4.17 (q, 2H, J = 7.2 Hz), 3.73 (s, 3H), 1.15
(t, 3H, J = 7.2 Hz); 13C{1H} NMR (CDCl3, 100 MHz) d 163.4,
160.3, 143.9, 138.2, 132.2, 131.1, 130.3, 128.4, 128.2, 128.1,
123.5, 120.3, 119.7, 114.2, 59.8, 51.4, 14.4; IR (neat) 2925 (m),
1715 (s, C=O), 1599 (m), 1487 (m), 1236 (s, C-O), 1090 (m),
1011 (m), 759 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C21H18BrNO4 + H 428.0497, found 428.0490.
2,4-Dimethoxycarbonyl-5-(4-methoxyphenyl)-3-methyl-N-
phenylpyrrole (4acd). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (50.2 mg, 0.168 mmol, 1.0
equiv), Schiff base 2c33 (34.6 mg, 0.168 mmol, 1.0 equiv), me-
thyl 2-butynoate (3d, 19.9 mg, 0.201 mmol, 1.2 equiv), and CsF
(51.3 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.1 mL). After
the reaction mixture was stirred for 6.0 h and then worked up,
the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4acd (45.4 mg, 0.119 mmol) in 71% yield
as a yellow liquid: TLC Rf 0.45 (20% EtOAc in hexanes as the
1
eluent); H NMR (CDCl3, 400 MHz) d 7.27-7.24 (m, 3H),
7.06-7.02 (m, 4H), 6.69 (d, 2H, J = 8.4 Hz), 3.72 (s, 3H), 3.64
(s, 3H), 3.62 (s, 3H), 2.62 (s, 3H); 13C{1H} NMR (CDCl3, 100
MHz) d 161.4, 158.9, 158.6, 143.5, 138.7, 131.8, 128.1, 128.0,
127.8, 123.1, 122.2, 117.1, 114.1, 112.6, 55.1, 51.1, 50.9, 12.5;
IR (neat) 2925 (m), 1717 (s, C=O), 1598 (w), 1472 (m), 1240
(s, C-O), 1122 (m), 1032 (m), 836 (m) cm-1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C22H21NO5 + H 380.1498, found
380.1484.
4-Ethoxycarbonyl-2-methoxycarbonyl-5-(naphthalen-1-yl)-
N-phenylpyrrole (4afb). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (50.2 mg, 0.168 mmol, 1.0
equiv), Schiff base 2f34 (38.3 mg, 0.168 mmol, 1.0 equiv), ethyl
acetylenecarboxylate (3b, 19.7 mg, 0.201 mmol, 1.2 equiv), and
CsF (51.1 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.0 mL).
After the reaction mixture was stirred for 8.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4afb (50.2 mg, 0.126 mmol) in 75% yield as
a yellow liquid: TLC Rf 0.45 (20% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.88 (d, 1H, J = 7.2 Hz),
7.79 (d, 1H, J = 8.0 Hz), 7.74 (d, 1H, J = 7.2 Hz), 7.63 (s, 1H),
7.54 (d, 2H, J = 7.6 Hz), 7.50-7.43 (m, 3H), 7.27 (t, 2H, J = 7.2
Hz), 7.13 (t, 2H, J = 7.4 Hz), 4.20 (q, 2H, J = 7.2 Hz), 3.78 (s,
3H), 1.29 (t, 3H, J = 7.2 Hz); 13C{1H} NMR (CDCl3, 100 MHz)
d 164.1, 160.2, 147.3, 142.9, 139.0, 133.9, 131.4, 128.6, 127.9,
127.7, 127.6, 125.8, 125.5, 125.3, 124.8, 123.9, 123.4, 121.9,
121.3, 113.6, 60.6, 53.3, 14.4; IR (neat) 2953 (m), 1731 (s,
C=O), 1599 (m), 1505 (m), 1446 (w), 1235 (s, C-O), 1029 (m),
778 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C25H21NO4 + H 400.1548, found 400.1550.
3,4-Di-n-propyl-2-methoxycarbonyl-5-(4-methoxyphenyl)-
N-phenylpyrrole (4acg). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (101 mg, 0.336 mmol, 1.0
equiv), Schiff base 2c33 (69.5 mg, 0.336 mmol, 1.0 equiv), 4-
octyne (3g, 44.6 mg, 0.403 mmol, 1.2 equiv), and CsF (103 mg,
0.672 mmol, 2.0 equiv) in CH3CN (4.1 mL). After the reaction
mixture was stirred for 8.0 h and then worked up, the residue
was purified by use of silica gel column chromatography (10%
EtOAc in hexanes as the eluent) to give the desired pyrrole 4acg
(19.6 mg, 0.051 mmol) in 15% yield as a yellow liquid: TLC
1
Rf 0.40 (15% EtOAc in hexanes as the eluent); H NMR
(CDCl3, 400 MHz) d 7.38-7.18 (m, 3H), 6.99-6.95 (m, 4H),
6.67 (d, 2H, J = 8.4 Hz), 3.71 (s, 3H), 3.66 (s, 3H), 2.54 (t, 2H,
J = 7.2 Hz), 2.31 (t, 2H, J = 7.0 Hz), 1.65-1.53 (m, 4H),
0.97-0.89 (m, 6H); 13C{1H} NMR (CDCl3, 100 MHz) d 160.4,
159.2, 144.3, 137.7, 131.8, 128.2, 128.1, 128.0, 124.3, 122.2,
116.2, 114.1, 112.6, 55.1, 51.3, 29.9, 28.8, 25.6, 25.4, 13.8; IR
(neat) 2953 (m), 1716 (s, C=O), 1599 (m), 1446 (m), 1235 (s,
C-O), 1095 (m), 1029 (m), 759 (m) cm-1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C25H29NO3 + H 392.2225, found
392.2236.
5-(4-Chlorophenyl)-4-ethoxycarbonyl-2-methoxycarbonyl-
N-phenylpyrrole (4adb). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (50.1 mg, 0.168 mmol, 1.0
equiv), Schiff base 2d34 (35.7 mg, 0.168 mmol, 1.0 equiv), ethyl
acetylenecarboxylate (3b, 19.8 mg, 0.201 mmol, 1.2 equiv), and
4-Ethoxycarbonyl-5-(furan-2-yl)-2-methoxycarbonyl-N-phe-
nylpyrrole (4agb). The Standard Procedure was followed by
use of 2-silylphenyl triflate 1a (50.4 mg, 0.168 mmol, 1.0
equiv), Schiff base 2g33 (28.4 mg, 0.168 mmol, 1.0 equiv), ethyl
ACS Paragon Plus Environment

Page 7 of 10
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
acetylenecarboxylate (3b, 19.9 mg, 0.202 mmol, 1.2 equiv), and
(3b, 19.4 mg, 0.202 mmol, 1.2 equiv), and CsF (51.3 mg, 0.336
mmol, 2.0 equiv) in CH3CN (2.0 mL). After the reaction
mixture was stirred for 6.0 h and then worked up, the residue
was purified by use of silica gel column chromatography (10%
EtOAc in hexanes as the eluent) to give the desired pyrrole 4ajb
(48.5 mg, 0.134 mmol) in 80% yield as a yellow liquid: TLC
CsF (51.8 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.2 mL).
After the reaction mixture was stirred for 8.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4agb (40.4 mg, 0.119 mmol) in 71% yield
as a yellow liquid: TLC Rf 0.45 (20% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.57 (s, 1H), 7.48 (d, 1H,
J = 4.8 Hz), 7.41 (d, 2H, J = 6.8 Hz), 7.32 (t, 1H, J = 6.2 Hz),
7.08 (d, 2H, J = 6.8 Hz), 6.80 (d, 1H, J = 6.4 Hz), 6.46 (dd, 1H,
J = 4.8, 1.6 Hz), 4.14 (q, 2H, J = 7.1 Hz), 3.71 (s, 3H), 1.15 (t,
3H, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 100 MHz) d 163.8,
160.1, 149.9, 148.4, 143.5, 139.6, 131.8, 129.4, 128.6, 124.0,
121.9, 116.5, 114.1, 111.6, 59.7, 51.1, 14.7; IR (neat) 2926 (s),
1716 (s, C=O), 1613 (m), 1472 (m), 1251 (s, C-O), 1117 (m),
1040 (m), 759 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C19H17NO5 + H 340.1185, found 340.1181.
1
Rf 0.45 (15% EtOAc in hexanes as the eluent); H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(CDCl3, 400 MHz) d 7.58 (s, 1H), 7.25-7.23 (m, 3H),
7.20-7.17 (m, 3H), 7.14-7.12 (m, 2H), 7.07-7.03 (m, 2H), 4.13
(q, 2H, J = 7.1 Hz), 4.06 (q, 2H, J = 7.1 Hz), 1.14 (t, 3H, J = 7.1
Hz), 1.09 (t, 3H, J = 7.1 Hz); 13C{1H} NMR (CDCl3, 100 MHz)
d 164.1, 163.8, 144.6, 137.8, 130.8, 128.9, 128.4, 128.2, 128.2,
127.9, 126.9, 123.4, 119.4, 114.3, 60.2, 59.8, 14.4, 14.2; IR
(neat) 2924 (s), 1714 (s, C=O), 1598 (w), 1470 (m), 1235 (s,
C-O), 1116 (s), 1039 (m), 759 (m) cm-1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C22H21NO4 + H 364.1548, found 364.1552.
(b) The same procedure was followed by use of 2-silylphenyl
triflate 1a (2.70 g, 9.05 mmol, 1.0 equiv), Schiff base 2j33 (1.73
g, 9.05 mmol, 1.0 equiv), ethyl acetylenecarboxylate (3b, 1.07
g, 10.9 mmol, 1.2 equiv), and CsF (2.74 g, 18.1 mmol, 2.0
equiv) in CH3CN (100 mL). The desired pyrrole 4ajb (2.57 g,
7.06 mmol) was obtained in 78% yield as a yellow liquid.
3-Ethoxycarbonyl-5-methoxycarbonyl-2-(thien-2-yl)-N-phe-
nylpyrrole (4ahb). The Standard Procedure was followed by
use of 2-silylphenyl triflate 1a (50.2 mg, 0.168 mmol, 1.0
equiv), Schiff base 2h35 (30.6 mg, 0.168 mmol, 1.0 equiv), ethyl
acetylenecarboxylate (3b, 20.1 mg, 0.202 mmol, 1.2 equiv), and
CsF (51.6 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.0 mL).
After the reaction mixture was stirred for 8.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4ahb (43.6 mg, 0.123 mmol) in 73% yield
as a yellow liquid: TLC Rf 0.45 (20% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.58 (s, 1H), 7.41 (d, 2H,
J = 6.4 Hz), 7.30-7.26 (m, 2H), 7.20 (d, 1H, J = 4.0 Hz), 7.12
(d, 2H, J = 6.4 Hz), 6.99 (dd, 1H, J = 7.2, 2.4 Hz), 4.20 (q, 2H,
J = 6.6 Hz), 3.71 (s, 3H), 1.17 (t, 3H, J = 6.6 Hz); 13C{1H} NMR
(CDCl3, 100 MHz) d 163.8, 160.1, 143.9, 139.9, 139.2, 132.1,
131.6, 129.1, 128.2, 127.9, 125.2, 123.4, 122.0, 114.1, 59.8,
51.3, 14.1; IR (neat) 2924 (m), 1715 (s, C=O), 1598 (w), 1470
(m), 1367 (m), 1234 (s, C-O), 1039 (m), 758 (m) cm-1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C19H17NO4S + H 356.0956,
found 356.0947.
3,4-Dimethoxycarbonyl-2-ethoxycarbonyl-5-phenyl-N-phe-
nylpyrrole (4aje). The Standard Procedure was followed by use
of 2-silylphenyl triflate 1a (50.7 mg, 0.168 mmol, 1.0 equiv),
Schiff base 2j33 (31.9 mg, 0.168 mmol, 1.0 equiv), dimethyl
acetylenedicarboxylate (3e, 28.9 mg, 0.202 mmol, 1.2 equiv),
and CsF (51.4 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.5 mL).
After the reaction mixture was stirred for 8.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4aje (50.4 mg, 0.124 mmol) in 74% yield as
yellow solids: TLC Rf 0.40 (20% EtOAc in hexanes as the
1
eluent); mp (recrystallized from EtOH) 141.2–143.5 °C; H
NMR (CDCl3, 400 MHz) d 7.25-7.24 (m, 3H), 7.20-7.17 (m,
3H), 7.13-7.11 (m, 2H), 7.06-7.03 (m, 2H), 4.18 (q, 2H, J =
7.0 Hz), 3.87 (s, 3H), 3.73 (s, 3H), 1.17 (t, 3H, J = 7.0 Hz);
13C{1H} NMR (CDCl3, 100 MHz) d 164.8, 162.2, 160.3, 144.5,
138.0, 130.5, 129.2, 128.5, 128.3, 128.2, 127.6, 127.2, 125.4,
121.2, 112.6, 60.1, 52.6, 51.5, 14.1; IR (neat) 2928 (m), 1738
(s, C=O), 1732 (s, C=O), 1599 (m), 1459 (m), 1235 (s, C-O),
1027 (m), 778 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C23H21NO6 + H 408.1447, found 408.1442.
2-Ethoxycarbonyl-4-methoxycarbonyl-5-phenyl-N-phe-
nylpyrrole (4aja). The Standard Procedure was followed by use
of 2-silylphenyl triflate 1a (50.3 mg, 0.168 mmol, 1.0 equiv),
Schiff base 2j33 (32.1 mg, 0.168 mmol, 1.0 equiv), methyl
acetylenecarboxylate (3a, 17.1 mg, 0.202 mmol, 1.2 equiv), and
CsF (51.7 mg, 0.336 mmol, 2.0 equiv) in CH3CN (2.2 mL).
After the reaction mixture was stirred for 6.0 h and then worked
up, the residue was purified by use of silica gel column
chromatography (10% EtOAc in hexanes as the eluent) to give
the desired pyrrole 4aja (47.6 mg, 0.136 mmol) in 81% yield as
a yellow liquid: TLC Rf 0.45 (15% EtOAc in hexanes as the
eluent); 1H NMR (CDCl3, 400 MHz) d 7.57 (s, 1H), 7.24-7.23
(m, 3H), 7.20-7.16 (m, 3H), 7.14-7.12 (m, 2H), 7.07-7.03 (m,
2H), 4.06 (q, 2H, J = 7.2 Hz), 3.76 (s, 3H), 1.08 (t, 3H, J = 7.2
Hz); 13C{1H} NMR (CDCl3, 100 MHz) d 164.0, 160.2, 144.4,
138.0, 130.6, 128.9, 128.4, 128.2, 128.2, 127.8, 127.0, 123.5,
119.5, 114.3, 60.2, 51.1, 14.4; IR (neat) 2926 (m), 1714 (s,
C=O), 1611 (m), 1470 (s), 1249 (s, C-O), 1118 (s), 1040 (m),
759 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C21H19NO4 + H 350.1392, found 350.1383.
2-Ethoxycarbonyl-4-methoxycarbonyl-5-(4-methoxyphenyl)-
N-phenylpyrrole (4aka). The Standard Procedure was followed
by use of 2-silylphenyl triflate 1a (50.3 mg, 0.168 mmol, 1.0
equiv), Schiff base 2k36 (37.1 mg, 0.168 mmol, 1.0 equiv),
methyl acetylenecarboxylate (3a, 17.1 mg, 0.202 mmol, 1.2
equiv), and CsF (51.2 mg, 0.336 mmol, 2.0 equiv) in CH3CN
(2.1 mL). After the reaction mixture was stirred for 6.0 h and
then worked up, the residue was purified by use of silica gel
column chromatography (10% EtOAc in hexanes as the eluent)
to give the desired pyrrole 4aka (54.4 mg, 0.142 mmol) in 85%
yield as yellow solids: TLC Rf 0.45 (20% EtOAc in hexanes as
the eluent); mp (recrystallized from EtOH) 138.6–140.9 °C; 1H
NMR (CDCl3, 400 MHz) d 7.57 (s, 1H), 7.26-7.23 (m, 3H),
7.07-7.03 (m, 4H), 6.70 (d, 2H, J = 7.2 Hz), 4.15 (q, 2H, J =
7.2 Hz), 3.72 (s, 3H), 3.68 (s, 3H), 1.16 (t, 3H, J = 7.2 Hz);
13C{1H} NMR (CDCl3, 100 MHz) d 163.9, 160.1, 159.1, 144.2,
137.6, 131.9, 128.4, 128.3, 128.2, 124.0, 122.3, 119.6, 114.4,
112.8, 60.1, 55.2, 51.2, 14.1; IR (neat) 2925 (m), 1714 (s, C=O),
1611 (m), 1470 (m), 1249 (s, C-O), 1117 (m), 1040 (m), 759
2,4-Diethoxycarbonyl-5-phenyl-N-phenylpyrrole (4ajb). (a)
The Standard Procedure was followed by use of 2-silylphenyl
triflate 1a (50.5 mg, 0.168 mmol, 1.0 equiv), Schiff base 2j33
(32.3 mg, 0.168 mmol, 1.0 equiv), ethyl acetylenecarboxylate
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 10
1
2
3
4
5
6
7
8
9
(m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H21NO5
+ H 380.1498, found 380.1491.
then worked up, the residue was purified by use of silica gel
column chromatography (10% EtOAc in hexanes as the eluent)
to give the desired pyrrole 4dbb (43.1 mg, 0.119 mmol) in 71%
yield as a yellow liquid: TLC Rf 0.45 (20% EtOAc in hexanes
as the eluent); 1H NMR (CDCl3, 400 MHz) d 8.35 (d, 1H, J =
7.2 Hz), 7.58 (s, 1H), 7.55 (t, 1H, J = 7.0 Hz), 7.29-7.25 (m,
3H), 7.18 (t, 1H, J = 7.2 Hz), 7.03 (d, 2H, J = 7.6 Hz), 4.15 (q,
2H, J = 7.2 Hz), 3.72 (s, 3H), 2.26 (s, 3H), 1.16 (t, 3H, J = 7.2
Hz); 13C{1H} NMR (CDCl3, 100 MHz) d 164.1, 160.8, 151.7,
148.8, 144.2, 140.1, 139.2, 137.8, 130.5, 128.2, 127.9, 127.0,
123.3, 119.4, 114.3, 59.9, 51.4, 21.4, 14.2; IR (neat) 2924 (m),
1715 (s, C=O), 1598 (w), 1470 (m), 1201 (s, C-O), 1120 (w),
1011 (w), 758 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C21H20N2O4 + H 365.1501, found 365.1512.
2-Methoxycarbonyl-3,4-di(4-methoxyphenyl)-N-4-methoxy-
phenylpyrrole (4bih). To a stirred solution of glycine methyl
ester hydrochloride (37.6 mg, 0.302 mmol, 1.0 equiv) in dry
CH3CN (2.5 mL) was added molecular sieves (4 Å, activated,
2.5 μm, powdered, 30.5 mg), Et3N (30.7 mg, 0.302 mmol, 1.0
equiv), and paraformaldehyde (9.41 mg, 0.302 mmol, 1.0
equiv) to generate Schiff base 2i28 at 0 °C under nitrogen atmos-
phere. After the reaction mixture was stirred at 0-10 °C for 1.0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
h,
4-methoxy-2-(trimethylsilyl)phenyl
trifluoromethanesulfonate37 (1b, 101 mg, 0.302 mmol, 1.0
equiv), bis(4-methoxyphenyl)acetylene (3h, 86.5 mg, 0.362
mmol, 1.2 equiv), and CsF (134 mg, 0.906 mmol, 3.1 equiv)
were added into the reaction mixture. The mixture was stirred
at 0-10 °C for 8.0 h and then quenched with water (10 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were dried over CaSO4 (s), filtered, and concentrated under
reduced pressure. It was then purified by use of silica gel col-
umn chromatography (20% EtOAc in hexanes as the eluent) to
give the desired pyrrole 4bih (81.5 mg, 0.184 mmol) in 61%
yield as a yellow liquid: TLC Rf 0.45 (25% EtOAc in hexanes
as the eluent); 1H NMR (CDCl3, 400 MHz) δ 7.32 (d, 2H, J =
8.8 Hz), 7.23 (d, 2H, J = 8.8 Hz), 7.07 (d, 2H, J = 8.4 Hz), 7.06
(s, 1H), 6.95 (d, 2H, J = 8.8 Hz), 6.88 (d, 2H, J = 8.4 Hz), 6.77
(d, 2H, J = 8.8 Hz), 3.84 (s, 3H), 3.82 (s, 3H), 3.76 (s, 3H), 3.49
(s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 161.6, 158.9,
158.9, 158.0, 136.2, 132.4, 131.8, 129.1, 129.0, 128.5, 126.9,
125.7, 124.8, 124.5, 113.8, 113.6, 113.5, 55.4, 55.2, 55.1, 51.3;
IR (neat) 2925 (m), 1715 (s, C=O), 1598 (w), 1464 (m), 1235
(s, C-O), 1120 (w), 1011 (w), 759 (m) cm-1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C27H25NO5 + H 444.1811, found
444.1823.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
NMR spectra, IR spectra, and crystallographic data
(PDF)
Crystallographic data for 4acb (CIF)
AUTHOR INFORMATION
Corresponding Author
*jrhwu@mx.nthu.edu.tw
ORCID: 0000-0002-9225-8484
Present Address
Department of Chemistry, National Tsing Hua University, Hsin-
chu 30013, Taiwan
4-Ethoxycarbonyl-2-methoxycarbonyl-N-3,4-dimethoxy-
phenyl-5-(4-methylphenyl) pyrrole (4cbb). The Standard
Procedure was followed by use of 2-silylayl triflate 1c (50.4 mg,
0.141 mmol, 1.0 equiv), Schiff base 2b34 (26.9 mg, 0.141 mmol,
1.0 equiv), ethyl acetylenecarboxylate (3b, 16.6 mg, 0.169
mmol, 1.2 equiv), and CsF (42.9 mg, 0.282 mmol, 2.0 equiv) in
CH3CN (2.1 mL). After the reaction mixture was stirred for 6.0
h and then worked up, the residue was purified by use of silica
gel column chromatography (15% EtOAc in hexanes as the
eluent) to give the desired pyrrole 4cbb (46.5 mg, 0.110 mmol)
in 78% yield as yellow solids: TLC Rf 0.40 (20% EtOAc in
hexanes as the eluent); mp (recrystallized from EtOH) 143.1–
145.3 °C; 1H NMR (CDCl3, 400 MHz) d 7.54 (s, 1H), 7.02-6.96
(m, 3H), 6.71 (s, 1H), 6.68 (d, 2H, J = 6.4 Hz), 6.48 (d, 1H, J =
6.4 Hz), 4.14 (q, 2H, J = 6.9 Hz), 3.83 (s, 3H), 3.71 (s, 3H), 3.66
(s, 3H), 2.25 (s, 3H), 1.17 (t, 3H, J = 6.9 Hz); 13C{1H} NMR
(CDCl3, 100 MHz) d 163.6, 160.2, 148.4, 148.0, 144.6, 138.0,
130.5, 130.4, 128.0, 127.2, 123.3, 120.6, 119.3, 114.2, 111.7,
109.7, 59.8, 55.9, 55.8, 51.4, 21.4, 14.3; IR (neat) 2930 (m),
1714 (s, C=O), 1515 (s), 1471 (m), 1237 (s, C-O), 1112 (s),
1029 (m), 760 (m) cm-1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C24H25NO6 + H 424.1760, found 424.1758.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
For financial support, we thank Ministry of Science and
Technology (MOST, Grant Nos. 106-2113-M-007-011-MY2 and
107-3017-F-007-002) and Ministry of Education (Grant Nos.
106N501CE1 and 107QR001I5) of R.O.C. We also thank the
MOST in Taiwan to support The Featured Areas Research Center
Program within the framework of the Higher Education Sprout
Project through the Frontier Research Center on Fundamental and
Applied Sciences of Matters. English in this manuscript has been
polished by Wallace Academic Editing.
REFERENCES
(1) Jusélius, J.; Sundholm, D. The aromatic pathways of porphins,
chlorins and bacteriochlorins. Phys. Chem. Chem. Phys. 2000, 2,
2145-2151.
(2) Fowles, J.; Bates, M. The Chemical Constituents in Cigarettes
and Cigarette Smoke: Priorities for Harm Reduction; Epidemiology
and Toxicology Group ESR: Kenepuru Science Centre; March 2000.
(3) Domagala, A.; Jarosz, T.; Lapkowski, M. Living on pyrrolic
foundations-Advances in natural and artificial bioactive pyrrole deriv-
atives. Eur. J. Med. Chem. 2015, 100, 176-187.
(4) Gholap, S. S. Pyrrole: An emerging scaffold for construction of
valuable therapeutic agents. Eur. J. Med. Chem. 2016, 110, 13-31.
(5) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P.
Pyrrole: a resourceful small molecule in key medicinal hetero-aromat-
ics. RSC Adv. 2015, 5, 15233-15266.
4-Ethoxycarbonyl-2-methoxycarbonyl-5-(4-methylphenyl)-
N-2-pyridylpyrrole (4dbb). The Standard Procedure was
followed by use of 2-silylaryl triflate 1d (50.1 mg, 0.167 mmol,
1.0 equiv), Schiff base 2b34 (31.8 mg, 0.167 mmol, 1.0 equiv),
ethyl acetylenecarboxylate (3b, 19.6 mg, 0.201 mmol, 1.2
equiv), and CsF (50.8 mg, 0.334 mmol, 2.0 equiv) in CH3CN
(2.1 mL). After the reaction mixture was stirred for 8.0 h and
ACS Paragon Plus Environment

Page 9 of 10
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(6) Organic Chemistry Portal. https://www.organic-chemis-
try.org/synthesis/heterocycles/pyrroles.shtm (accessed January 9,
2019).
(28) Swain, S. P.; Shih, Y.-C.; Tsay, S.-C.; Jacob, J.; Lin, C.-C.;
Hwang, K. C.; Horng, J.-C.; Hwu, J. R. Aryne-Induced Novel Tandem
1,2-Addition/(3+2) Cycloaddition to Generate Imidazolidines and Pyr-
rolidines. Angew. Chem. Int. Ed. 2015, 54, 9926-9930.
(29) Asikainen, M.; Jauhiainen, O.; Aaltonen, O.; Harlin, A. Con-
tinuous catalyst-free aromatization of γ-terpinene using air as an oxi-
dant. Green Chem. 2013, 15, 3230–3235.
(30) Hwu, J. R.; Swain, S. P. Silicon-Induced Phenanthrene For-
mation from Benzynes and Allenylsilanes. Chem. Eur. J. 2013, 19,
6556-6560.
(31) Ramaiah, D.; Muneer, M.; Gopidas, K. R.; Das, P. K.; Rath, N.
P.; George, M. V. Phototransformations of C-Benzoylaziridines. Dipo-
larophilic Trapping of Photogenerated Azomethine Ylides. J. Org.
Chem. 1996, 61, 4240 4246.
(32) Bohen, J. M.; Joullié, M. M.; Kaplan, F. A.; Loev, B. "Dry-
Column" Chromatography. A new technique for the undergraduate
laboratory. J. Chem. Educ. 1973, 50, 367-368.
(33) López-Pérez, A.; Adrio, J.; Carretero, J. C. Bis-Sulfonyl
Ethylene as Masked Acetylene Equivalent in Catalytic Asymmetric [3
+ 2] Cycloaddition of Azomethine Ylides. J. Am. Chem. Soc. 2008, 130,
10084-10085.
(34) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. Highly
Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides
Catalyzed by Copper(I)/TF-BiphamPhos Complexes. J. Am. Chem. Soc.
2008, 130, 17250-17251.
(35) Robles-Machín, R.; López-Pérez, A.; González-Esguevillas, M.;
Adrio, J.; Carretero, J. C. Pyrrole and Oligopyrrole Synthesis by 1,3-
Dipolar Cycloaddition of Azomethine Ylides with Sulfonyl
Dipolarophiles. Chem. Eur. J. 2010, 16, 9864-9873.
(7) Vessally, E. A new avenue to the synthesis of highly substituted
pyrroles: synthesis from N-propargylamines. RSC Adv. 2016, 6,
18619-18631.
(8) Chelucci, G. Metal-catalyzed dehydrogenative synthesis of pyr-
roles and indoles from alcohols. Coord. Chem. Rev. 2017, 331, 37-53.
(9) Zhou, N.-N.; Zhu, H.-T.; Yang, D.-S.; Guan, Z.-H. Recent de-
velopments in the group-1B-metal-catalyzed synthesis of pyrroles. Org.
Biomol. Chem. 2016, 14, 7136-7149.
(10) Khajuria, R.; Dham, S.; Kapoor, K. K. Active methylenes in
the synthesis of a pyrrole motif: an imperative structural unit of phar-
maceuticals, natural products and optoelectronic materials. RSC Adv.
2016, 6, 37039-37066.
(11) Olivier, W. J.; Smith, J. A.; Bissember, A. C. Methods for the
synthesis of annulated pyrroles via cyclisation strategies. Org. Biomol.
Chem. 2018, 16, 1216-1226.
(12) Quiclet-Sire, B.; Zard, S. Z. Convergent Routes to Pyrroles Ex-
ploiting the Unusual Radical Chemistry of Xanthates – An Overview.
Synlett 2017, 28, 2685-2696.
(13) Liu, Y.; Hu, H.; Wang, X.; Zhi, S.; Kan, Y.; Wang, C. Synthesis
of Pyrrole via a Silver-Catalyzed 1,3-Dipolar Cycloaddition/Oxidative
Dehydrogenative Aromatization Tandem Reaction. J. Org. Chem. 2017,
82, 4194-4202.
(14) Andreou, D.; Kallitsakis, M. G.; Loukopoulos, E.; Gabriel, C.;
Kostakis, G. E.; Lykakis, I. N. Copper-Promoted Regioselective
Synthesis of Polysubstituted Pyrroles from Aldehydes, Amines, and
Nitroalkenes via 1,2-Phenyl/Alkyl Migration. J. Org. Chem. 2018, 83,
2104-2113.
(15) Hong, D.; Zhu, Y.; Li, Y.; Lin, X.; Lu, P.; Wang, Y. Three-
Component Synthesis of Polysubstituted Pyrroles from a-
Diazoketones, Nitroalkenes, and Amines. Org. Lett. 2011, 13,
4668-4671.
(16) Hu, Y.; Wang, C.; Wang, D.; Wu, F.; Wan, B. Synthesis of
Tetrasubstituted Pyrroles from Terminal Alkynes and Imines. Org. Lett.
2013, 15, 3146-3149.
(17) Cyr, D. J. S.; Arndtsen, B. A. A New Use of Wittig-Type
Reagents as 1,3-Dipolar Cycloaddition Precursors and in Pyrrole
Synthesis. J. Am. Chem. Soc. 2007, 129, 12366-12367.
(18) Tietze, L. F. Domino Reactions in Organic Synthesis. Chem.
Rev. 1996, 96, 115-136.
(19) Padwa, A. Domino reactions of rhodium(II) carbenoids for al-
kaloid synthesis. Chem. Soc. Rev. 2009, 38, 3072-3081.
(20) Ardkhean, R.; Caputo, D. F. J.; Morrow, S. M.; Shi, H.; Xiong,
Y.; Anderson, E. A. Cascade polycyclizations in natural product syn-
thesis. Chem. Soc. Rev. 2016, 45, 1557-1569.
(21) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Lamellarins and
Related Pyrrole-Derived Alkaloids from Marine Organisms. Chem.
Rev. 2008, 108, 264-287.
(22) Bailly, C. Lamellarins: A tribe of bioactive marine natural
products. In Outstanding Marine Molecules: Chemistry, Biology, Anal-
ysis; La Barre, S., Kornprobst, J.-M., Eds.; Wiley-VCH Verlag GmbH
& Co. KGaA.: Weinheim, 2014; pp 377-386.
(23) Li, Q.; Jiang, J.; Fan, A.; Cui, Y.; Jia, Y. Total Synthesis of
Lamellarins D, H, and R and Ningalin B. Org. Lett. 2011, 13, 312-315.
(24) Fukuda, T.; Sudo, E.; Shimokawa, K.; Iwao, M. Palladium-
catalyzed cross-coupling of N-benzenesulfonyl-3,4-dibromopyrrole
and its application to the total syntheses of lamellarins O, P, Q, and R.
Tetrahedron 2008, 64, 328-338.
(25) Li, C.-J.; Trost, B. M. Green chemistry for chemical synthesis.
Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 13197-13202.
(26) Sheldon, R. A. Atom efficiency and catalysis in organic syn-
thesis. Pure Appl. Chem. 2009, 72, 1233-1246.
(27) Rivera, D. G.; Wessjohann, L. A. Supramolecular Compounds
from Multiple Ugi Multicomponent Macrocyclizations: Peptoid-based
Cryptands, Cages, and Cryptophanes. J. Am. Chem. Soc. 2006, 128,
7122-7123.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(36)
Conde, E.; Rivilla, I.; Larumbe, A.; Cossío, F. P.
Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential
Interrupted and Completed (3 + 2) Cycloadditions. J. Org. Chem. 2015,
80, 11755-11767.
(37) Baumgärtner, K.; Chincha, A. L. M.; Dreuw, A.; Rominger, F.;
Mastalerz,
M.
A
Conformationally
Stable
Contorted
Hexabenzoovalene. Angew. Chem. Int. Ed. 2016, 55, 15594-15598.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 10
1
2
3
4
5
6
Table of Contents
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
ACS Paragon Plus Environment