An atom-economic synthesis of functionalized pyrroles via a sequential metal-catalyzed three-component reaction

Article abstract of DOI:10.1016/j.tet.2014.01.037

A three-component reaction of one molecule of imine and two molecules of alkynoates is realized with the catalysis of Cu(I)-Fe(III) in a sequential manner to allow the direct synthesis of functionalized pyrroles, during which, one C-N bond and two C-C bonds are formed with high atom economy. This method benefits from easily available starting materials, low-cost catalysts, and convenient operations.

Full text of DOI:10.1016/j.tet.2014.01.037

Tetrahedron 70 (2014) 2472e2477
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Tetrahedron
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An atom-economic synthesis of functionalized pyrroles via
a sequential metal-catalyzed three-component reaction
*
Li Yufeng , Shi Jie, Wu Zhengguang, Wang Xinglong, Wu Xiaowei, Gu Jiachao,
Bu Hongzhong, Ma Hongfei
College of Science, Nanjing University of Technology, Nanjing 211816, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component reaction of one molecule of imine and two molecules of alkynoates is realized with
the catalysis of Cu(I)eFe(III) in a sequential manner to allow the direct synthesis of functionalized pyr-
roles, during which, one CeN bond and two CeC bonds are formed with high atom economy. This
method benefits from easily available starting materials, low-cost catalysts, and convenient operations.
Ó 2014 Published by Elsevier Ltd.
Received 29 October 2013
Received in revised form 8 January 2014
Accepted 20 January 2014
Available online 23 February 2014
Keywords:
Three-component reaction
Pyrroles
Metal catalysis
1. Introduction
In this context, we wish to describe our recent research on
a metal-catalyzed three-component reaction of an aldimine with
Pyrroles represent one of the most important five-membered
heterocycles that constitute the vast majority of drugs and bi-
ologically relevant molecules, such as antiviral, antibacterial,
chlorophyll, and so on.1 Besides, they are very important in-
termediates in synthetic chemistry2 and widely used in the field of
material design.3 As such, a variety of well-documented methods
have been dedicated to the construction of pyrroles and their de-
rivatives in the past.4 The Hantzsch reaction5 based on condensa-
two alkynoates for the synthesis of functionalized pyrroles. The
process was performed in a sequential manner including a Cu(I)-
catalyzed addition of methyl propionate to an aldimine giving 3a
and a following Fe(III)-catalyzed cyclization of 3a with another
alkynoate. One CeN bond and two CeC bonds are formed with
excellent atom economy in the reaction. And as far as we know,
cuprum and iron are both abundant and low-cost metals on Earth,
and the catalysts we used are easily recyclable by filtration.
tion of a-haloketones with 1,3-dicarbonyl compounds and amines,
the PaaleKnorr reaction6 involving cyclocondensation of 1,4-
2. Results and discussion
diketones with amines, and the Knorr reaction7 by condensation
of
a-aminoketones with b-keto esters or b-diketones are good
The reaction of one portion of aldimine (1a) with two portions
of methyl propionate (2a) was performed initially for catalyst
screening as well as condition optimization. As the manner A
(shown in Table 1), using CuCl (10 mol %) as the catalyst, only
a propargylamine type adduct (3a) was isolated in heated di-
chloroethane (50 ꢀC) for 5 h.13 When the reaction time was pro-
longed to 50 h under 80 ꢀC, functionalized pyrrole (4a) was
obtained in a lowered yield (Table 1, entry 2). The structure of 4a
was determined by NMR analysis. Increasing CuCl to 100 mol %, the
yield of 4a was not distinctly enhanced (Table 1, entry 3). CuCl2,
FeCl3, FeCl2, ZnCl2, PdCl2, and AgNO3 were screened for the reaction
and all of them gave neither 3a nor 4a. Fortunately, when adding
FeCl2 (10 mol %) to the CuCl-mediated system (after heated for 5 h),
4a was obtained in 64% yield (Table 1, entry 4). Increasing the
amount of FeCl2 (15 mol %) seemed to be little beneficial to the
conventional examples for pyrroles synthesis. Recently, modern
methods including transition metal-catalyzed self-assembly re-
actions,8,9 microwave-assisted approaches,10 and multibond-
forming strategies4a,11 have been increasingly applied in the con-
struction of substituted pyrroles. Indeed, in order to achieve higher
efficiency as well as good eco-compatibility, the adoption of mod-
ern thoughts and technologies for building complex molecules
from relatively simple materials has become a favoring trend in the
field of synthetic chemistry.12
* Corresponding author. Tel./fax: þ86 (0)25 58139483; e-mail address: yufengli@
njut.edu.cn (L. Yufeng).
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.01.037

L. Yufeng et al. / Tetrahedron 70 (2014) 2472e2477
2473
Table 1
Reaction conditiondoptimization
Entry
Substrates, mole ratio
Conducting manner, conditions
Product, yielda (%)
1
2
3
4
5
6
7
8
1a/2a¼1:2
1a/2a¼1:2
1a/2a¼1:2
1a/2a¼1:2
1a/2a¼1:2
1a/2a¼1:2
1a/2a¼1:2
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
3a/2a¼1:1
A, CuCl (10 mol %), DCE, 50 ꢀC, 5 h
3a, 95
A, CuCl (10 mol %), DCE, 50 ꢀC, 50 h
3a, 81; 4a, 12
3a, 77; 4a, 14
4a, 64
4a, 66
4a, 82
4a, 78
4a, 83
4a, 64
4a, 19
A, CuCl (100 mol %), DCE, 50 ꢀC, 50 h
A, CuCl (10 mol %), FeCl2 (10 mol %), DCE, 80 ꢀC, 24 h
A, CuCl (10 mol %), FeCl2 (15 mol %), DCE, 80 ꢀC, 24 h
A, CuCl (10 mol %), FeCl3 (15 mol %), DCE, 80 ꢀC, 24 h
A, CuCl (10 mol %), FeCl3$6H2O (15 mol %), DCE, 80 ꢀC, 24 h
B (step ii), FeCl3 (10 mol %), DCE, 80 ꢀC, 19 h
B (step ii), FeCl2 (10 mol %), DCE, 80 ꢀC, 19 h
B (step ii), ZnCl2 (10 mol %), DCE, 80 ꢀC, 19 h
B (step ii), CuCl2 (10 mol %), DCE, 80 ꢀC, 19 h
B (step ii), PdCl2 (10 mol %), DCE, 80 ꢀC, 19 h
B (step ii), AgNO3 (10 mol %), DCE, 80 ꢀC, 19 h
B (step ii), FeCl3 (10 mol %), toluene, 100 ꢀC, 19 h
B (step ii), FeCl3 (10 mol %), DMF, 100 ꢀC, 19 h
B (step ii), FeCl3 (10 mol %), dioxane, 100 ꢀC, 19 h
B (step ii), FeCl3 (10 mol %), ethanol, 80 ꢀC, 19 h
9
10
11
12
13
14
15
16
17
4a, 11
b
-
4a, 0
4a, 52
4a, 40
4a, 31
4a, 21
a
Isolated yield after purification by silica gel chromatography.
Compound 4a was observable in TLC but inseparable due to its low content.
b
reaction (Table 1, entry 5). Alternatively, when anhydrous FeCl3
(15 mol %, considering the practical reduction of FeCl3 with CuCl)
was adopted instead of FeCl2, the yield of 4a was enhanced to 82%
(Table 1, entry 6). Comparing to FeCl3, FeCl3$6H2O also worked well
and gave 4a in a good yield (Table 1, entry 7).
Table 2
Scope of aldimines and alkynoatesa
Next, the sequential process was divided into two steps to check
the exact action of the two catalysts (shown as conducting manner
B). A mixture of 1a and 2a in a ratio of 1:1 (mol) was treated, re-
spectively, with CuCl, CuCl2, FeCl2, FeCl3, ZnCl2, PdCl2, and AgNO3 in
dichloroethane at 50 ꢀC, and it was found that only CuCl exhibited
good activation giving a good yield of 3a. Then 3a was isolated and
treated with one portion of 2a in the presence of FeCl3, FeCl2, ZnCl2,
CuCl2, PdCl2, and AgNO3, respectively. After heated at 80 ꢀC for 19 h,
only FeCl3 and FeCl2 gave inspiring results (Table 1, entries 8 and 9).
When ZnCl2 and CuCl2 were used, both the reactions gave lowered
yields of 4a (Table 1, entries 10 and 11). While PdCl2 was employed
in the step ii, no 4a was isolated for its low contents (Table 1, entry
12). AgNO3 showed no activation on the reaction (Table 2, entry 13).
Furthermore, other solvents, such as toluene, N,N-dimethyl form-
amide, 1,4-dioxane, and ethanol, were proved to be unsuitable for
the step ii (Table 1, entries 14e17).
Following the manner B, the other alkyne substrates were then
examined for their possible adaption in pursuing for molecular
diversity. With the second alkyne motif fixed as 2a, phenyl-
acetylene, trimethylsilylacetylene, 1-propyn-3-ol, and propargyl
benzoate were, respectively, tested as the first alkyne motif. Phe-
nylacetylene’s reaction gave a high yield of 1,4-diphenylbuta-1,3-
diyne in accordance with a reported Cu(I)-catalyzed coupling.14
Both trimethylsilylacetylene15 and propargyl benzoate reactions
indeed gave good yields of the relevant adducts in Cu(I) catalyzed
addition, but the following Fe(III)-catalyzed cyclization couldn’t
take place. 1-Propyn-3-ol showed a bad selectivity in the Cu(I)-
Entry Substrates
Product
Yieldb (%)
1
2
3
1a (R1¼Ph, R2¼Ph);
2a (R3¼H)
82
85
84
4a
1b (R1¼4-MeC6H4, R2¼Ph);
2a (R3¼H)
4b
4c
1c (R1¼4-MeOC6H4, R2¼Ph);
2a (R3¼H)

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L. Yufeng et al. / Tetrahedron 70 (2014) 2472e2477
Table 2 (continued)
Table 2 (continued )
Entry Substrates
Product
Yieldb (%)
Entry Substrates
Product
Yieldb (%)
4
1d (R1¼3-MeC6H4, R2¼Ph);
83
2a (R3¼H)
12
1l (R1¼Ph, R2¼4-ClC6H4);
79
2a (R3¼H)
4d
4l
5
1e (R1¼3-t-Bu-C6H4, R2¼Ph);
2a (R3¼H)
80
13
1a (R1¼Ph, R2¼Ph);
2b (R3¼COOMe)
70
4e
4m
6
1f (R1¼3,5-(Me)2C6H3, R2¼Ph);
2a (R3¼H)
81
14
1b (R1¼4-MeC6H4, R2¼Ph);
2b (R3¼COOMe)
72
4f
4n
7
1g (R1¼4-ClC6H4, R2¼Ph);
2a (R3¼H)
62
15
1j (R1¼Ph, R2¼4-MeOC6H4);
2b (R3¼COOMe)
71
4g
4o
8
1h (R1¼4-FC6H4, R2¼Ph);
2a (R3¼H)
60
16
1p (R1¼4-MeC6H4, R2¼4-
MeOC6H4);
74
4h
2b (R3¼COOMe)
4p
4q
9
1i (R1¼Ph, R2¼4-MeC6H4);
2a (R3¼H)
84
17
1q (R1¼4-MeOC6H4, R2¼4-
MeOC6H4);
78
4i
2b (R3¼COOMe)
10
1j (R1¼Ph, R2¼4-MeOC6H4);
2a (R3¼H)
82
18
19
20
1r (R1¼4-NO2C6H4, R2¼Ph); 2a dc
0
0
0
(R3¼H)
1s (R1¼3-NO2C6H4, R2¼Ph); 2a dc
(R3¼H)
1t (R1¼2-NO2C6H4, R2¼Ph); 2a dc
4j
(R3¼H)
a
All reactions were conducted as the manner A with dichloroethane as the
solvent.
1k (R1¼Ph, R2¼4-OHC6H4);
2a (R3¼H)
85
b
c
11
Isolated yield of 4 after purification by silica gel chromatography.
No reaction.
catalyzed step, and the following step only gave an inseparable
mixture. Next, with the first alkyne fixed as 2a, the above men-
tioned acetylene compounds as well as dimethyl acetylenedi-
carboxylate (2b) were, respectively, examined for their behavior in
4k

L. Yufeng et al. / Tetrahedron 70 (2014) 2472e2477
2475
the additionecyclization step. Only 2b gave a satisfactory result
(Table 2, entries 13e17), and other substrates all exhibited too
lowered reactivity to provide the desirable products.
microscopic melting point apparatus. HPLC was PGENERAL
ꢀ
(chromatographic column, pgrandsil-STC-C18,
5 mm, 100 A,
4.6ꢁ250 mm; CH3OH/H2O (volume)¼9:1).
With the optimized reaction conditions in hand, we turned to
explore the scope of aldimines. Two typical aliphatic aldimines,
benzylidenecyclohexanamine and benzylidenebenzylamine, were,
respectively, treated at first with 2a in the presence of CuCl, and
both the two reactions gave inseparable products. Further treat-
ment of the above mixtures with FeCl3 was also fruitless. Compared
with aliphatic aldimines, N-arylbenzaldimines’ reactivities were
good and the corresponding pyrroles were obtained with satisfac-
tory yields (Table 2, entries 1e17), except that aldmines bearing
strong electron-withdrawing groups (eNO2) on the side of amines
gave no desirable products (Table 2, entries 18e20).
On the basis of the above experimental results, a possible Cu(I)e
Fe(III)-catalyzed mechanism for the sequential procedure was
depicted in Scheme 1. Cu(I)-promoted addition of 1 to 2a generates
propargylamine intermediate 3 as the literature presented.13a Un-
der the help of FeCl3, the aza-Michael addition occurs to form 5.16
This is well testified by that the direct treatment of 3a with 2a in
the absence of FeCl3 gives no any detectable intermediate or the
desired product. As soon as the intermediate 5 is formed, the
intramolecular 5-exo-dig cyclization takes place immediately to
give 6 under the activation of triple bond via the coordination of
FeCl3.17 Compound 6 transforms quickly into 4 as the tautomerized
product through a 1,3-hydrogen migration procedure.18
4.2. General synthesis of pyrroles 4
To a solution of methyl propionate (2a, 5.0 mmol) in di-
chloroethane (30 mL), CuCl (0.5 mmol) and aldimine (1, 5.0 mmol)
were added. The mixture was stirred at 50 ꢀC for 5 h. After the step
completed according to TLC analysis, another portion of alkynoate
(2a or 2b, 5.0 mmol) and FeCl3 (0.75 mmol) were added at room
temperature. The mixture was further stirred at 80 ꢀC for 19 h. The
mixture was filtered and the filtrate was evaporated in vacuo. The
residue was purified by flash chromatography on silica gel to give
desired pyrroles 4.
4.3. Characterization
4.3.1. Methyl 4-(2-methoxy-2-oxoethyl)-1,5-diphenyl-1H-pyrrole-3-
carboxylate (4a). A pale yellow viscous liquid, 82% yield. 1H NMR
(400 MHz, CDCl3):
3.0 Hz, 2H), 6.73 (s, 1H), 3.69 (s, 3H), 3.59 (s, 3H), 3.50 (s, 2H) ppm.
13C NMR (101 MHz, CDCl3):
173.04, 165.20, 139.28, 133.84, 130.57,
d
7.29e7.27 (m, 3H), 7.17 (s, 5H), 7.06 (dd, J¼6.6,
d
129.26, 129.01, 128.28, 127.95, 127.73, 127.26, 126.75, 125.54, 116.82,
115.03, 51.91, 50.98, 31.55 ppm.
4.3.2. Methyl
pyrrole-3-carboxylate (4b). A pale yellow viscous liquid, 85% yield.
1H NMR (400 MHz, CDCl3):
4-(2-methoxy-2-oxoethyl)-5-phenyl-1-(p-tolyl)-1H-
d
7.54 (s, 1H), 7.24 (d, J¼2.3 Hz, 2H),
7.12e7.09 (m, 3H), 7.04 (d, J¼8.2 Hz, 2H), 6.94 (d, J¼8.3 Hz, 2H), 3.80
(s, 3H), 3.72 (s, 5H), 2.29 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3):
d
173.07, 165.24, 137.13, 136.82, 133.86, 130.59, 129.80, 129.59,
128.26, 128.14, 127.98, 127.67, 126.49, 125.33, 116.66, 114.79, 51.88,
50.93, 31.57, 20.98 ppm.
4.3.3. Methyl 4-(2-methoxy-2-oxoethyl)-1-(4-methoxyphenyl)-5-
phenyl-1H-pyrrole-3-carboxylate (4c). A yellow viscous liquid, 84%
yield. 1H NMR (400 MHz, CDCl3):
d
7.42 (s, 1H), 7.15 (dd, J¼5.1,
1.7 Hz, 3H), 7.03e7.01 (m, 2H), 6.91e6.88 (m, 2H), 6.67 (d, J¼8.9 Hz,
2H), 3.73 (s, 3H), 3.65 (s, 3H), 3.63 (s, 3H), 3.62 (s, 2H) ppm. 13C NMR
Scheme 1. The plausible mechanism of the reaction.
(101 MHz, CDCl3):
d 173.07, 165.23, 158.57, 134.01, 132.35, 130.58,
128.25, 128.15, 128.04, 127.95, 127.65, 126.77, 126.14, 116.43, 114.27,
114.10, 55.39, 51.86, 50.91, 31.58 ppm.
3. Conclusion
4.3.4. Methyl 4-(2-methoxy-2-oxoethyl)-5-phenyl-1-(m-tolyl)-1H-
In conclusion, we have developed an eco-friendly method for
the direct synthesis of substituted pyrroles. Although the scope of
aldimine and acetylene substrates is some limited, the mild re-
action conditions, inexpensive catalyst, operational simplicity, good
yields, and high atomic economy make the method valuable for
pyrroles synthesis. And, how to inhibit the coupling of phenyl-
acetylene and trimethylsilylacetylene to acquire pyrroles based on
this method is a further project of us.
pyrrole-3-carboxylate (4d). A pale yellow viscous liquid, 83% yield.
1H NMR (400 MHz, CDCl3):
d 7.56 (s, 1H), 7.26e7.22 (m, 5H), 7.11
(dd, J¼6.6, 2.4 Hz, 4H), 3.80 (s, 3H), 3.72 (s, 5H), 2.25 (s, 3H) ppm. 13
C
NMR (101 MHz, CDCl3):
d 173.02, 165.21, 139.07, 133.82, 130.55,
128.68, 128.22, 127.98, 127.94, 127.68, 126.05, 125.70, 123.67, 122.70,
116.75, 114.88, 51.86, 50.93, 31.55, 21.23 ppm.
4.3.5. Methyl 1-(3-(tert-butyl)phenyl)-4-(2-methoxy-2-oxoethyl)-5-
phenyl-1H-pyrrole-3-carboxylate (4e). A yellow viscous liquid, 80%
4. Experimental section
4.1. General
yield. 1H NMR (400 MHz, CDCl3):
d
7.61 (s, 1H), 7.28 (d, J¼2.6 Hz,
1H), 7.25e7.23 (m, 4H), 7.12e7.09 (m, 4H), 3.81 (s, 3H), 3.74 (s, 2H),
3.73 (s, 3H), 1.08 (s, 9H) ppm. 13C NMR (101 MHz, CDCl3):
173.07,
d
165.24, 152.11, 138.81, 133.85, 130.64, 128.73, 128.27, 128.08, 127.68,
127.64, 123.92, 123.47, 121.85, 116.72, 114.86, 51.89, 50.96, 34.54,
31.04, 30.94 ppm.
All the reagents were purchased from commercial suppliers, and
were used without further purification. The 1H NMR and 13C NMR
spectra were performed with a Varian Unity Plus 400 MHz spec-
trometer in CDCl3. Chemical shifts are expressed in parts per mil-
4.3.6. Methyl 1-(3,5-dimethylphenyl)-4-(2-methoxy-2-oxoethyl)-5-
lion (
for 1H,
(Hz). Splitting patterns are designated as s (singlet), d (doublet), t
(triplet), (multiplet). Melting points were measured on
d
) using residual solvent protons as internal standards (
d
d
7.26
phenyl-1H-pyrrole-3-carboxylate (4f). A pale yellow viscous liquid,
77.0 for 13C). Coupling constants (J) are reported in hertz
81% yield. 1H NMR (400 MHz, CDCl3):
d
7.55 (s,1H), 7.25 (d, J¼2.1 Hz,
2H), 7.11 (dd, J¼6.5, 3.1 Hz, 2H), 6.90e6.85 (m, 2H), 6.67 (s, 2H), 3.81
m
(s, 3H), 3.73 (s, 3H), 3.72 (s, 2H), 2.19 (s, 6H) ppm. 13C NMR

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L. Yufeng et al. / Tetrahedron 70 (2014) 2472e2477
(101 MHz, CDCl3):
130.53, 128.81, 128.16, 127.93, 127.61, 123.25, 116.58, 114.69, 51.88,
50.93, 31.57, 21.13 ppm.
d
173.09, 165.27, 139.11, 138.66, 133.79, 130.80,
yield. 1H NMR (400 MHz, CDCl3):
d
7.22 (dd, J¼5.0, 1.9 Hz, 3H), 7.08
(dd, J¼6.5, 3.2 Hz, 2H), 7.04 (d, J¼8.3 Hz, 2H), 7.01e6.98 (m, 2H),
3.84 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.62 (s, 2H), 2.29 (s, 3H) ppm.
13C NMR (101 MHz, CDCl3):
d 172.33, 164.95, 162.13, 138.23, 136.61,
4.3.7. Methyl 1-(4-chlorophenyl)-4-(2-methoxy-2-oxoethyl)-5-
134.91, 130.78, 129.87, 129.23, 128.13, 128.10, 127.58, 117.30, 115.61,
52.29, 51.91, 51.59, 31.33, 21.13 ppm.
phenyl-1H-pyrrole-3-carboxylate (4g). A yellow viscous liquid, 62%
yield. 1H NMR (400 MHz, CDCl3):
d 7.54 (s, 1H), 7.29e7.27 (m, 3H),
7.25e7.22 (m, 2H), 7.11e7.08 (m, 2H), 7.02e6.99 (m, 2H), 3.81 (s,
4.3.15. Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(4-methoxyphenyl)-1-
3H), 3.73 (s, 3H), 3.71 (s, 2H) ppm. 13C NMR (101 MHz, CDCl3):
phenyl-1H-pyrrole-2,3-dicarboxylate (4o). A yellow viscous liquid,
d
172.94, 165.04, 137.81, 133.81, 133.07, 130.55, 130.28, 129.23,
71% yield. 1H NMR (400 MHz, CDCl3):
d
7.27 (d, J¼3.8 Hz, 3H),
128.47, 127.97, 127.72, 126.66, 117.13, 115.40, 51.94, 51.05, 31.48 ppm.
7.13e7.10 (m, 2H), 7.01e6.98 (m, 2H), 6.75e6.72 (m, 2H), 3.84 (s,
3H), 3.74 (s, 3H), 3.70 (s, 3H), 3.67 (s, 3H), 3.61 (s, 2H) ppm. 13C NMR
4.3.8. Methyl 1-(4-fluorophenyl)-4-(2-methoxy-2-oxoethyl)-5-
phenyl-1H-pyrrole-3-carboxylate (4h). A yellow viscous liquid, 60%
(101 MHz, CDCl3): d 172.37, 165.01, 162.00, 159.37, 137.67, 136.61,
132.02, 128.59, 128.27, 127.94, 121.91, 117.59, 115.52, 113.64, 55.14,
52.24, 51.93, 51.62, 31.34 ppm.
yield. 1H NMR (400 MHz, CDCl3):
d 7.53 (s, 1H), 7.27e7.25 (m, 3H),
7.09 (dd, J¼6.5, 3.0 Hz, 2H), 7.07e7.03 (m, 2H), 6.98e6.95 (m, 2H),
3.81 (s, 3H), 3.73 (s, 3H), 3.71 (s, 2H) ppm. 13C NMR (101 MHz,
4.3.16. Dimethyl 4-(2-methoxy-2-oxoethyl)-5-(4-methoxyphenyl)-1-
CDCl3):
d
172.93, 165.08, 160.22, 135.41, 134.01, 130.59, 130.40,
(p-tolyl)-1H-pyrrole-2,3-dicarboxylate (4p). A yellow viscous liquid,
128.36, 127.87, 127.30, 127.22, 116.84, 116.05, 115.82, 115.15, 51.86,
50.96, 31.48 ppm.
74% yield. 1H NMR (400 MHz, CDCl3):
d
7.05 (d, J¼8.3 Hz, 2H),
7.02e6.98 (m, 4H), 6.75e6.72 (m, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 3.69
(s, 3H), 3.68 (s, 3H), 3.60 (s, 2H), 2.29 (s, 3H) ppm. 13C NMR
4.3.9. Methyl
pyrrole-3-carboxylate (4i). A pale yellow viscous liquid, 84% yield.
1H NMR (400 MHz, CDCl3):
7.55 (s, 1H), 7.24 (d, J¼8.3 Hz, 3H),
7.06e7.03 (m, 4H), 6.98 (d, J¼8.1 Hz, 2H), 3.79 (s, 3H), 3.71 (s, 5H),
2.29 (s, 3H) ppm. 13C NMR (101 MHz, CDCl3):
173.05, 165.22,
4-(2-methoxy-2-oxoethyl)-1-phenyl-5-(p-tolyl)-1H-
(101 MHz, CDCl3): d 172.37, 164.99, 162.10, 159.33, 138.12, 136.59,
135.02, 132.01, 129.22, 127.61, 122.00, 117.28, 115.38, 113.61, 55.09,
52.22, 51.87, 51.54, 31.33, 21.11 ppm.
d
d
4. 3.17. Dimethyl 4-(2-methoxy-2-oxoethyl)-1,5-bis(4-
139.39, 137.52, 130.43, 129.02, 128.97, 127.97, 127.77, 127.67, 127.19,
126.73, 125.55, 116.64, 114.98, 51.82, 50.90, 31.57, 21.22 ppm.
methoxyphenyl)-1H-pyrrole-2,3-dicarboxylate (4q). A yellow vis-
cous liquid, 78%. 1H NMR (400 MHz, CDCl3):
d
7.04 (d, J¼8.9 Hz, 2H),
7.00 (d, J¼8.8 Hz, 2H), 6.77e6.75 (m, 2H), 6.74 (d, J¼4.7 Hz, 2H), 3.83
4.3.10. Methyl 4-(2-methoxy-2-oxoethyl)-5-(4-methoxyphenyl)-1-
(s, 3H), 3.76 (s, 3H), 3.75 (s, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.59 (s,
phenyl-1H-pyrrole-3-carboxylate (4j). A yellow viscous liquid, 82%
2H) ppm. 13C NMR (101 MHz, CDCl3):
d 172.42, 165.05, 162.12,
yield. 1H NMR (400 MHz, CDCl3):
d
7.47 (s, 1H), 7.19e7.16 (m, 3H),
159.32, 159.11, 136.84, 132.04, 130.38, 129.05, 127.61, 122.03, 117.29,
115.27, 113.70, 113.66, 55.31, 55.14, 52.26, 51.91, 51.59, 31.37 ppm.
6.99 (dd, J¼7.9, 1.5 Hz, 2H), 6.96e6.93 (m, 2H), 6.70 (d, J¼8.7 Hz,
2H), 3.72 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H), 3.62 (s, 2H) ppm. 13C NMR
(101 MHz, CDCl3):
d 173.11, 165.24, 159.12, 139.36, 133.71, 131.82,
Supplementary data
128.99, 127.57, 127.17, 125.55, 122.90, 116.45, 114.86, 113.76, 55.18,
51.88, 50.93, 31.57 ppm.
Experimental procedures, characterization data, and copies of
the 1H NMR and 13C NMR spectra for the products. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2014.01.037.
4.3.11. Methyl 5-(4-hydroxyphenyl)-4-(2-methoxy-2-oxoethyl)-1-
phenyl-1H-pyrrole-3-carboxylate (4k). A pale yellow solid, mp:
164e169 ꢀC, 85% yield. 1H NMR (400 MHz, CDCl3):
d 7.50e7.43 (m,
4H), 7.36e7.33 (m, 2H), 7.19 (d, J¼8.5 Hz, 2H), 6.78 (d, J¼8.5 Hz, 2H),
References and notes
6.29 (s, 1H), 3.72 (s, 3H), 3.51 (s, 3H), 3.46 (s, 2H) ppm. 13C NMR
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(101 MHz, CDCl3):
128.62, 128.16, 126.40,126.33, 126.02, 125.26, 115.00, 113.93, 52.09,
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d 171.29, 165.39, 155.20, 138.83, 131.37, 129.46,
4.3.12. Methyl 5-(4-chlorophenyl)-4-(2-methoxy-2-oxoethyl)-1-
phenyl-1H-pyrrole-3-carboxylate (4l). A pale yellow viscous liquid,
79% yield. 1H NMR (400 MHz, CDCl3):
d
7.57 (s, 1H), 7.28 (s, 2H),
7.25e7.22 (m, 2H), 7.08e7.03 (m, 5H), 3.81 (s, 3H), 3.74 (s, 3H), 3.70
(s, 2H) ppm. 13C NMR (101 MHz, CDCl3):
172.87, 165.04, 139.01,
d
133.86, 131.76, 129.50, 129.37, 129.18, 128.61, 128.36, 128.20, 127.51,
126.70, 125.57, 117.21, 115.16, 51.96, 51.02, 31.45 ppm.
4.3.13. Dimethyl
role-2,3-dicarboxylate (4m). A yellow viscous liquid, 70% yield. 1H
NMR (400 MHz, CDCl3):
4-(2-methoxy-2-oxoethyl)-1,5-diphenyl-1H-pyr-
d
7.15 (dd, J¼3.3, 2.8 Hz, 3H), 7.11 (dd, J¼5.1,
1.3 Hz, 3H), 7.03 (dd, J¼6.5, 3.2 Hz, 2H), 6.99 (dd, J¼6.5, 3.2 Hz, 2H),
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