One-pot three-component catalytic synthesis of fully substituted pyrroles from readily available propargylic alcohols, 1,3-dicarbonyl compounds and primary amines

Article abstract of DOI:10.1002/chem.200701132

A simple and highly efficient method for the preparation of fully substituted pyrroles, from readily accessible secondary propargylic alcohols, 1,3-dicarbonyl compounds and primary amines, has been developed. The one-pot multicomponent reaction, which is catalysed by the system [Ru(μ³- 2C₃H₄Me)(CO)(dppf)][SbF₆]/CF₃CO ₂H (dppf : 1,1′-bis(diphenylphosphanyl)ferrocene), involves initial propargylation of the 1,3-dicarbonyl compound promoted by CF ₃CO₂H and subsequent condensation between the resulting y-keto alkyne and the primary amine to afford a propargylated β-enamino ester or ketone, which undergoes a ruthenium-catalysed 5-exo-dig annulation to form the final pyrrole.

Full text of DOI:10.1002/chem.200701132

FULL PAPER
DOI: 10.1002/chem.200701132
One-Pot Three-Component Catalytic Synthesis of Fully Substituted Pyrroles
from Readily Available Propargylic Alcohols, 1,3-Dicarbonyl Compounds
and Primary Amines
Victorio Cadierno,* JosØ Gimeno,* and Noel Nebra[a]
Dedicated to Professor Miguel Yus and Professor Juan ForniØs on the occasion of their 60th birthdays
Abstract: Asimple and highly efficient
method for the preparation of fully
substituted pyrroles, from readily ac-
cessible secondary propargylic alcohols,
1,3-dicarbonyl compounds and primary
amines, has been developed. The one-
pot multicomponent reaction, which is
catalysed by the system [Ru(h3-2-
C3H4Me)(CO)
(dppf: 1,1’-bis(diphenylphosphanyl)fer-
rocene), involves initial propargylation
(dppf)]
U
of the 1,3-dicarbonyl compound pro-
moted by CF3CO2H and subsequent
condensation between the resulting g-
keto alkyne and the primary amine to
afford a propargylated b-enamino ester
or ketone, which undergoes a rutheni-
um-catalysed 5-exo-dig annulation to
form the final pyrrole.
Keywords: alkynes · annulation ·
multicomponent
nitrogen heterocycles · ruthenium
Introduction
difficulties, the application of multicomponent reactions
(MCRs) is a very appealing strategy since it allows the use
of readily available and simple precursors, with the transfor-
mations being performed in a single step.[6] Herein, we de-
scribe a novel method for the preparation of fully substitut-
ed pyrroles, through a one-pot three-component coupling re-
action in which easily accessible terminal secondary propar-
gylic alcohols, commercially available 1,3-dicarbonyl com-
pounds and primary amines are used as the starting
materials. This methodology represents a highly efficient
synthetic route to pentasubstituted pyrroles for which cata-
lytic approaches are scarce.
The pyrrole ring is not only a key structural attribute of
many bioactive natural products,[1] pharmaceutical substan-
ces[2] and organic conducting materials, such as polypyr-
roles,[3] but is also a useful and versatile building block in or-
ganic synthesis.[4] Although several general approaches to
these compounds are presently available, such as the classi-
cal Hantzsch and Paal–Knorr procedures, most of them in-
volve tedious multistep synthetic operations.[4] The most
recent strategies are based on palladium-, platinum-,
copper- and gold-catalysed cycloisomerisation or cyclisation
reactions of a variety of acyclic precursors, such as alkynyl-
imines,[5a,b] (Z)-(2-en-4-ynyl)amines[5c] or homopropargyl azi-
des,[5d,e] among others.[5f,g] Nevertheless, despite the new
useful developments, difficult access to the appropriate
starting materials limits the scope of these reactions. In par-
ticular, the design of a pyrrole ring with a varied set of sub-
stituents may be a critical target. In order to overcome these
Results and Discussion
We recently described a straightforward catalytic approach
to the synthesis of tetrasubstituted furans from terminal sec-
ondary propargylic alcohols and 1,3-dicarbonyl compounds
(Scheme 1).[7] The process, which proceeds in a one-pot
manner, involves initial trifluoroacetic acid promoted prop-
argylic substitution of the alkynol by the 1,3-dicarbonyl
compound[8] and subsequent cycloisomerisation of the re-
sulting g-keto alkyne A catalysed by the 16-electron allyl–
[a] Dr. V. Cadierno, Prof. Dr. J. Gimeno, N. Nebra
Departamento de Química Orgµnica
e Inorgµnica
Instituto Universitario de Química Organometµlica
“Enrique Moles” (Unidad Asociada al CSIC)
Universidad de Oviedo
Juliµn Clavería 8, 33006 Oviedo (Spain)
Fax : (+34)98-510-3446
ruthenium(II) complex [Ru(h3-2-C3H4Me)(CO)
N
N
(1). We have now found that when a primary amine is intro-
duced into the reaction medium pyrroles are selectively
formed instead of furans. The results obtained for the cou-
E-mail: vcm@uniovi.es
jgh@uniovi.es
Chem. Eur. J. 2007, 13, 9973 – 9981
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9973

Table 2. Synthesis of pyrroles 4a–g.[a]
Entry
R1; R2
t [h]
Pyrrole
Yield [%][b]
1
2
3
4
5
6
7
Me; OMe
Me; OBn
Me; OtBu
Me; Me
Et; Et
4
6
4
6
12
9
4a
4b
4c
4d
4e
4 f
4g
93
87
84
88
83
84
91
Scheme 1. Direct synthesis of furans from propargylic alcohols and 1,3-
dicarbonyl compounds. (dppf)][SbF6]
[Ru]=[Ru(h3-2-C3H4Me)(CO)
(1; dppf: 1,1’-bis(diphenylphosphanyl)ferrocene).
G
ACHTREUNG
Ph; Ph
Me; Ph
pling of several monosubstituted propargylic alcohols with
ethyl acetoacetate and aniline are collected in Table 1. The
reactions were performed in THF at 758C (sealed tube)
6
[a] Reactions performed in THF (0.5 mL) at 758C with propargylic alco-
hol 2d (1 mmol), the appropriate 1,3-dicarbonyl compound (1 mmol) and
aniline (1 mmol). Bn: benzyl. [b] Yield of isolated product.
Table 1. Synthesis of pyrroles 3a–k.[a]
Thus, under the same reaction conditions, other b-keto
esters (entries 1–3 in Table 2) as well as a variety of 1,3-di-
ketones (entries 4–7 in Table 2) also reacted with alkynol 2d
and aniline to afford the corresponding pyrroles 4a–g in ex-
cellent yields (83–93%) after 4–12 h. Interestingly, when the
nonsymmetric diketone 1-phenyl-1,3-butanedione (entry 7 in
Table 2) was used as the substrate, pyrrole 4g is chemoselec-
tively formed, that is, only the more activated acetyl group,
as opposed to the benzoyl unit, participates in the condensa-
tion process. The behaviour of alkynol 2d towards aniline
and tert-butyl acetoacetate also merits a comment (entry 3
in Table 2). Although the reaction leads to the expected pyr-
role 4c in 4 h (84% yield of isolated product), it further
evolves into the 1,2,4,5-tetrasubstituted derivative 6 (78%
yield) after 30 h (Scheme 2). Pyrrole 6 results from the ini-
Entry
R; propargylic alcohol
t [h]
Pyrrole
Yield [%][b]
1
2
3
4
5
6
7
8
Ph; 2a
3
2
6
2
7
7
7
3
3
8
6
3a
3b
3c
3d
3e
3 f
3g
3h
3i
70
87
81
94
78
82
73
72
71
68
94
2-C6H4OMe; 2b
3-C6H4OMe; 2c
4-C6H4OMe; 2d
2-C6H4Cl; 2e
3-C6H4Cl; 2 f
4-C6H4Cl; 2g
1-naphthyl; 2h
2-naphthyl; 2i
(E)-CH=CHPh; 2j
2-thienyl; 2k
9
10
11
3j
3k
[a] Reactions performed in tetrahydrofuran (THF; 0.5 mL) at 758C with
the appropriate propargylic alcohol (2a–k; 1 mmol), ethyl acetoacetate
(1 mmol) and aniline (1 mmol). [b] Yield of isolated product.
with 1 mmol of the alkynol ([alkynol]:[ethyl acetoacetate]:
[aniline] ratio=1:1:1) in the presence of 50 mol% of
CF3CO2H and 5 mol% of complex 1. This three-component
coupling reaction can be successfully applied to secondary
aryl alkynols, independently of the substitution pattern and
electronic properties of the aromatic ring (2a–i; entries 1–9
in Table 1), as well as to alkenyl (2j; entry 10 in Table 1)
and heteroaromatic (2k; entry 11 in Table 1) alkynols, with
the corresponding pyrroles 3a–k being obtained in 68–94%
yield (isolated product) with complete regioselectivity after
2–8 h. No formation of the corresponding furans or other re-
gioisomers of 3 was observed by GC/MS. By contrast, with
alkyl-monosubstituted alkynols such as 1-octyn-3-ol or 3-
butyn-2-ol, mixtures containing the expected pyrroles are
obtained, albeit in very low yields (<15% yield as deter-
mined by GC). The formation of several major uncharacter-
ised byproducts prevented the isolation of the pyrroles in
these cases.
Scheme 2. Synthesis of the tetrasubstituted pyrrole 6.
tial CF3CO2H-mediated hydrolysis of the tert-butyl ester
(Boc) group and subsequent ruthenium-catalysed decarbox-
ylation of the resulting carboxylic acid 5.[9] Therefore, this
MCR methodology with Boc-containing 1,3-dicarbonyl sub-
strates discloses a synthetic route to 1,2,4,5-tetrasubstituted
pyrroles.
The generality of this transformation has been also stud-
ied by using other 1,3-dicarbonyl compounds (see Table 2).
More attractive is the wide scope of the process with re-
spect to the nature of the amine (Table 3). Thus, we have
9974
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Chem. Eur. J. 2007, 13, 9973 – 9981

Multicomponent Synthesis of Pyrroles
FULL PAPER
Table 3. Synthesis of pyrroles 7a–q.[a]
Remarkably, our MCR can be also applied to the prepa-
À
ration of N H pyrroles. Although all attempts to generate
these species by using NH4OH or NH4Cl as sources of the
NH unit failed, these compounds are accessible by using
propargylamine. Thus, we have found that treatment of 2d
with ethyl acetoacetate and propargylamine, under the stan-
dard reaction conditions, leads to the slow but clean forma-
tion of 9 after 4 days (74% yield of isolated product;
Scheme 3). The reaction proceeds through the expected
propargylic pyrrole 7p (isolated in 56% yield after 19 h;
entry 16 in Table 3), which further undergoes scission of the
Entry
R
t [h]
Pyrrole
Yield [%][b]
1
2
3
4
5
6
7
8
4-C6H4OMe
3-C6H4OMe
2-C6H4OMe
4-C6H4Cl
3
3
3
4
6
3
3
8
6
7a
7b
7c
7d
7e
7 f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
94
90
95
94
78
92
85
88
87
73
92
75
72
78
74
56
76
4-C6H4I
[11]
À
C N bond,
a transformation probably involving the hy-
4-C6H4NO2
4-C6H4CO2Et
4-C6H4OH
3-C6H4C(=O)Me
4-C6H4C(=O)NH2
2-C6H4C(Me)=CH2
Et
Bn
furfuryl
CH2CH=CH2
CH2C CH
drolysis of the allenyl intermediate 8 (not detected by GC/
MS).
9
Amechanistic proposal for this three-component coupling
reaction, exemplified by the formation of pyrrole 3d, is de-
picted in Scheme 4. Two competitive pathways occur simul-
taneously. The first one involves an initial acid-promoted
propargylation of the b-keto ester to afford the g-keto
alkyne 10. In fact, this intermediate could be isolated (91%
yield) by treatment of a THF solution of 2d with ethyl ace-
toacetate (1 equiv) and CF3CO2H (0.5 equiv) at 758C for 3 h
(details are given in the Experimental Section). Subsequent
condensation between 10 and aniline generates the propar-
gylated b-enamino ester 11 which undergoes a ruthenium-
catalysed 5-exo-dig annulation to form the final pyrrole
3d.[12,13] Alternatively, intermediate 11 can be also generated
through propargylic substitution of 2d by the b-enamino
10
11
12
13
14
15
16
17
5
3
40
9
20
21
19
44
ꢀ
(S)-CHMePh
[a] Reactions performed in THF (0.5 mL) at 758C with propargylic alco-
hol 2d (1 mmol), ethyl acetoacetate (1 mmol) and the appropriate pri-
mary amine (1 mmol). [b] Yield of isolated product.
found that, with alkynol 2d and ethyl acetoacetate as model
compounds, several aromatic (entries 1–11 in Table 3) and
aliphatic
(entries 12–16
in
Table 3) primary amines can be
successfully employed in this
transformation to afford the
corresponding pyrroles 7a–p in
moderate to good yields (56–
95%). With respect to the func-
tional-group tolerance, this
methodology is compatible with
the presence in the amino
framework of alkoxy (7a–c),
hydroxy (7h), halide (7d,e),
nitro (7 f), ester (7g), ketone
(7i), amide (7j), olefin (7k,o),
propargyl (7p) and heteroaro-
matic (7n) substituents. It
should be noted that longer re-
action times are required when
aliphatic amines are employed
(entries 12–17 in Table 3). In
addition, the enantiomerically
pure pyrrole 7q (entry 17 in
Table 3) could be easily pre-
pared from commercially avail-
À
Scheme 3. Synthesis of the N H pyrrole 9.
able
(S)-(À)-a-methylbenzyl-
amine, with the stereogenic
centre in the initial amine not
being affected during the trans-
formation.[10]
Scheme 4. Proposed mechanism for the reaction.
Chem. Eur. J. 2007, 13, 9973 – 9981
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9975

V. Cadierno, J. Gimeno, and N. Nebra
indicated time (see Tables 1–3 and Schemes 2 and 3; the course of the re-
actions was monitored by regular sampling and analysis by GC/MS).
After removal of volatiles under vacuum, the residue was purified by
column chromatography (silica gel) with a mixture EtOAc/hexanes (1:15)
as the eluent (except for pyrroles 7h and 7j, which required a 1:1 mixture
of EtOAc/hexanes). Analytical and spectroscopic data for all of the com-
pounds synthesised are reported below.
ester 12 (detected in the reaction medium by monitoring the
course of the reaction by GC/MS), which results from the
initial condensation between ethyl acetoacetate and aniline.
In this respect, we have confirmed that treatment of 2d with
independently synthesised compound 12,[14] in THF at 758C
in the presence of 50 mol% of CF3CO2H and 5 mol% of
complex 1, cleanly generates pyrrole 3d in >95% yield (as
determined by GC) after 2 h.
2,5-Dimethyl-1,4-diphenylpyrrole-3-carboxylic acid ethyl ester (3a):[17b]
1
Yellow oil; yield: 70% (0.223 g); H NMR (300 MHz, CDCl3): d=1.05 (t,
J=7.2 Hz, 3H, CH3), 1.91 (s, 3H, CH3), 2.35 (s, 3H, CH3), 4.11 (q, J=
7.2 Hz, 2H, CH2), 7.26 (m, 3H, CHarom), 7.51 (m, 3H, CHarom), 7.34 ppm
(m, 4H, CHarom); 13C NMR (75 MHz, CDCl3): d=10.9, 12.3, 13.6 (s,
CH3), 58.9 (s, CH2), 111.8, 122.1, 126.5, 135.4, 136.1, 137.5 (s, =C, Carom),
125.6, 127.1, 127.9, 128.3, 129.1, 130.1 (s, CHarom), 165.7 ppm (s, C=O); IR
(Nujol): n˜ =1698 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 319 (100)
[M+], 290 (85) [M+ÀEt], 274 (20) [M+ÀOEt], 244 (15) [M+
ÀOEtÀ2Me], 230 (20) [M+ÀCO2EtÀMe]; HRMS (EI): m/z: calcd for
C21H21O2N: 319.15668; found: 319.15636.
Conclusion
In summary, an operationally simple and highly efficient
one-pot multicomponent reaction for the synthesis of fully
substituted pyrroles from secondary propargylic alco-
hols,[15,16] 1,3-dicarbonyl compounds and primary amines has
been developed in this work. The transformation constitutes
a straightforward alternative to the limited catalytic ap-
proaches to the synthesis of pentasubstituted pyrroles that
are presently available.[5c,16,17] The following points merit
highlighting: 1) the procedure stems from readily available
and inexpensive precursors, 2) it allows the direct introduc-
tion of carbonyl functionalities onto the pyrrolic skeleton,
3) this methodology is tolerant to the presence of a wide va-
riety of functional groups in the starting materials, and 4) it
is highly selective and allows the isolation of the desired pyr-
roles in good to excellent yields (56–95%). In conclusion,
selectivity, time/cost savings and experimental simplicity,
concepts that are considered by modern academic and in-
dustrial synthetic chemists in reaching the maximum effi-
ciency of a process, are clearly represented in this one-pot
catalytic transformation that provides an appealing method-
ology for the synthesis of highly functionalised pyrroles.
4-(2-Methoxyphenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic
acid
1
ethyl ester (3b):[17b] Yellow oil; yield: 87% (0.304 g); H NMR (300 MHz,
CDCl3): d=1.00 (t, J=7.0 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 2.33 (s, 3H,
CH3), 3.79 (s, 3H, OCH3), 4.06 (q, J=7.0 Hz, 2H, CH2), 6.96 (m, 2H,
CHarom), 7.25 (m, 4H, CHarom), 7.47 ppm (m, 3H, CHarom); 13C NMR
(75 MHz, CDCl3): d=11.0, 12.2, 13.6 (s, CH3), 55.0 (s, OCH3), 58.6 (s,
CH2), 109.9, 119.6, 127.2, 128.0, 128.1, 128.9, 131.4 (s, CHarom), 111.6,
117.4, 125.2, 126.6, 134.8, 137.6, 157.2 (s, =C, Carom), 165.8 ppm (s, C=O);
IR (Nujol): n˜ =1695 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 349
(100) [M+], 320 (35) [M+ÀEt], 304 (10) [M+ÀOEt], 288 (20) [M+
ÀOMeÀ2Me], 276 (60) [M+ÀCO2Et], 260 (15) [M+ÀOEtÀ3Me];
HRMS (EI): m/z: calcd for C22H23O3N: 349.16724; found: 349.16680.
4-(3-Methoxyphenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic
acid
ethyl ester (3c): Yellow oil; yield: 81% (0.283 g); 1H NMR (300 MHz,
CDCl3): d=1.05 (t, J=7.2 Hz, 3H, CH3), 1.91 (s, 3H, CH3), 2.32 (s, 3H,
CH3), 3.82 (s, 3H, OCH3), 4.10 (q, J=7.2 Hz, 2H, CH2), 6.81–6.93 (m,
3H, CHarom), 7.25 (m, 3H, CHarom), 7.44–7.55 ppm (m, 3H, CHarom);
13C NMR (75 MHz, CDCl3): d=10.9, 12.2, 13.6 (s, CH3), 54.8 (s, OCH3),
58.8 (s, CH2), 111.2, 115.7, 122.7, 127.9, 128.3, 129.1 (s, CHarom), 110.7,
121.8, 126.5, 135.3, 137.4, 137.5, 158.5 (s, =C, Carom), 165.6 ppm (s, C=O);
IR (Nujol): n˜ =1683 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 349
(100) [M+], 320 (55) [M+ÀEt], 304 (20) [M+ÀOEt], 288 (5) [M+
ÀOMeÀ2Me], 274 (15) [M+ÀOEtÀ2Me], 260 (10) [M+ÀOEtÀ3Me];
HRMS (EI): m/z: calcd for C22H23O3N: 349.16724; found: 349.16705.
4-(4-Methoxyphenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic
acid
Experimental Section
ethyl ester (3d): Yellow oil; yield: 94% (0.328 g); 1H NMR (300 MHz,
CDCl3): d=1.09 (t, J=7.0 Hz, 3H, CH3), 1.89 (s, 3H, CH3), 2.32 (s, 3H,
CH3), 3.84 (s, 3H, OCH3), 4.12 (q, J=7.0 Hz, 2H, CH2), 6.92 (m, 2H,
CHarom), 7.24 (m, 4H, CHarom), 7.48 ppm (m, 3H, CHarom); 13C NMR
(75 MHz, CDCl3): d=10.9, 12.3, 13.8 (s, CH3), 54.9 (s, OCH3), 58.8 (s,
CH2), 110.7, 121.6, 126.4, 128.4, 135.2, 137.6, 157.6 (s, =C, Carom), 112.6,
127.9, 128.2, 129.1, 131.1 (s, CHarom), 165.7 ppm (s, C=O); IR (Nujol): n˜ =
1698 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 349 (100) [M+], 320
(60) [M+ÀEt], 304 (15) [M+ÀOEt], 274 (10) [M+ÀOEtÀ2Me], 260 (10)
[M+ÀOEtÀ3Me]; HRMS (EI): m/z: calcd for C22H23O3N: 349.16724;
found: 349.16680.
General methods: Infrared spectra were recorded on a Perkin–Elmer
1720-XFT spectrometer. NMR spectra were recorded on a Bruker DPX-
300 instrument at 300 MHz (1H) or 75.4 MHz (13C). The chemical shift
values (d) are given in parts per million (ppm) and are referred to the re-
sidual peak of the deuterated solvent (CDCl3). DEPT experiments have
been carried out for all of the compounds reported. GC/MS measure-
ments were performed on Agilent 6890N equipment coupled to a 5973
mass detector (70 eV electron-impact ionisation) by using an HP-1MS
column. High-resolution mass spectra were recorded on a Finnigan-Mat
95 spectrometer. Elemental analyses were performed with a Perkin–
Elmer 2400 microanalyser. Optical rotations were measured by using a
4-(2-Chlorophenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic acid ethyl
1
Perkin–Elmer 241 polarimeter and are quoted in units of 10À1 degcm2 gÀ1
.
ester (3e): Yellow oil; yield: 78% (0.276 g); H NMR (300 MHz, CDCl3):
d=0.96 (t, J=7.1 Hz, 3H, CH3), 1.81 (s, 3H, CH3), 2.35 (s, 3H, CH3),
4.05 (q, J=7.1 Hz, 2H, CH2), 7.22–7.32 (m, 6H, CHarom), 7.47 ppm (m,
3H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.1, 12.5, 13.7 (s, CH3),
59.0 (s, CH2), 111.2, 119.3, 127.1, 134.9, 135.7, 135.9, 137.6 (s, =C, Carom),
125.8, 127.6, 128.5, 128.8, 129.3, 132.9 (s, CHarom), 165.7 ppm (s, C=O); IR
(Nujol): n˜ =1682 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 353 (40)
[M+], 318 (100) [M+ÀCl], 289 (90) [M+ÀEtÀCl], 272 (10) [M+
ÀOEtÀCl], 245 (20) [M+ÀCO2EtÀCl]; HRMS (EI): m/z: calcd for
C21H20O2ClN: 353.11771; found: 353.11752.
Flash chromatography was performed with Merck silica gel 60 (230–400
mesh). All reagents were obtained from commercial suppliers and used
without any further purification, with the exception of the complex
[Ru(h3-2-C3H4Me)(CO)
A
N
and 3-phenylamino-2-butenoic acid ethyl ester (12),[14] which were pre-
pared by following the methods reported in the literature.
General procedure for the catalytic reactions: The appropriate propargyl-
ic alcohol 2a–k (1 mmol), 1,3-dicarbonyl compound (1 mmol) and pri-
mary amine (1 mmol) were introduced into a sealed tube under a nitro-
gen atmosphere. THF (0.5 mL), [Ru(h3-2-C3H4Me)(CO)
G
G
4-(3-Chlorophenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic acid ethyl
1
0.049 g, 0.05 mmol) and CF3CO2H (37 mL, 0.5 mmol) were then added at
room temperature, and the resulting solution was heated at 758C for the
ester (3 f): Yellow oil; yield: 82% (0.290 g); H NMR (300 MHz, CDCl3):
d=1.06 (t, J=7.1 Hz, 3H, CH3), 1.88 (s, 3H, CH3), 2.32 (s, 3H, CH3),
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Multicomponent Synthesis of Pyrroles
FULL PAPER
4.11 (q, J=7.1 Hz, 2H, CH2), 7.19–7.31 (m, 6H, CHarom), 7.51 ppm (m,
3H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.1, 12.5, 13.8 (s, CH3),
59.1 (s, CH2), 110.7, 120.9, 127.0, 129.2, 132.9, 137.5, 138.4 (s, =C, Carom),
125.5, 127.8, 128.0, 128.1, 128.2, 129.0, 130.2 (s, CHarom), 165.6 ppm (s, C=
O); IR (Nujol): n˜ =1698 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 353
(100) [M+], 324 (80) [M+ÀEt], 308 (20) [M+ÀOEt], 278 (10) [M+
ÀOEtÀ2Me], 245 (30) [M+ÀCO2EtÀCl]; HRMS (EI): m/z: calcd for
C21H20O2ClN: 353.11771; found: 353.11756.
ÀEtÀMe], 250 (15) [M+ÀOEtÀ2Me], 237 (10) [M+ÀCO2EtÀMe];
HRMS (EI): m/z: calcd for C19H19O2NS: 325.11310; found: 325.11300.
4-(4-Methoxyphenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic
acid
methyl ester (4a): Yellow oil; yield: 93% (0.312 g); 1H NMR (300 MHz,
CDCl3): d=1.90 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.65 (s, 3H, OCH3),
3.85 (s, 3H, OCH3), 6.95 (m, 2H, CHarom), 7.25 (m, 4H, CHarom),
7.49 ppm (m, 3H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.2, 12.8 (s,
CH3), 50.4, 55.1 (s, OCH3), 110.6, 121.9, 126.7, 128.4, 135.6, 137.8, 157.9
(s, =C, Carom), 112.9, 128.2, 128.5, 129.4, 131.3 (s, CHarom), 166.4 ppm (s,
C=O); IR (Nujol): n˜ =1699 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%):
335 (100) [M+], 320 (20) [M+ÀMe], 304 (15) [M+ÀOMe], 274 (10) [M+
ÀOMeÀ2Me], 260 (10) [M+ÀOMeÀ3Me], 244 (5) [M+À2OMeÀ2Me];
HRMS (EI): m/z: calcd for C21H21O3N: 335.15159; found: 335.15125.
4-(4-Chlorophenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic acid ethyl
1
ester (3g): Yellow oil; yield: 73% (0.258 g); H NMR (300 MHz, CDCl3):
d=1.08 (t, J=7.1 Hz, 3H, CH3), 1.87 (s, 3H, CH3), 2.31 (s, 3H, CH3),
4.10 (q, J=7.1 Hz, 2H, CH2), 7.23–7.34 (m, 6H, CHarom), 7.50 ppm (m,
3H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.1, 12.6, 14.0 (s, CH3),
59.2 (s, CH2), 110.8, 121.1, 126.9, 134.9, 136.0, 137.4, 137.6 (s, =C, Carom),
127.5, 128.2, 128.6, 129.4, 131.7 (s, CHarom), 165.7 ppm (s, C=O); IR
(Nujol): n˜ =1699 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 353 (100)
[M+], 324 (80) [M+ÀEt], 308 (30) [M+ÀOEt], 280 (10) [M+ÀCO2Et],
278 (10) [M+ÀOEtÀ2Me], 245 (15) [M+ÀCO2EtÀCl]; HRMS (EI):
m/z: calcd for C21H20O2ClN: 353.11771; found: 353.11796.
4-(4-Methoxyphenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic
acid
benzyl ester (4b): Yellow solid; yield: 87% (0.358 g); 1H NMR
(300 MHz, CDCl3): d=1.88 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.83 (s, 3H,
OCH3), 5.14 (s, 2H, CH2), 6.87 (d, J=8.2 Hz, 2H, CHarom), 7.06 (m, 2H,
CHarom), 7.24 (m, 6H, CHarom), 7.49 ppm (m, 4H, CHarom); 13C NMR
(75 MHz, CDCl3): d=11.1, 12.7 (s, CH3), 55.1 (s, OCH3), 65.1 (s, CH2),
110.7, 121.9, 126.8, 128.7, 136.1, 136.5, 137.8, 158.0 (s, =C, Carom), 113.0,
127.4, 127.7, 128.0, 128.2, 128.5, 129.4, 131.4 (s, CHarom), 166.4 ppm (s, C=
O); IR (Nujol): n˜ =1694 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 411
(40) [M+], 334 (5) [M+ÀPh], 320 (100) [M+ÀBn], 304 (10) [M+ÀOBn],
276 (10) [M+ÀCO2Bn], 246 (10) [M+ÀCO2BnÀ2Me]; HRMS (EI): m/z:
calcd for C27H25O3N: 411.18289; found: 411.18278; elemental analysis
calcd (%) for C27H25O3N: C 78.81, H 6.12, N 3.40; found: C 78.96, H
6.05, N 3.55.
4-(1-Naphthyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic acid ethyl ester
(3h): Orange solid; yield: 72% (0.266 g); 1H NMR (300 MHz, CDCl3):
d=0.44 (t, J=7.0 Hz, 3H, CH3), 1.81 (s, 3H, CH3), 2.43 (s, 3H, CH3),
3.76 (q, J=7.0 Hz, 2H, CH2), 7.32–7.56 (m, 9H, CHarom), 7.83 ppm (m,
3H, CHarom); 13C NMR (75 MHz, CDCl3): d=10.8, 12.2, 12.8 (s, CH3),
58.4 (s, CH2), 111.9, 120.2, 127.1, 133.1, 133.5, 134.7, 135.7, 137.5 (s, =C,
C
arom), 124.8, 124.9, 125.0, 126.2, 126.4, 127.4, 127.6, 128.0, 128.2, 129.1 (s,
CHarom), 165.6 ppm (s, C=O); IR (Nujol): n˜ =1690 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 369 (100) [M+], 340 (60) [M+ÀEt], 309 (10) [M+
ÀOEtÀMe], 294 (15) [M+ÀOEtÀ2Me], 280 (15) [M+ÀCO2EtÀMe];
HRMS (EI): m/z: calcd for C25H23O2N: 369.17233; found: 369.17244; ele-
mental analysis calcd (%) for C25H23O2N: C 81.27, H 6.27, N 3.79; found:
C 81.13, H 6.31, N 3.83.
4-(4-Methoxyphenyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic acid tert-
butyl ester (4c): Yellow oil; yield: 84% (0.317 g); 1H NMR (300 MHz,
CDCl3): d=1.31 (s, 9H, C(CH3)3), 1.87 (s, 3H, CH3), 2.30 (s, 3H, CH3),
R
3.84 (s, 3H, OCH3), 6.92 (m, 2H, CHarom), 7.23 (m, 4H, CHarom),
7.48 ppm (m, 3H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.1, 12.4 (s,
CH3), 28.0 (s, C
N
N
4-(2-Naphthyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic acid ethyl ester
(3i): Orange solid; yield: 71% (0.262 g); 1H NMR (300 MHz, CDCl3):
d=0.98 (t, J=7.0 Hz, 3H, CH3), 1.96 (s, 3H, CH3), 2.38 (s, 3H, CH3),
4.09 (q, J=7.0 Hz, 2H, CH2), 7.28 (m, 2H, CHarom), 7.44–7.56 (m, 6H,
CHarom), 7.77 (s, 1H, CHarom), 7.85 ppm (m, 3H, CHarom); 13C NMR
(75 MHz, CDCl3): d=11.0, 12.3, 13.7 (s, CH3), 58.9 (s, CH2), 110.7, 121.8,
126.7, 131.7, 132.9, 133.8, 135.7, 137.5 (s, =C, Carom), 124.9, 125.3, 126.2,
127.2, 127.4, 128.0, 128.3, 129.1, 129.5 (s, CHarom), 165.7 ppm (s, C=O); IR
(Nujol): n˜ =1683 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 369 (100)
[M+], 340 (50) [M+ÀEt], 324 (15) [M+ÀOEt], 294 (20) [M+
ÀOEtÀ2Me], 280 (15) [M+ÀCO2EtÀMe]; HRMS (EI): m/z: calcd for
C25H23O2N: 369.17233; found: 369.17252; elemental analysis calcd (%)
for C25H23O2N: C 81.27, H 6.27, N 3.79; found: C 81.40, H 6.14, N 3.88.
126.4, 129.2, 134.9, 137.9, 157.8 (s, =C, Carom), 112.9, 128.2, 128.4, 129.3,
131.2 (s, CHarom), 165.5 ppm (s, C=O); IR (Nujol): n˜ =1698 cmÀ1 (s, C=
O); LRMS (EI, 70 eV): m/z (%): 377 (20) [M+], 320 (100) [M+ÀtBu],
304 (10) [M+ÀOtBu], 276 (10) [M+ÀCO2tBu], 260 (5) [M+
ÀOtBuÀ3Me]; HRMS (EI): m/z: calcd for C24H27O3N: 377.19854;
found: 377.19802.
1-[4-(4-Methoxyphenyl)-2,5-dimethyl-1-phenyl-3-pyrrolyl]-ethanone (4d):
1
Yellow oil; yield: 88% (0.281 g); H NMR (300 MHz, CDCl3): d=1.84 (s,
3H, CH3), 1.97 (s, 3H, CH3), 2.29 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 6.94
(m, 2H, CHarom), 7.24 (m, 4H, CHarom), 7.49 ppm (m, 3H, CHarom);
13C NMR (75 MHz, CDCl3): d=11.1, 13.1, 30.7 (s, CH3), 55.1 (s, OCH3),
113.6, 128.1, 128.6, 129.4, 131.4 (s, CHarom), 121.5, 121.7, 126.8, 128.8,
135.3, 137.5, 158.4 (s, =C, Carom), 197.9 ppm (s, C=O); IR (Nujol): n˜ =
1651 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 319 (20) [M+], 304
(100) [M+ÀMe], 289 (5) [M+À2Me], 276 (5) [M+ÀCOMe], 261 (10)
[M+ÀCOMeÀMe]; HRMS (EI): m/z: calcd for C21H21O2N: 319.15668;
found: 319.15641.
2,5-Dimethyl-1-phenyl-4-styrylpyrrole-3-carboxylic acid ethyl ester (3j):
1
Yellow oil; yield: 68% (0.235 g); H NMR (300 MHz, CDCl3): d=1.38 (t,
J=7.1 Hz, 3H, CH3), 2.14 (s, 3H, CH3), 2.29 (s, 3H, CH3), 4.33 (q, J=
7.1 Hz, 2H, CH2), 6.60 (d, J=16.5 Hz, 1H, =CH), 7.17–7.38 ppm (m,
11H, CHarom, =CH); 13C NMR (75 MHz, CDCl3): d=12.6, 12.8, 14.5 (s,
CH3), 59.4 (s, CH2), 111.3, 127.1, 135.1, 136.2, 137.5, 138.6 (s, =C, Carom),
120.4, 123.5, 125.9, 128.3, 128.5, 128.7, 129.3, 129.5 (s, CHarom, =CH),
166.1 ppm (s, C=O); IR (Nujol): n˜ =1699 cmÀ1 (s, C=O); LRMS (EI,
70 eV): m/z (%): 345 (100) [M+], 330 (2) [M+ÀMe], 316 (20) [M+ÀEt],
285 (10) [M+ÀOEtÀMe], 270 (20) [M+ÀOEtÀ2Me], 257 (15) [M+
ÀCO2EtÀMe]; HRMS (EI): m/z: calcd for C23H23O2N: 345.17233; found:
345.17218.
1-[2-Ethyl-4-(4-methoxyphenyl)-5-methyl-1-phenyl-3-pyrrolyl]-propan-1-
one (4e): Yellow oil; yield: 83% (0.288 g); 1H NMR (300 MHz, CDCl3):
d=0.93 (t, J=7.4 Hz, 3H, CH3), 1.03 (t, J=7.4 Hz, 3H, CH3), 1.80 (s,
3H, CH3), 2.22 (q, J=7.4 Hz, 2H, CH2), 2.67 (q, J=7.4 Hz, 2H, CH2),
3.85 (s, 3H, OCH3), 6.93 (m, 2H, CHarom), 7.25 (m, 4H, CHarom),
7.49 ppm (m, 3H, CHarom); 13C NMR (75 MHz, CDCl3): d=8.6, 11.0, 14.7
(s, CH3), 19.5, 35.6 (s, CH2), 55.1 (s, OCH3), 113.5, 128.4, 128.6, 129.2,
131.3 (s, CHarom), 120.7, 121.0, 126.5, 128.2, 137.7, 140.5, 158.2 (s, =C,
Carom), 200.7 ppm (s, C=O); IR (Nujol): n˜ =1651 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 347 (50) [M+], 332 (15) [M+ÀMe], 318 (100) [M+
ÀEt], 303 (5) [M+ÀEtÀMe], 274 (10) [M+À2EtÀMe]; HRMS (EI):
m/z: calcd for C23H25O2N: 347.18798; found: 347.18765.
4-(2-Thienyl)-2,5-dimethyl-1-phenylpyrrole-3-carboxylic acid ethyl ester
(3k): Orange oil; yield: 94% (0.306 g); 1H NMR (300 MHz, CDCl3): d=
1.12 (t, J=7.1 Hz, 3H, CH3), 1.94 (s, 3H, CH3), 2.31 (s, 3H, CH3), 4.15
(q, J=7.1 Hz, 2H, CH2), 6.94 (dd, J=3.4, 1.1 Hz, 1H, =CH), 7.04 (dd,
J=5.1, 3.4 Hz, 1H, =CH), 7.24 (m, 2H, CHarom), 7.29 (dd, J=5.1, 1.1 Hz,
1H, =CH), 7.50 ppm (m, 3H, CHarom); 13C NMR (75 MHz, CDCl3): d=
11.3, 12.5, 14.0 (s, CH3), 59.3 (s, CH2), 111.8, 114.1, 120.6, 128.8, 135.8,
137.5 (s, =C, Carom), 124.6, 126.2, 126.9, 128.1, 128.6, 129.4 (s, =CH,
CHarom), 165.6 ppm (s, C=O); IR (Nujol): n˜ =1697 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 325 (100) [M+], 296 (60) [M+ÀEt], 281 (20) [M+
[4-(4-Methoxyphenyl)-5-methyl-1,2-diphenyl-3-pyrrolyl]-phenylmetha-
none (4 f): Orange solid; yield: 84% (0.372 g); 1H NMR (300 MHz,
CDCl3): d=2.17 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 6.82 (d, J=8.2 Hz,
2H, CHarom), 6.97–7.35 (m, 15H, CHarom), 7.72 ppm (d, J=7.4 Hz, 2H,
CHarom); 13C NMR (75 MHz, CDCl3): d=11.6 (s, CH3), 55.0 (s, OCH3),
113.4, 126.9, 127.4, 127.5, 127.8, 128.7, 128.9, 129.8, 130.1, 130.7, 131.7 (s,
Chem. Eur. J. 2007, 13, 9973 – 9981
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9977

V. Cadierno, J. Gimeno, and N. Nebra
CHarom), 122.2, 122.8, 127.6, 127.9, 131.0, 135.7, 138.3, 138.8, 157.8 (s, =C,
1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxyl-
ic acid ethyl ester (7d): Yellow oil; yield: 94% (0.360 g); 1H NMR
(300 MHz, CDCl3): d=1.09 (t, J=7.1 Hz, 3H, CH3), 1.88 (s, 3H, CH3),
2.31 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.12 (q, J=7.1 Hz, 2H, CH2), 6.91,
7.19, 7.22 (d, J=8.5 Hz, 2H, CHarom), 7.50 ppm (d, J=8.5 Hz, 2H,
CHarom); 13C NMR (75 MHz, CDCl3): d=11.1, 12.7, 13.9 (s, CH3), 55.2 (s,
OCH3), 59.6 (s, CH2), 111.1, 122.2, 126.7, 128.3, 134.6, 135.7, 136.2, 157.9
(s, =C, Carom), 112.9, 129.5, 129.7, 131.3 (s, CHarom), 166.5 ppm (s, C=O);
IR (Nujol): n˜ =1699 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 383
(100) [M+], 368 (5) [M+ÀMe], 354 (30) [M+ÀEt], 338 (15) [M+ÀOEt];
HRMS (EI): m/z: calcd for C22H22O3ClN: 383.12827; found: 383.12751.
C
arom), 194.5 ppm (s, C=O); IR (Nujol): n˜ =1661 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 443 (100) [M+], 366 (20) [M+ÀPh], 338 (5) [M+
ÀCOPh]; HRMS (EI): m/z: calcd for C31H25O2N: 443.18798; found:
443.18768; elemental analysis calcd (%) for C31H25O2N: C 83.95, H 5.68,
N 3.16; found: C 83.77, H 5.76, N 3.27.
[4-(4-Methoxyphenyl)-2,5-dimethyl-1-phenyl-3-pyrrolyl]-phenylmetha-
none (4g): Orange solid; yield: 91% (0.347 g); 1H NMR (300 MHz,
CDCl3): d=2.01 (s, 3H, CH3), 2.15 (s, 3H, CH3), 3.71 (s, 3H, OCH3),
6.68 (m, 2H, CHarom), 7.67 (m, 2H, CHarom), 7.01–7.35 (m, 7H, CHarom),
7.50 ppm (m, 3H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.5, 12.8 (s,
CH3), 55.1 (s, OCH3), 113.1, 127.5, 128.2, 128.5, 129.4, 129.7, 131.0, 131.3
(s, CHarom), 120.5, 121.9, 126.0, 128.0, 134.4, 137.8, 139.7, 157.4 (s, =C,
Carom), 194.1 ppm (s, C=O); IR (Nujol): n˜ =1652 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 381 (100) [M+], 366 (10) [M+ÀMe], 304 (10) [M+
ÀPh], 289 (5) [M+ÀPhÀMe], 276 (5) [M+ÀCOPh]; HRMS (EI): m/z:
calcd for C26H23O2N: 381.17233; found: 381.17073; elemental analysis
calcd (%) for C26H23O2N: C 81.86, H 6.08, N 3.67; found: C 82.03, H
6.15, N 3.59.
1-(4-Iodophenyl)-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic
acid ethyl ester (7e): Yellow solid; yield: 78% (0.371 g); 1H NMR
(300 MHz, CDCl3): d=1.08 (t, J=7.1 Hz, 3H, CH3), 1.88 (s, 3H, CH3),
2.31 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.11 (q, J=7.1 Hz, 2H, CH2), 6.90
(d, J=8.5 Hz, 2H, CHarom), 7.20 (d, J=8.5 Hz, 2H, CHarom), 7.00 (d, J=
8.2 Hz, 2H, CHarom), 7.85 ppm (d, J=8.2 Hz, 2H, CHarom); 13C NMR
(75 MHz, CDCl3): d=11.2, 12.6, 14.0 (s, CH3), 55.2 (s, OCH3), 59.3 (s,
CH2), 94.0, 112.3, 122.2, 126.5, 128.3, 135.4, 137.5, 157.9 (s, =C, Carom),
112.9, 130.1, 131.3, 138.6 (s, CHarom), 166.1 ppm (s, C=O); IR (Nujol): n˜ =
1698 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 475 (100) [M+], 446
(30) [M+ÀEt], 430 (15) [M+ÀOEt], 400 (5) [M+ÀOEtÀ2Me], 348 (10)
[M+ÀI]; HRMS (EI): m/z: calcd for C22H22O3IN: 475.06388; found:
475.06343; elemental analysis calcd (%) for C22H22O3IN: C 55.59, H 4.67,
N 2.95; found: C 55.42, H 4.75, N 3.08.
3-(4-Methoxyphenyl)-2,5-dimethyl-1-phenylpyrrole (6): Yellow oil; yield:
72% (0.199 g); 1H NMR (300 MHz, CDCl3): d=2.09 (s, 3H, CH3), 2.14
(s, 3H, CH3), 3.84 (s, 3H, OCH3), 6.12 (s, 1H, =CH), 6.95 (d, J=8.5 Hz,
2H, CHarom), 7.28 (d, J=7.1 Hz, 2H, CHarom), 7.36–7.52 ppm (m, 5H,
CHarom); 13C NMR (75 MHz, CDCl3): d=12.1, 12.8 (s, CH3), 55.2 (s,
OCH3), 106.4 (s, =CH), 113.7, 127.7, 128.3, 128.8, 129.0 (s, CHarom), 120.6,
124.5, 128.4, 129.9, 138.8, 157.3 ppm (s, =C, Carom); LRMS (EI, 70 eV):
m/z (%): 277 (100) [M+], 262 (60) [M+ÀMe], 246 (5) [M+ÀOMe], 233
(5) [M+À3Me]; HRMS (EI): m/z: calcd for C19H19NO: 277.14611; found:
277.14591.
4-(4-Methoxyphenyl)-2,5-dimethyl-1-(4-nitrophenyl)pyrrole-3-carboxylic
acid ethyl ester (7 f): Red solid; yield: 92% (0.363 g); 1H NMR
(300 MHz, CDCl3): d=1.09 (t, J=7.1 Hz, 3H, CH3), 1.91 (s, 3H, CH3),
2.34 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.12 (q, J=7.1 Hz, 2H, CH2), 6.91
(d, J=8.5 Hz, 2H, CHarom), 7.20 (d, J=8.5 Hz, 2H, CHarom), 7.46 (d, J=
8.8 Hz, 2H, CHarom), 8.41 ppm (d, J=8.8 Hz, 2H, CHarom); 13C NMR
(75 MHz, CDCl3): d=11.3, 12.7, 14.0 (s, CH3), 55.2 (s, OCH3), 59.4 (s,
CH2), 112.3, 120.4, 126.2, 127.9, 134.9, 143.4, 147.4, 158.1 (s, =C, Carom),
112.9, 124.8, 129.2, 131.3 (s, CHarom), 165.7 ppm (s, C=O); IR (Nujol): n˜ =
1697 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 394 (100) [M+], 379
(5) [M+ÀMe], 365 (50) [M+ÀEt], 349 (20) [M+ÀOEt], 319 (10) [M+
ÀOEtÀ2Me]; HRMS (EI): m/z: calcd for C22H22O5N2: 394.15232; found:
394.15109; elemental analysis calcd (%) for C22H22O5N2: C 66.99, H 5.62,
N 7.10; found: C 66.83, H 5.70, N 7.06.
1,4-Bis(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic acid ethyl
ester (7a): Orange oil; yield: 94% (0.356 g); 1H NMR (300 MHz,
CDCl3): d=1.09 (t, J=7.1 Hz, 3H, CH3), 1.87 (s, 3H, CH3), 2.31 (s, 3H,
CH3), 3.83 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 4.11 (q, J=7.1 Hz, 2H,
CH2), 6.90 (d, J=8.5 Hz, 2H, CHarom), 7.22 (d, J=8.5 Hz, 2H, CHarom),
7.00 (d, J=8.8 Hz, 2H, CHarom), 7.15 ppm (d, J=8.8 Hz, 2H, CHarom);
13C NMR (75 MHz, CDCl3): d=11.1, 12.6, 14.1 (s, CH3), 55.1, 55.4 (s,
OCH3), 59.1 (s, CH2), 110.7, 121.5, 126.9, 128.7, 130.5, 135.8, 157.8, 159.4
(s, =C, Carom), 112.8, 114.5, 129.2, 131.4 (s, CHarom), 166.0 ppm (s, C=O);
IR (Nujol): n˜ =1694 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 379
(100) [M+], 364 (5) [M+ÀMe], 350 (30) [M+ÀEt], 334 (15) [M+ÀOEt],
320 (5) [M+ÀEtÀ2Me], 304 (10) [M+ÀOEtÀ2Me]; HRMS (EI): m/z:
calcd for C23H25O4N: 379.17781; found: 379.17766.
1-(4-Ethoxycarbonylphenyl)-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-
carboxylic acid ethyl ester (7g): Orange solid; yield: 85% (0.358 g);
1H NMR (300 MHz, CDCl3): d=1.08 (t, J=7.1 Hz, 3H, CH3), 1.42 (t, J=
7.1 Hz, 3H, CH3), 1.88 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.82 (s, 3H,
OCH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.42 (q, J=7.1 Hz, 2H, CH2), 6.90
(d, J=8.5 Hz, 2H, CHarom), 7.21 (d, J=8.5 Hz, 2H, CHarom), 7.33 (d, J=
8.5 Hz, 2H, CHarom), 8.20 ppm (d, J=8.5 Hz, 2H, CHarom); 13C NMR
(75 MHz, CDCl3): d=11.2, 12.6, 14.0, 14.2 (s, CH3), 55.1 (s, OCH3), 59.2,
61.3 (s, CH2), 111.6, 113.4, 122.4, 126.3, 130.6, 135.1, 141.7, 157.9 (s, =C,
Carom), 112.9, 128.2, 130.7, 131.3 (s, CHarom), 165.6, 165.8 ppm (s, C=O);
IR (Nujol): n˜ =1698 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 421
(100) [M+], 406 (5) [M+ÀMe], 392 (15) [M+ÀEt], 376 (15) [M+ÀOEt],
348 (10) [M+ÀCO2Et], 333 (5) [M+ÀCO2EtÀMe]; HRMS (EI): m/z:
calcd for C25H27O5N: 421.18837; found: 421.18848; elemental analysis
calcd (%) for C25H27O5N: C 71.24, H 6.46, N 3.32; found: C 71.01, H
6.57, N 3.45.
4-(4-Methoxyphenyl)-1-(3-methoxyphenyl)-2,5-dimethylpyrrole-3-carbox-
ylic acid ethyl ester (7b): Orange oil; yield: 90% (0.341 g); 1H NMR
(300 MHz, CDCl3): d=1.09 (t, J=7.1 Hz, 3H, CH3), 1.90 (s, 3H, CH3),
2.34 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.11 (q, J=
7.1 Hz, 2H, CH2), 6.78–7.02 (m, 5H, CHarom), 7.22 (d, J=8.7 Hz, 2H,
CHarom), 7.40 ppm (m, 1H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.1,
12.6, 14.0 (s, CH3), 55.1, 55.4 (s, OCH3), 59.1 (s, CH2), 110.9, 121.7, 126.6,
128.6, 135.5, 138.9, 157.8, 160.2 (s, =C, Carom), 112.8, 113.9, 114.2, 120.4,
130.0, 131.4 (s, CHarom), 165.9 ppm (s, C=O); IR (Nujol): n˜ =1699 cmÀ1 (s,
C=O); LRMS (EI, 70 eV): m/z (%): 379 (100) [M+], 364 (5) [M+ÀMe],
350 (30) [M+ÀEt], 334 (10) [M+ÀOEt], 320 (5) [M+ÀEtÀ2Me], 304 (5)
[M+ÀOEtÀ2Me]; HRMS (EI): m/z: calcd for C23H25O4N: 379.17781;
found: 379.17709.
1-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carbox-
ylic acid ethyl ester (7h): Yellow oil; yield: 88% (0.321 g); 1H NMR
(300 MHz, CDCl3): d=1.11 (t, J=7.1 Hz, 3H, CH3), 1.87 (s, 3H, CH3),
2.31 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.15 (q, J=7.1 Hz, 2H, CH2), 5.98
(br, 1H, OH), 6.90 (d, J=8.5 Hz, 4H, CHarom), 7.05 (d, J=8.5 Hz, 2H,
CHarom), 7.23 ppm (d, J=8.5 Hz, 2H, CHarom); 13C NMR (75 MHz,
CDCl3): d=11.1, 12.7, 14.0 (s, CH3), 55.2 (s, OCH3), 59.5 (s, CH2), 110.3,
121.5, 127.3, 128.7, 129.8, 136.3, 156.4, 157.8 (s, =C, Carom), 112.9, 116.1,
4-(4-Methoxyphenyl)-1-(2-methoxyphenyl)-2,5-dimethylpyrrole-3-carbox-
ylic acid ethyl ester (7c): Orange oil; yield: 95% (0.360 g); 1H NMR
(300 MHz, CDCl3): d=1.09 (t, J=7.1 Hz, 3H, CH3), 1.83 (s, 3H, CH3),
2.27 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.12 (q, J=
7.1 Hz, 2H, CH2), 6.90 (d, J=8.8 Hz, 2H, CHarom), 7.25 (d, J=8.8 Hz,
2H, CHarom), 7.04–7.19 (m, 3H, CHarom), 7.43 ppm (m, 1H, CHarom);
13C NMR (75 MHz, CDCl3): d=10.7, 12.3, 14.1 (s, CH3), 55.1, 55.6 (s,
OCH3), 59.0 (s, CH2), 110.5, 121.4, 126.3, 127.0, 128.9, 136.2, 155.6, 157.7
(s, =C,
C
arom), 112.0, 112.7, 120.7, 130.0, 130.1, 131.5 (s, CHarom),
129.2, 131.4 (s, CHarom), 166.8 ppm (s, C=O); IR (Nujol): n˜ =1663 (s, C=
+
166.1 ppm (s, C=O); IR (Nujol): n˜ =1698 cmÀ1 (s, C=O); LRMS (EI,
70 eV): m/z (%): 379 (100) [M+], 364 (5) [M+ÀMe], 350 (25) [M+ÀEt],
334 (15) [M+ÀOEt], 320 (5) [M+ÀEtÀ2Me], 306 (10) [M+ÀCO2Et];
HRMS (EI): m/z: calcd for C23H25O4N: 379.17781; found: 379.17740.
O), 3295 cmÀ1 (m, O H); LRMS (EI, 70 eV): m/z (%): 365 (100) [M ],
À
336 (50) [M+ÀEt], 320 (20) [M+ÀOEt], 292 (10) [M+ÀCO2Et], 275 (5)
[M+ÀCO2EtÀOH]; HRMS (EI): m/z: calcd for C22H23O4N: 365.16216;
found: 365.16238.
9978
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9973 – 9981

Multicomponent Synthesis of Pyrroles
FULL PAPER
1-(3-Acetylphenyl)-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic
acid ethyl ester (7i): Orange oil; yield: 87% (0.340 g); 1H NMR
(300 MHz, CDCl3): d=1.08 (t, J=7.0 Hz, 3H, CH3), 1.87 (s, 3H, CH3),
2.31 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.10 (q, J=
7.0 Hz, 2H, CH2), 6.90 (d, J=8.5 Hz, 2H, CHarom), 7.21 (d, J=8.5 Hz,
2H, CHarom), 7.46 (d, J=7.9 Hz, 1H, CHarom), 7.63 (dd, J=7.9, 7.9 Hz,
1H, CHarom), 7.84 (s, 1H, CHarom), 8.05 ppm (d, J=7.9 Hz, 1H, CHarom);
13C NMR (75 MHz, CDCl3): d=10.9, 12.4, 13.7 and 26.4 (s, CH3), 54.9 (s,
OCH3), 58.9 (s, CH2), 111.2, 122.0, 126.2, 128.1, 135.0, 138.0, 138.1, 157.7
(s, =C, Carom), 112.6, 127.6, 128.0, 129.5, 131.1, 132.4 (s, CHarom), 165.6,
196.6 ppm (s, C=O); IR (Nujol): n˜ =1651, 1694 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 391 (100) [M+], 376 (5) [M+ÀMe], 362 (20) [M+
ÀEt], 346 (15) [M+ÀOEt], 316 (10) [M+ÀOEtÀ2Me], 303 (15) [M+
ÀCO2EtÀMe]; HRMS (EI): m/z: calcd for C24H25O4N: 391.17781; found:
391.17699.
ÀOEt], 290 (5) [M+ÀCO2Et], 226 (50) [M+ÀPhÀ4Me]; HRMS (EI):
m/z: calcd for C23H25O3N: 363.18289; found: 363.18284.
1-Furfuryl-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic
acid
ethyl ester (7n): Orange oil; yield: 78% (0.275 g); 1H NMR (300 MHz,
CDCl3): d=1.05 (t, J=7.1 Hz, 3H, CH3), 2.16 (s, 3H, CH3), 2.62 (s, 3H,
CH3), 3.82 (s, 3H, OCH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.99 (s, 2H,
NCH2), 6.12 (d, J=3.1 Hz, 1H, =CH), 6.31 (dd, J=3.1, 2.0 Hz, 1H, =
CH), 6.88 (d, J=8.5 Hz, 2H, CHarom), 7.15 (d, J=8.5 Hz, 2H, CHarom),
7.35 ppm (d, J=2.0 Hz, 1H, =CH); 13C NMR (75 MHz, CDCl3): d=10.2,
11.4, 13.9 (s, CH3), 40.7 (s, NCH2), 55.1 (s, OCH3), 58.9 (s, CH2), 107.6,
110.3, 142.5 (s, =CH), 110.8, 122.0, 125.8, 128.9, 134.7, 150.1, 157.8 (s, =C,
Carom), 112.7 and 131.5 (s, CHarom), 165.8 ppm (s, C=O); IR (Nujol): n˜ =
1679 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%): 353 (100) [M+], 324
(5) [M+ÀEt], 308 (10) [M+ÀOEt], 280 (5) [M+ÀCO2Et], 226 (80) [M+
ÀFuÀ4Me]; HRMS (EI): m/z: calcd for C21H23O4N: 353.16216; found:
353.16182.
1-(4-Carbamoylphenyl)-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-car-
boxylic acid ethyl ester (7j): Orange solid; yield: 73% (0.286 g);
1H NMR (300 MHz, CDCl3): d=1.08 (t, J=7.1 Hz, 3H, CH3), 1.88 (s,
3H, CH3), 2.31 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.11 (q, J=7.1 Hz, 2H,
CH2), 6.20 (br, 2H, NH2), 6.90 (d, J=8.7 Hz, 2H, CHarom), 7.21 (d, J=
8.7 Hz, 2H, CHarom), 7.33 (d, J=8.4 Hz, 2H, CHarom), 7.97 ppm (d, J=
8.4 Hz, 2H, CHarom); 13C NMR (75 MHz, CDCl3): d=10.8, 12.3, 13.6 (s,
CH3), 54.8 (s, OCH3), 58.8 (s, CH2), 111.2, 122.0, 126.0, 127.9, 133.0,
134.7, 140.6, 157.5 (s, =C, Carom), 112.5, 128.1, 128.2, 130.9 (s, CHarom),
165.4, 168.0 ppm (s, C=O); IR (Nujol): n˜ =1625, 1691 cmÀ1 (s, C=O);
LRMS (EI, 70 eV): m/z (%): 392 (100) [M+], 363 (30) [M+ÀEt], 347
(20) [M+ÀOEt], 332 (5) [M+ÀOEtÀMe], 319 (10) [M+ÀCO2Et], 304
(10) [M+ÀCO2EtÀMe]; HRMS (EI): m/z: calcd for C23H24O4N2:
392.17306; found: 392.17327; elemental analysis calcd (%) for
C23H24O4N2: C 70.39, H 6.16, N 7.14; found: C 70.15, H 6.09, N 7.23.
1-Allyl-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic acid ethyl
ester (7o): Yellow oil; yield: 74% (0.231 g); H NMR (300 MHz, CDCl3):
1
d=1.05 (t, J=7.1 Hz, 3H, CH3), 2.06 (s, 3H, CH3), 2.51 (s, 3H, CH3),
3.83 (s, 3H, OCH3), 4.06 (q, J=7.1 Hz, 2H, CH2), 4.45 (br, 2H, NCH2),
4.82 (d, J=17.0 Hz, 1H, =CH2), 5.16 (d, J=10.5 Hz, 1H, =CH2), 5.90 (m,
1H, =CH), 6.86 (d, J=8.5 Hz, 2H, CHarom), 7.15 ppm (d, J=8.5 Hz, 2H,
CHarom); 13C NMR (75 MHz, CDCl3): d=10.0, 11.2, 14.0 (s, CH3), 45.7 (s,
NCH2), 55.1 (s, OCH3), 58.9 (s, CH2), 110.4, 121.8, 125.7, 129.0, 134.5,
157.7 (s, =C, Carom), 112.7, 131.4 (s, CHarom), 116.2 (s, =CH2), 132.7 (s, =
CH), 165.9 ppm (s, C=O); IR (Nujol): n˜ =1694 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 313 (100) [M+], 298 (5) [M+ÀMe], 284 (30) [M+
ÀEt], 268 (15) [M+ÀOEt], 238 (10) [M+ÀOEtÀ2Me], 225 (30) [M+
ÀCO2EtÀMe]; HRMS (EI): m/z: calcd for C19H23O3N: 313.16724; found:
313.16721.
4-(4-Methoxyphenyl)-2,5-dimethyl-1-propargylpyrrole-3-carboxylic acid
ethyl ester (7p): Yellow oil; yield: 56% (0.174 g); 1H NMR (300 MHz,
CDCl3): d=1.04 (t, J=7.1 Hz, 3H, CH3), 2.16 (s, 3H, CH3), 2.61 (s, 3H,
1-(2-Isopropenylphenyl)-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-car-
boxylic acid ethyl ester (7k): Yellow oil; yield: 92% (0.358 g); 1H NMR
(300 MHz, CDCl3): d=1.09 (t, J=7.1 Hz, 3H, CH3), 1.64 (s, 3H, CH3),
1.83 (s, 3H, CH3), 2.25 (s, 3H, CH3), 3.84 (s, 3H, OCH3), 4.10 (q, J=
7.1 Hz, 2H, CH2), 4.91 (br, 1H, =CH2), 5.07 (br, 1H, =CH2), 6.89 (d, J=
8.5 Hz, 2H, CHarom), 7.14–7.26 (m, 4H, CHarom), 7.42 ppm (m, 2H,
CHarom); 13C NMR (75 MHz, CDCl3): d=10.7, 12.3, 13.7, 21.4 (s, CH3),
54.9 (s, OCH3), 58.7 (s, CH2), 110.5, 121.9, 126.5, 128.5, 134.5, 135.4,
141.8, 142.9, 157.5 (s, =C, Carom), 112.4, 127.8, 128.6, 129.0, 129.5, 131.2 (s,
CHarom), 116.6 (s, =CH2), 165.7 ppm (s, C=O); IR (Nujol): n˜ =1681 cmÀ1
(s, C=O); LRMS (EI, 70 eV): m/z (%): 389 (100) [M+], 374 (50) [M+
ÀMe], 360 (15) [M+ÀEt], 344 (15) [M+ÀOEt], 329 (20) [M+
ÀOEtÀMe], 316 (25) [M+ÀCO2Et], 301 (15) [M+ÀCO2EtÀMe], 286
(10) [M+ÀCO2EtÀ2Me]; HRMS (EI): m/z: calcd for C25H27O3N:
389.19854; found: 389.19791.
ꢀ
CH3), 2.32 (t, J=2.3 Hz, 1H, C CH), 3.78 (s, 3H, OCH3), 4.06 (q, J=
7.1 Hz, 2H, CH2), 4.58 (d, J=2.3 Hz, 2H, NCH2), 6.87 (d, J=8.5 Hz, 2H,
CHarom), 7.14 ppm (d, J=8.5 Hz, 2H, CHarom); 13C NMR (75 MHz,
CDCl3): d=10.1, 11.3, 13.9 (s, CH3), 33.1 (s, NCH2), 55.1 (s, OCH3), 59.0
ꢀ
ꢀ
(s, CH2), 72.6 (s, CH), 77.6 (s, C), 111.0, 122.1, 125.4, 128.6, 134.2,
157.9 (s, =C, Carom), 112.7, 131.4 (s, CHarom), 165.7 ppm (s, C=O); IR
À1
ꢀ
ꢀ À
(Nujol): n˜ =1693 (s, C=O), 2122 (w, C C), 3279 cm (m, C H); LRMS
(EI, 70 eV): m/z (%): 311 (100) [M+], 296 (5) [M+ÀMe], 282 (40) [M+
ÀEt], 266 (20) [M+ÀOEt], 236 (15) [M+ÀOEtÀ2Me].
4-(4-Methoxyphenyl)-2,5-dimethyl-1-[(S)-1-phenylethyl]pyrrole-3-carbox-
ylic acid ethyl ester (7q): Orange oil; yield: 76% (0.287 g); [a]20 =À41.0
[c=1.0 in CHCl3]; 1H NMR (300 MHz, CDCl3): d=1.04 (t, J=7.1 Hz,
3H, CH3), 1.93 (d, J=7.4 Hz, 3H, CH3), 1.95 (s, 3H, CH3), 2.46 (s, 3H,
CH3), 3.83 (s, 3H, OCH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 5.65 (q, J=
7.4 Hz, 1H, NCH), 6.90 (d, J=7.4 Hz, 2H, CHarom), 7.13–7.38 ppm (m,
7H, CHarom); 13C NMR (75 MHz, CDCl3): d=11.5, 12.4, 14.0, 18.9 (s,
CH3), 52.8 (s, NCH), 55.1 (s, OCH3), 59.0 (s, CH2), 111.2, 122.6, 125.9,
129.2, 134.7, 141.1, 157.8 (s, =C, Carom), 112.7, 125.8, 127.1, 128.6, 131.5 (s,
CHarom), 166.1 ppm (s, C=O); IR (Nujol): n˜ =1693 cmÀ1 (s, C=O); LRMS
(EI, 70 eV): m/z (%): 377 (100) [M+], 332 (5) [M+ÀOEt], 272 (70) [M+
ÀOEtÀ4Me], 244 (30) [M+ÀCO2EtÀ4Me], 227 (30) [M+ÀCO2EtÀPh];
HRMS (EI): m/z: calcd for C24H27O3N: 377.19854; found: 377.19835. The
enantiomeric excess of this compound (>99% ee) was determined by
chiral HPLC analysis on a Hewlett–Packard 1100 LC apparatus by using
a CHIRACEL OD column (250”4.6 mm; mobile phase: n-hexane/iso-
propanol 90:10; flow rate: 0.4 mLminÀ1; T=308C; detection wavelength:
227 nm). To this end, a racemic mixture of 7q was prepared from racemic
a-methylbenzylamine and the chromatograms were compared (Figure 1).
1-Ethyl-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic acid ethyl
1
ester (7l): Yellow oil; yield: 75% (0.226 g); H NMR (300 MHz, CDCl3):
d=1.04 (t, J=7.1 Hz, 3H, CH3), 1.29 (t, J=7.3 Hz, 3H, CH3), 2.11 (s,
3H, CH3), 2.56 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 3.89 (q, J=7.3 Hz, 2H,
CH2), 4.05 (q, J=7.1 Hz, 2H, CH2), 6.88 (d, J=8.7 Hz, 2H, CHarom),
7.14 ppm (d, J=8.7 Hz, 2H, CHarom); 13C NMR (75 MHz, CDCl3): d=9.8,
10.9, 13.7, 15.3 (s, CH3), 38.1, 58.6 (s, CH2), 54.8 (s, OCH3), 110.0, 121.5,
124.7, 128.8, 133.6, 157.5 (s, =C, Carom), 112.4, 131.2 (s, CHarom), 165.7 ppm
(s, C=O); IR (Nujol): n˜ =1694 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z
(%): 301 (100) [M+], 286 (5) [M+ÀMe], 272 (90) [M+ÀEt], 256 (15)
[M+ÀOEt], 226 (10) [M+ÀOEtÀ2Me]; HRMS (EI): m/z: calcd for
C18H23O3N: 301.16724; found: 301.16721.
1-Benzyl-4-(4-methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic
acid
ethyl ester (7m): Yellow oil; yield: 72% (0.261 g); 1H NMR (300 MHz,
CDCl3): d=1.06 (t, J=7.2 Hz, 3H, CH3), 2.03 (s, 3H, CH3), 2.49 (s, 3H,
CH3), 3.83 (s, 3H, OCH3), 4.08 (q, J=7.2 Hz, 2H, CH2), 5.10 (s, 2H,
NCH2), 6.83–6.97 (m, 4H, CHarom), 7.18–7.35 ppm (m, 5H, CHarom);
13C NMR (75 MHz, CDCl3): d=10.0, 11.2, 13.7 (s, CH3), 46.7 (s, NCH2),
54.9 (s, OCH3), 58.7 (s, CH2), 110.5, 121.9, 125.7, 128.6, 134.5, 136.7, 157.5
(s, =C, Carom), 112.5, 125.3, 127.1, 128.6, 131.2 (s, CHarom), 165.7 ppm (s,
C=O); IR (Nujol): n˜ =1698 cmÀ1 (s, C=O); LRMS (EI, 70 eV): m/z (%):
363 (100) [M+], 348 (2) [M+ÀMe], 334 (5) [M+ÀEt], 318 (10) [M+
4-(4-Methoxyphenyl)-2,5-dimethylpyrrole-3-carboxylic acid ethyl ester
(9): Yellow oil; yield: 74% (0.201 g); 1H NMR (300 MHz, CDCl3): d=
1.11 (t, J=7.1 Hz, 3H, CH3), 2.08 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.81 (s,
3H, OCH3), 4.10 (q, J=7.1 Hz, 2H, CH2), 6.88 (d, J=8.5 Hz, 2H,
CHarom), 7.18 (d, J=8.5 Hz, 2H, CHarom), 8.26 ppm (s, 1H, NH);
13C NMR (75 MHz, CDCl3): d=11.1, 13.7, 14.1 (s, CH3), 55.1 (s, OCH3),
59.0 (s, CH2), 110.4, 121.9, 123.3, 128.5, 133.8, 157.7 (s, =C, Carom), 112.8,
Chem. Eur. J. 2007, 13, 9973 – 9981
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9979

V. Cadierno, J. Gimeno, and N. Nebra
Acknowledgements
This work was supported by the Ministerio de Educación y Ciencia
(MEC) of Spain (project CTQ2006-08485/BQU and Consolider Ingenio
2010 (CSD2007-00006)) and the Gobierno del Principado de Asturias
(FICYT project IB05-035). N.N. and V.C. thank the MEC and the Euro-
pean Social Fund for the award of a PhD grant and a “Ramón y Cajal”
contract, respectively.
[1] See, for example: a) A. Fürstner, Angew. Chem. 2003, 115, 3706–
3728; Angew. Chem. Int. Ed. 2003, 42, 3582–3603; b) H. Hoffmann,
T. Lindel, Synthesis 2003, 1753–1783; c) S. Agarwal, S. Cämmerer,
S. Filali, W. Frçhner, J. Knçll, M. P. Krahl, K. R. Reddy, H.-J. Knçlk-
er, Curr. Org. Chem. 2005, 9, 1601–1614; d) C. T. Walsh, S. Gar-
neau-Tsodikova, A. R. Howard-Jones, Nat. Prod. Rep. 2006, 23,
517–531; e) F. Bellina, R. Rossi, Tetrahedron 2006, 62, 7213–7256.
[2] See, for example: a) P. Cozzi, N. Mongelli, Curr. Pharm. Des. 1998,
4, 181–201; b) J. W. Huffman, Curr. Med. Chem. 1999, 6, 705–720;
c) M. Kidwai, R. Venkataramanan, R. Mohan, P. Sapra, Curr. Med.
Chem. 2002, 9, 1209–1228; d) J. W. Huffman, L. W. Padgett, Curr.
Med. Chem. 2005, 12, 1395–1411.
[3] See, for example: a) D. Curran, J. Grimshaw, S. D. Perera, Chem.
Soc. Rev. 1991, 20, 391–404; b) A. Deronzier, J.-C. Moutet, Curr.
Top. Electrochem. 1994, 3, 159–200; c) L. Groenendaal, E.-W.
Meijer, J. A. J. M. Vekemans, Electronic Materials: The Oligomer
Approach (Eds.: K. Müllen, G. Wegner), Wiley-VCH, Weinheim,
1997; d) A. Kros, R. J. M. Nolte, N. A. J. M. Sommerdijk, Adv.
Mater. 2002, 14, 1779–1782; e) N. J. L. Guernion, W. Hayes, Curr.
Org. Chem. 2004, 8, 637–651.
[4] See, for example: a) Pyrroles, The Synthesis Reactivity and Physical
Properties of Substituted Pyrroles, Part II (Ed.: R. A. Jones), Wiley,
New York, 1992; b) D. St. C. Black, Comprehensive Heterocyclic
Chemistry II, Vol. 2 (Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriv-
en), Elsevier, Oxford, 1996, pp. 39–117; c) R. J. Sundberg, Compre-
hensive Heterocyclic Chemistry II, Vol. 2 (Eds.: A. R. Katritzky,
C. W. Rees, E. F. V. Scriven), Elsevier, Oxford, 1996, pp. 119–206;
d) E. T. Pelkey, Prog. Heterocycl. Chem. 2005, 17, 109–141.
[5] a) A. V. Kelꢁin, A. W. Sromek, V. Gevorgyan, J. Am. Chem. Soc.
2001, 123, 2074–2075; b) J. T. Kim, V. Gevorgyan, Org. Lett. 2002, 4,
4697–4699; c) B. Gabriele, G. Salerno, A. Fazio, J. Org. Chem. 2003,
68, 7853–7861; d) D. J. Gorin, N. R. Davis, F. D. Toste, J. Am. Chem.
Soc. 2005, 127, 11260–11261; e) K. Hiroya, S. Matsumoto, M. Ashi-
kawa, K. Ogiwara, T. Sakamoto, Org. Lett. 2006, 8, 5349–5352;
f) O. V. Larionov, A. de Meijere, Angew. Chem. 2005, 117, 5809–
5813; Angew. Chem. Int. Ed. 2005, 44, 5664–5667; g) R. Martín,
M. R. Rivero, S. L. Buchwald, Angew. Chem. 2006, 118, 7237–7240;
Angew. Chem. Int. Ed. 2006, 45, 7079–7082.
Figure 1. Chromatograms of racemic 7q (top) and the enantiomerically
pure 7q (bottom) obtained from (S)-(À)-a-methylbenzylamine.
131.3 (s, CHarom), 165.9 ppm (s, C=O); IR (Nujol): n˜ =1702 (s, C=O),
+
3255 cmÀ1 (m, N H); LRMS (EI, 70 eV): m/z (%): 273 (100) [M ], 258
À
(5) [M+ÀMe], 244 (80) [M+ÀEt], 228 (20) [M+ÀOEt], 213 (5) [M+
ÀOEtÀMe], 198 [M+ÀOEtÀ2Me], 184 (10) [M+ÀOEtÀ3Me].
2-Acetyl-3-(4-methoxyphenyl)pent-4-ynoic acid ethyl ester (10): Asolu-
tion of 1-(4-methoxyphenyl)prop-2-yn-1-ol (2d; 0.162 g, 1 mmol), ethyl
acetoacetate (0.130 g, 1 mmol) and CF3CO2H (37 mL, 0.5 mmol) in THF
(0.5 mL) was heated at 758C for 3 h (in a sealed tube). After removal of
volatiles under vacuum, the residue was purified by column chromatogra-
phy (silica gel) with a mixture EtOAc/hexanes (1:20) as the eluent.
Alkyne 10 was isolated as a nonseparable mixture of two diastereoiso-
mers in approximately 1.2:1 ratio: yellow oil; yield: 91% (0.249 g); NMR
1
data for the major diastereoisomer: H NMR (300 MHz, CDCl3): d=1.27
[6] For recent reviews and highlights on pyrrole syntheses through
MCRs, see: a) G. Balme, Angew. Chem. 2004, 116, 6396–6399;
Angew. Chem. Int. Ed. 2004, 43, 6238–6241; b) N. T. Patil, Y. Yama-
moto, ARKIVOC 2007, 10, 121–141; c) D. M. Dꢁsouza, T. J. J.
Müller, Chem. Soc. Rev. 2007, 36, 1095–1108.
(t, J=7.1 Hz, 3H, CH2CH3), 1.96 (s, 3H, COCH3), 2.26 (d, J=2.5 Hz,
ꢀ
ꢀ
1H, C CH), 3.75 (s, 3H, OCH3), 3.97 (m, 3H, CH2, CHCHC CH), 4.19
ꢀ
(m, 1H, CHC CH), 6.82 (m, 2H, CHarom), 7.26 ppm (m, 2H, CHarom);
13C NMR (75 MHz, CDCl3): d=14.0 (s, CH2CH3), 30.6 (s, COCH3), 36.0
ꢀ
ꢀ
(s, CHC CH), 55.1 (s, OCH3), 61.7 (s, CH2), 66.1 (s, CHCHC CH), 71.8
[7] V. Cadierno, J. Gimeno, N. Nebra, Adv. Synth. Catal. 2007, 349,
382–394.
ꢀ
ꢀ
(s, CH), 83.3 (s, C), 114.0, 129.2 (s, CHarom), 129.5, 158.9 (s, Carom),
166.9, 200.3 ppm (s, C=O); NMR data for the minor diastereoisomer:
1H NMR (300 MHz, CDCl3): d=1.04 (t, J=7.0 Hz, 3H, CH2CH3), 2.27
[8] Brønsted acid catalysed propargylations of several organic sub-
strates, including 1,3-dicarbonyl compounds, with alkynols have
been reported: a) R. Sanz, A. Martínez, J. M. lvarez-GutiØrrez, F.
Rodríguez, Eur. J. Org. Chem. 2006, 1383–1386; b) R. Sanz, D.
Miguel, A. Martínez, J. M. lvarez-GutiØrrez, F. Rodríguez, Org.
Lett. 2007, 9, 727–730. In these works, only 5 mol% of the acid is
required to promote the propargylation process efficiently. In our
case, the use of larger quantities of acid (50 mol%) is imperative in
order to avoid the Meyer–Schuster isomerisation of the propargylic
alcohol catalysed by ruthenium complex 1: c) V. Cadierno, S. E.
García-Garrido, J. Gimeno, Adv. Synth. Catal. 2006, 348, 101–110;
d) V. Cadierno, J. Díez, S. E. García-Garrido, J. Gimeno, N. Nebra,
Adv. Synth. Catal. 2006, 348, 2125–2132.
ꢀ
(d, J=2.2 Hz, 1H, C CH), 2.34 (s, 3H, COCH3), 3.75 (s, 3H, OCH3),
ꢀ
ꢀ
3.97 (m, 3H, CH2, CHCHC CH), 4.32 (m, 1H, CHC CH), 6.82 (m, 2H,
CHarom), 7.26 ppm (m, 2H, CHarom); 13C NMR (75 MHz, CDCl3): d=13.7
ꢀ
(s, CH2CH3), 30.0 (s, COCH3), 36.0 (s, CHC CH), 55.1 (s, OCH3), 61.5
ꢀ
ꢀ
ꢀ
(s, CH2), 66.6 (s, CHCHC CH), 72.3 (s, CH), 83.1 (s, C), 113.9, 129.1
(s, CHarom), 129.5, 159.0 (s, Carom), 166.5, 200.6 ppm (s, C=O); IR (Nujol):
À1
ꢀ
ꢀ
n˜ =1722, 1738 (s, C=O), 2118 (w, C C), 3290 cm (m, C-H); LRMS
(EI, 70 eV): m/z (%): 274 (5) [M+], 245 (5) [M+ÀEt], 230 (30) [M+
ÀEtÀMe], 201 (90) [M+ÀCO2Et], 186 (40) [M+ÀCO2EtÀMe], 145 (100)
[M+ÀCH
U
G
9980
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9973 – 9981

Multicomponent Synthesis of Pyrroles
FULL PAPER
[9] This unusual transformation has been previously observed by us
while studying the coupling process depicted in Scheme 1 (see refer-
ence [7]). The intermediate carboxylic acid 5 could not be detected
by GC/MS, which indicates that its decarboxylation is a highly fav-
oured process.
sence of both CF3CO2H and complex 1 leads directly to pyrrole 3d
without detection of the intermediate b-enamino ester 11, albeit in
very low yield (approximately 20%; as determined by GC) after
24 h (compare with the catalysed reaction in entry 4 in Table 1; 2 h,
94% yield of isolated product).
[10] The enantiomeric excess of 7q (>99% ee; determined by chiral
HPLC analysis) was identical to that of the starting amine, a result
that confirms the complete stereospecificity of the reaction se-
quence.
[14] H. A. Stefani, I. M. Costa, D. O. Silva, Synthesis 2000, 1526–1528.
[15] Aone-pot four-component synthesis of 1,2,3,5-tetrasubstituted pyr-
roles from secondary propargylic alcohols, aryl halides, aldehydes
and primary amines has been reported. The process, which is cata-
lysed by a Pd/Cu/thiazolium salt/acetic acid system, generates the
corresponding tetrasubstituted pyrroles only in moderate yields (49–
59%): R. U. Braun, K. Zeitler, T. J. J. Müller, Org. Lett. 2001, 3,
3297–3300.
À
[11] Metal-mediated cleavage of propargylic C N bonds is a well-docu-
mented process. For a review on this topic, see: S. Escoubet, S. Gas-
taldi, M. Bertrand, Eur. J. Org. Chem. 2005, 3855–3873.
[12] Arelated reaction pathway has been proposed by Arcadi and co-
workers in the sequential AuIII-catalysed amination/annulation of
[16] Aclosely related one -pot three-component synthesis of fully substi-
tuted pyrroles from alkynol 2a, aniline and enolisable ketones, em-
ꢀ
the 2-propynyl-1,3-dicarbonyl compounds HC CCH2CH{C(=O)R}2
with primary amines to produce 1,2,3,5-substituted pyrroles: a) A.
Arcadi, S. D. Giuseppe, F. Marinelli, E. Rossi, Adv. Synth. Catal.
2001, 343, 443–446; b) A. Arcadi, S. Di Giuseppe, F. Marinelli, E.
Rossi, Tetrahedron: Asymmetry 2001, 12, 2715–2720. The intermedi-
ate b-enamino ester 11 was not detected by GC/MS, which indicates
its great tendency to undergo the annulation.
ploying [Cp*RuCl
(m2-SMe)2RuCp*Cl] (Cp: pentamethylcyclopenta-
G
dienyl; 10 mol%), NH4BF4 (20 mol%) and PtCl2 (20 mol%), has
been described. We note that 1) no 1,3-dicarbonyl compounds were
used as substrates in this catalytic reaction, 2) large excesses of both
the ketone (used as solvent) and aniline (5 equiv relative to 2a) are
required and 3) only moderate yields (44–58%) are attained after
100 h under refluxing conditions: Y. Nishibayashi, M. Yoshikawa, Y.
Inada, M. D. Milton, M. Hidai, S. Uemura, Angew. Chem. 2003, 115,
2785–2788; Angew. Chem. Int. Ed. 2003, 42, 2681–2684.
[13] We have observed that transformation of 10 into 3d is a highly fav-
oured process that can be exclusively promoted by CF3CO2H
(50 mol%, in THF at 758C). Nevertheless, under these conditions,
the sequential amination/annulation reaction takes place very slowly
and yields 3d in only 43% yield (as determined by GC) after 24 h
(compare with entry 4 in Table 1). This fact clearly indicates an
active role of the Lewis acid–ruthenium species in the reaction se-
quence. We note that related sequential amination/annulation reac-
tions of 2-propynyl-1,3-dicarbonyl compounds with amines catalysed
by trifluoroacetic acid have been described: A. S. Demir, A. Aybey,
M. Kayalar, ARKIVOC 2005, 15, 105–116. It is also interesting to
note that treatment of 10 with aniline, in THF at 758C, in the ab-
[17] a) R. Dhawan, B. A. Arndtsen, J. Am. Chem. Soc. 2004, 126, 468–
469; b) J. T. Binder, S. F. Kirsch, Org. Lett. 2006, 8, 2151–2153.
[18] V. Cadierno, J. Díez, S. E. García-Garrido, J. Gimeno, Chem.
Commun. 2004, 2716–2717.
[19] M. M. Midland, J. Org. Chem. 1975, 40, 2250–2252.
Received: July 23, 2007
Published online: September 14, 2007
Chem. Eur. J. 2007, 13, 9973 – 9981
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9981