Design of a versatile multicomponent reaction leading to 2-amino-5-ketoaryl pyrroles

Article abstract of DOI:10.1111/j.1747-0285.2009.00942.x

The design of an unprecedented multicomponent reaction to and synthesis of 2-amino-5-ketoaryl pyrroles are described. The compounds (14 examples) can be synthesized by reacting aminoacetophenone sulfonamides, (hetero)aromatic aldehydes, and malonodinitrile or cyanoacetic acid derivatives in one-pot manner. Pharmacophore features and potential applications of this new scaffold are discussed.

Full text of DOI:10.1111/j.1747-0285.2009.00942.x

ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2009.00942.x
Chem Biol Drug Des 2010; 75: 277–283
Research Article
Design of a Versatile Multicomponent Reaction
Leading to 2-amino-5-ketoaryl pyrroles
acceptors, e.g. Asn112 and Tyr174. Thus, 2-aminopyrroles are inter-
esting synthetic targets to obtain biologically active compounds.
Therefore, new synthetic routes toward this chemotype are of
demand. Herein, we would like to report the discovery of a versa-
tile 3-component reaction leading to 2-amino-5-ketoaryl pyrroles.
¨
Kan Wang and Alexander Domling*
Departments of Pharmaceutical Sciences and Chemistry, University of
Pittsburgh, 3501 Fifth Avenue, BST3 11019, Pittsburgh, PA 1526, USA
*Corresponding author: Alexander Dçmling, asd30@pitt.edu
The design of an unprecedented multicomponent
reaction to and synthesis of 2-amino-5-ketoaryl pyr-
roles are described. The compounds (14 examples)
can be synthesized by reacting aminoacetophenone
sulfonamides, (hetero)aromatic aldehydes, and
malonodinitrile or cyanoacetic acid derivatives in
one-pot manner. Pharmacophore features and
potential applications of this new scaffold are
discussed.
Pyrroles can be synthesized by a variety of classical and new multi-
component reactions (MCRs), including the Piloty–Robinson reaction
(2 equiv. aldehyde and hydrazine) (8,9), an in situ coupling–isomeri-
zation Stetter–Paal–Knorr variant (10), and the 3-CR of amino acids,
acylchlorides and dimethyl acetylenedicarboxylate (DMAD) (11), a 3-
CR of N-tosylimines, DMAD, and isocyanides (12), in addition to
classical synthesis such as the Paal–Knorr reaction (13,14). The use
of malondinitrile to form 5-membered ring cyclic adducts, e.g. am-
inopyrrole, has been reported (15). We recently described an opera-
tionally simple, efficient, and cheap access to cyanoacetamides
derived from methyl cyanoacetate and primary or secondary ali-
phatic amines (16). This procedure allows us to synthesize many dif-
ferent diversely substituted cyanoacetamides. Cyanoacetamides are
electronically activated methylene compounds, and regarding their
reactivity, they are related to malonodinitrile, which shows a very
versatile and interesting MCR chemistry (for a recent comprehensive
review, see 17). Having access to such a diversity of starting mate-
rials, we became interested in the design of new MCRs based on
these starting materials. Our design consideration for the herein
disclosed MCR was as follows.
Key words: 2-aminopyrrole, aminoacetophenone sulfonamides, cya-
noacetamides, multicomponent reaction
Received 23 October 2009, revised 5 December 2009 and accepted for
publication 6 December 2009
Introduction
The 2-aminopyrrole fragment is part of many different bioactive com-
pounds. Reported bioactivities include, IL-6 production inhibition (1),
IjB kinase b inhibition (2), intergrin antagonists (3), signal transduc-
tion modulators (4), antitumor (5), and antibacterial (6), just to name
a few. For example, a RELIBASE search of the Protein Data Bank for
the 2-aminopyrrole fragment results in 79 ligand hits (7). Notably,
the 2-aminopyrrole chemotype is planar and comprise two adjacent
hydrogen bond donor or alternatively hydrogen bond donor and
acceptor moieties, respectively, dependent on the protonation state
to interact with a protein target (Figure 1). Additionally, the flat pyr-
role ring system contributes to its extraordinary chemotype and is
the prerequisite to enter narrow and deep binding pockets in target
proteins. The reported kinase activity of certain 2-aminopyrroles can
certainly be attributed to this two pharmacophore features. Pyrroles
comprise electron-rich heteroaromates and can therefore undergo
favorable p–p interactions in proteins as exemplified in the interac-
tion with Phe97 in Figure 2. Additionally, the 2-aminopyrrole moiety
comprises a heterocycle-encompassed amidine with reduced basicity,
higher electron delocalization, and thus potentially better penetration
through biological membranes.
The versatile chemistry of toluenesulfonylmethyl isocyanide (Tosmic)
leading to pyrroles, imidazoles, and other heterocycles, according to
van Leusen, is critically dependent on the multifunctionality of the
Tosmic reagent (Figure 3). It incorporates strong a-acidity, an N,S-
acetale, the isocyanide moiety and the leaving group sulfinic acid.
The later property is crucial for the final aromatization of the inter-
mediate pyrrolidines and imidazolidines.
Thus, we intended to introduce an a-acidic reagent featured with a
leaving group (Ts) into malonodinitrile to test whether MCRs can be
performed incorporating a sulfinic acid elimination with concomitant
aromatization (Scheme 1).
Experimental Section
General procedure for 3-component reaction of aminoacetophenone
sulfonamides, (hetero) aromatic aldehydes, and malonodinitrile or
cyanoacetic acid derivatives: Add aldehyde (1.0 equiv.), amino-
acetophenone sulfonamide (1.0 equiv.), malonodinitrile or cyanoacetic
acid derivatives (1.0 equiv.), triethylamine (1.0 equiv.), and 2,2,2-triflu-
In Figure 2, two representative molecular interactions of small
molecular weight 2-aminopyrrole moieties with a protein target are
depicted. Key interactions involve the pyrrole-NH in hydrogen bond
277

¨
Wang and Domling
Figure 1: Pharmacophore features of the 2-aminopyrrole moiety.
oroethanol (0.2 M) in a 20-mL vial with a stir bar. The reaction was
allowed to heat to 70 ꢀC in an oil bath for 12 h. Then, the reaction
was cooled down to 0 ꢀC to yield a precipitate that is filtered. The
solid is washed with cold ethanol and dried in an oven to yield the
desired products as light yellow solid. In some cases where no pre-
cipitate appears, the target products were purified by silica gel chro-
matography. (For copies of the 1H and 13C NMR data see Data S1,
Supporting Information.)
2-Amino-5-benzoyl-4-(4-chlorophenyl)-1H-pyrrole-
3-carbonitrile (D1)
HRMS ESI-TOF for C18H12ClN3O (M+) found: m ⁄ z: 321.0658; Calc.
Mass 321.0669. 1H NMR (d6-DMSO (dimethyl sulphoxide),
600 MHz): 6.47 (s, 2H), 7.02 (d, J = 7.8 Hz, 2H), 7.08 (t, J = 7.2 Hz,
2H), 7.12 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 7.28 (t,
J = 7.2 Hz, 1H), 11.14 (s, 1H) ppm; 13C NMR (d6-DMSO, 150 MHz):
116.5, 121.0, 127.9, 128.0, 129.0, 131.1, 131.8, 131.9, 132.7, 134.5,
138.7, 150.9, 183.9 ppm.
Figure 2: Interaction motifs of the 2-aminopyrrole with two dif-
ferent molecular targets. Top: X-ray crystal structure of a pyrrol-
o(2,3-d)pyrimidine-based antifolate (yellow sticks) in complex with
human thymidylate synthetase (gray surface) (pdb identifier: 1JU6).
The 2-aminopyrrole moiety is involved in an extended hydrogen
bond network of Asn112 and a water molecule (marine blue ball),
which mediates other hydrogen bond contacts to Arg50 and Ala312.
Bottom: Pyrrole inhibitor (yellow sticks) with the pteridine reductase
1 (PRT1) (gray surface) from the parasite Trypanosoma brucei (pdb
identifier: 3BML). The hydrogen bond network interaction of the
2-aminopyrrole moiety with Tyr174 and Ser95 is highlighted (red
dotted lines). Noteworthy also is thep)p interaction of the ligand
planar pyrrole ring with the phenyl group of Phe97. Rendering soft-
ware PyMol is used.
Methyl 2-amino-5-benzoyl-4-(4-chlorophenyl)-1H-
pyrrole-3-carboxylate (D2)
HRMS ESL-TOF for C19H15ClN2O3 (M+) found: m ⁄ z: 354.0762; Calc.
1
Mass 354.0771. H NMR (d6-DMSO, 600 MHz): 3.46 (s, 3H), 6.23 (s,
2H), 6.92–6.96 (m, 4H), 7.01 (s, 2H), 7.12 (s, 2H), 7.21 (s, 1H), 10.95
(s, 1H) ppm; 13C NMR (d6-DMSO, 150 MHz): 50.6, 96.0, 122.3,
126.7, 127.6, 128.6, 130.2, 131.7, 132.9, 133.2, 133.6, 139.3, 150.0,
165.3, 184.8, ppm.
9.1, 21.2, 46.2, 104.3, 120.1, 126.0, 127.6, 127.7, 128.5, 128.8,
130.2, 131.7, 131.8, 131.9, 134.0, 139.9, 145.4, 164.9, 183.2 ppm.
(5-Amino-3-(4-chlorophenyl)-4-(pyrrolidine-1-
carbonyl)-1H-pyrrol-2-yl)(phenyl)methanone (D3)
HRMS ESL-TOF for C22H20ClN3O2 (M+) found: m ⁄ z: 393.1235; Calc.
Mass 393.1244. 1H NMR (d6-DMSO, 600 MHz): 1.55 (s, 4H), 3.10
(brs, 4H), 5.58 (s, 2H), 6.88 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 7.2 Hz,
2H), 7.05 (t, J = 7.2 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 7.23 (t,
J = 6.6 Hz, 1H), 10.80 (s, 1H), ppm; 13C NMR (d6-DMSO, 150 MHz):
2-Amino-5-benzoyl-N-butyl-4-(4-chlorophenyl)-1H-
pyrrole-3-carboxamide (D4)
HRMS ESL-TOF for C22H22ClN3O2 (M+) found: m ⁄ z: 395.1397; Calc.
1
Mass 395.1401. H NMR (d6-DMSO, 600 MHz): 0.71 (t, J = 7.2 Hz,
278
Chem Biol Drug Des 2010; 75: 277–283

New 2-Amino-5-Ketoaryl Pyrrole Three Component Reaction
126.0, 126.3, 126.6, 127.9, 127.9, 128.1, 128.7, 129.0, 129.1, 131.2,
132.2, 132.8, 138.0, 139.2, 149.2, 164.9, 183.7 ppm.
α-acidity
2-Amino-5-benzoyl-N-benzyl-4-(4-fluorophenyl)-
1H-pyrrole-3-carboxamide (D6)
R
H
HRMS ESL-TOF for C25H20FN3O2 (M+) found: m ⁄ z: 413.1530; Calc.
N+
α-addition
S
1
C–
Mass 413.1540. H NMR (d6-DMSO, 600 MHz): 4.17 (d, J = 6.0 Hz,
cycloaddition
O
O
2H), 5.52 (t, J = 5.4 Hz, 1H), 6.29 (s, 2H), 6.79 (t, J = 9.0 Hz, 2H),
6.95 (d, J = 7.8 Hz, 2H), 7.01 (t, J = 7.2 Hz, 2H), 7.04 (dd, J = 7.8,
5.4 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 7.18 (t, J = 7.8 Hz, 2H), 7.22 (t,
J = 6.6 Hz, 2H), 10.95 (s, 1H) ppm; 13C NMR (d6-DMSO, 150 MHz):
42.5, 99.9, 115.2 (d, J = 21 Hz), 121.6, 127.2, 127.4, 127.6, 128.3,
128.6, 129.9, 130.4 (d, J = 3 Hz), 131.1, 133.0 (d, J = 9 Hz), 139.2,
139.7, 149.3, 161.9 (d, J = 243 Hz), 165.5, 184.2, ppm.
leaving group
ability
N, S acetale
– H2O
H
NH2
R1
CHO
R1
N
R2
+
R2
R3
O
S
NC
B
2-Amino-5-benzoyl-N-cyclopropyl-4-(pyridin-4-yl)-
1H-pyrrole-3-carboxamide (D7)
Tol
O
HRMS ESL-TOF for C20H18N4O2 (M+) found: m ⁄ z: 346.1435; Calc. Mass
346.1430. 1H NMR (d6-DMSO, 600 MHz): )0.28 to )0.18 (m, 2H),
0.47–0.48 (m, 2H), 2.47 (m, 1H), 5.48 (s, 1H), 6.13 (s, 2H), 6.97 (d,
J = 6.0 Hz, 2H), 7.03 (t, J = 7.8 Hz, 2H), 7.16 (d, J = 7.2 Hz, 2H), 7.21
(t, J = 7.8 Hz, 1H), 8.21 (s, 2H), 11.03 (s, 1H), ppm; 13C NMR (d6-DMSO,
150 MHz): 6.4, 22.4, 100.4, 120.9, 126.1, 127.7, 128.4, 129.6, 130.5,
139.6, 142.7, 148.6, 149.0, 166.3, 184.0 ppm.
R3
R3
Tos
R3
R2
N
Tos
B
N
N
N
R1
B H
R2
R2
N
R1
HN
R1
Ts BH
Figure 3: Reactivity of Tosmic and the mechanism of Van Leu-
son reaction. The basic elimination of Tos in the last step produces
the aromatic heterocycle.
2-Amino-5-benzoyl-N-butyl-4-(pyridin-2-yl)-1H-
pyrrole-3-carboxamide (D8)
HRMS ESI-TOF (High resolution mass spectrometry using electron
spray ionization and time of flight): for C21H22N4O2 (M+) found m ⁄ z:
O
O
H
N
O
1
H2N
N
Ph
H
362.1747, Calc. Mass 362.1743. H NMR (d6-DMSO, 600 MHz): 0.76
H
+
TFE, TEA
70°C, 12 h
N
NC
CN
+
Cl
Ts
Ph
(t, J = 7.8 Hz, 3H), 1.00–1.10 (m, 2H), 1.25 (pent, J = 7.2 Hz, 2H), 3.07
(q, J = 6.0 Hz, 2H), 6.30 (s, 2H), 6.81 (d, J = 7.8 Hz, 1H), 7.02 (t,
J = 7.8 Hz, 2H), 7.09–7.13 (m, 1H), 7.14–7.20 (m, 4H), 8.16 (t,
J = 5.4 Hz, 1H), 8.55 (d, J = 4.8 Hz, 1H), 11.07 (s, 1H) ppm; 13C NMR
(d6-DMSO, 150 MHz): 13.4, 19.3, 30.7, 37.5, 99.2, 121.6, 122.4, 127.2,
128.1, 128.4, 129.5, 129.9, 135.8, 139.1, 147.7, 148.8, 153.3, 165.2,
183.5 ppm.
A1
B1
C1
73% D1
Cl
Scheme 1: The new 3-CR of (hetero)aromatic aldehydes, mal-
ondinitrile or cyanoacetic acid derivatives, and aminoacetophenone
sulfonamides.
3H), 0.90 (pent, J = 7. 8 Hz, 2H), 1.07 (pent, J = 7.2 Hz, 2H), 2.95
(q, J = 6.0 Hz, 1H), 5.09 (t, J = 5.4 Hz, 1H), 6.25 (s, 2H), 7.02 (t,
J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 4H),
7.20 (t, J = 7.2 Hz, 1H), 10.94 (s, 1H), ppm; 13C NMR (d6-DMSO,
150 MHz): 13.3, 19.2, 30.6, 37.5, 99.5, 120.8, 127.1, 127.6, 127.8,
129.3, 130.3, 132.2, 132.3, 132.8, 139.2, 164.8, 183.4 ppm.
2-Amino-N-benzyl-5-(4-bromobenzoyl)-4-(4-chloro-
2-hydroxyphenyl)-1H-pyrrole-3-carboxamide (D9)
HRMS ESL-TOF for C25H19BrClN3O3 (M+) found: m ⁄ z: 523.0295; Calc.
1
Mass 523.0298. H NMR (d6-DMSO, 600 MHz): 4.17 (dd, J = 14.4,
6.6 Hz, 1H), 4.24 (dd, J = 14.4, 6.6 Hz 1H), 5.77 (t, J = 5.4 Hz, 1H),
6.29 (s, 2H), 6.49 (dd, J = 7.8, 1.8 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H),
6.71 (d, J = 8.4 Hz, 1H), 6.93 (s, J = 7.2 Hz, 1H), 7.07 (d,
J = 8.4 Hz, 1H), 7.16–7.24 (m, 5H), 10.11 (s, 1H), 10.96 (s, 1H) ppm;
13C NMR (d6-DMSO, 150 MHz): 42.5, 115.7, 119.1, 120.5, 121.5,
123.4, 127.1, 127.2, 128.1, 128.6, 129.7, 130.3, 133.6, 134.0, 139.0,
139.1, 149.7, 156.4, 165.7, 182.7 ppm.
2-Amino-5-benzoyl-N-benzyl-4-(naphthalen-1-yl)-
1H-pyrrole-3-carboxamide (D5)
HRMS ESL-TOF for C29H23N3O2 (M+) found: m ⁄ z: 445.1769; Calc.
1
Mass 445.1790. H NMR (d6-DMSO, 600 MHz): 3.81 (dd, J = 15.6,
4.8 Hz, 1H), 4.05 (dd, J = 15.6, 6.6 Hz, 1H), 5.09 (t, J = 6.0 Hz, 1H),
6.90 (d, J = 8.4 Hz, 2H), 6.92 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 7.8 Hz,
2H), 7.05 (t, J = 7.2 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.14 (d,
J = 6.6 Hz, 1H), 7.48–7.52 (m, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.69 (t,
J = 4.8 Hz, 1H), 7.81 (t, J = 4.8 Hz, 1H), 11.09 (s, 1H) ppm; 13C
NMR (d6-DMSO, 150 MHz): 41.5, 99.8, 121.8, 124.8, 125.2, 125.9,
Triethylammonium 2-amino-5-benzoyl-4-(4-
chlorophenyl)-1H-pyrrole-3- carboxylate (D10)
1H NMR (d6-DMSO, 600 MHz): 1.14 (t, J = 7.2 Hz, 9H), 3.07 (q,
J = 7.2 Hz, 6H), 6.94 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H),
Chem Biol Drug Des 2010; 75: 277–283
279

¨
Wang and Domling
Table 1: Isolated yields of the synthesized 2-amino-5-ketoaryl
Table 1: (Continued)
pyrroles according to new multicomponent reaction (MCR)
Yield Structure
Yield
67
Structure
Ar1
Z
62
N
O
B
Et3N
NC
Z
+
+
O
NH
Ar1
H
O
HN
S O
CF3CH2OH H2N
70 °C
N
H
Ar2
O
A
N
NH
O
D
Ar2
O
O
H2N
N
H
O
C
H2N
N
Yield
73
Structure
Yield
45
Structure
H
D7
Cl
O
Cl
O
D8
OMe
N
O
Cl
O
60
32
Cl
H2N
H2N
N
H
N
OH
H
O
NH
O
Et3N.
OH
O
H2N
N
D1
D2
H
Cl
O
48
51
H2N
N
H
Cl
O
N
O
D10
NH
Br
O
H2N
N
H
D9
64
44
H2N
N
H
Cl
Cl
O
NH
D3
NH
O
D4
O
65
57
O
H2N
N
H
F
H2N
N
H
NH
O
NH
O
D12
O
O
D11
H2N
N
H
H2N
N
H
H
N
32
75
N
NH
D5
D6
O
O
NH
D6
H2N
N
H
O
O
H2N
N
H
D14
7.08 (t, J = 7.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.8 Hz,
1H), 8.98 (s, 1H), 9.39 (s, 1H), 10.89 (s, 1H) ppm; 13C NMR (d6-
DMSO, 150 MHz): 9.1, 46.2, 122.2, 123.8, 126.4, 127.8, 128.6,
129.0, 130.8, 131.4, 133.0, 133.5, 139.2, 164.8, 176.5, 186.1 ppm.
D13
J = 5.4 Hz, 1H), 6.25 (s, 2H), 6.93 (d, J = 7.2 Hz, 2H), 6.99–7.04 (m,
6H), 7.11 (d, J = 7.2 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H), 7.21 (d,
J = 7.2 Hz, 2H), 10.96 (s, 1H), ppm; 13C NMR (d6-DMSO, 150 MHz):
42.6, 100.0, 121.4, 127.2, 127.4, 127.6, 128.1, 128.3, 128.6, 129.9,
130.9, 132.7, 132.8, 133.1, 139.2, 139.7, 149.2, 165.4, 184.1 ppm.
2-Amino-5-benzoyl-N-benzyl-4-(4-chlorophenyl)-
1H-pyrrole-3-carboxamide (D11)
HRMS ESL-TOF for C25H20ClN3O2 (M+) found: m ⁄ z: 429.1247, calc.
1
Mass 429.1244. H NMR (d6-DMSO, 600 MHz): 4.18 (s, 2H), 5.61 (t,
280
Chem Biol Drug Des 2010; 75: 277–283

New 2-Amino-5-Ketoaryl Pyrrole Three Component Reaction
2-Amino-5-benzoyl-4-(4-chlorophenyl)-N-(prop-2-
properties, a-acidity and leaving group ability (18,19). The key and
primary step in malonodinitrile chemistry is the Knoevenagel con-
densation with oxocomponent. Thus, we mixed aminoacetophenone
sulfonamide, para-chlorobenzaldehyde, and malonodinitrile in the
presence of triethylamine (TEA). After 12 h of reflux in trifluoroetha-
nol (TFE) a solid precipitated, which to our own surprise consisted
of the 2-aminopyrrole (D1) as confirmed by NMR and HR-MS.
ynyl)-1H-pyrrole-3-carboxamide (D12)
HRMS ESL-TOF for C21H16ClN3O2 (M+) found: m ⁄ z: 377.0934; Calc.
1
Mass 377.0931. H NMR (d6-DMSO, 600 MHz): 3.04 (s, 1H), 3.82 (s,
2H), 5.56 (s, 1H), 6.31 (s, 2H), 7.05–7.10 (m, 4H), 7.16 (d,
J = 7.2 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H),
11.03 (s, 1H), ppm; 13C NMR (d6-DMSO, 150 MHz): 28.3, 73.3, 81.3,
99.3, 121.5, 127.7, 128.2, 128.4, 130.0, 130.8, 132.8, 132.9, 139.6,
149.3, 165.2, 184.3 ppm.
Next, we investigated the scope and limitations of this new MCR.
First, we investigated several a-acidic nitriles including cyanoacetic
acid, cyanoacetic acid methyl ester, and several cyanoacetamides.
All these reagents reacted smoothly and yielded the expected prod-
uct in moderate to good yields (D1–14). In the case of the cyano-
acetic acid, the TEA salt (D10) is isolated. We were especially
pleased that the cyanoacetamides derived from primary (D4–9) and
secondary amines (D3) reacted satisfactory. This is important
because of the great variability of this component. In case with ter-
minal alkyne chain (D12) or 3-indoyl function group (D13), reac-
tions are fine, also. Next, we investigated the aldehyde component.
We found that several substituted benzaldehydes including unpro-
tected salicylaldehyde (D9), electron-poor fluoro-benzaldehyde (D6),
and bulky naphthaldehyde (D5) reacted. Also, we were pleased to
find that heteroaromatic 2-, 3-, and 4-pyridine carbaldehyde (D7,
D14, and D8) resulted in the projected product. Unfortunately, we
also found that aliphatic aldehydes do not react accordingly; how-
ever, difficult-to-separate mixtures of products resulted. For the am-
inoacetophenone sulfonamide component, we tried only the parent
compound and the 4-bromo derivative, which expectedly reacted
both accordingly. Put conditions into scheme above table (Table 1).
N-(2-(1H-indol-3-yl)ethyl)-2-amino-5-benzoyl-4-
phenyl-1H-pyrrole-3-carboxamide (D13)
HRMS ESL-TOF for C28H24N4O2 (M+) found: m ⁄ z: 448.1903, calc.
Mass 448.1899. NMR (d6-DMSO, 600 MHz): 2.58 (t, J = 6.0 Hz, 2H),
3.30 (q, J = 6.0 Hz, 2H), 5.16 (t, J = 5.4 Hz, 1H), 6.41 (s, 2H), 6.84
(s, 1H), 6.90–7.02 (m, 5H), 7.03 (t, J = 7.2 Hz, 1H), 7.11 (t,
J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H),
7.38 (d, J = 7.2 Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 10.79 (s, 1H),
10.93 (s, 1H) ppm; 13C NMR (d6-DMSO, 150 MHz): 25.3, 39.5, 99.6,
111.6, 111.8, 118.5, 118.6, 121.3, 121.4, 123.0, 127.4, 127.5, 127.8,
128.1, 128.2, 129.9, 130.7, 132.1, 134.1, 136.7, 139.7, 149.4, 165.6,
184.1 ppm.
2-Amino-5-benzoyl-N-cyclohexyl-4-(pyridin-3-yl)-
1H-pyrrole-3-carboxamide (D14)
HRMS ESL-TOF for C23H24N4O2 (M+) found: m ⁄ z: 388.1903, calc.
Mass 388.1899. NMR (d6-DMSO, 600 MHz): 0.73–1.51 (m, 10H),
3.53 (s, 1H), 4.94 (s, 1H), 6.23 (s, 2H), 6.98–7.03 (m, 2H), 7.10 (dd,
J = 7.8, 2.1 Hz, 1H), 7.13–7.20 (m, 3H), 7.46 (s, 1H), 8.30 (s, 1H),
8.31 (s, 1H), 11.02 (s, 1H) ppm; 13C NMR (d6-DMSO, 150 MHz):
23.9, 25.4, 32.3, 46.7, 100.5, 121.7, 123.0, 127.8, 128.3, 128.4,
130.2, 130.6, 138.3, 139.5, 148.6, 149.2, 151.0, 164.4, 184.0 ppm.
A possible reaction mechanism is proposed in Scheme 2. The most
acidic component in the mixture, the cyanomethylene component
(A), adds onto the benzaldehyde carbonyl (B) and yields the a,b-
unsaturated nitrile (F) after dehydration (Knoevenagel condensa-
tion). Next, the second most acidic component the sulfonamide (C)
undergoes a Michael-type addition acting as a C-nucleophile. The
remaining sulfonamide is deprotonated and intramolecularly attacks
the nitrile to yield after tautomerization the pyrrolidine (E), acting
as an N-nucleophile. Finally, sulfinic acid abstraction affords the
final 2-aminopyrrole (D). This mechanism is supported by the recent
Results and Discussion
Thus, we synthesized aminoacetophenone sulfonamides according
to known procedures that should be spiked with both chemical
Ts
HN
O
TsHN
N
Ar2
Ar2
C
O
Ar1
CN
Ar1
O
Ar1
H
O
NC
Z
Z
+
Z
Z
F
A
B
Ar2
Ar2
Ar2
Ar1
O
Ar1
Z
O
Ar1
Z
Ar1
Z
O
Ar2
N
N
Ts
H2N
N
Ts
N
–TsHEt3N
H
H2N
H2N
E
Scheme 2: Proposed reaction
HN
D
mechanism of the 3-CR.
Chem Biol Drug Des 2010; 75: 277–283
281

¨
Wang and Domling
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O
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NH
NH
TEA
O
H2N
O
O
TFE, 70°C
N
S
H2N
N
O
O
H
75%
D11
E1
Scheme 3: A pyrrolidone E1 can be converted into the 2-amino-
pyrrole D11 using forced conditions, pointing to the pyrrolidone as
an intermediate of the new MCR.
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ence of TEA as a base (20). We repeated this work and prepared
compound (E1) and indeed we found that refluxing this isolated
intermediate in TFE in the presence of triethylamine yields the
expected 2-aminopyrrole (D11). Thus, slightly enhancing the tem-
perature of the reaction and switching from solvent ethanol to tri-
fluorethanol leads to a new hitherto unknown scaffold class
(Scheme 3).
In summary, we have described a new MCR of aminoacetophenone
sulfonamide, (hetero)-benzaldehydes, and malonodinitrile or cyano-
acetic acid derivatives. This unprecedented reaction gives efficient
access to the new scaffold class of 2-amino-5-ketoarylpyrroles.
Especially pleasing is the convenient work up, simply by filtration,
to yield NMR pure samples. Current efforts in our laboratories are
directed toward biological evaluation of this interesting new class
of compounds.
inopyrroles using
Chem;66:4427–4429.
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a
three-component reaction.
J
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Acknowledgment
17. Shestopalov A.M., Shestopalov A.A., Rodinovskayaa L.A. (2008)
Multicomponent reactions of carbonyl compounds and deriva-
tives of cyanoacetic acid: synthesis of carbo- and heterocycles.
Synthesis;1–25.
This research has been supported by grant GM087617 from the
National Institute of Health.
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Chem Biol Drug Des 2010; 75: 277–283

New 2-Amino-5-Ketoaryl Pyrrole Three Component Reaction
antiproliferative properties of diversely functionalized pyrrolines.
Bioorg Med Chem Lett;18:1392–1396.
Data S1. Details for the preparation of all new compounds,
1
including H, 13C spectral data.
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