Cyanoacetamides (IV): Versatile one-pot route to 2-quinoline-3-carboxamides

Article abstract of DOI:10.1021/co3000133

Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Herein, we describe scope of a valuable general protocol for the synthesis of arrays of 2-aminoquinoline-3-carboxamides from cyanoacetamides and 2-aminobenzaldehydes or heterocyclic derivatives via a Friedlaender reaction variation. In many cases, the reactions involve a very convenient work up by simple precipitation and filtration. More than 40 new products are described. We foresee our protocol and the resulting derivatives becoming very valuable to greatly expanding the scaffold space of cyanoacetamide derivatives.

Full text of DOI:10.1021/co3000133

Research Article
pubs.acs.org/acscombsci
Cyanoacetamides (IV): Versatile One-Pot Route to 2-Quinoline-3-
carboxamides
Kan Wang,† Eberhardt Herdtweck,‡ and Alexander Domling*,†,§
̈
†University of Pittsburgh, Drug Discovery Institute, Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261,
United States
‡Technische Universitat Munchen, Arcisstrasse 21, 80333 Munchen, Germany
̈
̈
̈
§University of Groningen, 9700 AB Groningen, the Netherlands
S
* Supporting Information
ABSTRACT: Cyanoacetic acid derivatives are the starting materials
for a plethora of multicomponent reaction (MCR) scaffolds. Herein,
we describe scope of a valuable general protocol for the synthesis of
arrays of 2-aminoquinoline-3-carboxamides from cyanoacetamides
and 2-aminobenzaldehydes or heterocyclic derivatives via a Fried-
lander reaction variation. In many cases, the reactions involve a very
̈
convenient work up by simple precipitation and filtration. More than
40 new products are described. We foresee our protocol and the
resulting derivatives becoming very valuable to greatly expanding the
scaffold space of cyanoacetamide derivatives.
KEYWORDS: cyanoacetic acid derivatives, multicomponent reaction, Friedlander reaction
̈
Recently the discovery of 2-aminoquinolines as potent and
uinoline is one of the most important heterocycles for
Q drug discovery, with a broad range of biological
selective anti-Alzheimer BACE1 inhibitors showing good
blood-brain barrier permeability, cellular activity, and animal
PKPD profile has proven to be a remarkably useful case study
to better understand their outstanding binding properties.
(Figure 2). The advanced 2-aminoquinoline derivative 3 was
evolved from a fragment-based drug discovery approach.5,6
Herein a fragment library of low molecular weight compounds
was screened using surface plasmon resonance (SPR)
technology and 2-aminoquinoline 1 was found as a weak hit
while also showing excellent ligand efficacy. The initial hit 1 was
also characterized by cocrystal structure analysis (Figure 2).6,7
Highly optimized compounds like 3, emerged and
intermediate compounds like 2 were structurally characterized
along the chemical optimization pathway (Figure 2). In all
three cocrystal structure analyses the amidine-like moiety of the
2-aminoquinoline forms a bifurcated electrostatic interaction
with the two catalytic Asp residues of the asp-protease BACE1.
Additionally, the phenyl ring of the 2-aminoquinoline under-
goes a T-shaped pi-pi interaction with the Tyr-71. A
substructure search with the 2-aminoquinoline (smiles [H]N-
([H])C1NC2C(CCCC2)CC1) in the protein
databank results in 9 cocrystal structures. Intriguingly, all the
structures show the two main interactions of 2-aminoquinoline
activities, from treatment from malaria (quinine, chloroquine
et al.), arthritis, lupus, asthma to allergies (e.g., singulair). The
2-aminoquinoline fragment exists in the skin cancer medicine
Aldara and many other medicines. Recently, many potential
biologically important 2-aminoquinoline analogous, such as
adenosine A2A receptor antagonists,1,2 β-secretase (BACE)
inhibitor,3 melanin-concentrating hormone (MCH) antagonist,
4
etc. (Figure 1), have been studied and developed.
Received: January 28, 2012
Revised: April 6, 2012
Published: April 9, 2012
Figure 1. Some marketed (2-amino)quinoline drugs.
© 2012 American Chemical Society
316
dx.doi.org/10.1021/co3000133 | ACS Comb. Sci. 2012, 14, 316−322

ACS Combinatorial Science
Research Article
Scheme 1. Different Synthetic Pathways to 2-Quinoline
Derivatives
Figure 2. Fragment-based drug discovery of potent anti-Alzheimer
BACE1 inhibitors. Left column: The small 2-aminoquinoline
containing molecules 1 (PDB 2OHL, orange sticks), 2 (PDB 2RSX,
green sticks), and 3 (PDB 3RSV, cyan sticks) cocrystallized in BACE1
(surface and stick representation). Only key amino acids important for
the herein discussion are shown in stick representation. Hydrogen
bonds are indicated by red dotted lines.
The direct condensation of 2-aminobenzaldehyde (4) with
cyanoacetamide (11) is rarely reported,13and the scope and
limitations are not described. On the basis of the recently
described facile and convenient access to multiple cyanoaceta-
mides as starting materials for an interesting group of
multicomponent and other reactions we herein would like to
report a more convenient method to prepare 2-aminoquino-
line-3-carboxamides (8) from aminobenzaldehydes and cya-
noacetamides.14−18
are a) electrostatic interactions of the amidine substructure and
b) pi-pi interactions to adjacent hydrophobic or aromatic
amino acids. Clearly, these two interactions very well
characterize the biological key interactions of the 2-amino-
quinoline moiety toward their protein targets. This taken
together with their other favorable properties such as cLog P =
1.7, tPSA = 38.4 and Mw = 144 Da, might explain the privileged
structure character of the 2-aminoquinoline.
RESULT AND DISCUSSION
■
2-Aminobenzaldehydes are of limited commercial availability or
they are quite expensive. In this report, starting material 2-
aminoaldehydes (4{1−8}, Scheme 2), which are available or are
conveniently in situ prepared by Fe/HCl reduction of the
corresponding cheap and commercial 2-nitrobenzaldehyde
(9{1−8}),19 were examined.
There are many classic named synthetic protocols for the
preparation of the quinoline heterocycle, such as the Combes
quinoline synthesis, the Conrad-Limpach synthesis, the
Doebner−Miller reaction, the Friedlander synthesis, the Skraup
̈
reaction, the Povarov reaction, Camps quinoline synthesis, the
Knorr quinoline synthesis, the Gould-Jacobs reaction, the
Niementowski quinoline synthesis and the Pfitzinger reaction.
Twenty-eight different cyanoacetamides (11{1−28}) starting
materials are prepared from methyl cyanoacetate (5) and
corresponding amines under neat conditions are recently
reported by us (Scheme 2).14 The structures and yields of
the obtained products (8{1−8,1−28}) are summarized in
Table 1.
All compounds precipitated while the reaction cooled down.
As a result, the purification was as easy as simply collecting the
solid after filtration. All products indicate excellent purity by
NMR and LC-MS (Supporting Information). We were able to
grow several single crystals suitable for X-ray structure
determination. Figure 3 shows the identity and orientation of
8{7,24} and 19a in the crystalline state. It is noteworthy that
the 2-aminoquinoline substructure makes extensive hydrogen
bonding contacts via the amidine substructure. The phenyl
substructure of the 2-aminoquinoline on the other hand makes
multiple intra- and intermolecular hydrophobic contacts
(Figure 4). The carbonyl oxygen of the 3-carboxamide forms
a 6-membered ring involving an intramolecular hydrogen
bridge in both structures.
Including among these classic name reactions, the Friedlander
̈
annulation is a general protocol to prepare quinoline
derivatives.8 However the condensation of 2-aminobenzalde-
hyde with other 1,3-dicarbonyl starting materials, such as ethyl
acetoacetate or dimethyl malonate, the condensation of 2-
aminobenzaldehyde with nitrile derivatives, which will generate
2-aminoquinoline, (e.g., 2-phenylacetonitril,9 2-(benzo[d]-
thiazol-2-yl)acetonitrile10 malonodinitrile11) is limited due to
the poor reactivity of nitrile group. For example, the
condensation of 2-aminobenzaldehyde (4) with cyanoacetic
acid ester (5) affords 2-hydroxy-3-cyanoquinoline (6), not the
desired 2-aminoquinoline-3-carboxylic acid ester (7). As a
useful starting material, ester 7 is hoped to be hydrolyzed under
basic conditions followed by amine coupling to afford diversity
of 2-aminoquinoline-3-carboxamides (8).12 As a result, an
alternative route uses Knoevenagel condensation of 2-nitro-
benzaldeydes (9) with cyanoacetic acid methyl esters to
produce acrylonitrile intermediates (10) following reduction/
cyclization under different conditions, such as Pd/C/H2, Fe/
HOAc, Zn/NH4Cl, etc., to generate 2-aminoquinoline-3-
carboxylic acid ester (7) (Scheme 1).
The intramolecular hydrogen bridge in 2-aminoquinoline-3-
carboxamides is an important observation as it can reduce the
hydrophilic character of the compounds in a biological setting
317
dx.doi.org/10.1021/co3000133 | ACS Comb. Sci. 2012, 14, 316−322

ACS Combinatorial Science
Research Article
Scheme 2. Starting Materials of Reactions
Table 1
compound
yield
compound
yield
compound
yield
8{1,1}
65
64
94
86
79
77
84
97
88
78
76
76
87
8{1,2}
78
96
76
78
77
87
98
90
67
76
67
78
8{1,3}
67
88
87
66
63
75
95
66
77
87
59
76
8{1,4}
8{1,5}
8{2,6}
8{2,7}
8{2,8}
8{2,9}
8{2,10}
8{2,13}
8{2,15}
8{3,18}
8{4,22}
8{5,24}
8{6,26}
8{7,24}
8{8,11}
8{8,28}
8{2,11}
8{2,2}
8{2,12}
8{2,14}
8{3,17}
8{4,20}
8{5,11}
8{6,11}
8{7,11}
8{7,27}
8{8,27}
8{2,16}
8{4,19}
8{4,23}
8{6,25}
8{6,19}
8{7,13}
8{8,6}
we observed similar intramolecular hydrogen bridges during
our synthesis of 2-aminothiophene-3-carboxamides.16,21
A one-pot strategy to synthesize target product from scratch
from the amine using cyanoacetic acid methyl ester (5) and 2-
aminobenzaldehyde (4) was also investigated (Scheme 3). For
example, 2-bromobenzylamine and methyl cyanoacetate are
neatly mixed together. After 1 h, 2-amino-4-chloro-benzalde-
hyde, NaOH and ethanol are added and heated in an oil bath.
The target product (12) was collected with high yield (90%).
The one-pot reaction was also performed with a diversity of
amines and 2-aminobenzaldehydes resulting in compound
library synthesis.
The condensation of 2-aminobenaldehyde with 2-cyano-N-
(prop-2-ynyl)acetamide in the presence of sodium hydroxide
generated 2-amino-N-(prop-1-ynyl)quinoline-3-carboxamide
(14). However, when the similar reaction have been performed
under weak basic conditions over longer time, for example, 1-
methylpiperidine, the desired compounds (8{4,21} and
8{8,21}) without isomerization were collected in high yield.
It is interesting that the formed proparyl amide was isomized to
more thermodynamic stable propynyl amide under strong basic
conditions (Scheme 4).
Some other Friedlander annulations have been examined,
̈
too. Generally, the condensation of 2-aminobenzaldehyde with
2-cyanoacetone derivatives, such as 3-oxo-3-phenylpropaneni-
trile (15) under mild or strong basic conditions, resulted in the
formation of 2-arylquinoline-3-carbonitrile (16); the ketone
products (17) were not found (Scheme 5). However, when 2-
aminonicotinaldehyde and 3-oxo-3-(2-phenyl-1H-indol-3-yl)-
propanenitrile (18) have been heated in ethanol under the
presence of sodium hydroxide only (2-amino-1,8-naphthyridin-
3-yl)(2-phenyl-1H-indol-3-yl)methanone (19a and 19b) was
isolated in high yield (89%), [structure was confirmed by single
crystal structure analysis of (Figure 3b)]. LC-MS curve did not
indicate the existence of nitrile product (20, Scheme 5).
Mechanism for the different products from similar starting
materials is not clear. Further investigation of this interesting
reaction is in progress.
and can potentially facilitate transmembrane transport.
Adjacent hydrogen bond donor and acceptor moieties in a
molecule can lead to the temporary formation of ring systems
and open conformations with differential exposure of the polar
groups to the solvent. The formation of an intramolecular
hydrogen bond mediated ring should effectively remove one
donor and one acceptor function from the surface of a molecule
and thus result in increased lipophilicity leading to an increase
of membrane permeability and a reduction of aqueous
solubility. In fact multiple measurements of the passive
permeability, the octanol/water partition coefficient and kinetic
solubility in related systems support this hypothesis.20 Recently
Furthermore, we developed a convenient transformation to
3-alkylpyrimido[4,5-b]quinolin-4(3H)-ones (21) from 2-ami-
318
dx.doi.org/10.1021/co3000133 | ACS Comb. Sci. 2012, 14, 316−322

ACS Combinatorial Science
Research Article
Figure 3. Crystal structures. A: Structure of 8{7,24}. B: Unit cell of 8{7,24} showing the inter- and intermolecular hydrogen contacts (Mercury
software). The amidine moiety is forming a bifurcated hydrogen bridge to a neighbor amidine (red dotted lines). The amide carbonyl is forming an
intermolecular hydrogen bridge to the adjacent amidine-NH2 thus forming a 6-membered ring (green dotted lines). Additionally the phenyl groups
form multiple staggered and T-shaped contacts with distances around 3.7 Å. C: Stick model of 8{7,24} showing the 6-membered ring featuring an
intermolecular hydrogen bridge of 2.13 Å. D: Structure of 19a. E: ORTEP drawing of 19a (ORTEP drawing with 50% ellipsoids).
Figure 4. Key short contacts of 8{7,24} in the crystal rendered with Pymol in a stereo picture. Intermolecular contacts between two amidine
moieties are 2.1 and 2.3 Å (yellow dotted lines). The intramolecular hydrogen bridge between the amide carbonyl and the amidine-NH2 is 2 Å (cyan
dotted lines). A intermolecular hydrogen bridge between the amide NH and the amide carbonyl is 1.95 Å short (yellow dotted line). Several short
phenyl phenyl contacts (∼3.7 Å) are shown as green dotted lines.
noquinoline-3-carboxamides (8). 1,1-Dimethoxy-N,N-dime-
thylmethanamine (DMFDMA) was added to 8 under neat
conditions and the reaction was allowed to stir for 10 min in
110 °C. The reaction was cooled down to room temperature
and some EtOH was added. The formed precipitate was filtered
and washed with EtOH to directly offer purified 21. However,
this reaction is sensitive to the amide side chain. In some cases,
when the side chain is large, for example, 2,2-dimethylpropyl
(22{4,23}), 1-(naphthalen-1-yl)ethyl (22{5,24}), or cyclohexyl
(22{7,27}), no desired compound 21, but dimethylamino
intermediate 22 was collected with high yields as a precipitate.
The structures and yields of the obtained products (21{1−8,1−
28} or 22{1−8,1−28}) are summarized in Table 2.
It is not surprisingly that free amino in 8{2,16} will
condensed with DMFDMA to afford compound 23 (eq 1).
319
dx.doi.org/10.1021/co3000133 | ACS Comb. Sci. 2012, 14, 316−322

ACS Combinatorial Science
Research Article
Scheme 3. One-Pot Three-Component 2-Aminoquinoline-3-
carboxamide Synthesis
product separation and purification by precipitation and diverse
product structures. Our procedure will be of general use due to
the privileged structure character of the 2-aminoquinoline.
Scheme 4. Isomerization of Proparyl Amide under Strong
Basic Conditions
EXPERIMENTAL SECTION
■
General Procedure for Preparing 2-Amino-6-chloro-
N-cyclopropylquinoline-3-carboxamide (8{2,6}). 2-
Amino-5-chlorobenzaldehyde (155 mg, 1 mmol), 2-cyano-N-
cyclopropylacetamide (124 mg, 1 mmol), NaOH (17.2 mg, 0.2
mmol), and ethanol (2 mL) were added into a 20 mL vial.
Then, it was heated in the 70 °C oil bath with stirring for 10
min. Then, it was cooled it down to 0 °C. The precipitate was
filtered and washed with cold ethanol. The title product (230
mg, 88%) was obtained as a yellow solid. HRMS ESL-TOF for
C13H12ClN3O (M+) Found: m/z 261.0663; Calcd Mass
1
261.0669. H NMR (d6-DMSO, 600 MHz): 8.77 (s, 1H),
8.27 (s, 1H), 7.75 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.47 (d, J =
8.4 Hz, 1H), 7.12 (s, 2H), 2.85−2.87 (m, 1H), 0.71−0.73 (m,
2H), 0.59−0.61 (m, 2H) ppm. 13C NMR (d6-DMSO, 150
MHz): 168.8, 156.8, 147.5, 137.1, 131.6, 127.4, 127.3, 126.0,
122.9, 116.6, 23.5, 19.0 ppm.
General Procedure of Preparing 7-Chloro-3-
cyclopropylpyrimido[4,5-b]quinolin-4(3H)-one (21{2,6}).
1,1-Dimethoxy-N,N-dimethylmethanamine (DMFDMA, 0.5
mL) was added into 2-amino-3-carboxamide (0.2 mmol), and
the reaction mixture was stirred for 10 min in 110 °C. The
reaction mixture was cooled down to room temperature and 1
mL EtOH was added. The precipitate was filtered and washed
In summary, we have developed a highly versatile, high
yielding and easy to perform one-pot synthesis of highly
substituted 2-aminoquinolines and heterocyclic derivatives. Key
features include broadly available stating materials, convenient
Scheme 5. Difference Products from Similar Starting Materials
320
dx.doi.org/10.1021/co3000133 | ACS Comb. Sci. 2012, 14, 316−322

ACS Combinatorial Science
Research Article
Table 2
compound
yield
compound
yield
compound
yield
21{1,2}
21{2,2}
21{2,9}
21{2,13}
21{3,17}
21{6,26}
22{4,23}
76
67
76
48
78
58
65
21{1,4}
65
57
53
56
65
64
72
21{1,5}
21{2,7}
21{2,11}
21{2,5}
21{6,25}
21{8,28}
22{7,27}
86
82
58
56
49
46
77
21{2,6}
21{2,10}
21{2,14}
21{6,19}
21{8,11}
22{5,24}
of 2-aminoquinolines as potent inhibitors of β-site amyloid precursor
protein cleaving enzyme 1 (BACE1). J. Med. Chem. 2011, 54, 5836−
5857.
with another 1 mL of EtOH. HRMS ESL-TOF for
C14H10ClN3O (M+) found: m/z 270.0516; Calcd Mass
1
271.0512; H NMR (d6-DMSO, 600 MHz): 9.24 (s, 1H),
(6) Murray, C. W.; Callaghan, O.; Chessari, G.; Cleasby, A.;
Congreve, M.; Frederickson, M.; Hartshorn, M. J.; McMenamin, R.;
Patel, S.; Wallis, N. Application of fragment screening by X-ray
crystallography to β-secretase. J. Med. Chem. 2007, 50, 1116−1123.
(7) Congreve, M.; Aharony, D.; Albert, J.; Callaghan, O.; Campbell,
J.; Carr, R. A. E.; Chessari, G.; Cowan, S.; Edwards, P. D.;
Frederickson, M. F.; McMenamin, R.; Murray, C. W.; Patel, S.;
Wallis, N. Application of fragment screening by X-ray crystallography
to the discovery of aminopyridines as inhibitors of β-secretase. J. Med.
Chem. 2007, 50, 1124−1132.
8.48 (s, 1H), 8.26 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.81 (d, J =
9.0 Hz, 1H), 2.51 (s, 1H), 1.13 (s, 2H), 1.00 (s, 2H) ppm. 13
C
NMR (d6-DMSO, 150 MHz): 162.3, 155.8, 152.1, 149.4, 138.3,
133.7, 131.9, 130.9, 128.0, 127.3, 116.9, 29.5, 6.5 ppm.
ASSOCIATED CONTENT
* Supporting Information
■
S
Proton and carbon NMR, HR MS characterization, and
experimental procedures.This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) Cheng, C.-C.; Yan, S.-J. The Friedlander Synthesis of Quinolines in
Organic Reactions, Vol. 28; Dauben, W. G., Eds; Hoboken, NJ, United
States, 1982.
AUTHOR INFORMATION
Corresponding Author
*E-mail: asd30@pitt.edu.
■
(9) Haddadin, M. J.; Zerdan, R. M. B.; Kurth, M. J.; Fettinger, J. C.
Efficient syntheses of the unknown quinolino[2,3-c]cinnolines:
Synthesis of neocryptolepines. Org. Lett. 2010, 12, 5502−5505.
(10) Hassan, A. Y. Some reactions of 2-cyanomethyl-1,3-
benzothiazole with expected biological activity. Phosphorus, Sulfur,
Silicon Relat. Elem. 2009, 184, 2856−2869.
Notes
The authors declare no competing financial interest.
(11) Kiran, B. M.; Mahadevan, K. M. Rediscovered synthesis of 3-
cyanoquinoline derivatives. Heterocyc. Commun. 2011, 12, 4.
(12) Jia, C.-S.; Dong, Y.-W.; Tu, S.-J.; Wang, G.-W. Microwave-
assisted solvent-free synthesis of substituted 2-quinolones. Tetrahedron
2007, 63, 892−897.
ACKNOWLEDGMENTS
This research has been partially supported by the NIH grant 5
P41 GM094055-02.
■
REFERENCES
(13) Chen, W.; Jiang, G. Syntheses of 3,4-dihydro-4-oxopyrimido-
[4,5-b]quinolines. Gaodeng Xuexiao Huaxue Xuebao 1990, 11, 532−
535.
■
(1) Harris, J. M.; Neustadt, B. R.; Liu, H.; Hao, J.; Stamford, A. W.
Amino-quinoxaline and Amino-quinoline compounds for use as
adenosine A2A receptor antagonists. Int. Patent WO 2009111442,
2009.
(2) Osakada, N. T., T.; Uchida, S.; Ono, S.; Nakazato, N. Quinoline
derivative. Jpn. Patent JP 2005132834, 2005.
(14) Wang, K.; Nguyen, K.; Huang, Y.; Domling, A. Cyanoacetamide
̈
multicomponent reaction (I): Parallel synthesis of cyanoacetamides. J.
Comb. Chem. 2009, 11, 920−927.
(15) Wang, K.; Domling, A. Design of a versatile multicomponent
̈
reaction leading to 2-amino-5-ketoaryl pyrroles. Chem. Biol. Drug Des.
2010, 75, 277−283.
(3) Baxter, E. 6-Substituted-thio-2-amino-quinoline derivatives useful
as inhibitors of β-secretase (BACE). Int. Patent WO 2009097278,
2009.
(4) Jiang, J.; Hoang, M.; Young, J. R.; Chaung, D.; Eid, R.; Turner,
C.; Lin, P.; Tong, X.; Wang, J.; Tan, C.; Feighner, S.; Palyha, O.;
Hreniuk, D. L.; Pan, J.; Sailer, A. W.; MacNeil, D. L.; Howard, A.;
Shearman, L.; Stribling, S.; Camacho, R.; Strack, A.; Van der Ploeg, L.
H. T.; Goulet, M. T.; DeVita, R. J. 2-Aminoquinoline melanin-
concentrating hormone (MCH)1R antagonists. Bioorg. Med. Chem.
Let. 2006, 16, 5270−5274.
(5) Cheng, Y.; Judd, T. C.; Bartberger, M. D.; Brown, J.; Chen, K.;
Fremeau, R. T.; Hickman, D.; Hitchcock, S. A.; Jordan, B.; Li, V.;
Lopez, S. W.; Luo, Y.; Michelsen, K.; Nixey, T.; Power, T. S.; Rattan,
C.; Sickmier, E. A.; St Jean, D. J.; Wahl, R. C.; Wen, P. H.; Wood, S.
From fragment screening to in vivo efficacy: Optimization of a series
(16) Wang, K.; Kim, D.; Domling, A. Cyanoacetamide MCR (III):
̈
Three-Component Gewald Reactions Revisited. J. Comb. Chem. 2009,
12, 111−118.
́
(17) Price, K. E.; Larrivee-Aboussafy, C.; Lillie, B. M.; McLaughlin, R.
W.; Mustakis, J.; Hettenbach, K. W.; Hawkins, J. M.; Vaidyanathan, R.
Mild and efficient DBU-catalyzed amidation of cyanoacetates. Org.
Lett. 2009, 11, 2003−2006.
(18) Wang, K.; Herdtweck, E.; Domling, A. One-pot synthesis of 2-
̈
amino-indole-3-carboxamide and analogous. ACS Comb. Sci. 2010, 13,
140−146.
(19) Diedrich, C. L.; Haase, D.; Christoffers, J. New
octahydropyrido[3,4-b]acridine scaffolds for combinatorial chemistry.
Synthesis 2008, 2199−2210.
321
dx.doi.org/10.1021/co3000133 | ACS Comb. Sci. 2012, 14, 316−322

ACS Combinatorial Science
Research Article
(20) Kuhn, B.; Mohr, P.; Stahl, M. Intramolecular hydrogen bonding
in medicinal chemistry. J. Med. Chem. 2010, 53, 2601−2611.
(21) Huang, Y.; Domling, A. The Gewald multicomponent reaction.
̈
Mol. Diversity 2011, 15, 3−33.
322
dx.doi.org/10.1021/co3000133 | ACS Comb. Sci. 2012, 14, 316−322