Cyanoacetamide MCR (III): Three-component Gewald reactions revisited

Article abstract of DOI:10.1021/cc9001586

Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Here we describe valuable general protocols for the synthesis of arrays of 2-aminothiophene-3carboxamides from cyanoacetamides, aldehydes or ketones, and sulfur via a Gewald-3CR variation, In many cases the reactions involve a very convenient work up by simple precipitation in water and filtration. More than 40 new products are described, We foresee our protocol and the resulting derivatives to become very valuable to greatly expanding the MCR scaffold space of cyanoacetamide derivatives.

Full text of DOI:10.1021/cc9001586

J. Comb. Chem. 2010, 12, 111–118
111
Cyanoacetamide MCR (III): Three-Component Gewald Reactions
Revisited
Kan Wang, Dabin Kim, and Alexander Do¨mling*
UniVersity of Pittsburgh, Drug DiscoVery Institute, Pittsburgh 15261
ReceiVed October 4, 2009
Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR)
scaffolds. Here we describe valuable general protocols for the synthesis of arrays of 2-aminothiophene-3-
carboxamides from cyanoacetamides, aldehydes or ketones, and sulfur via a Gewald-3CR variation. In many
cases the reactions involve a very convenient work up by simple precipitation in water and filtration. More
than 40 new products are described. We foresee our protocol and the resulting derivatives to become very
valuable to greatly expanding the MCR scaffold space of cyanoacetamide derivatives.
In 1966 the German chemist Prof. Karl Gewald discovered
that methylene-active carbonyl compounds reacted with
methylene-active nitriles and sulfur at ambient temperature
to yield 2-aminothiophenes.1 This reaction constitutes a very
versatile and useful multicomponent reaction (MCR).2-4 As
often found with MCRs, the reaction conditions are simple
and do not foresee protection from atmosphere or moisture
and are easily amenable to up-scaling (Figure 1).
In addition, this transformation is remarkable because it
consists of one of the few organic reactions incorporating
elemental sulfur at ambient temperature. Other examples are
the Asinger-3CR and the Wilgeroth Kindler reaction.5,6 The
importance of the Gewald reaction steams from the formation
of 2-aminothiophene which is abundantly used in the pharma-
ceutical industry to produce bioactive compounds.3,4 The
2-amino-3-carbonyl thiophene is bioisostere to the anthranilic
acid which per se is an important bioactive scaffold.7 As
opposed to anthranilic acid derivatives, however, which are
difficult to access and only a few are commercially available,
the Gewald-3CR allows virtually infinite access to substituted
bioisostere 2-amino-3-carboxythiophenes. A prominent example
of the thiophene-phenol bioisosterie is the atypical antipsychotic
blockbuster drug olanzepine for the treatment of schizophrenia
and bipolar disorder (Scheme 1).8 The pharmacokinetic/dynamic
properties of olanzapine are presumably even enhanced over
the bioisosteric clozapine.
In addition, Gewald-3CR primary products are the starting
materials for many other compound classes such as kinase
inhibitor thienopyrimidines 1,9 thienoquinazolines 2,10 py-
rimidines 3 and 4,11 diazocompounds 5,12 Schiff bases 6,13
tetracyclic thienopyrimidinones 7,14 and N-thieno-maleini-
cacid amides 915 as shown in Scheme 2, just to name a few.
The scope of the Gewald-3CR, however, in the past was
hampered by the almost exclusive use of structurally simple
not variable activated nitrile components, for example, mal-
onodinitrile, cyanoacetophenones,16 cyanoacetic acid esters, and
primary cyanoacetamides. Rarely, cyanoacetamides have been
used as potentially versatile component in the Gewald-3CR. In
cases where cyanoacetamides have been used they were based
on aromatic amides or hydrazides.17 In fact only very few
references could be found using aliphatic amine derived
cyanoacetamides in the Gewald-3CR.18 Thus the Gewald-3CR
can be described as a MCR with rather low dimensionality
similar to the Hantzsch dihydropyrimidine and the Biginelli
reaction, where the main variable component is the oxo
component.19 Examples of high dimensional MCRs are iso-
cyanide-based MCRs, for example, Ugi, Passerini, and van
Leusen reactions, where all of the components can be broadly
varied.20 To solve the problem of low dimensionality, we
describe herein a major extension of current Gewald-3CR by
introducing aliphatic cyanoacetamides as generally useful
components and thus rendering the Gewald MCR with ef-
fectively only one diversity point in the past into a MCR
comprising two highly variable inputs.
Recently, we communicated a versatile and experimentally
very simple access to arrays of cyanoacetamides by the
solventless mixing of methyl cyanoacetate and primary and
secondary amines and filtration of the formed products.21
Having easy access to such large arrays, we investigated the
versatile MCR chemistry of this compound class.22 We
intended to investigate the Gewald-3CR of cyanoacetamides,
and we herein report our results. First we reacted several
cyanoacetamides with methylene active oxo components and
sulfur in ethanol at 70 °C for several hours. Upon cooling
to room temperature, no product precipitated, and TLC and
HPLC MS analysis indicated several reaction products and
even some left starting materials. We then experimented with
addition of water and temperature, and indeed by pouring
the reaction mixture into water and cooling to 0 °C, we
noticed after some time the formation of significant precipi-
tate. Filtration of the precipitate and NMR and HPLC
analysis of it reveal Gewald products with purity of >95%
and good yields. To elaborate a general procedure, we
investigated several more reactions with different functional
groups in the side chains (hydrophilic and hydrophobic,
basic) and to our delight in all investigated cases we noticed
* To whom correspondence should be addressed. E-mail: asd30@pitt.edu.
10.1021/cc9001586  2010 American Chemical Society
Published on Web 12/03/2009

112 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Wang et al.
Figure 1. Simple to perform large scale open vessel Gewald-3CR (courtesy of Prof. Ulrich Jordis, Vienna).
Scheme 1. Gewald-3CR and Phenol-Thiophene Based
Biosisosterie between the Drugs Olanzapine and Clozapine
gel column chromatography. The products and their yield
are shown in Table 1.
Some additional observations were made. For the phenolic
starting material B17 the Gewald reaction with 1 equiv of
triethylamine base produced no target compound, but the
condensation product (D6,17). Addition of two more equiva-
lents of triethylamine, however, produced the product (C6,17)
in 82% yield (Scheme 3). The basic condition is critical for
the cyclization step.
Acetaldehyde (A1), which has a low boiling point, is not a
good starting material for the Gewald 3-CR. However, the
commercially available compound, 1,4-dithiane-2,5-diol (A1′),
which is the dimer of the precondensation product 2-mercapto
acetaldehyde (A1′′) of acetaldehyde and sulfur, is a good
substitute for acetaldehyde in the Gewald reaction.23
the formation of considerable product precipitation. Again
after filtration and drying we noticed exceptional high purity
in all cases. Next we synthesized an array of >40 Gewald
compounds in parallel by the above procedure. Over a wide
range of functional groups and substitutents, we isolated the
products in moderate to good to high yields but always in
excellent purity. We used 16 different ketones and aldehydes
(A1-A16, Figure 2). To figure scope and limitations of the
cyanoacetamide component we used 23 differentially sub-
stituted starting materials (B1-B24, Figure 2).
Other aldehyde with R-methylene moiety (A2-A7) also have
good Gewald reactivity. The reaction performs well by simply
mixing each 1 equiv of cyanoacetamides, sulfur, aldehyde, or
ketones and triethylamine in the ratio of 1:1:1:1 in ethanol
solvent, and generally good yields are obtained. A Boc protected
chiral ꢀ-amino aldehyde (A7) was treated into this reaction with
different cyanoacetamides to produce corresponding products
(C7-1,10,14,18,19,20,23) with good yield (70-90%). It is
interesting that two enantiomerically pure starting materials (A7
and B20) produce the thiophene C7,20 with not even traces of
another diastereomer observed (Scheme 4). There is no
significant racemization observed despite the fact that the
reaction is base promoted. But in the reaction with another
cyanoacetamide B23, which is derived from the methyl ester
of valine amino acid, the corresponding product C7,23 contains
The purification of products differs depending on the
solubility properties of the products. For some reactions, no
solid could be filtered after water addition; for a few
compounds, purities were less than 90% by HPLC-MS and
NMR analysis, these crude products were purified by silica

Three-Component Gewald Reactions Revisited
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 113
Scheme 2. Diversity of Secondary Reactions Based on the Initial Gewald-MCR
two diastereomers in a 2:1 ratio; the result indicates that strong
epimerization happens at the valine moiety under basic condi-
tions. 2-Deoxy-D-ribose (A8), which contains three free hy-
droxyl groups, does not produce the target product under the
conditions used here.
The Gewald reaction can be applied in the synthesis of
thiophenediazepine.24 For example the cyanoacetamides B23
could be prepared simply from methyl ester of (S)-valine
chloride salt with methyl cyanoacetate in the presence of 2
equiv of triethylamine without additional solvent. After
Gewald reaction with aldehyde and sulfur, the desired
thiophenes (C2,23, C6,23 and C7,23) are generated in good
yield. These intermediates would provide a different way to
thiophenediazepine-2,5-diones (E, Scheme 5). The detailed
cyclization conditions are in progress in our lab and will be
reported in the future.
Ketone starting materials produced far poorer result
compared to aldehyde staring materials. Cyclohexanone (A9)
only produced less than 20% yield with 3 cyanoacetamides
(B1, B6 and B11) under the conditions used. The corre-
sponding reaction with methyl cyanoacetate had obtained a
much higher yield. Acetophenone (A10) produced target
product C10,3 in less than 10% yield, and it is difficult to
purify the product. Other ketones, including acetone (A11),
2-butone (A12), (R)-camphor (A13), dimedone (A16), ethyl
acyacetate (A14), and ethyl pyruvate (A15) do not yield the
Gewald products at all under the herein described reaction
conditions; despite starting materials were observed after the
reactions were stopped. In many references therefore the use
of precondensed Knoevenagel intermediates is described.25
Discussion
We herein describe a convenient way to synthesize arrays
of Gewald thiophene-3-amides. The convenience of this pro-
cedure is based on two points: first, the reaction can be
performed in many cases in a way that the Gewald products
precipitate, and this leads to high quality products without the
need to run time and cost intensive purifications. Second, the
starting material class of cyanoacetamides was recently de-
scribed by us to be accessible in a very convenient way by
simply mixing methyl cyanoacetate with an appropriate primary
or secondary amine, thus leading to potentially large arrays of
starting materials for subsequent cyanoacetamide dependent
MCRs. This extension of the Gewald-3CR is significant since
Figure 2. Aldehyde and ketone starting materials.

114 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Wang et al.
Table 1. Gewald Reaction to Prepare 2-Amino-thiophene-carboxamides (Cn,m)

Three-Component Gewald Reactions Revisited
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 115
Table 1. Continued
in the past mostly simple and non variable malondinitrile,
cyanoacetic acid, and their esters or hydrazides where used.
Thus Gewald reaction variability in the past was mostly
confined to the variation of the R-methylene oxo component

116 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Wang et al.
Scheme 3. Different Products Depending on Added Base Amounts
Scheme 4. Gewald-3CR of Chiral Starting Materials
Scheme 6. Different Route to 2-Aminothiophene-3-
carboxamides
This route involves more steps and is less efficient, the yields,
although potentially higher per step, at the end are always
lower after several reaction steps. Additionally these reactions
often involve harsh conditions.26 The second herein described
route starts from cyanoacetamides, which are easily and
conveniently prepared from methyl cyanoacetate in a single
step and on a gram scale if needed. In a one-step three-
component Gewald reaction, 2-aminothiophene-3-carboxa-
mides can be produced in high diversity. The advantage of
the second route seems obvious.
Scheme 5. Amidation-Gewald-Cyclization Sequence to
Thiophenediazepine
The scope of this reaction is large (Table 1). Different
cyanoacetamides work fine in the Gewald-3CR, and many
function groups were tolerated (Figure 3), including alkenyl
(B6), alkynyl (B21), acetal (B8), alcohol hydroxyl (B14),
phenol (B17), indole (B10), ester (B23), secondary amino
(B22), and tertiary amino (B4, B7 and B19). Regarding the
R-methylene oxo component we observed that aldehydes are
superior substrates to ketones and generally react faster, more
completely and give higher yields. The more hydrophobic
the resulting Gewald product, the greater the isolated yield.
This is a direct consequence of the workup procedure by
aqueous precipitation. Amino acid side chains have been
introduced at several positions of the Gewald scaffold thus
rendering this chemistry potentially useful for the synthesis
of peptidomimetics (C4,m methionine; C3,m and Cn,2
phenylalanine; C5,m and Cn,23 valine; Cn,10 tryptophan).
Compound C7,23, for example can be considered as a
peptidomimetic containing the two valine amino acids
encompassed on a stiff Gewald heterocycle. To show the
potential to act as peptidomimetic we computationally
and the secondary reactions of their primary Gewald products.
The herein described and generally shown reaction of sulfur,
and cyanoacetamides, however renders the Gewald-3CR a truly
variable MCR with two points of diversity.
There are two routes to prepare 2-aminothiophene-3-
carboxamides (Scheme 6). The first route uses the classical
Gewald products 2-amino-3-cyanothiophene or 2-ami-
nothiophene-3-carboxylic methyl esters resulting from ma-
lonodinitrile or methyl cyanoacetate, and further transfor-
mations after several additional steps lead to 2-aminothiophene-
3-carboxamides. Thus, amide-substituted Gewald products
have been described from the corresponding esters by the
sequence saponification, activation and coupling or other
methods, however in poor yields and lengthy sequences.26

Three-Component Gewald Reactions Revisited
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 117
Figure 4. Stereoview of an overlap of an amphiphatic R-helix with
two valine in i and i+6 positions (orange sticks) with a Gewald
thiophene-derived dipeptide mimetic (blue sticks). The small
molecule derived from aldehyde A7, cyanoacetamide B23, sulfur
was deprotected and N-acylated and then energy minimized using
the MOLOC software.28 An important feature of the Gewald-
thiophene derivatives of cyanoacetamides is the intramolecular
hydrogen bonding of the 2-amino group with the 3-amide carbonyl,
reducing the conformational freedom of the amide group consider-
ably. In support of the above hypothetical structure, the intramo-
lecular hydrogen bridge can be seen in most of the published X-ray
structure analysis.4
Figure 3. Cyanoacetoamide starting materials.
herein all efforts are multiplied. Therefore we believe that
our described often chromatography free Gewald-3CR
procedure based on simple precipitation and filtration is an
advance in Gewald chemistry. Equally important is the
general use of cyanoacetic acid amides as highly variable
class of compounds in the Gewald-3CR which renders this
reaction a true MCR with two highly variable inputs instead
of mostly one in the past. Thus a skilled lab worker using
very simple equipment can synthesize hundreds of Gewald
products in a short time frame on a multi milligram scale
with very high purity including the synthesis of the required
cyanoacetamide building blocks.20 In summary, the herein
described modified Gewald-3CR procedure allows for the
robust, fast, resource saving, and efficient construction of
large arrays of highly substituted 3-amido-2-aminothiophenes.
optimized the 3D-structure and overlapped it with an R-helix.
As can be seen in Figure 4 there is a good overlap implying
that such molecule might act as R-helix mimetic. The R-helix
mimetics recently have become very important lead structures
to (ant-)agonize protein protein interactions, for example, in
p53/Hdm2, p53/Hdm4, or Bcl2 family members.27
Combinatorial chemistry is an important discipline in
organic chemistry and highly useful to the pharmaceutical
industry since the majority of drug discovery projects
currently rely on high throughput screening of large com-
pound collections. Gewald reactions have been described to
be purification intensive in the past. Improvements to
overcome this issue and to increase synthesis speed have
been solid phase bound synthesis.29 However, these methods
have attached issues, such as low compound generation and
the use of often special linker systems which compromise
the chemistry. Other generally used methods include mass
triggered automatic preparative HPLC or the faster and more
efficient SC-CO2-HPLC. The use of automatic HPLC
purification systems, however, is expensive and needs special
equipment. The best organic chemistry workup procedures
can avoid chromatography and can purify the products by
extraction and/or crystallization. These procedures are of
particular value in the context of parallel synthesis since
Experimental Section
2-Amino-5-benzyl-N-cyclohexylthiophene-3-carboxam-
ide (C3,12): General Condition of Gewald-3CR. A 20 mL
vial with stir bar is charged with 3-phenylpropanal (A3, 670
mg, 5 mmol), 2-cyano-N-cyclohexylacetamide (B12, 830 mg,
5 mmol), sulfur (160 mg, 5 mmol), and triethylamine (505
mg, 5 mmol) in ethanol (5 mL, 1.0 M solution). The reaction
is heated 60 °C in an oil bath for 10 h. Then, the reaction
was cooled down to room temperature. A batch of 50 mL

118 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Wang et al.
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ice water was poured into the mixture to yield a precipitate
which was filtered and washed with cold ethanol to obtain
1.490 g (95%) of the title compound as brown powder. HR-
MS ESL-TOF for C18H22N2OSNa (M+Na+) found: m/z:
1
337.1362; Calc. Mass: 337.1351. H NMR (CDCl3, 600
MHz): δ 7.31 (t, J ) 7.8 Hz, 2H), 7.19-7.25 (m, 3H), 6.37
(s, 1H), 5.96 (s, 2H), 5.41 (d, J ) 7.2 Hz, 1H), 3.92 (s, 2H),
3.80-3.90 (m, 1H), 1.97 (dd, J ) 12.6, 3.0 Hz, 2H), 1.73
(dt, J ) 12.6, 3.0 Hz, 2H), 1.38 (qt, J ) 13.2, 3.0 Hz, 2H),
1.12-1.18 (m, 3H) ppm; 13C NMR (CDCl3, 150 MHz): δ
165.0, 159.8, 139.8, 128.6, 128.5, 126.7, 125.8, 119.8, 108.4,
47.9, 36.0, 33.6, 25.6, 25.1 ppm.
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Gewald reaction (3.5 liter volume, 1 mol). This research has
been partially supported by Grant GM087617 from the
National Institutes of Health.
Supporting Information Available. Proton and carbon
NMR, HR MS characterization and experimental procedures.
This material is available free of charge via the Internet at
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(16) See for example: Baraldi, P. G.; Zaid, A. N.; Lampronti, I.;
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