Supported TBD-assisted solution phase diversification of formyl-aza-heterocycles through alkylation-knoevenagel one pot sequences

Article abstract of DOI:10.2174/138620711796367229

An efficient solution-phase parallel procedure to perform the structural diversification of some formyl-nitrogen heterocycles (A) using the reusable TBD supported base is described. The library synthesis is based in a consecutive Alkylation-Knoevenagel functionalisation that uses alkyl halides (B), Michael acceptors (C) and activated methylene compounds (D) as diversity elements.

Full text of DOI:10.2174/138620711796367229

570
Combinatorial Chemistry & High Throughput Screening, 2011, 14, 570-582
Supported TBD-Assisted Solution Phase Diversification of Formyl-Aza-
Heterocycles Through Alkylation-Knoevenagel One Pot Sequences
Abdelaziz El Maatougui1,2, Abel Crespo1, Artur M.S. Silva3 and Alberto Coelho*,1,2,4
2
1Combinatorial Chemistry Unit (COMBIOMED), Institute of Industrial Pharmacy (IFI), Faculty of Pharmacy, Center
for Research in Biological Chemistry and Molecular Materials, University of Santiago de Compostela, Santiago de
Compostela, 15782, Spain
3Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal
4Department of Organic Chemistry, University of Santiago de Compostela, Spain
Abstract: An efficient solution-phase parallel procedure to perform the structural diversification of some formyl-nitrogen
heterocycles (A) using the reusable TBD supported base is described. The library synthesis is based in a consecutive
Alkylation-Knoevenagel functionalisation that uses alkyl halides (B), Michael acceptors (C) and activated methylene
compounds (D) as diversity elements.
Keywords: Aza-Michael, Knoevenagel, polymer supported superbases, solution phase synthesis.
High efficiency based on environmentally friendly
concepts is strongly required for the synthetic organic
chemistry in the twenty first century. The efficiency involves
not only a short reaction process and higher yields in each
step, but also lower energy costs and reactions with less
waste (high atom economy), as well as cheap and easily
available starting materials and catalysts for the reaction
sequence, possible recyclability and lower or absence of
toxicity [1]. Aiming to satisfy these requirements, solution
phase library generation has been fuelled by the development
of successful concepts such as solid-supported reagents,
catalysts and scavengers combining the advantages of both
solid phase organic synthesis (for instance, inmobilization of
toxic reagents) and solution phase chemistry (mainly the
relative ease separating of spent reagents from the products
by simple filtration and monitoring the progress of the
reactions by LC-MS, TLC or standard NMR techniques) [2].
The research area of polymer-supported reagents and
especially supported acid, bases and catalysts (Fig. 1) has
grown rapidly in the last years, providing a new frontier in
the rapid production of a large number of chemical libraries
of structurally diverse molecules, and particularly with the
use of automation or parallel flow systems in multi-step
sequences [3]. Among them, the supported superbases
family has emerged as interesting tools for solution-phase
synthesis and high-throughput chemistry [4].
commercially available. Among them, 1,5,7- triazabicyclo
[4.4.0]dec-5-ene (TBD) is the prototype of a group of
guanidine bases which have a multitude of applications in
organic synthesis [7]. The silica gel–TBD (1) or polyst-
yrene–TBD (2) are to date the most employed examples. A
phosphacene derivate base with a similar basicity profile, the
supported version of the Schwezinger base, PS–BEMP (2-
tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-
diazaphosphorine) [6a, 8] (3; Fig. 1) has also been success-
fully used as a strong base for parallel synthesis in
combination with other polymeric reagents [9]. Other useful
reagents such as the less basic supported tetramethylguani-
dine (4) and carbonate on polystyrene (5) have been success-
fully employed for diverse transformations as well [10].
In the context of our ongoing efforts toward the
development of new efficient and clean methodologies for
the rapid generation of diverse heterocyclic libraries by using
supported reagents [11], we became interested in developing
a simple and straightforward synthetic route to obtain
disubstituted alkylidene-azaheterocycles such as indoles,
quinolones, pyridazinones and imidazoles, usually
considered as privileged structures in drug discovery [12],
containing an exocyclic ꢀ,ꢁ-unsaturated framework (Figs. 2,
3). Derivatisation of these heterocyclic pharmacophores
represents a convenient approach to generate chemical
diversity during lead identification and optimisation. The
resulting target molecules are important analogous of lead
structures in drug discovery such as the inhibitor of catechol-
O-methyltransferase (COMT), entacapone (7) [13], the
dynamin protein inhibitor (8) [14], the antiplatelet
pyridazinone (9) [15] or the antiproliferative acylthiourea
(10) [16] as well as the thyrphostins (11, 12) [17], a family of
synthetic protein tyrosine kinase inhibitors that selectively
inhibit the autophosphorylation receptor and are used to
study the receptor function (Fig. 2).
The synthetic study of polymer-supported superbase
reagents has grown from the pioneering work of the Tomoi´s
laboratory [5]. It was showed that N-alkylation of DBU upon
treatment with chloromethyl or bromoalkyl polystyrene
resins was highly reliable. The synthesis of this type of
reagents is normally based on this strategy [6], and some of
these polymer supported superbase reagents are now
*Address correspondence to this author at the Combinatorial Chemistry
Unit (COMBIOMED), Institute of Industrial Pharmacy (IFI), Faculty of
Pharmacy, Center for Research in Biological Chemistry and Molecular
Materials, University of Santiago de Compostela, Santiago de Compostela,
15782, Spain; Tel: +34-981563100, Ext. 15732; Fax: +34-981-528093;
E-mail: albertojose.coelho@usc.es
The general structure of the target molecules is shown in
the retrosynthetic scheme (Fig. 3). Two possible pathways
were designed to access the pretended library. The final
products ABC would require an initial N-alkylation
1386-2073/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Formyl-Aza-Heterocycles
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7 571
N
N
P
N
N
=
N
(CO3
)
0.5
N
N
N
N
N
N
N
N
N
AlCl3
PS
Si
PS
Si
PS
PS
4
5
6
1
2
3
PS-CO3
PS-BEMP
PS-TMG
Si-AlCl3
Si-TBD
PS-TBD
Fig. (1). Supported reagents employed in this work.
O
N
O
O
O
OEt
OEt
O
O2N
CN
N
N
N
CN
HO
N
N
OH
Entacapone
(9)
(7)
Antiplatelet pyridazinone
(8)
Dynamin protein inhibitor
NC
O
Me
O
CN
MeO
COOMe
N
N
N
H
CN
CN
O2N
O
MeO
S
Tyrphostin B44(-)
(11)
Antiproliferative acyl(thio)urea
(12)
Tyrphostin AG1714
(10)
Fig. (2). Prominent lead structures containing Knoevenagel-type fragments.
(pathway A) or Knoevenagel condensation (pathways B)
starting from the formyl-azaheterocycles A to give the
intermediates AB or AC. The formyl aza-heterocycles A1,
A2, A3 and A4 (Fig. 3) were selected as convenient starting
materials considering the reactivity of the formyl group and
the acidic NH of these synthons to generate a library of N-
alkylated-Knoevenagel compounds. These scaffolds are
commercially available (A2, A4) or easily prepared (A1, A3)
[18].
compatible base to achieve the one-pot procedure to access
the target structures following the pathway A (alkylation-
Knoevenagel), designing as a proof of concept, a reaction
model (see supplementary material) between the scaffolds
A1-3 and alkyl halides or ꢀ,ꢁ-unsaturated esters as
alkylating agents and methyl cyanoacetate as an activated
methylene compound. DBU, K2CO3, TEA were chosen for
these screening, considering the basicity profile required for
both transformations. Unfortunately, these experiments
showed low transformation rates and a different behaviour
depending on the studied scaffold and sequence used,
affording only traces of the desired compounds in the best
cases (0-5%) and complex mixtures of by-products. Among
them, DBU often successfully drived the alkylation step but
failed in the subsequent Knoevenagel step in all the starting
scaffolds.
An optimal combinatorial approach for a rapid library
generation would require a common effective, versatile and
reusable catalyst for both processes without intermediates
isolation. Taking into a account the key role of an efficient
base in the success of the double transformation
(alkylation+Knoevenagel) we first turned our attention to the
usefulness of the described methodologies for both reactions
in these heterocycles. It has been reported the use of
conventional bases (e.g. K2CO3, Et3N, TBD, MTBD, DBU
or BEMP) to perform the alkylation or the Michael addition
to quinolones [19], pyridazinones [20] and indoles or
imidazoles [21], while Knoevenagel condensation often
requires the use of specific reagents (AlCl3, piperidine,
Ac2O) [20, 21] depending on the reactivity of each scaffold.
Therefore, our preliminary efforts were aimed to find a
A sight of poor results obtained using conventional bases,
the use of supported superbases was envisioned as an
improved alternative that could avoid the use of high
temperatures, long reaction times and tedious workup of
intermediates. Although the catalytic activity of the
supported reagents (showed in Fig. 1) in key transformations
of organic chemistry such as Knoevenagel condensation or
alkylations with alkyl halides or Michael acceptors has been

572 Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7
El Maatougui et al.
W
Pathway A
Pathway B
X
N
HET
Y
Knoevenagel
Alkylation
H
ABC
Knoevenagel
W
Alkylation
H
HN
N
HET
N
HET
HET
X
O
O
Y
H
H
H
A
AC
AB
O
H
O
H
O
H
N
H
N
O
O
O
N
H
HN
H
N
H
N
A2
A1
A3
A4
Fig. (3). General structure of the targeted libraries, retrosynthetic scheme and structure of the starting scaffolds A.
reported [6, 7, 21, 22], the study of its behaviour and
reusability in one pot consecutive double functionalisations
in an effective manner is scarce. Therefore, the first stage of
the study involved a comprehensive screening process to
firstly choose the most efficient pathway (A or B) to follow
up and secondly to identify mild and selective alkylation
conditions by employing different alkyl halides or Michael
acceptors, which could be optimized for each scaffold and,
most importantly, would be compatible with the
experimental conditions of the Knoevenagel [22] reaction.
Pathway A showed to be the best option since Knoevenagel
reaction proceeds faster from N-blocked adducts and
consequently the further optimisations were performed using
this strategy.
key factor in the success of the one pot sequences. The best
results were obtained using THF for quinolone A1 and
pyridazinone A3, toluene for indole A2 and DMF for
imidazole A4 (entries 4, 14, 15, 16, 19, 20 and 27). MeCN
was efficient for the first step of alkylation but, as a general
rule, longer reaction times were required for the complete
conversion of the intermediates during the Knoevenagel
transformation (entry 5). Toluene was optimal only when
indole was employed as scaffold. This protocol was
monitored by thin layer chromatography or EI–MS.
The effect of the nature of the supported reagent on the
behaviour was carefully examined. (1) and (2) showed to be
the most effective and versatile reagents taking into account
the scaffold variability. Inversely, during the optimisation
process we found that the reactions using stronger PS–
BEMP (3) were slightly faster during the alkylation step (1.5
equiv of base, r.t., 10–20 min, with almost quantitative
yields) than PS–TBD (2) or Si–TBD (1) (which require 2.5
equiv of supported base and increased reaction times).
However, while the alkylation process proceeded almost
quantitatively by using either (1), (2) or (3), the Knoevenagel
condensation employing PS–BEMP (3) showed to be
problematic [longer reaction times (48–72 h) and presence of
by-products, (Table 1, entries 6, 7, 13 and 21)].
In order to define the scope and efficiency of these
methodologies, we have selected again two reaction models
(Table 1) using benzyl bromide and methyl acrylate as
alkylating reagents and methyl cyanoacetate as activated
methylene compound and screened a variety of reaction
conditions adaptable to the different scaffolds A1-4
employing the supported bases 1-5, chosen by its basicity
profile or effectiveness to catalyze the one pot reaction. As
an alternative to these reagents and considering its reported
application in Aza-Michael [23] and Knoevenagel reactions
[15] of its supported version, the silica-aluminium chloride
(6) was also tested as versatile and effective catalyst for the
Aza-Michael-Knoevenagel sequences.
Such behaviour was observed during consecutive
reactions, as in the case of scaffolds A1, A2 and A4. Other
supported bases such as PS-TMG (4) or PS-carbonate (5)
didn´t improve the results obtained using the polymeric
cyclic guanidines (1) or (2). Inversely, although silica-
The solubility of the scaffolds in several solvents (THF,
toluene, DMF, MeCN) was first examined, being this issue a

Formyl-Aza-Heterocycles
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7 573
Table 1. Optimisation Process Through the Two Model Reactions Designed
One pot Alkylat ion-Knoevenagel sequence
One pot Aza-Michael-Knoevenagel sequence
COOMe
(1.1 eq.)
Bn-Br (1.1 eq.)
R2
R1
HN
REAGENT (0.5 eq)
BASE (3.5 eq)
then
N
N
CN
COOMe
CN
COOMe
HET
HET
HET
then
CHO
NC
COOMe
NC
COOMe
(1.1 eq.)
(1.1 eq.)
A(1-4)
Entry
Scaffold
Supp. Regnt
Alk. Reagent
Solvent
Temp (ºC) (1st-2nd Step)
Yield(%)
1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A1
A2
A2
A2
A2
A2
A2
A2
A2
A3
A3
A3
A3
A3
A4
A4
A4
A4
Si-TBD (1)
PS-TBD (1)
Si-TBD (2)
PS-TBD (2)
PS-TBD (2)
PS-BEMP (3)
PS-BEMP (3)
PS-TMG (4)
PS-TMG (4)
PS-CO3 (5)
PS-CO3 (5)
Si-AlCl3 (6)
PS-BEMP (3)
Si-TBD (1)
PS-TBD (1)
PS-TBD (1)
PS-TMG (4)
PS-TMG (4)
PS-TBD (2)
PS-TBD (1)
PS-BEMP (3)
PS-TMG (4)
PS-CO3 (5)
PS-TBD (2)
PS-CO3 (4)
Si-AlCl3 (6)
PS-TBD (2)
BrCH2Ph
BrCH2Ph
THF
THF
40
40
72
70
2
3
H2C=CH2COOMe
H2C=CH2COOMe
H2C=CH2COOMe
BrCH2Ph
THF
40
60
4
THF
40
66
5
MeCN
THF
40
40a
20b,d
34b,d
25a
45
6
40
7
H2C=CH2COOMe
BrCH2Ph
THF
40
8
THF
40
9
H2C=CH2COOMe
BrCH2Ph
THF
40
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
40
14a,c
H2C=CH2COOMe
H2C=CH2COOMe
H2C=CH2COOMe
BrCH2Ph
rt-60
rt-60
40
30
0a
30b,d
rt-60
rt-60
rt-60
rt-60
rt-60
rt
65
BrCH2Ph
67
H2C=CH2COOMe
H2C=CH2COOMe
BrCH2Ph
78
44c
34a,c
50
H2C=CH2COOMe
BrCH2Ph
THF
rt
60
H2C=CH2COOMe
BrCH2Ph
THF
rt
30 b,d
48a,c
20
THF
rt
H2C=CH2COOMe
BrCH2Ph
DMF
rt
DMF
rt
20e
40a
0a
H2C=CH2COOMe
H2C=CH2COOMe
H2C=CH2COOMe
DMF
rt
DMF
70-rt
rt
DMF
72 a
a) Uncompleted Alkylation step. b) Uncompleted Knoevenagel step. c) 5 eq. of supported base used. d) presence of byproducts. e) a mixture of 1,4 and 3,4 regiosomers (ratio 1.5/1)
was obtained.
aluminium chloride (6) could catalysed efficiently the
Knoevenagel reaction from N-blocked heterocycles AB, this
reagent was ineffective to drive successfully the first step
(Aza-Michael) of the sequence starting from scaffolds A,
affording uncompleted N-alkylation reactions (entries 12 and
26) and was consequently discarded.
ions, we decided to study the differences between (1) and
(2). During these experiments we didn´t find significant
variations in reactivity between them using the optimal
solvents (see Table 2, entries 1, 2, 14 and 15) for each
heterocycle. This observation can be attributed to the fact
that (2) can swell efficiently in all the solvents used.
Consequently, the less expensive polystyrene version of
TBD was chosen for further assays.
Aiming to validate the claimed intrinsic advantages of
functionalised silicas [24] (such as no swelling and solvent
compatibility) over polystyrene resins for these transformat-

574 Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7
El Maatougui et al.
COOMe
(2)
N
COOMe
N
N
NC
N
PS-TBD
NC
N
MeOOC
N
O
COOMe
DMF, rt, 2h
then
H
MeOOC
H
NC
COOMe
traces <5%
A4C2D2
A4
Scheme 1. Aza-Michael-Knoevenagel sequences on imidazole A4.
A more intriguing challenge was the optimisation of the
Aza-Michael-Knoevenagel sequence on imidazole A4: N-
alkylation of asymmetrically substituted imidazoles usually
leads to formation of 1, 4 and 3, 4 regioisomeric mixtures
[25]. In the light of the poor results obtained by simple
alkylation using alkyl halides during the optimisation
process (entry 24), we turned to a different N-alkylation
strategy based on Aza-Michael reaction between A4 and
ꢀ,ꢁ-unsaturated esters which has been shown to lead to
highly regioselective alkylations [26]. The 1,4-substituted
product is favoured by intramolecular hydrogen bonding as
well as for steric reasons. Therefore, we screened a variety of
supported reagents for the Aza-Michael-Knoevenagel
sequence. Among them, PS-TBD (2) was again the most
effective catalyst, being slightly faster and more efficient
than PS-carbonate (5) in the Knoevenagel step (Entries 25
and 27).
methylene compound in the second step, we have obtained
almost exclusively the 1-alkyl-4-alkylidene-imidazoles ACD
after simply filtering the supported base and purification of
the obtained solid. The unequivocal identity of the isomer
was confirmed by NOE experiments (see supporting
information) as the desired 1-alkyl-4-disubstituted-imidazole
A4C2D2. These results can be explained considering the low
rates of the Knoevenagel condensation in the second step
from the 1-alkyl-5-formyl intermediate.
Encouraged by these successful results using PS-TBD
(2), the library production was performed using this reagent
as base in all sequences. Small subsets of alkyl halides B1–
B4 (benzyl bromide, methyl or ethyl iodides and ethyl
bromoacetate), acrylates C1–C5 and activated methylene
compounds D1–D4 (methyl, ethyl, isopropyl cyanoacetates
and malononitrile) (Fig. 4, Table 2) were employed as
building blocks to evaluate their functional group
compatibility and potential utility as a source of diversity.
Although two possible final regioisomers (Scheme 1)
were expected and the formation of the corresponding 1-
alkyl and 3-alkyl-imidazoles was detected by TLC in a
(10/1) ratio when PS-TBD (2) was used at rt in DMF,
surprisingly, after addition of the corresponding active
The results shown in the Table 2 indicate that PS-TBD
(2) has an optimal range of basicity to carry out these
syntheses in good yields under mild conditions, compared
with other related items. In addition to the catalytic efficacy
Fig. (4). Synthesis of densely substituted aza-heterocycles through one-pot consecutive functionalizations using PS-TBD (2).

Formyl-Aza-Heterocycles
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7 575
Table 2. Synthesis of Disubstituted Heterocycles Using PS-TBD (2)
O
Y
H
H
X
Y
W
O
H
N
N
Y
X
X
N
X
Y
N
N
H
N
W
W
W
A2
A1
A3
A4
Compound
W
X/Y
Yield (%)
Compound
W
X/Y
Yield (%)
A1B1D2
A1B3D1
A1B2D3
A1B4D3
A1B4D4
A1C2D3
A1C4D2
A1C3D3
A1C3D1
A1C1D2
A2B3D2
A2B2D2
A2C2D3
A2B1D1
A2B4D3
A2B2D4
A2C1D3
A2C4D3
CH3
CH2-COCH2CH3
CH2CH3
COOMe/CN
CN/CN
89a
72 a
64 a
70 a
63 a
66 b
70 b
68 b
54 b
63 b
65 c
74 c
78 c
72 c
67 c
63 c
70 d
78 d
A2C4D4
A2C3D2
A3B1D2
A3B3D3
A3B4D2
A3B2D1
A3B1D4
A3C1D3
A3C2D1
A3C4D2
A3C3D2
A3C2D4
A4C2D2
A4C2D1
A4C1D1
A4C2D3
A4C4D3
A4C5D2
CH2CH2COOEt
COOiPr/CN
COOMe/CN
COOMe/CN
COOEt/CN
COOMe/CN
CN/CN
68 d
75 d
69 e
65 e
72 e
70 e
57 e
52f
CH2CH2COOPh
CH3
COOEt/CN
COOEt/CN
COOiPr/CN
COOEt/CN
COOMe/CN
COOEt/CN
CN/CN
CH2Ph
CH2-CO CH2CH3
CH2Ph
CH2Ph
CH2CH2COOMe
CH2CH2COOEt
CH2CH2COOPh
CH2CH2COOPh
CH2CH2CN
CH2-CO CH2CH3
CH2CH3
CH2CH3
CH3
COOiPr/CN
COOEt/CN
CN/CN
CH2CH2CN
CH2CH2COOMe
CH2CH2COOEt
CH2CH2COOPh
CH2CH2COOMe
CH2CH2COOMe
CH2CH2COOMe
CH2CH2CN
65 f
62 f
66 f
50 f
72 g
74 g
84 g
71 g
72 g
65 g
COOMe/CN
COOMe/CN
COOMe/CN
COOEt/CN
CN/CN
COOMe/CN
COOMe/CN
COOiPr/CN
COOMe/CN
CN/CN
CH2CH2-COOCH3
CH3
CH2Ph
COOEt/CN
COOiPr/CN
COOEt/CN
COOEt/CN
CN/CN
CH2CH3
CH2CH2COOMe
CH2CH2COOEt
COOEt/CN
COOEt/CN
COOMe/CN
CH2CH2CN
CH2CH2COOEt
CH2CH2COO(CH2)2OEt
a) A1 (0.60 mmol), R1X (0.66 mmol), PS-TBD (1.5 mmol), THF, 40ºC, 1-3h., then activated methylene compound (0.66 mmol), 1-12h b) A1 (0.60 mmol), Michael acceptor (0.66
mmol), PS-TBD (0.12 mmol), THF, 60ºC, 1-3h., then activated methylene compound (0.66 mmol), 50ºC, 1-12h c) A2 (0.60 mmol), R1X (0.66 mmol), PS-TBD (1.5 mmol), toluene,
40ºC, 1-3h., then activated methylene compound (0.66 mmol), 60ºC, 1-12h d) A2 (0.60 mmol), Michael acceptor (0.66 mmol), PS-TBD (0.12 mmol), toluene, 60ºC, 1-3h., then
activated methylene compound (0.66 mmol), 1-12h. e) A3 (0.60 mmol), R1X (0.66 mmol), PS-TBD (1.5 mmol), THF, 40ºC, 1-3h., then activated methylene compound (0.66 mmol),
rt, 1-12h. f) A3 (0.60 mmol), Michael acceptor (0.66 mmol), PS-TBD (0.12 mmol), THF, 40ºC, 2h., then activated methylene compound (0.66 mmol), rt, 1-12h. g) A4 (0.60 mmol),
Michael acceptor (0.66 mmol), PS-TBD (0.12 mmol), DMF, rt, 2h., then activated methylene compound (0.66 mmol), 1-12h. The stereochemistry of all compounds was determined
through NMR experiments. Pyridazinone, quinolone and imidazole compounds have an E configuration and Z for indole derivatives. The E configuration was assigned
unambiguously from the 1H-coupled 13C NMR spectrum (see supporting information) [27].
observed during the Alkylation-Knoevenagel reactions, a
remarkable feature of the synthetic protocol documented
here concerns the recyclability of TBD on polystyrene. Once
the reaction had finished, the polymer-supported reagent was
separated from the reaction mixture by filtration, submitted
to a washing protocol (dioxane, CH2Cl2, diethyl ether) and
then dried under vacuum for 12 hours. The recovered
polymeric material was routinely reused (at least three times)
during library production without significant loss of activity
and with the average yield maintained within the series for
substrates of similar reactivity (e.g. A1B1D2: 85%,
A1C2D3: 64% and A4C2D1: 70%).
agel and aza-Michael–Knoevenagel functionalisations,
allowing to expand rapidly the molecular diversity of a
variety of formyl-aza-heterocycles.
EXPERIMENTAL SECTION
Commercially available starting materials, reagents and
solvents were purchased (Sigma-Aldrich) and used without
further purification. When necessary, solvents were dried by
standard techniques and distilled. The reactions were
monitored by thin-layer chromatography (TLC) with 2.5 mm
Merck silica gel GF 254 strips, and each one of the purified
compounds showed a single spot; unless stated otherwise,
UV light and/or iodine vapour were used for detection of
compounds. Purification of crude compounds was carried
out by preparative chromatography and/or then
recrystallization. The one pot reactions were performed on a
PLS (6ꢀ4) Organic Synthesiser from Advanced Chemtech.
In conclusion, a simple solution-phase approach has been
developed, easily adaptable to the parallel synthesis of
libraries of indoles, quinolones, pyridazinones and
imidazoles. Among the polymeric reagents screened, PS–
TBD (2) showed to be an efficient and reusable supported
superbase for the one-pot consecutive Alkylation–Knoeven-

576 Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7
El Maatougui et al.
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were
126.8, 126.7, 115.7, 114.0, 63.1, 55.2, 14.0. MS (70 eV) m/z
(%): 307 (M+, 100), 281 (11), 234 (54). HRMS m/z calcd. for
C17H13N3O3 (M+): 307.0957, found: 307.0967.
measured
using
a
Perkin-Elmer
1640
FTIR
spectrophotometer with samples as potassium bromide
pellets. The NMR spectra were recorded on Bruker AM300
and XM500 spectrometers. Chemical shifts are given as ꢀ
values against tetramethylsilane as internal standard and J
values are given in Hz. Mass spectra were obtained on a
Ethyl (2E)-3-(1-ethyl-1,4-dihydro-4-oxoquinolin-3-yl)-
2-cyanoacrylate (A1B2D3). Purification by preparative
chromatography using AcOEt/hexane (1:2) mp: 176-177ºC
(iso-PrOH); yield 64%. IR (KBr): ꢁmax/cm–1 2214 (CN),
1
1711 (CO), 1632 (CO), 1550 (Aromatics), 1247 (O-R). H-
Varian MAT-711 instrument.
A
complete structural
NMR (CDCl3 300 MHz), ꢀ (ppm): 9.07 (s, 1H, CH), 8.88 (s,
1H, CH), 8.51 (d, J=8.2 Hz, 1H, Aromatic), 7.79-7.73 (m,
1H, Aromatic), 7.54-7.46 (m, 2H, Aromatics), 4.34 (q, J=7.1
Hz, 2H, CH2), 4.31 (q, J=7.3 Hz, 2H, CH2), 1.60 (t, J= 7.3
Hz, 3H, CH3), 1.37 (t, J= 7.1 Hz, 3H, CH3). 13C-NMR
(CDCl3 75 MHz), ꢀ (ppm): 175.2, 162.8, 148.3, 144.5,
138.6, 133.3, 128.2, 127.3, 125.8, 117.2, 116.1, 113.4, 97.2,
62.2, 49.4, 14.4, 14.2. MS (70 eV) m/z (%): 296 (M+, 8), 251
(5), 223 (100), 105 (22). HRMS m/z calcd. for C17H16N2O3
(M+): 296.1161, found: 296.1168.
characterization, including IR, NMR, mass spectrometry for
the new compounds is provided. The starting material key
aza-formyl-heterocycles are commercial (A2 and A4) or
were obtained (A1 and A3) following a assisted two step
sequence previously described by our group [16, 21]. A copy
of the NMR, IR spectra of the A1 precursor as well as the
final compounds is provided in the supporting information.
General procedure for Alkylation-Knoevenagel seq-
uence (Method A): A coated Kimble vial was charged with
a mixture of the scaffold A1–A4 (0.60 mmol) in the
appropriate solvent [THF (3 mL) for A1 or A3, toluene for
A2, DMF for A4]. The supported organic base (1.5 mmol of
PS–TBD 2) and the alkyl halide (0.66 mmol) were added at
the appropriate temperature (rt for A4, 40°C for A1 and A3,
r.t. for A2). The sample was vortexed for 30-60 min to give
the corresponding N-blocked adduct. Addition of the
activated methylene compound (1.1 equiv, stirring for 1–12
h) to the adduct at the appropriate temperature (40°C for A1,
60°C for A2, r.t. for A3 and A4) in the corresponding
solvent, led to the final product. The supported reagent was
filtered by a fritted syringe in a Manifold Filtration System
(Visiprep®) and the filtrate was evaporated in vacuum. The
obtained solid or residue was purified by crystallization or
preparative chromatography. The PS-TBD (2) was washed
following the protocol: dioxane, CH2Cl2, diethyl ether and
reused at least three times without important loss of activity.
Isopropyl (2E)-3-(1-benzyl-1,4-dihydro-4-oxoquino-
lin-3-yl)-2-cyanoacrylate (A1B4D4). Purification by
preparative chromatography using AcOEt/hexane (1:4) mp:
210-212ºC (iso-PrOH); yield 53%. IR (KBr): ꢁmax/cm–1 2230
(CN), 1707 (CO), 1627 (CO), 1600 (Aromatics), 1092 (C-O-
1
C). H-NMR (CDCl3 300 MHz), ꢀ (ppm): 9.15 (s, 1H, CH),
8.89 (s, 1H, CH), 8.47 (d, J=8.2 Hz, 1H, Aromatic), 7.65-
7.48 (m, 1H, Aromatic), 7.45-7.32 (m, 5H, Aromatic), 7.25-
7.22 (m, 2H, Aromatic), 5.44 (s, 2H, CH2), 5.21-5.17 (m,
1H, CH), 1.35 (d, J=6.2 Hz, 6H, 2 x CH3). 13C-NMR (CDCl3
75 MHz), ꢀ (ppm): 175.7, 162.8, 148.3, 146.1, 139.1, 133.8,
133.7, 129.9, 129.2, 128.4, 127.6, 126.8, 126.3, 117.5, 114.1,
98.8, 97.5, 70.6, 58.5, 22.2. FAB (70 eV) m/z (%): 373 (M+,
5), 307 (100), 289 (12). HRMS m/z calcd. for C23H20N2O3
(M+): 372.1474, found: 372.1474.
Methyl (2E)-3-(1-methyl-1,4-dihydro-4-oxoquinolin-3-
yl)-2-cyanoacrylate (A1B1D2). Purification by preparative
chromatography using AcOEt/hexane (1:3). mp: 236-238ºC
(iso-PrOH); yield 77%. IR (KBr): ꢁmax/cm–1 2216 (CN),
(2E)-Ethyl-3-(1-benzyl-1,4-dihydro-4-oxoquinolin-3-yl)-
2-cyanoacrylate (A1B4D3). Purification by preparative
chromatography using AcOEt/hexane (1:4) mp: 218-219ºC
(iso-PrOH); yield 70%. IR (KBr): ꢁmax/cm–1 2233 (CN),
1
1710 (CO), 1626 (CO), 1550 (Aromatics), 1254 (O-R). H-
NMR (CDCl3 300 MHz), ꢀ (ppm): 9.04 (s, 1H, CH), 8.89 (s,
1H, CH), 8.51 (dd, J=6.5 J=1.4 Hz, 1H, Aromatic), 7.80-
7.74 (m, 1H, Aromatic), 7.55-7.48 (m, 2H, Aromatics), 3.96
(s, 3H, CH3), 3.90 (s, 3H, CH3). 13C-NMR (CDCl3 75 MHz),
ꢀ (ppm): 175.2, 163.1, 148.8, 146.4, 139.8, 133.8, 128.4,
127.3, 126.5, 117.5, 116.6, 113.4, 96.9, 53.4, 42.6. MS (70
eV) m/z (%): 268 (M+, 21), 237 (7), 210 (15), 209 (100).
HRMS m/z calcd. for C15H12N2O3 (M+): 268.0848, found:
268.0848.
1
1709 (CO), 1665 (CO), 1599 (Aromatics). H-NMR (CDCl3
300 MHz), ꢀ (ppm): 9.12 (s, 1H, CH), 8.88 (s, 1H, CH), 8.47
(d, J=8.2 Hz, 1H, Aromatic), 7.66-7.62 (m, 1H, Aromatics),
7.43-7.33 (m, 4H, Aromatics), 7.23-7.19 (m, 3H,
Aromatics), 5.42 (s, 2H, CH2), 4.34 (q, J= 7.2 Hz, 2H, CH2),
1.35 (t, J=7.2 Hz, CH3). 13C-NMR (CDCl3 75 MHz), ꢀ
(ppm): 175.4, 162.7, 148.2, 145.7, 139.1, 133.6, 133.3,
129.4, 128.8, 128.0, 127.2, 126.3, 125.9, 117.1, 117.0, 113.6,
97.9, 62.2, 58.1, 14.2. MS (70 eV) m/z (%): 358 (M+, 11),
285 (100), 91 (16). HRMS m/z calcd. for C22H18N2O3 (M+):
358.1317, found: 358.1320.
Ethyl
(Z)-3-(1-ethyl-1H-indol-3-yl)-2-cyanoacrylate
(A2B2D2). Purification by preparative chromatography
using AcOEt/hexane (1:4). mp: 185-186ºC (iso-PrOH); yield
74%. IR (KBr): ꢁmax/cm–1 2212 (CN), 1714 (CO), 1593
Ethyl 2-[3-(2,2-dicyanovinyl)-4-oxoquinolin-1(4H)-yl]
acetate (A1B3D1). Purification by preparative chromato-
graphy using AcOEt/hexane (1:3) mp: 155-156ºC (iso-
PrOH); yield 72%. IR (KBr): ꢁmax/cm–1 2218 (CN), 1739
1
(Aromatics), 1120 (C-O-C). H-NMR (CDCl3 300 MHz), ꢀ
(ppm): 8.58 (s, 1H, CH), 8.57 (s, 1H, CH), 7.83 (d, J= 8.5
Hz, 1H, Aromatic), 7.45-7.42 (m, 1H, Aromatic), 7.38-7.30
(m, 2H, Aromatics), 4.28 (q, J=7.2 Hz, 2H, CH2), 3.91 (s,
3H, OCH3), 1.56 (t, J=7.2 Hz, 3H, CH3). 13C-NMR (CDCl3
75 MHz), ꢀ (ppm): 164.9, 157.5, 146.5, 134.0, 133.7, 124.2,
123.0, 119.0, 118.9, 110.9, 110.4, 94.7, 53.1, 42.8, 15.5. MS
(70 eV) m/z (%): 254 (M+, 100), 239 (53), 223 (23), 179
(22), 140 (39). HRMS m/z calcd. for C15H14N2O2 (M+):
254.1055, found: 254.1058.
1
(CO), 1647 (CO), 1549 (Aromatics). H-NMR (CDCl3 300
MHz), ꢀ (ppm): 8.83 (s, 1H, CH), 8.50 (dd, J=6.4 Hz, J=1.4,
1H, Aromatic), 8.42 (s, 1H, CH), 7.79-7.73 (m, 1H,
Aromatic), 7.56-7.52 (m, 1H, Aromatic), 7.30-7.23 (m, 1H,
Aromatic), 4.91 (s, 2H, CH2), 4.30 (q, J= 7.1 Hz, 2H, CH2),
1.30 (t, J= 7.1 Hz, 3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢀ
(ppm): 174.5, 165.8, 152.9, 146.1, 139.0, 134.0, 128.3,

Formyl-Aza-Heterocycles
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7 577
2-[(1-Methyl-1H-indol-3-yl)-methylene]malononitrile
(A2B1D1). Purification by preparative chromatography
using AcOEt/hexane (1:4). mp: 192-194ºC (iso-PrOH); yield
82%. IR (KBr): ꢀmax/cm–1 2212 (CN), 1568 (Aromatics). 1H-
NMR (CDCl3 300 MHz), ꢁ (ppm): 8.42 (s, 1H, CH), 8.01 (s,
1H, CH), 7.73-7.70 (m, 1H, Aromatic), 7.45-7.34 (m, 3H,
Aromatics), 3.94 (s, 3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢁ
(ppm): 150.3, 137.2, 135.4, 128.0, 124.9, 123.8, 118.5,
116.0, 115.8, 111.1, 110.7, 34.7. MS (70 eV) m/z (%): 207
(M+, 100), 179 (15), 165 (18), 138 (12). HRMS m/z calcd.
for C13H9N3 (M+): 207.0796, found: 207.0799.
Aromatics), 5.40 (s, 2H, CH2), 3.91 (s, 3H, CH3). 13C-NMR
(CDCl3 75 MHz), ꢁ (ppm): 160.9, 158.3, 149.6, 144.6,
135.5, 135.2, 133.7, 129.9, 129.8, 129.0, 128.9, 128.8, 128.6,
128.2, 112.2, 110.2, 55.7, 53.9. MS (70 eV) m/z (%): 371
(M+, 100), 370 (33), 267 (19). HRMS m/z calcd. for
C22H17N3O3 (M+): 371.1269, found: 371.1275.
Isopropyl (2E)-3-(1,6-dihydro-1-methyl-6-oxo-3-phenyl-
pyridazin-4-yl)-2-cyanoacrylate (A3B1D4). Purification by
preparative chromatography using AcOEt/hexane (1:4). mp:
156-158ºC (iso-PrOH). Yield: 57%. IR (KBr): ꢀmax/cm–1
2354 (CN), 1721 (COO), 1701 (COO), 1664 (CO), 1585
1
Ethyl (Z)-3-(1-benzyl-1H-indol-3-yl)-2-cyanoacrylate
(A2B4D3). Purification by preparative chromatography
using AcOEt/hexane (1:4). mp: 130-131ºC (iso-PrOH).
Yield: 67%. IR (KBr): ꢀmax/cm–1 2209 (CN), 1747 (CO),
1578 (Aromatics), 1094 (C-O-C). 1H-NMR (CDCl3 300
MHz), ꢁ (ppm): 8.61 (s, 1H, CH), 8.60 (s, 1H, CH), 7.86-
7.83 (m, 1H, Aromatic), 7.37-7.27 (m, 6H, Aromatics), 7.18-
7.15 (m, 2H, Aromatics), 5.41 (s, 2H, CH2), 4.37 (q, J= 7.1
Hz, 2H, CH2), 1.39 (t, J= 7.1 Hz, 3H, CH3). 13C-NMR
(CDCl3 75 MHz), ꢁ (ppm): 164.3, 146.2, 136.7, 135.6,
134.5, 129.5, 129.0, 128.7, 127.2, 124.4, 123.1, 119.0, 118.6,
111.5, 110.8, 94.8, 62.3, 51.8, 14.7. MS (70 eV) m/z (%):
330 (M+, 75), 183 (1), 139 (2), 91(100). HRMS m/z calcd.
for C21H18N2O2 (M+): 330.1368, found: 330.1374.
(Aromatics), 1084 (C-O-C). H-NMR (CDCl3 300 MHz), ꢁ
(ppm): 7.89 (s, 1H, CH), 7.52 (s, 1H, CH), 7.49-7.44 (m, 3H,
Aromatics), 7.40-7.36 (m, 2H, Aromatics), 5.19-5.11 (m,
1H, CH), 3.89 (s, 3H, CH3), 1.34 (d, J=6.2 Hz, 6H, 2 x CH3).
13C-NMR (CDCl3 75 MHz), ꢁ (ppm): 160.3, 159.3, 149.4,
145.0, 135.9, 134.1, 130.3, 129.4, 129.3, 129.1, 113.0, 111.6,
72.2, 41.0, 22.0. MS (70 eV) m/z (%): 323 (M+, 14), 236
(100), 208 (31), 164 (65), 139 (26), 114 (27), 77 (32).
HRMS m/z calcd. for C18H17N3O3 (M+): 323.1269, found:
323.1273.
2-[(1-Ethyl-1,6-dihydro-6-oxo-3-phenylpyridazin-4-yl)-
methylidene]malononitrile (A3B2D1). Purification by
preparative chromatography using AcOEt/hexane (1:4). mp:
228-230ºC; (iso-PrOH). yield 80%. IR (KBr): ꢀmax/cm–1
1
Methyl (Z)-3-[1-(2-ethoxycarbonylmethyl)-1H-indol-
3-yl]-2-cyanoacrylate (A2B3D2). Purification by prepa-
rative chromatography using AcOEt/hexane (1:4). mp: 158-
159ºC (iso-PrOH); Yield: 72%. IR (KBr): ꢀmax/cm–1 2216
(CN), 1751 (CO), 1700 (CO), 1588 (Aromatics), 1099 (C-O-
2230 (CN), 1755 (CO), 1669 (CO), 1583 (Aromatics). H-
NMR (CDCl3 300 MHz), ꢁ (ppm): 7.54-7.52 (m, 4H,
Aromatics + 1H, CH), 7.47 (s, 1H, CH), 7.42-7.34 (m, 2H,
Aromatics), 4.31 (q, J= 7.1 Hz, 2H, CH2), 1.45 (t, J= 7.1 Hz,
3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢁ (ppm): 158.8,
155.1, 144.6, 134.8, 134.2, 130.7, 129.9, 129.7, 129.1, 112.5,
111.2, 92.1, 48.2, 13.8. MS (70 eV) m/z (%): 276 (M+, 18),
247 (18), 222 (17), 191 (31), 50 (100). HRMS m/z calcd. for
C16H12N4O (M+): 276.1011, found: 276.1014.
1
C). H-NMR (CDCl3 300 MHz), ꢁ (ppm): 8.58 (s, 1H, CH),
8.51 (s, 1H, CH), 7.85-7.82 (m, 1H, Aromatic), 7.39-7.30
(m, 3H, Aromatics), 4.94 (s, 2H, CH2), 4.24 (q, J= 7.1 Hz,
2H, CH2), 3.91 (s, 3H, OCH3), 1.28 (t, J= 7.1 Hz, 3H, CH3).
13C-NMR (CDCl3 75 MHz), ꢁ (ppm): 167.2, 164.5, 146.4,
136.9, 134.8, 128.5, 124.7, 123.3, 119.1, 118.4, 111.3, 110.5,
95.1, 62.7, 53.2, 49.0, 14.5. MS (70 eV) m/z (%): 312 (M+,
48), 239 (100), 207 (11), 152 (18). HRMS m/z calcd. for
C17H16N2O4 (M+): 312.1110, found: 312.1118.
Methyl (2E)-3-(1,6-dihydro-1-methyl-6-oxo-3-phenyl-
pyridazin-4-yl)-2-cyanoacrylate (A3B1D2). Purification by
preparative chromatography using AcOEt/hexane (1:4). mp:
220-221ºC (iso-PrOH). Yield: 79%. IR (KBr): ꢀmax/cm–1
2229 (CN), 1727 (CO), 1659 (CO), 1580 (Aromatics), 1083
(C-O-C). 1H-NMR (CDCl3 300 MHz), ꢁ (ppm): 7.92 (s, 1H,
-CH), 7.53-7.44 (m, 4H, Aromatics+ CH), 7.39-7.35 (m, 2H,
Aromatics), 3.92 (s, 3H, CH3), 3.89 (s, 3H, CH3). 13C-NMR
(CDCl3 75 MHz), ꢁ (ppm): 160.9, 158.9, 149.6, 144.6,
135.4, 133.7, 129.9, 129.1, 129.0, 128.7, 112.9, 110.3, 53.9,
40.5. MS (70 eV) m/z (%): 295 (M+, 100), 236 (100), 208
(35), 164 (30). HRMS m/z calcd. for C16H13N3O3 (M+):
295.0957, found: 295.0966.
Isopropyl (Z)-3-(1-ethyl-1H-indol-3-yl)-2-cyanoacry-
late (A2B2D4). Purification by preparative chromatography
using AcOEt/hexane (1:4). mp: 97-98ºC (iso-PrOH). Yield:
76%. IR (KBr): ꢀmax/cm–1 2214 (CN), 1743 (CO), 1100 (C-
1
O-C). H-NMR (CDCl3 300 MHz), ꢁ (ppm): 8.55 (s, 1H,
CH), 8.54 (s, 1H, CH), 7.84-7.81 (m, 1H, Aromatic), 7.44-
7.41 (m, 1H, Aromatic), 7.37-7.30 (m, 2H, Aromatics), 5.21-
5.04 (m, 1H, CH), 4.28 (q, J= 7.3 Hz, 3H, -CH2), 1.55 (t, J=
7.3 Hz, 2H, CH3), 1.36 (d, J= 6.3 Hz, 3H, CH3), 1.29 (d, J=
6.3 Hz, 3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢁ (ppm):
162.8, 146.1, 136.3, 133.4, 128.9, 124.1, 122.9, 118.9, 118.8,
110.9, 110.4, 94.5, 69.9, 42.7, 22.2, 21.9, 15.5. MS (70 eV)
m/z (%): 282 (M+, 57), 240 (100), 225 (67), 194 (21), 140
(54). HRMS m/z calcd. for C17H18N2O2 (M+): 282.1368,
found: 282.1372.
Ethyl (2E)-3-[1,6-dihydro-1-(ethoxycarbonylmethyl)-6-
oxo-3-phenylpyridazin-4-yl]-2-cyanoacrylate (A3B3D3). Pu-
rification by preparative chromatography using AcOEt/
hexane (1:4). mp: 141-142ºC (iso-PrOH). Yield: 75%. IR
(KBr): ꢀmax/cm–1 2232 (CN), 1762 (CO), 1730 (CO), 1673
1
(CO), 1584 (Aromatics), 1093 (C-O-C). H-NMR (CDCl3
300 MHz), ꢁ (ppm): 7.89 (d, J=1.2 Hz, 1H, H4), 7.55 (s, 1H,
CH), 7.51-7.42 (m, 3H, Aromatics), 7.40-7.29 (m, 2H,
Aromatics), 4.97 (s, 2H, CH2), 4.37 (q, J=7.1 Hz, 2H, CH2),
4.32 (q, J= 7.1 Hz, 2H, CH2), 1.36 (t, J= 7.1 Hz, 3H, CH3),
1.30 (t, J= 7.1 Hz, 3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢁ
(ppm): 166.8, 160.3, 158.5, 149.0, 145.2, 136.0, 133.4,
130.0, 129.6, 128.9, 128.8, 112.9, 110.9, 63.4, 61.9, 53.5,
14.1, 13.9. MS (70 eV) m/z (%): 381 (M+, 62), 308 (100),
Methyl (2E)-3-(1,6-dihydro-1-benzyl-6-oxo-3-phenyl-
pyridazin-4-yl)-2-cyano acrylate (A3B4D2). Purification
by preparative chromatography using AcOEt/hexane (1:3).
mp: 201-202ºC (iso-PrOH). Yield: 72%. IR (KBr): ꢀmax/cm–1
1
2230 (CN), 1739 (CO), 1662 (CO), 1583 (Aromatics). H-
NMR (CDCl3 300 MHz), ꢁ (ppm): 7.89 (s, 1H, CH), 7.52-
7.45 (m, 6H, Aromatics + CH), 7.38-7.30 (m, 5H,

578 Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7
El Maatougui et al.
262 (70), 234 (67), 164 (60). HRMS m/z calcd. for
C20H19N3O5 (M+): 381.1325, found: 381.1328.
2H, CH2), 3.70 (s, 3H, OCH3), 2.94 (t, J= 6.7 Hz, 2H, CH2),
1.35 (t, J= 7.1 Hz, 3H, -CH3). 13C-NMR (CDCl3 75 MHz), ꢁ
(ppm): 175.2, 170.1, 162.7, 148.0, 145.8, 138.3, 133.4,
128.4, 127.1, 125.9, 116.8, 115.7, 113.4, 97.8, 62.2, 52.4,
49.6, 32.8, 14.2. MS (70 eV) m/z (%): 354 (M+, 7), 310 (5),
281 (100). HRMS m/z calcd. for C19H18N2O5 (M+):
354.1216, found: 354.1220.
General procedure for Michael-Knoevenagel seq-
uence (Method B): A coated Kimble vial was charged with
a mixture of the scaffold A1–A4 (0.60 mmol) in the
appropriate solvent [THF (3 mL) for A1 or A3, toluene for
A2, DMF for A4]. The supported organic base (0.12 mmol
of PS–TBD 2) and the Michael acceptor (0.72 mmol) were
added at the appropriate temperature (rt for A4, 60°C for
scaffolds A1, A2, A3). The sample was vortexed for 30-60
min to give the corresponding N-blocked adduct. Addition of
Ethyl
(2E)-3-[1-(2-phenoxycarbonylethyl)-1,4-dihy-
dro-4-oxoquinolin-3-yl]-2-cyanoacrylate (A1C3D3). Puri-
fication by preparative chromatography using AcOEt/hexane
(1:4). mp: 195-196ºC (iso-PrOH). Yield: 68%. IR (KBr):
the activated methylene compound (1.1 equiv, stirring for 1–
12 h) to the adduct at the appropriate temperature (40°C for
A1, 60°C for A2, rt for A3 and A4) in the corresponding
solvent, led to the final product. The supported reagent was
filtered by a fritted syringe in a Manifold Filtration System
(Visiprep®) and the filtrate was evaporated in vacuum. The
obtained solid or residue was purified by crystallization or
preparative chromatography. The PS-TBD (2) was washed
following the protocol: dioxane, CH2Cl2, diethyl ether and
reused at least three times without important loss of activity.
ꢀ
max/cm–1 2219 (CN), 1752 (COO), 1719 (COO), 1632 (CO),
1586 (Aromatics), 1095 (C-O-C). 1H-NMR (CDCl3 300
MHz), ꢁ (ppm): 9.15 (s, 1H, CH), 8.83 (s, 1H, CH), 8.53 (dd,
J=6.4, J=1.5Hz, 1H, Aromatic), 7.82-7.76 (m, 1H,
Aromatic), 7.60-7.50 (m, 2H, Aromatics), 7.39-7.33 (m, 2H,
Aromatics), 7.26-7.21 (m, 1H, Aromatic), 7.06-6.90 (m, 2H,
Aromatics), 4.67 (t, J= 6.8 Hz, 2H, CH2), 4.36 (q, J= 7.1 Hz,
2H, CH2), 3.23 (t, J= 6.8 Hz, 2H, CH2), 1.37 (t, J= 7.1 Hz,
3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢁ (ppm): 175.2,
168.9, 163.0, 150.3, 148.5, 146.1, 138.7, 134.0, 130.0, 128.9,
127.7, 126.7, 126.4, 121.6, 117.3, 116.1, 114.1, 98.7, 62.7,
49.8, 33.5, 14.64. MS (70 eV) m/z (%): 416 (M+, 2), 344
(23), 343 (100), 281 (6). HRMS m/z calcd. for C24H20N2O5
(M+): 416.1372, found: 416.1375.
Methyl
(2E)-3-[1-(2-ethoxycarbonylethyl)-1,4-dihy-
dro-4-oxoquinolin-3-yl]-2-cyanoacrylate (A1C4D2). Puri-
fication by preparative chromatography using AcOEt/hexane
(1:4). mp: 186-187ºC (iso-PrOH). Yield: 70%. IR (KBr):
ꢀ
max/cm–1 2220 (CN), 1717 (CO), 1624 (CO), 1584
Phenyl 2-[3-(2,2-dicyanovinyl)-quinolin-1(4H)-yl]ace-
tate (A1C3D1). Purification by preparative chromatography
using AcOEt/hexane (1:4). mp: 185-187ºC (iso-PrOH).
Yield 54%. IR (KBr): ꢀmax/cm–1 2221 (CN), 1752 (COO),
1643 (CO), 1585 (Aromatics), 1158 (C-O-C). 1H-NMR
(CDCl3 300 MHz), ꢁ (ppm): 9.09 (s, 1H, CH), 8.40 (s, 1H,
CH), 8.53 (d, J=7.1 Hz, 1H, Aromatic), 7.83-7.80 (m, 1H,
Aromatic), 7.60-7.54 (m, 2H, Aromatics), 7.41-7.36 (m, 2H,
Aromatics), 7.28-7.03 (m, 1H, Aromatic), 7.05 (d J=7.7 Hz,
2H, Aromatics), 4.67 (t, J= 6.8 Hz, 2H, CH2), 3.23 (t, J= 6.8
Hz, 2H, CH2). 13C-NMR (CDCl3 75 MHz), ꢁ (ppm): 168.9,
162.1, 153.4, 150.4, 147.0, 144.5, 138.1, 134.4, 130.0, 129.1,
127.5, 127.0, 126.9, 121.5, 116.3, 114.1, 50.1, 33.3. MS (70
eV) m/z (%): 369 (M+, 8), 276 (11), 234 (52), 94 (38), 55
(100). HRMS m/z calcd. for C22H15N3O3 (M+): 369.1113,
found: 369.1119.
(Aromatics), 1093 (C-O-C). 1H-NMR (CDCl3 300 MHz), ꢁ
(ppm): 9.10 (s, 1H, CH), 8.81 (s, 1H, CH), 8.47 (d, J=8.2 Hz,
1H, Aromatic), 7.74-7.70 (m, 1H, Aromatic), 7.48-7.45 (m,
2H, Aromatics), 4.54 (t, J= 6.7 Hz, 2H, -CH2), 4.15 (q, J=
7.2 Hz, 2H, CH2), 3.86 (s, 3H, OCH3), 2.91 (t, J= 6.7 Hz,
2H, CH2), 1.20 (t, J=7.2 Hz, CH3). 13C-NMR (CDCl3 75
MHz), ꢁ (ppm): 175.2, 169.6, 163.2, 148.4, 145.9, 138.3,
133.4, 128.3, 127.2, 125.9, 116.8, 115.8, 113.3, 97.2, 61.5,
53.0, 49.6, 33.0, 14.0. MS (70 eV) m/z (%): 354 (M+, 16),
323 (4), 295 (100), 267 (16). HRMS m/z calcd. for
C19H18N2O5 (M+): 354.1216, found: 354.1220.
Methyl (2E)-3-[1-(2-cyanoethyl)-1,4-dihydro-4-oxoqu-
inolin-3-yl]-2-cyanoacrylate (A1C1D2) Purification by
preparative chromatography using AcOEt/hexane (1:3). mp:
200-201ºC (iso-PrOH). Yield: 63%. IR (KBr): ꢀmax/cm–1
2218 (CN), 1704 (CO), 1633 (CO), 1588 (Aromatics), 1091
(C-O-C). 1H-NMR (CDCl3 300 MHz), ꢁ (ppm): 9.01 (s, 1H,
CH), 8.82 (s, 1H, CH), 8.51 (d, J=8.2 Hz, 1H, Aromatic),
7.80-7.76 (t, J=7.2 Hz, 1H, Aromatic), 7.54-7.41 (m, 2H,
Aromatics), 4.56 (t, J= 6.8 Hz, 2H, CH2). 3.89 (s, 3H,
OCH3), 3.00 (t, J= 6.8 Hz, 2H, CH2). 13C-NMR (CDCl3 75
MHz), ꢁ (ppm): 162.3, 148.0, 144.6, 138.0, 137.0, 133.9,
128.8, 126.3, 117.1, 115.0, 114.9, 106.2, 98.1, 77.1, 53.1,
49.1, 17.9. MS (70 eV) m/z (%): 307 (M+, 5), 276 (5), 248
(100), 195 (8). HRMS m/z calcd. for C17H13N3O3 (M+):
307.0957, found: 307.0960.
Ethyl (Z)-3-[1-(2-cyanoethyl)-1H-indol-3-yl]-2-cyan-
oacrylate (A2C1D3). Purification by preparative chromato-
graphy using AcOEt/hexane (1:4). mp: 153-154ºC (iso-
PrOH). Yield 80%. IR (KBr): ꢀmax/cm–1 2215 (CN), 1721
1
(CO), 1589 (Aromatics), 1039 (C-O-C). H-NMR (CDCl3
300 MHz), ꢁ (ppm): 8.55 (s, 1H, CH), 8.54 (s, 1H, CH), 7.86
(dd, J=5.1, J=1.6 Hz, 1H, Aromatic), 7.45-7.33 (m, 3H,
Aromatics), 4.57 (t, J= 6.9 Hz, 2H, CH2), 4.37 (q, J= 7.1 Hz,
2H, CH2), 2.94 (t, J= 6.9 Hz, 2H, CH2), 1.35 (t, J= 7.1 Hz,
3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢁ (ppm): 164, 145.8,
138.0, 135.9, 133.0, 128.0, 124.9, 123.5, 118.0, 116.5, 111.5,
110.2, 96.3, 62.5, 43.3, 19.4, 14.7. MS (70 eV) m/z (%): 293
(M+, 100), 253 (64), 225 (26), 179 (9). HRMS m/z calcd. for
C17H15N3O2 (M+): 293.1164, found: 293.1170.
Ethyl (2E)-3-[1-(2-methoxycarbonylethyl)-1,4-dihydro-4-
oxoquinolin-3-yl]-2-cyanoacrylate (A1C2D3). Purification
by preparative chromatography using AcOEt/hexane (1:4).
mp: 173-174ºC (iso-PrOH). Yield 66%. IR (KBr): ꢀmax/cm–1
2212 (CN), 1725 (COO), 1627 (CO), 1610 (CO), 1593
Ethyl (Z)-3-{1-[2-(methoxycarbonylethyl)]-1H-indol-
3-yl}-2-cyanoacrylate
(A2C2D3).
Purification
by
1
(Aromatics), 1092 (C-O-C). H-NMR (CDCl3 300 MHz), ꢁ
preparative chromatography using AcOEt/hexane (1:4). mp:
(ppm): 9.11 (s, 1H, CH), 8.80 (s, 1H, CH), 8.48-8.46 (m, 1H,
Aromatic), 7.75-7.70 (m, 1H, Aromatic), 7.49-7.42 (m, 2H,
Aromatics), 4.55 (t, J= 6.7 Hz, 2H, CH2). 4.33 (q, J= 7.1 Hz,
85-87ºC (iso-PrOH). Yield: 78%. IR (KBr): ꢀmax/cm–1 2215
1
(CN), 1732 (CO), 1586 (Aromatics), 1095 (C-O-C). H-
NMR (CDCl3 300 MHz), ꢁ (ppm): 8.54 (s, 1H, CH), 8.53 (s,

Formyl-Aza-Heterocycles
Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7 579
1H, CH), 7.83-7.80 (m, 1H, Aromatic), 7.44-7.29 (m, 3H,
Aromatics), 4.55 (t, J= 6.9 Hz, 2H, CH2). 4.34 (q, J= 7.0 Hz,
2H, CH2), 3.70 (s, 3H, CH3), 2.94 (t, J= 6.9 Hz, 2H, CH2),
1.38 (t, J= 7.0 Hz, 3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢀ
(ppm): 171.0, 164.2, 146.1, 136.2, 134.1, 128.8, 124.4,
123.2, 119.1, 118.5, 110.8, 110.7, 94.9, 62.3, 52.6, 43.2,
34.7, 14.7. MS (70 eV) m/z (%): 326 (M+, 100), 312 (36),
253 (32), 239 (24). HRMS m/z calcd. for C18H18N2O4 (M+):
326.1267, found: 326.1270.
using AcOEt/hexane (1:4). mp: 113-114ºC (iso-PrOH).
Yield: 50%. IR (KBr): ꢁmax/cm–1 2210 (CN), 1733 (COO),
1700 (COO), 1656 (CO), 1589 (Aromatics), 1100 (C-O-C).
1H-NMR (CDCl3 300 MHz), ꢀ (ppm): 7.89 (s, 1H, CH), 7.50
(s, 1H, CH), 7.48-7.43 (m, 3H, Aromatics), 7.37-7.34 (m,
2H, Aromatics), 5.29-5.11 (m, 1H, CH), 4.55 (t, J=7.1 Hz,
2H, CH2), 3.67 (s, 3H, OCH3), 2.91 (t, J= 7.1 Hz, 2H, CH2),
1.34 (d, J=6.2 Hz, 6H, 2 x CH3). 13C-NMR (CDCl3 75
MHz), ꢀ (ppm): 171.9, 160.0, 158.0, 149.4, 145.0, 135.2,
133.2, 130.3, 129.7, 129.3, 129.1, 113.5, 111.8, 72.2, 52.3,
48.0, 32.8, 22.0. MS (70 eV) m/z (%): 395 (M+, 1), 295 (18),
253 (25), 222 (47), 164 (42), 59 (100). HRMS m/z calcd. for
C21H21N3O5 (M+): 395.1481, found: 395.1487.
Ethyl (Z)-3-{1-[2-(ethoxycarbonylethyl)]-1H-indol-3-
yl}-2-cyanoacrylate (A2C4D3). Purification by preparative
chromatography using AcOEt/hexane (1:4). mp: 78-80ºC
(iso-PrOH) Yield: 78%. IR (KBr): ꢁmax/cm–1 2226 (CN),
1731 (CO), 1587 (Aromatics), 1092 (C-O-C). 1H-NMR
(CDCl3 300 MHz), ꢀ (ppm): 8.54 (s, 1H, -CH), 8.53 (s, 1H, -
CH), 7.80 (d, J= 6.8 Hz, 1H, Aromatic), 7.45-7.42 (m, 1H,
Aromatic), 7.37-7.28 (m, 2H, Aromatics), 4.54 (t, J= 6.8 Hz,
2H, CH2). 4.33 (q, J= 7.1 Hz, 2H, CH2), 4.15 (q, J= 7.1 Hz,
2H, CH2), 2.89 (t, J= 6.8 Hz, 2H, CH2), 1.38 (t, J= 7.1 Hz,
3H, CH3), 1.21 (t, J= 7.1 Hz, 3H, CH3). 13C-NMR (CDCl3 75
MHz), ꢀ (ppm): 170.6, 164.2, 146.1, 139.7, 136.3, 134.1,
128.8, 124.4, 123.1, 119.0, 118.5, 110.8, 94.8, 62.3, 61.7,
43.3, 34.9, 14.7, 14.4. MS (70 eV) m/z (%): 340 (M+, 100),
253 (31), 225 (35), 179 (27), 140 (24). HRMS m/z calcd. for
C19H20N2O4 (M+): 340.1423, found: 340.1425.
Ethyl (2E)-3-[1-(2-cyanoetil)-1,6-dihydro-6-oxo-3-phenyl-
pyridazin-4-yl]-2-cyanoacrylate (A3C1D3). Purification by
preparative chromatography using AcOEt/hexane (1:4) mp:
173-174ºC (iso-PrOH). Yield: 52%. IR (KBr): ꢁmax/cm–1
2235 (CN), 1739 (CO), 1669 (CO), 1584 (Aromatics), 1094
1
(C-O-C). H-NMR (CDCl3 300 MHz), ꢀ (ppm): 7.90 (s, 1H,
CH), 7.54 (s, 1H, CH), 7.51-7.47 (m, 3H, Aromatics), 7.45-
7.38 (m, 2H, Aromatics), 4.53 (t, J= 6.7 Hz, 2H, CH2), 4.38
(q, J=7.1 Hz, 2H, CH2), 2.98 (t, J= 6.7 Hz, 2H, CH2), 1.38 (t,
J= 7.1 Hz, 3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢀ (ppm):
160.2, 158.3, 148.9, 136.1, 133.2, 130.2, 129.6, 129.0, 128.9,
128.5, 116.7, 112.9, 111.2, 63.5, 47.7, 16.5, 13.9. MS (70
eV) m/z (%): 348 (M+, 68), 319 (29), 275 (32), 266 (65), 222
(100), 164 (19). HRMS m/z calcd. for C19H16N4O3 (M+):
348.1222, found: 348.1229.
Methyl (Z)-3-{1-[2-(phenoxycarbonylethyl)]-1H-indol-
3-yl}-2-cyanoacrylate (A2C3D2). Purification by prepa-
rative chromatography using AcOEt/hexane (1:4). M.P: 106-
107ºC (iso-PrOH). Yield: 75%. IR (KBr): ꢁmax/cm–1 2214
(CN), 1757 (CO), 1711 (CO), 1580 (Aromatics), 1094 (C-O-
Methyl 3-[4-(2,2-dicyanovinyl)-1,6-dihydro-6-oxo-3-
phenylpyridazin-4-yl]propanoate (A3C2D1). Purification
by preparative chromatography using AcOEt/hexane (1:4).
mp: 127-128ºC (iso-PrOH). Yield: 65%. IR (KBr): ꢁmax/cm–1
2235 (CN), 1736 (COO), 1670 (CO), 1588 (Aromatics),
1
C). H-NMR (CDCl3 300 MHz), ꢀ (ppm): 8.61 (s, 1H, CH),
8.59 (s, 1H, CH), 7.86 (d, J= 8.4 Hz, 1H, Aromatic), 7.51 (d,
J= 8.4 Hz, 1H, Aromatic), 7.41-7.36 (m, 4H, Aromatics),
7.33-7.22 (m, 1H, Aromatic), 7.09 (d, J= 7.8 Hz, 1H,
Aromatic). 7.00 (d, J= 7.8 Hz, 1H, Aromatic), 4.67 (t, J= 6.8
Hz, 2H, CH2), 3.91 (s, 3H, CH3), 3.18 (t, J= 6.8 Hz, 2H,
CH2). 13C-NMR (CDCl3 75 MHz), ꢀ (ppm): 170.2, 168.7,
146.3, 136.5, 134.0, 129.9, 129.9, 128.0, 126.6, 126.4, 124.6,
123.2, 121.8, 121.7, 119.2, 110.8, 94.6, 43.2, 35.0, 32.2. MS
(70 eV) m/z (%): 374 (M+, 28), 239 (100), 179 (23), 94 (37).
HRMS m/z calcd. for C22H18N2O4 (M+): 374.1267, found:
374.1266.
1
1092 (C-O-C). H-NMR (CDCl3 300 MHz), ꢀ (ppm): 7.58-
7.50 (m, 5H, Aromatics), 7.47 (s, 1H, CH), 7.34 (s, 1H, CH),
4.38 (t, J=6.9 Hz, 2H, CH2), 3.67 (s, 3H, OCH3), 2.90 (t, J=
6.9 Hz, 2H, CH2). 13C-NMR (CDCl3 75 MHz), ꢀ (ppm):
171.5, 158.2, 154.9, 144.5, 134.4, 134.0, 130.8, 129.9, 129.7,
129.1, 113.2, 111.1, 91.9, 52.3, 48.2, 32.7. MS (70 eV) m/z
(%): 334 (M+, 22), 303 (16), 275 (26), 247 (50), 234 (100),
222 (25), 191 (23). HRMS m/z calcd. for C18H14N4O3 (M+):
334.1065, found: 334.1068.
Isopropyl (Z)-3-{1-[2-(ethoxycarbonylethyl)]-1H-indol-
3-yl}-2-cyanoacrylate (A2C4D4). Purification by pre-
parative chromatography using AcOEt/hexane (1:4). mp:
101-102ºC (iso-PrOH). Yield: 68%. IR (KBr): ꢁmax/cm–1
2211 (CN), 1711 (CO), 1641 (CO), 1097 (C-O-C). 1H-NMR
(CDCl3 300 MHz), ꢀ (ppm): 8.56 (s, 1H, -CH), 8.55 (s, 1H, -
CH), 7.83 (d, J= 7.3 Hz, 1H, Aromatic), 7.45-7.41 (m, 1H,
Aromatic), 7.39-7.30 (m, 3H, Aromatics), 5.29-5.15 (m, 1H,
CH), 4.56 (t, J= 6.8 Hz, 2H, CH2), 4.16 (q, J= 7.1 Hz, 2H,
CH2), 2.90 (t, J= 6.8 Hz, 2H, CH2), 1.37 (d, J= 6.2 Hz, 6H, 2
x CH3), 1.22 (t, J= 7.1 Hz, 3H, CH3). 13C-NMR (CDCl3 75
MHz), ꢀ (ppm): 170.1, 164.0, 145.9, 136.1, 134.0, 128.5,
124.4, 123.0, 119.1, 118.8, 110.7, 109.3, 95.3, 70.1, 61.7,
43.3, 35.0, 22.2, 14.5. MS (70 eV) m/z (%): 354 (M+, 56),
340 (30), 312 (56), 225 (100), 179 (66), 140 (70). HRMS m/z
calcd. for C20H22N2O4 (M+): 354.1579, found: 354.1583.
Methyl (2E)-3-{1-[2-(ethoxycarbonylethyl)]-1,6-dihy-
dro-6-oxo-3-phenylpyridazin-4-yl}-2-cyanoacrylate (A3C
4D2). Purification by preparative chromatography using
AcOEt/hexane (1:4). mp: 151-152ºC (iso-PrOH). Yield:
62%. IR (KBr): ꢁmax/cm–1 2135 (CN), 1736 (COO), 1703
1
(COO), 1665 (CO), 1588 (Aromatics), 1093 (C-O-C). H-
NMR (CDCl3 300 MHz), ꢀ (ppm): 7.91 (s, 1H, CH), 7.49-
7.44 (m, 4H, 3H Aromatics+ 1H CH), 7.37-7.33 (m, 2H,
Aromatics), 4.54 (t, J= 7.1 Hz, 2H, CH2), 4.13 (q, J= 7.1 Hz,
2H, CH2), 3.91 (s, 3H, OCH3), 2.88 (t, J= 7.1 Hz, 2H, CH2),
1.20 (t, J= 7.1 Hz, 3H, CH3). 13C-NMR (CDCl3 75 MHz), ꢀ
(ppm): 171.2, 161.3, 158.8, 150.0, 145.0, 135.7, 134.0,
130.0, 129.8, 129.3, 129.1, 113.3, 110.8, 61.2, 54.3, 48.1,
33.0, 14.5. MS (70 eV) m/z (%): 381 (M+, 11), 336 (12), 282
(17), 267 (100), 222 (46), 164 (19). HRMS m/z calcd. for
C20H19N3O5 (M+): 381.1324, found: 381.1325.
Isopropyl (2E)-3-{1-[2-(methoxycarbonylethyl)]-1,6-
dihydro-6-oxo-3-phenylpyridazin-4-yl}-2-cyanoacrylate
(A3C2D4). Purification by preparative chromatography
Methyl (2E)-3-{1,6-dihydro-6-oxo-1-[2-(phenoxycarb-
onylethyl)]-3-phenylpyridazin-4-yl}-2-cyanoacrylate (A3
C3D2). Purification by preparative chromatography using

580 Combinatorial Chemistry & High Throughput Screening, 2011, Vol. 14, No. 7
El Maatougui et al.
AcOEt/hexane (1:4). mp: 113-114ºC (iso-PrOH). Yield:
66%. IR (KBr): ꢀmax/cm–1 2134 (CN), 1743 (COO), 1707
Ethyl (E)-3-{1-[2-(methoxycarbonyl)ethyl]-1H-imida-
zol-4-yl}-2-cyanoacrylate (A4C2D3). Purification by
preparative chromatography using AcOEt/hexane (1:4). mp:
136.1-138.3ºC (iso-PrOH). Yield: 71%. IR (KBr): ꢀmax/cm–1
2221 (CN), 1735 (COO), 1713 (COO), 1609 (CO). 1H-RMN
(CDCl3, 300 MHz), ꢁ (ppm): 8.30 (s, 1H, C=CH), 8.10 (s,
1H, H5), 7.74 (s, 1H, H3), 4.41 (t, J=7.1 Hz, 2H, CH2), 4.39
(t, J=6.2 Hz, 2H, CH2), 4.35 (s, 3H, OCH3), 2.87 (t, J=6.2
Hz, 2H, CH2), 1.42 (t, J=7.2 Hz, 3H, OCH3). 13C-RMN
(CDCl3, 75.5 MHz), ꢁ (ppm): 170.3, 162.5, 148.1, 139.1,
135.9, 125.9, 116.2, 99.1, 62.1, 52.2, 42.9, 35.1, 14.0. MS
(70 eV) m/z (%): 277 (M+, 91), 232 (80), 205 (100), 146
(87). HRMS m/z calcd. for C13H15N3O4 (M+): 277.1063,
found: 277.1063.
1
(COO), 1662 (CO), 1581 (Aromatics), 1108 (C-O-C). H-
NMR (CDCl3 300 MHz), ꢁ (ppm): 7.92 (s, 1H, CH), 7.53 (s,
1H, CH), 7.48-7.43 (m, 3H, Aromatics), 7.37-7.16 (m, 5H,
Aromatics), 6.96 (d, J=6.7 Hz, 2H, Aromatics), 4.68 (t,
J=6.7 Hz, 2H, CH2), 3.92 (s, 3H, CH3), 3.14 (t, J= 6.7 Hz,
2H, -CH2). 13C-NMR (CDCl3 75 MHz), ꢁ (ppm): 169.8,
162.2, 158.9, 150.9, 149.8, 145.3, 135.8, 134.0, 130.4, 129.9,
129.7, 129.4, 129.2, 126.3, 121.8, 113.3, 110.9, 54.35, 48.05,
33.29. HRMS m/z calcd. for C24H19N3O5 (M+): 429.1324,
found: 429.1325.
Methyl (E)-3-{1-[2-(methoxycarbonyl)ethyl]-1H-imi-
dazol-4-yl}-2-cyanoacrylate (A4C2D2). Purification by
preparative chromatography using AcOEt/hexane (1:4). mp:
163.2-165.3ºC. (iso-PrOH). Yield: 72%. IR (KBr): ꢀmax/cm–1
2220 (CN), 1735 (COO), 1715 (COO), 1608 (CO). 1H-RMN
(CDCl3, 300 MHz), ꢁ (ppm): 8.07 (s, 1H, C=CH), 7.87 (s,
1H, H5), 7.52 (s, 1H, H3), 4.17 (t, J=6.2 Hz, 2H, CH2), 3.71
(s, 3H, OCH3), 3.54 (s, 3H, OCH3), 2.66 (t J=6.2 Hz, 2H,
CH2). 13C-RMN (CDCl3, 75.5 MHz), ꢁ (ppm): 170.3, 163.1,
148.4, 139.2, 135.9, 126.0, 116.1, 98.6, 52.9, 52.2, 42.9,
35.1. MS (70 eV) m/z (%): 263 (M+, 87), 232 (61), 204
(100). HRMS m/z calcd. for C12H13N3O4(M+): 263.0906,
found: 263.0910.
Methyl
(E)-3-{1-[2-(2-ethoxyethoxy)carbonyl]ethyl-
1H-imidazol-4-yl}-2-cyanoacrylate (A4C5D2). Purification
by recrystalisation. Yield: 65%. mp: 98.3-99.8 ºC (iso-
PrOH). IR (KBr): ꢀmax/cm–1 2134 (CN), 1743 (COO), 1707
1
(COO), 1662 (CO), 1581 (Aromatics), 1108 (C-O-C). H-
RMN (CDCl3, 300 MHz), ꢁ (ppm): 8.25 (s, 1H, C=CH), 8.05
(s, 1H, H5), 7.71 (s, 1H, H3), 4.35 (t, J=6.3 Hz, 2H, CH2),
4.27 (t, J=4.7 Hz, 2H, CH2), 3.90 (s, 3H, OCH3), 3.61 (t,
J=4.7 Hz, 2H, CH2), 3.51 (q, J=7.0 Hz, 2H, CH2), 2.88 (t,
J=6.3 Hz, 2H, CH2), 1.21 (t, J=7.0 Hz, 2H, CH3). 13C-RMN
(CDCl3, 75.5 MHz), ꢁ (ppm): 169.9, 163.1, 148.2, 139.4,
135.7, 126.1, 116.1, 98.4, 67.8, 66.4, 64.3, 52.9, 42.8, 35.3,
14.8. MS-CI (70 eV) m/z (%): 325 (6), 324 (40), 323 (57),
322 (100), 321 (10). HRMS m/z calcd. for C15H19N3O5 (M+):
321.3285, found: 321.3290.
Methyl 3-[4-(2,2-dicyanovinyl)-1H-imidazol-1-yl)pró-
panoate (A4C2D1). Purification by preparative chromato-
graphy using AcOEt/hexane (1:4). mp: 141.2-143.4ºC (iso-
PrOH). Yield: 74%. IR (KBr): ꢀmax/cm–1 2218 (CN), 1718
1
(COO), 1611 (CO). H-RMN (CDCl3, 300 MHz), ꢁ (ppm):
ACKNOWLEDGEMENTS
7.75 (s, 1H, C=CH), 7.55 (s, 2H, H5 + H3), 4.18 (t,, J=6.1 Hz,
2H, CH2), 3.54 (s, 3H, OCH3), 2.66 (t, J=6.1 Hz, 2H, CH2).
13C-RMN (CDCl3, 75.5 MHz), ꢁ (ppm): 170.3, 151.9, 139.8,
135.5, 127.2, 113.9, 113.7, 63.8, 52.3, 43.0, 35.0. MS (70
eV) m/z (%): 230 (M+, 58), 171 (100), 157 (100). HRMS m/z
calcd. for C11H10N4O2 (M+): 230.0804, found: 230.0814.
Thanks are due to University of Aveiro, FCT and
FEDER for funding the Organic Chemistry Research (Unity
and Project POCI/QUI/58838/2004). A. Coelho is researcher
of the Isidro Parga Pondal program (Xunta de Galicia,
Spain).
2-[(1-(2-Cyanoethyl)-1H-imidazol-4-yl)methylene]ma-
lononitrile (A4C1D1). Purification by recrystalisation. mp:
SUPPLEMENTARY MATERIAL
194.1-196.3ºC (iso-PrOH). Yield: 84%. IR (KBr): ꢀmax/cm–1
1
Supplementary material (copies of all the NMR, C13, IR
and mass spectra for disubstituted heterocycles ABD and
ACD) is available online at publisher’s website.
2205 (CN), 1605 (CO). H-RMN (DMSO-d6, 300 MHz), ꢁ
(ppm): 8.25 (s, 1H, C=CH), 8.09 (s, 1H, H5), 8.06 (s, 1H,
H3), 4.38 (t, J=6.3 Hz, 2H, CH2), 3.10 (t, J=6.3 Hz, 2H,
CH2). 13C-RMN (DMSO-d6, 75.5 MHz), ꢁ (ppm): 151.9,
141.4, 135.2, 131.0, 118.3, 115.5, 113.8, 74.8, 42.5, 19.3.
MS (70 eV) m/z (%): 197 (M+, 97), 157 (100), 130 (40).
HRMS m/z calcd. for C10H7N5 (M+): 197.0701, found:
197.0708.
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Sundberg, R. J. Indoles; Academic Press: London, 1996.
For A3B1D2 the vicinal coupling constant of the olefinic proton
with the CN is considerably larger (JH-CN = 13.8 Hz) than that with
the ester (J H-COOMe = 7.1 Hz). For A4C2D2, J H-CN = 13.4 Hz. For
For publications related to the catalysis of Knovoenagel reaction by
supported reagents, see: (a) Isobe, K.; Hoshi, T.; Suzuki, T.;
Hagiwara, H. Knoevenagel reaction in water catalyzed by amine
supported on silica gel. Mol. Divers., 2005, 9, 317-320. (b)
A1B1D2, J
= 14.0 Hz. For A2B3D2, J
= 7.0 Hz. (See
H-CN
H-CN
supporting information).
Received: December 22, 2010
Revised: February 23, 2011
Accepted: March 30, 2011