Efficient consecutive alkylation-Knoevenagel functionalisations in formyl aza-heterocycles using supported organic bases

Article abstract of DOI:10.1055/s-2006-951559

An efficient solution-phase parallel procedure to perform the structural diversification of some formyl aza-heterocycles employing supported organic bases (PS-BEMP, PS-TBD or Si-TBD) is described. The library synthesis is based on a consecutive alkylation-Knoevenagel functionalisation that employs alkyl halides, Michael acceptors, and malonic acid derivatives as diversity elements. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951559

3324
LETTER
Efficient Consecutive Alkylation–Knoevenagel Functionalisations in Formyl
Aza-Heterocycles Using Supported Organic Bases
Efficient
C
onsecut
l
ive Alk
b
ylation–Kno
e
evenagel
F
r
unctiona
t
lisation
o
s
Coelho,a Abdelaziz El-Maatougui,b Enrique Raviña,b José A. S. Cavaleiro,a Artur M. S. Silva*a
a
Departamento de Química, Universidade de Aveiro, 3810-193 Aveiro, Portugal
Fax +351(234)370084; E-mail: arturs@dq.ua.pt
b
Departamento de Química Orgánica, Laboratorio de Química Farmacéutica, Facultad de Farmacia, Universidad de Santiago de
Compostela, 15782 Santiago de Compostela, Spain
Received 8 August 2006
which have a multitude of applications in organic synthe-
sis.8,9 Currently, several TBD-supported reagents are
commercially available, with the polystyrene–TBD (2) or
silica gel–TBD (3) being to date the most employed ex-
Abstract: An efficient solution-phase parallel procedure to per-
form the structural diversification of some formyl aza-heterocycles
employing supported organic bases (PS–BEMP, PS–TBD or Si–
TBD) is described. The library synthesis is based on a consecutive
alkylation–Knoevenagel functionalisation that employs alkyl ha- amples. Although several works describing the applica-
lides, Michael acceptors, and malonic acid derivatives as diversity
elements.
tions and versatility of these bases have been recently
published (not only as stoichiometric reagents but also as
Key words: supported bases, catalysis, consecutive functionalisa-
tions, Knoevenagel condensation, Michael addition
catalysts or scavengers), to the best of our knowledge its
usefulness in consecutive functionalisations of pharmaco-
logically interesting scaffolds have not been reported.
Currently, combinatorial methods focusing on small or-
ganic molecules are mainly dominated by two strategies:
solid-phase synthesis1 and with increasing importance so-
lution-phase parallel protocols.2 The use of supported re-
agents and scavengers is an excellent way to expedite
organic synthesis by simplifying the purification process,
since standard purification procedures (such as chroma-
tography, liquid–liquid extraction, and crystallisation) can
be time-consuming and difficult to scale up. Supported re-
agents have remarkable advantages3 over their solution-
phase counterparts, the biggest one being the ability to use
incompatible reagents simultaneously, along with the pos-
sibility to do multiple transformations in a single pot, im-
mobilisation of toxic reagents, and an increased
selectivity. Although there are often important issues of
reaction kinetics to be addressed when using such re-
agents, the relative ease of separating the spent reagents
from the products by simple filtration and monitoring the
process by thin layer chromatography, can render this an
attractive option for rapid analogue synthesis.4
N
N
N
P
N
N
N
N
N
N
N
Si
PS
PS
1
2
3
PS–BEMP
PS–TBD
Si–TBD
Figure 1 Structures of the employed supported bases
Nitrogen heterocycles are ubiquitous systems in nature
and are consequently usually considered as privileged
structures in drug discovery.10 Derivatisation of these het-
erocyclic pharmacophores represents a convenient ap-
proach to generate chemical diversity during lead
identification and optimisation. During the course of our
program to develop new synthetic strategies to obtain
functionalised heterocyclic libraries, the formyl aza-het-
erocycles A1, A2 and A3 were selected as convenient
starting materials (Figure 2).
Supported organic bases and catalysts have increased
their applications in fine chemical synthesis as a conse-
quence of the emergent field of combinatorial chemistry.
Especially interesting for solution-phase synthesis and
high-throughput chemistry are PS–BEMP and polymer-
bound TBD reagents.5 PS–BEMP (2-tert-butylimino-2-
diethylamino-1,3-dimethylperhydro-1,3,2-diazaphospho-
rine)6 (1; Figure 1) has been used successfully as a strong
base for parallel synthesis in combination with other
polymeric reagents.7 1,5,7-Triazabicyclo[4.4.0]dec-5-ene
(TBD) is the prototype of a group of guanidine bases
By exploiting the reactivity of the formyl group and
the acidic NH of these valuable scaffolds, we present
here a straightforward and effective one-pot strategy to
expand the chemical diversity of quinolones, indoles
and pyridazinones using supported TBD or BEMP bases
in alkylation–Knoevenagel or aza-Michael–Knoevenagel
sequences (Figure 3).
The selected scaffolds A are commercially available [3-
formyl indole, (A2)] or are readily prepared. The synthe-
sis of pyridazinone A3 was previously described11 while
quinolone A1 was easily obtained in a new and conve-
nient approach through Vielsmeier reaction on 2¢-ami-
noacetophenone (AA)12 and subsequent acidic hydrolysis
SYNLETT 2006, No. 19, pp 3324–3328
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951559; Art ID: D24206ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Consecutive Alkylation–Knoevenagel Functionalisations
3325
O
H
O
H
O
H
N
N
R1
R2
N
HET
O
HN
O
HET
A
O
N
=
R3
H
N
H
H
H
H
A2
A1
A3
Figure 2 General structure of targeted libraries, retrosynthetic scheme and structure of the scaffolds A
Aza-Michael–Knoevenagel sequence
Method B
Alkylation–Knoevenagel sequence
Method A
R2
R2
(C1–4)
R1X (B1–4)
B:
R1
HN
N
N
HET
HET
HET
CHO
CHO
B:
CHO
AC
AB
A
R3
R4
B:
R3
R4
B:
TBD
TBD
PS
Si
(D1–4)
(D1–4)
B:
R1
BEMP
R2
PS
N
R4
N
R4
HET
HET
R3
R3
ACD
ABD
HET: Indole, 4(1H)-Quinolone, Pyridazin-3(2H)-one.
R1 = Me, Et, CH2COOEt, Bn; R2 = COOMe, COOEt, CN, COOPh; R3 = CN, COOMe, COOEt, COOiPr; R4 = CN
Figure 3 Synthesis of densely substituted aza-heterocycles through one-pot consecutive functionalisations using supported bases
of 4-chloro-3-formylquinoline (Q1) with 85% formic acid Previous studies on these heterocycles described the use
(Scheme 1).
of conventional bases (e.g., K2CO3, Et3N, TBD, MTBD,
DBU or BEMP) to perform the alkylation or Michael ad-
dition to quinolones,14 pyridazinones15 and indoles.16 The
Knoevenagel condensation required the use of specific re-
agents (AlCl3 or piperidine), depending on the reactivity
of each scaffold. Consequently, our preliminary efforts
were aimed to find a compatible combination of conven-
tional bases to achieve the one-pot procedure to access the
target structures. Unfortunately, these experiments
showed a different behaviour depending on the studied
scaffold (A1–A3) and sequence used. Generally low
yields were obtained as a consequence of the complex pu-
rification process. Therefore, the use of supported bases
was envisioned as an improved alternative that could
avoid the use of high temperatures, long reaction times
and tedious workup of intermediates.
The first stage of the study involved a comprehensive
screening process to identify mild and selective alkylation
conditions by employing different alkyl halides B or
Michael acceptors C, which could be optimised for each
scaffold and, most importantly, would be compatible with
the experimental conditions of the subsequent
Knoevenagel8b,13 reaction. A small subset of alkyl halides
B1–B4 (benzyl bromide, methyl or ethyl iodides and ethyl
bromoacetate), acrylates C1–C4 (methyl, ethyl, phenyl
acrylates and acrylonitrile) and malonic acid derivatives
D1–D4 (methyl and ethyl cyanoacetates and malononi-
trile) (Figure 3) was employed as building blocks to eval-
uate their functional group compatibility and potential
utility as a source of diversity.
O
O
H
Cl
H
85% HCOOH–H2O,
DMF, 70 °C
1. POCl3, DMF
O
O
2. H2O, 35%
NH2
80%
N
H
N
AA
Q1
A1
Scheme 1 Synthesis of 3-formyl-4-quinolone (A1)
Synlett 2006, No. 19, 3324–3328 © Thieme Stuttgart · New York

3326
A. Coelho et al.
LETTER
O
N
O
N
O
N
O
O
N
O
N
COOMe
CN
COOEt
CN
COOi-Pr
CN
CN
COOEt
CN
COOMe
CN
CN
N
O
CN
O
A1B3D1 (72%)
(0.5/12)
A1B2D3 (64%)
(0.5/12)
A1B1D2 (77%)
(0.5/12)
A1B4D3 (70%)
(0.5/14)
A1B4D4 (63%)
(0.5/8)
A1C1D2 (63%)
(0.5/16)
O
O
O
O
O
COOEt
CN
CN
CN
O
COOEt
COOMe
MeOOC
NC
N
N
CN
CN
N
N
CN
COOEt
CN
N
CN
N
N
N
Ph
Ph
COO
COO
COOMe
COOEt
A1C2D3 (66%)
(0.5/14)
A1C4D2 (70%)
(0.5/16)
A1C3D3 (68%)
(0.5/14)
A1C3D1 (54%)
(0.5/8)
A3C1D3 (52%)
(0.5/4)
A3C2D1 (65%)
(0.5/4)
O
O
O
O
O
O
EtOOC
PhOOC
MeOOC
O
N
N
N
N
N
N
N
N
N
N
N
N
CN
CN
COOMe
CN
COOi-Pr
CN
COOMe
CN
COOEt
CN
COOMe
O
COOMe
Ph
Ph
Ph
Ph
Ph
Ph
A3C4D2 (62%)
(0.5/4)
A3C3D2 (66%)
(0.5/4)
A3C2D4 (50%)
(0.5/4)
A3B1D2 (69%)
(0.5/4)
A3B3D3 (65%)
(0.5/4)
A3B4D2 (72%)
(0.5/4)
CN
CN
CN
CN
O
O
*
*
*
*
COOEt
N
COOEt
COOEt
COOMe
N
N
N
N
N
CN
CN
CN
N
N
COOi-Pr
Ph
Ph
COOEt
COOMe
COO
CN
A3B2D1 (70%)
(0.5/4)
A2C1D3 (70%)
(0.5/12)
A2C4D3 (78%)
(0.5/12)
A2C2D3 (78%)
(0.5/12)
A2C3D2 (75%)
(0.5/12)
A3B1D4 (57%)
(0.5/4)
CN
CN
CN
CN
CN
CN
*
COOi-Pr
COOMe
N
COOMe
COOEt
N
COOi-Pr
CN
N
N
N
N
O
COOEt
O
A2B1D1 (72%)
(0.5/12)
A2B3D2 (65%)
(0.5/14)
A2B2D2 (74%)
(0.5/12)
A2B4D3 (67%)
(0.5/14)
A2B2D4 (63%)
(0.5/8)
A2C4D4 (68%)
(0.5/8)
Figure 4 Representative structures of diversely functionalised heterocycles produced. Yields (%) and vortex/reaction times (h) are reported
in parentheses. All reactions were performed with 2 as preferable base.19
* The stereochemistry of all compounds was determined through NMR experiments,11 with pyridazinone and quinolone compounds having an
E configuration and Z for indole derivatives. The E configuration was assigned unambiguously from the 1H-coupled 13C NMR spectrum. For
example for A3B1D2 the vicinal coupling constant of the olefinic proton with the CN is considerably larger (J = 13.8 Hz) than that with the
ester (J = 7.1 Hz).
In order to define the scope and efficiency of these meth- formation. Toluene was optimal only when indole was
odologies, we have screened a variety of reaction condi- employed as scaffold. The observed order of reactivity of
tions adaptable to the different scaffolds A employing the these scaffolds towards the alkylation process was: pyr-
supported bases 1, 2 or 3. With the aim to validate the idazinone > quinolones > indole. This protocol was mon-
claimed intrinsic advantages of functionalised silicas17 itored by thin-layer chromatography or EI–MS technique.
(such as no swelling, solvent compatibility) over polysty- During these experiments we experienced that the reac-
rene resins for these transformations, we decided to study tions employing stronger PS–BEMP were slightly faster
the differences between 2 and 3.
during the alkylation process (1.5 equiv of base, r.t., 10–
20 min, with almost quantitative yields) than PS–TBD (2)
or Si–TBD (3) (which require 2.5 equiv of supported base
and increased reaction times). While the alkylation pro-
Alkylation–Knoevenagel Sequence (Method A)
The solubility of the scaffolds in several solvents (THF, cess proceeded almost quantitatively by using either 1, 2
toluene, DMF, MeCN) as well as the swelling of the bases or 3, the Knoevenagel condensation employing PS–
1–3 during the two processes was first examined. The best BEMP showed to be problematic [longer reaction times
results were obtained using tetrahydrofuran for quinolone (48–72 h)]. Such behaviour was also observed during con-
A1 and pyridazinone A3 and toluene for indole A2. Ace- secutive reactions, as in the case of scaffolds A1 and A2.
tonitrile was efficient for the first step of alkylation but Therefore, the library production was performed employ-
longer reaction times were required for the complete con- ing PS–TBD (2) as base for all sequences.
version of the intermediate during the Knoevenagel trans-
Synlett 2006, No. 19, 3324–3328 © Thieme Stuttgart · New York

LETTER
Efficient Consecutive Alkylation–Knoevenagel Functionalisations
3327
(5) Relative base strength of supported bases used in this study;
the pKa values reported for the conjugated acids of their
corresponding non-supported analogues are: TBD: 25.44
(MeCN, 25 °C), BEMP: 27.63 (MeCN, 25 °C); see ref. 6a.
Supported reagents employed in this work were purchased
from Fluka (PS–BEMP), Argonaut (PS–TBD) and Silicycle
(Si–TBD).
(6) (a) Schwesinger, R.; Willaredt, J.; Schemper, H.; Keller, M.;
Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435.
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2004, 923. (c) Graybill, T. L.; Thomas, S.; Wang, M. A.
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Fernández Mayorales, A.; Fiandos, J. M.; García-Ochoa, S.;
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Chem., Int. Ed. Engl. 1997, 36, 2261. (b) Fringuelli, F.;
Pizzo, F.; Vittoriani, C.; Vaccaro, L. Chem. Commun. 2004,
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Lett. 1997, 38, 7337. (d) Organ, M. G.; Dixon, C. E.
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2005, 46, 2445.
Aza-Michael–Knoevenagel Sequence (Method B)
Although the scope of Michael reaction using these re-
agents has been well reported,8a,b to the best of our knowl-
edge, no examples of aza-Michael reactions18 using 1, 2 or
3 have been described. Whereas alkylation of A1–A3 with
alkyl halides required two to three equivalents of support-
ed base, aza-Michael reaction of A1–A3 with acrylates C
proceeded employing catalytic amounts (20% mol) of
base 1–3. These supported bases afforded readily the aza-
Michael-adducts under mild conditions. Although PS–
BEMP (1) can be employed for this sequence, long reac-
tion times were required for the Knoevenagel step for the
scaffolds A1 and A2 and small quantities of byproducts
were present in the mixture.
The remarkable effectiveness and compatibility of the
supported bases 2 and 3 was confirmed for both sequenc-
es. All the studied bases successfully catalyse the first
transformation of the sequence (alkylation or aza-Micha-
el), independent of their basicity profile. PS–TBD (2) was
a more versatile reagent taking into account the scaffold
variability. It is important to note that, in the present
study, we did not observe the claimed significant differ-
ences between Si–TDB (3) and PS–TBD (2), probably
due to the fact that the latter can swell sufficiently in the
solvents used. Consequently, for the library production
(Figure 4), the more effective and less expensive PS–TBD
(2) was routinely employed.
In conclusion, a simple solution-phase approach has been
developed, easily adaptable to the parallel synthesis of in-
doles, quinolones and pyridazinones.20 These sequences
are not only novel but also constitute the first examples of
a consecutive alkylation–Knoevenagel and aza-Michael–
Knoevenagel one-pot functionalisations allowing to ex-
pand rapidly the molecular diversity of quinolone, indole
and pyridazinone libraries by using PS–TBD (2) as a rec-
ommended supported organic base.
(9) Ye, W.; Xu, J.; Tan, C.-T.; Tan, C.-H. Tetrahedron Lett.
2005, 46, 6875.
(10) (a) Smith, J. T.; Zeiler, H. J. History and Introduction In
Handbook of Experimental Pharmacology, Vol. 127;
Springer: Berlin, 1998, 1–11. (b) Pharmaceutical
Substances: Synthesis, Patents, Applications; Kleemann, A.;
Engel, J., Eds.; Thieme: Stuttgart, 2001. (c) Riesbeck, K. J.
Chemother. 2002, 14, 3. (d) Milata, V.; Claramunt, R.;
Elguero, J.; Zalupski, P. Targets Heterocycl. Syst. 2000, 4,
167. (e) Brown, E. M.; Reeves, D. S. Antibiot. Chemother.
1997, 419. (f) Hirai, K. Nippon Kagaku Ruoho Gakkai
Zusshi 2005, 53, 349. (g) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893.
(11) Sotelo, E.; Fraiz, N.; Yáñez, M.; Laguna, R.; Cano, E.; Brea,
J.; Raviña, E. Bioorg. Med. Chem. Lett. 2002, 12, 1575.
(12) Amaresh, R. R.; Perumal, P. T. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1997, 36, 541.
(13) For publications related to the catalysis of Knoevenagel
reaction by supported reagents, see: (a) Isobe, K.; Hoshi, T.;
Suzuki, T.; Hagiwara, H. Mol. Divers. 2005, 9, 317.
(b) Zeng, R.; Fu, X.; Gong, C.; Sui, Y.; Ma, X.; Yang, X. J.
Mol. Catal. A: Chem. 2005, 229, 1; and references cited
therein. (c) Strohmeier, G. A.; Kappe, C. O. Angew. Chem.
Int. Ed. 2004, 43, 621.
Acknowledgment
Thanks are due to University of Aveiro, FCT and FEDER for
funding the Organic Chemistry Research (Unity and Project POCI/
QUI/58835/2004) as well as Xunta de Galicia for its financial
support to Alberto Coelho. We also thank the Agencia Española de
Cooperación Internacional for a grant to Abdelaziz El Maatougui.
References and Notes
(1) Zaragoza, F.; Dörwald, X. Organic Synthesis on Solid
Phase, Vol. 2; Wiley-VCH: Weinheim, 2002.
(2) (a) Boger, D. L.; Desharnais, J.; Capps, K. Angew. Chem.
Int. Ed. 2003, 42, 4138. (b) An, H.; Dan Cook, P. Chem.
Rev. 2000, 100, 3311. (c) Nefzi, A.; Ostresch, J. M.;
Houghten, R. A. Chem. Rev. 1997, 97, 449.
(3) (a) Kirschning, A.; Monenschein, A.; Wittemberg, R.
Angew. Chem. Int. Ed. 2001, 40, 650. (b) Ley, S. V.;
Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.;
Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.;
Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815.
(4) Collins, I. J. Chem. Soc., Perkin Trans. 1 2000, 2845.
(14) (a) Hadjeri, M.; Mariotte, A. M.; Boomendjel, A. Chem.
Pharm. Bull. 2001, 49, 1352. (b) Baket, D.; Sasaki, H.;
Kinoshita, T.; Tsutsumi, H.; Sakane, K. Bull. Chem. Soc.
Jpn. 1996, 69, 1371.
(15) Brown, D. J. In The Pyridazines I, Chemistry of Heterocyclic
Compounds; Taylor, E. C.; Wipf, P., Eds.; Wiley: New
York, 2000, 56.
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LETTER
(16) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(17) (a) www.silicycle.com. (b) www.sigma-aldrich.com.
(18) For publications related to the aza-Michael reaction by
supported reagents, see: (a) Fetterly, B. M.; Jana, N. K.;
Verkade, J. G. Tetrahedron 2006, 62, 440. (b) Bartoli, G.;
Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massaccessi,
M.; Torregiani, E. J. Org. Chem. 2005, 70, 169.
(19) Representative Procedure for the Alkylation–
Knoevenagel (Method A) or Aza-Michael–Knoevenagel
(Method B) Sequences: In a coated Kimble vial was
charged a mixture of the scaffold A1–A3 (0.60 mmol) in the
appropriate solvent [THF (3 mL) for A1 or A3, toluene for
A2]. The supported organic base (1.5 mmol of PS–TBD 2
for method A, 0.12 mmol for method B) and the alkyl halide
(0.66 mmol; method A) or the Michael acceptor (0.72 mmol;
method B) were added at the appropriate temperature (40 °C
for A1 and A3, r.t. for A2 in method A, 60 °C for all
scaffolds in method B). The sample was vortexed for 30 min
to give the corresponding N-blocked adduct. Addition of the
appropriate malonic acid derivative (1.1 equiv, stirring for
4–14 h; see Figure 4) to the adduct at the appropriate
temperature (40 °C for A1, 60 °C for A2, r.t. for A3 in
method A; 50 °C, 60 °C and r.t. for A1, A2 and A3,
7.50–7.64 (m, 1 H, Ar), 7.33–7.43 (m, 4 H, Ar), 7.19–7.23
(m, 3 H, Ar), 5.42 (s, 2 H, CH2), 4.34 (q, J = 7.2 Hz, 2 H,
CH2), 1.35 (t, J = 7.2 Hz, 3 H, CH3). MS (70 eV): m/z (%) =
358 (11) [M+], 285 (100), 91 (16). HRMS: m/z [M+] calcd for
C22H18N2O3: 358.1317; found: 358.1316. A2B4D3: mp
130–131 °C (i-PrOH); yield: 67%. IR (KBr): 2209 (CN),
1747 (CO), 1578 (Ar), 1094 (COC) cm–1. 1H NMR (300
MHz, CDCl3): d = 8.61 (s, 1 H, CH), 8.60 (s, 1 H, CH), 7.83–
7.86 (m, 1 H, Ar), 7.27–7.35 (m, 6 H, Ar), 7.15–7.18 (m, 2
H, Ar), 5.41 (s, 2 H, CH2), 4.37 (q, J = 7.1 Hz, 2 H, CH2),
1.39 (t, J = 7.1 Hz, 3 H, CH3). MS (70 eV): m/z (%) = 330
(75) [M+], 183 (1), 139 (2), 91 (100). A3B1D2: mp 220–221
°C (i-PrOH); yield: 79%. IR (KBr): 2229 (CN), 1727 (CO),
1659 (CO), 1580 (Ar), 1083 (COC) cm–1. 1H NMR (300
MHz, CDCl3): d = 7.92 (s, 1 H, CH), 7.44–7.53 (m, 4 H, Ar
+ CH), 7.35–7.39 (m, 2 H, Ar), 3.92 (s, 3 H, CH3), 3.89 (s, 3
H, CH3). MS (70 eV): m/z (%) = 295 (100) [M+], 236 (100),
208 (35), 164 (30). HRMS: m/z [M+] calcd for C16H13N3O3:
295.0957; found: 295.0955. A1C4D2: mp 186–187 °C (i-
PrOH); yield: 70%. IR (KBr): 2220 (CN), 1717 (CO), 1624
(CO), 1584 (Ar), 1093 (COC) cm–1. 1H NMR (300 MHz,
CDCl3): d = 9.10 (s, 1 H, CH), 8.81 (s, 1 H, CH), 8.47 (d,
J = 8.2 Hz, 1 H, Ar), 7.70–7.74 (m, 1 H, Ar), 7.45–7.48 (m,
2 H, Ar), 4.54 (t, J = 6.7 Hz, 2 H, CH2), 4.15 (q, J = 7.2 Hz,
2 H, CH2), 3.86 (s, 3 H, CH3), 2.91 (t, J = 6.7 Hz, 2 H, CH2),
1.20 (t, J = 7.2 Hz, 3 H, CH3). MS (70 eV): m/z (%) = 354
(16) [M+], 323 (4), 295 (100), 267 (16). A2C1D3: mp 153–
154 °C (i-PrOH); yield: 80%. IR (KBr): 2215 (CN), 1721
(CO), 1589 (Ar), 1039 (COC) cm–1. 1H NMR (300 MHz,
CDCl3): d = 8.55 (s, 1 H, CH), 8.54 (s, 1 H, CH), 7.86 (dd,
J = 1.6, 5.1 Hz, 1 H, Ar), 7.35–7.45 (m, 3 H, Ar), 4.57 (t, J =
6.9 Hz, 2 H, CH2), 4.37 (q, J = 7.1 Hz, 2 H, CH2), 2.94 (t,
J = 6.9 Hz, 2 H, CH2), 1.35 (t, J = 7.1 Hz, 3 H, CH3). MS (70
eV): m/z (%) = 293 (100) [M+], 253 (64), 225 (26), 179 (9).
A3C2D1: mp 127–128 °C (i-PrOH); yield: 65%. IR (KBr):
2235 (CN), 1736 (COO), 1670 (CO), 1588 (Ar), 1092
(COC) cm–1. 1H NMR (300 MHz, CDCl3): d = 7.51–7.55 (m,
5 H, Ar), 7.47 (s, 1 H, CH), 7.34 (s, 1 H, CH), 4.38 (t, J = 6.9
Hz, 2 H, CH2), 3.67 (s, 3 H, CH3), 2.90 (t, J = 6.9 Hz, 2 H,
CH2). MS (70 eV): m/z (%) = 334 (22) [M+], 303 (16), 275
(26), 247 (50), 234 (100), 222 (25), 191 (23).
respectively in method B) in the corresponding solvent, led
to the Knoevenagel product after simple filtration of the
supported reagents by a fritted syringe. Evaporation of the
solvent and purification by a parallel short chromatographic
filtration (on silica gel) employing a vacuum manifold
(Visiprep®) to remove the small excess of malonic acid
derivative afforded pure samples that were characterised by
spectroscopic and analytical data.
(20) Complete details of the synthesis and spectral characteristics
of the compounds obtained will be published elsewhere in a
full paper. All compounds gave satisfactory spectral data (1H
NMR, 13C NMR, FTIR, MS). Yields given correspond to the
isolated pure compounds. Chromatographic filtration for all
compounds was carried out using EtOAc–hexane (1:4) as
eluent mixture. Selected physical and spectral data for some
compounds are as follows: A1B4D3: mp 218–219 °C (i-
PrOH); yield: 70%. IR (KBr): 2233 (CN), 1709 (CO), 1665
(CO), 1599 (Ar) cm–1. 1H NMR (300 MHz, CDCl3): d = 9.12
(s, 1 H, CH), 8.88 (s, 1 H, CH), 8.47 (d, J = 8.2 Hz, 1 H, Ar),
Synlett 2006, No. 19, 3324–3328 © Thieme Stuttgart · New York