Green chemistry approaches to the Knoevenagel condensation: Comparison of ethanol, water and solvent free (dry grind) approaches

Article abstract of DOI:10.1016/S0040-4039(02)00480-X

We report a comparative study of the Knoevenagel condensation with a variety of substituted benzaldehydes (17 examples) and cyanoamides (3 examples), using three different methodologies: (a) traditional ethanol reflux; (b) water reflux; and (c) solvent fr

Full text of DOI:10.1016/S0040-4039(02)00480-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3117–3120
Green chemistry approaches to the Knoevenagel condensation:
comparison of ethanol, water and solvent free (dry grind)
approaches
Adam McCluskey,a,* Philip J. Robinson,b Tim Hill,a Janet L. Scottc and J. Kate Edwardsa
aChemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan NSW 2308, Australia
bChildren’s Medical Research Institute, Westmead Hospital, Wentworthville, Sydney, Australia
cCentre for Green Chemistry, PO Box 2, Monash University, Victoria 3800, Australia
Received 23 January 2002; revised 28 February 2002; accepted 8 March 2002
Abstract—We report a comparative study of the Knoevenagel condensation with a variety of substituted benzaldehydes (17
examples) and cyanoamides (3 examples), using three different methodologies: (a) traditional ethanol reflux; (b) water reflux; and
(c) solvent free conditions. Almost without exception these reactions proceeded faster, more cleanly and in higher yields when the
reactions were conducted in a solvent-free fashion. Additionally, our solvent free approach allowed the use of nitrobenzaldehydes,
which failed to yield the desired products under traditional and water based approaches. © 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
produced and lowering of energy costs, but also in the
development of new methodologies towards previously
unobtainable materials, using existing technologies.4
At the commencement of the new century, a shift in
emphasis in chemistry is apparent with the desire to
develop more environmentally friendly routes to a myr-
iad of materials. This shift is most apparent in the
growth of Green Chemistry.1–3 Green chemistry
approaches not only hold out significant potential for
reduction of by-products, a reduction in the waste
Of all of the existing areas of chemistry, medicinal and
pharmaceutical chemistry, with their traditionally large
waste:product ratio,5 are perhaps the most ripe for
greening. However, in these fields, particularly during
lead compound development, the end product is of
Scheme 1. Reagents and conditions: (i) mix at rt; (ii) EtOH reflux for 2 h overnight, piperidine (cat.); (iii) water reflux for 2 h
overnight, piperidine (cat.); (iv) grind gently, piperidine (cat.).
Keywords: Green chemistry; solvent free; Knoevenagel condensations.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00480-X

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A. McCluskey et al. / Tetrahedron Letters 43 (2002) 3117–3120
paramount importance and the route taken is often
viewed as largely irrelevant. The introduction of combi-
natorial chemistry, which has become almost univer-
sally linked with lead compound development, appears
in many applications to be contrary to the principles of
green chemistry as, once again, focus is on the desired
product with little concern for the overall efficiency of
the process with regards transforming reactants into
products with the least possible production of waste. As
a result, one of the questions that our group is explor-
ing is:
Within our group we are actively investigating potential
drug intervention strategies for control of signal trans-
duction pathways. In doing so we typically design small
Table 1. Reaction of functionalised benzaldehydes with cyanoamides 3a–c
Entry
Benzaldehyde
R1
EtOH reflux (%)
H2O (%)
Solvent-free (%)
1
2
3
4
5
6
7
8
Benzaldehyde
3-OH-
4-OH-
3,4-di-OH-
2,4-di-OH-
3,4-di-OCH3-
2-OH-
2-Cl-
4-OCH3-
3-Br-
4-Cl-
3-NO2-
3-OCH3-
4-NO2-
4-CO2H-
3-OH, 4-OCH3-
4-N(CH3)2-
CH2CH3
42
49
30
53
46
48
40
42
45
45
25
17
26
0
46
56
52
40
24
64
64
53
61
40
35
46
40
80
37
88
40
68
99
94
\99
58
69
74
68
64
97
94
74
87
\99
97
9
10
11
12
13
14
15
16
17
58
65
63
67
99
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
Benzaldehyde
3-OH-
4-OH-
3,4-di-OH-
2,4-di-OH-
3,4-di-OCH3-
2-OH-
2-Cl-
4-OCH3-
3-Br-
4-Cl-
3-NO2-
3-OCH3-
4-NO2-
4-CO2H-
3-OH, 4-OCH3-
4-N(CH3)2-
(CH2)4CH3
37
57
50
57
11
45
38
13
65
19
66
0
30
0
83
97
81
55
58
53
66
46
44
44
61
11
44
45
33
28
27
60
40
74
\99
\99
89
\99
\99
97
\99
81
79
43
97
96
58
12
48
\99
44
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
Benzaldehyde
3-OH-
4-OH-
3,4-di-OH-
2,4-di-OH-
3,4-di-OCH3-
2-OH-
2-Cl-
4-OCH3-
3-Br-
4-Cl-
3-NO2-
3-OCH3-
4-NO2-
4-CO2H-
3-OH, 4-OCH3-
4-N(CH3)2-
p-MeO-PhCH2
10
35
39
36
39
58
52
39
42
45
34
9
24
0
22
45
55
50
47
50
54
40
34
37
48
16
17
32
37
31
22
34
43
55
96
95
93
85
71
\99
98
49
68
38
96
69
99
51
58
69
99

A. McCluskey et al. / Tetrahedron Letters 43 (2002) 3117–3120
3119
focused drug libraries of ca. 25–50 compounds.
Although subtle variations in synthetic methodology
will occur depending upon the choice of target, the
drug design process is typically an iterative one. Thus,
the development of a targeted library provides the ideal
opportunity to examine the broad applicability of a
under three different sets of reaction conditions: (i)
traditional ethanol reflux overnight; (ii) dry grind in a
mortar and pestle; and (iii) overnight reflux in water.
Product yields are shown in Table 1.7
Traditional Knoevenagel conditions (Table 1, ethanol
reflux) afford poor (0%, Table 1 entries 14, 29, 31 and
48) to excellent yields (97%, Table 1 entry 33) of the
anticipated condensation products. Typically, however,
the isolated product yields are moderate at best (40–
60%) and require significant purification. A more seri-
ous limitation is the –NO2 group sensitivity with poor
yields being observed via the traditional route (17, 0, 0,
0, 9 and 0%, Table 1 entries 12, 14, 29, 31 46 and 48,
respectively).
synthetic approach, examining
functionality.
a wide range of
In this particular instance we required a facile route to
libraries of highly functionalised cyanoamido benzalde-
hyde derivatives. After examination of the available
options Knoevenagel condensation chemistry was
deemed to be the most expedient approach. Accord-
ingly we set about examining methodologies amenable
to solution-phase synthesis approaches.
Similar examination of the Knoevenagel condensations
using water as a solvent showed a slight improvement
upon the isolated product yields ranging from 11 (Table
1 entry 26) to 88% (Table 1 entry 16). Although we also
note that the typical yield is in the order of 40–70%.
Additionally, difficulties were still encountered in the
use of –NO2-substituted benzaldehydes (46, 80, 33, 27,
37 and 22, Table 1 entries 12, 14, 29, 31 46 and 48,
respectively). However, these reactions were con-
founded, from the green perspective, by the require-
As can be seem from Scheme 1, our approach is
elegantly simple: commencing from methyl cyanoac-
etate (1) and a variety of substituted amines (2a–c)
allows for the generation of substituted cyano amides
(3a–c) in excellent yields (data not shown). This reac-
tion proceeds in the absence of solvent or heating.6
The base (piperidine) catalysed reactions of preformed
3a–c with substituted benzaldehydes (see Table 1 for
details of ring substituents) were subsequently examined
ment
for
extractive
isolation
followed
by
Figure 1. (a) GC trace obtained for the reaction of 3-nitrobenzaldehyde with cyanoamide 3b. The main image shows the results
of solvent-free reaction with the expected product at ca. 18 min and traces of 3-nitrobenzaldehyde at 8 min and cyanoamide 3b
at 9 min. (b) The insert shows the equivalent GC-trace obtained via the traditional EtOH reflux methodology. In this latter case
no trace of the Knoevenagel product is observed.

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A. McCluskey et al. / Tetrahedron Letters 43 (2002) 3117–3120
References
recrystallisation to afford material of a suitable quality
for biological examination.
1. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford Science Publications: New York, 1998.
2. Anastas, P.; Williamson, T. Green Chemistry, Frontiers in
Benign Chemical Synthesis and Procedures; Oxford Science
Publications, 1998.
3. Clark, J. H. Green Chem. 1999, 1, 1.
4. Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun.
2001, 2159–2169.
5. As estimated by determination of the E-factor: Sheldon,
R. A. Chem. Ind. 1997, 12.
In our final series of experiments we set out to examine
the equivalent solvent-free reaction. Simple mixing
(gentle grinding) of the cyanoamides (3) and benzalde-
hydes in the presence of a single drop of piperidine
rapidly afforded the anticipated Knoevenagel product
in a typically excellent yield (up to >99%), with the
notable exception of the reaction with 4-nitrobenzalde-
hyde and 3b (12%, Table 1 entry 31). The solvent-free
approach afforded excellent yields of most other
nitrobenzaldehydes examined during the course of this
study (74, >99, 96, 69 and 51%, Table 1 entries 12, 14,
29, 46 and 48, respectively). In the majority of instances
our solvent-free approaches generated materials of
sufficient purity for subsequent biological testing. This
is in sharp contrast to the outcomes of the solution or
aqueous suspension based methodologies, where, when
conversion to product is poor, a plethora of by-prod-
ucts are detected. Fig. 1 highlights a typical GC-trace
obtained after a solvent-free synthesis protocol with
essentially a single product observed, whereas in the
more traditional approaches (ethanol reflux) no con-
densation product was observed (Fig. 1 insert) and the
reaction mixture is significantly more complex.
6. Gazit, A.; Osherov, N.; Gilon, C.; Levitzki, A. J. Med.
Chem. 1996, 39, 4905–4911.
7. Representative procedure for the preparation of 2-cyano-3-
(3-hydroxy-phenyl)-N-propyl-acrylamide (Table 1 entry 2).
Ethanol reflux: 3-Hydroxybenzaldehyde (122 mg, 1 mmol)
was dissolved in ethanol (10 mL) containing 2-cyano-N-
propyl-acetamide (3a) (126 mg, 1 mmol) and piperidine (5
mg, cat.) and the mixture refluxed for 2 h. After cooling
the precipitated material was collected and the ethanol
removed in vacuo. Both materials were combined and
recrystallised from ethanol/water to yield 96.7 mg (49%) of
the title compound. Spectral and physical data obtained
are in agreement with those obtained previously.
Water reflux: 3-Hydroxybenzaldehyde (122 mg, 1 mmol)
was suspended in water (10 mL) along with 2-cyano-N-
propyl-acetamide (3a) (126 mg, 1 mmol) and piperidine (5
mg, cat.) and the heterogeneous mixture was stirred rapidly
and refluxed for 2 h. After cooling the product was
extracted with dichloromethane (2×10 mL), dried over
MgSO4, the solvent removed in vacuo and the residue
recrystallised from ethanol water to yield 128.9 mg (56%)
of the title compound.
The search for more environmentally acceptable routes
to Knoevenagel products is by no means new with
Davis et al. recently reporting the combined use of
[6-mim]PF6 and supercritical CO2 as a green alternative
in the synthesis of Knoevenagel products.8 However,
this approach still requires access to novel solvents, and
equipment. Specialised equipment is required too for
microwave mediated Knoevenagel condensations.9,10
Solvent free: 3-Hydroxybenzaldehyde (122 mg, 1 mmol)
was placed in a mortar followed by 2-cyano-N-propyl-acet-
amide (3a) (126 mg, 1 mmol) to which was added one drop
of piperidine. These materials were then mixed using a
pestle for ca. 5 min during which time a colour change
occurred (the change is typically colourless to yellow or
orange). The mixture was then allowed to stand at room
temperature until it solidified, transferred to a round-bot-
tomed flask and dried under high vacuum (which facilitates
the removal of water and residual piperidine) to afford
227.9 mg (99%) of the title compound, identical to that
prepared via ethanol reflux.
In conclusion, we have shown, in this instance, it is
possible to apply the tenets of green chemistry to a
medicinal setting in the development of solvent-free
approaches to the generation of biologically interesting
molecules using Knoevenagel chemistry. Our approach
can be adapted towards the use of semi-automated
synthesis protocols.
Acknowledgements
8. Morrison, D. W.; Forbes, D. C.; Davis, J. H., Jr. Tetra-
hedron Lett. 2001, 42, 6053–6055.
9. Che´rouvrier, J. R.; Boissel, J.; Carreaux, F.; Bazureau, J.
P. Green Chem. 2001, 3, 165–169.
10. Mitra, A. K.; De, A.; Karchaudhuri, N. Synth. Commun.
1999, 29, 2731–2739.
This work received financial support from the Univer-
sity of Newcastle and the Centre for Green Chemistry
(ARC).