Magnesium perchlorate as efficient Lewis acid for the Knoevenagel condensation between β-diketones and aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.02.093

A new protocol for the Knoevenagel condensation between β-diketones and aliphatic and aromatic aldehydes promoted by Mg(ClO₄)₂ under mild conditions is reported.

Full text of DOI:10.1016/j.tetlet.2008.02.093

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2555–2557
Magnesium perchlorate as efficient Lewis acid for the Knoevenagel
condensation between b-diketones and aldehydes
Giuseppe Bartoli, Marcella Bosco, Armando Carlone, Renato Dalpozzo,
Patrizia Galzerano, Paolo Melchiorre, Letizia Sambri *
`
Universita di Bologna, Dipartimento di Chimica Organica ‘A, Mangini’, v.le Risorgimento 4, 40136 Bologna, Italy
Received 17 January 2008; revised 15 February 2008; accepted 18 February 2008
Available online 21 February 2008
Abstract
A new protocol for the Knoevenagel condensation between b-diketones and aliphatic and aromatic aldehydes promoted by
Mg(ClO4)2 under mild conditions is reported.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Knoevenagel condensation; Magnesium perchlorate; b-Diketones; Aldehydes; Mild reaction conditions
The Knoevenagel condensation is a well-known organic
reaction largely employed in order to form C–C bonds for
the synthesis of important derivatives in perfume, polymer,
and pharmaceutical applications.1 The Knoevenagel
adducts, in fact, are useful intermediates for further trans-
formations, such as Diels–Alder and Michael additions.2
The classical Knoevenagel condensation (Scheme 1) has
been carried out by reacting a methylene active compound
with an aldehyde or a ketone in the presence of a base.1,3
Recently, alternative procedures employed heterogeneous
catalysts, such as zeolites,4 clays,5 layered double hydro-
xides (LDHs),6 and hydrotalcites.7 Various protocols
carried out in ionic liquids8 have also been developed. On
the contrary, relatively few examples of condensation med-
iated by Lewis acids such as TiCl4,9 ZnCl2,10 CeCl3Á7H2O/
NaI, 11 and HClO4–SiO212 have been reported. Frequently,
high reaction temperatures4a,5,12,13 or microwave irradia-
tion12,14 are necessary to promote the reaction indepen-
dently from the employed catalytic system.
Methylene active compounds carrying two electron-
withdrawing groups, such as malononitrile, cyanoacetates,
malonates, and b-ketoesters, are generally used in the
known condensations. However, only few examples of b-
diketones as starting materials are reported.12,15 Very
likely, such compounds are less reactive than the other ones
since their attitude to form a stable cyclic enol.
Since our interest in the last years in the use of metal
perchlorates as Lewis acids,16 and since their ability to
coordinate 1,3-bidentate substrates,17 in order to extend
their applicability we investigated the possibility to pro-
mote a Knoevenagel condensation between b-diketones
with aldehydes in the presence of a perchlorate salt.
On the other hand, perchlorate salts of alkaline and
alkaline earth metals showed to be very active in promoting
a large variety of reactions,18 in some cases being more
powerful than metal triflates.16b,17c,19 Concerning the risk
connected with the use of such salts, it has been demon-
strated that such perchlorates are not dangerous chemicals
R1
R2
EWG1
EWG2
O
EWG1
cat.
O
+
R1
R2
O
EWG2
3
2
1
O
EWG1 and EWG2= -CN, -C-OR, -C-R, P(OR)2,SO2R, SOR
Scheme 1.
*
Corresponding author. Tel.: +39 0512093624; fax: +39 0512093654.
E-mail address: letizia.sambri@unibo.it (L. Sambri).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.093

2556
G. Bartoli et al. / Tetrahedron Letters 49 (2008) 2555–2557
Table 2
if not employed under highly acidic conditions and not
exposed to high temperatures (>300–500 °C).20
Reaction of dicarbonyl compounds 4 with aldehydes 5 (1.2 equiv) in the
presence of Mg(ClO4)2 (10 mol %) and MgSO4 (20 mol %) at rt
To test the reactivity of b-diketones we chose the reac-
tion of acetoacetone 4a with benzaldehyde 5a in the pres-
ence of various catalytic systems, under solvent free
conditions at room temperature. We checked the conver-
sion by NMR at maximum after 70 h, (Table 1).
O
O
O
O
O
Mg(ClO4)2 (10 mol %)
MgSO4 (20 mol %)
+
R1
R2
R1
R2
R3
5a-j
4a-d
t o
r.t. nea r THF (3.5M)
6
R3
The best reaction conditions required the use of a
10 mol % of Mg(ClO4)2, and a 20 mol % of MgSO4 (Table
1, entry 1) to obtain a 65% of conversion in the desired
product without any traces of by-products. On the other
hand, an increase in temperature (40 °C) led to the forma-
tion of the side product 7aa, derived from the attack of ace-
toacetone on the Knoevenagel adduct, right after 30 h
(Table 1, entry 2). The addition of MgSO4 as a catalyst
was necessary very likely to adsorb the water formed dur-
ing the condensation. In fact the reaction carried out only
in the presence of Mg(ClO4)2 was slower (55% vs 65% of
conversion, Table 1, entries 1 and 3). As in other reac-
tions,16a,17d Mg(ClO4)2 showed to be more effective than
Zn(ClO4)2Á6H2O (Table 1, entries 1 and 4). The attempt
to increase the conversion by the addition of a catalytic
amount of Et3N was unsuccessful: after 48 h the conver-
sion in the desired product was 55% but a 5% of the side
product 7aa was also detected (Table 1, entry 5).
Entry
R1
R2 R3
Time Yieldsa (%) Product
(h)
(E/Z ratio)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
i-Bu
OEt
OEt
Me
Me C6H4
70
70
48
24
70
48
48
90
70
90
24
24
90
54
70
55
6aa
6ab
6ac
6ad
6ae
6af
6ag
6ah
6bb
6bd
6bi
Me p-NO2–C6H4
Me m-NO2–C6H4
Me p-CN–C6H4
Me p-Br–C6H4
Me n-C3H7
86b
78b
70b
65
70
Me n-C5H11
67
Me Ph(CH2)2
Et p-NO2–C6H4
Et p-CN–C6H4
Et 5-NO2-2-furyl
Et Ph–C„C
Me p-NO2–C6H4
Me p-NO2–C6H4
Me p-CN–C6H4
73c
62b
10
11
12
13
14
15
16
a
80b
81b
63
6bj
75 (1:7)
88b (1:3)
76b (1:2.5) 6dd
6cb
6db
Me trans-PhCH@CH 90
30
6ak
Isolated yields.
Reaction carried out in THF (3.5 M).
A 5% of the isomer 8ah was also detected.
b
c
Notably, the reaction works well under neat conditions,
the addition of a solvent slows the conversion rate.
The reaction with aliphatic aldehydes is generally faster
The protocol was applied to other substrates.21 Results
are reported in Table 2. Acetoacetone 4a smoothly reacted
with both aromatic and aliphatic aldehydes 5a–h (Table 2,
entries 1–8). The presence of an electron-withdrawing
group on the aromatic aldehyde, such as NO2 and CN,
increases the reactivity and very good yields in the desired
product 6 were obtained (Table 2, entries 2–4).
than those with aromatic ones. In particular, despite the
presence of a-protons in the aliphatic aldehydes only the
a,b-unsaturated systems 6 are obtained and no isomerization
to b,c-unsaturated22 ones was detected, (Table 2, entries 6
and 7). Only the reaction of 3-phenylpropanal 5h required
longer reaction times, and traces of by-product 8ah
(Fig. 1), an isomer of the desired product 6ah, was observed.
Increasing the bulkiness of the diketone system
(R1 = R2 = Et, 4b), the reactivity essentially did not change
(Table 2, entries 9–12) and the expected products were
obtained in good yields. The reaction of 4b with the substi-
tuted heteroaromatic aldehyde 5i was faster than those with
an aromatic one giving 6bi in very good yield. Moreover, the
reaction of 4b with an unsaturated aldehyde like 5j gave only
6bj as product, and no 1,4-addition product was detected.
On the other hand, an asymmetric and bulkier system like
6-methylheptane-2,4-dione 4c took longer time to give 6cb
in good yields even if two isomeric products are formed,
the Z-isomer being predominant, (Table 2, entry 13).
Table 1
Reaction of acetoacetone 4a with benzaldehyde 5a (1.2 equiv) under
various conditions
O
O
O
O
O
O
O
catalyst
r.t. neat
+
+
O
Ph
4a
5a
6aa
Ph
Ph
7aa
O
Entry Catalyst
Time (h) Conversiona in 6aa (7aa)
1
Mg(ClO4)2 10 mol %
MgSO4 20 mol %
Mg(ClO4)2 10 mol %
MgSO4 20 mol %
70
65 (0)
65 (3)
The protocol works also with active systems generally
used in classical Knoevenagel condensation different from
diketones. Ethyl 3-oxobutanoate 4d reacted with aromatic
2
30b
3
4
Mg(ClO4)2 10 mol %
70
55 (0)
52 (0)
Zn(ClO4)2Á6H2O 10 mol % 70
O
O
O
OH
MgSO4 20 mol %
5
Mg(ClO4)2 10 mol %
MgSO4 20 mol %
Et3N 10 mol %
48
55 (5)
6ah
8ah
Ph
Fig. 1.
Ph
a
Calculated from 1H NMR.
Reaction carried out at 40 °C.
b

G. Bartoli et al. / Tetrahedron Letters 49 (2008) 2555–2557
2557
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aldehydes to give a mixture of Z- and E-isomeric alkenes,
(Table 2, entries 14 and 15).
We tried to extend the procedure to a,b-unsaturated
aldehydes, but unfortunately not very satisfactory results
were obtained, (Table 2, entries 16). In fact in the reaction
of 4a with cinnamaldehyde the desired product 6ak was
obtained in 30% yields, together with a mixture of starting
materials and unidentified by-products.
In some cases, when the aldehyde is solid and does not
dissolve in the diketone, the addition of a minimum
amount of solvent is necessary to solubilize the reagents.
THF proved to be the best choice, and the reactions were
carried out under concentrated conditions (3.5 M).
In conclusion, we have demonstrated another interesting
application of Mg(ClO4)2 to act as a Lewis acid in promot-
ing the synthesis of trisubstituted functionalized alkenes via
a Knoevenagel condensation between poorly reactive
b-diketones and aliphatic and aromatic aldehydes. The
protocol works also with more reactive systems like b-keto-
esters. The reaction conditions are very mild, in fact the
condensation works at room temperature, in the absence
or with a minimum amount of solvent. Notably, this pro-
cedure led only to the Knoevenagel products, any side-
product derived from a subsequent Michael addition of
the b-diketone was never detected. In addition, the reaction
with aliphatic aldehydes gave generally only the desired
product, in contrast to other reported examples.
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Locatelli, M.; Melchiorre, P.; Sambri, L. J. Org. Chem. 2006, 71,
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21. General procedure for the Knoevenagel condensation: In a two necked
flask equipped with a magnetic stirring bar, Mg(ClO4)2 (0.10 mmol),
MgSO4 (0.20 mmol), b-keto derivative 4 (1.0 mmol) and aldehyde 5
(1.2 mmol) were added. If the system was completely solid, THF
(0.29 ml) was added to dissolve the reagents. The mixture was stirred
at rt. CH2Cl2 was added to the crude reaction mixture. Filtration on
Celite and removal of the solvent by rotary evaporation gave the
Acknowledgments
This research was carried out within the framework of
the National Project ‘Stereoselezione in Sintesi Organica’
supported by MIUR, Rome, and FIRB National Project
‘Progettazione, preparazione e valutazione farmacologica
di nuove molecole organiche quali potenziali farmaci
innovativi’.
crude product. The substituted olefin
6 was purified by flash
chromatography on silica gel with the appropriate mixture of
hexane/Et2O.
Spectroscopic data for selected compounds follow: 3-Butylidenepen-
tane-2,4-dione (6af): H NMR (CDCl3, 400 MHz): d (ppm) = 0.90 (t,
1
References and notes
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