Synthesis of β-hydroxymalonates: the direct aldol addition of malonates to aldehydes in the presence of SiCl4 and i-Pr2EtN

Article abstract of DOI:10.1016/j.tetlet.2009.10.057

The direct aldol addition of malonates to aromatic, hetero-aromatic and unsaturated aldehydes leading to β-hydroxymalonates is described. The stability of these products, the trimethyl silyl protection of the hydroxyl group as well as the role of both SiC

Full text of DOI:10.1016/j.tetlet.2009.10.057

Tetrahedron Letters 50 (2009) 7318–7321
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Synthesis of b-hydroxymalonates: the direct aldol addition of malonates
to aldehydes in the presence of SiCl4 and i-Pr2EtN
a
b
b
Antonio Massa a, , Arrigo Scettri , Rosanna Filosa , Laura Capozzolo
*
a Dipartimento di Chimica, Università di Salerno, Via Ponte Don Melillo 84084, Fisciano (SA), Italy
b Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo 84084, Fisciano (SA), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct aldol addition of malonates to aromatic, hetero-aromatic and unsaturated aldehydes leading to
b-hydroxymalonates is described. The stability of these products, the trimethyl silyl protection of the
hydroxyl group as well as the role of both SiCl4 and i-Pr2EtN in attaining the final products are also
discussed.
Received 1 September 2009
Revised 6 October 2009
Accepted 9 October 2009
Available online 15 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aldol addition
Malonate
SiCl4
i-Pr2EtN
b-Hydroxymalonate
1. Introduction
This lack is in contrast with the large use of malonates in
organocatalysed Michael reactions1 as well as in the Knoevenagel
In spite of the progress of organocatalysis1 and metal-catalysed
methodologies,2 the aldol addition of readily enolizable 1,3-dicar-
bonyl compounds, such as b-ketoesters and malonates, to alde-
hydes still remains a difficult challenge. According to Sodeoka
and co-workers, the most accepted explanation of this methodo-
logical gap is mainly attributed to the instability of the resulting
b-hydroxymalonates and to the difficulty in generating efficient
malonate nucleophiles.3 Another reason can also be related to
the inadequacy of the current methodologies that favour the elim-
ination or the retro-aldol process instead of the aldol reaction
(Scheme 1).4 As a consequence, there are only few examples that
describe efficient synthesis of b-hydroxymalonates and related
compounds. The aldol addition of metal enolates of malonates
synthesis of alkylidenemalonates.4 Moreover, even if b-hydroxy-
malonates are considered as the intermediates of Knoevenagel
condensation (reaction II, Scheme 1), they have been isolated only
rarely.4
In this complex framework, a straightforward aldol addition of
methylene-active compounds to aldehydes should take into ac-
count the following conditions: (a) possibility to stop the reaction
at aldol step and to suppress both the retro-aldol (I) and the elim-
ination processes (II) (Scheme 1); (b) easy generation of nucleo-
phile and (c) mild work-up to avoid product decomposition.
In the course of our studies about the use of Denmark’s system,9
silicon tetrachloride activated by a Lewis base, in vinylogous aldol
reactions,10 we realised that this system could be the ideal candi-
date for aldol addition of malonates to aldehydes for the following
reasons. The selective activation of electrophilic functional groups
in the presence of SiCl4 allowed the use of many preformed nucle-
ophiles such as silylenolethers and allylstannanes.9,10 However, to
the best of our knowledge, there is no report about the in situ gen-
has been successfully achieved only with
a-alkoxy aldehydes in
the presence of ZnCl2.5 Moreover b-hydroxymalonates have been
obtained indirectly in oxy-Michael reactions,6 and b-ketosters have
been used as nucleophiles in the addition to activated aldehydes7
and to acetals.3,8 While free b-hydroxy adducts have been obtained
only in one case,7 the driving force for a general addition of meth-
ylene-active compounds seems related to the obtaining of the final
products as O-protected compounds.3,4,6,8 In this case the main
disadvantage is the necessity of additional steps to obtain the
corresponding free aldol adducts.
OH
O
CO2R
CO2R
CO2R
+
R'
CH2(CO2R)2
R'
H
R'
(I)
(II)
CO2R
* Corresponding author. Tel.: +39 089 969565; fax: +39 089 969603.
E-mail address: amassa@unisa.it (A. Massa).
Scheme 1. b-Hydroxymalonate chemistry: (I) retro-aldol, (II) Knoevenagel
condensation.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.057

A. Massa et al. / Tetrahedron Letters 50 (2009) 7318–7321
7319
Table 1
eration of the nucleophilic species. It is noteworthy that in SiCl4-
mediated reactions, i-Pr2EtN is usually added to scavenge adventi-
tious HCl. Our idea is to exploit the basicity of i-Pr2EtN for the
in situ generation of effective nucleophiles by the reversible depro-
Aldol addition of malonate diesters to benzaldehyde under different reaction
conditions
Entry
R
Lewis Base
(1 equiv)
Temp. aldol
step (°C)
Time (h)
Yield 4a (%)
4b
tonation of activated methylene groups (DMSOpKa of dimethyl
1
2
3
4
5
6
7
Et
Et
Et
Et
Me
t-Bu
t-Bu
p-tolyl-SO–Me
p-tolyl-SO–Me
4-Ph-PyNO
4-Ph-PyNO
4-Ph-PyNO
4-Ph-PyNO
4-Ph-PyNO
À78 °C
À50 °C
À50 °C
À20 °C
À20 °C
À20 °C
À20 °C
18
18
18
7
7
7
4a 15
4a 28
4a 28
4a 43
4b 44
4c 55
4c 82b
malonate and related esters is about 15.9).
Another consequence of the activation of the carbonyl groups
by SiCl4 is the obtaining of the addition products as –O–SiCl3-pro-
tected hydroxyl compounds.9a,10b Then these labile species are
mildly hydrolysed in aqueous NaHCO3 work-up to afford the final
products. In this way, the formation of –O–SiCl3-protected adducts
could allow the addition of malonates to stop at the aldol step and
suppress the undesired processes in Scheme 1.
7
a
Yields refer to chromatographic pure compounds.
TMS protection was performed at À20 °C.
b
On the basis of these ideas, herein, we disclose a reliable meth-
od for the aldol reaction of aromatic, hetero-aromatic and unsatu-
rated aldehydes with malonates mediated by SiCl4 and i-Pr2EtN. In
preliminary experiments, benzaldehyde, chosen as representative
substrate, was submitted to treatment with diethyl malonate 2a
in the presence of SiCl4 (1 equiv), rac-methyl p-tolyl sulfoxide,
the Lewis base for the activation of SiCl4 (1 equiv). and i-Pr2EtN
(2 equiv) under different reaction conditions (Scheme 2).
Preliminary experiments at À78 °C showed a rather low conver-
sion, as analysed by 1H NMR on the crude, for the presence of the
starting materials. Unfortunately any attempt on purification of 3a
by chromatographic methods led to extensive decomposition.6 In
order to obtain a product easy to handle and with a better stability,
we thought to protect the hydroxyl group as a trimethyl silyl ether
(Scheme 3). The protection reaction, performed directly on the
crude product 3a, afforded 4a only in a yield that probably re-
flected the poor efficiency of the first step (Table 1, entry 1). How-
ever, 4a was easily purified by chromatography and isolated as a
pure compound. Higher yields were obtained increasing the reac-
tion temperature of the aldol addition at À20 °C (Table 1, entries
1–4). At À50 °C and at À20 °C, 4-Ph-pyridine-N-oxide was used
as the Lewis base because of the decomposition of methyl p-tolyl
sulfoxide (entries 2 and 3).
Then the reactivity of different alkyl malonates was examined
under similar conditions (Table 1, entries 5–7). When the alkyl
groups were changed to tert-butyl, a quantitative conversion of
3c was observed, yielding an essentially pure compound (entries
6 and 7). However, TMS protection at rt of 3c gave 4c only in mod-
erate yield with the concomitant isolation of the starting materials
1 and 2c (Table 1, entry 6). Further optimisation of the protection
reaction at À20 °C afforded 4c in 82% yield calculated for the two
consecutive steps (Table 1, entry 7).
The possibility of retro-aldol process at different temperature
was confirmed by simple experiments, treating 3c with i-Pr2EtN
in CH2Cl2 (Scheme 4).
The formation of the aldehyde and 2c was observed only at rt
while at À20 °C 3c was quantitatively recovered unreacted. On
the contrary neither at rt nor at À20 °C, the Knoevenagel products,
corresponding to the dehydration of b-hydroxymalonates were
detected.
Then, under the optimised conditions, a series of control exper-
iments highlighted the importance of both SiCl4 and i-Pr2EtN to ob-
tain the final products (Table 2). For example, when 2c was reacted
in the presence of SiCl4 or i-Pr2EtN alone, the starting materials
were recovered unreacted (Table 2, entries 1–3). However compa-
rable yields were obtained in the absence of the Lewis base, point-
ing out that in this case the activation of SiCl4 was not necessary
(Table 2, entries 4 and 5).
O
OH
SiCl4, Lewis base
CO2Et
CH2(CO2Et)2
+
Ph
H
Ph
DIPEA, CH2Cl2,
-78 °C
OH
O
CO2Et
3a
1a
2a
CO2tBu
CO2tBu
(iPr)2EtN
CH2(CO2tBu)2
Ph
+
H
Decomposed during
chromatography
Ph
CH2Cl2, r.t., 6h
1
2c
3c
Scheme 2. Diethyl malonate addition to benzaldehyde in the presence of SiCl4/i-
Pr2EtN.
(iPr)2EtN
CH2Cl2,
-20°C, 6h
O
OH
1) SiCl4, Lewis Base
DIPEA, CH2Cl2,
NO REACTION
CO2R
Ph
H
CH2(CO2R)2
+
Scheme 4. Stability of b-hydroxymalonate in the presence of i-Pr2EtN at rt and
À20 °C.
Ph
2) NaHCO3, H2O
CO2R
1
2
3
Table 2
1) Me3SiCl, CH2Cl2
DIPEA, rt, 2h
2) NaHCO3, H2O
Control experiments in the presence of tert-butyl malonate and benzaldehyde
Entry SiCl4
(equiv)
Lewis base 4-Ph-
PyNO
i-Pr2EtN
(equiv)
Conversion 3ca
(%)
OSiMe3
1
2
3
4
5
0
0
0
2
0
0
2
2
—
—
—
90
90
1
1
1
1
CO2R
1 equiv
1 equiv
0
Ph
CO2R
4
a
Determined by 1H NMR analysis on the crude.
Scheme 3. Aldol addition and trimethyl silylation.

7320
A. Massa et al. / Tetrahedron Letters 50 (2009) 7318–7321
O
On the basis of these experiments the pathway of the process
OH
1) SiCl4, DIPEA
CH2Cl2, -20 °C
can be proposed as reported in Scheme 5. The main steps are rea-
sonably the reversible deprotonation of malonate 2 by i-Pr2EtN, the
activation of the aldehyde 1 and the in situ protection of 3 by
means of SiCl4. Even if we were unable to isolate the O–SiCl3 inter-
mediates 6, any attempt of in situ TMS protection failed and we
recovered 3c in quantitative way (Scheme 6). This is a proof that,
after the addition step mediated by SiCl4, the hydroxyl group is
not free for a further reaction.
CO2tBu
CH2(CO2tBu)2
+
R
H
R
2) NaHCO3, H2O
CO2tBu
1
2
3
1) Me3SiCl, CH2Cl2
DIPEA, -20°C, 2h
2) NaHCO3, H2O
Once the general features of the method were examined, we
turned our attention to expand the substrate scope. Therefore a
series of representative hetero-aromatic, unsaturated and aromatic
aldehydes were reacted with tert-butyl malonate 2c under the
optimised conditions (Table 3, Scheme 7). As previously observed
for benzaldehyde (Table 3, see also entry 1), the addition of tert-bu-
tyl malonate was particularly efficient and very good conversions
of 3 were observed (Table 3, entries 3–9). Among the tested sub-
strates, the electron-rich para-methoxybenzaldehyde showed a
lower reactivity and a longer reaction time was required to attain
OSiMe3
CO2tBu
R
CO2tBu
4
Scheme 7. Aldol addition of tert-butyl malonate to several aldehydes.
a satisfactory result (Table 3, entries 2–3). Moreover the a,b-unsat-
urated aldehyde gave exclusively 1,2-addition (Table 3, entry 9)
while the aliphatic aldehyde 3-phenylpropanal proved to be com-
pletely unreactive (Table 3, entry 10). As previously observed, in
spite of the good purity of the crude products, any attempt at puri-
fication of 3 by chromatography was unsuccessful. Therefore we
performed the same TMS protection of 3 and we obtained good
to high yields of 4 for all the tested compounds. However, the iso-
lated yields were lower for 4d, 4e, 4g and 4l for the formation of
the starting materials 1 and 2c as by-products (Table 3, entries 3,
4, 6 and 9). On the contrary the reaction of b-hydroxymalonate
derivative of 2-Cl-benzaldehyde 3i was slower probably for the
steric hindrance of chlorine substituent. In this case, even after
24 h at 0 °C we observed on the crude product a mixture of about
50/50 of 3i/4i and we obtained a 30% isolated yield of 4i (Table 3,
entry 8).
In conclusion, we have described a very efficient direct aldol
addition of malonates to aromatic, hetero-aromatic and unsatu-
rated aldehydes to give b-hydroxymalonates. Both SiCl4 and of i-
Pr2EtN were necessary to obtain the final products. Even if b-
hydroxymalonates were obtained in high conversion, any attempt
at purification of these materials by chromatographic methods led
to extensive decomposition. Therefore we converted b-hydroxy-
malonates in more stable and easy to purify TMS-O-protected
compounds.
OSiCl3
O
SiCl4
(iPr)2EtN
CO2R
-CH(CO2R)2
R'
CH2(CO2R)2
+
R'
H
CH2Cl2, -20 °C
2
CO2R
5
1
6
NaHCO3, H2O
OH
R'
CO2R
CO2R
3
Scheme 5. Proposed mechanistic pathway for the aldol step.
O
OH
1) SiCl4, (iPr)2EtN
Because of the uniqueness of this approach, further studies are
currently underway to develop an asymmetric version and to ex-
pand the scope of the reaction with respect to both the electrophile
and methylene-active components.
CH2Cl2,-20 °C, 7h
CO2tBu
CH2(CO2tBu)2
+
Ph
H
Ph
2) Me3SiCl, 18h
3) NaHCO3, H2O
CO2tBu
3c
1
2c
Scheme 6. Attempt at in situ TMS protection.
2. Experimental section
2.1. General procedure for aldol reaction
Table 3
In a flame-dried, 2-necked, round-bottomed flask, malonate
diester (1.1 equiv, 0.44 mmol) was added to a solution of i-Pr2EtN
(2.0 equiv, 0.80 mmol), SiCl4 (1.1 equiv, 0.44 mL of 1.0 M solution
in CH2Cl2) and aldehyde (0.40 mmol) in dry dichloromethane
(2.0 mL) under nitrogen at À20 °C. At the end of the reaction, the
mixture was quenched with saturated aqueous NaHCO3 (5 mL), ex-
tracted with 15 Â 3 mL of CH2Cl2 and dried over anhydrous
Na2SO4. After removing the solvent under reduced pressure, the
crude oil was analysed by 1H NMR and submitted to TMS
protection.
Aldol addition of tert-butyl malonate to several aldehydes
Entry
R
Time (h)
Conversion 3 (%)a
Yield 4 (%)b
1
2
3
4
5
6
7
8
9
Ph
7
7
24
7
7
7
7
7
7
24
3c
90
4c
82
n.d.
58
53
80
55
85
30c
59
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
4-CNC6H4
2-Furyl
2-ClC6H4
PhCH@CH
PhCH2CH2
3d
3d
3e
3f
3g
3h
3i
Low conv.
70
65
85
75
90
75
70
—
4d
4e
4f
4g
4h
4i
3l
4l
10
2.2. General procedure for trimethyl silyl protection
a
Conversions were determined on the basis of 1H NMR analysis and mass bal-
ance of the crude product.
b
Diisopropylethylamine (1.37 equiv, 0.55 mmol) and trimethyl
silyl chloride (1.25 equiv, 0.50 mmol) were added to a solution of
Yields refer to chromatographic pure compounds.
c
TMS protection was performed at 0 °C for 24 h.

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7321
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Acknowledgement
We are grateful to MIUR for financial support
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