A general and practical preparation of alkylidene Meldrum's acids

Article abstract of DOI:10.1016/j.tetlet.2007.08.012

Although many methods have been reported for the Knoevenagel condensation of aldehydes and Meldrum's acid, most are not general or use unconventional reagents and conditions. We have found that alkylidene Meldrum's acids form readily in benzene solution u

Full text of DOI:10.1016/j.tetlet.2007.08.012

Tetrahedron Letters 48 (2007) 7072–7074
A general and practical preparation of alkylidene Meldrum’s acids
Aaron M. Dumas, Adam Seed, Alexander K. Zorzitto and Eric Fillion*
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received 5 June 2007; revised 1 August 2007; accepted 2 August 2007
Available online 8 August 2007
Abstract—Although many methods have been reported for the Knoevenagel condensation of aldehydes and Meldrum’s acid, most
are not general or use unconventional reagents and conditions. We have found that alkylidene Meldrum’s acids form readily in benz-
ene solution under mild pyrrolidinium acetate catalysis, and that this reaction is general, highly functional group compatible, and
can be scaled-up easily.
Ó 2007 Elsevier Ltd. All rights reserved.
5-Alkenyl-2,2-dimethyl-1,3-dioxane-4,6-diones (alkylid-
ene Meldrum’s acids, AMAs 3) are highly reactive 1,1-
diactivated alkenes that have been used extensively as
acceptors in 1,4-addition of a variety of organometallic
reagents,1 as dienophile and diene in Diels–Alder and
hetero-Diels–Alder reactions, respectively,2 and as a
versatile synthon in various other reactions.3 In conjunc-
tion with ongoing research in our laboratories involving
catalytic C–C bond forming reactions using AMAs,4 we
have prepared a large number of, especially, 5-(1-aryl-
methylidene) Meldrum’s acids derived from benzalde-
hydes. For the preparation of mono-substituted AMAs,
the most convenient method is the Knoevenagel conden-
sation of Meldrum’s acid 1 with an aldehyde 2. This
reaction has been studied extensively, and a wide range
of conditions have been reported to carry out this seem-
ingly simple transformation.5
used. Unfortunately we have been unable to predict
which aldehydes will condense smoothly under which
conditions, leading to a frustrating guessing game. Com-
peting addition of 1 onto 3 can be circumvented by
in situ addition of a nucleophile to the AMA, forming
an adduct from which the AMA can be regenerated in
a second step. Methoxide,7 amines,8 and thiols9 have
been successfully used in this manner, but this is an
unsatisfactory solution in terms of atom and step econ-
omy. To further our own research, and to remove some
of the difficulties involved with preparing AMAs, we
therefore sought a Knoevenagel condensation that
would be practical, general, and scaleable.
Qualitative observation of reactions in which significant
amounts of 4 have formed led us to believe that the equi-
librium between 3 and 4 was being shifted to the right by
precipitation of the bis-Meldrum’s acid adducts, which
are generally poorly soluble in polar and non-polar sol-
vents. We therefore reasoned that formation of 3 could
be maximized by performing the reactions in dilute
organic solvent (benzene10) to prevent precipitation of
4. Since both the condensation of 1 and 2, and reversion
of 4 to 3 are known to be catalyzed by amino acids,11
However, as noted by Snyder as early as 1961, the con-
densation can be complicated by competing Michael
addition of Meldrum’s acid to AMA 3 to form products
of type 4 (Scheme 1).6 It has been our experience that
certain alkylidenes are more prone to Michael addition
than others depending on the condensation conditions
O
O
O
O
O
O
O
-H2O
1
O
O
+
O
O
O
O
Ar
+H2O
O
O
Ar
O
O
4
1
2
3
Ar
Scheme 1.
*
Corresponding author. Tel.: +1 519 888 4567x32470; fax: +1 519 746 0435; e-mail: efillion@uwaterloo.ca
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.012

A. M. Dumas et al. / Tetrahedron Letters 48 (2007) 7072–7074
7073
A TBAB (10 mol %)
O
O
H2O, rt, 2 h
O
O
O
O
O
O
O
B H2O, 75 ˚C, 2 h
O
O
+
O
O
Ph
4a
O
O
C pyrrolidinium
acetate (10 mol %)
PhH, rt, 24 h
O
O
3a
Ph
A
B
C
13
7
97
:
:
:
87
93
3
Scheme 2.
catalytic pyrrolidinium acetate was added to facilitate
both reactions. This hypothesis was tested on the reac-
tion of benzaldehyde and Meldrum’s acid, which in
our experience is the most problematic condensation
(Scheme 2). For example, conditions reported by Ren
et al. (Scheme 2, A) to give 3a in 69% yield5b are irrepro-
duceable, and in our hands gave a white powder consist-
ing of a mixture of 13:87 3a and 4a, along with 6%
benzaldehyde. The conditions of Bigi et al.5a (Scheme
2, B), who did not report this exact reaction and which
does work as reported for other benzaldehydes, gave a
mixture of 3a and 4a in a 7:93 ratio. In contrast, reac-
tions run in 0.2 M PhH with 10 mol % pyrrolidinium
acetate (Scheme 2, C) yielded essentially pure 3a.12
From this, 3a was isolated in 85% yield after a simple
aqueous work-up. Previously we had prepared 3a via
condensation of Meldrum’s acid with trimethyl ortho-
formate, followed by addition of PhMgBr to the result-
ing 5-(methoxymethylene) Meldrum’s acid.4a
out that under the conditions described, no formation of
4 was detected by H NMR analysis of the crude reac-
1
tion mixture. While electron-rich methoxy-substituted
benzaldehydes reacted easily at room temperature
(entries 1–3), electron-withdrawing CF3 substituents
decreased conversion, likely due to slower elimination
of water from the initially formed aldol product. This
was easily overcome by performing the reactions at
50 °C; again, an EWG substitution at any position is
handled well (entries 4–6). Alkyl substituents (Me) at
any position can be used, with a higher reaction concen-
tration to increase conversion (entries 7–9). Chlorine at
all positions, and other halogens, are tolerated as well
(entries 10–15). This was gratifying, as these benzaldehy-
des had often proven quite difficult to condense under
other conditions.14
Functional group compatibility was shown by smooth
condensation with nitro-, nitrile-, ketone-, ester-, and
phenol-containing benzaldehydes (entries 16–20). At
50 °C, 4-cyanobenzaldehyde produced a roughly 1:1
mixture of 3 and 4; increasing the temperature to
80 °C prevented precipitation of 4 and favored forma-
tion of 3. The reaction proved to be highly chemoselec-
tive, as no condensation with the ketone was observed
for 4-acetylbenzaldehyde. Vanillin and its acetate con-
densed cleanly without opening of Meldrum’s acid by
the phenol or cleavage of the labile ester.
To demonstrate the utility and functional group com-
patibility of this method, benzaldehydes with various
functionalities and substitution patterns were reacted
under these conditions (Table 1).13 It should be pointed
Table 1. Condensation of benzaldehydes with Meldrum’s acid
pyrrolidinium
acetate (10 mol %)
O
O
O
O
+
ArCHO
O
O
Aldehydes other than simple benzaldehydes also con-
dense smoothly under these conditions (Table 2). Naph-
thyl and furyl, as well as branched aliphatic, aldehydes
are tolerated. Reaction with straight-chain aliphatic
aldehydes (i.e. acetaldehyde) led to a complex mixture
even when reacted at 0 °C. Cinnamaldehyde condensed
cleanly without double bond isomerization.
PhH (0.2 M), 24 h
O
temperature
O
Ar
Entry Ar
Temperature (°C) Yield (%)
1
2
3
4
5
6
7a
8a
9a
10
11
12
13
14
15
16
17
18a
19
20
2-(OMe)C6H4
3-(OMe)C6H4
4-(OMe)C6H4
2-(CF3)C6H4
3-(CF3)C6H4
4-(CF3)C6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2,4-(Cl)2C6H4
2-BrC6H4
2-FC6H4
rt
rt
rt
84
88
88
83
82
71
85
80
77
73
60
72
78
76
84
81
68
71
79
76
50
50
50
50
50
50
50
50
50
50
50
50
50
80
50
50
Table 2. Condensation of naphthyl, furyl, and aliphatic aldehydes
pyrrolidinium
O
O
O
acetate (10 mol %)
O
O
+
O
O
PhH (0.2 M), 24 h
O
temperature
R
O
R
Entry
R
Temperature (°C)
Yield (%)
4-(NO2)C6H4
4-(CN)C6H4
4-AcC6H4
3-(OMe)-4-(OH)C6H3
3-(OMe)-4-(OAc)C6H3 50
1
2
3
4
5
1-Naphthyl
2-Naphthyl
2-Furyl
Isopropyl
trans-Ph(CH)2
50
50
50
rt
92
89
79
78
84
50
a Concentration 0.5 M.

7074
A. M. Dumas et al. / Tetrahedron Letters 48 (2007) 7072–7074
Soedin. 1991, 579–599; (c) McNab, H. Chem. Soc. Rev.
1978, 7, 345–358.
O
O
O
pyrrolidinium
acetate (10 mol %)
4. (a) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org.
Chem. 2005, 70, 1316–1327; (b) Fillion, E.; Dumas, A. M.;
Kuropatwa, B. A.; Malhotra, N. R.; Sitler, T. C. J. Org.
Chem. 2006, 71, 409–412; (c) Fillion, E.; Wilsily, A. J. Am.
Chem. Soc. 2006, 128, 2774–2775; (d) Fillion, E.; Wilsily,
A.; Liao, E.-T. Tetrahedron: Asymmetry 2006, 17, 2957–
2959.
MeO
MeO
O
O
PhH (0.2 M), rt, 24 h
MeO
MeO
1 mmol, 85% yield
10 mmol, 92% yield
Scheme 3.
5. In water: (a) Bigi, F.; Carloni, S.; Ferrari, L.; Maggi, R.;
Mazzacani, A.; Sartori, G. Tetrahedron Lett. 2001, 42,
5203–5205; Using surfactants: (b) Ren, Z.; Cao, W.;
Weiqi, T.; Jing, X. Synth. Commun. 2002, 32, 1947–1952;
Using modified silica-gel catalyst: (c) Isobe, K.; Hoshi, T.;
Suzuki, T.; Hagiwara, H. Mol. Divers. 2005, 4, 317–320; In
ionic liquid: (d) Hu, Y.; Wei, P.; Huang, H.; Le, Z.-G.;
Chen, Z.-C. Synth. Commun. 2005, 35, 2955–2960; (e)
Darvatkar, N. B.; Deorukhkar, A. R.; Bhilare, S. V.;
Salunkhe, M. M. Synth. Commun. 2006, 36, 3043–3051; By
microwave irradiation: (f) Abdallah-El Ayoubi, S.; Texier-
Boullet, F.; Hamelin, J. Synthesis 1994, 258–260.
6. Hedge, J. A.; Kruse, C. W.; Snyder, H. R. J. Org. Chem.
1961, 26, 3166–3170.
Since we often need large quantities of AMAs for
methodology development, the preparation of 5-[1-
(3,4-dimethoxyphenyl)methylene]-Meldrum’s acid was
attempted on small and larger scale. As shown in
Scheme 3, the reaction can be performed just as easily
on 10 times the scale of the general procedure (yielding
2.6 g of AMA).
The above examples amply demonstrate the generality
and usefulness of this condensation procedure for the
synthesis of diverse AMAs. Problems associated with
other methods are avoided, all the reagents are conven-
tional and commercially available, and purification and
isolation of the products is simple.
7. Margaretha, P.; Polansky, O. E. Tetrahedron Lett. 1969,
10, 4983–4986.
8. Chhabra, B. R.; Bolte, M. L.; Crow, W. D. Aust. J. Chem.
1984, 37, 1795–1797.
9. Eberle, M.; Lawton, R. G. Helv. Chim. Acta 1988, 71,
1974–1982.
10. Reported as solvent for the preparation of 2- and 3-
indolydene Meldrum’s acids: Benzies, D. W. M.; Fresn-
eda, P. M.; Jones, R. A.; McNab, H. J. Chem. Soc., Perkin
Trans. 1 1986, 1651–1654.
11. Buzinkai, J. F.; Hrubowchak, D. M.; Smith, F. X.
Tetrahedron Lett. 1985, 26, 3195–3198.
Acknowledgments
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC),
the Canadian Foundation for Innovation, The Ontario
Innovation Trust, and the University of Waterloo. We
gratefully acknowledge the Merck Frosst Centre for
Therapeutic Research, Boehringer Ingelheim (Canada)
Ltd. (Young Investigator Award to E.F.), and Astra-
Zeneca Canada Inc. (AstraZeneca Award to E.F.) for
unrestricted support of this research. A.M.D. thanks
the Government of Ontario and NSERC for graduate
scholarships.
12. Ratios determined by 1H NMR analysis of the crude
reaction mixture. The following characteristic peaks were
integrated to determine the ratios: benzaldehyde, d ꢀ 10.0
(s, 1H); 3a, d ꢀ 8.6 (s, 1H); 4a, d ꢀ 4.68–4.61 (m, 3H).
13. General procedure: Aldehyde (1.0 mmol, 1.0 equiv),
Meldrum’s acid (158 mg, 1.1 mmol, 1.1 equiv) and dry
benzene (distilled from Na/benzophenone, 5.0 mL, 0.2 M)
were added to a glass vial equipped with a magnetic
stirbar. To this was added 200 lL of a 0.5 mM solution of
pyrrolidinium acetate in benzene (prepared by dropwise
addition of AcOH to pyrrolidine in benzene, 0.1 mmol,
10 mol %) at room temperature. The vial was capped
tightly and stirred at the appropriate temperature (heated
reactions performed in preheated oil-baths) for 24 h.
Products can be purified either by diluting the reaction
with EtOAc, washing the mixture with saturated NaHCO3
solution, drying over MgSO4, and concentrating dry or by
removal of benzene by rotary evaporation and recrystal-
lizing the resulting solid from MeOH.
References and notes
1. Enantioselective additions of organozinc reagents to
AMAs derived from aldehydes: (a) Kno¨pfel, T. F.;
Zarotti, P.; Ichikawa, T.; Carreira, E. M. J. Am. Chem.
Soc. 2005, 127, 9682–9683; (b) Watanabe, T.; Kno¨pfel, T.
F.; Carreira, E. M. Org. Lett. 2003, 5, 4557–4558.
2. Fillion, E.; Dumas, A. M.; Hogg, S. A. J. Org. Chem.
2006, 71, 9899–9902, and references cited therein.
3. For reviews on Meldrum’s acid in synthesis see: (a) Chen,
B.-C. Heterocycles 1991, 32, 529–597; (b) Strozhev, M. F.;
14. For example, as reported by Bigi (Ref. 5a), the conden-
sation of 4-chlorobenzaldehyde with Meldrum’s acid in
water gave an 86:14 mixture of 3:4, from which the AMA
was isolated in 60% yield.
´
Lielbriedis, I. E.; Neiland, O. Ya. Khim. Geterotsikl.