On the synthesis of 5-ethyl Meldrum's acid

Article abstract of DOI:10.1002/jhet.5570430217

Reductive alkylation of Meldrum's acid with acetaldehyde can give, depending on the experimental conditions, e ither a new dimer (5-[3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)butyl]-2,2-dimethyl-1,3-dioxane-4, 6-dione) or ethyl Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione). A best way to obtain this latter product is synthesis of 1-ethoxyethylidene Meldrum's acid from reaction of Meldrum's acid with triethyl orthoacetate, followed by a sodium borohydride reduction.

Full text of DOI:10.1002/jhet.5570430217

Mar-Apr 2006
365
On the Synthesis of 5-Ethyl Meldrum's Acid
Rufine Akué-Gédu, Hayate El-Hafidi and Benoît Rigo
*
Groupe de Recherche sur l'Inhibition de la Prolifération Cellulaire (EA 2692)
Ecole des Hautes Etudes d'Ingénieurs, 13 rue de Toul, 59046 Lille, France
e-mail: rigo@hei.fr
Daniel Couturier
Laboratoire d'Ingénierie Moléculaire, Université des Sciences et Technologies, 59655 Villeneuve d'Ascq, France
Received June 29, 2005
Reductive alkylation of Meldrum's acid with acetaldehyde can give, depending on the experimental con-
ditions, either a new dimer (5-[3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)butyl]-2,2-dimethyl-1,3-dioxane-
4,6-dione) or ethyl Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione). A best way to obtain this latter
product is synthesis of 1-ethoxyethylidene Meldrum's acid from reaction of Meldrum's acid with triethyl
orthoacetate, followed by a sodium borohydride reduction.
J. Heterocyclic Chem., 43, 365 (2006).
In conjunction with an ongoing program [1], we needed
obtained in good yields (85%) [5]. Thus we carried out a
Knoevenagel reaction between acetaldehyde hemiacetal
and the sodium salt of Meldrum's acid formed in-situ in
methanol. After acidification, the resulting product was
reduced with sodium borohydride [4,10]. Surprisingly, a
new dimer 6 was isolated in 40% yield (Scheme 1).
A possible mechanism for the formation of dimer 6 is
described in Scheme 1: Compound 4, which is vinylogue
to Meldrum's acid, is strongly acidic [11], and reacts with
sodium methoxide (or another sodium salt), to yield salt 7.
Michael addition of 7 to polarized ethylenic 4 gives salt 8.
Dimer 6 was then obtained after acidification and sodium
borohydride reduction of the double bound of 8
(Scheme 1) [4].
a convenient supply of 5-ethyl Meldrum's acid (1) [2].
Because the selective monoalkylation of Meldrum's acid 2
is difficult and that the dialkylated product 3 generally pre-
dominates [3], we choose to use a reductive alkylation
between acetaldehyde and Meldrum's acid and to reduce
the alkylidene derivative 4, following the general method
of Smith [4] (Figure 1).
In another experiment, following more closely literature
procedures [5], the sodium salt of Meldrum's acid was
formed in tetrahydrofuran, and then isolated. A solution of
acetaldehyde hemiacetal in methanol was then slowly
added to a suspension of this salt in the same solvent.
Acidification of the residue obtained after evaporation
leads, according to NMR, to a mixture of 4 (5-10%), 5 (85-
90%) and 9 (0-5%). When this reaction was repeated in a
methanol/dichloromethane solvent, the acidification step
being performed in dichloromethane, alkylidene
Meldrum's derivative 4 was obtained in more than 95%
yield (NMR). This compound was not isolated, but the
dichloromethane solution of compound 4 was directly
treated with sodium borohydride, giving an 85% yield of
the desired product 1.
Figure 1
Concerning the synthesis of compounds 4, in order to
avoid a Michael reaction of Meldrum's acid with the ethyl-
enic product 4, giving dimer 5 [2c,5-9], Polanski and
Margaretha recommend intercepting 4 with sodium
methoxide. After acidification, 4 was described to be

366
R. Akué-Gédu, H. El-Hafidi and B. Rigo
Vol. 43
Scheme 1
It is necessary to point out the necessity to proceed very
carefully when using old literature for the attribution of a
structure to dimers obtained from the reaction of
Meldrum's acid with aldehydes. Indeed compound 9a
related to dimer 9 has already been obtained in the reaction
of Meldrum's acid with butyraldehyde [12]. No spectral
data were provided for this compound, which was missas-
signed as dimer 5a in another publication [5] (Figure 2). In
the same way, structure 5 was attributed to the product
obtained from the reaction of Meldrum's acid with
acetaldehyde in dimethylformamide or from its reaction
with crotonaldehyde (…obviously as the result of occur-
rence of a reverse aldol reaction [8]…). Because of iden-
tity of melting point (147-150 °C), we believe that the
product thus isolated was in fact dimer 9.
Figure 2
terature [2c,5-10], we were not able to find any authentic
description of dimer 5. In the same way, to the best of our
knowledge, dimer 6 observations or characterization were
not reported.
The results described above are strongly dependent upon
the exact temperature and duration of the reaction (as well
as the physical states of sodium borohydride (powder vs.
pellets) and more convenient synthesis were needed. A
Interestingly, although many mentions on the easy
Michael reaction of Meldrum's acid with ethylenic com-
pounds such as 4 (to give dimers like 5) can be found in lit-

Mar-Apr 2006
On the Synthesis of 5-Ethyl Meldrum's Acid
367
possibility to obtain compound 1 is a one-pot reduction
[13] of enol 10 [14a,b], obtained by using a slightly modi-
fied literature procedure for acylation of Meldrum's acid
[14a] (42% total yield) (Scheme 2). However, a best syn-
thesis of ethyl compound 1 is the sodium borohydride
reduction in acetic acid (72%), of 1-ethoxyethylidene
Meldrum's acid 11. This product was very easily obtained
from the reaction of Meldrum's acid with triethyl orthoac-
etate in dichloromethane solution (reflux 120 h, 93%)
[14c]. It is to be noted that the reaction must be conducted
under inert atmosphere to avoid hydrolysis to compound
10. The hydrolysis occurs also quantitatively and very
rapidly, when 11 is stirred in hydrated tetrahydrofuran.
This synthesis of enol 10 is easier to perform and gives a
purer product than the previous acetylation of Meldrum'
acid [14a,b] (Scheme 2).
methanol to dichloromethane). A strong influence of the
solvent in equilibrium as indicated in Scheme 3 was
already observed, often by NMR methods [6,8,12,16].
EXPERIMENTAL
Melting points were determined using an Electrothermal appa-
1
13
ratus and are uncorrected. H and C NMR spectra were
obtained on a Varian Gemini 2000 at 200 and 50 MHz, respec-
tively. IR spectra were carried out in ATR mode on a FTIR
Bruker Tensor 27. Thin layer chromatography was performed on
precoated Kieselgel 60F
plates. Microanalyses were per-
254
formed by the "Service Central de Microanalyses" of CNRS in
Vernaison, France.
5–Ethyl–2,2–dimethyl–1,3–dioxane–4,6–dione (1) from 5-
Ethylidene-2,2-dimethy–1,3–dioxane–4,6–dione (4).
A solution of sodium methoxide in methanol (28%, 90.3 g,
1.67 mol) was added to a stirred suspension of Meldrum's acid
(241 g, 1.67 mol) in tetrahydrofuran (500 mL). After one hour,
the sodium salt of Meldrum's acid was filtered, washed with ace-
tone then dried under vacuum. Acetaldehyde (470 mL, 8.37 mol)
was slowly added to ice cooled methanol (1370 mL), giving a
solution of acetaldehyde hemiacetal. The solution of acetalde-
hyde hemiacetal was rapidly added to a suspension of the sodium
salt of Meldrum's acid in dichloromethane (1000 mL). The reac-
tion is very fast (5 min). The resulting solution was quickly (2
min) acidified with 1 M hydrochloric acid. The organic phase
Scheme 2
was decanted then dried (MgSO ). The solution of product 4 was
4
not evaporated but used directly in the next step. If isolated, com-
pound 4 presents the same physical properties as described in lit-
-1
erature [5,7], mp 52-53 °C (51-53 °C) [2c], IR ν cm : 1765,
1
1740, 1630; H NMR (deuteriochloroform) δ ppm: 1.75 (s, 6H),
2.50 (d, J = 7.5 Hz, 3H), 8.03 (q, J = 7.5 Hz, 1H).
The dichloromethane solution of 4 obtained in the preceding
step was cooled at 0 °C (ice/salt bath) then sodium borohydride
powder (12 g, 0.319 mol) was slowly (15 min) added. The ice
bath was removed and the solution was allowed to rise to room
temperature. Excess of reducing agent was quenched by addition
of methanol (50 mL) and then acidification with 1 N hydrochloric
acid. The organic phase was decanted then dried (MgSO ). The
4
oil obtained upon evaporation was purified by preparative chro-
matography (Si60, 200-400 mesh, 1 Kg, ethyl acetate/heptane
1/1), giving 1 as a white powder (244 g, 85%): mp (ethyl acetate)
These results indicate that when compounds such as 1 or
4 are desired, a proper choice of experimental conditions
can lead to good yields, without the need of the more
sophisticated methods sometimes recommended in litera-
ture [7,12,15]. Furthermore this shows how the acidity
(and reactivity) of alkylidene Meldrum's acid derivatives
can be tuned by a slight change in solvent polarity (from
108-109°C (107-109°C) [15]; TLC (SiO , ethyl acetate/ heptane
2
1/1) 0.45; 'H NMR (deuteriochloroform) δ ppm: 1.06 (t, J = 7.4
Hz, 3H), 1.77 (s, 3H), 1.79 (s, 3H), 2.17 (dq, J = 4.9, 7.4 Hz, 2H),
13
3.50 (t, J = 4.9 Hz, 1 H); C NMR (deuteriochloroform) δ ppm:
10.6, 20.0, 26.8, 28.3, 47.0, 104.7, 165..4.
Synthesis of 1 from 10.
Scheme 3
A solution of Meldrum's acid (30.0 g, 0.208 mol), triethy-
lamine (34.8 ml, 0.250 mol) and dimethylaminopyridine (1.0 g,
0.008 mol) in dichloromethane (200 mL) was magnetically
stirred in a cooled bath (inner temperature: -25 °C). A solution of
acetyl chloride (18.0 g, 0.230 mol) in dichloromethane (50 mL)
was added during 1 hour while keeping the temperature between
-20 and -25 °C, then the cooling bath was removed. The mixture
was stirred at room temperature for 12 hours to give enol 10,
identical to the compound described in literature [14].

368
R. Akué-Gédu, H. El-Hafidi and B. Rigo
Vol. 43
Dichloromethane (100 mL) and acetic acid (160 mL) were added,
and then sodium borohydride powder (10.1 g, 0.267 mol) was
added over 75 min. After stirring for 12 hours, the solution was
acidified with 36% HCl, and then washed 2 times with water. The
aqueous phase was extracted with dichloromethane and this
organic phase was washed with water. The combined organic
phases were washed once with water, dried (Na SO ) and evapo-
rated. The residue was purified by preparative chromatography
(Si60, 200-400 mesh, 500 g, ethyl acetate/heptane 1/1), giving 1
as a white powder (15 g, 42%), identical to the compound
obtained from 4.
upon evaporation was purified by preparative chromatography
(Si60, 200-400 mesh, 500 g, ethyl acetate/heptane 1/1) giving 1
(4.1 g, 40%) and 6 as a white powder mp 115-117 °C (4 g, 40%).
-1
1
IR
ν cm 1780, 1740, 1205; H NMR (deuteriochloroform) δ
ppm: 1.16 (d, J = 7.1 Hz, 3H), 1.75, (s, 3H), 1.77 (s, 3H), 1.79 (s,
3H), 1.81 (s, 3H), 1.64-2.01 (m, 2H), 2.01-2.15 (m, 1H), 2.15-
2.34 (m, 1H) , 2.46–2.65 (m, 1H), 3.59 (d, J = 2.8 Hz, 1H) , 3.60
2
4
13
(t, J = 4.90 Hz, 1H); C NMR δ ppm: 16.4, 24.2, 26.5, 27.0,
28.1, 28.3, 30.9, 32.9, 45.8, 50.4, 104.6, 104.8, 164.2, 164.8,
165.0, 165.1.
Anal. Calcd. for C
H O : C, 56.13; H, 6.48; O, 37.39.
16 22 8
Found: C, 55.83; H, 6.75; O, 37.72.
Synthesis of 1 from 11.
5-(1-Hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione
(10) from 11.
Crude compound 11 obtained from 25 g of Meldrum's acid
(0.173 mol) was dissolved in a mixture of dichloromethane (100
mL) and acetic acid (155 mL). The solution was kept at 20 °C by
using a large water bath while sodium borohydride powder (9 g,
0.238 mol) was added over 45 min. The mixture was stirred at
room temperature for 12 hours to give quantitatively Meldrum's
derivative 1. Acetic acid was evaporated, and then the residue
was partitioned between water and dichloromethane. After dry-
ing and evaporation of the solvents, crystallized compound 1 was
washed with heptane to give 18.8 g (63%) of product identical to
the compound obtained from 4. It is not necessary to purify this
product by preparative chromatography before using it in other
reactions [1].
The crude compound 11 obtained from 12.5 g of Meldrum's
acid (87 mmol) was dissolved in a mixture of tetrahydrofuran (10
mL) and water (2.3 g, 130 mmol). The solution was stirred for 4
hours giving quantitatively a solution of enol 10. After drying
(Na SO ) the solvents were evaporated. The residue crystallized
2
4
in a diethyl ether/heptane mixture, to give 9.7 g (60%) of crystal-
lized 10, identical to the compound obtained following the litera-
1
ture [14a]. H NMR (deuteriochloroform) δ ppm: 1.74 (s, 6H),
2.68 (s, 3H).
5-(1-Ethoxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione
(11).
5-[1-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)ethyl]-2,2-
dimethyl-1,3-dioxane-4,6-dione (5).
A solution of Meldrum's acid (25 g, 0.173 mol) and triethyl
orthoacetate (95 mL, 85 g, 0.520 mol) in dichloromethane (125
mL) was stirred for 120 hours in a water bath heated at 50 °C
(nitrogen). Solvents were evaporated (rotary evaporator then 0.05
mmHg, bath temperature: 20 °C) to give a slightly yellow residue
containing 93% (NMR) of enol ether 11, identical to the com-
pound obtained following the literature [14c], and 5-6 % of
diethyl malonate. The crude mixture was used directly in the next
A solution of acetaldehyde hemiacetal in methanol (acetalde-
hyde: 100 mL, 1.70 mol; methanol 675 mL) was added (30 min)
to a solution of the sodium salt, formed in-situ by adding MeONa
(16 g, 28% in methanol, 0.29 mol) to Meldrum's acid (41.8 g,
0.29 mol) in methanol (500 mL). The mixture was stirred for 15
min, and then methanol was evaporated. Dichloromethane (500
mL) was added then the mixture was acidified with 1 N
hydrochloric acid. The aqueous phase was extracted three time
with methylene dichloride, then the organic phase was dried
(Na SO ) and evaporated giving a mixture of 4, 5 and 9. Upon
1
syntheses. H NMR (deuteriochloroform) δ ppm: 1.51 (t, J = 7.1
Hz, 3H), 1.70, (s, 6H), 2.73 (s, 3H), 4.43 (t, J = 7.1 Hz, 2H).
REFERENCES AND NOTES
2
4
addition of ether dimer 5 (82 g, 90%) deposed as a viscous,
slightly yellow oil which was purified by preparative chromatog-
raphy (Si60, 200-400 mesh, 500 g, ethyl acetate/heptane 1/1); IR
ν cm 1775, 1740, 1640, 1200; H NMR (deuteriochloroform) δ
ppm: 1.51 (d, J = 6.7 Hz, 3H), 1.79 (s, 6H), 1.83 (s, 6 H),
3.30–3.50 (m, 1H), 4.28 (d, J = 6 Hz, 2 H).
[1] R. Akué-Gédu, J.-P. Hénichart, D. Couturier and B.Rigo,
Tetrahedron Lett., 45, 9197 (2004).
-1
1
[2] For the structure of Meldrum's acid, see A. N. Meldrum, J.
Chem. Soc., 93, 598 (1908); D. Davidson and S. A Bernhard,. J. Amer.
Chem. Soc., 70, 3426 (1948); For reviews of the chemistry of Meldrum's
acid, see [a] H. McNab, Chem. Soc. Rev., 7, 345 (1978); [b] B.-C. Chen,
Heterocycles, 32, 529 (1991); [c] F. J. Kunz, P. Margaretha and O. E.
Polansky, Chimia, 24, 165 (1970); [d] T. Tsuno and K. Sugiyama, Trends
Heterocyclic Chem., 7, 91 (2001).
Anal. Calcd. for C
H O : C, 53.50; H, 5.77; O, 40.73.
14 18 8
Found: C, 53.11; H, 5.98; O, 40.97.
5-[3-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)butyl]-2,2-
dimethyl-1,3-dioxane-4,6-dione (6).
[3]. For the alkylation of Meldrum's acid [a] under phase transfer
conditions: C.-C. Chan and X. Huang, Synthesis, 452 (1982); [b] under
A solution of acetaldehyde hemiacetal in methanol (acetalde-
hyde: 20.5 mL, 0.350 mol; methanol 140 mL) was added (10
min) to a suspention of the sodium salt of Meldrum's acid (10 g,
0.060 mol) (cf. preparation of 1 from 4) in methanol (100 mL).
The mixture was stirred for 30 min, and then neutralized with 1 N
hydrochloric acid. Sodium borohydride pellets, (1.1 g, 0.030
mol) were added to the solution. The mixture was stirred for 30
min then acidified with 1 N hydrochloric acid. The solvent was
evaporated in part, dichloromethane was added and the solution
was washed with water. The organic phase was decanted then
DMSO and Et N conditions: B.-C. Chen and P. Lue, Org. Prep. Proc.
3
Int., 24, 185 (1992); [c] under Michael conditions: C.-C. Chan and X. I.
A. N. Huang, Synthesis, 224 (1984); [d] under Mitsunobu conditions: T.
K. M. Shing, L.-H. Li and K. Narkunan, J. Org. Chem., 62, 1617 (1997);
[e] under palladium-catalyzed conditions: B. M. Trost and V. J. Gerusz, J.
Amer. Chem. Soc., 117, 5156 (1995).
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Lett., 2325 (1979).
[5] P. Margaretha and O. E. Polansky, Tetrahedron Lett., 4983
(1969).
[6] F. Bigi, S. Carloni, L. Ferrari, R. Maggi, A. Mazzacani and
G.Sartori, Tetrahedron Lett., 42, 5203 (2001).
dried (Na SO ) to give a mixture of 1 and 6. The oil obtained
2
4

Mar-Apr 2006
On the Synthesis of 5-Ethyl Meldrum's Acid
369
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3
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3
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