One Pot Synthesis of Monoalkylated and Mixed, Dialkylated Meldrum's Acid Derivatives

Article abstract of DOI:10.1081/SCC-120027234

A simple one pot method, involving sequential Knoevenagel condensation of Meldrum's acid with aromatic aldehydes, conjugate reduction of ylidene Meldrum's acid using sodium borohydride followed by alkylation, to prepare mixed dialkylated derivatives of Meldrum's acid is described.

Full text of DOI:10.1081/SCC-120027234

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One Pot Synthesis of Monoalkylated and Mixed,
Dialkylated Meldrum's Acid Derivatives
Uday V. Desai a , D. M. Pore a , R. B. Mane a , S. B. Solabannavar a & P. P. Wadgaonkar b
a Department of Chemistry, Shivaji University, Kolhapur, 416 004, India
b Polymer Division, National Chemical Laboratory, Pune, India
Version of record first published: 16 Aug 2006.
To cite this article: Uday V. Desai , D. M. Pore , R. B. Mane , S. B. Solabannavar & P. P. Wadgaonkar (2004): One
Pot Synthesis of Monoalkylated and Mixed, Dialkylated Meldrum's Acid Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:1, 25-32
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 1, pp. 25–32, 2004
One Pot Synthesis of Monoalkylated
and Mixed, Dialkylated Meldrum’s
Acid Derivatives
1
1
Uday V. Desai,1, D. M. Pore, R. B. Mane,
*
S. B. Solabannavar,1 and P. P. Wadgaonkar2
1Department of Chemistry, Shivaji University, Kolhapur, India
2Polymer Division, National Chemical Laboratory, Pune, India
ABSTRACT
A simple one pot method, involving sequential Knoevenagel conden-
sation of Meldrum’s acid with aromatic aldehydes, conjugate reduction
of ylidene Meldrum’s acid using sodium borohydride followed by
alkylation, to prepare mixed dialkylated derivatives of Meldrum’s acid is
described.
Key Words: Meldrum’s acid; Knoevenagel condensation; Aldehyde.
Meldrum’s acid (2,2-dimethyl-1, 3-dioxane-4, 6-dione) is an active
methylene compound with rigid cyclic structure and high acidity (pKa ¼ 4.9)
*
Correspondence: Uday V. Desai, Department of Chemistry, Shivaji University,
Kolhapur 416 004, India; E-mail: uprabhu_desai@rediffmail.com.
25
DOI: 10.1081/SCC-120027234
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

26
Desai et al.
and can undergo hydrolysis very easily.[1] It is well known that Meldrum’s
acid can undergo Knoevenagel condensation,[2a–e] Michael condensation,[3]
acylation with acid chlorides[4,5] as well as acids.[6,7] The reports on alkylation
studies of Meldrum’s acid reveal that unlike dialkyl malonates it has a strong
tendency to undergo bis alkylation even with one mole equivalent of alkyl
halide[10] and only in exceptional cases monoalkylation results.[11–13] The
interest in the synthesis of monoalkylated Meldrum’s acid as well as mixed
dialkylated Meldrum’s acid continues to evolve due their use in the synthesis
of dialkylated malonates as well as barbiturates.
The difficulties to prepare dialkylated Meldrum’s acid wherein the two
alkyl substituents are different, can be overcome by alkylation of
monoalkylated Meldrum’s acid, which in turn is prepared by the methods
which include: 1) Knoevenagel condensation of Meldrum’s acid with
carbonyl compounds to ylidene Meldrum’s acid followed by conjugate
reduction with sodium borohydride[14a] or sodium tellurohydride[15] or by
cuprous chloride catalyzed conjugate Grignard addition to ylidene Meldrum’s
acid;[16] 2) by condensation of Meldrum’s acid with aromatic aldehydes in
presence of formic acid and triethylamine;[17] 3) by reduction of acylated
Meldrum’s acid with sodium cyanoborohydride;[18] and 4) by reductive
alkylation of Meldrum’s acid with carbonyl compounds using borane-
triethylamine.[19] All these methods require a multistep reaction sequence to
be carried out separately. We herein report a simple, one pot method for the
preparation of monoalkylated as well as mixed dialkylated Meldrum’s acids.
The Knoevenagel condensation of Meldrum’s acid with various
aldehydes is a key step of the sequence of reactions and for that plethora
of reagents are available.[2a–e,20a–b] Until recently, it was believed that
1,2-elimination of b-hydroxy intermediate, 3 (Sch. 1) in the reaction is
inhibited by protic solvents as retro Knoevenagel reaction prevails. However,
it has been demonstrated by Li[21] that, reaction can be effected in protic
solvent like ethanol in the presence of potassium phosphate as a mild base or
in water alone in the absence of any catalyst.[22–24] Recently potassium
phosphate has also been used in the synthesis of hexasubstituted cyclotri-
phosphazenes,[25] as well as dithiocarbamates.[26]
In view of our continued interest in the chemistry of Meldrum’s
acid,[10,11] we ventured to undertake the one pot synthesis of monoalkylated as
well as mixed dialkylated Meldrum’s acid by sequential Knoevenagel
condensation, sodium borohydride reduction and alkylation. The reaction
sequence was carried out in ethanol medium but in the absence of catalyst, the
yields of Knoevenagel condensation products, 4, being moderate (50–60%,
TLC), it was catalyzed by the use of potassium phosphate as a base catalyst.
This specific solvent-base combination not only effects Knoevenagel
condensation of Meldrum’s acid, 2, with aromatic aldehydes, 1 to give

Meldrum’s Acid
27
Scheme 1.
arylidene Meldrum’s acids, 4 in high yields (85 to 90%) but also permits the
reduction of 4 with sodium borohydride in the same pot to furnish
monoalkylated Meldrum’s acids, 5, which can be either isolated or can be
alkylated with various alkyl halides to yield mixed dialkylated Meldrum’s
acids, 6, in the same pot (Sch. 1).
The overall sequence of reactions was carried out at room temperature
and can be monitored easily by TLC. Further, the reaction can be arrested at
any desired stage viz. at arylidene Meldrum’s acid stage 4, at monoalkylation
product stage 5, or can be taken directly to get mixed dialkylated Meldrum’s
acid, 6. The results obtained during the condensation of various aldehydes
with Meldrum’s acid, followed by reduction and alkylation are summarized in
Tables 1 and 2.
In summary, the potassium phosphate catalyzed procedure described
herein is a convenient and easy method to prepare either exclusively
monoalkylated or mixed dialkylated Meldrum’s acids in high overall yields.
The resultant monoalkylated Meldrum’s acids, 5 on refluxing with alcohol, are
known to give a-monosubstituted malonic acid half esters, which are
otherwise difficult to prepare and are highly useful for the preparation of a-
substituted acrylic esters.[27–29]
EXPERIMENTAL
Meldrum’s acid was prepared according to the reported procedure.[1]
Various aldehydes (E. Merck, Lancaster and Sd Fine chemicals) and

28
Desai et al.
Table 1. Preparation of dialkylated Meldrum’s acid 6.
Melting point
Entry
R
R0
Time (h) Yield (%)a Obs. 8C
Lit. 8C
a
b
c
d
e
f
Ph
Ph
CH3
C2H5
4
4.5
5
90
84
84
91
76
76
91
72
70
120
131
228
84
119-12011
—
23011
—
Ph
Ph-CH2
CH3
C2H5
4-MeOPh
4-MeOPh
4-MeOPh
4-Cl Ph
4-Cl Ph
4-Cl Ph
4.5
5
112
164
80
—
—
Ph-CH2
CH3
C2H5
4.5
5.5
6
g
h
i
—
—
114
145
Ph-CH2
6
—
aYields refer to pure isolated products.
potassium phosphate (Across) were used as received. IR spectra were recorded
on Perkin–Elmer-298 instrument while PMR spectra were recorded on Bruker
(200 MHz) in CDCl3 as a solvent and d values are expressed in ppm. The mass
spectra were recorded on Finnigan mat 1020 spectrometer.
Typical Procedure
Preparation of 5-benzyl-5-methyl-2,2-dimethyl-1,3-dioxan-4,6-dione, 6a:
To a stirred solution of Meldrum’s acid (0.72 g, 5 mmol) in ethanol (20 mL)
Table 2. Preparation of monoalkylated Meldrum’s acid 5.
Melting point
Entry
R
Time (h)
Yield (%)a
Obs. 8C
Lit. 8C
a
b
c
d
e
f
Ph
2.5
2.0
2.5
4.0
2.0
2.5
3.0
2.5
77
91
84
82
79
91
63
82
79
84
80–8113
8513
—
4-MeOPh
4-ClPh
3-ClPh
4MePh
4HOPh
2 O2NPh
2ClPh
127
104
110
130
122
124
—
111–11230
120
—
g
h
12630
aYields refer to pure isolated products.

Meldrum’s Acid
29
was added potassium phosphate (0.2 g, 0.94 mmol) followed by solution of
benzaldehyde (0.53 g, 5 mmol) in ethanol (5 mL). Stirring was continued until
completion of reaction (TLC) and to it sodium borohydride (0.4 g, 10.5 mmol)
was added. On completion of reduction (TLC), methyl iodide (1 g, 7 mmol)
was added and the reaction mixture was further stirred until alkylation is over
(TLC). Water (20 mL) was added and mixture was extracted with ether. The
ether extract was washed with water repeatedly, dried over anhydrous sodium
sulphate and solvent was removed to get 6a (1.12 g, 90%), mp 1208C (Lit13 mp
119–1208C).
The monoalkylated Meldrum’s acid derivative, 5a can be obtained by
carrying out the workup of the reaction mixture after reduction with sodium
borohydride is over.
Spectral data of new 5,5-dialkylated Meldrum’s acid, 6:
6b. 0.63 (3H, s), 0.96 (3H, t), 1.55 (3H, s), 2.20 (2H, q), 3.31 (3H, s),
4.14 (2H, q), 7.2–7.3 (5H, m).
6d. 0.38 (3H, s), 1.61 (3H, s), 1.73 (3H, s), 3.28 (2H, s), 3.76 (3H, s),
6.28 (2H, d), 7.10 (2H, d). MS m/z (%): 278 (Mþ, 23), 148 (15), 121 (100), 77
(30).
6e. 0.74 (3H, s), 0.97 (3H, t), 1.58 (3H, s), 2.21 (2H, q), 3.27 (3H, s),
3.76 (3H, s), 6.80 (2H, d), 7.10 (2H, d). MS m/z (%): 292 (Mþ, 5), 206 (16),
121(100), 77 (6).
6f. 0.64 (3H, s), 0.72 (3H, s), 3.41 (4H, m), 3.76 (3H, s), 6.78 (2H, d),
7.2 (7H, m). MS m/z (%): 354 (Mþ, 4), 91 (37), 121 (100) 77 (7).
6g. 0.98 (3H, s), 1.55 (3H, s), 1.68 (3H, s), 3.23 (2H, s), 7.04 (2H, d),
7.18 (2H, d). MS m/z (%): 282 (Mþ, 5), 196 (84), 180 (17), 145 (27), 125
(100), 89 (28) 115 (36).
6h. 0.78 (3H, s), 0.98 (3H, t), 1.60 (3H, s), 2.2 (2H, q), 3.29 (2H, s), 7.16
(2H, d), 7.24 (2H, d).
6i. 0.62 (3H, s), 0.75 (3H, s), 3.42 (2H, s), 3.44 (2H, s), 7.16 to 7.28 (9H,
m) MS m/z (%): 358 (Mþ, 15), 272 (100), 289 (32), 256 (17), 226 (17), 125
(22), 91 (32).
Spectral data of new monoalkylated Meldrum’s acids: 5:
5c. 1.57 (3H,S), 1.73 (3H, s), 3.45 (2H, d), 3.73 (1H, t), 7.25 (4H, s); MS
m/z (%): 268 (Mþ, 4), 182 (100), 139 (31), 103 (37), 77 (15).
5d. 1.61 (3H, s), 1.77 (3H, s), 3.45 (2H, d), 3.76 (1H, t), 7.23–7.34 (4H,
m); MS m/z (%): 268 (Mþ, 3), 182 (46), 138 (55), 131 (100), 77 (41.3).
5f. 1.48 (3H, s), 1.73 (3H, s), 2.19 (1H, s), 3.44 (2H, d), 3.73 (1H, t),
6.75 (2H, d), 7.18 (2H, d); MS m/z (%): 250 (Mþ, 11), 164 (100), 147 (30),
120 (42), 107 (68), 91 (33), 77 (16), 65 (20).

30
Desai et al.
5g. 1.78 (3H, s), 1.82 (3H, s), 3.65 (2H, d), 4.21 (1H, t), 7.45 to 8.03
(4H, m).
ACKNOWLEDGMENT
One of the authors (UVD) thanks UGC, New Delhi, for financial
assistance.
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Received in the USA July 15, 2003