Organic reactions in ionic liquids: Alkylation of Meldrum's acid

Article abstract of DOI:10.1081/SCC-120022170

The room temperature ionic liquid N-butylpyridinium tetrafluoroborate, [bpy]BF₄ is used as a "green" recyclable alternative to classical molecular solvents for the alkylation of Meldrum's acid.

Full text of DOI:10.1081/SCC-120022170

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Organic Reactions in Ionic Liquids: Alkylation of
Meldrum's Acid
b
a b
c
Ce Su , Zhen-Chu Chen
& Qin-Guo Zheng
a
Ningbo Institute of Technology, Zhejiang University, Ningbo, P.R. China
b
c
Department of Chemistry, Zhejiang University (Xi-Xi Campus), Hangzhou, P.R. China
Pharmaceutical Sciences Research Institute, Aston University, Aston Triangle, Birmingham,
UK
Version of record first published: 19 Aug 2006.
To cite this article: Ce Su, Zhen-Chu Chen & Qin-Guo Zheng (2003): Organic Reactions in Ionic Liquids: Alkylation of Meldrum's
Acid, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:16,
2817-2822
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 16, pp. 2817–2822, 2003
Organic Reactions in Ionic Liquids:
Alkylation of Meldrum’s Acid
Ce Su, Zhen-Chu Chen,1,2,* and Qin-Guo Zheng3
2
1
Ningbo Institute of Technology, Zhejiang University,
Ningbo, P.R. China
2
Department of Chemistry, Zhejiang University
(
Xi-Xi Campus), Hangzhou, P.R. China
Pharmaceutical Sciences Research Institute,
3
Aston University, Aston Triangle, Birmingham, UK
ABSTRACT
The room temperature ionic liquid N-butylpyridinium tetrafluoro-
4
borate, [bpy]BF isuesd asa ‘‘green’’ recyclable alternative to
classical molecular solvents for the alkylation of Meldrum’s acid.
Ionic liquids have been the subject of considerable interest as
environmentally benign reaction media for organic synthetic chemistry
in the last few years. These solvents possess a number of interesting
*
Correspondence: Zhen-Chu Chen, Ningbo Institute of Technology, Zhejiang
University, Ningbo 315104, P.R. China; Department of Chemistry, Zhejiang
University (Xi-Xi Campus), Hangzhou 310028, P.R. China.
2
817
DOI: 10.1081/SCC-120022170
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2
818
Su, Chen, and Zheng
properties, notably their lack of vapor pressure, ease of reuse, lack of
[
1]
flammability, and large accessible temperature range. To date some of
the more important reactionshave been carried out and inve st igated in
[
2]
ionic liquids, for example, Diels–Alder reactions, Wittig reactions,
[3]
[4]
[5]
Heck reactions, Michael additions, Suzuki cross-coupling reactions,
[6]
[7]
epoxidations, and Cr(salen) catalyzed asymmetric ring opening reac-
[9]
[8]
tionsof epoxides,
lipase-catalyzed ammoniolysis, 1,3-dipolar cycloaddition reactions,
Ni(0) catalyzed coupling reactionsof aryl halides,
[
10]
[11]
[
12]
[13]
oxidation of aromatic aldehydes,
mediated radical polymerizations,
hydroformylation reactionsof alkenes,
photochemical reactions,
hydrogenation, isomerization, and
Cu(I)
[
14]
[
15]
the Knoevengel and Robinson
[16]
annulation reactions etc.
These encouraging results prompted us to investigate the range of
organic reactions possible in ionic liquids for developing clean synthesis.
The alkylationsof active methylene compoundsare very important
methods for the formation of carbon–carbon bond in organic synthesis.
We were interested in the reaction of isopropylidene malonate
(
1; 2,2-dimethyl-4, 6-dioxo-1,3-dioxane, Meldrum’sacid), it hashigh
acidity (PK ¼ 4.97) and rigid cyclic structure, and can undergo alkyl-
a
ation easily to form alkylated products which are important inter-
[
17]
mediates in organic synthesis.
halides(Sch. 1) wasexamined in [bpy]BF
The reactionsof 1 with variousalkyl
ꢀ
[
18]
at 60–70 C using triethyl-
4
amine asba se ; the productswere conveniently extracted with ether, and
almost exclusive dialkylation to form 3 was seen in all cases. The results
are outlined in Table1.
These reactions were carried out, typically as 1 mmol of 1 in [bpy]BF4
2 mL) using 2.5 mmol of alkyl halide 2 and 2.5 mmol of NEt . Reactions
3
(
were complete in 4–12 h as sh own in Table1. The dialkylated products
3
were characterized by H NMR, IR, m.p., and elemental analysis which
1
[
17]
were consistent with literature data. The ionic liquid can be recovered
by treatment with CH C1 (5 mL), filtration of precipitate and removal of
solvent. The recovered solvent has been recycled numerous times with no
2
2
O
O
O
O
O
O
O
Et N
CH2R
3
RCH X
+
2
Ionic Liquid
bpy BF4
0-70°C
CH R
2
O
6
3
1
2
_
+
BF4
CH CH CH CH
3
N
bpy BF4 =
2
2
2
Scheme 1.

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Alkylation of Meldrum’s Acid
Table 1. Dialkylation of isopropylidene malonate.
2819
ꢀ
c
Time (h) T ( C) Yield (%)
Entry Product
R
X
1
2
3
4
5
6
7
8
9
1
1
3a
3b
3c
3d
3d
3d
3e
3e
3f
H
I
5
7
60
60
70
60
60
60
65
65
60
70
65
82
80
75
90
88
89
86
86
CH
CH
3
3
I
CH
2
CH
2
Br
C1
C1
C1
Br
Br
C1
10
4
C H
6
5
5
5
a
C H
6
4
b
C
6
H
4
p-NO
p-NO -C H
5
2
-C
6
H
5
5
a
5
2
6
CH
2
¼CH
12
12
6
31
78
85
0
1
3g
3h
a-Aphthalenyl C1
C H CO Br
6
5
a
4
The using second times recovered ionic liquid [bpy]BF .
b
4
The using third times recovered ionic liquid [bpy]BF .
c
Isolated yields based on isopropylidene malonate 1.
appreciable decrease in yield (Table 1 Entries 5, 6, 8), with only small
mechanical losses.
In conclusion, room temperature ionic liquid [bpy]BF , isan attrac-
4
tive clean synthetic alternative to classical molecular solvents for alkyl-
ation of Meldrum’s acid. The present reaction represents the first example
of the alkylation of active methylene compoundsin ionic liquid ,s and
further studies on the alkylation of other active methylene compounds
in ionic liquidsare in progre ss in our laboratory. Room temperature ionic
liquids are neoteric solvents, and studies are under way to demonstrate
their obvious potential as an alternative to classical molecular solvents
for organic synthesis.
EXPERIMENTAL
Melting pointswere determined on a X -Data microscopic melting
4
1
point apparatusand were uncorrected.
H NMR and spectra were
obtained at 400 MHz (AVANCE DMX400, Bruker) or 90 MHz
EM90) in CDCl using TMS as an internal standard. Infrared spectra
(
3
were recorded on a VECTOR 22 (Bruker) spectrometer at r.t. MS were
obtained by electron impact at 70 eV (HP5989B). Elemental analyses
were performed on a EA-1110 instrument.

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820
Su, Chen, and Zheng
General Procedure
In a typical reaction, isopropylidene malonate 1 1 mmol (144 mg) was
dissolved in ionic liquid [bpy]BF (2.0 mL), then triethylamine (2.5 mmol)
4
and alkyl halide 2 (2.5 mmol) were added respectively. The resulting
ꢀ
mixture was st irred for 4–12 h at 60–70 C, until TLC indicatescomplete
disappearence of starting material 1. The reaction mixture isthen
extracted with ethyl ether (3 Â 10 mL) exhaustively. After removal of
the solvent, the product was purified by crystallization or chromato-
graphy on silica gel (petroleum-ethyl acetate 4:1). The used ionic liquid
can be recycled by disolving in CH C1 (5 mL), then filtrating the pre-
2
2
cipitate and removing of solvent.
Physical and Spectroscopic Data
ꢀ
ꢀ
[17]
a. Colorless crystal; m.p. 59–60 C (Lit. 60 C ). IR (KBr) ꢀmax
3
¼
À1 1
1
1
774, 1732, 1380, 1370 cm . H NMR (CDC1 , 80 MHz): ꢁ ¼ 1.65 (s, 6H),
3
.54 (s, 6H).
3
ꢀ
ꢀ
[17]
b. Colorless crystal; m.p. 39–41 C (Lit. 40–41 C ). IR (KBr) ꢀmax
761, 1729, 1388, 1372 cm . H NMR (CDC1 , 80 MHz): ꢁ ¼ 0.91 (t, 6H),
¼
À1 1
1
1
3
.68 (s, 6H), 2.01 (q, 4H).
3
ꢀ
ꢀ
[17]
c. Colorless crystal; m.p. 85–86 C (86–87 C ). IR (KBr) ꢀmax
¼
À1
1
1
4
765, 1726, 1385, 1376 cm . H NMR (CDC1 , 80 MHz): ꢁ ¼ 1.92 (t,
3
H), 1.67 (s, 6H), 1.25 (m, 8H), 0.81 (t, 6H).
3
ꢀ ꢀ
[17]
d. Colorless crystal; m.p. 232–233 C (Lit. 232–233 C ). IR (KBr)
À1
1
ꢀmax ¼ 1760, 1727, 1381, 1370, 760, 700 cm
.
H NMR (CDC13,
4
00 MHz): ꢁ ¼ 7.20–7.30 (m, 10H), 3.46 (s, 4H), 0.63 (s, 6H).
ꢀ
ꢀ
[17]
e. Colorless crystal; m.p. 257–258 C (Dec.) (Lit. 258–259 C ). IR
3
À1
1
(
4
4
KBr) ꢀmax ¼ 1763, 1732, 1518, 1378, 1341, 854 cm . H NMR (CDC1 ,
3
00 MHz): ꢁ ¼ 8.18 (d, J ¼ 8.8 Hz, 4H), 7.40 (d, J ¼ 8.8 Hz, 4H), 3.58 (s,
H), 0.74 (s, 6H).
3
f. Yellow oil. IR (film): ꢀ
1
¼ 3018, 2928, 1757, 1738, 1444, 1351,
3
max
À1
1
216, 759 cm . H NMR (CDC1 , 400 MHz): ꢁ ¼ 5.69 (m, 2H), 5.20 (dd,
J ¼ 10.1, 6.0 Hz, 4H), 2.74 (d, J ¼ 7.6 Hz, 4H), 1.69 (s, 6H). Anal. calcd.
for C H O : C, 64.27; H, 7.19; O, 28.54. Found C, 64.35; H, 7.21;
1
2
16
4
O, 28.55.
ꢀ
3
g. White solid; m.p. 128–130 C; IR (KBr): ꢀ
À1
¼ 3019, 1759, 1734,
max
1
1
215, 757, 669 cm
.
H NMR (CDC1 , 400 MHz): ꢁ ¼ 8.32 (d,
3
J ¼ 8.6 Hz, 2H), 7.72–7.79 (m, 4H), 7.36–7.59 (m, 8H), 4.15 (s, 4H),
þ
0.44 (s, 6H). MS (EI): 424 (5.20, M ), 207 (5.94), 165 (8.17), 153

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Alkylation of Meldrum’s Acid
2821
(9.96), 152 (13.9), 142 (18.0), 141 (100), 115 (19.2), 43 (9.8). Anal. calcd.
for C H O C, 79.22; H, 5.70; O, 15.08. Found C, 79.24; H, 5.71; O,
2
8
24
4
1
5.10.
3
ꢀ
ꢀ
[17]
h. White solid; m.p. 206–207 C (Dec.) (207–208 C ). IR (KBr):
À1
1
ꢀmax ¼ 1750, 1715, 1682, 1391, 1375, 748, 685 cm . H NMR (CDC1 ,
3
4
00 MHz): ꢁ ¼ 7.91 (d, J ¼ 7.5 Hz, 4H), 7.59 (t, J ¼ 7.3 Hz, 2H), 7.46
(
t, J ¼ 7.8 Hz, 4H), 3.94 (s, 4H), 2.18 (s, 6H).
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Received in Japan November 12, 2002