Mendeleev Commun., 2002, 12(2), 57–58
Alkylation of malonic and acetoacetic esters in an ionic liquid
Galina V. Kryshtal, Galina M. Zhdankina and Sergei G. Zlotin*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
1
0.1070/MC2002v012n02ABEH001563
1
-Butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF ]) has been used as a recyclable medium in the alkylation of
6
malonic and acetoacetic esters with alkyl, benzyl and prenyl halides.
The alkylation of malonic and acetoacetic esters is widely used
of 1 with 2.5 equiv. of benzyl chloride 3e under the same con-
ditions afforded dibenzyl derivative 5 (yield 64%) as the only
isolated product (Table 1).
1
(a)–(c)
for the synthesis of polyfunctional compounds.
Classical
1
(a)–(c)
alkylation procedures,
alkylations in dipolar aprotic sol-
vents2
(a),(b)
and under phase-transfer catalysis conditions
3(a)–(f)
The K CO -promoted reactions of the ambident anion of
2
3
are often complicated by using flammable organic solvents and
difficulties in their regeneration, as well as in the regeneration of
phase-transfer catalysts and in the isolation of reaction products.
These problems can be solved by performing reactions in
organic ionic liquids, which are of interest as an alternative to
acetoacetic ester 2, with 3a,d,e in [bmim][PF ] proceeded in a
6
less selective manner to give, along with C-alkylation products
6a,d,e, vinyl ethers 7a,d,e. The ratio 6:7 varied from 88:12
to 60:40 depending on the alkylating agent. The fraction of
O-alkylation products 7a,d,e in [bmim][PF ] was generally higher
6
4
(a),(b)
1(a),(b)
common organic solvents.
These melts, of which 1,3-di-
than those obtained under classical
and phase-transfer
catalysis1
4,15
conditions (Table 2). This fact may be explained
alkylimidazolium tetrafluoroborates and hexafluorophosphates
containing poorly coordinating ion pairs have received most
by a higher polarity of [bmim][PF ] than that of the most com-
monly used organic solvents and, consequently, by a higher
6
attention,5
(a)–(c)
are good solvents for both organic and inorganic
16
compounds. They are moisture stable, not flammable and, what
likelihood of the S 1 mechanism of alkylation in the ionic liquid.
N
4
(a),(b)
is very important, can be easily recovered and reused.
Due
Unlike 3e, more reactive benzyl bromide 3e' reacted with 2 in
to the ionic nature, they can serve as polar solvents and phase-
transfer catalysts simultaneously.
[bmim][PF ] under milder conditions to afford C-alkylation pro-
6
1
duct 6e (yield 50%), which, according to H NMR spectra, was
Many applications of these melts in C–C coupling reactions,
not contaminated with ether 7 (there are no vinyl protons in the
d range 4.8–5.2 ppm). This difference in the behaviour of 3e
and 3e' is not unexpected because less electrone-withdrawing
6
7(a)–(c)
Wittig,8
for instance, in the Friedel–Crafts, Diels–Alder,
9
10
11(a)–(c)
Horner–Emmons, Knoevenagel and Heck
have been
reported. To the best of our knowledge, there is only one
example of the C-alkylation of carbanions in ionic liquids, the
base-promoted cycloalkylation of phenylacetonitrile with 1,4-
dibromobutane in 1-butyl-3-methylimidazolium hexafluorophos-
leaving groups (particularly, Br compared to Cl) usually reduce
the portion of O-alkylation.1
7(a),(b)
The reaction of 2 with prenyl
chloride 3f in [bmim][PF ] gave only C-alkylation product 6f,
which was also obtained under classical
6
1
(a),(b)
and phase-transfer
1
2
14,15
phate ([bmim][PF ]). It is unclear whether the reaction can be
catalysis
conditions (Table 2).
6
1
2
used for the monoalkylation of phenylacetonitrile. There is
no information on the base-promoted alkylation of ambident
carbanions in ionic liquids; only Pd (dba) -catalysed C-allyla-
Tables 1 and 2 indicate that the yields of compounds 4–7
obtained in [bmim][PF ], as well as under the classical and phase-
6
transfer catalysis conditions, are similar. Reactions in ionic
liquids are preferable besause of the simplicity of product isola-
2
3
tion of dimethylmalonate with (E)-1,3-diphenyl-3-acetoxyprop-
1
3
9,18
1
-ene was published.
Here, we report the first example of the base-promoted alkyla-
tion and solvent regeneration. Compounds 4–7 can be isolated
by evaporation at a reduced pressure (2 torr) from their solu-
tions in the non-volatile ionic liquid.5 This procedure is tech-
nologically attractive but inconvenient in small-scale preparations
(~10 mmol) owing to the irregularity of boiling of the reaction
mixture. In laboratory conditions, it seems reasonable to use the
extraction of alkylation products with diethyl ether (which is
(c)
tion of malonic 1 and acetoacetic 2 esters in an ionic liquid. We
found that malonic ester 1 regioselectively reacts with alkyl,
benzyl and prenyl halides 3a–f (1:3 ratio £ 1.5) in [bmim][PF6]
in the presence of K CO to afford monosubstituted malonates
2
3
4
a–f in 53–80% yield. The reactions were carried out at 85–130 °C
for 5–20 h (until starting compound 1 disappeared; TLC moni-
immiscible with [bmim][PF ]) followed by distillation. The ionic
6
toring). Two substituents can be introduced into diethyl malonate
liquid was recovered by filtration from inorganic salts followed by
1
if an excess of an alkylating agent is used. Indeed, the reaction
the removal of volatile impurities at 40–60° (2 torr). In all cases,
Table 1 K CO -Promoted alkylation of diethylmalonate in [bmim][PF ].
2
3
6
i
ii
RCH(COOEt)2
a–f
CH (COOEt)
(PhCH ) C(COOEt)
2
2
2
2 2
4
1
5
Reagents: i, 1,5 equiv. RHal (3a–f), 2 equiv. K CO , 6 equiv. [bmim][PF ]; ii, 2.5 equiv. PhCH Cl (3e), 2 equiv. K CO , 6 equiv. [bmim][PF ].
2
3
6
2
2
3
6
Reported yield of
4
a–f, 5 (%)
Yield of
a–f, 5 (%)
Compound
R
Hal
t/h
T/°C
a
4
EtONa/EtOH
(
Phase-transfer catalysis
(PTC)
1:3:EtONa = 1:1:1)
(a)
85c
4a
4b
4c
4d
4e
4f
5
Bu
Pr
cyclopentyl
Am
PhCH2
(Me) C=CHCH2
PhCH2
Br
Br
Br
Br
Cl
Cl
Cl
12
20
15
15
5
85–90
80
54
57
70
72
53
64
80–901
i
1(a)
c
85–90
120–130
110–120
120–130
90–95
65-80
45
1
(a)
d
70
80
21
i
1(a)
d
72
70
1
(b)
e
51–57
1
(a)
e
5
7
50
84
46
2
b
120–130
—
a
b
1(a) c
3(e),(f) d
Yield of distilled compounds. 1:3:EtONa = 1:2:2.
1:3:NaOH :PTC = 1:1:2:1, CH Cl , 40 °C, 1 h.
1:3:K CO :BTEA-Cl = 1:1.5:1.5:0.1, DMF,
2 3
aq
2
2
2
(b) e
2(a)
5
0–65 °C, 6–9 h.
1:3:NaOH :BTEA-Cl = 1:1:2:0.1, 40–45 °C, 2 h.
aq
–
57 –