KOH-promoted synthesis of oxirane functional derivatives from diethyl bromomalonate and aldehydes under phase-transfer catalysis conditions

Article abstract of DOI:10.1016/j.mencom.2013.01.008

The Darzens condensation of diethyl bromomalonate with aromatic or isoprenoid aldehydes under heterogeneous conditions (KOH/MeCN) in the presence of Bu₄NPF₆ as a recoverable phase-transfer catalyst afforded the corresponding diethyl 3-R-oxirane-2,2-dicarboxylates in high yields.

Full text of DOI:10.1016/j.mencom.2013.01.008

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 24–25
KOH-promoted synthesis of oxirane functional derivatives
from diethyl bromomalonate and aldehydes under
phase-transfer catalysis conditions
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. Fax: +7 499 135 5328; e-mail: zlotin@ioc.ac.ru
DOI: 10.1016/j.mencom.2013.01.008
The Darzens condensation of diethyl bromomalonate with aromatic or isoprenoid aldehydes under heterogeneous conditions (KOH/
MeCN) in the presence of Bu4NPF6 as a recoverable phase-transfer catalyst afforded the corresponding diethyl 3-R-oxirane-2,2-
dicarboxylates in high yields.
CO2Et
Oxirane-2,2-dicarboxylates are the valuable intermediates in the
synthesis of natural compounds containing dihydrofuran (e.g.,
furanomycin, cryptoresinol)1 or tetrahydrofuran (indole alkaloids)2
fragments and can be used as protease inhibitors.3 They are
commonly prepared by epoxidation of methylidenemalonates
with some inorganic (H2O2,4 sodium hypochlorite5) or organic
(mCPBA,6 oxidoiodanes,7 TADOOH8) oxidants, or by the reac-
tions of aldehydes with carbenes generated in situ from dialkyl
diazomalonates9 or iodonium ylides,10 their yields being signi-
ficantly substrate dependent.
CHO
CO2Et
i
O
+
BrCH(CO2Et)2
O2N
O2N
1a
2
3a
Scheme 1 Reagents and conditions: i, KOH (1.2 equiv.), PTC (5 mol%),
MeCN, 20°C, 3 h.
Table 1 Comparison of various PTCs in the reaction between 1a and 2.
A well-recognized method to access oxiranes is the Darzens
condensation of carbonyl compounds with a-halogenocarboxylic
acid derivatives. It can be efficiently processed under hetero-
geneous conditions in the presence of phase-transfer catalysts
(PTC), in particular those immobilized on a polymer matrix
(polymer-supported PTC).11 Surprisingly, just three examples
of the use of bromomalonic esters as starting compounds in
this reaction have been reported so far. In 198312 some of us
unexpectedly obtained 3-substituted oxirane (50% yield) in the
reaction of b,b-dichloroacrolein or its vinylogue with diethyl
bromomalonate under PTC-conditions. The K2CO3-promoted
condensation of diethyl bromomalonate with crotonaldehyde
afforded the corresponding epoxy cyclopropane derivative in
20% yield.13 Recently,14 the structure of diethyl 3-(pent-1-enyl)-
oxirane-2,2-dicarboxylate was hypothetically assigned to an out-
of-range product of cyclopropanation reaction without its con-
firmation by experimental data. Herein, we report a simple and
efficient synthesis of 3-R-oxirane-2,2-dicarboxylates (R =Alk or
Ar) 3 by a solid base-promoted (KOH) reaction of aldehydes 1
with diethyl bromomalonate 2 in the presence of an available and
reusable PTC such as tetrabutylammonium hexafluorophosphate
(Bu4NPF6).
At first, we studied the model reaction between 4-nitrobenz-
aldehyde 1a and bromomalonate 2 in acetonitrile, which had been
used as the solvent in similar condensation of benzaldehydes
with chloroacetic ester.11(b) The reaction between compounds 1a
and 2 (Scheme 1) did not occur in the presence of finely powdered
solid KOH (1.2 equiv.). However, upon PTC addition (5 mol%)
oxirane 3a was formed in reasonable to high yields. Table 1
summarizes the results of four studied PTCs (BnEt3NCl, Bu4NBr,
Bu4NBF4, and Bu4NPF6). Hexafluorophosphate salt Bu4NPF6
that had been recently recognized as an efficient reusable PTC15
exhibited the best catalytic performance. Importantly, it is nearly
insoluble both in water and in Et2O11(a),(b) and this solubility
profile allowed us to completely recover the PTC by simply
Isolated yield
of 3a (%) [cycle]
Catalyst recovery
(%) [cycle]
Entry
PTC
1
2
3
4
5
—
0
74
83
87
—
0
BnEt3NCl
Bu4NBr
Bu4NBF4
Bu4NPF6
0
55
94 [1], 94 [2], 95 [3] 95 [1], 93 [2], 92 [3]
filtrating it off the Et2O/water two-phase mixture during the
work-up procedure† and reuse it three times in the model reaction
with no noticeable disprovement of the reaction rate or product
yield (Table 1, entry 5).
Benzaldehydes 1a–f bearing either acceptor or donor substi-
tuents in the aromatic ring and isoprenoid aldehydes 1g,h reacted
similarly to afford the corresponding oxiranes 3a–h (Scheme 2).
The yields of products 3 were comparable with (in case of 3a) or
higher than (in case of 3b–d,g) those achieved by alternative
methods (Table 2, entries 1–4,7). The yields remained high
†
General procedure for the synthesis of diethyl 3-R-oxirane-2,2-dicar-
boxylates 3a–h. Aldehyde 1a–h (1 mmol), bromomalonate 2 (0.24 g,
1 mmol), Bu4NPF6 (0.02 g, 5 mol%) and MeCN (3 ml) were mixed and
stirred for 30 min. Powdered KOH (0.07 g, 1.2 mmol) was added, the
heterogeneous mixture was stirred at ambient temperature for the specified
time. The solvent was removed under reduced pressure. Water (5 ml) and
Et2O (10 ml) were added to the residue and the solid catalyst was filtered
out of the two-phase solvent system, dried in air and reused in the second
run of the same or similar reaction without further purification. The organic
layer was separated and the aqueous layer was extracted with Et2O (3×5 ml).
The combined organic layers were washed with water (3×5 ml), dried with
anhydrous MgSO4 and concentrated under reduced pressure. Purification
by column chromatography (SiO2, eluent: hexane; hexane–EtOAc, 9:1)
afforded analytically pure compounds 3a–h.
For NMR spectra of compounds 3a–h, see Online Supplementary
Materials.
© 2013 Mendeleev Communications. All rights reserved.
– 24 –

Mendeleev Commun., 2013, 23, 24–25
CO2Et
CO2Et
mediates for the synthesis of various cyclopropane functional
i
+
R
BrCH(CO2Et)2
derivatives.16
R
O
O
In summary, an efficient heterogeneous catalytic system for
reactions of diethyl bromomalonate with aldehydes has been
developed and its potency for the synthesis of diethyl 3-alkyl- or
3-aryloxirane-2,2-dicarboxylates has been demonstrated.
2
1a–h
3a–h
Scheme 2 Reagents and conditions: i, KOH (1.2 equiv.), Bu4NPF6 (5 mol%),
MeCN, 20°C.
Table 2 Yields of oxiranes 3 in reactions of 1a–h with 2.
This work was supported by the Presidium of the Russian
Academy of Sciences (the basic research program PRAS-8).
Alde-
hyde
Isolated
yield (%)
Entry
R
t/h Oxirane
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.01.008.
1
2
3
4
5
6
7
8
1a
1b
1c
1de
1e
1f
4-O2NC6H4
6
3
3a
3b
95 (lit.,5 97)a
83 (lit.,7 51)b
89c (lit.,9 54)d
79 (lit.,9 62)d
97
Ph
4-ClC6H4
12 3c
30 3d
3
4
4-MeOC6H4
4-MeO2CC6H4
4-HC(O)C6H4
Me2CHCH2
Me2C=CH(CH2)2C(Me)CH
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3e
3f
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R2
R2
R1
i
CHO
R1
+
O
BrCH(CO2Et)2
EtO2C
CO2Et
2
4a–d
5a–d
16 P. Tang and Y. Qin, Synthesis, 2012, 2969.
a R1 = Ph, R2 = H
b R1 = R2 = H
c R1 = Me, R2 = H
d R1 = H, R2 = Me
Scheme 3 Reagents and conditions: i, K2CO3 (or LiOH) (1.5 equiv.),
Bu4NPF6 (5 mol%), PhMe, 20°C.
Received: 17th September 2012; Com. 12/3979
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