Synthesis of bis-spiro cyclopropanes based on Meldrum's acid by milling

Article abstract of DOI:10.1002/jccs.201400320

Reaction of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) with various solid aldehydes in the presence of cyanogen bromide and solid sodium ethoxide (EtONa) leads to the selective and efficient formation of bis-spiro cyclopropanes based on Meldrum's acid at the range of 0 °C to room temperature. The products were obtained in good to excellent yields. Structure elucidation is carried out by ¹H NMR, ¹³C NMR, FT-IR spectroscopy, mass analyses and X-ray crystallography techniques. A possible mechanism for the formation of products is also discussed under solvent-free condition.

Full text of DOI:10.1002/jccs.201400320

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis of Bis-spiro Cyclopropanes Based on Meldrum’s Acid by Milling
Elmira Kashani,a Nader Noroozi Pesyan,a* Tuncay Tunçb and Ertan Ôahinc
aDepartment of Organic Chemistry, Faculty of Chemistry, Urmia University, 57159, Urmia, Iran
bDepartment of Science Education, Aksaray University, 68000, Aksaray, Turkey
cDepartment of Chemistry, Faculty of Science, Atatürk University, 25240 Erzurum, Turkey
(Received: Aug. 2, 2014; Accepted: Nov. 20, 2014; Published Online: ??; DOI: 10.1002/jccs.201400320)
Reaction of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s acid) with various solid aldehydes in the
presence of cyanogen bromide and solid sodium ethoxide (EtONa) leads to the selective and efficient for-
mation of bis-spiro cyclopropanes based on Meldrum’s acid at the range of 0 °C to room temperature. The
products were obtained in good to excellent yields. Structure elucidation is carried out by 1H NMR, 13
C
NMR, FT-IR spectroscopy, mass analyses and X-ray crystallography techniques. A possible mechanism
for the formation of products is also discussed under solvent-free condition.
Keywords: Meldrum’s acid; Aldehyde; Cyanogen bromide; Bis-spiro cyclopropanes; Milling;
Solid sodium ethoxide.
INTRODUCTION
solvent like benzene and dichloromethane, and four com-
pounds were obtained.13
The cyclopropyl group is an important structure in
many herbal compounds which displays antifungal,1 anti-
bacterial, antiviral, and some enzyme inhibition activi-
ties.2-4 For example, bicifadine and its analogs.5
Recently, we have reported the cyclopropanation of
some b-dicarbonyls such as malononitrile14 and Meldrum’s
acid15 in the reaction of aliphatic and aromatic aldehydes
and BrCN in the presence of triethylamine under solvent
condition. More recently, we also have reported the cyclo-
propanation of malononitrile under solvent-free condition
by milling.16 Nevertheless, the reaction of (thio)barbituric
acids as a symmetrical barbituric acids,17a,b unsymmetrical
barbituric acids,17c and dimedone17d with aldehydes, dial-
dehydes17e and ketones17f,g gave spiro dihydrofurans in the
presence of BrCN and triethylamine under the same condi-
tion (Fig. 1).
Nowadays, the development of solvent-free reaction
is one of the advantages in organic synthesis. There are sev-
eral reports in the literature about cyclopropanation under
solvent-free condition such as microwave assisted sol-
vent-free cyclopropanation of some b-dicarbonyls via
K2CO3,6 stereoselective synthesis of cis-1-carbomethoxy-
2-aryl-3,3-dicyanocyclopropanes by grinding,7 reactions
of C60 with active methylene compounds in the presence of
a base under high-speed vibration grinding (HSVM)8 and
rhodium(II)-catalyzed enantioselective cyclopropanation.9
Ball milling as a solvent-free technique has been ex-
tensively used as a new synthetic route e.g. Suzuki-Miyaura
coupling,10a Suzuki reaction,10b Aldol condensation,10c
asymmetric organocatalytic Aldol reaction,10d solid phase
synthesis of 2,2¢-dihydroxy-1,1¢-binaphthyl (BINOL)10e
and oxidation reaction.10f In addition to this, ball milling is
a useful method to produce ferrite nanoparticles,11a Chevrel
phase superconductor11b and etc. Attrition or mechanical
milling is a typical top-down method in preparing nano-
particles.12 Therefore, this technique should be considered
as a potentially attractive solution for solvent-free synthe-
sis. Of course, the reaction of aldehyde with Meldrum’s
acid in the presence of stabilized bismuthonium ylides af-
forded Meldrum’s acid based cyclopropane in presence of
On the other hand, Meldrum’s acid is a highly inter-
esting class of compounds, and it possesses biological and
pharmaceutical properties. Also it performs as a source of
geminal dicarboxylic acid which gets a lot of attention in
the chemistry and pharmacology.18 5-Arylidene and/or 5-
alkylidene derivatives of Meldrum’s acid are useful inter-
mediates for cycloaddition reaction and for the synthesis of
heterocyclic compounds with potential pharmaceutical ac-
tivity.19 There are some reports about the hydrolysis of
Meldrum’s acid ring in some organic compounds including
Meldrum’s acid ring moiety for the formation of corre-
sponding di- and/or mono-carboxylic acid derivatives.20
Despite our research in related studies, no report was
found about the cyclopropanation of Meldrum’s acid via
BrCN under solvent-free condition (ball milling) in the
* Corresponding author. E-mail: pesyan@gmail.com
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Article
Kashani et al.
Reaction of Meldrum’s acid (1b¢) with vari-
ous solid aldehydes (2a-m) and with liquid
aldehydes (2n-s) in the presence of BrCN
and solid EtONa (see also Table 1)
Scheme 1
methylene proton of 1b¢, and after that it formed sodium
2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ide (5), and finally
EtONa converted to ethanol. The nucleophilic attack of 5 to
BrCN formed an intermediate 6. Intramolecular rearrange-
ment of 6 formed 5-bromo-2,2-dimethyl-1,3-dioxane-4,6-
dione (7) followed by the loss of HCN. The EtONa as a
base captured the proton of active methylene in 7 formed
salt 4 (Scheme 2, path a). In this reaction, the reaction mix-
ture became moist when mixed and milled in a Teflon-
faced screw cap tube vessel. This observation indicated the
ethanol releasing in reaction. Unfortunately, all attempts
failed to separate or characterize 5, 6 and 7. In this reaction,
no 2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-carbonitrile (8)
Fig. 1. Structures of some spiro heterocyclic com-
pounds (12-14),17a-d 15, triethylammonium-2-
bromo-5,5-dimethylcyclohexane-1,3-dione-2-
ide (16a¢),17f triethylammonium 5-bromo-2,2-
dimethyl-4,6-dioxo-1,3-dioxan-5-ide (16b¢),15
triethylammonium-5-bromo barbiturate salts
(17),17a-c dimedone (1a¢), 1,3-indandione (18),
full substituted cyclopropanes based on indan-
dione (19),21 malononitrile (20), triethylammo-
nium bromodicyanomethanide (21)14 and so-
dium bromodicyanomethanide (22).16
presence of solid EtONa at room temperature. Based on
these concepts, herein, we have accomplished the new
methodology transformation of aldehydes and Meldrum’s
acid to bis-spiro cyclopropanes based on Meldrum’s acid in
the presence of BrCN and solid EtONa by milling.
Proposed mechanism for the formation of 4
Scheme 2
under solvent-free condition (ball milling)
RESULTS AND DISCUSSION
This paper describes the one-pot reaction of Meldrum’s
acid (1b¢) with various solid aldehydes and cyanogen bro-
mide (BrCN) in the presence of solid EtONa that afforded
full-substituted bis-spiro cyclopropanes based on Meldrum’s
acid ring moieties (3). This reaction also provided new salt
of sodium 5-bromo-2,2-dimethyl-4,6-dioxo-1,3-dioxan-
5-ide (4) in moderate to good yield at room temperature by
milling (Scheme 1 and Table 1, entries 1-8).
In the present research work, we found that the salt of
4 play the major rule for the formation of 3 according to our
previous works that we proposed a plausible mechanism
for each of the salt formation (Fig. 1).14,16,17a-f The mecha-
nism of the formation of 4 is shown in Scheme 2 under sol-
vent-free condition. It was assumed that the Meldrum’s
acid 1b¢ reacted with EtONa as a base which captured
2
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Synthesis of Bis-spiro Cyclopropanes
Table 1. One-pot reaction of Meldrum's acid 1b' with various solid aldehydes (2a-2m)[a] and
liquid aldehydes (2n-2s)[b] mediated by BrCN in the presence of solid EtONa by
milling
Entry
R
Product
M.p. (°C)
Yield (%)
1
2
3
4
5
6
7
8
p-NO2-C6H4 (2a)
m-NO2-C6H4 (2b)
o-NO2-C6H4 (2c)
4-CN-C6H4 (2d)
p-Br-C6H4 (2e)
3a
3b
3c
3d
3e
3f
201-203 (202–203)15
192-193 (192–194)15
197-199 (198–199)15
202-204 (204–205)15
193-194 (192–193)15
177-179 (178–180)15
177-180 (178–179)15
70
65
80
70
75
2,4-di-Cl-C6H3 (2f)
p-Cl-C6H4 (2g)
80
75
3g
[c]
9i
3,4,5-tri-CH3O-C6H2 (2h)
3-OH-4-CH3O-C6H3 (2i)
4-OH-3-CH3O-C6H3 (2j)
p-(CH3)2N-C6H4 (2k)
2-Pyrrolyl (2l)
50[d]15
70[e]15
75[e]15
85[e]
75[e]
90[e]
55
9
10
11
12
13
14
15
16
17
18
9j
9k
9l
174-176 (175–177)15,23
180-182 (182–184)15
9-Anthranyl (2m)
H (2n)
CH3 (2o)
CH3CH2 (2p)
CH3CH2CH2 (2q)
p-CH3O-C6H4 (2s)
9m
3n
3o
3p
3q
9s[f]
195-197 (194–196)15
216-218 (decomps.) (217–218)15
215–217 (216–218)15
210–212 (212–214)15
203–205 (204–205)15
125–127 (126–128)15
60
70
65
70
[a] Reaction mixture to become viscous and carried out by milling. [b] Liquid at 1 atmosphere
and 0 °C to room temperature and reaction was carried out by stirring. [c] Mixtures of 3h and
9h were obtained. [d] Yield refers to 3h. [e] Yield refers to 9i-9m, respectively. [f] Exclusively
Knoevenagel adduct was obtained.
was observed (Scheme 2, path b). We performed the reac-
forms (keto-enol forms) while the salts of 4 and 5 can exist
in some mesomeric forms (Scheme 3). In 1b¢, the peak at
3531 cm-1 corresponds to hydroxyl group of the enolic
form. In contrast the stretching frequencies at 3549, 3477
and 3415 cm-1 in 5 and also stretching frequencies at 3431,
3194 cm-1 in 4 corresponds to hydroxyl groups of water ab-
sorbed to the salts adducts (Fig. 2). These salts have hydro-
philic property. We also examined and measured the so-
dium ion emission by flame photometry in the salt of 4 (see
tion of 1b¢ with BrCN and solid EtONa in the absence of al-
dehydes under the same condition and the 4 was obtained
and isolated in moderate yield. We also performed the reac-
tion of 1b¢ with solid EtONa for obtaining of 5 and then
compared the FT IR spectrum of 1b¢ with those 5 and 4 to-
gether. The carbonyl stretching frequencies of 5 and 4
shifted to low frequency than that of 1b¢ due to the reso-
nance of the negative charge with carbonyl groups in 5 and
4 (Fig. 2). Compound 1b¢ can exists in two tautomeric
Scheme 3 Mesomeric and resonance forms of 4 and 5
Fig. 2. Comparison of the FT IR spectra of 1b¢ (red), 4
(purple) and 5 (blue).
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Article
Kashani et al.
supplementary material). Other evidence for the formation
of 4 (the existence of bromine atom in this molecule) was
performed by Beilstein test and the wet silver nitrate test22
(Precipitate of pale yellow silver bromide). These data are
confirmed that are in good agreement with each other for
the proposed structure of 4.
spectively. 13C NMR spectrum of this compound shows six
distinct peaks. The presence of two plane of symmetry in
3n, in 13C NMR spectrum of this molecule, the four car-
bonyl groups of C4, C6, C2² and C4² have equivalent
chemical shifts and show a peak at d 160.3 ppm (Fig. 3).
Other cyclopropane derivatives 3a-3r (with exception 3n)
shows two distinct peaks for carbonyl groups because of a
plane of symmetry (Fig. 3). These observations are the best
evidence for supporting the cyclopropanation and the
structure of 3n as a representative under solvent-free con-
dition (solid aldehydes by milling and liquid aldehydes by
stirring). Other evidences for the cyclopropanation is the
chemical shift value of cyclopropane CH proton that ap-
peared in high field (a singlet at d 2.92 ppm for 3n, a quartet
at d 3.33 ppm for 3o and a distinct singlet derived from aro-
matic aldehydes as representative) and the X-ray crystallo-
graphic data for 3g (see later).
Proposed mechanism for the formation of 3 is shown
in Scheme 4 under solvent-free condition. First, the
Knoevenagel condensation of 1b¢ with equimolar of alde-
hydes 2 afforded the corresponding 5-arylidene-2,2-di-
methyl-1,3-dioxane-4,6-dione (9). The Michael addition of
the compound 4 (as a nucleophile) with 9 as a key interme-
diate gave the intermediate 10. In this reaction, the com-
pound 4 plays either nucleophile or electrophile character,
respectively. Finally, an intramolecular reaction of 10
(C-attack to the carbon atom as an electrophile containing
bromine) with removal of bromide ion afforded 3 in good
yield. In intermediate 10, no O-attack was occurred for the
formation of 11. Two geminal oxygen atoms on carbon
atom in 10 have inductive effect on each other. For this rea-
son, the geminal oxygen atom prevents the O-attacking of
oxygen anion to the electrophile for the formation of 11.
Therefore, the C-attack was favored (Scheme 4). Unfortu-
nately, all attempts failed to separate or characterize 10.
As mentioned above, the reason of the unsuccessful
intramolecular O-attack in 10 was because of inductive ef-
fect of oxygen atoms on Meldrum’s acid ring moiety in in-
termediate 10 and decreased the nucleophile ability of oxy-
gen anion in this intermediate. In contrast, in the similar in-
termediates derived from (thio)barbituric acids (24a¢-24c¢)
and dimedone (25) forced O-attack and resulted in spiro
dihydrofuranes (12a¢-12c¢ and 15), respectively. Like
Meldrum’s acid 1b¢, the C-attack, in the intermediate (23)
derived from 1,3-indandione 18, also occurred21 and formed
full-substituted cyclopropane based on 1,3-indandione
(19) in the presence of I2/DMAP system (Figure 1 and
Scheme 5). It seems that the reason of C-attack was arisen
from inductive effect of fused phenyl ring moiety in inter-
mediate 23 (Scheme 5). Also the C-attack was occurred
and 1,1,2,2,3-aryltetracyanocyclopropanes (27) were ob-
tained in excellent yields via the intermediates 26a² and
26b² by interfering of the salts of 2114 and 22,16 respec-
tively (Scheme 5).
Proposed mechanism for the formation of 3
Scheme 4
under solvent-free condition
1
Representatively, in H NMR spectrum of 3n (de-
rived from formaldehyde), two geminal methyl groups on
Meldrum’s acid moieties show two singlets at d 1.84 and
1.91 ppm and methylene show a singlet at d 2.92 ppm, re-
Fig. 3. Representatively, two planes of symmetry and
equivalency of four carbonyl groups in 3n and a
plane of symmetry in 3 (except 3n).
4
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Synthesis of Bis-spiro Cyclopropanes
The condition of intramolecular C- and O-
are summarized in Table 1, entries 14-18 (for more infor-
mation see supplementary material).
Scheme 5
attacking in intermediates 1015 and 23-25,17
26a²14 and 26b²
16
X-Ray structure determination of 3g
For further study, an X-ray diffraction analysis of 3g
was undertaken (Fig. 4). Single crystal of 3g was obtained
as colorless crystal by slow evaporation from methanol at
room temperature. Two spiro Meldrum’s acid moieties in
the molecular structure have boat conformer and have the
same direction (Fig. 5 (d)). Two carbonyl oxygen atoms of
each Meldrum’s acid moiety have weak interactions with
the second Meldrum’s acid moiety in the same side and the
corresponding distances are shown in parenthesis {C10 =
O1·····O4 = C16 (2.838 Å) and C11 = O2·····O3 = C15
(2.854 Å)} (Fig. 5 (a and b)). These weak interactions and
the boat conformations from different views are shown in
Fig. 5. The torsion angle between C3-C4-C7-H7 (H7 is the
hydrogen atom on cyclopropane) is equal of 48.85°. The
selected bond lengths, angles and torsion angles for 3g are
summarized in Table 2.
For the crystal structure determination, the single-
crystal of the compound 3g was used for data collection on
a Bruker SMART BREEZE CCD diffractometer. The
graphite-monochromatized Mo Ka radiation (l = 0.71073
Å) and oscillation scans technique with Dw = 5° for one im-
age were used for data collection. The lattice parameters
were determined by the least-squares methods on the basis
of all reflections with F2 > 2s(F2). Integration of the inten-
sities, correction for Lorentz and polarization effects and
cell refinement was performed using Bruker SAINT
The different reactivity of variously substituted alde-
hydes in the reaction with b-dicarbonyl compounds could
be rationalized taking into account that the reaction occurs
in two steps, i.e. the nucleophilic attack and the dehydra-
tion.20b Electron-withdrawing substituents facilitate the
first step, meanwhile electron donor substituents facilitate
the loss of water giving a conjugated stabilized a,b-unsatu-
rated carbonyl compounds. Further, in these latter cases no
trace of bis adduct was observed. In contrast, aldehydes
possessing electron-withdrawing substituents facilitate the
formation of bis-adduct.15
It has been reported that only Knoevenagel condensa-
tion was occurred in aldehyde possessing strong electron-
donor substituents in the reaction with barbituric acids.23 In
the reaction of 1b¢ with solid aldehydes 2a-2m in the pres-
ence of BrCN and solid EtONa, the Knoevenagel adducts
(9i-9m) were obtained (Table 1, entries 9-13). Presumably,
the hindrance effect in 2m led to formation of 9m. Instead,
the existence of acidic NH group on 9l and OH group upon
9i and 9j caused the 4 as a nucleophile to be able to capture
acidic proton on NH and/or OH group prior to Michael ad-
dition to b-carbon position of Knoevenagel adducts 9i-
9m.15
For more generality of these reactions, we performed
the reaction of some liquid aldehydes with 1b¢ and BrCN in
the presence of solid EtONa by stirring under solvent-free
condition (Scheme 1, path b). The results of these reactions
Fig. 4. ORTEP drawing of 3g with the atom-number-
ing scheme. Displacement ellipsoids are drawn
at the 40% probability level.
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Article
Kashani et al.
SHELXL-97.25 H atoms were positioned geometrically and
refined using a riding model. The final difference Fourier
maps showed no peaks of chemical significance. Crystal
data for 3g: C19H17O8Cl; crystal system, space group:
monoclinic, P21/n (no:14); unit cell dimensions: a =
11.206(3), b = 10.092(3), c = 18.414(5) Å, a = 90, b =
90.363(2), g = 90°; volume: 2082.4(10) Å3; Z = 2; absorp-
tion coefficient: 0.232 mm-1; q range for data collection 2.1
– 28.6°; refinement method: full-matrix least-square on F2;
data/parameters: 4344/290; goodness-of-fit on F2: 1.048;
final R indices [I > 2s(I)]: R1 = 0.0583, wR2 = 0.171; R indi-
ces (all data): R1 = 0.071, wR2 = 0.185; largest diff. peak and
hole: 461 and -0.486 e Å-3. Crystallographic data for the
compound 3g (excluding structure factors) have been de-
posited with the Cambridge Crystallographic data Centre
as the supplementary publication No. CCDC-996329. This
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif and also from CCDC, 12 Union Road,
Cambridge, UK (fax: +44-1223-336033, e-mail: deposit@
ccdc.cam.ac.uk).
Table 2. Selected bond lengths (d, Å), angles (è) and torsion
angles (ö) for 3g
Bond length (Å), angles (è, °)
Atom
and torsion angles (ö, °)
C7-H7
C7-C8
C7-C9
C8-C9
C4-C7
C4-C7-H7
C7-C9-C8
C7-C8-C9
0.979
1.508
1.524
1.531
1.498
112.02
59.15
60.20
60.66
176.22
-9.98
3.37
C8-C7-C9
C2-C3-C4-C7
C4-C7-C8-C15
C4-C7-C9-C11
C3-C4-C7-H7
C5-C4-C7-C9
C10-C9-C7-H7
C16-C8-C7-H7
C12-O7-C11-C9
C17-O5-C15-C8
C10-O1·····O4-C16
C11-O2·····O3-C15
48.85
14.93
5.40
-8.32
-3.13
4.45
-60.60a
63.96a
[a] See Fig. 5 (c).
As mention above in introduction section, com-
pounds 3 are useful and applicable compounds in different
study fields as an advantage. For instance, these com-
pounds can hydrolyze to produce tetracarboxylic acids
(28), vicinal dicarboxylic acids (29) that the later com-
pound is the starting material for the preparation of various
organic compounds such as; bidentate ligands, supramole-
cules and other useful trisubstituted cyclopropanes (Scheme
6).
(Bruker AXS Inc, 2012) software.24 The structure was
solved by direct methods using SHELXS-9725 and refined
by a full-matrix least-squares procedure using the program
Conversion of 3 to some useful and applica-
ble trisubstituted cyclopropanes as an ad-
vantage
Scheme 6
Fig. 5. Two weak interactions, corresponding dis-
tances (O·····O) between two carbonyl groups
of Meldrum’s acid moieties (a, b) and dihedral
angles between two carbonyls (c) and boat con-
former of Meldrum’s acid rings (d) in 3g from
different view sides.
6
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Synthesis of Bis-spiro Cyclopropanes
EXPERIMENTAL
data (Table 1).15
General procedures for the preparation of 3 under sol-
vent-free condition by stirring: Representatively, in a 10 mL
with Teflon-faced screw cap tube equipped with an ice-bath the
mixtures of 0.11 g benzaldehyde (1.0 mmol), 0.29 g Meldrum’s
acid (2.0 mmol) and 0.13 g cyanogen bromide (1.2 mmol) and
0.14 g solid EtONa (2.0 mmol) are mixed, stirred by a magneti-
cally stirrer and homogenized at 0 °C to room temperature. Tef-
lon-faced screw cap tube prevents the evaporation of cyanogen
bromide. The reaction progression was monitored by thin layer
chromatography (TLC). After completion of reaction, similar to
the milling reaction work-up initially, the reaction mixture was
extracted by water (2 × 5 mL) twice to remove the residue of
EtONa and 4, then residue benzaldehyde and Meldrum’s acid was
removed by extraction with fresh ethanol (2 × 5 mL). Spectro-
scopic data and physical properties of obtained 3 were compared
with their reported reference (Table 1).15
General: The drawing and nomenclature of compounds
were done by ChemDraw Ultra 8.0 and ChemBioDraw Ultra 12.0
version softwares, respectively. IR spectra were recorded in the
region 4000- 400 cm-1 on a NEXUS 670 FT IR spectrometer by
using KBr disks. The 1H and 13C NMR spectra were measured on
Bruker 300 FT-NMR at 300 and 75 MHz, respectively. 1H and 13
C
NMR spectra were obtained on solution in CDCl3 as solvent using
TMS as internal standard. The 1H NMR data are reported as (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, bs =
broad singlet, coupling constant(s) in Hz). The reaction comple-
tion were monitored by TLC with silica gel-coated plates
(EtOAc: n-hexane/ 8:10/ v:v). The mass analysis performed using
mass spectrometer (Agilent Technology (HP) type, MS Model:
5973 network Mass selective detector Electron Impact (EI) 70
eV), ion source temperature was 230 °C (Tehran University, Teh-
ran, Iran). The flame photometry analyzing of Na+ in 4 was re-
corded on CORNING 410 flame photometer (Urmia University,
Urmia, Iran). Melting points were determined with a digital melt-
ing point apparatus (Electrothermal) and were uncorrected.
Cyanogen bromide was synthesized based on reported refer-
ences.26 Solid EtONa was prepared with dissolving of freshly
metal sodium in appropriate absolute ethanol and then remained
ethanol was evaporated. Solid EtONa was kept in vacuumed des-
iccator. Compounds 1b¢, 2a-s and used solvents purchased from
Merck and Aldrich without further purification.
CONCLUSIONS
In summary, we have presented and developed a ver-
satile one-pot reaction of Meldrum’s acid with aliphatic
and aromatic aldehydes and cyanogen bromide to selec-
tively afforded bis-spiro cyclopropanes based on Meldrum’s
acid in the presence of solid EtONa by milling at room tem-
perature in good yields. The experimental results indicated
that the aromatic aldehydes are more reactive than that of
aliphatic. The aromatic aldehydes possessing electron-
withdrawing substituent are more reactive than that of elec-
tron-donating substituent. The aromatic aldehydes pos-
sessing strong electron-donating substituent gave exclu-
sively Knoevenagel adducts. Similarly, the reaction of
Meldrum’s acid with liquid aldehydes and cyanogen bro-
mide in the presence of solid EtONa was also afforded
bis-spiro cyclopropanes based on Meldrum’s acid by stir-
ring at room temperature in good yields.
General procedures for the preparation of 3 under sol-
vent-free condition by milling: Representatively, in a 10 mL
with Teflon-faced screw cap tube equipped with an ice-bath the
mixtures of 0.05 g (0.48 mmol) cyanogen bromide (BrCN), 0.14 g
(0.96 mmol) Meldrum’s acid and 0.072 g (0.48 mmol) 3-nitro-
benzaldehyde and 0.14 g (2.0 mmol) solid EtONa are mixed,
milled by a magnetically stirrer and homogenized at 0 °C to room
temperature. Teflon-faced screw cap tube prevents the evapora-
tion of cyanogen bromide (Caution! The cyanogen bromide is
toxic. It is better that the milling should be carried out in a well-
ventilated hood). After 5 minutes the homogenized mixture per-
turbed to be viscously by milling (indicating the releasing of
EtOH). The reaction progression was monitored by thin layer
chromatography (TLC) every ten minutes and the TLC solvent
was the mixture of EtOAc and n-hexane (EtOAc: n-hexane/ 8:10/
v:v). Initially, the reaction mixture was extracted by water (2 × 5
mL) twice to remove the residue of EtONa and 4, then residue
3-nitrobenzaldehyde and Meldrum’s acid was removed by extrac-
tion with fresh ethanol (2 × 5 mL). The solvent evaporated by re-
duced pressure and dried. Spectroscopic data and physical prop-
erties of obtained 3b were compared with their reported reference
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support by the
Research Council of Urmia University. Also the authors ac-
knowledge the Aksaray University, Science and Technol-
ogy Application and Research Center, Aksaray, Turkey, for
the use of the Bruker SMART BREEZE CCD diffractome-
ter (purchased under grant No. 2010K120480 of the State
of Planning Organization).
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J. Chin. Chem. Soc. 2015, 62, 000-000