Phase transfer catalyzed enantioselective cyclopropanation of 4-nitro-5-styrylisoxazoles

Article abstract of DOI:10.1039/c2cc30401e

Heavily substituted cyclopropane esters were prepared in high yields, complete diastereoselection and high (up to 96%) enantioselectivity. The reaction described herein entailed reacting 4-nitro-5-styrylisoxazoles, a class of cinnamate synthetic equivalent, with 2-bromomalonate esters under the catalysis of 5 mol% of a Cincona derived phase-transfer catalyst. The reaction allowed multi-gram preparation of desired products. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30401e

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COMMUNICATION
Phase transfer catalyzed enantioselective cyclopropanation of
4-nitro-5-styrylisoxazolesw
Claudia Del Fiandra,z Linda Piras,z Francesco Fini, Paolo Disetti, Maria Moccia and
Mauro F. A. Adamo*
Received 17th January 2012, Accepted 23rd February 2012
DOI: 10.1039/c2cc30401e
Heavily substituted cyclopropane esters were prepared in
high yields, complete diastereoselection and high (up to 96%)
enantioselectivity. The reaction described herein entailed reacting
4-nitro-5-styrylisoxazoles, a class of cinnamate synthetic equivalent,
with 2-bromomalonate esters under the catalysis of 5 mol% of a
Cincona derived phase-transfer catalyst. The reaction allowed
multi-gram preparation of desired products.
cyclopropanation of 2-bromocyclopentenone under catalysis of a
Cinchona-derived quaternary ammonium salt.14 This reaction
furnished bicyclic cyclopropanes with excellent diastereoselection,
good enantioselectivity but only modest yields. Our group has
developed 3-methyl-4-nitro-5-styrylisoxazole 1a (Table 1) a
novel class of cinnamate equivalent which showed a remarkable
reactivity as a Michael acceptor towards stabilized (soft)
nucleophiles.15 Compound 1a possesses two electrophilic alkenes
conjugated to a nitro group.
Cyclopropanes are found in many biologically active molecules1
and hold a unique combination of reactivity and structural
properties.2 This saturated three member cycle is present in over
4000 natural isolates and 100 biologically active compounds,
for example terpenes, pheromones, fatty acid metabolites,
nonproteinogenic amino acids,3 possessing antiviral, antibacterial
and antitumor activity.4 Notably, pyrethroids, one of the most
widespread and highly potent class of insecticides, contain the
cyclopropane unit as the pharmacophore.5 The reactivity of
cyclopropanes could be steered by introduction of an appropriate
substituent which imparts them a high synthetic versatility.2a,5a,6 It
is not surprising, therefore, that stereoselective cyclopropanation
has been intensively investigated and enantioselective procedures
for the Simmons–Smith reaction and other organometallic-based
catalyses have been reported.7 Pioneered by Aggarwal and Dai,8
the affirmation of organocatalysis9 delivered a number of high
enantioselective cyclopropanation protocols, for example those
reported by Gaunt et al.10 and Kunz and MacMillan.11 Recently,
Michael Initiated Ring Closing (MIRC) processes appeared in
the literature,12 particularly by W. J. Wang,12c Cordova et al.,12d,g
Yan et al.,12i Y. Wang,12h and Tiecco.12j These methodologies
gave densely substituted cyclopropanes in good yields and good
to excellent diastereo- and enantio-selectivity.
As shown by us15 and recently confirmed by the group of
Shibata,16 mild stabilized nucleophiles reacted exclusively with
the soft exocyclic alkene, while strong un-stabilized nucleophiles,
Table 1 Representative results of the screening of Cinchona-derived
catalysts 3, 4, 5, 6a
Entrya Cat. Temp/1C T/h
Conv.b [%] eec [%] Isomer
1
2
3
4
5
6
7
8
3a
4a
5a
6a
4b
5b
4a
4a
4b
4b
20
20
20
20
20
20
ꢀ20
ꢀ37
ꢀ37
ꢀ37
1.5
3
Z 95
Z 95
Z 95
Z 95
Z 95
Z 95
Z 95
Z 95
Z 95
Z 95
58
76
25
56
76
16
81
83
86
89
(ꢀ)
(+)
(ꢀ)
18
18
0.25
1.5
18
48
24
24
Asymmetric phase transfer catalysis (PTC) is highly popular
in industrial setup as it uses low cost and safe reagents and is
easy to scale up.13 However, cyclopropanation has been scarcely
studied under phase transfer catalysis. Shiori described the
(+)
(+)
(ꢀ)
(+)
(+)
(+)
(+)
9
10d
Centre for Synthesis and Chemical Biology (CSCB), Department of
Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons
in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland.
E-mail: madamo@rcsi.ie; Fax: +353 1 4022168
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, and spectra of new compounds. See
DOI: 10.1039/c2cc30401e
a
Reaction conditions: styrylisoxazole 1a (0.1 mmol), toluene (1.0 mL),
cat. 3, 4, 5, 6 (10 mol%), dimethyl 2-bromomalonate 2 (0.2 mmol),
b
K3PO4 50% w/w (1.0 mmol). Conversion was determined by
1H NMR analysis. The enantiomeric excess (ee) of the product was
c
d
determined by chiral stationary phase HPLC. Reaction was carried
out using 5.0 mL of toluene and cat. (5 mol%).
z These authors contributed equally.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3863–3865 3863

e.g. ꢀOH15,17,18 or ꢀCF3,16 reacted exclusively at the C-5 of the
isoxazole ring. Compounds 1a–l (Table 3) are stable solids that
can be obtained in large quantities (10–100 mmol) as single
E-isomers by reacting commercially available 3,5-dimethyl-4-
nitroisoxazole and an aromatic or heteroaromatic aldehyde.15a
The 4-nitroisoxazol-5-yl core present in compounds 1a–l and
in adducts thereof could be opened to display a carboxylic
acid using the Sarti-Fantoni reaction, an operationally simple
procedure involving treatment of 4-nitroisoxazoles with an
excess aqueous NaOH.17
Table 2 Cyclopropanation of 1a using different malonate derivativesa
Entrya
Prod.
R
X
Conv.b [%]
ee.c [%]
1
2
3
4
7a
7m
7n
7a
CH3
C2H5
4-OCH3–C6H4
CH3
Br
Br
Br
Cl
Z 95
Z 95
Z 70
Z 40
89
76
66
46
We have shown that compounds 1a–l were optimal reagents
for enantioselective Michael reaction running under phase
transfer catalysis,18 we envisaged, therefore, that compound
1a was a suitable substrate for MIRC cyclopropanation
(Table 1). At the onset of this study, we have reacted 4-nitro-5-
styrylisoxazole 1a and dimethyl-2-bromomalonate 2a (2 equiv.)
in the presence of various inorganic bases and organic solvents.
This study identified K3PO4 50% w/w and toluene as the most
suitable media. With optimal conditions in hands, we have
screened a few quaternary ammonium salts derived from
Cinchona alkaloids as catalysts (Table 1). This study showed
immediately promising results: starting material 1a was fully
converted in 1.5 h, giving compound 7a in 58% ee exclusively
as the trans isomer when catalyst 3a was used (Table 1, entry 1).
Several information were collected from the screening of
few related Cincona based phase transfer catalysts 3–6: (i) the
C-9 OH must be free (compare entries 3 and 6), probably for a
crucial hydrogen bond exerted between 2-bromomalonate
enolate and the catalyst; (ii) best results were obtained when
an heteroatom was present in the ortho position of the aryl
group (compare entries 8 and 9, Table 1); (iii) remarkable
improvement was obtained by decreasing the temperature from
r.t. to ꢀ37 1C (86% ee, Table 1, entry 9); (iv) improvement of the
ee was noticed by diluting the reaction media from 0.1 M to
0.02 M (89% ee, Table 1, entry 10). Significantly, we have shown
that catalyst loading could be limited to 5 mol% without
decrease of conversion and enantioselectivity (Table 1, entry 10).
With a set of optimized conditions, we have studied the effect
of varying the substituent on malonates 2 (Table 2). Hence,
4-nitro-5-styrylisoxazole 1a was reacted with malonates possessing
different alkyl or aryl group (Table 2, compare entries 1–3)
or a different halogen (Table 2, compare entries 1 and 4).
Sterically encumbered bromomalonates reacted efficiently but
furnished desired cyclopropanes with reduced enantioselectivity
(Table 2, entries 2 and 3). Replacement of bromide with chloride
reduced the reaction conversion as well as the enantiopurity of
cyclopropane obtained (Table 2, entry 4). This set of experiment
confirmed 2-bromo-dimethylmalonate as the best reagent for the
cyclopropanation of substrate 1a.
a
Reaction conditions: styrylisoxazole 1a (0.1 mmol), toluene (5.0 mL),
cat. 4b (5 mol%), dialkyl 2-halo-malonate 2 (0.2 mmol), K3PO4 50%
w/w (1.0 mmol). Conversion was determined by 1H NMR analysis.
b
c
The enantiomeric excess (ee) of the product was determined by chiral
stationary phase HPLC.
Table 3 Catalytic asymmetric cyclopropanation of styrylisoxazole
1a–l with dimethyl 2-bromomalonatea
Entry R1
Prod. Yieldb [%] eec [%] Isomer
1
2
3
4
5
6
7
8
C6H5
7ad
7bd
7c
7d
7e
7f
7g
7h
7i
93
99
99
91
99
98
99
97
99
93
99
95
89
90
91
92
87
87
86
96
93
94
84
90
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(ꢀ)
4-OCH3–C6H4
2,3-Cl2–C6H3
2-Cl–C6H4
4-F–C6H4
2-Thienyl
2-Furyl
2-OMe–C6H4
2-Br–C6H4
2,4-OMe–C6H3
n-Heptyl
9
10
11
12
7j
7k
2,3-O(CH2)2–C6H3 7l
a
Reaction conditions: styrylisoxazole 1a–k (0.1 mmol), toluene (5.0 mL),
cat. 4b (5 mol%), dimethyl 2-bromomalonate 2 (0.2 mmol), K3PO4 50%
b
w/w (0.5 mmol). Isolated yields after flash column chromatography.
c
The enantiomeric excess (ee) of the product was determined by chiral
d
stationary phase HPLC. Reaction performed on a 5.0 mmol scale.
enantiomeric excess (Table 3, entries 7 and 8); (iii) alkyl
substituted isoxazole 1k reacted equally well giving aliphatic
cyclopropane 7k in comparable yield and ee. Notably, substrate
1l, holding a 1,4-dioxane substituent, gave the corresponding
cyclopropane of the opposite absolute stereochemistry and in
similar high ee. The modality of facial discrimination operated
by catalysts 3 towards alkene 1a is still unclear and it is subject
of current intense investigation. The identification of two
substrates 1a and 1l which displayed opposite high enantio-
selectivity is encouraging and is likely to furnish insights on the
interaction between the alkene substrate and the phase transfer
catalyst. Gaining knowledge of this mechanistic detail will
be crucial to further optimization of this reaction, in parti-
cular for the obtainment of cyclopropanes ent-7 in high
enantiopurity. The use of a quasi-enantiomeric catalyst derived
from quinine gave, under this set of optimized conditions,
compounds ent-7 in comparable yield but in low 48–64% ee.
However, data herein reported showed that stereochemistry of
The scope of reaction was shown by reacting styryilisoxazoles
1a–l with dimethyl-2-bromomalonate 2a under the catalysis of
4b (Table 3). The results collected pointed out the following
facts: (i) compounds containing either electron withdrawing
or electron donating groups were equally good substrates;
importantly, it was verified that at least compounds 7a, 7b,
and 7d could be obtained on a multigram preparative (5 mmol)
scale (Table 3, entry 1) without loss of yield or enantioselectivity;
(ii) substrates containing aromatic heterocycles were also good
substrates giving products 7f and 7g in excellent yields and good
c
3864 Chem. Commun., 2012, 48, 3863–3865
This journal is The Royal Society of Chemistry 2012

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Scheme 1 Oxidation of the isoxazole moiety and subsequent methylation
with trimethylsilyl diazomethane.
cyclopropanes is substrate dependent (Table 3, compare
entries 1 and 12). Therefore, it is possible that preparation
of ent-7 in high enantiomeric purity will require a different set
of optimized conditions hitherto unexplored. In this regard,
the example of substrate 1l is a strong proof of concept. The
carboxylic functionality was then unveiled from Michael
adducts 7a and 7b which were efficiently converted to the
corresponding esters 8a and 8b by treatment with KMnO4
followed by esterification. This latter step was conducted
to facilitate the chromatographic purification of compounds
8 (Scheme 1), although compound 10 could be equally
isolated.19 The enantiomeric excess of compounds 8a, 8b
reflected those of starting materials 7a, 7b thus demonstrating
the stereochemical stability of compounds under the conditions
adopted.
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In conclusion, we have described a novel high enantioselective
Michael-Initiated Ring Closure (MIRC) reaction leading to densely
functionalized cyclopropanes that run under phase transfer
catalysis. The methodology described is significant as (i) it
furnishes trans-cyclopropylisoxazoles 7a–k as a single diastereo-
isomer, in excellent yields and good to excellent ees; (ii) it was
complemented by a novel oxidative procedure for the removal of
the 4-nitroisoxazole core which furnished acids or esters in good
yields; (iii) the reaction is scalable to give at least 1.5–1.7 g of
functionalized cyclopropanes 7a,b,d; (iv) the reaction required
only 5 mol% of the catalyst. This study delivers to the scientific
community a novel enantioselective synthesis of cyclopropanes
and confirms 4-nitro-5-styrylisoxazoles as useful synthons for
organic synthesis, particularly when used in combination with
phase transfer catalysis.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3863–3865 3865