Synthesis of activated cyclopropanes by an MIRC strategy: An enantioselective organocatalytic approach to spirocyclopropanes

Article abstract of DOI:10.1002/ejoc.201100562

An efficient cyclopropanation, by a Michael-initiated ring-closing (MIRC) reaction of 2-arylidene-1,3-indandiones and 2-arylidene malononitriles, has been developed by using different α-monohalogenated methylene active compounds with triethylamine. The first enantioselective cyclopropanation to spirocyclopropanes derived by the reaction of 2-arylidene-1,3-indandiones and dimethyl bromomalonate with a commercially available α,α-L- diarylprolinol as the organocatalyst and K₂CO₃ as the additive has been accomplished. The spirocyclopropanes were isolated in high yield and up to 85% ee. Notably, the asymmetric one-pot sequential approach to spirocyclopropanes proved to be a feasible process. A simple triethylamine-promoted domino cyclopropanation of 2-arylidene-1,3-indandiones and 2-arylidenemalononitriles with α-monohalogenated methylene-active compounds has been efficiently developed. Spirocyclopropanes derived from 2-arylidene-1,3-indandiones were synthesized with up to 85% ee by using dimethyl bromomalonate and α,α-L-diarylprolinol/K₂CO₃ system. Copyright

Full text of DOI:10.1002/ejoc.201100562

FULL PAPER
DOI: 10.1002/ejoc.201100562
Synthesis of Activated Cyclopropanes by an MIRC Strategy: An
Enantioselective Organocatalytic Approach to Spirocyclopropanes[‡]
Alessio Russo,[a] Sara Meninno,[a] Consiglia Tedesco,[a] and Alessandra Lattanzi*[a]
Keywords: Organocatalysis / Spiro compounds / Amino alcohols / Domino reactions / Michael-initiated ring-closing
reaction
An efficient cyclopropanation, by a Michael-initiated ring-
closing (MIRC) reaction of 2-arylidene-1,3-indandiones and
2-arylidene malononitriles, has been developed by using dif-
ferent α-monohalogenated methylene active compounds
idene-1,3-indandiones and dimethyl bromomalonate with a
commercially available α,α- -diarylprolinol as the organocat-
alyst and K2CO3 as the additive has been accomplished. The
spirocyclopropanes were isolated in high yield and up to
L
with triethylamine. The first enantioselective cyclopropan- 85% ee. Notably, the asymmetric one-pot sequential ap-
ation to spirocyclopropanes derived by the reaction of 2-aryl-
proach to spirocyclopropanes proved to be a feasible process.
Ley,[10] Cordova,[11] and Wang[12] to be suitable catalysts for
the highly stereoselective cyclopropanation of enals and en-
ones by iminium–enamine catalysis using readily available
alkyl halides. The feasibility of noncovalent catalysis, by a
two-step MIRC strategy, promoted by cinchona-based thio-
ureas was exploited by Connon and co-workers to access
functionalized cyclopropanes starting from nitroalkenes
and dimethyl chloromalonate.[13a] High diastereocontrol
and modest enantiocontrol was achieved in the process (up
to 47% ee), which was later improved by Yan and co-
workers up to 99% ee.[13b] We have recently demonstrated
that easily available α,α-diarylprolinols are also able to pro-
mote this cyclopropanation reaction with high diastereo-
selectivity and modest enantioselectivity (up to 49% ee).[14]
With the aim to widen the scope of highly functionalized
cyclopropanes accessible by the MIRC strategy, we turned
our attention toward the combination of α-halogenated
active methylene compounds and poorly investigated al-
kenes such as 2-arylidene-1,3-indandiones and 2-arylidene
malononitriles (Scheme 1).
Introduction
Cyclopropanes are subunits found in many natural prod-
ucts and pharmaceuticals.[1] Moreover, they serve as highly
valuable synthetic intermediates amenable to facile ring
opening and ring enlargement to give a wide number of
functionalized products and complex heterocycles.[2] There-
fore, the development of asymmetric methods for their syn-
thesis has attracted considerable attention as attested to by
the huge expansion of this area in recent years.[3] Common
methodologies for asymmetric cyclopropanation include
diastereoselective Simmons–Smith-type processes.[4] Metallo-
carbenoid reagents are the most investigated and general
methods to produce cyclopropanes from alkenes with high
stereocontrol.[5] Michael-initiated ring-closing (MIRC) re-
actions have been successfully applied to obtain cyclo-
propanes.[6] In this case, conjugate addition to an electron-
poor alkene generates an enolate that then undergoes intra-
molecular ring closure. In a domino process, the final cyclo-
propanes can be directly obtained. Less conveniently, a two-
step procedure is required whenever the cyclization of the
first adduct must proceed under different reaction condi-
tions. In this context, elegant asymmetric methods for the
cyclopropanation of electron-poor alkenes, such as enals,
enones, α,β-unsaturated esters, amides, and nitriles, have
been reported, using sulfur and nitrogen ylides, by Aggar-
wal and co-workers,[7] and more recently organocatalytic
versions by the groups of Gaunt,[8] and MacMillan.[9] Chi-
ral nonracemic amines have been reported by the groups of
Scheme 1. MIRC approach to obtain densely functionalized cyclo-
propanes; EWG = electron-withdrawing group.
[‡] MIRC = Michael-initiated ring-closing reaction.
[a] Dipartimento di Chimica e Biologia, Università di Salerno,
Via Ponte don Melillo, 84084 Fisciano, Italy
Fax: +39-089-969603
Herein, we report an effective and simple domino pro-
cedure for their cyclopropanation using triethylamine,
which served as a platform to pursue the challenging task
of developing an enantioselective catalytic version by ex-
E-mail: lattanzi@unisa.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100562.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5096–5103

Synthesis of Activated Cyclopropanes by an MIRC Strategy
ploiting noncovalent catalysis mediated by commercially
available bifunctional organocatalysts.
The scope of this simple methodology to obtain highly
functionalized cyclopropanes was then studied by using 2a
as the alkylating agent (Table 2).
Results and Discussion
Table 2. Triethylamine-catalyzed cyclopropanation of 1 and 4 with
2a.[a]
A few methods were elaborated for the cyclopropanation
of 2-arylidenemalononitriles and 2-arylidene-1,3-indan-
diones, which generally required special techniques, namely,
electrocatalysis,[15] or oxidative addition promoted by mo-
lecular iodine and bases under mechanical milling condi-
tions.[16] An organometallic approach using α-dihaloge-
nated methylene active compounds has also been exploited
for their synthesis.[17] Monohalomalonates were used with
potassium carbonate in THF for the cyclopropanation of
different electron-poor alkenes to afford the corresponding
cyclopropanes in variable yield.[18] A variety of α-monohalo-
genated active methylene compounds are commercially
available, and thus, we investigated cyclopropanation by re-
acting them with 2-arylidene-1,3-indandiones and 2-arylid-
ene malononitriles in the presence of common organic
bases. Compound 1a was treated with dimethyl bromo-
malonate (2a) in CHCl3 at room temperature with amines
(Table 1).
Entry
R
3
Yield R3
5
Yield
3 [%][b]
5 [%][b]
1
2
3
4
5
6
7
8
9
Ph
3a
3f
3g
3h
3i
3j
3k
3l
92
88
88
83
98
99
94
94
–
Ph
5a
5b
5c
5d
99
99
99
93
–
–
–
–
–
4-tBuC6H4
2-CH3C6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
2-ClC6H4
3,5-(tBu)2C6H3
cyclohexyl
4-CH3OC6H4
4-CF3C6H4
2-CH3C6H4
–
–
–
–
–
3m
Table 1. Base-catalyzed cyclopropanation of 1a with different α-
monohalogenated active methylene compounds.[a]
[a] Reaction conditions:
1
(0.2 mmol),
4 (0.2 mmol), 2a
(0.24 mmol), Et3N (0.2 mmol) in CHCl3 (1 mL). [b] Yield of iso-
lated product.
Spirocyclopropanes 3 were isolated in high yield irrespec-
tive of the substitution pattern on the phenyl ring. The cy-
clopropanation of the aliphatic derivative 1m did not pro-
ceed (Table 2, entry 9). More reactive 2-arylidene malo-
nitriles were converted into cyclopropanes 5 in excellent
yields (Table 2, entries 1–4).
We then turned our attention to the development of an
asymmetric procedure for the cyclopropanation of these
compounds using reagent 2a. We hypothesized that a bi-
functional organocatalyst with a basic and an acidic group
would have been able to provide noncovalent activation of
the alkene through hydrogen bonding and the pronucleo-
phile through deprotonation. As part of our interest in de-
veloping asymmetric processes organocatalyzed by bifunc-
tional promoters, we envisaged easily available cinchona
alkaloids and α,α-diarylprolinols as suitable catalysts for cy-
clopropanation.[19] They were first used under stoichiomet-
ric loadings; alkene 1a and donor 2a were reacted at room
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), base
(0.2 mmol) in CHCl3 (1 mL). [b] Yield of isolated product.
Tertiary and secondary amines of different pKa afforded temperature in toluene (Table 3). Although the cyclo-
cyclopropane 3a after a short reaction time in good to high propane was easily formed when using cinchona alkaloids,
yield. Triethylamine proved to be the best base, leading to compound 3a was recovered as a racemic product, except
the cyclopropane in 92% yield (Table 1, entry 3). A variety when using cinchonine as the catalyst (Table 3, entries 1–4).
of α-bromomethylene-active compounds were treated with
Unexpectedly, cyclopropanation did not proceed under
compound 1a, employing triethylamine as the base. The identical conditions when using cinchona-derived thioureas
corresponding cyclopropanes 3 were obtained in quantita- developed by Soòs and co-workers.[20,21] Pleasingly, α,α-di-
tive yields after short reaction times (Table 1, entries 6–9), arylprolinols 6 afforded the product in good to high yield
except when using bromonitromethane. In this case, the for- with an encouraging level of enantioselectivity (Table 3, en-
mation of the product was not observed (Table 1, entry 10). tries 5–8). Indeed, commercially available compound 6d
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A. Russo, S. Meninno, C. Tedesco, A. Lattanzi
FULL PAPER
Table 3. Asymmetric stoichiometric cyclopropanation of 1a with 2a of conversion and enantioselectivity, whereas halogenated,
using chiral bases.[a]
ethereal, and polar aprotic solvents proved to be unsuitable
media.[24] Further optimization of the amount of K2CO3,
temperature, and dilution was studied by using catalyst 6d.
The best result was attained when working at –30 °C em-
ploying 50 mol-% of the basic additive, which enabled the
isolation of cyclopropane 3a in 92% yield and 67% ee
(Table 4, entry 13).
Table 4. Optimization of the asymmetric cyclopropanation of 1a
with 2a using 6 (50 mol-%) and basic additives.[a]
Entry
Catalyst Additive
(equiv.)
t
[h]
Yield
ee
Entry
Catalyst
t [h]
Yield 3a [%][b]
ee 3a [%][c]
3a [%][b] 3a [%][c]
1
2
3
4
5
6
7
quinine
quinidine
cinchonine
cinchonidine
6a
6b
6c
6d
6d
24
20
24
21
23
23
22
22
24
93
91
86
95
76
87
87
86
92
rac
5
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6d
6d
6d
6d
6d
–
24
19
21
24
23
21
24
22
24
28
60
22
26
23
24
65
99
97
64
96
99
68
80
66
58
82
75
92
74
60
18
rac
12
18
27
7
19
29
10
21
50
61
67
49
69
Et3N (1)
30
rac
32
29
35
45
58
Na2CO3 (1)
NaHCO3 (1)
K2CO3 (1)
Rb2CO3 ()
CaCO3 (1)
Cs2CO3 (1)
NaOAc (1)
K2CO3 (0.5)
K2CO3 (1)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
K2CO3 (0.5)
8
9[d]
9
10[d]
11[e]
12[e]
13[f]
14[f,g]
15[f,h]
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst
(0.2 mmol) in toluene (1 mL). [b] Yield of isolated product. [c] De-
termined by HPLC on Chiralpak AD-H column. [d] Reaction per-
formed at –20 °C.
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol),
6
(0.1 mmol), additive (x mmol) in toluene (1 mL). [b] Isolated yield
after flash chromatography. [c] Determined by HPLC on Chiralpak
AD-H column. [d] The reaction was carried out with 30 mol-% of
catalyst 6a. [e] Reaction performed at –20 °C. [f] Reaction per-
formed at –30 °C. [g] The reaction was carried out with 30 mol-%
of catalyst 6d. [h] Reaction carried out at C = 0.1 m.
gave 3a in 86% yield and 45% ee (Table 3, entry 8). The
enantiomeric excess could be improved to 58% when per-
forming the reaction at –20 °C (Table 3, entry 9). The cyclo-
propanation of compound 4a with 2a catalyzed by quinine
and catalyst 6a was also studied under the same conditions,
leading in both cases to racemic product 5a. To reduce the
amount of catalyst employed, the cyclopropanation was
carried out by adding some basic additives to remove HBr
formed during the reaction, thus regenerating the unpro-
tonated catalyst.
The applicability of this system was then evaluated with
a selection of 2-arylidene-1,3-indandiones under optimal re-
action conditions (Table 5).[25]
The cyclopropanation of 1a was investigated by using
catalyst 6a (50 mol-%) with an array of bases (1 equiv.) in
toluene at room temperature (Table 4). In the absence of
any additive, the product was isolated in satisfactory yield,
but with reduced ee (entry 1 vs. entry 5 in Table 3). The
addition of triethylamine as an additive afforded racemic
compound 3a in high yield, which implied the occurrence
of a competitive racemic pathway (Table 4, entry 2).[22]
Nevertheless, a high conversion to cyclopropane 3a was
achieved together with a variable degree of enantiocontrol
when using inorganic bases (Table 4, entries 3–9). We were
pleased to observe that potassium carbonate enabled the
formation of product 3a in excellent yield and almost com-
parable enantioselectivity to that achieved under stoichio-
metric amounts of catalyst 6a (Table 4, entry 5 vs. entry 5
in Table 3).[23] An attempt to reduce the catalyst loading to
30 mol-% significantly lowered both the yield and enantio-
selectivity (Table 4, entry 10). Solvent screening conducted
with the most effective catalyst 6d showed that in aromatic
solvents, such as chlorobenzene and m-xylene, comparable
results to those found in toluene were achieved in terms
Table 5. Substrate scope of 2-arylidene-1,3-indandiones 1 in the
asymmetric cyclopropanation with 2a.[a]
Entry
R
t [h]
Yield 3 [%][b]
ee 3 [%][c]
1[d]
2[d]
3
4
5
Ph
a
f
g
h
j
k
l
n
26
24
27
26
24
24
47
48
92
73
85
85
96
74
79
84
67
60
83
63
60
68
60
85
4-tBuC6H4
2-CH3C6H4
4-CH3OC6H4
4-ClC6H4
2-ClC6H4
3,5-(tBu)2C6H3
2-CH3OC6H4
6
7[d]
8
[a] Reaction conditions:
1 (0.2 mmol), 2a (0.24 mmol), 6d
(0.1 mmol), K2CO3 (0.1 mmol) in chlorobenzene (1 mL) at –30 °C.
[b] Isolated yield after flash chromatography. [c] Determined by
HPLC on chiral columns. [d] In toluene as the solvent.
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Synthesis of Activated Cyclopropanes by an MIRC Strategy
2-Arylidene-1,3-indandiones with electron-donating or
Cyclopropane 3g was obtained in good yield and, no-
-withdrawing substituents in the para and meta positions tably, the level of enantioselectivity illustrated in Table 5
afforded the product in high yield and up to 67% ee was maintained. To the best of our knowledge, this repre-
(Table 5, entries 1, 2, 4, 5, and 7). Steric hindrance at the sents the first example of an enantioselective one-pot se-
ortho position, such as in alkenes 1g, 1k, and 1n, was found quential domino cyclopropanation.
to be beneficial in terms of enantiocontrol, leading to cyclo-
propanes with 83, 68, and 85% ee, respectively (Table 5, en-
tries 3, 6, and 8).[26] The absolute configuration of cyclopro-
panes 3 was assigned to be S by analogy to the structure
Conclusions
An efficient and simple synthesis of densely function-
alized cyclopropanes has been developed by an MIRC ap-
proach by using commercially available α-monohalogenated
active methylene compounds and 2-arylidene-1,3-indan-
diones or 2-arylidene malononitriles in the presence of tri-
ethylamine. The first asymmetric route to spirocyclo-
propanes from 2-arylidene-1,3-indandiones and dimethyl
bromomalonate, using a commercially available α,α-l-di-
arylprolinol as the organocatalyst and K2CO3 as additive,
has been disclosed. The enantioenriched products were ob-
tained in good yields and with moderate to good enantio-
selectivity. The present methodology illustrates the potential
of noncovalent catalysis, using easily available promoters
such as β-amino alcohols, in the enantioselective cyclo-
propanation of less common, more challenging alkenes.
Interestingly, an unprecedented example of an asymmetric
one-pot sequential approach to cyclopropanes has been de-
veloped.
determined by single-crystal X-ray analysis performed on
compound 3k (Figure 1).[27]
Figure 1. X-ray molecular structure of compound 3k. Thermal el-
lipsoids are drawn at the 20% probability level.
Experimental Section
The diester moieties in compounds 3 could be eventually
manipulated in a few steps to generate cyclopropane amino
acids.[28] This class of cyclopropanes is widespread in nature
and they generally show interesting biologically activities
and find application in peptidomimetics.[29]
General Methods: All reactions requiring dry or inert conditions
were conducted in flame-dried glassware under a positive pressure
of nitrogen. Reactions were monitored by TLC on silica gel plates
(0.25 mm) and visualized by UV light or by phosphomolybdic acid/
ethanol spray test. Flash chromatography was performed on silica
1
gel (60, particle size: 0.040–0.063 mm). H and 13C NMR spectra
Hitherto, few examples of a one-pot sequential domino
route to racemic cyclopropanes have been investigated, de-
spite the notable synthetic and economic advantages de-
rived from the one-pot combination of commercially avail-
able compounds to produce highly functionalized cyclic
products.[30] Hence, the enantioselective one-pot sequential
approach to the synthesis of cyclopropanes 3 was investi-
gated (Scheme 2). Typical reaction conditions for the
Knoevenagel condensation of representative ortho-tolual-
dehyde and 1,3-indandione were found to be compatible
with the enantioselective MIRC route herein developed.
were recorded on a 400 MHz spectrometer at room temperature in
CDCl3. Chemical shifts for protons are reported by using residual
CHCl3 as an internal reference (δ = 7.26 ppm). Carbon spectra
were referenced to the shift of the 13C signal of CDCl3 (δ =
77.0 ppm). Optical rotations were performed by using an Na lamp.
FTIR spectra were recorded as thin films on KBr plates and ab-
sorption maxima are reported in cm–1. ESI mass spectra are re-
ported in the form of m/z. Elementary analyses were performed by
using a CHNS elementary analyzer. Melting points were recorded
with a digital Electrothermal 9100 apparatus. Solvents were puri-
fied and dried by standard procedures prior to use. Petroleum ether
with a boiling range of 60–80 °C was used. Anhydrous p-xylene,
toluene, chlorobenzene, and CH3CN were purchased and used as
received. 2-Bromomalononitrile and 3-bromopentane-2,4-dione
were prepared by using known protocols.[31] Cinchona-derived
thioureas and prolinol 6c were synthesized by following procedures
reported in the literature.[32] Alkenes 1 and 4 were prepared by
using general procedures reported in the literature.[33] Catalysts 6a,
6b, and 6d, quinine, quinidine, cinchonine, cinchonidine, salts, and
all other reagents were purchased from Aldrich and used as re-
ceived. Cyclopropanes 5a, 5b, 3a, 3d, 3i are known com-
pounds.[16,17] Enantiomeric excesses of cyclopropanes 3 were deter-
mined by HPLC (UV dual λ absorbance detector) using Daicel
Chiralpak AD-H and AS-H columns.
Scheme 2. Enantioselective one-pot domino approach to cyclo-
propane 3g.
Eur. J. Org. Chem. 2011, 5096–5103
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A. Russo, S. Meninno, C. Tedesco, A. Lattanzi
FULL PAPER
General Procedure for the Cyclopropanation of Compounds 1 and 4
with Triethylamine: In a sample vial, alkenes 1 or 4 (0.20 mmol),
appropriate monohalogenated active methylene compound
(0.24 mmol), and NEt3 (28 μL, 0.20 mmol) were dissolved in
CHCl3 (1.0 mL). The reaction was stirred at room temperature un-
til completion (monitored by TLC, PE/AcOEt, 7:3 or 1:1). The
mixture was directly purified by flash chromatography (eluent pure
chloroform) to give products 3 or 5.
CHCl3), ee 67%. HPLC analysis with Chiralpak column AD-H,
n-hexane/2-propanol (90:10), 1.0 mLminϪ1, detection at 254 nm;
minor enantiomer tR = 17.9 min, major enantiomer tR = 22.1 min.
(S)-Dimethyl 3-(4-tert-Butylphenyl)-1Ј,3Ј-dioxo-1Ј,3Ј-dihydrospiro-
(cyclopropane-1,2Ј-indene)-2,2-dicarboxylate (3f): White solid; m.p.
79.1–82.3 °C. [α]2D8 = –73.3 (c = 0.5, CHCl3), ee 60%. IR (KBr):
ν
˜
= 2956, 1752, 1713, 1595, 1434, 1244, 1151, 757 cm–1. 1H
max
NMR (CDCl3, 400 MHz): δ = 8.00–7.98 (m, 1 H), 7.97–7.95 (m, 1
H), 7.86–7.82 (m, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 7.25 (d, J =
8.4 Hz, 2 H), 4.09 (s, 1 H), 3.85 (s, 3 H), 3.76 (s, 3 H), 1.29 (s, 9
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 194.8, 191.4, 164.9,
162.9, 143.0, 141.1, 135.6, 135.2, 129.8, 126.9, 124.9, 124.7, 123.2,
123.1, 53.7, 53.2, 51.2, 45.3, 42.8, 34.5, 31.2 ppm. MS (ESI): m/z
(%) = 443.37 (100) [M + Na+], 459.21 (8) [M + K+]. C25H24O6
(420.46): calcd. C 71.41, H 5.75; found C 71.68, H 5.86; HPLC
analysis with Chiralpak column AS-H, n-hexane/2-propanol
(90:10), 1.0 mLminϪ1, detection at 254 nm; minor enantiomer tR
= 10.3 min, major enantiomer tR = 13.5 min.
1Ј,3Ј-Dioxo-3-phenyl-1Ј,3Ј-dihydrospiro(cyclopropane-1,2Ј-indene)-
2,2-dicarbonitrile (3b): White solid; m.p. 222.1–224.9 °C. IR (KBr):
ν
˜
= 3028, 2925, 2250, 1748, 1716, 1591, 1239, 1223, 753,
max
698 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.16–7.98 (m, 4 H),
7.51–7.28 (m, 5 H), 4.07 (s, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 189.3, 187.5, 142.4, 140.8, 136.9, 136.8, 129.7, 129.4,
129.1, 126.4, 124.2, 124.1, 110.6, 108.8, 44.0, 42.2, 19.4 ppm. MS
(ESI): m/z (%) = 299.41 (24) [M + H+], 321.44 (100) [M + Na+].
C19H10N2O2 (298.30): m/z calcd. C 76.50, H 3.38, N 9.39; found C
76.65, H 3.47, N 9.50.
2,2-Diacetyl-3-phenylspiro(cyclopropane-1,2Ј-indene)-1Ј,3Ј-dione
(S)-Dimethyl 1Ј,3Ј-Dioxo-3-o-tolyl-1Ј,3Ј-dihydrospiro(cyclopropane-
1,2Ј-indene)-2,2-dicarboxylate (3g): Yellow solid; m.p. 145.1–
(3c): Yellow solid; m.p. 50.6–54.6 °C. IR (KBr): νmax = 3027, 2925,
˜
1709, 1595, 1356, 1239, 750, 699 cm–1. 1H NMR (CDCl3,
400 MHz): δ = 7.99–7.96 (m, 2 H), 7.87–7.85 (m, 2 H), 7.38–7.29
(m, 5 H), 3.94 (s, 1 H), 2.38 (s, 3 H), 2.19 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 198.2, 197.1, 195.4, 193.0, 142.9, 141.1,
135.7, 135.5, 130.6, 130.2, 128.1, 128.0, 123.2, 123.1, 66.2, 47.8,
45.2, 30.8, 28.8 ppm. MS (ESI): m/z (%) = 355.37 (100) [M + Na+],
371.33 (30) [M + K+]. C21H16O4 (332.36): calcd. C 75.89, H 4.85;
found C 76.07, H 3.91.
147.8 °C. [α]2D9 = –34.5 (c = 0.5, CHCl ), ee 83%. IR (KBr): ν
˜
3
max
= 2954, 1754, 1713, 1594, 1435, 1244, 1152, 748 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 8.03–8.00 (m, 1 H), 7.98–7.96 (m, 1 H),
7.87–7.85 (m, 2 H), 7.21–7.19 (m 2 H), 7.16–7.09 (m, 2 H), 4.03 (s,
1 H), 3.85 (s, 3 H), 3.71 (s, 3 H), 2.18 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 194.7, 191.5, 165.0, 163.0, 142.7, 141.1,
138.3, 135.7, 135.3, 130.0, 129.0, 128.9, 128.0, 125.4, 123.2, 123.1,
53.6, 53.1, 51.3, 45.0, 41.5, 19.9 ppm. MS (ESI+): m/z (%) = 379.23
Dimethyl
1,1-dicarboxylate (5c): Colorless oil. ν
2,2-Dicyano-3-[4-(trifluoromethyl)phenyl]cyclopropane- (100) [M + H+], 401.39 (15) [M + Na+]. C22H18O6 (378.38): calcd.
(KBr) 3012, 2959, 2925, C 69.83, H 4.79; found C 69.98, H 4.88, HPLC analysis with Chi-
ralpak column AS-H, n-hexane/2-propanol (90:10), 1.0 mLminϪ1
649 cm–1. H NMR (CDCl3, 400 MHz): δ = 6.69 (d, J = 8.3 Hz, 2 detection at 254 nm; minor enantiomer tR = 10.7 min, major en-
˜
max
2853, 2360, 2253, 1741, 1623, 1438, 1068, 1019, 909, 861, 737,
,
1
H), 7.52 (d, J = 8.2 Hz, 2 H), 4.00 (s, 1 H), 3.99 (s, 3 H), 3.80 (s,
3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 163.1, 161.1, 131.9
(q, J = 35.1 Hz), 131.0, 129.3, 126.1, 122.1, 111.3, 109.2, 55.1, 54.2,
46.2, 39.4, 16.4 ppm. MS (ESI): m/z (%) = 351.45 (100) [M – H+].
C16H11F3N2O4 (352.27): calcd. C 54.55, H 3.15, N 7.95; found C
54.78, H 3.30, N 8.10.
antiomer tR = 13.3 min.
(S)-Dimethyl 3-(4-Methoxyphenyl)-1Ј,3Ј-dioxo-1Ј,3Ј-dihydrospiro-
(cyclopropane-1,2Ј-indene)-2,2-dicarboxylate (3h): Yellow gum.
[α]2D7 = –59.8 (c = 0.4, CHCl ), ee 63%. IR (KBr): ν
= 2954,
˜
3
max
2839, 1751, 1712, 1660, 1594, 1516, 1435, 1250, 1181, 1152,
761 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.00–7.98 (m, 1 H),
7.96–7.94 (m, 1 H), 7.86–7.82 (m, 2 H), 7.23 (d, J = 8.7 Hz, 2 H),
6.81 (d, J = 8.7 Hz, 2 H), 4.09 (s, 1 H), 3.84 (s, 3 H), 3.78 (s, 3 H),
3.74 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 194.8, 191.5,
164.9, 162.9, 159.1, 142.9, 141.2, 135.5, 135.3, 131.3, 123.2, 123.1,
121.8, 113.4, 55.1, 53.7, 53.2, 51.3, 45.3, 42.5 ppm. MS (ESI ): m/z
(%) = 417.26 (100) [M + Na+]. C22H18O7 (394.38): m/z calcd. C
67.00, H 4.60; found C 67.25, H 4.69; HPLC analysis with Chi-
Dimethyl 2,2-Dicyano-3-o-tolylcyclopropane-1,1-dicarboxylate (5d):
White wax. ν
(KBr) 3001, 2958, 2924, 2853, 2249, 1747, 1437,
˜
max
1251, 1205, 1084, 913, 762, 736 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 7.35–7.28 (m, 3 H), 7.24–7.21 (m, 1 H), 4.01 (s, 3 H), 3.92 (s,
1 H), 3.81 (s, 3 H), 2.44 (s, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 163.6, 161.7, 138.3, 131.1, 129.7, 127.1, 126.4, 125.8,
112.0, 109.7, 54.9, 54.0, 46.2, 39.9, 19.5, 16.4 ppm. MS (ESI): m/z
(%) = 297.55 (100) [M – H+]. C16H14N2O4 (298.30): calcd. C 64.42,
H 4.73, N 9.39; found C 64.61, H 4.82, N 9.47.
ralpak column AD-H, n-hexane/2-propanol (70:30), 1.0 mLminϪ1
detection at 254 nm; minor enantiomer tR = 17.1 min, major en-
antiomer tR = 19.9 min.
,
General Procedure for the Asymmetric Cyclopropanation of Com-
pounds 1: A sample vial charged with a mixture of alkene 1
(0.20 mmol), K2CO3 (14 mg, 0.10 mmol), and (S)-α-bis(3,5-dimeth-
ylphenyl)-2-pyrrolidinemethanol 6d (31 mg, 0.10 mmol) in anhy-
drous toluene or chlorobenzene (1.0 mL) was sonicated in a water
bath at room temperature. Then, dimethyl 2-bromomalonate
(32 μL, 0.24 mmol) was added and the reaction was stirred at
–30 °C until completion (monitored by TLC, PE/AcOEt, 7:3). The
mixture was directly purified by flash chromatography (eluent:
chloroform) to give enantiomerically enriched cyclopropanes 3.
The absolute configuration of compounds 3 was assigned as S by
analogy to the structure determined by single-crystal X-ray analysis
performed on compound 3k.
(S)-Dimethyl 3-(4-Chlorophenyl)-1Ј,3Ј-dioxo-1Ј,3Ј-dihydrospiro(cy-
clopropane-1,2Ј-indene)-2,2-dicarboxylate (3j): White solid; m.p.
158.8–160.1 °C. [α]2D6 = –77.2 (c = 0.5, CHCl3), ee 60%. IR (KBr):
ν
= 2954, 1752, 1713, 1595, 1496, 1435, 1244, 1151, 759 cm–1.
˜
max
1H NMR (CDCl3, 400 MHz): δ = 8.03–7.99 (m, 1 H), 7.98–7.96
(m, 1 H), 7.89–7.85 (m, 2 H), 7.27–7.23 (m, 4 H), 4.09 (s, 1 H),
3.86 (s, 3 H), 3.73 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 194.3, 191.5, 164.5, 162.7, 142.8, 141.2, 135.8, 135.5, 133.9, 131.5,
128.4, 128.1, 123.3, 123.2, 53.8, 53.2, 51.0, 44.9, 41.4 ppm. MS (ESI
): m/z (%) = 421.37 (100) [M + Na+], 437.33 (30) [M +K+].
C21H15ClO6 (398.80): m/z calcd. C 63.25, H 3.79; found C 63.41,
H 3.84; HPLC analysis with Chiralpak column AD-H, n-hexane/
2-propanol (90:10), 1.0 mLminϪ1, detection at 254 nm; minor en-
antiomer tR = 26.3 min, major enantiomer tR = 30.2 min.
(S)-Dimethyl 1Ј,3Ј-Dioxo-3-phenyl-1Ј,3Ј-dihydrospiro(cyclopropane-
1,2Ј-indene)-2,2-dicarboxylate (3a):[17b] [α]2D7 = –58.7 (c = 0.4,
5100
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5096–5103

Synthesis of Activated Cyclopropanes by an MIRC Strategy
(S)-Dimethyl 3-(2-Chlorophenyl)-1Ј,3Ј-dioxo-1Ј,3Ј-dihydrospiro(cy-
clopropane-1,2Ј-indene)-2,2-dicarboxylate (3k): White solid; m.p.
155.0–156.2 °C. [α]2D8 = –34.3 (c = 0.5, CHCl3), ee 68%. IR (KBr):
Crystal data: C21H15ClO6, monoclinic, space group P21, Z = 2,
a = 8.064(3) Å, b = 12.817(4) Å, c = 9.571(4) Å, β = 109.557(7)°,
V = 932.2(6) Å3, Dx = 1.421 gcm–3, μcalcd. = 2.137 mm–1.
ν
= 2955, 1754, 1714, 1595, 1436, 1336, 1245, 1151, 1047,
˜
max
Enantioselective One-Pot Sequential Synthesis of Cyclopropane 3g:
In a sample vial, 1,3-indandione (29 mg, 0.20 mmol) and o-tolual-
dehyde (23 μL, 0.20 mmol) were dissolved in chlorobenzene (1 mL)
containing piperidine (2 mol-%) and molecular sieves (≈ 80 mg).
The reaction was stirred at 60 °C for 5 h [monitored by TLC, PE/
AcOEt (7:3) as the eluent]. Catalyst 6d (31 mg, 0.10 mmol) and
K2CO3 (14 mg, 0.10 mmol) were subsequently added at room tem-
perature and the mixture was sonicated. Then, dimethyl 2-bromo-
malonate (32 μL, 0.24 mmol) was added and the reaction was
stirred at –30 °C for 27 h. Purification by flash chromatography
(eluent: chloroform) gave cyclopropane 3g.
754 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.01–7.99 (m, 1 H),
7.92–7.90 (m, 1 H), 7.85–7.79 (m, 3 H), 7.29–7.24 (m, 3 H), 4.04
(s, 1 H), 3.86 (s, 3 H), 3.75 (s, 3 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 194.4, 190.8, 164.7, 163.1, 142.7, 141.3, 135.6, 135.3,
135.1, 131.2, 129.3, 129.1, 126.6, 123.1, 53.8, 53.3, 50.9, 45.1,
39.7 ppm. MS (ESI ): m/z (%) = 421.21 (100) [M + Na+].
C21H15ClO6 (398.80): m/z calcd. C 63.25, H 3.79; found C 63.45,
H 3.85; HPLC analysis with Chiralpak column AD-H, n-hexane/
2-propanol (90:10), 1.0 mLminϪ1, detection at 254 nm; minor en-
antiomer tR = 13.8 min, major enantiomer tR = 15.6 min.
(S)-Dimethyl 3-(3,5-Di-tert-butylphenyl)-1Ј,3Ј-dioxo-1Ј,3Ј-dihydro-
spiro(cyclopropane-1,2Ј-indene)-2,2-dicarboxylate (3l): White solid;
m.p. 191.7–192.4 °C. [α]2D8 = –94.7 (c = 0.6, CHCl3), ee 60%. IR
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for new compounds and HPLC
traces are presented.
(KBr): ν
= 2959, 1750, 1712, 1590, 1431, 1248, 1156, 752 cm–1.
˜
max
1H NMR (CDCl3, 400 MHz): δ = 8.00–7.98 (m, 1 H), 7.97–7.92
(m, 1 H) 7.85–7.81 (m, 2 H), 7.18 (br. s, 1 H), 7.17 (br. s, 2 H),
4.13 (s, 1 H), 3.86 (s, 3 H), 3.78 (s, 3 H), 1.29 (s, 18 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 195.1, 190.9, 165.0, 162.9, 150.0,
143.1, 140.9, 135.6, 135.1, 128.9, 124.7, 123.0, 121.7, 53.7, 53.2,
51.5, 45.5, 44.1, 34.8, 31.3 ppm. MS (ESI+): m/z (%) = 499.32 (100)
[M + Na+]. C29H32O6 (476.57): m/z calcd. C 73.09, H 6.77; found
C 73.27, H 6.89; HPLC analysis with Chiralpak column AD-H, n-
hexane/2-propanol 90:10, mLminϪ1, detection at 254 nm; minor
enantiomer tR = 5.1 min, major enantiomer tR = 6.6 min.
Acknowledgments
Ministero Italiano dell’Università e della Ricerca (MIUR), PRIN
2008, and the University of Salerno are acknowledged for financial
support. Dr. P. Iannece is thanked for elemental and MS analyses.
X-ray diffraction data were collected at IBB-CNR (Naples, Italy);
M. Amendola and G. Sorrentino are acknowledged for technical
assistance.
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ν
= 2954, 2938, 1752, 1713, 1597, 1436, 1249, 1152, 1027,
˜
max
755 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.03–7.98 (m, 1 H),
7.91–7.87 (m, 1 H), 7.84–7.81 (m, 2 H), 7.74–7.72 (m, 1 H), 7.29–
7.25 (m, 1 H), 6.99–6.95 (m, 1 H), 6.71–6.69 (m, 1 H), 3.87 (s, 3
H), 3.80 (s, 1 H), 3.72 (s, 3 H), 3.18 (s, 3 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 195.4, 190.5, 165.1, 163.2, 157.0, 142.9,
141.1, 135.2, 135.0, 134.6, 131.2, 129.3, 122.9, 122.5, 120.3, 118.9,
109.7, 54.5, 53.6, 53.0, 50.5, 44.9, 37.9 ppm. MS (ESI+ ): m/z (%)
= 417.26 (100) [M + Na+]. C22H18O7 (394.38): m/z calcd. C 67.00,
H 4.60; found C 67.30, H 4.67; HPLC analysis with Chiralpak
column AD-H, n-hexane/2-propanol 70:30, 1.0 mLminϪ1, detec-
tion at 254 nm; minor enantiomer tR = 6.5 min, major enantiomer
tR = 8.2 min.
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2183 independent reflections).
Flack parameter is 0.06(4). The ORTEP plot was obtained by
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Eur. J. Org. Chem. 2011, 5096–5103
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5101

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[23]
[6]
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.
[24]
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[26]
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