Stereoselective synthesis of functionalized cyclopropane derivatives via α-thiocyanate ketone-based three-component reaction

Article abstract of DOI:10.1055/s-0030-1260096

α-Thiocyanate ketone-based three-component reactions have been established for the stereoselective synthesis of functionalized electron-deficient trans-cyclopropanes. The multicomponent reactions were conducted by reacting readily available and inexpensiv

Full text of DOI:10.1055/s-0030-1260096

PAPER
2459
Stereoselective Synthesis of Functionalized Cyclopropane Derivatives via
a-Thiocyanate Ketone-Based Three-Component Reaction
Functionalized
e
C
ycloprop
i
ane De
-
rivative
Y
ue Wu, Ying Li, Hui Feng, Qiong Wu, Bo Jiang,* Feng Shi, Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, Laboratory of Green Synthetic Chemistry for Functional Materials,
Xuzhou Normal University, Xuzhou, Jiangsu, 221116, P. R. of China
Fax +86(516)83500065; E-mail: jiangchem@xznu.edu.cn; E-mail: laotu@xznu.edu.cn
Received 30 March 2011; revised 19 May 2011
nomic, operationally simple, selective synthesis of spiro-
substituted trans-cyclopropanes under mild,
environmentally friendly conditions.
Abstract: a-Thiocyanate ketone-based three-component reactions
have been established for the stereoselective synthesis of function-
alized electron-deficient trans-cyclopropanes. The multicomponent
reactions were conducted by reacting readily available and inexpen-
sive starting materials under microwave irradiation. The procedures
are very facile, highly stereoselective, and avoids the use of ylides.
Over the past several years, our group has developed var-
ious multicomponent reactions (MCRs) that can provide
easy access to useful functionalized multiple-ring struc-
tures of chemical and pharmaceutical interest.12,13 For ex-
ample, a new, four-component domino reaction was
established as a way to provide easy access to the synthe-
sis of multifunctionalized quinazoline derivatives.12a
When aliphatic aldehydes were employed to replace their
aromatic counterparts in the above reaction, the reaction
was found to proceed along another pathway, leading to
Key words: multicomponent reactions, cyclopropanes, stereose-
lectivity, microwave heating
The cyclopropane subunit plays an important role in or-
ganic chemistry because of its strained structure, interest-
ing bonding characteristics, and value as an internal
mechanistic probe.1 It is also found as a basic structural
unit that is widely present in a variety of naturally occur-
ring compounds and rationally designed pharmaceutical
agents with biological activity.2 For these reasons, cyclo-
propanes have attracted much attention from organic
chemists.3,4
the
formation
of
multi-functionalized
tricyc-
lo[6.2.2.01,6]dodecanes.12b
As a continuation of our research on the development of
MCRs,12,13 we would like to report another stereoselective
three-component approach based on Meldrum’s acid, that
generates spirosubstituted trans-cyclopropane derivatives
that are of chemical and biomedical importance. This re-
action was achieved by reacting Meldrum’s acid, aromatic
aldehydes, and a-thiocyanate ketones in the presence of a
catalytic amount of sodium ethoxide (NaOEt) under mi-
crowave irradiation, and avoided the use of ylides
(Scheme 1).
The most important and useful methods for the prepara-
tion of cyclopropanes include Simmons–Smith cyclopro-
panation,5 transition-metal-mediated carbene transfer
from aliphatic diazo compounds to carbon–carbon double
bonds,6 the combination of ylides with electron-deficient
olefins through Michael-initiated ring closure (MIRC),7,8
and base-catalyzed cyclopropanation reactions between
a-halogenated compounds and electron-deficient olefins.9
Moreover, the observation that cyano-substituted alkenes
can be converted into the corresponding cyclopropanes
with high stereoselectivity has also attracted great atten-
tion.8b,10 However, multicomponent reactions involving
the stereoselective synthesis of cyclopropane-spirosubsti-
tuted Meldrum’s acid have not been thoroughly explored.
There are only a few reports on the preparation of spiro-
substituted cis-1,2-cyclopropane, for example, the two-
component reaction between arsonium salt and the ben-
zylidene derivative of Meldrum’s acid,11a,b or triphenyl-
arsine-catalyzed reaction of bromides with the same
benzylidene derivative.11c These reactions suffer from
long reaction times, expensive and toxic catalysts, and
narrow substrate scope. Therefore, the search continues
for better derivatives of Meldrum’s acid that can be used
in a multicomponent strategy for the straightforward, eco-
O
Ar1
Ar2
O
O
O
Ar1
O
O
O
EtOH, NaOEt
MWI
+
+
H
O
O
SCN
O
Ar2
O
1
2
3
4
Scheme 1
a-Thiocyanate ketones have attracted great attention as in-
teresting intermediates due to their easy transformation
into highly valuable molecules that can be applied to both
organosulfur and heterocyclic chemistry.14 Our strategy
of synthesizing the highly multifunctionalized spiro-
substituted trans-cyclopropane 4 through the reaction of
Meldrum’s acid with an aldehyde and a-thiocyanate ke-
tones, was based on the fact that (1) Meldrum’s acid (1)
can be converted into the corresponding benzylidene de-
rivative (A) through base-catalyzed reaction with aromat-
ic aldehydes; (2) a-thiocyanate ketones 3, which possess
a strong nucleophilic center, favor reaction with the
SYNTHESIS 2011, No. 15, pp 2459–2465
x
x.
x
x
.
2
0
1
1
Advanced online publication: 08.07.2011
DOI: 10.1055/s-0030-1260096; Art ID: H34811SS
© Georg Thieme Verlag Stuttgart · New York

2460
F.-Y. Wu et al.
PAPER
Meldrum’s acid benzylidene derivative, providing the ro, fluoro, bromo or nitro groups were all found to be suit-
spirosubstituted trans-cyclopropanes because the thiocy- able for the reaction with Meldrum’s acid (1) and a-
anate acts as a good leaving group. This process avoids thiocyanate ketones 3 to obtain electron-deficient trans-
the use of arsenic reagent, thus minimizing environmental cyclopropanes in very good yields of 74–85% under mi-
pollution.
crowave heating. We also utilized 1-(3-nitrophenyl)-2-
thiocyanatoethanone instead of 1-(4-nitrophenyl)-2-thio-
cyanatoethanone for this reaction, and found that it can re-
act with 1 and various aromatic aldehydes 2 to afford the
corresponding spiro-cyclopropanes within 13–17 minutes
in very good yields (76–87%). Unfortunately, both a-thio-
cyanate ketones with electron-donating groups and alde-
hydes with electron-donating groups failed to give the
desired product 4.
Our initial experiments were focused on the one-pot,
three-component reaction of Meldrum’s acid (1), 1-(4-ni-
trophenyl)-2-thiocyanatoethanone (3a) and 4-bromobenz-
aldehyde (2a) using a range of inexpensive and readily
available base catalysts under microwave irradiation
(Table 1). It was found that when the reaction was carried
out in ethanol using sodium ethoxide as a base catalyst,
the desired product was obtained in a good yield (Table 1,
entry 5). Other bases did not give such satisfactory results.
The reaction was then performed in the presence of sodi-
um ethoxide at a range of temperatures in a sealed vessel
under microwave irradiation for 15 minutes. The yield of
product 4a was found to increase from 59 to 81% as the
temperature was increased from 75 to 95 °C (Table 1, en-
try 6). However, a further increase in reaction temperature
to 125 °C failed to improve the yield of product 4a. As a
result, the spirosubstituted trans-cyclopropanes can be
synthesized in a one-pot, three-component reaction that
avoids the need to separate intermediates and reduces the
number of associated time-consuming and costly purifica-
tion processes required.
Table 2 Synthesis of Compound 4 under Microwave Irradiationa
Entry
4
Ar1
Ar2
Time Yield
(min) (%)b
1
2
4a
4b
4c
4d
4e
4f
4-BrC6H4
3,4-Cl2C6H4
4-O2NC6H4
3-FC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
3-O2NC6H4
15
17
14
15
13
15
16
15
17
14
81
85
74
82
87
84
85
81
76
86
3
4
5
4-FC6H4
6
3-O2NC6H4
4-O2NC6H4
3-FC6H4
After optimization of the conditions, to assess this ap-
proach, particularly in regard to library construction, the
methodology was evaluated by using a range of a-thiocy-
anate ketones and aldehydes. As revealed in Table 2,
commercially available aromatic aldehydes bearing chlo-
7
4g
4h
4i
8
9
3-ClC6H4
3,4-Cl2C6H4
10
4j
Table 1 Catalyst Optimization for the Synthesis of 4aa
a Reaction conditions: NaOEt (0.3 equiv), 95 °C, EtOH, MW.
b Isolated yield.
Br
O2N
O
CHO
O
In order to further expand the scope of the present method,
Meldrum’s acid was replaced by malononitrile or cy-
anoacetamide (Scheme 2). Although many methods have
been reported for the synthesis of cyclopropanes,8 all of
the present methods are limited either by the inaccessibil-
ity of precursors, the requirement for multi-step process-
es, or by their operational complexity. Central to our
approach was the development of a simple method, using
readily available starting materials and simple experimen-
tal procedures, for the rapid synthesis of diverse cyclopro-
pane derivatives.
O
O
EtOH, NaOEt
+
O
+
O
MWI
O
O
O
O
Br
SCN
1
2a
3a
NO2
4a
Entry
Catalyst
none
Temp (°C) Time (min) Yield (%)b
1
2
3
4
5
6
7
75
75
15
15
15
15
15
15
15
trace
14
piperidine
K2CO3
Cs2CO3
NaOEt
NaOEt
NaOEt
Ar1
Ar2
CN
R
Ar1
75
20
CN
EtOH, NaOEt
MWI
O
+
+
H
O
O
75
29
R
Ar2
SCN
75
59
5
2
3
6
95
81
Scheme 2
125
78
Seven aldehydes and four a-thiocyanate ketones were
chosen to validate the approach through the construction
a Reactions performed in EtOH.
b Isolated yield.
Synthesis 2011, No. 15, 2459–2465 © Thieme Stuttgart · New York

PAPER
Functionalized Cyclopropane Derivatives
2461
Table 3 Synthesis of Compounds 6 under Microwave Irradiationa
Entry
Product
6a
Ar1
Ar2
R
Time (min)
Yield (%)b
1
2
4-BrC6H4
4-ClC6H4
4-FC6H4
Ph
CN
14
14
13
15
16
12
13
15
18
15
84
82
81
92
91
90
88
86
89
76
6b
6c
Ph
CN
3
Ph
CN
4
6d
6e
4-MeC6H4
4-MeOC6H4
4-HO-3-O2NC6H4
4-BrC6H4
4-BrC6H4
4-O2NC6H4
4-O2NC6H4
Ph
CN
5
Ph
CN
6
6f
Ph
CN
7
6g
4-MeOC6H4
4-ClC6H4
Ph
CN
8
6h
6i
CN
9
CONH2
CONH2
10
6j
3-ClC6H4
a Reaction conditions: K2CO3 (0.3 equiv), 95 °C, EtOH, MW.
b Isolated yield.
of a small library of cyclopropane derivatives. In all these
cases, the reactions proceeded smoothly to give the corre-
sponding cyclopropanes 6 in the presence of potassium
carbonate in good yields; the results are summarized in
Table 3.
The formation of 4 is expected to proceed through initial
condensation of the aldehyde with Meldrum’s acid to af-
ford the arylidene derivative A, which further undergoes
Michael addition in situ with a-thiocyanate ketones to
yield intermediate B, which is then cyclized to afford the
product 4 (Scheme 3).
Ar2
O
O
Ar1
Figure 1 ORTEP diagram of 6a
O
O
O
O
O
O
+
Ar1
SCN
diation. Particularly valuable features of this method in-
clude its operational simplicity, increased safety for
small-scale, high-speed syntheses, and broader substrate
scope.
O
O
O
1
2
A
O
O
Ar1
O
O
Ar1
Ar2
O
– SCN
O
O
O
Microwave irradiation was carried out with Initiator 2.5 Microwave
Synthesizers from Biotage, Uppsala, Sweden. Melting points were
determined in open capillaries and are uncorrected. IR spectra were
recorded with an FTIR Tensor 27 spectrometer in KBr pellets and
are reported in cm–1. 1H NMR spectra were measured with a Bruker
SCN
O
Ar2
4
B
Scheme 3
DPX 400 MHz spectrometer in DMSO-d6 or CDCl3 (100 MHz, 13
C
The structures of cyclopropanes 4 and 6 were confirmed NMR) with chemical shifts (d) given in ppm relative to TMS as in-
by their IR, 1H NMR, 13C NMR and mass spectra. Further-
ternal standard. ESI-MS was determined with an LCQ Advantage
HPLC/MS instrument (Thermo Finnigan). HRMS (ESI) were deter-
more, the attribution of relative stereochemistry was un-
mined with a microTOF-QII HRMS/MS instrument (Bruker). X-
equivocally determined by X-ray diffraction of a single
ray crystallographic analysis was performed with a Siemens
SMART CCD and a Siemens P4 diffractometer.
crystal of 6a (Figure 1).15
In summary, we have demonstrated a rapid and direct
method for the one-pot, three-component synthesis of
spiro-substituted trans-cyclopropanes as well as polysub-
stituted trans-cyclopropanes in good to excellent yields.
The MCRs were conducted by reacting readily available
and inexpensive starting materials under microwave irra-
Preparation of Electron-Deficient Cyclopropanes 4; General
Procedure
In a 10-mL reaction vial, Meldrum’s acid (1; 0.16 g, 1.1 mmol), al-
dehyde 2 (1 mmol), a-thiocyanate ketone 3 (1 mmol), NaOEt
(0.02 g, 0.3 mmol) and EtOH (2.0 mL) were mixed and stirred at r.t.
Synthesis 2011, No. 15, 2459–2465 © Thieme Stuttgart · New York

2462
F.-Y. Wu et al.
PAPER
The mixture was heated for 13–17 min at 95 °C under microwave
irradiation. Upon completion (reaction monitored by TLC), the re-
action mixture was cooled to r.t., the solid product was collected by
Büchner filtration and washed with acetone to give the pure product
4.
ArH), 4.40 (d, J = 9.6 Hz, 1 H, CH), 4.05 (d, J = 9.2 Hz, 1 H, CH),
1.77 (s, 3 H, CH3), 1.73 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 190.4, 164.3, 161.8 (1JC–F
=
241.7 Hz), 161.4, 150.2, 140.4, 133.4 (3JC–F = 8.4 Hz), 130.1
(3JC–F = 8.5 Hz), 129.5, 126.4 (4JC–F = 2.4 Hz), 124.1, 116.7 (2JC–F
=
22.9 Hz), 115.7 (2JC–F = 21.0 Hz), 105.8, 42.7, 38.3, 27.5, 26.9.
1-(4-Bromophenyl)-6,6-dimethyl-2-(4-nitrobenzoyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4a)
Yield: 383 mg (81%); yellow solid; mp 237–239 °C.
HRMS (ESI): m/z [M – H]+ calcd for C21H15FNO7: 412.0827;
found: 412.0826.
IR (KBr): 3003, 1767, 1733, 1694, 1603, 1528, 1456, 1392, 1351,
1321, 1269, 1213, 1187, 1109, 1066, 1008, 997, 916, 854, 841, 819,
735 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.40 (d, J = 8.4 Hz, 2 H, ArH),
8.15 (d, J = 8.8 Hz, 2 H, ArH), 7.63–7.58 (m, 4 H, ArH), 4.91 (d,
J = 9.2 Hz, 1 H, CH), 4.24 (d, J = 9.2 Hz, 1 H, CH), 1.68 (s, 3 H,
CH3), 1.67 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 190.5, 164.3, 161.5, 150.1,
140.4, 132.1, 131.1, 130.0, 129.5, 124.1, 122.4, 112.7, 105.8, 42.8,
38.3, 27.6, 26.9.
1-(4-Fluorophenyl)-6,6-dimethyl-2-(3-nitrobenzoyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4e)
Yield: 359 mg (87%); yellow solid; mp 164–166 °C.
IR (KBr): 3042, 1771, 1739, 1694, 1615, 1534, 1518, 1475, 1455,
1394, 1353, 1310, 1267, 1227, 1207, 1176, 1094, 1057, 1025, 999,
920, 837, 782, 730, 703 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.64 (s, 1 H, ArH), 8.51 (d,
J = 8.0 Hz, 1 H, ArH), 8.39–8.33 (m, 1 H, ArH), 7.90 (t, J = 8.0 Hz,
1 H, ArH), 7.71 (dd, J = 5.5, 8.4 Hz, 2 H, ArH), 7.25 (t, J = 8.8 Hz,
2 H, ArH), 4.96 (d, J = 9.2 Hz, 1 H, CH), 4.27 (d, J = 9.6 Hz, 1 H,
CH), 1.68 (s, 3 H, CH3), 1.66 (s, 3 H, CH3).
HRMS (ESI): m/z [M – H]+ calcd for C21H15BrNO7: 471.9991;
found: 472.0026.
13C NMR (100 MHz, DMSO-d6): d = 189.9, 164.3, 162.3 (1JC–F
=
244.4 Hz), 161.5, 148.0, 137.1, 134.2, 132.2 (3JC–F = 8.4 Hz),
130.8, 127.8, 126.8 (4JC–F = 2.7 Hz), 122.4, 115.7 (2JC–F = 21.5 Hz),
105.7, 42.9, 38.1, 27.5, 26.9.
1-(3,4-Dichlorophenyl)-6,6-dimethyl-2-(4-nitrobenzoyl)-5,7-di-
oxaspiro[2.5]octane-4,8-dione (4b)
Yield: 394 mg (85%); yellow solid; mp 224–225 °C.
HRMS (ESI): m/z [M – H]+ calcd for C21H15FNO7: 412.0827;
found: 412.0828.
IR (KBr): 1766, 1731, 1694, 1604, 1556, 1528, 1481, 1449, 1393,
1379, 1340, 1314, 1279, 1225, 1110, 1066, 996, 921, 859, 842, 817,
744 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.40 (d, J = 8.4 Hz, 2 H, ArH),
8.16 (d, J = 8.4 Hz, 2 H, ArH), 7.95 (s, 1 H, ArH), 7.71–7.67 (m,
2 H, ArH), 4.97 (d, J = 9.2 Hz, 1 H, CH), 4.29 (d, J = 9.6 Hz, 1 H,
CH), 1.70 (s, 3 H, CH3), 1.68 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 191.0, 178.8, 166.4, 163.4,
163.3, 150.6, 138.8, 131.9, 131.6, 129.5, 125.3, 125.2, 124.1, 105.9,
41.7, 38.5, 27.6, 26.9.
6,6-Dimethyl-1-(3-nitrobenzoyl)-2-(3-nitrophenyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4f)
Yield: 370 mg (84%); yellow solid; mp 230–231 °C.
IR (KBr): 3086, 3005, 1760, 1736, 1696, 1615, 1536, 1489, 1437,
1397, 1352, 1319, 1264, 1227, 1200, 1094, 1063, 1000, 918, 841,
709 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.68–8.67 (m, 1 H, ArH), 8.58
(s, 1 H, ArH), 8.52 (dd, J = 1.6, 8.0 Hz, 1 H, ArH), 8.38 (d,
J = 8.0 Hz, 1 H, ArH), 8.25 (dd, J = 8.0, 1.6 Hz, 1 H, ArH), 8.16 (d,
J = 7.6 Hz, 1 H, ArH), 7.90 (t, J = 8.0 Hz, 1 H, ArH), 7.73 (t,
J = 8.0 Hz, 1 H, ArH), 5.13 (d, J = 9.6 Hz, 1 H, CH), 4.47 (d,
J = 9.6 Hz, 1 H, CH), 1.71 (s, 3 H, CH3), 1.68 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 189.7, 164.0, 161.7, 148.0,
147.7, 137.0, 136.8, 134.3, 133.2, 130.8, 129.7, 127.8, 124.6, 123.6,
122.6, 112.7, 105.9, 41.6, 38.4, 27.7, 27.0.
HRMS (ESI): m/z [M – H]+ calcd for C21H15N2O9: 439.0772; found:
439.0737.
HRMS (ESI): m/z [M – H]+ calcd for C21H14Cl2NO7: 462.0142;
found: 462.0144.
6,6-Dimethyl-1-(4-nitrobenzoyl)-2-(4-nitrophenyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4c)
Yield: 326 mg (74%); yellow solid; mp 216–218 °C.
IR (KBr): 3116, 1767, 1732, 1694, 1604, 1526, 1454, 1390, 1349,
1321, 1271, 1212, 1110, 1067, 995, 917, 848, 792, 702 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.41 (d, J = 8.8 Hz, 2 H, ArH),
8.27 (d, J = 8.4 Hz, 2 H, ArH), 8.18 (d, J = 8.8 Hz, 2 H, ArH), 7.94
(d, J = 8.8 Hz, 2 H, ArH), 5.02 (d, J = 9.6 Hz, 1 H, CH), 4.42 (d,
J = 9.2 Hz, 1 H, CH), 1.70 (s, 3 H, CH3), 1.68 (s, 3 H, CH3).
6,6-Dimethyl-1-(3-nitrobenzoyl)-2-(4-nitrophenyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4g)
Yield: 374 mg (85%); yellow solid; mp 221–223 °C.
13C NMR (100 MHz, DMSO-d6): d = 190.2, 164.1, 161.5, 150.2,
147.6, 140.3, 138.4, 131.4, 129.6, 124.1, 123.1, 106.0, 41.7, 38.7,
27.7, 26.9.
HRMS (ESI): m/z [M – H]+ calcd for C21H15N2O9: 439.0772; found:
439.0740.
IR (KBr): 3089, 1774, 1743, 1698, 1614, 1535, 1520, 1449, 1396,
1346, 1304, 1264, 1221, 1207, 1177, 1088, 1054, 1022, 995, 922,
849, 707 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.67–8.65 (m, 1 H, ArH),
8.54–8.51 (m, 1 H, ArH), 8.39–8.36 (m, 1 H, ArH), 8.27 (d,
J = 8.8 Hz, 2 H, ArH), 7.95 (d, J = 8.8 Hz, 2 H, ArH), 7.90 (t,
J = 8.0 Hz, 1 H, ArH), 5.07 (d, J = 9.6 Hz, 1 H, CH), 4.44 (d,
J = 9.6 Hz, 1 H, CH), 1.70 (s, 3 H, CH3), 1.68 (s, 3 H, CH3).
1-(3-Fluorophenyl)-6,6-dimethyl-2-(4-nitrobenzoyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4d)
Yield: 339 mg (82%); yellow solid; mp 210–212 °C.
IR (KBr): 1767, 1733, 1693, 1625, 1528, 1490, 1456, 1396, 1385,
1323, 1285, 1202, 1065, 998, 920, 842, 782, 760, 716 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.84 (s, 1 H, ArH), 8.48 (d,
J = 8.4 Hz, 1 H, ArH), 8.28 (d, J = 7.6 Hz, 1 H, ArH), 7.74 (t,
J = 8.0 Hz, 1 H, ArH), 7.43–7.35 (m, 3 H, ArH), 7.34–7.30 (m, 1 H,
13C NMR (100 MHz, DMSO-d6): d = 189.6, 164.0, 161.6, 148.0,
147.6, 138.4, 136.9, 134.3, 131.4, 130.9, 127.9, 123.1, 122.6, 119.6,
105.9, 41.6, 38.4, 27.7, 27.0.
HRMS (ESI): m/z [M – H]+ calcd for C21H15N2O9: 439.0772; found:
439.0800.
Synthesis 2011, No. 15, 2459–2465 © Thieme Stuttgart · New York

PAPER
Functionalized Cyclopropane Derivatives
2463
1-(3-Fluorophenyl)-6,6-dimethyl-2-(3-nitrobenzoyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4h)
Yield: 335 mg (81%); yellow solid; mp 232–233 °C.
2-Benzoyl-3-(4-bromophenyl)cyclopropane-1,1-dicarbonitrile
(6a)8c
Yield: 294 mg (84%); yellow solid; mp 156–158 °C (Lit.8c 169–
170 °C).
IR (KBr): 3084, 1759, 1737, 1697, 1615, 1592, 1537, 1477, 1445,
1397, 1385, 1353, 1314, 1284, 1234, 1215, 1152, 1089, 1064, 1023,
1000, 912, 899, 865, 808, 790 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.83 (s, 1 H, ArH), 8.49 (dd,
J = 0.8, 8.0 Hz, 1 H, ArH), 8.27 (d, J = 7.6 Hz, 1 H, ArH), 7.74 (t,
J = 8.0 Hz, 1 H, ArH), 7.51 (m, 2 H, ArH), 7.28 (s, 2 H, ArH), 4.36
(d, J = 9.6 Hz, 1 H, CH), 4.02 (d, J = 9.2 Hz, 1 H, CH), 1.78 (s, 3 H,
CH3), 1.73 (s, 3 H, CH3).
2-Benzoyl-3-(4-chlorophenyl)cyclopropane-1,1-dicarbonitrile
(6b)8d
Yield: 251 mg (82%); yellow solid; mp 165–168 °C (Lit.8d 175–
176 °C).
2-Benzoyl-3-(4-fluorophenyl)cyclopropane-1,1-dicarbonitrile
(6c)8e
Yield: 235 mg (81%); yellow solid; mp 151–152 °C (Lit.8e 156 °C).
13C NMR (100 MHz, DMSO-d6): d = 189.9, 164.3, 161.8 (1JC–F
=
241.4 Hz), 161.5, 148.0, 137.0, 134.3, 133.4 (3JC–F = 8.3 Hz),
130.8, 130.1 (3JC–F = 8.5 Hz), 127.9, 126.4 (4JC–F = 2.3 Hz), 122.5,
116.7 (2JC–F = 22.8 Hz), 115.7 (2JC–F = 20.4 Hz), 105.8, 42.5, 37.9,
27.5, 26.9.
2-Benzoyl-3-p-tolylcyclopropane-1,1-dicarbonitrile (6d)8c
Yield: 263 mg (92%); yellow solid; mp 156–157 °C (Lit.8c 161–
162 °C).
HRMS (ESI): m/z [M – H]+ calcd for C21H15FNO7: 412.0827;
found: 412.0800.
2-Benzoyl-3-(4-methoxyphenyl)cyclopropane-1,1-dicarboni-
trile (6e)
Yield: 275 mg (91%); yellow solid; mp 154–156 °C.
1-(3-Chlorophenyl)-6,6-dimethyl-2-(3-nitrobenzoyl)-5,7-dioxa-
spiro[2.5]octane-4,8-dione (4i)
Yield: 326 mg (76%); yellow solid; mp 222–223 °C.
IR (KBr): 3039, 2246, 1679, 1613, 1598, 1581, 1519, 1493, 1468,
1450, 1408, 1344, 1297, 1254, 1228, 1183, 1029, 1000, 835, 821,
741, 683, 653, 631 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.27–8.25 (m, 2 H, ArH), 7.79
(t, J = 7.6 Hz, 1 H, ArH), 7.68–7.61 (m, 4 H, ArH), 7.01 (d,
J = 8.8 Hz, 2 H, ArH), 5.00 (d, J = 8.4 Hz, 1 H, CH), 4.03 (d,
J = 8.4 Hz, 1 H, CH), 3.80 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): d = 190.4, 159.9, 135.3, 134.7,
130.4, 129.0, 122.2, 114.0, 113.0, 112.9, 55.2, 38.4, 34.8, 15.1.
HRMS (ESI): m/z [M + Na]+ calcd for C19H14N2NaO2: 325.0948;
IR (KBr): 3087, 1761, 1739, 1694, 1628, 1535, 1444, 1397, 1352,
1315, 1282, 1263, 1223, 1201, 1092, 1061, 1021, 1000, 922, 877,
839, 792, 734, 707 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.85 (s, 1 H, ArH), 8.48 (m, 1 H,
ArH), 8.29 (d, J = 7.6 Hz, 1 H, ArH), 7.74 (t, J = 7.6 Hz, 1 H, ArH),
7.40 (dd, J = 7.4, 13.7 Hz, 1 H, ArH), 7.22 (d, J = 8.0 Hz, 1 H,
ArH), 7.14–7.09 (m, 2 H, ArH), 4.40 (d, J = 9.6 Hz, 1 H, CH), 4.06
(d, J = 9.2 Hz, 1 H, CH), 1.77 (s, 3 H, CH3), 1.73 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 189.8, 164.2, 161.5, 148.0,
137.0, 134.2, 133.2, 132.9, 130.8, 129.9, 129.6, 129.0, 127.8, 122.5,
112.7, 105.8, 42.3, 38.0, 27.6, 27.0.
HRMS (ESI): m/z [M – H]+ calcd for C21H15ClNO7: 428.0521;
found: 428.0511.
found: 325.0939.
2-Benzoyl-3-(4-hydroxy-3-nitrophenyl)cyclopropane-1,1-dicar-
bonitrile (6f)
Yield: 300 mg (90%); yellow solid; mp 212–214 °C.
IR (KBr): 3095, 2248, 1676, 1630, 1594, 1542, 1494, 1447, 1414,
1345, 1325, 1258, 1230, 1177, 1080, 980, 845, 753, 706, 687 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 11.35 (s, 1 H, OH), 8.30–8.27
(m, 3 H, ArH), 7.88 (dd, J = 2.0, 8.8 Hz, 1 H, ArH), 7.81–7.77 (m,
1 H, ArH), 7.66 (t, J = 8.0 Hz, 2 H, ArH), 7.19 (d, J = 8.8 Hz, 1 H,
ArH), 5.11 (d, J = 8.0 Hz, 1 H, CH), 4.12 (d, J = 8.0 Hz, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 190.0, 152.2, 13.7, 135.7,
135.3, 134.7, 129.1, 129.0, 125.9, 121.7, 119.1, 112.8, 112.6, 37.1,
34.7, 15.3.
1-(3,4-Dichlorophenyl)-6,6-dimethyl-2-(3-nitrobenzoyl)-5,7-di-
oxaspiro[2.5]octane-4,8-dione (4j)
Yield: 398 mg (86%); yellow solid; mp 229–230 °C.
IR (KBr): 3081, 1760, 1738, 1697, 1615, 1580, 1539, 1478, 1450,
1395, 1351, 1311, 1280, 1225, 1202, 1136, 1088, 1063, 1035, 998,
923, 910, 872, 806 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.84 (s, 1 H, ArH), 8.51–8.49 (m,
1 H, ArH), 8.32–8.28 (m, 2 H, ArH), 7.76 (t, J = 8.0 Hz, 2 H, ArH),
7.64 (t, J = 7.6 Hz, 1 H, ArH), 4.45 (d, J = 9.2 Hz, 1 H, CH), 4.19
(d, J = 9.2 Hz, 1 H, CH), 1.79 (s, 3 H, CH3), 1.75 (s, 3 H, CH3).
HRMS (ESI): m/z [M + H]+ calcd for C18H12N3O4: 334.0823; found:
334.0833.
13C NMR (100 MHz, DMSO-d6): d = 189.7, 164.1, 161.6, 148.0,
136.9, 134.3, 131.9, 131.8, 131.6, 130.9, 130.8, 130.5, 130.3, 127.9,
122.5, 105.8, 41.5, 38.1, 27.6, 27.0.
HRMS (ESI): m/z [M – H]+ calcd for C21H14Cl2NO7: 462.0142;
found: 462.0143.
2-(4-Bromophenyl)-3-(4-methoxybenzoyl)cyclopropane-1,1-di-
carbonitrile (6g)
Yield: 334 mg (88%); yellow solid; mp 153–154 °C.
IR (KBr): 3034, 2251, 1659, 1604, 1573, 1512, 1494, 1428, 1391,
1341, 1260, 1173, 1113, 1074, 1012, 957, 850, 791, 743, 626 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.27 (d, J = 8.8 Hz, 2 H, ArH),
7.67 (s, 4 H, ArH), 7.17 (d, J = 8.8 Hz, 2 H, ArH), 5.03 (d,
J = 8.4 Hz, 1 H, CH), 4.07 (d, J = 8.0 Hz, 1 H, CH), 3.91 (s, 3 H,
OCH3).
13C NMR (100 MHz, DMSO-d6): d = 190.6, 164.0, 160.3, 132.7,
132.1, 131.0, 130.4, 128.3, 127.1, 114.2, 114.0, 113.0, 82.3, 55.7,
41.6.
Preparation of Cyclopropanes 6; General Procedure
In a 10-mL Emrys reaction vial, the malononitrile or cyanoacet-
amide 5 (1.5 mmol), aldehyde 2 (1 mmol), a-thiocyanate ketone 3
(1 mmol), K2CO3 (0.04 g, 0.3 mmol) and EtOH (2.0 mL) were
mixed and stirred at r.t. The mixture was heated for 12–18 min at
95 °C under microwave irradiation. Upon completion (reaction
monitored by TLC), the reaction mixture was cooled to r.t. and the
solid product was collected by Büchner filtration and subsequently
washed with acetone to give the pure product 6.
HRMS (ESI): m/z [M + H]+ calcd for C19H14BrN2O2: 381.0234;
found: 381.0248.
Synthesis 2011, No. 15, 2459–2465 © Thieme Stuttgart · New York

2464
F.-Y. Wu et al.
PAPER
2-(4-Bromophenyl)-3-(4-chlorobenzoyl)cyclopropane-1,1-di-
carbonitrile (6h)
Yield: 330 mg (86%); yellow solid; mp 144–146 °C.
References
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IR (KBr): 3073, 2258, 1667, 1592, 1490, 1425, 1403, 1331, 1299,
1250, 1179, 1092, 1068, 1009, 968, 882, 845, 821, 781, 713 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.30 (d, J = 8.4 Hz, 2 H, ArH),
7.73 (d, J = 8.4 Hz, 2 H, ArH), 7.67 (s, 4 H, ArH), 5.07 (d,
J = 8.4 Hz, 1 H, CH), 4.09 (d, J = 8.4 Hz, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 189.3, 139.7, 134.1, 131.5,
131.3, 131.0, 130.1, 129.1, 122.6, 112.7, 112.6, 37.9, 34.4, 15.5.
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HRMS (ESI): m/z [M – H]+ calcd for C18H9BrClN2O: 382.9581;
found: 382.9575.
2-Benzoyl-1-cyano-3-(4-nitrophenyl)cyclopropanecarbox-
amide (6i)
Yield: 298 mg (89%); yellow solid; mp 213–214 °C.
IR (KBr): 3439, 3398, 3308, 3200, 2185, 1687, 1646, 1622, 1578,
1507, 1448, 1348, 1306, 1246, 1186, 1107, 1040, 978, 894, 849,
785 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.25 (d, J = 8.4 Hz, 2 H, ArH),
7.84 (d, J = 7.6 Hz, 2 H, ArH), 7.65–7.57 (m, 3 H, ArH), 7.49 (t,
J = 7.6 Hz, 2 H, ArH), 5.21 (d, J = 4.4 Hz, 1 H, CH), 4.97 (d,
J = 4.8 Hz, 1 H, CH), 4.84 (s, 2 H, NH2).
13C NMR (100 MHz, DMSO-d6): d = 192.5, 161.8, 149.5, 146.9,
134.3, 133.6, 128.9, 128.8, 128.7, 123.8, 117.9, 70.0, 55.2, 50.2.
HRMS (ESI): m/z [M – H]+ calcd for C18H12N3O4: 334.0822; found:
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334.0821.
2-(3-Chlorobenzoyl)-1-cyano-3-(4-nitrophenyl)cyclopropane-
carboxamide (6j)
Yield: 280 mg (76%); yellow solid; mp 236–238 °C.
IR (KBr): 3413, 3327, 3222, 2186, 1692, 1636, 1568, 1512, 1409,
1347, 1221, 1109, 1014, 981, 889, 805, 745, 689 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.28 (d, J = 8.8 Hz, 2 H, ArH),
8.02 (s, 1 H, ArH), 7.93 (d, J = 7.6 Hz, 1 H, ArH), 7.74–7.68 (m,
3 H, ArH), 7.56 (t, J = 8.0 Hz, 1 H, ArH), 7.33 (s, 2 H, NH2), 5.36
(d, J = 2.0 Hz, 1 H, CH), 4.88 (d, J = 1.8 Hz, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): d = 191.8, 161.6, 149.4, 146.9,
136.4, 133.8, 133.3, 130.8, 128.9, 128.3, 127.3, 123.8, 117.9, 70.0,
55.3, 50.1.
HRMS (ESI): m/z [M – H]+ calcd for C18H11ClN3O4: 368.0432;
found: 368.0411.
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Supporting Information for this article is available online at
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Acknowledgment
We are grateful for financial support from the National Science
Foundation of China (21072163 and 21002083), PAPD of Jiangsu
Higher Education Institutions, Sci. Foundation in Interdisciplinary
Major Res. Project of XZNU (No. 09XKXK01), and Graduate
Foundation of XZNU (No. 2010YLB031).
Synthesis 2011, No. 15, 2459–2465 © Thieme Stuttgart · New York

PAPER
Functionalized Cyclopropane Derivatives
2465
(14) (a) Bisogno, F. R.; Cuetos, A. Green Chem. 2009, 11, 452.
(b) El-Din, A. S. Sulfur Lett. 2003, 26, 35.
(15) Single-crystal growth was carried out in ethanol at room
temperature. X-ray crystallographic analysis was performed
with a Siemens SMART CCD and a Siemens P4
C18H11BrN2O; formula weight: 351.20; crystal dimensions
0.48 × 0.40 × 0.30 mm; triclinic; space group P1;
a = 8.0590(10) Å, b = 10.3631(12) Å, c = 11.2581(13) Å,
a = 63.9500(10)°, b = 69.676(2)°, g = 67.348(2)°;
m = 2.702 mm–1; V = 761.34(16) Å3; Z = 2;
diffractometer (graphite monochromator, MoKa radiation
l = 0.71073 Å). Crystal data for 6a: Empirical formula:
D(calcd) = 1.532 Mg/m3; F(000) = 352, S = 1.058,
R1 = 0.0526, wR2 = 0.1288
Synthesis 2011, No. 15, 2459–2465 © Thieme Stuttgart · New York