Organocatalytic conjugate addition of 1-bromonitroalkanes to α,β-unsaturated aldehydes: synthesis of nitrocyclopropanes

Article abstract of DOI:10.1016/j.tet.2008.11.060

A variety of secondary amines were studied as the catalyst in the conjugate addition of 1-bromonitromethane to α,β-unsaturated aldehydes. Proline was identified as the best catalyst for this reaction. MeOH/AcONa system was found to provide much better yie

Full text of DOI:10.1016/j.tet.2008.11.060

Tetrahedron 65 (2009) 802–806
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Tetrahedron
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Organocatalytic conjugate addition of 1-bromonitroalkanes to
aldehydes: synthesis of nitrocyclopropanes
a,b-unsaturated
*
Jun-min Zhang, Zhi-peng Hu, Shuang-qi Zhao, Ming Yan
The Industrial Institute of Fine Chemicals and Synthetic Drugs, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of secondary amines were studied as the catalyst in the conjugate addition of 1-bromonitro-
Received 22 September 2008
Received in revised form 7 November 2008
Accepted 18 November 2008
Available online 25 November 2008
methane to
MeOH/AcONa system was found to provide much better yields than CHCl3/Et3N system reported before.
Good yields of nitrocyclopropane products were obtained with a variety of -aryl acroleins. Several
substituted 1-bromonitromethanes were also examined in the reaction. Both 1-bromonitroethane and 1-
phenyl-1-bromonitromethane gave the corresponding nitrocyclopropanes in good yields. The diastereo-
selectivity of the reaction was strongly affected by the steric hindrance of 1-bromonitroalkanes.
Ó 2008 Elsevier Ltd. All rights reserved.
a,b-unsaturated aldehydes. Proline was identified as the best catalyst for this reaction.
b
Keywords:
Nitrocyclopropane
Synthesis
Conjugate addition
1-Bromonitroalkane
a,b-Unsaturated aldehyde
Organocatalysis
1. Introduction
ketones via a LUMO lowing mechanism.13 Ley and co-workers
reported the first organocatalytic nitrocyclopropanation of cyclo-
Cyclopropane structural units have been widely found in a great
number of drugs and natural products.1 These compounds exhibit
various useful biological activities, such as enzyme inhibition, in-
secticidal, antifungal, herbicidal, antimicrobial, antitumor, and an-
tiviral activities.2 The small and rigid ring structure of
cyclopropanes is also appealing for the preparation of complex
hexenone with bromonitromethane using proline tetrazole cata-
lyst.14 The corresponding nitrocyclopropanes were obtained in
good yields and enantioselectivities, however, application of pro-
line and several other secondary amines in this reaction only pro-
vided low yield of products. Encouraged by this work, we explored
the conjugate addition of bromonitromethane to a,b-unsaturated
molecules with
a
defined orientation of pendant functional
aldehydes catalyzed by secondary amines. The expected nitro-
cyclopropanes were obtained in good yields and these results are
groups.3 In addition the strain associated with the three-membered
ring allows cyclopropanes to undergo a variety of synthetically
useful ring-opening reactions.4,5 The synthetic methods of cyclo-
propanes have been extensively studied,6,7 including the asym-
metric synthetic versions.8 Nitrocyclopropanes are a class of special
cyclopropane compounds. They are presented in some natural
products, such as the peptidolactone hormaomycin and the
broad-spectrum antibiotic Trovafloxacin.9,10 Furthermore nitro-
cyclopropanes can be converted into a wide range of useful com-
pounds.11 Several synthetic methods of nitrocyclopropanes have
been developed, such as the reaction of nitroalkyl carbene with
´
reported in this paper. During our initial study, Cordova and co-
workers reported the asymmetric nitrocyclopropanation of a,b-
unsaturated aldehydes with bromonitromethane using chiral
secondary amines as the catalyst.15
2. Results and discussion
Initially a number of secondary amines (I–V) were examined as
the catalyst for the reaction of cinnamaldehyde (1a) and bromo-
nitromethane (2a). The nitrocyclopropanes 3a and 3a0 were
obtained in methanol with AcONa as the base additive. The ex-
periment results of the catalyst screen are summarized in Table 1.
The relative configurations of 3a and 3a0 were assigned via NOESY
alkenes, conjugate addition of
a-halogenated nucleophiles to
nitroolefins.12 In recent years secondary amines, for example, pro-
line and its derivatives, imidazolidinones, are found to be extremely
powerful catalysts for activation of a,b-unsaturated aldehydes and
´
spectra and were consistent with the data reported by Cordova and
co-workers.15
The reaction did not occur in the absence of secondary amine
catalysts. Piperidine (I), morpholine (II), and pyrrolidine (III)
* Corresponding author. Tel./fax: þ86 20 39332672.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.060

J.-m. Zhang et al. / Tetrahedron 65 (2009) 802–806
803
Table 1
Table 3
The reaction of 1a and 2a catalyzed by secondary aminesa
Reaction of 1-bromonitroalkanes (2) with cinnamaldehyde (1a) catalyzed by
prolinea
NO2
Catalyst (10 mol%)
AcONa (100 mol%)
NO2
CHO
( )-Proline (10 mol%)
O2N
Ph
R
O2N
Ph
R
R
CHO
+
+
Br
NO2
O
AcONa (100 mol%)
NO2
MeOH, r.t., 3h
MeOH, r.t.
+
+
CHO
Ph
CHO
Ph
CHO
Ph
Br
CHO
Ph
1a
2a
3a
3a'
1a
2
3
3'
COOH
COOMe
N
H
Entry
1-Bromonitroalkane (2)
Product (3/30)b
Yieldc/%
N
H
N
H
N
H
N
H
1
2
3
4
5
R¼H (2a)
3a/3a0 (61/39)
3i/3i0 (16/84)
3j/3j0 (<1/99)
3k/3k0 (6/94)
d
62
63
I
II
III
IV
V
R¼CH3 (2b)
R¼Ph (2c)
R¼Et (2d)
60
29d
de
c
Entry
Catalyst
Time/h
Yieldb/%
3a/3a0
R¼COOEt (2e)
1
2
3
4
5
6
7
8
I
II
5
5
5
1
3
48
8
5
31
37
49/51
50/50
51/49
45/55
61/39d
66/34
53/47
52/48f
a
Cinnamaldehyde 1a (1 mmol), 1-bromonitroalkane 2 (1.1 mmol), AcONa
III
IV
IV
IV
IV
V
40
64
67
71
(1.1 mmol), (ꢀ)-proline (0.1 mmol), and 4.0 mL methanol were used in the reaction.
b
The ratios of 3/30 were determined by GC analysis.
c
Isolated yield of combined 3 and 30.
d
The yield was determined by 1H NMR.
No nitrocyclopropane product could be isolated.
39e
29
e
a
Cinnamaldehyde 1a (0.25 mmol), bromonitromethane 2a (0.26 mmol), catalyst
For a comparison, we carried out the reaction under this condition.
The reaction was found to be rather slow and only low yield of 3a
and 3a0 was obtained after 8 h (Table 1, entry 7). The result suggests
that MeOH/AcONa is the better reaction system than CHCl3/Et3N.
The carboxylic acid group of proline seemed having important ef-
fect on its catalytic activity, since proline methyl ester (V) showed
significantly lower catalytic activity (Table 1, entry 8).
(0.025 mmol), AcONa (0.26 mmol), and 1.0 mL methanol were used.
b
GC yield of combined 3a and 3a0.
c
The ratios of 3a/3a0 were determined by GC analysis.
The ee values of 3a and 3a0 were 5.2% and 10.5%, respectively, as determined by
d
chiral GC.
e
Cinnamaldehyde 1a (0.25 mmol), bromonitromethane 2a (0.26 mmol), proline
(0.025 mmol), Et3N (0.26 mmol), and 1.0 mL CHCl3 were used in this case.
f
The ee values of 3a and 3a0 were 5.6% and 7.5%, respectively.
A variety of
reaction with bromonitromethane and the results are listed in
Table 2. Cinnamaldehyde and other -aryl acroleins are suitable
substrates for the reaction and good yields of nitrocyclopropanes (3
and 30) were obtained. The electron-withdrawing and electron-
donating substituents on phenyl ring were tolerated very well
(Table 2, entries 2–8). Diastereoselectivities of the reaction were
low and generally 3 were obtained in excess. Acrolein and croto-
naldehyde were also examined in the reaction, however, no nitro-
cyclopropane products could be isolated.
A couple of substituted bromonitromethanes were explored in
the reaction and the results are summarized in Table 3. 1-Bromo-
nitroethane (2b) and 1-bromo-1-phenylnitromethane (2c) also
provided good yield of nitrocyclopropanes.
Interestingly, diastereoselectivities of the reaction were
inversed with the introduction of substituents and 30 was obtained
as the major isomer. In the case of 1-bromo-1-phenylnitromethane
(2c), 3j0 was afforded as the only isomer. The relative configurations
of these compounds were assigned by NOSEY spectra (Fig. 1) and
H–H coupling constants.
a,b-unsaturated aldehydes were investigated in the
provided a mixture of 3a and 3a0 in low yields. (S)-Proline (IV) was
found to be better catalyst for the reaction. Compounds 3a and 3a0
were obtained in 64% yield after 1 h (Table 1, entry 4). The yield
could be improved slightly with extension of reaction time (Table 1,
entries 5 and 6). It is noted that the ratio of 3a/3a0 increased with
the reaction process (Table 1, entries 4–6). Compound 3a seemed to
be the thermodynamically favorable product and 3a0 seemed to be
the kinetically favorable product. The epimerization of 3a0 to 3a was
supposed through the base-catalyzed enolization of aldehyde or
proline-catalyzed formation of the enamine intermediate. The
enantioselectivity of the reaction was very low (5.2% ee and 10.5%
ee for 3a and 3a0, respectively) as determined by chiral GC analysis.
b
´
In the study of Cordova and co-workers, the same reaction was
carried out in CHCl3/Et3N system with (S)-proline as the catalyst.15
Table 2
Reaction of
by prolinea
a,b-unsaturated aldehydes (1) with bromonitromethane (2a) catalyzed
While 1-bromonitropropane (2d) was used, the corresponding
nitrocyclopropanes 3k/3k0 were obtained in low yield. An in-
separable by-product 4 was observed by 1H NMR and GC–MS
analyses (34% yield as estimated by 1H NMR), which was proposed
to be the original addition product without elimination of the
NO2
NO2
( )-Proline (10 mol%)
CHO
AcONa (100 mol%)
+
+
Br
NO2
MeOH, r.t., 3h
R
CHO
R
CHO
R
1
2a
3
3'
Entry
Aldehyde (1)
Product (3/30)b
Yieldc/%
1
2
3
4
5
6
7
8
R¼Ph (1a)
3a/3a0 (61/39)
3b/3b0 (62/38)
3c/3c0 (53/47)
3d/3d0 (58/42)
3e/3e0 (53/47)
3f/3f0 (58/42)
3g/3g0 (55/45)
3h/3h0 (60/40)
62
61
65
58
60
61
68
67
O2N
R¼4-NO2C6H4 (1b)
R¼4-CH3C6H4 (1c)
R¼4-OMeC6H4 (1d)
R¼2-OMeC6H4 (1e)
R¼4-ClC6H4 (1f)
R¼3-ClC6H4 (1g)
R¼2-ClC6H4 (1h)
0.90
CH3
O2N
CH3
H
O2N
4.17
H
H
H
H
2.47
H
H
H
H
H
O
O
H
H
O
0.31
2.67
1.0
3j'
a
3i
3i'
a,b-Unsaturated aldehyde 1 (1 mmol), bromonitromethane 2a (1.1 mmol),
AcONa (1.1 mmol), (ꢀ)-proline (0.1 mmol), and 4.0 mL methanol were used in the
1H NMR 9.29 ppm (CHO) 1H NMR 9.64 ppm (CHO) 1H NMR 9.74 ppm (CHO)
reaction.
b
The ratios of 3/30 were determined by GC analysis.
Isolated yield of combined 3 and 30.
Figure 1. The NOESY spectral analysis of compounds 3i, 3i0, and 3j0 (the value beside
the bended arrow indicates the intensity of NOE signal).
c

804
J.-m. Zhang et al. / Tetrahedron 65 (2009) 802–806
Br
nitrocyclopropanes were obtained with a number of b-aryl
O2N
acroleins. Several substituted 1-bromonitromethanes, such as 1-
bromonitroethane and 1-phenyl-1-bromonitromethane, are also
suitable substrates for this transformation. The diastereo-
selectivity of the reaction is strongly affected by the steric hin-
drance of 1-bromonitroalkanes. Further studies are underway to
develop efficient asymmetric catalytic nitrocyclopropanation
reactions and to explore other catalytic reactions with 1-
bromonitroalkanes.
CHO
4
Figure 2.
bromide (Fig. 2).16 The big steric hindrance of 4 hampered the
consequent intramolecular cyclopropanation reaction. The similar
compound was also reported in the reaction of bromonitromethane
with enones.14a The reaction with ethyl 2-bromo-nitroacetate (2e)
was unsuccessful and very complicated products were formed,
which did not allow for further separation and qualitative
determination.
4. Experimental section
4.1. General details
All solvents were used as commercial anhydrous grade without
further purification. The flash column chromatography was carried
out over silica gel (230–400 mesh), purchased from Qingdao
Haiyang Chemical Co., Ltd. Melting points were recorded on an
electrothermal digital melting point apparatus. 1H and 13C NMR
spectra were recorded on a Bruker AVANCE 400 MHz spectrometer
as solutions in CDCl3. Chemical shifts in 1H NMR spectra are
Base on the present experimental results and the comparison
15
´
with the results of Cordova and co-workers, a reaction mecha-
nism of proline-catalyzed nitrocyclopropanation is proposed
(Scheme 1). Cinnamaldehyde is activated via formation of iminium
cation (VI) with proline, which is attacked by 1-bromonitroalkane
anion. Hydrogen bonding between the carboxyl group of proline
with the nitro group is suggested to provide a pre-organized
reported in parts per million (ppm, d) downfield from the internal
standard Me4Si (TMS,
spectra are reported relative to the central line of the chloroform
d
¼0 ppm). Chemical shifts in 13C NMR
signal (
d
¼77.0 ppm). High-resolution mass spectra were obtained
O
O
R
with the Thermo MAT 95XP mass spectrometer. The low resolution
mass spectra were obtained at the Thermo Trace GC Ultra-DSQII
and Agilent 6120 (Quadrupole LC-MS) mass spectrometer. Infrared
(IR) spectra were recorded on a Bruker Tensor 37 spectrophoto-
meter. Data are represented as follows: frequency of absorption
(cmꢁ1), intensity of absorption (vs¼very strong, s¼strong,
m¼medium, w¼weak). GC yield of nitrocyclopropanes and enan-
tiomeric excesses were determined by GC (Agilent 6890N) using
a Varian capillary column CP-Chirasil-DexCB (25 mꢂ0.25 mm,
COOH
H
O
O
COOH
N
H
O
N
Br
NO2
Br
R
N
N
Ph
Ph
VI
Ph
O
O
COOH
N
O
N
H
- Br -
O
H2O
Br
NO2
R
N
R
H
VIII
Ph
0.25 mm, # CP7502).
VII
Ph
NO2
NO2
NO2
R
R
R
4.2. Typical experimental procedure for proline-catalyzed
O
N
O
Ph
addition of 1-bromonitroalkanes to
aldehydes
a,b-unsaturated
Ph
Ph
3'
COOH
3
IX
Scheme 1. Proposed reaction mechanism of proline-catalyzed nitrocyclopropanation.
The mixture of (ꢀ)-proline (0.1 mmol) and cinnamaldehyde 1
(1 mmol) in 4.0 mL methanol was stirred for 5 min at room tem-
perature. 1-Bromonitroalkane 2 (1.1 mmol) and AcONa (1.1 mmol)
were added. The reaction mixture was stirred for 3 h at room
temperature. The solvent was evaporated under vacuum and the
residue was purified by flash column chromatography over silica
gel (EtOAc/petroleum ether) to provide nitrocyclopropane 3.
transition state and to accelerate the reaction. The resulted en-
amine intermediate (VII) undergoes the intramolecular nucleo-
philic attack to afford the intermediate (VIII). The consequent
hydrolysis of VIII gives 30 and regenerates the catalyst. Compound
30 can be epimerized through the enamine intermediate (IX) to
provide 3. Due to the electrostatic repulsion between the nitro
group and the carbonyl group, 30 is less stable and the balance fa-
vors the formation of 3. The experiment fact that the ratio of 3a/3a0
(R¼H) increases with the extension of reaction time (Table 1),
supports this hypothesis. However, the epimerization can be
hampered by increasing the volume of R group. The ratio of 3/30
changes from 61/39 to 16/84, to 4/96, and to 1/99, while the R group
is H, Me, Et, and Ph, respectively. The steric repulsion of the R group
with the pyrrolidine ring is probable to inhibit the formation of
intermediate IX.
4.3. Spectral data of nitrocyclopropanes (3)17
4.3.1. Compound 3a
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.28 (d, J¼3.2 Hz, 1H),
7.35–7.26 (m, 5H), 5.33 (dd, J¼4.8, 3.6 Hz, 1H), 3.85 (dd, J¼11.2,
4.8 Hz, 1H), 3.42 (dt, J¼11.2, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
¼193.0, 130.2, 128.9, 128.7, 126.8, 62.4, 38.5, 36.1; IR (thin film)
n
/cmꢁ1: 2855 (w), 1714 (s), 1634 (m), 1548 (s), 1499 (w), 1364 (s),
698 (m); HRMS (EI) calcd for C10H9NO3 (Mþ): 191.0582, found:
191.0585.
3. Conclusion
4.3.2. Compound 3a0
In conclusion, the conjugate addition of 1-bromonitroalkanes
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.69 (d, J¼4.8 Hz, 1H),
to
a
,b
-unsaturated aldehydes was achieved with proline as the
7.42–7.17 (m, 5H), 4.82 (dd, J¼8.4, 4.8 Hz, 1H), 4.00 (dd, J¼8.0,
catalyst. MeOH/AcONa system was found to provide much better
yields than CHCl3/Et3N system reported before. Good yields of
4.8 Hz, 1H), 2.71 (ddd, J¼8.0, 8.0, 4.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3):
d
¼193.2, 133.2, 129.1, 128.53, 128.45, 66.5, 39.2, 32.5.

J.-m. Zhang et al. / Tetrahedron 65 (2009) 802–806
805
4.3.3. Compound 3b
4.3.11. Compound 3f
Yellow solid. 1H NMR (400 MHz, CDCl3):
d
¼9.51 (d, J¼2.0 Hz,
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.34 (d, J¼2.0 Hz, 1H),
1H), 8.20 (d, J¼8.8 Hz, 2H), 7.44 (d, J¼8.4 Hz, 2H), 5.35 (dd,
J¼4.8, 4.0 Hz, 1H), 3.90 (dd, J¼11.2, 4.8 Hz, 1H), 3.62 (ddd,
7.30 (d, J¼6.8 Hz, 2H), 7.18 (d, J¼6.4 Hz, 2H), 5.26 (dd, J¼3.8, 2.8 Hz,
1H), 3.78 (dd, J¼8.8, 3.6 Hz, 1H), 3.44 (dt, J¼8.8, 2.8 Hz, 1H); 13C
J¼11.2, 3.6, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
¼192.0,
NMR (100 MHz, CDCl3):
d¼192.7, 134.4, 130.1, 129.0, 128.7, 62.4,
147.8, 140.4, 127.9, 124.4, 62.4, 38.0, 35.7; IR (thin film)
n
/cmꢁ1
:
38.3, 35.6; IR (thin film) n
/cmꢁ1: 2924 (m), 2854 (m), 1714 (s), 1551
2855 (w), 1713 (s), 1604 (m), 1552 (s), 1519 (s), 1348 (s), 856
(m); HRMS (EI) calcd for C10H8N2O5 (Mþ): 236.0433, found:
236.0435.
(s), 1495 (m), 1364 (m), 1094 (m), 1015 (m), 827 (m); HRMS (EI)
calcd for C10H8ClNO3 (Mþ): 225.0193, found: 225.0192.
4.3.12. Compound 3f0
4.3.4. Compound 3b0
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.64 (d, J¼4.0 Hz, 1H),
Yellow solid. 1H NMR (400 MHz, CDCl3):
d
¼9.70 (d, J¼4.4 Hz,
7.34 (d, J¼6.8 Hz, 2H), 7.12 (d, J¼6.8 Hz, 2H), 4.77 (dd, J¼6.6, 4.0 Hz,
1H), 8.24 (d, J¼8.8 Hz, 2H), 7.37 (d, J¼8.8 Hz, 2H), 4.88 (dd, J¼8.4,
4.8 Hz, 1H), 4.08 (dd, J¼7.8, 4.4 Hz, 1H), 2.79 (ddd, J¼8.0, 8.0, 4.4 Hz,
1H), 3.95 (dd, J¼6.0, 4.0 Hz, 1H), 2.66 (ddd, J¼6.4, 6.4, 3.6 Hz, 1H);
13C NMR (100 MHz, CDCl3):
38.9, 31.7.
d
¼192.8, 134.5, 131.8, 129.3, 128.2, 66.3,
1H); 13C NMR (100 MHz, CDCl3):
66.0, 38.9, 31.4.
d
¼192.2, 147.9, 137.4, 129.9, 124.0,
4.3.13. Compound 3g
4.3.5. Compound 3c
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.36 (d, J¼2.8 Hz, 1H),
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.26 (d, J¼2.8 Hz, 1H),
7.29–7.12 (m, 4H), 5.28 (dd, J¼4.8, 3.6 Hz, 1H), 3.80 (dd, J¼11.2,
7.17–7.09 (m, 4H), 5.27 (dd, J¼3.8, 3.2 Hz, 1H), 3.80 (dd, J¼8.8,
4.8 Hz, 1H), 3.46 (dt, J¼11.2, 3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
4.0 Hz, 1H), 3.37 (dt, J¼9.2, 2.8 Hz, 1H), 2.32 (s, 3H); 13C NMR
d
¼192.5, 135.18, 132.2, 130.2, 129.1, 128.85, 127.0, 62.2, 38.2, 35.6; IR
(100 MHz, CDCl3):
d
¼193.1, 138.5, 129.6, 128.6, 126.7, 62.5, 38.6,
(thin film) n
/cmꢁ1: 2925 (w), 2852 (w), 1714 (m), 1636 (s), 1549 (m),
36.0, 21.1; IR (thin film)
(w), 1363 (s), 1122 (m), 807 (w); HRMS (EI) calcd for C11H11NO3
(Mþ): 205.0739, found: 205.0737.
n
/cmꢁ1: 2925 (w), 1715 (s), 1549 (s), 1456
1364 (m), 1082 (w), 784 (w); HRMS (EI) calcd for C10H8ClNO3 (Mþ):
225.0193, found: 225.0195.
4.3.14. Compound 3g0
4.3.6. Compound 3c0
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.67 (d, J¼4.4 Hz,
Yellow oil. 1H NMR (400 MHz, CDCl3):
d¼9.66 (d, J¼4.0 Hz, 1H),
1H), 7.33–7.06 (m, 4H), 4.79 (dd, J¼8.4, 4.8 Hz, 1H), 3.96 (dd,
7.21–7.00 (m, 4H), 4.76 (dd, J¼6.4, 3.6 Hz, 1H), 3.95 (dd, J¼6.2,
J¼7.8, 4.8 Hz, 1H), 2.69 (ddd, J¼8.0, 8.0, 4.8 Hz, 1H); 13C NMR
3.6 Hz, 1H), 2.66 (ddd, J¼6.4, 6.4, 4.0 Hz, 1H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3):
125.1, 66.1, 38.8, 31.7.
d
¼192.6, 135.22, 134.9, 130.5, 128.89, 127.1,
(100 MHz, CDCl3):
32.4, 29.7.
d
¼193.3, 138.6, 129.8, 128.5, 127.2, 62.7, 39.3,
4.3.15. Compound 3h
4.3.7. Compound 3d
Yellow oil. 1H NMR (400 MHz, CDCl3):
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.43 (d, J¼2.0 Hz, 1H),
d
¼9.27 (d, J¼3.2 Hz, 1H),
7.38–7.25 (m, 4H), 5.22 (dd, J¼4.0, 3.2 Hz, 1H), 3.73 (dd, J¼8.6,
7.16 (d, J¼8.4 Hz, 2H), 6.85 (d, J¼8.8 Hz, 2H), 5.25 (dd, J¼4.8, 3.6 Hz,
1H), 3.78 (dd, J¼11.2, 4.8 Hz, 1H), 3.78 (s, 3H), 3.36 (dt, J¼11.2,
3.6 Hz, 1H), 3.56 (ddd, J¼8.8, 2.8, 2.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3):
34.7; IR (thin film) n
d
¼192.1, 134.7, 130.5, 129.9, 127.9, 127.3, 127.0, 62.8, 37.6,
3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
114.4, 62.7, 55.26, 38.7, 35.8; IR (thin film)
d¼193.1, 159.6, 129.9, 122.1,
/cmꢁ1: 2925 (m), 2853 (m), 1715 (s), 1550 (s),
n
/cmꢁ1: 2926 (m), 2852
1479 (m), 1441 (m), 1364 (s), 1131 (w), 755 (m); HRMS (EI) calcd for
C10H8ClNO3 (Mþ): 225.0193, found: 225.0190.
(m), 1714 (s), 1613 (m), 1549 (s), 1517 (s), 1366 (m), 1251 (m), 1180
(m), 834 (m); HRMS (EI) calcd for C11H11NO4 (Mþ): 221.0688,
found: 221.0685.
4.3.16. Compound 3h0
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.70 (d, J¼3.6 Hz,
4.3.8. Compound 3d0
1H), 7.45–7.08 (m, 4H), 4.75 (dd, J¼6.4, 4.0 Hz, 1H), 4.13 (dd,
Yellow oil. 1H NMR (400 MHz, CDCl3):
d¼9.65 (d, J¼4.8 Hz, 1H),
J¼6.4, 4.0 Hz, 1H), 2.65 (ddd, J¼6.6, 6.6, 3.8 Hz, 1H); 13C NMR
7.08 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 4.74 (dd, J¼8.0, 4.8 Hz,
1H), 3.94 (dd, J¼8.0, 4.8 Hz, 1H), 3.80 (s, 3H), 2.64 (ddd, J¼8.0, 8.0,
(100 MHz, CDCl3):
65.8, 38.1, 31.0.
d
¼193.2, 135.4, 131.0, 129.7, 128.6, 128.2, 127.2,
4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
114.6, 66.6, 55.35, 39.3, 32.2.
d¼193.3, 159.8, 128.0, 125.1,
4.3.17. Compound 3i
Colorless oil. 1H NMR (400 MHz, CDCl3):
1H), 7.41–7.18 (m, 5H), 3.89 (d, J¼11.2 Hz, 1H), 3.27 (dd, J¼11.2,
5.6 Hz, 1H), 1.90 (s, 3H); 13C NMR (100 MHz, CDCl3):
¼195.2, 130.2,
129.4, 128.9, 128.4, 69.0, 39.7, 38.9, 12.8; IR (thin film)
/cmꢁ1: 2921
(s), 2851 (s), 1713 (s), 1539 (s), 1450 (m), 1390 (w), 1351 (m), 1113
(m), 699 (m); HRMS (EI) calcd for C11H11NO3 (Mþ): 205.0739,
found: 205.0736.
d
¼9.29 (d, J¼6.0 Hz,
4.3.9. Compound 3e
Yellow oil. 1H NMR (400 MHz, CDCl3):
d¼9.21 (d, J¼3.2 Hz,
d
1H), 7.33–6.84 (m, 4H), 5.15 (dd, J¼4.8, 3.6 Hz, 1H), 3.82 (s, 3H),
n
3.62 (dd, J¼10.8, 4.8 Hz, 1H), 3.38 (dt, J¼10.8, 3.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3):
d
¼192.9, 157.5, 129.9, 129.7, 120.5, 118.7,
110.5, 62.6, 55.3, 37.8, 31.9; IR (thin film) n
/cmꢁ1: 2841 (w), 1714
(s), 1604 (m), 1547 (s), 1498 (m), 1364 (s), 1252 (s), 1025 (m), 755
(m); HRMS (EI) calcd for C11H11NO4 (Mþ): 221.0688, found:
221.0683.
4.3.18. Compound 3i0
Colorless oil. 1H NMR (400 MHz, CDCl3):
d
¼9.64 (d, J¼4.4 Hz,
1H), 7.39–7.20 (m, 5H), 4.19 (d, J¼8.0 Hz,1H), 2.61 (dd, J¼8.0, 4.4 Hz,
4.3.10. Compound 3e0
1H), 1.54 (s, 3H); 13C NMR (100 MHz, CDCl3):
128.9, 128.4, 72.5, 41.4, 37.2, 16.6.
d
¼194.7, 131.8, 129.8,
Yellow oil. 1H NMR (400 MHz, CDCl3):
d
¼9.67 (d, J¼5.2 Hz, 1H),
7.33–6.84 (m, 4H), 4.86 (dd, J¼8.0, 5.2 Hz, 1H), 4.02 (dd, J¼8.0,
4.8 Hz, 1H), 3.84 (s, 3H), 2.73 (ddd, J¼8.0, 8.0, 5.2 Hz, 1H); 13C NMR
4.3.19. Compound 3j0
(100 MHz, CDCl3):
65.9, 55.4, 38.2, 29.5.
d
¼194.3, 157.9, 129.9, 127.6, 121.3, 120.6, 110.7,
White solid. Mp 131–132 ꢃC; 1H NMR (400 MHz, CDCl3):
d
¼9.74
(d, J¼4.0 Hz, 1H), 7.37–7.15 (m, 8H), 6.89–6.86 (m, 2H), 4.31 (d,

806
J.-m. Zhang et al. / Tetrahedron 65 (2009) 802–806
J¼8.0 Hz, 1H), 3.23 (dd, J¼8.0, 4.0 Hz, 1H); 13C NMR (100 MHz,
Marcos, I. S.; Basabe, P.; Urones, J. G. Mini-Rev. Org. Chem. 2006, 3, 291; (d) Lebel,
H.; Marcoux, J. F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
7. Recent publications of synthesis of cyclopropanes, see: (a) Ibrahem, I.; Zhao, G.-L.;
CDCl3):
d
¼194.0, 131.6, 131.3, 130.3, 129.0, 128.7, 128.5, 128.1, 127.9,
80.1, 40.2, 37.0; IR (thin film) n
/cmꢁ1: 2924 (w), 1703 (s), 1549 (s),
´
´
Rios, R.; Vesely, J.; Sunden, H.; Dziedzic, P.; Cordova, A. Chem.dEur. J. 2008, 14,
7867; (b) Rios, R.; Sunde´n, H.; Vesely, J.; Zaho, G.-L.; Dziedzic, P.; Co´rdova, A.
Adv. Synth. Catal. 2007, 349, 1028; (c) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W.
J. Am. Chem. Soc. 2007, 129, 10886; (d) Hartikka, A.; Arvidsson, P. I. J. Org.
Chem. 2007, 72, 5874; (e) Xu, Z.-H.; Zhu, S.-N.; Sun, X.-L.; Tang, Y.; Dai, L.-X.
Chem. Commun. 2007, 1960; (f) Ferreira, V. F.; Leao, R. A. C.; da Silva, F. de. C.;
Pinheiro, S.; Lhoste, P.; Sinou, D. Tetrahedron: Asymmetry 2007, 18, 1217; (g)
Oudeyer, S.; Le´onel, E.; Paugam, J. P.; Sulpice-Gaillet, C.; Ne´de´lec, J.-Y. Tetra-
hedron 2006, 62, 1583; (h) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen,
D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024; (i) Du, H.;
Long, J.; Shi, Y. Org. Lett. 2006, 8, 2827; (j) Itagaki, M.; Masumoto, K.; Suenobu,
K.; Yamamoto, Y. Org. Process Res. Dev. 2006, 10, 245; (k) McAllister, G. D.;
Oswald, M. F.; Paxton, R. J.; Raw, S. A.; Taylor, R. J. K. Tetrahedron 2006, 62,
6681; (l) Mekonnen, A.; Carlson, R. Synthesis 2006, 1657; (m) Werner, H.;
Herrerias, C. I.; Glos, M.; Gissibl, A.; Fraile, J. M.; Pe´rez, I.; Mayoral, J. A.; Reiser,
O. Adv. Synth. Catal. 2006, 348, 125.
1448 (m), 1338 (m), 1127 (m), 1043 (m), 712 (m); HRMS (EI) calcd
for C16H13NO3 (Mþ): 267.0895, found: 267.0890.
4.3.20. Compound 3k0
Colorless oil. 1H NMR (400 MHz, CDCl3):
d
¼9.60 (d, J¼4.4 Hz,
1H), 7.38–7.23 (m, 5H), 4.13 (d, J¼8.0 Hz,1H), 2.65 (dd, J¼8.0, 4.0 Hz,
1H), 1.68 (q, J¼7.6 Hz, 2H), 0.94 (t, J¼8.0 Hz, 3H); MS (EI) m/e¼219.1
(Mþ), 190.1, 173.0, 145.0, 131.0, 128.0, 115.0, 105.0, 91.0, 76.9, 65.0,
51.0, 39.0, 29.0.
Acknowledgements
8. For the review of asymmetric synthesis of cyclopropanes, see: (a) Li, A.-H.; Dai,
L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341; (b) Aggarwal, V. K.; Winn, C. L.
Acc. Chem. Res. 2004, 37, 611.
We thank the National Natural Science Foundation of China (No.
20772160), NCET plan of Ministry of Education of China, Guangz-
hou Bureau of Science and Technology for the financial support of
this study.
9. Peptidolactone hormaomycin, see: (a) Andres, N.; Wolf, H.; Za¨hner, H.; Ro¨ssner,
E.; Zeek, A.; Ko¨nig, W. A.; Sinnwell, V. Helv. Chim. Acta 1989, 72, 426; (b)
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Org. Chem. 1992, 57, 3757; (h) Kocor, M.; Kroszczynski, W. Synthesis 1976, 813.
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S. I.; Yufit, D. S.; Howard, J. A. K.; Khrustalev, V. N.; Belokon, Y. N.; de
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References and notes
1. For the review of cyclopropanes as the structure motif in drugs and natural
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Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008,
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13. For the review of activation of
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(b) Ouellet, S. G.; Walji, A. M.; Macmillan, D. W. C. Acc. Chem. Res. 2007, 40,
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16. Compound 4: 1H NMR (CDCl3, 400 MHz)
d
¼9.54 (CHO); MS (EI) m/e¼299.0 and
301.0 (Mþ).
17. The diastereoisomers 3 and 30 are inseparable by column chromatography.
Their 1H NMR and 13C NMR data were obtained by analyzing the NMR spectra
of 3/30 mixtures. However, IR and MS spectroscopic data could not be assigned
individually for 3 and 30.