Boron trifluoride mediated ring-opening reactions of trans -2-aryl-3-nitro-cyclopropane-1,1-dicarboxylates. Synthesis of aroylmethylidene malonates as potential building blocks for heterocycles

Article abstract of DOI:10.1021/jo402848v

trans-2-Aryl-3-nitro-cyclopropane-1,1-dicarboxylates, upon treatment with BF₃·OEt₂, undergo ring-opening rearrangement and the Nef reaction to give aroylmethylidene malonates. The products are found to be potential precursors for het

Full text of DOI:10.1021/jo402848v

Note
pubs.acs.org/joc
Boron Trifluoride Mediated Ring-Opening Reactions of trans-2-Aryl-
3-nitro-cyclopropane-1,1-dicarboxylates. Synthesis of
Aroylmethylidene Malonates as Potential Building Blocks for
Heterocycles
Thangavel Selvi and Kannupal Srinivasan*
School of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: trans-2-Aryl-3-nitro-cyclopropane-1,1-dicarbox-
ylates, upon treatment with BF3·OEt2, undergo ring-opening
rearrangement and the Nef reaction to give aroylmethylidene
malonates. The products are found to be potential precursors
for heterocycles, such as imidazoles, quinoxalines, and benzo[1,4]thiazines.
yclopropanes having vicinal donor−acceptor (D−A)
Even though the nitrocyclopropanes 1 were prepared as early as
1969,8 their chemical properties have been scarcely explored.
They were shown to undergo reactions with nucleophiles, such
as sodiomalonate, sodium methoxide, and ammonia, to give ring-
opened products with the loss of the nitro group.11 A derivative
of 1 (Ar = Ph and R = Et) has been reduced to the corresponding
aminocyclopropane,10 and in a recent report, a C−C bond of this
derivative has been photochemically cleaved.12 Except for these
reactions, no other reactions of 1 have been reported to date.
This prompted us to investigate the Lewis acid mediated
reactions of 1, and the study led to a facile access of
aroylmethylidene malonates 2 (Scheme 1). Only dialkyl
C
substituents are important building blocks in organic
synthesis.1 Because of the activation bestowed by the
substituents, they readily undergo ring-opening upon treatment
with Lewis acids to give 1,3-zwitterionic intermediates (also
referred to as 1,3-dipoles) (Figure 1). These zwitterions
Scheme 1. BF3·OEt2-Mediated Ring-Opening Reactions of
D−A Nitrocyclopropanes 1
Figure 1. Common reactions of D−A cyclopropanes.
participate in many formal [3 + n] (n = 2, 3, 4) cycloaddition
reactions with apt dipolarophiles to yield a variety of carbo- and
heterocyclic compounds.2 In addition, the zwitterions combine
with nucleophiles in SN1 fashion (or electrophiles) to give acyclic
products1b,3 or undergo ring-enlargement to give rearrangement
products.4 Sometimes, the D−A cyclopropanes are directly
attacked by nucleophiles in stereodefined SN2 fashion to give the
corresponding ring-opened products.5
Within the class of D−A cyclopropanes, nitrosubstituted ones
have received considerable attention owing to their unique
chemical reactivity.6 They mainly undergo nucleophilic ring-
opening reactions5 or isomerization to isooxazoline-N-oxi-
des4b−e and seldom take part in formal cycloaddition reactions.7
Among various nitrocyclopropanes, we are interested in trans-2-
aryl-3-nitro-cyclopropane-1,1-dicarboxylates (1) because of their
easy accessibility in both racemic and chiral forms. These D−A
nitrocyclopropanes have been synthesized by Michael-initiated
ring-closure (MIRC) methodology involving base-induced
addition of malonates to bromo nitroolefins8 or halomalonates
to nitroolefins,9 followed by ring closure or the oxidative
cyclization of Michael adducts of nitroolefins with malonates.10
benzoylmethylidene malonates are known in the series13,14 and
have been generally prepared by the Wittig reaction of the
corresponding oxomalonates with benzoylmethylene triphenyl-
phosphorane.13 Nevertheless, these compounds have been
frequently used as Michael acceptors in several synthetic
studies.13,15
The requisite trans-2-aryl-3-nitro-cyclopropane-1,1-dicarbox-
ylates (1) for the present study were prepared by an iodine/1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)-mediated direct cycliza-
tion of Michael adducts of nitrostyrenes with diethylmalonate
(3). We had adopted this procedure earlier for the preparation of
trans-2-aroyl-3-aryl-cyclopropane-1,1-dicarboxylates from the
Michael adducts of chalcones with diethylmalonate.16 An
advantage of our procedure over Fan’s procedure,10 which uses
Received: December 23, 2013
Published: April 1, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Note
iodobenzenediacetate and tetrabutylammonium iodide for the
cyclization and affords mixtures of trans- and cis-cyclopropanes
(dr 95:5), is the exclusive formation of trans-cyclopropanes. This
may be due to DBU-induced isomerization of cis-cyclopropanes,
if any formed, to more stable trans-diastereomers under the
reaction conditions. We prepared an assortment of nitro-
cyclopropane dicarboxylates 1a−1l in high yields simply by
stirring the respective Michael adducts with iodine (2 equiv) and
DBU (2 equiv) in dichloromethane (DCM) at room temper-
ature for 10−25 min (Table 1, entries 1−12). The presence of
Table 2. Optimization of Reaction Conditions for Ring-
Opening of 1
a
b
entry
Lewis acid (equiv)
solvent
yield (%)
c
1
2
3
4
5
6
7
8
9
AlCl3 (1.0)
DCM
DCM
DCM
DCM
DCM
1,2-DCE
toluene
THF
33
SnCl4 (1.0)
53
81
49
BF3·OEt2 (1.0)
BF3·OEt2 (0.5)
BF3·OEt2 (1.5)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
BF3·OEt2 (1.0)
FeCl3 (1.0)
a
Table 1. Preparation of D−A Nitrocyclopropanes 1
d
80
62
49
e
NR
DCM
DCM
12
7
b
10
ZnCl2 (1.0)
entry
Ar
time (min)
yield (%)
a
The reaction was conducted with 1a (1 mmol), Lewis acid (x mmol),
1
2
Ph (3a)
15
15
15
10
10
10
15
10
20
15
20
25
94 (1a)
89 (1b)
86 (1c)
96 (1d)
92 (1e)
89 (1f)
82 (1g)
97 (1h)
85 (1i)
98 (1j)
58 (1k)
49 (1l)
b
c
and solvent (5 mL). Isolated yield. Diethyl phenacylmalonate is
4-MeC6H4 (3b)
d
produced as a byproduct in 65% yield. The reaction time was 20 h.
3
4-OMeC6H4 (3c)
4-ClC6H4 (3d)
e
No reaction even after 3 days.
4
5
4-NO2C6H4 (3e)
3,4-(OMe)2C6H3 (3f)
3,4,5-(OMe)3C6H2 (3g)
2,6-Cl2C6H3 (3h)
2-I-4,5-(OMe)2C6H2 (3i)
1-naphthyl (3j)
and thus formed 2a in meager amounts in 24 h (entries 9 and 10).
On the other hand, TiCl4, InCl3, MgI, and the metal triflates,
AgOTf, Cu(OTf)2, In(OTf)3, Sc(OTf)3, and Yb(OTf)3, did not
bring any change in 1a. Thus, we selected BF3·OEt2 (1 equiv) in
DCM at room temperature for 24 h as optimal reaction
conditions (entry 3) for the ring-opening reaction.
We then examined the scope of the ring-opening reaction for
other D−A nitrocyclopropanes 1b−1l under the optimized
conditions (Table 3). The substrates 1b−1d, which possess
electron-donating and halogen substituents in the p-position of
the phenyl ring, underwent facile ring-opening and gave the
aroylmethylidene malonates 2b−2d in good yields (entries 2−
4). The reaction failed in the case of substrate 1e, which bears an
electron-withdrawing p-nitrophenyl ring, most likely due to the
difficulty involved in the generation of a positive charge on the
6
7
8
9
10
11
12
2-furyl (3k)
2-thienyl (3l)
a
The reaction was conducted with 3 (1 mmol), iodine (2 mmol), and
b
DBU (2 mmol) in CH2Cl2 (5 mL). Isolated yield; all are single trans-
diastereomers.
different mono- and polysubstituted phenyl (1a−1i), naphthyl
(1j), and heteroaryl (1k−1l) rings are tolerated; however, the
yield was low for cyclopropanes having heteroaryl rings. In fact,
the cyclization did not work in the case of N-methylpyrrole or N-
methylindole ring-containing Michael adduct. The reaction
might proceed via formation of the iodinated-Michael adduct A,
followed by base-promoted SN2-type ring closure.
Table 3. Ring-Opening Reactions of D−A
Nitrocyclopropanes 1
Next, we selected the nitrocyclopropane dicarboxylate 1a as a
model substrate and treated it with different Lewis acids to
understand the mode of reactivity of this type of cyclopropane
(Table 2). Since similar trans-2-aroyl-3-aryl-cyclopropane-1,1-
dicarboxylates have been ring-opened with AlCl317 and SnCl4,16
we first tested the suitability of these Lewis acids. When treated
with AlCl3 (1 equiv) in DCM at room temperature for 24 h, 1a
gave a mixture of diethyl benzoylmethylidene malonate (2a,
33%) and the corresponding saturated compound, diethyl
phenacylmalonate (65%) (entry 1). On the other hand, SnCl4
gave 53% of 2a and a complicated mixture under the conditions
(entry 2). When BF3·OEt2 was employed as the Lewis acid, 1a
underwent smooth ring-opening and afforded 2a in 81% isolated
yield after 24 h (entry 3). Upon reducing the amount of Lewis
acid to 50 mol %, the reaction did not go to completion and only
49% of 2a was obtained after 24 h (entry 4). Increasing the
amount of Lewis acid to 1.5 equiv gave 2a in almost similar yield
at a shorter reaction time of 20 h (entry 5). Change of solvent to
1,2-dichloroethane or toluene lowered the yield of 2a (24 h),
whereas, in tetrahydrofuran, 1a remained inert even after 3 days
(entries 6−8). We also screened a number of other Lewis acids.
Of them, FeCl3 and ZnCl2 caused ring-opening in 1a very slowly
a
entry
Ar
time (h)
yield (%)
1
2
Ph (1a)
24
12
12
24
24
12
10
24
24
10
81 (2a)
86 (2b)
86 (2c)
79 (2d)
4-MeC6H4 (1b)
3
4-OMeC6H4 (1c)
4-ClC6H4 (1d)
4
b
5
4-NO2C6H4 (1e)
3,4-(OMe)2C6H3 (1f)
3,4,5-(OMe)3C6H2 (1g)
2,6-Cl2C6H3 (1h)
2-I-4,5-(OMe)2C6H2 (1i)
1-naphthyl (1j)
NR
6
91 (2f)
94 (2g)
7
b
8
NR
9
85 (2i)
80 (2j)
10
11
12
c
2-furyl (1k)
−
d
e
2-thienyl (1l)
2
27 (2l)
a
b
c
Isolated yield. No reaction. The reaction produces a complicated
mixture instantaneously even at −15 °C. The reaction was carried out
at −15 °C. The yield was 33% when conducted using FeCl3 (1 equiv)
d
e
at −15 °C for 3 h.
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Note
Scheme 2. Mechanism for the Formation of 2
Scheme 3. Comparison of Electrophilic Centers in Chalcones
and Aroylmethylidene Malonates 2
of the Lewis acid to the malonyl and nitro moieties. However,
only path a is followed due to more resonance stabilization
offered to the carbanion by the malonyl unit. The zwitter ionic
intermediate B so generated eliminates the nitro group to give
the ion-pair C, which, upon recombination, yields the nitro
compound D. The Nef reaction18 of D in the presence of BF3·
OEt2 furnishes the product 2. Since there is no considerable
amount of water in the reaction, we presume that the Nef
reaction takes place via nitronic acid−BF3 complex E, oxaziridine
F, and hydroxynitroso intermediate G analogous to the
mechanism reported by Ballini and co-workers.19
The product aroylmethylidene malonates could act as
potential synthetic precursors like chalcones. Chalcones possess
two electrophilic centers in 1,3-positions and undergo mainly
Michael addition/cyclocondensation with nucleophiles (Scheme
3). Unlike chalcones, aroylmethylidene malonates possess two
electrophilic centers in 1,2-positions and thus can exhibit a
distinctive pattern of reactivity. Their use in asymmetric Michael
addition and conjugate addition−cyclization has been docu-
mented.13,15 However, other synthetic potentials of these
compounds largely remain unexplored.
respective benzylic carbon in the zwitter ion intermediate (entry
5) (see mechanism). Among substrates 1f−1i, which possess
polysubstituted phenyl rings, except 1h, all others gave the
corresponding ring-opened products (entries 6−9); especially,
trimethoxyphenyl-group-containing cyclopropane 1g gave an
excellent yield of 94% (entry 7). The reason for the failure of the
reaction for 1h (entry 8) may be attributed to the electron-
withdrawing inductive effect of the o-chloro substituents. The
ring-opening also works well for the naphthyl cyclopropane 1j
(entry 10). Unfortunately, the substrate 1k having a furyl ring
was incompatible for the reaction and gave a complicated mixture
at room temperature as well as at −15 °C (entry 11). However,
the thienyl cyclopropane 1l furnished the corresponding ring-
opened product 2l at −15 °C, albeit in low yield (27%) (entry
12).
To demonstrate the utility of aroylmethylidene malonates in
heterocyclic synthesis, we carried out a few reactions (Scheme 4).
The cyclocondensation of 2a and 2d with acetamidine
hydrochloride in the presence of triethylamine in DCM gave
the imidazole derivatives 4a and 4b after monodecarbethox-
We propose the mechanism shown in Scheme 2 for the
formation of aroylmethylidene malonates 2 from the nitro-
cyclopropanes 1. There are two possible modes of ring-opening
for this type of cyclopropanes (paths a and b) upon coordination
Scheme 4. Applications of Aroylmethylidene Malonates in Heterocycle Synthesis
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The Journal of Organic Chemistry
Note
Diethyl 2-Nitro-3-(4-nitrophenyl)-cyclopropane-1,1-dicarbox-
ylation of the malonyl unit. When treated with ortho-phenyl-
enediamines in ethanol, 2a−2c afforded quinoxalines 5a−5d in
excellent yields with the loss of the malonyl unit. Similarly, the
treatment of 2a and 2b with o-aminothiophenol furnished
benzo[1,4]thiazine derivatives 6a and 6b. The heterocycles
synthesized herein are present as substructures in many
pharmaceutically relevant agents and natural products.20
Particularly, quinoxaline 5d was known to be an excellent
inhibitor of platelet-derived growth factor receptor tyrosine
kinase.21
In conclusion, we have developed a new iodine−DBU-
mediated procedure for the preparation of 2-aryl-3-nitro-
cyclopropane-1,1-dicarboxylates as single trans-diastereomers.
These nitrocyclopropanes, when treated with BF3·OEt2, afforded
synthetically useful aroylmethylidene malonates through ring-
opening, rearrangement, and the Nef reaction. We have also
proved the utility of the products in the synthesis of
pharmaceutically important heterocycles, such as imidazoles,
quinoxalines, and benzo[1,4]thiazines.
ylate 1e:10 Yellow oil; yield: 324 mg (92%); H NMR (400 MHz,
1
CDCl3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 5.44 (d, J =
6.0 Hz, 1H), 4.38−4.28 (m, 2H), 4.25 (d, J = 6.0 Hz, 1H), 4.10−4.01 (m,
2H), 1.32 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 162.8, 162.7, 148.0, 137.4, 129.6, 123.9, 65.9,
63.4, 63.2, 46.1, 36.6, 13.8 ppm.
Diethyl 2-(3,4-Dimethoxyphenyl)-3-nitro-cyclopropane-1,1-
1
dicarboxylate 1f: Yellow semisolid; yield: 327 mg (89%); H NMR
(400 MHz, CDCl3): δ 6.81 (s, 2H), 6.77 (s, 1H), 5.38 (d, J = 6.0 Hz,
1H), 4.33−4.29 (m, 2H), 4.15 (d, J = 6.0 Hz, 1H), 4.05−4.01 (m, 2H),
3.87 (s, 3H), 3.86 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.2 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.4, 163.2, 149.2, 149.1,
122.5, 120.6, 111.3, 111.0, 66.5, 63.0, 62.7, 56.0, 55.9, 46.4, 37.4, 13.87,
13.85 ppm; MS (ESI): m/z 390.05 [M + Na+]. Anal. Calcd for
C17H21NO8: C 55.58, H 5.76, N 3.81; found: C 55.47, H 5.88, N 3.92.
Diethyl 2-Nitro-3-(3,4,5-trimethoxyphenyl)-cyclopropane-1,1-
dicarboxylate 1g: Yellow solid; yield: 326 mg (82%); m.p.: 122−124
°C; 1H NMR (400 MHz, CDCl3): δ 6.45 (s, 2H), 5.38 (d, J = 5.6 Hz,
1H), 4.38−4.25 (m, 2H), 4.14 (d, J = 5.6 Hz, 1H), 4.11−3.91 (m, 2H),
3.85 (s, 6H), 3.82 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.2 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.2, 163.1, 153.4, 138.2,
125.8, 105.4, 66.4, 63.0, 62.6, 60.8, 56.2, 46.3, 37.6, 13.8, 13.7 ppm;
HRMS (ESI) calcd for C18H23NO9: 420.1265 [M + Na+], found:
420.1252.
Diethyl 2-(2,6-Dichlorophenyl)-3-nitro-cyclopropane-1,1-
dicarboxylate 1h: White solid; yield: 365 mg (97%); m.p.: 76−78
°C; 1H NMR (400 MHz, CDCl3): δ 7.34−7.32 (m, 2H), 7.23−7.19 (m,
1H), 5.31 (d, J = 6.4 Hz, 1H), 4.39−4.24 (m, 2H), 4.20−4.05 (m, 2H),
3.94 (d, J = 6.0 Hz, 1H), 1.31 (t, J = 7 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 164.2, 162.9, 136.5, 130.0, 128.7,
126.9, 69.4, 63.0, 62.8, 45.8, 34.5, 13.8, 13.6 ppm; MS (ESI): m/z 398.00
[M + Na+]. Anal. Calcd for C15H15Cl2NO6: C 47.89, H 4.02, N 3.72;
found: C 47.97, H 4.15, N 3.83.
EXPERIMENTAL SECTION
■
General Remarks. Melting points were determined by the open
capillary tube method and are uncorrected. The H and 13C NMR
1
spectra were recorded on a 400 MHz NMR spectrometer. High-
resolution mass spectra (ESI) were recorded on a Q-TOF mass
spectrometer. Low-resolution mass spectra (ESI) were recorded on an
LC mass spectrometer. Elemental analyses were performed on a CHN
analyzer. Thin-layer chromatography (TLC) was performed on
precoated alumina sheets and detected under UV light. Silica gel
(100−200 mesh) was used for column chromatography.
General Procedure for the Synthesis of Nitrocyclopropanes
1a−1l. To a mixture of Michael adduct 3 (1 mmol) and DBU (0.3 mL; 2
mmol) in dichloromethane (3 mL) was added iodine (508 mg; 2 mmol).
The reaction mixture was stirred at ambient temperature for 15−25 min.
After the reaction was complete, the reaction mixture was quenched
with aq. Na2S2O3 and extracted with dichloromethane. The organic layer
was washed with water and dried (anhydrous Na2SO4), and the solvent
was removed under reduced pressure. The crude product was purified
by column chromatography using 5−10% ethyl acetate/hexane to give
nitrocyclopropane 1.
Diethyl 2-(2-Iodo-4,5-dimethoxyphenyl)-3-nitro-cyclopropane-
1,1-dicarboxylate 1i: Yellow semisolid; yield: 419 mg (85%); 1H
NMR (400 MHz, CDCl3): δ 7.25 (s, 1H), 6.59 (m, 1H), 5.30 (d, J = 6.0
Hz, 1H), 4.38−4.26 (m, 2H), 4.18−4.02 (m, 3H), 3.86 (s, 3H), 3.84 (s,
3H), 1.32 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 163.5, 163.0, 149.6, 149.1, 125.8, 122.0, 112.3,
88.0, 68.2, 63.0, 62.9, 56.2, 56.1, 46.6, 41.8, 13.90, 13.87 ppm; HRMS
(ESI) calcd for C17H20INO8: 516.0126 [M + Na+], found: 516.0121.
Diethyl 2-(Naphthalen-1-yl)-3-nitro-cyclopropane-1,1-dicarbox-
ylate 1j:10 Crystalline white solid; yield: 350 mg (98%); m.p.: 82−84
°C; 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 7.86−7.81 (m, 2H),
7.63−7.59 (m, 1H), 7.54−7.51 (m, 1H), 7.45−7.40 (m, 2H), 5.57 (d, J =
6.0 Hz, 1H), 4.56 (d, J = 5.6 Hz, 1H), 4.42−4.37 (m, 2H), 3.79−3.66 (m,
2H), 1.36 (t, J = 7.0 Hz, 3H), 0.58 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 163.7, 162.1, 133.6, 132.1, 129.3, 128.6, 127.0,
126.4, 126.3, 126.2, 124.9, 123.9, 66.3, 63.1, 62.4, 45.9, 36.7, 13.9, 13.2
ppm.
Diethyl 2-(Furan-2-yl)-3-nitro-cyclopropane-1,1-dicarboxylate
1k:10 Brown oil; yield: 172 mg (58%); 1H NMR (400 MHz, CDCl3):
δ 7.34 (s, 1H), 6.35−6.31 (m, 2H), 5.35 (d, J = 6.0 Hz, 1H), 4.35−4.25
(m, 2H), 4.23−4.10 (m, 2H), 4.08 (d, J = 5.6 Hz, 1H), 1.29 (t, J = 7.2 Hz,
3H), 1.14 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
162.9, 162.7, 144.3, 142.9, 110.9, 109.8, 65.8, 63.1, 62.9, 45.4, 30.4,
13.80, 13.75 ppm.
Diethyl 2-Nitro-3-(thiophen-2-yl)-cyclopropane-1,1-dicarboxylate
1l:10 Brown oil; yield: 153 mg (49%); 1H NMR (400 MHz, CDCl3): δ
7.26−7.24 (m, 1H), 6.98−6.94 (m, 2H), 5.38 (d, J = 5.6 Hz, 1H), 4.35−
4.27 (m, 2H), 4.21 (d, J = 7.2 Hz, 1H), 4.13−4.05 (m, 2H), 1.28 (t, J =
7.2 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 162.8, 162.7, 132.2, 127.6, 127.1, 126.3, 65.8, 63.1, 62.9, 46.8,
32.5, 13.9, 13.8 ppm.
General Procedure for Ring-Opening of Nitrocyclopropanes
2a−2l. To a solution of nitrocyclopropane 1 (1 mmol) in dichloro-
methane (5 mL) was added BF3·OEt2 (0.13 mL; 1 mmol). The reaction
mixture was stirred at room temperature for 24 h (12 h for 1b, 1c, and 1f;
10 h for 1g and 1j; and 2 h at −15 °C for 1l). The mixture was quenched
with water, and the organic layer was separated. The layer was washed
Diethyl 2-Nitro-3-phenyl-cyclopropane-1,1-dicarboxylate 1a:10
1
Colorless oil; yield: 289 mg (94%); H NMR (400 MHz, CDCl3): δ
7.36−7.30 (m, 5H), 5.41 (d, J = 6.0 Hz, 1H), 4.35−4.27 (m, 2H), 4.20
(d, J = 6.0 Hz, 1H), 4.03−3.96 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 0.98 (t, J
= 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.3, 163.2,
130.3, 128.7, 128.5, 128.3, 66.2, 63.0, 62.7, 46.2, 37.5, 13.9, 13.7 ppm.
Diethyl 2-(4-Methylphenyl)-3-nitro-cyclopropane-1,1-dicarbox-
ylate 1b:10 Colorless oil; yield: 286 mg (89%); H NMR (400 MHz,
1
CDCl3): δ 7.16−7.11 (m, 4H), 5.37 (d, J = 6.0 Hz, 1H), 4.37−4.24 (m,
2H), 4.15 (d, J = 6.0 Hz, 1H), 4.07−3.95 (m, 2H), 2.32 (s, 3H), 1.30 (t, J
= 7.2 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3): δ 163.4, 163.2, 138.4, 129.4, 128.2, 127.2, 66.3, 63.0, 62.6, 46.3,
37.4, 21.1, 13.9, 13.8 ppm.
Diethyl 2-(4-Methoxyphenyl)-3-nitro-cyclopropane-1,1-dicarbox-
ylate 1c:10 Yellow oil; yield: 289 mg (86%); H NMR (400 MHz,
1
CDCl3): δ 7.19 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.36 (d, J =
6.0 Hz, 1H), 4.31−4.28 (m, 2H), 4.13 (d, J = 6.0 Hz, 1H), 4.03−4.00 (m,
2H), 3.79 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 163.4, 163.2, 159.7, 129.5, 122.1, 114.1,
66.5, 63.0, 62.6, 55.3, 46.4, 37.1, 13.9, 13.8 ppm.
Diethyl 2-(4-Chlorophenyl)-3-nitro-cyclopropane-1,1-dicarbox-
ylate 1d:10 Yellow oil; yield: 330 mg (96%); H NMR (400 MHz,
1
CDCl3): δ 7.32 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 5.37 (d, J =
6.0 Hz, 1H), 4.35−4.26 (m, 2H), 4.14 (d, J = 6.0 Hz, 1H), 4.08−3.99 (m,
2H), 1.31 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 163.4, 163.2, 159.7, 129.5, 122.1, 114.1, 66.5,
63.0, 62.6, 55.3, 46.4, 37.1, 13.9, 13.8 ppm.
3656
dx.doi.org/10.1021/jo402848v | J. Org. Chem. 2014, 79, 3653−3658

The Journal of Organic Chemistry
Note
with water and dried (anhydrous Na2SO4), and the solvent was removed
under reduced pressure. The crude product was purified by wash
column using 5−10% ethyl acetate/hexane.
General Procedure for the Synthesis of Imidazoles 4a and 4b.
To a solution of aroylmethylidene malonate 2 (1 mmol) in
dichloromethane (5 mL) were added acetamidine hydrochloride (95
mg; 1 mmol) and triethylamine (0.14 mL; 1 mmol). The reaction
mixture was stirred at room temperature for 1 h. The reaction mixture
was diluted with water, and the organic layer was separated. The layer
was washed with water and dried (anhydrous Na2SO4), and the solvent
was removed under reduced pressure. The crude product was purified
by wash column using 70−90% ethyl acetate/hexane.
Ethyl (2-Methyl-5-phenyl-1H-imidazol-4-yl)-acetate 4a: Yellow
semisolid; yield: 232 mg (95%); 1H NMR (400 MHz, CDCl3): δ 8.21
(s, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.6 Hz, 2H), 7.27−7.22 (m,
1 H), 4.13 (q, J = 7.2 Hz, 2H), 3.71 (s, 2H), 2.29 (s, 3H), 1.21 (t, J = 7.2
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 171.1, 144.2, 132.4,
131.8, 128.7, 127.11, 127.06, 123.9, 61.2, 32.3, 14.1, 13.4 ppm; HRMS
(ESI) calcd for C14H16N2O2: 245.1285 [M + H+], found 245.1283.
Ethyl [5-(4-Chlorophenyl)-2-methyl-1H-imidazol-4-yl]-acetate 4b:
Yellow semisolid; yield: 259 mg (93%); 1H NMR (400 MHz, CDCl3): δ
7.42 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.80 (s, 1H), 4.18 (q, J
= 7.2 Hz, 2H), 3.72 (s, 2H), 2.39 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 170.8, 144.2, 133.0, 132.7, 130.6, 128.9,
Diethyl 2-(2-Oxo-2-phenyl-ethylidene)malonate 2a:13 Yellow oil;
yield: 224 mg (81%); 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.4
Hz, 2H), 7.85 (s, 1H), 7.65−7.61 (m, 1H), 7.53−7.49 (m, 2H), 4.38−
4.27 (m, 4H), 1.36 (t, J = 7.0 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ 189.2, 164.5, 162.9, 136.5, 136.1, 135.4,
134.2, 129.0, 128.8, 62.5, 62.0, 14.0, 13.7 ppm.
Diethyl 2-[2-(4-Methylphenyl)-2-oxo-ethylidene]malonate 2b:
1
Yellow oil; yield: 249 mg (86%); H NMR (400 MHz, CDCl3): δ
7.88−7.83 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 4.37−4.26 (m, 4H), 2.43
(s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 188.7, 164.6, 163.0, 145.4, 136.2, 135.6, 133.7,
129.7, 129.0, 62.4, 61.9, 21.8, 14.0, 13.8 ppm; HRMS (ESI) calcd for
C16H18O5: 291.1227 [M + H+], found: 291.1232.
Diethyl 2-[2-(4-Methoxyphenyl)-2-oxo-ethylidene]malonate 2c:
Yellow oil; yield: 263 mg (86%); 1H NMR (400 MHz, CDCl3): δ 7.96
(d, J = 8.8 Hz, 2H), 7.84 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 4.37−4.28 (m,
4H), 3.89 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 187.4, 164.7, 164.5, 163.0, 136.0, 135.5,
131.3, 129.3, 114.2, 62.4, 61.9, 55.6, 14.0, 13.8 ppm; HRMS (ESI) calcd
for C16H18O6: 307.1176 [M + H+], found: 307.1181.
128.3, 122.4, 61.5, 31.8, 14.1, 13.6 ppm; HRMS (ESI) calcd for
C14H15ClN2O2: 279.0895 [M + H+], found: 279.0895.
Diethyl 2-[2-(4-Chlorophenyl)-2-oxo-ethylidene]malonate 2d:
Yellow oil; yield: 246 mg (79%); H NMR (400 MHz, CDCl3): δ
7.93−7.90 (m, 2H), 7.79 (s, 1H), 7.50−7.47 (m, 2H), 4.38−4.28 (m,
4H), 1.36 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 188.0, 164.3, 162.8, 140.8, 136.9, 134.8, 134.4,
130.2, 129.3, 62.5, 62.0, 14.0, 13.8 ppm; HRMS (ESI) calcd for
C15H15ClO5: 311.0681 [M + H+], found: 311.0687.
General Procedure for the Synthesis of Quinoxalines 5a−5d
and Benzo[1,4]thiazines 6a and 6b. To a solution of aroylmethy-
lidene malonate 2 (1 mmol) in ethanol (5 mL) was added o-
phenylenediamine (108 mg, 1 mmol), 4,5-dimethyl-1,2-phenylenedi-
amine (136 mg, 1 mmol), or o-aminothiophenol (0.11 mL; 1 mmol).
The reaction mixture was stirred at room temperature for 15 min for
5a−5d and 20 min for 6a and 6b. The reaction mixture was diluted with
water, and the organic layer was separated. The layer was washed with
water and dried (anhydrous Na2SO4), and the solvent was removed
under reduced pressure. The crude product was purified by wash
column using 5−10% ethyl acetate/hexane.
Diethyl 2-[2-(3,4-Dimethoxyphenyl)-2-oxo-ethylidene]malonate
1
2f: Yellow oil; yield: 306 mg (91%); H NMR (400 MHz, CDCl3): δ
7.84 (s, 1H), 7.60 (d, J = 10.4 Hz, 1H), 7.54 (s, 1H), 6.92 (d, J = 8.4 Hz,
1H), 4.37−4.29 (m, 4H), 3.97 (s, 3H), 3.94 (s, 3H), 1.36 (t, J = 7.2 Hz,
3H), 1.28 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
187.3, 164.8, 163.0, 154.5, 149.6, 136.1, 135.2, 129.5, 124.3, 110.3, 110.1,
62.4, 61.9, 56.22, 56.11, 56.0, 14.0, 13.8 ppm; HRMS (ESI) calcd for
C17H20O7: 337.1282 [M + H+], found: 337.1279.
Diethyl 2-[2-Oxo-2-(3,4,5-trimethoxyphenyl)-ethylidene]-
malonate 2g: Yellow oil; yield: 344 mg (94%); 1H NMR (400 MHz,
CDCl3): δ 7.79 (s, 1H), 7.21 (s, 2H), 4.38−4.27 (m, 4H), 3.94 (s, 3H),
3.92 (s, 6H), 1.36 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ 187.9, 164.6, 163.0, 153.3, 143.8, 136.4,
135.2, 131.2, 106.4, 62.5, 62.0, 61.0, 56.4, 14.0, 13.8 ppm; MS (ESI): m/
z 388.98 [M + Na+]; HRMS (ESI) calcd for C18H22O8: 367.1387 [M +
H+], found: 367.1384. Anal. Calcd for C18H22O8: C 59.01, H 6.05;
found: C 59.25, H 6.17.
2-Phenyl-quinoxaline 5a:22 White solid; yield: 185 mg (90%); m.p.:
74−76 °C [lit. 73−75 °C]; 1H NMR (400 MHz, CDCl3): δ 9.33 (s, 1H),
8.21−8.11 (m, 4H), 7.81−7.72 (m, 2H), 7.59−7.51 (m, 3H) ppm; 13C
NMR (100 MHz, CDCl3): δ 150.8, 142.3, 141.3, 140.6, 135.8, 129.3,
129.2, 128.6, 128.5, 128.12, 128.09, 126.5 ppm.
2-(4-Methylphenyl)-quinoxaline 5b:23 White solid; yield: 209 mg
(95%); m.p.: 88−90 °C [lit. 90−92 °C]; 1H NMR (400 MHz, CDCl3):
δ 9.31 (s, 1H), 8.15−8.10 (m, 4H), 7.79−7.71 (m, 2H), 7.37 (d, J = 8.0
Hz, 2H), 2.45 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 151.9,
143.3, 142.4, 141.5, 140.5, 134.0, 130.2, 129.9, 129.6, 129.3, 129.1, 127.5,
21.4 ppm.
2-(4-Methoxyphenyl)-quinoxaline 5c:24 White solid; yield: 229 mg
1
(97%); m.p.: 92−94 °C [lit. 92 °C]; H NMR (400 MHz, CDCl3): δ
Diethyl 2-[2-(2-Iodo-4,5-dimethoxyphenyl)-2-oxo-ethylidene]-
9.29 (s, 1H), 8.19−8.08 (m, 4H), 7.78−7.69 (m, 2H), 7.08 (d, J = 8.4
Hz, 2H), 3.90 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 161.5,
151.5, 143.1, 142.4, 141.3, 130.2, 129.41, 129.35, 129.1, 129.04, 128.99,
114.6, 55.4 ppm.
1
malonate 2i: Yellow oil; yield: 393 mg (85%); H NMR (400 MHz,
CDCl3): δ 7.76 (s, 1H), 7.34 (s, 1H), 7.13 (s, 1H), 4.36−4.27 (m, 4H),
3.93 (s, 3H), 3.89 (s, 3H), 1.33 (m, 6H) ppm; 13C NMR (100 MHz,
CDCl3): δ 190.4, 164.6, 162.9, 152.5, 149.1, 136.4, 135.1, 134.0, 123.0,
113.6, 83.6, 62.4, 62.0, 56.4, 56.2, 14.0, 13.9 ppm; HRMS (ESI) calcd for
C17H19IO7: 463.0248 [M + H+], found: 463.0244.
Diethyl 2-(2-Naphthalen-1-yl-2-oxo-ethylidene)malonate 2j: Yel-
low oil; yield: 261 mg (80%); 1H NMR (400 MHz, CDCl3): δ 8.78 (d, J
= 8.4 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.96−7.89 (m, 2H), 7.80 (s, 1H),
7.66−7.62 (m, 1H), 7.59−7.51 (m, 2H), 4.35 (q, J = 7.2 Hz, 2H), 4.18
(q, J = 6.8 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H) ppm;
13C NMR (100 MHz, CDCl3): δ 191.9, 164.5, 163.0, 138.4, 135.8, 134.5,
133.9, 133.4, 130.7, 130.4, 128.7, 128.6, 126.9, 125.7, 124.3, 62.4, 62.0,
14.1, 13.7 ppm; MS (ESI): m/z 349.02 [M + Na+]. Anal. Calcd for
C19H18O5: C 69.93, H 5.56; found: C 70.18, H 5.73.
Diethyl 2-(2-Oxo-2-thiophen-2-yl-ethylidene)malonate 2l: Yellow
oil; yield: 76 mg (27%); 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 4.0
Hz, 1H), 7.77 (d, J = 4.8 Hz, 1H), 7.73 (s, 1H), 7.19 (t, J = 4.4 Hz, 1H),
4.40−4.32 (m, 4H), 1.35 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 6.9 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 180.3, 164.7, 162.8, 144.0, 137.2,
136.2, 133.8, 133.0, 128.7, 62.6, 62.1, 14.0, 13.9 ppm; HRMS (ESI) calcd
for C13H14O5S: 283.0635 [M + H+], found: 283.0638.
6,7-Dimethyl-2-phenylquinoxaline 5d:21 White solid; yield: 215 mg
(92%); m.p.: 124−126 °C [lit. 124 °C]; 1H NMR (400 MHz, CDCl3): δ
9.22 (s, 1H), 8.18−8.16 (m, 2H), 7.91 (s, 1H), 7.86 (s, 1H), 7.57−7.48
(m, 3H), 2.51 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 151.0,
142.4, 141.2, 140.8, 140.6, 140.1, 137.1, 129.8, 129.1, 128.7, 128.2, 127.4,
20.34, 20.31 ppm.
Diethyl 2-(3-Phenyl-2H-benzo[1,4]thiazin-2-yl)malonate 6a: Yel-
1
low semisolid; yield: 326 mg (85%); H NMR (400 MHz, CDCl3): δ
8.11−8.08 (m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.47−7.45 (m, 3H), 7.35−
7.29 (m, 2H), 7.17 (t, J = 7.4 Hz, 1H), 4.93 (d, J = 10.8 Hz, 1H), 4.25−
4.20 (m, 2H), 3.76−3.64 (m, 2H), 3.53 (d, J = 10.8 Hz, 1H), 1.26 (t, J = 7
Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ
166.5, 166.2, 155.4, 142.8, 137.1, 130.9, 128.6, 128.1, 128.0, 127.9, 127.1,
127.0, 119.4, 61.99, 61.95, 51.7, 32.8, 14.0, 13.4 ppm; HRMS (ESI) calcd
for C21H21NO4S: 384.1264 [M + H+], found: 384.1262.
Diethyl 2-[3-(4-Methylphenyl)-2H-benzo[1,4]thiazin-2-yl]-
malonate 6b: Yellow semisolid; yield: 381 mg (96%); 1H NMR (400
MHz, CDCl3): δ 8.0 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 1.2 Hz, 1H), 7.56−
7.25 (m, 4H), 7.17−7.13 (m, 1H), 4.91 (d, J = 10.8 Hz, 1H), 4.22 (q, J =
3657
dx.doi.org/10.1021/jo402848v | J. Org. Chem. 2014, 79, 3653−3658

The Journal of Organic Chemistry
Note
7.2 Hz, 2H), 3.72 (q, J = 7.2 Hz, 2H), 3.53 (d, J = 11.2 Hz, 1H), 2.40 (s,
3H), 1.26 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.0 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ 166.6, 166.3, 155.3, 142.9, 141.4, 134.2, 129.3,
128.1, 128.0, 127.7, 127.0, 126.8, 119.3, 62.0, 61.9, 51.7, 32.7, 21.5, 14.0,
13.5 ppm; HRMS (ESI) calcd for C22H23NO4S: 398.1421 [M + H+],
found: 398.1417.
(12) Cai, S.; Zhang, S.; Zhao, Y.; Wang, D. Z. Org. Lett. 2013, 15, 2660.
(13) (a) Yamazaki, S.; Kumagai, H.; Takada, T.; Yamabe, S.;
Yamamoto, K. J. Org. Chem. 1997, 62, 2968. (b) Yamazaki, S.;
Kataoka, H.; Yamabe, S. J. Org. Chem. 1999, 64, 2367. (c) Yamazaki, S.;
Iwata, Y. J. Org. Chem. 2006, 71, 739.
(14) Dimethyl benzoylmethylidene malonate has been isolated as an
intermediate in the synthesis of isooxazoles from tandem 1,3-dipolar
cycloaddition of cyclopropene-1,1-diesters and nitrile oxides; see: Chen,
S.; Ren, J.; Wang, Z. Tetrahedron 2009, 65, 9146.
(15) (a) Morikawa, S.; Yamazaki, S.; Furusaki, Y.; Amano, N.; Zenke,
K.; Kakiuchi, K. J. Org. Chem. 2006, 71, 3540. (b) Morikawa, S.;
Yamazaki, S.; Tsukada, M.; Izuhara, S.; Morimoto, T.; Kakiuchi, K. J.
Org. Chem. 2007, 72, 6459. (c) Yamazaki, S.; Kashima, S.; Kuriyama, T.;
Iwata, Y.; Morimoto, T.; Kakiuchi, K. Tetrahedron: Asymmetry 2009, 20,
1224.
(16) Sathishkannan, G.; Srinivasan, K. Org. Lett. 2011, 13, 6002.
(17) (a) Yang, G.; Shen, Y.; Li, K.; Sun, Y.; Hua, Y. J. Org. Chem. 2011,
76, 229. (b) Yang, G.; Sun, Y.; Shen, Y.; Chai, Z.; Zhou, S.; Chu, J.; Chai,
J. J. Org. Chem. 2013, 78, 5393.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: srinivasank@bdu.ac.in.
■
Notes
The authors declare no competing financial interest.
(18) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
(19) Ballini, R.; Bosica, G.; Fiorini, D.; Petrini, M. Tetrahedron Lett.
2002, 43, 5233.
ACKNOWLEDGMENTS
■
The authors thank the Science and Engineering Research Board
(SERB), India, for financial support and DST-FIST for the
instrument facility at School of Chemistry, Bharathidasan
University, India. T.S. thanks the Department of Science and
Technology (DST) for an INSPIRE fellowship.
(20) (a) Madsen, C.; Jensen, A. A.; Liljefors, T.; Kristiansen, U.;
Nielsen, B.; Hansen, C. P.; Larsen, M.; Ebert, B.; Bang-Andersen, B.;
Krogsgaard-Larsen, P.; Frølund, B. J. Med. Chem. 2007, 50, 4147. (b) Jin,
Z. Nat. Prod. Rep. 2009, 26, 382. (c) Billaud, E. M. F.; Rbah-Vidal, L.;
Vidal, A.; Besse, S.; Tarrit, S.; Askienazy, S.; Maisonial, A.; Moins, N.;
Madelmont, J.-C.; Miot-Noirault, E.; Chezal, J.-M.; Auzeloux, P. J. Med.
Chem. 2013, 56, 8455. (d) Calderone, V.; Spogli, R.; Martelli, A.;
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