Cascade Oxa-Michael-Henry Reaction of Salicylaldehydes with Nitrostyrenes via Ball Milling: A Solvent-Free Synthesis of 3-Nitro-2 H -chromenes

Article abstract of DOI:10.1055/s-0035-1560964

Cascade oxa-Michael-Henry reactions of salicylaldehyde derivatives with β-nitrostyrenes catalyzed by potassium carbonate via solvent-free ball milling are demonstrated. The corresponding 3-nitro-2H-chromene products were obtained in moderate to excellent yields. This method offers significant advantages, particularly in terms of high yields, short reaction times and mild conditions.

Full text of DOI:10.1055/s-0035-1560964

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 407–412
paper
407
S.-X. Liu et al.
Paper
Synthesis
Cascade Oxa-Michael–Henry Reaction of Salicylaldehydes with
Nitrostyrenes via Ball Milling: A Solvent-Free Synthesis of 3-Nitro-
2H-chromenes
Shui-Xiang Liua
Chun-Man Jia*a,b
Bo-Yuan Yaoa
Xiang-Long Chena
Qi Zhang*a,b
a Hainan Provincial Key Lab of Fine Chemistry (Hainan
University), Haikou, Hainan 570228, P. R. of China
zhangqi@hainu.edu.cn
hnfinechem@163.com
b Key Study Center of the National Ministry of Education
for Tropical Resources Utilization (Hainan University),
Haikou, Hainan 570228, P. R. of China
Received: 24.08.2015
Accepted after revision: 23.10.2015
Published online: 07.12.2015
actions to succeed, and the reactions were generally more
efficient when aqueous salicylaldehyde was used.10 There-
fore, a method with both mild reaction conditions and high
efficiency would prove highly beneficial.
DOI: 10.1055/s-0035-1560964; Art ID: ss-2015-h0497-op
Abstract Cascade oxa-Michael–Henry reactions of salicylaldehyde de-
rivatives with β-nitrostyrenes catalyzed by potassium carbonate via sol-
vent-free ball milling are demonstrated. The corresponding 3-nitro-2H-
chromene products were obtained in moderate to excellent yields. This
method offers significant advantages, particularly in terms of high
yields, short reaction times and mild conditions.
In the last decade, the ball-milling technique has
emerged as a powerful tool, offering a new, environmental-
ly friendly and cost-effective strategy in organic synthesis.11
This particular method tends to provide high reaction
yields and shorter reaction times, without the need for sol-
vents.12,13
Key words solvent-free, ball milling, cascade, oxa-Michael–Henry re-
action, 3-nitro-2H-chromenes
Significant progress has been made in the use of me-
chanical milling techniques in synthetic chemistry.11,14
Some recent examples of mechanical ball-milling tech-
niques in organic synthesis include C–H bond functional-
ization of acetanilides,15 C–N coupling of arylsulfonamides
and carbodiimides,16 and the formation of 2-substituted
1H-indoles17 and 1H-pyrazoles.18 The first mechanochemi-
cally induced cascade reaction was reported by Kaupp and
co-workers in 1999.19 Here, the reaction of trans-1,2-diben-
zoylethene with primary or secondary enamine esters or
enamine ketones in a ball mill afforded the corresponding
pyrrole or indole products in nearly quantitative yields.
Studies describing mechanochemically induced cascade re-
actions can be frequently found in the literature.20 However,
to the best of our knowledge, milling techniques for the cas-
cade reaction of salicylaldehydes with β-nitrostyrenes have
not been reported as yet. We now present the mechano-
chemical activation of cascade oxa-Michael–Henry reac-
tions as a novel, as well as ‘green’, protocol for the produc-
tion of bioactive heterocyclic 3-nitro-2H-chromenes.
Previous studies have used different bases to carry out
this type of cascade reaction in solution.21 For this reason,
we initially investigated the influence of the base on the
cascade oxa-Michael–Henry reaction. Reactions were con-
ducted in a ball-milling apparatus at a rotational frequency
of 15 Hz at room temperature for a total of three hours [6 ×
3-Nitro-2H-chromenes represent important nitro-bear-
ing heterocyclic compounds.1 Studies of these derivatives
have been extensively reported in recent years, mainly due
to the fact that these compounds prove to be easily accessi-
ble and feature high biological activities.2 Several methods
are known to be suitable for the synthesis of 3-nitro-2H-
chromenes;3,4 among them, the cascade reaction of salicyl-
aldehydes or their corresponding imines5 with unsaturated
nitro compounds is probably the most widely used ap-
proach. The corresponding products are formed according
to an oxa-Michael/Henry/dehydration sequence, with often
tedious workup requirements.6 Many of these procedures
are catalyzed by a variety of bases7–9 in an organic solvent
(e.g., toluene, CH2Cl2, CHCl3, DMSO). However, solvents may
be toxic and harmful to the environment. Furthermore,
long reaction times (4–6 days) and/or harsh reaction condi-
tions (100 °C in an inert gas atmosphere) are often required
for these reactions to proceed. In contrast to the traditional
synthetic procedures in solution, Yan and co-workers re-
ported the reaction of salicylaldehydes with β-nitrosty-
renes catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO)
in the absence of a solvent. Unfortunately, a large excess of
the salicylaldehyde (4–10 equiv) was required for these re-
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S.-X. Liu et al.
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Synthesis
(30 minutes + 5 minute break)]. Silicon dioxide was chosen
as the milling auxiliary, and the reaction progress was con-
tinuously monitored by thin-layer chromatography.
Table 1 Cascade Oxa-Michael–Henry Reaction of 1a with 2a Using
Different Additivesa
NO2
NO2
O
Table 1 shows the results of the cascade reaction of sa-
licylaldehyde (1a) with β-nitrostyrene (2a) using different
additives. It should be noted that none of the desired prod-
uct 3aa was formed when no base was added (Table 1, en-
try 1). Presumably, 4-(dimethylamino)pyridine offers im-
proved activity characteristics for this type of cascade reac-
tion relative to other organic bases (e.g., DABCO, Et3N,
DIPEA; Table 1, entries 3–5 and 11). Interestingly, the reac-
tion proceeded quickly when potassium carbonate was
used as an additive, resulting in the best obtained yield of
25% among all bases examined at 20 mol% (Table 1, entry
7). In contrast, an adverse effect on the reaction was ob-
served when hydrated potassium carbonate was used, re-
sulting in a slight product loss (Table 1, entry 6). Strong
bases (e.g., NaOH, DBU) resulted in a significant decrease in
the yields obtained (Table 1, entries 8 and 9). Furthermore,
weak bases such as L-proline and pyridine exhibited a low
efficiency for catalyzing the reaction (Table 1, entries 2 and
12). The use of cesium carbonate resulted in a similar prod-
uct yield as the reaction catalyzed by hydrated potassium
carbonate (Table 1, entry 10).
Unfortunately, all observed yields still proved to be in-
adequate at this point. Therefore, we focused our attention
on determining the influence of the potassium carbonate
concentration on the product yield. As a consequence, we
used potassium carbonate in stoichiometric amounts in-
stead of catalytic amounts. The results obtained clearly
show that there is a significant increase in the reaction rate
and the product yield (Table 1, entries 13–16); when an in-
creased amount (0.75 equiv) of potassium carbonate was
used, the product 3aa was formed in 68% yield (Table 1, en-
try 14). Increasing the amount of potassium carbonate to
1.5 equivalents, however, did not significantly improve the
yield further (Table 1, entry 15).
Various other reaction conditions were investigated in
an effort to further improve the product yield. Interestingly,
increasing the ratio of 1a/2a from 1.0 in the initial experi-
ments to 1.3 and 1.5 resulted in higher observed yields of
3aa of 76% and 78%, respectively (Table 2, entries 1 and 2).
Improving the rotational frequency from 15 Hz to 20 Hz
also led to an increased product yield, along with a 2-hour
decrease in the reaction time (Table 2, entries 1 and 3). The
best result of 85% yield of 3aa was obtained at a rotational
frequency of 25 Hz within 30 minutes (Table 2, entry 4).
Decreased yields were observed when the reaction was
performed at a higher rotational frequency (e.g., 30 Hz; Ta-
ble 2, entry 5). This latter finding is most likely due to prod-
uct and/or substrate degradation resulting from the in-
base
ball milling
H
+
O
OH
1a
2a
Additive
3aa
Amount (mol%) Yieldb (%) of 3aa
Entry
1
2
–
–
0
5
L-proline
DMAP
DABCO
Et3N
20
20
20
20
20
20
20
20
20
20
20
50
75
150
150
3
16
14
10
20
25
17
18
22
12
7
4
5
6
K2CO3·1.5H2O
K2CO3
NaOH
DBU
7
8
9
10
11
12
13
14c
15c
16c
Cs2CO3
DIPEA
pyridine
K2CO3
K2CO3
K2CO3
NaOH
65
68
69
53
a Reaction conditions: salicylaldehyde (1a; 0.2 mmol, 1.0 equiv), β-nitrosty-
rene (2a; 0.2 mmol, 1.0 equiv), SiO2 (500 mg); ball-milling conditions: [6 ×
(30 min + 5 min break)] at 15 Hz.
b Isolated yields, obtained via chromatographic purification on silica gel.
c Ball-milling conditions: [4 × (30 min + 5 min break)] at 15 Hz.
creased amount of energy per impact. Furthermore, the for-
mation of various side products was observed. It is worth
noting that the amount of base (0.5–1.5 equiv) proved to
have no significant influence on the product yields, as the
reaction time was increased until the starting material was
completely consumed (Table 2, entries 4, 6 and 7). On the
other hand, if the substrates could not be mixed in an effi-
cient manner, such as when silicon dioxide was not added,
a poor product yield and partial polymerization of β-nitro-
styrene was observed (Table 2, entry 8). However, the addi-
tion of a relatively large amount of silicon dioxide resulted
in a drastic yield decrease, most likely due to diluted re-
agent concentrations (Table 2, entry 9). As a consequence,
the optimal reaction conditions with respect to ball-milling
time, base loading and ratio of reagents are as follows: mill-
ing frequency = 25 Hz for 30 minutes, reagent ratio
(1a/2a/K2CO3) = 1.3:1.0:0.75.
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Table 2 Further Optimization of the Cascade Oxa-Michael–Henry Re-
action of 1a with 2aa
Table 3 Cascade Oxa-Michael–Henry Reaction of Salicylaldehyde De-
rivatives 1 with β-Nitrostyrenes 2a
O
NO2
NO2
O
NO2
K2CO3
NO2
R2
K2CO3
H
H
+
R1
R1
O
+
ball milling
R2
ball milling
OH
O
OH
3aa–gj
1
2
1a
2a
3aa
Entry
R1 (Substrate 1) R2 (Substrate 2)
Product 3 Yieldb (%)
Entry
Time (h)
Rotational
Reagent ratios
Yieldb (%)
frequency (Hz) (1a/2a/K2CO3)
of 3aa
1
2
H (1a)
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3bj
3cj
85
94
71
97
91
85
83
74
70
86
60
64
67
60
64
1
3
15
15
20
25
30
25
25
25
25
1.3:1:0.75
1.5:1:0.75
1.3:1:0.75
1.3:1:0.75
1.3:1:0.75
1.3:1:0.5
76
78
81
85
74
82
84
70
61
H (1a)
2-O2NC6H4 (2b)
3-O2NC6H4 (2c)
2-BrC6H4 (2d)
3-BrC6H4 (2e)
2,4-Cl2C6H3 (2f)
2-Cl-5-NO2C6H3 (2g)
2-FC6H4 (2h)
3-MeOC6H4 (2i)
Ph (2j)
2
3
3
H (1a)
3
1
4
H (1a)
4
0.5
0.5
2
5
H (1a)
5
6
H (1a)
6
7
H (1a)
7
0.5
0.5
0.5
1.3:1:1.5
8
H (1a)
8c
9d
1.3:1:0.75
1.3:1:0.75
9
H (1a)
10
11
12
13
14
15
5-Br (1b)
5-CF3 (1c)
4-Br (1d)
4-Cl (1e)
5-CO2Me (1f)
5-Me (1g)
a Reaction conditions: 0.20-mmol scale, using SiO2 (500 mg); ball-milling
conditions: 5-min break between each 30-min interval.
b Isolated yields, obtained via chromatographic purification on silica gel.
c SiO2 was not added.
Ph (2j)
Ph (2j)
3dj
3ej
Ph (2j)
d SiO2 (2 g) was added.
Ph (2j)
3fj
Having established the optimal reaction conditions, we
subsequently investigated a range of different salicylalde-
hyde derivatives 1 and β-nitrostyrenes 2 in an effort to
evaluate the scope of this cascade process. The correspond-
ing results are summarized in Table 3.
Ph (2j)
3gj
a Reaction conditions: salicylaldehyde 1 (0.26 mmol, 1.3 equiv), β-nitrosty-
rene 2 (0.2 mmol, 1.3 equiv), K2CO3 (0.15 mmol, 0.75 equiv), SiO2 (500
mg); ball-milling conditions: 30 min at 25 Hz.
b Isolated yields obtained via chromatography on silica gel, without any
aqueous workup.
The reactivity of this reaction type was shown to be
mainly determined by the electronic properties and the po-
sitions of the substituents on the phenyl ring of the ni-
troalkene moiety (Table 3, entries 1–9). In general, elec-
tron-deficient nitroalkene derivatives exhibit a higher reac-
tivity than electron-rich species (Table 3, entries 2, 4 and 5
vs entry 9). Electron-withdrawing functional groups such
as nitro and bromo at the 2-position on the phenyl ring of
the β-nitrostyrene species result in the formation of the de-
sired products 3ab and 3ad in 94% and 97% yield, respec-
tively (Table 3, entries 2 and 4). β-Nitrostyrenes bearing
two electron-withdrawing groups on the phenyl ring can
also provide the corresponding products in excellent yields,
namely 85% and 83% for 3af and 3ag, respectively (Table 3,
entries 6 and 7). Overall, salicylaldehyde derivatives bear-
ing an electron-deficient or electron-rich aryl group under-
go the cascade oxa-Michael–Henry reaction with β-nitro-
styrene efficiently, resulting in the formation of the corre-
sponding 3-nitro-2H-chromenes in good yields (Table 3,
entries 10–15). Here, the use of 5-bromosalicylaldehyde
(1b) provided the best product yield of 86% (3bj; Table 3,
entry 10).
In order to demonstrate the reliability and reproducibil-
ity of this synthetic approach, the cascade reaction of salic-
ylaldehyde (1a) and β-nitrostyrene (2a) was performed on
a gram scale (10 mmol). In doing so, compound 3aa could
be isolated in 80% yield (2.02 g) upon a simple column chro-
matographic purification. Celite® and sodium chloride were
also tested as grinding aids in an effort to further optimize
the reaction conditions, resulting in a product yield of 3aa
of 73% and 79%, respectively; however, these isolated yields
remain lower than the 85% yield obtained with silicon diox-
ide as the grinding aid.
According to reports published previously,22 the sug-
gested reaction mechanism for this sequence involves oxa-
Michael/Henry/dehydration steps. The synthesis proceeds
via cascade nucleophilic additions and a Henry condensa-
tion. In the presence of base, a nucleophilic phenolate anion
is believed to attack the β-nitroalkene species, resulting in
the formation of the corresponding intermediates. The lat-
ter may undergo an intramolecular condensation reaction
to form the 4-hydroxy-3-nitrochromane derivatives. A sub-
sequent dehydration process would then afford the target
compounds 3aa–gj.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 407–412

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Synthesis
In summary, we have developed a general procedure for
the production of 3-nitro-2H-chromene derivatives via the
cascade oxa-Michael–Henry reaction of salicylaldehyde de-
rivatives with β-nitrostyrenes promoted by potassium car-
bonate and solvent-free ball milling with product yields up
to 97%. This method, which has significant advantages in
terms of high yields, short reaction times and mild condi-
tions, may prove useful in the green and efficient synthesis
of bioactive heterocyclic 3-nitro-2H-chromene derivatives.
Further studies to support this hypothesis are currently un-
derway in our laboratory.
3-Nitro-2-(2-nitrophenyl)-2H-chromene (3ab)
Eluent: PE–EtOAc, 20:1; yield: 56 mg (94%); yellow solid; mp 143.0–
144.0 °C.
Rf = 0.25 (PE–EtOAc, 7:1).
IR (KBr): 1648, 1604, 1534, 1517, 1456, 1335, 1119, 764 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.17 (s, 1 H, CH=), 7.93 (d, J = 9.1 Hz, 1
arom), 7.53–7.44 (m, 2 Harom), 7.42 (s, 1 H, CH), 7.37–7.24 (m, 3 Harom),
.
H
7.01 (t, J = 7.5 Hz, 1 Harom), 6.82 (d, J = 8.2 Hz, 1 Harom).
13C NMR (126 MHz, CDCl3): δ = 153.00, 148.71, 139.49, 134.78,
132.95, 130.96, 130.51 (d, J = 6.3 Hz), 130.31, 128.01, 125.41, 123.15,
117.53 (d, J = 13.2 Hz), 68.90.
HRMS (APCI––TOF): m/z [M]– calcd for C15H10N2O5: 298.0590; found:
298.0589.
Ethyl acetate, light petroleum ether and dichloromethane were dis-
tilled prior to use. All other solvents, reagents and chemicals were
used as obtained from commercial sources. Flash column chromatog-
raphy was performed with 100–200 mesh silica gel. 1H NMR and 13C
NMR spectra were recorded on a Bruker Avance 500 NMR spectrome-
ter, and TMS was used as a reference. 1H NMR spectroscopic data are
represented as follows: chemical shift (ppm), multiplicity (s = singlet,
d = doublet, t = triplet, dd = doublet of doublets, m = multiplet), cou-
pling constants in hertz (Hz), integration, assignment. 13C NMR spec-
troscopic data are reported in ppm. IR spectra were recorded on a
Bruker Tensor 27 spectrometer and are reported in wavenumbers
(cm–1). High-resolution mass spectra were measured on a Shimadzu
LCMS-IT-TOF spectrometer (APCI). All melting points were deter-
mined using a digital melting point apparatus and are uncorrected.
The starting β-nitrostyrene and salicylaldehyde derivatives were pre-
pared according to literature procedures.23,24
3-Nitro-2-(3-nitrophenyl)-2H-chromene (3ac)
Eluent: PE–EtOAc, 20:1; yield: 42 mg (71%); yellow solid; mp 146.5–
147.5 °C.
Rf = 0.4 (PE–EtOAc, 7:1).
IR (KBr): 1646, 1604, 1534, 1514, 1459, 1344, 1325, 1121 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.53 (s, 1 H, CH=), 8.27 (s, 1 Harom),
8.24 (d, J = 10.4 Hz, 1 Harom), 7.87 (d, J = 8.9 Hz, 1 Harom), 7.71–7.66 (m,
2 Harom), 7.42 (t, J = 7.8 Hz, 1 Harom), 7.11 (t, J = 7.5 Hz, 1 Harom), 6.94 (d,
J = 8.2 Hz, 1 Harom), 6.90 (s, 1 H, CH).
13C NMR (126 MHz, DMSO-d6): δ = 152.79, 148.54, 140.20, 139.18,
135.29, 133.96, 131.93, 131.32, 131.22, 124.84, 123.45, 122.36,
118.36, 117.24, 72.67.
HRMS (APCI––TOF): m/z [M]– calcd for C15H10N2O5: 298.0590; found:
298.0584.
3-Nitro-2H-chromenes 3aa–3gj; General Procedure
2-(2-Bromophenyl)-3-nitro-2H-chromene (3ad)
Reactions were conducted in a ball-milling apparatus (Retsch MM400
Mixer Mill, Retsch GmbH, Haan, Germany; volume of stainless steel
vial: 10 mL; diameter of stainless steel balls: 10.0 mm). In a typical
experiment, a salicylaldehyde 1 (0.26 mmol, 1.3 equiv), a β-nitrosty-
rene 2 (0.2 mmol, 1 equiv) and K2CO3 (0.15 mmol, 0.75 equiv) were
ball-milled with 500 mg SiO2 for 30 min [2 × (15 min + 5 min break)]
at 25 Hz. The reaction mixture was then transferred directly onto a
flash column, without any additional workup step, and was subjected
to chromatographic purification on silica gel [eluent(s) given below]
to afford the corresponding 3-nitro-2H-chromene 3aa–gj.
Eluent: PE–EtOAc, 300:1; yield: 64 mg (97%); yellow solid; mp 115.5–
116.5 °C.
Rf = 0.25 (PE–EtOAc, 100:1).
IR (KBr): 1647, 1603, 1511, 1456, 1334, 1222, 1120, 762, 573 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.16 (s, 1 H, CH=), 7.67 (d, J = 6.6 Hz, 1
arom), 7.35 (dd, J = 7.6, 1.6 Hz, 1 Harom), 7.33–7.28 (m, 1 Harom), 7.22–
.
H
7.16 (m, 3 Harom), 7.03 (s, 1 H, CH), 7.01 (t, J = 7.5 Hz, 1 Harom), 6.83 (d,
J = 8.2 Hz, 1 Harom).
13C NMR (126 MHz, CDCl3): δ = 153.09, 140.31, 134.86, 134.50,
134.00, 131.15, 130.38, 130.28, 128.08, 127.81, 124.29, 122.69,
117.73, 117.51, 73.13.
HRMS (APCI––TOF): m/z [M]– calcd for C15H10BrNO3: 330.9844; found:
330.9842.
3-Nitro-2-phenyl-2H-chromene (3aa)
Eluent: hexane–EtOAc, 1000:1; yield: 43 mg (85%); yellow solid; mp
93.0 °C.
Rf = 0.2 (hexane–EtOAc, 60:1).
1H NMR (500 MHz, CDCl3): δ = 8.06 (s, 1 H, CH=), 7.41–7.28 (m, 7
2-(3-Bromophenyl)-3-nitro-2H-chromene (3ae)
H
arom), 7.00 (t, J = 7.5 Hz, 1 Harom), 6.87 (d, J = 8.7 Hz, 1 Harom), 6.59 (s, 1
Eluent: hexane–CH2Cl2, 20:1; yield: 60 mg (91%); yellow solid; mp
114.5–115.5 °C.
H, CH).
13C NMR (126 MHz, CDCl3): δ = 153.57, 141.17, 136.79, 134.35,
130.47, 129.50, 129.33, 128.87, 127.05, 122.56, 117.95, 117.30, 74.27.
The 1H NMR and 13C NMR data for this compound are in accordance
with the literature data.9
HRMS (APCI––TOF): m/z [M]– calcd for C15H11NO3: 253.0739; found:
Rf = 0.1 (hexane–CH2Cl2, 80:1).
IR (KBr): 1647, 1602, 1510, 1457, 1334, 1222, 1119, 762 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.16 (s, 1 H, CH=), 7.67 (dd, J = 8.0, 1.7
Hz, 1 Harom), 7.35 (dd, J = 7.6, 1.6 Hz, 1 Harom), 7.31 (m, 1 Harom), 7.22–
7.15 (m, 3 Harom), 7.04 (s, 1 H, CH), 7.01 (t, J = 8.0 Hz, 1 Harom), 6.83 (d,
J = 8.2 Hz, 1 Harom).
.
253.0738.
13C NMR (126 MHz, CDCl3): δ = 153.10, 140.30, 134.87, 134.51,
134.00, 131.16, 130.39, 130.28, 128.09, 127.82, 124.29, 122.70,
117.74, 117.51, 73.14.
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HRMS (APCI––TOF): m/z [M]– calcd for C15H10BrNO3: 330.9844; found:
330.9844.
13C NMR (126 MHz, CDCl3): δ = 159.85, 153.56, 141.08, 138.23,
134.32, 130.46, 129.92, 129.31, 122.57, 119.21, 117.93, 117.27,
114.62, 113.06, 74.11, 55.25.
HRMS (APCI––TOF): m/z [M]– calcd for C16H13NO4: 283.0845; found:
2-(2,4-Dichlorophenyl)-3-nitro-2H-chromene (3af)
283.0845.
Eluent: PE–EtOAc, 200:1; yield: 55 mg (85%); yellow solid; mp 155.0–
156.0 °C.
6-Bromo-3-nitro-2-phenyl-2H-chromene (3bj)
Rf = 0.2 (PE–EtOAc, 100:1).
Eluent: hexane–Et2O, 160:1; yield: 57 mg (86%); yellow solid; mp
136.5–137.5 °C.
IR (KBr): 1649, 1605, 1506, 1457, 1333, 1223, 1071, 759 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.52 (s, 1 H, CH=), 7.80 (s, 1 Harom),
7.66 (d, J = 9.1 Hz, 1 Harom), 7.38 (dd, J = 17.7, 8.8 Hz, 2 Harom), 7.30 (d,
J = 8.4 Hz, 1 Harom), 7.09 (t, J = 7.4 Hz, 1 Harom), 6.95 (s, 1 H, CH), 6.85 (d,
J = 8.2 Hz, 1 Harom).
13C NMR (126 MHz, DMSO-d6): δ = 152.53, 139.59, 135.67, 135.19,
134.33, 132.79, 131.90, 131.70, 130.49, 130.06, 128.48, 123.35,
118.26, 117.15, 70.31.
Rf = 0.3 (hexane–Et2O, 80:1).
IR (KBr): 1649, 1592, 1521, 1337, 1320, 1063 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.01 (s, 1 H, CH=), 7.39–7.29 (m, 5
Harom), 7.18 (d, J = 8.1 Hz, 1 Harom), 7.14 (dd, J = 8.1, 1.7 Hz, 1 Harom),
.
7.05 (d, J = 1.2 Hz, 1 Harom), 6.57 (s, 1 H, CH).
13C NMR (126 MHz, CDCl3): δ = 153.90, 141.17, 136.24, 131.09,
129.76, 128.99, 128.41, 128.10, 127.06, 125.98, 120.73, 116.94, 74.59.
HRMS (APCI––TOF): m/z [M]– calcd for C15H9Cl2NO3: 320.9959; found:
320.9959.
HRMS (APCI––TOF): m/z [M]– calcd for C15H10BrNO3: 330.9844; found:
330.9840.
2-(2-Chloro-5-nitrophenyl)-3-nitro-2H-chromene (3ag)
Eluent: hexane–EtOAc, 90:1; yield: 55 mg (83%); yellow solid; mp
206.0–207.0 °C.
3-Nitro-2-phenyl-6-(trifluoromethyl)-2H-chromene (3cj)
Eluent: 100% PE; yield: 40 mg (60%); yellow solid; mp 112.0 °C.
Rf = 0.15 (PE).
Rf = 0.2 (hexane–EtOAc, 30:1).
IR (KBr): 1649, 1607, 1558, 1509, 1498, 1336, 1304, 1271, 1244 cm–1
.
IR (KBr): 1656, 1620, 1520, 1337, 1302, 1193, 1160, 1121, 1058 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.62 (s, 1 H, CH=), 8.25 (dd, J = 8.8,
2.7 Hz, 1 Harom), 7.99–7.93 (m, 2 Harom), 7.71 (d, J = 7.5 Hz, 1 Harom),
7.41 (t, J = 7.8 Hz, 1 Harom), 7.12 (t, J = 7.4 Hz, 1 Harom), 7.08 (s, 1 H, CH),
6.87 (d, J = 8.2 Hz, 1 Harom).
13C NMR (126 MHz, DMSO-d6): δ = 152.35, 147.18, 140.07, 139.14,
135.46, 135.27, 132.56, 132.00, 131.92, 126.74, 123.65, 123.18,
117.98, 117.15, 70.51.
1H NMR (500 MHz, CDCl3): δ = 8.05 (s, 1 H, CH=), 7.60 (s, 1 Harom), 7.56
(d, J = 9.9 Hz, 1 Harom), 7.42–7.30 (m, 5 Harom), 6.96 (d, J = 8.6 Hz, 1
H
arom), 6.64 (s, 1 H, CH).
13C NMR (126 MHz, CDCl3): δ = 155.81, 142.09, 136.15, 130.91 (d, J =
3.5 Hz), 129.93, 129.09, 127.76, 127.49, 127.46, 127.05, 125.53–
124.46 (m), 122.53, 117.82 (d, J = 18.0 Hz), 74.88.
HRMS (APCI––TOF): m/z [M]– calcd for C16H10F3NO3: 321.0613; found:
HRMS (APCI––TOF): m/z [M – NO2]– calcd for C15H9ClNO3: 286.0271;
found: 286.0271.
321.0615.
7-Bromo-3-nitro-2-phenyl-2H-chromene (3dj)
Eluent: 100% PE; yield: 42 mg (64%); yellow solid; mp 133.0–134.0 °C.
Rf = 0.1 (PE).
2-(2-Fluorophenyl)-3-nitro-2H-chromene (3ah)
Eluent: PE–EtOAc, 2000:1; yield: 40 mg (74%); yellow solid; mp
141.5–142.5 °C.
IR (KBr): 1651, 1591, 1515, 1320, 1130, 1064, 821, 697 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.02 (s, 1 H, CH=), 7.37–7.33 (m, 5
arom), 7.18 (d, J = 8.1 Hz, 1 Harom), 7.14 (dd, J = 8.1, 1.8 Hz, 1 Harom),
.
Rf = 0.3 (PE–EtOAc, 100:1).
IR (KBr): 1650, 1605, 1512, 1457, 1325, 1219, 1120, 1070, 754 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.12 (s, 1 H, CH=), 7.36–7.30 (m, 3
.
H
7.05 (d, J = 1.2 Hz, 1 Harom), 6.57 (s, 1 H, CH).
13C NMR (126 MHz, CDCl3): δ = 153.90, 141.16, 136.23, 131.09,
129.77, 129.00, 128.42, 128.10, 127.06, 125.98, 120.73, 116.94, 74.58.
HRMS (APCI––TOF): m/z [M]– calcd for C15H10BrNO3: 330.9844; found:
H
H
arom), 7.20 (t, J = 7.5 Hz, 1 Harom), 7.13 (m, 1 Harom), 7.06–6.98 (m, 2
arom), 6.93 (s, 1 H, CH), 6.83 (d, J = 8.2 Hz, 1 Harom).
13C NMR (126 MHz, CDCl3): δ = 161.42, 159.43, 153.30, 139.74,
134.46, 131.56 (d, J = 8.4 Hz), 130.25 (d, J = 45.8 Hz), 128.22 (d, J = 2.8
Hz), 124.31 (d, J = 3.6 Hz), 123.69 (d, J = 13.7 Hz), 122.65, 117.66,
117.26, 116.31 (d, J = 21.7 Hz), 68.31.
HRMS (APCI––TOF): m/z [M – NO2]– calcd for C15H10FO: 225.0716;
found: 225.0725.
330.9846.
7-Chloro-3-nitro-2-phenyl-2H-chromene (3ej)
Eluent: PE–EtOAc, 400:1; yield: 38 mg (67%); yellow solid; mp
127.0 °C.
Rf = 0.16 (PE–EtOAc, 120:1).
2-(3-Methoxyphenyl)-3-nitro-2H-chromene (3ai)
IR (KBr): 1644, 1598, 1515, 1318, 1074, 824, 700 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.02 (s, 1 H, CH=), 7.37–7.31 (m, 5
arom), 7.25 (d, J = 5.1 Hz, 1 Harom), 6.98 (dd, J = 8.2, 1.9 Hz, 1 Harom),
.
Eluent: PE–EtOAc, 170:1; yield: 40 mg (70%); yellow solid; mp 64.0–
65.0 °C.
H
Rf = 0.3 (PE–EtOAc, 60:1).
6.88 (d, J = 1.4 Hz, 1 Harom), 6.57 (s, 1 H, CH).
13C NMR (126 MHz, CDCl3): δ = 154.03, 141.06, 139.86, 136.27,
130.99, 129.75, 128.99, 128.36, 127.06, 123.09, 117.82, 116.57, 74.55.
IR (KBr): 2925, 2854, 1645, 1606, 1510, 1454, 1379, 1326, 1283 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.04 (s, 1 H, CH=), 7.31 (t, J = 6.5 Hz, 2
arom), 7.22 (t, J = 7.9 Hz, 1 Harom), 7.04–6.82 (m, 5 Harom), 6.55 (s, 1 H,
CH), 3.75 (s, 3 H, OCH3).
.
H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 407–412

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Paper
Synthesis
HRMS (APCI––TOF): m/z [M]– calcd for C15H10ClNO3: 287.0349; found:
287.0351.
(3) Wang, X. F.; Peng, L.; An, J.; Li, C.; Yang, Q. Q.; Lu, L. Q.; Gu, F. L.;
Xiao, W. J. Chem. Eur. J. 2011, 17, 6484.
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2005, 44, 4442. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
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Methyl 3-Nitro-2-phenyl-2H-chromene-6-carboxylate (3fj)
Eluent: PE–CH2Cl2, 10:1; yield: 37 mg (60%); yellow solid; mp 174.0–
175.0 °C.
Rf = 0.2 (PE–CH2Cl2, 3:1).
IR (KBr): 1721, 1655, 1611, 1520, 1444, 1323, 1268, 1206, 1134, 1069
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.07 (s, 1 H, CH=), 8.05 (d, J = 2.1 Hz, 1
arom), 7.99 (dd, J = 8.6, 2.1 Hz, 1 Harom), 7.38–7.32 (m, 5 Harom), 6.90 (d,
H
J = 8.6 Hz, 1 Harom), 6.63 (s, 1 H, CH), 3.91 (s, 3 H, OCH3).
13C NMR (126 MHz, CDCl3): δ = 165.70, 157.05, 141.64, 136.35,
135.52, 132.18, 129.83, 129.02, 128.35, 127.05, 124.68, 117.56,
117.26, 75.02, 52.29.
HRMS (APCI––TOF): m/z [M]– calcd for C17H13NO5: 311.0794; found:
311.0792.
(9) Climent, M. J.; Iborra, S.; Sabater, M. J.; Vidal, J. D. Appl. Catal. A:
Gen. 2014, 481, 27.
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C.; Clark, T. D.; Mack, J. Tetrahedron Lett. 2012, 53, 4510.
(c) Thorwirth, R.; Stolle, A.; Ondruschka, B. Green Chem. 2010,
12, 985.
(12) (a) Mack, J.; Fulmer, D.; Stofel, S.; Santos, N. Green Chem. 2007,
9, 1041. (b) Zhu, X.; Li, Z.; Jin, C.; Xu, L.; Wu, Q.; Su, W. Green
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Green Chem. 2013, 15, 1659.
6-Methyl-3-nitro-2-phenyl-2H-chromene (3gj)
Eluent: PE–EtOAc, 1000:1; yield: 34 mg (64%); yellow solid; mp
122.0 °C.
Rf = 0.15 (PE–EtOAc, 100:1).
IR (KBr): 2926, 2854, 1648, 1503, 1455, 1384, 1332, 1209, 1070, 701
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.02 (s, 1 H, CH=), 7.37 (dd, J = 6.7, 3.0
Hz, 2 Harom), 7.32 (d, J = 2.2 Hz, 2 Harom), 7.31 (d, J = 1.6 Hz, 1 Harom),
7.12 (t, J = 7.3 Hz, 2 Harom), 6.77 (d, J = 8.9 Hz, 1 Harom), 6.56 (s, 1 H, CH),
2.29 (s, 3 H, CH3).
(14) (a) Tullberg, E.; Schacher, F.; Peters, D.; Frejd, T. Synthesis 2006,
1183. (b) Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V.
K. J. Am. Chem. Soc. 2002, 124, 6244. (c) Bernhardt, F.; Trotzki,
R.; Szuppa, T.; Stolle, A.; Ondruschka, B. Beilstein J. Org. Chem.
2010, 6, 1.
13C NMR (126 MHz, CDCl3): δ = 151.47, 141.20, 136.85, 135.16,
132.02, 130.53, 129.54, 129.40, 128.82, 127.02, 117.79, 117.05, 74.14,
20.41.
HRMS (APCI––TOF): m/z [M]– calcd for C16H13NO3: 267.0895; found:
267.0891.
(15) Juribasić, M.; Užarević, K.; Gracin, D.; Ćurić, M. Chem. Commun.
2014, 50, 10287.
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(17) Zille, M.; Stolle, A.; Wild, A.; Schubert, U. S. RSC Adv. 2014, 4,
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(18) Paveglio, G. C.; Longhi, K.; Moreira, D. N.; München, T. S.; Tier, A.
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Acknowledgment
Financial support was provided by the National Natural Science Foun-
dation of China (Grant Nos. 21261008, 21562018, 21471069) and the
International Science and Technology Cooperation Projects of Hainan
Province (Grant No. KJHZ2014-05).
(19) Kaupp, G.; Schmeyers, J.; Kuse, A.; Atfeh, A. Angew. Chem. Int. Ed.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 407–412