Convenient one-pot synthesis of 3-aryl-2H-chromene- 4-carbonitriles via a tandem O-alkylationknoevenagel condensation

Article abstract of DOI:10.3987/COM-11-12203

3-Aryl-2H-chromene-4-carbonitriles were synthesized through one-pot tandem reaction of easily available 2-(2-hydroxyphenyl)acetonitrile (1) and 2-bromo-1-arylethanones (2) under the condition of K₂CO ₃/dioxane. These functionalized chromenes could be useful building-blocks for estrogen receptor ligands and other related heterocycles.

Full text of DOI:10.3987/COM-11-12203

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HETEROCYCLES, Vol. 83, No. 6, 2011, pp. 1355 - 1361. © The Japan Institute of Heterocyclic Chemistry
Received, 8th March, 2011, Accepted, 5th April, 2011, Published online, 13th April, 2011
DOI: 10.3987/COM-11-12203
CONVENIENT ONE-POT SYNTHESIS OF 3-ARYL-2H-CHROMENE-
4-CARBONITRILES
VIA
A
TANDEM
O-ALKYLATION-
KNOEVENAGEL CONDENSATION
Yanhong Chen, Haoyue Xiang, Yuyuan Xie, and Chunhao Yang*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
SIBS, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203
P. R. China; e-mail: chyang@mail.shcnc.ac.cn
Abstract – 3-Aryl-2H-chromene-4-carbonitriles were synthesized through
one-pot tandem reaction of easily available 2-(2-hydroxyphenyl)acetonitrile (1)
and 2-bromo-1-arylethanones (2) under the condition of K2CO3/dioxane. These
functionalized chromenes could be useful building-blocks for estrogen receptor
ligands and other related heterocycles.
INTRODUCTION
2H-Chromenes exist widely in plants. They have attracted widespread interest in view of their various
biological activities, especially as potentially useful pesticides,1 endothelin-A selective receptor
antagonists,2 and potassium channel-opening vasodilators.3 Some 2H-chromenes are effective
photoaffinity reagents for the cytochrome P450 superfamily of enzymes and probably other proteins as
well.4 3-Phenyl substituted 2H-chromenes belong to trans-1,2-diphenylethenes, which are an important
scaffold for estrogen receptor modulators.5
So far, considerable literatures have reported the synthesis of 2H-chromenes, but very few methods are
known to synthesize 4-substituted 3-aryl-2H-chromenes. Besides the classic synthesis by the reaction of
Grignard reagent with 3-arylchroman-4-ones,5b,6 Tech-Peng Loh’s group has reported the synthesis of
4-amide substituted 3-aryl-2H-chromenes by palladium-catalyzed direct arylation of cyclic enamides with
aryl silanes.7 José Barluenga’ group synthesized this type of compounds by cyclization of aryl propargyl
ethers followed by Suzuki reaction.8 Both reported methods needed expensive palladium catalyst.

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Herein, we synthesized 4-cyano substituted 3-aryl-2H-chromenes through metal-free one-step reaction of
easily available 2-(2-hydroxyphenyl)acetonitrile (1) and 2-bromo-1-arylethanones (2) under the condition
of K2CO3/dioxane. These chromenes are important building-blocks for other 4-substituted
3-aryl-2H-chromenes because of the presence of functional cyano and vinyl groups.
RESULTS AND DISCUSSION
A few of methods have been reported to synthesize 2-(2-hydroxyphenyl)acetonitrile (1). Most of them
used highly toxic cyanide.9 Nakamura reported hydrolysis, decarboxylation and rearrangement of methyl
4H-benzo[e][1,2]oxazine-3-carboxylate through two steps.10 Ryozo Maeda employed reduction,
diazotization and hydrolysis of 2-nitrophenylacetonitrile.11 However, 1H-indazole-3-carbonitrile was
gained under the same condition as the latter by our lab. Finally, compound (1) was synthesized by
demethylation of 2-(2-methoxyphenyl)acetonitrile by BBr3 for the first time.
Then 2-(2-hydroxyphenyl)acetonitrile (1) was reacted with 2-bromo-1-phenylethanone (2a) to optimize
the reaction conditions (Table 1). Initially, the effect of base was examined. We found that strong or
moderate base such as MeONa and Ca(OH)2 gave little product (entries 1 and 2). DMAP reacted with the
compound (2a) to give quaternary ammonium, which was demonstrated by LC-MS (entry 3). DBU gave
a trace amount of the product (entry 4). K2CO3 was much better than Cs2CO3, giving the desired product
with moderate yield (entries 5 and 6). However, the intermediate 2-(2-(2-oxo-2-phenylethoxy)-
phenyl)acetonitrile (3a) was not completely converted to the product even after 24 h.
The solubility of K2CO3 in organic solvent was also taken into consideration. One of the strategies was to
add 0.5 mL of water into the reaction. But the yield was not improved as expected (entry 7). The other
strategy was to try different solvents. When the reaction was carried out in acetone or dioxane instead of
toluene, the reaction could be finished within 4 h and the yield was dramatically increased (entries 8 and
9). Interestingly the polar solvent DMF hardly gave any product (entry 10).
The microwave-assisted reaction could not shorten the reaction time and its main product was the
intermediate (entry 11). The amount of base could be decreased into 1.2 equivalent without influencing
the reaction (entry 12).
o
Finally, we investigated the effect of the reaction temperature. When lowering the temperature to 80 C,
the starting material was converted to the intermediate within 4 h (entry 13). Prolonging the reaction time,
the intermediate could be converted to the product slowly.
o
Under the optimized reaction condition (1.2 eq K2CO3, dioxane, 120 C), we investigated the scope and
the limitations of the reaction employing a variety of 2-bromo-1-arylethanones with the compound (1).
The results were summarized in Table 2.

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1357
Table 1. The annulation reaction of 2-(2-hydroxyphenyl)acetonitrile with 2-bromo-1-phenylethanonea
NC
O
NC
CN
O
Br
O
base
O
OH
solvent
3a
4a
1
2a
Entry
Base
Solvent
Time (h)
Temperature (oC) Yield (%)d
1
2
3
4
5
6
7
8
MeONa
Ca(OH)2
DMAP
DBU
toluene
toluene
toluene
toluene
toluene
toluene
toluene/water
acetone
dioxane
DMF
5
24
2
1
1
24
24
4
120
120
120
120
120
120
120
80
120
120
130
120
80
trace
0
0
trace
9
63
37
82
90
0
8
90
0
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
4
10
11
12
13
0.25
0.5
4
b
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
c
c
4
aReaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), base (1.5 mmol), solvent (5 mL).
bThe reaction was assisted by microwave.
cBase (0.6 mmol).
dThe isolated yield.
When R2 was hydrogen, substitution with electron-donating groups on phenyl group gave very excellent
yield (88-99%), such as methyl and methoxy (entries 1 and 2); substitution with electron-withdrawing
groups such as chlorine, fluorine or trifluoromethyl gave moderate yield (58-71%, entries 3, 4, 6, 7, and
9). However, when phenyl group was substituted with nitro at the para or ortho position, there was almost
no desired product but only complex side products (entries 5 and 8). To our delight, the bulky substrates
such as 2-bromo-1-(naphthalen-2-yl)ethanone and 2-bromo-1,2-diphenylethanone reacted smoothly and
gave good yield (entries 10 and 11). Heterocycles such as 2-bromo-1-(thiophen-2-yl)ethanone could be
also reacted with compound (1) with an acceptable yield (entry 12).

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Table 2. The annulation reaction of 2-(2-hydroxyphenyl)acetonitrile with 2-bromo-1-arylethanonesa
NC
O
CN
R2
R1
R2
OH
R1
K2CO3/dioxane, 4 h
Reflex
Br
2
O
4a
1
Entry
1
2
3
4
5
6
7
8
R1
R2
H
H
H
H
H
H
H
H
Yield (%)b
4-MeOPh
4-MePh
4-ClPh
99
91
71
58
0
63
63
0
4-FPh
4- O2NPh
4-CF3Ph
3-ClPh
2- O2NPh
9
2,4-difluorophenyl
naphthalen-2-yl
Ph
H
H
Ph
H
68
88
80
29
10
11
12
thiopheny-2-yl
aReaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), base (0.6 mmol), solvent (5 mL).
bThe isolated yield.
In summary, a convenient method was discovered to synthesize 3-aryl-2H-chromene-4-carbonitriles
through one-pot tandem reaction of easily available 2-(2-hydroxyphenyl)acetonitrile (1) and
2-bromo-1-arylethanones (2) under the condition of K2CO3/dioxane, which was general to aryl ring with
electron-donating and electron-withdrawing groups. These functionalized chromenes could be useful
building-blocks for estrogen receptor ligands and other related heterocycles.
EXPERIMENTAL
Except the starting material (1), the other chemical reagents were commercial products and used without
1
purification in all cases. Solvents were dried by standard methods. H and 13C NMR spectra were
recorded on Varian Mercury-300 and Varian Mercury-400 spectrometers. MS and HRMS spectra were
recorded on a MAT-95 spectrometer. Melting points were measured by Büchi 510 melting point
apparatus and were uncorrected.
2-(2-Hydroxyphenyl)acetonitrile (1)
To a solution of 2-(2-methoxyphenyl)acetonitrile (9.4 g, 64 mmol) in 200 mL of absolute CH2Cl2 was
added 80 mL of 4 N BBr3 in CH2Cl2 at 0 °C slowly. Then the reaction mixture was stirred at room
temperature overnight and added into ice-water under stirring. The resulting white precipitate was filtered,

HETEROCYCLES, Vol. 83, No. 6, 2011
1359
washed with water and dried. The crude solid was purified by column chromatography on silica gel
(petroleum ether/EtOAc = 2:1) to gain 4.4 g white solid. Yield: (52%); mp 122-123 °C (lit.,10 mp
118.5-119 °C).
The general procedure of 3-aryl-2H-chromene-4-carbonitrile (4)
A mixture of 2-(2-hydroxyphenyl)acetonitrile (0.5 mmol), 2-bromo-1-arylethanone (0.5 mmol) and
K2CO3 (0.6 mmol) in 5 mL of dioxane was heated under reflux for 4 h. The solvent was evaporated under
reduced pressure. The residue was purified by column chromatography on silica gel, with petroleum
ether/EtOAc (30:1) as eluent to give the desired product.
3-Phenyl-2H-chromene-4-carbonitrile (4a)
White solid, mp 47-49 °C. 1H NMR (300 MHz, CDCl3):  7.60 (m, 2H), 7.50 (m, 4H), 7.28 (t, J = 7.9Hz,
1H), 7.07 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 5.11 (s, 2H). 13C NMR (100 MHz, CDCl3):  152.4,
146.2, 134.3, 130.9, 130.3, 129.0, 127.4, 125.6, 122.5, 119.1, 116.1, 115.3, 106.4, 68.3. MS (EI) m/z (%):
233 (M+, 100). HRMS (EI) calcd. for C16H11NO, 233.0841; found 233.0837.
3-(4-Methoxyphenyl)-2H-chromene-4-carbonitrile (4b)
White solid, mp 126-128 °C. 1H NMR (300 MHz, CDCl3):  7.58 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 7.6 Hz,
1H), 7.25 (t, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H),
5.07 (s, 2H), 3.87 (s, 3H).13C NMR (100 MHz, CDCl3):  161.1, 152.3, 145.8, 130.4, 129.0, 126.5, 125.4,
122.4, 119.4, 116.1, 115.8, 114.4, 104.6, 68.2, 55.4. MS (EI) m/z (%): 263 (M+, 100). HRMS (EI) calcd.
for C17H13NO2, 263.0946; found 263.0953.
3-(4-Tolyl)-2H-chromene-4-carbonitrile (4c)
White solid, mp 98-100 °C. 1H NMR (300 MHz, CDCl3):  7.51 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 7.6 Hz,
1H), 7.30 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H),
5.08 (s, 2H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3):  152.4, 146.2, 140.8, 131.4, 130.6, 129.7, 127.3,
125.5, 122.4, 119.2, 116.1, 115.5, 105.6, 68.3, 21.4. MS (EI) m/z (%): 247 (M+, 100). HRMS (EI) calcd.
for C17H13NO, 247.0997; found 247.0998.
3-(4-Chlorophenyl)-2H-chromene-4-carbonitrile (4d)
Yellow solid, mp 129-131 °C. 1H NMR (300 MHz, CDCl3):  7.54 (d, J = 8.5 Hz, 2H), 7.52 – 7.44 (m,
3H), 7.28 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 5.07 (s, 2H). 13C NMR
(100 MHz, CDCl3):  152.4, 144.6, 136.4, 132.7, 131.1, 129.3, 128.7, 125.7, 122.6, 118.9, 116.2, 115.1,
106.9, 68.1. MS (EI) m/z (%): 267 (M+, 100), 269 (M+2, 33). HRMS (EI) calcd. for C16H10NOCl,
267.0451; found 267.0450.
3-(4-Fluorophenyl)-2H-chromene-4-carbonitrile (4e)
Yellow solid, mp 106-107 °C. 1H NMR (300 MHz, CDCl3):  7.64 – 7.56 (m, 2H), 7.49 (d, J = 7.6 Hz,

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1H), 7.32 – 7.24 (m, 1H), 7.19 (t, J = 8.6 Hz, 2H), 7.07 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 5.07
(s, 2H).13C NMR (100 MHz, CDCl3):  163.6 (d, J = 251 Hz), 152.4, 144.9, 131.0, 130.4, 129.6, 129.5,
125.6, 122.6, 118.9, 116.4, 116.2, 116.1, 115.2, 106.5, 68.2. MS (EI) m/z (%): 251 (M+, 100). HRMS (EI)
calcd. for C16H10NOF, 251.0746; found 251.0740.
3-(4-(Trifluoromethyl)phenyl)-2H-chromene-4-carbonitrile (4f)
Yellow solid, mp 132-134 °C. 1H NMR (300 MHz, CDCl3):  7.76 (d, J = 8.3Hz, 2H), 7.71 (d, J = 8.3 Hz,
2H), 7.51 (d, J = 7.9 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H),
5.11 (s, 2H). 13C NMR (100 MHz, CDCl3):  152.5, 144.1, 137.9, 131.9 (d, J = 32 Hz), 131.5, 127.8,
126.1, 126.0, 125.9, 123.5 (d, J = 271 Hz), 122.7, 118.7, 116.3, 114.7, 108.2, 68.0. MS (EI) m/z (%): 301
(M+, 100). HRMS (EI) calcd. for C17H10NOF3, 301.0715; found 301.0720.
3-(3-Chlorophenyl)-2H-chromene-4-carbonitrile (4g)
Yellow solid, mp 100-101 °C. 1H NMR (300 MHz, CDCl3):  7.56 – 7.46 (m, 3H), 7.47 – 7.40 (m, 2H),
7.29 (td, J = 8.1, 1.0 Hz, 1H), 7.07 (td, J = 7.5, 1.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.07 (s, 2H). 13C
NMR (100 MHz, CDCl3):  152.5, 144.3, 136.1, 135.0, 131.3, 130.4, 130.3, 127.3, 125.8, 125.7, 122.6,
118.8, 116.3, 114.8, 107.6, 68.1. MS (EI) m/z (%): 267 (M+, 100), 269 (M+2, 33). HRMS (EI) calcd. for
C16H10NOCl, 267.0451; found 267.0452.
3-(2, 4-Difluorophenyl)-2H-chromene-4-carbonitrile (4h)
Yellow solid, mp 133-135 °C. 1H NMR (300 MHz, CDCl3):  7.61 (dd, J = 14.7, 8.4 Hz, 1H), 7.48 (d, J =
13
7.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.12 – 6.97 (m, 2H), 6.94 (d, J = 7.8 Hz, 2H), 5.01 (s, 2H). C
NMR (100 MHz, CDCl3):  164.0 (dd, J = 253, 12 Hz), 160.3 (dd, J = 251, 12 Hz), 152.7, 140.6, 131.5,
131.1 (dd, J = 10, 4.9 Hz), 125.7, 122.6, 118.8 (dd, J = 15, 3.3 Hz), 118.7, 116.3, 114.5, 112.3 (dd, J = 21,
3.2 Hz), 109.6, 105.0 (t, J = 25 Hz), 67.7 (d, J = 6.8 Hz). MS (EI) m/z (%): 269 (M+, 100). HRMS (EI)
calcd. for C16H9NOF2, 269.0652; found 269.0645.
3-(Naphthalen-2-yl)-2H-chromene-4-carbonitrile (4i)
Yellow solid, mp 118-119 °C. 1H NMR (300 MHz, CDCl3):  8.09 (s, 1H), 8.00 – 7.84 (m, 3H), 7.69 (d,
J = 8.6 Hz, 1H), 7.62 – 7.52 (m, 3H), 7.28 (t, J = 8.6 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 6.95 (d, J = 8.1 Hz,
1H), 5.21 (s, 2H). 13C NMR (100 MHz, CDCl3):  152.5, 146.0, 133.8, 132.9, 131.7, 130.9, 128.9, 128.5,
127.7, 127.6, 127.5, 126.9, 125.7, 124.1, 122.5, 119.2, 116.2, 115.4, 106.6, 68.4. MS (EI) m/z (%): 283
(M+, 100). HRMS (EI) calcd. for C20H13NO, 283.0997; found 283.1000.
2, 3-Diphenyl-2H-chromene-4-carbonitrile (4j)
Yellow solid, mp 109-111 °C. 1H NMR (300 MHz, CDCl3):  7.56 – 7.52 (m, 3H), 7.43 – 7.36 (m, 3H),
7.37 – 7.18 (m, 6H), 7.03 (t, J = 8.1 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.22 (s, 1H). 13C NMR (100 MHz,
CDCl3):  150.6, 147.0, 136.4, 135.0, 131.1, 130.0, 129.2, 128.8, 128.7, 127.7, 127.6, 125.4, 122.1, 118.8,

HETEROCYCLES, Vol. 83, No. 6, 2011
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116.9, 115.4, 107.2, 78.8. MS (EI) m/z (%): 309 (M+, 45), 232 (M-C6H5, 100). HRMS (EI) calcd. for
C22H15NO, 309.1154; found 309.1159.
3-(Thiophen-2-yl)-2H-chromene-4-carbonitrile (4k)
1
Yellow solid, mp 119-120 °C. H NMR (300 MHz, CDCl3):  7.77 (d, J = 3.4 Hz, 1H), 7.56 (d, J = 5.2
Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 5.2 Hz, 1H), 7.07 (t, J = 7.6 Hz,
13
1H), 6.92 (d, J = 7.6 Hz, 1H), 5.13 (S, 2H). C NMR (100 MHz, CDCl3):  152.4, 137.5, 136.2, 130.5,
129.3, 129.1, 128.3, 125.6, 122.6, 119.3, 116.1, 101.9, 67.6. MS (EI) m/z (%): 239 (M+, 100). HRMS (EI)
calcd. for C14H9NOS, 239.0405; found 239.0405.
ACKNOWLEDGEMENTS
This work was financially supported by National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program”，China(No.2009ZX09301-001), the National Natural Science
Foundation of China (21072205).
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