Selective synthesis of cyano-functionalized 2-aryl-4 h -chromenes and 2-amino-4 H -chromene-3-carbonitriles by catalyst-tuned reactions of 2-hydroxychalcones with 2-substituted acetonitriles

Article abstract of DOI:10.1055/s-0032-1317945

A selective synthesis of 4H-chromenes by the reactions of 2-hydroxychalcone derivatives with acetonitriles substituted with electron-withdrawing groups is described. Under catalyst-free conditions, the reactions give cyano-functionalized 2-aryl-4H-chromenes, whereas in the presence of sodium bicarbonate, 2-amino-4H-chromene-3-carbonitriles are obtained in excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317945

334▌
PAPER
paper
Selective Synthesis of Cyano-Functionalized 2-Aryl-4H-chromenes and
2-Amino-4H-chromene-3-carbonitriles by Catalyst-Tuned Reactions of
2-Hydroxychalcones with 2-Substituted Acetonitriles
Cyano-Functionalized 2-Aryl-4H-chromenes and 2-Amino-4H-chromene-3-carbonitriles
Guodong Yin,* Houqiang Shi, Liqianyun Xu, Xianhong Wei, Qing Tao
Hubei Key Laboratory of Pollutant Analysis and Reuse Technology, College of Chemistry and Environmental Engineering,
Hubei Normal University, Huangshi 435002, P. R. of China
Fax +86(714)6515602; E-mail: gdyin@hbnu.edu.cn
Received: 24.10.2012; Accepted after revision: 03.12.2012
scaffolds by means of sequential Knoevenagel condensa-
tion, Michael addition, and intramolecular cyclization re-
actions.4–7 However, in most reported reactions, the cyano
group is converted through intramolecular cyclization
Abstract: A selective synthesis of 4H-chromenes by the reactions
of 2-hydroxychalcone derivatives with acetonitriles substituted
with electron-withdrawing groups is described. Under catalyst-free
conditions, the reactions give cyano-functionalized 2-aryl-4H-
chromenes, whereas in the presence of sodium bicarbonate, 2-ami- into an imine moiety that subsequently isomerizes to give
no-4H-chromene-3-carbonitriles are obtained in excellent yields.
an amino group. In a continuation of our efforts to develop
new synthetic protocols for constructing heterocyclic
frameworks,8 we report an efficient reaction of 2-hy-
droxychalcones with substituted acetonitriles under cata-
lyst-free conditions to give novel cyano-functionalized 2-
aryl-4H-chromenes, and in the presence of a base to give
2-amino-4H-chromene-3-carbonitriles as the major prod-
ucts.
Key words: heterocycles, nitriles, catalysis, chromenes
Chromenes are common structural motifs in a number of
biologically active and natural compounds.1 Among the
various kinds of chromene systems, 4H-chromenes carry-
ing dicyanomethyl or cyano(ethoxycarbonyl)methyl sub-
stituents at the 4-position are of particular interest. For
example, the cyano-functionalized chromeno[2,3-b]pyri-
dine 1 inhibits mitogen-activated protein kinase-activated
protein kinase 2 (MK-2) and suppress the expression of
tumor necrosis factor-α (TNF-α) in U937 cells.2 The tu-
mor antagonist HA14-1 2 and related compounds exhibit
binding activity to the surface pocket of cancer-implicated
Bcl-2 protein and induce apoptosis or programmed cell
death in follicular lymphoma B cells and leukemia HL-60
cells.3
Initially, we examined the reaction of 2-hydroxychalcone
(3a) with malononitrile (4a) to give (2-phenyl-4H-chro-
men-4-yl)malononitrile (5a) in various solvents under
catalyst-free conditions. Our preliminary experiment
showed that the reaction gave low yields of 5a in metha-
nol or ethanol (Table 1, entries 1 and 2), whereas the prod-
uct was obtained in moderate-to-good yields (40–75%) in
propan-1-ol, tert-butyl alcohol, tetrahydrofuran, acetoni-
trile, 1,2-dichloroethane, or benzene (entries 3–8). No re-
actions occurred in N,N-dimethylformamide (entry 9) or
dimethyl sulfoxide (entry 10), even at 110 °C. However,
to our delight, the reaction proceeded smoothly in reflux-
ing toluene, giving the product 5a in 85% yield after 8 h
(entry 11). Extending the reaction time did not significant-
ly improve the yield (entry 12), whereas decreasing the re-
action temperature resulted in a low yield of 5a (entry 13).
NC
CN
EtO2C
CN
CN
Br
CO2Et
NH2
MeO
O
N
NH2
O
1
2
MK-2 inhibitor
Bcl-2 protein inhibitor
Having determined the optimal conditions (toluene, re-
flux, 8 h), we then examined the reactions of a variety of
2-hydroxychalcone derivatives with malononitrile to es-
tablish the scope of the transformation. The results are
summarized in Table 2. We observed that substrates in
which R1 = H and R2 was a phenyl ring optionally bearing
an electron-donating (methoxy) or an electron-withdraw-
ing substituent (chloro or fluoro) reacted smoothly to give
the corresponding products 5b–d in excellent yields (85–
90%) (Table 2, entries 2–4). The corresponding hetaryl-
group substituted substrates in which R2 was a 2-furyl or
2-thienyl group were also suitable substrates for the reac-
tions and gave the corresponding products 5e and 5f in
83% and 80% yield, respectively (entries 5 and 6). How-
ever, when R2 was a methyl group, the expected product
5g was not detected (entry 7). Substrates in which R1 was
a chloro group gave the corresponding products 5h and 5i
Figure 1 Examples of biologically active cyano-functionalized 4H-
chromenes
Acetonitrile derivatives carrying electron-withdrawing
substituents, such as malononitrile, (phenylsulfonyl)ace-
tonitrile, ethyl cyanoacetate, or methyl cyanoacetate are
important building blocks in organic synthesis because of
the presence of active methylene and cyano functional
groups. Recently, such substituted acetonitriles have been
widely used in the synthesis of 2-amino-4H-chromene
SYNTHESIS 2013, 45, 0334–0340
Advanced online publication: 03.01.2013
DOI: 10.1055/s-0032-1317945; Art ID: SS-2012-F0837-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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Cyano-Functionalized 2-Aryl-4H-chromenes and 2-Amino-4H-chromene-3-carbonitriles
335
Table 1 Optimization of Reaction Conditions for the Synthesis of 5a
Table 2 Synthesis of Novel Cyano-Functionalized 2-Aryl-4H-
chromenes 5 under Catalyst-Free Conditions
NC
CN
O
R3
CN
O
conditions
R1
R1
+
NC
CN
R2
toluene
OH
O
+
NC
R3
reflux, 6–12 h
R2
OH
O
3a
4a
5a
3
4
5
Entrya
Solvent
Temp (°C)
Time (h)
Yieldb (%)
Entrya
R1
R2
Ph
R3
CN
Product Yieldb (%)
1
MeOH
EtOH
PrOH
t-BuOH
THF
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
110
12
12
12
12
12
12
12
12
8
< 5
10
45
75
52
69
40
74
0
1
H
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
85
88
90
85
83
80
2
2
4-MeOC6H4 CN
3
3
4-ClC6H4
4-FC6H4
2-furyl
2-thienyl
Me
CN
4
4
CN
5
5
CN
6
MeCN
DCE
6
CN
7
c
7
CN
5g
5h
5i
–
8
benzene
DMF
8
Ph
CN
80
9
9
4-FC6H4
Ph
CN
81
10
11
12
13
DMSO
PhMe
PhMe
PhMe
110
8
0
10
11
12
13
14
15
16
17
18
SO2Ph
5j
82 (5:1)
85 (5:1)
81 (5:1)
79 (5:1)
85 (5:1)
86 (5:1)
84 (3:1)
85 (3:1)
82 (2:1)
reflux
80
8
85
76
40
4-MeOC6H4 SO2Ph
5k
5l
8
4-ClC6H4
4-FC6H4
2-furyl
2-thienyl
Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
CO2Et
CO2Et
CO2Me
50
8
5m
5n
5o
5p
5q
5r
a All reactions were performed with 3a (0.5 mmol) and 4a (0.5 mmol)
in the appropriate solvent (3 mL).
b Isolated yield.
in 80% and 81% yield, respectively (entries 8 and 9). Be-
cause the phenylsulfonyl group is present in many biolog-
ically and pharmacologically active compounds,9–11 we
also examined the reactions of 2-(phenylsulfonyl)acetoni-
trile with 2-hydroxychalcones, and we obtained the corre-
sponding products 5j–o in 79–86% overall yields (entries
4-FC6H4
Ph
a All reactions were performed with 3 (0.5 mmol) and 4 (0.5 mmol) in
toluene (3 mL).
1
b Isolated yield; ratios of diastereoisomers (in parentheses) were cal-
culated from 1H NMR analyses.
10–15). H NMR spectroscopy showed that these prod-
ucts consisted of mixtures of two diastereoisomers in an
approximate molar ratio of 5:1. Similarly, treatment of
ethyl cyanoacetate or methyl cyanoacetate with 2-hy-
droxychalcones gave the corresponding products 5p–r in
82–85% yields (entries 16–18); the approximate molar ra-
tios of the two diastereoisomers were 3:1 (R3 = CO2Et) or
2:1 (R3 = CO2Me), respectively.
c None of the expected product was obtained.
H
H
R3
CN
R3
CN
R1
From thermodynamic considerations and by comparison
with data reported in the literature,12,13 the structure of the
major diastereoisomers of 5j–r is likely to have an erythro
configuration (Figure 2). The erythro configuration of 5o
was confirmed by X-ray crystallographic analysis (Figure
3).14 It is important to note that single diastereoisomers of
5j–r can be obtained by crystallization of the mixtures
from hexane.
R1
H
O
H
O
R2
R2
(S,R)*-5j–r
(R,R)*-5j–r
erythro
threo
Figure 2 Proposed configuration of erythro- and threo-diastereoiso-
mers of 5j–r
© Georg Thieme Verlag Stuttgart · New York
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336
G. Yin et al.
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Table 3 Synthesis of 2-Amino-4H-chromene-3-carbonitriles 6 in the
Presence of Sodium Bicarbonate
R2
O
O
R1
R3
R1
R2
NaHCO3, EtOH
r.t., 12 h
NC
R3
+
O
NH2
OH
3
4
6
Entrya
R1
R2
Ph
R3
Product
Yieldb (%)
1
2
3
4
H
H
H
H
CN
6a
6d
6e
6j
96
89
94
4-FC6H4
2-furyl
Ph
CN
CN
c
SO2Ph
–
a All reactions were performed with 3 (0.5 mmol), 4 (0.5 mmol), and
NaHCO3 (0.5 mmol) in EtOH (3 mL) at r.t.
b Isolated yield.
Figure 3 X-ray structure of compound 5o
c No reaction occurred.
It has been reported4 that substituted acetonitriles can be
used to synthesize 2-amino-4H-chromene-3-carbonitriles
in the presence of a base. We therefore examined the re-
action of 2-hydroxychalcone (3a) with malononitrile (4a)
under similar conditions to those reported in the litera-
ture.4a,11,15 By screening several bases (sodium carbonate,
sodium bicarbonate, and triethylamine) and several sol-
vents (toluene, acetonitrile, ethanol, and N,N-dimethylform-
amide), we found that the reaction in anhydrous ethanol
for 12 hours at room temperature in the presence of sodi-
um bicarbonate as the base gave 2-amino-4-(2-oxo-2-
phenylethyl)-4H-chromene-3-carbonitrile (6a)15a in 96%
yield (Table 3, entry 1). Product 5a was not formed under
these conditions. Two representative substrates (2E)-1-(4-
fluorophenyl)-3-(2-hydroxyphenyl)prop-2-en-1-one and
(2E)-1-(2-furyl)-3-(2-hydroxyphenyl)prop-2-en-1-one gave
the corresponding products 6d and 6e in 89% and 94%
yield, respectively (entries 2 and 3). However, when 2-
phenylsulfonyl acetonitrile was used, no reaction oc-
curred, probably as a result of steric hindrance by the phe-
nylsulfonyl group (entry 4).
NC
CN
O
NC
CN
NC
CN
(ii)
(iii)
Ph
Ph
OH
OH
O
O
Ph
I
II
5a
B–
BH
(iv)
(i)
NC
CN
Ph
Ph
4a
NC
CN
O
O
O
(v)
CN
Ph
O–
III
O
NH2
OH
6a
3a
Scheme 1 A possible mechanism for the reactions
In summary, we have developed a method for the selec-
tive synthesis of 4H-chromenes by the reaction of 2-hy-
droxychalcone derivatives with substituted acetonitriles.
Under catalyst-free conditions, the reactions give the cor-
responding cyano-functionalized 2-aryl-4H-chromenes 5,
whereas in the presence of sodium bicarbonate, the corre-
sponding 2-amino-4H-chromene-3-carbonitriles 6 are ob-
tained in excellent yields at room temperature. Because
the starting materials are easily accessible and the reac-
tions give good yields, this new synthetic approach has
potential applications in the synthesis of various function-
alized 4H-chromenes, which are of considerable interest
as potential biologically active compounds or pharmaceu-
ticals.
A possible mechanism for these reactions was proposed,
taking 2-hydroxychalcone (3a) as an example (Scheme 1).
First, chalcone 3a reacts with malononitrile (4a) through
a Michael addition reaction to form intermediate I (step
i).16 This intermediate is converted into intermediate II by
an intramolecular cyclization reaction (step ii).17 The ex-
pected product 5a is then obtained by elimination of water
from intermediate II (step iii). In the presence of base,
however, I can instead be easily converted into the anionic
intermediate III (step iv). Because of the lower degree of
steric hindrance, the anion attacks the carbon atom of the
cyano group to form an imine, which isomerizes to form
the 4-substituted 2-amino-4H-chromene-3-carbonitrile 6a
(step v).4a,15a
Synthesis 2013, 45, 334–340
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Cyano-Functionalized 2-Aryl-4H-chromenes and 2-Amino-4H-chromene-3-carbonitriles
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1H NMR (300 MHz, CDCl3): δ = 3.87 (d, J = 5.2 Hz, 1 H), 4.36–
4.40 (m, 1 H), 5.62 (d, J = 5.1 Hz, 1 H), 7.10–7.24 (m, 4 H), 7.34–
7.41 (m, 2 H), 7.72–7.77 (m, 2 H).
All chemicals were obtained from commercial sources and used
without further purification. All organic solvents were dried and
freshly distilled before use. 1H and 13C NMR spectra were recorded
on Bruker AV 300-MHz spectrometers with CDCl3 as the solvent.
Chemical shifts are reported relative to TMS as internal standard.
High-resolution mass spectra (ESI) were recorded on Bruker
micrOTOF-QII. IR spectra were obtained as KBr pellet samples on
a Nicolet 5700 FTIR spectrometer. Flash column chromatography
was performed on silica gel (200–300 mesh). The X-ray crystal
structure determination for compound 5o was performed on a Bruk-
er SMART APEX CCD system.
13C NMR (75 MHz, CDCl3): δ = 32.4, 38.0, 91.8 (d, 5JC–F = 1.6 Hz),
111.2, 111.5, 115.6 (d, 2JC–F = 21.8 Hz), 116.1, 117.7, 124.8, 127.3
3
4
(d, JC–F = 8.4 Hz), 128.3, 128.9 (d, JC–F = 3.3 Hz), 130.8, 151.8,
153.0, 163.7 (d, 1JC–F = 248.6 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C18H11FN2NaO: 313.0748;
found: 313.0751.
[2-(2-Furyl)-4H-chromen-4-yl]malononitrile (5e)
Yellow solid; yield: 109 mg (83%); mp 112–113 °C.
IR (KBr): 894, 1008, 1233, 1396, 1633, 1683, 2255, 2919 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.88 (d, J = 5.0 Hz, 1 H), 4.35–
4.38 (m, 1 H), 5.69 (d, J = 5.1 Hz, 1 H), 6.49 (dd, J1 = 3.4 Hz,
J2 = 1.8 Hz, 1 H), 6.77 (d, J = 3.4 Hz, 1 H), 7.17–7.22 (m, 2 H),
7.33–7.47 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 32.3, 37.6, 90.6, 108.9, 111.3,
111.4, 111.5, 116.2, 117.7, 124.7, 128.3, 130.2, 143.5, 146.1, 147.0,
151.5.
2-Aryl-4H-chromenes 5; General Procedure
A mixture of chalcone 3 (0.5 mmol) and the appropriate substituted
acetonitrile 4 (0.5 mmol) in anhyd toluene (3 mL) was refluxed until
the chalcone disappeared (TLC; 6–12 h). The mixture was then
cooled to r.t. and purified directly by column chromatography (sili-
ca gel, PE then PE–EtOAc) to give a yellow solid. Single diastereo-
isomers of 5j–r were prepared by crystallization of the mixtures
from hexane. Characterization data for 5j–r are for the single dia-
stereoisomers.
(2-Phenyl-4H-chromen-4-yl)malononitrile (5a)
Yellow solid; yield: 116 mg (85%); mp 116–117 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C16H10N2NaO2: 285.0634;
found: 285.0647.
IR (KBr): 759, 918, 1007, 1232, 1391, 1489, 1653, 2256, 2923
cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.86 (d, J = 5.3 Hz, 1 H), 4.35–
4.39 (m, 1 H), 5.67 (d, J = 5.1 Hz, 1 H), 7.17–7.25 (m, 2 H), 7.33–
7.46 (m, 5 H), 7.74–7.77 (m, 2 H).
[2-(2-Thienyl)-4H-chromen-4-yl]malononitrile (5f)
Yellow solid; yield: 110 mg (80%); mp 117–118 °C.
IR (KBr): 982, 1061, 1239, 1420, 1572, 1649, 2255, 2922, 3096
cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.88 (d, J = 5.1 Hz, 1 H), 4.33–
4.36 (m, 1 H), 5.69 (d, J = 5.1 Hz, 1 H), 7.08 (dd, J1 = 4.7 Hz,
J2 = 3.6 Hz, 1 H), 7.18–7.23 (m, 2 H), 7.33–7.42 (m, 3 H), 7.48
(J = 3.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 32.3, 38.0, 91.0, 111.3, 111.5,
116.1, 117.7, 124.8, 125.6, 126.7, 127.6, 128.3, 130.3, 136.0, 149.4,
151.7.
13C NMR (75 MHz, CDCl3): δ = 32.4, 38.1, 92.1, 111.3, 111.6,
116.2, 117.7, 124.7, 125.3, 128.3, 128.5, 129.8, 130.2, 132.7, 151.9,
153.8.
HRMS (ESI): m/z [M + Na]+ calcd for C18H12N2NaO: 295.0842;
found: 295.0845.
[2-(4-Methoxyphenyl)-4H-chromen-4-yl]malononitrile (5b)
Yellow solid; yield: 133 mg (88%); mp 128–129 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C16H10N2NaOS: 301.0406;
found: 301.0421.
IR (KBr): 805, 1032, 1247, 1301, 1506, 1616, 1659, 2235, 2926
cm–1.
(6-Chloro-2-phenyl-4H-chromen-4-yl)malononitrile (5h)
1H NMR (300 MHz, CDCl3): δ = 3.81 (d, J = 5.2 Hz, 1 H), 3.83 (s,
3 H), 4.32–4.35 (m, 1 H), 5.54 (d, J = 5.0 Hz, 1 H), 6.94 (d, J = 8.7
Hz, 2 H), 7.16–7.25 (m, 2 H), 7.32–7.41 (m, 2 H), 7.69 (d, J = 8.7
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 32.4, 38.1, 55.4, 90.3, 111.4,
111.7, 113.9, 116.4, 117.6, 124.6, 125.2, 126.8, 128.3, 130.1, 152.0,
153.6, 160.9.
Yellow solid; yield: 122 mg (80%); mp 123–124 °C.
IR (KBr): 917, 1012, 1091, 1275, 1338, 1668, 2252, 2922 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.88 (d, J = 5.0 Hz, 1 H), 4.33–
4.36 (m, 1 H), 5.66 (d, J = 5.1 Hz, 1 H), 7.19 (J = 8.7 Hz, 1 H),
7.31–7.38 (m, 2 H), 7.43–7.46 (m, 3 H), 7.72–7.75 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 32.3, 37.9, 91.6, 110.9, 111.2,
117.6, 119.2, 125.3, 127.9, 128.6, 129.5, 130.0, 130.4, 132.3, 150.6,
153.8.
HRMS (ESI): m/z [M + Na]+ calcd for C19H14N2NaO2: 325.0947;
found: 325.0953.
HRMS (ESI): m/z [M + Na]+ calcd for C18H11ClN2NaO: 329.0452;
found: 329.0458.
[2-(4-Chlorophenyl)-4H-chromen-4-yl]malononitrile (5c)
Yellow solid; yield: 138 mg (90%); mp 129–130 °C.
IR (KBr): 766, 1014, 1225, 1457, 1662, 2258, 2926 cm–1.
[6-Chloro-2-(4-fluorophenyl)-4H-chromen-4-yl]malononitrile
(5i)
1H NMR (300 MHz, CDCl3): δ = 3.81 (d, J = 5.3 Hz, 1 H), 4.37–
4.40 (m, 1 H), 5.66 (d, J = 5.1 Hz, 1 H), 7.19–7.26 (m, 2 H), 7.33–
7.43 (m, 4 H), 7.70 (d, J = 8.6 Hz, 2 H).
Yellow solid; yield: 131 mg (81%); mp 133–135 °C.
IR (KBr): 955, 1019, 1228, 1413, 1609, 1664, 2257, 2918 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.89 (d, J = 4.9 Hz, 1 H), 4.33–
4.36 (m, 1 H), 5.60 (d, J = 5.0 Hz, 1 H), 7.10–7.19 (m, 3 H), 7.31–
7.38 (m, 2 H), 7.70–7.75 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 32.4, 38.0, 92.3, 111.2, 111.5,
116.0, 117.7, 124.9, 126.6, 128.3, 128.8, 130.3, 131.1, 135.8, 151.8,
152.8.
HRMS (ESI): m/z [M + Na]+ calcd for C18H11ClN2NaO: 329.0452;
found: 329.0455.
13C NMR (75 MHz, CDCl3): δ = 32.4, 37.9, 91.3 (d, 5JC–F = 1.5 Hz),
2
110.9, 111.2, 115.7 (d, JC–F = 21.8 Hz), 117.5, 119.2, 127.4 (d,
4
3JC–F = 8.5 Hz), 127.9, 128.5 (d, JC–F = 3.3 Hz), 129.6, 130.5,
[2-(4-Fluorophenyl)-4H-chromen-4-yl]malononitrile (5d)
Yellow solid; yield: 123 mg (85%); mp 125–126 °C.
150.4, 153.0, 163.8 (d, 1JC–F = 248.9 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C18H10ClFN2NaO: 347.0358;
IR (KBr): 919, 1010, 1108, 1229, 1395, 1614, 1657, 2259, 2937
cm–1.
found: 347.0355.
© Georg Thieme Verlag Stuttgart · New York
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(2-Phenyl-4H-chromen-4-yl)(phenylsulfonyl)acetonitrile (5j)
Yellow solid; yield: 159 mg (82%); mp 127–129 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C21H15NNaO4S: 400.0614;
found: 400.0619.
IR (KBr): 928, 1027, 1077, 1235, 1338, 1663, 2242, 2913 cm–1.
(Phenylsulfonyl)[2-(2-thienyl)-4H-chromen-4-yl]acetonitrile
(5o)
1H NMR (300 MHz, CDCl3): δ = 4.10 (d, J = 5.2 Hz, 1 H), 4.87–
4.90 (m, 1 H), 5.69 (d, J = 5.0 Hz, 1 H), 7.13–7.41 (m, 7 H), 7.64–
7.81 (m, 5 H), 8.09 (d, J = 7.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 34.8, 66.1, 93.3, 112.3, 117.2,
117.7, 124.5, 125.4, 127.8, 128.4, 129.3, 129.4, 129.6, 129.8, 133.3,
135.3, 136.8, 152.3, 152.5.
Yellow solid; yield: 169 mg (86%); mp 148–150 °C.
IR (KBr): 845, 1075, 1234, 1323, 1655, 2237, 2892 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.12 (d, J = 2.4 Hz, 1 H), 4.80–
4.83 (m, 1 H), 5.55 (d, J = 5.1 Hz, 1 H), 7.02–7.14 (m, 4 H), 7.25–
7.38 (m, 3 H), 7.64–7.69 (m, 2 H), 7.78 (t, J = 7.6 Hz, 1 H), 8.08 (d,
J = 7.6 Hz, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C23H17NNaO3S: 410.0821;
13C NMR (75 MHz, CDCl3): δ = 34.7, 66.0, 92.2, 112.3, 117.1,
117.6, 124.7, 125.1, 126.2, 127.4, 127.8, 129.4, 129.6, 129.8 (2C),
135.4, 136.6, 148.2, 152.0.
found: 410.0813.
[2-(4-Methoxyphenyl)-4H-chromen-4-yl](phenylsulfonyl)ace-
tonitrile (5k)
Yellow solid; yield: 177 mg (85%); mp 143–145 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C21H15NNaO3S2: 416.0386;
found: 416.0399.
IR (KBr): 936, 1027, 1252, 1452, 1607, 1663, 2233, 2918, 3014
cm–1.
Crystal structure: C21H15NO3S2, triclinic, space group P1,
a = 7.727(4), b = 10.194(5), c = 12.377(6) Å, α = 91.253(5)°,
β = 107.610(5)°, γ = 96.044(5)°, U = 922.6(7) Å3, T = 296(2) K,
Z = 12, DC = 1.227 mg·m–3, λ = 0.71073 Å, F(000)408, crystal size
0.20 × 0.20 × 0.15 mm3. Absorption coefficient: 0.310 mm–1, re-
flections collected: 5155, independent reflections: 3200
[R(int) = 0.0118], refinement by full-matrix least-squares on F2,
data/restraints/parameters 32001/1/224, goodness-of-fit on
F2 = 1.031, final R indices [I>2s(I)] R1 = 0.0549, wR2 = 0.1614, R
indices (all data) R1 = 0.0645, wR2 = 0.1716, largest diff. peak and
hole 0.692 and –0.806 e·Å–3.
1H NMR (300 MHz, CDCl3): δ = 3.84 (s, 3 H), 4.10 (s, 1 H), 4.85
(s, 1 H), 5.56 (d, J = 4.8 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 2 H), 7.11–
7.31 (m, 4 H), 7.60–7.79 (m, 5 H), 8.07 (d, J = 7.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 34.8, 55.3, 66.1, 91.5, 112.4,
113.7, 117.3, 117.6, 124.4, 125.9, 126.8, 127.8, 129.3, 129.5, 129.8,
135.3, 136.8, 152.2, 152.3, 160.5.
HRMS (ESI): m/z [M + Na]+ calcd for C24H19NNaO4S: 440.0927;
found: 440.0931.
[2-(4-Chlorophenyl)-4H-chromen-4-yl](phenylsulfonyl)aceto-
nitrile (5l)
Yellow solid; yield: 171 mg (81%); mp 139–140 °C.
Ethyl Cyano(2-phenyl-4H-chromen-4-yl)acetate (5p)
Yellow solid; yield: 134 mg (84%), mp 102–104 °C.
IR (KBr): 816, 1083, 1232, 1327, 1636, 2242, 2940 cm–1.
IR (KBr): 918, 1046, 1228, 1387, 1656, 1736, 2256, 2908, 2979
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H), 3.72 (d,
J = 5.2 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.42–4.45 (m, 1 H), 5.59
(d, J = 5.2 Hz, 1 H), 7.10–7.43 (m, 7 H), 7.70 (d, J = 7.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 13.8, 37.1, 46.5, 62.9, 94.5, 115.4,
117.2, 118.2, 124.1, 125.1, 128.3, 128.4, 129.2, 129.3, 133.3, 152.2,
152.4, 164.5.
1H NMR (300 MHz, CDCl3): δ = 4.09 (d, J = 2.5 Hz, 1 H), 4.87–
4.89 (m, 1 H), 5.71 (d, J = 5.0 Hz, 1 H), 7.13–7.31 (m, 4 H), 7.37
(d, J = 8.7 Hz, 2 H), 7.62–7.79 (m, 5 H), 8.08 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 34.7, 66.0, 93.8, 112.3, 117.0,
117.7, 124.7, 126.7, 127.8, 128.6, 129.3, 129.6, 129.8, 131.8, 135.3,
135.4, 136.8, 151.5, 152.1.
HRMS (ESI): m/z [M + Na]+ calcd for C23H16ClNNaO3S: 444.0432;
found: 444.0436.
HRMS (ESI): m/z [M + Na]+ calcd for C20H17NNaO3: 342.1101;
found: 342.1106.
[2-(4-Fluorophenyl)-4H-chromen-4-yl](phenylsulfonyl)acetoni-
trile (5m)
Yellow solid; yield: 160 mg (79%), mp 138–139 °C.
Ethyl Cyano[2-(4-fluorophenyl)-4H-chromen-4-yl]acetate (5q)
Yellow solid; yield: 143 mg (85%); mp 87–88 °C.
IR (KBr): 820, 1027, 1231, 1336, 1634, 2264, 2942 cm–1.
IR (KBr): 835, 1038, 1234, 1394, 1636, 1736, 2252, 2914, 2987
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H), 3.72 (d,
J = 5.1 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 4.41–4.45 (m, 1 H), 5.53
(d, J = 5.1 Hz, 1 H), 7.07–7.36 (m, 6 H), 7.67–7.72 (m, 2 H).
1H NMR (300 MHz, CDCl3): δ = 4.08 (d, J = 2.5 Hz, 1 H), 4.87–
4.90 (m, 1 H), 5.67 (d, J = 5.0 Hz, 1 H), 7.10–7.32 (m, 6 H), 7.66–
7.80 (m, 5 H), 8.09 (d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 34.7, 66.0, 93.1, 112.3, 115.3 (d,
3
2JC–F = 21.7 Hz), 117.1, 117.7, 124.6, 127.4 (d, JC–F = 8.3 Hz),
13C NMR (75 MHz, CDCl3): δ = 13.8, 37.1, 46.5, 62.9, 94.3 (d,
127.9, 129.3, 129.5 (d, 4JC–F = 3.3 Hz), 129.6, 129.8, 135.3, 136.8,
2
5JC–F = 1.6 Hz), 115.3, 115.6 (d, JC–F = 21.7 Hz), 117.1, 118.1,
151.7, 152.2, 163.4 (d, 1JC–F = 247.6 Hz).
124.2, 127.1 (d, 3JC–F = 8.4 Hz), 128.3, 129.3, 129.5, (d, 4JC–F = 3.5
Hz), 151.6, 152.1, 163.4 (d, 1JC–F = 248.9 Hz), 164.4.
HRMS (ESI): m/z [M + Na]+ calcd for C23H16FNNaO3S: 428.0727;
found: 428.0741.
HRMS (ESI): m/z [M + Na]+ calcd for C20H16FNNaO3: 360.1006;
found: 360.1005.
[2-(2-Furyl)-4H-chromen-4-yl](phenylsulfonyl)acetonitrile (5n)
Yellow solid; yield: 160 mg (85%); mp 136–137 °C.
Methyl Cyano(2-phenyl-4H-chromen-4-yl)acetate (5r)
Yellow solid; yield: 125 mg (82%); mp 106–108 °C.
IR (KBr): 915, 1014, 2884, 1234, 1396, 1628, 1674, 2239 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.12 (d, J = 2.4 Hz, 1 H), 4.83–
4.86 (m, 1 H), 5.73 (d, J = 5.0 Hz, 1 H), 6.45 (dd, J1 = 3.2 Hz,
J2 = 1.8 Hz, 1 H), 6.69 (d, J = 3.4 Hz, 1 H), 7.10–7.32 (m, 4 H), 7.44
(s, 1 H), 7.63–7.79 (m, 3 H), 8.07 (d, J = 7.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 34.2, 66.0, 91.9, 108.2, 111.3,
112.3, 117.2, 117.6, 124.6, 127.9, 129.3, 129.6, 129.8, 135.3, 136.7,
143.2, 145.0, 147.5, 151.9.
IR (KBr): 922, 1050, 1229, 1392, 1654, 1744, 2253, 2915, 2954
cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.72 (d, J = 5.2 Hz, 1 H), 3.77 (s,
3 H), 4.41–4.45 (m, 1 H), 5.57 (d, J = 5.2 Hz, 1 H), 7.13–7.42 (m,
7 H), 7.70–7.73 (m, 2 H).
Synthesis 2013, 45, 334–340
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cyano-Functionalized 2-Aryl-4H-chromenes and 2-Amino-4H-chromene-3-carbonitriles
339
13C NMR (75 MHz, CDCl3): δ = 37.1, 46.5, 53.5, 94.6, 115.2,
117.2, 118.1, 124.1, 125.1, 128.3, 128.4, 129.2, 129.3, 133.3, 152.2,
152.6, 165.0.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (ESI): m/z [M + Na]+ calcd for C19H15NNaO3: 328.0944;
found: 328.0940.
References
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2-Amino-4H-chromene-3-carbonitriles 6; General Procedure
A mixture of chalcone 3 (0.5 mmol), acetonitrile 4 (0.5 mmol), and
NaHCO3 (42 mg, 0.5 mmol) in anhyd EtOH (3 mL) was stirred at
r.t. until the chalcone disappeared (TLC, 12 h). The solvent was
then removed under reduced pressure. The mixture was poured into
H2O (15 mL) and extracted with EtOAc (3 × 15 mL). The combined
organic layers were dried over (MgSO4), filtered, and concentrated
to give a residue that was purified by column chromatography (sil-
ica gel, PE–EtOAc) to give a yellow solid.
2-Amino-4-(2-oxo-2-phenylethyl)-4H-chromene-3-carbonitrile
(6a)15a
Yellow solid; yield: 139 mg (96%); mp 129–131 °C.
IR (KBr): 759, 1050, 1274, 1405, 1648, 2181, 3199, 3442 cm–1.
(4) (a) Costa, M.; Areias, F.; Abrunhosa, L.; Venâncio, A.;
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Balasubramanyam, P.; Reddy, G. C.; Salvanna, N. Helv.
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1H NMR (300 MHz, CDCl3): δ = 3.88 (d, J = 5.7 Hz, 2 H), 4.33 (t,
J = 5.7 Hz, 1 H), 4.71 (s, 2 H), 6.96 (d, J = 8.1 Hz, 1 H), 7.05 (t,
J = 7.3 Hz, 1 H), 7.16–7.26 (m, 2 H), 7.40–7.56 (m, 3 H), 7.90 (d,
J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 30.6, 47.3, 58.5, 116.3, 120.0,
123.3, 125.0, 128.0, 128.1, 128.3, 128.6, 133.2, 136.7, 149.2, 160.9,
197.5.
HRMS (ESI): m/z [M + Na]+ calcd for C18H14N2NaO2, 313.0947;
found: 313.0950.
2-Amino-4-[2-(4-fluorophenyl)-2-oxoethyl]-4H-chromene-3-
carbonitrile (6d)
Yellow solid; yield: 137 mg (89%); mp 101–102 °C.
IR (KBr): 836, 1051, 1229, 1412, 1602, 1648, 2183, 2927, 3440
cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.36 (d, J = 5.7 Hz, 2 H), 4.32 (t,
J = 5.7 Hz, 1 H), 4.71 (s, 2 H), 7.03–7.22 (m, 5 H), 7.90–7.95 (m, 2
H), 7.97 (d, J = 8.1 Hz, 1 H).
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6785. (b) Chen, W. L.; Cai, Y. F.; Fu, X.; Liu, X. H.; Lin, L.
L.; Feng, X. M. Org. Lett. 2011, 13, 4910.
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2011, 1389.
13C NMR (75 MHz, CDCl3): δ = 30.6, 47.2, 58.4, 115.8 (d, 2JC–F
=
=
=
21.8 Hz), 116.3, 120.0, 123.2, 125.0, 128.1, 128.2, 130.7 (d, 3JC–F
4
1
9.3 Hz), 133.2 (d, JC–F = 3.0 Hz), 149.2, 160.9, 163.8 (d, JC–F
(8) (a) Yin, G. D.; Wang, Z. H.; Chen, A. H.; Gao, M.; Wu, A.
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(d) Lian, M.; Li, Q.; Zhu, Y. P.; Yin, G. D.; Wu, A. X.
Tetrahedron 2012, 68, 9598. (e) Yin, G. D.; Fan, L.; Ren, T.
B.; Zheng, C. Y.; Tao, Q.; Wu, A. X.; She, N. F. Org.
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Alfinito, P.; Bray, J. A.; Cosmi, S. A.; Johnston, G. H.;
Kenney, T.; Koury, E.; Winneker, R. C.; Deecher, D. C.;
Trybulski, E. J. Bioorg. Med. Chem. 2009, 17, 7802.
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Koryakova, A. G.; Kovalenko, S. M.; Mitkin, O. D.; Okun,
I. M.; Ravnyeyko, I. M.; Tkachenko, S. E.; Zaremba, O. V.
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253.6 Hz), 195.9.
HRMS (ESI): m/z [M + Na]+ calcd for C18H13FN2NaO2: 331.0853;
found: 331.0851.
2-Amino-4-[2-(2-furyl)-2-oxoethyl]-4H-chromene-3-carboni-
trile (6e)
Yellow solid; yield: 132 mg (94%); mp 125–127 °C.
IR (KBr): 972, 1052, 1228, 1462, 1651, 2187, 2925, 3441 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.23 (d, J = 5.7 Hz, 2 H), 4.27 (t,
J = 5.9 Hz, 1 H), 4.81 (s, 2 H), 6.50 (dd, J1 = 3.6 Hz, J2 = 1.7 Hz, 1
H), 6.94–7.07 (m, 2 H), 7.14–7.27 (m, 3 H), 7.54–7.56 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 30.8, 47.1, 58.0, 112.3, 116.2,
117.5, 119.9, 122.9, 124.9, 128.1, 128.3, 146.6, 149.1, 152.6, 160.9,
186.5.
HRMS (ESI): m/z [M + Na]+ calcd for C16H12NaN2O3: 303.0740;
found: 303.0736.
(11) Dias, T. A.; Proença, M. F. Tetrahedron Lett. 2012, 53,
5235.
Acknowledgment
(12) Curini, M.; Epifano, F.; Chimichi, S.; Montanari, F.;
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Ilovaisky, A. I.; Feducovich, S. K.; Belyakov, P. A.;
Nikishin, G. I. Adv. Synth. Catal. 2008, 350, 591.
We gratefully acknowledge support received from the National
Natural Science Foundation of China (Grant 21102042).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 334–340

340
G. Yin et al.
PAPER
(14) Crystallographic data for compound 5o have been deposited
with the accession number CCDC 901984, and can be
obtained free of charge from the Cambridge
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Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk; Web site:
www.ccdc.cam.ac.uk/conts/retrieving.html.
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Synthesis 2013, 45, 334–340
© Georg Thieme Verlag Stuttgart · New York