One-pot synthesis of tetrahydrochromene derivatives catalyzed by lipase

Article abstract of DOI:10.1016/j.tet.2011.09.137

An efficient and green one-pot synthesis route for tetrahydrochromene derivatives was developed. Lipase from Porcine pancreas (PPL) shows excellent catalytic activity and exerts good adaptability to different substrates in the reaction. All the reactions

Full text of DOI:10.1016/j.tet.2011.09.137

Tetrahedron 67 (2011) 9582e9587
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of tetrahydrochromene derivatives catalyzed by lipase
*
Jiang-Cheng Xu, Wan-Mei Li, Hui Zheng, Yi-Feng Lai, Peng-Fei Zhang
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2011
Received in revised form 23 September 2011
Accepted 27 September 2011
Available online 5 October 2011
An efficient and green one-pot synthesis route for tetrahydrochromene derivatives was developed. Li-
pase from Porcine pancreas (PPL) shows excellent catalytic activity and exerts good adaptability to dif-
ferent substrates in the reaction. All the reactions go smoothly and provide tetrahydrochromene
derivatives with isolate yield up to 97% under room temperature. This lipase-catalyzed multistep con-
version method has provided a new strategy to synthesize chromene derivatives and expanded the
application of enzyme in organic synthesis.
Keywords:
Enzymatic reactions
Promiscuity
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Multistep conversions
One-pot synthesis
Tetrahydrochromene derivatives
1. Introduction
biochemists recently.12 The term ‘promiscuity’ refers to secondary
activities of an enzyme in addition to its primary physiological
Tetrahydrochromene moiety is an important class of benzo-
pyran derivatives founded in many natural products.1 The de-
rivatives have biological activities such as antioxidant, spamolytic,
anticancer, antibacterial, antianaphylactic, and anti-HIV activity.2
Furthermore, these compounds exhibit unique pharmacological
activity. Enzyme promiscuity is hypothesised to contribute to the
natural evolution of enzymes and provides new possibilities for
exploiting enzymatic synthesis in organic chemistry.13 The past few
years we have seen significant advances related to this latest skill of
certain enzymes. Several enzymes have fully been exhibited great
advantages and potential in organic transformations like aldol re-
action, Michael addition, DielseAlder reaction, Knoevenagel re-
action, Mannich reaction, and Hantzsch-type reaction.14e19
Following our interest in catalysis by enzymes, our research
group has previously used enzymes as reusable catalyst for Knoe-
venagel condensation and esterification reactions,20 Mannich re-
action,21 and synthesis of spirooxindole derivatives reactions.22
However, natural enzymes, which are capable of catalyzing multi-
ple reactions are very scarce, and only a few single-enzyme mul-
tistep conversions have been reported.23 Furthermore, designing
chemical reaction in aqueous medium attracts more and more at-
tention in recent years.24 Here we report the unprecedented effi-
cient and convenient lipase (PPL)-catalyzed one-pot multiple
reaction for synthesizing tetrahydrochromene derivatives in the
presence of water, which expands the application of enzymes in
organic synthesis.
activities including treatment of human inflammatory TNFa-me-
diated diseases, Alzheimer’s disease, amyotrophic lateral sclerosis,
Huntington’s disease, and Parkinson’s disease.3 Moreover, func-
tionally substituted chromenes have played increasing roles in
synthetic approaches to promising compounds in the field of me-
dicinal chemistry.1c,4 For example, 2-amino-4H-chromene de-
rivatives bearing a nitrile functionality arise from their potential
application in the treatment of psoriatic arthritis and rheumatoid,
and in cancer therapy.5
Numerous methods have been reported for the synthesis of
tetrahydrochromene derivatives.6e10 However, the reported
methods still have drawbacks such as long reaction time, high re-
action temperature, using toxic organic solvents, and so on. To the
best of our knowledge, there is no report about this reaction cata-
lyzed by enzyme. The significant biological activity and recent
synthetic advances of enzyme encouraged the development of bi-
ologically promising analogs that were more facile and clean than
the original natural products.11 Research in the area of biocatalytic
promiscuity has attracted significant attention from chemists and
2. Results and discussion
In order to find the most suitable enzyme for the envisaged one-
pot synthesis of tetrahydrochromene derivatives reaction, we
tested the reaction of benzaldehyde 1a, malononitrile 2a, and
* Corresponding author. E-mail address: chxyzpf@hotmail.com (P.-F. Zhang).
0040-4020/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.137

J.-C. Xu et al. / Tetrahedron 67 (2011) 9582e9587
9583
cyclohexane-1,3-dione 3a (1 mmol, respectively) as model sub-
strates with various additives using the EtOH as the reaction media.
The results were summarized in Table 1.
effect on the catalytic activity of PPL. Among the tested solvents,
including DMSO, CH3CN, EtOH, acetone, THF, CH2Cl2, toluene,
hexane, and water, EtOH leads to a highest yield of 86% (entry 3 vs
entries 1e2 and 4e9, Table 2). This may be attributed to the proton
nature of the solvent and that it accelerates the reaction compared
to other solvents. However, pure water leads to trace yield, which
may be due to the insolubility of the substrates in pure water.
In previous studies of enzymatic promiscuity, water has been
considered to play an important role in enzymes’ activity, generally
leading to an improvement in their activity.25 In order to optimize
the water/ethanol ratio for this specific reaction, some experiments
were performed (Fig. 1). It was found that the best ratio between
EtOH and water was 4:1 (v/v). In this case, the yield is as high as
96%. However, once the water content surpassed 20%, the yield of
tetrahydrochromene product declined sharply, which may be due
to the insolubility of the substrates. All these results indicated ob-
viously that water was essential in this promiscuous biocatalysis
reaction.
Table 1
Optimization of the reaction conditionsa
Entry
Catalyst
Yieldb (%)
1
2
3
4
No enzyme
Cellulase
Trypsin from Porcine pancreas
Pepsin from hog stomach
Trace
Trace
60
52
5
6
7
8
b
a
a
a
-Amylase
Trace
5
76
-Amylase from Aspergillus oryzae
-Amylase from hog pancreas
-Amylase from Bacillus subtilis
9
9
Amano lipase M from Mucor javanicus
Amano lipase AK from Pseudomonas fluorescens
Lipase AY30
Amano lipase A from Aspergillus niger
Lipase from Porcine pancreas
Lipase from Porcine pancreasc
Bovine serum albumin (BSA)
18
100
80
60
40
20
0
10
11
12
13
14
15
Trace
Trace
24
86
Trace
Trace
a
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), cyclo-
hexane-1,3-dione (1 mmol), enzyme (30 mg), and EtOH (4 mL) were shaken at
160 rpm at 35 ꢀC for 1 h.
b
Isolated yields.
c
Lipase from Porcine pancreas predenatured with urea at 100 ꢀC for 24 h.
0
20
40
60
80
100
We found that only trace product was detected (entry 1, Table 1),
if no enzyme was added as catalyst. Several enzymes displayed
Water content [%]
detectable catalytic activities for this reaction, including a-amylase
from hog pancreas, trypsin from Porcine pancreas, pepsin from hog
stomach, amano lipase A from Aspergillus niger, amano lipase M
Fig. 1. Influence of water on the PPL-catalyzed one-pot synthesis of tetrahy-
drochromenes. Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol),
cyclohexane-1,3-dione (1 mmol), PPL (30 mg), and solvent (5 mL) were shaken at
160 rpm at 35 ꢀC for 1 h; deionized water from 0% to 100% [water/ethanol, v/v];
product yield was determined by HPLC.
from Mucor javanicus, a-amylase from Bacillus subtilis, and a-am-
ylase from Aspergillus oryzae showed moderate catalytic activity for
this reaction (entries 3, 4, 6e9, and 12, Table 1). Notably, lipase from
Porcine pancreas (PPL) displayed an especially significant catalytic
activity (entry 13, Table 1). When reactions were incubated with
denatured PPL or bovine serum albumin (BSA), no product was
detected (entries 14 and 15, Table 1). All the results suggest that the
tertiary structure and the specific spatial conformation of PPL are
responsible for the one-pot synthesis of chromene derivatives.
We screened the reaction in various organic solvents using PPL
as catalyst (Table 2). The results revealed that solvent shows great
In order to improve the activity of enzyme, other influencing
factors such as temperature, concentration of catalyst, and reaction
time have also been investigated (Table 3). The results showed that
the desired products were obtained in yields up to 96% when 30 mg
of PPL in 5 mL solvent at 35 ꢀC/1 h were used.
Table 3
Optimization of the reaction conditionsa
Entry
PPL amount (mg)
Temp (ꢀC)
Time (h)
Yieldb (%)
Table 2
PPL-catalyzed reaction of benzaldehyde, malononitrile, and cyclohexane-1,3-dione
1
2
3
4
5
6
7
8
30
30
30
30
30
10
20
40
50
30
30
30
30
20
30
35
40
50
35
35
35
35
35
35
35
35
1
1
1
1
1
1
1
1
56
89
96
94
84
60
84
95
95
52
82
94
95
in different solventsa
Entry
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DMSO
35
35
35
35
35
35
35
35
35
Trace
20
86
16
23
Trace
Trace
Trace
Trace
CH3CN
Ethanol
Acetone
THF
CH2Cl2
Toluene
n-Hexane
Water
9
1
10
11
12
13
0.25
0.5
0.75
2
a
a
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), cyclo-
hexane-1,3-dione (1 mmol), PPL (30 mg), and solvent (5 mL) were shaken at
160 rpm at 35 ꢀC.
Reaction conditions: benzaldehyde (1 mmol), malononitrile (1 mmol), cyclo-
hexane-1,3-dione (1 mmol), and solvent: EtOH (4 mL)/water (1 mL) were shaken at
160 rpm.
b
b
Isolated yields.
Isolated yields.

9584
J.-C. Xu et al. / Tetrahedron 67 (2011) 9582e9587
We have also employed various different aromatic or aliphatic
addition, and then 10 is obtained. Thirdly, after enolization and
addition to the cyano group, the intermediate 12 is formed, and the
desired product 4a is obtained via isomerization. We will study this
proposed mechanism further in detail.
aldehydes, 1,3-dicarbonyl compounds, and malononitrile or cyano-
acetic esteras substrates in order to investigate the generality for the
scope of this new catalysis method. The results are summarized in
Table 4. Gratifyingly, we found that nearly all of the corresponding
products were obtained in excellent yields. But the reaction with
cyanoacetic ester offered a lower yield compared to that with
malononitrile, which is probably because of the lower reactivity of
cyanoacetic ester. Although many substrates and conditions were
applied in this reaction to measure the enantioselectivity, there is no
obvious optical activity of obtained products and we will undertake
related further research to improve it.
3. Conclusion
In summary, we herein report an unprecedented lipase (PPL)-
catalyzed one-pot synthesis of tetrahydrochromene derivatives
reaction in the presence of water. This reaction can be carried out
under mild conditions and covers a great range of substrates. This
novel protocol provides an efficient, environmental friendly syn-
thetic route for tetrahydrochromene derivatives, and extends the
application of enzymes in pharmaceutical industry.
Table 4
Synthesis of different tetrahydrochromene derivatives 4 catalyzed by PPLa
4. Experimental
4.1. General
Commercial reagents were used without further purification,
unless otherwise indicated. All solvents were distilled prior to use.
Reactions were performed in oven-dried glassware. Analytical TLC
was performed on Merck precoated TLC (silica gel 60 F254) plates.
Melting points were recorded on an X4-Data microscopic melting
point apparatus and are uncorrected. EIMS were acquired on a Bruker
Esquire 3000 plus spectrometer. ESI-MS: Thermo Finnigan LCQ Ad-
vantage instrument in m/z. HRMS: Agilent 6210 TOF instrument. 1H
and 13C NMR were recorded on a Bruker Avance 400 spectrometer at
400 MHz in DMSO-d6 using TMS as internal standard. C18 column
was used in the HPLC experiments with MeOH/water¼50:50 (v/v),
1.0 mL/min and UV detection at 254 nm. All the known products
were characterized by comparing the 1H NMR data with those re-
ported in the literature. The structures of new compounds were
confirmed by 1H, 13C NMR, MS, and HRMS-ESI. All enzymes were
purchased from Acros, Aldrich, and TCI and used directly: Amano
lipase AK from Pseudomonas fluorescens (EC, 3.1.1.3), Amano lipase M
from M. javanicus (EC, 3.1.1.3), Amano lipase A from A. niger (EC,
3.1.1.3), Lipase AY30 (EC, 3.1.1.3), lipase acrylic resin from Candida
antarctica (EC, 3.1.1.3), lipase from Porcine pancreas (EC, 3.1.1.3).
Entry
Products
R1
R2
R3
Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
Ph
Ph
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
H
96
94
95
95
96
94
96
97
96
96
93
94
95
93
93
92
92
91
93
93
91
89
92
92
93
92
81
83
78
76
78
2-NO2eC6H4
2-NO2eC6H4
3-NO2eC6H4
3-NO2eC6H4
4-NO2eC6H4
4-NO2eC6H4
2-CF3eC6H4
2-CF3eC6H4
4-OHeC6H4
4-OHeC6H4
3,4-Di-OCH3eC6H4
3,4-Di-OCH3eC6H4
2-OCH3eC6H4
2-OCH3eC6H4
3-CH3eC6H4
3-CH3eC6H4
4-OCH3eC6H4
4-OCH3eC6H4
2-CleC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4s
4t
4.2. General procedure for the synthesis of
tetrahydrochromene derivatives
4u
4v
4w
4x
4y
4z
4a0
4b0
4c0
4d0
4e0
2-CleC6H4
Furan-2-yl
Furan-2-yl
n-Propyl
A suspension of aromatic aldehydes (1 mmol), malononitrile or
cyanoacetic ester (1 mmol), 1,3-dicarbonyl compounds (1 mmol),
and 30 mg PPL in 4 mL EtOH in the presence of water (1 mL) was
shaken at 35 ꢀC and 160 rpm for 1 h to complete the reaction
(monitored by TLC), and the reaction was terminated by filtering off
the enzyme. Then the filtered liquor was kept at ꢁ8 ꢀC overnight.
The precipitated product was filtered and washed with water and
cooled EtOH to afford the pure 4[aee0].
CN
CN
n-Propyl
4-NO2eC6H4
4-NO2eC6H4
2-CF3eC6H4
4-OHeC6H4
3-CH3eC6H4
COOEt
COOEt
COOEt
COOEt
COOEt
H
a
Reaction conditions: aromatic or aliphatic aldehydes (1 mmol), malononitrile or
cyanoacetic ester (1 mmol), 1,3-dicarbonyl compounds (1 mmol), PPL (30 mg),
ethanol (4 mL), and water (1 mL) were shaken at 160 rpm at 35 ꢀC.
4.2.1. 2-Amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-
b
Isolated yields.
carbonitrile (4a). White crystalline solid: mp 213e215 ꢀC (lit.26a
212e214 ꢀC); 1H NMR (DMSO-d6,
d
, ppm): 7.29e7.26 (m, 2H),
7.19e7.14 (m, 3H), 7.00 (s, 2H), 4.18 (s, 1H), 2.67e2.54 (m, 2H),
2.35e2.20 (m, 2H), 1.99e1.83 (m, 2H); 13C NMR (DMSO-d6,
, ppm):
The experiments clearly showed an increased reaction rate
when the synthesis of tetrahydrochromene reaction was catalyzed
by the PPL as compared to other enzymes. Based on the mechanism
of lipase-catalyzed16,19,23 carbonecarbon formation which has been
widely accepted, we propose a mechanism for the synthesis of
tetrahydrochromene derivative as shown in Scheme 1. Firstly, 1a
and 2a form 5 quickly by Knoevenagel condensation, while the 1,3-
dicarbonyl compound is pre-activated by the lipase. After the
transfer of a proton, intermediate 7 is converted to 8. Secondly,
intermediate 6, which is also pre-activated by the lipase, is attacked
by 8, which leads to a new CeC bond formation via Michael
d
195.6,165.0,158.5,141.7,132.0,129.7,129.3,128.0,127.4,119.2,112.8,
56.8, 36.2, 32.6, 26.4, 19.8; MS (EI): m/z¼266.
4.2.2. 2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (4b). White crystalline solid: mp 224e225 ꢀC
(lit.8 224 ꢀC); 1H NMR (DMSO-d6,
d, ppm): 7.30e7.26 (m, 2H), 7.19e7.13
(m, 3H), 7.01 (s, 2H), 4.17 (s, 1H), 2.56e2.46 (m, 2H), 2.27e2.07 (dd,
J1¼16.0 Hz, J2¼60.4 Hz, 2H), 1.03 (s, 3H), 0.94 (s, 3H); 13C NMR (DMSO-
d6,
d, ppm): 195.3, 162.2, 158.2, 144.5, 128.1 (CHꢂ2), 126.9 (CHꢂ2),

J.-C. Xu et al. / Tetrahedron 67 (2011) 9582e9587
9585
H
N
H
H
H
CN
O
N
NC
5
CN
H
CN
2a
H
O
H
O
H
H
Lipase
H
N
fast
H
H
His
Asp
O
1a
6
NC
N
H
O
+N
H
H
9
H
O
H
H
H
H
His
O
H
Asp
O
O
O
Lipase
O
H
O
N
H
+N
N
O
H
N
H
H
7
3a
Asp
His
8
O
O
His
N
His
N
Asp
Asp
H
H
H
O
H
O
H
H
H
O
O
N
H
O
H H
O
O
O
N
H
H
O
O
O
O
H
H
O
C
N
N
NH2
H
NH
C
N
CN
C
CN
CN
His
N
10
12
4a
Asp
11
N
H
O
Scheme 1. Proposed mechanism.
1
126.3, 119.5, 112.5, 58.2, 49.9, 35.6, 31.8 (CHꢂ2), 28.4, 26.8; MS (EI): m/
z¼294.
mp 211e212 ꢀC (lit.8 210 ꢀC); H NMR (DMSO-d6,
d, ppm): 8.10e8.08
(d, 1H, J¼7.6), 7.99 (s, 1H), 7.69e7.61 (m, 2H), 7.20 (s, 2H), 4.42 (s, 1H),
2.56 (s, 2H), 2.30e2.10 (m, 2H), 1.05 (s, 3H), 0.96 (s, 3H); 13C NMR
4.2.3. 2-Amino-4-(2-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chro-
(DMSO-d6, d, ppm): 195.7, 163.1, 158.6, 147.7, 146.9, 134.1, 129.9, 121.7,
121.6, 119.3, 111.7, 57.1, 56.0, 49.8, 35.3, 31.7, 28.2, 26.7; MS (EI): m/
z¼339.
mene-3-carbonitrile (4c). Yellow crystalline solid: mp 196e198 ꢀC
(lit.26b 196e198 ꢀC); 1H NMR (DMSO-d6,
d, ppm): 7.81e7.79 (dd,
J1¼1.2 Hz, J2¼8.0 Hz, 1H), 7.66e7.62 (m, 1H), 7.43e7.37 (m, 2H), 7.19 (s,
2H), 4.94 (s, 1H), 2.60e2.57 (m, 2H), 2.29e2.11 (m, 2H), 1.96e1.77 (m,
2H); MS (EI): m/z¼311.
4.2.7. 2-Amino-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chro-
mene-3-carbonitrile (4g). Yellow crystalline solid: mp 234e236 ꢀC
(lit.26b 235e236 ꢀC); 1H NMR (DMSO-d6,
d, ppm): 8.18e8.16 (d,
4.2.4. 2-Amino-7,7-dimethyl-4-(2-nitrophenyl)-5-oxo-5,6,7,8-
J¼8.4 Hz, 2H), 7.49e7.46 (d, J¼8.8 Hz, 2H), 7.20 (s, 2H), 4.38 (s, 1H),
2.70e2.58 (m, 2H), 2.37e2.22 (m, 2H), 2.01e1.88 (m, 2H); MS (EI): m/
z¼311.
tetrahydro-4H-chromene-3-carbonitrile (4d). Yellow crystalline
solid: mp 224e226 ꢀC (lit.26b 223e224 ꢀC); 1H NMR (DMSO-d6,
d,
ppm): 7.83e7.80 (dd, J1¼1.2 Hz, J2¼8.4 Hz, 1H), 7.67e7.63 (m, 1H),
7.43e7.35 (m, 2H), 7.21 (s, 2H), 4.95 (s, 1H), 2.56e2.43 (q, 2H,
J¼17.6 Hz), 2.22e1.99 (dd, J1¼8.0 Hz, J2¼35.6 Hz, 2H), 1.01 (s, 3H),
0.88 (s, 3H); MS (EI): m/z¼339.
4.2.8. 2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4h). Yellow crystalline
solid: mp 178e180 ꢀC (lit.8 179 ꢀC); 1H NMR (DMSO-d6,
d, ppm):
8.19e8.17 (d, J¼8.4 Hz, 2H), 7.48e7.46 (d, J¼8.4 Hz, 2H), 7.21 (s,
2H), 4.39 (s, 1H), 2.60e2.55 (m, 2H), 2.29e2.10 (dd,
J1¼16.4 Hz, J2¼60.0 Hz, 2H), 1.05 (s, 3H), 0.97 (s, 3H); MS (EI): m/
z¼339.
4.2.5. 2-Amino-4-(3-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chro-
mene-3-carbonitrile (4e). Yellow crystalline solid: mp 201e202 ꢀC
(lit.26c 198e200 ꢀC); 1H NMR (DMSO-d6,
d, ppm): 8.09e8.02 (m, 2H),
7.71e7.69 (d, J¼8.0 Hz, 1H), 7.63e7.59 (t, J¼8.0 Hz, 1H), 7.21 (s, 2H),
4.44 (s, 1H), 2.70e2.58 (m, 2H), 2.37e2.22 (m, 2H), 2.01e1.90 (m, 2H);
4.2.9. 2-Amino-5-oxo-4-(2-(trifluoromethyl)phenyl)-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4i). Yellow crystalline
13C NMR (DMSO-d6,
d, ppm): 195.6, 164.8, 158.3, 147.5, 146.7, 134.0,
129.7, 121.5 (CHꢂ2), 119.2, 112.6, 56.9, 36.2, 35.3, 26.5, 19.7; MS (EI): m/
solid: mp 210e211 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 7.64e7.57
z¼311.
(m, 2H), 7.40e7.31 (m, 2H), 7.04 (s, 2H), 4.55 (s, 1H), 2.72e2.57
(m, 2H), 2.32e2.14 (m, 2H), 2.00e1.88 (m, 2H); 13C NMR (DMSO-
4.2.6. 2-Amino-7,7-dimethyl-4-(3-nitrophenyl)-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4f). Yellow crystalline solid:
d6,
d
, ppm): 195.5, 160.1, 156.1, 132.9, 128.9, 127.8, 126.0 (CHꢂ2),
119.1, 114.2, 113.9, 58.1, 35.2, 30.6, 27.8, 19.8; MS (EI): m/z¼334;

9586
J.-C. Xu et al. / Tetrahedron 67 (2011) 9582e9587
HRMS-ESI: calcd for C17H13F3N2O2 (MþH)þ: 335.0929; found:
223e225 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 7.18e7.14 (m, 1H), 6.98 (s,
335.0925.
1H, Ph-H), 6.93e6.94 (d, J¼8.4 Hz, 2H), 4.12 (s,1H), 2.06 (s, 2H), 2.26
(s, 3H), 2.26e2.08 (m, 2H), 1.03 (s, 3H), 0.96 (s, 3H); 13C NMR
4.2.10. 2-Amino-7,7-dimethyl-5-oxo-4-(2-(trifluoromethyl)phenyl)-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4j). Yellow crystalline
(DMSO-d6, d, ppm): 195.2, 162.1, 158.1, 144.4, 137.0, 128.0, 127.5,
124.1, 119.5, 112.5, 58.3, 49.9, 35.5, 31.8, 28.4, 26.7, 21.1; MS (EI): m/
z¼308; HRMS-ESI: calcd for C19H20N2O2 (MþH)þ: 309.1525; found:
309.1528.
solid: mp 216e218 ꢀC (lit.26c 218e220 ꢀC); 1H NMR (DMSO-d6,
d,
ppm): 7.64e7.57 (m, 2H), 7.39e7.36 (t, J¼7.6 Hz, 1H), 7.29e7.27 (d,
J¼8.0 Hz, 1H), 7.07 (s, 2H), 4.56 (s, 1H), 2.60e2.55 (m, 2H), 2.25e2.03
(dd, J1¼15.6 Hz, J2¼73.6 Hz, 2H), 1.04 (s, 3H), 0.97 (s, 3H); MS (EI): m/
z¼362.
4.2.19. 3-Amino-4-(4-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-2-carbonitrile (4s). Yellow crystalline solid: mp
190e192 ꢀC; 1H NMR (DMSO-d6,
d
, ppm): 7.07e7.05 (d, J¼8.4 Hz,
4.2.11. 2-Amino-4-(4-hydroxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
2H), 6.97 (s, 2H), 6.84e6.82 (d, J¼8.8 Hz, 2H), 4.13 (s, 1H), 3.70 (s,
chromene-3-carbonitrile (4k). Yellow crystalline solid: mp 234e236 ꢀC
3H), 2.63e2.54 (m, 2H), 2.33e2.19 (m, 2H), 1.97e1.79 (m, 2H); 13C
(lit.26b 234e236 ꢀC); 1H NMR (DMSO-d6,
d
, ppm): 9.25 (s, 1H),
6.94e6.92 (m, 4H), 6.66e6.64 (d, J¼8.8 Hz, 2H), 4.07 (s, 1H), 2.59e2.56
(m, 2H), 2.29e2.19 (m, 2H), 1.97e1.85 (m, 2H); 13C NMR (DMSO-d6,
NMR (DMSO-d6, d, ppm): 195.7, 164.0, 158.3, 157.9, 136.8, 128.1
(CHꢂ2), 119.7, 114.0, 113.6 (CHꢂ2), 58.4, 54.9, 36.3, 34.6, 26.4, 19.7;
d,
MS (EI): m/z¼296.
ppm): 195.5, 163.7, 158.0, 155.7, 135.0 (CHꢂ2), 127.9, 119.8, 114.8
(CHꢂ2), 114.0, 58.5, 36.4, 34.5, 26.5, 19.9; MS (EI): m/z¼282.
4.2.20. 2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4t). Yellow crystalline
4.2.12. 2-Amino-4-(4-hydroxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
solid: mp 199e201 ꢀC (lit.26a 201 ꢀC); 1H NMR (DMSO-d6,
d, ppm):
tetrahydro-4H-chromene-3-carbonitrile (4l). Yellow crystalline
7.05e7.03 (d, J¼8.8 Hz, 2H), 6.97 (s, 2H), 6.84e6.82 (d, J¼8.4 Hz,
2H), 4.11 (s, 1H), 3.70 (s, 3H), 2.55e2.44 (m, 2H), 2.26e2.06 (dd,
J1¼16.0 Hz, J2¼22.4 Hz, 2H), 1.03 (s, 3H), 0.94 (s, 3H); 13C NMR
solid: mp 205e206 ꢀC (lit.9 204e205 ꢀC); 1H NMR (DMSO-d6,
d,
ppm): 9.26 (s, 1H), 6.93e6.91 (m, 4H), 6.66e6.64 (d, J¼8.4 Hz, 2H),
4.05 (s, 1H), 2.49e2.43 (m, 2H), 2.25e2.06 (dd, J1¼16.0 Hz,
J2¼60.4 Hz, 2H), 1.02 (s, 3H), 0.94 (s, 3H); MS (EI): m/z¼310.
(DMSO-d6,
d
, ppm): 195.3, 161.8, 158.1, 157.6, 136.6, 128.0 (CHꢂ2),
119.6, 113.4 (CHꢂ2), 58.4, 54.9, 49.9, 34.7, 31.8, 28.4, 26.8; MS (EI):
m/z¼324.
4.2.13. 2-Amino-4-(3,4-dimethoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (4m). White crystalline solid: mp
4.2.21. 2-Amino-4-(2-chlorophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
227e229 ꢀC (lit.26d 228e231 ꢀC); 1H NMR (DMSO-d6,
d, ppm): 6.96 (s,
chromene-3-carbonitrile (4u). Yellow crystalline solid: mp
2H), 6.86e6.84 (d, J¼8.4 Hz, 1H), 6.72 (s, 1H), 6.65e6.63 (dd, J1¼2.0 Hz,
J2¼8.0 Hz, 1H), 4.14 (s, 1H), 3.71 (s, 3H), 3.70 (s, 3H), 2.65e2.58 (m, 2H),
2.31e2.26 (m, 2H), 1.98e1.87 (m, 2H); MS (EI): m/z¼326.
212e214 ꢀC (lit.26c 210e212 ꢀC); 1H NMR (DMSO-d6,
d, ppm):
7.36e7.33 (m, 1H), 7.28e7.24 (m, 1H), 7.21e7.17 (m, 2H), 7.03 (s, 2H),
4.70 (s, 1H), 2.66e2.56 (m, 2H), 2.33e2.17 (m, 2H), 2.00e1.83 (m,
2H); MS (EI): m/z¼300.
4.2.14. 2-Amino-4-(3,4-dimethoxyphenyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4n). White crystal-
line solid: mp 191e193 ꢀC (lit.26e 178e180 ꢀC); 1H NMR (DMSO-d6,
4.2.22. 2-Amino-4-(2-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4v). Yellow crystalline
d
, ppm): 6.96 (s, 2H), 6.87e6.85 (d, 1H, J¼8.4 Hz), 6.69e6.68 (d,
solid: mp 209e210 ꢀC (lit.26c 214e215 ꢀC); 1H NMR (DMSO-d6,
d,
J¼2.0 Hz, 1H), 6.66e6.64 (dd, J1¼2.0 Hz, J2¼8.0 Hz, 1H), 4.12 (s, 1H),
3.71 (s, 3H), 3.70 (s, 3H), 2.52e2.49 (m, 2H), 2.28e2.08 (m, 2H), 1.03
(s, 3H), 0.97 (s, 3H); MS (EI): m/z¼354.
ppm): 7.37e7.35 (m, 1H), 7.28e7.25 (m, 1H), 7.21e7.16 (m, 2H), 7.05
(s, 2H), 4.70 (s, 1H), 2.57e2.46 (m, 2H), 2.27e2.05 (dd, J1¼16.0 Hz,
J2¼69.6 Hz, 2H), 1.04 (s, 3H), 0.98 (s, 3H); MS (EI): m/z¼328.
4.2.15. 2-Amino-4-(2-methoxyphenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
4.2.23. 2-Amino-4-(furan-2-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chro-
chromene-3-carbonitrile (4o). Yellow crystalline solid: mp 200e201 ꢀC
mene-3-carbonitrile (4w). Black crystalline solid: mp 199e200 ꢀC;
(lit.26f 200e202 ꢀC); 1H NMR (DMSO-d6,
d, ppm): 7.17 (s, 2H),
1H NMR (DMSO-d6,
d
, ppm): 7.48 (d, J¼0.8 Hz, 1H), 7.09 (s, 2H),
6.98e6.94 (m, 2H), 6.86e6.82 (m, 2H), 4.53 (s, 1H,), 3.76 (s, 3H),
2.65e2.55 (m, 2H), 2.33e2.19 (m, 2H), 1.99e1.84 (m, 2H); MS (EI): m/
z¼296.
6.32e6.31 (q, J¼1.6 Hz,1H), 6.06e6.05 (d, J¼2.8 Hz,1H), 4.33 (s,1H),
2.60e2.57 (t, J¼2.0 Hz, 2H), 2.34e2.31 (t, J¼6.8 Hz, 2H), 2.00e1.85
(m, 2H); 13C NMR (DMSO-d6,
d, ppm): 195.5, 165.1, 159.2, 155.7,
141.7,119.5, 111.4, 110.3, 105.0, 55.2, 36.1, 28.9, 26.4, 19.7; MS (EI): m/
z¼256; HRMS-ESI: calcd for C14H12N2O3 (MþH)þ: 257.0848; found:
257.0845.
4.2.16. 2-Amino-4-(2-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4p). Yellow crystalline
solid: mp 203e205 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 7.17e7.13 (t,
J¼8.0 Hz, 1H), 6.99e6.97 (d, J¼7.2 Hz, 1H), 6.95e6.93 (d, J¼8.0 Hz,
1H), 6.86e6,83 (m, 3H), 4.47 (s, 1H), 3.74 (s, 3H), 2.52e2.46 (m, 2H),
2.26e2.03 (m, 2H), 1.03 (s, 3H), 0.96 (s, 3H); MS (EI): m/z¼324.
4.2.24. 2-Amino-4-(furan-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (4x). Black crystalline solid:
mp 201e203 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 7.48e7.47 (d,
J¼0.8 Hz, 1H), 7.08 (s, 2H), 6.32e6.31 (q, J¼1.6 Hz, 1H), 6.058e6.051
(d, J¼2.8 Hz,1H), 4.32 (s,1H), 2.55e2.42 (dd, J1¼18.0 Hz, J2¼34.0 Hz,
2H), 2.30e2.14 (dd, J1¼16.0 Hz, J2¼48.0 Hz, 2H), 1.04 (s, 3H), 0.98 (s,
4.2.17. 2-Amino-5-oxo-4-(m-tolyl)-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (4q). White crystalline solid: mp 248e249 ꢀC; 1H NMR
(DMSO-d6,
J¼8.4 Hz, 2H), 4.14 (s, 1H), 2.67e2.57 (m, 2H), 2.34e2.20 (m, 2H), 2.26
(s, 3H), 1.98e1.82 (m, 2H); 13C NMR (DMSO-d6,
, ppm): 195.7, 164.3,
d, ppm): 7.17e7.14 (m, 1H), 6.98 (s, 1H), 6.95e6.92 (d,
3H); 13C NMR (DMSO-d6,
d, ppm): 195.3, 163.2, 159.2, 155.7, 141.7,
119.5,110.4, 110.3,105.0, 55.3, 49.8, 31.7, 28.9, 28.3, 26.5; MS (EI): m/
z¼284; HRMS-ESI: calcd for C16H16N2O3 (MþH)þ: 285.1161; found:
285.1157.
d
158.4, 144.7, 137.2, 128.2,127.6, 127.2, 124.2, 119.7, 113.8, 58.2, 36.3, 35.3,
26.4, 21.0; MS (EI): m/z¼280; HRMS-ESI: calcd for C17H16N2O2
(MþH)þ: 281.1212; found: 281.1210.
4.2.25. 2-Amino-5-oxo-4-propyl-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (4y). White crystalline solid: mp 188e190 ꢀC; 1H
4.2.18. 2-Amino-7,7-dimethyl-5-oxo-4-(m-tolyl)-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (4r). White crystalline solid: mp
NMR (DMSO-d6,
d
, ppm): 6.87 (s, 2H), 3.16e3.14 (t, J¼4.8 Hz, 1H),
2.49e2.47 (m, 2H), 2.37e2.30 (m, 2H), 1.99e1.83 (m, 2H), 1.46e1.27

J.-C. Xu et al. / Tetrahedron 67 (2011) 9582e9587
9587
(m, 2H), 1.22e1.12 (m, 2H), 0.85e0.82 (t, J¼7.2 Hz, 3H); 13C NMR
References and notes
(DMSO-d6, d, ppm): 196.0, 164.6, 159.5, 120.1, 113.7, 55.3, 37.4, 36.4,
1. (a) Lu, D.; Li, Y.; Gong, Y. J. Org. Chem. 2010, 75, 6900; (b) Stachulski, A. V.; Berry,
N. G.; Low, A. C. L.; Moores, S. L.; Row, E.; Warhurst, D. C.; Adagu, I. S.; Rossignol,
J. F. J. Med. Chem. 2006, 49, 1450; (c) Elinson, M. N.; Dorofeev, A. S.; Miloserdov,
F. M.; Ilovaisky, A. I.; Feducovich, S. K.; Belyakov, P. A.; Nikishina, G. I. Adv. Synth.
Catal. 2008, 350, 591; (d) Sun, W.; Cama, L. J.; Birzin, E. T.; Warrier, S.; Locco, L.;
Mosley, R.; Hammond, M. L.; Rohrer, S. P. Bioorg. Med. Chem. Lett. 2006, 16, 1468;
(e) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G. Q.; Barluenga, S.;
Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939.
29.1, 26.4, 20.0, 17.6, 14.0; MS (EI): m/z¼232; HRMS-ESI: calcd for
C13H16N2O2 (MþH)þ: 233.1212; found: 233.1208.
4.2.26. 2-Amino-7,7-dimethyl-5-oxo-4-propyl-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (4z). White crystalline solid: mp
181e183 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 6.88 (s, 2H), 3.14e3.12 (t,
2. (a) Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J. Med. Chem. 1993, 28,
517; (b) Terao, K.; Niki, E. J. Free Radical Biol. Med. 1986, 2, 193; (c) Deng, J. Z.;
Sun, D. A.; Starck, S. R.; Hecht, S. M.; Cerny, R. L.; Engen, J. R. J. Chem. Soc.,
Perkin Trans. 1 1999, 1147; (d) Maloney, D. J.; Hecht, S. M. Org. Lett. 2005, 7,
4297; (e) Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi, T.; Fujioka, T.;
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Lee, K. H. Tetrahedron 2001, 57, 1559; (f) Triggle, D. J. Cell. Mol. Neurobiol. 2003,
23, 293.
J¼4.4 Hz,1H), 2.45e2.31 (dd, J1¼18.0 Hz, J2¼38.4 Hz, 2H), 2.29e2.15
(dd, J1¼16.0 Hz, J2¼36.8 Hz, 2H), 1.49e1.28 (m, 2H), 1.21e1.10 (m,
2H), 1.01 (s, 3H), 0.99 (s, 3H), 0.84e0.81 (t, J¼7.2 Hz, 3H); 13C NMR
(DMSO-d6, d, ppm): 196.0, 162.9, 159.6, 120.0, 112.5, 55.3, 50.0, 37.1,
31.7, 29.1, 28.5, 26.6, 17.7, 14.0; MS (EI): m/z¼260. HRMS-ESI: calcd
for C15H20N2O2 (MþH)þ: 261.1525; found: 261.1521.
3. (a) Gourdeau, H.; Leblond, L.; Hamelin, B.; Desputeau, C.; Dong, K.; Kianicka, I.;
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4.2.27. Ethyl 2-amino-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carboxylate (4a0). Yellow crystalline solid: mp
181e182 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 8.56 (s, 2H), 8.42e8.39 (d,
J¼8.8 Hz, 1H), 8.25e8.23 (d, J¼8.8 Hz, 2H), 4.38e4.32 (q, J¼7.2 Hz,
2H), 3.99 (s, 1H), 2.43e2.35 (m, 2H), 2.21e2.10 (m, 2H), 1.98e1.82
(m, 2H), 1.34e1.31 (t, J¼7.2 Hz, 3H); 13C NMR (DMSO-d6,
d, ppm):
195.4, 161.1, 152.6, 149.2, 145.2, 137.2 (CHꢂ2), 131.6, 129.7, 124.1
(CHꢂ2), 122.4, 114.8, 106.6, 99.9, 62.7, 58.8, 13.9; MS (EI): m/z¼358.
4.2.28. Ethyl 2-amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,
8-tetrahydro-4H-chromene-3-carboxylate (4b0). Yellow crystalline sol-
id: mp 185e186 ꢀC (lit.26g 185e187 ꢀC); 1H NMR (DMSO-d6,
d, ppm):
8.12e8.10 (d, J¼8.4 Hz, 2H), 7.72 (s, 2H), 7.42e7.41 (d, J¼8.4 Hz, 2H),
4.61 (s, 1H), 3.97e3.91 (m, 2H), 2.61e2.47 (m, 2H), 2.31e2.05 (dd,
J1¼16.0 Hz, J2¼86.8 Hz, 2H),1.10e1.05 (m, 6H), 0.89 (s, 3H); MS (EI): m/
z¼386.
6. Curini, M.; Rosati, O.; Marcotullio, M. C.; Montanari, F.; Campagna, V.; Pace, V.;
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4.2.29. Ethyl 2-amino-5-oxo-4-(2-(trifluoromethyl)phenyl)-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (4c0). White crystalline
solid: mp 178e180 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 7.71 (s, 2H),
11. Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 12, 2209.
7.49e7.46 (m, 2H), 7.30e7.21 (m, 2H), 5.14 (s, 1H), 3.93e3.87 (m,
2H), 2.62e2.59 (m, 2H), 2.31e2.21 (m, 2H), 1.96e1.74 (m, 2H),
0.96e0.92 (t, J¼7.2 Hz, 3H); MS (EI): m/z¼381.
12. (a) De Souza, R. O. M. A.; Antunes, O. A. C.; Kroutil, W. J. Org. Chem. 2009, 74,
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ꢀ
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22. Chai, S. J.; Lai, Y. F.; Xu, J. C.; Zheng, H.; Zhu, Q.; Zhang, P. F. Adv. Synth. Catal.
2011, 353, 371.
4.2.30. Ethyl 2-amino-4-(4-hydroxyphenyl)-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (4d0). White crystalline
solid: mp 226e227 ꢀC; 1H NMR (DMSO-d6,
d, ppm): 9.09 (s, 1H),
7.47 (s, 2H), 6.93e6.90 (d, J¼8.8 Hz, 2H), 6.58e6.56 (d, J¼8.4 Hz,
2H), 4.42 (s, 1H), 3.97e3.92 (q, J¼6.8 Hz, 2H), 2.63e2.59 (m, 2H),
2.33e2.19 (m, 2H), 1.97e1.78 (m, 2H), 1.11e1.08 (t, J¼7.2, 3H); MS
(EI): m/z¼329.
4.2.31. Ethyl 2-amino-5-oxo-4-(m-tolyl)-5,6,7,8-tetrahydro-4H-chro-
mene-3-carboxylate (4e0). Yellow crystalline solid: mp 196e198 ꢀC
(lit.26h); 1H NMR (DMSO-d6,
d, ppm): 8.361 (s, 2H), 7.09e7.05 (m, 1H),
6.95 (s, 1H), 6.93e6.88 (m, 2H), 4.95 (s, 1H), 3.97e3.92 (q, J¼7.2 Hz,
2H), 2.66e2.58 (m, 2H), 2.41e2.33 (m, 2H), 2.23 (s, 3H), 1.87e1.81 (m,
2H), 1.11e1.08 (t, J¼6.8 Hz, 3H); MS (EI): m/z¼327.
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Acknowledgements
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This work was supported by the National Natural Science
Foundation of China (No. 21076052), Science and Technology Plan
of Zhejiang Province (2011C24004), and Key Sci-tech Innovation
Team of Zhejiang Province (2010R50017).
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.09.137.