An Efficient and Ecofriendly Three-Component Reaction for the Rapid Synthesis of 2-Amino-4 H -chromenes Catalyzed by a DABCO-Based Ionic Liquid

Article abstract of DOI:10.1055/s-0037-1610123

An efficient, economical, and green strategy for the construction of biologically relevant 2-amino-4 H -chromene scaffolds via a tandem Knoevenagel-Pinner cyclization-Michael reaction has been successfully developed. In the presence of DABCO-based ionic l

Full text of DOI:10.1055/s-0037-1610123

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
Synthesis
C.-B. Li et al.
Paper
An Efficient and Ecofriendly Three-Component Reaction for
the Rapid Synthesis of 2-Amino-4H-chromenes Catalyzed by a
DABCO-Based Ionic Liquid
Cheng-Bin Li
Yu-Wei Li
Da-Zhen Xu*
National Engineering Research Center of Pesticide (Tianjin),
State Key Laboratory and Institute of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin
300071, People’s Republic of China
xudazhen@nankai.edu.cn
Received: 11.04.2018
Accepted after revision: 17.05.2018
Published online: 02.07.2018
DOI: 10.1055/s-0037-1610123; Art ID: ss-2018-h0224-op
NC
CN
O
OH
O
H
NH2
N
CN
Abstract An efficient, economical, and green strategy for the con-
struction of biologically relevant 2-amino-4H-chromene scaffolds via a
tandem Knoevenagel–Pinner cyclization–Michael reaction has been
successfully developed. In the presence of DABCO-based ionic liquids,
two different 2-amino-4H-chromene derivatives, 2-amino-4-(indol-3-
yl)-4H-chromenes and 2-amino-4-(pyrazol-4-yl)-4H-chromenes, were
prepared in good to excellent yields (81–97%) within short reaction
times under mild conditions. All the products are purified by simple
crystallization. The catalyst could be recycled for at least five times.
HO
O
O
MeO
O
NH2
Inhibitor of MK-2
rhodomyrtone
OMe
MeO
Br
N
CN
CN
Key words 2-amino-4H-chromene, green chemistry, ionic liquid, mul-
ticomponent reaction, salicylaldehyde
R
HO
O
N
N
O
NH2
H
IRSP inhibitor (R = H)
IRAP inhibitor (R = Ac)
MX58151
Chromene frameworks are important structural compo-
nents in biologically active and natural products. They are
1
Figure 1 Significant structures of the chromene-containing com-
currently explored as privileged structures in therapeutic
pounds
2
agents and pharmacological relevance molecules. Among
the various structural patterns, 2-amino-4H-chromenes are
3
substituted indole9 and pyrazolone10 moieties have been
developed. Although some certain merits have been
achieved in these protocols, they still suffer from one or
more drawbacks, such as high reaction temperature, long
reaction times, catalysts containing transition metals, un-
satisfactory yields, and burdensome product isolation pro-
cedures. Therefore, the development of a more green and
efficient procedure leading to 2-amino-4H-chromene de-
rivatives is crucial in terms of synthetic technology.
Multicomponent reactions (MCRs), involving the gener-
ation of complex target molecules between three or more
simple materials via a single synthetic operation step, have
emerged as a powerful tool for drug discovery in recent
considered as key cores in the synthesis of pigments, agro-
4
5
chemicals, cosmetics, and drugs. A few selected signifi-
cant examples of biologically active compounds are shown
in Figure 1.
On the other hand, 3-substituted indoles as well as pyr-
azolone derivatives are core structural motifs found in nu-
6,7
merous therapeutic agents and natural products that of-
ten exhibit a wide spectrum of biological activities. Molec-
ular scaffolds with more than two kinds of bioactive
heterocycles in a one nucleus might enhance the biological
activities or integrate properties of both from a biological
8
point of view. Hence, various methods for the synthesis of
2-amino-4H-chromene heterocycles assimilated with 3-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
Synthesis
C.-B. Li et al.
Paper
R2
N
R4
R4
R3
R3
N
R2
4a–l
81–97%)
CN
(
R1
[
DABCO-H][HSO4]
(10 mol%)
CHO
CN
O
NH2
R1
+
CN
EtOH (0.1 mL)
OH
R5
60 °C
HN
N
Me
O
6a–f
90–97%)
Me
(
CN
N
R1
O
N
O
NH2
R5
Scheme 1 The synthesis of 2-amino-4H-chromenes in the presence of a DABCO-base IL catalyst
years.11 MCRs are endowed with high atom economy, ease
Table 1 Optimization Study for One-Pot Synthesis of 2-Amino-4H-
chromene
of operation, simplified purification processes, and the pos-
a
12
sibility of automatization, and they also provide a unique
way for constructing complex organic molecules from sim-
ple and readily available substrates in modern drug discovery.13
In recent years, we have outlined efficient methodolo-
gies for MCRs by using DABCO-based ionic liquid (IL) cata-
HN
CHO
OH
CN
CN
2
IL-Cat (10 mol%)
Conditions
+
+
CN
N
H
14
lysts. As a continuation of our interests in IL-catalyzed or-
ganic reactions, here, we wish to report a highly efficient
one-pot process for the synthesis of 2-amino-4-(indol-3-
1a
3a
O
NH2
4a
yl)-4H-chromene
and
2-amino-4-(pyrazol-4-yl)-4H-
b
Entry Catalyst (10 mol%)
Solvent
Temp (°C)Time (min) Yield (%)
chromene derivatives via tandem Knoevenagel–Pinner cy-
clization–Michael multicomponent reaction catalyzed by
DABCO-based ILs (Scheme 1).
15
1
2
[DABCO-H][AcO]
[DABCO-H]Cl
neat
neat
neat
neat
neat
neat
neat
neat
DCE
50
50
50
50
50
50
60
30
60
60
60
60
60
60
60
60
60
60
60
150
150
80
90
87
85
92
71
82
95
71
63
55
51
67
97
97
96
93
87
0
Six different types of DABCO-based ILs were synthe-
sized according to our previously reported procedure (Fig-
3
[DABCO-H][BF4]
4
[DABCO-H][HSO
4
]
80
14
ure 2), and their use was examined in a optimization ex-
periment for the synthesis of a 2-amino-4H-chromene de-
rivative. The model substrates used were salicylaldehyde
5
[DABCO-C
4
]Cl
150
150
60
6
[DABCO-C
3
OH]Cl
7
[DABCO-H][HSO
[DABCO-H][HSO
[DABCO-H][HSO
4
4
4
]
]
]
(
1a), malononitrile (2), and 1H-indole (3a) in a survey of the
reaction parameters; the results are presented in Table 1.
8
240
240
240
240
240
60
9
H
10
[DABCO-H][HSO4]
MeCN
dioxane
N
N
N
N
X
Cl
1
1
1
2
[DABCO-H][HSO
4
4
]
]
[DABCO-C4]Cl
[DABCO-H][HSO
2
H O
[
[
[
[
DABCO-H][AcO], X = AcO
N
OH
13
[DABCO-H][HSO4]
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DABCO-H]Cl, X = Cl
N
Cl
4c
DABCO-H][BF4], X = BF4
DABCO-H][HSO4], X = HSO4
1
1
1
1
1
[DABCO-H][HSO
5c,d [DABCO-H][HSO
6c,e [DABCO-H][HSO
4
4
4
4
]
]
]
]
60
[DABCO-C3OH]Cl
120
240
120
300
60
Figure 2 Structures of the DABCO-base ionic liquid catalysts
7c,f
8
[DABCO-H][HSO
–
Initially, the six DABCO-based IL catalysts were evaluat-
ed under neat conditions at 50 °C. It was found that these
ILs were all efficient catalysts for this tandem reaction and
afforded the desired product 4a in moderate to good yields
1
9c
H
2
SO
4
complex
a
Reaction conditions: salicylaldehyde (1a, 122 mg, 1 mmol), malononitrile
2, 66 mg, 1 mmol), indole (3a, 117 mg, 1 mmol), IL catalyst (0.1 mmol, 10
mol%), solvent (1 mL).
Isolated yield.
EtOH (0.1 mL) was used.
5
3
(
(Table 1, entries 1–6). Among them, a high yield of 92% was
b
achieved using [DABCO-H][HSO ] for 80 min (Table 1, entry
4
c
4
). Thus, [DABCO-H][HSO ] was adopted as the IL catalyst
4
d
mol% of catalyst was used.
mol% of catalyst was used.
and its conditions for use were evaluated next. The experi-
mental results showed that enhancing reaction tempera-
e
f
The catalyst was reused for fifth time.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
Synthesis
C.-B. Li et al.
Paper
ture to 60 °C was advantageous to the transformation (Table
, entry 7). When solvents were employed in the reaction,
the progress was often very slow and afforded the product
a in poor yields except in the case of ethanol, in which
case 4a was obtained an excellent 97% yield (Table 1, en-
tries 9–13). We found that using a small amount of EtOH
dole, salicylaldehydes bearing sterically hindered multisub-
stituent groups often afforded lower yields, e.g. the forma-
tion of 4h and 4i.
1
4
Inspired by these remarkable results, and in order to
confirm the generality of this new efficient methodology,
we then investigated a multicomponent reaction of salicyl-
aldehydes 1, malononitrile (2), and pyrazolones 5 under
identical conditions. The results are shown in Scheme 3. As
expected, the desired products, 2-amino-4-(pyrazol-4-yl)-
4H-chromenes 6a–f, were obtained in high yields (90–97%).
Even using a salicylaldehyde containing a strong electron-
(0.1 mL) as the solvent allowed the reaction mixtures to stir
sufficiently, and these conditions were selected as opti-
mum (Table 1, entry 14). When the catalyst loadings were
decreased to 5 mol% or 3 mol%, product 4a was also obtain
in good yields (Table 1, entries 15 and 16). In addition, the
IL catalyst afforded the product 4a in 87% yield even after
reuse for five times (Table 1, entry 17). Importantly, the
product 4a was not observed without the use of a catalyst
even after prolonged reaction times (5 h) (Table 1, entry
withdrawing group (NO ) gave a good 95% yield of 6c with-
2
in 120 min. Compared to 5-methyl-2-phenyl-2,4-dihydro-
3H-pyrazol-3-one (5a), 5-methyl-2,4-dihydro-3H-pyrazol-
3-one (5b) is a more reactive substrate in the reaction, and
5b often provided higher yields than that of 5a (6a vs 6e, 6b
vs 6f).
1
8). When H SO was used as the catalyst, complex mix-
2 4
tures only were obtained (Table 1, entry 19).
Having optimized the reaction conditions (Table 1, en-
try 14), the substrate scope of various salicylaldehydes 1
and indoles 3 was examined for the preparation of 2-ami-
no-4-(indol-3-yl)-4H-chromenes 4 via a multicomponent
tandem Knoevenagel–Pinner cyclization–Michael reaction
Moreover, when we replaced malononitrile (2) with di-
medone (7) in the multicomponent reaction the main prod-
ucts under the optimized conditions were xanthenes 8.
These results indicate that this procedure is also facile and
efficient for the synthesis of 1-oxo-hexahydroxanthene de-
rivatives. The results of the reaction between salicylalde-
hydes 1 and dimedone (7) are shown in Scheme 4.
On the basis of previous studies and the experimental
results, a plausible mechanism for the formation of the 2-
amino-4H-chromenes, using 4a as an example, is proposed
in Scheme 5. In the presence of the IL catalyst, firstly, salicyl-
in the presence of [DABCO-H][HSO ] (10 mol%) in ethanol.
4
The results are summarized in Scheme 2. The findings re-
vealed that all the reactions proceeded well to deliver the
desired products 4a–l in good to high yields (81–97%).
Among the different substituted indoles, 5-nitro-1H-indole
and 1-methyl-1H-indole and gave slightly lower product
yields of 4d and 4f, respectively. In reactions with 1H-in-
R2
N
R4
[DABCO-H][HSO4]
R4
CHO
OH
CN
(10 mol%)
R3
R1
R3
+
+
CN
N
R2
EtOH (0.1 mL)
60 °C
CN
R1
1
2
3
O
NH2
4
Me
HN
HN
HN
HN
HN
N
OMe
Br
NO2
Me
CN
CN
CN
CN
CN
CN
O
NH2
O
NH2
O
NH2
O
NH2
O
NH2
O
NH2
4a
4b
4c
4d
4e
4f
1 h, 92%
1 h, 88%
1
h, 97%
0.5 h, 96%
HN
1.5 h, 95%
HN
1
.5 h, 83%
HN
HN
HN
HN
OMe
Me
Me
Br
CN
O2N
CN
CN O2N
NH2
CN Cl
NH2
CN Cl
NH2
CN
O
NH2
O
NH2
O
4i
O
O
O
NH2
Br
4j
4
g
4h
4k
1 h, 94%
4l
.5 h, 95%
2 h, 90%
0
1
h, 93%
2 h, 81%
3 h, 85%
Scheme 2 One-pot synthesis of 2-amino-4-(indol-3-yl)-4H-chromene derivatives. Reagents and conditions: salicylaldehyde (1 mmol), malononitrile (66
mg, 1 mmol), indole (1 mmol), [DABCO-H][HSO ] (21 mg, 0.1 mmol), EtOH (0.1 mL), 60 °C. Yields are those of isolated products.
4
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
Synthesis
C.-B. Li et al.
Paper
R5
N
O
O
Me
[DABCO-H][HSO4]
(10 mol%)
[
DABCO-H][HSO4]
NH
CHO
CHO
CN
R1
OH
O
(
10 mol%)
+
+
R1
N
O
Me
CN
+
+
O
EtOH (0.1 mL)
O
N
R5
CN
EtOH (0.1 mL)
60 °C
OH
OH
O
O
60 °C
1
1
2
R1
7
7
R1
5
O
NH2
O
6
8
Ph
Ph
Ph
N
NH
N
NH
N NH
OH
O
OH
O
O
Me
CN
O
Me
CN
O
Me
O
O
Cl
Cl
O2N
CN
O
O
O
NH2
O
NH2
O
NH2
8a
8b
1.5 h, 95%
6a
6b
6c
1
.5 h, 92%
2
0 min, 94%
60 min, 90%
120 min, 95%
Scheme 4 One-pot synthesis of 1-oxo-hexahydroxanthene derivatives.
Reagents and conditions: salicylaldehyde (1 mmol), dimedone (280 mg,
Ph
HN NH
N
NH
HN NH
O
2
mmol), [DABCO-H][HSO ] (21 mg, 0.1 mmol), EtOH (0.1 mL), 60 °C.
4
O
O
Me
Me
CN
Me
Yields are those of isolated products.
CN
Cl
CN
O
NH2
O
NH2
O
6f
60 min, 96%
NH2
aldehyde (1a) and malononitrile (2) formed the cyclization
product A via intermediate M-1 by a Knoevenagel–Pinner
cyclization sequence. Then A undergoes a Michael-type ad-
dition with 1H-indole (3a) via intermediate M-2 to afford
the desired product 4a.
6e
6
d
6
0 min, 92%
20 min, 97%
Scheme 3 One-pot synthesis of 2-amino-4-(pyrazol-4-yl)-4H-
chromene derivatives. Reagents and conditions: salicylaldehyde (1
mmol), malononitrile (66 mg, 1 mmol), pyrazolone (1 mmol), [DABCO-
In conclusion, it was demonstrated that the IL catalyst
H][HSO ] (21 mg, 0.1 mmol), EtOH (0.1 mL), 60 °C. Yields are those of
4
isolated products.
[DABCO-H][HSO ] acts as a highly efficient, reusable, and
4
inexpensive catalyst in the one-pot multicomponent syn-
thesis of various 2-amino-4H-chromene derivatives. This
procedure offers several significant advantages, such as eas-
ily available starting materials, simple procedure, rapid re-
actions, and higher yields. All the products are purified just
CN
O
N
H
H
CN
NH
N
N
O
HSO4
A
H
M-1
N
Knoevenagel
reaction
CHO
OH
CN
CN
+
3a
CN
CN
OH
CN
1a
2
HSO4
N
H
N
N
O
N
H
H
N
HSO4
M-2
HN
CN
O
NH2
4a
Scheme 5 Plausible mechanism for the synthesis of 2-amino-4H-chromenes
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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Synthesis
C.-B. Li et al.
Paper
by simple crystallization. Furthermore, this procedure is
also applicable to the synthesis of 1-oxo-hexahydroxanthe-
nes.
2-Amino-4-(5-nitro-1H-indol-3-yl)-4H-chromene-3-carbonitrile
(4d)
Red solid; yield: 276 mg (83%); mp 225–227 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 5.16 (s, 1 H, CH), 7.01–7.14 (m, 4 H,
6
ArH), 7.23–7.27 (m, 2 H, NH ), 7.54–7.62 (m, 2 H, ArH), 7.97 (d, J = 8.8
2
Hz, 1 H, ArH), 8.24 (s, 1 H, ArH), 11.77 (s, 1 H, NH).
Unless otherwise indicated, all reagents were obtained from commer-
cial suppliers used without further purification. TLC plates were visu-
alized by exposure to UV light. All melting points were taken on an X-
13
C NMR (100 MHz, DMSO-d ): δ = 32.5, 56.1, 112.8, 115.9, 116.4,
6
117.1, 121.1, 121.9, 123.4, 125.1, 127.7, 128.7, 129.7, 140.5, 140.7,
148.9, 160.6.
4
Digital Melting Point Apparatus without correction. NMR spectra
were recorded with TMS as the internal standard in DMSO-d6 solu-
tions.
Anal. Calcd for C18H12N O : C, 65.06; H, 3.64; N, 16.86. Found: C,
4
3
65.19; H, 3.71; N, 16.98.
2
-Amino-4H-chromenes 4 and 6; General Procedure
2
-Amino-4-(2-methyl-1H-indol-3-yl)-4H-chromene-3-carboni-
A 10-mL round-bottomed flask was charged with salicylaldehyde (1
mmol), malononitrile (1 mmol), carbon-based nucleophile (1 mmol),
trile (4e)9g
Yellow solid; yield: 277 mg (92%); mp 185–187 °C.
[
DABCO-H][HSO ] (21 mg, 10 mol%), and EtOH (0.1 mL). It was then
4
1
H NMR (400 MHz, DMSO-d ): δ = 2.44 (s, 3 H, CH ), 5.06 (s, 1 H, CH),
6
3
vigorously stirred at 60 °C until the reaction was complete (TLC). Af-
ter completion of the reaction, cold water (5 mL) was added and the
mixture was filtered and washed with cold water to remove the cata-
lyst and afford the crude product as a pale yellow solid that was puri-
fied by recrystallization (EtOAc/hexane 3:1) without column purifica-
6.77 (t, J = 7.0 Hz, 3 H, ArH), 6.91–7.00 (m, 4 H, ArH), 7.04 (d, 1 H,
ArH), 7.21 (t, J = 9.0 Hz, 2 H, NH ), 10.85 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d
116.1, 117.9, 118.7, 120.5, 123.9, 124.8, 127.0, 128.3, 129.8, 132.6,
135.9, 149.0, 160.1.
2
): δ = 11.7, 31.4, 56.6, 111.1, 114.4,
6
tion. After removing solvent under vacuum and extraction (Et O), the
2
catalyst [DABCO-H][HSO ] could be reused for the same reaction in
4
next run.
2-Amino-4-(1-methyl-1H-indol-3-yl)-4H-chromene-3-carboni-
trile (4f)
9g
2
-Amino-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrile (4a)9g
Yellow solid; yield: 265 mg (88%); mp 205–207 °C.
Yellow solid; yield: 279 mg (97%); mp 205–207 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 3.73 (s, 3 H, CH ), 5.00 (s, 1 H, CH),
6
3
1
H NMR (400 MHz, DMSO-d ): δ = 4.99 (s, 1 H, CH), 6.84 (d, J = 6.8 Hz,
6.87 (s, 2 H, NH ), 6.93 (t, J = 7.4 Hz, 1 H, ArH), 6.99 (t, J = 7.2 Hz, 1 H,
2
6
1
7
H, ArH), 6.87 (d, J = 7.6 Hz, 1 H, ArH), 6.99–7.09 (m, 4 H, CH, ArH),
.17–7.21 (m, 1 H, ArH), 7.24 (d, J = 8.0 Hz, 1 H, ArH), 7.30 (m, 1 H,
ArH), 7.04–7.10 (m, 3 H, ArH), 7.19 (t, J = 8.0 Hz, 1 H, ArH), 7.26 (s, 1 H,
ArH), 7.30 (d, J = 7.6 Hz, 1 H,), 7.37 (d, J = 8.4 Hz, 1 H, ArH).
ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 10.94 (s, 1 H, NH).
13
C NMR (100 MHz, DMSO-d ): δ = 32.7, 32.8, 44.8, 56.6, 110.4, 116.3,
6
13
C NMR (100 MHz, DMSO-d ): δ = 32.8, 56.6, 112.1, 116.2, 118.9,
118.6, 119.1, 121.3, 121.6, 124.2, 124.8, 126.0, 127.8, 128.3, 129.7,
137.7, 148.8, 160.
6
1
1
18.9, 119.1, 121.3, 121.4, 123.5, 124.1, 124.8, 125.6, 128.3, 129.7,
37.3, 148.8, 160.5.
2-Amino-4-(1H-indol-3-yl)-6-nitro-4H-chromene-3-carbonitrile
2
-Amino-4-(5-methoxy-1H-indol-3-yl)-4H-chromene-3-carboni-
(4g)
9g
trile (4b)
Yellow solid; yield: 309 mg (93%); mp 228–230 °C.
Red solid; yield: 305 mg (96%); mp 189–191 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 5.21 (s, 1 H, CH), 6.93 (t, J = 7.4 Hz,
6
1
H NMR (400 MHz, DMSO-d ): δ = 3.66 (s, 3 H, CH ), 4.98 (s, 1 H, CH),
1 H, ArH,), 7.08 (t, J = 7.4 Hz, 1 H, ArH), 7.15 (s, 2 H, NH ), 7.28 (d,
2
6
3
6
.71–6.74 (m, 1 H, ArH), 6.79 (s, 1 H, ArH), 6.86 (s, 2 H, NH ), 7.00 (t,
J = 8.0 Hz, 1 H, ArH), 7.33 (d, J = 9.2 Hz, 1 H, ArH), 7.40 (d, J = 8.4 Hz, 1
2
J = 7.2 Hz, 1 H, ArH), 7.07 (d, J = 8.0 Hz, 1 H, ArH), 7.12 (d, J = 7.2 Hz, 1
H, ArH), 7.19 (t, J = 8.2 Hz, 1 H, ArH), 7.26 (m, 2 H, ArH), 10.79 (s, 1 H,
NH).
H, ArH), 7.46 (s, 1 H, ArH), 7.98 (s, 1 H, ArH), 8.07–8.10 (m, 1 H, ArH),
11.11 (s, 1 H, NH).
13
C NMR (100 MHz, DMSO-d ): δ = 32.6, 56.4, 112.5, 117.9, 118.3,
6
13
C NMR (100 MHz, DMSO-d ): δ = 32.9, 55.6, 56.7, 101.4, 111.0,
118.5, 119.3, 120.6, 121.7, 124.2, 125.4, 125.5, 125.8, 137.4, 144.1,
153.3, 159.7.
6
1
1
12.8, 116.2, 119.1, 121.4, 124.1, 124.3, 124.9, 126.1, 128.3, 129.8,
32.5, 149.0, 153.3, 160.7.
Anal. Calcd for C18H12N O : C, 65.06; H, 3.64; N, 16.86. Found: C,
4
3
65.17; H, 3.73; N, 16.94.
2
-Amino-4-(5-bromo-1H-indol-3-yl)-4H-chromene-3-carboni-
9g
trile (4c)
2-Amino-6,8-dibromo-4-(1H-indol-3-yl)-4H-chromene-3-carbo-
Yellow solid; yield: 348 mg (95%); mp 163–165 °C.
nitrile (4h)
1
H NMR (400 MHz, DMSO-d ): δ = 5.51 (s, 1 H, CH), 6.36 (s, 1 H, ArH),
Yellow solid; yield: 361 mg (81%); mp 213–215 °C.
6
6
.45 (s, 1 H, ArH), 6.90–7.54 (m, 8 H, ArH, NH ), 11.15 (s, 1 H, NH).
1
2
H NMR (400 MHz, DMSO-d ): δ = 5.09 (s, 1 H, CH), 6.94 (t, J = 7.4 Hz,
6
13
C NMR (100 MHz, DMSO-d ): δ = 30.8, 56.5, 90.0, 111.7, 114.2,
1 H, ArH), 7.07 (t, J = 7.4 Hz, 3 H, NH , ArH), 7.25 (d, J = 7.2 Hz, 2 H,
2
6
1
1
16.7, 118.6, 121.1, 123.9, 125.1, 127.2, 128.2, 129.6, 135.8, 150.3,
57.4, 160.0.
ArH), 7.37 (t, J = 7.2 Hz, 2 H, ArH), 7.75 (s, 1 H, ArH), 11.06 (s, 1 H, NH).
13
C NMR (100 MHz, DMSO-d ): δ = 33.2, 56.7, 111.0, 112.4, 116.4,
6
1
1
18.2, 118.5, 119.3, 120.5, 121.4, 124.0, 125.4, 128.3, 131.5, 133.7,
37.3, 145.3, 160.0.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
Synthesis
C.-B. Li et al.
Paper
13
Anal. Calcd for C18H11Br N O: C, 48.57; H, 2.49; N, 9.44. Found: C,
C NMR (100 MHz, DMSO-d ): δ = 12.3, 29.2, 54.7, 116.1, 119.7,
2
3
6
48.71; H, 2.57; N, 2.63.
121.2, 123.2, 124.9, 125.0, 128.4, 129.3, 129.4, 138.6, 147.3, 149.1,
60.8.
1
3
-Amino-1-(1H-indol-3-yl)-1H-benzo[f]chromene-2-carbonitrile
9i
(4i)
2-Amino-6-chloro-4-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-
17
pyrazol-4-yl)-4H-chromene-3-carbonitrile (6b)
Yellow solid; yield: 287 mg (85%); mp 198–200 °C.
1
White solid; yield: 341 mg (90%); mp 201–203 °C.
H NMR (400 MHz, DMSO-d ): δ = 5.09 (s, 1 H, CH), 6.93 (t, J = 7.4 Hz,
6
1
2
7
H, ArH), 7.05–7.08 (m, 4 H, NH , ArH), 7.21–7.26 (m, 3 H, ArH),
H NMR (400 MHz, DMSO-d ): δ = 2.06 (s, 3 H, CH ), 4.81 (s, 1 H, CH),
6 3
2
.35–7.39 (m, 3 H, ArH), 7.74 (s, 1 H, ArH), 11.06 (s, 1 H, NH).
6.93 (s, 2 H, NH ), 7.04 (d, J = 8.8 Hz, 1 H, ArH), 7.14 (s, 1 H, ArH), 7.20
2
1
3
(t, J = 7.4 Hz, 1 H, ArH), 7.26–7.29 (m, 1 H, ArH), 7.43 (t, J = 8.0 Hz, 2 H,
ArH), 7.74 (d, J = 8.0 Hz, 2 H, ArH), 11.11 (s, 1 H, NH).
C NMR (100 MHz, DMSO-d ): δ = 33.2, 56.8, 111.0, 112.4, 116.4,
6
1
1
18.2, 118.5, 119.3, 120.5, 121.7, 124.0, 125.4, 128.3, 131.5, 133.7,
37.3, 145.3, 160.0.
13
C NMR (100 MHz, DMSO-d ): δ = 12.1, 29.3, 54.2, 118.1, 119.7,
6
121.0, 125.2, 128.3, 128.6, 129.3, 138.2, 147.3, 148.0, 160.6.
2
-Amino-4-(2-methyl-1H-indol-3-yl)-6-nitro-4H-chromene-3-
9a
carbonitrile (4j)
2-Amino-4-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)-6-nitro-4H-chromene-3-carbonitrile (6c)
Yellow solid; yield: 312 mg (90%); mp 237–239 °C.
1
Yellow solid; yield: 370 mg (95%); mp 205–207 °C.
H NMR (400 MHz, DMSO-d ): δ = 2.51 (s, 3 H, CH ), 5.25 (s, 1 H, CH),
.83 (t, J = 7.0 Hz, 1 H, ArH), 6.97 (d, J = 9.2 Hz, 2 H, ArH), 7.07 (s, 2 H,
6
3
1
6
H NMR (400 MHz, DMSO-d ): δ = 2.12 (s, 3 H, CH ), 4.93 (s, 1 H, CH),
6
3
NH ), 7.27–7.34 (m, 2 H, ArH), 7.77 (s, 1 H, ArH), 8.09 (d, J = 8.0 Hz, 1
7.11 (s, 2 H, NH ), 7.19 (t, J = 7.2 Hz, 1 H, ArH), 7.25 (d, J = 8.8 Hz, 1 H,
2
2
H, ArH), 11.03 (s, 1 H, NH).
ArH), 7.42 (t, J = 7.8 Hz, 2 H, ArH), 7.73 (d, J = 8.0 Hz, 2 H, ArH), 8.01 (s,
1
3
1 H, ArH), 8.09–8.12 (m, 1 H, ArH), 11.09 (s, 1 H, NH).
C NMR (100 MHz, DMSO-d ): δ = 11.7, 31.2, 56.4, 111.4, 113.5,
6
13
1
1
17.5, 117.6, 119.1, 120.6, 124.2, 125.4, 125.6, 126.7, 133.3, 135.9,
44.1, 153.4, 159.3.
C NMR (100 MHz, DMSO-d ): δ = 12.1, 29.4, 54.4, 117.6, 119.5,
6
119.6, 120.6, 124.2, 124.5, 125.1, 125.2, 129.3, 144.1, 147.3, 153.8,
60.0.
Anal. Calcd for C20H15N O : C, 61.69; H, 3.88; N, 17.99. Found: C,
1
2
-Amino-6-chloro-4-(2-methyl-1H-indol-3-yl)-4H-chromene-3-
5
4
carbonitrile (4k)
61.77; H, 3.95; N, 18.10.
Yellow solid; yield: 316 mg (94%); mp 224–226 °C.
1
3-Amino-1-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)-1H-benzo[f]chromene-2-carbonitrile (6d)
H NMR (400 MHz, DMSO-d ): δ = 2.50 (s, 3 H, CH ), 5.09 (s, 1 H, CH),
6
3
17
6
.80 (t, J = 7.6 Hz, 1 H, ArH), 6.86 (s, 2 H, NH ), 6.91–6.99 (m, 3 H,
2
ArH), 7.11 (d, J = 8.8 Hz, 1 H, ArH), 7.25 (d, J = 8.4 Hz, 2 H, ArH), 10.93
Yellow solid; yield: 363 mg (92%); mp 193–195 °C.
(
1
s, 1 H, NH).
1
H NMR (400 MHz, DMSO-d ): δ = 1.96 (s, 3 H, CH ), 5.25 (s, 1 H, CH),
6
3
3
C NMR (100 MHz, DMSO-d ): δ = 11.7, 31.3, 56.3, 111.2, 113.7,
6.91 (s, 2 H, NH ), 7.18 (t, J = 7.2 Hz, 1 H, ArH), 7.25 (d, J = 9.2 Hz, 1 H,
6
2
1
1
17.6, 118.2, 118.9, 120.6, 120.9, 126.2, 126.7, 128.3, 129.1, 133.0,
35.9, 147.9, 159.9.
ArH), 7.40–7.45 (m, 3 H, ArH), 7.50–7.53 (m, 1 H, ArH), 7.71 (d, J = 8.0
Hz, 2 H, ArH), 7.89 (t, J = 8.8 Hz, 2 H, ArH), 8.01 (d, J = 7.6 Hz, 1 H, ArH),
1
1.12 (s, 1 H, NH).
Anal. Calcd for C19H14ClN O: C, 67.96; H, 4.20; N, 12.51. Found: C,
3
13
68.09; H, 4.35; N, 12.63.
C NMR (100 MHz, DMSO-d ): δ = 12.3, 26.7, 55.5, 114.4, 116.5,
6
1
1
20.7, 123.2, 124.8, 127.1, 128.5, 128.9, 129.1, 130.5, 130.6, 146.7,
60.0.
2-Amino-6-chloro-4-(5-methoxy-1H-indol-3-yl)-4H-chromene-3-
carbonitrile (4l)
2-Amino-4-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4H-
chromene-3-carbonitrile (6e)
6
White solid; yield: 334 mg (95%); mp 211–213 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 3.68 (s, 3 H, CH ), 5.02 (s, 1 H, CH),
Yellow solid; yield: 260 mg (97%); mp 217–219 °C.
6
3
6
.76 (t, J = 10.2 Hz, 2 H, ArH), 6.96 (s, 2 H, NH ), 7.13 (t, J = 9.6 Hz, 2 H,
1
2
H NMR (400 MHz, DMSO-d ): δ = 1.98 (s, 3 H, CH ), 4.64 (s, 1 H, CH),
6 3
ArH), 7.28 (t, J = 9.8 Hz, 3 H, ArH), 10.86 (s, 1 H, NH).
6
.73 (s, 2 H, NH ), 6.96 (d, J = 8.0 Hz, 1 H, ArH), 7.01–7.06 (m, 2 H,
2
13
C NMR (100 MHz, DMSO-d ): δ = 32.8, 55.6, 56.3, 101.2, 111.1,
ArH,), 7.16–7.20 (m, 1 H, ArH), 10.49 (br s, 2 H, NH).
6
1
1
12.9, 118.2, 118.5, 121.1, 124.3, 125.9, 126.5, 128.2, 128.4, 129.1,
32.5, 147.8, 153.4, 160.5.
13
C NMR (100 MHz, DMSO-d ): δ = 10.4, 29.1, 55.4, 105.5, 116.0,
6
121.4, 124.0, 124.8, 128.1, 129.4, 137.1, 148.9, 159.6, 160.6.
Anal. Calcd for C19H14ClN O : C, 64.87; H, 4.01; N, 11.94. Found: C,
3
2
64.96; H, 4.19; N, 12.12.
2-Amino-6-chloro-4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-
yl)-4H-chromene-3-carbonitrile (6f)
10a
2
-Amino-4-(5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
Yellow solid; yield: 291 mg (96%); mp 229–231 °C.
16
yl)-4H-chromene-3-carbonitrile (6a)
1
H NMR (400 MHz, DMSO-d ): δ = 2.02 (s, 3 H, CH ), 4.64 (s, 1 H, CH),
6
3
Yellow solid; yield: 324 mg (94%); mp 167–169 °C.
6
.81 (s, 2 H, NH ), 6.99–7.01 (m, 2 H, ArH), 7.23 (d, J = 7.2 Hz, 1 H,
2
1
H NMR (400 MHz, DMSO-d ): δ = 1.96 (s, 3 H, CH ), 4.84 (s, 1 H, CH),
ArH), 10.49 (br s, 2 H, NH).
6
3
6
.81 (s, 2 H, NH ), 6.99 (d, J = 8.4 Hz, 1 H, ArH), 7.04–7.12 (m, 2 H,
13
2
C NMR (100 MHz, DMSO-d ): δ = 10.3, 29.1, 55.1, 104.9, 118.1,
6
ArH), 7.16–7.23 (m, 2 H, ArH), 7.41 (t, J = 8.0 Hz, 2 H, ArH), 7.74 (d,
J = 8.0 Hz, 2 H, ArH).
121.1, 126.2, 128.0, 128.1, 137.1, 147.8, 159.6, 160.3.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
Synthesis
C.-B. Li et al.
Paper
9
-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-3,3-dimethyl-
(5) (a) Andreani, L. L.; Lapi, E. Bull. Chim. Farm. 1960, 99, 583.
(b) Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J. Med.
Chem. 1993, 28, 517. (c) Shanthi, G.; Perumal, P. T.; Rao, U.;
Sehgal, P. K. Indian J. Chem., Sect. B 2009, 48, 1319.
18
2,3,4,9-tetrahydro-1H-xanthen-1-one (8a)
White solid; yield: 337 mg (92%); mp 211–213 °C.
1
H NMR (400 MHz, DMSO-d ): δ = 0.89 (s, 6 H, CH ), 0.99 (s, 3 H, CH ),
6
3
3
(
6) (a) Deng, J.; Sanchez, T.; Neamati, N.; Briggs, J. M. J. Med. Chem.
006, 49, 1684. (b) Contractor, R.; Samudio, I. J.; Estrov, Z.;
1
.05 (s, 3 H, CH ), 2.01–2.35 (m, 8 H, CH ), 5.06 (s, 1 H, CH), 6.93–7.00
3
2
2
(m, 3 H, ArH), 7.07–7.12 (m, 1 H, ArH), 10.43 (s, 1 H, OH).
Harris, D.; McCubrey, J. A.; Safe, S. H.; Andreeff, M.; Konopleva,
M. Cancer Res. 2005, 65, 2890.
13
C NMR (100 MHz, DMSO-d ): δ = 26.7, 28.4, 29.7, 32.1, 41.1, 50.9,
6
102.9, 111.2, 115.8, 124.6, 126.1, 127.3, 128.9, 150.1, 165.2.
(
7) (a) McDonald, E.; Jones, K.; Brough, P. A.; Drysdale, M. J.;
Workman, P. Curr. Top. Med. Chem. 2006, 6, 1193. (b) Elguero, J.;
Goya, P.; Jagerovic, N.; Silva, A. M. S. Targets Heterocycl. Syst.
2002, 6, 52. (c) Jyothi, M.; Merugu, R. Int. J. PharmTech Res. 2015,
7
3
-Chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-
,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (8b)18
8
, 80; http://sphinxsai.com.
8) Kausar, N.; Al Masum, A.; Islam, M. M.; Das, A. R. Mol. Divers.
017, 21, 325.
9) (a) Singh, N.; Allam, B. K.; Raghuvanshi, D. S.; Singh, K. N. Adv.
Synth. Catal. 2013, 355, 1840. (b) Rajesh, U. C.; Wang, J.;
Prescott, S.; Tsuzuki, T.; Rawat, D. S. ACS Sustainable Chem. Eng.
White solid; yield: 381 mg (95%); mp 238–240 °C.
(
(
1
H NMR (400 MHz, DMSO-d ): δ = 0.89–1.04 (m, 12 H, CH ), 2.05–2.51
6
3
2
(
m, 8 H, CH ), 5.03 (s, 1 H, CH), 6.90–7.15 (m, 3 H, ArH), 10.57 (s, 1 H,
2
OH).
13
C NMR (100 MHz, DMSO-d ): δ = 26.6, 28.1, 28.1, 29.6, 32.1, 50.8,
6
1
10.8, 117.8, 127.3, 128.1, 128.3, 149.0, 165.0, 196.1.
2015, 3, 9. (c) Rai, P.; Srivastava, M.; Yadav, S.; Singh, J.; Singh, J.
Catal. Lett. 2015, 145, 2020. (d) Ghosh, P. P.; Das, A. R. J. Org.
Chem. 2013, 78, 6170. (e) Thakur, A.; Reddy, P. L.; Tripathi, M.;
Rawat, D. S. New J. Chem. 2015, 39, 6253. (f) Chen, W.; Cai, Y.;
Fu, X.; Liu, X.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 4910.
(g) Khalafi-Nezhad, A.; Nourisefat, M.; Panahi, F. Org. Biomol.
Chem. 2015, 13, 7772. (h) Ganesan, A.; Kothandapani, J.;
Nanubolu, J. B.; Ganesan, S. S. RSC Adv. 2015, 5, 28597.
(i) Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2007, 48, 6785.
(j) Rajesh, U. C.; Kholiya, R.; Thakur, A.; Rawat, D. S. Tetrahedron
Lett. 2015, 56, 1790.
Funding Information
This work was financially supported by the National Natural Science
Foundation of China (NSFC) (No. 21302101), and National Training
Programs of Innovation and Entrepreneurship for Undergraduates
(Nos. 201710055080, 201710055085). We also thank the Nankai Uni-
versity State Key Laboratory of Elemento-Organic Chemistry for sup-
port.
N
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l
N
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ut ra
l
Secince
F
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n
d
oaitn
of
C
h
n
i
a
2(
1
3
0
2
1
0
1)
(
10) (a) Kumaravel, K.; Vasuki, G. Green Chem. 2009, 11, 1945.
b) Elinson, M. N.; Nasybullin, R. F.; Ryzhkov, F. V.; Egorov, M. P.
C. R. Chim. 2014, 17, 437. (c) Li, M.; Gu, Y. Adv. Synth. Catal. 2012,
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11) Wessjohann, L. A.; Rivera, D. G.; Vercillo, O. E. Chem. Rev. 2009,
09, 796.
12) de Graaff, C.; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41,
969.
(
Supporting Information
3
Supporting information for this article is available online at
(
(
(
https://doi.org/10.1055/s-0037-1610123.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
1
3
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G