Pseudo three-component approach to coumarin-annulated azepines: Synthesis of coumarin[3,4-: B] azepines

Article abstract of DOI:10.1039/c7ra09289j

A series of coumarin-annulated azepines were synthesized via acid-catalyzed condensation of 3-amino-4-hydroxycoumarin with two equivalents of substituted acetophenones in toluene with moderate to good yields. A plausible mechanism for this pseudo three-component reaction was proposed.

Full text of DOI:10.1039/c7ra09289j

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Pseudo three-component approach to coumarin-
annulated azepines: synthesis of coumarin[3,4-b]
Cite this: RSC Adv., 2017, 7, 45269
azepines†
a
Kiran B. Manjappa,a Yu-Ting Peng,a Teau-Jiuan Lioub and Ding-Yah Yang
*
Received 22nd August 2017
Accepted 15th September 2017
A series of coumarin-annulated azepines were synthesized via acid-catalyzed condensation of 3-amino-4-
hydroxycoumarin with two equivalents of substituted acetophenones in toluene with moderate to good
yields. A plausible mechanism for this pseudo three-component reaction was proposed.
DOI: 10.1039/c7ra09289j
rsc.li/rsc-advances
While various efforts have been focused on the preparation
of benzazepines and coumarin-fused heterocycles, the synthesis
Introduction
of coumarin-annulated azepines have not been well-explored in
the literature.12 Scheme 1 outlines the previous preparation of
benzazepines 1 and 2 via acid-catalyzed condensation of ace-
tophenone with 2-uoroaniline in toluene under reux condi-
tions and with 2-aminophenol under microwave irradiation
conditions, respectively. The uorine atom of 2-uoroaniline
serves as a leaving group in the synthesis of 2,4-diphenyl-3H-1-
benzazepine 1,13 whereas the hydroxyl group of 2-aminophenol
functions as a nucleophile in the pseudo three-component
synthesis of diphenyloxazepine 2.14 Recently graphene nano-
sheets have also been used to prepare dibenzo[1,4]diazepine 3
in water.15 Nevertheless, none of the reported methods has
focused on the preparation of coumarin[3,4-b]azepines. In our
continuing efforts to develop new methodology for the prepa-
ration of coumarin-fused heterocycles16 and to subsequently
investigate their potential biological or functional properties,
we made an attempt to synthesize the coumarin-fused azepine
Azepines, unsaturated seven-membered heterocycles with
a nitrogen replacing a carbon at one position, are one of the most
well-known molecules that exhibit a wide range of therapeutic
activities.1 Their activities are generally imparted when the aze-
pines are fused with other molecular scaffolds such as benzene.
Apart from this, the annulated 1,4- and 1,5-diazepine derivatives
are also found to be the privileged heterocycles with various
potent biological properties. These molecular skeletons are
frequently seen in many pharmaceuticals2 currently available on
the markets. For instance, benzene-annulated azepines (benza-
zepines) such as benazepril are ACE inhibitors used primarily in
the treatment of hypertension;3 fenoldopam is used as an anti-
hypertensive agent;4 lorcaserinis is a weight-loss drug;5 and var-
enicline is a prescription medication used to treat nicotine
addiction.6 Fig. 1 shows structures of some biologically important
annulated azepine/diazine derivatives which are the active
components of the existing drugs. On the other hand, coumarins
represent another important class of heterocycles that have wide
applications in the areas of medicinal chemistry7 and functional
materials.8 Similar to that of azepines, when coumarins are fused
with other molecular scaffolds, the resulting compounds may
also exhibit unique or even unprecedented properties. For
example, phenanthridine-annulated coumarins have been found
to possess negative thermochromic properties;9 pyran-annulated
coumarins have been reported to exhibit molecular switching
properties;10 pyrrole-annulated coumarins have been demon-
strated to possess redox-switching properties.11
aDepartment of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard,
Xitun District, Taichung 40704, Taiwan. E-mail: yang@thu.edu.tw
bDepartment of Applied English, Chaoyang University of Technology, No. 168, Jifeng E.
Rd., Wufeng District, Taichung 41349, Taiwan
† Electronic supplementary information (ESI) available: General procedure for the
synthesis of 4a–4o and CIF les. CCDC 1568068–1568070. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c7ra09289j
Fig.
derivatives.
1 Structures of some biologically active azepine/diazine
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the coumarin[3,4-b]azepine 4a. To our delight, the pseudo
three-component approach proved to be successful. The
molecular structure of 4a was elucidated by spectroscopic data
as well as by the ORTEP crystal analysis.19 In the 1H NMR spectra
of 4a, two characteristic broad singlet absorption peaks at the
chemical shi of 2.19 and 4.99 ppm were observed, which were
assigned to the methylene protons anked by the two phenyl
rings in the azepine moiety. A similar observation has been
previously reported in the literature for 2,4-diaryl-3H-1-benza-
zepines.20 Since the yield of the target compound 4a was found
to be mere 32%, the optimizations of reaction conditions were
then under taken. Table 1 lists the results of optimization of
reaction parameters for 4a. The combination of p-TsOH and
ꢀ
molecular sieves (4 A) was found to be the best reaction
conditions. As the loading of p-TsOH decreased from 1.0 to 0.5
equiv. (entries 1 and 2), the yield of 4a increased from 32 to
57%. The highest yield (80%) was recorded when 0.2 equiv. of
p-TsOH was employed (entry 3). Among the Lewis acids
screened, only Yb(OTf)3 showed considerable activity (entry 6,
64%) and the rest of them were found be below average (entries
4 and 8). These results prompted us to employ the conditions of
0.2 equiv. of p-TsOH (entry 3) in the subsequent reactions re-
ported in the present study.
Scheme 1 Synthetic methods for benzazepines and their derivatives.
Aer successfully realizing the preparation of coumarin-
annulated azepine 4a, we then turned our attention to investi-
gate the scope and limitation of this pseudo three-component
reaction. A series of acetophenones bearing different substitu-
ents at either ortho or para position of the aromatic ring were
examined. Fig. 2 lists the structures and yields of the prepared
coumarin[3,4-b]azepines 4a–o. The results suggested that
substrates with either an electron-donating group such as OMe
and phenyl or an electron-withdrawing group such as Br, NO2,
and CN substituted at the para position of acetophenone all
gave the corresponding products 4b–f with yields between
60–70%, indicating that the inductive effect of the para-
substituents has little inuence on the reaction yield. Never-
theless, both para-amino substituted acetophenones such as 1-
derivatives in a multi-component manner. Herein we report the
acid-catalyzed pseudo three-component synthesis of coumarin
[3,4-b]azepines by sequential condensations of 3-amino-4-
hydroxycoumarin with two equiv. of substituted acetophe-
nones. For present methodology, the substrate scope is inves-
tigated and a possible reaction mechanism is deduced.
Results and discussion
The proposed synthesis of coumarin[3,4-b]azepine 4a is shown
in Scheme 2. It started with nitration of commercially available
4-hydroxycoumarin (5) with sodium nitrite and nitric acid in
acetic acid to give 3-hydroxy-4-nitrocoumarin17 (6) and followed
by the Pd/C reduction under hydrogen atmosphere to yield the
3-amino-4-hydroxycoumarin (7).18 Final reuxing of amino-
coumarin 7 with two equivalent of acetophenone in the pres-
ence of one equivalent of p-TsOH in toluene for 12 h afforded
Table 1 Optimization of reaction parameters for 4aa
Entry
Acid
Equiv.
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
p-TsOH
p-TsOH
p-TsOH
FeCl3
AlCl3
Yb(OTf)3
SnCl4
1.0
0.5
0.2
0.2
0.2
0.2
0.2
0.2
12
12
6
12
12
10
12
12
32
57
80
nrc
16
64
nrc
42
ZnCl2
Scheme 2 Preparation of compound 4a and its ORTEP crystal
structure.19
a
b
In entries 3 to 8, 4 A MS was added. Isolated yield. c No reaction.
ꢀ
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Fig. 2 Structures of the prepared coumarin[3,4-b]azepines 4a–o.
(4-(dimethylamino)phenyl)ethan-1-one and 1-(4-morpholino-
In order to gain more insights into the mechanism of this
phenyl)ethan-1-one gave the respective products 4g and 6h pseudo three-component reaction, we performed an experiment
with low yields. This observation may be attributed to the strong by introducing just one equiv. of acetophenone to react with
resonance effect of p-amino group rendering 3-acetophenone aminocoumarin 7. In this control reaction, compound 4a was
less susceptible to nucleophilic attack by aminocoumarin. For obtained as the major product, along with a trace amount of
compounds containing hetero aryl groups like 4-acetylpyridine, a minor product. This minor product was isolated and further
2-acetylfuran, and 2-acetylthiophene, they can all serve as characterized by spectroscopic analysis to be the imine 8
substrates for this reaction to afford the corresponding azepines (Scheme 3). In the proton NMR spectrum, a singlet peak at
4i–k in moderate yields. The substrates bearing methyl, 2.75 ppm was clearly observed and assigned to be the methyl
methoxy, or bromo at the ortho position at the phenyl ring of absorption of 8. The detection of formation of the intermediate
acetophenone generally suffered for low yields, presumably due imine 8 in this pseudo three-component reaction provides solid
to the steric hindrance caused by the ortho substituent. evidence that the mechanism involves the rst condensation of
Consequently, the even bulkier substrates such as o-nitro- aminocoumarin with acetophenone to give the imine 8.
acetophenone and 1-(naphthalen-2-yl)ethan-1-one failed to give
Scheme 4 depicts the proposed mechanism for this pseudo
any of the expected azepines. When propiophenone was three-component synthesis of coumarin-annulated azepines in
employed as the aromatic ketone substrate, the azepine 4o was details. It presumably starts with dehydration of 3-amino-4-
obtained in 57% yield. This observation suggests that the hydroxycoumarin (7) with acetophenone to give the imine 8
substrate scope of this reaction is not limited to methyl ketones which is in equilibrium with the enamine 9. The enamine 9
only. Nevertheless, when the ketone substrate was further
extended from propiophenone to isopropyl phenyl ketone, no
expected product was observed. Fig. 3 shows the X-ray crystal
structures of 4j and 4n.19 It is noteworthy that the prepared
azepines all exist in the imine forms on the azepine ring, except
for compound 4i. In proton NMR spectra of 4i, the observation
of an intramolecular hydrogen bonding absorption peak at
12.14 ppm along with two small doublets (J ¼ 1.6 Hz) olenic
hydrogen absorptions at 8.24 and 8.22 ppm clearly indicates
that 4i exists in the enamine form. The reason why only 4i exists
in the enamine form in solution is currently under
investigation.
Fig. 3 ORTEP crystal structures of 4j (left) and 4n (right).
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spectra were recorded using 1725XFT-IR spectrophotometer.
High resolution mass spectra (HRMS) were obtained on
a Thermo Fisher Scientic Finnigan MAT95XL spectrometer
using magnetic sector analyzer1 H NMR (400 MHz) and 13C
NMR (100, or 150 MHz) spectra were recorded on a Varian
Scheme 3 Formation of the intermediate 8 and its conversion to the VXR300 or Bruker 400/600 spectrometer. Chemical shis were
product 4a.
reported in parts per million on the dscale relative to an internal
standard (tetramethylsilane, or appropriate solvent peaks) with
coupling constants given in hertz. 1H NMR multiplicity data are
denoted by s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet). Analytical thin-layer chromatography (TLC) was
carried out on Merck silica gel 60G-254 plates (25 mm) and
developed with the solvents mentioned. Visualization was
accomplished by using portable UV light, ninhydrin spray and
iodine chamber. Flash chromatography was performed in
columns of various diameters with Merck silica gel (230–400
mesh ASTM 9385 kieselgel 60H) by elution with the solvent
systems. Solvents, unless otherwise specied, were reagent
grade and distilled once prior to use. All new compounds
exhibited satisfactory spectroscopic and analytical data.
Synthesis of 4-hydroxy-3-nitrocoumarin (6)
To a stirred suspension of 4-hydroxycoumarin (5, 4.0 g,
24.67 mmol, 1.0 equiv.) in AcOH (50 mL) was added sodium
nitrite (17 mg, 0.25 mmol, 0.01 equiv.) in one portion and HNO3
(3.5 mL) drop wise. The resulting mixture was stirred at room
temperature for 5 min and followed by heating at 70 ꢀC for
Scheme 4 Proposed mechanism for the formation of 4a.
30 min in an oil bath. As the brown solution attained to room
temperature, the pure compound crystallized out from the
solution. These crystals were ltered, washed with hexanes (6 ꢁ
further reacts with the second molecule of acetophenone to
form the tertiary alcohol 10. The subsequent dehydration to
remove the second water molecule affords the imine 11 which
again is in equilibrium with the enamine 12. The intra-
molecular addition of enamine to the 4-position of the
coumarin ring of 12 yields the cyclized 13. The elimination of
the third water molecule along with deprotonation of 13
furnishes the 16. Final acid-catalyzed isomerization of 14
affords the product azepine 4a. This methodology provides an
easy and quick access to the coumarin[3,4-b]azepines.
50 mL), and dried in vacuo to afford 3-nitro-4-hydroxycoumarin
(6) as off-yellow shiny crystals. 4.6 g; yield 90%; Rf ¼ 0.15 (10%
MeOH/DCM); mp 176–177 ꢀC (lit.16 177 ꢀC); 1H NMR (CDCl3,
300 MHz) d 9.41 (bs, 1H), 7.88 (dd, J ¼ 7.8, 1.5 Hz, 1H), 7.52 (td,
J ¼ 8.1, 1.8 Hz, 1H), 7.24–7.16 (m, 2H).
Synthesis of 3-amino-4-hydroxycoumarin (7)
To a suspension of 4-hydroxy-3-nitrocoumarin (6, 4.0 g, 22.58
mmol) in ethanol (200 mL) was added 10% Pd/C (50 mg) at
room temperature. The resulting solution was stirred under H2
atmosphere for 6 h at that temperature. Aer the completion of
the reaction, the suspension was ltered through the celite pad,
washed extensively with MeOH (3 ꢁ 30 mL), acetone (3 ꢁ 30
mL), and concentrated to afford an off-white solid. 2.82 g; yield
82%; Rf ¼ 0.16 (10% MeOH/DCM); mp 216 ꢀC (lit.17 222–224 ꢀC);
1H NMR (CDCl3, 300 MHz) d 8.19 (bs, 2H), 7.84 (dd, J ¼ 8.0,
1.6 Hz, 1H), 7.47 (td, J ¼ 7.6, 1.6 Hz, 1H), 7.25–7.21 (m, 2H).
Conclusions
In summary, we have demonstrated that coumarin-annulated
azepines can be efficiently constructed via p-TsOH-catalyzed
pseudo three-component coupling of 3-amino-4-hydroxycoumarin
with two equiv. of acetophenone. The scope of the reaction is
illustrated by preparation of 15 coumarin[3,4-b]azepine analogs
with moderate to good yields. The biological evaluation of the
prepared coumarin-annulated azepines is currently underway.
General procedure for the preparation of coumarin-fused
azepines (4)
To a 100 mL round bottom ask was charged with 3-amino-4-
hydroxycoumarin (1.0 equiv.), acetophenone derivative (2.1
Experimental
Instrumentation
ꢀ
equiv.), p-TsOH (0.2 equiv.), and 4 A molecular sieves in anhy-
drous toluene (25 mL). The resulting mixture was reuxed for
Melting points were determined on a Mel-Temp melting point about 8–10 h. The dark solution was allowed to attain to the
apparatus in open capillaries and are uncorrected. Infrared (IR) room temperature and the solvent was evaporated in vacuo. The
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residue was redissolved in DCM (50 mL), ltered, and washed
with copious amounts of DCM. The resulting solvent was
concentrated in vacuo and the product was subjected to ash
column chromatography to afford the coumarin-fused azepine
derivative.
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4a. Off-yellow solid; yield 80%; Rf ¼ 0.42 (30% EtOAc/
hexanes); mp 220–221 ꢀC; 1H NMR (CDCl3, 400 MHz) d 7.89
(dd, J ¼ 8.0, 1.6 Hz, 2H), 7.83 (dd, J ¼ 7.8, 1.2 Hz, 1H), 7.62–7.60
(m, 2H), 7.50–7.40 (m, 5H), 7.38 (s, 1H), 7.39–7.35 (m, 1H), 7.33–
7.29 (m, 3H), 5.01 (bs, 1H), 2.18 (bs, 1H); 13C NMR (CDCl3, 150
MHz) d 159.9, 152.0, 150.2, 138.4, 137.7, 136.0, 132.4, 131.1,
131.0, 129.8, 129.4, 129.1, 128.7, 128.5, 127.9, 124.4, 124.2,
119.7, 119.2, 117.2, 36.9; IR nmax (ATR) 3427, 3062, 1721, 1602,
1446, 1280, 1186, 1067, 765, 690 cmꢂ1; HRMS (EI) calcd for
C
25H17NO2 [M+] 363.1259 found 363.1252.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
The authors thank the Ministry of Science and Technology of
the Republic of China, Taiwan, for nancially supporting this
research under Contract No. MOST 105-2113-M-029-001.
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