Formation of epoxychromeno[4,3-c]isoquinolines through diastereoselective one-pot IMDA reaction of 4-chloro-3-[(1E)-3-oxo-3-phenyl-1-propen-1-yl]-2H-chromen-2-one and furfurylamine

Article abstract of DOI:10.1007/s13738-020-01999-8

Abstract: An intramolecular Diels–Alder mediated reaction of (2E)-3-(4-chloro-2-methylene-2H-chromen-3-yl)-1-phenyl-2-propen-1-one, which was obtained in situ from the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde and Wittig reagent, with furfuryl

Full text of DOI:10.1007/s13738-020-01999-8

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-01999-8
ORIGINAL PAPER
Formation of epoxychromeno[4,3‑c]isoquinolines
through diastereoselective one‑pot IMDA reaction
of 4‑chloro‑3‑[(1E)‑3‑oxo‑3‑phenyl‑1‑propen‑1‑yl]‑2H‑chromen‑2‑one
and furfurylamine
Abdolali Alizadeh1 · Kaveh Amir Ashjei Asalemi1 · Behnaz Farajpour1 · Mohammad Reza Halvagar2
Received: 7 May 2020 / Accepted: 7 July 2020
© Iranian Chemical Society 2020
Abstract
An intramolecular Diels–Alder mediated reaction of (2E)-3-(4-chloro-2-methylene-2H-chromen-3-yl)-1-phenyl-2-propen-
1-one, which was obtained in situ from the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde and Wittig reagent,
with furfurylamine leads to fused epoxychromeno[4,3-c]isoquinolines. Reaction performed in one-pot condition and only
one diastereomer was obtained. In this method, the key step for the formation of the fnal product is IMDA reaction.
Graphic abstract
A series of fused epoxychromeno[4,3-c]isoquinoline compounds containing chromene skeleton have been synthesized
through the cyclization strategy, from 4-chloro-2-oxo-2H-chromene-3-carbaldehyde, Wittig reagent, and furfurylamine. The
reactions were carried out under refux condition in DCM/toluene.
Keywords 4-Chloro-2-oxo-2H-chromene-3-carbaldehyde · Wittig reagent · (2E)-3-(4-chloro-2-methylene-2H-chromen-
3-yl)-1-phenyl-2-propen-1-one · Furfurylamine · IMDA reaction · Coumarin-based heterocycles · One-pot process ·
Diastereoselective
Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-020-01999-8) contains
supplementary material, which is available to authorized users.
Coumarins are one of the most common and valuable
naturally occurring structures in chemistry and biologi-
cal chemistry [1–3]. These structures are widely found in
plants and many of them extracted successfully and applied
* Abdolali Alizadeh
aalizadeh@modares.ac.ir; abdol_alizad@yahoo.com
Extended author information available on the last page of the article
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
in biological and pharmaceutical purposes [4]. Investigations
showed that coumarin-based heterocycles exhibit diferent
biological activities compared to simple coumarin deriva-
tives so adding a heterocycle moiety to coumarin structure
either as linking group or as a fused part of whole structure
could be a powerful and general tool to synthesize new range
of coumarins for evaluation of their biological activities [5,
6]. A survey in the literature revealed that scientists tried
diferent methods to synthesize new coumarin heterocyclic
derivatives. For instance, Yang and co-workers applied a
four-component Ugi reaction to achieve this goal. They used
coumarin-3-carboxylic, isocyanides, anilines, and diferent
aldehydes to obtain chromeno[3,4-c]pyrrole-3,4-diones
[7]. Another application of multicomponent reaction in the
synthesis of coumarin-based heterocycles was reported by
Shi et al. [8]. The fnal 3-pyrrolyl coumarin was obtained
through the four-component reaction between arylglyoxal,
dialkyl acetylenedicarboxylates, amines, and 4-hydroxycou-
marin. Besides multicomponent reaction, some scientists
used the metal catalyst for the synthesis of fused coumarins.
For example, the Snieckus group reported the synthesis of
coumestan derivatives using a Suzuki–Miyaura cross-cou-
pling strategy followed by cyclization with acid catalysis
[9]. Another application of metal catalysts in this way is
reported by Xu et al. [10]. This cascade reaction includes the
addition of the broad range of prepared dialkynyl zincs to
3-bromo-4-acetoxycoumarins in the presence of palladium/
copper catalyst. With this method, furocoumarins could be
obtained in good-to-high yields.
novel classes of coumarin-based bicyclic compounds start-
ing from coumarin core and utilizing IMDA as a key reac-
tion in the synthesis of epoxychromeno[4,3-c]isoquinolines.
First, we initiate to prepare starting materials. Wittig rea-
gent 2 was prepared based on the reported procedures start-
ing from acetophenone [19]. 4-Chloro-2-oxo-2H-chromene-
3-carbaldehyde 1 also synthesized through the procedure
reported by China Raju [20] (Scheme 1).
Experimental section
Melting points were measured on an Electrothermal 9100
apparatus. IR spectra were recorded as KBr pellets on a
1
NICOLET FT-IR 100 spectrometer. H NMR (500 and
300 MHz) and 13C NMR (125 and 75 MHz) spectra were
obtained using Bruker DRX-500 AVANCE and Bruker
DRX-300 AVANCE spectrometers. NMR spectra at room
temperature were recorded in DMSO-d6. Chemical shifts
are reported in parts per million (δ) downfeld from an
internal tetramethylsilane reference. Coupling constants (J
values) are reported in Hertz (Hz), and spin multiplicities
are indicated by the following symbols: bs (broad singlet),
s (singlet), d (doublet), t (triplet), m (multiplet). Elemental
analyses for C, H, and N were performed using a Heraeus
CHN–O–Rapid analyzer. All the products were recrystal-
lized from CH3CN for CHN analysis. Mass spectra were
recorded on a FINNIGAN-MATT 8430 mass spectrometer
operating at an ionization potential of 20 or 70 eV. All the
reagents and solvents were purchased from Merck or Aldrich
without any purifcation.
In addition of heterocyclic coumarins, many methods
have been developed for synthesis of fused chromene,
especially fused chromenones. Reddy and co-workers used
Rh2(OAc)4 for catalysis formation of fused furochromenone
structures [11]. Another multicomponent reaction has been
developed for synthesis of pyrrole-fused chromanones by
Ghandi et al. [10, 12]. Among all these methods, few reports
have been addressed about epoxychromenes due to their
complex structure. Mikhalchenko group studied new bicy-
clic chromenes and investigated their analgesic activity [13].
Among various methods and approaches, intramolecular
Diels–Alder reaction has found a notable place in organic
chemistry and displayed multiple applications in organic
syntheses such as macrocyclization, natural product syn-
thesis, and formation of molecular complexity [14–17].
Also, multiple carbon–carbon or carbon–heteroatom bond
formation, high atom economy, and stereoselective product
have made this reaction to one of the main topics in organic
synthesis. Samant and co-workers employed IMDA to syn-
thesize a new class of fuorescent coumarin-based hetero-
cycles [18].
General procedure for preparation of phenacyl
bromide derivatives
This compound was prepared based on reported proce-
dures in the literature [21, 22]. A solution of acetophenone
(50 mmol, 6 g) in 30 ml CHCl3 was introduced to a 100-ml
three-neck round-bottom fask. The fask was equipped with
a pressure-equalizing dropping funnel, which charged with
the solution of bromine (52.5 mmol, 8.4 g) in 5 ml CHCl3.
The apparatus was placed in a 60 °C oil bath on a magnetic
Based on the signifcant role of coumarin-based heterocy-
clic compounds in diferent aspects of chemistry and biolog-
ical chemistry, we focused our attempts on the synthesis of
Scheme 1 Synthetic route for the preparation of starting materials
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Journal of the Iranian Chemical Society
3
stirrer, and bromine was added dropwise over 30 min. The
reaction was carried out in an open vessel condition, so that
the produced HBr could leave the fask. After the addition
of bromine, the reaction was refuxed for another 2 h. Then,
the reaction mixture was cooled to room temperature and
the solvent was removed under vacuum and 15 ml hexane
was added to the residue. The mixture was placed in the
refrigerator for a day. The resulting solid was fltered and
washed with water.
CH7), 7.27 (1H, d, JHH = 8.2 Hz, CH1), 7.31 (1H, t,
3JHH = 7.6 Hz, CH3), 7.53 (1H, d, JHH = 7.7 Hz, CH2),
3
3
7.61 (2H, d, JHH = 8.3 Hz, 2CHmeta of Ph), 7.71 (1H, t,
3JHH = 8.3 Hz, CHpara of Ph) 7.71 (1H, s, CH5 of furan),
8.03 (1H, d, 3JHH =7.9 Hz, CH4), 8.05 (2H, d, 3JHH =8.3 Hz,
2CHortho of Ph), 8.12 (1H, s, NH), 8.56 (3H, s, NH3). 13C
NMR (75.46 MHz, DMSO-d6): δC 34.91 (CH10a), 37.56
(CH10), 40.86 (CH2NH3), 57.14 (CH62), 79.97 (CH9),
85.13 (C6a), 94.86 (C10b), 110.27 (CH3 of furan), 110.90
(CH4 of furan), 114.22 (C4a), 116.64 (CH1), 122.37 (CH3),
123.40 (CH4), 128.73 (2CHortho of Ph), 128.74 (2CHmeta of
Ph), 131.20 (CH2), 132.97 (CHpara of Ph), 133.54 (CH7),
136.50 (Cipso of Ph), 136.77 (CH8), 143.54 (CH5 of furan),
147.27 (C2 of furan), 147.62 (C4b), 152.01 (C12a), 161.25
(COO of chromene), 195.60 (C=O). Crystal data for 5a
C23H17NO4 (CCDC 1903316): MW = 415.56, Monoclinic,
C 2/c, a = 14.262(3) Å, b = 17.824(4) Å, c = 14.919(3) Å,
α = 90.00, β = 107.15 (3), γ = 90.00, V = 3623.9(14) Å3,
Z = 8, Dc = 1.361 mg/m3, F (000) = 1552, radiation, Mo
Kα (λ = 0.71073 Å), 1.881 ≤ 2θ ≤ 26.899, intensity data
were collected at 293(2) K with a STOE IPDS-2T dif-
fractometer, and employing ω/2θ scanning technique, in
the range of − 18 ≤ h ≤ 18, − 22 ≤ k ≤ 22, -18 ≤ l ≤ 18; the
structure was solved by a direct method, all non-hydrogen
atoms were positioned and anisotropic thermal parameters
refned from 2614 independent refections with R (into)=0.
1813 by a full-matrix least-squares technique converged to
R1=0.0428, wR2=0.0623 [I>2sigma(I)].
General procedure for preparation of Wittig reagent
(1‑phenyl‑2‑(triphenyl‑λ5‑phosphanylidene)
ethan‑1‑one)
This compound was prepared based on reported procedures
in the literature [19].
General procedure for synthesis
of 4‑chloro‑3‑formylcoumarin
This is a known compound, and it was prepared according
to procedures reported in the literature [20, 23].
General procedure for one‑pot synthesis
of compounds 5a–g
4-Chloro-3-formylcoumarin (1 mmol, 208 mg) and Wit-
tig reagent (1 mmol, 380 mg) were introduced to a 25-ml
round-bottom fask. Then, CH2Cl2 (10 ml) was added to
fask and reaction mixture was stirred at room temperature
for about a day. Afterward, furfurylamine (2 mmol, 194 mg)
was added to fask following by addition of 10 ml toluene
as a co-solvent and the mixture was refuxed for 4–5 h until
consumption of starting materials. The resulting solid was
fltered and washed with ethyl acetate.
(6aR,9S,10S,10aR)‑10‑(4‑Bromobenzoyl)‑5,9,10,10a‑tetrahy‑
dro‑6H,11H‑6a,9‑epoxychromeno[4,3‑c]isoquinolin‑11‑one
(5b) White powder, mp = 190–191 °C, 0.315 g, yield:
70%. IR (KBr) (νmax, cm−1): 3324 (NH), 1671 (C=O),
1611 (C=C), 1550 and 1492 (Ar), 1218 (C–O of lac-
tone), 1066 (C–O of ether). Anal. Calcd for C23H16BrNO4
(450.28): C, 61.35; H, 3.58; N, 3.11%. Found: C, 61.36;
H, 3.55; N, 3.12%. MS (EI, 70 eV): m/z (%)=451 (M++2,
1), 450 (M++1, 1), 449 (M+, 1), 353 (14), 266 (48), 252
(11), 251 (28), 248 (11), 185 (16), 183 (16), 97 (21), 81
(6aR,9S,10S,10aR)‑10‑Benzoyl‑5,9,10,10a‑tetrahydro‑6H,11H
‑6a,9‑epoxychromeno[4,3‑c]isoquinolin‑11‑one (5a) White
powder, mp= 205–206 °C, 0.302 g, yield: 82%. IR (KBr)
(νmax, cm−1): 3340 (NH), 1653 (C=O), 1608 (C=C),
1547 and 1448 (Ar), 1217 (C–O of lactone), 1062 (C–O
of ether). Anal. Calcd for C23H17NO4 (371.39): C, 74.38;
H, 4.61; N, 3.77%. Found: C, 74.42; H, 4.59; N, 3.78%.
MS (EI, 70 eV): m/z (%)=371 (M+, 8), 342 (10), 274 (8),
273 (34), 267 (14), 266 (71), 252 (20), 251 (37), 249 (9),
248 (30), 238 (15), 236 (8), 115 (8), 105 (41), 81 (100),
77 (24), 53 (17). 1H NMR (300 MHz, DMSO-d6): δH 3.01
(1H, d, 3JHH =3.6 Hz, CH10a), 3.77 (1H, dd, 3JHH =14.0 Hz,
3JHH =3.7 Hz, CH26), 3.90 (1H, d, 3JHH =4.1 Hz, CH10), 3.97
(1H, d, 3JHH =14.0 Hz, CH26), 4.04 (2H, s, CH2NH3), 5.21
1
(100), 53 (20). H NMR (500 MHz, DMSO-d6): δH 2.97
(1H, d, 3JHH =3.6 Hz, CH10a), 3.81 (1H, dd, 3JHH =14.0 Hz,
3JHH =3.7 Hz, CH26), 3.86 (1H, t, 3JHH =4.1 Hz, CH10), 3.93
(1H, d, 3JHH =14.0 Hz, CH26), 4.04 (2H, s, CH2NH3), 5.21
(1H, d, JHH = 4.6 Hz, CH9), 6.14 (1H, d, JHH = 5.7 Hz,
3
3
CH8), 6.49 (1H, d, 3JHH =2.8 Hz, CH4 of furan), 6.53 (1H,
d, JHH = 5.7 Hz, CH7), 6.54 (1H, d, JHH = 2.8 Hz, CH3
3
3
of furan), 7.25 (1H, d, JHH = 8.2 Hz, CH1), 7.31 (1H, d,
3
3JHH =7.6 Hz, CH3), 7.54 (1H, d, 3JHH =7.7 Hz, CH2), 7.70
(2H, d, JHH = 8.3 Hz, 2CH of Ar), 7.72 (1H, s, CH5 of
3
furan), 7.98 (2H, d, 3JHH =8.3 Hz, 2CH of Ar), 8.05 (1H, d,
3JHH =7.6 Hz, CH4), 8.16 (1H, s, NH), 8.58 (3H, s, NH3).
13C NMR (125 MHz, DMSO-d6): δC 35.39 (C10a), 38.34
(C10), 41.28 (CH2NH3), 57.53 (CH62), 80.36 (C9), 85.60
3
3
(1H, d, JHH = 4.6 Hz, CH9), 6.12 (1H, d, JHH = 5.7 Hz,
CH8), 6.48 (1H, d, 3JHH =2.8 Hz, CH4 of furan), 6.51 (1H,
d, 3JHH =2.8 Hz, CH3 of furan), 6.54 (1H, d, 3JHH =5.8 Hz,
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Journal of the Iranian Chemical Society
(C6a), 95.21 (C10b), 110.71 (CH3 of furan), 111.35 (CH4 of
furan), 114.66 (C4a), 117.10 (CH1), 122.87 (CH3), 123.86
(CH4), 127.54 (Cipso-Br), 130.75 (2CH of Ar), 131.67 (CH2),
132.22 (2CH of Ar), 133.93 (CH7), 136.31 (CH8), 137.05
(Cipso-C=O), 143.99 (CH5 of furan), 147.73 (C2 of furan),
148.09 (C4b), 152.46 (C12a), 161.75 (COO of chromene),
195.51 (COPh).
NMR (500 MHz, DMSO-d6): δH 2.99 (1H, d, 3JHH =3.6 Hz,
CH10a), 3.80 (1H, dd, JHH = 14 Hz, JHH = 3.7 Hz, CH62),
3.88 (1H, t, 3JHH =4.1 Hz, CH10), 3.96 (1H, d, 2JHH =14 Hz,
2
4
CH62), 4.06 (2H, s, CH2NH3), 5.22 (1H, d, JHH = 4.6 Hz,
3
3
CH9), 6.15 (1H, d, JHH = 5.7 Hz, CH8), 6.50 (1H, t,
3
3JHH = 2.8 Hz, CH4 of furan), 6.53 (1H, d, JHH = 5.8 Hz,
CH7), 6.54 (1H, d, 3JHH =2.8 Hz, CH3 of furan), 7.28 (1H, d,
3JHH =8.2 Hz, CH1), 7.33 (1H, t, 3JHH =7.6 Hz, CH3), 7.55
(1H, t, 3JHH =7.7 Hz, CH2), 7.58 (2H, d, 3JHH =8.3 Hz, 2CH
of Ar), 7.73 (1H, s, CH5 of furan), 8.00 (1H, d, 3JHH =7.9 Hz,
CH4), 8.06 (1H, s, NH), 8.07 (2H, d, 3JHH =8.3 Hz, 2CH of
Ar), 8.45 (3H, s, NH3). 13C NMR (125 MHz, DMSO-d6):
δC 34.94 (CH10a), 37.88 (CH10), 40.84 (CH2NH3), 57.11
(CH26), 79.93 (CH9), 85.17 (C6a), 94.76 (C10b), 110.26 (CH3
of furan), 110.91 (CH4 of furan), 114.22 (C4a), 116.66
(CH1), 122.43 (CH3), 123.41 (CH4), 128.82 (2CH of Ar),
130.20 (2CH of Ar), 131.23 (CH2), 133.50 (CH7), 135.53
(Cipso-C=O), 136.61 (CH8), 137.93 (Cipso-Cl), 143.55 (CH5
of furan), 147.30 (C2 of furan), 147.67 (C4b), 152.03 (C12a),
161.31 (COO of chromene), 194.86 (C=O).
(6aR,9S,10S,10aR)‑10‑(2‑Chlorobenzoyl)‑5,9,10,10a‑tetrahy‑
dro‑6H,11H‑6a,9‑epoxychromeno[4,3‑c]isoquinolin‑11‑one
(5c) White powder, mp=193–194 °C, 0.287 g, yield: 71%.
IR (KBr) (νmax, cm−1): 3281 (NH), 1652 (C=O), 1610
(C=C), 1550 and 1494 (Ar), 1214 (C–O of lactone), 1058
(C–O of ether). Anal. Calcd for C23H16ClNO4 (405.83):
68.07; H, 3.97; N, 3.45%. Found: C, 68.09; H, 3.96; N,
3.45%. MS (EI, 70 eV): m/z (%) = 407 (M++2, 2), 406
(M++1, 2), 405 (M+, 6), 377 (8), 376 (7), 307 (7), 267 (25),
266 (100), 252 (30), 251 (56), 248 (37), 238 (17), 141 (15),
139 (42), 111 (18), 81 (94), 53 (22). 1H NMR (500 MHz,
3
DMSO-d6): δH 2.93 (1H, d, JHH = 3.7 Hz, CH10a), 3.63
3
2
(1H, t, JHH = 4.0 Hz, CH10), 3.79 (1H, dd, JHH = 14 Hz,
4JHH =3.5 Hz, CH26), 3.94 (1H, d, 2JHH =14 Hz, CH62), 4.05
(6aR,9S,10S,10aR)‑10‑(4‑Methoxybenzoyl)‑5,9,10,10a
‑tetrahydro‑6H,11H‑6a,9‑epoxychromeno[4,3‑c]isoquino‑
lin‑11‑one (5e) White powder, mp=207–208 °C, 0.276 g,
yield: 69%. IR (KBr) (νmax, cm−1): 3288 (NH), 1661 (C=O),
1607 (C=CC=C), 1550 and 1495 (Ar), 1255, 1222, 1170
and 1028 (C–O). Anal. Calcd for C24H19NO5 (401.41):
C, 71.81; H, 4.77; N, 3.49%. Found: C, 71.8; H, 4.76; N,
3.46%. MS (EI, 70 eV): m/z (%) = 401 (M+, 4), 305 (7),
303 (14), 267 (17), 266 (81), 252 (12), 251 (36), 248 (12),
238 (9), 236 (14), 136 (11), 135 (100), 81 (75), 53 (6). 1H
NMR (500 MHz, DMSO-d6): δH 3.01 (1H, s, CH10a), 3.82
(3H, s, OMe), 3.83 (1H, b, CH62), 3.90 (1H, b, CH10), 3.94
(1H, b, CH62), 4.03 (2H, s, CH2NH3), 5.18 (1H, s, CH9),
6.10 (1H, s, CH8), 6.48 (1H, s, CH4 of furan), 6.53 (1H, s,
7CH), 6.55 (1H, s, CH3 of furan), 7.02 (2H, s, 2CH of Ar),
7.26 (1H, s, CH1), 7.30 (1H, s, CH3), 7.53 (1H, s, CH2),
7.71 (1H, s, CH5 of furan), 8.02 (1H, s, CH4), 8.03 (2H, s,
2CH of Ar), 8.15 (1H, s, NH), 8.57 (3H, s, NH3). 13C NMR
(125 MHz, DMSO-d6): δC 35.43 (CH10a), 37.74 (CH10),
41.33 (CH2NH3), 55.97 (OMe), 57.28 (CH62), 80.43 (CH9),
85.56 (C6a), 95.41 (C10b), 110.64 (CH3 of furan), 111.34
(CH4 of furan), 114.43 (2CH of Ar), 114.71 (C4a), 117.04
(CH1), 122.87 (CH3), 123.80 (CH4), 130.18 (Cipso-C=O),
130.99 (2CH of Ar), 131.59 (CH2), 134.07 (CH7), 136.81
(CH8), 143.94 (CH5 of furan), 147.70 (C2 of furan), 148.22
(C4b), 152.47 (C12a), 161.65 (COO of chromene), 163.42
(Cipso-OMe), 194.32 (C=O).
(2H, s, CH2NH3), 5.11 (1H, d, JHH = 4.1 Hz, CH9), 6.30
3
3
(1H, d, JHH = 5.6 Hz, CH8), 6.49 (1H, s, CH4 of furan),
6.54 (1H, d, JHH = 2.6 Hz, CH3 of furan), 6.57 (1H, d,
3
3JHH =5.6 Hz, CH7), 7.30 (1H, d, 3JHH =8.6 Hz, CH1), 7.33
(1H, t, 3JHH =7.5 Hz, CH3), 7.44 (1H, t, 3JHH =7.2 Hz, CH
of Ar), 7.49 (1H, t, 3JHH =7.2 Hz, CH of Ar), 7.52 (1H, d,
3JHH =7.6 Hz, CH of Ar), 7.56 (1H, t, 3JHH =7.5 Hz, CH2),
7.72 (1H, s, CH5 of furan), 7.83 (1H, d, 3JHH =7.6 Hz, CH of
Ar), 8.02 (1H, d, 3JHH =7.9 Hz, CH4), 8.12 (1H, s, NH), 8.50
(3H, s, NH3). 13C NMR (125 MHz, DMSO-d6): δC 34.93
(CH10a), 38.30 (C10), 40.80 (CH2NH3), 61.36 (CH62), 79.37
(CH9), 85.30 (C6a), 94.40 (C10b), 110.25 (CH4 of furan),
110.89 (CH3 of furan), 114.16 (C4a), 116.69 (CH1), 122.50
(CH3), 123.45 (CH4), 127.64 (CH of Ar), 129.24 (CH of
Ar), 129.50 (CH of Ar), 130.23 (CH of Ar), 131.29 (CH2),
131.83 (Cipso-Cl), 133.66 (CH7), 136.70 (CH8), 139.49
(Cipso-C=O), 143.52 (CH5 of furan), 147.43 (C2 of furan),
147.64 (C4b), 152.00 (C12a), 161.61 (COO of chromene),
198.44 (C=O).
(6aR,9S,10S,10aR)‑10‑(4‑Chlorobenzoyl)‑5,9,10,10a‑tetrahy‑
dro‑6H,11H‑6a,9‑epoxychromeno[4,3‑c]isoquinolin‑11‑one
(5d) Pale yellow powder, mp=186–187 °C, 0.299 g, yield:
74%. IR (KBr) (νmax, cm−1): 3329 (NH), 1672 (C=O), 1611
(C=C), 1550 and 1439 (Ar), 1218 (C–O of lactone), 1091
and 1051 (C–O of ether). Anal. Calcd for C23H16ClNO4
(405.83): C, 68.07; H, 3.97; N, 3.45%. Found: C, 68.09;
H, 3.94; N, 3.44%. MS (EI, 70 eV): m/z (%)=407 (M++2,
2), 406 (M++1, 2), 405 (M+, 7), 377 (8), 307 (19), 267
(24), 266 (98), 252 (27), 251 (62), 249 (9), 248 (29), 238
(6aR,9S,10S,10aR)‑10‑(4‑Methylbenzoyl)‑5,9,10,10a‑tetrahy‑
dro‑6H,11H‑6a,9‑epoxychromeno[4,3‑c]isoquinolin‑11‑one
(5f) White powder, mp=201–202 °C, 0.3 g, yield: 78%. IR
(KBr) (νmax, cm−1): 3374 (NH), 1669 (C=O), 1611 (C=C),
1
(17), 141 (16), 139 (44), 111 (24), 81 (100), 53 (21). H
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Journal of the Iranian Chemical Society
1550 and 1495 (Ar), 1220 (C–O of lactone), 1053 (C–O of
ether). Anal. Calcd for C24H19NO4 (385.41): C, 74.79; H,
4.97; N, 3.63%. Found: C, 74.76; H, 4.98; N, 3.60%. MS
(EI, 70 eV): m/z (%)=385 (M+, 6), 288 (7), 287 (25), 267
(24), 266 (100), 252 (24), 251 (53), 248 (29), 238 (15), 139
(22), 119 (28) 91 (14), 81 (78), 53 (17). 1H NMR (500 MHz,
DMSO-d6): δH 2.37 (3H, s, Me), 3.01 (1H, d, 3JHH =3.8 Hz,
130.08 (2CH of Ar), 131.74 (CH2), 133.83 (CH7), 137.27
(CH8), 142.06 (Cipso-C=O), 143.97 (CH5 of furan), 147.78
(C4b), 148.23 (C2 of furan), 150.25 (Cipso-NO2), 152.45
(C12a), 161.84 (COO of chromene), 195.85 (C=O).
Results and discussion
CH10a), 3.80 (1H, dd, JHH = 14 Hz, JHH = 4.0 Hz, CH62),
3.87 (1H, t, 3JHH =4.3 Hz, CH10), 3.93 (1H, d, 2JHH =14 Hz,
3
3
After preparation of starting materials, we interested in the
reaction of furfurylamine 3, Wittig reagent 2, and 4-chloro-
2-oxo-2H-chromene-3-carbaldehyde 1, so at the beginning,
we reacted 3-formylcoumarin 1 with Wittig reagent 2 in
EtOH and the product 3 was isolated. Then, this product 3
was reacted with furfurylamine 4 in toluene and the product
5 was isolated and characterized using IR, mass spectros-
copy, 1H NMR, 13C NMR, and single-crystal X-ray analysis.
When the reaction was performed, we realized that two
equivalents of furfurylamine consumed in the reaction.
Analysis of mass spectroscopy, 1H NMR, and 13C NMR con-
frmed this suggestion, so we assumed a proposed structure,
but when the single-crystal analysis was done, we found
that one equivalent of furfurylamine appeared in the fnal
product and another equivalent of that emerged as the salt
of furfurylamine in NMR spectra (Scheme 2).
CH62), 4.05 (2H, s, CH2NH3), 5.19 (1H, d, JHH = 4.8 Hz,
3
CH9), 6.11 (1H, dd, 3JHH =5.7 Hz, 3JHH =1.5 Hz, CH8), 6.48
(1H, dd, 3JHH =3.1 Hz, 3JHH =1.7 Hz, CH4 of furan), 6.51
(1H, d, 3JHH =5.7 Hz, CH7), 6.56 (1H, d, 3JHH =3.1 Hz, CH3
3
of furan), 7.26 (1H, d, JHH = 8.3 Hz, CH1), 7.32 (2H, d,
3JHH =8.0 Hz, 2CH of Ar), 7.33 (1H, t, 3JHH =7.0 Hz, CH3),
7.54 (1H, t, 3JHH =7.3 Hz, CH2), 7.72 (1H, dd, 3JHH =1.7 Hz,
3
3JHH = 0.8 Hz, CH5 of furan), 7.94 (2H, d, JHH = 8.0 Hz,
2CH of Ar), 8.04 (1H, d, 3JHH =7.6 Hz, CH4), 8.12 (1H, s,
NH), 8.57 (3H, s, NH3). 13C NMR (125 MHz, DMSO-d6): δC
21.58 (Me), 34.95 (CH10a), 37.37 (CH10), 40.88 (CH2NH3),
57.10 (CH62), 79.99 (CH9), 85.14 (C6a), 94.93 (C10b), 110.28
(CH3 of furan), 110.92 (CH4 of furan), 114.25 (C4a), 116.64
(CH1), 122.37 (CH3), 123.40 (CH4), 128.37 (2CH of Ar),
129.27 (2CH of Ar), 131.19 (CH2), 133.58 (CH7), 134.32
(Cipso-C=O), 136.45 (CH8), 143.28 (Cipso-Me), 143.56 (CH5
of furan), 147.26 (C2 of furan), 147.63 (C4b), 152.03 (C12a),
161.23 (COO of chromene), 195.06 (C=O).
After confrmation of the structure by X-ray analysis, we
decided to perform the reaction in one-pot condition. Many
solvents were employed for this goal, and the mixture of
DCM and toluene afords the best result (Table 1).
(6aR,9S,10S,10aR)‑10‑(4‑Nitrobenzoyl)‑5,9,10,10a‑tetrahy‑
dro‑6H,11H‑6a,9‑epoxychromeno[4,3‑c]isoquinolin‑11‑one
(5g) Yellow powder, mp = 209–210 °C, 0.348 g, yield:
84%. IR (KBr) (νmax, cm−1): 3350 (NH), 1664 (C=O),
1608 (C=C), 1534 and 1350 (NO2), 1213 (C–O of lac-
tone), 1046 (C–O of ether). Anal. Calcd for C23H16N2O6
(416.38): C, 66.34; H, 3.87; N, 6.73%. Found: C, 66.35;
H, 3.85; N, 6.74%. MS (EI, 70 eV): m/z (%)=416 (M+, 5),
318 (15), 267 (10), 266 (52), 251 (33), 248 (11), 150 (10),
81 (100), 53 (4). 1H NMR (500 MHz, DMSO-d6): δH 2.96
(1H, d, 3JHH =3.6 Hz, CH10a), 3.83 (1H, dd, 3JHH =14.0 Hz,
3JHH =3.7 Hz, CH26), 3.86 (1H, d, 3JHH =4.1 Hz, CH10), 3.94
(1H, d, 3JHH =14.0 Hz, CH26), 4.04 (2H, s, CH2NH3), 5.26
In the frst step, Wittig reagent and 3-formylcoumarin
reacted in room temperature, and then, furfurylamine was
added to reaction pot following by the addition of toluene as
co-solvent and the reaction heated up to 80 °C. With opti-
mized conditions in hand, the scope of reaction investigated
with diferent starting acetophenones and the results are
shown in Table 2. An exploration in the 1H NMR and 13
C
NMR showed that only one diastereomer formed during the
3
3
(1H, d, JHH = 4.6 Hz, CH9), 6.18 (1H, d, JHH = 5.7 Hz,
3
CH8), 6.48 (1H, d, JHH = 5.8 Hz, CH7), 6.55 (1H, s,
CH4 of furan), 6.56 (1H, s, CH3 of furan), 7.26 (1H, d,
3JHH =8.2 Hz CH1), 7.32 (1H, d, 3JHH =7.6 Hz CH3), 7.54
(1H, d, 3JHH =7.7 Hz CH2), 7.72 (1H, s, CH5 of furan), 8.05
(1H, d, 3JHH =7.9 Hz, CH4), 8.12 (1H, s, NH), 8.19 (2H, d,
3JHH =8.3 Hz, 2CH of Ar), 8.29 (2H, d, 3JHH =8.3 Hz, 2CH
of Ar), 8.50 (3H, s, NH3). 13C NMR (125 MHz, DMSO-
d6): δC 35.44 (CH10a), 38.96 (CH10), 41.26 (CH2NH3),
58.02 (CH62), 80.37 (CH9), 85.66 (C6a), 95.06 (C10b), 110.63
(CH4 of furan), 111.33 (CH3 of furan), 114.61 (C4a), 117.15
(CH1), 122.89 (CH3), 123.89 (CH4), 124.27 (2CH of Ar),
Scheme 2 Proposed structure of the reaction products
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Journal of the Iranian Chemical Society
Table 1 Optimization of solvents for one-pot condition
Entry
Solvent
Temperature
(°C)
Yield (%)a
1
2
3
4
5
6
7
8
EtOH
CH3CN
THF
80
80
70
70
25
80
80
100
45
55
30
25
45
82
20
35
MeOH
CH2Cl2
DCM/toluene
Toluene
Toluene
All runs were performed on a 1-mmol scale (1: 1 mmol, 2a: 1 mmol,
3: 1 mmol), and the reaction was run at refux temperature
Fig. 1 ORTEP diagram of compound 5a
aIsolated yield
Table 2 Two-step
and
one-pot
synthetic
pathway
to
epoxychromeno[4,3-c]isoquinolines 5
Entry
R1
Product 5
Yield (%)a
1
2
3
4
5
6
7
H
4-Br
2-Cl
5a
5b
5c
5d
5e
5f
82
78
74
71
69
84
69
4-Cl
4-MeO
4-Me
4-NO2
5g
All runs were performed on a 1-mmol scale (1, 1 mmol; 2, 1 mmol;
4, 1 mmol), and the reaction was run at two steps in one pot; in frst
step, 1 and 2 was mixed in DCM and and the reaction mixture was
stirred at room temperature for about a day; in the second step, fur-
furylamine (2 mmol, 194 mg) was added to fask following by addi-
tion of 10 ml toluene as a co-solvent and the mixture was refuxed for
4–5 h
Scheme 3 A plausible mechanism for the formation of 5
1
band also appeared at 1653 cm−1. The H NMR and 13C
NMR spectra confrmed the proposed mechanism, but the
furfurylamine salt is also seen in the spectrum (See ESI).
The fnal validation of the structure came from X-ray analy-
sis (Fig. 1).
aIsolated yield
reaction. With the optimal condition in hand, we started to
develop the scope of the reaction.
Based on aforded product, a proposed mechanism for this
transformation is shown in Scheme 3.
All the characteristic data of all products were gathered.
The molecular ion peak of 5a appeared at 371 m/z value
in mass spectroscopy, which confrmed the proposed struc-
ture. The IR spectrum showed a band at 3340 cm−1 which
is related to NH absorption bands. The carbonyl absorption
Apparently, the addition of Wittig reagent 2 to 4-chloro-
3-formylcoumarin 1 afords Wittig coumarin 3. In the fol-
lowing, the nucleophilic addition of furfurylamine 4 to
this coumarin leads to intermediate 7. This intermediate
1 3

Journal of the Iranian Chemical Society
6. X. Wang, K.F. Bastow, C.-M. Sun, Y.-L. Lin, H.-J. Yu, M.-J.
Don, T.-S. Wu, S. Nakamura, K.-H. Lee, J. Med. Chem. 47, 5816
(2004)
performs an intramolecular Diels–Alder reaction to aford
the fnal epoxychromeno[4,3-c]isoquinoline 5.
7. C. Che, S. Li, X. Jiang, J. Quan, S. Lin, Z. Yang, Org. Lett. 12,
4682 (2010)
8. H. Wang, X. Liu, X. Feng, Z. Huang, D. Shi, Green Chem. 15,
3307–3311 (2013)
Conclusions
9. C.A. James, A.L. Coelho, M. Gevaert, P. Forgione, V. Snieckus,
J. Org. Chem. 74, 4094 (2009)
Briefy, we developed a one-pot diastereoselective strategy
to obtain a valuable new class of bicyclic-fused coumarins
from the available starting materials. The key reaction in this
strategy is an intramolecular Diels–Alder reaction. Good-to-
high yields, stereoselectivity, metal-free and one-pot condi-
tion are some of the advantages of this reaction.
10. L. Chen, Y. Li, M.-H. Xu, Org. Biomol. Chem. 8, 3073 (2010)
11. G. Karthik, T. Rajasekaran, B. Sridhar, B.S. Reddy, Tetrahedron
70, 8148 (2014)
12. M. Ghandi, A.-T. Ghomi, M. Kubicki, Tetrahedron 69, 3054
(2013)
13. O. Mikhalchenko, I. Il’ina, A. Pavlova, E. Morozova, D. Korcha-
gina, T.Y. Tolstikova, E. Pokushalov, K. Volcho, N. Salakhutdi-
nov, Med. Chem. Res. 22, 3026 (2013)
Acknowledgements We gratefully acknowledge the support of this
14. E.J. Thomas, Acc. Chem. Res. 24, 229 (1991)
15. M. Juhl, D. Tanner, Chem. Soc. Rev. 38, 2983 (2009)
16. J.W. Johannes, S. Wenglowsky, Y. Kishi, Org. Lett. 7, 3997 (2005)
17. M.M. Heravi, V.F. Vavsari, RSC Adv. 5, 50890 (2015)
18. A.I. Khatri, S.D. Samant, Tetrahedron Lett. 55, 2362 (2014)
19. H. Kuroda, E. Hanaki, H. Izawa, M. Kano, H. Itahashi, Tetrahe-
dron 60, 1913 (2004)
work by the Tarbiat Modares University Research Council.
References
1. K.N. Venugopala, V. Rashmi, B. Odhav, BioMed. Res. Int. 2013,
1 (2013)
20. J.A. Kumar, G. Saidachary, G. Mallesham, B. Sridhar, N. Jain,
S.V. Kalivendi, V.J. Rao, B.C. Raju, Eur. J. Med. Chem. 65, 389
(2013)
2. M.A. Musa, J.S. Cooperwood, M.O.F. Khan, Curr. Med. Chem.
15, 2664 (2008)
21. R.H. Vekariya, H.D. Patel, Tetrahedron 70, 3949 (2014)
22. I. Saikia, A.J. Borah, P. Phukan, Chem. Rev. 116, 6837 (2016)
23. A.Y. Bochkov, I.O. Akchurin, O.A. Dyachenko, V.F. Traven,
Chem. Comm. 49, 11653 (2013)
3. S. Emami, S. Dadashpour, Eur. J. Med. Chem. 102, 611 (2015)
4. F.G. Medina, J.G. Marrero, M. Macías-Alonso, M.C. González,
I. Córdova-Guerrero, A.G.T. García, S. Osegueda-Robles, Nat.
Prod. Rep. 32, 1472 (2015)
5. R. Hoerr, M. Noeldner, CNS Drug Rev. 8, 143 (2002)
Afliations
Abdolali Alizadeh1 · Kaveh Amir Ashjei Asalemi1 · Behnaz Farajpour1 · Mohammad Reza Halvagar2
1
2
Department of Chemistry, Tarbiat Modares University, P.O.
Box 14115-175, Tehran, Iran
Chemistry and Chemical Engineering Research Center
of Iran (CCERCI), Pajohesh Blvd, 17th Km of Tehran-Karaj
Highway, Tehran 1496813151, Iran
1 3