Synthesis of pterocarpans through palladium-catalyzed oxyarylation of alkoxy-2H-chromenes with o-iodophenols

Article abstract of DOI:10.1016/j.tet.2020.131638

The oxyarylation of alkoxy-2H-chromenes (1a-e) with o-iodophenols substituted by electron-withdrawing (CHO) and electron-donating (OMe) groups is studied under two experimental conditions: a) Pd(OAc)₂, Ag₂CO₃ in PEG-400 at 140 °C, 10 min and b) oxime-based palladacycle, DIPEA, in PEG-400 at 150 °C, 3–4 h. Pterocarpans are obtained in moderate to good chemical yields.

Full text of DOI:10.1016/j.tet.2020.131638

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pterocarpans through palladium-catalyzed oxyarylation
of alkoxy-2H-chromenes with o-iodophenols
a
a
a
b
ꢀ
Francisco V. Gaspar , Julio C.F. Barcellos , Jose F. Cívicos , Pedro Merino ,
Carmen Najera **, Paulo R.R. Costa a
Laboratorio de Química Bioorganica, Instituto de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saúde,
c
,
, *
ꢀ
a
ꢀ
^
^
ꢀ
Bloco H, Ilha da Cidade Universitaria, 21941-590, Rio de Janeiro, RJ, Brazil
b
ꢀ
Instituto de Biocomputacion y Física de Sistemas Complejos (BIFI), Campus San Francisco, Facultad de Ciencias, Universidad de Zaragoza, E-50009,
Zaragoza, Spain
c
ꢀ
Centro de Innovacion en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99, 03080, Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The oxyarylation of alkoxy-2H-chromenes (1a-e) with o-iodophenols substituted by electron-
withdrawing (CHO) and electron-donating (OMe) groups is studied under two experimental condi-
tions: a) Pd(OAc)2, Ag2CO3 in PEG-400 at 140 ꢀC, 10 min and b) oxime-based palladacycle, DIPEA, in PEG-
400 at 150 ꢀC, 3e4 h. Pterocarpans are obtained in moderate to good chemical yields.
© 2020 Published by Elsevier Ltd.
Received 23 July 2020
Received in revised form
18 September 2020
Accepted 20 September 2020
Available online xxx
Keywords:
Palladium
Oxyarylation
Pterocarpans
2H-chromenes
o-Iodophenols
1. Introduction
D-ring [2e].
In 1995, Larock and co-workers [3] reported the first examples
The oxyarylation reaction was discovered by Horino and Inoue
in 1971 and represented an unparalleled tool for obtaining poly-
functionalized compounds bearing benzofuran-scaffolds [1aec].
The oxyarylation of alkoxy-2H-chromenes with alkoxy-o-mercury
substituted phenols was used in the synthesis of natural pter-
ocarpans, coumestans and analogues [2] (Fig.1) [2a-d] subgroups of
the isoflavonoids comprising several bioactive products. Under
these conditions the mercury-palladium exchange as well as the
carbo-palladation step occurs at room temperature and the pre-
cursors are easily prepared from available alkoxy phenols bearing
different patterns of oxygenation [2a-d], but the stoichiometric use
of palladium salts and the need of organomercurial intermediates
are severe limitations. However, these conditions are still eventu-
ally used to prepare compounds substituted by alkoxy groups at the
of the palladium-catalyzed synthesis of non-natural pterocarpans
through the oxyarylation of 6-MeO-2H-chromen with o-iodophe-
nols in the presence of 5 mol% of Pd(OAc)2 and 10 mol% of PPh3.
Under these conditions, moderate yields of pterocarpans were
obtained with o-iodophenols substituted by electron-withdrawing
groups (Fig. 1). However, the presence of a methoxy group at o-
iodophenol lead to adducts in lower yields.
Antus and Kiss reported the oxyarylation of 6-MeO-2H-chro-
mene with o-iodophenol in the presence of silver carbonate as base,
ꢀ
in acetone (Fig. 1) [4]. Costa and Najera broadened the scope of this
reaction using 2H-chromene and 6-Cl-2H-chromene as olefins and
p-substituted o-iodophenols under MW heating. Moderate to good
yields of non-natural pterocarpans were obtained when these
phenols were substituted by electron-withdrawing groups (Fig. 1)
but low yield was observed when dihydronaphthalene was oxy-
arylated with electron-rich 5-methoxy-o-iodophenol [5,6].
A
cationic mechanism for these oxyarylations was firstly proposed by
Antus [6a] and confirmed by electrospray mass spectrometry
studies [6b]. The cationic mechanism was also suggested for other
* Corresponding author.
** Corresponding author.
E-mail addresses: cnajera@ua.es (C. Najera), lqb.submissions@gmail.com
(P.R.R. Costa).
ꢀ
https://doi.org/10.1016/j.tet.2020.131638
0040-4020/© 2020 Published by Elsevier Ltd.

F.V. Gaspar, J.C.F. Barcellos, J.F. Cívicos et al.
Tetrahedron xxx (xxxx) xxx
Fig. 1. Selected examples of oxyarylation of 2H-chromenes.
oxyarylations [6c,6d,6e]. These reactions were also accomplished in
the absence of a Lewis acid, using an oxime-palladacycle as pre-
catalyst [5]. Low yield in the oxyarylation of 6,7-dimethoxy-2H-
chromene with 5-methoxy-o-iodophenol was also reported by
Kakuda [7] in the synthesis of antiproliferative pterocarpans iso-
2. Results and discussion
The synthesis of 2H-chromenes (1a-e) is shown in Scheme 1.
Firstly, the O-alkylation of phenols 4a-e was carried out with
propargyl bromide to furnish compounds 5a-e in excellent yields.
Among the approaches available to prepare 2H-chromenes, the
thermic cyclization of O-propargylated phenol ethers 5 is less costly
and can lead to 1 with several oxygenated substituents at the ar-
omatic ring [10a,b]. The use of microwave heating in PEG-400
ꢀ
lated from the Brazilian flora [8] (Fig. 1). Costa and Najera reported
the oxyarylation of alkoxy-1,2-dihydronaphthalenes with o-iodo-
phenol substituted by electron-withdrawing groups at the para
position, leading to adducts in good to excellent yields when PEG-
400 was used as solvent [9]. In this solvent, it was observed the in
situ generation of palladium nanoparticles, faster reactions (10 min
for Pd(OAc)2 and 3e4 h for an oxime-based palladacycle) and better
chemical yields when compared to the use of acetone as solvent
under MW heating [5].
In this paper, we report the synthesis of pterocarpans (3)
through a catalytic oxyarylation of 2H-chromenes (1) with o-
iodophenols (2) under appropriate reaction conditions (Fig. 2).
Fig. 2. Synthesis of pterocarpans (3) through a catalytic oxyarylation of 2H-chromenes
(1) with o-iodophenols (2).
Scheme 1. Synthesis of 2H-chromenes 1a-e.
2

F.V. Gaspar, J.C.F. Barcellos, J.F. Cívicos et al.
Tetrahedron xxx (xxxx) xxx
(170 ꢀC, 15 min) allowed the preparation of 2H-chromenes 1a and
1c from symmetric 5a and 5c in 60% and 56% yield, respectively,
after flash chromatography. Unfortunately, 1b was obtained from
5b as a 1:1 mixture with a regioisomer (structure not shown, see
supplementary material). Although 1b could be obtained in mod-
erate yield in pure form (48%), it was laborious to purify by chro-
matography. In contrast, the cyclization of 5d and 5e was more
regioselective and small amounts of the corresponding
regioisomers of 1d and 1e could be easily removed by flash chro-
matography. Even though, under thermal conditions (N,N-dieth-
ylaniline or xylene under reflux) the reported reactions time were
too long [10a,b], in our hands, using PEG-400 as solvent at 220 ꢀC,
2H-chromenes were prepared in 1.5 h, in similar reasonable
chemical yields and these conditions are useful for gram-scale re-
actions (Scheme 1).
An alternative route to prepare 1b is shown in Scheme 2. When
aldehyde 6 was allowed to react with allyl bromide intermediate 7
was obtained and was then submitted to a Wittig olefination to
produce 8 in 82% yield. In the presence of Grubbs 2nd generation
catalyst, a metathesis reaction took place, leading to 1b in 69% (48%
overall yield) [11].
This approach could be eventually used to prepare other 2H-
chromenes. On the other hand, o-iodophenols 2a and 2e are
commercially available, while 2b-d were prepared by iodination of
the corresponding phenols [12,13].
Next, we examined the oxyarylation of 1a-e with o-iodophenol
(2a) (Scheme 3) and based on our previous experience [5,9], two
experimental conditions were selected for this study, Conditions A:
Pd(OAc)2 (10 mol%), Ag2CO3 (1.1 equiv) in PEG-400 at 140 ꢀC and
Conditions B: oxime-based palladacycle (5 mol%), Cy2NH (3 equiv),
in PEG-400 at 150 ꢀC.
Concerning oxyarylations of 2H-chromenes 1a-e with o-iodo-
phenol (2a) under Conditions A (Scheme 3), reactions were very
fast (ca. 10 min) and pterocarpans 3aa, 3ba, 3da and 3ea were
regioselectively obtained in moderate to good yields. However, 2H-
chromene 1c was unstable in the presence of silver carbonate, even
at rt, and the expected adduct 1ca was not formed under these
reaction conditions. Under Conditions B (Scheme 3), oxyarylations
of 1a,b,d,e with 2a were slower and 3e4 h of reaction time was
required to obtain the corresponding pterocarpans 3aa, 3ba, 3da
and 3ea in moderate to good yields. However, the oxyarylation of 1c
with 2a under Conditions B led to the expected pterocarpan 3ca
along with a secondary product 9 (Scheme 4). After 4 h of reaction it
was possible to identify by 1H NMR the presence of products 3ca
and 9, as a ~1:1 mixture. The mixture of 3ca and 9 was separated
and their structures established. We have tried to favor the
Scheme 3. Oxyarylation of 1a-e with 2a. Synthesis of pterocarpans.
Scheme 4. Effect of SPhos in the regioselectivity of the oxyarylation of 1c with 2a.
formation of 3ca using phosphine ligands. After some screening
experiments, a 66:37 mixture of 3ca:9 was formed in the presence
of SPhos (Scheme 4) and 3ca could be obtained in pure form by
flash chromatography, in 51% yield, along with 22% of 9.
It is worth to mention that while in adducts 3 the oxygen of the
o-iodophenol (2) appears attached to the benzylic carbon of the
olefin (1), in 9 is the aromatic ring of the o-iodophenol which is
attached this carbon. This suggests that these products may be
Scheme 2. Alternative synthesis of 2H-chromene 1b.
3

F.V. Gaspar, J.C.F. Barcellos, J.F. Cívicos et al.
Tetrahedron xxx (xxxx) xxx
originated from regioisomeric mechanistic pathway (see mecha-
nistic discussion).
3. Mechanistic considerations
In Scheme 5 are shown the results obtained for the oxyarylation
of olefins 1a-e with substituted o-iodophenols 2b-e. Under Con-
ditions A, 2H-chromene 1a reacted with electron-poor o-iodo-
phenols 2b and 2c leading respectively, to 3 ab and 3ac in moderate
to good yields. The simultaneous presence of a methoxy group and
an aldehyde group at the structure of o-iodophenol, as in 2d, lead to
a decrease in the yield of adduct 3ad to 25%. The oxyarylation of 2H-
chromen 1b with 2c led to 3bc in 50% yield. Finally, in the oxy-
arylation of this 2H-chromen with electron-rich o-iodophenol 2e
(absence of electron-withdrawing group) under the same reaction
conditions led to natural pterocarpan 3be in moderate 29% yield.
2H-Chromene 1d led to 3dc under both reaction conditions, but
better yield (59%) was obtained under Conditions B. Finally, under
Conditions A, 2H-chromene 1e was oxyarylated with 2b leading the
expected adduct 3eb in 40% yield. The oxyarylation of this 2H-
chromene with 2c led to pterocarpan 3ec in moderate yield under
Conditions A and B. Also, in this case oxyarylation with electron-
rich o-iodophenol 2e led to 3ee in moderate 28% yield under con-
ditions A.
Based on the literature and in our previous results we propose
that under Conditions A (TS1) a cationic mechanism is operating
[14e16]. The oxyarylation reaction would starts with the attack of
an electrophilic cationic palladium specie (ArPdþ) to the double
bound of 2H-chromene 1 (Scheme 6). This step would be fast for
our electron-rich olefins originating a
s-complex, which can lead to
a positive transition state precursor of adducts, were a partial
positive charge is developed at the b-carbon and is not stabilized by
the aromatic ring at 2H-chromene moiety (TS1). The resulting
palladacycle intermediate undergoes a reductive elimination of the
Pd0 and the formation of the ether linkage in 3 with retention of the
configuration at the benzylic carbon.
As under Conditions A the oxyarylations of 2H-chromenes 1
with iodophenols 2 afforded exclusively 3, the regiochemistry un-
der these conditions seems to be controlled mainly by steric in-
teractions between the incoming aryl group and the aromatic
group at the olefin in the transition state, as occurs in the Heck
reaction [15,16].
It is worth to mention that the regioselectivity in the arylation of
substituted styrenes with cationic arylpalladium species was pre-
viously addressed by Fristrup and co-workers [17]. They observed
that the rate of formation of stilbenes, the main products in these
Heck reactions, is not dependent on the electronic effect of the
substituent at the styrene moiety. In the proposed TS leading to the
Scheme 6. Mechanistic rationalization for the oxyarylation of 1 with 2 under Condi-
Scheme 5. Oxyarylation of 1a-e with 2b-e.
tions A.
4

F.V. Gaspar, J.C.F. Barcellos, J.F. Cívicos et al.
Tetrahedron xxx (xxxx) xxx
main product, a partial positive charge is developed at the
b-carbon
was pure enough to ne next step.
and
r
¼ 0. However, the rate of the regioisomeric products
increased for electron-releasing groups. In this case, in the corre-
sponding TS a partial positive charge is developed at the benzylic
5.1.1. 1-Methoxy-4-(prop-2-yn-1-yloxy)benzene (6a) [20]
Yellow oil, (97.3 mg, 60% yield). 1H NMR (400 MHz, CDCl3)
d:
carbon and, as consequence,
our mechanistic rationalization.
r
¼ ꢁ0.74. These results [17] support
6.94 (d, J ¼ 9.2 Hz, 2H), 6.86 (d, J ¼ 9.4 Hz, 2H), 4.62 (d, J ¼ 2.7 Hz,
2H), 3.74 (s, 3H), 2.59 (t, J ¼ 2.4 Hz, 1H). 13C NMR (101 MHz, CDCl3):
Under Conditions B, oxyarylation of 1 with 2 were also regio-
selective for the majority of 2H-chromenes, leading to pterocarpans
3. The exception was the oxyarylation of 1c with 2a, which fur-
nished a mixture of 3ca and 9 (ca. 1:1, in the absence of ligands).
Once it is known that palladium catalyzed reactions in water can go
through a cationic mechanism, even in the absence of a silver salt
[14] and since PEG-400 is relatively polar and the temperature
employed is high (150 ꢀC), we can accept a cationic mechanism
under these reaction conditions. It is worth to mention that in this
case the partial positive charge at the benzylic carbon is stabilized
by resonance by the two methoxy groups, but the possible
regioisomer of adduct 3ca was not observed in the reaction me-
dium. Following the reaction by TLC one can observe the formation
of a possible intermediate which is not present at the end of the
reaction, which is transformed in 9. Unfortunately, we didn’t suc-
ceed to purify this compound and establish its structure.
d
154.4, 151.7, 116.16, 114.6, 79.1, 75.6, 56.5, 55.5.
5.1.2. 1-Methoxy-3-(prop-2-yn-1-yloxy)benzene (6b) [20]
Yellow oil, (126.5 mg, 78% yield). 1H NMR (400 MHz, CDCl3)
d:
7.19 (t, J ¼ 8.6 Hz,1H), 6.59e6.53 (m, 3H), 4.67e4.65 (m, 2H), 3.78 (s,
3H), 2.52 (t, J ¼ 2.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)
d: 160.5,
158.5, 129.6, 106.9, 101.2, 78.3, 75.3, 55.5, 55.0.
5.1.3. 1,3-Dimethoxy-5-(prop-2-yn-1-yloxy)benzene (6c) [21]
Yellow oil, (153.8 mg, 80% yield). 1H NMR (500 MHz, CDCl3)
d:
6.15 (s, 1H), 6.12 (s, 1H), 4.64 (d, J ¼ 2.4 Hz, 1H), 3.76 (s, 3H), 2.52 (s,
1H). 13C NMR (126 MHz, CDCl3)
55.3.
d: 161.4, 159.3, 93.7, 78.3, 75.5, 55.8,
5.1.4. 1,2-Dimethoxy-4-(prop-2-yn-1-yloxy)benzene (6d) [22]
Theoretical studies (DFT) were undergone to try to corroborate
our proposed mechanistic rationalization but, unfortunately, the
results obtained were not conclusive.
Yellow oil, (157.6 mg, 82% yield). 1H NMR (500 MHz, CDCl3)
d:
6.74 (d, J ¼ 8.7 Hz, 1H), 6.55 (d, J ¼ 2.8 Hz, 1H), 6.45 (dd, J ¼ 8.7,
2.8 Hz, 1H), 4.60 (d, J ¼ 2.4 Hz, 2H), 3.80 (d, J ¼ 8.2 Hz, 6H). 13C NMR
(126 MHz, CDCl3)
75.5, 56.5, 55.9.
d: 152.2, 150.0, 144.2, 111.8, 104.55, 101.4, 79.0,
4. Conclusions
Pterocarpans could be prepared in moderate to good yield by
oxyarylation of 2H-chromenes with o-iodophenols using two
experimental conditions: a) Pd(OAc)2, Ag2CO3 in PEG-400 at 140 ꢀC,
10 min and b) oxime-based palladacycle, DIPEA, in PEG-400 at
150 ꢀC, 3e4 h. Aldehydes are only scarce used in oxyarylation re-
actions [9,18]. In the prepared pterocarpans, these groups can be
used as precursor of other chemical functionalities or to connect
the structure to another bioactive compound or to a carrier group
[19]. Work is now in progress to better evaluate the mechanism of
these oxyarylations and to study the antiproliferative effect of the
synthesized compounds.
5.1.5. 5-(Prop-2-yn-1-yloxy)benzo[d] [1,3]dioxole (6e) [23]
Yellow oil, (158.6 mg, 90% yield). 1H NMR (400 MHz, CDCl3)
d:
6.73 (d, J ¼ 8.5 Hz, 7H), 6.59 (d, J ¼ 2.4 Hz, 7H), 6.43 (dd, J ¼ 8.5,
2.5 Hz, 7H), 5.95e5.93 (m, 14H), 4.63 (d, J ¼ 2.3 Hz, 15H), 2.53 (t,
J ¼ 2.1 Hz, 7H). 13C NMR (126 MHz, CDCl3)
d: 152.8, 148.1, 142.2,
107.8, 106.3, 101.1, 98.6, 78.5, 75.3, 56.8.
5.2. Typical procedure for the preparation of 2H-chromenes
In a sealed reaction tube with a magnetic stirring bar was added
1 mmol of 6a-d and PEG 400 (1.0 mL). Then the reaction tube was
sealed with the cap and stirred at 170 ꢀC for 15 min at 300w in a
microwave synthesizer (CEM Discover®SP), The reaction was
extracted with 15 mL of EtOAc, the organic layer was washed with
distilled H2O (5 mL) and brine (3 ꢂ 5 mL), the organic phase was
dried with anhydrous MgSO4, filtered and evaporated under vac-
uum. The pure compounds was obtained after flash chromatog-
raphy (EtOAc/hexane; from 5/95).
5. Experimental section
All commercially available reagents and solvents were used
without further purification. 1H and 13C NMR spectra were recorded
in CDCl3 at 400 or 500 MHz for 1H NMR and 101 or 126 MHz for 13
C
NMR using TMS as internal standard (0.00 ppm). The following
abbreviations are used to describe peak patterns where appro-
priate. All coupling constants (J) are given in Hz and chemical shifts
in ppm. 13C NMR spectra were referenced to CDCl3 at 77.16 ppm.
Low-resolution electron impact (GC-EI) mass spectra were ob-
tained at 70 eV with a Shimadzu QP-5000 instrument, and HRMS
(GC-EI) were recorded with a Finnigan MAT 95 S instrument.
Analytical TLC was performed with Schleicher & Schuell F1400/LS
silica gel plates, and the spots were visualized under UV light
5.3. Typical procedure B for the preparation of 2H-chromenes
In a sealed reaction tube with a magnetic stirring bar was added
1 mmol of 6a-d and PEG 400 (1.0 mL). Then the reaction tube was
sealed with the cap and stirred at 220 ꢀC for 1 h and, The reaction
was extracted with 15 mL of EtOAc, the organic layer was washed
with distilled H2O (5 mL) and brine (3 ꢂ 5 mL), the organic phase
was dried with anhydrous MgSO4, filtered and evaporated under
vacuum. The pure compounds was obtained after flash chroma-
tography (EtOAc/hexane; from 5/95).
(
l
¼ 254 nm). For flash chromatography, Merck silica gel 60
(0.040e0.063 mm) was employed.
5.1. General procedure for the preparation of aryl propargyl ethers
To a mixture of phenols 4aed (1 mmol), K2CO3 (1.5 mmol) and
acetone (2.0 mL) was slowly added propargyl bromide (1.2 mmol)
under magnetic stirring at rt. After 18 h, the reaction was diluted
with EtOAc (15 mL), the organic layer was washed with H2O (5 mL)
and brine (3 ꢂ 5 mL), dried over anhydrous sodium sulfate, and
filtered. The solvent was evaporated in vacuo and the resulting oil
5.3.1. 6-Methoxy-2H-chromene (1a) [20]
Yellow oil, (89.2 mg, 55% yield). 1H NMR (500 MHz, CDCl3)
d:
6.65 (d, J ¼ 8.7 Hz, 1H), 6.59 (s, 1H), 6.47 (d, J ¼ 3.0 Hz, 1H), 6.31 (s,
1H), 5.73 (dt, J ¼ 9.8, 3.6 Hz,1H), 4.67 (dd, J ¼ 3.6,1.9 Hz, 2H), 3.67 (s,
3H). 13C NMR (101 MHz, CDCl3)
55.3.
d: 161.4, 159.4, 93.7, 78.5, 75.6, 55.8,
5

F.V. Gaspar, J.C.F. Barcellos, J.F. Cívicos et al.
Tetrahedron xxx (xxxx) xxx
5.3.2. 7-Methoxy-2H-chromene (1b) [20]
127.0, 124.6, 120.8, 110.63, 109.9, 108.8, 103.2, 74.7, 66.1, 56.2, 39.6.
HRMS (EI) calculated for C16H14O3: 254.0943; found: 254.0938.
Yellow oil, (72.9 mg, 45% yield). 1H NMR (500 MHz, CDCl3)
d:
6.89 (d, J ¼ 8.3 Hz, 1H), 6.44 (dd, J ¼ 8.3, 2.5 Hz, 1H), 6.39 (t,
J ¼ 5.1 Hz, 2H), 5.64 (dt, J ¼ 9.7, 3.6 Hz, 1H), 4.81 (dd, J ¼ 3.5, 1.8 Hz,
5.4.3. 1,3-Dimethoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]
chromene (3ca)
2H), 3.79 (s, 3H). 13C NMR (101 MHz, CDCl3)
124.2, 118.86, 115.6, 106.8, 101.6, 65.5, 55.3.
d: 160.4, 155.2, 127.2,
White solid, (28.9 mg, 51% yield) mp 122 ꢀC. IR (KBr) nmax: 2965,
2911, 1610, 1471, 1230 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d: 7.24 (dd,
5.3.3. 5,7-Dimethoxy-2H-chromene (1c) [21]
J ¼ 7.3, 0.6 Hz, 1H), 7.16 (td, J ¼ 7.9, 1.3 Hz, 1H), 6.88 (dd, J ¼ 8.2, 6.7,
2.9 Hz, 2H), 6.16 (d, J ¼ 2.3 Hz, 1H), 6.10 (d, J ¼ 2.3 Hz, 1H), 5.61 (d,
J ¼ 6.5 Hz, 1H), 4.26e4.20 (m, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.65 (t,
Yellow oil, (124.9 mg, 65% yield). 1H NMR (500 MHz, CDCl3)
d:
6.69 (d, J ¼ 9.8 Hz, 1H), 6.04 (d, J ¼ 1.3 Hz, 1H), 5.59 (d, J ¼ 9.9 Hz,
1H), 4.73 (dd, J ¼ 3.7, 1.7 Hz, 1H), 3.79 (s, 1H), 3.77 (s, 1H). 13C NMR
J ¼ 11.1 Hz, 1H), 3.47e3.40 (m, 1H). 13C NMR (101 MHz, CDCl3)
d:
(126 MHz, CDCl3)
65.3, 55.5, 55.3.
d: 160.9, 156.1, 155.9, 119.4, 116.5, 105.4, 93.5, 91.8,
161.8, 160.9, 159.5, 157.4, 129.1, 127.0, 124.5, 120.6, 110.5, 101.6, 93.3,
92.5, 74.8, 66.2, 56.0, 55.4, 39.4. HRMS (EI) calculated for C17H16O4:
284.1049; found: 284.1039.
5.3.4. 6,7-Dimethoxy-2H-chromene (1d) [22]
Yellow oil, (86.4 mg, 45% yield). 1H NMR (500 MHz, CDCl3)
d:
5.4.4. 2,3-Dimethoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]
chromene (3da)
6.52 (s, 1H), 6.42 (s, 1H), 6.35 (d, J ¼ 9.7 Hz, 1H), 5.66 (s, 1H), 4.73 (s,
2H), 3.83 (d, J ¼ 6.1 Hz, 6H)$13C NMR (126 MHz, CDCl3)
d
: 151.5,
White solid, (28.9 mg, 51% yield) mp 110 ꢀC. IR (KBr) nmax: 2942,
150.5, 145.5, 126.4, 121.2, 116.4, 112.0, 102.6, 67.4, 58.5, 57.9.
1612, 1310,1280 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d: 7.26 (d,
J ¼ 7.3 Hz, 1H), 7.19 (td, J ¼ 7.8, 1.3 Hz, 1H), 6.99 (s, 1H), 6.91 (td,
J ¼ 7.5, 0.8 Hz, 1H), 6.86 (d, J ¼ 8.0 Hz, 1H), 6.49 (s, 1H), 5.48 (d,
J ¼ 6.5 Hz, 1H), 4.36e4.14 (m, 1H), 3.90 (s, 3H), 3.85 (s, 4H),
5.3.5. 6H- [1,3]Dioxolo[4,5-g]chromene (1e) [22]
Yellow oil, (96.8 mg, 55% yield). 1H NMR (500 MHz, CDCl3)
d:
6.39 (s,1H), 6.31 (s,1H), 6.23 (d, J ¼ 9.7 Hz,1H), 5.80 (s, 2H), 5.58 (dt,
3.75e3.47 (m, 2H). 13C NMR (101 MHz, CDCl3)
d: 159.3, 150.6, 149.9,
J ¼ 9.7, 3.7 Hz, 1H), 4.62 (dd, J ¼ 3.6, 1.6 Hz, 2H). 13C NMR (101 MHz,
144.3, 129.2, 127.2, 124.8, 121.0, 112.25, 110.6, 110.2, 100.8, 77.9, 66.5,
56.4, 56.0, 40.3. HRMS (EI) calculated for C17H16O4: 284.1049;
found: 284.1039.
CDCl3)
65.3.
d: 149.4, 147.4, 141.8, 124.7, 119.0, 115.5, 105.9, 100.9, 98.5,
5.4. General procedure for the oxyarylation of 2H-chromenes
5.4.5. Dihydro-6H-benzofuro[3,2-c] [1,3],dioxolo[4,5-g]chromene
(3ea)
Conditions A: In a reaction tube were added the 2H-chromene
(1a-f) (0.25 mmol) and the 2-iodophenol (2a-e) (2 equiv.), dicy-
clohexylamine (0.5 mmol, 0.099 mL), p-hydroxyacetophenone
oxime derived palladacycle (7 mg, 5 mol%) and PEG 400 (2 mL) and
stirred at 150 ꢀC. The reaction was monitored till completion by
TLC. The reaction mixture was extracted with EtOAc (5 mL), washed
with brine (5 ꢂ 10 mL) and then 1 M HCl solution was added to pH
2. The organic phase was dried with anhydrous MgSO4, filtered and
evaporated under vacuum. Pure compounds were obtained after
flash chromatography (from 1:9, EtOAc/hexane).
White solid, (32.1 mg, 60% yield) mp 100e103 ꢀC. IR (KBr) nmax
:
:
2952, 2931, 1594, 1538, 1350 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d
7.25 (d, J ¼ 7.8 Hz, 1H), 7.22e7.15 (m, 1H), 6.95 (s, 1H), 6.91 (td,
J ¼ 7.4, 0.9 Hz, 1H), 6.85 (d, J ¼ 8.0 Hz, 1H), 6.46 (s, 1H), 5.94 (dd,
J ¼ 12.1, 1.3 Hz, 2H), 5.45 (d, J ¼ 6.6 Hz, 1H), 4.25 (dd, J ¼ 9.3, 3.4 Hz,
1H), 3.61 (dd, J ¼ 6.7, 4.3 Hz, 2H). 13C NMR (101 MHz, CDCl3)
d:
159.3, 150.6, 149.9, 144.3, 129.2, 127.2, 124.8, 121.0, 112.2, 110.6,
110.2, 100.8, 77.9, 66.6, 56.4, 56.0, 40.3. HRMS (EI) calculated for
C
16H12O4: 268.0736; found: 268.0714.
Conditions B: In a reaction tube were added the 2H-chromene
(1a-f) (0.25 mmol) and the 2-iodophenol (2a-e) (2 equiv.), Ag2CO3
(0.28 mmol), Pd(OAc)2 (10 mol%) and PEG 400 (2 mL) and the re-
action mixture was stirred at 140 ꢀC. The reaction was monitored
till completion by TLC and the same work-up as above was
performed.
5.4.6. 2-Methoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene-8-
carbaldehyde (3 ab)
White solid, (35.5 mg, 63% yield) mp 133e135 ꢀC. IR (KBr) nmax
:
:
3021, 2985, 1692, 1448, 1315 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d
9.85 (s, 1H), 7.82 (s, 1H), 7.73 (d, J ¼ 8.2 Hz, 1H), 7.03 (s, 1H), 6.94 (d,
J ¼ 8.3 Hz, 1H), 6.87 (s, 1H), 5.67 (d, J ¼ 7.4 Hz, 1H), 4.30 (dd, J ¼ 10.8,
4.7 Hz, 1H), 3.81 (s, 2H), 3.66 (dd, J ¼ 23.0, 12.6 Hz, 1H). 13C NMR
5.4.1. 2-Methoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene
(3aa)
(101 MHz, CDCl3) d: 190.3, 164.6, 154.4, 149.5, 134.0, 130.8, 128.6,
125.6, 119.6, 118.5, 117.5, 113.9, 110.3, 79.5, 66.3, 55.7, 39.8, 30.1, 29.1.
HRMS (EI) calculated for C17H14NaO4: 305.0789; found: 305.0784.
White solid, (20.3 mg, 40% yield) mp 55 ꢀC. IR (KBr) nmax: 2972,
2911, 1642, 1430, 1250 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d: 7.24 (d,
J ¼ 7.3 Hz, 1H), 7.18 (t, J ¼ 7.5 Hz, 1H), 7.05 (d, J ¼ 2.3 Hz, 1H),
5.4.7. 2-Methoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene-9-
6.94e6.82 (m, 4H), 5.49 (d, J ¼ 6.3 Hz, 1H), 4.25 (q, J ¼ 10.9 Hz, 1H),
carbaldehyde (3ac)
3.80 (s, 3H), 3.69e3.56 (m, 2H). 13C NMR (101 MHz, CDCl3)
d: 159.2,
White solid, (31.6 mg, 56% yield) mp 135e137 ꢀC. IR (KBr) nmax
:
:
154.3, 149.5, 129.2, 127.1, 124.8, 121.0, 120.4, 118.4, 117.4, 114.0, 110.2,
77.9, 66.6, 55.8, 40.5. HRMS (EI) calculated for C16H14O3: 254.0943;
found: 254,0932.
3044, 2996, 1695, 1460, 1322 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d
9.85 (s, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.12 (s, 1H), 6.88 (s, 2H), 5.76 (d,
J ¼ 7.3 Hz, 1H), 4.32 (dd, J ¼ 10.5, 4.3 Hz, 1H), 3.95 (s, 2H), 3.85e3.77
(m, 3H). 13C NMR (101 MHz, CDCl3)
d: 164.6, 154.4, 149.4, 128.5,
5.4.2. 3-Methoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene
126.7, 121.1, 119.2, 118.6, 117.7, 113.8, 109.9, 80.1, 66.1, 55.7, 40.0.
HRMS (ESI) calculated for C17H14NaO4: 305.0789; found: 305.0784.
(3ba) [23]
White solid, (27.4 mg, 54% yield) mp 55e57 ꢀC. IR (KBr) nmax
:
:
2953, 2889, 1630, 1480, 1258 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d
5.4.8. 2,10-Dimethoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]
chromene-8-carbaldehyde (3ad)
7.30e7.24 (m, 2H), 7.22e7.16 (m, 1H), 6.91 (dd, J ¼ 8.3, 6.7, 3.0 Hz,
2H), 6.58 (t, J ¼ 8.3 Hz, 2H), 5.68 (d, J ¼ 6.6 Hz, 1H), 4.25 (dd, J ¼ 11.0,
5.0, 0.8 Hz, 1H), 3.95 (s, 3H), 3.66 (t, J ¼ 11.1 Hz, 1H), 3.54e3.46 (m,
White solid, (15.6 mg, 25% yield) mp 145 ꢀC. IR (KBr) nmax: 3072,
2974, 1671, 1482, 1318 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d: 9.85 (s,
1H). 13C NMR (101 MHz, CDCl3)
d: 160.2, 159.5, 156.6, 130.6, 129.2,
1H), 7.45 (s, 1H), 7.38 (s, 1H), 7.12 (s, 1H), 6.88 (s, 2H), 5.76 (d,
6

F.V. Gaspar, J.C.F. Barcellos, J.F. Cívicos et al.
Tetrahedron xxx (xxxx) xxx
J ¼ 7.3 Hz, 1H), 4.32 (dd, J ¼ 10.5, 4.3 Hz, 1H), 3.95 (s, 2H), 3.85e3.77
5.4.14. 9-Methoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]
(m, 3H). 13C NMR (101 MHz, CDCl3)
d: 190.3, 154.3, 153.4, 149.4,
[1,3],dioxolo[4,5 g]chromene (3ee)
145.3, 131.6, 128.7, 120.8, 119.3, 118.4, 117.8, 113.9, 112.3, 80.2, 66.3,
56.1, 55.8, 40.3. HRMS (ESI) calculated for C18H16NaO5: 335.0889;
found: 335.0889.
White solid, (16.7 mg, 28% yield) mp 140 ꢀC. IR (KBr) nmax: 2894,
1613, 1415, 1277 cmꢁ1 1H NMR (400 MHz, CDCl3)
. d: 7.12 (d,
J ¼ 8.9 Hz,1H), 6.93 (s, 1H), 6.45 (d, J ¼ 6.9 Hz, 2H), 5.93 (dd, J ¼ 11.8,
1.1 Hz, 2H), 5.45 (d, J ¼ 6.5 Hz, 1H), 4.33e4.11 (m, 1H), 3.77 (s, 3H),
3.71e3.39 (m, 2H). 13C NMR (101 MHz, CDCl3)
d: 161.0, 160.4, 150.9,
5.4.9. 3-Methoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene-9-
carbaldehyde (3bc)
148.7, 142.5, 124.7, 118.9, 111.8, 108.7, 106.3, 101.2, 98.8, 96.8, 78.9,
66.7, 55.4, 39.5. HRMS (EI) calculated for C17H14O5: 299.0919;
found: 299.0914.
White solid, (28.2 mg, 50% yield) mp 140 ꢀC. IR (KBr) nmax: 3015,
2980, 1683, 1475, 1312 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d: 9.93 (s,
1H), 7.46 (dd, J ¼ 7.4, 1.4 Hz, 1H), 7.42 (d, J ¼ 7.5 Hz, 1H), 7.32e7.30
(m, 1H), 6.67 (dd, J ¼ 8.6, 2.5 Hz, 1H), 6.47 (d, J ¼ 2.5 Hz, 1H), 5.62 (d,
J ¼ 6.8 Hz, 1H), 4.35e4.28 (m, 1H), 3.80 (s, 2H), 3.76 (d, J ¼ 10.5 Hz,
5.4.15. 3,5-Dimethoxy-2-(3-methylbenzofuran-2-yl)phenol (9)
White solid, (18.1 mg, 22% yield) mp 135 ꢀC. IR (KBr) nmax: 3420,
2932,2846 1596, 1479 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d: 7.30 (dd,
2H). 13C NMR (101 MHz, CDCl3)
d: 191.5, 161.2, 160.1, 156.5, 138.0,
J ¼ 9.0, 5.7, 1.6 Hz, 1H), 7.23 (dd, J ¼ 7.6, 1.6 Hz, 1H), 6.67 (d,
134.5, 131.8, 125.0, 124.2, 111.6, 109.4, 101.6, 78.3, 65.7, 55.3, 40.3,
29.6. HRMS (ESI) calculated for C17H14NaO4:305.0789; found:
305.0788.
J ¼ 1.9 Hz, 1H), 6.33 (d, J ¼ 1.9 Hz, 1H), 5.39 (s, 1H), 3.87 (s, 3H), 3.72
(s, 3H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3)
d: 158.8, 156.2, 154.1,
153.5, 150.9, 131.6, 129.2, 120.4, 120.3, 116.0, 111.6, 110.3, 94.5, 88.4,
55.9, 55.7, 12.5. HRMS (EI) calculated for C17H16O4: 284.1049;
found: 284.1042.0.
5.4.10. 3,9-Dimethoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]
chromene (3be)
White solid, (16.4 mg, 29% yield) mp 130e135 ꢀC. IR (KBr) nmax
:
:
3008, 2890, 1710, 1461, 1310 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d
Declaration of competing interest
7.35 (d, J ¼ 8.5 Hz, 1H), 7.06 (d, J ¼ 8.8 Hz, 1H), 6.57 (dd, J ¼ 8.5,
2.5 Hz, 1H), 6.38 (dd, J ¼ 8.7, 3.9, 2.4 Hz, 3H), 5.44 (d, J ¼ 6.8 Hz, 1H),
4.18 (dd, J ¼ 10.7, 4.8 Hz, 1H), 3.72 (s, 2H), 3.69 (s, 3H), 3.56 (t,
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
J ¼ 10.9 Hz, 1H), 3.51e3.40 (m, 1H). 13C NMR (101 MHz, CDCl3)
d:
161.0, 160.9, 160.6, 156.5, 131.8, 124.6,119.0, 112.3, 109.1, 106.3, 101.5,
101.5, 96.8, 96.8, 78.5, 66.5, 55.4. HRMS (ESI) calculated for
Acknowledgments
C
17H16NaO4: 307.0946; found: 307.0941.
This work was financially supported by CAPES (Brazil) for the
fellowship (Process CSF-PVE-88887.127573/2016e00). This
research was also supported by the Spanish Ministerio de Econo-
5.4.11. 6a,11a-Dihydro-6H-benzofuro[3,2-c] [1,3],dioxolo[4,5-g]
chromene-9-carbaldehyde (3ec)
ꢀ
mía y Competitividad (MINECO) Agencia Estatal de Investigacion
White solid, (35.5 mg, 60% yield) mp 141e143 ꢀC. IR (KBr) nmax
:
:
(AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU)
(projects CTQ2016-76782-P, CTQ2016-81797-REDC, FEDER-
CTQ2016-76155-R and RED2018-102387-T) and Government of
3059, 2950, 1690, 1490, 1295 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d
9.93 (s, 1H), 7.46 (dd, J ¼ 7.5, 1.1 Hz, 1H), 7.41 (d, J ¼ 7.5 Hz, 1H), 7.31
(s, 1H), 6.94 (s, 1H), 6.46 (s, 1H), 6.46 (s, 1H), 6.46 (s, 1H), 5.95 (dd,
J ¼ 11.9, 1.2 Hz, 2H), 5.56 (d, J ¼ 6.1 Hz, 1H), 4.28 (dd, J ¼ 9.8, 6.2 Hz,
1H), 3.84 (t, J ¼ 6.0 Hz, 1H), 3.70 (dd, J ¼ 5.4, 2.0 Hz, 1H). 13C NMR
ꢀ
Aragon (Grupos de Referencia, E34-R17). The authors thankfully
acknowledge the resources from the supercomputers “Memento”
and “Cierzo”, technical expertise and assistance provided by BIFI-
ZCAM (Universidad de Zaragoza, Spain).
(101 MHz, CDCl3) d: 191.6, 160.1, 151.0, 149.1, 142.4, 138.2, 134.5,
125.2, 124.5, 111.4, 109.6, 108.8, 101.5, 99.0, 78.9, 66.1, 40.5. HRMS
(EI) calculated for C17H12O5: 296.0685; found: 296.0675.
Appendix A. Supplementary data
5.4.12. 2,3-Dimethoxy-6a,11a-dihydro-6H-benzofuro[3,2-c]
chromene-9 carbaldehyde (3dc)
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131638.
White solid, (36.8 mg, 59% yield) mp 136 ꢀC. IR (KBr) nmax: 3019,
2974, 2948, 1690, 1325 cmꢁ1. 1H NMR (400 MHz, CDCl3)
d: 9.94 (s,
References
1H), 7.46 (d, J ¼ 7.5 Hz, 1H), 7.42 (d, J ¼ 7.5 Hz, 1H), 7.33 (s, 1H), 7.27
(d, J ¼ 0.9 Hz, 1H), 6.99 (s, 1H), 6.49 (s, 1H), 5.60 (d, J ¼ 6.5 Hz, 1H),
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2981, 2923, 1695, cmꢁ1. 1H NMR (400 MHz, CDCl3)
d: 9.81 (s, 1H),
7.78 (d, J ¼ 1.6 Hz, 1H), 7.69 (dd, J ¼ 8.3, 1.7 Hz, 1H), 6.89 (d,
J ¼ 9.5 Hz, 2H), 6.42 (s, 1H), 6.03e5.72 (m, 3H), 5.57 (d, J ¼ 7.0 Hz,
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for C17H12NaO5: 319.0582; found: 319.0557.
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8