Synthesis and Transformation of 5-Acetyl-2-aryl-6-hydroxybenzofurans into Furanoflavanone Derivatives

Article abstract of DOI:10.1055/s-0039-1690001

Tandem palladium-catalyzed Sonogashira cross-coupling and heteroannulation of 3-bromo-2,4-dihydroxy-5-iodoacetophenone with arylacetylenes followed by the base-mediated Claisen-Schmidt aldol condensation of the intermediate 5-acetyl-2-aryl-7-bromo-6-hydro

Full text of DOI:10.1055/s-0039-1690001

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
paper
A
en
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
Synthesis and Transformation of 5-Acetyl-2-aryl-6-hydroxybenzo-
furans into Furanoflavanone Derivatives
Malose J. Mphahlele*
Temitope O. Olomola1
Department of Chemistry, College of Science, Engineering and
Technology, University of South Africa, Private Bag X06, Florida
1710, South Africa
mphahmj@unisa.ac.za
Received: 22.03.2019
Accepted after revision: 13.06.2019
Published online: 28.06.2019
droxy acetylbenzofurans as the key intermediates for the
syntheses.14,15 However, the methodology is limited to the
synthesis of C-2 unsubstituted or 3-carbo-substituted de-
rivatives. Conventional methods for the synthesis of o-hy-
droxy acetylbenzofurans involve multiple steps that result
in reduced yields or mixtures of the isomeric 5-acetyl-4-hy-
droxybenzofuran and 5-acetyl-6-hydroxybenzofuran deriv-
atives.16
DOI: 10.1055/s-0039-1690001; Art ID: ss-2019-z0192-op
Abstract Tandem palladium-catalyzed Sonogashira cross-coupling
and heteroannulation of 3-bromo-2,4-dihydroxy-5-iodoacetophenone
with arylacetylenes followed by the base-mediated Claisen–Schmidt al-
dol condensation of the intermediate 5-acetyl-2-aryl-7-bromo-6-hy-
droxybenzofurans with benzaldehyde derivatives afforded the corre-
sponding linear 2-arylbenzofuranchalcone hybrids. The presence of the
o-hydroxy-trans-,-unsaturated carbonyl moiety in the prepared fu-
ranochalcone hybrids facilitated acid-mediated cycloisomerization into
the corresponding linear furanoflavanones. The structures of the pre-
pared compounds were confirmed using a combination of spectromet-
ric techniques complemented with single crystal XRD analysis.
OR
H3CO
OH
OH
O
O
O
Keywords 3-bromo-2,4-dihydroxy-5-iodoacetophenone,Sonogashira
cross-coupling, furanochalcones, furanoflavanones, X-ray
OCH3
OH
O
H3CO
1: R = CH3 (a); H (b)
Although 2-phenylbenzofuran derivatives are widely
distributed in plants and constitute basic structure of neoli-
gnans,2 majority of the naturally occurring linear and angu-
lar furanoflavanoids lack an aryl substituent on the C-2 po-
sition of the five-membered ring.3 Cissampeloflavone (1a)
and ridiculuflavonylchalcone B (1b) shown in Figure 1 rep-
resent the first examples of furanoflavonoids substituted
with an aryl group at C-2 position of ring D.4 These 2,3-di-
carbo-substituted furanoflavanoids were first isolated from
a Venezuelan plant Cissampelos pareira and Brazilian plant
Aristolochia ridicula, respectively, along with the analogous
6-aryl-8H-furo[2,3-g]chromen-8-one derivatives.5–7 The
most commonly used approach towards linear8–10 and an-
gular benzofuran-appended chalcone hybrids11,12 and their
corresponding furanoflavanones,9,12 furanoflavones,11 and
furanoflavonol derivatives8,13 involves the use of the o-hy-
Figure 1 Structures of cissampeloflavone (1a) and ridiculuflavonylchal-
cone B (1b), respectively
The first total synthesis of analogues of cissampelofla-
vone (1a) was reported recently and it involved C-3 benzoy-
lation of 2-(4-methoxyphenyl)-5H-furo[3,2-g]chromen-5-
one 3, prepared in turn, in 45% yield via palladium chloride-
catalyzed intramolecular C–H cyclization of 7-{[2-bromo-1-
(4-methoxyphenyl)vinyl]oxy}-5-hydroxy-4H-chromen-4-
one 2 as shown in Scheme 1.17 ortho-Halogenated phenols
constitute important scaffolds for transition-metal-cata-
lyzed carbon–carbon and/or carbon–heteroatom bond for-
mation to afford either linear or angular benzofuran deriva-
tives, exclusively.18–28 Among the cross-coupling reactions,
tandem palladium-catalyzed Sonogashira cross-coupling of
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
OH
O
O
OH
O
O
Br
O
OCH3
OBn
PdCl2, K2CO3, DMF, microwave
130 °C, 10 min
OCH3
OBn
O
H3CO
H3CO
2
3
Scheme 1 Synthesis of 2-(4-methoxyphenyl)-5H-furo[3,2-g]chromen-5-one derivative 3
o-halogenophenols with terminal acetylenes and subse-
quent cycloisomerization of the intermediate alkynylated
derivative represents the most convenient and efficient
method for the construction of linear or angular 2-arylben-
zofurans in the presence22,24 or absence24–28 of the protec-
tive groups. We have initiated a research program to exploit
this valuable methodology for the synthesis of polycyclic
flavonoid derivatives.
In continuation with our research on the reactivity of
mixed dihalogenated o-hydroxyacetophenones,27,28 we de-
cided to prepare 3-bromo-2,4-dihydroxy-5-iodoacetophe-
none for use as a scaffold for tandem Sonogashira cross-
coupling with arylacetylenes. The main aim was to employ
the resultant o-hydroxy acetylbenzofurans as scaffolds for
sequential Claisen–Schmidt aldol condensation and cy-
cloisomerization or oxidative cyclization of the intermedi-
ate furanochalcones to append a six-membered heterocy-
clic moiety onto the benzofuran moiety.
Literature search revealed several reagents for the iodin-
ation of 2,4-dihydroxyacetophenone, which include the use
of iodine monochloride in acetic acid at room tempera-
ture,22 2 equivalents of pyridinium iodochloride in metha-
nol under reflux,25 or I2/HIO3 mixture in aqueous ethanol
under reflux for 5 minutes26,27 to afford 2,4-dihydroxy-3,5-
diiodoacetophenone. Sodium iodide/potassium iodate
(NaI/KIO3) mixture in acetic acid at room temperature, on
the other hand, afforded a mixture of 2,4-dihydroxy-3-io-
doacetophenone and 2,4-dihydroxy-3,5-diiodoacetophe-
none in 74% and 7% yield, respectively.21 2,4-Dihydroxy-3-
iodoacetophenone, was isolated in 98% directly from the re-
action of 2,4-dihydroxyacetophenone with iodine and po-
tassium iodate mixture in aqueous ethanol.29 The isomeric
5-iodo-substituted derivative was only accessible from the
2,4-bis(methoxymethoxy)acetophenone with 1.2 equiva-
lents of N-iodosuccinamide (NIS) in dimethylformamide
(DMF) at 50 °C.29,30 We required the 3-bromo-2,4-dihy-
droxy-5-iodoacetophenone as a precursor for the site-se-
lective Sonogashira cross-coupling with terminal acetyl-
enes to afford the 5-acetyl-2-aryl-7-bromo-6-hydroxyben-
zofurans without the need for protection of the hydroxyl
group(s). Protection of the phenolic functionality was
found to be essential to achieve good yields of the benzofu-
ran derivatives in the case of Sonogashira cross-coupling re-
actions of mono- or diiodinated resorcinol or 2,4-dihy-
droxyacetophenone.31 Attempted C-5 iodination of 2,4-di-
hydroxyacetophenone (4) with NIS in DMF or acetonitrile at
room temperature afforded in our hands 2,4-dihydroxy-
3,5-diiodoacetophenone (90%) as the sole product. Treat-
ment of 4 with NIS (1 equiv) in acetic acid at room tempera-
ture for 18 hours followed by aqueous workup and purifica-
tion by silica gel column chromatography afforded two
products in sequence characterized using NMR and IR spec-
troscopy as 2,4-dihydroxy-5-iodoacetophenone (5, 40%)
and 2,4-dihydroxy-3,5-diiodoacetophenone (5′, 30%). We
then opted for the use of 1.0 equivalent of p-toluenesulfonic
acid (p-TsOH) as an additive to a mixture of 4 and NIS (1
equiv) in acetonitrile at room temperature. To our delight,
we isolated after 14 hours by silica gel column chromatog-
raphy compound 5 as the major product (60%) along with
the 2,4-dihydroxy-3,5-diiodoacetophenone as the minor
1
product (15%). The H NMR spectrum of 2,4-dihydroxy-5-
iodoacetophenone (5) revealed the presence of a set of sin-
glets in the aromatic region at  = 6.41 and 8.14 corre-
sponding to H-3 and H-6, respectively. These signals distin-
guished this compound from the isomeric 3-iodo- or the
2,4-dihydroxy-3,5-diiodoacetophenone, which were the
main products formed when using other iodinating
agents.21,23,25,32,33 2,4-Dihydroxy-5-iodoacetophenone (5)
was, in turn, treated with 1.0 equivalent of N-bromosuccin-
imide (NBS) in acetic acid at room temperature for 30 min-
utes to afford 3-bromo-2,4-dihydroxy-5-iodoacetophenone
1
(6) in 85% yield. The H NMR spectrum of this mixed 3,5-
dihalogenated 2,4-dihydroxyacetophenone revealed the
presence of a singlet in the aromatic region at  = 8.25,
which corresponds to H-6. We took advantage of the ease of
Csp2–I bond to undergo transition-metal-catalyzed cross-
coupling in the presence of other halogen atoms33 and sub-
jected compound 6 to the Sonogashira cross-coupling reac-
tion conditions. The use of tetrakis(triphenylphos-
phine)palldium(0) [Pd(PPh3)4] as source of active Pd(0) cat-
alyst in the presence of CuI as co-catalyst and cesium
carbonate as a base in THF or DMF at room temperature led
to recovery of the substrate. The more active dichloro-
bis(triphenylphosphine)palladium(II) [PdCl2(PPh3)2] was
then used as the source of active Pd(0) catalyst in the pres-
ence of copper iodide (CuI) as co-catalyst and cesium car-
bonate as a base in 4:1 DMF/water (Scheme 2). The reaction
was found to be slow at room temperature, but to be com-
plete within 1 hour at 50 °C to afford upon silica gel column
chromatography in sequence traces of the dimer and the
1
cross-coupled product. The H NMR spectra of the cross-
coupled products revealed the presence of increased num-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

C
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
O
O
O
O
I
I
CH3
(i)
(ii)
(iii)
CH3
CH3
CH3
OH
5 (60%)
Ar1
HO
OH
O
HO
OH
OH
HO
Br
6 (85%)
Br
7a–d
4
Scheme 2 Sequential halogenation of 4 into 6 followed by alkynylation–heteroannulation into 7a–d [Ar1 = C6H5 (7a), 3-FC6H4 (7b), 4-FC6H4 (7c), and 4-
CH3OC6H4 (7d)]. Reagents and conditions: (i) NIS, p-TsOH, RT, CH3CN, 14 h; (ii) NBS, AcOH, RT, 3 h; (iii) Ar1C≡CH, PdCl2(PPh3)2, Cs2CO3, aq DMF, 50 °C, 1 h.
ber of proton signals in the aromatic region and a singlet
around  = 13.20 corresponding to the hydroxyl proton.
Their 13C NMR spectra revealed the absence of the Csp2–I
signal around  = 75.2 and the absence of two singlets in the
region  = 80–100 typical for the acetylene moiety, thus
ruling out the structure of the alkynyl isomer. Moreover,
their high-resolution mass spectra revealed the presence of
the 79Br and 81Br containing molecular ions in the ratio 1:1
thus confirming carbon–carbon bond formation through
the weak Csp2–I bond. A combination of these spectroscop-
ic data corroborated the structures of the cross-coupled
products as the 5-acetyl-2-aryl-7-bromo-6-hydroxybenzo-
furans 7a–d (Scheme 2). The presence of a lipophilic bro-
mine atom on the fused benzo ring of a benzofuran moiety
has been found to impart significant biological activity for
the 2-carbo-substituted arylbenzofuran derivatives.34
The benzofuran derivatives 7a–d contain the acetyl
moiety, which could facilitate Claisen–Schmidt aldol con-
densation to afford chalcone derivatives substituted with a
hydroxyl group ortho to the trans-,-unsaturated carbonyl
framework. Surprisingly, examples of such benzofuran-
chalcone hybrids are less documented in the literature.9,10
Compounds 7a–d were, in turn, subjected to Claisen–
Schmidt aldol condensation with benzaldehyde derivatives
in the presence of aqueous 30% NaOH in ethanol at room
temperature for 48 hours to afford after aqueous workup
and silica gel column chromatography, the corresponding
2-arylbenzofuran-appended chalcones 8a–r in appreciable
yields (Scheme 3, Table 1). The E-geometry around the vi-
nylic framework of these chalcones was confirmed by the
typical set of doublets around  = 7.60 and 7.90 with cou-
pling constant values Jtrans = 15.3–15.5 Hz, which corre-
spond to the -H and -H, respectively. Moreover, single
crystal X-ray diffraction (XRD) analysis of compound 8e
distinctly confirmed their structure and the E-geometry
around the olefinic framework (Figure 2).35 In the context of
the X-ray analyses, crystallographic numbering has been
used in place of the systematic numbering. There is intra-
molecular hydrogen bonding between the oxygen acceptor
(O1) and the -hydrogen bond donor [d(O(2)–
H(2)·O(3) = 1.74 Å].
Table 1 Substitution Pattern and Percentage Yields of the Furanochal-
cones 8a–r
Ar1
C6H5
Ar2
C6H5
Yield (%)
87 (8a)
88 (8b)
88 (8c)
84 (8d)
91 (8e)
92 (8f)
92 (8g)
87 (8h)
92 (8i)
92 (8j)
81 (8k)
95 (8l)
89 (8m)
86 (8n)
88 (8o)
93 (8p)
82 (8q)
86 (8r)
3-FC6H4
4-FC6H4
4-CH3OC6H4
C6H5
C6H5
C6H5
C6H5
3-FC6H4
3-FC6H4
3-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
3-FC6H4
4-FC6H4
C6H5
3-FC6H4
4-FC6H4
4-CH3OC6H4
C6H5
4-FC6H4
4-CH3OC6H4
C6H5
3-FC6H4
4-FC6H4
4-CH3OC6H4
O
O
Ar2
Ar2CHO, NaOH (aq), EtOH, RT, 48 h
CH3
OH
Ar1
Ar1
O
O
OH
Br
Br
7a–d
8a–r
Scheme 3 Synthesis of furanochalcones 8a–r
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

D
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
coupling constant values of C(7)H proton, J = 3.2 Hz and
12.4 Hz (vicinal diaxial coupling) indicated it to be axial in
the quasi chair conformation of the flavanone ring, with the
phenyl substituent (Ar2) in equatorial position. This quasi-
chair conformation is, in fact, evident in the single crystal
X-ray diffraction structure of furanoflavanone 9e shown in
Figure 3.41
O
O
Ar2
H2SO4, EtOH, reflux, 4 h
Ar1
Ar1
Ar2
O
O
OH
O
Br
8a–r
Br
9a–r
Figure 2 Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagram (50% prob-
ability level) of 8e; for clarity, hydrogen atoms are omitted
Scheme 4 Cycloisomerization of o-hydroxyfuranochalcones 8a–r into
furanoflavanones 9a–r
Very few examples of the naturally occurring furanofla-
vanoid derivatives substituted at the C-2 position of the
benzofuran moiety with carbon-based substituent have
been reported in the literature36–39 and their synthesis re-
main surprisingly less explored.4,18,39,40 The o-hydroxy-
trans-,-unsaturated carbonyl moiety represents suitable
scaffold for possible cycloisomerization or oxidative cy-
clization to afford analogues of the naturally occurring fu-
ranoflavanones, furanoflavones, furanoisoflavones, and fu-
ranoflavonols. We took advantage of the proximity of the
nucleophilic hydroxyl group to the trans-,-unsaturated
carbonyl moiety in compounds 8a–r to effect cycloisomeri-
zation to append a six-membered heterocyclic ring onto
the benzofuran scaffold. Compound 8a was subjected to
standard cycloisomerization conditions, which involved the
use of sulfuric acid in ethanol under reflux for 4 hours to
afford upon aqueous workup and purification by silica gel
column chromatography a product characterized using a
combination of NMR and IR spectroscopic techniques as the
furanoflavanone 9a in 50% yield (Scheme 4, Table 2). These
reaction conditions were extended to furanochalcones 8b–r
to afford novel furanoflavanones 9b–r. The 1H NMR spectral
data of compounds 9a–r are distinguished from those of the
corresponding chalcone precursors by the absence of a set
of doublets corresponding to the olefinic proton signals and
the presence in the aliphatic region of two sets of doublet of
doublets (dd) for the diastereotopic methylene protons
around  = 3.01 and 3.20 as well as the methine proton sig-
nal around  = 5.60. In all cases, the methine proton exhib-
its significantly different vicinal H–H coupling constants,
Jvic = 3.40–4.50 Hz and Jvic = 11.00–12.00 Hz, which indi-
cates that different torsion angles exist between this proton
and each of the methylene protons. This observation would
require the methine proton (7-HX) to be gauche to one of
the methylene protons (6-Ha) with Jvic = 3.40–4.50 Hz (vici-
nal axial equatorial coupling constant) and anti to the other
(6-Hb) with Jvic = 11.00–12.00 Hz (vicinal diaxial coupling
constant) in a quasi-chair conformation of the flavanone
ring with phenyl substituent in equatorial positions. The
Table 2 Substitution Pattern and Percentage Yields of the Furanoflava-
nones 9a–r
Ar1
C6H5
Ar2
C6H5
Yield (%)
50 (9a)
60 (9b)
55 (9c)
60 (9d)
55 (9e)
50 (9f)
55 (9g)
60 (9h)
50 (9i)
70 (9j)
60 (9k)
50 (9l)
50 (9m)
60 (9n)
55 (9o)
60 (9p)
60 (9q)
60 (9r)
3-FC6H4
4-FC6H4
4-CH3OC6H4
C6H5
C6H5
C6H5
C6H5
3-FC6H4
3-FC6H4
3-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
3-FC6H4
4-FC6H4
C6H5
3-FC6H4
4-FC6H4
4-CH3OC6H4
C6H5
4-FC6H4
4-CH3OC6H4
C6H5
3-FC6H4
4-FC6H4
4-CH3OC6H4
Figure 3 ORTEP diagram (50% probability level) of 9e; for clarity, hy-
drogen atoms are omitted
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

E
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
In summary, 3-bromo-2,4-dihydroxy-5-iodoacetophe-
none (6) undergoes tandem palladium-catalyzed Sonogas-
hira cross-coupling–heteroannulation to afford o-hydroxy
acetylbenzofurans 7. The reaction is high yielding without
the need for protection of the phenolic functionality, an es-
sential step in the case of Sonogashira cross-coupling reac-
tions of mono- or diiodinated resorcinol or the 2,4-dihy-
droxyacetophenone.31 Claisen–Schmidt aldol condensation
of the o-hydroxy acetylbenzofurans 7 with benzaldehyde
derivatives afforded novel benzofuran–chalcone hybrids 8
appended with a trans-,-unsaturated carbonyl moiety
adjacent the hydroxyl group. The presence of the o-hy-
droxy-trans-,-unsaturated carbonyl moiety in the pre-
pared furanochalcone hybrids 8 facilitated annulation of
the six-membered heterocyclic ring onto the benzofuran
framework to afford the 2-aryl-substituted furanoflava-
nones 9 in moderate to high yields. Efforts are currently un-
derway in the laboratory to employ this strategy towards
the synthesis of analogues of the naturally occurring cis-
sampeloflavone (1a).
1-(2,4-Dihydroxy-3,5-diiodophenyl)ethanone (5′)
Yellow solid; yield: 0.80 g (15%); mp 173–175 °C (Lit.42 mp 177 °C).
IR (ATR): 677, 730, 796, 1037, 1076, 1142, 1253, 1281, 1319, 1349,
1362, 1404, 1453, 1613 cm–1
.
1H NMR (300 MHz, CDCl3):  = 2.60 (3 H, s, CH3), 6.42 (1 H, br s, 4-OH),
8.07 (1 H, s, H-6), 13.59 (1 H, s, 2-OH).
13C NMR (75 MHz, CDCl3):  = 26.2, 69.1, 75.5, 116.2, 141.0, 159.7,
163.5, 201.4.
1-(3-Bromo-2,4-dihydroxy-5-iodophenyl)ethanone (6)
A stirred solution of 5 (1.00 g, 3.60 mmol) in AcOH (25 mL) was treat-
ed with NBS (0.64 g, 3.60 mmol) and left to stir at RT for 30 min. The
mixture was then poured into ice-cold H2O and the resulting precipi-
tate was filtered and washed with H2O to afford 6 as a pale yellow sol-
id; yield: 1.09 g (85%); mp 171–173 °C (EtOH).
IR (ATR): 795, 1044, 1149, 1256, 1285, 1411, 1621, 3252 cm–1
1H NMR (300 MHz, DMSO-d6):  = 2.61 (3 H, s, CH3), 8.25 (1 H, s, 6-H),
11.06 (1 H, br s, 4-OH), 13.38 (1 H, br s, 2-OH).
13C NMR (75 MHz, DMSO-d6):  = 26.9, 75.2, 98.3, 115.9, 140.6, 159.8,
160.7, 203.3.
.
HRMS (ES–): m/z [M – H]– calcd for C8H579BrIO3: 354.8467; found:
354.8470.
Melting points were recorded on a Thermocouple digital melting
point apparatus and are uncorrected. IR spectra were recorded as
powders using a Bruker VERTEX 70 FT-IR spectrophotometer (Bruker
Optics, Billerica, MA, USA) with a diamond ATR (attenuated total re-
flectance) accessory by using the thin-film method. Merck Kieselgel
60 (0.063–0.200 mm) (Merck KGaA, Frankfurt, Germany) was used as
stationary phase for column chromatography. NMR spectra were ob-
tained as CDCl3 or DMSO-d6 solutions using Varian 300 MHz NMR
spectrometer (Varian Inc., Palo Alto, CA, USA) or 500 MHz NMR spec-
trometers (Agilent Technologies, Oxford, UK) and the chemical shifts
are quoted relative to the TMS peak. High-resolution mass spectra
(ESMS) were recorded using Waters Synapt G2 Quadrupole Time-of-
flight mass spectrometer (Waters Corp., Milford, MA, USA) at the Uni-
versity of Stellenbosch Central Analytical Facility (CAF).
Tandem Sonogashira Cross-Coupling and Heteroannulation of 6;
General Procedure
A mixture of 6 (0.50 g, 1.40 mmol), PdCl2(PPh3)2 (0.05 g, 0.07 mmol),
CuI (0.03 g, 0.14 mmol), Cs2CO3 (0.55 g, 1.68 mmol) in 4:1 DMF/H2O
(v/v, 20 mL) was placed in a two-necked round-bottomed flask
equipped with a condenser and a rubber septum. The mixture was
flushed with argon for 30 min and a solution of the required pheny-
lacetylene derivative (1.2 equiv) in DMF (2 mL) was introduced by
means of a syringe via a rubber septum. A balloon filled with argon
was connected at the top of the condenser and the mixture was left to
stir at 50 °C for 1 h. The mixture was allowed to cool, poured into
crushed ice, and the product was extracted with CHCl3. The combined
organic phases were dried (anhyd MgSO4) and filtered. The solvent
was evaporated under reduced pressure on a rotary evaporator and
the residue was purified by silica gel column chromatography with
4:1 hexane/EtOAc (v/v) as an eluent to afford the desired product 7.
Iodination of 2,4-Dihydroxyacetophenone (4)
A stirred solution of 4 (2.00 g, 13.1 mmol) in CH3CN (20 mL) was
treated with p-TsOH·H2O (2.50 g, 13.1 mmol) at 0 °C and after 5 min,
NIS (2.96 g, 13.1 mmol) was added. The reaction mixture was allowed
to warm up to RT and stirred at this temperature for 14 h. The mix-
ture was quenched with an ice-cold aq Na2S2O3 solution. The resulting
precipitate was filtered and purified by silica gel column chromatog-
raphy with 9:1 toluene/CHCl3 mixture (v/v) as an eluent to afford 1-
(2,4-dihydroxy-5-iodophenyl)ethanone (5) and 1-(2,4-dihydroxy-
3,5-diiodophenyl)ethanone (5′) in sequence.
1-[7-Bromo-6-hydroxy-2-phenylbenzofuran-5-yl]ethanone (7a)
Yellow solid; yield: 0.28 g (60%); mp 162–164 °C.
IR (ATR): 758, 1061, 1153, 1243, 1330, 1368, 1415, 1638 cm–1
.
1H NMR (300 MHz, CDCl3):  = 2.72 (3 H, s, CH3), 7.00 (1 H, s, H-3),
7.38–7.49 (3 H, m, H-4′ and H-3′,5′), 7.84 (2 H, dd, J = 1.2, 8.3 Hz, H-
2′,6′), 7. 92 (1 H, s, H-4), 13.21 (1 H, br s, OH).
13C NMR (75 MHz, CDCl3):  = 26.9, 93.0, 101.3, 117.4, 121.9, 122.2,
124.9, 128.9, 129.1, 129.2, 156.8, 157.3, 157.6, 203.9.
HRMS (ES–): m/z [M – H]– calcd for C16H1079BrO3: 328.9814; found:
328.9821.
1-(2,4-Dihydroxy-5-iodophenyl)ethanone (5)
White solid; yield: 2.19 g (60%); mp 184–186 °C.
IR (ATR): 889, 1190, 1223, 1314, 1579, 1614, 1634, 3263 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 2.54 (3 H, s, CH3), 6.41 (1 H, s, H-3),
8.14 (1 H, s, H-6), 11.50 (1 H, s, 4-OH), 12.36 (1 H, s, 2-OH).
13C NMR (75 MHz, DMSO-d6):  = 27.3, 74.0, 102.5, 115.9, 142.1,
1-[7-Bromo-2-(3-fluorophenyl)-6-hydroxybenzofuran-5-yl]etha-
none (7b)
Yellow solid; yield: 0.32 g (66%); mp 189–191 °C.
163.5, 163.9, 202.1.
HRMS (ES–): m/z [M – H]– calcd for C8H6IO3: 276.9362; found:
IR (ATR): 776, 861, 1056, 1177, 1218, 1364, 1417, 1483, 1577, 1608,
1643 cm–1
.
276.9351.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

F
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
1H NMR (500 MHz, DMSO-d6):  = 2.74 (3 H, s, CH3), 7.24 (1 H, t, J = 8.0
Hz, H-4′), 7.52–7.56 (2 H, m, H-3 and H-6′), 7.64–7.69 (2 H, m, H-
2′,3′), 8.28 (1 H, s, H-4), 13.13 (1 H, br s, OH).
(E)-1-[7-Bromo-2-(3-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
3-phenylprop-2-en-1-one (8b)
Orange solid; yield: 0.22 g (88%); mp 245–247 °C.
13C NMR (125 MHz, DMSO-d6):  = 27.5, 92.0, 104.5, 111.6 (d,
2JC,F = 23.8 Hz), 116.3 (d, 2JC,F = 21.2 Hz), 118.1, 121.0 (d, 4JC,F = 2.7 Hz),
121.8, 124.9, 131.4 (d, 3JC,F = 8.7 Hz), 131.7 (d, 3JC,F = 8.6 Hz), 155.3 (d,
4JC,F = 3.2 Hz), 156.2, 157.3, 162.9 (d, 1JC,F = 243.9 Hz), 205.6.
HRMS (ES–): [M – H]– calcd for C16H979BrFO3: 346.9719; found:
346.9723.
IR (ATR): 721, 773, 841, 854, 1144, 1205, 1280, 1361, 1396, 1422,
1570, 1639 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.05–7.13 (2 H, overlapping signals, H-
3 and 4′), 7.41–7.49 (4 H, m, -H and ArH), 7.53–7.67 (1 H, m, ArH),
7.63–7.67 (1 H, m, ArH), 7.68–7.74 (3 H, m, ArH), 8.00 (1 H, d,
Jtrans = 15.4 Hz, -H), 8.15 (1 H, s, H-4), 13.84 (1 H, br s, OH).
13C NMR (75 MHz, DMSO-d6):  = 92.4, 104.7, 111.8 (d, 2JC,F = 23.9 Hz),
1-[7-Bromo-2-(4-fluorophenyl)-6-hydroxybenzofuran-5-yl]etha-
none (7c)
2
4
116.4 (d, JC,F = 21.2 Hz), 121.1 (d, JC,F = 2.9 Hz), 121.5, 124.5, 128.6,
3
3
129.3, 129.5, 129.9, 131.5 (d, JC,F = 8.6 Hz), 131.7, 131.8 (d, JC,F = 8.5
Hz), 134.8, 146.4, 155.3, 156.5, 158.8, 163.0 (d, 1JC,F = 243.7 Hz), 194.0.
Yellow solid; yield: 0.30 g (62%); mp 202–204 °C.
HRMS (ES+): m/z [M + H]+ calcd for C23H1579BrFO3: 437.0189; found:
437.0191.
IR (ATR): 797, 835, 1063, 1155, 1218, 1372, 1419, 1504, 1613, 1635
cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 2.76 (3 H, s, CH3), 7.35 (2 H, t, J = 8.9
Hz, H-3′,5′), 7.51 (1 H, s, H-3), 7.93 (2 H, dd, J = 5.4, 8.9 Hz, H-2′,6′),
8.31 (1 H, s, H-4), 13.19 (1 H, br s, OH).
(E)-1-[7-Bromo-2-(4-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
3-phenylprop-2-en-1-one (8c)
13C NMR (75 MHz, DMSO-d6):  = 27.6, 92.0, 103.0, 116.7 (d,
Orange solid; yield: 0.22 g (88%); mp 209–211 °C.
IR (ATR): 723, 834, 1147, 1233, 1422, 1515, 1573, 1603, 1640 cm–1
1H NMR (300 MHz, CDCl3):  = 6.97 (1 H, s, H-3), 7.17 (2 H, t, J = 8.8
Hz, H-3′,5′), 7.46–7.48 (3 H, m, ArH), 7.68–7.73 (3 H, m, -H and ArH),
7.84 (2 H, t, J = 8.8 Hz, H-2′,6′), 7.99 (1 H, d, Jtrans = 15.4 Hz, -H), 8.12
(1 H, s, H-4), 13.86 (1 H, br s, OH).
4
2JC,F = 22.1 Hz), 118.0, 122.1, 124.7, 125.8 (d, JC,F = 3.2 Hz), 127.3 (d,
.
3JC,F = 8.5 Hz), 155.8, 156.2, 157.1, 162.9 (d, 1JC,F = 247.0 Hz), 206.7.
HRMS (ES–): m/z [M – H]– calcd for C16H979BrFO3: 346.9719; found:
346.9725.
1-[7-Bromo-6-hydroxy-2-(4-methoxyphenyl)benzofuran-5-
yl]ethanone (7d)
2
13C NMR (75 MHz, CDCl3):  = 93.3, 101.1, 116.1 (d, JC,F = 22.2 Hz),
4
3
117.8, 119.8, 121.1, 121.9, 125.6 (d, JC,F = 3.4 Hz), 126.9 (d, JC,F = 8.4
Hz), 128.8, 129.1, 131.2, 134.4, 146.2, 156.4, 157.9 (d, 1JC,F = 256.4 Hz),
158.8, 164.8, 193.1.
HRMS (ES–): m/z [M – H]– calcd for C23H13F79BrO3: 435.0032; found:
Yellow solid; yield: 0.34 g (67%); mp 180–182 °C.
IR (ATR): 823, 1018, 1154, 1247, 1373, 1417, 1504, 1613, 1635 cm–1
1H NMR (300 MHz, DMSO-d6):  = 2.71 (3 H, s, CH3), 3.80 (3 H, s,
OCH3), 7.02 (2 H, d, J = 8.5 Hz, H-3′,5′), 7.25 (1 H, s, H-3), 7.74 (2 H, d,
J = 8.5 Hz, H-2′,6′), 8.16 (1 H, s, H-4), 13.12 (1 H, br s, OH).
.
435.0021.
(E)-1-[7-Bromo-6-hydroxy-2-(4-methoxyphenyl)benzofuran-5-
yl]-3-phenylprop-2-en-1-one (8d)
13C NMR (75 MHz, DMSO-d6):  = 27.4, 55.5, 91.7, 100.8, 114.7, 117.5,
121.6, 122.2, 123.7, 126.4, 155.9, 156.6, 156.7, 160.2, 205.4.
Brown solid; yield: 0.21 g (84%); mp 202–204 °C.
IR (ATR): 853, 1035, 1145, 1249, 1422, 1569, 1614, 1640 cm–1
HRMS (ES–): m/z [M – H]– calcd for C17H1279BrO4: 358.9919; found:
358.9937.
.
1H NMR (300 MHz, CDCl3):  = 3.86 (3 H, s, OCH3), 6.87 (1 H, s, H-3),
6.98 (2 H, d, J = 8.7 Hz, H-3′,5′), 7.42–7.47 (3 H, m, ArH), 7.66–7.71 (3
H, m, -H and H-2′′,6′′), 7.78 (2 H, d, J = 8.7 Hz, H-2′,6′), 7.96 (1 H, d,
Jtrans = 15.5 Hz, H-), 8.06 (1 H, s, H-4), 13.85 (1 H, br s, OH).
Base-Catalyzed Claisen–Schmidt Condensation of 7a–d; (E)-1-(7-
Bromo-6-hydroxy-2-phenylbenzofuran-5-yl)-3-phenylprop-2-en-
1-one (8a); Typical Procedure
13C NMR (75 MHz, CDCl3):  = 55.4, 93.2, 99.6, 114.3, 117.7, 119.9,
120.7, 122.0, 122.3, 126.5, 128.8, 129.1, 131.1, 134.5, 146.0, 156.8,
157.5, 158.6, 160.4, 193.1.
HRMS (ES–): m/z [M – H]– calcd for C24H1679BrO4: 447.0232; found:
447.0218.
A mixture of benzofuran 7a (0.20 g, 0.60 mmol) and benzaldehyde
(0.127 g, 1.2 mmol, 1.2 equiv) was dissolved in EtOH (10 mL), and 30%
(w/v) aq KOH (3 mL) was added. The mixture was left to stir for 48 h
at RT and then poured onto ice-cold dilute HCl. The resultant precipi-
tate was filtered on a Büchner funnel and then purified by column
chromatography on silica gel using 4:1 toluene/EtOAc (v/v) as an elu-
ent to afford 8a as an orange solid; yield: 0.22 g (87%); mp 243–
244 °C.
(E)-1-(7-Bromo-6-hydroxy-2-phenylbenzofuran-5-yl)-3-(3-fluo-
rophenyl)prop-2-en-1-one (8e)
IR (ATR): 720, 760, 856, 1145, 1280, 1422, 1571, 1641 cm–1
.
Red solid; yield: 0.24 g (91%); mp 210–212 °C.
1H NMR (300 MHz, CDCl3):  = 7.05 (1 H, s, H-3), 7.37–7.50 (6 H, m, -
H and ArH), 7.69–7.74 (3 H, m, ArH), 7.86–7.89 (2 H, m, ArH), 7.99 (1
H, d, Jtrans = 15.5 Hz, H-), 8.14 (1 H, s, H-4), 13.86 (1 H, br s, OH).
13C NMR (75 MHz, CDCl3):  = 93.3, 101.4, 117.8, 119.9, 121.2, 122.0,
124.9, 128.8, 128.9, 129.1, 129.2, 129.2, 131.2, 134.4, 146.2, 157.0,
157.4, 158.8, 193.1.
IR (ATR): 756, 851, 980, 1146, 1230, 1421, 1574, 1640 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.01 (1 H, s, H-3), 7.13–7.19 (1 H, m, H-
4′), 7.35–7.48 (6 H, m, ArH), 7.65 (1 H, d, Jtrans = 15.5 Hz, -H), 7.82–
7.92 (3 H, m, -H and ArH), 8.06 (1 H, s, H-4), 13.73 (1 H, br s, OH).
2
13C NMR (75 MHz, CDCl3):  = 93.3, 101.4, 114.6 (d, JC,F = 21.9 Hz),
2
117.6, 118.0 (d, JC,F = 21.4 Hz), 121.1, 121.2, 122.0, 124.9, 125.0 (d,
HRMS (ES–): m/z [M – H]– calcd for C23H1479BrO3: 417.0127; found:
417.0115.
3
4JC,F = 2.9 Hz), 128.9, 129.1, 129.2, 130.7 (d, JC,F = 8.2 Hz), 136.6 (d,
4
3JC,F = 7.8 Hz), 144.5 (d, JC,F = 2.8 Hz), 157.0, 157.4, 158.8, 163.0 (d,
1JC,F = 247.4 Hz), 192.7.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

G
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
HRMS (ES–): m/z [M – H]– calcd for C23H1379BrFO3: 435.0032; found:
(E)-1-[7-Bromo-2-(3-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
435.0034.
3-(4-fluorophenyl)prop-2-en-1-one (8i)
Orange solid; yield: 0.24 g (92%); mp 232–234 °C.
(E)-1-[7-Bromo-2-(3-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
3-(3-fluorophenyl)prop-2-en-1-one (8f)
IR (ATR): 777, 827, 1139, 1157, 1218, 1237, 1418, 1446, 1509, 1565,
1600, 1638 cm–1
.
Orange solid; yield: 0.24 g (92%); mp 223–225 °C.
1H NMR (300 MHz, DMSO-d6):  = 7.26–7.37 (3 H, m, H-3′ and H-
2′,6′), 7.50–7.60 (1 H, m, H-4′), 7.62 (1 H, s, H-3), 7.76 (2 H, d, J = 8.0
Hz, H-3′′,5′′), 7.92 (1 H, d, Jtrans = 15.4 Hz, -H), 8.02–8.07 (2 H, dd,
J = 5.6, 8.0 Hz, H-2′′,6′′), 8.15 (1 H, d, Jtrans = 15.4 Hz, -H), 8.77 (1 H, s,
H-4), 13.89 (1 H, br s, OH).
IR (ATR): 776, 873, 1140, 1238, 1264, 1360, 1425, 1446, 1486, 1571,
1616, 1640 cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 7.20–7.34 (2 H, m, H-6′ and H-6′′),
7.48–7.56 (3 H, m, H-3 and ArH), 7.72 (3 H, d, J = 7.9 Hz, ArH), 7.82–
7.90 (2 H, m, -H and ArH), 8.22 (1 H, d, Jtrans = 15.5 Hz, -H), 8.68 (1
H, s, H-4), 13.79 (1 H, br s, OH).
13C NMR (75 MHz, DMSO-d6):  = 92.4, 104.6, 111.8 (d, 2JC,F = 23.9 Hz),
2
2
116.4 (d, JC,F = 21.4 Hz), 116.5 (d, JC,F = 21.8 Hz), 118.5, 121.2 (d,
3JC,F = 7.9 Hz), 122.0, 124.4, 131.4, 131.5, 131.5, 131.8 (d, 3JC,F = 8.7 Hz),
13C NMR (75 MHz, DMSO-d6):  = 92.7, 104.6, 111.7 (d, 2JC,F = 24.1 Hz),
3
4
2
2
2
132.3 (d, JC,F = 8.8 Hz), 145.2, 155.4 (d, JC,F = 3.2 Hz), 156.5, 158.7,
163.0 (d, 1JC,F = 243.7 Hz), 164.2 (d, 1JC,F = 250.2 Hz), 193.9.
115.4 (d, JC,F = 22.1 Hz), 116.2 (d, JC,F = 21.2 Hz), 118.2 (d, JC,F = 20.8
4
4
Hz), 121.0, 123.4 (d, JC,F = 2.1 Hz), 123.4 (d, JC,F = 1.9 Hz), 124.4,
3
3
HRMS (ES–): m/z [M – H]– calcd for C23H1279Br F2O3: 452.9938; found:
452.9910.
126.5, 131.3 (d, JC,F = 8.3 Hz), 131.5 (d, JC,F = 8.8 Hz), 131.7 (d,
3JC,F = 8.5Hz), 137.4 (d, 3JC,F = 7.9 Hz), 144.2 (d, 4JC,F = 2.9 Hz), 155.0 (d,
4JC,F = 3.9 Hz), 156.7, 158.4 (d, JC,F = 241.3 Hz), 161.3, 164.6, 167.7 (d,
1
1JC,F = 226.0 Hz), 193.6.
(E)-1-[7-Bromo-6-hydroxy-2-(4-fluorophenyl)benzofuran-5-yl]-
3-(4-fluorophenyl)prop-2-en-1-one (8j)
HRMS (ES–): m/z [M – H]– calcd for C23H1279BrF2O3: 452.9938; found:
452.9919.
Orange solid; yield: 0.24 g (92%); mp 227–229 °C.
IR (ATR): 715, 734, 824, 1029, 1157, 1200, 1217, 1402, 1421, 1503,
(E)-1-[7-Bromo-2-(4-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
3-(3-fluorophenyl)prop-2-en-1-one (8g)
1576, 1641 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 7.35 (4 H, dt, J = 8.8, 11.0 Hz, H-
3′′,5′′, H-3′,5′), 7.48 (1 H, s, H-3), 7.92 (1 H, d, Jtrans = 15.5 Hz, -H), 7.97
(2 H, t, J = 8.8 Hz, H-2′′,6′′), 8.04 (2 H, t, J = 8.8 Hz, H-2′,6′), 8.13 (1 H, d,
Jtrans = 15.5 Hz, -H), 8.73 (1 H, s, H-4), 13.88 (1 H, br s, OH).
Orange solid; yield: 0.24 g (92%); mp 254–255 °C.
IR (ATR): 833, 846, 1147, 1232, 1360, 1402, 1421, 1503, 1576, 1601,
1643 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 7.31–7.40 (3 H, m, H-4′′ and H-
3′,5′), 7.49 (1 H, s, H-3), 7.53 (1 H, dd, J = 7.7, 9.0 Hz, H-3′′), 7.75 (1 H,
d, J = 7.7 Hz, H-6′′), 7.87–7.94 (2 H, m, -H and H-2′′), 7.98 (2 H, t,
J = 7.7 Hz, H-2′,6′), 8.24 (1 H, d, Jtrans = 15.4 Hz, -H), 8.76 (1 H, s, H-4),
13.77 (1 H, br s, OH).
2
13C NMR (125 MHz, DMSO-d6):  = 92.3, 103.0, 116.5 (d, JC,F = 21.7
2
3
Hz), 116.6 (d, JC,F = 22.0 Hz), 118.3, 122.2, 124.0, 127.4 (d, JC,F = 8.5
Hz), 128.6, 129.3, 131.5 (d, JC,F = 3.1 Hz), 132.3 (d, JC,F = 8.8 Hz),
145.1, 155.9, 156.5, 158.5, 162.9 (d, JC,F = 247.1 Hz), 164.2 (d,
4
3
1
1JC,F = 250.0 Hz), 193.9.
2
13C NMR (125 MHz, DMSO-d6):  = 92.4, 103.0, 115.4 (d, JC,F = 22.0
HRMS (ES–): m/z [M – H]– calcd for C23H1279BrF2O3: 452.9938; found:
452.9955.
2
2
Hz), 116.7 (d, JC,F = 22.1 Hz), 118.3 (d, JC,F = 21.4 Hz), 118.5, 122.2,
123.1, 124.2, 125.9 (d, 4JC,F = 2.8 Hz), 126.6 (d, 4JC,F = 2.2 Hz), 127.5 (d,
3JC,F = 8.4 Hz), 131.4 (d, JC,F = 8.5 Hz), 137.4 (d, JC,F = 8.5 Hz), 144.6,
3
3
(E)-1-[7-Bromo-6-hydroxy-2-(4-methoxyphenyl)benzofuran-5-
yl]-3-(4-fluorophenyl)prop-2-en-1-one (8k)
1
4
155.9, 157.6 (d, JC,F = 257.5 Hz), 159.4, 162.0 (d, JC,F = 3.3 Hz), 162.9
(d, 1JC,F = 243.9 Hz), 193.9.
Brown solid; yield: 0.21 g (81%); mp 223–225 °C.
HRMS (ES–): m/z [M – H]– calcd for C23H1279BrF2O3: 452.9938; found:
IR (ATR): 826, 1144, 1221, 1251, 1424, 1505, 1568, 1613, 1639 cm–1
.
452.9932.
1H NMR (300 MHz, CDCl3):  = 3.86 (3 H, s, OCH3), 6.86 (1 H, s, H-3),
6.98 (2 H, d, J = 8.8 Hz, H-3′,5′), 7.15 (2 H, t, J = 8.5 Hz, H-3′′,5′′), 7.60 (1
H, d, Jtrans = 15.4 Hz, -H), 7.69 (2 H, t, J = 8.5 Hz, H-2′′,6′′), 7.77 (2 H, d,
J = 8.8 Hz, H-2′,6′), 7.92 (1 H, d, Jtrans = 15.4 Hz, -H), 8.03 (1 H, s, H-4),
13.82 (1 H, br s, OH).
(E)-1-(7-Bromo-6-hydroxy-2-phenylbenzofuran-5-yl)-3-(4-fluo-
rophenyl)prop-2-en-1-one (8h)
Brown solid; yield: 0.23 g (87%); mp 217–219 °C.
IR (ATR): 757, 827, 1144, 1222, 1401, 1420, 1507, 1576, 1638 cm–1
.
13C NMR (75 MHz, CDCl3):  = 55.4, 93.2, 99.6, 114.2, 114.3, 116.3 (d,
1H NMR (300 MHz, CDCl3):  = 7.02 (1 H, s, H-3), 7.15 (2 H, t, J = 8.6
Hz, H-3′′,5′′), 7.35–7.40 (1 H, m, H-4′), 7.46 (2 H, t, J = 7.3 Hz, ArH),
7.60 (1 H, d, Jtrans = 15.4 Hz, -H), 7.69 (2 H, t, J = 8.6 Hz, H-2′′,6′′),
7.81–7.87 (2 H, m, ArH), 7.92 (1 H, d, Jtrans = 15.4 Hz, -H), 8.08 (1 H, s,
H-4), 13.82 (1 H, br s, OH).
4
2JC,F = 22.0 Hz), 119.6 (d, JC,F = 2.2 Hz), 120.6, 122.0, 122.3, 126.5,
3
127.6, 130.7 (d, JC,F = 8.6 Hz), 133.2, 144.6, 157.5, 158.5 (d,
1JC,F = 242.0 Hz), 158.6, 160.4, 192.9.
HRMS (ES–): m/z [M – H]– calcd for C24H1579BrFO4: 465.0138; found:
465.0157.
13C NMR (75 MHz, CDCl3):  = 93.3, 101.4, 116.3 (d, JC,F = 22.0 Hz),
2
117.7, 119.5 (d, 4JC,F = 2.4 Hz), 121.1, 122.0, 124.9, 128.9, 129.1, 129.2,
(E)-1-(7-Bromo-6-hydroxy-2-phenylbenzofuran-5-yl)-3-(4-chlo-
rophenyl)prop-2-en-1-one (8l)
3
130.7, 130.7 (d, JC,F = 9.0 Hz), 144.8, 156.9, 157.4, 158.8, 164.4 (d,
1JC,F = 252.8 Hz), 192.8.
Red solid; yield: 0.26 g (95%); mp 214–216 °C.
HRMS (ES–): [M – H]– calcd for C23H1379BrFO3: 435.0032; found:
435.0021.
IR (ATR): 730, 818, 1091, 1142, 1401, 1420, 1490, 1563, 1637 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

H
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
1H NMR (300 MHz, DMSO-d6):  = 7.42–7.56 (6 H, m, H-3, ArH), 7.85–
7.92 (3 H, m, -H and H-3′′,5′′), 7.98 (2 H, d, J = 8.4 Hz, H-2′′,6′′), 8.18
(1 H, d, Jtrans = 15.4 Hz, -H), 8.73 (1 H, s, H-4), 13.86 (1 H, br s, OH).
(E)-1-[7-Bromo-2-(3-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
3-(4-methoxyphenyl)prop-2-en-1-one (8p)
Brown solid; yield: 0.25 g (93%); mp 215–218 °C.
13C NMR (75 MHz, DMSO-d6):  = 92.3, 103.1, 118.2, 121.9, 122.2,
124.1, 125.1, 129.1, 129.4, 129.5, 129.7, 131.5, 133.7, 136.2, 144.8,
156.5, 156.8, 158.5, 193.8.
HRMS (ES–): m/z [M – H]– calcd for C23H1379Br35ClO3: 450.9737; found:
450.9724.
IR (ATR): 773, 820, 1035, 1142, 1172, 1238, 1259, 1510, 1564, 1607,
1635 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.88 (3 H, s, OCH3), 6.97 (2 H, d, J = 8.8
Hz, H-3′′,5′′), 7.04 (1 H, s, H-3), 7.06–7.19 (1 H, m, H-4′), 7.38–7.56 (3
H, m, H-2′,6′ and H-3′), 7.60 (1 H, d, Jtrans = 15.3 Hz, -H), 7.66 (2 H, d,
J = 8.8 Hz, H-2′′,6′′), 7.95 (1 H, d, Jtrans = 15.3 Hz, -H), 8.10 (1 H, s, H-
4), 14.02 (1 H, br s, OH).
(E)-1-[7-Bromo-2-(4-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
3-(4-chlorophenyl)prop-2-en-1-one (8m)
2
13C NMR (75 MHz, CDCl3):  = 55.5, 93.2, 102.6, 111.8 (d, JC,F = 23.8
2
4
Orange solid; yield: 0.24 g (89%); mp 252–254 °C.
Hz), 114.6, 115.9 (d, JC,F = 21.3 Hz), 117.1, 118.1, 120.5 (d, JC,F = 3.0
3
Hz), 121.3, 121.5, 127.1, 130.5 (d, JC,F = 8.5 Hz), 130.7, 131.3 (d,
IR (ATR): 820, 1146, 1203, 1229, 1275, 1422, 1504, 1567, 1579, 1643
3JC,F = 8.3 Hz), 146.2, 155.8, 156.8, 159.0, 162.2, 163.0 (d, JC,F = 246.0
1
cm–1
.
Hz), 193.0.
1H NMR (500 MHz, CDCl3):  = 6.99 (1 H, s, H-3), 7.18 (2 H, t, J = 8.7
Hz, H-3′,5′), 7.45 (2 H, d, J = 8.5 Hz, H-3′′,5′′), 7.64 (2 H, d, J = 8.5 Hz, H-
2′′,6′′), 7.69 (1 H, d, Jtrans = 15.4 Hz, -H), 7.86 (2 H, t, J = 8.7 Hz, H-
2′,6′), 7.94 (1 H, d, Jtrans = 15.4 Hz, -H), 8.12 (1 H, s, H-4), 13.76 (1 H,
br s, OH).
HRMS (ES–): m/z [M – H]– calcd for C24H1579BrFO4: 465.0138; found:
465.0126.
(E)-1-[7-Bromo-2-(4-fluorophenyl)-6-hydroxybenzofuran-5-yl]-
3-(4-methoxyphenyl)prop-2-en-1-one (8q)
13C NMR (125 MHz, CDCl3):  = 93.4, 101.1, 116.10 (d, 2JC,F = 22.1 Hz),
117.8, 120.4, 121.1, 122.0, 125.6 (d, JC,F = 3.4 Hz), 126.9 (d, JC,F = 8.3
Hz), 129.4, 129.9, 132.9, 137.1, 144.6, 156.6, 157.0, 158.9, 163.2 (d,
1JC,F = 250.0 Hz), 192.9.
HRMS (ES–): m/z [M – H]– calcd for C23H1279Br35ClFO3: 468.9642;
found: 468.9661.
4
3
Brown solid; yield: 0.22 g (82%); mp 238–239 °C.
IR (ATR): 820, 1032, 1175, 1226, 1286, 1423, 1504, 1567, 1605, 1639
cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.88 (3 H, s, OCH3), 6.98 (3 H, m, H-3
and H-3′′,5′′), 7.16 (2 H, t, J = 8.5 Hz, H-3′,5′), 7.57 (1 H, d, Jtrans = 15.3
Hz, -H), 7.66 (2 H, d, J = 8.5 Hz, H-2′′,6′′), 7.84 (2 H, t, J = 8.5 Hz, H-
2′,6′), 7.96 (1 H, d, Jtrans = 15.3 Hz, -H), 8.10 (1 H, s, H-4), 14.01 (1 H,
br s, OH).
(E)-1-[7-Bromo-6-hydroxy-2-(4-methoxyphenyl)benzofuran-5-
yl]-3-(4-chlorophenyl)prop-2-en-1-one (8n)
13C NMR (75 MHz, CDCl3):  = 55.5, 93.2, 101.2, 114.6, 116.0 (d,
Red solid; yield: 0.25 g (86%); mp 215–217 °C.
4
2JC,F = 22.1 Hz), 117.2, 118.0, 120.9, 121.8, 125.7 (d, JC,F = 3.4 Hz),
IR (ATR): 819, 1025, 1090, 1141, 1249, 1420, `505, 1562, 1615, 1636
126.8 (d, 3JC,F = 8.3 Hz), 127.2, 130.7, 146.1, 156.3, 156.7, 158.8, 162.2,
163.1 (d, 1JC,F = 249.8 Hz), 193.0.
HRMS (ES–): m/z [M – H]– calcd for C24H1579BrFO4: 465.0138; found:
cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.86 (3 H, s, OCH3), 6.84 (1 H, s, H-
3), 6.96 (2 H, d, J = 8.5 Hz, H-3′,5′), 7.42 (2 H, d, J = 8.5 Hz, H-3′′,5′′),
7.57–7.66 (3 H, m, -H, H-2′′,6′′), 7.75 (2 H, d, J = 8.5 Hz, H-2′,6′), 7.87
(1 H, d, Jtrans = 15.5 Hz, -H), 7.99 (1 H, s, H-4), 13.78 (1 H, br s, OH).
465.0129.
(E)-1-[7-Bromo-6-hydroxy-2-(4-methoxyphenyl)benzofuran-5-
yl]-3-(4-methoxyphenyl)prop-2-en-1-one (8r)
13C NMR (75 MHz, DMSO-d6):  = 55.4, 93.2, 99.5, 114.3, 117.5, 120.2,
120.6, 121.9, 122.3, 126.4, 129.4, 129.9, 132.9, 137.0, 144.4, 156.8,
157.5, 158.5, 160.3, 192.7.
Red solid; yield: 0.25 g (86%); mp 199–201 °C.
HRMS (ES–): m/z [M – H]– calcd for C24H1579Br35ClO4: 480.9842; found:
480.9843.
IR (ATR): 820, 1030, 1224, 1249, 1423, 1501, 1511, 1567, 1606, 1633
cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.85 (3 H, s, OCH3), 3.87 (3 H, s,
OCH3), 6.83 (1 H, s, H-3), 6.95 (4 H, d, J = 8.8 Hz, H-3′,5′ and H-3′′,5′′),
7.52 (1 H, d, Jtrans = 15.3 Hz, -H), 7.63 (2 H, d, J = 8.8 Hz, H-2′′,6′′), 7.75
(2 H, d, J = 8.8 Hz, H-2′,6′), 7.91 (1 H, d, Jtrans = 15.3 Hz, -H), 8.00 (1 H,
s, H-4).
13C NMR (75 MHz, DMSO-d6):  = 55.4, 55.5, 93.0, 99.6, 114.3, 114.5,
117.2, 117.7, 120.5, 122.1, 126.4, 127.2, 130.7, 133.2, 145.8, 156.6,
157.3., 158.5, 160.3, 162.1, 192.9.
(E)-1-(7-Bromo-6-hydroxy-2-phenylbenzofuran-5-yl)-3-(4-me-
thoxyphenyl)prop-2-en-1-one (8o)
Orange solid; yield: 0.24 g (88%); mp 187–189 °C.
IR (ATR): 826, 1025, 1141, 1172, 1223, 1421, 1510, 1560, 1603, 1632
cm–1
.
1H NMR (300 MHz, DMSO-d6):  = 3.84 (3 H, s, OCH3), 7.05 (2 H, d,
J = 8.8 Hz, H-3′′ and H-5′′), 7.41–7.55 (4 H, m, H-3, H-4′ and H-3′,5′),
7.88–7.95 (5 H, m, -H, H-2′,6′ and H-2′′,6′′), 8.05 (1 H, d, Jtrans = 15.4
Hz, -H), 8.74 (1 H, s, H-4).
HRMS (ES–): m/z [M – H]– calcd for C25H1879BrO5: 477.0338; found:
477.0353.
13C NMR (75 MHz, DMSO-d6):  = 55.9, 92.3, 103.2, 114.9, 118.3,
118.5, 122.1, 123.8, 125.1, 127.5, 129.2, 129.5, 129.6, 132.0, 146.5,
156.3, 156.6, 158.6, 162.4, 193.8.
HRMS (ES–): m/z [M – H]– calcd for C24H1679BrO4: 447.0232; found:
447.0252.
Furanoflavanones 9a–r; 9-Bromo-6,7-dihydro-2,7-diphenylfu-
ro[3,2-g]chromen-5-one (9a); Typical Procedure
A stirred solution of furanochalcone 8a (0.20 g, 0.48 mmol) in EtOH
(10 mL) was treated with concd H2SO4 (2 mL). The mixture was re-
fluxed for 4 h and then poured into ice-cold H2O. The precipitate was
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

I
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
filtered and then purified by column chromatography on silica gel us-
ing 9:1 toluene/EtOAc (v/v) as an eluent to afford 9a as a cream solid;
yield: 0.10 g (50%); mp 213–214 °C.
1H NMR (300 MHz, CDCl3):  = 3.04 (1 H, dd, J = 3.9, 17.0 Hz, 6-Ha),
3.14 (1,H, dd, J = 11.6, 17.0 Hz, 6-Hb), 3.87 (3 H, s, OCH3), 5.63 (1 H, dd,
J = 3.9, 11.6 Hz, H-7), 6.90 (1 H, s, H-3), 6.99 (2 H, d, J = 8.9 Hz, H-3′,5′),
7.39–7.48 (3 H, m, C6H5), 7.54–7.57 (2 H, m, C6H5), 7.80 (2 H, d, J = 8.9
Hz, H-2′,6′), 8.07 (1 H, s, H-4).
13C NMR (75 MHz, CDCl3):  = 44.1, 55.4, 79.9, 93.2, 100.1, 114.3,
118.0, 119.0, 122.1, 124.8, 125.9, 126.6, 128.6, 128.8, 138.5, 155.6,
156.9, 157.9, 160.5, 191.3.
IR (ATR): 753, 881, 1006, 1160, 1185, 1276, 1354, 1414, 1469, 1494,
1571, 1616, 1683 cm–1
.
1H NMR (500 MHz, CDCl3):  = 3.06 (1 H, dd, J = 3.4, 16.9 Hz, 6-Ha),
3.15 (1 H, dd, J = 12.1, 16.9 Hz, 6-Hb), 5.65 (1 H, dd, J = 3.4, 12.1 Hz, H-
7), 7.07 (1 H, s, H-3), 7.40 (2 H, t, J = 7.2 Hz, ArH), 7.44–7.52 (4 H, m,
ArH), 7.56 (2 H, d, J = 7.2 Hz, ArH), 7.88 (2 H, d, J = 7.2 Hz, ArH), 8.13 (1
H, s, H-4).
HRMS (ES+): m/z [M + H]+ calcd for C24H1879BrO4: 449.0388; found:
449.0397.
13C NMR (125 MHz, CDCl3):  = 44.1, 80.0, 93.4, 101.9, 118.5, 119.1,
124.5, 125.0, 125.9, 128.6, 128.8, 128.9, 129.2, 129.3, 138.4, 155.9,
157.0, 157.8, 191.2.
9-Bromo-7-(3-fluorophenyl)-6,7-dihydro-2-phenylfuro[3,2-
g]chromen-5-one (9e)
HRMS (ES+): m/z [M + H]+ calcd for C23H1679BrO3: 419.0283; found:
Brown solid; yield: 0.11 g (55%); mp 177–179 °C.
419.0285.
IR (ATR): 759, 782, 1147, 1184, 1229, 1280, 1333, 1413, 1444, 1469,
1491, 1568, 1592, 1616, 1684 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.04 (1 H, dd, J = 4.5, 16.8 Hz, 6-Ha),
3.11 (1 H, dd, J = 11.0, 16.8 Hz, 6-Hb), 5.63 (1 H, dd, J = 4.5, 11.0 Hz, H-
7), 7.06–7.12 (2 H, m, H-3 and H-4′′), 7.28–7.50 (6 H, m, ArH), 7.83–
7.88 (2 H, m, ArH), 8.11 (1 H, s, H-4).
9-Bromo-2-(3-fluorophenyl)-6,7-dihydro-7-phenylfuro[3,2-
g]chromen-5-one (9b)
Yellow solid; yield: 0.12 g (60%); mp 220–222 °C.
IR (ATR): 691, 752, 776, 839, 1161, 1192, 1269, 1282, 1336, 1413,
1474, 1575, 1617, 1681 cm–1
.
13C NMR (75 MHz, CDCl3):  = 44.0, 79.1, 93.4, 101.8, 113.1 (d,
2
2JC,F = 22.9 Hz), 115.6 (d, JC,F = 21.1 Hz), 118.5, 119.0, 121.4 (d,
1H NMR (500 MHz, CDCl3):  = 3.07 (1 H, dd, J = 3.4, 16.9, Hz, 6-Ha),
3.15 (1 H, dd, J = 12.1, 16.9 Hz, 6-Hb), 5.65 (1 H, dd, J = 3.4, 12.1 Hz, H-
7), 7.06–7.12 (2 H, m, H-3 and H-4′), 7.40–7.48 (4 H, m, ArH), 7.56 (3
H, d, J = 7.7 Hz, C6H5), 7.64 (1 H, d, J = 7.7 Hz, C6H5), 8.13 (1H, s, H-4).
4JC,F = 3.0 Hz), 124.7, 125.0, 128.9, 129.2, 129.3, 130.5 (d, 3JC,F = 8.2 Hz),
3
1
140.9 (d, JC,F = 7.9 Hz), 155.5, 157.0, 157.9, 163.0 (d, JC,F = 247.0 Hz),
190.7.
HRMS (ES+): m/z [M + H]+ calcd for C23H1579BrFO3: 437.0189; found:
437.0195.
13C NMR (125 MHz, CDCl3):  = 44.1, 80.0, 93.4, 103.0, 111.9 (d,
2
2JC,F = 23.8 Hz), 116.1 (d, JC,F = 21.4 Hz), 118.8, 119.3, 120.7 (d,
4JC,F = 3.1 Hz), 124.2, 125.9, 128.7, 128.9, 130.6 (d, 3JC,F = 8.4 Hz), 131.3
(d, 3JC,F = 8.4 Hz), 138.3, 156.1, 156.3 (d, 4JC,F = 3.1 Hz), 157.0, 163.1 (d,
1JC,F = 247.0 Hz), 191.1.
9-Bromo-2,7-bis(3-fluorophenyl)-6,7-dihydrofuro[3,2-
g]chromen-5-one (9f)
HRMS (ES+): m/z [M + H]+ calcd for C23H1579BrFO3: 437.0189; found:
Yellow solid; yield: 0.10 g (50%); mp 208–210 °C.
437.0193.
IR (ATR): 684, 770, 875, 1169, 1191, 1280, 1336, 1415, 1448, 1487,
1580, 1593, 1618, 1685 cm–1
.
1H NMR (500 MHz, CDCl3):  = 3.07 (1 H, dd, J = 4.3, 16.4 Hz, 6-Ha),
3.12 (1 H, dd, J = 10.7, 16.4 Hz, 6-Hb), 5.64 (1 H, dd, J = 4.3, 10.7 Hz, H-
7), 7.06–7.12 (3 H, m, H-3, H-4′ and H-4′′), 7.31 (2 H, t, J = 8.3 Hz, H-
6′), 7.41–7.46 (2 H, m, H-3′ and H-3′′), 7.56 (1 H, d, J = 8.0 Hz, ArH),
7.65 (1 H, d, J = 8.8 Hz, ArH), 8.13 (1 H, s, H-4).
9-Bromo-2-(4-fluorophenyl)-6,7-dihydro-7-phenylfuro[3,2-
g]chromen-5-one (9c)
Pale yellow solid; yield: 0.11 g (55%); mp 251–254 °C.
IR (ATR): 751, 820, 1159, 1181, 1232, 1282, 1340, 1377, 1408, 1419,
1473, 1506, 1615, 1683 cm–1
.
13C NMR (125 MHz, CDCl3):  = 44.0, 79.2 (d, 4JC,F = 1.9 Hz), 93.5, 102.9,
1H NMR (300 MHz, CDCl3):  = 3.05 (1 H, dd, J = 3.9, 17.0 Hz, 6-Ha),
3.15 (1 H, dd, J = 11.6, 17.0 Hz, 6-Hb), 5.65 (1 H, dd, J = 3.9, 11.6 Hz, H-
7), 7.00 (1 H, s, H-3), 7.16 (2 H, t, J = 8.8 Hz, H-3′,5′), 7.39–7.50 (3 H, m,
C6H5), 7.53–7.58 (2 H, m, C6H5), 7.85 (2 H, t, J = 8.8 Hz, H-2′,6′), 8.11 (1
H, s, H-4).
2
2
2
112.0 (d, JC,F = 23.8 Hz), 113.1 (d, JC,F = 22.8 Hz), 115.6 (d, JC,F = 21.2
2
4
Hz), 116.1 (d, JC,F = 21.4 Hz), 118.8, 119.2, 120.7 (d, JC,F = 3.1 Hz),
4
3
121.4 (d, JC,F = 3.1 Hz), 124.4, 130.5 (d, JC,F = 8.2 Hz), 130.6 (d,
3JC,F = 8.3 Hz), 131.2 (d, JC,F = 8.5 Hz), 140.8 (d, JC,F = 7.3 Hz), 155.8,
3
3
4
1
156.5 (d, JC,F = 3.1 Hz), 157.0, 163.0 (d, JC,F = 247.0 Hz), 163.1 (d,
13C NMR (75 MHz, CDCl3):  = 44.1, 80.0, 93.4, 101.6, 116.1 (d,
1JC,F = 246.4 Hz), 190.6.
4
2JC,F = 22.1 Hz), 118.5, 119.1, 124.4, 125.6 (d, JC,F = 3.7 Hz), 125.9,
HRMS (ES–): m/z [M – H]– calcd for C23H1279BrF2O3: 452.9938; found
452.9920.
3
1
127.0 (d, JC,F = 8.4 Hz), 128.7, 128.9, 138.3, 154.4 (d, JC,F = 244.2 Hz),
155.9, 156.8, 164.9, 191.2.
HRMS (ES+): m/z [M + H]+ calcd for C23H1579BrFO3: 437.0189; found:
437.0191.
9-Bromo-7-(3-fluorophenyl)-2-(4-fluorophenyl)-6,7-dihydrofu-
ro[3,2-g]chromen-5-one (9g)
Pale yellow solid; yield: 0.11 g (55%); mp 252–254 °C.
9-Bromo-6,7-dihydro-2-(4-methoxyphenyl)-7-phenylfuro[3,2-
IR (ATR): 781, 820, 868, 1147, 1158, 1182, 1229, 1280,1342, 1419,
g]chromen-5-one (9d)
1506, 1596, 1615, 1685 cm–1
.
Yellow solid; yield: 0.12 g (60%); mp 227–230 °C.
1H NMR (500 MHz, CDCl3):  = 3.06 (1 H, dd, J = 4.5, 16.8 Hz, 6-Ha),
3.11 (1 H, dd, J = 10.9, 16.8 Hz, 6-Hb), 5.63 (1 H, dd, J = 4.5, 10.9 Hz, H-
7), 7.00 (1 H, s, H-3), 7.09 (1 H, t, J = 8.7 Hz, H-4′′), 7.17 (2 H, t, J = 8.6
IR (ATR): 752, 827, 1002, 1015, 1151, 1181, 1250, 1339, 1412, 1452,
1470, 1506, 1612, 1678 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

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M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
Hz, H-3′,5′), 7.31 (2 H, t, J = 8.7 Hz, H-2′′ and H-3′′), 7.42 (1 H, dd,
J = 8.0, 13.8 Hz, H-6′′), 7.85 (2 H, t, J = 8.6 Hz, H-2′,6′), 8.11 (1 H, s, H-
4).
13C NMR (125 MHz, CDCl3):  = 44.0, 79.4, 93.4, 101.6, 115.8 (d,
2
2JC,F = 21.7 Hz), 116.1 (d, JC,F = 22.1 Hz), 118.5, 119.1, 124.6, 125.6 (d,
4JC,F = 3.5 Hz), 127.0 (d, 3JC,F = 8.3 Hz), 127.8 (d, 3JC,F = 8.3 Hz), 134.2 (d,
1
4JC,F = 3.3 Hz), 155.7, 156.9, 157.0, 163.3 (d, JC,F = 250.3 Hz), 164.8 (d,
4
13C NMR (125 MHz, CDCl3):  = 44.0, 79.1 (d, JC,F = 1.8 Hz), 93.4,
1JC,F = 255.6 Hz), 190.9.
2
2
101.53, 101.54, 113.1 (d, JC,F = 22.9 Hz), 115.6 (d, JC,F = 21.1 Hz),
116.1 (d, JC,F = 22.1 Hz), 118.5, 119.1, 121.3 (d, JC,F = 3.0 Hz), 124.6,
HRMS (ES+): m/z [M + H]+ calcd for C23H1479BrF2O3: 455.0094; found:
455.0078.
2
4
125.6 (d, 4JC,F = 3.3 Hz), 127.0 (d, 3JC,F = 8.3 Hz), 130.5 (d, 3JC,F = 8.2 Hz),
3
1
140.9 (d, JC,F = 7.2 Hz), 155.6, 157.0, 163.0 (d, JC,F = 247.0 Hz), 163.3
(d, 1JC,F = 250.2 Hz), 190.6.
9-Bromo-7-(4-fluorophenyl)-6,7-dihydro-2-(4-methoxyphe-
nyl)furo[3,2-g]chromen-5-one (9k)
HRMS (ES–): m/z [M – H]– calcd for C23H1279BrF2O3: 452.9938; found:
452.9930.
Yellow solid; yield: 0.12 g (60%); mp 254–256 °C.
IR (ATR): 827, 1016, 1151, 1183, 1225, 1260, 1341, 1412, 1473, 1506,
1611, 1679 cm–1
.
9-Bromo-7-(4-fluorophenyl)-6,7-dihydro-2-phenylfuro[3,2-
g]chromen-5-one (9h)
1H NMR (300 MHz, CDCl3):  = 3.03 (1 H, dd, J = 4.0, 16.9 Hz, 6-Ha),
3.12 (1 H, dd, J = 11.4, 16.9 Hz, 6-Hb), 3.88 (3 H, s, OCH3), 5.61 (1 H, dd,
J = 4.0, 11.4 Hz, H-7), 6.91 (1 H, s, H-3), 6.99 (2 H, d, J = 8.7 Hz, H-3′,5′),
7.15 (2 H, t, J = 8.7 Hz, H-3′′,5′′), 7.54 (2 H, t, J = 8.7 Hz, H-2′,6′), 7.80 (2
H, d, J = 8.9 Hz, H-2′′,6′′), 8.08 (1 H, s, H-4).
Cream solid; yield: 0.12 g (60%); mp 230–232 °C.
IR (ATR): 761, 883, 1152, 1226, 1274, 1283, 1338, 1415, 1471, 1513,
1569, 1616, 1682 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.03 (1 H, dd, J = 4.0, 16.9 Hz, 6-Ha),
3.13 (1 H, dd, J = 11.5, 16.9 Hz, 6-Hb), 5.62 (1 H, dd, J = 4.0, 11.5 Hz, H-
7), 7.07 (1 H, s, H-3), 7.15 (2 H, t, J = 8.6 Hz, H-3′′,5′′), 7.38–7.56 (5 H,
m, ArH), 7.87 (2 H, dt, J = 2.4, 8.6 Hz, H-2′′,6′′), 8.12 (1 H, s, H-4).
13C NMR (75 MHz, CDCl3):  = 44.1, 55.4, 79.3, 93.2, 100.0, 114.4,
2
115.8 (d, JC,F = 21.9 Hz), 118.0, 118.9, 122.0, 124.9, 126.6, 127.8 (d,
4
3JC,F = 8.5 Hz), 129.0, 134.3 (d, JC,F = 3.4 Hz), 155.4, 158.1, 158.7 (d,
1JC,F = 271.3 Hz), 164.4, 191.0.
13C NMR (75 MHz, CDCl3):  = 44.1, 79.4, 93.3, 101.8, 115.8 (d,
2JC,F = 21.6 Hz), 118.5, 119.0, 124.6, 125.0, 127.8 (d, JC,F = 8.2 Hz),
HRMS (ES–): m/z [M – H]– calcd for C24H1579BrFO4: 465.0134; found:
465.0134.
3
128.9, 129.2, 129.3, 134.2 (d, 4JC,F = 2.9 Hz), 155.7, 157.0, 157.8, 162.8
(d, 1JC,F = 247.6 Hz), 191.0.
HRMS (ES+): m/z [M + H]+ calcd for C23H1579BrFO3: 437.0189; found:
9-Bromo-7-(4-chlorophenyl)-6,7-dihydro-2-phenylfuro[3,2-
g]chromen-5-one (9l)
437.0191.
Cream solid; yield: 0.10 g (50%); mp 201–203 °C.
9-Bromo-2-(3-fluorophenyl)-7-(4-fluorophenyl)-6,7-dihydrofu-
ro[3,2-g]chromen-5-one (9i)
IR (ATR): 759, 838, 907, 1014, 1149, 1272, 1339, 1414, 1469, 1492,
1571, 1617, 1682 cm–1
.
Yellow solid; yield: 0.10 g (50%); mp 225–227 °C.
1H NMR (300 MHz, CDCl3):  = 3.02 (1 H, dd, J = 4.4, 16.9 Hz, 6-Ha),
3.10 (1 H, dd, J = 11.0, 16.9 Hz, 6-Hb), 5.61 (1 H, dd, J = 4.4, 11.0 Hz, H-
7), 7.06 (1 H, s, H-3), 7.37–7.53 (7 H, m, ArH), 7.82–7.93 (2 H, m, ArH),
8.09 (1 H, s, H-4).
13C NMR (75 MHz, CDCl3):  = 44.0, 79.2, 93.4, 101.8, 118.5, 119.0,
124.6, 125.0, 127.3, 128.9, 129.1, 129.2, 129.3, 134.5, 136.9, 155.6,
157.0, 157.9, 190.8.
IR (ATR): 779, 832, 1162, 1191, 1225, 1285, 1339, 1415, 1486, 1513,
1598, 1619, 1684 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.03 (1 H, dd, J = 4.0, 16.9 Hz, 6-Ha),
3.13 (1 H, dd, J = 11.4, 16.9 Hz, 6-Hb), 5.62 (1 H, dd, J = 4.0, 11.4 Hz, H-
7), 7.05–7.10 (2 H, m, H-3 and H-4′), 7.14 (2 H, t, J = 8.5 Hz, H-3′′,5′′),
7.43 (1 H, dd, JH,H = 8.0 Hz, JH,F = 5.8 Hz, H-6′), 7.51–7.58 (3 H, m, H-3′
and H-2′′,6′′), 7.64 (1 H, d, J = 8.0 Hz, H-2′), 8.13 (1 H, s, H-4).
HRMS (ES+): m/z [M + H]+ calcd for C23H1579Br35ClO3: 452.9893; found:
452.9886.
13C NMR (75 MHz, CDCl3):  = 44.0, 79.4, 93.4, 102.9, 111.9 (d,
2
2
2JC,F = 23.8 Hz), 115.8 (d, JC,F = 21.7 Hz), 116.1 (d, JC,F = 20.8 Hz),
4
3
118.8, 119.2, 120.7 (d, JC,F = 3.0 Hz), 124.3, 127.8 (d, JC,F = 8.4 Hz),
9-Bromo-7-(4-chlorophenyl)-2-(4-fluorophenyl)-6,7-dihydrofu-
ro[3,2-g]chromen-5-one (9m)
130.6 (d, 3JC,F = 8.3 Hz), 131.3 (d, 3JC,F = 8.6 Hz), 134.1 (d, 4JC,F = 3.3 Hz),
4
1
155.9, 156.4 (d, JC,F = 3.4 Hz), 157.0, 162.8 (d, JC,F = 247.9 Hz), 163.1
(d, 1JC,F = 246.5 Hz), 190.9.
Cream solid; yield: 0.10 g (50%); mp 260–262 °C.
IR (ATR): 821, 836, 1158, 1227, 1276, 1342, 1412, 1473, 1505, 1602,
HRMS (ES–): m/z [M – H]– calcd for C23H1279BrF2O3: 452.9938; found:
452.9918.
1620, 1683 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.03 (1 H, dd, J = 4.3, 16.7 Hz, 6-Ha),
3.11 (1 H, dd, J = 10.9, 16.7 Hz, 6-Hb), 5.62 (1 H, dd, J = 4.3, 10.9 Hz, H-
7), 7.00 (1 H, s, H-3), 7.17 (2 H, t, J = 8.8 Hz, H-3′,5′), 7.43 (2 H, d, J = 8.7
Hz, H-3′′,5′′), 7.50 (2 H, d, J = 8.7 Hz, H-2′′,6′′), 7.85 (2 H, dd, JH,H = 8.8
Hz, JH,F = 5.2 Hz, H-2′,6′), 8.11 (1 H, s, H-4).
9-Bromo-2,7-bis(4-fluorophenyl)-6,7-dihydrofuro[3,2-
g]chromen-5-one (9j)
Orange solid; yield: 0.14 g (70%); mp 275–277 °C.
IR (ATR): 823, 1156, 1224, 1278, 1360, 1420, 1474, 1505, 1620, 1684
13C NMR (125 MHz, CDCl3):  = 43.9, 79.3, 93.4, 101.5, 116.1 (d,
cm–1
.
4
2JC,F = 22.1 Hz), 118.5, 119.1, 124.6, 125.6 (d, JC,F = 3.4 Hz), 127.0 (d,
1H NMR (500 MHz, CDCl3):  = 3.05 (1 H, dd, J = 3.5, 16.9 Hz, 6-Ha),
3.13 (1 H, dd, J = 12.0, 16.9 Hz, 6-Hb), 5.63 (1 H, dd, J = 3.5, 12.0 Hz, H-
7), 7.01 (1 H, s, H-3), 7.15 (2 H, t, J = 8.7 Hz, H-3′,5′), 7.18 (2 H, t, J = 8.7
Hz, H-3′′,5′′), 7.54 (2 H, dd, JH,H = 8.7 Hz, JH,F = 5.3 Hz, H-2′′,6′′), 7.86 (2
H, dd, JH,H = 8.7 Hz, JH,F = 5.3 Hz, H-2′,6′), 8.13 (1 H, s, H-4).
3JC,F = 8.4 Hz), 127.3, 129.1, 134.6, 136.8, 155.6, 156.97, 157.98, 163.3
(d, 1JC,F = 250.3 Hz), 190.7.
HRMS (ES+): m/z [M + H]+ calcd for C23H1479Br35ClFO3: 470.9799;
found: 470.9821.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

K
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
9-Bromo-7-(4-chlorophenyl)-6,7-dihydro-2-(4-methoxyphe-
nyl)furo[3,2-g]chromen-5-one (9n)
1H NMR (300 MHz, CDCl3):  = 3.01 (1 H, dd, J = 3.5, 16.9 Hz, 6-Ha),
3.15 (1 H, dd, J = 11.9, 16.9 Hz, 6-Hb), 3.84 (3 H, s, OCH3), 5.58 (1 H, dd,
J = 3.5, 11.9 Hz, H-7), 6.95–6.99 (3 H, m, H-3 and H-3′′,5′′), 7.15 (2 H, t,
J = 8.8 Hz, H-3′,5′), 7.47 (2 H, d, J = 8.4 Hz, H-2′′,6′′), 7.83 (2 H, t,
JH,H = 8.8 Hz, JH,F = 5.3 Hz, H-2′,6′), 8.09 (1 H, s, H-4).
Yellow solid; yield: 0.12 g (60%); mp 236–238 °C.
IR (ATR): 822, 1016, 1151, 1183, 1259, 1339, 1412, 1443, 1472, 1506,
1616, 1678 cm–1
.
13C NMR (75 MHz, CDCl3):  = 43.8, 55.3, 79.8, 93.3, 101.5, 114.2,
1H NMR (300 MHz, CDCl3):  = 3.02 (1 H, dd, J = 4.3, 16.8 Hz, 6-Ha),
3.10 (1 H, dd, J = 11.0, 16.8 Hz, 6-Hb), 3.87 (3 H, s, OCH3), 5.62 (1 H, dd,
J = 4.3, 11.0 Hz, H-7), 6.91 (1 H, s, H-3), 6.99 (2 H, d, J = 8.9 Hz, H-3′,5′),
7.43 (2 H, d, J = 8.6 Hz, H-3′′,5′′), 7.50 (2 H, d, J = 8.6 Hz, H-2′′,6′′), 7.80
(2 H, d, J = 8.9 Hz, H-2′,6′), 8.06 (1 H, s, H-4).
13C NMR (75 MHz, CDCl3):  = 44.0, 55.4, 79.2, 93.2, 100.0, 114.4,
118.0, 118.9, 122.0, 125.0, 126.6, 127.3, 129.1, 134.5, 137.0, 155.3,
156.9, 158.0, 160.5, 190.8.
2
4
116.1 (d, JC,F = 22.2 Hz), 118.4, 119.1, 124.3, 125.6 (d, JC,F = 3.4 Hz),
126.9 (d, 3JC,F = 8.5 Hz), 127.5, 130.3, 156.0, 156.7, 156.9, 159.8, 163.2
(d, 1JC,F = 249.9 Hz), 191.5.
HRMS (ES–): m/z [M – H]– calcd for C24H1579BrFO4: 465.0138; found:
465.0134.
9-Bromo-6,7-dihydro-2,7-bis(4-methoxyphenyl)furo[3,2-
g]chromen-5-one (9r)
HRMS (ES+): m/z [M + H]+ calcd for C24H1779Br35ClO4: 482.9999; found:
482.9995.
Orange solid; yield: 0.12 g (60%); mp 175–178 °C.
IR (ATR): 794, 829, 1030, 1151, 1177, 1252, 1338, 1413, 1471, 1507,
1616, 1686 cm–1
.
9-Bromo-6,7-dihydro-7-(4-methoxyphenyl)-2-phenylfuro[3,2-
g]chromen-5-one (9o)
1H NMR (300 MHz, CDCl3):  = 3.01 (1 H, dd, J = 3.4, 16.9 Hz, 6-Ha),
3.15 (1 H, dd, J = 12.0, 16.9 Hz, 6-Hb), 3.84 (3 H, s, OCH3), 3.87 (3 H, s,
OCH3), 5.58 (1 H, dd, J = 3.4, 12.0 Hz, H-7), 6.91 (1 H, s, H-3), 6.97 (2 H,
d, J = 8.7 Hz, H-3′′,5′′), 6.99 (2 H, d, J = 8.7 Hz, H-3′,5′), 7.47 (2 H, d,
J = 8.7 Hz, H-2′′,6′′), 7.80 (2 H, d, J = 8.7 Hz, H-2′,6′), 8.07 (1 H, s, H-4).
13C NMR (75 MHz, CDCl3):  = 43.9, 55.3, 55.4, 79.7, 93.2, 100.1, 114.2,
114.3, 118.0, 119.0, 122.1, 124.7, 126.6, 127.5, 130.5, 155.7, 156.9,
157.8, 159.8, 160.4, 191.6.
Orange solid; yield: 0.11 g (55%); mp 177–179 °C.
IR (ATR): 742, 759, 827, 1030, 1150, 1181, 1253, 1339, 1414, 1470,
1516, 1618, 1682 cm–1
.
1H NMR (300 MHz, CDCl3):  = 3.02 (1 H, dd, J = 3.4, 16.9 Hz, 6-Ha),
3.15 (1 H, dd, J = 11.9, 16.9 Hz, 6-Hb), 3.84 (3 H, s, OCH3), 5.58 (1 H, dd,
J = 3.4, 11.9 Hz, H-7), 6.97 (2 H, d, J = 8.0 Hz, H-3′′,5′′), 7.05 (1 H, s, H-
3), 7.35–7.50 (5 H, m, ArH), 7.86 (2 H, d, J = 8.0 Hz, H-2′′,6′′), 8.10 (1 H,
s, H-4).
13C NMR (75 MHz, CDCl3):  = 43.9, 55.3, 79.8, 93.3, 101.9, 114.2,
118.5, 119.1, 124.4, 125.0, 127.5, 128.9, 129.2, 129.3, 130.4, 155.9,
157.0, 157.7, 159.9, 191.5.
HRMS (ES+): m/z [M + H]+ calcd for C25H2079BrO5: 479.0494; found:
479.0502.
Funding Information
HRMS (ES+): m/z [M + H]+ calcd for C24H1879BrO4: 449.0388; found:
449.0383.
The authors thank the University of South Africa and the National Re-
search Foundation (NRF) in South Africa (NRF GUN: 118554) for fi-
nancial support.()
9-Bromo-2-(3-fluorophenyl)-6,7-dihydro-7-(4-methoxyphe-
nyl)furo[3,2-g]chromen-5-one (9p)
Orange solid; yield: 0.12 g (60%); mp 192–194 °C.
Acknowledgment
IR (ATR): 784, 821, 834, 883, 929, 1031, 1171, 1252, 1414, 1464, 1484,
1513, 1615, 1683 cm–1
.
We are grateful to the University of Stellenbosch Central Analytical
Facility and the University of the Witwatersrand for mass spectro-
metric analysis and X-ray data, respectively.
1H NMR (300 MHz, CDCl3):  = 3.03 (1 H, dd, J = 3.5, 16.9 Hz, 6-Ha),
3.16 (1 H, dd, J = 11.8, 16.9 Hz, 6-Hb), 3.84 (3 H, s, OCH3), 5.59 (1 H, dd,
J = 3.5, 11.8 Hz, H-7), 6.97 (2 H, d, J = 8.6 Hz, H-3′′,5′′), 7.05–7.15 (2 H,
m, H-3 and H-4′), 7.43 (1 H, dd, J = 2.2, 7.9 Hz, H-6′), 7.47 (2 H, d,
J = 8.6 Hz, H-2′′,6′′), 7.55 (1 H, dd, J = 2.2, 7.9 Hz, H-2′), 7.62–7.65 (1 H,
d, J = 8.6 Hz, H-3′), 8.12 (1 H, s, H-4).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690001.
13C NMR (75 MHz, CDCl3):  = 43.8, 55.3, 79.8, 93.4, 103.0, 111.9 (d,
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
2
2JC,F = 23.7 Hz), 114.2, 116.0 (d, JC,F = 21.3 Hz), 118.8, 119.3, 120.7 (d,
4JC,F = 3.0 Hz), 124.1, 127.5, 130.3, 130.6 (d, 3JC,F = 8.4 Hz), 130.7, 131.3
(d, 3JC,F = 8.6 Hz), 156.2, 157.0, 159.9, 163.1 (d, 1JC,F = 246.1 Hz), 191.4.
References
HRMS (ES+): m/z [M + H]+ calcd for C24H1779BrFO4: 467.0294; found:
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9-Bromo-2-(4-fluorophenyl)-6,7-dihydro-7-(4-methoxyphe-
nyl)furo[3,2-g]chromen-5-one (9q)
Yellow solid; yield: 0.12 g (60%); mp 216–218 °C.
IR (ATR): 813, 831, 1032, 1154, 1176, 1222, 1254, 1335, 1468, 1504,
1516, 1614, 1684 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

L
M. J. Mphahlele, T. O. Olomola
Paper
Synthesis
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L