Synthesis of 8-carbo substituted 2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones and their thienoangelicin derivatives

Article abstract of DOI:10.1016/j.jfluchem.2019.109395

Tandem Sonogashira cross-coupling and heteroannulation of 7-hydroxy-8-iodo-2-(trifluoromethyl)chromen-4-one with terminal acetylenes afforded the 8-carbo–substituted 2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones 2a–i. The latter were reacted with methyl mercaptoacetate in the presence of triethylamine to afford the corresponding 7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one derivatives 3a–i. The structures of the prepared compounds were characterized using a combination of NMR (¹H-, ¹³C & ¹⁹F-), IR and mass spectroscopic techniques, and confirmed by single X-ray crystal structures of 8-(3-fluorophenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2b) and 2-phenyl-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one (3a). The highlight of this investigation is the conversion of 2-(trifluoromethyl)–substituted 4H-furo[2,3-h]chromen-4-ones into trifluoromethyl–substituted thienoangelicin analogues.

Full text of DOI:10.1016/j.jfluchem.2019.109395

Journal Pre-proof
Synthesis of 8-carbo substituted
2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones and their
thienoangelicin derivatives
Temitope O. Olomola, Malose J. Mphahlele
PII:
S0022-1139(19)30336-7
DOI:
https://doi.org/10.1016/j.jfluchem.2019.109395
FLUOR 109395
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Journal of Fluorine Chemistry
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Revised Date:
Accepted Date:
25 September 2019
9 October 2019
10 October 2019
Please cite this article as: Olomola TO, Mphahlele MJ, Synthesis of 8-carbo substituted
2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones and their thienoangelicin derivatives,
Journal of Fluorine Chemistry (2019), doi: https://doi.org/10.1016/j.jfluchem.2019.109395
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Synthesis of 8-carbo substituted 2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones and
their thienoangelicin derivatives
Temitope O. Olomola# and Malose J. Mphahlele* mphahmj@unisa.ac.za
Department of Chemistry, College of Science, Engineering and Technology, University of
South Africa, Private Bag X06, Florida 1710, South Africa
# On research leave from Obafemi Awolowo University, Ile-Ife, Osun state, Nigeria.
* Author for correspondence:
Highlights:
 Tandem
alkynylation-cycloisomerization
of
7-hydroxy-8-iodo-2-
(trifluoromethyl)chromen-4-one afforded the 2-(trifluoromethyl)furochromen-4-ones.
 Redox reaction of the 2-(trifluoromethyl)furochromen-4-ones with methyl
mercaptoacetate afforded dihydrothienocoumarin derivatives.
 The X-ray crystal structures of representative compounds from each series were
determined.
Graphical Abstract
Synthesis of 8-carbo substituted 2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones and their
thienoangelicin derivatives
1

Abstract
Tandem Sonogashira cross-coupling and heteroannulation of 7-hydroxy-8-iodo-2-
(trifluoromethyl)chromen-4-one with terminal acetylenes afforded the 8-carbo–substituted 2-
(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones 2a–i. The latter were reacted with methyl
mercaptoacetate in the presence of triethylamine to afford the corresponding 7,8-dihydro-5H-
furo[2,3-h]thieno[2,3-c]chromen-5-one derivatives 3a–i. The structures of the prepared
13
19
compounds were characterized using a combination of NMR (1H-, C & F-), IR and mass
spectroscopic techniques, and confirmed by single X-ray crystal structures of 8-(3-
fluorophenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2b) and 2-phenyl-7-
(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one (3a). The highlight
of this investigation is the conversion of 2-(trifluoromethyl)–substituted 4H-furo[2,3-
h]chromen-4-ones into trifluoromethyl–substituted thienoangelicin analogues.
Keywords:
chromen-4-ones;
Sonogashira
cross-coupling;
furochromen-4-ones;
dihydrothienoangelicins; thienoangelicins; X-ray crystal structures
1. Introduction
2

The naturally occurring khellin (A) and visnagin (B) shown in Figure 1 exhibit anti-
inflammatory properties [1] and these furo[3,2-c]chromones are used clinically for the
treatment of bronchial asthma and renal colics [2]. The analogous furocoumarins, on the other
hand, exhibit a wide range of biological properties including photochemotherapeutic [3,4],
antitumor [5], antioxidant [6] and anti-inflammatory [7] activities. Angelicin (D) [8] and
sphondin (E) [9] represented in Figure 1, for example, are angular furocoumarins with
therapeutic potential as anti-inflammatory drugs on airway inflammation. The propensity for
the pyrone and furan rings to undergo photocycloaddition reactions in the case of the linear
furocoumarins such as psoralen (C) and to a lesser extend angelicin derivatives has been
suggested to cause undesirable side effects in their medical use [10]. However, annulation of
an additional ring onto the photoreactive pyrone double bond has been found to generally
reduce the phototoxicity of the furocoumarin derivatives [11].
The two main approaches towards the synthesis of furocoumarins involve either
construction of the furan ring onto a suitably functionalized pyrone scaffold [12] or construction
of the six-membered heterocyclic ring onto an ortho-hydroxy carbonylbenzofuran framework
[13]. Among these strategies, the methodology of fusing a furan ring on a coumarin nucleus of
allyloxy- or propargyloxycoumarins [14], 7-(2-oxopropoxy)- or 7-(2-hydroxyethoxy)-2H-
chromen-2-ones [15], and ortho-hydroxy styrylcoumarins [16], for example, has been widely
applied for the synthesis of linear or angular furocoumarins and their difurocoumarin
derivatives. Tandem copper catalysed cross-coupling of 8-iodo-7-hydroxycoumarin with
terminal acetylenes has also been employed for the synthesis of angular furocoumarins [17,18].
Fluorinated organic compounds often show unique physical and chemical behaviour that
can be utilized in pharmaceutics and materials science. A trifluoromethyl group, for example,
is known to enhance lipid solubility and metabolic stability of a molecule, and to lead to reduced
side effects [19]. Moreover, the presence of this strongly electron-withdrawing group on the 2-
3

position of a chromen-4-one skeleton has been found to have a major impact on the reactivity
of the pyrone ring towards nitrogen-, sulfur- and carbon-based nucleophiles [20]. The reaction
of 2-(trifluoromethyl)chromen-4-one or 7-(trifluoromethyl)norkhellin with alkyl
mercaptoacetates, for example, has been found to promote 1,4-nucleophilic ring addition
instead of ring fission to afford trifluoromethyl–substituted dihydrothienocoumarins or
dihydrothienopsoralens, respectively [20-22]. We considered the molecular framework of the
readily accessible 7-hydroxy-8-iodo-2-(trifluoromethyl)chromen-4-one, which has recently
been shown to undergo palladium catalysed Suzuki cross-coupling with arylboronic acids to
afford the 8-carbo–substituted 7-hydroxy-2-(trifluoromethyl)chromen-4-ones [23]. We
envisaged that this ortho-iodohydroxychromenone derivative would undergo tandem palladium
catalysed Sonogashira cross-coupling and cycloisomerization with terminal acetylenes to afford
the 8-carbo–substituted 4H-furo[2,3-h]chromen-4-ones. In our view, the presence of the 2-
trifluoromethyl group on the resulting furochromenone framework would facilitate subsequent
1,4-nucleophilic ring addition reaction with methyl mercaptoacetate to afford novel
trifluoromethyl–substituted dihydrothienoangelicin analogues.
2. Results and Discussion
In order to proof the above assumptions, we synthesised 7-hydroxy-8-iodo-2-
(trifluoromethyl)chromen-4-one (1) from commercially available 2,4-dihydroxyacetophenone
following literature protocol [23,24]. This was achieved via initial condensation of 2,4-
dihydroxyacetophenone with trifluoroacetic anhydride in the presence pyridine (1.0 equivalent)
at 80 °C for 10 h [24]. Site-selective halogenation of the intermediate 7-hydroxy-2-
(trifluoromethyl)chromen-4-one with iodine in chloroform in the presence of pyridine afforded
4

1 in analogy with the literature precedent [23]. The proximity of the Csp2–I bond to the
nucleophilic hydroxyl group was exploited by subjecting compound 1 to terminal acetylenes in
the presence of dichlorobis(triphenylphosphine)palladium(II) and copper(I) iodide catalyst
mixture, triphenylphosphine as ligand and triethylamine as a base in dimethyl formamide under
reflux for 2 h (Scheme 1). Aqueous work-up and purification by column chromatography on
silica gel afforded in each case in sequence, a homocoupled dimer and a cross-coupled product.
A combination of nuclear magnetic resonance (NMR), infrared (IR) and mass spectroscopic
data confirmed the structures of the cross-coupled products as the 8-carbo–substituted 2-
(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones 2a–i (refer to Table 1 for substitution
pattern). The signal for the trifluoromethyl group resonates as a singlet around δ -71.3 ppm in
1
19F-NMR spectra of the corresponding substrates 2a–i. The H- and 13C-NMR spectra of
compounds 2a–h, for example, revealed the presence of increased number of signals in the
aromatic region. Likewise, the `1H-NMR spectrum of 2i revealed set of multiplets in the
aliphatic region 1.70–2.70 ppm corresponding to the cyclohexenyl ring. The absence of a set of
carbon singlets in the region δ 80–100 ppm of the 13C-NMR spectra of compounds 2a–i, which
are typical for the acetylene moiety ruled out the possibility of the intermediate 8-alkynylated
derivatives. Moreover, the accurate calculated m/z values of these products were consistent
with the assigned structures.
The strong electron-withdrawing property of the trifluoromethyl group (–CF3) has been
found to enhance the electrophilic character at cationic sites in superelectrophiles resulting in
greater positive-charge delocalisation [25]. Its presence on the C2 position of a chromen-4-one
scaffold causes activation of the pyrone ring towards sulfur-based nucleophiles to convert the
chromen-4-one scaffold into a chromen-2-one ring and at the same time append an additional
ring on the pyrone double bond [20-22]. These literature precedents encouraged us to subject
compounds 2a–i to methyl mercaptoacetate (3 equiv.) in the presence of triethylamine as
5

catalyst at 100 °C with thin layer chromatography (tlc) monitoring (Scheme 2). The reaction
was found to be complete within 2 h and the mixtures were in each case quenched with aqueous
ethanol followed by filtration of the precipitate and recrystallization. Characteristic signals in
the 1H-NMR spectra of these products recorded as CDCl3 or DMSO-d6 solutions at 300 MHz
are a set of doublet of doublets (dd) in the region δ 3.90–4.00 ppm integrating for two protons
and another multiplet around δ 5.10 ppm integrating for a single proton. The long range
coupling of the chemically non-equivalent (diastereotopic) methylene protons to fluorine atoms
(4JHF) was not observed and these protons resonate as a pair of doublet of doublets at this
frequency. The multiplet for the methine proton resonates significantly downfield due to the
combined electronegativity of sulphur and strong electron withdrawing inductive effect of the
19
trifluoromethyl group. Their F-NMR spectra confirmed the presence of an intense doublet
around δ -73.1 ppm with coupling constant value J = 8.9 Hz corresponding to the
trifluoromethyl group. The structures of these compounds were assigned based on combination
of NMR, IR and mass spectroscopic data as the 7,8-dihydro-5H-furo[2,3-h]thieno[2,3-
c]chromen-5-one (dihydrothienoangelicin) derivatives 3a–i.
Single crystals suitable for X-ray diffraction (XRD) analysis were obtained for compounds
2b and 3a, respectively, and the structures of the 8-carbo–substituted 2-(trifluoromethyl)-4H-
furo[2,3-h]chromen-4-ones 2a–i and 7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one
(dihydrothienoangelicin) derivatives 3a–i were thus distinctly confirmed by X-ray analysis
(Figure 2). The crystallographic numbering for both compounds has been used in the context
of the X-ray analysis, and differs with the systematic numbering for series 2a–i and 3a–i. The
furochromenone framework of 2b (Figure 2a) is essentially co-planar with the 3-fluorophenyl
substituent slightly twisted out of the plane of planarity with torsion angle C(2)-C(1)-C(7)-O(1)
of 10.1°. There is disorder of fluorine atom of the phenyl group with a site occupancy of
0.56:0.44. This positional disorder, which brings the position of fluorine atom at two sites, one
6

with a higher occupancy and the other with lower occupancy is known to be prevalent when
fluorine atom is present in an ortho or meta position with any given functional group in an
organic molecule [27,28]. The phenyl substituent of 3a, on the other hand, is coplanar with the
tetracyclic framework with torsion angle C(12)-C(13)-C(14)-C(19) of 1.6° (Figure 2b).
Disorder in both cases has not been observed for the trifluoromethyl (–CF3) group, which is
more prone to disorder [29]. Crystallographic parameters for compounds 2b and 3a are
summarized in Table 3 [26].
In summary, tandem Sonogashira cross-coupling and heteroannulation of 7-hydroxy-8-
iodo-2-(trifluoromethyl)chromen-4-one with terminal acetylenes afforded novel 8-carbo
substituted
2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-ones.
The
presence
of
trifluoromethyl group at the 2-position of the pyrone ring facilitated 1,4-nucleophilic ring
addition with methyl mercaptoacetate to afford series of trifluoromethyl–substituted
dihydrothienoangelicin analogues. These results represent the first synthesis of thienoangelicin
analogues and, more so angular furocoumarin derivatives substituted at position-2 of the furan
ring with a carbon-based group. The X-ray crystal structures of compounds 2b and 3a were
determined. The results of this study corroborate previous studies which indicated that the
fluorine atom tends to get disordered over different positions in the molecule, particularly when
this atom is present in an ortho or meta position with any given functional group in an organic
molecule. The trifluoromethyl substituted heterocycles prepared in this investigation represent
suitable candidates for further studies of chemical transformation and biological activity.
3. Experimental
3.1. General
7

The melting points (mp.) were recorded on a Thermocouple digital melting point apparatus
(Mettler Toledo LLC, Columbus, OH, USA). The infrared (IR) spectra were recorded as
powders using a Bruker VERTEX 70 FT-IR Spectrometer (Bruker Optics, Billerica, MA, USA)
with a diamond ATR (attenuated total reflectance) accessory by using the thin-film method.
Merck kieselgel 60 (0.063–0.200 mm) (Merck KGaA, Frankfurt, Germany) was employed as a
13
19
stationary phase for column chromatography. The NMR (1H-, C- and F-) spectra were
recorded using Varian Mercury 300 MHz NMR spectrometer (Varian Inc., Palo Alto, CA,
USA) and the chemical shifts are quoted relative to the solvent peaks. The low- and high-
resolution mass spectra were recorded at an ionization potential of 70 eV using Micromass
Autospec-TOF (double focusing high resolution) instrument (Waters Corp., Milford, MA,
USA).
3.2. Synthesis of 7-hydroxy-8-iodo-2-(trifluoromethyl)chromene-4-one (1).
3.2.1. 7-Hydroxy-2-(trifluoromethyl)chromen-4-one
A stirred solution of 2,4-dihydroxyacetophenone (5.00 g, 32.9 mmol) in trifluoroacetic
anhydride (10 mL) was treated with pyridine (2.60 g, 32.9 mmol) and the mixture was heated
at 80 °C for 4 h. The cooled reaction mixture was treated with 1 M hydrochloric acid (5 mL)
and the product was extracted with chloroform. The combined organic phases were washed
with water, dried over anhydrous MgSO4, and then concentrated in vacuo on a rotary
evaporator. The crude product was purified by column chromatography on using silica gel using
9:1 toluene-ethyl acetate mixture (v/v) as an eluent to afford 7-hydroxy-2-
(trifluoromethyl)chromen-4-one as a yellow solid (4.80 g, 63%), mp. 210–212 °C (Lit. [31]
208–210 ℃); νmax (ATR) 634, 724, 830, 847, 868, 925, 1074, 1132, 1164, 1191, 1230, 1250,
1278, 1395, 1557, 1660 cm-1 ; δH (300 MHz, DMSO-d6) 6.86 (1H, s, H-3), 6.91 (1H, d, J = 2.2
Hz, H-8), 6.98 (1H, dd, J = 2.2 and 8.8 Hz, H-6), 7.89 (1H, d, J = 8.8 Hz, H-5), 11.14 (1H, br
s, OH); δC (75 MHz, DMSO-d6) 102.9, 111.0 (q, 3JCF = 2.6 Hz), 116.5, 116.7, 119.1 (q, 1JCF =
8

2
273.8 Hz), 127.4, 150.6 (q, JCF = 38.3 Hz), 157.4, 164.3, 175.4; δF (282 MHz, DMSO-d6) -
70.5 (s, -CF3); HRMS (ES+): m/z [M – H]- calc for C10H4O3F3: 229.0113; found 229.0110.
3.2.2. 7-Hydroxy-8-iodo-2-(trifluoromethyl)chromen-4-one (1)
A stirred mixture of 7-hydroxy-2-(trifluoromethyl)chromen-4-one (2.00 g, 8.69 mmol) and
iodine (8.82 g, 34.8 mmol) in chloroform (30 mL) in a round-bottomed flask was treated with
pyridine (2.75 g, 34.8 mmol). The reaction mixture was stirred at room temerature 16 h and
then quenched with saturated aqueous solution of Na2S2O3 (60 mL). The resulting precipitate
was filtered and purified using silica gel column chromatography with 3:1 toluene-ethyl acetate
mixture (v/v) as an eluent to afford 2 as an off-white solid (2.38 g, 77%); mp. 208–209 °C (lit.
[23] 205–206 °C); νmax (ATR) 528, 765, 827, 867, 930, 1148, 1163, 1192, 1216, 1265, 1283,
1407, 1514, 1549, 1578, 1652 cm-1; δH (300 MHz, DMSO-d6) 6.98 (1H, s, H-3), 7.07 (1H, d, J
= 8.8 Hz, H-6), 7.90 (1H, d, J = 8.8 Hz, H-5), 11.95 (1H, br s, OH); δC (75 MHz, DMSO-d6)
74.8, 111.1 (q, 3JCF = 2.6 Hz), 115.0, 117.4, 119.1 (q, 1JCF = 273.9 Hz), 127.1, 151.0 (q, 2JCF =
38.6 Hz), 156.7, 164.3, 175.6; δF (282 MHz, DMSO-d6) -70.3 (s, -CF3); HRMS (ES+): m/z [M
– H]- calc for C10H3O3F3I: 354.9079; found 354.9062.
3.3. Typical procedure for the tandem Sonogashira cross-coupling and cycloisomerization
of 2.
A mixture of 2 (0.50 g, 1.40 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.05 g,
0.07 mmol), copper(I) iodide (0.03 g, 0.14 mmol), triphenylphosphine (0.02 g, 0.08 mmol) and
triethylamine (0.17 g, 1.68 mmol) in 4:1 DMF-water (v/v, 20 mL) was placed in a two necked
round-bottomed flask equipped with a stirrer bar, condenser and a rubber septum. The mixture
was flushed with argon gas for 30 minutes and a solution of phenylacetylene derivative (1.2
equiv.) in DMF (2 mL) was introduced via a rubber septum by means of a syringe. A balloon
filled with argon was connected to the top of the condenser and the mixture was left to stir at
70 °C for 2 h. The mixture was allowed to cool and then poured into crushed ice. The product
9

was extracted into chloroform and the combined organic phases were washed with water and
dried over anhydrous MgSO4. The salt was filtered off and the solvent was evaporated under
reduced pressure on a rotary evaporator. The residue was purified by column chromatography
on using silica gel using 9:1 toluene-ethyl acetate mixture (v/v) as an eluent. The following
compounds were prepared in this fashion.
8-Phenyl-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2a)
Yellow solid (0.32 g, 69%), mp. 195–196 ℃; νmax (ATR) 545, 653, 689, 736, 756, 905,
919, 975, 1085, 1120, 1136, 1161, 1192, 1215, 1263, 1281, 1316, 1334, 1414, 1463, 1613, 1668
cm-1; δH (300 MHz, CDCl3) 6.80 (1H, s, H-3), 7.36 (1H, s, H-9), 7.42–7.53 (3H, m, H-3′,4′,5′),
7.63 (1H, d, J = 8.8 Hz, H-6), 7.90 (2H, d, J = 8.3 Hz, H-2′,6′), 8.11 (1H, d, J = 8.8 Hz, H-5);
δC (75 MHz, CDCl3) 98.2, 111.1, 111.2 (q, 3JCF = 2.6 Hz), 118.7 (q, 1JCF = 273.9 Hz), 119.1,
119.7, 121.5, 125.2, 129.0, 129.1, 129.6, 149.8, 151.6 (q, 2JCF = 39.2 Hz), 157.8, 158.4, 176.5;
δF (282 MHz, DMSO-d6) -71.3 (s); HRMS (ES+): m/z [M + H]+ calc for C18H10O3F3: 331.0582;
found 331.0585.
8-(3-Fluorophenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2b)
Brown solid (0.35 g, 72%), mp. 200–201 ℃; νmax (ATR) 515, 652, 683, 736, 768, 821, 846,
911, 1075, 1085, 1117, 1139, 1183, 1213, 1264, 1282, 1330, 1412, 1482, 1572, 1596, 1613,
1672 cm-1; δH (300 MHz, CDCl3) 6.80 (1H, s, H-3), 7.11 (1H, td, J = 8.4 and 2.5 Hz, H-4′),
7.38 (1H, s, H-9), 7.46 (1H, td, J = 5.8 and 8.1 Hz, H-6′), 7.55–7.72 (3H, overlapping signals,
H-6 and H-2′,5′), 8.12 (1H, d, J = 8.8 Hz, H-5); δC (75 MHz, CDCl3) 99.3, 111.1, 111.3 (q, 3JCF
2
2
1
= 2.6 Hz), 112.1 (d, JCF = 23.9 Hz), 116.5 (d, JCF = 21.3 Hz), 118.7 (q, JCF = 274.0 Hz),
118.9, 119.8, 120.8 (d, 4JCF = 3.1 Hz), 122.0, 130.7 (d, 3JCF = 8.4 Hz), 131.1 (d, 3JCF = 8.5 Hz),
2
4
1
149.9, 151.7 (q, JCF = 39.2 Hz), 156.4 (d, JCF = 3.2 Hz), 158.4, 163.1 (d, JCF = 246.7 Hz),
176.4; δF (282 MHz, CDCl3) -71.3 (s, -CF3), -111.8 (td, JFH = 5.8 and 9.0 Hz, 3-F); HRMS
(ES+): m/z [M + H]+ calc for C18H9O3F4: 349.0488; found 349.0489.
10

8-(4-Fluorophenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2c)
Pale green solid (0.33 g, 67%), mp. 215–216 ℃; νmax (ATR) 530, 613, 657, 737, 771, 808,
912, 977, 1083, 1119, 1139, 1155, 1191, 1213, 1282, 1334, 1411, 1467, 1502, 1616, 1672 cm-
1; δH (300 MHz, CDCl3) 6.78 (1H, s, H-3), 7.17 (2H, t, J = 8.7 Hz, H-3′,5′), 7.26 (1H, s, H-9),
7.59 (1H, d, J = 8.8 Hz, H-6), 7.86 (2H, t, J = 8.7 Hz, H-2′,6′), 8.09 (1H, d, J = 8.8 Hz, H-5);
δC (75 MHz, CDCl3) 97.9, 111.0, 111.2 (q, 3JCF = 2.6 Hz), 116.2 (d, 2JCF = 22.1 Hz), 118.7 (q,
1JCF = 274.0 Hz), 119.0, 119.7, 121.5, 125.4 (d, 4JCF = 3.4 Hz), 127.1 (d, 3JCF = 8.5 Hz), 149.8,
151.6 (q, 2JCF = 39.2 Hz), 156.9, 158.3, 163.4 (d, 1JCF = 250.7 Hz), 176.4; δF (282 MHz, CDCl3)
-71.3 (s, -CF3), -110.4 (tt, JFH = 5.2 and 8.4 Hz, 4-F); HRMS (ES+): m/z [M + H]+ calc for
C18H9O3F4: 349.0488; found 349.0480.
8-(3-Chlorophenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2d)
Pale yellow solid (0.29 g, 57%), mp. 212–213 ℃; νmax (ATR) 533, 657, 684, 738, 767, 830,
871, 925, 977, 1085, 1119, 1147, 1184, 1204, 1279, 1325, 1414, 1458, 1472, 1612, 1651, 1667
cm-1; δH (300 MHz, CDCl3) 6.80 (1H, s, H-3), 7.34–7.46 (3H, overlapping signals, H-9, H-
4′,5′), 7.61 (1H, d, J = 8.8 Hz, H-6), 7.76 (1H, dt, J = 1.6 and 7.3 Hz, H-6′), 7.87 (1H, t, J = 1.6
Hz, H-2′), 8.12 (1H, d, J = 8.8 Hz, H-5); δC (75 MHz, CDCl3) 99.3, 111.1, 111.3 (q, 3JCF = 2.6
Hz), 118.6 (q, 1JCF = 274.0 Hz), 118.8, 119.8, 122.0, 123.1, 125.1, 129.5, 130.3, 130.7, 135.2,
2
149.9, 151.7 (q, JCF = 39.3 Hz), 156.2, 158.4, 176.3; δF (282 MHz, CDCl3) -71.3 (s, -CF3);
HRMS (ES+): m/z [M + H]+ calc for C18H9O3ClF3: 365.0192; found 365.0190.
8-(4-Chlorophenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2e)
Yellow solid (0.32 g, 63%), mp. 229–231 ℃; νmax (ATR) 528, 656, 736, 770, 808, 912,
976, 1081, 1118, 1144, 1191, 1213, 1280, 1334, 1406, 1468, 1590, 1617, 1669 cm-1; δH (300
MHz, CDCl3) 6.79 (1H, s, H-3), 7.32 (1H, s, H-9), 7.44 (2H, d, J = 8.6 Hz, H-3′,5′), 7.60 (1H,
d, J = 8.8 Hz, H-6), 7.80 (2H, d, J = 8.6 Hz, H-2′,6′), 8.10 (1H, d, J = 8.8 Hz, H-5); δC (75 MHz,
CDCl3) 98.6, 111.0, 111.2 (q, 3JCF = 2.6 Hz), 118.7 (q, 1JCF = 274.0 Hz), 119.0, 119.8, 121.8,
11

126.3, 127.5, 129.3, 135.5, 149.8, 151.6 (q, 2JCF = 39.2 Hz), 156.6, 158.3, 176.4; δF (282 MHz,
CDCl3) -71.3 (s, -CF3); HRMS (ES+): m/z [M + H]+ calc for C18H9O3ClF3: 365.0192; found
365.0189.
8-(p-Tolyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2f)
Light brown solid (0.35 g, 72%), mp. 193–194 ℃; νmax (ATR) 529, 658, 737, 767, 817,
914, 975, 1083, 1117, 1139, 1163, 1191, 1215, 1262, 1283, 1333, 1415, 1465, 1504, 1615, 1651
cm-1, 1672; δH (300 MHz, CDCl3) 2.41 (3H, s, CH3), 6.78 (1H, s, H-3), 7.26–7.29 (3H, s
overlapping d, H-3′,5′ and H-9), 7.59 (1H, d, J = 8.8 Hz, H-6), 7.76 (2H, d, J = 8.0 Hz, H-2′,
6′), 8.07 (1H, d, J = 8.8 Hz, H-5); δC (75 MHz, CDCl3) 21.4, 97.4, 110.9, 111.1 (q, 3JCF = 2.7
Hz), 118.7 (q, 1JCF = 273.9 Hz), 119.2, 119.6, 121.1, 125.1, 126.3, 129.7, 139.8, 149.7, 151.6
(q, 2JCF = 39.0 Hz), 158.1, 158.2, 176.5; δF (282.2 MHz, CDCl3) -71.3 (s, -CF3); HRMS (ES+):
m/z [M + H]+ calc for C19H12O3F3: 345.0739; found 345.0741.
8-(4-Methoxyphenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2g)
Yellow solid (0.31 g, 61%), mp. 196–197 ℃; νmax (ATR) 737, 763, 802, 833, 917, 976,
1024, 1087, 1117, 1147, 1176, 1188, 1208, 1254, 1277, 1335, 1418, 1503, 1589, 1614, 1645,
1667 cm-1; δH (300 MHz, CDCl3) 3.88 (3H, s, OCH3), 6.79 (1H, s, H-3), 7.00 (2H, d, J = 8.8
Hz, H-3′,5′), 7.21 (1H, s, H-9), 7.59 (1H, d, J = 8.8 Hz, H-6), 7.82 (2H, d, J = 8.8 Hz, H-2′,6′),
8.07 (1H, d, J = 8.8 Hz, H-5); δC (75 MHz, CDCl3) 55.4, 96.5, 110.9, 111.1 (q, 3JCF = 2.6 Hz),
114.5, 118.7 (q, 1JCF = 274.0 Hz), 119.3, 119.7, 120.9, 121.8, 126.7, 149.7, 151.6 (q, 2JCF = 39.1
Hz), 158.0, 158.2, 160.7, 176.6; δF (282 MHz, CDCl3) -71.3 (s, -CF3); HRMS (ES+): m/z [M +
H]+ calc for C19H12O4F3: 361.0688; found 361.0685.
8-(3,5-Dimethoxyphenyl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2h)
Yellow solid (0.38 g, 69%), mp. 230–231 ℃; νmax (ATR) 530, 655, 736, 767, 815, 884,
943, 1032, 1087, 1114, 1146, 1193, 1212, 1270, 1329, 1413, 1461, 1571, 1603, 1667 cm-1; δH
(300 MHz, CDCl3) 3.88 (6H, s, 2 × OCH3), 6.51 (1H, d, J = 1.8 Hz, H-4′), 6.79 (1H, s, H-3),
12

7.01 (2H, d, J = 1.8 Hz, H-2′,6′), 7.31 (1H, s, H-9), 7.60 (1H, d, J = 8.8 Hz, H-6), 8.09 (1H, d,
J = 8.8 Hz, H-5); δC (75 MHz, CDCl3) 55.5, 98.6, 101.9, 103.2, 111.0, 111.2 (q, 3JCF = 2.7 Hz),
118.7 (q, 1JCF = 273.9 Hz), 119.0, 119.7, 121.5, 130.7, 149.8, 151.6 (q, 2JCF = 39.2 Hz), 157.6,
158.2, 161.2, 176.4; δF (282 MHz, CDCl3) -71.3 (s, -CF3); HRMS (ES+): m/z [M + H]+ calc for
C20H14O5F3: 391.0793; found 391.0788.
8-(Cyclohex-1-en-1-yl)-2-(trifluoromethyl)-4H-furo[2,3-h]chromen-4-one (2i)
Brown solid (0.32 g, 68%), mp. 179–180 ℃; νmax (ATR) 525, 652, 737, 764, 826, 863,
1084, 1112, 1144, 1186, 1201, 1252, 1266, 1326, 1415, 1460, 1609, 1647, 1668 cm-1; δH (300
MHz, CDCl3) 1.67–1.75 (2H, m, H-5′), 1.76–1.89 (2H, m, H-4′), 2.18–2.34 (2H, m, H-3′),
2.36–2.49 (2H, m, H-6′), 6.70 (1H, t, J = 4.0 Hz, H-2′), 6.76 (1H, s, H-3), 6.79 (1H, s, H-9),
7.50 (1H, d, J = 8.7 Hz, H-6), 8.03 (1H, d, J = 8.7 Hz, H-5); δC (75 MHz, CDCl3) 21.9, 22.1,
24.8, 25.5, 96.8, 110.7, 111.0 (q, 3JCF = 2.7 Hz), 118.7 (q, 1JCF = 274.0 Hz), 118.9, 119.4, 121.0,
126.4, 128.5, 149.7, 151.6 (q, 2JCF = 39.0 Hz), 158.1, 159.3, 176.6; δF (282 MHz, CDCl3) -71.3
(s, -CF3); HRMS (ES+): m/z [M + H]+ calc for C18H14O3F3: 335.0895; found 335.0895.
4.4. Typical procedure for reaction of 2a–i with methyl mercaptoacetate to afford 3a–i.
A mixture of 2a (0.20 g, 0.61 mmol), methyl mercaptoacetate (0.33 g, 3.10 mmol) and
Et3N (0.1 mL) was heated at 100 °C for 2 h. After cooling, the reaction mixture was diluted
with 25% aqueous ethanol (10 mL) and filtered on a sintered funnel. The solid product was
washed with cold aqueous ethanol and then purified by column chromatography on silica gel
using 9:1 toluene-ethyl acetate mixture (v/v) as an eluent to afford 3a as a solid. The following
compounds were prepared in this fashion.
2-Phenyl-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one (3a)
White solid (0.16 g, 68%), mp. 263–264 ℃; νmax (ATR) 451, 689, 757, 794, 1079, 1113,
1148, 1269, 1358, 1608, 1702 cm-1; δH (300 MHz, DMSO-d6) 3.96 (1H, dd, J = 4.0 and 19.0
Hz, 8-Ha), 4.04 (1H, dd, J = 9.9 and 19.0 Hz, 8-Hb), 5.05–5.24 (1H, m, H-7), 7.41–7.56 (3H,
13

m, H-3′,4′,5′), 7.65 (1H, d, J = 8.7 Hz, H-10), 7.72 (1H, d, J = 8.7 Hz, H-9), 7.80 (1H, s, H-3),
7.98 (2H, d, J = 7.2 Hz, H-2′,6′); δC (75 MHz, DMSO-d6) 36.5, 47.1 (q, 2JCF = 30.5 Hz), 99.3,
109.4, 113.0, 118.2, 122.0, 122.2, 125.4, 126.7 (q, 1JCF = 277.9 Hz), 129.3, 129.6, 129.9, 146.6,
148.8, 156.0, 156.1, 157.0; δF (282 MHz, DMSO-d6) -73.1 (d, JFH = 8.9 Hz, -CF3); HRMS
(ES+): m/z [M + H]+ calc for C20H12O3F3S: 389.0459; found 389.0460.
2-(3-Fluorophenyl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-
one (3b)
Pale yellow solid (0.15 g, 64%), mp. 270–271 ℃; νmax (ATR) 456, 688, 746, 761, 788, 854,
1081, 1114, 1151, 1183, 1267, 1353, 1568, 1608, 1705 cm-1; δH (300 MHz, DMSO-d6) 3.93
(1H, dd, J = 4.0 and 18.8 Hz, 8-Ha), 4.02 (1H, dd, J = 9.9 and 18.8 Hz, 8-Hb), 5.06–5.20 (1H,
m, H-7), 7.24 (1H, t, J = 8.5 Hz, H-4′), 7.53 (1H, td, J = 6.2 and 8.1 Hz, H-2′), 7.62(1H, d, J =
8.7 Hz, H-10), 7.66 (1H, d, J = 8.7 Hz, H-9), 7.70–7.78 (2H, m, H-5′,6′), 7.82(1H, s, H-3); δC
2
2
(75 MHz, DMSO-d6) 36.5, 47.1 (q, JCF = 30.2 Hz), 100.6, 109.3, 112.0 (d, JCF = 23.8 Hz),
113.0, 116.5 (d, 2JCF = 21.1 Hz), 118.0, 121.3, 122.3, 122.4, 126.7 (q, 1JCF = 278.3 Hz), 131.5
(d, 3JCF = 8.9 Hz), 131.7 (d, 3JCF = 8.4 Hz), 146.6, 148.6, 155.5 (d, 4JCF = 3.0 Hz), 155.9, 156.1,
162.9 (d, 1JCF = 243.7 Hz); δF (282 MHz, DMSO-d6) -73.0 (d, JFH = 8.9 Hz), -112.19 to -112.10
(m, 3-F); HRMS (ES+): m/z [M + H]+ calc for C20H11O3F4S: 407.0365; found 407.0365.
2-(4-Fluorophenyl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-
one (3c)
White solid (0.17 g, 73%), mp. 226–227 ℃; νmax (ATR) 449, 594, 609, 758, 795, 958, 1076,
1106, 1157, 1193, 1237, 1265, 1505, 1606, 1707 cm-1; δH (300 MHz, CDCl3) 3.77 (1H, dd, J =
4.2 and 18.2 Hz, 8-Ha), 3.85 (1H, dd, J = 9.9 and 18.2 Hz, 8-Hb), 4.37–4.54 (1H, m, H-7),7.16
(2H, t, J = 8.6 Hz, H-3′,5′), 7.21–7.26 (2H, overlapping signals, H-3, H-10), 7.47 (1H, d, J =
8.6 Hz, H-9), 7.82 (2H, t, J = 8.6 Hz, H-2′,6′); δC (75 MHz, CDCl3) 36.4, 47.7 (q, 2JCF = 31.6
2
4
Hz), 97.9, 108.9, 112.6, 116.2 (d, JCF = 22.1 Hz), 118.8, 119.6, 123.6, 125.62 (d, JCF = 3.4
14

1
3
Hz), 125.63 (q, JCF = 278.1 Hz), 127.0 (d, JCF = 8.4 Hz), 146.2, 146.7, 156.1, 156.2, 156.5,
1
163.3 (d, JCF = 250.2 Hz); δF (282 MHz, CDCl3) -74.1 (d, JH,F = 8.1 Hz, -CF3), -110.78 to -
110.69 (m, 4-F); HRMS (ES+): m/z [M + H]+ calc for C20H11O3F4S: 407.0365; found 407.0352.
2-(3-Chlorophenyl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-
one (3d)
White solid (0.19 g, 82%), mp. 277–278 ℃; νmax (ATR) 455, 563, 663, 685, 761, 790, 948,
1019, 1074, 1108, 1159, 1187, 1267, 1353, 1474, 1557, 1605, 1704 cm-1; δH (300 MHz, DMSO-
d6) 3.95 (1H, dd, J = 3.9 and 19.0 Hz, 8-Ha), 4.03 (1H, dd, J = 9.9 and 19.0 Hz, 8-Hb), 5.06–
5.20 (1H, m, H-7), 7.42–7.57 (2H, m, H-4′,5′), 7.64 (1H, d, J = 8.7 Hz, H-10), 7.69 (1H, d, J =
8.7 Hz, H-9), 7.87–7.92 (2H, overlapping signals, H-6′, H-3), 7.99 (1H, t, J = 1.6 Hz, H-2′); δC
(75 MHz, DMSO-d6) 36.5, 47.2 (q, 2JCF = 30.7 Hz), 100.7, 109.4, 113.1, 118.1, 122.3, 122.4,
123.9, 124.9, 126.7 (q, 1JCF = 278.5 Hz), 128.6, 131.3, 131.4, 134.4, 146.7, 148.6, 155.3, 155.9,
156.2; δF (282.2 MHz, DMSO-d6) -73.0 (d, JFH = 8.9 Hz, -CF3); HRMS (ES+): m/z [M + H]+
calc for C20H11O3ClF3S: 423.0070; found 423.0070.
2-(4-Chlorophenyl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-
one (3e)
White solid (0.21 g, 91%), mp. 240–241 ℃; νmax (ATR) 481, 745, 799, 953, 1010, 1076,
1095, 1106, 1159, 1195, 1263, 1345, 1492, 1606, 1709 cm-1; δH (300 MHz, DMSO-d6) 3.93
(1H, dd, J = 3.9 and 18.8 Hz, 8-Ha), 4.02 (1H, dd, J = 10 and 18.8 Hz, 8-Hb), 5.06–5.13 (1H,
m, H-7), 7.53 (2H, d, J = 8.6 Hz, H-3′,5′), 7.61(1H, d, J = 8.7 Hz, H-10), 7.65 (1H, d, J = 8.7
Hz, H-9), 7.75(1H, s, H-3), 7.92 (2H, d, J = 8.6 Hz, H-2′,6′); δC (75 MHz, DMSO-d6) 36.5, 47.1
(q, 2JCF = 30.3 Hz), 99.9, 109.3, 113.0, 118.1, 122.1, 122.2, 126.7 (q, 1JCF = 277.9 Hz), 126.9,
128.1, 129.5, 134.3, 146.5, 148.6, 155.7, 155.9, 156.1; δF (282 MHz, DMSO-d6) -73.0 (d, JH,F
= 8.9 Hz, -CF3); HRMS (ES+): m/z [M + H]+ calc for C20H11O3ClF3S: 423.0070; found
423.0060.
15

2-(p-Tolyl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-one (3f)
White solid (0.15 g, 64%), mp. 261–262 ℃; νmax (ATR) 493, 644, 746, 793, 957, 1014,
1031, 1077, 1105, 1157, 1193, 1262, 1351, 1506, 1606, 1622, 1706 cm-1; δH (300 MHz, DMSO-
d6) 2.36 (3H, s, CH3), 3.94 (1H, dd, J = 3.9 and 18.8 Hz, 8-Ha), 4.03 (1H, dd, J = 10.0 and 18.8
Hz, 8-Hb), 5.04–5.21 (1H, m, H-7),7.31 (2H, d, J = 8.1 Hz, H-3′,5′), 7.61(1H, d, J = 8.7 Hz, H-
10), 7.65–7.70 (2H, overlapping signals, H-3 and H-9), 7.84 (2H, d, J = 8.1 Hz, H-2′,6′); δC (75
MHz, DMSO-d6) 21.4, 36.5, 47.1 (q, 2JCF = 30.4 Hz), 98.4, 109.3, 113.0, 118.3, 121.7, 122.1,
125.3, 126.6, 126.7 (q, 1JCF = 278.3 Hz), 130.1, 139.7, 146.5, 148.8, 156.0, 157.2; δF (282 MHz,
DMSO-d6) -73.0 (d, JFH = 8.9 Hz, -CF3); HRMS (ES+): m/z [M + H]+ calc for C21H14O3F3S:
403.0616; found 403.0616.
2-(4-Methoxyphenyl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-5-
one (3g)
Pale Yellow solid (0.15 g, 65%), mp. 253–254 ℃; νmax (ATR) 447, 612, 754, 767, 784,
953, 1023, 1040, 1072, 1107, 1168, 1198, 1253, 1268, 1342, 1484, 1590, 1609, 1716 cm-1 ; δH
(300 MHz, DMSO-d6) 3.82 (3H, s, OCH3), 3.94 (1H, dd, J = 4.0 and 19.0 Hz, 8-Ha), 4.02 (1H,
dd, J = 9.9 and 19.0 Hz, 8-Hb), 5.04–5.20 (1H, m, H-7), 7.06 (2H, d, J = 8.8 Hz, H-3′,5′), 7.56–
7.60 (2H, overlapping signals, H-3, 10), 7.65 (1H, d, J = 8.6 Hz, H-9), 7.89 (2H, d, J = 8.8 Hz,
H-2′, 6′); δC (75 MHz, DMSO-d6) 36.5, 47.1 (q, 2JCF = 30.8 Hz), 55.8, 97.3, 109.2, 113.0, 115.0,
118.5, 121.3, 121.9, 122.0, 126.7 (q, 1JCF = 277.9 Hz), 127.0, 146.4, 148.7, 155.9, 156.0, 157.2,
160.7; δF (282.2 MHz, DMSO-d6) -73.0 (d, JFH = 8.9 Hz, -CF3); HRMS (ES+): m/z [M + H]+
calc for C21H14O4F3S: 419.0565; found 419.0563.
2-(3,5-Dimethoxyphenyl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-
c]chromen-5-one (3h)
Pale yellow solid (0.16 g, 70%), mp. 256–258 ℃; νmax (ATR) 469, 744, 792, 818, 853, 953,
1014, 1032, 1060, 1080, 1104, 1157, 1192, 1205, 1258, 1335, 1429, 1567, 1592, 1606, 1711
16

cm-1; δH (300 MHz, DMSO-d6) 3.82 (6H, s, 2 × OCH3), 3.94 (1H, dd, J = 4.0 and 19.0 Hz, 8-
Ha), 4.03 (1H, dd, J = 9.9 and 19.0 Hz, 8-Hb), 5.05–5.21 (1H, m, H-7), 6.54 (1H, t, J = 2.1 Hz,
H-4′), 7.10 (2H, d, J = 2.1 Hz, H-2′,6′), 7.62 (1H, d, J = 8.7 Hz, H-10), 7.69 (1H, d, J = 8.7 Hz,
2
H-9), 7.86 (1H, s, H-3); δC (75 MHz, DMSO-d6) 36.5, 47.1 (q, JCF = 30.7 Hz), 55.9, 100.0,
102.1, 103.1, 109.3, 113.0, 118.2, 122.0, 122.1, 126.7 (q, 1JCF = 278.0 Hz), 131.0, 146.6, 148.7,
156.97, 156.01, 156.8, 161.3; δF (282 MHz, DMSO-d6) -73.0 (d, JFH = 8.9 Hz, -CF3); HRMS
(ES+): m/z [M + H]+ calc for C22H16O5F3S: 449.0671; found 449.0663.
2-(Cyclohex-1-en-1-yl)-7-(trifluoromethyl)-7,8-dihydro-5H-furo[2,3-h]thieno[2,3-c]chromen-
5-one (3i)
White solid (0.16 g, 68%), mp. 235–236 ℃; νmax (ATR) 445, 636, 746, 794, 959, 1009,
1073, 1103, 1154, 1193, 1263, 1350, 1374, 1554, 1606, 1620, 1643, 1706 cm-1 ; δH (300 MHz,
DMSO-d6) 1.52–1.69 (2H, m, H-5′), 1.69–1.83 (2H, m, H-4′), 2.14–2.31 (2H, m, H-3′), 2.32–
2.45 (2H, m, H-6′), 3.93 (1H, dd, J = 4.0 and 19.0 Hz, 8-Ha), 4.02 (1H, dd, J = 9.9 and 19.0 Hz,
8-Hb), 5.03–5.20 (1H, m, H-7), 6.60 (1H, t, J = 3.7 Hz, H-2′), 7.02 (1H, s, H-3), 7.57 (2H, s, H-
9,10); δC (75 MHz, DMSO-d6) 21.9, 22.1, 24.6, 25.4, 36.5, 47.1 (q, 2JCF = 30.6 Hz), 97.6, 109.0,
112.8, 118.0, 121.6, 121.9, 126.7 (q, 1JCF = 277.8 Hz), 126.8, 127.9, 146.4, 148.8, 155.8, 156.0,
158.4; δF (282.2 MHz, DMSO-d6) -73.0 (d, JFH = 8.9 Hz); HRMS (ES+): m/z [M + H]+ calc for
C20H16O3F3S: 393.0772; found 393.0770.
3.5. Data Collection and Refinement of 2b and 3a.
Intensity data were determined on a Bruker Venture D8 Photon CMOS diffractometer
(Bruker AXS, Madison, WI, USA) with graphite-monochromated MoKα1 (λ = 0.71073 Å)
radiation at 173 K using an Oxford Cryostream 600 cooler. Data reduction was performed using
the program SAINT+, version 6.02 [31]. Data reduction was carried out using the program
SAINT+, version 6.02 and empirical absorption corrections were made using SADABS [31].
The space group assignments were made using XPREP [31]. The structures were solved in the
17

WinGX [32] Suite of programs using direct methods through using SHELXS-97 [33], and
refined using full-matrix least-squares/difference Fourier techniques on F2 using SHELXL-
2017 [33]. All C-bound H atoms were placed at idealized positions and refined as riding atoms
with isotropic parameters 1.2 times those of their parent atoms. The positional disorder of the
F atom (labelled F4A and F4B) of 2b was resolved by finding alternative positions in the
difference Fourier map and their site occupancies refined to 0.560(5) and 0.440(5). Diagrams
and publication material for 2b and 3a were generated using ORTEP-3 [32] and PLATON [34].
Funding: This project was funded by the University of South Africa and the National Research
Foundation (GUN: 118554).
Conflict of interest: The authors declare no conflict of interest.
Acknowledgements: We thank the University of Stellenbosch Central Analytical Facility
(CAF) and the University of the Witwatersrand for mass spectrometric and X-ray analyses,
respectively. We also acknowledge helpful discussion and input by Dr Marole M. Maluleka.
18

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22

Figures
Figure 1: Structures of naturally occurring furo[3,2-c]chromones and furocoumarin analogues.
OMeO
R
O
O
O
O
O
O
O
O
CH3
R
Khellin, R = OCH3 (A)
Visnagin, R = H (B)
Psoralen (C)
Angelicin, R = H (D)
Sphondin, R = OCH3 (E)
Figure 2(a)
Figure 2(b)
23

Figure 2: Oak Ridge Thermal Ellipsoid Plot (ORTEP) diagrams (50% probability level) of 2b
(Figure 2a) and 3a (Figure 2b). For clarity, hydrogen atoms are not labelled.
24

Scheme
Scheme 1: Synthesis of the 2,5-dicarbo substituted 4H-furo[2,3-h]chromen-4-ones 2a–i.
O
O
, PdCl (PPh ) , CuI, PPh ,
R
2
3 2
3
K2CO3, DMF (aq), 70 oC, 2 h
O
O
CF3
HO
O
CF3
I
R
1
2a–i
Scheme 2: Synthesis of dihydrothienoangelicin analogues 3a–i.
CF3
O
S
HSCH2CO2Me, Et3N
100 oC, 2 h
O
O
CF3
O
O
O
R
R
2a–i
3a–i
25

Tables
Table 1: Designation of R for 2a–i and corresponding percentage yields.
Entry
Designation of R
C6H5-
%Yield of 2
69 (2a)
72 (2b)
67 (2c)
57 (2d)
63 (2e)
72 (2f)
1
2
3
4
5
6
7
8
9
3-FC6H4-
4-FC6H4-
3-ClC6H4-
4-ClC6H4-
4-MeC6H4-
4-MeOC6H4-
3,5-MeO(C6H3)-
Cyclohex-1-en-1-yl
61 (2g)
69 (2h)
68 (2i)
Table 2: Designation of R and the corresponding percentage yields for 3a–i.
Entry
Designation of R
C6H5-
%Yield of 3
68 (3a)
64 (3b)
73 (3c)
82 (3d)
91 (3e)
64 (3f)
1
2
3
4
5
6
7
8
9
3-FC6H4-
4-FC6H4-
3-ClC6H4-
4-ClC6H4-
4-MeC6H4-
4-MeOC6H4-
3,5-MeO(C6H3)-
-Cyclohex-1-en-1-yl
65 (3g)
70 (3h)
68 (3i)
26

Table 3. Crystal data and structure refinement for 2b and 3a.
CCDC-1954710
CCDC-1954888
C20H11F3O3S
388.35
Formula
C18H8F4O3
348.24
Formula weight
Temperature
Wavelength
Crystal system
173(2) K
0.71073 Å
Triclinic
173(2) K
0.71073 Å
Monoclinic
Space group
P-1
P21/n
Unit cell dimensions
a = 4.8321(4) Å
b = 9.8738(9) Å
c = 15.1458(12) Å
a = 7.3355(3) Å
b = 29.0389(10) Å
c = 8.3463(3) Å
α = 100.432(3)°
β = 97.039(3)°
γ = 93.871(3)°
α= 90°
β= 108.811(2)°
γ = 90°
Volume
3
3
702.34(10) Å
2
1682.92(11) Å
Z
4
Density (calculated)
3
3
1.647 Mg/m
1.533 Mg/m
Absorption coefficient
-1
-1
0.147 mm
0.243 mm
F(000)
352
792
Crystal size
3
3
0.746 x 0.096 x 0.054 mm
3.137 to 27.999°
3331/0/236
15487
0.359 x 0.213 x 0.090 mm
2.672 to 28.000°
4050/0/244
Theta range for data collection
Data/ restraints/ parameters
Measured reflections
θmin/θmax
22573
3.137/27.999°
0.0390
2.672/28.000°.
0.0267
Rint
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
1.044
1.043
R1 = 0.0541,
wR2 = 0.1228
R1 = 0.0329,
wR2 = 0.0833
27

R indices (all data)
R1 = 0.0745,
R1 = 0.0399,
wR2 = 0.0869
wR2 = 0.1331
Extinction coefficient
n/a
n/a
Largest diff. peak and hole
-3
-3
0.318/-0.270 e.Å
0.343/-0.233 e.Å
28