Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin: Experimental and computational evidence for intramolecular and intermolecular C-F?H-C bonds

Article abstract of DOI:10.3762/bjoc.16.22

4-(2-Fluorophenyl)-7-methoxycoumarin (6) was synthesized by Pechmann reaction under mild conditions via a three-step reaction. The solution-state ¹H NMR spectra of 6 showed a strong intramolecular interaction between F and H5 (J_FH = 2.6 Hz) and ¹³C NMR suggested that this C-F?H-C coupling is a through-space interaction. The 2D ¹⁹F-{¹H} HOESY and ¹H-{¹⁹F} 1D experiments were done to confirm this F?H interaction. The single crystal X-ray structure and the DFT-optimized structure showed that the fluorinated phenyl ring favors the orientation with the fluorine atom closer to H5 than H3. The X-ray structure also showed the existence of the intermolecular C-F?H-C interaction.

Full text of DOI:10.3762/bjoc.16.22

Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin:
experimental and computational evidence for intramolecular
and intermolecular C–F···H–C bonds
Vuyisa Mzozoyana*, Fanie R. van Heerden and Craig Grimmer
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 190–199.
School of Chemistry and Physics, University of KwaZulu-Natal,
Private Bag X01, Scottsville, 3209, Pietermaritzburg, South Africa
doi:10.3762/bjoc.16.22
Received: 16 October 2019
Accepted: 04 February 2020
Published: 10 February 2020
Email:
Vuyisa Mzozoyana* - mzozoyanav@ukzn.ac.za
* Corresponding author
Associate Editor: J. A. Murphy
Keywords:
© 2020 Mzozoyana et al.; licensee Beilstein-Institut.
License and terms: see end of document.
DFT; F···H hydrogen bond; fluorinated phenylcoumarin; Pechmann
reaction; through-space coupling
Abstract
4-(2-Fluorophenyl)-7-methoxycoumarin (6) was synthesized by Pechmann reaction under mild conditions via a three-step reaction.
The solution-state 1H NMR spectra of 6 showed a strong intramolecular interaction between F and H5 (JFH = 2.6 Hz) and
13C NMR suggested that this C–F···H–C coupling is a through-space interaction. The 2D 19F-{1H} HOESY and 1H-{19F} 1D ex-
periments were done to confirm this F···H interaction. The single crystal X-ray structure and the DFT-optimized structure showed
that the fluorinated phenyl ring favors the orientation with the fluorine atom closer to H5 than H3. The X-ray structure also showed
the existence of the intermolecular C–F···H–C interaction.
Introduction
Coumarins constitute one of the big classes of naturally occur- quantities of coumarins. Due to an insufficient natural supply to
ring compounds. The first coumarin was isolated from the tonka meet this demand for these compounds, numerous methods for
bean (Dipteryx odorata) in 1820 and, to date, more than 1300 the synthesis of these compounds have been developed, exam-
coumarins have been identified from natural sources [1,2]. ples are the Pechmann condensation [10,11], Stille coupling
Coumarins have been reported to play a vital role as food and reaction [12], Knoevenagel condensation [13], Heck coupling
cosmetics constituents, cigarette additives, and dye-sensitized reaction [14], Kostanecki reaction, Baylis–Hillman reaction
solar cells [3,4]. In addition, coumarins possess some biologi- [15], Michael reaction [16], Suzuki–Miyaura cross-coupling
cal activities such as anti-inflammatory [5], antitumor [6], anti- reaction [17], Negishi cross-coupling reaction [18] and Wittig
oxidant [7], antibacterial [8], hepatoprotective, anticoagulant, reaction [17]. The concept of the incorporation of fluorine into
antiviral and antithrombotic activities [9]. The variety of uses of organic molecules has gained much interest since Fried and
these compounds resulted in an increase in demand for large Sabo reported the improvement of the therapeutic index of
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Beilstein J. Org. Chem. 2020, 16, 190–199.
cortisol by the incorporation of a fluorine atom in the 9α posi- The C–F···H–C interaction is amongst the weakest of hydrogen
tion of the structure [19]. Since then, the fluorine-containing bonding phenomena because a carbon acid (C–H) is weak,
drugs have come onto the market and they are amongst the best- therefore is a weak donor, and the acceptor is non-polarizable,
selling pharmaceutical drugs, including Lipitor®, Prevacid®, therefore is a poor acceptor [34-36]. Wang and co-workers re-
Advair Discus® and Lexapro® [20-22]. The incorporation of ported the existence of the C–F···H–C intramolecular hydrogen
fluorine may improve the activity of biologically active com- bond in the structure of aromatic triazole foldmers [37]. In their
pounds as it imparts a variety of properties such as enhanced study, using crystallographic and DFT data, they concluded that
binding interaction, metabolic stability, and reaction selectivity their folded conformers are held by C–F···H–C hydrogen bonds.
by changing physical and chemical properties [23-26].
To further these studies, we have synthesized a fluorine-con-
taining phenylcoumarin in order to study the fluorine-hydrogen
Hydrogen bonds (HBs) are associated with highly electronega- bond. The crystal structure and solution-state NMR data of the
tive atoms (oxygen, nitrogen, fluorine) and have been observed coumarin 6 were studied to examine any C–F···H–C hydrogen
to govern the conformational structure of some molecules as bond interactions. DFT calculations were performed to deter-
well as the alignment of the molecules within a crystal struc- mine the preferred conformations of the structure that might ex-
ture [27-29]. Moreover, HBs have been reported to play a vital hibit a C–F···H–C hydrogen bond.
role in a ligand–receptor interaction that determines the biologi-
cal activity of a molecule. Oxygen and nitrogen have been
proven to be good hydrogen-bond acceptors which form strong Synthesis of 2-fluorophenylcoumarin 6
intermolecular and intramolecular hydrogen bonds, however, 4-(2-Fluorophenyl)-7-methoxycoumarin (6) was synthesized
fluorine is still denied hydrogen-bond acceptor status by some under mild conditions via a three-step reaction (Scheme 1) and
Results and Discussion
scientists.
the first step was the synthesis of the fluorinated β-keto ester 3.
Methyl acetoacetate (2) was treated with MgCl2, Et3N and
There is evidence of the existence of C–F···H interaction in n-BuLi in DCM and then with 2-fluorobenzoyl chloride (1) to
organic molecules [30,31]. Early reports by Glusker and yield methyl 2-fluorobenzoylacetate (3) [38,39]. These reac-
co-workers in 1983 and 1994 showed C–F···H interactions in tions are very rare in the literature, however, there are similar
structures found in the Cambridge Crystallographic Data Centre reactions for the synthesis of β-keto esters as reported by
database [32]. Similar evidence was reported by Howard, Sijbesma et al. [40] and Anwar [41]. The second step of the
O’Hagan, Desiraju and their co-workers where the C–F···H synthesis was the Pechmann reaction, commonly used for the
interaction was observed, although the conclusions of the two synthesis of coumarins [42,43]. Methyl 2-fluorobenzoylacetate
groups were different – O’Hagan et al. concluded that fluorine (3) was reacted with resorcinol (4) in the presence of H2SO4 at
is not a good hydrogen-bond acceptor, whereas Desiraju et al. 35 °C, and 7-hydroxy-4-(2-fluorophenyl)coumarin (5) [39,44]
concluded that the interaction has genuine hydrogen-bond char- was obtained as a light yellow solid. The last step of the synthe-
acter [24,33-36].
sis was the methylation of the hydroxy group of coumarin 5
Scheme 1: Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin (6).
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Beilstein J. Org. Chem. 2020, 16, 190–199.
with dimethyl sulfate, to form 4-(2-fluorophenyl)-7-methoxy- NMR characterization of a structurally similar 7-hydroxy-
coumarin (6).
coumarin performed in DMSO-d6 has the signal for H5 re-
ported as a singlet [44].
Discussion
During the synthesis of coumarin 6, solution-state NMR spec- Since coumarins 6 and 5 have similar structure, the only differ-
troscopy was used to characterize compounds 3, 5, and 6 (1H ence is at position seven, 6 has a methoxy group while 5 has a
and 13C spectra are available in Supporting Information File 1). hydroxy group, a similar study was carried out for coumarin 5
The 1H spectrum of coumarin 6 showed H···F interactions for (Figure S10b, Supporting Information File 1).
H3′, H4′, H5′ and H6′ which is typical through-bond (TB) cou-
pling. However, the peaks that caught our particular attention The question posed at this point was “is this a through-bond
were the singlet peak at 6.25 ppm and a doublet-of-doublets (TB) or through-space (TS) effect”?
(dd) peak at 7.16 ppm assigned to H3 and H5, respectively
(Figure 1). The H5 signal was expected to be a doublet (not a To answer this question, we analysed a 13C-{1H} spectrum of
dd) due to 3J coupling to H6, since an H,H-COSY experiment coumarin 6 dissolved in CDCl3 and the signal corresponding to
does not show coupling between H5 and H8 (Figure S9, Sup- C5 was found to be a doublet (J = 1.4 Hz) but the signals corre-
porting Information File 1). It became clear that the splitting of sponding to C4 and C4a were singlets, and this indicates that
the signal from H5 was due to coupling with the 19F atom by this coupling is not a TB effect, because if it were a TB effect,
comparing the spectra from the 1H and 1H-{19F} experiments the signals for C4 and C4a would also likely be split. Similar
(Figure 1) which showed the H5 peak as a doublet with 19F splitting of C5 was observed in coumarin 5, also in different
decoupling. While the doublet-of-doublets signal for H5 solvents as shown in Figure 2 and there was no splitting of the
collapses into a doublet with 19F decoupling, there are no sig- signals corresponding to C4 and C4a as shown in Figures S22
nificant changes in the line-shape for the signal of H3 with 19F and S21 (Supporting Information File 1). These observations
decoupling (Figure 1).
were not found in the similar derivatives of coumarin 5
(7-hydroxy-4-(3-fluorophenyl)coumarin and 7-hydroxy-4-(4-
To determine whether the observation of 19F–H5 coupling for fluorophenyl)coumarin) found in the literature where the fluo-
coumarin 6 was a solvent dependent phenomenon, a compari- rine atom is in the third (C3') and the fourth (C4') position, re-
son was made between the 1H and 1H-{19F} spectra in CDCl3 spectively, of the phenyl ring [39]. The spectra for these deriva-
and acetone-d6. Splitting of the H5 signal was observed in both tives showed an H5 signal as a doublet (not doublet-of-doublets
solvents (Figure 1) suggesting that the 19F–H5 coupling for as observed in coumarin 5 and 6) and C5 as a singlet, indicat-
coumarin 6 is solvent independent. A literature report of the ing that they do not possess the through-space F···H5 or/and
Figure 1: 1H NMR spectra for the “aromatic” region of coumarin 6; comparison of 1H spectrum and 1H-{19F} spectrum in CDCl3 and 1H spectrum and
1H-{19F} spectrum in acetone-d6.
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Figure 2: 13C NMR spectra for coumarin 5 and 6; showing the splitting of the signal corresponding to C5.
F···C5 coupling since the fluorine atom is a bit further away and H3···19F indicates that neither the H3···19F nor the H5···19F
from H5 and C5. interaction limits the C4–C1′ bond rotation.
To confirm our findings, we further ran a 19F,1H-HOESY ex- The geometry of coumarin 6 (single molecule, gas phase) was
periment and it showed clear H5···19F and H3···19F coupling optimized using the B3LYP functional and the 6-311G basis
(Figure 3). Evidence of a HOESY interaction between H5···19F set, as implemented in Gaussian-09W (Rev. C.01) [45]. The
Figure 3: 19F,1H-HOESY NMR spectrum for coumarin 6 illustrating two through-space interactions.
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Beilstein J. Org. Chem. 2020, 16, 190–199.
superposition of the single-crystal X-ray structure (red) and the
optimized structure (green) is shown in Figure 4.
Figure 5: DFT-optimized structure for coumarin (6).
Figure 4: Superposition of single-crystal X-ray structure (red) and
DFT-optimized structure (green); RMSD 0.3 Å (hydrogen atoms
omitted for clarity).
observed between F and H5 but not between F and H3, as in
Figure 1, where there is an obvious change to the shape of the
signal corresponding to H5 but a negligible change to the shape
The DFT optimized geometric structure is shown in Figure 5 of the signal corresponding to H3, with the application of {19F}
and has a dihedral angle, Φ (C2'–C1'–C4–C4a) of 65.3°. decoupling. However, the F–H HOESY spectrum in Figure 3
Following the optimization, the dihedral angle Φ was varied shows coupling between the fluorine atom and both H5 and H3.
through a 360° rotation to examine the effect of changing the The authors interpretation of these observations (Figure 1 and
relative position of the fluorinated ring and the energy profile Figure 3) is that, in solution, rotation of the fluorophenyl ring
for this variation is shown in Figure 6. When Φ = 5°, the F···H5 (about C4–C1’) is permitted but that the average geometry of
distance is at its shortest (dF···H5 = 2.0 Å) and the fluorinated coumarin 6 has the fluorine atom closer to H5 than H3.
ring is almost coplanar with the coumarin ring, and the mole-
cule is at its least stable conformation due to the electron–elec- The theoretical NMR data for twenty-four conformations of
tron (e–e) repulsion of H5 and fluorine. The second least stable coumarin 6 were obtained from Gaussian 09W (Rev C.01) at
conformation is found at Φ = 185°, with the fluorine atom and the B3LYP/6-311G level. Geometry optimization and calcula-
H3 in close proximity (dF···H3 = 2.0 Å).
tion of NMR parameters for TMS and CCl3F at the same level
provided reference chemical shifts for 1H, 13C, and 19F. The
Examples of through-space coupling between fluorine and chemical shifts for the lowest energy structure (Φ = 65.3°) and
hydrogen atoms in organic molecules are reported in the chemi- the most unstable conformer (Φ = 5°) are used as examples
cal literature [46,47], with magnitudes as large as 7 Hz for 7JHF (Table 1). The theoretical chemical shifts for the carbons
[46]
appeared to be shifted downfield relative to the experimental
carbon peaks (for both stable and unstable conformers) as
One report of TS-coupling between F and H atoms comments shown by ‘change’ (Δ = −ve, experimental − theoretical) in
that “...it appears that significant coupling only occurs when the Table 1.
proton–fluorine closest approach distance is within the sum of
the van der Waals radii of hydrogen and fluorine (c. 2.55 Å)...” Comparing the experimental and the calculated 13C NMR
[47]. During rotation of the fluorophenyl ring (Figure 6), the chemical shifts for both the optimized and least-stable DFT-
F–H distance (for both F–H5 and F–H3) varies between 2 and generated conformations, the RMSD values were found to be
5 Å, so for some part of the rotation, both the distances F–H5 8.84 ppm and 8.79 ppm, respectively. The RMSD value for the
and F–H3 fall inside the limit of ≈2.55 Å, although not simulta- calculated 1H NMR chemical shifts of the optimized conformer
neously. For a fixed geometry like that of the crystal structure, was found to be substantially smaller (RMSD = 0.14 ppm) than
this would suggest that through-space F–H coupling would be that for the least-stable conformer (RMSD = 0.57 ppm).
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Figure 6: Plots of relative energy (black trace, no units), interatomic distance F–H5 (red trace, Å), interatomic distance F–H3 (blue trace, Å) as a func-
tion of dihedral angle Φ C2’–C1’–C4–C4a (°).
Table 1: Experimental and theoretical (gas phase) 1H and 13C chemical shift (δ) for atoms within six bonds from fluorine for coumarin 6 and RSMD
values.
Atom
C/H
Exp
δ (ppm)
Φ = 65.3° a
Φ = 5° b
δ (ppm)
Δ(ppm)c
δ (ppm)
Δ(ppm)c
C2
C3
H3
C4
C4a
C5
160.9
112.5
6.25
150.5
112.4
127.8
7.16
113.5
123.2
159.1
116.3
7.29
131.5
7.50
130.5
7.35
124.7
7.23
169.1
118.4
6.00
158.0
120.8
135.0
6.97
121.4
135.2
172.8
123.0
7.20
137.5
7.52
132.6
7.37
138.0
7.31
−8.2
−5.9
0.25
−7.5
−8.4
−7.2
0.19
−7.9
−12.0
−13.7
−6.7
0.09
−6.0
−0.02
−2.1
−0.02
−13.3
−0.08
170.1
117.7
6.75
152.6
120.2
139.2
8.16
119.7
130.6
173.7
126.8
7.30
138.6
7.46
132.7
7.39
136.9
8.06
−9.2
−5.2
−0.50
−2.1
−7.8
−11.4
−1.00
−6.2
H5
C6
C1'
C2'
C3'
H3'
C4'
H4'
C5'
H5'
C6'
H6'
−7.4
−14.6
−10.5
−0.01
−7.1
0.04
−2.2
−0.04
−12.2
−0.83
RMSD values
13C NMR = 8.84 ppm
1H NMR = 0.138 ppm
13C NMR = 8.79 ppm
1H NMR = 0.569 ppm
aConformer with Φ = 65 °. bConformer with Φ = 5 °. cExperimental – theoretical, e.g., C2: 160.9 − 169.1 = −8.2 ppm.
The theoretical coupling constants at the same 24 geometries pling constants (F···C or F···H) for selected nuclei of interest
from geometry scan for coumarin 6 were obtained using the were obtained using a scaling factor calculated from the ob-
same functional and level of theory (B3LYP/6-311G). The cou- served and calculated 1JFC value for CFCl3 [48]. Selected
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graphs of the plots of nJFH and nJFC as a function of rotation of
the fluorophenyl ring are included in Supporting Information
File 1.
Figures S18 and S19 show the magnitude of 5JFH and 6JFH be-
tween the fluorine atom and H3 and H5, respectively. It can be
seen that, at the B3LYP/6-311G) level, when coupling between
F and either H3 or H5 is large enough to be observed in an
NMR spectrum (magnitude ≈1–11 Hz for H5, ≈1–5 Hz for H3),
coupling to the other nucleus is near zero and may not
necessarily be observed. This is consistent with the idea of
an average angle in solution that places the fluorine atom closer
to H5 than H3, since F–H5 coupling is obvious in the experi-
mental NMR spectrum (Figure 1), while F–H3 coupling is not.
A similar prediction is made for coupling between F–C5 and
F–C3 (Figures S14 and S17 in Supporting Information File 1).
At angles that would manifest in an experimental F–H5 cou-
pling of ≈2.5 Hz, with near-zero F–H3 coupling, Gaussian
predicts small F–C coupling to both C5 and C3. This is consis-
tent with the experimental observation of 5JFC ≈ 1.4 Hz
between F and C5 and no observed coupling between F
and C3, in the 13C-{1H} spectrum. Gaussian also predicts F–C
coupling between the fluorine atom and carbons C4 and C4a,
magnitude <1 Hz and 1–1.5 Hz, respectively. While the <1 Hz
Figure 7: Short contacts within the single-crystal X-ray structure of
coumarin 6.
F–C4 coupling might not be noticeable in the 13C-{1H} spec- and H5 for the optimized structure is 2.807 Å which is relative-
trum, it should be possible to see F–C4a coupling of 1–1.5 Hz, ly close to that of the crystal structure (2.547 Å). Selected com-
since the F–C5 coupling is observable at a similar magnitude. parisons are shown in Table 2.
The model (B3LYP/6-311G) seems to work reasonably well for
coupling between F and H3, H5, C3, C4, and C5 but not for
Table 2: Comparison of some features of the X-ray crystal structure
C4a.
and DFT optimized structure of 6: Through-space (TS) and dihedral
angle (Φ).
The single crystal X-ray analysis of coumarin 6 was carried out
as it has not been reported previously [CCDC No.: 1868146].
The crystals of 6 were obtained by slow evaporation of metha-
nol/dichloromethane and were found to be of the monoclinic
crystal system with space group C2/c (Figure 7).
Run
Dihedral
angle (°)
TS distance (Å)
F···C5
F···H5
H6···H3
Φ
6 (exp)
6 (DFT)
difference
2.547
2.807
0.260
2.934
3.174
0.24
2.535
2.874
0.339
54.44
65.27
10.83
The crystal structure shows that the fluorinated phenyl ring is at
a torsion angle (Φ, C2'–C1'–C4–C4a angle) of 54.44° to the
coumarin moiety. The F···H5 TS-distance of 2.547 Å is small
enough to induce some rotational constraint on the C4 and C1' Conclusion
bond, as the constraint was observed at an F···H distance of The synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin (6) via
2.9 Å [37]. The short contact interactions show that there are the Pechmann reaction was successful. The solution-state 1H
C–F···H–C intermolecular interactions to the neighboring mole- and 13C NMR spectra of 6 showed that there is a strong intra-
cules (F–H6 and F–H5; different molecules) that play a crucial molecular interaction between F and H5 (JFH = 2.6 Hz) and
role in crystal packing (Figure 7).
suggest that this interaction is through-space C–F···H–C cou-
pling, since C5 is coupled to F (JFC = 1.4 Hz) whereas C4 and
As mentioned above, the structure of coumarin 6 was opti- C4a are not. The 2D HOESY spectrum shows the F···H5 cou-
mized and the dihedral angle, Φ (C2'–C1'–C4–C4a) was found pling and also F···H3 coupling, seemingly weaker than F···H5
to be 65.3° (Figure 5), which is comparible close to that found since splitting of the H3 signal is not observed in the 1H and
in the crystal structure (Φ = 54.4°). The TS distance between F 1H-{19F} 1D spectra. The single crystal X-ray structure showed
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Beilstein J. Org. Chem. 2020, 16, 190–199.
that the fluorinated phenyl ring is orientated in a manner that 3JH,H = 7.6 Hz, 4JH,F = 6.2 Hz, 4JH,H = 1.9 Hz, 1H, H6');
brings the fluorine atom closer to H5 than H3. The same orien- 13C NMR (100 MHz, CDCl3) 49.6 (d, 2hJC,F = 8.1 Hz, C2),
tation was observed in the DFT-optimized (B3LYP/6-311G) 52.3 (C4), 116.7 (d, 2JC,F = 24.1 Hz, C3'), 124.7 (d, 3JC,F =
structure. The X-ray data also showed the intermolecular 2.9 Hz, C6'), 129.3 (d, 2JC,F = 21.7 Hz, C1'), 131.0 (d, 4JC,F =
C–F···H–C interactions which, together with other interactions, 2.3 Hz, C5'), 135.5 (d, 3JC,F = 9.6 Hz, C4'), 162.2 (d, 1JC,F =
are resposible for the crystal packing.
254.3 Hz, C2’), 167.8 (d, 3hJC,F = 3.0 Hz, C3), 190.1 (d,
TSJC,F = 3.7 Hz, C1).
Experimental
General
Synthesis of 7-hydroxy-4-(2-fluorophenyl)coumarin (5): To
All reagents (including solvents) were purchased from the a mixture of resorcinol (2.0 g, 18 mmol) and methyl 2-fluo-
chemical suppliers Aldrich, Fluka and Merck. For all moisture- robenzoylacetate (3.5 g, 18 mmol) was added H2SO4 (8 mL,
sensitive reactions, the glassware was thoroughly dried in an 75%). The temperature of a stirred mixture was increased to
oven at ca. 140 °C for 12 h prior to use, and anhydrous solvents 35 °C. After stirring for 5 h, the mixture was poured into
were used under inert conditions. Qualitative thin-layer chroma- crushed ice and neutralized with a NaOH solution. The mixture
tography (TLC, silica gel 60254, aluminum backed) was used to was filtered under vacuum and the residue was washed with
monitor the reactions. Visualization of the TLC plates was plenty of water. The resulting product was purified by silica gel
achieved using an iodine tank and/or fluorescence on exposure column chromatography with 60% EtOAc in hexane as eluent
to short wavelength ultraviolet light (254 nm). For purification, and 5 was obtained as a light yellow solid (4.2 g, 91%), mp
column chromatography (silica gel 60, 0.040–0.063 mm) or 204–207 °C, TLC Rf 0.45 (hexane/EtOAc, 2:3). 1H NMR
centrifugal chromatography conducted on a Harrison Research (400 MHz, DMSO-d6) 6.24 (s, 1H, H3), 6.77 (dd, 3JH,H =
Chromatotron model 7924T (glass plates coated with silica gel 8.6 Hz, 4JH,H = 2.4 Hz, 1H, H6), 6.81 (d, 4JH,H = 2.4 Hz, 1H,
60 PF254 containing gypsum, 2 and 4 mm thick layer) was used. H8), 7.03 (dd, 3JH,H = 8.6 Hz, 1hJH,F = 2.6 Hz, 1H, H5),
7.37–7.45 (m, 2H, H3', H6'), 7.50 (td, 3JH,H = 7.5 Hz, 4JH,H =
Nuclear magnetic resonance (NMR) spectra were recorded on a 1.8 Hz, 1H, H5'), 7.61 (m, 1H, H4'), 10.67 (s, 1H, OH);
Bruker Avance 400 spectrometer equipped with a 5 mm BBOZ 13C NMR (100 MHz, DMSO-d6) 102.6 (C8), 110.7 (C4a),
probe at frequencies of 400 MHz, 100 MHz, and 376 MHz for 112.1 (C3), 113.4 (C6), 116.1 (d, 2JC,F = 21.3 Hz, C3'), 122.7
1H, 13C, and 19F, respectively. High-resolution mass spectrome- (d, 2JC,F = 15.3 Hz, C1'), 125.2 (d, 3JC,F = 3.6 Hz, C6'), 127.9
try (HRMS) was performed on a Waters LCT Premier time-of- (d, 2hJC,F = 1.6 Hz, C5), 130.8 (d, 4JC,F = 2.9 Hz, C5'), 132.0
flight mass spectrometer.
(d, 3JC,F = 8.2 Hz, C4'), 150.3 (C4), 155.2 (C8a), 158.6 (d,
1JC,F = 248.6 Hz, C2'), 160.0 (C2), 161.6 (C7); HRMS–ESI+
Synthesis of methyl 2-fluorobenzoylacetate (3): To a stirred (m/z): [M + Na]+ calcd for C15H9O3FNa, 279.0433; found,
mixture of MgCl2 (2.0 g, 21 mmol) and Et3N (2.1 g, 21 mmol) 279.0437,
in dry DCM (15 mL) at room temperature, methyl acetoacetate
(2, 2.0 g, 17 mmol) was added slowly. The mixture was stirred Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin (6): A
for 30 min before the temperature was reduced to 0 °C. n-BuLi mixture of 7-hydroxy-4-(2-fluorophenyl)coumarin (5 ,0.77 g,
(20 mL of a 1.6 M in hexane, 32 mmol) was added slowly into 3.0 mmol), dimethyl sulfate (0.76 g, 6.0 mmol) and K2CO3
the mixture and the mixture was stirred for a further 30 min. (0.83 g, 6.0 mmol) was refluxed in acetone (20 mL) for 4 h. The
2-Fluorobenzoyl chloride (1, 2.7 g, 17 mmol) was added drop- reaction mixture was cooled to room temperature and and brine
wise into the mixture and the mixture was stirred for 15 min. (50 mL) was added then extracted with ethyl acetate
The reaction mixture was allowed to reach room temperature (3 × 40 mL). The organic layer was dried over anhydrous
and was stirred overnight. To the reaction, was added 5 M HCl MgSO4 and the solvent was removed in vacuo. The resulting
(8 mL) and distilled water (10 mL) and the mixture was light yellow product was purified by silica gel column chroma-
extracted with DCM (3 × 30 mL). The organic layer was dried tography with 60% EtOAc in hexane as eluent and 6 was ob-
over anhydrous MgSO4 and the solvent was removed in vacuo. tained as a yellow crystalline solid (0.78 g, 2.9 mmol, 97%), mp
The resulting yellow product was purified by silica gel column 167–170 ºC, TLC Rf 0.54 (hexanes/EtOAc, 3:2). 1H NMR
chromatography with 10% EtOAc in hexane as eluent and 3 (400 MHz, CDCl3) 3.88 (s, 3H, OMe), 6.25 (s, 1H, H3), 6.79
was obtained as a light orange viscous liquid (2.7 g, 81%), TLC (dd, 3JH,H = 8.9 Hz, 4JH,H = 2.5 Hz, 1H, H6), 6.89 (d, 4JH,H =
Rf 0.50 (hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3) 3.76 2.5 Hz, 1H, H8), 7.16 (dd, 3JH,H = 8.9 Hz, 1hJH,F = 2.5 Hz, 1H,
(s, 3H, H4), 4.01 (d, 1hJH,F = 3.4 Hz, 2H, H2), 7.15 (ddd, H5), 7.23 (dd, 3JH,H = 7.8 Hz, 4JH,F = 4.5 Hz, 1H, H6'), 7.29
3JH,F = 12.1 Hz, 3JH,H = 8.5 Hz, 4JH,H = 1.0 Hz, 1H, H3'), 7.26 (td, 3JH,H = 3JH,F = 7.8 Hz, 4JH,H = 1.8 Hz, 1H, H3'), 7.35 (td
(t, 3JH,H = 7.6 Hz, 1H, H5'), 7.57 (m, 1H, H4'), 7.95 (ddd, 3JH,H = 7.8 Hz, 4JH,H = 1.8 Hz, 1H, H5'), 7.50 (m, 1H, H4');
197

Beilstein J. Org. Chem. 2020, 16, 190–199.
5. Emmanuel-Giota, A. A.; Fylaktakidou, K. C.; Litinas, K. E.;
13C NMR (100 MHz, CDCl3) 55.8 (OMe), 101.0 (C8), 112.4
(C4a), 112.5 (C3), 113.5 (C6), 116.3 (d, 2JC,F = 21.9 Hz, C3'),
123.2 (d, 2JC,F = 15.4 Hz, C1'), 124.7 (d, 3JC,F = 3.7 Hz, C6'),
127.8 (d, 2hJC,F = 1.4 Hz, C5), 130.5 (d, 4JC,F = 3.1 Hz, C5'),
131.5 (d, 3JC,F = 7.9 Hz, C4'), 150.5 (C4), 155.7 (C8a), 159.1
(d, 1JC,F = 250.0 Hz, C2'), 160.9 (C2), 163.0 (C7). HRMS–ESI+
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The authors would like to acknowledge the Ph.D. thesis by
Vuyisa Mzozoyana (University of KwaZulu-Natal, South
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The authors gratefully acknowledge National Research Founda-
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ORCID® iDs
Vuyisa Mzozoyana - https://orcid.org/0000-0002-6679-1541
Fanie R. van Heerden - https://orcid.org/0000-0002-5710-7525
Craig Grimmer - https://orcid.org/0000-0002-6788-4731
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A non-peer-reviewed version of this article has been previously published
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