Assembling the prenylneoflavone system through a Pechmann condensation/Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis sequence

Article abstract of DOI:10.1007/s00706-020-02584-8

Abstract: The multistep synthesis of a prenylneoflavone through a sequence of the Mitsunobu reaction/Claisen rearrangement/olefin cross-metathesis reaction has been accomplished in 5% yield over six steps starting from commercially available 3-methoxyacet

Full text of DOI:10.1007/s00706-020-02584-8

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02584-8
ORIGINAL PAPER
Assembling the prenylneofavone system through a Pechmann
condensation/Mitsunobu reaction/Claisen rearrangement/olefn
cross‑metathesis sequence
Oleg A. Lozinski1,2,3 · J. Bistodeau2 · C. Bennetau‑Pelissero4 · Vladimir P. Khilya1 · S. Shinkaruk2
Received: 27 November 2019 / Accepted: 21 March 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
The multistep synthesis of a prenylneofavone through a sequence of the Mitsunobu reaction/Claisen rearrangement/olefn
cross-metathesis reaction has been accomplished in 5% yield over six steps starting from commercially available 3-meth-
oxyacetophenone. The sequence is shown to be compatible with a Pechmann condensation which proved to be a robust and
cost-efective method for the assembling of the α-pyrone core. The results open doors to a general approach to the prenyl-
neofavone system starting from phenol and acetophenone derivatives.
Graphic abstract
Keywords Prenyl · Flavonoids · Alkenes · Heterocycles · Metathesis
Introduction
Prenyl group plays an important role in the enhancement of
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-020-02584-8) contains
supplementary material, which is available to authorized users.
bioactivity [1] being responsible for protein–protein bind-
ing through the specifc attachment to the prenyl binding
domains [2]. For a range of oxygen-containing heterocy-
cles, the presence of prenyl group is linked to the increased
potency of estrogenic activity profle [3]. Notably, 8-pre-
nylnaringenin (8PN, 1, Fig. 1) is considered to be the most
potent estrogenic favonoid known [4].
* Oleg A. Lozinski
lozinskioleg@gmail.com
1
Taras Shevchenko National University of Kyiv, Kyiv,
Ukraine
In addition, targeting proteases is an efective antiviral
strategy in suppressing viral genome replication to cure
CoV infection [5]. Angiotensin-converting enzyme (ACE)
inhibitors are blockbusters among protease inhibitors on the
market [6]. Zhou et al. confrmed that 2019-nCoV uses the
same cell entry receptor—angiotensin-converting enzyme II
2
University of Bordeaux, ISM, UMR 5255, CNRS, Bordeaux,
France
3
University of Bordeaux, Neurocentre Magendie, UMR 1215,
INSERM, Bordeaux, France
4
University of Bordeaux, ARNA, UMR 1212,
INSERM/CNRS, Bordeaux, France
Vol.:(0123456789)
1 3

O. A. Lozinski et al.
Results and discussion
Our studies in the requisite 4-(3-methoxyphenyl)-8-(3-meth-
ylbut-2-en-1-yl)-2-oxo-2H-chromen-7-yl acetate (3) synthe-
sis (Scheme 1) commenced with close examination of the
strategy and the means of the synthesis that should meet
the criteria required in terms of cost-efective and feasible
design. The synthetic task falls into two groups of questions:
the prenyl group installment and the α-pyrone ring assem-
bling, respectively.
Two approaches towards the prenylcoumarin motif are
distinguished: (1) starting from salicylic aldehydes and cin-
namates through the tandem Claisen rearrangement/Wittig
olefnation/cyclization sequence [9] and (2) using preformed
coumarin skeleton via the Mitsunobu reaction/Claisen rear-
rangement/olefn cross-metathesis reaction sequence [10].
The latter was used by Tischer and Metz for the synthesis
of the naturally occurring 8-prenylnaringenin (1), 6-prenyl-
naringenin (4), 6-prenylgenistein (5), and 6-prenylquercetin
(6) (Fig. 1).
Fig. 1 Compounds 1, 2, and 4–6
(ACE2)—as SARS-CoV [7]. This represents protease inhibi-
tors as attractive targets in search for the treatment of 2019-
nCoV. Interestingly, the prenylated derivative of quercetin
2 (Fig. 1) exhibited the highest inhibitory efects on the
papain-like protease [PLpro] in SARS-CoV (IC50 =3.7 μM)
[5].
It has drawn our attention as the excellent example of the
synergy of up-to-date olefn cross-metathesis reaction and
conventionally used the Claisen rearrangement in a single
synthetic sequence through which prenyl group can be read-
ily installed.
A set of prenylation methods have been reported up to
date [8]. The prenylneofavone system assembling is of par-
ticular interest due to the fact that neofavones represent one
of the most ubiquitous classes of naturally occurring oxygen-
containing heterocycles that still remain poorly investigated.
However, to extend the substrate scope of this approach
it may be advantageous to start from aromatic compounds
Scheme 1
1 3

Assembling the prenylneofavone system through a Pechmann condensation/Mitsunobu…
such as phenols. As part of our ongoing research program in
the feld of the chemistry of oxygen-containing heterocycles
[11] we aimed to build a bridge between the conventionally
used and the most state-of-the art methods. Thus, we chose
the Pechmann condensation to study its compatibility with
the Mitsunobu reaction/Claisen rearrangement/olefn cross-
metathesis reaction sequence to access prenylneofavones
starting from aromatic compounds such as 3-methoxyace-
tophenone (7) (Scheme 1).
manner employing the idea of the synergy of cost-efective
and powerful means to organic synthesis.
The foregoing synthetic blueprint demonstrates the key
scissions in the retrosynthesis of the prenylneofavone 3 via
the synthetic strategy shown in the Scheme 1.
To assemble the pivotal neofavone system, the two-
step conversion of 3-methoxyacetophenone (7) into
7-hydroxy-4-(3-methoxyphenyl)-2H-chromen-2-one (8)
was efected via the Claisen condensation of 7 into ethyl
3-(3-methoxyphenyl)-3-oxopropanoate (9) in 40% yield, fol-
lowed by the Pechmann condensation of 9 with resorcinol in
the presence of sulfuric acid to obtain neofavone 8 in 52%
yield (Scheme 2) [12].
In view of the presence of multiple reaction centers in two
aromatic rings of a neofavone, its ortho-functionalization
must be efectively achieved through the Claisen rearrange-
ment. A series of groups has been reported in the literature
as prenyl synthons, namely 2-methylbut-3-en-2-yl, prenyl,
and allyl [8].
With neofavone 8 in hand, our attention turned to pre-
nyl group installment in the neofavone core. The prenyl
group installment strategy relied upon the sequence of the
Mitsunobu reaction and the Claisen rearrangement with
the following olefn cross-metathesis reaction. Therefore,
subsequent treatment of 8 with DIAD, PPh3 in THF at 0 °C
resulted in 7-allyloxy-4-(3-methoxyphenyl)-2H-chromen-2-
one (10) formation in 78% yield (Scheme 3).
Nevertheless, the selective Claisen rearrangement is a
challenging task because of the isomer formation in the com-
petent Claisen–Cope rearrangement [8]. At the same time,
allyl group has been reported to be the versatile synthon of
prenyl group in the Mitsunobu reaction/Claisen rearrange-
ment/olefn cross-metathesis reaction sequence [8].
This approach relies upon the Mitsunobu alkylation
which is not water sensitive and, therefore, takes an advan-
tage of time-saving benefts compared to a classical alkyla-
tion using alkyl halides and bases in a dry solvent. It enables
proceeding on the next step without further purifcation of
the coumarin obtained via the Pechmann condensation.
Therefore, the Pechmann condensation/Mitsunobu alkyla-
tion/Claisen rearrangement/olefn cross-metathesis reaction
sequence represents the approach through which the pre-
nylneofavone synthesis can be readily achieved in a cheap
In the 1H NMR spectrum of O-allyl product 10 recorded
in CDCl3 the doublet at 4.61 ppm, the doublet of doublet of
triplets at 5.34–5.45 ppm and at 6.05 ppm are consistent with
OH substitution with allyl moiety.
The Claisen rearrangement proved to be the most chal-
lenging step required extensive troubleshooting for reaction
conditions optimization. Thermal and Lewis acid catalysis
factors are considered [8]. It has been reported that in con-
trast to the boron trichloride catalyst, upon treatment with
Et2AlCl, a range of substituted allylchlorophenyl ethers bear-
ing electron-withdrawing groups on the aromatic ring under-
took the Claisen rearrangement to aford allylchlorophenols
in quantitative yields [13].
Scheme 2
However, the attempted reaction of 7-allyloxyneofavone
10 with Et2AlCl at the same conditions resulted in dealkyla-
tion of 7-allyloxyneofavone 10 (Scheme 3, Table 1) to give
neofavone 8 in 87% yield. Therefore, we chose to proceed
Scheme 3
1 3

O. A. Lozinski et al.
Table 1 The optimization
of the reaction conditions of
the Claisen rearrangement of
O-allyl product 10
Entry
T/°C
Time/h
Solvent
W
Catalyst
11
Yield/%
1
2
3
4
5
6
r.t
70
160
230
230
230
24
20
2
7
20
20
Toluene
DCM
DMF
DMF
DMF
DMF
–
Et2AlCl
–
–
–
13
–
–
–
–
300
300
300
300
300
–
a
Eu(fod)3
60
aFod refers to 6,6,7,7,8,8,8-heptafuoro-2,2-dimethyl-3,5-octanedionate
on the Claisen rearrangement with thermal conditions in
the microwave-assisted synthesis of the compound 11 [14].
Interestingly, Eu(fod)3 had a marked efect upon 8-allyl-7-
hydroxy-4-(3-methoxyphenyl)-2H-chromen-2-one (11) for-
mation. Thus, heating in microwaves 7-allyloxyneofavone
10 at 230 °C in DMF for 20 h recovered starting material
only, while the addition of Eu(fod)3 (9 mol%) gave rise to
60% yield of C-allylated product 11 (Table 1), set for the
further step in the olefn cross-metathesis reaction.
second-generation Grubbs catalyst failed in the conditions
identical to those reported by Hastings et al. [15, 16]. We
envisaged that the olefn cross-metathesis reaction with
8-allylneofavone 12 would proceed in relatively low yield
of the target 3,3′-dimethylallyl product 3 in view of the steric
hindrance factor that requires a higher temperature for this
reaction. Therefore, in contrast with the approach reported
by Tischer and Metz (2-methyl-2-butene, the second-gener-
ation Grubbs catalyst (1 mol%), benzene, room temperature,
overnight, 73% yield for a mixture) the suggested rapid heat-
ing in microwaves (100 °C, 300 W) of the 8-allylneofavone
12, 2-methyl-2-butene, the second-generation Grubbs cata-
lyst (5 mol%) in DCM under argon allowed us to overcome
this problem successively to isolate the pivotal product 3 in
65% yield. The demonstrated 6 steps synthesis of the target
compound 3 proceeded in an overall yield of 5%.
1H NMR spectrum of 8-allyl-7-hydroxyneofavone 11
shows the signal at 8.12 ppm assigned to OH, while the
absence of H8, the doublet at 3.63 ppm, the multiplets at
5.00–5.12 ppm and 5.95–6.11 ppm indicate the CO-bond
cleavage and the substitution of C-8 with allyl group.
Acetylation of 11 with acetyl chloride was then under-
taken to facilitate the product solubility in the olefn cross-
metathesis reaction conditions (Scheme 3). It furnished
the acetylated product 12 in 79% yield. The singlet at
2.35 ppm in the 1H NMR spectrum (acetone-d6) of 12 and
the absence of the singlet at 8.12 ppm assigned to OH in the
1H NMR spectrum (acetone-d6) of 8-allyl-7-hydroxy-4-(3-
methoxyphenyl)-2H-chromen-2-one (11) are associated with
the OH substitution with acetyl group.
The 1H NMR spectrum (acetone-d6) of 3,3′-dimethylal-
lyl product 3 reveals two singlets at 1.69 ppm and 1.87 ppm
assigned to two CH3 groups in addition to the absence of the
corresponding multiplet at 5.01–5.14 ppm assigned to the
olefnic=CH2 moiety in the 1H NMR spectrum (acetone-d6)
of the compound 12.
With 7-acetoxyneofavone 12 in hand, its further elabo-
ration to the 3,3′-dimethylallyl derivative 3 was pursued
through the olefn cross-metathesis reaction with the second-
generation Grubbs catalyst (Scheme 4).
Conclusion
The prenylneofavone system assembling has been achieved
in six steps in 5% overall yield using the Pechmann conden-
sation with the sequence of the Mitsunobu reaction/Claisen
Notably, Pahari et al. reported that attempted the
olefin cross-metathesis reaction in the presence of the
Scheme 4
1 3

Assembling the prenylneofavone system through a Pechmann condensation/Mitsunobu…
rearrangement/olefn cross-metathesis reaction. It allowed
extending the substrate scope for abovementioned prenyla-
tion approach with regard to the prenylneofavone system
assembling starting from phenols. The present approach will
be useful in medicinal chemistry to modulate the bioactivity
of drug candidates through the structural modifcation of
oxygen-containing heterocycles with the lipophilic prenyl
group. It is of particular interest for the creation of protease
inhibitors against the CoV infection.
was added dropwise 5 cm3 sulfuric acid over 30 min, fol-
lowed by the heating of the reaction mixture at 65 °C for
7 h. The reaction mixture was then cooled down to the room
temperature and poured into 50 cm3 of distilled water and
then extracted with chloroform (3 × 50 cm3). The solvent
was removed under reduced pressure; the viscous brown oil
was dissolved in the 0.5 M solution of potassium hydroxide
(100 cm3) and extracted with DCM (3×50 cm3). The aque-
ous layer was acidifed with HCl (15% aq) until pH 1 and
then extracted with chloroform (3 × 50 cm3). The organic
layer was dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure. The oil residue was re-
crystallized from MeOH to give 8. White solid; yield: 0.50 g
(52%); m.p.: 242 °C (Ref. [12]. 241–243 °C).
Experimental
Reaction progress and identity of obtained compounds were
monitored by TLC on Merck 60 F254 silica gel plates. NMR
spectra were recorded on Bruker Avance 300 (spectrom-
eter frequency for 1H: 300 MHz) spectrometer at 298 K in
DMSO-d6, CDCl3, and acetone-d6. The TMS signal was
used as an internal standard. The results of elemental analy-
ses for C, H, and N were found to be in good agreement
(0.2%) with the calculated values. Compound 8 was syn-
thesized according to a procedure published in the literature
[12]. All reagents and solvents used were of commercial
quality without further purifcation.
7‑Allyloxy‑4‑(3‑methoxyphenyl)‑2H‑chromen‑2‑one
(10, C19H16O4) To a stirred solution of 0.88 g 8 (1 equiv,
3.28 mmol), 1.07 g triphenylphosphine (1.24 equiv,
4.07 mmol) and 0.4 cm3 allyl alcohol (1.79 equivalents,
5.87 mmol) in 20 cm3 distilled THF was added dropwise
a solution of 1.10 cm3 diisopropyl azodicarboxylate (1.71
equiv, 5.61 mmol) in 20 cm3 distilled THF under argon at
0 °C over 10 min. The reaction was stirred at room tem-
perature overnight. Then it was quenched with brine and
washed with it several times until no precipitate formed.
The aqueous layer was extracted with Et2O (3 × 50 cm3)
and the layers were separated. The combined organics were
dried over anhydrous MgSO4 and the volatiles were removed
under reduced pressure. The crude product was purifed by
silica gel column chromatography (cyclohexane/Et2O, from
8:2 to 7:3) to give 10. White solid; yield: 0.79 g (78%); 1H
NMR (CDCl3, 300 MHz): δ=3.86 (s, 3H, CH3O), 4.61 (d,
2H, J=5.7 Hz, OCH2), 5.34–5.45 (ddt, 2H, J=44.5, 17.2,
1.7 Hz,=CH2), 6.05 (ddt, 1H, J=17.3, 10.5, 5.3 Hz,=CH–),
6.23 (s, 1H, H3), 6.81 (dd, 1H, J = 8.9, 2.6 Hz, H8), 6.90
(d, 1H, J=2.5 Hz, H6′), 6.95 (t, 1H, J=2.1 Hz, H2′), 7.03
(td, 2H, J=11.5, 2.7 Hz, H6, H5′), 7.42 (dd, 2H, J=11.5,
2.7 Hz, H4′, H5) ppm; 13C NMR (CDCl3, 75 MHz):
δ = 53.58, 69.82, 101.98, 111.83, 112.57, 112.82, 114.08,
114.99, 118.58, 120.70, 128.05, 129.97, 132.17, 137.35,
155.67, 156.67, 160.31, 161.22, 162.24 ppm.
Ethyl 3‑(3‑methoxyphenyl)‑3‑oxopropanoate (9) Die-
thyl carbonate (4.94 g, 41.85 mmol, 1.03 equiv) was
added dropwise to the solution of 5.07 g sodium hydride
(211.28 mmol, 5.2 equiv) and 6.02 g 3-methoxyacetophe-
none (7, 40.63 mmol, 1 equiv) in 50 cm3 distilled THF under
argon. The reaction mixture was then stirred at refux for
6 h. The resulting mixture was cooled down to the room
temperature, a beige precipitate was observed. It was then
fltered out and the fltrate was acidifed with HCl (15% aq)
and extracted with EtOAc (3×50 cm3). The organic layer
was washed with brine and dried over anhydrous MgSO4.
The solvent was removed under reduced pressure, and the
residue was purifed by silica gel column chromatography
(cyclohexane/EtOAc, 8:2) to give 9. Brown oil; yield: 3.72 g
(40%); b.p.: 123 °C/0.3 Torr) (Ref. [17]. 123 °C/0.3 Torr);
1H NMR of keto form: (CDCl3, 300 MHz): δ = 1.24 (t,
3H, J = 6 Hz, CH3CH2), 3.84 (s, 3H, CH3O), 3.96 (s, 2H,
CH2), 4.20 (q, 2H, J=9 Hz, CH3CH2), 7.10–7.14 (m, 1H,
H2′); 7.34–7.39 (m, 1H, H5′), 7.46–7.50 (m, 2H, H4′, H6′)
ppm; 1H NMR of enol form (CDCl3, 300 MHz): δ=1.32 (t,
3H, J = 6 Hz, CH3CH2), 3.82 (s, 3H, CH3O), 4.25 (q, 2H,
J=9 Hz, CH3CH2), 5.64 (s, 1H,=CH–), 6.97–7.01 (m, 1H,
H2′), 7.30–7.33 (m, 3H, H4′, H5′, H6′), 12.57 (s, 1H, OH)
ppm [18].
8‑Allyl‑7‑hydroxy‑4‑(3‑methoxyphenyl)‑2H‑chromen‑2‑one
(11, C19H16O4) To a solution of 0.65 g 10 (1 equiv,
2.11 mmol) in 12 cm3 DMF was added 0.22 g Eu(fod)3
(9 mol%). The vial was sealed and heated at 230 °C under
microwaves for 20 h (START SYNTH Microwave synthesis
labstation, 300 W). The reaction mixture was then washed
with the aqueous HCl (15% aq) (3×50 cm3) and extracted
with EtOAc (3×40 cm3) and the layers were separated. The
combined organics were dried over anhydrous MgSO4 and
the volatiles were removed under reduced pressure. The
viscous brown oil was dissolved in the 0.5 M solution of
7‑Hydroxy‑4‑(3‑methoxyphenyl)‑2H‑chromen‑2‑one (8) To
a stirred solution of 0.803 g 9 (3.62 mmol, 1 equiv) and
0.52 g resorcinol (4.71 mmol, 1.3 equiv) in 8 cm3 EtOH
1 3

O. A. Lozinski et al.
potassium hydroxide (100 cm3) and extracted with DCM
(6 × 30 cm3). The aqueous layer was acidifed with HCl
(15% aq) and extracted with chloroform (5×40 cm3). The
organic layer was dried over anhydrous MgSO4, the solvent
was removed under reduced pressure to give. The crude
product was purifed by silica gel column chromatography
(cyclohexane/Et2O, from 8:2 to 7:3) to give 11. Light yellow
solid; yield: 0.39 g (60%); 1H NMR (acetone-d6, 300 MHz):
δ = 3.63 (d, 2H, J = 6.3 Hz, –CH2–), 3.89 (s, 3H, CH3O),
5.00–5.12 (dd, 2H, J=10.0, 17.1 Hz,=CH2), 5.95–6.11 (m,
1H,=CH–), 6.12 (s, 1H, H3), 6.92 (d, 1H, J=8.9 Hz, H6′),
7.01–7.16 (m, 3H, H2′, H6, H5), 7.25 (d, 1H, J= 8.8 Hz,
H4′), 7.47 (t, 1H, J=8.1 Hz, H5′), 8.12 (s, 1H, OH) ppm;
13C NMR (acetone-d6, 76 MHz): δ=26.84, 55.46, 102.49,
110.52, 111.63, 112.58, 113.65, 114.69, 114.97, 121.78,
125.84, 129.84, 135.39, 137.31, 153.79, 156.00, 158.81,
159.94, 160.20 ppm.
(acetone-d6, 300 MHz): δ=1.69 (s, 3H, CH3), 1.87 (s, 3H,
CH3), 2.38 (s, 3H, CH3CO), 3.52 (d, 2H, J=7.1 Hz, –CH2–),
3.89 (s, 3H, CH3O), 5.19 (t, 1H, J=7.1 Hz, –CH–), 6.33 (s,
1H, H3), 7.02–7.20 (m, 4H, 2′, H6′, H6, H5), 7.40 (dd, 1H,
′
J=8.8, 5.8 Hz, H4), 7.44–7.57 (m, 1H, H5′) ppm; 13C NMR
(acetone-d6, 76 MHz): δ=17.06, 20.51, 26.61, 54.09, 54.90,
113.87, 115.25, 116.77, 118.698, 120.63, 121.55, 125.21,
126.53, 127.00, 130.63, 132.79, 136.76, 151.61, 152.82,
155.35, 159.34, 160.02, 168.97 ppm.
Acknowledgements Oleg Lozinski thanks Erasmus Mundus and Dr.
Aline Marighetto for providing with such a brilliant opportunity to
broaden horizons in Organic Chemistry. We would like to thank Dr. V.
Ishchenko and Dr. S. Vasylevskyi for their support.
References
8‑Allyl‑4‑(3‑methoxyphenyl)‑2‑oxo‑2H‑chromen‑7‑yl acetate
(12, C21H18O5) To a stirred solution of the crude product of
11 (1 equiv, 0.33 g, 1.08 mmol) in 1 cm3 pyridine was added
0.46 cm3 acetyl chloride (6 equiv). The reaction mixture
was stirred at refux for 6 h. The mixture was poured into
distilled water and then extracted with DCM. The organic
layer was dried over anhydrous MgSO4 and the solvent
removed under reduced pressure. The brown oil was purifed
by silica gel column chromatography (cyclohexane/EtOAc,
8:2) to give 12. Brown solid; yield: 0.3 g (79%); 1H NMR
(acetone-d6, 300 MHz): δ=2.35 (s, 3H, CH3CO), 3.57 (dt,
2H, J=6.3, 1.6 Hz, –CH2–), 3.88 (s, 3H, CH3O), 5.01–5.14
(qq, 2H, J=6.3, 1.5 Hz,=CH2), 5.83–6.04 (m, 1H,=CH-),
6.33 (s, 1H, H3), 7.07–7.15 (m, 4H, H2′, H6′, H6, H5),
7.36–7.59 (m, 2H, H4′, H5′) ppm; 13C NMR (acetone-d6,
76 MHz): δ=20.55, 27.72, 55.46, 113.88, 114.01, 115.27,
115.60, 117.36, 118.98, 120.64, 121.27, 125.45, 129.99,
134.55, 137.76, 151.86, 153.40, 155.31, 159.29, 160.60,
169.05 ppm.
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Publisher’s Note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional afliations.
1
9:1) to give 3. Brown oil; yield: 0.06 g (65%); H NMR
1 3