Synthesis of fused 1,2-naphthoquinones with cytotoxic activity using a one-pot three-step reaction

Article abstract of DOI:10.1039/d1ob00205h

A method for the synthesis of fused 1,2-naphthoquinones, as analogues of biologically active natural terpene quinones, is described. The intermediate polycyclic naphthalenes were prepared by a one-pot palladium-catalysed process from simple alkynes, one o

Full text of DOI:10.1039/d1ob00205h

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Biomolecular Chemistry
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Synthesis of fused 1,2-naphthoquinones with
cytotoxic activity using a one-pot three-step
reaction†
Cite this: Org. Biomol. Chem., 2021,
19, 3434
Anton A. Nechaev,a Pratap R. Jagtap, a Ema Bažíková,a Johana Neumannová,a
a
Ivana Císařováb and Eliška Matoušová
*
A method for the synthesis of fused 1,2-naphthoquinones, as analogues of biologically active natural
terpene quinones, is described. The intermediate polycyclic naphthalenes were prepared by a one-pot
palladium-catalysed process from simple alkynes, one of which was made from an optically pure
biomass-derived levoglucosenone. The prepared methoxy-substituted naphthalenes were subsequently
transformed in one step to 1,2-naphthoquinones by a trivalent-iodine-mediated oxidation. The naphtho-
quinone products were found to have cytotoxic properties.
Received 2nd February 2021,
Accepted 18th March 2021
DOI: 10.1039/d1ob00205h
rsc.li/obc
Naphthalene and naphthoquinone moieties are present in
To this end, we proposed a palladium-catalysed tandem
many biologically active compounds occurring in nature.1 reaction which would combine three catalytic steps: cyclic car-
Their properties include cytotoxic,2–6 antibacterial,7,8 and bopalladation, Suzuki cross-coupling and the Heck reaction,
other activities.9–19 More specifically, a 1,3-dihydronaphtho transforming alkynes 1 directly to fused naphthalenes 3
[2,3-c]furan skeleton can be found among naturally occurring (Scheme 1). To achieve a good selectivity in the tandem reac-
lignans,11,16,20 of which justicidin B (Fig. 1) displays a remark- tion, we planned to use 2-bromo-substituted arylboronic acids,
ably wide range of biological properties.21 The previously pub- which should ensure that the rate of the first carbopalladation
lished syntheses of compounds with this structural motif are step (via oxidative addition to the C–I bond) is higher than
usually based on the formation of the middle ring, either by
cycloaddition,22–30 electrocyclisation,31,32 photocyclisation,33
or base-mediated34,35 and metal-catalysed36–41 cyclisations.
The related 1,2-naphthoquinones are less abundant in
nature than 1,4-naphthoquinones, and the same applies to
the reports of their syntheses. The preparation of o-naphtho-
quinones fused with aliphatic ring or rings, as e.g. in manso-
none
D or miltirone, has been rather scarce in the
literature.17,42–46 For this reason, and also to achieve higher
structural diversity for future bioactivity screening, we aimed
to develop a new method for the synthesis of such com-
pounds, preferably performing several metal-catalysed steps
in one pot to achieve better efficiency and atom economy.47–49
Fused benzene rings were synthesised by a related one-pot
process previously.50–52
Fig. 1 Natural products with naphthalene and o-naphthoquinone
cores.
aDepartment of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8,
128 00 Praha 2, Czech Republic. E-mail: eliska.matousova@natur.cuni.cz
bDepartment of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova
8, 128 00 Praha 2, Czech Republic
†Electronic supplementary information (ESI) available: Additional experiments
and characterisation data; copies of 1H and 13C NMR spectra for all new com-
pounds; cytotoxicity data for 3ba, 4a, 4b and 5a; and X-ray data for 5a. CCDC
1985309. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob00205h
Scheme 1 Proposed one-pot synthesis of naphthalenes 3 and their
oxidation to 1,2-naphthoquinones 4 or 5.
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Table 1 Substrate scope of the cyclisation/Suzuki and Heck reactions
that of the Heck reaction (i.e. the third step). Because of the
rigidity of the benzylic double bond in dienes 2, a 6-endo
mode should be preferred in the Heck reaction over a 5-exo
cyclisation. In addition, we planned to develop an oxidation
method to convert the methoxy-substituted products 3 to
o-naphthoquinones 4 or 5, structurally similar to natural
terpene quinones (such as those in Fig. 1), and evaluate their
cytotoxic properties.
As a starting material we chose a simple alkyne 1a (Fig. 2),
which was prepared from cyclohexenone in three steps, two of
which do not require purification. An optically pure starting
compound 1b was obtained by a similar three-step procedure
from a biomass-derived levoglucosenone, which is a versatile
chiral building block53–55 that provides a greener alternative to
conventional chemicals. Besides, we prepared two nitrogen-
containing alkynes 1c and 1d (see the ESI† for details).
We began our study by exploration of the stepwise pro-
cedure for the synthesis of naphthalenes 3. Regarding the con-
ditions, after several attempts we found that our previously
reported conditions56 for Suzuki cross-coupling (5 mol% of Pd
(PPh3)4, 2 equiv. of Cs2CO3, THF/H2O, 70 °C) can be used for
the first part of the synthesis, providing good yields of bro-
mides 2 despite the presence of the aromatic C–Br bond. The
All yields in Table 1 are isolated yields. Conditions for the tandem
reaction: Pd(PPh3)4 (4 mol%), Cs2CO3 (2 equiv.), boronic acid (1.6 eq.),
70 °C, THF/H2O (4 : 1). Conditions for the Heck reaction: XphosPd G2
(10 mol%), XPhos (20 mol%), K2CO3 (2 equiv.), 110 °C, DMF/H2O
(4 : 1). a Conditions: Pd2(dba)3 (10 mol%), P(o-tol)3 (20 mol%), Cs2CO3
(2 equiv.), DMF/H2O (10 : 1). b At 130 °C. c At 80 °C, mixture of E/Z
isomers (9.7 : 1). d At 80 °C, mixture of E/Z isomers (2.4 : 1).
e Inseparable mixture. f Mixture of E/Z isomers (2.5 : 1). g Partial hydro-
lysis of the ester group was observed. h Mixture of E/Z isomers (3.2 : 1).
i In DMF/H2O.
following Heck reaction was initially performed with
a
methoxy-substituted product 2aa using Pd2(dba)3 as a catalyst
and XPhos as a ligand in DMF/H2O at 110 °C, providing the
product of 6-endo cyclisation 3aa in 60% isolated yield.
Notably, the corresponding 5-exo product was not observed in
the reaction mixture. Screening of palladium sources and
ligands showed that the best combination was either Pd(OAc)2
with XPhos or dppf ligands, or XPhosPd G2 with an additional
XPhos ligand (see the ESI† for the optimisation details). The
latter catalytic system gave the best 1H NMR yield (70%) and
was therefore used in the following investigation of the scope.
First, we explored the scope for reactions of alkyne 1a with
at all (products 2ag and 2ah were not observed). On the other
hand, the ester-substituted and heteroaromatic boronic acids
were well tolerated in the first step, but the corresponding
Suzuki products 2ai, 2aj and 2ak showed only poor reactivity
in the Heck reaction. In the case of naphthalene 3ai, only 16%
of the desired ester product was isolated, and the formation of
a small amount of the corresponding carboxylic acid was
observed. Its mass was determined by MS and product-specific
signals appeared in the 1H NMR spectra but we were unable to
obtain a pure compound.
Other alkynes 1b, 1c and 1d were tested in the reactions
with both 5- and 4-methoxy- and with 5-fluoro-substituted
phenylboronic acids. Alkyne 1b gave good yields of methoxy-
substituted products 2ba and 2bb (70 and 88%), the first of
which underwent the following Heck reaction smoothly (64%
yield of 3ba), and the latter yielded only 36% of 3bb. The
fluoro-substituted boronic acid behaved well in the first reac-
tion, producing 62% of 2bf, but the next step resulted in an
inseparable mixture of compounds. In the case of the nitro-
gen-containing alkynes 1c and 1d, the yields of both reactions
were good with all the three above-mentioned boronic acids,
with generally better overall yields for 1d, including a notice-
able excellent 91% yield of naphthalene 3da. However, both
a
series of 2-bromo-substituted (hetero)arylboronic acids
(Table 1). The results showed that the substituent in position 5
of the boronic acid had almost no influence on the outcome,
the yields being similarly good for both methoxy (2aa, 3aa)
and fluoro substituents (2af, 3af), as for an unsubstituted aro-
matic ring (2ad, 3ad). Methoxy substituents were generally well
tolerated in the cyclisation/Suzuki reaction – compounds 2ab,
2ac and 2ae were isolated in good yields of 81, 93, and 67%,
respectively. Unfortunately, out of the three, only 2ab reacted
in the following Heck reaction step, yielding the naphthalene
product 3ab in 55% isolated yield. The 6-fluoro-substituted
arylboronic acids did not participate in the reaction sequence
Fig. 2 Substrates used in this work (Mbs
= 4-methoxybenzene-
sulfonamide).
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steps required longer reaction times and/or higher tempera- degassing than the Suzuki step. Regarding the base and
tures compared to the reactions with oxygen-containing sub- solvent, replacing K2CO3 with Cs2CO3 improved the outcome
strates 1a and 1b. In a few cases, especially with alkyne 1d, the slightly, but using different solvents slowed down the Heck
formation of the undesired Z-isomer of 2 was observed in the reaction and it never proceeded to completion (entries 4–6,
Suzuki reaction. In particular, 2cb, 2db, 2df and 2di were pro- and Table S2 in the ESI†).
duced as inseparable mixtures of E and Z isomers, in E/Z
Screening experiments in deuterated solvents (entries 7–16)
ratios ranging from 9.7 : 1 for 2cb to 2.4 : 1 for 2db. In the reac- enabled us to rapidly identify the best catalytic system for the
tion of 1d with the methoxycarbonyl-substituted boronic acid, one-pot reaction. It was the combination of Pd2(dba)3 with tri
the corresponding product 2di was formed in 63% yield, but, (o-tolyl)phosphine that improved the 1H NMR yield of the final
similarly as with 2ai, the following Heck reaction conditions product 3aa to 72% with no remaining intermediate 2aa
caused hydrolysis of the ester group and no naphthalene detected (entry 12). Out of the other electron-rich ligands,
product 3di was isolated.
tricyclohexylphosphine provided the second best yield of 50%
After having studied both reactions individually, we began (entry 10), but the bulky trimesityl- and tributylphosphine
our investigation of the conditions suitable for a one-pot reac- gave only low yields of the naphthalene product (entries 14
tion which would comprise all the three catalytic steps and 15).
(Table 2). Firstly, we subjected starting material 1a directly to
The optimised conditions for the one-pot process were then
the optimised Heck reaction conditions, in an attempt at a applied to the other substrates 1 with 2-bromo-5-methoxyphe-
one-pot synthesis of 3aa, but only a mixture of products was nylboronic acid (Scheme 2). To our delight, we obtained the
obtained, with approximately 15% yield of the intermediate
2aa and 7% yield of the final product 3aa (entry 1). Changing
the catalyst to Pd(PPh3)4 used in the Suzuki reaction, but with
6 equiv. of the base and in a higher boiling DMF/H2O solvent
system, increased the yield of naphthalene 3aa to 20% (entry
2). We found that higher temperature was necessary for the
Heck reaction to occur, while the first two steps proceeded
easily at 70 °C with full consumption of starting alkyne 1a in
less than two hours. Therefore, in all the following experi-
ments, we set up the reaction at 70 °C, later increasing the
temperature to 110 °C, without monitoring the reaction
between the steps. It was also found during optimisation that
the Heck reaction required much more thorough solvent
Scheme 2 One-pot three-step tandem reaction of alkynes 1 providing
naphthalenes 3.
Table 2 Optimisation of the one-pot cyclisation/Suzuki/Heck reaction
Entry Catalyst
Ligand
Base
Solvent
Time at 70 °C [h] Time at 110 °C [h] Yielda of 2aa [%] Yielda of 3aa [%]
b
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Herrmanne
XPhos
—
XPhos
—
—
—
K2CO3
K2CO3
K2CO3
DMF/H2O (4 : 1)
DMF/H2O (10 : 1)
DMF/H2O (10 : 1)
—
3
3
2
2
20
2
2
15
11
5
0
6
15
8
47
Traces
14
16
0
0
20
0
7
20
26
26
26
30
34
30
Traces
50
60
72
60
4
Cs2CO3 DMF/H2O (10 : 1)
Cs2CO3 Dioxane/H2O (15 : 1)
3
16c
3
Cs2CO3 Toluene/H2O (10 : 1)
2
d
—
K2CO3
DMF-d7/D2O (10 : 1) 1.5
3
3
3
3
3
4
4
4
PPh3
dppf
PCy3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(mes)3
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
9
10
11
12
13
14
15
16
TTBP·HBF4 Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
Cs2CO3 DMF-d7/D2O (10 : 1) 1.5
4
4
14
28
—
0
a 1H NMR yield; 3,4,5-trichloropyridine was used as the internal standard. b 2 equiv. of the base used. c At 100 °C. d 0.5 equiv. of CsOPiv was
added. e trans-Di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II).
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oxygen-containing products 3aa and 3ba in 61 and 58% iso- demethylation. There have been only a few examples of such
lated yields, respectively. In both cases, it meant an increase in direct oxidations in the literature, mostly to prepare 1,4-
the yield in comparison with the results for the stepwise naphthoquinones using either ceric ammonium nitrate
process, where the overall yields were 49% of 3aa and 45% of (CAN),60 Dess–Martin periodinane,61 or [bis(trifluoroacetoxy)
3ba (compare Scheme 2 with Table 1). Even better results were iodo]benzene (PIFA)62,63 as an oxidant.
observed for the nitrogen-containing starting materials 1c and
In the case of substrate 3aa, however, oxidation with CAN
1d, providing naphthalenes 3ca in 76% yield and 3da in 82% gave only 9% yield of the desired quinone 4a (Table 3, entry 1),
yield, which was a great improvement in overall yields (pre- and a pentavalent IBX reagent did not bring about the oxi-
viously 37 and 66%).
dation at all. A more thorough screening revealed that the tri-
Both the one-pot reaction and the cyclisation/Suzuki reac- valent iodine reagents (PIFA, PIDA and PhI(OPiv)2) under
tion were also attempted using the corresponding pinacol bor- acidic conditions were the oxidants of choice for this trans-
onates and BF3K salts instead of boronic acids. We found that formation. Under basic conditions, on the other hand, we
the reactivity of pinacol esters was very similar to that of free observed only low yields of the naphthoquinone product (see
boronic acids in both steps; the reactions with esters were entry 7 and additional optimisation experiments in the ESI†).
cleaner but with slightly lower yields. BF3K salts, on the other The best results were obtained with sulphuric acid as an addi-
hand, reacted only sluggishly under the same conditions (see tive (compare entries 3–6), which in combination with PIDA
the ESI† for the detailed experimentation).
provided the highest isolated yield of quinone 4a (84%, entry
As the next step in the synthesis of o-naphthoquinones with 9). These conditions were also suitable for the regioisomeric
a natural-product-like skeleton, we studied the oxidation of the naphthalene 3ab, which was transformed into product 5a in
two methoxy-substituted naphthalene products 3aa and 3ab to 71% isolated yield (entry 14). The structure of compound 5a
the corresponding quinones. A two-step approach consisting was unequivocally confirmed by single-crystal X-ray analysis
of methyl cleavage followed by oxidation, which is the most (Fig. 3).
common approach,42–45,57–59 was not successful in our case as
The optimised conditions were then used for the oxidation
3aa failed to produce the corresponding naphthol when of levoglucosenone-derived compounds 3ba and 3bb. Despite
treated with BBr3. Therefore, we focused on a direct oxidative the presence of an acid-labile acetal group in their structure,
Table 3 Oxidation of naphthalenes 3 to naphthoquinones 4 and 5
Entry, substrate
Oxidant
Additive
Temp. [°C]
Time [min]
Product, yielda [%]
1, 3aa
2, 3aa
3, 3aa
4, 3aa
5, 3aa
6, 3aa
7, 3aa
8, 3aa
CANb
—
0 to r.t.
0
60
5
5
35
5
5
30
30
5
5
30
5
4a, 9
4a, 32 (31)
4a, 41
4a, 40
4a, 49
4a, 84
4a, 20
4a, 54
4a, 85 (84)
5a, 42
5a, 35
5a, 17
5a, 62
5a, (71)
4b, (52)
5b, (24)
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
PIFAd
BF3·Et2Oc
BF3·Et2O
TMSOTf
TfOH
−15
−15 to 0
−15
H2SO4
NaHCO3
−15
e
−12 to r.t.
−15
PIFA
H2SO4
H2SO4
H2SO4
H2SO4
BF3·Et2O
H2SO4
H2SO4
H2SO4
H2SO4
9, 3aa
PIDAf
−15
−15
10, 3ab
11, 3ab
12, 3ab
13, 3ab
14, 3ab
15, 3ba
16, 3bb
PIDA
PIFA
−15 to r.t.
−15
PIDA
PIDAg
−35 to 10
−35 to r.t.
−15 to r.t.
−15 to 5
60
40
20
40
PIDAg
PIFA
PIFA
a 1H NMR yield; 3,4,5-trimethoxybenzaldehyde was used as the internal standard. Isolated yield in brackets. b 5 equiv. of the oxidant used, MeCN/
H2O (4 : 1) as a solvent. CAN = ammonium cerium(IV) nitrate. c 3 equiv. of the additive used. d PIFA = [bis(trifluoroacetoxy)iodo]benzene. e 2 equiv.
of the base used. f PIDA = (diacetoxyiodo)benzene. g MeCN/H2O (3 : 1) used as a solvent.
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Experimental
General procedure for the cyclisation/Suzuki reaction
Iodide 1 (1 mmol) was dissolved in 9.1 mL of THF or DMF fol-
lowed by addition of (hetero)arylboronic acid (1.5 mmol),
Cs2CO3 (2.0 mmol) and water (0.9 mL). The reaction mixture
was degassed and backfilled with argon (2×); then Pd(PPh3)4
(4 mol%) was added and the degassing procedure was repeated
twice more. The reaction mixture was stirred at 70 °C (or 80 °C
for DMF) until the full conversion of the starting material was
observed by TLC, and then cooled down and extracted with
water (25 mL) and EtOAc (2 × 25 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude mixture was subjected to
column chromatography delivering the desired Heck/Suzuki
product 2.
Fig. 3 PLATON plot of naphthoquinone 5a showing displacement ellip-
soids drawn at the 30% probability level.
the corresponding regioisomeric o-naphthoquinone products
4b and 5b were formed in both cases, albeit in lower isolated
yields: 52 and 24%, respectively (Table 3, entries 15 and 16).
Nitrogen-containing compounds 3ca and 3da were subjected
to the same conditions too, but the starting naphthalenes
mostly decomposed during the reaction and only traces of the
corresponding quinone products were observed.
General procedure for the Heck reaction
Compound 2 (1.0 mmol), K2CO3 (2.0 mmol), XPhos (20 mol%)
and XPhosPd G2 (10 mol%) were dissolved in DMF (8 mL) and
stirred for 5 minutes before water (2 mL) was added. The reac-
tion mixture was degassed and backfilled with argon (3×) and
stirred at 110 °C for an indicated time. Upon completion, it
was cooled down, filtered through a sand/cotton layer and
extracted between brine (2 × 20 mL) and EtOAc (20 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude mixture was
subjected to column chromatography providing the desired
product 3.
Regarding the mechanism of the oxidation, since the usual
nucleophilic attack of a free phenolic hydroxyl group on iodine
is not possible in this case, we suppose that the activation of
the ortho position next to the methoxy substituent occurs as an
attack of the electron-rich aromatic ring on the electrophilic
iodine atom of the reagent. This step would be later followed
by elimination of methanol, similarly as described in the work
of Kita.64 Such a mechanism would rationalise the necessity of
using acidic conditions in this reaction because the methoxy
group would become a better leaving group by protonation.
The cytotoxic activity of product 3ba and three of the pre-
pared 1,2-naphthoquinones was evaluated on five cell lines,
including four human cancer cell lines and normal dermal
fibroblasts. Naphthalene 3ba did not show any cytotoxic pro-
perties, but all the tested naphthoquinones 4a, 4b and 5a dis-
played activities against the two tested leukemic cell lines and
cervical carcinoma cells with IC50 values in the range of 1.5 to
6.3 μmol L−1. However, the mentioned quinones were also
toxic for normal human fibroblasts at concentrations of the
same order of magnitude (see the ESI† for details of cyto-
toxicity screening and description of the used method).
General procedure for the one-pot tandem reaction
Compound 1 (0.2 mmol), arylboronic acid (0.3 mmol) and
Cs2CO3 (1.2 mmol) were dissolved in DMF (1.8 mL) and water
(0.18 mL). The reaction mixture was degassed and backfilled
with argon (3×), or degassed by bubbling Ar through the
mixture for 5 minutes. Then Pd2(dba)3 (0.02 mmol) and P(o-
tol)3 (0.04 mmol) were added; the mixture was degassed again
and stirred for an indicated time at 70 or 80 °C, and then at
110 or 130 °C. Upon completion, the reaction mixture was
cooled down, diluted with toluene and concentrated under
reduced pressure. The crude mixture was subjected to column
chromatography on silica gel providing the desired naphtha-
lene product 3.
Conclusions
General procedure for the oxidation
In summary, biologically active fused 1,2-naphthoquinones
were synthesised using a palladium-catalysed one-pot reaction Naphthalene 3 (0.3 mmol) was suspended in 2,2,2-trifluor-
(with up to 82% isolated yield) and a one-step oxidation of the oethanol (TFE) or MeCN (1.8 mL) under an argon atmosphere
resulting naphthalenes with trivalent iodine reagents in up to and cooled down to an indicated temperature. Sulphuric acid
84% isolated yield. Two of the naphthoquinone products were (1.8 mmol), preliminarily mixed with water (0.6 mL), followed
prepared in optically pure forms starting from levoglucose- by PIDA or PIFA (0.6 mmol), were added to the mixture and
none, which is available from renewable sources. The prepared stirred vigorously for an indicated time and temperature. Upon
compounds were subjected to cytotoxicity screening, showing completion, the reaction was quenched at 0 °C by a slow
that the studied 1,2-naphthoquinones were active against three addition of saturated aqueous NaHCO3 and the mixture was
human cancer cell lines in μM concentrations. Thus, the extracted between water (15 mL) and EtOAc (2 × 15 mL). The
results can serve as a background for further studies of this combined organic layers were dried over Na2SO4, filtered and
interesting class of compounds.
concentrated under reduced pressure. The crude product was
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purified by column chromatography on silica gel yielding the 14 D. Delorme, Y. Ducharme, C. Brideau, C.-C. Chan,
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was supported by the Czech Science Foundation
(project no. 16-22419Y), funding of Charles University (project
PRIMUS/17/SCI/14), and Charles University Research Centre
(programme UNCE/SCI/014). We are grateful to Dr Helena
Mertlíková-Kaiserová and her group for cytotoxicity testing. We
also thank Circa Group Pty Ltd for kindly supplying a sample
of levoglucosenone.
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