Transition-Metal-Free One-Pot Synthesis of Naphthoquinonefuran Derivatives through Sequential Nucleophilic Substitution-Nucleophilic Addition Reaction

Article abstract of DOI:10.1021/acs.joc.0c00513

A transition-metal-free route for tandem one-pot synthesis of naphthoquinonefuran derivatives from 2-hydroxynaphthoquinones has been developed. The sequentially accomplished process comprises an intermolecular alkynylation of sp2-carbon at the 3 position of 2-hydroxynaphthoquinones with arylethynyl bromides, followed by a base-promoted intramolecular nucleophilic annulation reaction. A broad range of functional groups is compatible with this reaction, and diverse naphtho[2,3-b]furan-4,9-diones can be obtained with good yields and excellent regioselectivity.

Full text of DOI:10.1021/acs.joc.0c00513

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Note
Transition-Metal-Free One-Pot Synthesis of
Naphthoquinonefuran Derivatives Through Sequential
Nucleophilic Substitution–Nucleophilic Addition Reaction
Xiang Li, Peng Sun, Kaijun Xie, Dun Zhou, Jinsong Peng, Aihong Fan, Jing Zhang, and Chunxia Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00513 • Publication Date (Web): 17 Jun 2020
Downloaded from pubs.acs.org on June 17, 2020
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Transition-Metal-Free One-Pot Synthesis of Naphthoquinonefuran
Derivatives Through Sequential Nucleophilic Substitution–Nucleophilic
Addition Reaction
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Xiang Li,†,# Peng Sun,†,‡,# Kaijun Xie,† Dun Zhou,† Jinsong Peng,*,† Aihong Fan,† Jing
Zhang,† and Chunxia Chen*,†,‡
† College of Chemistry, Chemical Engineering and Resource Utilization, Northeast
Forestry University, Harbin, 150040, P. R. China. ‡Material Science and
Engineering College, Northeast Forestry University, Harbin, 150040, P. R. China.
# Xiang Li and Peng Sun contributed equally to this work.
Abstract
O
O
OH
O
NaOMe/TBAB
DMA, 120 ℃, 24 h
Transition metal-free
R1
R1
Ar
Br
Ar
+
O
O
R1 = EWG, EDG
47-81% yield
26 examples
One-pot tandem reaction
Wide substrate scope
Good to high yields
High regioselectivity
A
transition-metal-free route for tandem one-pot synthesis of
naphthoquinonefuran derivatives from 2-hydroxynaphthoquinones has been
developed. The sequentially accomplished process comprises an intermolecular
alkynylation of sp2-carbon at the 3 position of 2-hydroxynaphthoquinones with
arylethynyl bromides, followed by a base-promoted intramolecular nucleophilic
annulation reaction. A broad range of functional groups are compatible with this
reaction, and diverse naphtho[2,3-b]furan-4,9-diones can be obtained with good
yields and excellent regioselectivity.
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As an important privileged scaffold, the naphthofuroquinone is a well-known
pharmacophoric unit present in natural products, drugs and drug candidates.1 A
great number of naphthofuroquinones have exhibited diverse biological activities
such as antitumor,2 anti-inflammatory,2a anti-leukemic activity,3 trypanocidal,4
cytotoxic activity toward KB5 and Vero cells,6 inhibitor of HaCaT cell growth,7 and
inhibitor of human keratinocyte hyperproliferation.8 The wide spectrum of
biological activities has attracted widespread interest in the field of medicinal
chemistry, therefore, much effort has been focused on the synthetic methods of
naphthofuroquinone derivatives. Over the past decades, base-catalyzed,9
bromine-mediated,10 different annulation11-15 (such as thermal cyclization,11
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photoaddition,12
oxidative
cycloaddition,13
Diels-Alder
cycloaddition/aromatization,14 oxidative cyclization/isomerization,15) one-pot
cascade,16 and transition-metal-catalyzed17 syntheses of the naphthofuroquinone
skeleton have been reported.
Tandem reactions, through the integration of two or more distinct
transformations into one-pot processes, play an important role in the rapid
buildup of molecular complexity and diversity.18 As a dual functionalized
compounds, haloalkynes have emerged as versatile building blocks for the
construction of heterocycle through a sequential one-pot procedure in recent
years.19 Impressive effort has also been devoted to the development of transition
metal-catalyzed methodologies for the syntheses of diverse heterocyclic
architectures (Scheme 1a). For instance, benzo[b]furans,20 indoles and 1,2-
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benzothiazine 1,1-dioxides backbones,21 imidazole-fused or quinolinone-fused
isoquinolines,22 flavonoids,23 and isocoumarin24 have been constructed through
the nucleophilic addition/Pd-catalyzed C-H bond cyclization by Wang,20 Urabe,21
Wu and Jiang,24 and our group,22,23 respectively. Compared with the well-
developed transition metal-catalyzed methods using haloalkynes as the building
blocks, metal-free examples for heterocycle preparation are much less
documented. Gevorgyan25a pioneered the study of haloalkynes serving as a source
of both X+ and acetylide ions, and demonstrated a metal-free one-step synthesis of
alkynylepoxides from easily available enolizable ketones (Scheme 1b). In addition,
Jørgensen25b described an organocatalytic enantioselective direct α-alkynylation
of β-ketoesters and 3-acyl oxindoles in the presence of K2CO3 (Scheme 1b).
Inspired by Gevorgyan and Jørgensen’s works25 and our ongoing studies on the
chemistry of haloalkynes,22,23 herein, we design a simple one-pot and transition
metal-free protocol to obtain naphthofuroquinone derivatives by the alkynylation
of 2-hydroxynaphthoquinones with alkynyl bromides and subsequent
intramolecular nucleophilic addition (Scheme 1c).
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Wang’s previous work revealed that alkynyl bromides can undergo
nucleophilic addition by phenols to generate (Z)-2-bromovinyl phenyl ethers
regio- and stereoselectively with high yields in the presence of Cs2CO3 using DMF
as the solvent at 110 ℃.20 On the other hand, Gevorgyan demonstrated that
alkynyl bromides can also be used as equivalents of the corresponding Br+ ion and
nucleophilic acetylide ions in the presence of stronger base (KHMDS) to afford a
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mixture of brominated and alkynated products.25 Due to the dual nature of
haloalkynes, we first needed to address chemical selectivity issue (nucleophilic
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addition20 vs bromination25,26 or alkynation25) when using
naphthoquinones as the substrates (Scheme 1c).
2-hydroxy-1,4-
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Scheme 1. The construction of heterocyclic architectures using haloalkynes
(a) transition metal-catalyzed
benzo[b]furans20
Nucleophilic
Addtion
indoles21
R
H
annulation
X
R
isoquinolines22
flavonoids23
metal-catalyzed
Nu:
X = Cl, Br, I
Nu
X
isocoumarin24
(b) transition metal-free
Gevorgyan25a
R3
O
R2
R2
O
Br
Br+and
R3
t-BuONa, THF
R2
R1
+
R1
R3
R2
Jørgensen25b
O
O
CO2tBu
3 mol% organocatalyst
CO2tBu
Br
EWG
+
o-xylene/CHCl3 = 7:1
K2CO3, 74-99% yield
88-97% ee
EWG
dihydrocinchonidine derived chiral phase-transfer catalyst
(c) this work
O
O
OH
O
base
R1
R1
Ar
Br
Ar
+
metal-free
O
O
R1 = EWG, EDG
Scheme 2. Fundamental Data for Reaction Condition Optimizationa
O
O
OH
O
NaOMe/TBAB
Ph
Ph
(1.5 eq.)
2a
Br
+
DMA, 120 ℃, 24 h
65%
O
1a
O
3a
modified parameters based on standard conditions
base/yieldb
solvent/yieldb
DMF, 53%
additivec/yieldb
____, 0%
CsF, 46%
PivONa, 41%
DMSO, 40%
NMP, 32%
TBAC, 26%
TBAI, 36%
BTEAC, 48%
Cs2CO3, 15%
KOAc, 13%
MeCN, 12%
1,4-dioxane, 30%
Toluene, 36%
trace: THF, DCE
time/yieldb
Et3N, 11%
18-crown-6, 56%
TBAB, 41%d; 56%e
temperature/yieldb
80 ℃, trace
KOH, 9%
trace: K2CO3, Li2CO3, KHCO3
HCOONa, NaOAc, KF, K3PO4
t-BuOK, t-BuONa, t-BuOLi
NaOH, Pyridine, DBU
12 h, 33%
48 h, 67% (63%)f
100 ℃,42%
140 ℃, 62%
a
1a
2a
Reaction conditions:
(0.2 mmol),
(0.3 mmol), base (3 equiv), additive (3 equiv) and solvent
b
c
(1.0 mL), 24 h, air.
Isolated yields after chromatography.
Abbreviations: TBAB =
tetrabutylammonium bromide, TBAC = tetrabutylammonium chloride, TBAI = tetrabutylammonium
iodide, BTEAC= benzyltriethylammonium chloride. d TBAB (1 equiv) was used. e TBAB (2 equiv)
was used. f One millimole scale.
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2-Hydroxy-1,4-naphthoquinone (1a) and bromoethynylbenzene (2a) as
model substrates were selected for sequential alkynylation and intramolecular
annulation reaction to construct the naphthofuroquinone 3a (Scheme 2). Based
on the results by Gevorgyan,25 Wang,20 and others,21-24 some new investigations
are carried out using the bromoethynylbenzene (2a) as the reagent. First, the
nature and careful selection of base was very important to the reaction outcome,
shown in the left column of Scheme 2. Various bases such as weak bases (Cs2CO3,
K2CO3, Li2CO3, KHCO3, KF, K3PO4, KOAc, and NaOAc), strong bases (NaOtBu, KOtBu,
LiOtBu, KOH, and NaOH), organic bases (Et3N, pyridine and DBU) gave the desired
product 3a from a trace quantity to 15% yield; the product 3a can be obtained in
46 and 41% yields when CsF and PivONa were respectively used; and NaOMe gave
a better result and provided 3a in 65% yield. Second, with NaOMe as the base,
polar solvents (DMA, DMF, DMSO, and NMP) generally provided better results
than those obtained in less-polar solvents such as 1,4-dioxane, acetonitrile, THF,
and DCE; non-polar toluene can give a comparable yield of 36% with DMSO (the
second column, Scheme 2). Third, the additive was found to be essential for the
efficient formation of furonaphthoquinone 3a. In the absence of the additive, no
expected naphthofuroquinone product 3a was obtained in all the cases (right
column, Scheme 2). The above result indicated that the use of TBAB can increase
the dissociation of Csp-Br bond probably through the formation of stable
tetrabutylammonium acetylide. Thus, TBAB, TBAC, TBAI, BTEAC, and 18-crown-6
were explored as the additive. It was found that a higher ratio of TBAB relative to
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1a is preferable to afford a better result [41% (1:1), 56% (2:1), and 65% (3:1)],
however, the use of chloride or iodide analogues (TBAC, TBAI, and BTEAC) to
effect the transformation afforded inferior results than TBAB. Finally, a set of
experiments were carried out to reveal the role of the reaction temperature and
time (right and second column, Scheme 2), 120 ℃ for 24 h was found to be suitable
for this tandem reaction. In addition, the reaction can be carried out on a 1.0 mmol
scale without compromising the yield (63% vs 65%, Scheme 2). In general, in the
presence of combinations of TBAB and NaOMe, the synthesis of
naphthofuroquinones 3 was conducted in a one-pot fashion using DMA as the
solvent at 120 ℃ for 24 h.
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With the optimized reaction conditions in hand, the scope of this tandem
annulation reaction was then examined. A variety of diversely substituted
furonaphthoquinone 3 was obtained in moderate to good yields (Tables 1 and 2).
Firstly, the scope and generality of haloalkyne substrates were explored in this
process (Table 1). The nature of halogen at the alkynyl halide was examined. It
was found that alkynyl iodide is superior over the chloride and bromide analogues
in that reaction. The yield for the alkynyl halide substrates follows the order
alkynyl iodide > alkynyl bromide > alkynyl chloride. As shown in Table 1, a great
variety of substituted aryl and heteroaryl bromoacetylenes 2a-2r can be
converted into the naphthofuroquinones 3 in moderate to good yields (48-79%).
The standard reaction conditions were compatible with various groups including
diverse alkyl substituents (methyl, ethyl, n-propyl, n-butyl, n-pentyl, and tert-
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butyl), methoxy, bromine, chlorine, trifluoromethyl and ester functionality. In
general, the para-, metal-, and ortho-substituted aryl bromoacetylenes 2b-2q can
smoothly undergo sequential alkynylation/annulation reaction to afford the
desired products in good yields. The electronic nature of the aromatic motifs
heavily affected the reaction outcome, the introduction of electron-donating
substituents (alkyl and methoxy) can afford higher yields than electron-
withdrawing substituents (Cl, Br, CF3, and ester). The presence of stronger
electron-withdrawing substituents (such as CN and NO2, 2s and 2t) at the
aromatic ring led to failed reactions under standard reaction conditions. For the
para-alkyl substituted aryl bromoacetylenes 2b-2f, with the length of carbon
chain (from C1 to C5) increasing, the yield increased from 67% to 79%. When
extending the substrate scope to alkyl bromoacetylene 2u, unfortunately, the
reaction cannot proceed to give the corresponding product 3au. It is worth noting
that the reaction of methyl ester substrate 2l and 2-hydroxy-1,4-naphthoquinone
1a generated the n-butyl ester product 3al in 54% through tandem annulation
reaction and subsequent a sodium methoxide-promoted transesterification of
methyl ester with TBAB. Secondly, we then explored the scope of 2-hydroxy-1,4-
naphthoquinone substrates using bromoethynylbenzene 2a as the coupling
partner (Table 2). A variety of substituents on the aryl moiety were applicable,
affording the corresponding cyclized products 3ba-3ga in good yields (65-76%,
Table 2). Both electron- donating (−Me, −OMe) and -withdrawing groups (−F, −Cl,
and −Br) were tolerant under the reaction conditions. The electronic nature of the
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aromatic motifs of 2-hydroxy-1,4-naphthoquinone skeleton did not seem to affect
the efficiency: these substituents can be incorporated at the C6 and C7 positions
and gave the corresponding products with similar yields.
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Table 1. Variation of the Alkynyl Bromide Substratesa,b
O
O
OH
O
NaOMe/TBAB
R
R
Br
+
DMA, 120 ℃, 24 h
2a-w
O
-
O
1a
3aa 3aw
O
O
O
O
O
O
O
O
Ph
CH3
C2H5
X = Cl, 45%
X = Br, 65%
X = I, 70%
O
3aa
O
3ab, 67%
3ac, 69%
O
O
O
O
O
n-C3H7
n-C4H9
n-C5H11
O
O
O
3ad, 73%
3ae, 75%
3af, 79%
O
O
O
O
O
O
OMe
Cl
O
O
O
3ag, 71%
3ah, 71%
3ai, 58%
O
O
O
O
O
O
O
O
Br
CF3
O-n-C4H9
O
O
3aj, 54%
3ak, 48%
3al,c 54%
O
O
O
CH3
OCH3
Cl
O
O
O
O
O
O
3am, 66%
3an, 72%
3ao, 52%
O
O
O
Br
Cl
O
O
O
S
O
O
O
3ap, 54%
3aq, 58%
3ar, 78%
O
O
O
O
O
O
CN
NO2
O
O
O
3as, 0%
3at, 0%
3au, 0%
a Standard conditions unless otherwise stated: 1a (0.2 mmol), 2 (0.3 mmol), MeONa (3 equiv),
c
TBAB (2 equiv) and DMA (1.0 mL), 120 ℃, 24 h, air. b Yield of isolated product. Methyl 4-
(bromoethynyl)benzoate 2l was used.
Table 2. Scope of 2-Hydroxynaphthoquinonesa,b
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O
O
O
OH
O
NaOMe/TBAB
R1
DMA, 120 ℃, 24 h
R1
Ph
Ph
Br
+
2a
O
1b-g
3ba 3ga
-
7
8
9
O
O
O
O
F
Cl
Br
O
O
O
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O
O
3ba, 73%
3ca, 65%
3da, 70%
O
O
O
MeO
Me
O
O
O
MeO
O
O
O
3ea, 76%
3fa, 74%
3ga, 75%
a Standard conditions unless otherwise stated: 1 (0.2 mmol), 2a (0.3 mmol), MeONa (3 equiv),
TBAB (2 equiv) and DMA (1.0 mL), 120 ℃, 24 h, air. b Yield of isolated product.
On the basis of the above results, a plausible reaction pathway for the one-pot
tandem synthesis of naphthofuroquinone derivatives was outlined in Scheme 3. A
sodium methoxide-promoted deprotonation of 2-hydroxynaphthoquinones 1
produced sodium enolate, which was then brominated at the 3-position of 1 to
form the intermediate 4 using the alkynylbromide 2 as the source of Br+.26 The
tautomeric isomer 5 in the keto-form from 4 undergwent a nucleophilic attack by
the produced arylacetylide 6 to give the alkynated intermediate 7, which was
transformed into 3-alkynated hydroxynaphthoquinone 8 through a keto–enol
tautomeric process.
A sodium methoxide-promoted deprotonation and
subsequent intramolecular nucleophilic addition of enolate anion to conjugated
ynone furnished the cyclized product 3. To prove the mechanism, the intermediate
427 was used to react with ethynylbenzene in the presence of sodium methoxide
in DMA at 120 ℃ for 24 h, 3aa can be obtained in 72% yield.
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R
C4H9
C4H9 N-C4H9
C4H9
6
-OMe
O
O
H
O
O
H
O
O
TBAB
Br
Br
Br
R
O
O
O
1
4
5
2
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-OMe

O
O
H
O
O
O

O

R


8

R
O
7
R
O
O
3
H
OMe
Scheme 3. Proposed Mechanism for the tandem synthesis of
Naphthofuroquinones 3.
In conclusion, we have developed a transition metal-free tandem formal [3+2]
approach for rapid syntheses of diverse naphtho[2,3-b]furan-4,9-dione
derivatives through a base-promoted alkynylation and subsequent intramolecular
addition reaction of 2-hydroxynaphthalene-1,4-diones with aryl bromoacetylenes.
The success of this one-pot domino reaction heavily relies on the careful selection
of proper base and additive. The combination of sodium methoxide and TBAB was
found to be essential for the efficient formation of furonaphthoquinones. This
method allows the synthesis of a variety of multi-substituted furonaphthoquinone
derivatives with good functional group tolerance and yields. Considering
considerable valance of the products for medicinal science, this tandem reaction
could be of synthetic utility for the discovery of drugs.
Experimental Section
General Information. Chemicals were all purchased from commercial suppliers
and used without further purification unless otherwise stated. Solvents were
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dried and purified according to the standard procedures before use. Reactions
were monitored by analytical thin-layer chromatography (TLC). All reactions
were conducted in dried glassware. Purification of reaction products was done by
flash chromatography with 230−400 mesh silica gel. Hydroxynaphthoquinones
1a−1g28 and alkynyl halides 222b were prepared according to the literature
methods. Melting points were determined on a melting point apparatus in open
capillaries and are uncorrected. Infrared spectra of samples were recorded from
4,000 to 500 cm−1 in ATR (attenuated total reflectance) mode using an FT-IR
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instrument. H NMR spectra were recorded on a 500 MHz spectrometer, and 13C
NMR spectra were recorded at 126 MHz. Unless otherwise stated,
deuterochloroform (CDCl3) was used as a solvent. Chemical shifts (δ) are given in
parts per million downfield relative to tetramethylsilane (TMS). Chemical shifts
for carbon resonances are reported in parts per million and are referenced to the
carbon resonance of the solvent CHCl3 (δ = 77.16 ppm). The splitting patterns are
reported as s (singlet), d (doublet), dd (double doublet), td (triplet of doublet), t
(triplet), q (quartet), br (broad), and m (multiplet). Coupling constants are given
in hertz. High-resolution mass spectra were recorded on a BIO TOF Q mass
spectrometer equipped with an electrospray ion source (ESI), operated in the
positive mode.
General procedures for the synthesis of 2-arylnaphtho[2,3-b]furan-4,9-
diones 3. A 10 mL vial equipped with a magnetic stirring bar was charged with 2-
hydroxynaphthalene-1,4-diones 1 (0.2 mmol, 1.0 equiv), alkynyl bromides 2
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(0.3mmol, 1.5 equiv), and then sodium methoxide (0.6 mmol, 32.4 mg) and
tetrabutylammonium bromide (TBAB, 0.4 mmol, 129.8 mg) were added. Finally,
DMA (1.0 mL) was added to the mixture via syringe at room temperature under
air. The tube was sealed and put into a preheated oil bath at 120 ℃ for 24 h. The
mixture was cooled to room temperature, quenched with water (5 mL), and
diluted with ethyl acetate (5 mL). The layers were separated, and the aqueous
layer was extracted with 2 × 5 mL of ethyl acetate. The combined organic extracts
were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo.
The crude product was then purified by flash chromatography on silica gel (H),
eluting with the mixture of ethyl acetate and petroleum ether (1:5).
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2-Phenylnaphtho[2,3-b]furan-4,9-dione (3aa). The reaction was carried out on a
1.0 mmol scale. Red solid, mp 248-252 ℃ (lit.15b mp 249-251 ℃); yield, 63% (172.5
mg, Eluent: EtOAc/petroleum ether = 1/5); 1H NMR (500 MHz, CDCl3) δ 8.26 – 8.23
(m, 1H), 8.20 – 8.18 (m, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.78 – 7.73 (m, 2H), 7.51 –
7.44 (m, 3H), 7.19 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 180.8, 173.1, 160.3,
151.6, 134.0, 133.7, 133.1, 132.8, 132.4, 130.3, 129.1, 128.3, 127.0, 126.9, 125.6,
103.0.
2-(p-Tolyl)naphtho[2,3-b]furan-4,9-dione (3ab). Yield, 67% (38.6 mg, Eluent:
EtOAc/petroleum ether = 1/5); yellow solid, mp 264–267 ℃ (lit.15b mp 266-
267 ℃); 1H NMR (500 MHz, CDCl3) δ 8.25 – 8.21 (m, 1H), 8.18 (dd, J = 7.2, 1.4 Hz,
1H), 7.79 – 7.72 (m, 4H), 7.29 – 7.26 (m, 2H), 7.12 (s, 1H), 2.40 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 180.9, 172.9, 160.7, 151.3, 140.7, 134.0, 133.5, 133.1, 132.9,
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132.5, 129.8, 126.9, 126.8, 125.6, 125.5, 102.3, 21.5.
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2-(4-Ethylphenyl)naphtho[2,3-b]furan-4,9-dione (3ac). Yield, 69% (41.7 mg, Eluent:
EtOAc/petroleum ether = 1/5); yellow solid, mp 186–188 ℃ (lit.29 mp 186-189 ℃);
1H NMR (500 MHz, CDCl3) δ 8.19 – 8.16 (m, 1H), 8.12 (dd, J = 7.1, 1.4 Hz, 1H), 7.74
(d, J = 8.1 Hz, 2H), 7.71 – 7.65 (m, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 2.64 (q,
J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 181.0, 173.0,
160.7, 151.3, 147.0, 134.0, 133.6, 133.1, 132.9, 132.6, 128.7, 126.9, 126.8, 125.8,
125.6, 102.3, 28.9, 15.3.
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2-(4-Propylphenyl)naphtho[2,3-b]furan-4,9-dione (3ad). Yield, 73% (46.1 mg,
Eluent: EtOAc/petroleum ether = 1/5); yellow solid, mp 166–169 ℃ (lit.29 mp 167-
169 ℃); 1H NMR (500 MHz, CDCl3) δ 8.19 – 8.16 (m, 1H), 8.14 – 8.10 (m, 1H), 7.74
(d, J = 8.2 Hz, 2H), 7.71 – 7.65 (m, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.07 (s, 1H), 2.57 (t,
J = 7.5 Hz, 2H), 1.65 – 1.57 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 181.0, 173.0, 160.8, 151.3, 145.5, 134.0, 133.6, 133.1, 132.9, 132.6, 129.2,
126.9, 126.8, 125.8, 125.6, 102.3, 38.0, 24.3, 13.8.
2-(4-Butylphenyl)naphtho[2,3-b]furan-4,9-dione (3ae). Yield, 75% (49.6 mg,
Eluent: EtOAc/petroleum ether = 1/5); yellow solid, mp 174–175 ℃; IR (KBr,
cm−1): 2958, 2776, 1663, 1614, 1594, 1487, 1457, 1439, 1364, 1259; 1H NMR (500
MHz, CDCl3) δ 8.19 – 8.15 (m, 1H), 8.14 – 8.08 (m, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.71
– 7.65 (m, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.07 (s, 1H), 2.60 (t, J = 7.5 Hz, 2H), 1.59 –
1.53 (m, 2H), 1.35 – 1.27 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 179.9, 171.9, 159.7, 150.3, 144.7, 132.9, 132.5, 132.1, 131.9, 131.5, 128.2,
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125.9, 125.8, 124.7, 124.5, 101.3, 34.6, 32.3, 21.3, 12.9. HRMS (ESI) m/z: [M+H]+
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Calcd for C22H19O3 331.1329; Found 331.1327.
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2-(4-Pentylphenyl)naphtho[2,3-b]furan-4,9-dione (3af). Yield, 79% (54.4 mg,
Eluent: EtOAc/petroleum ether = 1/5); yellow solid, mp 163–164 ℃; IR (KBr,
cm−1): 3119, 2924, 1662, 1615, 1595, 1487, 1456, 1439, 1370, 1353, 958; 1H NMR
(500 MHz, CDCl3) δ 8.19 – 8.16 (m, 1H), 8.12 (dd, J = 7.2, 1.7 Hz, 1H), 7.74 (d, J =
8.2 Hz, 2H), 7.71 – 7.65 (m, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.07 (s, 1H), 2.59 (t, J = 8.0
Hz, 2H), 1.61 – 1.55 (m, 2H), 1.30 – 1.24 (m, 4H), 0.83 (t, J = 6.9 Hz, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 179.9, 171.9, 159.8, 150.3, 144.8, 132.9, 132.5, 132.1,
131.9, 131.5, 128.2, 125.9, 125.8, 124.8, 124.6, 101.3, 34.9, 30.4, 29.9, 21.5, 13.0.
HRMS (ESI) m/z: [M+H]+ Calcd for C23H21O3+ 345.1485; Found 345.1484.
2-(4-(tert-Butyl)phenyl)naphtho[2,3-b]furan-4,9-dione (3ag). Yield, 71% (46.9 mg,
Eluent: EtOAc/petroleum ether = 1/5); orange solid, mp 170–172 ℃ (lit.29 mp
169-172 ℃); 1H NMR (500 MHz, CDCl3) δ 8.19 – 8.16 (m, 1H), 8.12 (dd, J = 7.3, 1.4
Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.70 – 7.65 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.08
(s, 1H), 1.29 (s, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 179.9, 171.9, 159.6, 152.9,
150.3, 132.9, 132.5, 132.1, 131.9, 131.5, 125.9, 125.8, 125.1, 124.5, 124.4, 101.4,
34.0, 30.1.
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2-(4-Methoxyphenyl)naphtho[2,3-b]furan-4,9-dione (3ah). Yield, 71% (46.9 mg,
Eluent: EtOAc/petroleum ether = 1/5); red solid, mp 213–215 ℃ (lit.15b mp 215-
216 ℃); 1H NMR (500 MHz, CDCl3) δ 8.25 – 8.22 (m, 1H), 8.20 – 8.16 (m, 1H), 7.83
(d, J = 8.8 Hz, 2H), 7.77 – 7.71 (m, 2H), 7.05 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.88 (s,
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3H). 13C{1H} NMR (126 MHz, CDCl3) δ 181.0, 172.8, 161.3, 160.6, 151.1, 134.0,
133.5, 133.1, 133.0, 132.7, 127.3, 126.9, 126.8, 121.1, 114.6, 101.4, 55.5.
2-(4-Chlorophenyl)naphtho[2,3-b]furan-4,9-dione (3ai). Yield, 58% (35.8 mg,
Eluent: EtOAc/petroleum ether = 1/5); red solid, mp 276–278 ℃ (lit.10 mp 276-
277.5 ℃); 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 6.2 Hz, 1H), 8.13 (d, J = 6.4 Hz,
1H), 7.76 (d, J = 8.2 Hz, 2H), 7.72 – 7.67 (m, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.11 (s,
1H). 13C{1H}NMR (126 MHz, CDCl3) δ 179.6, 172.0, 158.1, 150.7, 135.3, 133.1,
132.7, 132.0, 131.8, 131.3, 128.4, 126.0, 125.9, 125.8, 125.7, 102.3.
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2-(4-Bromophenyl)naphtho[2,3-b]furan-4,9-dione (3aj). Yield, 54% (38.4 mg,
Eluent: EtOAc/petroleum ether = 1/5); brown solid, mp 267–269 ℃ (lit.10 mp 267-
268 ℃); 1H NMR (500 MHz, CDCl3) δ 8.18 – 8.16 (m, 1H), 8.12 (dd, J = 7.1, 1.7 Hz,
1H), 7.71 – 7.66 (m, 4H), 7.56 – 7.52 (m, 2H), 7.12 (s, 1H). 13C{1H} NMR (126 MHz,
CDCl3) δ 179.6, 172.0, 158.1, 150.7, 133.1, 132.7, 132.0, 131.8, 131.4, 131.3, 126.2,
126.0, 125.9, 125.9, 123.7, 102.3.
2-(4-(Trifluoromethyl)phenyl)naphtho[2,3-b]furan-4,9-dione (3ak). Yield, 48%
(32.8 mg, Eluent: EtOAc/petroleum ether = 1/5); light yellow solid, mp 205–
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209 ℃; IR (KBr, cm−1): 2784, 1662, 1598, 1445, 1385, 1366, 1113; H NMR (500
MHz, CDCl3) δ 8.19 (d, J = 6.3 Hz, 1H), 8.15 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 7.5 Hz,
2H), 7.77 – 7.64 (m, 4H), 7.24 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 179.6, 172.1,
157.5, 150.8, 133.1, 132.8, 132.1, 132.0, 131.7, 131.2, 129.6, 129.2, 127.4, 126.0,
+
125.9, 123.0, 122.3, 102.9. HRMS (ESI) m/z: [M+H]+ Calcd for C19H10F3O3
343.0577; Found 343.0585.
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Butyl 4-(4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-2-yl)benzoate (3al). Yield, 54%
(40.3 mg, Eluent: EtOAc/petroleum ether = 1/5); light yellow solid, mp 203–
205 ℃; IR (KBr, cm−1): 2775, 1714, 1664, 1596, 1537, 1440, 1365, 1287, 1222,
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1109, 957; H NMR (500 MHz, CDCl3) δ 8.21 – 8.17 (m, 1H), 8.15 – 8.12 (m, 1H),
8.08 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.73 – 7.67 (m, 2H), 7.23 (s, 1H),
4.29 (t, J = 6.6 Hz, 2H), 1.74 – 1.69 (m, 2H), 1.47 – 1.39 (m, 2H), 0.93 (t, J = 7.4 Hz,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 179.5, 172.1, 164.8, 157.9, 151.0, 133.1,
132.8, 132.0, 131.7, 131.2, 131.0, 130.7, 129.3, 126.0, 125.9, 124.3, 103.6, 64.2,
29.7, 18.3, 12.8. HRMS (ESI) m/z: [M+H]+ Calcd for C23H19O5 375.1227; Found
+
375.1220.
2-(m-Tolyl)naphtho[2,3-b]furan-4,9-dione (3am). Yield, 66% (38.4 mg, Eluent:
EtOAc/petroleum ether = 1/5); yellow solid, mp 241–243 ℃; IR (KBr, cm−1): 2777,
1668, 1615, 1594, 1540, 1486, 1457, 1366, 956; 1H NMR (500 MHz, CDCl3) δ 8.18
(dd, J = 7.2, 1.5 Hz, 1H), 8.12 (dd, J = 7.2, 1.5 Hz, 1H), 7.72 – 7.64 (m, 3H), 7.61 (d, J
= 7.8 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 2.37 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 179.8, 172.0, 159.6, 150.4, 137.9, 133.0, 132.6, 132.1,
131.9, 131.4, 130.1, 128.0, 127.2, 125.9, 125.8, 125.1, 121.8, 101.8, 20.4. HRMS
(ESI) m/z: [M+H]+ Calcd for C19H13O3+ 289.0859; found 289.0857.
2-(3-Methoxyphenyl)naphtho[2,3-b]furan-4,9-dione (3an). Yield, 72% (47.1 mg,
Eluent: EtOAc/petroleum ether = 1/5); yellow solid, mp 206–211 ℃; IR (KBr,
cm−1): 2779, 1669, 1614, 1595, 1532, 1473, 1366, 1218; 1H NMR (500 MHz, CDCl3)
δ 8.18 – 8.15 (m, 1H), 8.12 – 8.10 (m, 1H), 7.71 – 7.65 (m, 2H), 7.39 (d, J = 7.7 Hz,
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1H), 7.32 – 7.29 (m, 2H), 7.10 (s, 1H), 6.90 (dd, J = 8.1, 2.1 Hz, 1H), 3.82 (s, 3H).
13C{1H} NMR (126 MHz, CDCl3) δ 179.8, 172.0, 159.2, 159.1, 150.5, 133.0, 132.6,
132.0, 131.8, 131.4, 129.2, 128.5, 125.9, 125.8, 117.1, 115.4, 109.4, 102.2, 54.5.
HRMS (ESI) m/z: [M+H]+ Calcd for C19H13O4+ 305.0808; Found 305.0807.
2-(3-Chlorophenyl)naphtho[2,3-b]furan-4,9-dione (3ao). Yield, 52% (33.7 mg,
Eluent: EtOAc/petroleum ether = 1/5); brown solid, mp 299–302 ℃ (lit.10 mp 300-
301 ℃); 1H NMR (500 MHz, CDCl3) δ 8.27 – 8.25 (m, 1H), 8.22 – 8.20 (m, 1H), 7.90
(s, 1H), 7.81 – 7.75 (m, 3H), 7.48 – 7.41 (m, 2H), 7.23 (s, 1H). 13C{1H} NMR (126
MHz, CDCl3) δ 181.4, 173.9, 157.0, 151.9, 134.7, 134.5, 133.9, 133.5, 132.7, 132.6,
131.8, 131.5, 130.0, 128.0, 127.8, 127.7, 127.6, 109.2.
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2-(3-Bromophenyl)naphtho[2,3-b]furan-4,9-dione (3ap). Yield, 54% (38.1 mg,
Eluent: EtOAc/petroleum ether = 1/5); yellow solid, mp 288–290 ℃; IR (KBr,
cm−1): 2831, 2779, 1666, 1615, 1595, 1441, 1271, 1073; 1H NMR (500 MHz, CDCl3)
δ 8.27 – 8.25 (m, 1H), 8.22 – 8.19 (m, 1H), 8.06 (s, 1H), 7.82 – 7.75 (m, 3H), 7.57 (d,
J = 7.9 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.22 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3)
δ 180.6, 173.2, 158.5, 151.9, 134.1, 133.8, 133.1, 133.0, 132.8, 132.2, 130.7, 130.2,
128.4, 127.1, 127.0, 124.1, 123.3, 103.9. HRMS (ESI) m/z: [M+H]+ Calcd for
C18H10O3Br+ 352.9808; Found 352.9804 (100%), 354.9787 (84%).
2-(2-Chlorophenyl)naphtho[2,3-b]furan-4,9-dione (3aq). Yield, 58% (35.9 mg,
Eluent: EtOAc/petroleum ether = 1/5); orange solid, mp 185–187 ℃ (lit.10 mp
185-186 ℃); 1H NMR (500 MHz, CDCl3) δ 8.20 – 8.17 (m, 1H), 8.16 – 8.14 (m, 1H),
8.04 (dd, J = 7.8, 1.7 Hz, 1H), 7.73 – 7.69 (m, 2H), 7.62 (s, 1H), 7.46 (dd, J = 7.8, 1.3
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Hz, 1H), 7.37 – 7.29 (m, 2H). 13C{1H} NMR (126 MHz, CDCl3) δ 179.6, 172.2, 155.3,
150.2, 133.0, 132.8, 132.1, 131.7, 130.9, 130.8, 130.1, 129.7, 128.3, 126.3, 126.0,
126.0, 125.9, 107.5.
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2-(Thiophen-2-yl)naphtho[2,3-b]furan-4,9-dione (3ar). Yield, 78% (43.7 mg,
Eluent: EtOAc/petroleum ether = 1/5); red solid, mp 218–222 ℃; IR (KBr, cm−1):
3113, 2026, 1661, 1615, 1492, 1371, 1355, 1233; 1H NMR (500 MHz, CDCl3) δ 8.24
– 8.22 (m, 1H), 8.18 (dd, J = 7.3, 1.6 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.62 (dd, J = 3.7,
1.0 Hz, 1H), 7.47 (dd, J = 5.0, 1.0 Hz, 1H), 7.15 – 7.13 (m, 1H), 7.01 (s, 1H). 13C{1H}
NMR (126 MHz, CDCl3) δ 179.6, 171.7, 154.7, 149.9, 133.0, 132.6, 132.0, 131.8,
131.5, 129.8, 127.4, 127.3, 126.1, 125.9, 125.8, 101.6. HRMS (ESI) m/z: [M+H]+
Calcd for C16H9O3S+ 281.0267; Found 281.0260.
7-Fluoro-2-phenylnaphtho[2,3-b]furan-4,9-dione (3ba). Yield, 73% (43.7 mg,
Eluent: EtOAc/petroleum ether = 1/5); red solid, mp 205–206 ℃; IR (KBr, cm−1):
2779, 1667, 1616, 1532, 1456, 1370, 1353, 1264; 1H NMR (500 MHz, CDCl3) δ 8.17
(dd, J = 8.5, 5.3 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.45 – 7.39 (m, 3H), 7.35 – 7.31 (m,
1H), 7.14 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 178.5, 170.6, 165.3 (166.3,
1
3
164.3, d, JC-F = 257 Hz), 159.8, 150.3, 134.7 (134.8, 134.7, d, JC-F = 8 Hz), 131.7,
129.5, 129.0 (129.0, 128.9, d, 3JC-F = 9 Hz), 128.5 (128.6, 128.5, d, 4JC-F = 5 Hz), 128.1,
127.1, 124.6, 119.4 (119.5, 119.3, d, 2JC-F = 23 Hz), 113.0 (113.1, 112.9, d, 2JC-F = 24
+
Hz), 102.1. HRMS (ESI) m/z: [M+H]+ Calcd for C18H10FO3 293.0609; Found
293.0608.
7-Chloro-2-phenylnaphtho[2,3-b]furan-4,9-dione (3ca). Yield, 65% (40.1 mg,
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Eluent: EtOAc/petroleum ether = 1/5); pink solid, mp 201–203 ℃; IR (KBr, cm−1):
2831, 2779, 1667, 1615, 1479, 1367, 1256, 1099; 1H NMR (500 MHz, CDCl3) δ 8.14
(s, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 7.3 Hz, 2H), 7.63 (d, J = 8.2 Hz, 1H), 7.45
– 7.39 (m, 3H), 7.13 (s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 178.8, 170.7, 159.8,
150.2, 140.0, 133.1, 132.5, 131.7, 130.3, 129.5, 128.1, 127.5, 127.1, 126.0, 124.6,
102.0. HRMS (ESI) m/z: [M+H]+ Calcd for C18H10ClO3+ 309.0313; Found 309.0312.
7-Bromo-2-phenylnaphtho[2,3-b]furan-4,9-dione (3da). Yield, 70% (49.8 mg,
Eluent: EtOAc/petroleum ether = 1/5); yellow solid, mp 214–217 ℃; IR (KBr,
cm−1): 2836, 2780, 1662, 1618, 1594, 1441, 1273, 1070; 1H NMR (500 MHz, CDCl3)
δ 8.30 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.84 – 7.80 (m, 3H), 7.45 – 7.38 (m, 3H), 7.13
(s, 1H). 13C{1H} NMR (126 MHz, CDCl3) δ 178.9, 170.7, 159.7, 150.0, 135.5, 133.0,
131.6, 130.6, 129.5, 129.0, 128.5, 128.1, 127.5, 127.1, 124.6, 102.0. HRMS (ESI)
m/z: [M+Na]+ Calcd for C18H9O3Br+ 374.9627; Found 374.9627 (100%), 376.9606
(98%).
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7-Methoxy-2-phenylnaphtho[2,3-b]furan-4,9-dione (3ea). Yield, 76% (49.2 mg,
Eluent: EtOAc/petroleum ether = 1/5); orange soild, mp 218–221 ℃; IR (KBr,
cm−1): 2815, 2776, 1669, 1613, 1489, 1369, 1261, 1181; 1H NMR (500 MHz, CDCl3)
δ 8.18 (d, J = 8.6 Hz, 1H), 7.90 - 7.87 (m, 2H), 7.66 (d, J = 2.7 Hz, 1H), 7.51 - 7.42 (m,
3H), 7.21 (dd, J = 8.6, 2.7 Hz, 1H), 7.17 (s, 1H), 3.98 (s, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ 181.8, 174.1, 161.2, 161.1, 152.6, 135.1, 134.7, 134.1, 133.9, 133.5, 131.3,
130.6, 128.0, 119.2, 117.5, 111.5, 104.3, 56.6. HRMS (ESI) m/z: [M+H]+ Calcd for
+
C19H13O4 305.0808; Found 305.0806.
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6-Methoxy-2-phenylnaphtho[2,3-b]furan-4,9-dione (3fa). Yield, 74% (48.9 mg,
Eluent: EtOAc/petroleum ether = 1/5); orange solid, mp 225–229 ℃; IR (KBr,
cm−1): 2819, 1662, 1614, 1583, 1533, 1477, 1454, 1363, 1219, 1188; 1H NMR (500
MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 1H), 7.83 – 7.80 (m, 2H), 7.59 (d, J = 2.7 Hz, 1H),
7.44 – 7.37 (m, 3H), 7.14 (dd, J = 8.6, 2.7 Hz, 1H), 7.11 (s, 1H), 3.91 (s, 3H). 13C{1H}
NMR (126 MHz, CDCl3) δ 179.7, 171.6, 163.1, 158.8, 150.9, 134.3, 131.0, 129.1,
128.3, 128.1, 127.4, 125.1, 124.4, 118.5, 110.3, 101.8, 55.0. HRMS (ESI) m/z:
[M+H]+ Calcd for C19H13O4+ 305.0808; found 305.0807.
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7-Methyl-2-phenylnaphtho[2,3-b]furan-4,9-dione (3ga). Yield, 75% (43.2 mg,
Eluent: EtOAc/petroleum ether = 1/5); red soild, mp 204–206 ℃; IR (KBr, cm−1):
2779, 1664, 1611, 1595, 1547, 1484, 1456, 1363, 941; 1H NMR (500 MHz, CDCl3)
δ 8.02 (d, J = 7.8 Hz, 1H), 7.98 (s, 1H), 7.84 – 7.82 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H),
7.44 – 7.36 (m, 3H), 7.12 (s, 1H), 2.45 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ
179.8, 172.4, 159.2, 150.6, 144.2, 133.2, 131.8, 131.5, 129.8, 129.2, 128.1, 127.4,
+
126.4, 126.2, 124.5, 102.0, 20.8. HRMS (ESI) m/z: [M+H]+ Calcd for C19H13O3
289.0859; Found 289.0859.
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at http://pubs.acs.org.
1H and 13C NMR spectra of the products and High-resolution mass spectra of new
compounds (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: jspeng1998@163.com, ccx1759@163.com
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ORCID
Jinsong Peng: 0000-0002-7822-4560
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the Fundamental Research Funds for
the Central Universities (2572019CG06), and Natural Science Foundation of
Heilongjiang Province (LC2018003, B2017002).
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