Palladium(II)-catalyzed synthesis of 2 H,3′ H -Spiro[benzofuran-3, 2′-naphthoquinones]

Article abstract of DOI:10.1021/jo400852z

2H,3′H-Spiro[benzofuran-3,2′-naphthoquinones], constituting a new spiroheterocyclic skeleton, were synthesized starting from 2-aryloxymethyl-1,4-naphthoquinones by means of a palladium(II)-catalyzed reaction, which is a new spirocyclic transformation. Und

Full text of DOI:10.1021/jo400852z

Article
pubs.acs.org/joc
Palladium(II)-Catalyzed Synthesis of 2H,3′H‑Spiro[benzofuran-3,2′-
naphthoquinones]
Pieter Claes, Jan Jacobs, Bart Kesteleyn, Tuyen Nguyen Van,† and Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium
S
* Supporting Information
ABSTRACT: 2H,3′H-Spiro[benzofuran-3,2′-naphthoqui-
nones], constituting a new spiroheterocyclic skeleton, were
synthesized starting from 2-aryloxymethyl-1,4-naphthoqui-
nones by means of a palladium(II)-catalyzed reaction, which
is a new spirocyclic transformation. Under optimal conditions,
i.e. 10 mol % of palladium(II) acetate, 15 mol % of 3,5-
dichloropyridine, and 5 mol % of trifluoroacetic acid in acetic acid at 110 °C, various 2H,3′H-spiro[benzofuran-3,2′-
naphthoquinones] were synthesized in yields strongly dependent on the substitution pattern of the aryloxy group. Unsubstituted
or ortho-substituted 2-aryloxymethyl-1,4-quinones were found to rearrange toward the corresponding 2-(4-hydroxyaryl)-1,4-
quinones upon treatment with trifluoroacetic acid.
spiro[benzofuran-3,2′-naphthoquinone] structural motif has
never been prepared before. Even though several methods to
synthesize structurally similar spiroheterocyclic compounds
exist in the literature,3 the oxygen atom is always directly
connected to the spirocyclic carbon.
INTRODUCTION
■
Our research group has been involved substantially in the
synthesis of bioactive heterocyclic quinones and related natural
products.1 During our study of the tetracyclic benzopyrano-
naphthoquinone derivative 2a, its synthesis was envisaged by
means of a palladium(II)-catalyzed intramolecular oxidative
coupling.2 Thus, 2-phenoxymethyl-1,4-naphthoquinone 1a was
reacted with 1 equiv of palladium(II) acetate in boiling acetic
acid for 14 h, yielding a single compound. Surprisingly, the
obtained compound contained two aliphatic CH2’s and had the
same mass as 2-phenoxymethyl-1,4-naphthoquinone (1a).
Moreover, a quaternary carbon was present at 58 ppm (13C
NMR, CDCl3), indicative of an aliphatic quaternary center next
to an electron-withdrawing group or atom. Thus, the molecular
skeleton of the spirocyclization product 2H,3′H-spiro-
[benzofuran-3,2′-naphthalene]-1′,4′-dione (3a) was proposed,
which was isolated in 38% yield (Scheme 1).
RESULTS AND DISCUSSION
■
The starting 2-aryloxymethyl-1,4-quinones 1 were synthesized
by means of a radical aryloxymethylation of naphthoquinone 4
using phenoxyacetic acids 5 in water with ammonium persulfate
as a radical initiator and a catalytic amount of AgNO3 as a
radical transfer agent.4 In order to ensure full solubility of the
starting phenoxyacetic acids 5, acetonitrile had to be added as a
cosolvent. Thus, 2-aryloxymethyl-1,4-naphthoquinones 1a−j
were synthesized in 46−89% yield (Scheme 2).
Initially, it was investigated whether or not the spirocycliza-
tion could be a Friedel−Crafts type reaction by reacting a
myriad of hard and soft metal salts with 2-phenoxymethyl-1,4-
naphthoquinone (1a) in glacial acetic acid. None of the tested
metal salts, i.e. LiCl, MgBr2, TiCl4, (NH4)2Ce(NO3)6, FeCl3,
AgOAc, AlCl3, NiCl3, Co2(SO4)3, SnCl4, and Cu(OTf)2,
yielded the desired spiroquinone 3a. Strong acids, such as
CF3COOH, pTsOH, H2SO4, and TfOH, also did not effect the
desired conversion. As quinones oxidize Pd(0) to Pd(II),
palladium-catalyzed reactions in quinone chemistry are limited
to Pd(II) catalysis.5 Therefore, we attempted to optimize the
conversion following the reaction conditions reported by Stolz
et al.,6 i.e. 40 mol % of ethyl nicotinate and 10 mol % of
Pd(OAc)2 in 4/1 tert-amyl alcohol/AcOH. Disappointingly, no
conversion of 1a was observed. It appeared that, no matter
which ligand was used, the palladium complex only remained
In the present study, this surprising reaction was thoroughly
investigated. To the best of our knowledge, the 2H,3′H-
Scheme 1. Formation of 2H,3′H-Spiro[benzofuran-3,2′-
naphthalene]-1′,4′-dione (3a)
Received: May 3, 2013
© XXXX American Chemical Society
A
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Scheme 2. Synthesis of 2-Aryloxymethyl-1,4-naphthoquinones 1
stable in pure acetic acid and decomposed in all other solvents
or combinations thereof (4/1 tert-amyl alcohol/AcOH, DMF,
DMA, or pinacolone). Together with the fact that addition of 1
equiv of NaOAc leads to a complex mixture (Table 1, entry 2),
more electron poor the ligand, the faster the reaction. However,
most reactions end prematurely due to decomposition of the
palladium complex (entries 5−8). Only 3,5-dichloropyridine
(entry 4) led to full conversion, but the reaction was very
sluggish and took 12 days to attain completion. When ligands
were introduced bearing two coordinating nitrogen atoms such
as 2,2′-bipyridines and phenanthrolines, little (entry 9) or no
conversion (entries 10−13) toward spiroquinone 3a was
observed. In addition, the conditions recently reported by Li
et al.,7 in which 20 mol % of N-acetylglycine was used as the
ligand and hexafluoroisopropyl alcohol as the solvent, were
tested but no significant conversion was observed even when
the solvent was changed to acetic acid.
When the amount of ligand was varied between 10 and 40
mol %, the reaction time could be reduced to 7 days using 15 or
30 mol % of ligand (Table 2, entries 2 and 5) without lowering
the yield. For further experiments, it was decided to work with
15 mol % of ligand. When 5−15 mol % of trifluoroacetic acid
(TFA) was added, the reaction time could be reduced to 4
days. When 5 mol % of TFA was used, compound 3a was
obtained in 62% yield (entry 7), while more TFA led to lower
yields (entries 8 and 9). The addition of stronger acids (p-
toluenesulfonic acid, methanesulfonic acid, and trifluorometha-
nesulfonic acid) led to significant decomposition of the
palladium complex, and no full conversion was observed after
4 days. Replacement of TFA by the higher boiling
heptafluorobutyric acid (HFBA) did not result in an increased
yield (entry 10).
Table 1. Ligand Screening for the Spirocyclization Reaction
using 40 mol % Pyridine Ligand in Acetic Acid
a
entry
PyrL
ethyl nicotinate
t
result
1
2
20 h no conversn to 3a
ethyl nicotinate + 1 equiv NaOAc 20 h complex reaction
mixture
3
pyridine-3-carbonitrile
3,5-dichloropyridine
5-bromo-2-chloropyridine
2,5-dichloropyridine
2,6-dibromopyridine
2-chloro-3-nitropyridine
2,2′-bipyridinyl
23 h no conversn to 3a
12 d 3a (53%)
4
5
20 h 29% conversn to 3a
6
7 h
26% conversn to 3a
7
18 h 15% conversn to 3a
23 h <10% conversn to 3a
15 h <10% conversn to 3a
15 h no conversn to 3a
15 h no conversn to 3a
8
9
10
11
4,4′-dibromo-2,2′-bipyridine
2,2′-bipyridine-3,3′-dicarboxylic
acid
12
13
1,10-phenanthroline-5,6-dione
5-chloro-1,10-phenanthroline
15 h no conversn to 3a
15 h no conversn to 3a
The yield of the spirocyclization reaction was strongly
dependent on the substitution pattern of the aryloxy group of
the starting 2-(aryloxymethyl)-1,4-naphthoquinones 1 (Scheme
3). While meta- and para-substituted aryloxy groups gave
spiroquinones 3 in good yields, little (1b) or no (1e)
conversion was observed in the case of meta-substituted aryloxy
a
All reactions were monitored by LC-MS and stopped when no
further conversion was observed.
it can be concluded that a protic acid should play a crucial role
in the reaction mechanism. From Table 1 it is clear that the
a
Table 2. Fine Tuning of the Catalytic Cycle for the Spirocyclization Reaction toward Spironaphthoquinone 3a
entry
n
m
HA
t (days)
yield (%)
entry
n
m
HA
t (days)
yield (%)
1
2
3
4
5
10
15
20
25
30
−
−
−
−
−
−
−
−
−
−
7
7
9
8
7
38
53
30
38
52
6
40
15
15
15
15
−
5
−
12
4
53
62
42
35
49
7
TFA
TFA
TFA
HFBA
8
10
15
5
4
9
4
10
4
a
HFBA = CF3(CF2)2COOH.
B
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a
Scheme 3. Synthesis of 2H,3′H-Spiro[benzofuran-3,2′-naphthalene]-1′,4′-diones 3
a
DCP = 3,5-dichloropyridine.
Scheme 4. Proposed Catalytic Cycle of the Spirocyclization Reaction of 2-Aryloxymethyl-1,4-naphthoquinones 1 toward
a
Spironaphthoquinones 3
a
HA = HOAc, TFA.
8a.4 9,10 Acid-mediated regeneration of the palladium complex
followed by tautomerization finally leads to spiroquinone 3. It is
believed that the addition of TFA accelerates the hydrolysis of
palladium enolate 8b, thus giving rise to shorter reaction times.
It should be noted that the reaction is a cycloisomerization and
does not need a cooxidant as do most other palladium(II)-
catalyzed reactions.4,11
c,
groups. Replacement of acetic acid by hexafluoroisopropyl
alcohol also did not give any reaction. Apart from the fact that
only one reactive position is available for cyclization, there is no
satisfying explanation so far for this observation. In the case of
meta-substituted compounds, regioisomers were formed in a
ratio of about 5/1. Interestingly, in the case of naphthoquinone
1f, the reaction was complete after only 15 h. This is attributed
to the electron-donating properties combined with the sterically
favored position of the methoxy group. Other apparent
differences in yield based on the electronic nature of the
substituents were not observed.
On the basis of the aforementioned observations, a reaction
mechanism is proposed. Initial coordination of the palladium
catalyst with the naphthoquinone moiety, which behaves as a π-
acid ligand, increases the electron deficiency of the palladium
center.8 Arene palladation of the naphthoquinone−Pd(II)
complex 6 leads to the organopalladium intermediate 7
(Scheme 4). This intermediate 7 will undergo an intra-
molecular Michael addition leading to palladium enolate
Application of the optimized spirocyclization conditions to
aryloxymethylbenzoquinones 11 led only to complex reaction
mixtures. 2H,3′H-Spiro[benzofuran-3,2′-benzoquinones] 12
could only be synthesized in low yields using a full 1 equiv
of palladium(II) acetate in boiling acetic acid. This is attributed
to the high reactivity of the benzoquinone moiety, which also
explains the lower yields of the radical alkylation reaction in
comparison to 2-aryloxymethyl-1,4-naphthoquinones 1. Next,
the synthesis of the six-membered-ring spiroquinone 15 was
envisaged starting from 2-(2-phenoxyethyl)-1,4-naphthoqui-
none 14, which was prepared starting from 1,4-naphthoquinone
4 and 3-phenoxypropionic acid 13 under the aforementioned
C
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Scheme 5. Synthesis of 2H,3′H-Spiro[benzofuran-3,2′-benzoquinones] 12 and 3′H-Spiro[chroman-3,2′-naphthalene]-1′,4′-
dione (15)
radical reaction conditions. However, as the intermediate
radical is not stabilized, 2-(2-phenoxyethyl)-1,4-naphthoqui-
none 14 could only be obtained in 11% yield. The
spirocyclization reaction of 14 was found to be significantly
slower than that of phenoxymethyl-1,4-naphthoquinone 1a and
was stopped after 5 days. From this reaction, 3′H-spiro-
[chroman-3,2′-naphthalene]-1′,4′-dione (15) was isolated in
38% yield, together with 22% of starting material 14 (Scheme
5). No reaction was observed when substrates structurally
related to phenoxymethyl-1,4-naphthoquinone 1a such as 3-
methyl-2-phenoxymethyl-1,4-naphthoquinone (16), N-mesyl-,
N-acyl-, or N-benzoyl-2-phenylaminomethyl-1,4-naphthoqui-
nones, and 2-phenoxymethylchromen-4-one were subjected to
the optimized spirocyclization conditions or to reaction with a
full 1 equiv of palladium(II) acetate.
Scheme 6. Synthesis of 2-(4-Hydroxybenzyl)-1,4-quinones
17 and 18a
During the reaction optimization it was found that when 2-
phenoxymethyl-1,4-naphthoquinone (1a) was stirred overnight
at room temperature in pure TFA, 2-(4-hydroxybenzyl)-1,4-
naphthoquinone 17a was formed in 74% yield as the sole
reaction product (Scheme 6). All attempts to execute this
Claisen rearrangement on aryloxymethylnaphthoquinones 1
bearing a meta- and para-substituted aryloxy group gave
complex mixtures. Aryloxymethylnaphthoquinones 1b,e bear-
ing an ortho-substituted aryloxy group did react via this Claisen
rearrangement pathway to provide the corresponding phenols
17b,c, but in the case of 2-(2-methoxyphenoxymethyl)-1,4-
naphthoquinone (1e) the yield was low due to the formation of
several side products. For 3-methyl-2-phenoxymethyl-1,4-
naphthoquinone (16), the Claisen rearrangement did occur,
but only after 3 days, and resulted in the formation of 2-(4-
hydroxybenzyl)-3-methyl-1,4-naphthoquinone (17d) in 60%
yield. Claisen rearrangement of 2-phenoxymethyl-1,4-benzo-
quinone 11a yielded 2-(4-hydroxybenzyl)-1,4-benzoquinone
18a in 64% yield. No reaction was observed upon treatment of
N-mesyl-, N-acyl-, or N-benzoyl-2-phenylaminomethyl-1,4-
naphthoquinones or 2-phenoxymethylchromen-4-one with
TFA.
In conclusion, a new spiroheterocyclic molecular skeleton
was synthesized starting from 2-aryloxymethyl-1,4-naphthoqui-
nones 1 and 2-(2-phenoxyethyl)-1,4-naphthoquinone (13)
using palladium(II) catalysis. Under optimal conditions, 10
mol % of palladium(II) acetate, 15 mol % of 3,5-
dichloropyridine, and 5 mol % of trifluoroacetic acid in acetic
acid at 110 °C were used. Good yields were obtained for meta-
and para-substituted aryloxymethyl-1,4-naphthoquinones 1.
Unfortunately, the reaction seems to be limited to naph-
thoquinone substrates. Unsubstituted or ortho-substituted 2-
aryloxymethyl-1,4-quinones 1, 16, and 11a were found to
D
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133.9 (CHAr), 134.0 (CHAr), 134.2 (CHAr), 139.9 (Cquat), 146.4
(Cquat), 157.9 (Cquat), 184.7 (CO), 184.8 (CO). IR (cm−1): ν
1660 (CO), 1583, 1296 (C−O), 1250 (C−O). MS (ES+; m/z (%)):
279 (M + H+, 100). HRMS (ES+): calcd for [C18H15O3]+ 279.1021,
found 279.1025.
rearrange toward the corresponding 2-(4-hydroxyaryl)-1,4-
quinones 17 and 18 upon treatment with trifluoroacetic acid.
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR spectra were
recorded at 300 MHz using TMS as internal standard, 13C NMR
spectra were recorded at 75 MHz, and 19F NMR spectra were
recorded at 282 MHz using CFCl3 as internal standard. Peak
assignments were performed with the aid of APT and HSQC spectra.
Mass spectra were recorded using a direct inlet system (70 eV) with a
VL detector (ES, 4000 V). The reported melting points are not
corrected. Flash chromatography was carried out using a glass column
with silica gel (particle size 0.035−0.07 mm, pore diameter ca. 6 nm)
or by means of an automated flash chromatography system. Solvent
systems were determined via initial TLC analysis (silica gel).
Preparative TLC was performed on plates (F254) measuring 20 cm
× 20 cm × 2 mm. HRMS spectra were recorded using a tandem TOF
spectrometer. The reaction progress was monitored by means of LC
analysis. All solvents and chemicals were used without further
purification.
2-(4-Methylphenoxymethyl)-1,4-naphthoquinone (1d): 4.31 g,
1
62%; yellow needles; mp 145.5 °C. H NMR (CDCl3): δ 2.30 (3H,
s, CH3), 5.05 (2H, d, J = 2.2 Hz, CH2O), 6.89 (2H, d, J = 8.3 Hz, 2 ×
CHAr), 7.11 (2H, d, J = 8.3 Hz, 2 × CHAr), 7.18 (1H, t, J = 2.2 Hz,
CH-3), 7.73−7.80 (2H, m, 2 × CHAr), 8.07−8.15 (2H, m, 2 × CHAr).
13C NMR (CDCl3): δ 20.6 (CH3), 63.7 (CH2O), 114.6 (2 × CHAr),
126.4 (2 × CHAr), 130.2 (2 × CHAr), 131.0 (Cquat), 132.1 (Cquat),
133.9 (2 × CHAr), 134.2 (Cquat), 146.4 (Cquat), 155.8 (Cquat), 184.6
(CO), 184.7 (CO). IR (cm−1): ν 1659 (CO), 1628, 1509,
1296, 1244 (C−O), 1232 (C−O). MS (ES+; m/z (%)): 279 (M + H+,
100). HRMS (ES+): calcd for [C18H15O3]+ 279.1021, found 279.1015.
2-(2-Methoxyphenoxymethyl)-1,4-naphthoquinone (1e): 3.68 g,
1
50%; yellow solid; mp 193 °C. H NMR (CDCl3): δ 3.91 (3H, s,
CH3O), 5.16 (2H, d, J = 1.8 Hz, CH2O), 6.87−7.02 (4H, m, 4 ×
CHAr), 7.23 (1 H, t, J = 1.8 Hz, CH-3), 7.74−7.80 (2H, m, 2 × CHAr),
8.08−8.15 (2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 56.0 (CH3O),
65.0 (CH2O), 112.2 (CHAr), 114.2 (CHAr), 121.0 (CHAr), 122.5
(CHAr), 126.4 (CHAr), 126.5 (CHAr), 132.04 (Cquat), 132.07 (Cquat),
133.9 (CH-3), 134.0 (2 × CHAr), 146.4 (Cquat), 147.3 (Cquat), 149.8
(Cquat), 184.8 (2 × CO). IR (cm−1): ν 1659 (CO), 1589, 1505,
1253, 1230 (C−O), 739. MS (ES+; m/z (%)): 295 (M + H+, 100).
HRMS (ES+): calcd for [C18H15O4]+ 295.0970, found 295.0964.
2-(3-Methoxyphenoxymethyl)-1,4-naphthoquinone (1f): 4.19 g,
Synthesis of 2-Aryloxymethyl-1,4-naphthoquinones 1 and
16. To a solution of 37.5 mmol of phenoxyacetic acid 5 in 80 mL of
distilled water and 80 mL of acetonitrile were successively added 3.95
g (25 mmol, 1.5 equiv) of 1,4-naphthoquinone (4) and 1.27 g (7.5
mmol) of AgNO3. The mixture was heated to 80 °C until dissolution
was complete. The resulting solution was stirred vigorously while a
solution of 8.56 g (37.5 mmol) of ammonium peroxydisulfate in 80
mL of distilled water was added dropwise. Throughout the addition,
the reaction mixture was maintained at 80 °C. After the addition was
complete, the mixture was stirred for 5 min at 80 °C and was then
cooled to 5−10 °C in an ice bath. The precipitated solid was collected
by suction filtration, washed with 50 mL of cold water, and pressed to
remove most of the liquid. Inorganic contaminants, usually present in
small amounts, were removed by dissolving the solid in 350 mL of
boiling acetone and filtering the hot solution. Concentration of the
filtrate in vacuo gave a dark red crude product, which was recrystallized
from ethanol. In the case of 3-methyl-2-phenoxymethyl-1,4-naph-
thoquinone (16), 2-methyl-1,4-naphthoquinone was used.
1
57%; yellow solid; mp 130.0 °C. H NMR (CDCl3): δ 3.81 (3H, s,
CH3O), 5.07 (2H, d, J = 2.2 Hz, CH2O), 6.55−6.61 (3H, m, 3 ×
CHAr), 7.17−7.24 (2H, m, CH-3 and CHAr), 7.74−7.80 (2H, m, 2 ×
CHAr), 8.07−8.15 (2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 55.4
(CH3O), 63.6 (CH2O), 101.3 (CHAr), 106.8 (CHAr), 107.3 (CHAr),
126.4 (2 × CHAr), 130.2 (CHAr), 132.1 (Cquat), 133.9 (CHAr), 134.0
(CHAr), 134.2 (CHAr), 138.7 (Cquat), 146.2 (Cquat), 159.1 (Cquat),
161.0 (Cquat), 184.6 (CO), 184.7 (CO). IR (cm−1): ν 1657 (C
O), 1588, 1298, 1249 (C−O). MS (ES+; m/z (%)): 295 (M + H+,
100). HRMS (ES+): calcd for [C18H15O4]+ 295.0970, found 295.0969.
2-(4-Methoxyphenoxymethyl)-1,4-naphthoquinone (1g): 3.38 g,
1
46%; yellow crystals; mp 136.1−137.1 °C. H NMR (CDCl3): δ 3.77
2-Phenoxymethyl-1,4-naphthoquinone (1a): 4.10 g, 62%; yellow
needles; mp 163 °C (lit.12 mp 163−164 °C). H NMR (CDCl3): δ
1
(3H, s, CH3O), 5.02 (2H, d, J = 2.2 Hz, CH2O), 6.82−6.96 (4H, m, 4
× CHAr), 7.18 (1 H, t, J = 2.2 Hz, CH-3), 7.19−7.80 (2H, m, 2 ×
CHAr), 8.07−8.14 (2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 55.8
(CH3O), 64.3 (CH2O), 114.9 (2 × CHAr), 115.7 (2 × CHAr), 126.4
(CHAr), 126.5 (CHAr), 132.1 (Cquat), 133.9 (CH-3), 134.0 (CHAr),
134.2 (CHAr), 146.5 (Cquat), 152.0 (Cquat), 154.5 (Cquat), 184.7 (C
O), 184.8 (CO), one trisubstituted olefinic carbon is not observed.
IR (cm−1): ν 1659, 1508, 1234. MS (ES+; m/z (%)): 295 (M + H+,
100). HRMS (ES−): calcd for [C18H13O4]− 293.0814, found 293.0822.
2-(4-tert-Butylphenoxymethyl)-1,4-naphthoquinone (1h): 5.29 g,
5.05 (2H, d, J = 2.0 Hz, CH2O), 6.98−7.02 (3H, m, 3 × CHAr), 7.17
(1H, t, J = 2.0 Hz, CH-3), 7.29−7.34 (2H, m, 2 × CHAr), 7.72−7.78
(2H, m, CH-6 and CH-7), 8.07−8.13 (2H, m, CH-5 and CH-8). 13C
NMR (CDCl3): δ 63.5 (CH2O), 114.8 (2 × CHAr), 121.8 (CHAr),
126.4 and 126.5 (CH-5 and CH-8), 129.8 (2 × CHAr), 132.1 (Cquat),
133.9 and 134.0 (CH-6 and CH-7), 134.2 (CH-3), 146.3 (Cquat),
157.9 (Cquat), 184.7 (CO), 184.8 (CO), one trisubstituted
olefinic carbon is not observed. IR (cm−1): ν 1659 (CO), 1586,
1299, 1240 (C−O). MS (ES+; m/z (%)): 265 (M + H+, 100). HRMS
(ES+): calcd for [C17H11O3]− 263.0708, found 263.0716.
1
66%; yellow solid; mp 139.0 °C. H NMR (CDCl3): δ 1.31 (9H, s,
(CH3)3C), 5.07 (2H, d, J = 2.2 Hz, CH2O), 6.93 (2H, d, J = 9.1 Hz, 2
× CHAr), 7.19 (1 H, t, J = 2.2 Hz, CH-3), 7.34 (2H, d, J = 9.1 Hz, 2 ×
CHAr), 7.74−7.80 (2H, m, 2 × CHAr), 8.07−8.16 (2H, m, 2 × CHAr).
13C NMR (CDCl3): δ 31.6 ((CH3)3C), 34.2 ((CH3)3C), 63.7
(CH2O), 114.3 (2 × CHAr), 126.4 (CHAr), 126.5 (CHAr), 126.6 (2
× CHAr), 132.1 (Cquat), 133.9 (CHAr), 134.0 (CHAr), 134.2 (CHAr),
144.5 (Cquat), 146.5 (Cquat), 155.6 (Cquat), 184.7 (CO), 184.8 (C
O), one trisubstituted olefinic carbon is not observed. IR (cm−1): ν
1661 (CO), 1591, 1512, 1297, 1245 (C−O). MS (ES+; m/z (%)):
321 (M + H+, 100). HRMS (ES+): calcd for [C21H21O3]+ 321.1491,
found 321.1479.
2-(4-Fluorophenoxymethyl)-1,4-naphthoquinone (1i): 4.16 g,
59%; yellow crystals; mp 158.6−159.0 °C. 1H NMR (CDCl3): δ
5.04 (2H, d, J = 2.0 Hz, CH2O), 6.91−7.05 (4H, m, 4 × CHAr), 7.17
(1H, s, CH-3), 7.75−7.81 (2H, m, 2 × CHAr), 8.09−8.13 (2H, m, 2 ×
CHAr). 13C NMR (CDCl3): δ 64.3 (CH2O), 115.8 (JCF = 6.9 Hz, 2 ×
CHAr), 116.2 (JCF = 23.2 Hz, 2 × CHAr), 126.5 (CHAr), 126.5 (CHAr),
132.1 (Cquat), 134.0 (CHAr), 134.1 (CHAr), 134.3 (CH-3), 146.0
(Cquat), 154.0 (Cquat) 157.8 (JCF = 238.8 Hz, Cquat), 184.6 (CO),
2-(2-Methylphenoxymethyl)-1,4-naphthoquinone (1b): 5.08 g,
73%; yellow crystals; mp 160.0 °C. H NMR (CDCl3): δ 2.34 (3H,
1
s, CH3), 5.09 (2H, d, J = 2.2 Hz, CH2O), 6.89−6.95 (2H, m, 2 ×
CHAr), 7.16−7.22 (3H, m, 2 × CHAr and CH-3), 7.74−7.81 (2H, m, 2
× CHAr), 8.09−8.16 (2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 16.5
(CH3), 63.5 (CH2O), 111.1 (CHAr), 121.4 (CHAr), 126.4 (CHAr),
126.5 (CHAr), 127.0 (Cquat), 127.1 (CHAr), 131.1 (CHAr), 132.00
(Cquat), 132.03 (Cquat), 133.8 (CH-3), 133.9 (CHAr), 134.2 (CHAr),
146.6 (Cquat), 155.9 (Cquat), 184.7 (CO), 184.8 (CO). IR (cm−1):
ν 1657 (CO), 1588, 1296, 1245 (C−O), 748. MS (ES+; m/z (%)):
279 (M + H+, 100). HRMS (ES+): calcd for [C18H15O3]+: 279.1021,
found 279.1008.
2-(3-Methylphenoxymethyl)-1,4-naphthoquinone (1c): 6.19 g,
1
89%, yellow solid; mp 166.5 °C. H NMR (CDCl3): δ 2.35 (3H, s,
CH3), 5.07 (2H, d, J = 2.2 Hz, CH2O), 6.78−6.84 (3H, m, 3 × CHAr),
7.17−7.23 (2H, m, CHAr and CH-3), 7.74−7.80 (2H, m, 2 × CHAr),
8.08−8.15 (2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 21.6 (CH3),
63.5 (CH2O), 111.6 (CHAr), 115.6 (CHAr), 122.6 (CHAr), 126.4
(CHAr), 126.5 (CHAr), 129.5 (CHAr), 132.02 (Cquat), 132.03 (Cquat),
E
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184.7 (CO), one trisubstituted olefinic carbon is not observed. 19F
NMR (CDCl3): δ −125.03 - −122.60 (1F, m). IR (cm−1): ν 1655,
1506, 1206. MS (ES+; m/z (%)): 281 (M − H+, 70). HRMS (ES−):
calcd for [C17H10FO3]− 281.0614, found 281.0628.
2.25 (3H, s, CH3), 3.29 (2H, s, CH2CO), 4.29 (1H, d, Jab = 9.3 Hz,
CHaHbO), 5.42 (1H, d, Jab = 9.3 Hz, CHaHbO), 6.50 (2H, s, 2 ×
CHAr), 6.68 (1H, s, CHAr), 7.76−7.89 (2H, m, 2 × CHAr), 8.10−8.20
(2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 21.6 (CH3), 48.8 (CH2C
O), 58.2 (Cspiro), 77.8 (CH2O), 111.5 (CHAr), 121.7 (CHAr), 123.4
(CHAr), 124.7 (Cquat), 126.8 (CHAr), 128.4 (CHAr), 134.7 (Cquat),
134.8 (CHAr), 134.9 (CHAr), 135.6 (Cquat), 140.8 (Cquat), 160.2
(Cquat), 194.0 (CO), 194.1 (CO). IR (cm−1): ν 1687 (CO),
1591, 1253 (C−O), 1245 (C−O), 759. MS (ES+; m/z (%)): 279 (M +
H+, 100). HRMS (ES+): calcd for [C18H15O3]+ 279.1021, found
279.1012.
2-(4-Chlorophenoxymethyl)-1,4-naphthoquinone (1j): 1.49 g,
20%; yellow needles; mp 165.9−166.0 °C (lit.13 mp 167−169.5 °C).
1H NMR (CDCl3): δ 5.21 (2H, s, CH2O), 6.84 (2H, d, J = 8.5 Hz, 2 ×
CHAr), 7.21 (1H, s, CH-3), 7.24 (2H, d, J = 8.5 Hz, 2 × CHAr), 7.78−
7.81 (2H, m, 2 × CHAr), 8.14−8.19 (2H, m, 2 × CHAr). 13C NMR
(CDCl3): δ 63.9 (CH2O), 116.1 (2 × CHAr), 126.5 (CHAr), 126.5
(CHAr), 126.7 (Cquat), 129.7 (2 × CHAr), 132.0 (Cquat), 132.0 (Cquat),
134.0 (CHAr), 134.1 (CHAr), 134.3 (CH-3), 145.8 (Cquat), 156.5
(Cquat), 184.6 (CO), 184.7 (CO). IR (cm−1): ν 1655, 1596, 1221.
MS (ES+; m/z (%)): 299 (M + H+, 93). HRMS (ES−): calcd for
[C17H10ClO3]− 297.0319, found 297.0314.
2H,3′H-Spiro[4-methylbenzofuran-3,2′-naphthalene]-1′,4′-dione
1
(3cb): 31 mg, 11%; white solid. mp 179.5 °C. H NMR (CDCl3): δ
2.20 (3H, s, CH3), 3.23 (1H, d, Jab = 16.2 Hz, CHaHbCO), 3.53
(1H, d, Jab = 16.2 Hz, CHaHbCO), 4.43 (1H, d, Jab = 8.8 Hz,
CHaHbO), 4.48 (1H, d, Jab = 8.8 Hz, CHaHbO), 6.74 (1H, d, J = 8.3
Hz, CHAr), 6.78 (1H, d, J = 7.7 Hz, CHAr), 7.17 (1H, t, J = 7.7 Hz,
CHAr), 7.80−7.85 (2H, m, 2 × CHAr), 8.09−8.14 (1H, m, CHAr),
8.18−8.22 (1H, m, CHAr). 13C NMR (CDCl3): δ 19.5 (CH3), 47.5
(CH2−CO), 60.0 (Cspiro), 79.7 (CH2O), 108.1 (CHAr), 123.7
(CHAr), 126.4 (Cquat), 127.0 (CHAr), 128.2 (CHAr), 130.1 (CHAr),
134.8 (CHAr), 135.0 (CHAr), 135.3 (Cquat), 135.5 (Cquat), 160.3
(Cquat), 194.4 (CO), 195.4 (CO), one trisubstituted olefinic
carbon is not observed. IR (cm−1): ν 1691 (CO), 1682 (CO),
1591, 1463, 1288 (C−O), 985. MS (ES+; m/z (%)): 279 (M + H+,
100). HRMS (ES+): calcd for [C18H15O3]+ 279.1021, found 279.1011.
2H,3′H-Spiro[5-methylbenzofuran-3,2′-naphthalene]-1′,4′-dione
(3d): 189 mg, 68%; bright orange solid; mp 108.5 °C. 1H NMR
(CDCl3): δ 2.09 (3H, s, CH3), 3.28 (1H, d, Jab = 16.2 Hz, CHaHbC
O), 3.31 (1H, d, Jab = 16.2 Hz, CHaHbCO), 4.28 (1H, d, Jab = 9.3
Hz, CHaHbO), 5.36 (1H, d, Jab = 9.3 Hz, CHaHbO), 6.44 (1H, d, J =
1.7 Hz, CH-4), 6.75 (1H, d, J = 8.5 Hz, CH-7), 6.95 (1H, dd, J = 8.5
and 1.7 Hz, CH-6), 7.78−7.88 (2H, m, 2 × CHAr), 8.12−8.20 (2H, m,
2 × CHAr). 13C NMR (CDCl3): δ 20.8 (CH3), 48.7 (CH2−CO),
58.4 (Cspiro), 77.9 (CH2O), 110.5 (CHAr), 124.1 (CHAr), 126.8
(CHAr), 127.6 (Cquat), 128.4 (CHAr), 130.4 (Cquat), 130.8 (CHAr),
134.6 (Cquat), 134.8 (CHAr), 134.9 (CHAr), 135.6 (Cquat), 157.9
(Cquat), 194.0 (CO), 194.2 (CO). IR (cm−1): ν 1692 (CO),
1591, 1490, 1246 (C−O), 759. MS (ES+; m/z (%)): 279 (M + H+,
100). HRMS (ES+): calcd for [C18H15O3]+ 279.1021, found 279.1016.
2H,3′H-Spiro[6-methoxybenzofuran-3,2′-naphthalene]-1′,4′-
dione (3fa): 180 mg, 61%; yellow solid; mp 129 °C. 1H NMR
(CDCl3): δ 3.29 (2H, s, CH2CO), 3.71 (3H, s, OCH3), 4.30 (1H, d,
Jab = 8.8 Hz, CHaHbO), 5.44 (1H, d, Jab = 8.8 Hz, CHaHbO), 6.23 (1H,
dd, J = 8.4 and 2.2 Hz, CH-5), 6.42 (1H, d, J = 2.2 Hz, CH-7), 6.50
(1H, d, J = 8.4 Hz, CH-4), 7.77−7.87 (2H, m, 2 × CHAr), 8.11−8.20
(2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 48.8 (CH2CO), 55.6
(OCH3), 57.8 (Cspiro), 78.3 (CH2O), 97.1 (CHAr), 106.9 (CHAr),
119.6 (Cquat), 124.0 (CHAr), 126.8 (CHAr), 128.4 (CHAr), 134.6
(Cquat), 134.8 (CHAr), 134.9 (CHAr), 135.6 (Cquat), 161.4 (Cquat),
161.9 (Cquat), 194 (CO), 194.0 (CO). IR (cm−1): ν 1687 (C
O), 1595, 1498, 1281 (C−O), 1147 (C−O). MS (ES+; m/z (%)): 295
(M + H+, 100). HRMS (ES+): calcd for [C18H15O4]+ 295.0970, found
295.0969.
3-Methyl-2-phenoxymethyl-1,4-naphthoquinone (16): 4.87 g,
1
70%; yellow crystals; mp 110.4 °C. H NMR (CDCl3): δ 2.33 (3H,
s, CH3), 5.13 (2H, s, CH2O), 6.96−7.00 (3H, m, 3 × CHAr), 7.23−
7.34 (2H, m, 2 × CHAr), 7.67−7.77 (2H, m, 2 × CHAr), 8.09−8.17
(2H, m, 2 × CHAr). 13C NMR (CDCl3): δ 13.3 (CH3), 60.7 (OCH2),
114.8 (2 × CHAr), 121.5 (CHAr), 126.5 (CHAr), 126.7 (CHAr), 129.7
(2 × CHAr), 131.9 (Cquat), 132.2 (Cquat), 133.8 (CHAr), 133.9 (CHAr),
140.1 (Cquat), 148.4 (Cquat), 158.5 (Cquat), 183.7 (CO), 185.3 (C
O). IR (cm−1): ν 1664, 1589, 1294. MS (ES+; m/z (%)): 279 (M +
H+, 25). HRMS (ES−): calcd for [C18H13O3]− 277.0865, found
277.0873.
Synthesis of 2′H,3H-Spiro[benzofuran-3,2′-naphthoqui-
nones] 3. In a 10 mL vial were added 3,5-dichloropyridine (0.15
mmol, 22 mg), trifluoroacetic acid (0.05 mmol, 6 mg), palladium(II)
acetate (0.10 mmol, 22 mg), 2-aryloxymethyl-1,4-naphthoquinones 1
(1 mmol), and 4 mL of acetic acid. The flask was sealed, and the
contents were stirred at 110 °C for 4 days. The reaction mixture was
then diluted with chloroform, filtered over a pad of Celite, washed
once with water and twice with aqueous sodium hydrogen carbonate,
and dried (MgSO4), and the solvent was evaporated in vacuo. Flash
chromatography on silica gel with ethyl acetate/hexane (1/9) yielded
2′H,3H-spiro[benzofuran-3,2′-naphthoquinones] 3. Upon (LC−)MS
analysis most spiroquinones were found to give very poor mass
spectrometric ionizations. The regioisomeric spironaphthoquinones
3c,f were further separated by means of preparative HPLC.
2H,3′H-Spiro[benzofuran-3,2′-naphthalene]-1′,4′-dione (3a):
1
164 mg, 62%; yellow crystals; mp 88.0 °C. H NMR (CDCl3): δ
3.30 (1H, d, Jab = 16.8 Hz, CHaHbCO), 3.32 (1H, d, Jab = 16.8 Hz,
CHaHbCO), 4.31 (1H, d, Jab = 8.8 Hz, CHaHbO), 5.43 (1H, d, Jab
=
8.8 Hz, CHaHbO), 6.64−6.73 (2H, m, 2 × CHAr), 6.86 (1H, d, J = 8.3
Hz, CHAr), 7.17 (1H, dxt, J = 1.6 and 7.2 Hz, CHAr), 7.78−7.87 (2H,
m, 2 × CHAr), 8.12−8.22 (2H, m, 2 × CHAr). 13C NMR (CDCl3): δ
48.8 (CH2CO), 58.4 (Cspiro), 77.6 (CH2O), 110.9 (CHAr), 121.0
(CHAr), 123.8 (CHAr), 126.8 (CHAr), 127.5 (Cquat), 128.5 (CHAr),
130.3 (CHAr), 134.6 (Cquat), 134.9 (CHAr), 134.9 (CHAr), 135.6
(Cquat), 159.9 (Cquat), 193.9 (CO), 194.0 (CO). IR (cm−1): ν
1694, 1590. MS (ES−; m/z (%)): 263 (M − H+, 100). HRMS (ES+):
calcd for [C17H13O3]+ 265.0865, found 265.0856.
2H,3′H-Spiro[7-methylbenzofuran-3,2′-naphthalene]-1′,4′-dione
1
(3b): 58 mg, 21%; yellow solid; mp 160.0 °C. H NMR (CDCl3): δ
2H,3′H-Spiro[4-methoxybenzofuran-3,2′-naphthalene]-1′,4′-
1
2.21 (3H, s, CH3), 3.28 (1H, d, Jab = 16.2 Hz, CHaHbCO), 3.30
(1H, d, Jab = 16.2 Hz, CHaHbCO), 4.29 (1H, d, Jab = 9.1 Hz,
CHaHbO), 5.42 (1H, d, Jab = 9.1 Hz, CHaHbO), 6.46 (1H, d, J = 7.7
Hz, CH-6), 6.59 (1H, t, J = 7.7 Hz, CH-5), 6.97 (1H, d, J = 7.7 Hz,
CH-4), 7.76−7.85 (2H, m, 2 × CHAr), 8.09−8.19 (2H, m, 2 × CHAr).
13C NMR (CDCl3): δ 15.25 (CH3), 48.79 (CH2CO), 58.70 (Cspiro),
dione (3fb): 38 mg, 13%; pale white solid; mp 156.5 °C. H NMR
(CDCl3): δ 3.17 (1H, d, Jab = 16.5 Hz, CHaHbCO), 3.49 (3H, s,
OCH3), 3.58 (1H, d, Jab = 16.5 Hz, CHaHbCO), 4.35 (1H, d, Jab
=
9.1 Hz, CHaHbO), 5.00 (1H, d, Jab = 9.1 Hz, CHaHbO), 6.36 (1H, d, J
= 8.3 Hz, CHAr), 6.52 (1H, d, J = 8.3 Hz, CHAr), 7.16 (1H, t, J = 8.3
Hz, CHAr), 7.72−7.82 (2H, m, 2 × CHAr), 8.10−8.15 (2H, m, 2 ×
CHAr). 13C NMR (CDCl3): δ 47.3 (CH2CO), 58.8 (OCH3), 58.1
(Cspiro), 80.0 (CH2O), 103.8 (CHAr), 115.5 (Cquat), 126.1 (CHAr),
128.1 (CHAr), 131.4 (CHAr), 134.1 (CHAr), 134.38 (2 × CHAr),
134.44 (Cquat), 136.3 (Cquat), 156.5 (Cquat), 161.6 (Cquat), 194.1 (C
O), 195.2 (CO). IR (cm−1): ν 1687 (CO), 1594, 1464, 1248
(C−O), 1093 (C−O), 753. MS (ES+; m/z (%)): 295 (M + H+, 100).
HRMS (ES+) calcd for [C18H15O4]+: 295.0970, found 295.0964.
2H,3′H-Spiro[5-methoxybenzofuran-3,2′-naphthalene]-1′,4′-
76.73 (CH2O), 120.86 (CH-5), 121.16 (CH-6), 121.24 (Cquat), 126.73
(CHAr), 128.43 (CHAr), 131.41 (CH-4), 134.66 (Cquat), 134.80
(CHAr), 134.87 (CHAr), 135.62 (Cquat), 158.32 (Cquat), 193.95 (C
O), 194.14 (CO), one trisubstituted olefinic carbon is not observed.
IR (cm−1): ν 1689 (CO), 1592, 1247 (C−O), 753. MS (ES+; m/z
(%)): 279 (M + H+, 100). HRMS (ES+): calcd for [C18H15O3]+
279.1021, found 279.1005.
2H,3′H-Spiro[6-methylbenzofuran-3,2′-naphthalene]-1′,4′-dione
(3ca): 142 mg, 51%; yellow solid; mp 108.5 °C. 1H NMR (CDCl3): δ
dione (3g): 174 mg, 59%; orange crystals; mp 133.4 °C. H NMR
1
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(CDCl3): δ 3.28 (1H, d, Jab = 16.5 Hz, CHaHbCO), 3.32 (1H, d, Jab
= 16.5 Hz, CHaHbCO), 3.57 (3H, s, OCH3), 4.29 (1H, d, Jab = 9.1
Hz, CHaHbO), 5.34 (1H, d, Jab = 9.1 Hz, CHaHbO), 6.23 (1H, d, J =
2.8 Hz, CH-4), 6.69 (1H, dd, J = 2.8 and 8.8 Hz, CH-6), 6.77 (1H, d, J
= 8.8 Hz, CH-7), 7.77−7.86 (2H, m, 2 × CHAr), 8.08−8.20 (2H, m, 2
× CHAr). 13C NMR (CDCl3): δ 48.6 (CH2CO), 56.0 (OCH3), 58.8
(Cspiro), 78.0 (CH2O), 110.6 (CH-4), 110.8 (CH-7), 114.7 (CH-6),
126.8 (CHAr), 128.4 (CHAr), 134.6 (Cquat), 134.82 (CHAr), 134.86
(CHAr), 135.5 (Cquat), 154.1 (Cquat), 154.2 (Cquat), 193.7 (CO),
194.0 (CO), one trisubstituted olefinic carbon is not observed. IR
(cm−1): ν 1686, 1483. MS (ES+; m/z (%)): 293 (M − H+, 100).
HRMS (ES+): calcd for [C18H15O4]+ 295.0970, found 295.0964.
2H,3′H-Spiro[5-tert-butylbenzofuran-3,2′-naphthalene]-1′,4′-
dione (3h): 227 mg, 71%; orange solid; mp 145.0 °C. 1H NMR
(CDCl3): δ 1.06 (9H, s, (CH3)3C), 3.29 (1H, d, Jab = 16.2 Hz,
CHaHbCO), 3.33 (1H, d, Jab = 16.2 Hz, CHaHbCO), 4.30 (1H, d,
Jab = 9.3 Hz, CHaHbO), 5.38 (1H, d, Jab = 9.3 Hz, CHaHbO), 6.64 (1H,
d, J = 2.2 Hz, CH-4), 6.77 (1H, d, J = 8.5 Hz, CH-7), 7.18 (1H, dd, J =
2.2 8.5 Hz, CH-6), 7.77−7.88 (2H, m, 2 × CHAr), 8.09−8.14 (1H, m,
CHAr), 8.19−8.22 (1H, m, CHAr). 13C NMR (CDCl3): δ 31.5
((CH3)3C), 34.3 ((CH3)3C), 48.6 (CH2CO), 58.7 (Cspiro), 77.7
(CH2O), 110.1 (CHAr), 120.6 (CHAr), 126.5 (CHAr), 127.0 (Cquat),
127.2 (CHAr), 128.4 (CHAr), 134.8 (2 × CHAr), 135.7 (Cquat), 144.0
(Cquat), 157.7 (Cquat), 194.0 (CO), 194.2 (CO), one
trisubstituted olefinic carbon is not observed. IR (cm−1): ν 1690
(CO), 1497 (C−O), 1263 (C−O), 1342, 820. MS (ES+; m/z (%)):
dissolving the solid in 350 mL of boiling acetone and filtering the hot
solution. Concentration of the filtrate in vacuo gave a dark red crude
product, which was recrystallized from ethanol. For the aryloxymethyl-
1,4-benzoquinone derivatives 11b−d full dissolution of the starting
materials did not occur at 65 °C and small amounts of acetonitrile
were added until full dissolution occurred.
2-Phenoxymethyl-1,4-benzoquinone (11a): 6.53 g, 61%; mp 138
°C (Lit.3 137−138 °C), 1H NMR (CDCl3): δ 4.92 (2H, d, OCH2, J =
1.7 Hz), 6.74−6.85 (2H, m, 2 × CH), 6.94−7.03 (4H, m, 4 × 
CH), 7.28−7.36 (2H, m, 2 × CH). 13C NMR (CDCl3): δ 63.1
(OCH2), 114.7 (2 × CH), 121.9 (CH), 129.8 (2 × CH),
131.9 (CH), 136.5 (CH), 136.8 (CH), 144.2 (Cquat), 157.8
(Cquat), 186.9 (CO), 187.3 (CO). IR (cm−1): ν 1651 (CO),
1600, 1496, 1247 (C−O). MS (ES−; m/z (%)): 213 (M − H, 35).
HRMS (ES−): calcd for [C13H9O3]− 213.0552, found 213.0561.
2-(4-Methoxyphenoxymethyl)-1,4-benzoquinone (11b): 4.27 g,
1
35%; red powder; mp 146.0 °C. H NMR (CDCl3): δ 3.78 (3H, s,
OCH3), 4.87 (2H, d, CH2O, J = 1.7 Hz), 6.78−6.98 (7H, m, CH-3,5,6
and 4 × CHAr), 13C NMR (CDCl3): δ 55.8 (OCH3), 63.9 (OCH2),
114.9 (2 × CHAr), 115.7 (2 × CHAr), 131.8 (CH), 136.5 (CH),
136.8 (CH), 144.4 (Cquat), 151.9 (Cquat), 154.6 (Cquat), 186.9 (C
O), 187.3 (CO). IR (cm−1): ν 1646, 1231. MS (ES−; m/z (%)):
244 (M−, 100). HRMS (ES−): calcd for [C14H11O4]− 243.0657, found
243.0664.
2-(4-Fluorophenoxymethyl)-1,4-benzoquinone (11c): 3.95 g,
1
34%; brown needles; mp 158.9 °C. H NMR (CDCl3): δ 4.91 (2H,
+
338 (M + NH4 , 100). HRMS (ES+): calcd for [C21H24NO3]+
d, CH2O, J = 1.7 Hz), 6.74−7.23 (7H, m, CH-3,5,6 and 4 × CHAr),
13C NMR (CDCl3): δ 63.9 (OCH2), 115.8 (2 × CHAr, JC−F = 8.1 Hz),
116.2 (2 × CHAr, JC−F = 23.1 Hz), 131.9 (CH), 136.5 (CH),
136.8 (CH), 144.0 (Cquat), 153.9 (Cquat), 157.9 (Cquat, JC−F = 240.0
Hz), 186.8 (CO), 187.2 (CO). 19F NMR (CDCl3): δ −122.37 to
−122.46 (1F, m). IR (cm−1): ν 1649, 1506, 1219. MS (ES−; m/z
(%)): 231 (M − H+, 100). HRMS (ES−): calcd for [C13H8FO3]−
231.0458, found 231.0467.
338.1756, found 338.1749.
2H,3′H-Spiro[5-fluorobenzofuran-3,2′-naphthalene]-1′,4′-dione
1
(3i): 150 mg, 53%; yellow crystals; mp 154.6−155.1 °C. H NMR
(CDCl3): δ 3.29 (1H, d, Jab = 16.2 Hz, CHaHbCO), 3.32 (1H, d, Jab
= 16.2 Hz, CHaHbCO), 4.34 (1H, d, J = 8.8 Hz, CHaHbO), 5.38
(1H, d, J = 8.8 Hz, CHaHbO), 6.37 (1H, dd, JHF = 2.8 Hz, JHF = 8.3
Hz, CH-4), 6.77 (1H, dd, JHH = 8.8 Hz, JHF = 4.4 Hz, CH-7), 6.86
(1H, ddd, JHH = 2.8 and 8.8 Hz, JHF = 8.3 Hz, CH-6), 7.79−7.89 (2H,
m, 2 × CHAr), 8.09−8.22 (2H, m, 2 × CHAr). 13C NMR (CDCl3): δ
48.6 (CH2CO), 58.7 (Cspiro), 78.8 (CH2O), 110.0 (JCF = 19.6 Hz,
CH-4), 111.3 (JCF = 3.5 Hz, CH-7), 116.7 (JCF = 24.2 Hz, CH-6),
127.0 (CHAr), 128.5 (CHAr), 128.6 (Cquat), 134.4 (Cquat), 135.1 (2 ×
CHAr), 135.4 (Cquat), 156.0 (Cquat), 157.2 (JCF = 238.8 Hz, Cquat),
193.4 (CO), 195.6 (CO). 19F NMR (CDCl3): −122.20- −122.58
(1F, m). IR (cm−1): ν 1686, 1482. MS (ES−; m/z (%)): 281 (M − H+,
100). HRMS (ES−): calcd for [C17H10FO3]− 281.0614, found
281.0612.
2-(4-Chlorophenoxymethyl)-1,4-benzoquinone (11d): 6.47 g,
1
52%; yellow needles; mp 155.8 °C. H NMR (CDCl3): δ 4.89 (2H,
dd, CH2O, J = 1.1 and 2.5 Hz), 6.77−6.95 and 7.25−7.30 (7H, m,
CH-3,5,6 and 4 × CHAr). 13C NMR (CDCl3): δ 63.5 (OCH2), 116.0
(2 × CHAr), 126.8 (Cquat), 129.7 (2 × CHAr), 131.9 (CH), 136.5
(CH), 136.8 (CH), 143.7 (Cquat), 156.4 (Cquat), 186.7 (CO),
187.1 (CO). IR (cm−1): ν 1648, 1626, 1491, 1249. MS (ES−; m/z
(%)): 247 and 249 (M − H+, 100 and 32). HRMS (ES−): calcd for
[C13H8ClO3]− 247.0162, found 247.0172.
Synthesis of 2′H,3H-Spiro[benzofuran-3,2′-benzoquinones]
12. A solution of 2-aryloxymethyl-1,4-benzoquinones 11 (1.5 mmol)
and palladium(II) acetate (1.5 mmol, 0.37 g) in acetic acid (30 mL)
was heated under reflux for 14 h. The reaction mixture was poured
into water and extracted with dichloromethane. The combined organic
extracts were washed with water and with a saturated solution of
sodium hydrogen carbonate and dried (MgSO4), and the solvent was
evaporated in vacuo. Flash chromatography on silica gel or preparative
TLC with ethyl acetate/hexane (1/4) yielded 2′H,3H-spiro-
[benzofuran-3,2′-benzoquinones] 12. Upon (LC−)MS analysis most
spiroquinones were found to give very poor mass spectrometric
ionizations.
2H,3′H-Spiro[benzofuran-3,2′-benzene]-1′,4′-dione (12a): 22 mg,
7%; pale white crystals; mp 114.5 °C. 1H NMR (CDCl3): δ 3.09 (1H,
d, Jab = 16.5 Hz, CHaHbCO), 3.14 (1H, d, Jab = 16.5 Hz, CHaHbC
O), 4.21 (1H, d, J = 9.9 Hz, CHaHbO), 5.24 (1H, d, J = 9.9 Hz,
CHaHbO), 6.81 (2H, m, 2 × CHAr), 6.94 (2H, s, 2 × CH), 7.00−
7.05 (1H, m, CHAr), 7.18−7.88 (1H, m CHAr). 13C NMR (CDCl3): δ
48.2 (CH2CO), 58.0 (Cspiro), 77.5 (CH2O), 111.1 (CHAr), 121.1
(CHAr), 123.5 (CHAr), 127.0 (Cquat), 130.6 (CHAr), 141.2 (CH),
141.7 (CH), 159.8 (Cquat), 194.9 (CO), 195.6 (CO). IR
(cm−1): ν 1682, 1478. MS (ES−; m/z (%)): 213 (M − H+, 100).
HRMS (ES+): calcd for [C13H11O3]+ 215.0708, found 215.0704.
2H,3′H-Spiro[5-methoxybenzofuran-3,2′-benzene]-1′,4′-dione
(12b): 44 mg, 12%; yellow crystals; mp 129.7 °C. 1H NMR (CDCl3):
δ 3.08 (1H, d, Jab = 16.5 Hz, CHaHbCO), 3.15 (1H, d, Jab = 16.5 Hz,
CHaHbCO), 3.71 (3H, s, OCH3), 4.20 (1H, d, J = 9.1 Hz,
2H,3′H-Spiro[5-chlorobenzofuran-3,2′-naphthalene]-1′,4′-dione
(3j): 206 mg, 69%; brown oil. 1H NMR (CDCl3): δ 3.29 (1H, d, Jab
=
16.2 Hz, CHaHbCO), 3.31 (1H, d, Jab = 16.2 Hz, CHaHbCO),
4.33 (1H, d, J = 9.1 Hz, CHaHbO), 5.36 (1H, d, J = 9.1 Hz, CHaHbO),
6.61 (1H, d, J = 2.2 Hz, CHAr), 6.74−6.81 (1H, m, CHAr), 7.07−7.18
(1H, m, CHAr), 7.78−7.89 (2H, m, 2 × CHAr), 8.11−8.19 (2H, m, 2 ×
CHAr). 13C NMR (CDCl3): δ 48.5 (CH2CO), 58.5 (Cspiro), 78.4
(CH2O), 111.9 (CHAr), 116.8 (Cquat), 123.9 (CHAr), 125.7 (Cquat),
127.0 (CHAr), 128.5 (CHAr), 129.5 (Cquat), 130.3 (CHAr), 135.2 (2 ×
CHAr), 135.4 (Cquat), 158.7 (Cquat), 193.5 (CO), 193.6 (CO). IR
(cm−1): ν 1693, 1474. MS (ES−; m/z (%)): 297 (M − H+, 100).
HRMS (ES−): calcd for [C17H10ClO3]− 297.0319, found 297.0314.
Synthesis of 2-Aryloxymethyl-1,4-benzoquinones 11. To 125
mL of distilled water, the appropriate phenoxyacetic acid 5 (50 mmol),
5.40 g (50 mmol) of 1,4-benzoquinone 10, and 1 g (6 mmol) of
AgNO3 were added successively. The mixture was then heated to 60−
65 °C until dissolution was complete. The resulting solution was
stirred vigorously while a solution of 13.7 g (60 mmol) of ammonium
peroxydisulfate in 25 mL of water was added at a rate of 0.5 mL/min
for the first 40 min and then at a rate of 0.25 mL/min for the last 20
min. Throughout the addition, the reaction mixture was maintained at
60−65 °C. After the addition was complete, the mixture was stirred for
5 min at 65 °C and was then cooled to 5−10 °C using an ice bath. The
precipitated solid was collected by suction filtration, washed with 50
mL of cold water, and pressed to remove most of the liquid. Inorganic
contaminants, usually present in small amounts, were removed by
G
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CHaHbO), 5.19 (1H, d, J = 9.1 Hz, CHaHbO), 6.57−6.63 (1H, m,
and the solvent was evaporated in vacuo. Flash chromatography on
silica gel with 1/9 ethyl acetate/hexane yielded 3′H-spiro[chroman-
3,2′-naphthalene]-1′,4′-dione (15); 106 mg, 36%; white needles; mp
94.2−94.8 °C. 1H NMR (CDCl3): δ 2.12 (1H, ddd, J = 14.2, 7.6, and
5.0 Hz, CHaCHbCH2O), 2.30 (1H, ddd, J = 14.2, 5.3, and 3.3 Hz,
CHaCHbCH2O), 3.13 (1H, d, J = 16.2 Hz, CHaHbCO), 3.64 (1H,
d, J = 16.2 Hz, CHaHbCO), 4.11−4.25 (2H, m, CH2O), 6.88−6.94
(2H, m, 2 × CHAr), 7.04−7.08 (1H, m, CHAr), 7.17−7.26 (1H, m,
CHAr), 7.78−7.81 (2H, m, 2 × CHAr), 8.05−8.15 (2H, m, 2 × CHAr).
13C NMR (CDCl3): δ 33.1 (CH2CH2O), 49.3 (Cspiro), 51.3 (CH2−
CO), 61.8 (CH2O), 117.8 (CHAr), 120.9 (CHAr), 122.3 (Cquat),
126.3 (CHAr), 128.3 (CHAr), 128.3 (CHAr), 129.0 (CHAr), 133.3
(Cquat), 134.4 (CHAr), 134.8 (CHAr), 154.9 (Cquat), 195.2 (CO),
198.3 (CO), one trisubstituted olefinic carbon is not observed. IR
(cm−1): ν 1691 (CO), 1595 (CHAr), 1492, 1292, 1226, 755. MS
(ES+; m/z (%)): 278 (M + H+, 3), 86 (39), 84 (64), 49 (100). HRMS
(ES+): calcd for [C18H15O3]+ 279.1021, found 279.1014.
Synthesis of 2-(4-Hydroxybenzyl)-1,4-quinones 17 and 18a.
A solution of 2-phenoxymethyl-1,4-quinones (1.5 mmol) in 6 mL of
trifluoroacetic acid was stirred for 15 h (for 2-phenoxymethyl-1,4-
quinones 1a,b,e and 11a) or 3 days (for 3-methyl-2-phenoxymethyl-
1,4-naphthoquinone (10)) at room temperature. Subsequently,
trifluoroacetic acid was evaporated in vacuo, and the residue was
dissolved in 20 mL of chloroform. This solution was washed with
water, saturated aqueous NaHCO3, and brine (3 × 10 mL). Drying
over MgSO4 and evaporation of the solvent in vacuo gave the crude
product, which was purified further by means of column
chromatography on silica gel (solvent system petroleum ether/ethyl
acetate). 2-(4-Hydroxybenzyl)-1,4-benzoquinone (18a) quickly poly-
merizes after purification; therefore, no HRMS or elementary analysis
could be recorded. Attempts to derivatize this compound 18a by
acetylation resulted in a complex mixture.
CHAr), 6.73−6.80 (2H, m, 2 × CHAr), 6.95 (2H, br. s, 2 × CH). 13
C
NMR (CDCl3): δ 48.1 (CH2CO), 56.2 (OCH3), 58.4 (Cspiro), 77.9
(CH2O), 110.1 (CHAr), 111.1 (CHAr), 115.2 (CHAr), 127.9 (Cquat),
141.2 (CH), 141.7 (CH), 153.9 (Cquat), 154.3 (Cquat), 195.0
(CO), 195.4 (CO). IR (cm−1): ν 1678, 1482, 1470. MS (ES−; m/
z (%)): 243 (M − H+, 100). HRMS (ES−): calcd for [C14H12O4]−
244.0741, found 244.0717.
2H,3′H-Spiro[5-fluorobenzofuran-3,2′-benzene]-1′,4′-dione
(12c): 70 mg, 20%; yellow viscous oil. 1H NMR (CDCl3): δ 3.10 (1H,
d, Jab = 16.5 Hz, CHaHbCO), 3.15 (1H, d, Jab = 16.5 Hz, CHaHbC
O), 4.26 (1H, d, J = 9.4 Hz, CHaHbO), 5.22 (1H, d, J = 9.4 Hz,
CHaHbO), 6.71−6.95 (3H, m, 3 × CHAr), 6.96 (2H, s, 2 × CH).
13C NMR (CDCl3): δ 48.1 (CH2CO), 58.3 (Cspiro), 78.2 (CH2O),
110.8 (JCF = 25.4 Hz, CHAr), 111.5 (JCF = 8.1 Hz, CHAr), 117.0 (JCF
=
24.2 Hz, CHAr), 128.0 (JCF = 8.1 Hz, Cquat), 141.1 (CH), 141.9 (
CH), 150.9 (Cquat), 157.3 (JCF = 238.8 Hz, Cquat), 194.6 (CO),
195.0 (CO). 19F NMR (CDCl3): −122.82 to −122.89 (1F, m). IR
(cm−1): ν 1684, 1482. MS (ES−; m/z (%)): 231 (M − H+, 100).
HRMS (ES+): calcd for [C13H10FO3]+ 233.0609, found 233.0614.
2H,3′H-Spiro[5-chlorobenzofuran-3,2′-benzene]-1′,4′-dione
(12d): 71 mg, 19%; yellow crystals; mp 129.7 °C. 1H NMR (CDCl3):
δ 3.09 (1H, d, Jab = 16.5 Hz, CHaHb-CO), 3.15 (1H, d, Jab = 16.5
Hz, CHaHbCO), 4.23 (1H, d, J = 9.9 Hz, CHaHbO), 5.23 (1H, d, J
= 9.9 Hz, CHaHbO), 6.79 (1H, d, J = 8.3 Hz, CHAr), 6.96 (3H, br s, 2
× CH and CHAr), 7.17 (1H, dd, J = 2.2 and 8.3 Hz, CHAr). 13C
NMR (CDCl3): δ 48.0 (CH2−CO), 58.0 (Cspiro), 78.2 (CH2O),
112.1 (CHAr), 123.7 (CHAr), 128.8 (Cquat), 125.8 (Cquat), 130.6
(CHAr), 141.0 (CH), 141.9 (CH), 158.5 (Cquat), 194.4 (CO),
194.9 (CO). IR (cm−1): ν 1686, 1474. MS (ES−; m/z (%)): 247
and 249 (M − H+, 100 and 35). HRMS (ES−): calcd for
[C13H8ClO3]− 247.0168, found 247.0161.
Synthesis of 2-(2-Phenoxyethyl)-1,4-naphthoquinone (14).
A mixture of 1,4-naphthoquinone (4; 30 mmol, 4.74 g), silver nitrate
(9 mmol, 1.5 g), and 3-phenoxypropionic acid (13; 45 mmol, 7.47 g)
in acetonitrile was heated to 85 °C, and to the stirred reaction mixture
was added a solution of ammonium persulfate (60 mmol, 13.68 g) in
demineralized water (30 mL) dropwise over 30 min, after which the
reaction mixture was kept at the same temperature for 24 h. A second
portion of 3-phenoxypropionic acid (45 mmol, 7.47 g) was added in
one portion, followed by the addition of a second portion of a solution
of ammonium persulfate (60 mmol, 13.68 g) in demineralized water
(30 mL). The resulting reaction mixture was stirred for 24 h at 85 °C.
Water (1 L) was added, and the aqueous solution was extracted with
ethyl acetate. The combined organic extracts were washed with a
saturated solution of sodium hydrogen carbonate and dried over
MgSO4, and the solvent was evaporated in vacuo. The crude reaction
mixture, which contained still about 80% of 1,4-naphthoquinone 4,
was chromatographed over a short column of silica gel using 1/9 ethyl
acetate/petroleum ether. Recrystallization from ethyl acetate afforded
pure 2-(2-phenoxyethyl)-1,4-naphthoquinone (14): 918 mg, 11%; mp
141.4−142 °C, yellow crystals. 1H NMR (CDCl3): δ 3.06 (2H, td, J =
6.1 and 1.3 Hz, CH2CH2O), 4.24 (2H, t, J = 6.1 Hz, CH2CH2O),
6.88−6.98 (4H, m, 3 × CHAr and CH-3), 7.25−7.30 (2H, m, 2 ×
CHAr), 7.71−7.77 (2H, m, 2 × CHAr), 8.06−8.13 (2H, m, 2 × CHAr).
13C NMR (CDCl3): δ 29.9 (CH2CH2O), 65.1 (CH2O), 114.5 (2 ×
CHAr), 121.1 (CHAr), 126.1 (CHAr), 126.6 (CHAr), 129.5 (2 × CHAr),
132.1 (2 × Cquat), 133.7 (CHAr), 133.8 (CHAr), 136.7 (CH-3), 147.7
(Cquat), 158.4 (Cquat), 184.9 (CO), 185.9 (CO). IR (cm−1): ν
1655 (CO), 1620, 1602, 1593 (CHAr), 1307, 1257, 768. MS (ES+;
m/z (%)): 278 (M + H+, 100). HRMS (ES−): calcd for [C18H13O3]−
277.0865, found 277.0874.
Synthesis of 3′H-Spiro[chroman-3,2′-naphthalene]-1′,4′-
dione (15). In a 10 mL vial were added 3,5-dichloropyridine (0.15
mmol, 22 mg), trifluoroacetic acid (0.05 mmol, 6 mg), palladium(II)
acetate (0.10 mmol, 22 mg), 2-(2-phenoxyethyl)-1,4-naphthoquinone
(14; 1.0 mmol), and 4 mL of acetic acid. The vial was sealed with a
septum, and the contents were stirred at 110 °C for 4 days. The
reaction mixture was then diluted with chloroform, washed once with
water and twice with sodium hydrogen carbonate, and dried (MgSO4),
2-(4-Hydroxybenzyl)-1,4-naphthoquinone (17a): 293 mg, 74%;
brown crystals; mp 159.6−160.2 °C. 1H NMR (CDCl3): δ 3.83 (2H, s,
CH2Ar), 5.08 (1H, br s, ArOH), 6.61 (1H, s, CH-3), 6.80 (2H, d, J =
8.3 Hz, 2 × CHAr), 7.11 (2H, d, J = 8.3 Hz, 2 × CHAr), 7.70−7.76
(2H, m, 2 × CHAr), 8.02−8.13 (2H, m, 2 × CHAr). 13C NMR
(CDCl3): δ 35.0 (CH2Ar), 115.8 (2 × CHAr), 126.2 (CHAr), 126.8
(CHAr), 128.8 (Cquat), 130.8 (2 × CHAr), 132.2 (Cquat), 132.3 (Cquat),
133.8 (CHAr), 133.9 (CHAr), 135.6 (CH-3), 151.3 (Cquat), 154.6
(Cquat), 185.2 (CO), 185.4 (CO). IR (cm−1): ν 3395 (OH), 1650
(CO), 1593, 1509, 1265, 1220. MS (ES+; m/z (%)): 265 (M + H+,
100). HRMS (ES−): calcd for [C17H11O3]− 263.0708, found 263.0704.
2-(4-Hydroxy-3-methylbenzyl)-1,4-naphthoquinone (17b): 305
mg, 73%; green solid; mp 151.0 °C. 1H NMR (CDCl3): δ 2.23
(3H, s, CH3), 3.79 (2H, s, CH2Ar), 5.10 (1H, br. s, ArOH), 6.61 (1H,
s, CH-3), 6.73 (1H, d, J = 7.9 Hz, CH-5′ or CH-6′), 6.94 (1H, d, J =
7.9 Hz, CH-5′ or CH-6′), 6.98 (1H, s, CH-2′), 7.71−7.74 (2H, m,
CH-6 and CH-7), 8.02−8.11 (2H, m, CH-5 and CH-8). 13C NMR
(CDCl3): δ 15.9 (CH3), 35.0 (CH2Ar), 115.3 (CH-5′ or CH-6′),
124.4 (Cquat), 126.2 and 126.8 (CH-5 and CH-8), 128.1 (CH-5′ or
CH-6′), 128.6 (Cquat), 132.1 (CH-2′), 132.2 (Cquat), 132.3 (Cquat
)
133.9 and 133.9 (CH-6 and CH-7), 135.6 (CH-3), 151.5 (Cquat),
153.0 (Cquat), 185.3 (CO), 185.6 (CO). IR (cm−1): ν 3380
(OH), 1652 (CO), 1595, 1336, 1267. MS (ES+; m/z (%)): 279 (M
+ H+, 100). HRMS (ES+): calcd for [C18H13O3]− 277.0865, found
277.0862.
2-(4-Hydroxy-3-methoxybenzyl)-1,4-naphthoquinone (17c): 185
1
mg, 42%; yellow crystals; mp 169.0 °C. H NMR (CDCl3): δ 3.83
(2H, s, CH2Ar), 3.88 (3H, s, OCH3), 5.55 (1H, br. s, ArOH), 6.61
(1H, s, CH-3), 6.74−6.75 (2H, m, 2 × CHAr), 6.88 (1H, d, J = 8.8 Hz,
CH-5′ or CH-6′), 7.72−7.75 (2H, m, CH-6 and CH-7), 8.03−8.13
(2H, m, CH-5 and CH-8). 13C NMR (CDCl3): δ 35.5 (CH2Ar), 56.0
(OCH3), 111.9 (CHAr), 114.8 (CHAr), 122.4 (CHAr), 126.2 and 126.8
(CH-5 and CH-8), 128.4 (Cquat), 132.2 (Cquat), 132.3 (Cquat) 133.8
and 133.9 (CH-6 and CH-7), 135.6 (CH-3), 144.7 (Cquat), 146.8
(Cquat), 151.3 (Cquat), 185.3 (CO), 185.4 (CO). IR (cm−1): ν
3355 (OH), 1652 (CO), 1590, 1517, 1274, 1234. MS (ES+; m/z
(%)): 295 (M + H+, 100). HRMS (ES−): calcd for [C18H13O4]−
293.0814, found 293.0809.
H
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2-(4-Hydroxybenzyl)-3-methyl-1,4-naphthoquinone (17d): 250
mg, 60%; orange crystals; mp 50.5 °C. H NMR (CDCl3): δ 2.25
2-Phenylaminomethyl-1,4-dimethoxynaphthalene (635 mg, 2.16
mmol) and Et3N (0.33 mL, 1.1 equiv.) were dissolved in 4 mL of
dry dichloromethane. The mixture was cooled to 0 °C, and acetyl
chloride or benzoyl chloride (1.1 equiv) was added dropwise. The
mixture was warmed to room temperature and stirred overnight. Next,
Et3NHCl was filtered off and the filtrate was extracted once with brine
(5 mL). Purification by column chromatography on silica gel (PE/EA)
gave the corresponding N-protected 2-phenylaminomethyl-1,4-dime-
thoxynaphthalenes.
1
(3H, s, CH3), 3.94 (2H, s, CH2Ar), 5.43 (1H, br s, ArOH), 6.73 (2H,
d, J = 8.3 Hz, 2 × CHAr), 7.09 (2H, d, J = 8.3 Hz, 2 × CHAr), 7.66−
7.72 (2H, m, 2 × CHAr), 8.04−8.10 (2H, m, 2 × CHAr). 13C NMR
(CDCl3): δ 13.3 (CH3), 31.7 (CH2Ar), 115.6 (2 × CHAr), 126.4
(CHAr), 126.6 (CHAr), 129.9 (2 × CHAr), 130.0 (Cquat), 132.1 (Cquat),
132.2 (Cquat), 133.6 (CHAr), 133.6 (CHAr), 144.3 (Cquat), 145.7
(Cquat), 154.4 (Cquat), 185.0 (CO), 185.7 (CO). IR (cm−1): ν
(cm−1) 3481 (OH), 1653 (CO), 1514. MS (ES+; m/z (%)): 279
(M + H+, 65). HRMS (ES−): calcd for [C18H13O3]− 277.0870, found
277.0825.
N-Acetyl-2-phenylaminomethyl-1,4-dimethoxynaphthalene: 449
1
mg, 62%; yellow crystals; mp 80 °C. H NMR (CDCl3): δ 1.94 (3H,
CH3CO), 3.44 (3H, s, OCH3), 3.97 (3H, s, OCH3), 5.18 (2H, s,
CH2O), 6.84 (1H, s, CH-3), 7.0.1−7.06 (2H, m, 2 × CHAr), 7.20−
7.33 (3H, m, 3 × CHAr), 7.43−7.52 (2H, m, CH-6 and CH-7), 7.88−
7.93 (1H, m, CH-5 or CH-8), 8.19−8.23 (1H, m, CH-5 or CH-8). 13C
NMR (CDCl3): δ 22.9 (CH3CO), 46.7 (CH2N), 55.8 (OCH3), 62.2
(OCH3), 104.6 (CH-3), 122.1 (CHAr), 122.5 (CHAr), 125.5 (CHAr),
125.6 (Cquat), 126.4 (Cquat), 126.4 (Cquat), 126.6 (CHAr), 128.1
(CHAr), 128.4 (2 × CHAr), 129.7 (2 × CHAr), 142.9 (Cquat), 147.8
(Cquat), 152.1 (Cquat), 171.0 (CO). IR (cm−1): ν 1645 (CO),
1631, 1594 (CHAr), 1494, 1369, 1228 (C−N), 670. MS (ES+; m/z
(%)): 336 (M + H+, 100). HRMS (ES+): calcd for [C21H22NO3]+
336.1600, found 336.1593.
2-(4-Hydroxybenzyl)-1,4-benzoquinone (18a): 206 mg, 64%; red
1
viscous oil. H NMR (CDCl3): δ 3.66 (2H, d, J = 1.4 Hz, CH2Ar),
6.06 (1H, br s, ArOH), 6.37 (1H, dd, J = 1.6 and 3.9 Hz, CH-3),
6.72−6.79 (2H, m, CH-5 and CH-6), 6.80 (2H, d, J = 8.3 Hz, 2 ×
CHAr), 7.04 (2H, d, J = 8.3 Hz, 2 × CHAr). 13C NMR (CDCl3): δ 34.5
(CH2Ar), 115.9 (2 × CHAr), 128.2 (Cquat), 130.7 (2 × CHAr), 133.2
(CH), 136.5 (CH), 136.9 (CH), 149.3 (Cquat), 154.9 (Cquat),
187.6 (CO), 188.2 (CO). IR (cm−1): ν 3372 (OH), 1651 (C
O), 1513. MS (ES−; m/z (%)): 213 (M − H+, 100). Due to the
instability of this compound, no HRMS or elementary analysis could
be performed.
N-Benzoyl-2-phenylaminomethyl-1,4-dimethoxynaphthalene:
418 mg, 51%; white solid; mp 143.0 °C. H NMR (CDCl3): δ 3.62
Synthesis of N-protected 2-Phenylaminomethyl-1,4-naph-
thoquinones. 2-Formyl-1,4-dimethoxynapthalene (1 g, 4.62 mmol)
and aniline (426 mg, 4.62 mmol, 1 equiv) were dissolved in 10 mL of
dry methanol and stirred at room temperature for 1 h in a dry flask
fitted with a CaCl2 tube. Next, the reaction mixture was cooled to 0 °C
and NaBH4 (175 mg, 4.62 mmol, 1 equiv) was added portionwise and
the reaction mixture was warmed to room temperature. After 30 min,
the solvent was evaporated in vacuo and the residue dissolved in
EtOAc (10 mL) which was washed with brine (2 × 10 mL). Drying
over MgSO4 and evaporation of the solvent in vacuo yielded 1.26 g
(94%) of pure 2-phenylaminomethyl-1,4-dimethoxynaphthalene as a
yellow oil which solidified upon standing.
2-Phenylaminomethyl-1,4-dimethoxynaphthalene: 1.26 g, 94%;
orange solid; mp 96.5 °C. 1H NMR (CDCl3): δ 3.94 (6H, s,
2xOCH3), 4.51 (2H, s, CH2O), 6.71−6.76 (3H, m, 3 × CHAr), 6.82
(1H, s, CH-3), 7.20 (2H, td, J = 2.2 and 6.9 Hz, 2 × CHAr), 7.45−7.58
(2H, m, CH-6 and 7), 8.07 (1H, dd, J = 1.1 and 8.3 Hz, CH-5 or CH-
8), 8.23 (1H, dd, J = 1.1 and 8.3 Hz, CH-5 or CH-8), NH not
observed. 13C NMR (CDCl3): δ 43.5 (CH2N), 55.8 (OCH3), 62.6
(OCH3), 104.4 (CH-3), 113.2 (2 × CHAr), 117.9 (CHAr), 122.0
(CHAr), 122.6 (CHAr), 125.6 (CHAr), 126.3 (Cquat), 126.9 (CHAr),
127.4 (Cquat), 128.8 (Cquat), 129.5 (2 × CHAr), 147.4 (Cquat), 148.7
(Cquat), 152.4 (Cquat). IR (cm−1): ν 3377 (NH), 1600 (CHAr), 1505,
1374, 1091 (C−N), 752. MS (ES+; m/z (%)): 294 (M + H+, 100).
HRMS (ES+): calcd for [C19H20NO2]+ 294.1494, found 294.1484.
2-Phenylaminomethyl-1,4-dimethoxynaphthalene was dissolved in
10 mL of pyridine and , cooled to 0 °C, and mesyl chloride (0.35 mL,
5.67 mmol, 1.3 equiv) was added dropwise. The reaction mixture was
warmed to room temperature and stirred for 1 h. Next, the reaction
mixture was poured into 20 mL of ice water and extracted with EtOAc
(3 × 10 mL). The combined organic fractions where washed with HCl
(2 M, 3 × 10 mL) and brine (10 mL). Drying over MgSO4 and
evaporation of the solvent in vacuo yielded 1.36 g (84%) of pure N-
mesyl-2-phenylaminomethyl-1,4-dimethoxynapthalene.
1
(3H, s, OCH3), 3.92 (3H, s, OCH3), 5.43 (2H, s, CH2O), 6.91−7.06
(5H, m, 5 × CHAr), 7.12−7.22 (4H, m, 4 × CHAr), 7.36−7.50 (4H, m,
4 × CHAr), 7.96 (1H, d, J = 7.7 Hz, CH-5 or CH-8), 8.22 (1H, d, J =
7.7 Hz, CH-5 or CH-8). 13C NMR (CDCl3): δ 47.9 (CH2N), 55.8
(OCH3), 62.4 (OCH3), 104.0 (CH-3), 122.1 (CHAr), 122.5 (CHAr),
125.6 (CHAr), 125.9 (Cquat), 126.4 (Cquat), 126.8 (CHAr), 127.0
(CHAr), 127.9 (2 × CHAr), 128.0 (2 × CHAr), 128.5 (Cquat), 128.7 (2
× CHAr), 129.1 (2 × CHAr), 129.8 (CHAr), 136.3 (Cquat), 143.5
(Cquat), 147.6 (Cquat), 152.3 (Cquat), 171.3 (CO). IR (cm−1): ν 1637
(CO), 1594, 1366, 1090 (C−O). MS (ES+; m/z (%)): 398 (M +
H+, 100). HRMS (ES+): calcd for [C26H24NO3]+ 398.1756, found
398.1757.
To a stirred solution of an N-protected 2-phenylaminomethyl-1,4-
dimethoxynapthalene (2 mmol) in CH3CN (8 mL) was added a
solution of cerium ammonium nitrate (2.74 g, 5 mmol, 2.5 equiv) in
water (8 mL). The reaction mixture was stirred for 10 min at room
temperature. Next, the reaction mixture was poured into 20 mL of
CH2Cl2 and washed two times with brine. Drying over MgSO4 and
evaporation of the solvent in vacuo yielded pure N-protected 2-
phenylaminomethyl-1,4-naphthoquinones.
N-Mesyl-2-phenylaminomethyl-1,4-naphthoquinone: 490 mg,
1
66%; yellow solid; mp 220.5 °C. H NMR (CDCl3): δ 3.00 (3H,
CH3SO2), 4.92 (2H, d, J = 1.7 Hz, CH2O), 7.14 (1H, t, J = 1.7 Hz,
CH-3), 7.30−7.35 (1H, m, CHAr), 7.38−7.47 (4H, m, 4 × CHAr),
7.69−7.77 (2H, m, CH-6 and CH-7), 8.01−8.08 (2H, m, CH-5 and
CH-8). 13C NMR (CDCl3): δ 37.3 (CH3SO2), 49.4 (CH2N), 126.5
(CHAr), 128.0 (2 × CHAr), 128.5 (CHAr), 129.9 (2 × CHAr), 132.0
(Cquat), 132.1 (Cquat), 133.9 (CHAr), 134.3 (CHAr), 135.5 (CHAr),
139.4 (Cquat), 145.6 (Cquat), 184.5 (CO), 184.9 (CO). IR (cm−1):
ν 1659 (CO), 1595 (CHAr), 1338 (SO), 1306, 1160 (SO),
1093 (C−N), 774. MS (ES+; m/z (%)): 342 (M + H+, 100). HRMS
(ES+): calcd for [C18H16NO4S]+ 342.0800, found 342.0802.
N-Mesyl-2-phenylaminomethyl-1,4-dimethoxynaphthalene: 1.36
g, 84%; pale white solid; mp 131.5 °C. 1H NMR (CDCl3): δ 3.04 (3H,
CH3SO2), 3.67 (3H, s, OCH3), 3.93 (3H, s, OCH3), 5.10 (2H, s,
CH2O), 6.85 (1H, s, CH-3), 7.18−7.34 (3H, m, 3 × CHAr), 7.42−7.52
(2H, m, 5 × CHAr),7.42−7.52 (2H, m, CH-6 and CH-7), 7.92−7.95
(1H, m, CH-5 or CH-8), 8.16−8.20 (1H, m, CH-5 or CH-8). 13C
NMR (CDCl3): δ 37.8 (CH3SO2), 49.0 (CH2N), 55.8 (OCH3), 62.7
(OCH3), 104.4 (CH-3), 122.1 (CHAr), 122.6 (CHAr), 124.1 (Cquat),
125.8 (CHAr), 126.5 (Cquat), 126.8 (CHAr), 128.3 (CHAr), 128.3
(Cquat), 128.9 (2 × CHAr), 129.5 (2 × CHAr), 139.3 (Cquat), 147.8
(Cquat), 152.1 (Cquat). IR (cm−1): 1597 (CHAr), 1338 (SO), 1154
(SO), 771. MS (ES+; m/z (%)): 201 (M − PhNMs−, 100). HRMS
(ES+): calcd for [C13H13O2]+ 201.0916, found 201.0915.
N-Acetyl-2-phenylaminomethyl-1,4-naphthoquinone: 604 mg,
90%; amber solid; mp 164.0 °C. H NMR (CDCl3): δ 2.00 (3H, s,
1
CH3CO), 4.89 (2H, d, J = 1.7 Hz, CH2O), 6.92 (1H, t, J = 1.7 Hz,
CH-3), 7.24−7.51 (5H, m, 5 × CHAr), 7.70−7.77 (2H, m, CH-6 and
CH-7), 8.03−8.10 (2H, m, CH-5 and CH-8). 13C NMR (CDCl3): δ
22.6 (CH3CO), 48.6 (CH2N), 126.2 (CHAr), 126.4 (CHAr), 127.6
(2 × CHAr), 128.4 (CHAr), 130.0 (2 × CHAr), 132.0 (Cquat), 132.1
(Cquat), 133.88 (CHAr), 133.93 (CHAr), 134.0 (CHAr), 143.1 (Cquat),
145.8 (Cquat), 171.1 (NCO), 184.7 (2 × CO). IR (cm−1): ν 1658
(CO), 1299, 782. MS (ES+; m/z (%)): 306 (M + H+, 100). HRMS
(ES+): calcd for [C19H16NO3]+ 306.1130, found 306.1123.
N-Benzoyl-2-phenylaminomethyl-1,4-naphthoquinone: 795 mg,
1
quantitative; yellow solid; mp 180.5 °C. H NMR (CDCl3): δ 5.04
I
dx.doi.org/10.1021/jo400852z | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2H, d, J = 1.7 Hz, CH2O), 6.90 (1H, t, J = 1.7 Hz, CH-3), 6.99−7.22
(8H, m, 8 × CHAr), 7.27−7.30 (2H, m, 2 × CHAr), 7.59−7.65 (2H, m,
CH-6 and CH-7), 7.92−8.01 (2H, m, CH-5 and CH-8). 13C NMR
(CDCl3): δ 49.4 (CH2N), 126.3 (CHAr), 126.5 (CHAr), 127.1 (2 ×
CHAr), 128.0 (2 × CHAr), 129.1 (2 × CHAr), 129.5 (2 × CHAr), 130.4
(CHAr), 132.06 (Cquat), 132.14 (Cquat), 133.91 (CHAr), 133.96 (CHAr),
134.1 (CHAr), 135.0 (Cquat), 143.6 (Cquat), 145.9 (Cquat), 170.7 (NC
O), 184.8 (CO), 184.9 (CO). IR (cm−1): ν 1644 (CO), 1632
(CO), 1365, 1299, 700. MS (ES+; m/z (%)): 368 (M + H+, 100).
HRMS (ES+): calcd for [C24H18NO3]+ 368.1287, found 368.1289.
Synthesis of 2-Phenoxymethylchromen-4-one. 2-Phenoxyme-
thylchromen-4-one was synthesized following a literature procedure
describing the synthesis of 2-(4-chlorophenoxy)methylchromen-4-
Lett. 2009, 11, 4938−4941. (c) Zhao, Y.; Zhang, Y.; Wang, J.; Li, H.;
Wu, L.; Liu, Z. Synlett 2010, 15, 2352−2356. (d) Moon, Y.; Hong, S.
Chem. Commun. 2012, 48, 7191−7193. (e) Rao, M. L. N.; Giri, S. RSC
Adv. 2012, 2, 12739−12750.
(6) (a) Ferreira, E. M.; Stolz, B. M. J. Am. Chem. Soc. 2003, 125,
9578−9578. (b) Zhang, H.; Ferreira, E. M.; Stolz, B. M. Angew. Chem.,
Int. Ed. 2004, 43, 6144−6148.
(7) Li, G.; Leow, D.; Wan, L.; Yu, J.-Q. Angew. Chem., Int. Ed. 2013,
52, 1245−1247.
(8) (a) Backvall, J.-E.; Bystrom, S. E.; Nordberg, R. E. J. Org. Chem.
̈
̈
́
1984, 49, 4619−4631. (b) Albeniz, A. C.; Espinet, P.; Martín-Ruiz, B.
Chem. Eur. J. 2001, 7, 2481−2489. (c) Hull, K. L.; Sanford, M. S. J.
Am. Chem. Soc. 2007, 129, 11904−11905. (d) Yin, G.; Wu, Y.; Liu, G.
J. Am. Chem. Soc. 2010, 132, 11978−11987.
one:14 1.50 g, 56%; white crystals; mp 96.5 °C. H NMR (CDCl3): δ
1
4.98 (2H, d, J = 1.2 Hz, CH2O), 6.54 (1H, s, CH-3), 6.96−7.05 (3H,
m, 3 × CHAr), 7.29−7.36 (2H, m, 2 × CHAr), 7.41 (1H, dt, J = 8.1, 1.1
Hz, CH-8), 7.46 (1H, d, J = 8.1 Hz, CH-8), 7.65−7.68 (1H, ddd, J =
8.1, 7.4, 1.7 Hz, CH-6), 8.19 (1H, dd, J = 1.4 and 8.0 Hz, CH-5). 13C
NMR (CDCl3): δ 65.7 (CH2O), 109.6 (CH-3), 114.8 (2 × CHAr),
118.0 (CHAr), 122.0 (CHAr), 124.0 (Cquat), 125.3 (CHAr), 125.6
(CHAr), 129.7 (2 × CHAr), 133.9 (CHAr), 156.1 (Cquat), 157.6 (Cquat),
163.9 (Cquat), 177.7 (CO). IR (cm−1): ν 1647 (CO), 1466, 1355,
1243 (C−O), 1220 (C−O), 751. MS (ES+; m/z (%)): 253 (M + H+,
100). HRMS (ES+): calcd for [C16H13O3]+ 253.0865, found 253.0859.
́ ́
(9) (a) Albeniz, C. A.; Catalina, M. M.; Espinet, P.; Redon, R.
Organometallics 1999, 18, 5571. (b) Culkin, D. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 5816−5817.
(10) Lyons, T. W.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2011,
133, 4455−4464.
(11) (a) Andappan, M. M. S.; Nilsson, P.; Larhed, M. Chem.
Commun. 2004, 2, 218−219. (b) Pathak, T. P.; Gligorich, K. M.;
Welm, B. E.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 7870−7871.
(c) Zheng, C.; Wang, D.; Stahl, S. S. J. Am. Chem. Soc. 2012, 134,
16496−16499. (d) Jana, R.; Pathak, T. P.; Jensen, K. H.; Sigman, M. S.
Org. Lett. 2012, 14, 4074−4077. (e) Izawa, Y.; Zheng, Z.; Stahl, S. S.
Angew. Chem., Int. Ed. 2013, 52, 3672−3675.
ASSOCIATED CONTENT
■
(12) Jacobsen, N.; Torssell, K. Liebigs Ann. Chem. 1972, 763, 135−
147.
(13) Aldersly, M. F.; Chishti, S. H.; Dean, F. M.; Douglas, M. F.;
Ennis, D. S. J. Chem. Soc., Perkin Trans. I 1990, 8, 2163−2174.
(14) Guryar, M. K.; Bagavant, G. Curr. Sci. India 1978, 47, 683−4.
S
* Supporting Information
1
Figures giving H and 13C NMR spectra of all compounds
discussed. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for N.D.K.: norbert.dekimpe@UGent.be.
■
Present Address
†Institute of Chemistry, Vietnam Academy of Science &
Technology, 18 Hoang Quoc Viet, Cau Giay, Ha Noi, Viet
Nam.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are indebted to the “Research Foundation Flanders (FWO-
Vlaanderen)” for financial support of this research.
■
REFERENCES
■
(1) (a) Kesteleyn, B.; Nguyen Van, T.; De Kimpe, N. Tetrahedron
1999, 59, 2091−2102. (b) Kesteleyn, B.; Van Puyvelde, L.; De Kimpe,
N. J. Org. Chem. 1999, 64, 438−440. (c) Kesteleyn, B.; Van Puyvelde,
L.; De Kimpe, N. J. Org. Chem. 1999, 64, 1173−1179. (d) Kesteleyn,
B.; De Kimpe, N. J. Org. Chem. 2000, 65, 635−639. (e) Kesteleyn, B.;
De Kimpe, N. J. Org. Chem. 2000, 65, 640−644. (f) Nguyen Van, T.;
De Kimpe, N. Tetrahedron 2003, 59, 5941−5946. (g) Claessens, S.;
Jacobs, J.; Van Aeken, S.; Abbaspour Tehrani, K.; De Kimpe, N. J. Org.
Chem. 2008, 73, 7555−7559.
(2) (a) Itahara, T. J. Org. Chem. 1985, 50, 5546−5550. (b) Yogo, M.;
Ito, C.; Furukawa, H. Chem. Pharm. Bull. 1991, 39, 328−334.
(c) Singh, P. K.; Rohtagi, B. K.; Khanna, R. N. Synth. Commun. 1992,
22, 987−993.
(3) (a) Huang, C.; Liu, B. Chem. Commun. 2010, 46, 5280−5282.
(b) Takenaga, N.; Uchiyama, T.; Kato, D.; Fujioka, H.; Dohi, T.; Kita,
Y. Heterocycles 2011, 82, 1327−1336.
(4) Jacobsen, N.; De Franco, R. J.; Benson, R. E. Org. Synth. 1977, 56,
68−71.
(5) (a) Knolker, H.-J.; Reddy, K. R. Heterocycles 2003, 60, 1049−
̈
́
1052. (b) Molina, M. T.; Navarro, C.; Moreno, A.; Csaky, A. G. Org.
̈
J
dx.doi.org/10.1021/jo400852z | J. Org. Chem. XXXX, XXX, XXX−XXX