Transition metal-free direct C-H functionalization of quinones and naphthoquinones with diaryliodonium salts: Synthesis of aryl naphthoquinones as β-secretase inhibitors

Article abstract of DOI:10.1021/jo501467v

A novel ligand-free, transition metal-free direct C.H functionalization of quinones with diaryliodonium salts has been developed for the first time. The transformation was promoted only through the use of a base and gave aryl quinone derivatives in moderate to good yields. This methodology provided an effective and easy way to synthesize β-secretase inhibitors. The radical trapping experiments showed that this progress was the radical mechanism.

Full text of DOI:10.1021/jo501467v

Article
pubs.acs.org/joc
Transition Metal-Free Direct C−H Functionalization of Quinones and
Naphthoquinones with Diaryliodonium Salts: Synthesis of Aryl
Naphthoquinones as β‑Secretase Inhibitors
Dawei Wang,* Bingyang Ge, Liang Li, Jie Shan, and Yuqiang Ding*
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering,
Jiangnan University, Wuxi 214122, Jiangsu, China
S
* Supporting Information
ABSTRACT: A novel ligand-free, transition metal-free direct C−H
functionalization of quinones with diaryliodonium salts has been
developed for the first time. The transformation was promoted only
through the use of a base and gave aryl quinone derivatives in
moderate to good yields. This methodology provided an effective and
easy way to synthesize β-secretase inhibitors. The radical trapping
experiments showed that this progress was the radical mechanism.
commercially available are expensive, and catalysts are also
needed in this transformation, which greatly limited their
application with aryl acids as starting materials. Therefore, the
search for an effective synthetic method for quinone derivatives is
still a scientific and important issue.
Diaryliodonium salts have attracted considerable attention in
modern organic chemistry, particularly with regard to transition
metal-catalyzed cross-couplings through α-arylation reaction and
C−H activation, over the past decade.7 Recently, scientists have
attempted to use diaryliodonium salts as coupling reagents in the
field of metal-free chemistry.8 On the basis of the advantages of
the easy synthesis and high reactivity of diaryliodonium salts,
herein, we present the first ligand-free, transition metal-free
direct arylation of quinones with diaryliodonium salts in
moderate to good yields.
INTRODUCTION
■
Quinone derivatives are important and common building blocks,
and convenient precursors for many biological compounds,
including pharmaceuticals, medicine, etc.1 They are distributed
in many practical compounds and show some biological
activities.2 Interestingly, aryl-substituted quinones were used as
anticancer compounds, antibiotics, pigments, and dyes because
of their special properties.3 Over the years, several methods have
been used for the synthesis of aryl-substituted quinones. For
example, diazonium salts are used as the common method to
synthesize quinone derivatives,4 but they pose a great danger
because they are unstable and explosive. Very recently,
arylboronic acids have been shown to be efficient, mild reagents
for the reaction of quinones to arylquinones (Scheme 1).5 In
Scheme 1. Transition Metal-Free C−H Functionalization of
Quinones with Diaryliodonium Salts
RESULTS AND DISCUSSION
■
On the basis of our ongoing efforts and the development of a new
methodology,9 the simple quinone and diphenyliodonium salt
were selected as model substrates to try the reaction. The
reaction mixture was set up in toluene at room temperature.
However, none of the desired product was checked. When
Na2CO3 was added to the reaction mixture, it was found that the
desired product was separated in 21% yield. Next, the screened
solvents were tested, whereby a strong solvent-dependent
phenomenon was observed. CH2Cl2, THF, and DMF led to a
very low reactivity, but DCE was found to be the optimal solvent.
As in the previously reported cases, the reaction did not work
well when organic alkali or a weak base NaOAc was applied. The
desired product was attained in good yield when NaOH was
used, and the reaction reached completion within 12 h (Table 1).
2009, Molina et al. reported the first coupling of quinones with
arylboronic acids by using a palladium catalyst.5a Later, Baran
described the iron-catalyzed direct functionalization of a variety
of quinones with several boronic acids in moderate to good
yields.5c Zhang and Yu reported FeS-catalyzed direct arylation
with arylboronic acids through an aryl radical transfer pathway.5d
Singh,5e Demchuk,5b Komeyama,5f and Maiti5g also reported
their results in this area.6 However, most of aryl acids
Received: June 5, 2014
Published: August 29, 2014
© 2014 American Chemical Society
8607
dx.doi.org/10.1021/jo501467v | J. Org. Chem. 2014, 79, 8607−8613

The Journal of Organic Chemistry
Article
a
provides an alternative strategy to use an unsymmetric iodonium
where one arene (less valuable) does not transfer.
Table 1. Screening of Reaction Conditions
Additionally, this reaction of transition metal-free direct
arylation of quinones with diphenyliodonium salts provides an
efficient route for the synthesis of aryl-substituted quinone
derivatives, which are effective inhibitors of β-secretase
(BACE1).10 It is widely believed that halting the production of
β-amyloid peptide through the inhibition of BACE1 is an
attractive therapeutic modality for the treatment of Alzheimer’s
b
entry
base
none
solvent
yield (%)
1
toluene
toluene
benzene
CH2Cl2
THF
<5
21
11
<5
<5
<5
<5
47
31
56
53
70
42
58
34
disease (AD).11 Bermejo-Bescos
́
et al. showed that several
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KHCO3
KOH
arylquinones and their derivatives are effective inhibitors of β-
3
secretase (Scheme 2).6
4
Given the methodology mentioned above, 2-phenylnaphtha-
lene-1,4-dione (A) was synthesized only from naphthoquinones
while producing a 71% yield. For another inhibitor of BACE1, 2-
(4-hydroxyphenyl)naphthalene-1,4-dione (B) was synthesized
under the conditions of BBr3 to remove methyl group protection
in two total steps (Scheme 3).
To evaluate the applicability of this new method to a gram
scale synthesis, we performed the direct C−H functionalization
of 2.0 g of naphthoquinone with diphenyliodonium salt. Full
conversion was achieved, and a pure inhibitor (A) of BACE1 was
obtained in 72% yield (Scheme 4).
5
6
DMF
dioxane
DCE
7
8
9
DCE
10
11
12
13
14
15
DCE
tBuOK
NaOH
Na2CO3
Cs2CO3
NaOAc
DCE
DCE
DCE
DCE
DCE
To unambiguously elucidate this transformation, a preliminary
mechanism study was conducted. According to the literature,
diaryliodonium salts are easy to turn into aryl radicals via
decomposition, and a radical mechanism has been proposed in
reactions involving high-valence iodonium salts.12 Here, 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was added to this
reaction mixture as a radical scavenger (Scheme 5). Therefore,
the reaction mixture of quinone and diphenyliodonium triflate
was set up under 1.0 equiv of TEMPO, and the result showed
that nearly no product (<5%) was detected even after a
prolonged reaction time under the optimized conditions. These
experiments indicated that radical intermediates were involved in
this reaction, which are consistent with the literature.13
In conclusion, a novel method for ligand-free, transition metal-
free direct arylation of quinones with diaryliodonium salts has
been developed. This reaction provides an easy, convenient
method with respect to aryl-substituted quinones. Two inhibitors
of BACE1, A and B, were easily synthesized with this
methodology. The radical trapping experiments showed that
this progress was the aryl radical mechanism.
a
Conditions: 1a (2.0 mmol, 1.0 equiv), 2a (1.5 equiv), base (1.5
b
equiv), 8 mL of solvent, 12 h, reflux. Isolated yields based on 1a.
Given this new method, representative diaryliodonium salts
were prepared to investigate the scope of the reaction substrate.
The results are summarized in Table 2. Generally, all the
quinones were converted completely to produce the correspond-
ing aryl-substituted quinones. Moderate to good isolated yields
were obtained regardless of steric hindrance of substituent
groups. For the diaryliodonium salts with an electron-with-
drawing group, the desired product was separated in low yield
(Table 2, entry 11). It should be noted that the highest yield
(80%) was obtained in the case of di(p-methoxyaryl)iodonium
salts (Table 2, entry 6).
The coupling reactions of naphthoquinone with diary-
liodonium salts were also explored under the optimized
conditions (Table 3). In most cases, the reaction proceeded
well and the corresponding products were separated in good to
excellent yields. Both ortho-substituted and meta-substituted
diaryliodonium salts were suitable for this transformation.
Compared to the reported methods, this methodology provides
a very easy method for the synthesis of aryl quinones, although
moderate yields were realized in most cases. After all, transition
metal-free and easy reaction conditions are good complements to
other methods (Figure 1).
The coupling of quinones with diaryliodonium salts provides
an easy method for the synthesis of aryl-substituted quinones;
however, another aryl group was formed as a byproduct, which is
a huge waste, especially for a very valuable aryl component. Next,
we investigated unsymmetric diaryliodonium salts to solve this
problem. As shown in Table 4, both benzoquinone and
naphthoquinone were suitable for this transformation. However,
the ratio of the two corresponding products was not good. In
most cases, poor chemoselectivity of two products was found. In
general, the ratio of the two corresponding products with
naphthoquinones as subtrates is slightly higher than that with
benzoquinones. The best result was obtained with a 1:2.2 ratio,
when diaryliodonium salts have a strong electron-donating group
(Table 4, entry 6). Although the ratio is not good, after all, this
EXPERIMENTAL SECTION
■
General Procedure for the Reaction of Quinones and
Diaryliodonium Salts. A mixture of 1,4-quinone (1a) (216.0 mg,
2.0 mmol), diphenyliodonium salt (2a) (1290.0 mg, 3.0 mmol), and
NaOH (120 mg, 1.5 equiv) in DCE (2.0 mL) was stirred at reflux for 12
h. Upon completion of the reaction, the mixture was evaporated to give
the residue, which was then purified by column chromatography on
silica gel (1:10 ethyl acetate/petroleum ether) to provide the
corresponding product as a pale yellow solid (257.9 mg, 70%).
2-Phenyl[1,4]benzoquinone (3a). Faint yellow solid. Mp: 115−
117 °C. Known compound:5c 257.9 mg, 70%. H NMR (400 MHz,
1
CDCl3): δ 7.52−7.42 (m, 5H), 6.84−6.90 (m, 3H).
2-p-Tolyl[1,4]benzoquinone (3b). Orange solid. Mp: 137−138
°C. Known compound:5c 257.7 mg, 65%. 1H NMR (400 MHz, CDCl3):
δ 7.39 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.88−6.77 (m, 3H),
2.40 (s, 3H).
2-(4-Methoxyphenyl)[1,4]benzoquinone (3c). Yellow solid.
Mp: 106−108 °C. Known compound:5c 342.3 mg, 80%. H NMR
1
(400 MHz, CDCl3): δ 7.48 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H),
6.88−6.77 (m, 3H), 3.86 (s, 3H).
8608
dx.doi.org/10.1021/jo501467v | J. Org. Chem. 2014, 79, 8607−8613

The Journal of Organic Chemistry
Article
a
Table 2. Substrate Expansion of Quinones
a
b
Conditions: 1a (2.0 mmol, 1.0 equiv), 2 (1.5 equiv), NaOH (1.5 equiv), 8 mL of solvent, 12 h, reflux. Isolated yields based on 1a.
2-Biphenyl-4-yl[1,4]benzoquinone (3d). Faint yellow solid. Mp:
= 11.6, 4.5 Hz, 1H), 7.29−7.21 (m, 2H), 7.10 (d, J = 7.2 Hz, 1H), 6.82
(m, 3H), 2.18 (s, 3H).
2-(4-Iodophenyl)[1,4]benzoquinone (3h). Light yellow solid.
Mp: 133−135 °C. Known compound:5c 235.8 mg, 38%. 1H NMR (400
MHz, CDCl3): δ 7.80 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 6.91−
6.80 (m, 3H).
2-(4-Isopropylphenyl)[1,4]benzoquinone (3i). Yellow solid.
Mp: 47−50 °C. Known compound:15h 320.8 mg, 71%. 1H NMR (400
MHz, CDCl3): δ 7.43 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 6.90−
6.78 (m, 3H), 2.95 (dt, J = 13.8, 6.9 Hz, 1H), (d, J = 8.3 Hz, 6H), 1.28 (d,
J = 6.9 Hz, 6H).
199−200 °C. Known compound:14a 369.1 mg, 71%. H NMR (400
1
MHz, CDCl3): δ 7.73−7.55 (m, 6H), 7.47 (t, J = 7.5 Hz, 2H), 7.39 (t, J =
7.4 Hz, 1H), 6.88 (m, 3H).
2-(4-tert-Butylphenyl)[1,4]benzoquinone (3e). Orange solid.
Mp: 73−75 °C. Known compound:5c 302.8 mg, 63%. H NMR (400
1
MHz, CDCl3): δ 7.48 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 6.88−
6.79 (m, 3H), 1.35 (s, 9H).
2-(4-Ethoxyphenyl)[1,4]benzoquinone (3f). Yellow solid. Mp:
104−106 °C. Known compound:14b 282.9 mg, 62%. H NMR (400
1
MHz, CDCl3): δ 7.47 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.87−
6.77 (m, 3H), 4.08 (q, J = 7.0 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H).
2-o-Tolyl[1,4]benzoquinone (3g). Yellow oil. Known com-
2-(4-Bromophenyl)[1,4]benzoquinone (3j). Orange solid. Mp:
pound:5c 269.2 mg, 65%. H NMR (400 MHz, CDCl3): δ 7.34 (dt, J
101−102 °C. Known compound:4 114.4 mg, 22%. 1H NMR (400 MHz,
1
8609
dx.doi.org/10.1021/jo501467v | J. Org. Chem. 2014, 79, 8607−8613

The Journal of Organic Chemistry
Article
a
Table 3. Substrate Expansion of Naphthoquinones
a
b
Conditions: 4a (2.0 mmol, 1.0 equiv), 2 (1.5 equiv), NaOH (1.5 equiv), 8.0 mL of solvent, 12 h, reflux. Isolated yields based on 4a.
3-(3,6-Dioxocyclohexa-1,4-dienyl)benzonitrile (3k). Pale yel-
low solid. Unstable compound and mp characterization failed. Known
compound:5c 45.8 mg, 11%. H NMR (400 MHz, CDCl3): δ 7.80 (s,
1
1H), 7.77 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.58 (t, J = 8.0 Hz,
1H), 6.93−6.88 (m, 3H).
2-(3,5-Dimethylphenyl)[1,4]benzoquinone (3l). Pale yellow
solid. Mp: 101−102 °C. Known compound:5f 313.9 mg, 74%. 1H
NMR (CDCl3, 400 MHz): δ 7.10 (1H, s), 7.08 (2H, s), 6.80−6.87 (3H,
m), 2.36 (6H, s).
2-(3-Methoxyphenyl)[1,4]benzoquinone (3m). Yellow solid.
Mp: 113−114 °C. Known compound:15g 299.6 mg, 70%. 1H NMR (400
MHz, CDCl3): δ 7.39−7.32 (m, 1H), 7.05 (d, J = 7.9 Hz, 1H), 7.00 (d, J
= 6.5 Hz, 2H), 6.88−6.79 (m, 3H), 3.84 (s, 3H).
2-Naphthalen-2-yl[1,4]benzoquinone (3n). Pale yellow solid.
Mp: 173−174 °C. Known compound:5d 280.6 mg, 60%. 1H NMR (400
MHz, CDCl3): δ 8.05 (s, 1H), 7.95−7.84 (m, 3H), 7.60−7.50 (m, 3H),
6.91 (m, 3H).
2-m-Tolylcyclohexa-2,5-diene-1,4-dione (3o). Yellow solid.
Figure 1. Comparison with main methods in the literature.
Mp: 76−78 °C. Known compound:5c 245.1 mg, 62%. H NMR (400
1
MHz, CDCl3): δ 7.38−7.24 (m, 4H), 6.90−6.78 (m, 3H), 2.41 (s, 3H).
2-Phenyl[1,4]naphthoquinone (5a). Faint yellow solid. Mp:
CDCl3): δ 7.57 (d, 2H, J = 8.7 Hz), 7.35 (d, 2H, J = 8.7 Hz), 6.88−6.81
(m, 3H).
115−117 °C. Known compound:5a 332.3 mg, 71%. H NMR (400
1
8610
dx.doi.org/10.1021/jo501467v | J. Org. Chem. 2014, 79, 8607−8613

The Journal of Organic Chemistry
Article
a
Table 4. Substrate Expansion of Unsymmetric Diaryliodonium Salts
a
b
1
Conditions: 1a or 4a (0.5 mmol, 1.0 equiv), Ar1Ar2IOTf (1.5 equiv), NaOH (1.5 equiv), 2 mL of DCE, 12 h, reflux. Determined by H NMR.
c
Isolated yields based on 1a or 4a.
2-o-Tolyl[1,4]naphthoquinone (5d). Pale yellow oil. Known
compound:15c 302.9 mg, 61%. 1H NMR (400 MHz, CDCl3): δ 8.15 (dd,
J = 9.4, 6.3 Hz, 2H), 7.84−7.74 (m, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.28
(dd, J = 10.2, 5.9 Hz, 2H), 7.18 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H), 2.23 (s,
3H).
Scheme 2. Two Selected Inhibitors of BACE1
2-(4-tert-Butylphenyl)[1,4]naphthoquinone (5e). Faint yellow
oil. New compound: 394.8 mg, 68%. 1H NMR (400 MHz, CDCl3): δ
8.19 (m, 1H), 8.12 (m, 1H), 7.77 (m, 2H), 7.52 (dd, J = 17.4, 8.4 Hz,
4H), 7.08 (s, 1H), 1.36 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 185.1
(s), 184.5 (s), 153.5 (s), 147.9 (s), 134.6 (s), 133.7 (s), 133.76 (s), 132.5
(s), 132.1 (s), 130.5 (s), 129.2 (s), 127.0 (s), 125.9 (s), 125.5 (s), 34.8
(s), 31.2 (s). HRMS: calcd for C20H19O2 [M + H]+ 291.1385, found
291.1382.
MHz, CDCl3): δ 8.22−8.17 (m, 1H), 8.16−8.10 (m, 1H), 7.82−7.74
(m, 2H), 7.61−7.56 (m, 2H), 7.51−7.46 (m, 3H), 7.09 (s, 1H).
2-p-Tolyl[1,4]naphthoquinone (5b). Orange solid. Mp: 103−104
°C. Known compound:15f 327.9 mg, 66%. 1H NMR (400 MHz,
CDCl3): δ 8.19 (m, 1H), 8.12 (m, 1H), 7.80−7.75 (m, 2H), 7.49 (d, J =
8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 2.42 (s, 3H).
2-(4-Methoxyphenyl)[1,4]naphthoquinone (5c). Yellow solid.
Mp: 132−133 °C. Known compound:15b 407.0 mg, 77%. 1H NMR (400
MHz, CDCl3): δ 8.17 (m, 1H), 8.10 (m, 1H), 7.79−7.72 (m, 2H), 7.58
(d, J = 8.5 Hz, 2H), 7.04 (s, 1H), 6.99 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H).
2-(4-Ethoxyphenyl)[1,4]naphthoquinone (5f). Yellow solid.
1
Mp: 115−117 °C. New compound: 361.6 mg, 65%. H NMR (400
MHz, CDCl3): δ 8.17 (m, 1H), 8.14- 8.08 (m, 1H), 7.80−7.73 (m, 2H),
7.57 (d, J = 8.9 Hz, 2H), 7.05 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 4.10 (q, J
= 7.0 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
185.21 (s), 184.86 (s), 160.77 (s), 147.45 (s), 133.73 (s), 133.71 (s),
8611
dx.doi.org/10.1021/jo501467v | J. Org. Chem. 2014, 79, 8607−8613

The Journal of Organic Chemistry
Article
2-(3,5-Dimethylphenyl)[1,4]naphthoquinone (5k). Yellow
solid. Mp: 122−125 °C. New compound: 366.8 mg, 70%. H NMR
Scheme 3. Synthesis of BACE1 Inhibitors A and B
1
(400 MHz, CDCl3): δ 8.16 (dd, J = 10.0, 5.0 Hz, 1H), 8.11 (dd, J = 5.9,
3.1 Hz, 1H), 7.80−7.73 (m, 2H), 7.17 (s, 2H), 7.11 (s, 1H), 7.04 (s, 1H),
2.38 (s, 6H). 13C NMR (101 MHz, CDCl3): δ 185.2 (s), 184.6 (s), 148.5
(s), 138.1 (s), 135.0 (s), 133.8 (s), 133.8 (s), 133.4 (s), 132.6 (s), 132.1
(s), 131.8 (s), 127.2 (s), 127.0 (s), 125.9 (s), 21.3 (s). HRMS: calcd for
C18H15O2 [M + H]+ 263.1072, found 263.1075.
2-(3-Methoxyphenyl)[1,4]naphthoquinone (5l). Pale yellow
solid. Mp: 98−99 °C. Known compound:15f 390.6 mg, 74%. 1H NMR
(400 MHz, CDCl3): δ 8.21−8.15 (m, 1H), 8.14−8.07 (m, 1H), 7.81−
7.74 (m, 2H), 7.38 (t, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.15 (d, J = 7.9 Hz,
1H), 7.11 (s, 1H), 7.08 (s, 1H), 7.02 (dd, J = 8.3, 2.4 Hz, 1H), 3.86 (s,
3H).
[2,2′]Binaphthalenyl-1,4-dione (5m). Light yellow solid. Mp:
169−171 °C. Known compound:15c 369.1 mg, 65%. H NMR (400
1
MHz, CDCl3) δ 8.25−8.20 (m, 1H), 8.15 (d, J = 9.0 Hz, 2H), 7.93 (d, J =
8.5 Hz, 2H), 7.90−7.87 (m, 1H), 7.82−7.77 (m, 2H), 7.65 (d, J = 8.5 Hz,
1H), 7.57−7.54 (m, 2H), 7.21 (s, 1H).
2-(4-Hydroxyphenyl)[1,4]naphthoquinone (6) (B). Substrate 5c
(0.5 mmol) was dissolved in dry CH2Cl2 (5 mL) and cooled to −78 °C,
and 1 mL of BBr3 (1.0 M in CH2Cl2) was added dropwise while the
mixture was being stirred under a nitrogen atmosphere. After addition,
the reaction mixture was stirred at −78 °C for 1 h, warmed to rt, and
stirred overnight. The reaction was terminated by careful dropwise
addition of water. The layers were separated; the organic phase was
washed with H2O, and the combined aqueous layers were evaporated to
dryness. The residue was purified by column chromatography on silica
gel to provide the corresponding product (101 mg, 81%). Orange solid.
Mp: 171−174 °C. Known compound.6 1H NMR (400 MHz, CDCl3): δ
8.12−8.07 (m, 1H), 8.05−8.01 (m, 1H), 7.73−7.65 (m, 2H), 7.49−7.41
(m, 2H), 6.96 (s, 1H), 6.90−6.82 (m, 2H), 5.69 (s, 1H).
Scheme 4. Direct C−H Functionalization of Naphthoquinone
to Synthesis of BACE1 Inhibitor A on a Gram Scale
Scheme 5. Mechanism of the Verification Test
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Detailed experimental procedures and H NMR data for 3a−p
and 5a−m. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: wangdw@jiangnan.edu.cn.
*E-mail: yding@jiangnan.edu.cn.
■
133.62 (s), 132.63 (s), 132.17 (s), 131.09 (s), 127.01 (s), 125.88 (s),
125.50 (s), 114.56 (s), 63.65 (s), 14.76 (s). HRMS: calcd for C18H15O3
[M + H]+ 279.1021, found 279.1019.
Notes
The authors declare no competing financial interest.
2-(4-Ethylphenyl)[1,4]naphthoquinone (5g). Orange solid. Mp:
67−68 °C. Known compound:15d 387.9 mg, 74% (yellow solid, 99.6 mg,
ACKNOWLEDGMENTS
1
■
76%). H NMR (400 MHz, CDCl3): δ 8.19 (m, 1H), 8.12 (m, 1H),
We gratefully acknowledge financial support of this work by the
National Natural Science Foundation of China (21401080 and
21371080), the Natural Science Foundation of Jiangsu Province
(BK20130125), the 333 Talent Project of Jiangsu Province
(BRA2012165), and MOE & SAFEA for the 111 Project
(B13025).
7.80−7.75 (m, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H),
7.07 (s, 1H), 2.72 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).
2-m-Tolyl[1,4]naphthoquinone (5h). Yellow solid. Mp: 117−119
°C. Known compound:15a 288.2 mg, 58%. 1H NMR (400 MHz,
CDCl3): δ 8.22−8.16 (m, 1H), 8.16−8.08 (m, 1H), 7.82−7.74 (m, 2H),
7.41−7.27 (m, 4H), 7.07 (s, 1H), 2.43 (s, 3H).
2-Biphenyl-4-yl[1,4]naphthoquinone (5i). Yellow solid. Mp:
174−175 °C. Known compound:15e 465.2 mg, 75%. H NMR (400
1
REFERENCES
■
MHz, CDCl3): δ 8.24−8.19 (m, 1H), 8.16−8.12 (m, 1H), 7.81−7.78
(m, 2H), 7.73−7.64 (m, 6H), 7.48 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.4 Hz,
1H), 7.14 (s, 1H).
(1) (a) Gould, S. J. Chem. Rev. 1997, 97, 2499. (b) Liu, J.-K. Chem. Rev.
2006, 106, 2209. (c) Babula, P.; Mikelova, R.; Kizek, R.; Havel, L.;
Sladky, Z. Ceska Slov. Farm. 2006, 55, 151. (d) Koyama, J. Recent Pat.
Anti-Infect. Drug Discovery 2006, 1, 113. (e) Babula, P.; Adam, V.; Havel,
L.; Kizek, R. Ceska Slov. Farm. 2007, 56, 114. (f) Verma, R. P. Anti-
Cancer Agents Med. Chem. 2006, 6, 489. (g) Bishop, K. J. M.; Klajn, R.;
Grzybowski, B. A. Angew. Chem., Int. Ed. 2006, 45, 5348.
2-(4-Isopropylphenyl)[1,4]naphthoquinone (5j). Light yellow
oil. New compound: 419.4 mg, 76%. 1H NMR (400 MHz, CDCl3): δ
8.20−8.16 (m, 1H), 8.14−8.09 (m, 1H), 7.79−7.75 (m, 2H), 7.53 (d, J =
8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.07 (s, 1H), 2.97 (dt, J = 13.8, 6.9
Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 185.2
(s), 184.6 (s), 151.3 (s), 148.0 (s), 134.6 (s), 133.8 (s), 133.8 (s), 132.6
(s), 132.1 (s), 130.9 (s), 129.5 (s), 127.1 (s), 126.7 (s), 125.9 (s), 34.1
(s), 23.8 (s). HRMS: calcd for C19H17O2 [M + H]+ 277.1229, found
277.1227.
(2) (a) Miller, R. F.; Huang, S. J. Antibiot. 1995, 48, 520. (b) Zhang, B.;
Salituro, G.; Szalkowski, D.; Li, Z.; Zhang, Y.; Royo, I.; Viella, D.; Diez,
M. T.; Pelaez, F.; Ruby, C.; Kendall, R. L.; Mao, X.; Griffin, P.; Calaycay,
J.; Zierath, J. R.; Heck, J. V.; Smith, R. G.; Moller, D. E. Science 1999, 284,
̈
8612
dx.doi.org/10.1021/jo501467v | J. Org. Chem. 2014, 79, 8607−8613

The Journal of Organic Chemistry
Article
974. (c) Fotso, S.; Maskey, R. P.; Grun-Wollny, I.; Schulz, K.-P.; Munk,
(b) Wen, J.; Zhang, R.-Y.; Chen, S.-Y.; Zhang, J.; Yu, X.-Q. J. Org. Chem.
̈
M.; Laatsch, H. J. Antibiot. 2003, 56, 931. (d) Coleman, R. S.; Felpin, F.-
X.; Chen, W. J. Org. Chem. 2004, 69, 7309. (e) Nikolovska-Coleska, Z.;
Xu, L.; Hu, Z.; Tomita, Y.; Li, P.; Roller, P. P.; Wang, R.; Fang, X.; Guo,
R.; Zhang, M.; Lippman, M. E.; Yang, D.; Wang, S. J. Med. Chem. 2004,
2012, 77, 766. (c) Castro, S.; Fernan
Rodríguez, F. Chem. Commun. 2012, 48, 9089.
́ ́
dez, J. J.; Vicente, R.; Fananas, F. J.;
(14) (a) Kvalnes, D. E. J. Am. Chem. Soc. 1934, 56, 2478. (b) Aihara, J.;
Kushibiki, G.; Matsunaga, Y. Bull. Chem. Soc. Jpn. 1973, 46, 3584.
(15) (a) Zhang, S.; Song, F.; Zhao, D.; You, J. Chem. Commun. 2013,
49, 4558. (b) Wang, X.; Ye, Y.; Ji, G.; Xu, Y.; Zhang, S.; Feng, J.; Zhang,
Y.; Wang, J. Org. Lett. 2013, 15, 3730. (c) Sidhu, G. S.; Pardhasaradhi,
M.; Babu, M. H. Indian J. Chem. 1976, 14, 218. (d) Guenther, R. H.;
Szewczyk, J. R. PCT Int. Appl. WO 2011113060, 2011. (e) Shcherban,
A. I. Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol. 1979, 22, 290.
(f) Rao, M. L. N.; Giri, S. RSC Adv. 2012, 2, 12739. (g) Liu, Y.; Zhang, S.;
Wang, G. Desalination 2013, 316, 127. (h) Walensky, L. D.; Stewart, M.
L.; Cohen, N. PCT Int. Appl. WO 2011094708, 2011.
47, 2430. (f) Viault, G.; Gree
Chem. 2011, 7, 1233.
́ ́
, D.; Das, S.; Yadav, J. S.; Gree, R. Eur. J. Org.
(3) Bechtold, T. In Handbook of Natural Colorants; Bechtold, T.,
Mussak, R., Eds.; Wiley: New York, 2009; p 151.
(4) Honraedt, A.; Callonnec, F. L.; Grognec, E. L.; Fernandez, V.;
Felpin, F.-X. J. Org. Chem. 2013, 78, 4604.
(5) (a) Molina, M. T.; Navarro, C.; Moreno, A.; Csaky, A. G. Org. Lett.
2009, 11, 4938. (b) Demchuk, O. M.; Pietrusiewicz, K. M. Synlett 2009,
7, 1149. (c) Fujiwara, Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.; Bel,
M. D.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 3292. (d) Wang, J.;
Wang, S.; Wang, G.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2012, 48,
11769. (e) Singh, P. P.; Aithagani, S. K.; Yadav, M.; Singh, V. P.;
Vishwakarma, R. A. J. Org. Chem. 2013, 78, 2639. (f) Komeyama, K.;
Kashihara, T.; Takaki, K. Tetrahedron Lett. 2013, 54, 1084. (g) Deb, A.;
Manna, S.; Maji, A.; Dutta, U.; Maiti, D. Eur. J. Org. Chem. 2013, 5251.
́
(6) Ortega, A.; Rincon
Martín-Aragon, S.; Molina, M. T.; Csak
2011, 21, 2183.
́
, A.; Jimen
́
ez-Aliaga, K. L.; Bermejo-Bescos
́
, P.;
́
́
y, A. G. Bioorg. Med. Chem. Lett.
̈
(7) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299−5358.
(b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−1169.
(c) Xiao, Z.-C.; Xia, C.-F. Youji Huaxue 2013, 33, 2119.
(8) For some reviews and papers, see: (a) Collins, B. S. L.; Suero, M.
G.; Gaunt, M. J. Angew. Chem., Int. Ed. 2013, 52, 5799. (b) Peng, J.;
Chen, C.; Wang, Y.; Lou, Z.-B.; Li, M.; Xi, C.-J.; Chen, H. Angew. Chem.,
Int. Ed. 2013, 52, 7574. (c) Guo, J.; Dong, S.-X.; Zhang, Y.-L.; Kuang, Y.-
L.; Liu, X.-H.; Lin, L.-L.; Feng, X.-M. Angew. Chem., Int. Ed. 2013, 52,
10245. (d) Ho, J. S.; Misal Castro, L. C.; Aihara, Y.; Tobisu, M.; Chatani,
N. Asian J. Org. Chem. 2014, 3, 48. (e) Su, X.; Chen, C.; Wang, Y.; Chen,
J.-J.; Lou, Z.-B.; Li, M. Chem. Commun. 2013, 49, 6752. (f) Hu, R.-B.;
Zhang, H.; Zhang, X.-Y.; Yang, S.-D. Chem. Commun. 2014, 50, 2193.
(g) Suero, M. G.; Bayle, E. D.; Collins, B. S. L.; Gaunt, M. J. J. Am. Chem.
Soc. 2013, 135, 5332. (h) Xu, Q.-L.; Gao, H.-Y.; Yousufuddin, M.; Ess,
D. H.; Kurti, L. J. Am. Chem. Soc. 2013, 135, 14048. (i) Lv, T.-Y.; Wang,
Z.; You, J.-S.; Lan, J.-B.; Gao, G. J. Org. Chem. 2013, 78, 5723.
(j) Wagner, A. M.; Sanford, M. S. J. Org. Chem. 2014, 79, 2263.
(k) Umierski, N.; Manolikakes, G. Org. Lett. 2013, 15, 188. (l) Gigant,
N.; Boissarie, L. C.; Belhomme, M. C.; Poisson, T.; Pannecoucke, X.;
Gillaizeau, I. Org. Lett. 2013, 15, 278. (m) Guo, F.-L.; Han, J.-W.; Mao,
S.; Li, J.; Geng, X.; Yu, J.-J.; Wang, L.-M. RSC Adv. 2013, 3, 6267.
(n) Bhong, B. Y.; Shelke, A. V.; Karade, N. N. Tetrahedron Lett. 2013, 54,
739. (o) Cullen, S. C.; Shekhar, S.; Nere, N. K. J. Org. Chem. 2013, 78,
12194. (p) Wang, D.; Ye, X.; Shi, X. Org. Lett. 2010, 12, 2088. (q) Wang,
D.; Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli, S. K.; Akhmedov, N.
G.; Zhang, H.; Liu, X.; Petersen, J. P.; Shi, X. J. Am. Chem. Soc. 2012, 134,
9012.
(9) For selected recent papers from our group, see: (a) Yang, W.;
Wang, D.; Song, Q.; Zhang, S.; Wang, Q.; Ding, Y. Organometallics 2013,
32, 4130. (b) Li, L.; Wu, F.; Zhang, S.; Wang, D.; Ding, Y.; Zhu, Z.
Dalton Trans. 2013, 42, 4539. (c) Liu, X.; Zhang, S.; Ding, Y. Dalton
Trans. 2012, 41, 5897. (d) Zhang, S.; Ding, Y. Organometallics 2011, 30,
633. (e) Zhang, S.; Shi, L.; Ding, Y. J. Am. Chem. Soc. 2011, 133, 20218.
(f) Yang, W.; Zhang, S.; Ding, Y.; Shi, L.; Song, Q. Chem. Commun.
2011, 47, 5310. (g) Yang, W.; Fu, H.; Song, Q.; Zhang, M.; Ding, Y.
Organometallics 2011, 30, 77.
(10) Hadden, M. K.; Hill, S. A.; Davenport, J.; Matts, R. L.; Blagg, B. S.
Bioorg. Med. Chem. 2009, 17, 634.
(11) (a) Citron, M. Neuroscience 2004, 5, 677. (b) Findeis, M. A.
Pharmacol. Ther. 2007, 116, 266.
(12) (a) Lubinkowski, J. J.; Arrieche, C. G.; McEwen, W. E. J. Org.
Chem. 1980, 45, 2076. (b) Dektar, J. L.; Hacker, N. P. J. Org. Chem. 1990,
55, 639. (c) Chen, D.; Takai, K.; Ochiai, M. Tetrahedron Lett. 1997, 38,
8211.
(13) (a) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.;
Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044.
8613
dx.doi.org/10.1021/jo501467v | J. Org. Chem. 2014, 79, 8607−8613