Substituent-enabled oxidative dehydrogenative cross-coupling of 1,4-naphthoquinones with alkenes

Article abstract of DOI:10.1021/jo501419s

A Rh-catalyzed oxidative dehydrogenative cross-coupling of 1,4-naphthquinones with alkenes was achieved by using a substituent-enabled C(sp²)-H functionalization (SEF) strategy. The method shows high functional group tolerance, broad substrate scope, and great potential for further functional transformations.

Full text of DOI:10.1021/jo501419s

Article
pubs.acs.org/joc
Substituent-Enabled Oxidative Dehydrogenative Cross-Coupling of
1,4-Naphthoquinones with Alkenes
Chi Zhang,†,§ Meining Wang,‡,§ Zhoulong Fan,‡ Li-Ping Sun,*,† and Ao Zhang*,‡
†Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
‡CAS Key Laboratory of Receptor Research and Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute
of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: A Rh-catalyzed oxidative dehydrogenative
cross-coupling of 1,4-naphthquinones with alkenes was
achieved by using a substituent-enabled C(sp2)−H function-
alization (SEF) strategy. The method shows high functional
group tolerance, broad substrate scope, and great potential for
further functional transformations.
INTRODUCTION
■
1,4-Naphthoquinones (1,4-NQs) are a class of aromatic motifs
that are widely present among natural products and synthetic
analogues.1 Even simple 1,4-NQs bearing limited substituents
generally possess a wide spectrum of biological activities. For
example, alkylamino-substituted 1,4-NQ (I) (Figure 1) showed
Figure 1. Representative bioactive 1,4-naphthoquinolines.
dose-dependent antiangiogenic activity in rat aortic ring assay.2a
Phenylamino substituted 1,4-NQ (II) belongs to a class of
antimycrobacterial agents.2b 1,4-NQ (III) bearing a benzyla-
mino substituent is an analogue of vitamin K possessing
neuroprotective effects against neuronal oxidative stress.2c
Therefore, 1,4-NQs are ideal medicinal hits or leads for the
development of novel derivatives with higher potency through
further structural modification.
Because of their electron-deficient character, 1,4-NQs are
generally used as substrates for transition-metal-catalyzed
addition,3a nucleophilic addition,3b or cycloaddition3c reactions
(eq a, Figure 2) to provide new 1,4-NQs with substituents
exclusively on the quinone ring as that in I−III. Direct and
regioselective C−H functionalization on the phenyl part of 1,4-
NQs, however, is rare. In 2012, Kakiuchi and co-workers
reported a ruthenium-catalyzed C−H alkylation of anthraqui-
none with alkenes leading to new anthracenes bearing four alkyl
groups on the two phenyl rings (eq b, Figure 1).4
Figure 2. Reported reactions of 1,4-NQs and our proposal.
transition-metal-catalyzed oxidative dehydrogenative cross-
coupling of arenes with alkenes,5 we initially conducted a
rhodium-catalyzed oxidative Heck-type alkenylation6,7 by
During our studies on the development of 1,4-NQ
derivatives, there is a need to introduce an alkenyl functionality
at the C5 position. In view of the rapid advances in the
Received: June 26, 2014
Published: July 30, 2014
© 2014 American Chemical Society
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treating 1,4-NQ with methyl acrylate (eq c, Figure 2).
Unfortunately, no reaction occurred. We envisioned that the
failure of this reaction was due to the electron-deficiency of the
1,4-NQ substrate leading to formation of a weak coordination
between the metal catalyst and substrate, which was insufficient
to activate the C5−H and then to trigger subsequent
dehydrogenative cross-coupling.
Table 1. Optimization of Substrates and Reaction
Conditions
a
Very recently, we found that the electron deficiency and poor
metal coordination of 1,4-NQs could be compensated by
introducing an alkylamino group to the 1,4-NQ substrates;
therefore, a one-pot cascade process including C−H activation,
oxidative addition, and cyclization was readily achieved leading
to formation of tetracyclic naphthoxazole derivatives (IV).8
Inspired by this result, we decided to reconduct the Rh-
catalyzed oxidative dehydrogenative cross-coupling of 1,4-NQs
with alkenes using the same substituent-enabled Csp2−H
functionalization (SEF) strategy (Figure 2) to yield the
expected alkenylated products V.
b
entry
R1
oxidant (equiv)
solvent
yield (%)
c
1
H
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
Ag2CO3 (2)
DCE
DCE
DCE
DCE
DCE
dioxane
THF
t-AmOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
c
2
OH
0
c
3
OMe
0
c
4
NH2
12
d
5
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
NHPr-n
57
d
6
50
d
7
55
d
8
48
d
9
27
d
10
11
12
13
14
15
16
17
18
19
NaOAc (2)
46
d
RESULTS AND DISCUSSION
CsOAc (2)
11
■
d
Cu(OAc)2·H2O (1)
Cu(OAc)2·H2O (0.5)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.1)
Cu(OAc)2·H2O (0.2)
Cu(OAc)2·H2O (0.2)
none
68
To find the optimal substituent to maximally compensate the
electron deficiency of 1,4-NQs and to enhance the catalyst-
substrate coordination, a series of substituents were screened by
using [RhCp*Cl2]2 (2.5 mol %) and AgSbF6 (10 mol %) as the
catalytic system, Cu(OAc)2·H2O (2 equiv) as the oxidant, and
methyl (2a) or benzyl (2c) acrylate as the alkenylation agent in
DCE at 120 °C for 12 h. It was found that 1-hydroxyl-
substituted 1,4-NQ was unstable under the reaction conditions,
and 1-methoxy NQ did not promote the reaction at all (entries
2 and 3, Table 1). 1.4-NQ with a free amino substituent ignited
the coupling reaction slowly and provided the corresponding
product in 12% yield (entry 4). The yield was increased
dramatically when the n-propylamino moiety was introduced as
the C2-substituent (57%, entry 5). Meanwhile, other reaction
parameters were also optimized. DCE was found to be more
effective than t-AmOH, dioxane, and THF (entries 5−8).
Oxidants other than Cu(OAc)2·H2O decreased the yield
(entries 9−11). Interestingly, when the loading of Cu(OAc)2·
H2O was decreased from 2 to 0.2 equiv, the desired product
3ca was produced in 80% isolated yield (entries 5 and 12−15).
Control experiments showed that without [RhCp*Cl2]2,
AgSbF6, Cu(OAc)2·H2O, or O2, the reaction either did not
occur or offered product in much lower yields (entries 16−19).
With the optimized conditions in hand, the scope of the
alkenylation reaction was extended to various alkenes (Scheme
1). It was found that methyl acrylate (2a), ethyl acrylate (2b),
benzyl acrylate (2c), and n-butyl acrylate (2d) all reacted with
2-(propylamino)-1,4-NQ (1a) smoothly and provided the
corresponding alkenylation products in excellent yields (80−
94%). Meanwhile, electron-neutral styrenes, although slightly
less active, also took part in the coupling and offered 5-
alkenylated 1,4-NQs 3e and 3f in moderate yields (51% and
40%, respectively). The olefinic substrate was further extended
to other various α,β-unsaturated systems such as sulfone 2g,
phosphate 2h, and nitrile 2i and all reacted with 1,4-NQ (1)
very well, generating the expected products in good yields (61−
68%). It was found that an additional phenyl substituent at the
C2 of 1,4-NQs was well tolerated, and the corresponding
products were formed in good yields (3bb−hb). Form the
variously substituted alkenes tested above, it was apparent that
electron-deficient alkenes reacted well, whereas low yields were
obtained for the electron-rich alkenes (styrenes).
d
78
d
86 (80)
d
33
d
d
d
d
,
e
f
16
0
,
5
,
g
Cu(OAc)2·H2O (0.2)
7
a
The reactions were performed with 1,4-NQ (1) (0.1 mmol), alkene 2
(0.2 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), and
oxidant in solvent (0.5 mL) in a sealed tube under air at 120 °C for 12
b
h. Yields determined by 1H NMR analysis using 1,2-dibromomethane
c
as internal standard (isolated yield in parentheses). Methyl acrylate
(2a) was used. Benzyl acrylate (2c) was used. Without AgSbF6.
d
e
f
g
Without [RhCp*Cl2]2. Under N2.
a,b
Scheme 1. Substrate Scope with Various Olefins
a
The reactions were performed with 1,4-NQ (1) (0.1 mmol), alkene 2
(0.2 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), and
Cu(OAc)2·H2O (20 mol %) in DCE (0.5 mL) in a sealed tube under
b
c
air at 120 °C. Isolated yields are listed. Z/E (1:3).
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Figure 3. Substrate scope with diversified 1,4-NQs. Key: (a) 50 mol % Cu(OAc)2·H2O was used.
To further explore the scope and limitation of the reaction,
1,4-NQs bearing diversified substituents were evaluated. As
shown in Figure 3, 1,4-NQs containing a bulky alkylamino
group were well tolerated, and products 3j−l were obtained in
62−80% yields. Additional halogen- or amino-substituted
substrates were also tolerant, leading to the corresponding
products 3m−o in slightly lower yields (48−75%). Meanwhile,
a C3-methyl or phenyl substituent in 1,4-NQs (1) had no
impact om the reaction, and products 3p and 3q were obtained
in 90% and 74% yields, respectively. Although the existence of
C8-hydroxy might cause additional coordination with the
catalyst, the expected product 3r was still obtained in moderate
yield. 1-(Phenylamino)- and 1-(benzylamino)-substituted 1,4-
NQs also took part in the reaction, smoothly yielding products
3s and 3t in 51% and 58% yields, respectively. However, the
reaction with (p-methoxyphenyl)amino-substituted substrate
occurred very sluggishly, likely due to the electron-donating
property of the methoxy group interfering with the
tautomerization of the substrate during the catalysis. All of
the reactions showed high C5-regioselectivity, which was
confirmed by the HMBC spectrum. For example, in the
HMBC spectra of compound 3ba, typical correlations between
the quaternary carbon C-10 (δC = 130.1 ppm) and vinyl H-11
(δH = 8.73 ppm), as well as correlations between C-10 and H-3
(δH = 5.68 ppm), were observed, suggesting the alkene group
sits at C-5 rather than C-8 (Supporting Information). The
newly formed C5 alkenyl moiety was exclusively E-configurated
except 3i (Z/E = 1:3) as determined by the NMR spectra.
Although the exact mechanism of the reaction was unclear, a
possible pathway similar to our recent report8 could be
proposed. As shown in Scheme 2, rhodacycle A would be
formed as the key intermediate through tautomerization of the
1,4-NQ substrates followed by C5−H activation. This
hypothesis was supported by the kinetic isotope effect (KIE)
of 1.49 (KH/KD) observed from reactions of substrates 1p and
[D-5]-1p with methyl acrylate, implying that cleavage of the
C5−H bond was involved in the rate-determining step.
Meanwhile, we also conducted reaction of diethylamino-
Scheme 2. Mechanism Study and Supporting Reactions
substituted substrate 1u with ethyl acrylate and found that
compound 3ua was obtained in low yield, together with the de-
ethyl side product 3ub in 13% yield. Compound 3ub likely
formed through intermediate B that was generated from
proposed intermediate A via Hofmann-like elimination. This
result suggested that the NH substituent in 1,4-NQs was crucial
for the tautomerization.
It must be mentioned that compounds 3p, 3s ,and 3t (Figure
3) are the corresponding C5-alkenylated products of the
bioactive 1,4-NQs I−III (Figure 1); therefore, these com-
pounds can be used directly for biological assays.
On the basis of the above data and precedent literature,8 a
plausible mechanism is proposed in Scheme 3. The reaction
cycle is likely initiated by tautomerization of 1a to phenol 1a′,
which then undergoes a well-known Rh(III)-catalyzed C−H
9
activation with the assistance of AgSbF6 to form a five-
membered rhodacycle C. Insertion of alkene 2a to the Rh−
Cphenyl bond would generate a seven-membered species D.
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2H), 1.79−1.63 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 184.5, 181.8, 167.0, 147.0, 146.0, 136.8, 135.2, 131.8,
131.7, 130.6, 128.0, 120.7, 102.3, 51.8, 44.2, 21.6, 11.5; EI-MS (m/z)
299 (M+); HRMS (EI) calcd for C17H17NO4 (M+) 299.1158, found
299.1163.
Scheme 3. Proposed Mechanism
(E)-Ethyl 3-(5,8-dioxo-6-(propylamino)-5,8-dihydronaphthalen-
1
1-yl)acrylate (3ba): red solid, 29 mg (93%); mp = 108−109 °C; H
NMR (300 MHz, CDCl3) δ 8.73 (d, J = 15.9 Hz, 1H), 8.09 (d, J = 7.5
Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 6.15 (d, J =
15.9 Hz, 1H), 5.78 (s, 1H), 5.68 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.11
(m, 2H), 1.75−1.61 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.4
Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 184.0, 181.3, 166.1, 146.4,
145.2, 136.4, 134.8, 131.3, 131.2, 130.1, 127.5, 120.8, 101.8, 60.1, 43.7,
21.1, 13.9, 11.1; EI-MS (m/z) 313 (M+); HRMS (EI) calcd for
C18H19NO4 (M+) 313.1314, found 313.1315.
(E)-Ethyl 3-(5,8-dioxo-7-phenyl-6-(propylamino)-5,8-dihydro-
naphthalen-1-yl)acrylate (3bb): red solid, 27 mg (70%); mp = 97−
99 °C; 1H NMR (300 MHz, CDCl3) δ 8.62 (d, J = 15.9 Hz, 1H), 8.17
(d, J = 7.4 Hz, 1H), 7.63 (m, 2H), 7.42−7.32 (m, 3H), 7.27 (m, 2H),
6.11 (d, J = 15.9 Hz, 1H), 5.83 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.51
(m, 2H), 1.32 (m, 5H), 0.68 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz,
CDCl3) δ 183.8, 182.9, 166.5, 146.2, 143.6, 137.4, 135.7, 134.3, 131.7,
131.5, 131.3(2), 130.6, 127.8(3), 127.7, 121.2, 116.2, 60.5, 46.3, 23.2,
14.4, 11.0; EI-MS (m/z) 389 (M+); HRMS (EI) calcd for C24H23NO4
(M+) 389.1627, found 389.1633.
Subsequent β-H elimination of the intermediate D leads to
formation of intermediate E, which then undergoes isomer-
ization to afford final product 3a. Rh(III) would be regenerated
under the oxidation of Cu(OAc)2·H2O. Meanwhile, reduced
copper is then oxidized by air.
In summary, we have developed a Rh-catalyzed oxidative
dehydrogenative cross-coupling of 1,4-naphthquinones with
alkenes by using a substituent-enabled Csp2−H functionaliza-
tion (SEF) strategy. This is the earliest example of rhodium-
catalyzed oxidative Heck-type alkenylations on the electron-
deficient naphthoquiones. Excellent C5-regioselectivity and
vinyl E-stereoselectivity were achieved in the product. The
method shows high functional group tolerance, broad substrate
scope, and great potential for further functional trans-
formations.
(E)-Benzyl 3-(5,8-dioxo-6-(propylamino)-5,8-dihydronaphthalen-
1
1-yl)acrylate (3ca): red solid, 30 mg (80%); mp = 75−76 °C; H
NMR (300 MHz, CDCl3) δ 8.79 (d, J = 15.9 Hz, 1H), 8.09 (d, J = 7.6
Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.46−7.28
(m, 5H), 6.20 (d, J = 15.9 Hz, 1H), 5.79 (s, 1H), 5.69 (s, 1H), 5.26 (s,
2H), 3.11 (m, 2H), 1.76−1.61 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 184.0, 181.3, 165.8, 146.4, 145.9, 136.3,
135.7, 134.8, 131.3, 131.2, 130.2, 128.1(2), 127.8(2), 127.7, 127.6,
120.3, 101.8, 65.9, 43.8, 21.1, 11.1; EI-MS (m/z) 375 (M+); HRMS
(EI) calcd for C23H21NO4 (M+) 375.1471, found 375.1466.
(E)-Benzyl 3-(5,8-dioxo-7-phenyl-6-(propylamino)-5,8-dihydro-
naphthalen-1-yl)acrylate (3cb): orange solid, 29 mg (64%); mp =
1
106−107 °C; H NMR (300 MHz, CDCl3) δ 8.68 (d, J = 15.8 Hz,
1H), 8.17 (d, J = 7.3 Hz, 1H), 7.62 (m, 7.5, 2H), 7.41−7.26 (m, 10H),
6.15 (d, J = 15.9 Hz, 1H), 5.84 (s, 1H), 5.20 (s, 2H), 2.52 (m, 2H),
1.43−1.26 (m, 2H), 0.68 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 183.7, 182.9, 166.2, 146.9, 143.6, 137.2, 136.2, 135.6, 134.3,
131.7, 131.5, 131.3(2), 130.7, 128.5(2), 128.3(2), 128.1, 127.8,
127.7(3), 120.7, 116.2, 66.2, 46.3, 23.2, 11.0; EI-MS (m/z) 451
(M+); HRMS (EI) calcd for C29H25NO4 (M+) 451.1784, found
451.1782.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed in glassware
containing a Teflon-coated stir bar. All solvents and chemical reagents
were obtained from commercial sources and used without further
purification. 1H and 13C NMR spectra were recorded with
tetramethylsilane as an internal reference. High-resolution mass
spectrometry (HRMS) analysis was recorded by electron ionization
(EI-TOF). Flash column chromatography on silica gel (200−300
mesh) was used for the routine purification of reaction products. The
column output was monitored by TLC on silica gel (100−200 mesh)
precoated on plates (15 × 50 mm) and spots were visualized by UV
light at 254 or 365 nm. Alkenes 2 were purchased directly from
commercial sources. Substrates 1 were either commercially available or
prepared by following literature procedures that include the character-
ization data for the known 2-amino-1,4-naphthoquinones.8,10
(E)-Butyl 3-(5,8-dioxo-6-(propylamino)-5,8-dihydronaphthalen-
1
1-yl)acrylate (3d): red solid, 27 mg (79%); mp = 85−87 °C; H
NMR (300 MHz, CDCl3) δ 8.73 (d, J = 15.9, 1H), 8.11 (d, J = 7.6 Hz,
1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 6.16 (d, J =
15.8 Hz, 1H), 5.78 (s, 1H), 5.69 (s, 1H), 4.21 (t, J = 6.5 Hz, 2H), 3.12
(m, 2H), 1.68 (m, 4H), 1.43 (m, 2H), 1.06−0.87 (m, 6H); 13C NMR
(126 MHz, CDCl3) δ 184.0, 181.3, 166.2, 146.4, 145.2, 136.4, 134.8,
131.3, 131.2, 130.1, 127.5, 120.8, 101.9, 64.0, 43.8, 30.3, 21.1, 18.8,
13.3, 11.1. EI-MS (m/z) 341 (M+); HRMS (EI) calcd for C20H23NO4
(M+) 341.1627, found 341.1618.
(E)-2-(Propylamino)-5-styrylnaphthalene-1,4-dione (3e): red
solid, 16 mg (51%); mp = 167−169 °C; 1H NMR (300 MHz,
CDCl3) δ 8.45 (d, J = 16.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.89 (d,
J = 7.6 Hz, 1H), 7.56 (m, 3H), 7.33 (m, 3H), 6.93 (d, J = 16.2 Hz,
1H), 5.71 (s, 1H), 5.67 (s, 1H), 3.10 (m, 2H), 1.69 (m, 2H), 0.99 (t, J
= 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 185.2, 181.8, 146.2,
139.2, 137.1, 134.3, 131.5, 131.3, 130.9, 128.7(2), 128.2(2), 127.4,
126.6(2), 126.0, 102.5, 43.7, 21.2, 11.1; EI-MS (m/z) 317 (M+);
HRMS (EI) calcd for C21H19NO2 (M+) 317.1416, found 317.1400.
(E)-5-(4-Chlorostyryl)-2-(propylamino)naphthalene-1,4-dione
(3f): red solid, 14 mg (40%); mp = 152−153 °C; 1H NMR (300 MHz,
CDCl3) δ 8.40 (d, J = 16.3 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.84 (d,
J = 7.8 Hz, 1H), 7.51 (m, 3H), 7.30 (m, 2H), 6.84 (d, J = 16.2 Hz,
1H), 5.72 (s, 1H), 5.66 (s, 1H), 3.10 (m, 2H), 1.75−1.61 (m, 2H),
General Procedure for Synthesis of 5-Alkenylated 1,4-
Naphthoquinones. A solution of C2-amino-1,4-naphthoquinones 1
(0.1 mmol), alkene 2 (0.2 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6
(10 mol %), and Cu(OAc)2·H2O (20 mol %) in DCE (0.5 mL) was
stirred in a sealed tube at 120 °C for 12−24 h. The reaction was then
cooled to room temperature, concentrated in vacuum, and purified by
column chromatography using petroleum ether/ethyl acetate to afford
the corresponding olefinated products 3.
(E)-Methyl 3-(5,8-dioxo-6-(propylamino)-5,8-dihydronaphtha-
len-1-yl)acrylate (3a): red solid, 28 mg (94%); mp = 126−128 °C;
1H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 16.0 Hz, 1H), 8.10 (d, J =
7.5 Hz, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 6.16 (d,
J = 16.0 Hz, 1H), 5.78 (s, 1H), 5.68 (s, 1H), 3.80 (s, 3H), 3.12 (m,
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0.99 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 185.1, 181.7,
146.2, 138.8, 135.6, 134.2, 133.0, 131.5, 131.0, 129.8, 129.3, 128.8,
128.4(2), 127.7(2), 126.2, 102.4, 43.7, 21.2, 11.1; EI-MS (m/z) 351
(M+); HRMS (EI) calcd for C21H18ClNO2 (M+) 351.1026, found
351.1005.
(E)-5-(2-(Phenylsulfonyl)vinyl)-2-(propylamino)naphthalene-1,4-
dione (3ga): orange solid, 25 mg (66%); mp = 160−162 °C; 1H NMR
(300 MHz, CDCl3) δ 8.71 (d, J = 15.3 Hz, 1H), 8.08 (d, J = 6.2 Hz,
3H), 7.62−7.52 (m, 5H), 6.56 (d, J = 15.3 Hz, 1H), 5.83 (s, 1H), 5.69
(s, 1H), 3.12 (m, 2H), 1.77−1.60 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ 183.9, 181.4, 147.0, 145.18, 140.6,
8.11 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.7 Hz,
1H), 6.15 (d, J = 15.9 Hz, 1H), 5.86 (s, 1H), 5.71 (s, 1H), 3.80 (s,
3H), 2.93 (d, J = 6.2 Hz, 2H), 0.99 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 184.5, 181.8, 166.9, 147.3, 145.9, 136.7, 135.2, 131.7, 131.6,
130.6, 128.0, 120.7, 102.2, 53.9, 51.8, 32.4, 27.5(3); EI-MS (m/z) 327
(M+); HRMS (EI) calcd for C19H21NO4 (M+) 327.1471, found
327.1476.
(E)-Ethyl 3-(6-((adamantan-1-ylmethyl)amino)-5,8-dioxo-5,8-di-
hydronaphthalen-1-yl)acrylate (3l): red solid, 31 mg (74%); mp =
1
190−192 °C; H NMR (300 MHz, CDCl3) δ 8.75 (d, J = 15.9 Hz,
1H), 8.13 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.7
Hz, 1H), 6.16 (d, J = 15.9 Hz, 1H), 5.89 (s, 1H), 5.73 (s, 1H), 4.27 (q,
J = 7.1 Hz, 2H), 2.83 (d, J = 6.3 Hz, 2H), 2.00 (s, 3H), 1.78−1.53 (m,
12H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 184.6,
181.9, 166.6, 147.5, 145.7, 136.9, 135.3, 131.8, 131.6, 130.6, 128.0,
121.2, 102.2, 60.6, 54.4, 40.5(3), 36.8(3), 34.5, 28.1(3), 14.4; EI-MS
(m/z) 419 (M+); HRMS (EI) calcd for C26H29NO4 (M+) 419.2097,
found 419.2091.
135.2, 134.6, 133.3, 131.8, 131.6, 131.0, 129.2(3), 128.5, 127.9(2),
101.8, 44.2, 21.5, 11.5; ESI-MS (m/z) 382 ([M + H]+); HRMS (ESI):
calcd for C21H20NO4S ([M + H]+) 382.1113, found 382.1104.
(E)-3-Phenyl-5-(2-(phenylsulfonyl)vinyl)-2-(propylamino)-
naphthalene-1,4-dione (3gb): red solid, 31 mg (68%); mp = 68−70
1
°C; H NMR (300 MHz, CDCl3) δ 8.71 (d, J = 15.3 Hz, 1H), 8.16
(m, 1H), 8.01 (d, J = 7.3 Hz, 2H), 7.66−7.31 (m, 8H), 7.31−7.21 (m,
2H), 6.56 (d, J = 15.3 Hz, 1H), 5.84 (s, 1H), 2.51 (m, 2H), 1.40−1.28
(m, 2H), 0.67 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
182.7, 182.2, 144.6, 143.4, 140.2, 134.9, 134.2, 133.7, 132.7, 131.3,
131.0, 130.9(2), 130.7, 128.7(3), 128.0, 127.5(2), 127.3(3), 115.6,
45.9, 22.7, 10.5; EI-MS (m/z) 457 (M+); HRMS (EI) calcd for
C27H23NO4S (M+) 457.1348, found 457.1344.
(E)-Ethyl 3-(6-(3-chloropropylamino)-5,8-dioxo-5,8-dihydro-
naphthalen-1-yl)acrylate (3m): orange solid, 18 mg (52%); mp
1
=98−100 °C; H NMR (300 MHz, CDCl3) δ 8.71 (d, J = 15.9 Hz,
1H), 8.10 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.58 (t, J = 7.6
Hz, 1H), 6.16 (d, J = 15.9 Hz, 1H), 5.86 (s, 1H), 5.74 (s, 1H), 4.26 (q,
J = 6.9 Hz, 2H), 3.62 (m, 2H), 3.45−3.33 (m, 2H), 2.18−2.05 (m,
2H), 1.33 (t, J = 7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 184.5,
181.6, 166.5, 146.7, 145.5, 136.9, 135.3, 131.8, 131.7, 130.4, 128.0,
121.4, 102.7, 60.6, 42.0, 40.0, 30.6, 14.4; EI-MS (m/z) 347 (M+);
HRMS (EI) calcd for C18H18ClNO4 (M+) 347.0924, found 347.0925.
(E)-Ethyl 3-(6-(2,2-difluoroethylamino)-5,8-dioxo-5,8-dihydro-
naphthalen-1-yl)acrylate (3n): yellow solid, 25 mg (75%); mp =
(E)-Dimethyl 2-(5,8-dioxo-6-(propylamino)-5,8-dihydronaphtha-
len-1-yl)vinyl-phosphonate (3ha): orange solid, 22 mg (63%); mp =
1
107−108 °C; H NMR (300 MHz, CDCl3) δ 8.44 (dd, JH−P = 22.1,
17.6 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.62 (m, 2H), 5.95 (dd, JH−P
=
19.7, 17.6 Hz, 1H), 5.81 (s, 1H), 5.66 (s, 1H), 3.87 (s, 3H), 3.83 (s,
3H), 3.11 (m, 2H), 1.68 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR
(151 MHz, CDCl3) δ 184.4, 181.7, 150.3, 147.0, 135.1, 131.8, 131.6,
130.3, 128.0, 116.1, 114.8, 102.1, 52.9, 52.8, 44.2, 21.6, 11.5; EI-MS
(m/z) 349 (M+); HRMS (EI) calcd for C17H20NO5P (M+) 349.1079,
found 349.1085.
(E)-Dimethyl 2-(5,8-dioxo-7-phenyl-6-(propylamino)-5,8-dihy-
dronaphthalen-1-yl)vinyl phosphonate (3hb): red solid, 26 mg
(61%); mp = 101−102 °C; 1H NMR (300 MHz, CDCl3) δ 8.39 (dd,
JH−P = 21.9, 17.6 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.72−7.52 (m,
2H), 7.40−7.29 (m, 3H), 7.25 (m, 2H), 5.94 (dd, JH−P = 19.5, 17.5 Hz,
1H), 5.80 (s, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 2.48 (m, 2H), 1.30 (m,
2H), 0.66 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 183.5,
182.8, 150.4(2), 143.7, 135.3, 134.3, 131.8, 131.4, 131.3(2), 130.4,
127.9, 127.7(3), 116.2, 114.7, 52.7(2), 46.3, 23.1, 11.0; EI-MS (m/z)
425 (M+); HRMS (EI) calcd for C23H24NO5P (M+) 425.1392, found
425.1389.
1
160−162 °C; H NMR (300 MHz, CDCl3) δ 8.68 (d, J = 16.0 Hz,
1H), 8.12 (d, J = 7.3 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.61 (t, J = 7.6
Hz, 1H), 6.18 (d, J = 15.8 Hz, 1H), 5.87 (m, 3H), 4.27 (q, J = 6.9 Hz,
2H), 3.60 (t, J = 13.4 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H); 13C NMR
(151 MHz, CDCl3) δ 184.8, 181.2, 166.5, 146.6, 145.2, 137.0, 135.4,
132.1, 131.6, 130.0, 128.1, 121.7, 113.1 (t, J = 243.1 Hz), 103.9, 60.7,
44.6 (t, J = 25.7 Hz), 14.3; EI-MS (m/z) 335 (M+); HRMS (EI) calcd
for C17H15F2NO4 (M+) 335.0969, found 335.0969.
(E)-Ethyl 3-(6-(3-(tert-butoxycarbonyl(methyl)amino)-
propylamino)-5,8-dioxo-5,8-dihydronaphthalen-1-yl)acrylate (3o):
red solid, 21 mg (48%); mp = 89−91 °C; 1H NMR (300 MHz,
CDCl3) δ 8.73 (d, J = 16.0 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.69 (d,
J = 7.5 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 6.16 (d, J = 15.9 Hz, 1H),
5.69 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.32 (t, J = 6.4 Hz, 2H), 3.24−
3.12 (m, 2H), 2.84 (s, 3H), 1.82 (s, 2H), 1.45 (s, 9H), 1.33 (t, J = 7.1
Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 184.5, 181.7, 166.6, 156.3,
155.6, 147.0, 145.8, 136.9, 135.2, 131.7, 130.6, 128.0, 121.2, 102.0,
79.9, 60.6, 45.5, 39.3, 34.3, 28.5(3), 25.8, 14.4; EI-MS (m/z) 442
(M+); HRMS (EI) calcd for C24H30N2O6 (M+) 442.2104, found
442.2088.
(E)-Methyl 3-(7-methyl-5,8-dioxo-6-(propylamino)-5,8-dihydro-
naphthalen-1-yl)acrylate (3p): red solid, 28 mg (90%); mp = 93−
94 °C; 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J = 15.9 Hz, 1H), 8.04
(d, J = 7.3 Hz, 1H), 7.56 (m, 2H), 6.12 (d, J = 15.9 Hz, 1H), 5.61 (s,
1H), 3.79 (s, 3H), 3.46 (m, 2H), 2.17 (s, 3H), 1.71−1.54 (m, 2H),
0.96 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 184.9, 182.2,
167.0, 146.4, 145.4, 136.6, 134.9, 131.6, 131.4, 130.6, 127.7, 120.4,
113.3, 51.8, 47.2, 24.1, 11.4, 11.2; EI-MS (m/z) 313 (M+); HRMS
(EI) calcd for C18H19NO4 (M+) 313.1314, found 313.1312.
(E)-Methyl 3-(5,8-dioxo-7-phenyl-6-(propylamino)-5,8-dihydro-
naphthalen-1-yl)acrylate (3q): red solid, 28 mg (74%); mp = 89−
91 °C; 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J = 15.9 Hz, 1H), 8.16
(d, J = 7.2 Hz, 1H), 7.72−7.54 (m, 2H), 7.42−7.31 (m, 3H), 7.27 (m,
2H), 6.11 (d, J = 15.9 Hz, 1H), 5.84 (s, 1H), 3.73 (s, 3H), 2.51 (m,
2H), 1.41−1.27 (m, 2H), 0.68 (t, J = 7.4 Hz, 3H); 13C NMR (151
MHz, CDCl3) δ 183.8, 182.8, 166.9, 146.4, 143.6, 137.2, 135.6, 134.3,
131.8, 131.5, 131.3(2), 130.6, 127.9, 127.8(2), 127.7, 120.7, 116.2,
51.7, 46.3, 23.2, 11.0; EI-MS (m/z) 375 (M+); HRMS (EI) calcd for
C23H21NO4 (M+) 375.1471, found 375.1462.
3-(5,8-Dioxo-6-(propylamino)-5,8-dihydronaphthalen-1-yl)-
acrylonitrile (3i). The title compound was obtained as an inseparable
1
mixture of E,Z isomers: orange solid, 16 mg (60%); H NMR (400
MHz, CDCl3) δ 8.64 (d, J = 16.5 Hz, 1H), 8.19 (m, 1H), 7.96−7.67
(m, 1H), 7.66 (d, J = 3.7 Hz, 1H), 5.86 (s, 1H), 5.73 (d, J = 11.2 Hz,
1H), 5.66 (m, 1H), 3.17 (m, 2H), 1.83−1.67 (m, 2H), 1.05 (t, J = 7.4
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 184.1, 181.4, 152.0, 147.1,
147.0, 136.1, 135.4, 134.7, 134.5, 131.9(2), 131.8, 131.6, 130.9, 130.4,
128.7, 128.4, 117.8, 116.8, 102.1, 101.7, 98.9, 97.2, 44.2, 21.6, 11.5; EI-
MS (m/z) 266 (M+); HRMS (EI) calcd for C16H14N2O2 (M+)
266.1055, found 266.1050.
(E)-Ethyl 3-(6-(cyclopropylmethylamino)-5,8-dioxo-5,8-dihydro-
naphthalen-1-yl)acrylate (3j): red solid, 20 mg (62%); mp = 107−
1
109 °C; H NMR (300 MHz, CDCl3) δ 8.71 (d, J = 15.9 Hz, 1H),
8.09 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.5 Hz,
1H), 6.14 (d, J = 15.9 Hz, 1H), 5.87 (s, 1H), 5.64 (s, 1H), 4.25 (dd, J
= 13.9, 6.9 Hz, 2H), 2.97 (m, 2H), 1.31 (t, J = 6.9 Hz, 3H), 1.09 (s,
1H), 0.60 (d, J = 7.2 Hz, 2H), 0.27 (d, J = 3.9 Hz, 2H); 13C NMR
(126 MHz, CDCl3) δ 184.5, 181.7, 166.5, 146.8, 145.7, 136.8, 135.3,
131.7(2), 130.5, 128.0, 121.2, 102.4, 60.6, 47.5, 14.3, 9.7, 3.8(2); EI-
MS (m/z) 325 (M+); HRMS (EI) calcd for C19H19NO4 (M+)
325.1314, found 325.1312.
(E)-Methyl 3-(6-(neopentylamino)-5,8-dioxo-5,8-dihydronaph-
thalen-1-yl)acrylate (3k): orange solid, 26 mg (80%); mp = 146−
1
147 °C; H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 15.9 Hz, 1H),
7630
dx.doi.org/10.1021/jo501419s | J. Org. Chem. 2014, 79, 7626−7632

The Journal of Organic Chemistry
Article
(E)-Methyl 3-(4-hydroxy-5,8-dioxo-6-(propylamino)-5,8-dihydro-
Author Contributions
§These authors contributed equally to this work.
naphthalen-1-yl)acrylate (3r): red solid, 12 mg (38%); mp = 145−
1
146 °C; H NMR (300 MHz, CDCl3) δ 12.20 (s, 1H), 8.64 (d, J =
Notes
16.0 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.9 Hz, 1H), 6.14
(d, J = 16.0 Hz, 1H), 5.78 (s, 1H), 5.67 (s, 1H), 3.79 (s, 3H), 3.12 (m,
2H), 1.70 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H); 13C NMR (126 MHz,
CDCl3) δ 186.5, 183.7, 167.1, 163.2, 146.6, 145.3, 138.5, 130.0, 128.9,
122.6, 120.2, 114.3, 102.7, 51.7, 44.3, 21.6, 11.5; EI-MS (m/z) 315
(M+); HRMS (EI) calcd for C17H17NO5 (M+) 315.1107, found
315.1109.
(E)-Methyl 3-(5,8-dioxo-6-(phenylamino)-5,8-dihydronaphtha-
len-1-yl)acrylate (3s): red solid, 17 mg (51%); mp = 187−189 °C;
1H NMR (300 MHz, CDCl3) δ 8.71 (d, J = 15.9 Hz, 1H), 8.20 (d, J =
7.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.42
(m, 3H), 7.21 (m, 2H), 6.39 (s, 1H), 6.20 (d, J = 15.9 Hz, 1H), 3.81
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 185.3, 181.9, 166.8, 145.4,
143.6, 137.4, 136.8, 135.3, 132.0, 131.6, 130.2, 129.7(2), 128.2, 125.5,
122.4(2), 121.2, 105.0, 51.8. EI-MS (m/z) 333 (M+); HRMS (EI)
calcd for C20H15NO4 (M+) 333.1001, found 333.1005.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants of Chinese National
Sciences Foundation (81125021, 81373277), National Science
& Technology Major Project on “Key New Drug Creation and
Manufacturing Program”, China (Nos. 2012ZX09103-101-035
amd 2012ZX09301001-001). Supporting grants from the
“Interdisciplinary Cooperation Team” Program for Science
and Technology Innovation (CAS) and a grant from the State
Key Laboratory of Drug Research (SIMM1302KF-08),
Shanghai Institute of Materia Medica, are also appreciated.
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138 °C; H NMR (300 MHz, CDCl3) δ 8.68 (d, J = 15.9 Hz, 1H),
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1-yl)acrylate (3ua): red solid, 13 mg (39%); mp = 94−96 °C; H
NMR (400 MHz, CDCl3) δ 8.82 (d, J = 15.9 Hz, 1H), 8.02 (d, J = 7.4
Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 6.21 (d, J =
15.9 Hz, 1H), 5.84 (s, 1H), 4.29 (q, J = 6.9 Hz, 2H), 3.57−3.45 (m,
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(E)-Ethyl 3-(6-(ethylamino)-5,8-dioxo-5,8-dihydronaphthalen-1-
yl)acrylate (3ub): red solid, 4 mg (13%); mp = 87−89 °C; 1H
NMR (300 MHz, CDCl3) δ 8.74 (d, J = 16.1 Hz, 1H), 8.12 (d, J = 7.4
Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 6.16 (d, J =
15.9 Hz, 1H), 5.69 (s, 2H), 4.27 (q, J = 6.7 Hz, 2H), 3.28−3.11 (m,
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166.6, 146.8, 145.7, 136.9, 135.3, 131.8, 131.7, 130.6, 128.0, 121.3,
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calcd for C17H17NO4 (M+) 299.1158, found 299.1154.
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dibromomethane as the internal standard (experimental data in the
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* Supporting Information
Copies of NMR spectra of all new compounds and kinetic
isotope effect experimental data. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: chslp@cpu.edu.cn.
*E-mail: aozhang@simm.ac.cn.
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