Naphthoquinone-directed C-H annulation and Csp3-H bond cleavage: One-pot synthesis of tetracyclic naphthoxazoles

Article abstract of DOI:10.1021/jo500572u

One-pot synthesis of tetracyclic naphthoxazole derivatives from electron-deficient naphthoquinones and alkynes was achieved via Rh(III)-catalyzed C-H activation and Csp³-H bond cleavage for the first time. This approach proceeds through a tandem cascade process involving substrate tautomerization, C-H activation, oxidative addition, cyclization, and aromatization. In addition, broad substrate scope, simple starting materials, and steric tolerance make this strategy of great practicality.

Full text of DOI:10.1021/jo500572u

Article
pubs.acs.org/joc
3
Naphthoquinone-Directed C−H Annulation and Csp −H Bond
Cleavage: One-Pot Synthesis of Tetracyclic Naphthoxazoles
Meining Wang,† Chi Zhang,‡ Li-Ping Sun,‡ Chunyong Ding,† and Ao Zhang*,†
†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
‡Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
S
* Supporting Information
ABSTRACT: One-pot synthesis of tetracyclic naphthoxazole
derivatives from electron-deficient naphthoquinones and alkynes
3
was achieved via Rh(III)-catalyzed C−H activation and Csp −H
bond cleavage for the first time. This approach proceeds through
a tandem cascade process involving substrate tautomerization,
C−H activation, oxidative addition, cyclization, and aromatiza-
tion. In addition, broad substrate scope, simple starting
materials, and steric tolerance make this strategy of great
practicality.
more complex tetraheterocycles as the 1:2 coupling products.4p
With the hydroxyl group of 1-naphthol as the directing group,
Miura’s group reported a highly efficient synthesis of
INTRODUCTION
Naphthoxazoles fused with an additional aryl or aliphatic ring
are present in many biologically active and pharmaceutically
relevant natural products and synthetic analogues and,
■
naphthopyrans through a Rh-catalyzed oxidative annulation
(eq 1, Scheme 1).4c Since the tautomerization of quinones to
therefore, constitute challenging molecular targets for both
synthetic and medicinal chemistry studies.1 For example,
the corresponding phenols is common, we envisioned that
quinones themselves might be used directly as “masked”
pseudopteroxazole 1 (Figure 1) is a marine natural product
phenolic substrates to trigger similar C−H activations. To the
best of our knowledge, direct usage of the electron-deficient
quinones as the directing group in Rh-catalyzed C−H
functionalization has not been reported yet.5 Herein, we
present the first example of naphthoquinone-induced Rh(III)-
3
catalyzed C−H activation combined with a Csp −H bond
cleavage, leading to the tetracyclic naphthoxazole networks
formed in a one-pot reaction (eq 2, Scheme 1). The structural
novelty of reaction products and high efficiency of such a one-
pot process, together with the wide substrate scope, make this
Figure 1. Biologically active tetracyclic naphthoxazoles.
approach highly appealing.
RESULTS AND DISCUSSION
■
isolated in 1999 possessing potent growth inhibition against
Mycobacterium tuberculosis H37Rv.1a Compounds 2 and 3 are
Our initial experiment was performed by treating 2-
propylamino-1,4-naphthoquinone (5a) with diphenylacetylene
cytotoxic agents capable of intercalating into the DNA base
pairs.1d,e Herqueioxazole 4 was isolated very recently as a
metabolite of marine-derived fungus Penicillium sp. showing
significant inhibition against Staphylococcus aureus sortase A.1f
Despite that numerous preparative methods for bicyclic
benzoxazoles and tricyclic naphthoxazoles are available,2
synthetic strategies toward complex frameworks of tetracyclic
naphthoxazoles using simple starting materials through a one-
pot process have not been reported yet.
Rh(III)-catalyzed oxidative coupling of arenes with alkynes
has been extensively explored recently.3−5 This approach not
only allows convenient synthesis of various bi- or tricyclic
compounds but also enables the construction of structurally
(6a, 1.5 equiv) in the presence of [Cp*RhCl2]2 (0.05 equiv)
and Cu(OAc)2·H2O (2 equiv) in t-AmOH at 100 °C for 6 h.
To our delight, tetracyclic naphthoxazole 7aa was obtained in
12% yield, along with a small amount of naphthoxazole acetate
8aa (Table 1, entry 1). To improve the yield of 7aa, we
conducted a systematic optimization of the reaction conditions.
It was found that AgSbF6 is a critical enhancer to the yield
(entry 4). The side product could be greatly suppressed by
lowering the Cu(OAc)2·H2O loading; however, the yield of 7aa
Received: March 11, 2014
Published: April 18, 2014
© 2014 American Chemical Society
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Scheme 1. Rh(III)-Catalyzed Phenol-Directed Oxidative Coupling and Our Work
a b
,
Table 1. Optimization of the Reaction Conditions
entry
catalytic system (amount [equiv])
Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (2)
solvent
T (°C)
7aa:8aa
yield of 7aa (%)
1
2
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
HFIP
100
120
120
100
120
120
120
120
120
120
70
6:1
12
c
3
AgSbF6 (0.2)
4
Cu(OAc)2·H2O (2)/AgSbF6 (0.2)
Cu(OAc)2·H2O (2)/AgSbF6 (0.2)
5:1
53
73
66
33
59
26
39
37
<5
<5
62
68
64
5
6:1
6
Cu(OAc)2·H2O (2)/AgSbF6 (0.2)/AgOAc (2)
Cu(OAc)2·H2O (0.5)/Ag2CO3 (1)
Cu(OAc)2·H2O (0.5)/AgSbF6 (0.2)/Mn(OAc)3·2H2O (1.5)
AgSbF6 (0.2)/Mn(OAc)3·2H2O (2)
Cu(OAc)2·H2O (1)/AgSbF6 (0.2)
4:1
7
3:1
8
14:1
9:1
9
10
11
12
13
14
15
16
19:1
5:1
Cu(OAc)2·H2O (2)/AgSbF6 (0.2)
c
[Ru(p-cymene)Cl2]2 (0.05)/Cu(OAc)2·H2O (2)
m-xylene
t-AmOH
t-AmOH
t-AmOH
t-AmOH
100
120
120
120
120
100-
100-
19:1
6:1
c
[Cp*IrCl2]2 (0.05)/Cu(OAc)2·H2O (2)
Cu(OAc)2·H2O (1.5)/AgSbF6 (0.2)/O2
Cu(OAc)2·H2O (2)/AgSbF6 (0.2)/TEMPO (2)
Cu(OAc)2·H2O (2)/AgSbF6 (0.1)/H2O (5)
4.6:1
a
Conditions: A mixture of naphthoquinone (0.1 mmol), alkyne (0.15 mmol), catalyst, and solvent (0.5 mL) was stirred in sealed tubes at 120 °C for
b
c
6 h. Isolated yields. Without [Cp*RhCl2]2
was also reduced (entry 10). Cooxidants were also used, but the
total yields were low (entries 6−8 and 14). Control
experiments showed that no product was observed in the
absence of either [Cp*RhCl2]2 (entry 2) or Cu(OAc)2·H2O
(entry 3). Water had little influence on the reaction yield (entry
16). Finally, a high yield of 73% was achieved for 7aa by using
[Cp*RhCl2]2 (0.05 equiv), Cu(OAc)2·H2O (2 equiv), and
AgSbF6 (0.2 equiv) in t-AmOH at 120 °C for 6 h (entry 5).
Next, we set out to investigate the scope of this
transformation (Scheme 2). First, with 2-propylamino-1,4-
naphthoquinone (5a) as the model substrate, a series of alkynes
6 were tested as the coupling partners. All the reactions
proceeded smoothly, and products 7ab−7ak were obtained in
moderate to good yields. Reactions using terminal alkynes and
TMS-protected alkynes failed. It was found that substrates 5
bearing various N-alkyl substituents reacted with diphenylace-
tylene 6a smoothly, and the corresponding naphthoxazoles
7ba−7fa were obtained in 54−76% yields. Surprisingly,
naphthoquinones 5 containing a bulky N-alkyl group were
well-tolerated, and products 7ga and 7ia were obtained in high
yields of 95% and 93%. Substrates 5 with a larger N-substituent
gave corresponding products 7ha and 7ja in 74% and 64%
yields, respectively. Notably, functionalized N-alkyl in 1,4-
naphthoquinone 5 was stable, and compound 7ka was obtained
in 45% yield. Much higher yield (82%) was achieved for the
morpholine-substituted product 7la. Finally, variations in the
1,4-naphthoquinone skeleton of 5 were exploited as well
(Scheme 2). Introducing a MeO− or BnO− to the phenyl ring
was acceptable, although the yields were somewhat lower (47%
for 7ma, 46% for 7na). However, fusing an additional phenyl
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a b
,
Scheme 2. Substrate Scope of the Tandem Reaction
Scheme 3. Reaction of 6a with Naphthoquinolines 5r and 5s
products formed. Besides, simple naphthoquinone lacking the
amino substituent did not give the corresponding product
under the same conditions, either. These results suggested that
the reaction likely proceeded in a tandem cascade fashion rather
than stepwise, and both the aromatic H-5 and free N-H are
necessary to initiate the catalytic reaction. In addition, to
determine whether a Cu(II)-catalyzed radical process6 was
involved in the reaction, TEMPO was added as a radical
scavenger to the reaction of 5a and 6a, and no significant loss in
the yield of 7aa was observed (Table 1, entry 15).
Further, a series of deuterium-labeling experiments were
conducted. It was found that, in the absence of acetylene 6a,
treating substrate 5a along with [Cp*RhCl2]2, AgSbF6, and
Cu(OAc)2·H2O in CD3OD resulted in the partially deuterated
reactant at 3- and 5-positions (eq 1, Scheme 4), indicating that
Scheme 4. Experiments with Isotopically Labeled
Compounds
a
Regioisomeric ratios were determined as 1:1 by respective isolated
yields.
b
Reaction conditions: 5a−5q (0.4 mmol), 6a−6k (0.6 mmol), [Cp*
RhCl2]2 (0.05 equiv), Cu(OAc)2·H2O (2 equiv), AgSbF6 (0.2 equiv),
t-AmOH (2 mL), sealed tubes, 120 °C, 6 h.
ring to the naphthoquinone system led to formation of
pentacyclic product 7oa in high yield (86%). Substrates 5p and
5q with a methyl or phenyl group on the benzoquinonyl ring
also went through the reaction smoothly, and products 7pa and
7qa were obtained in 70% and 89% yields, respectively.
All the compounds were fully characterized by spectroscopic
data, and their structures were further confirmed by the single-
crystal X-ray analysis of 7aa (see the Supporting Information).
To validate the efficiency and practicality of this cascade
reaction, coupling of 2-propylamino-1,4-naphthoquinone (5a)
and diphenylacetylene (6a) was conducted on a gram scale, and
tetracyclic product 7aa was delivered smoothly without
significant loss of the yield.
the C−H activation is reversible. Further, it was found that
reaction of 5a and 6i in the presence of CD3OD led to both
deuterated product and recovered reactant (eq 2), suggesting
that the cascade reaction was ignited by the C5−H activation. In
addition, two parallel independent reactions of substrates 5p
and [D-5]-5p with 6a demonstrated a kinetic isotope effect
(KIE) of KH/KD = 3.34. These results indicated that cleavage of
the C5−H bond was involved in the rate-determining step.
On the basis of the results above, a plausible mechanism was
proposed to the present catalytic process. As shown in Scheme
5, the reaction cycle is likely started by tautomerization of 5a to
phenol 5a′, which then undergoes a well-known Rh(III)-
catalyzed C−H activation to form a five-membered rhodacycle
A.3,4 Insertion of alkyne 6a to the Rh−Cphenyl bond would
To gain some mechanistic insights to the present cascade
process, several supplementary reactions were performed. As
shown in Scheme 3, we first tested the reactions of alkyne 6a
with 5-methoxy-2-(propylamino)-1,4-naphthoquinone (5r) and
2-(pyrrolidin-1-yl)-1,4-naphthoquinone (5s) and found that no
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then purified by column chromatography to give the 2-amino-1,4-
naphthoquinones 5.
2-(Propylamino)naphthalene-1,4-dione (5a). Red solid. H NMR
Scheme 5. Proposed Mechanistic Pathway
1
(300 MHz, CDCl3): δ 8.09 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 7.7 Hz,
1H), 7.72 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 5.90 (brs, 1H),
5.73 (s, 1H), 3.15 (m, 2H), 1.72 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H).
1
2-(Butylamino)naphthalene-1,4-dione (5b). Red solid. H NMR
(300 MHz, CDCl3): δ 8.07 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz,
1H), 7.69 (m, 1H), 7.58 (m, 1H), 5.87 (brs, 1H), 5.70 (s, 1H), 3.15
(m, 2H), 1.65 (m, 2H), 1.41 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H).
1
2-(Pentylamino)naphthalene-1,4-dione (5c). Red solid. H NMR
(300 MHz, CDCl3): δ 8.07 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz,
1H), 7.70 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 5.88 (brs, 1H),
5.70 (s, 1H), 3.15 (m, 2H), 1.67 (m, 2H), 1.36 (m, 4H), 0.90 (t, J =
6.6 Hz, 3H).
2-(Isopentylamino)naphthalene-1,4-dione (5d). Red solid. 1H
NMR (300 MHz, CDCl3): δ 8.08 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6
Hz, 1H), 7.70 (td, J = 7.5, 1.2 Hz, 1H), 7.58 (td, J = 7.5, 1.2 Hz, 1H),
5.84 (brs, 1H), 5.71 (s, 1H), 3.17 (m, 2H), 1.67 (m, 1H), 1.56 (m,
2H), 0.94 (d, J = 6.5 Hz, 6H).
1
2-(Hexylamino)naphthalene-1,4-dione (5e). Red solid. H NMR
(300 MHz, CDCl3): δ 8.08 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 7.6 Hz,
1H), 7.70 (t, J = 7.5 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 5.87 (brs, 1H),
5.71 (s, 1H), 3.15 (m, 2H), 1.67 (m, 2H), 1.33 (m, 6H), 0.88 (t, J =
5.9 Hz, 3H).
2-((3-Phenylpropyl)amino)naphthalene-1,4-dione (5f). Red solid.
1H NMR (300 MHz, CDCl3): δ 8.08 (d, J = 7.7 Hz, 1H), 8.02 (d, J =
7.6 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H), 7.28 (m,
2H), 7.18 (m, 3H), 5.88 (brs, 1H), 5.68 (s, 1H), 3.17 (m, 2H), 2.72 (t,
J = 7.5 Hz, 2H), 2.01 (m, 2H).
2-(Isobutylamino)naphthalene-1,4-dione (5g). Red solid. 1H
NMR (300 MHz, CDCl3): δ 8.08 (d, J = 7.6 Hz, 1H), 8.02 (d, J =
7.6 Hz, 1H), 7.70 (td, J = 7.6, 1.3 Hz, 1H), 7.59 (td, J = 7.6, 1.2 Hz,
1H), 5.97 (brs, 1H), 5.71 (s, 1H), 2.99 (m, 2H), 1.98 (m, 1H), 0.99
(d, J = 6.7 Hz, 6H).
produce a seven-membered species B. Subsequent reductive
elimination of the intermediate B leads to formation of
intermediate C. Rh(III) would be regenerated under the
oxidation of Cu(OAc)2·H2O. The intermediate C would then
7
2-(Neopentylamino)naphthalene-1,4-dione (5h). Red solid. 1H
NMR (300 MHz, CDCl3): δ 8.08 (d, J = 7.4 Hz, 1H), 8.03 (d, J = 7.5
Hz, 1H), 7.71 (t, J = 7.1 Hz, 1H), 7.59 (t, J = 7.1 Hz, 1H), 5.99 (brs,
1H), 5.75 (s, 1H), 2.94 (d, J = 6.2 Hz, 2H), 1.01 (s, 9H).
2-((Cyclopropylmethyl)amino)naphthalene-1,4-dione (5i). Red
3
proceed through a Csp −H cleavage/shift to form intermediate
D, which then undergoes a cyclization, followed by oxidative
aromatization, to yield final product 7aa.
In summary, we have developed a rhodium-catalyzed process
to construct tetracyclic naphthoxazole derivatives by oxidative
coupling of electron-deficient quinones with alkynes. Mecha-
nism studies indicated that this one-pot reaction involves a
tandem cascade process including tautomerization/C−H
activation/oxidative addition/cyclization/aromatization. This
protocol not only represents a novel one-pot approach to
access the tetracyclic naphthoxazoles but also showcases the
1
solid. H NMR (300 MHz, CDCl3): δ 8.07 (d, J = 7.6 Hz, 1H),
8.03 (d, J = 7.6 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5 Hz,
1H), 5.98 (brs, 1H), 5.68 (s, 1H), 3.00 (m, 2H), 1.11 (m, 1H), 0.62
(m, 2H), 0.29 (m, 2H).
2-((Adamantan-1-ylmethyl)amino)naphthalene-1,4-dione (5j).
Red solid. 1H NMR (300 MHz, CDCl3): δ 8.06 (d, J = 7.6 Hz,
1H), 8.01 (d, J = 7.6 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.57 (t, J = 7.5
Hz, 1H), 6.01 (brs, 1H), 5.74 (s, 1H), 2.83 (d, J = 6.3 Hz, 2H), 1.99
(m, 3H), 1.67 (m, 6H), 1.56 (m, 6H).
3
capacity of combining a C−H activation and a Csp −H bond
cleavage to form a heterocyclic complex for the first time.
tert-Butyl (3-((1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)-
propyl)(methyl)carbamate (5k). Red solid. 1H NMR (300 MHz,
CDCl3): δ 8.07 (d, J = 7.7 Hz, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.69 (t, J
= 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 6.47 (brs, 0.44H), 5.92 (brs,
0.29H), 5.70 (s, 1H), 3.31 (t, J = 6.5 Hz, 2H), 3.19 (m, 2H), 2.84 (s,
3H), 1.83 (m, 2H), 1.45 (s, 9H).
2-((2-(Tetrahydro-2H-pyran-4-yl)ethyl)amino)naphthalene-1,4-
dione (5l). Red solid. 1H NMR (300 MHz, CDCl3): δ 8.08 (d, J = 7.5
Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.60 (t, J =
7.5 Hz, 1H), 5.83 (brs, 1H), 5.71 (s, 1H), 3.96 (m, 2H), 3.37 (m, 2H),
3.21 (m, 2H), 1.63 (m, 5H), 1.34 (m, 2H).
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
purifications. 1H and 13C NMR spectra were recorded with
tetramethylsilane as an internal reference. High-resolution mass
spectrometry (HRMS) analysis was recorded by electrospray
ionization (ESI-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 glass plates (15 × 50 mm), and spots
were visualized by UV light at 254 or 365 nm. Alkynes 6 were
purchased or prepared according to the literature.8 Substrates 5 were
either commercially available or prepared by following literature
procedures.9
8-Methoxy-2-(propylamino)naphthalene-1,4-dione (5m). Red
1
solid. H NMR (300 MHz, CDCl3): δ 7.74 (d, J = 7.4 Hz, 1H),
7.61 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.02 (brs, 1H), 5.62
(s, 1H), 3.96 (s, 3H), 3.09 (m, 2H), 1.66 (m, 2H), 0.96 (t, J = 7.2 Hz,
3H).
8-(Benzyloxy)-2-(propylamino)naphthalene-1,4-dione (5n). Red
General Procedure for Preparation of 2-Amino-1,4-naph-
thoquinones 5. To a solution of naphthoquinones (5 mmol) in
MeOH (10 mL) were added amines (5 mmol) slowly. The mixture
was stirred at room temperature for 1 h, concentrated in vacuo, and
1
solid. H NMR (300 MHz, CDCl3): δ 7.78 (d, J = 7.6 Hz, 1H), 7.61
(t, J = 8.2 Hz, 1H), 7.55 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H),
7.32 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.08 (brs, 1H), 5.66
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(s, 1H), 5.26 (s, 2H), 3.11 (m, 2H), 1.71 (m, 2H), 0.99 (t, J = 7.4 Hz,
21.4 Hz), 115.1, 114.8, 114.4 (d, J = 21.7 Hz), 98.2, 21.9, 10.6. EI-MS
(m/z): 425 (M+). HRMS (EI): calcd for C27H17F2NO2 (M+),
425.1227; found, 425.1226.
3H).
1
2-(Propylamino)anthracene-1,4-dione (5o). Red solid. H NMR
(300 MHz, CDCl3): δ 8.56 (s, 2H), 7.98 (d, J = 7.4 Hz, 2H), 7.59 (m,
2H), 6.00 (brs, 1H), 5.84 (s, 1H), 3.16 (m, 2H), 1.72 (m, 2H), 1.02 (t,
J = 7.3 Hz, 3H).
2-Methyl-3-(propylamino)naphthalene-1,4-dione (5p). Red solid.
1H NMR (300 MHz, CDCl3): δ 8.04 (d, J = 7.6 Hz, 1H), 7.95 (d, J =
7.8 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 5.72
(brs, 1H), 3.48 (m, 2H), 2.20 (s, 3H), 1.64 (m, 2H), 0.97 (t, J = 7.4
Hz, 3H).
2-Phenyl-3-(propylamino)naphthalene-1,4-dione (5q). Red solid.
1H NMR (300 MHz, CDCl3): δ 8.11 (dd, J = 7.7, 0.8 Hz, 1H), 8.06
(m, 1H), 7.71 (td, J = 7.5, 1.3 Hz, 1H), 7.60 (td, J = 7.5, 1.3 Hz, 1H),
7.33 (m, 5H), 5.95 (brs, 1H), 2.55 (m, 2H), 1.35 (m, 2H), 0.69 (t, J =
7.4 Hz, 3H).
9-Ethyl-4,5-bis(4-ethylphenyl)benzo[4,5]chromeno[7,6-d]oxazole
(7ae). Yellow solid, 108 mg (61%). mp = 141−143 °C. 1H NMR (300
MHz, CDCl3): δ 7.58 (d, J = 7.8 Hz, 1H), 7.25 (m, 4H), 7.19 (s, 1H),
7.15 (m, 3H), 7.01 (d, J = 8.2 Hz, 2H), 6.50 (d, J = 7.0 Hz, 1H), 3.02
(q, J = 7.6 Hz, 2H), 2.68 (q, J = 7.6 Hz, 2H), 2.57 (q, J = 7.6 Hz, 2H),
1.49 (t, J = 7.6 Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H), 1.17 (t, J = 7.6 Hz,
3H). 13C NMR (101 MHz, CDCl3): δ 168.1, 150.0, 149.9, 144.7,
143.5, 138.5, 133.6, 132.5, 131.4, 130.9, 128.8, 128.7, 128.6, 127.2,
120.5, 120.1, 115.8, 115.7, 98.3, 28.6 (2), 22.3, 15.4, 15.2, 11.1. EI-MS
(m/z): 445 (M+). HRMS (EI): calcd for C31H27NO2 (M+), 445.2042;
found, 445.2040.
9-Ethyl-4,5-bis(4-methoxyphenyl)benzo[4,5]chromeno[7,6-d]-
1
oxazole (7af). Yellow solid, 86 mg (48%). mp = 150−151 °C. H
NMR (300 MHz, CDCl3): δ 7.57 (d, J = 8.3 Hz, 1H), 7.25 (m, 3H),
7.15 (m, 3H), 6.92 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 6.49
(d, J = 7.4 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.02 (q, J = 7.6 Hz,
2H), 1.49 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 168.1,
159.5, 158.8, 150.0, 149.8, 140.5, 138.5, 133.7, 132.2, 130.3, 128.7,
127.6, 126.5, 120.4, 120.0, 115.7, 115.4, 114.7, 114.6, 113.1, 98.2, 55.2
(2), 22.3, 11.1. EI-MS (m/z): 449 (M+). HRMS (EI): calcd for
C29H23NO4 (M+), 449.1627; found, 449.1631.
5-Methoxy-2-(propylamino)naphthalene-1,4-dione (5r). Red
solid. H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 7.6 Hz, 1H),
1
7.51 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 5.61 (s, 1H), 5.57
(brs, 1H), 3.94 (s, 3H), 3.06 (m, 2H), 1.65 (m, 2H), 0.96 (t, J = 7.4
Hz, 3H).
2-(Pyrrolidin-1-yl)naphthalene-1,4-dione (5s). Red solid. 1H NMR
(300 MHz, CDCl3): δ 7.99 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 7.4 Hz,
1H), 7.62 (t, J = 6.9 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 5.65 (s, 1H),
3.83 (m, 2H), 3.38 (m, 2H), 1.93 (m, 4H).
9-Ethyl-4,5-bis(4-(trifluoromethyl)phenyl)benzo[4,5]chromeno-
[7,6-d]oxazole (7ag). Yellow solid, 149 mg (71%). mp = 181−183 °C.
1H NMR (400 MHz, CDCl3): δ 7.70 (d, J = 8.1 Hz, 3H), 7.50 (d, J =
General Procedure for Synthesis of Naphthoxazole Deriv-
atives. A solution of 2-amino-1,4-naphthoquinones 5 (0.4 mmol),
alkynes 6 (0.6 mmol), [Cp*RhCl2]2 (0.05 equiv), AgSbF6 (0.2 equiv),
and Cu(OAc)2·H2O (0.8 mmol) in t-AmOH (2 mL) was stirred in
sealed glass tubes (10 mL) at 120 °C for 6 h. The reaction was then
cooled to room temperature, diluted with EtOAc, and filtered. The
filtrate was concentrated in vacuo and purified by column
chromatography using petroleum ether/ethyl acetate (v/v = 2:1) to
give the oxazole derivatives 7.
9-Ethyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole (7aa).
Yellow solid, 113 mg (73%). mp = 153−155 °C. 1H NMR (300
MHz, CDCl3): δ 7.60 (d, J = 8.4 Hz, 1H), 7.33 (m, 5H), 7.20 (m, 7H),
6.49 (d, J = 7.4 Hz, 1H), 3.03 (q, J = 7.6 Hz, 2H), 1.50 (t, J = 7.6 Hz,
3H). 13C NMR (126 MHz, CDCl3): δ 168.2, 150.0 (2), 140.7, 138.6,
135.3, 134.0, 133.2, 131.1, 129.1, 129.0, 128.7, 128.6, 127.7, 127.6,
120.6, 120.1, 116.3, 116.1, 115.8, 98.5, 22.4, 11.1. EI-MS (m/z): 389
(M+). HRMS (EI): calcd for C27H19NO2 (M+), 389.1416; found,
389.1418.
9-Ethyl-4,5-di-p-tolylbenzo[4,5]chromeno[7,6-d]oxazole (7ab).
Yellow solid, 110 mg (66%). mp = 133−135 °C. 1H NMR (400
MHz, CDCl3): δ 7.62 (d, J = 8.3 Hz, 1H), 7.27 (m, 5H), 7.17 (m, 3H),
7.03 (d, J = 8.1 Hz, 2H), 6.53 (m, 1H), 3.06 (q, J = 7.6 Hz, 2H), 2.42
(s, 3H), 2.32 (s, 3H), 1.53 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 168.1, 150.0, 149.9, 140.5, 138.5, 138.4, 137.1, 133.5, 132.3,
131.2, 130.9, 129.8, 128.8, 128.6, 128.4, 120.5, 120.0, 115.8, 115.6,
98.3, 22.3, 21.3 (2), 11.1. EI-MS (m/z): 417 (M+). HRMS (EI): calcd
for C29H23NO2 (M+), 417.1729; found, 417.1734.
8.3 Hz, 2H), 7.42 (d, J = 8.2 Hz, 4H), 7.32 (t, J = 7.9 Hz, 1H), 7.21 (s,
1H), 6.45 (d, J = 7.3 Hz, 1H), 3.07 (q, J = 7.6 Hz, 2H), 1.54 (t, J = 7.6
Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 168.5, 149.4, 149.0, 140.9,
138.7, 137.0, 132.0, 131.5, 130.7 (q, J = 32.8 Hz), 130.3 (q, J = 32.5
Hz), 129.3, 128.7, 126.4 (d, J = 3.6 Hz), 125.0 (d, J = 3.7 Hz), 124.0
(q, J = 273.2 Hz), 123.7 (q, J = 273.6 Hz), 120.4, 120.1, 117.1, 116.5,
116.0, 99.1, 22.4, 11.1. EI-MS (m/z): 525 (M+). HRMS (EI): calcd for
C29H17F6 NO2 (M+), 525.1163; found, 525.1159.
9-Ethyl-4,5-di(thiophen-2-yl)benzo[4,5]chromeno[7,6-d]oxazole
(7ah). Yellow solid, 83 mg (52%). mp = 205−206 °C. 1H NMR (300
MHz, CDCl3): δ 7.59 (t, J = 5.6 Hz, 2H), 7.26 (m, 3H), 7.19 (s, 2H),
7.07 (m, 1H), 6.94 (m, 1H), 6.48 (d, J = 7.3 Hz, 1H), 3.02 (q, J = 7.6
Hz, 2H), 1.49 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
168.2, 149.1, 146.8, 140.8, 138.5, 135.6, 135.2, 133.5, 129.9, 128.8,
128.7, 128.4, 128.3, 128.2, 126.7, 119.8, 119.7, 116.2, 116.1, 107.2,
98.8, 22.3, 11.1. EI-MS (m/z): 401 (M+). HRMS (EI): calcd for
C23H15NO2S2 (M+), 401.0544; found, 401.0536.
9-Ethyl-4,5-dipropylbenzo[4,5]chromeno[7,6-d]oxazole (7ai).
1
Yellow solid, 86 mg (67%). mp = 72−73 °C. H NMR (300 MHz,
CDCl3): δ 7.55 (d, J = 8.3 Hz, 1H), 7.36 (m, 1H), 6.99 (s, 1H), 6.79
(d, J = 7.3 Hz, 1H), 2.99 (q, J = 7.6 Hz, 2H), 2.40 (m, 4H), 1.70 (m,
2H), 1.56 (m, 2H), 1.46 (t, J = 7.6 Hz, 3H), 1.01 (m, 6H). 13C NMR
(126 MHz, CDCl3): δ 167.9, 152.9, 150.0, 140.3, 138.3, 132.1, 128.7,
120.8, 120.2, 114.9, 112.6, 110.6, 97.7, 32.7, 28.4, 22.3, 21.3, 21.1, 14.3,
13.9, 11.1. EI-MS (m/z): 321 (M+). HRMS (EI): calcd for C21H23NO2
(M+), 321.1729; found, 321.1727.
4,5-Bis(4-chlorophenyl)-9-ethylbenzo[4,5]chromeno[7,6-d]-
1
oxazole (7ac). Yellow solid, 114 mg (64%). mp = 162−164 °C. H
4-Butyl-9-ethyl-5-phenylbenzo[4,5]chromeno[7,6-d]oxazole
1
(7aj). Yellow solid, 92 mg (63%). mp = 88−90 °C. H NMR (300
NMR (300 MHz, CDCl3): δ 7.61 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.3
Hz, 2H), 7.24 (m, 2H), 7.18 (m, 4H), 7.14 (m, 2H), 6.43 (d, J = 7.4
Hz, 1H), 3.02 (q, J = 7.6 Hz, 2H), 1.49 (t, J = 7.6 Hz, 3H). 13C NMR
(101 MHz, CDCl3): δ 168.3, 149.5, 149.1, 140.7, 138.6, 134.7, 133.8,
133.5, 132.4, 132.1, 130.2, 129.6, 128.6, 128.1, 120.3, 120.0, 116.6,
115.7, 115.5, 98.7, 22.3, 11.1. EI-MS (m/z): 457 (M+). HRMS (EI):
calcd for C27H17Cl2NO2 (M+), 457.0636; found, 457.0633.
MHz, CDCl3): δ 7.64 (d, J = 8.3 Hz, 1H), 7.55 (m, 2H), 7.44 (m, 4H),
7.06 (s, 1H), 6.93 (d, J = 7.3 Hz, 1H), 3.01 (q, J = 7.6 Hz, 2H), 2.42
(m, 2H), 1.59 (m, 2H), 1.48 (t, J = 7.6 Hz, 3H), 1.33 (m, 2H), 0.86 (t,
J = 7.3 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 168.1, 150.6, 150.0,
140.5, 138.5, 134.8, 131.8, 129.0, 128.9, 128.7, 128.3, 120.9, 120.2,
115.9, 113.7, 112.8, 98.2, 30.3, 26.8, 22.8, 22.3, 13.8, 11.1. EI-MS (m/
z): 369 (M+). HRMS (EI): calcd for C25H23NO2 (M+), 369.1729;
found, 369.1723.
9-Ethyl-4,5-bis(4-fluorophenyl)benzo[4,5]chromeno[7,6-d]-
1
oxazole (7ad). Yellow solid, 102 mg (60%). mp = 155−157 °C. H
NMR (300 MHz, CDCl3): δ 7.61 (d, J = 8.1 Hz, 1H), 7.27 (m, 3H),
7.18 (d, J = 5.5 Hz, 2H), 7.14 (s, 1H), 7.08 (t, J = 8.2 Hz, 2H), 6.88 (t,
J = 8.5 Hz, 2H), 6.45 (d, J = 7.2 Hz, 1H), 3.02 (q, J = 7.5 Hz, 2H),
1.49 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 167.8, 162.1
(d, J = 250 Hz), 161.8 (d, J = 248 Hz), 149.2, 148.9, 140.2, 138.2,
132.4, 132.3 (d, J = 8.0 Hz), 130.5 (d, J = 3.6 Hz), 130.4 (d, J = 8.3
Hz), 129.5 (d, J = 3.2 Hz), 128.2, 119.9, 119.6, 115.9, 115.9 (d, J =
9-Ethyl-4-methyl-5-propylbenzo[4,5]chromeno[7,6-d]oxazole
1
(7ak). Yellow solid, 44 mg (38%). mp = 75−77 °C. H NMR (300
MHz, CDCl3): δ 7.57 (dd, J = 8.3, 0.7 Hz, 1H), 7.39 (m, 1H), 7.02 (s,
1H), 6.75 (d, J = 6.6 Hz, 1H), 3.00 (q, J = 7.6 Hz, 2H), 2.44 (m, 2H),
1.94 (s, 3H), 1.72 (m, 2H), 1.47 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.4
Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 167.9, 152.5, 150.0, 140.3,
138.4, 133.0, 128.8, 120.3, 119.9, 115.1, 112.5, 106.1, 97.8, 32.9, 22.4,
4557
dx.doi.org/10.1021/jo500572u | J. Org. Chem. 2014, 79, 4553−4560

The Journal of Organic Chemistry
Article
21.1, 13.8, 12.3, 11.2. EI-MS (m/z): 293 (M+). HRMS (EI): calcd for
C19H19NO2 (M+), 293.1416; found, 293.1416.
120.2, 116.3, 116.2, 115.7, 98.7, 34.4, 28.7. EI-MS (m/z): 417 (M+).
HRMS (EI): calcd for C29H23NO2 (M+), 417.1729; found, 417.1728.
9-Cyclopropyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole
(7ia). Yellow solid, 149 mg (93%). mp = 203−205 °C. 1H NMR (400
MHz, CDCl3): δ 7.60 (d, J = 8.3 Hz, 1H), 7.39 (m, 3H), 7.34 (m, 2H),
7.28 (m, 3H), 7.21 (m, 3H), 7.14 (s, 1H), 6.51 (d, J = 7.3 Hz, 1H),
2.30 (m, 1H), 1.35 (m, 2H), 1.23 (m, 2H). 13C NMR (126 MHz,
CDCl3): δ 168.6, 150.0, 140.2, 138.9, 135.3, 134.1, 133.2, 131.1, 129.1,
129.0, 128.6, 128.5, 127.7, 127.6, 120.3, 119.9, 116.3, 116.0, 115.5,
98.3, 9.6, 9.3. EI-MS (m/z): 401 (M+). HRMS (EI): calcd for
C28H19NO2 (M+), 401.1416; found, 401.1414.
9-Ethyl-5-methyl-4-propylbenzo[4,5]chromeno[7,6-d]oxazole
1
(7ak′). Yellow solid, 43 mg (37%). mp = 86−88 °C. H NMR (400
MHz, CDCl3): δ 7.58 (d, J = 8.2 Hz, 1H), 7.40 (m, 1H), 7.03 (s, 1H),
6.81 (d, J = 7.3 Hz, 1H), 3.03 (q, J = 7.6 Hz, 2H), 2.41 (m, 2H), 2.16
(s, 3H), 1.60 (m, 2H), 1.51 (t, J = 7.6 Hz, 3H), 1.04 (t, J = 7.4 Hz,
3H). 13C NMR (126 MHz, CDCl3): δ 167.9, 149.9, 149.4, 140.4,
138.3, 132.0, 128.7, 120.8, 120.2, 114.9, 112.3, 110.6, 97.8, 28.6, 22.3,
20.8, 17.1, 14.2, 11.1. EI-MS (m/z): 293 (M+). HRMS (EI): calcd for
C19H19NO2 (M+), 293.1416; found, 293.1415.
4,5-Diphenyl-9-propylbenzo[4,5]chromeno[7,6-d]oxazole (7ba).
Yellow solid, 96 mg (60%). mp = 123−125 °C. 1H NMR (300
MHz, CDCl3): δ 7.60 (d, J = 8.4 Hz, 1H), 7.32 (m, 5H), 7.23 (m, 6H),
7.18 (s, 1H), 6.49 (d, J = 7.4 Hz, 1H), 2.97 (t, J = 7.5 Hz, 2H), 1.98
(m, 2H), 1.08 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ
167.2, 150.0, 149.9, 140.6, 138.6, 135.3, 134.0, 133.2, 131.1, 129.1,
129.0, 128.7, 128.6, 127.7, 127.6, 120.6, 120.1, 116.3, 116.2, 115.8,
98.5, 30.7, 20.5, 13.9. EI-MS (m/z): 403 (M+). HRMS (EI): calcd for
C28H21NO2 (M+), 403.1572; found, 403.1563.
9-((3r,5r,7r)-Adamantan-1-yl)-4,5-diphenylbenzo[4,5]chromeno-
[7,6-d]oxazole (7ja). Yellow solid, 126 mg (64%). mp = 141−143 °C.
1H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 1H), 7.40 (m,
3H), 7.35 (m, 2H), 7.29 (m, 3H), 7.22 (m, 4H), 6.52 (d, J = 7.3 Hz,
1H), 2.26 (m, 6H), 2.19 (s, 3H), 1.88 (m, 6H). 13C NMR (101 MHz,
CDCl3): δ 173.1, 150.0, 149.8, 140.3, 138.4, 135.3, 134.0, 133.1, 131.1,
129.1, 129.0, 128.5, 127.7, 127.6, 120.5, 120.1, 116.2, 115.6, 98.6, 40.4,
36.5, 36.3, 28.0. EI-MS (m/z): 495 (M+). HRMS (EI): calcd for
C35H29NO2 (M+), 495.2198; found, 495.2197.
9-Butyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole (7ca).
Yellow solid, 105 mg (63%). mp = 107−108 °C. 1H NMR (300
MHz, CDCl3): δ 7.61 (d, J = 8.3 Hz, 1H), 7.28 (m, 12H), 6.49 (d, J =
7.4 Hz, 1H), 2.99 (t, J = 7.6 Hz, 2H), 1.92 (m, 2H), 1.49 (m, 2H),
0.99 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 167.4, 150.0,
149.9, 140.6, 138.6, 135.3, 134.0, 133.1, 131.1, 129.1, 128.9, 128.6,
128.5, 127.7, 127.6, 120.5, 120.1, 116.2, 116.1, 115.7, 98.5, 29.1, 28.5,
22.3, 13.7. EI-MS (m/z): 417 (M+). HRMS (EI): calcd for C29H23NO2
(M+), 417.1729; found, 417.1735.
tert-Butyl(2-(4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazol-9-
yl)ethyl)(methyl)carbamate (7ka). Yellow solid, 93 mg (45%). mp =
1
143−145 °C. H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.3 Hz,
1H), 7.39 (m, 3H), 7.34 (m, 2H), 7.29 (m, 3H), 7.23 (m, 3H), 7.19 (s,
1H), 6.55 (d, J = 7.4 Hz, 1H), 3.81 (t, J = 6.8 Hz, 2H), 3.24 (m, 2H),
2.93 (m, 3H), 1.43 (m, 9H). 13C NMR (126 MHz, CDCl3): δ 164.6,
155.4, 150.1, 150.0, 140.8, 138.6, 135.3, 134.0, 133.2, 131.1, 129.1,
129.0, 128.8, 128.6, 127.7 (2), 120.7, 120.2, 116.3, 116.2, 116.0, 98.5,
79.8, 47.0, 34.4, 29.7, 28.4. EI-MS (m/z): 518 (M+). HRMS (EI):
calcd for C33H30N2O4 (M+), 518.2206; found, 518.2205.
9-Isobutyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole (7da).
1
Yellow solid, 90 mg (54%). mp = 125−127 °C. H NMR (300 MHz,
4,5-Diphenyl-9-((tetrahydro-2H-pyran-4-yl)methyl)benzo[4,5]-
chromeno[7,6-d]oxazole (7la). Yellow solid, 150 mg (82%). mp =
CDCl3): δ 7.61 (d, J = 8.4 Hz, 1H), 7.33 (m, 5H), 7.25 (m, 3H), 7.18
(m, 4H), 6.50 (d, J = 7.4 Hz, 1H), 2.87 (d, J = 7.2 Hz, 2H), 2.35 (m,
1H), 1.07 (d, J = 6.7 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 166.7,
150.0, 149.9, 140.6, 138.6, 135.3, 134.0, 133.2, 131.1, 129.1, 129.0,
128.6, 128.5, 127.7, 127.6, 120.6, 120.1, 116.2 (2), 115.7, 98.5, 37.7,
27.7, 22.5. EI-MS (m/z): 417 (M+). HRMS (EI): calcd for C29H23NO2
(M+), 417.1729; found, 417.1721.
1
140−142 °C. H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 7.7 Hz,
1H), 7.36 (m, 3H), 7.30 (m, 3H), 7.22 (m, 5H), 7.15 (s, 1H), 6.51 (d,
J = 6.9 Hz, 1H), 3.98 (dd, J = 11.4, 3.0 Hz, 2H), 3.44 (td, J = 11.7, 1.6
Hz, 2H), 2.94 (d, J = 7.1 Hz, 2H), 2.25 (m, 1H), 1.74 (d, J = 11.3 Hz,
2H), 1.50 (m, 2H). 13C NMR (126 MHz, CDCl3): δ 167.0, 151.5,
142.1, 140.0, 136.7, 135.4, 134.6, 132.5, 130.6, 130.4, 130.2, 130.0,
129.2, 129.1, 122.1, 121.5, 117.7, 117.6, 117.3, 99.9, 69.2, 37.4, 35.5,
34.3. EI-MS (m/z): 459 (M+). HRMS (EI): calcd for C31H25NO3
(M+), 459.1834; found, 459.1833.
9-Pentyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole (7ea).
1
Yellow solid, 115 mg (67%). mp = 90−91 °C. H NMR (300 MHz,
CDCl3): δ 7.61 (d, J = 8.3 Hz, 1H), 7.26 (m, 12H), 6.49 (d, J = 7.3 Hz,
1H), 2.98 (t, J = 7.7 Hz, 2H), 1.94 (m, 2H), 1.42 (m, 4H), 0.93 (t, J =
6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 167.4, 150.0, 149.9,
140.6, 138.6, 135.3, 134.0, 133.2, 131.1, 129.1, 129.0, 128.6, 128.5,
127.7, 127.6, 120.5, 120.1, 116.2, 116.1, 115.7, 98.5, 31.4, 28.8, 26.7,
22.3, 13.9. EI-MS (m/z): 431 (M+). HRMS (EI): calcd for C30H25NO2
(M+), 431.1885; found, 431.1894.
9-Ethyl-1-methoxy-4,5-diphenylbenzo[4,5]chromeno[7,6-d]-
1
oxazole (7ma). Yellow solid, 78 mg (47%). mp = 157−158 °C. H
NMR (300 MHz, CDCl3): δ 7.29 (m, 8H), 7.17 (m, 3H), 6.67 (d, J =
8.2 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 3.98 (s, 3H), 3.05 (q, J = 7.6 Hz,
2H), 1.50 (t, J = 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 168.6,
151.1, 150.0, 147.6, 139.9, 139.6, 135.6, 134.1, 131.1, 129.1, 128.8,
128.2, 127.7, 127.6, 125.8, 122.0, 116.3, 116.2, 113.0, 107.2, 99.9, 55.9,
22.3, 11.1. EI-MS (m/z): 419 (M+). HRMS (EI): calcd for C28H21NO3
(M+), 419.1521; found, 419.1521.
9-Phenethyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole
(7fa). Yellow solid, 141 mg (76%). mp = 163−165 °C. 1H NMR (300
MHz, CDCl3): δ 7.61 (d, J = 8.3 Hz, 1H), 7.28 (m, 17H), 6.51 (d, J =
7.3 Hz, 1H), 3.29 (m, 4H). 13C NMR (101 MHz, CDCl3): δ 166.3,
150.0, 140.6, 140.2, 138.5, 135.2, 134.0, 133.2, 131.1, 129.1, 128.9,
128.7, 128.6, 128.5, 128.3, 127.7, 127.6, 126.5, 120.6, 120.1, 116.2,
116.1, 115.8, 98.5, 33.1, 30.7. EI-MS (m/z): 465 (M+). HRMS (EI):
calcd for C33H23NO2 (M+), 465.1729; found, 465.1728.
9-Isopropyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole
(7ga). Yellow solid, 153 mg (95%). mp = 180−181 °C. 1H NMR (400
MHz, CDCl3): δ 7.66 (d, J = 8.3 Hz, 1H), 7.40 (m, 3H), 7.34 (m, 2H),
7.29 (m, 3H), 7.23 (m, 4H), 6.54 (d, J = 7.3 Hz, 1H), 3.35 (m, 1H),
1.55 (d, J = 7.0 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ 171.4,
150.0, 149.9, 140.6, 138.5, 135.3, 134.1, 133.2, 131.1, 129.1, 129.0,
128.6 (2), 127.7, 127.6, 120.6, 120.2, 116.3, 116.2, 115.8, 98.6, 29.1,
20.6. EI-MS (m/z): 403 (M+). HRMS (EI): calcd for C28H21NO2
(M+), 403.1572; found, 403.1566.
1-(Benzyloxy)-9-ethyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]-
1
oxazole (7na). Yellow solid, 91 mg (46%). mp = 179−181 °C. H
NMR (300 MHz, CDCl3): δ 7.64 (d, J = 7.3 Hz, 2H), 7.39 (m, 6H),
7.29 (m, 2H), 7.24 (m, 2H), 7.19 (m, 4H), 6.75 (d, J = 8.2 Hz, 1H),
6.41 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H), 3.04 (q, J = 7.5 Hz, 2H), 1.49 (t,
J = 7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 168.4, 150.0 (2),
147.8, 140.0, 139.6, 137.0, 135.6, 134.1, 131.1, 129.1, 128.8, 128.5,
128.3, 127.8, 127.7, 127.6, 126.9, 126.1, 122.0, 116.2, 113.4, 108.7,
99.9, 70.3, 22.4, 11.0. EI-MS (m/z): 495 (M+). HRMS (EI): calcd for
C34H25NO3 (M+), 495.1834; found, 495.1839.
10-Ethyl-5,6-diphenylnaphtho[1′,2′,3′:4,5]chromeno[7,6-d]-
1
oxazole (7oa). Red solid, 151 mg (86%). mp = 171−173 °C. H
NMR (300 MHz, CDCl3): δ 8.19 (s, 1H), 7.79 (d, J = 8.1 Hz, 1H),
7.27 (m, 3H), 7.22 (m, 6H), 7.16 (m, 2H), 7.05 (m, 2H), 6.77 (m,
1H), 3.06 (q, J = 7.6 Hz, 2H), 1.52 (t, J = 7.6 Hz, 3H). 13C NMR (126
MHz, CDCl3: δ 167.8, 153.2, 150.8, 140.3, 138.9, 137.3, 134.6 (2),
131.4, 129.3, 128.9, 128.6, 128.3, 127.7, 127.4, 126.9, 126.0, 123.7,
122.9, 121.3, 118.8, 117.5, 115.9, 96.5, 22.4, 11.3. EI-MS (m/z): 439
(M+). HRMS (EI): calcd for C31H21NO2 (M+), 439.1572; found,
439.1570.
9-(tert-Butyl)-4,5-diphenylbenzo[4,5]chromeno[7,6-d]oxazole
(7ha). Yellow solid, 123 mg (74%). mp = 186−188 °C. 1H NMR (400
MHz, CDCl3): δ 7.67 (d, J = 8.2 Hz, 1H), 7.40 (m, 3H), 7.35 (m, 2H),
7.29 (m, 3H), 7.22 (m, 4H), 6.54 (d, J = 7.3 Hz, 1H), 1.58 (s, 9H).
13C NMR (126 MHz, CDCl3): δ 173.6, 150.0, 149.9, 140.6, 138.5,
135.4, 134.1, 133.2, 131.2, 129.1, 129.0, 128.6 (2), 127.7, 127.6, 120.6,
4558
dx.doi.org/10.1021/jo500572u | J. Org. Chem. 2014, 79, 4553−4560

The Journal of Organic Chemistry
Article
9-Ethyl-7-methyl-4,5-diphenylbenzo[4,5]chromeno[7,6-d]-
101-035, 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, were also appreciated.
1
oxazole (7pa). Yellow solid, 112 mg (70%). mp = 168−169 °C. H
NMR (300 MHz, CDCl3): δ 7.57 (d, J = 8.4 Hz, 1H), 7.36 (m, 5H),
7.26 (d, J = 8.5 Hz, 2H), 7.19 (m, 4H), 6.45 (d, J = 7.3 Hz, 1H), 3.04
(q, J = 7.6 Hz, 2H), 2.57 (s, 3H), 1.49 (t, J = 7.6 Hz, 3H). 13C NMR
(126 MHz, CDCl3): δ 167.6, 149.5, 146.2, 139.9, 138.8, 135.5, 134.3,
132.7, 131.1, 129.1, 128.7, 128.3, 127.6, 127.5, 127.4, 120.3, 118.1,
116.1, 116.0, 115.6, 108.1, 22.4, 11.4, 9.9. EI-MS (m/z): 403 (M+).
HRMS (EI): calcd for C28H21NO2 (M+), 403.1572; found, 403.1573.
9-Ethyl-4,5,7-triphenylbenzo[4,5]chromeno[7,6-d]oxazole (7qa).
Yellow solid, 165 mg (89%). mp = 197−199 °C. 1H NMR (300 MHz,
CDCl3): δ 7.87 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.48 (m,
2H), 7.38 (m, 4H), 7.27 (m, 3H), 7.19 (d, J = 7.9 Hz, 2H), 7.10 (m,
3H), 6.52 (d, J = 7.4 Hz, 1H), 3.03 (q, J = 7.6 Hz, 2H), 1.47 (t, J = 7.5
Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 167.8, 149.4, 145.5, 140.6,
137.8, 135.5, 133.7, 133.6, 133.0, 131.1, 130.6, 129.3, 128.8, 128.4,
128.0, 127.7, 127.5, 127.4, 120.6, 119.4, 116.4, 116.2, 116.1, 112.6,
22.5, 11.5. EI-MS (m/z): 465 (M+). HRMS (EI): calcd for C33H23NO2
(M+), 465.1729; found, 465.1727.
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1
tate (8aa). Yellow solid, 21 mg (12%). mp = 133−135 °C. H NMR
(300 MHz, CDCl3): δ 7.65 (d, J = 8.3 Hz, 1H), 7.35 (m, 5H), 7.23 (m,
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ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of NMR spectra of all new compounds and substrates 5,
X-ray single-crystal analysis, and the kinetic isotope effect
experiment. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: aozhang@simm.ac.cn.
■
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
■
This work was supported by grants of the Chinese National
Sciences Foundation (81125021, 81373277), National Science
& Technology Major Project on “Key New Drug Creation and
Manufacturing Program”, China (Numbers: 2012ZX09103-
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