Reaction of 1-nitroso-2-naphthols with α-functionalized ketones and related compounds: The unexpected formation of decarbonylated 2-substituted naphtho[1,2-d][1,3]oxazoles

Article abstract of DOI:10.1021/jo3022956

Reactions between 1-nitroso-2-naphthols and α-functionalized ketones such as α-bromo-, α-chloro-, α-mesyloxy-, α-tosyloxy-, and α-hydroxy ketones under basic conditions delivered 2-substituted naphtho[1,2-d][1,3]oxazoles in a single synthetic operation. T

Full text of DOI:10.1021/jo3022956

Article
pubs.acs.org/joc
Reaction of 1‑Nitroso-2-naphthols with α‑Functionalized Ketones
and Related Compounds: The Unexpected Formation of
Decarbonylated 2‑Substituted Naphtho[1,2‑d][1,3]oxazoles
Nayyef Aljaar,† Chandi C. Malakar,† Jurgen Conrad,† Wolfgang Frey,‡ and Uwe Beifuss†,*
̈
†Bioorganische Chemie, Institut fur Chemie, Universitat Hohenheim, Garbenstraße 30, D-70599 Stuttgart, Germany
̈
̈
‡Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Reactions between 1-nitroso-2-naphthols and
α-functionalized ketones such as α-bromo-, α-chloro-, α-mesyloxy-,
α-tosyloxy-, and α-hydroxy ketones under basic conditions
delivered 2-substituted naphtho[1,2-d][1,3]oxazoles in a single
synthetic operation. The product formation was accompanied by
the unexpected loss of the CO group from the α-functionalized
ketones. With aryl bromides, allyl bromides, α-bromo diketones,
α-bromo cyanides, α-bromoesters, and α-bromo ketoesters as
substrates the formation of naphtho[1,2-d][1,3]oxazoles was also
observed. The transformations were performed in 1,2-dichloro-
ethane or acetonitrile under reflux and gave the corresponding naphthoxazoles with yields ranging between 52% and 85%.
PTP-1B inhibitors,8 lysophosphatidic acid acyltransferase-β
INTRODUCTION
■
inhibitors,9 5-HT3 receptor partial agonists,10 estrogen receptor-
β agonists,11 and melatonin receptor agonists.12 In addition,
annulated oxazoles are increasingly gaining importance in
materials science, especially in the field of fluorescent materials.13
Consequently, the development of synthetic methods for the
preparation of functionalized annulated oxazoles has received
considerable attention.14 To date, various methods have
been reported for the synthesis of 2-alkylated and 2-arylated
benzoxazoles, as well as related heterocycles. Among the
more traditional approaches are reactions between 2-amino-
phenols and carboxylic acid derivatives, such as carboxylic
acids,15a,c,d,g−i carboxylic acid chlorides,15b,d,e carboxylic acid
anhydrides,15f and carboxylic amides;15h,i reactions between
2-aminophenols and aldehydes followed by oxidation;16
intramolecular cyclizations of N-(2-haloaryl)carboxamides
under strong basic conditions;17 and the ring contraction
of 1,4-benzoxazinones.18 More recently, a number of Cu-
catalyzed approaches to the benzoxazole ring system have
been discovered, including the intramolecular cyclization of
N-(2-haloaryl)carboxamides,19 the intramolecular oxidative
C−O coupling of N-(2-aryl)carboxamides,20 the reaction
between 1,2-dihaloarenes and carboxamides,21 as well as the
reaction between 2-bromoanilines and acyl chlorides.21a There is
also a couple of methods that are based on the functionaliza-
tion of the 2-position of the benzoxazole ring. They include a
number of Pd-catalyzed cross-coupling reactions22 as well as the
A number of natural products containing benzoxazole or
naphthoxazole moieties are known,1 including the antimyco-
bacterial pseudopteroxazole from the West Indian gorgonian
coral Pseudopterogorgia elisabethae,2 UK-1 from Streptomyces sp.
517-02,3 AJI9561 from Streptomyces sp. AJ9561,4 salviamine B
and isosalviamine E from Salvia yunnanensis,5a as well as
salvianen and neosalvianen from Salvia mitiorrhiza5b (Figure 1).
Figure 1. Natural products with annulated oxazole moieties.
Special Issue: Robert Ireland Memorial Issue
Received: October 16, 2012
Benzoxazoles and naphthoxazoles exhibit a wide range of phar-
macologically important biological activities. They have been
shown to act as cathepsin inhibitors,6 topoisomerase II inhibitors,7
© XXXX American Chemical Society
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Scheme 1. Unexpected Formation of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a)
transition-metal-catalyzed direct arylation of benzoxazoles with
activated aryls.23 Another approach to 2-alkylated and 2-arylated
annulated oxazoles is based on the reaction of o-hydroxy nitroso
aryls with alkyl halides and benzyl halides.24 However, it seems
that scope and limitations of this method have not been explored
in depth. Apart from the synthesis of 2-alkylated and 2-arylated
derivatives, the preparation of annulated oxazoles carrying a
functional group such as a carbonyl, an ester, or a nitrile group at
C-2 is also of great interest.14,25
Table 1. Optimization of the Reaction between 1-Nitroso-2-
naphthol (1a) and α-Bromo Acetophenone (2a)
Here, we report the preparation of 2-arylated as well as
2-functionalized naphthoxazoles from the reaction of 1-nitroso-
2-naphthols with α-functionalized ketones, α-bromo diketones,
aryl bromides, allyl bromides, α-bromo cyanides, α-bromoest-
ers, and α-bromo ketoesters.
molar
ratio
yield of
entry
1a:2a
base (equiv)
solvent
THF
T (°C) t (h) 3a (%)
1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
2:1
2:1
2:1
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
K3PO4 (3)
Cs2CO3 (3)
reflux
reflux
reflux
reflux
85
6.5
3
40
55
32
43
42
41
53
49
24
37
70
80
72
58
2
C2H4Cl2
CH3COCH3
CH3CN
DMF
3
3
RESULTS AND DISCUSSION
4
3
■
5
3
Inspired by earlier results showing that benzyl bromides can
undergo reaction with 1-nitroso-2-naphthols to produce 2-aryl-
substituted naphtho[1,2-d][1,3]oxazoles,24 we envisioned that
2-aroyl naphtho[1,2-d][1,3]oxazoles could be obtained in a
similar fashion if the benzyl bromides were replaced with α-
functionalized acetophenones. To synthesize the 2-benzoyl-
substituted naphtho[1,2-d][1,3]oxazole 4a, the reaction
between 1 equiv of 1-nitroso-2-naphthol (1a) and 2 equiv of
α-bromo acetophenone (2a) was performed. It was found
that after 3 h at reflux in 1,2-dichloroethane under basic
conditions the nitrosonaphthol was fully consumed. How-
ever, it came as a surprise when, instead of the expected
2-benzoylnaphtho[1,2-d][1,3]oxazole (4a), the corresponding
2-phenylated compound 3a was isolated as the sole product in
55% (Scheme 1).
6
o-C6H4Cl2
C2H4Cl2
C2H4Cl2
85
3
7
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
4
8
4.5
3
9
C2H5ONa (3) C2H4Cl2
10
11
12
13
14
NaOH (3)
K2CO3 (3)
K2CO3 (3)
K2CO3 (2)
K2CO3 (1)
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
C2H4Cl2
3
3
3
3
3
than that observed with K2CO3 (Table 1, entry 2). Then, the
influence of the ratio of 1a and 2a on the outcome of the
reaction was studied (Table 2, entries 1, 11, and 12).
Interestingly, the yield of 3a could be increased to 70% and
80%, respectively, when the ratio of 1a and 2a was changed
from 1:2 to 1:1 and 2:1, respectively. Best results were observed
when a 2:1 mixture of 1a and 2a was employed (Table 1,
entry 12). Under these conditions, 3a could be isolated in 80%
yield. Reduction of the amount of K2CO3 to 2 and 1 equiv,
respectively, was associated with a drop of the yield (Table 1,
entries 13 and 14). Remarkably enough, under all reaction con-
ditions the decarbonylated product 3a was formed exclusively.
Not even a trace of ketone 4a was formed.
Although the mechanism of the transformation is not known
in detail (vide infra), it is clear that Br⊖ acts as a leaving group.
This is why we studied whether the Br atom in 2a can be
replaced by other typical leaving groups. As expected, α-chloro
acetophenone (2b) can also be employed as a substrate (Table
2, entry 1). However, the yield of 3a dropped to 60%. The Br
atom can also be replaced by a mesyloxy as well as a tosyloxy
group. The yield of 3a amounted to 76% and 85%, respectively
This unexpected result implies that the reaction between 1a
and 2a is accompanied by a decarbonylation. As most of
the few decarbonylations of ketones need to be performed
in the presence of transition metals26 or under photochemical
conditions,27 it was decided to study the reaction between
2-nitroso-1-naphthols 1 and α-functionalized acetophenones 2
in greater detail. First, the model reaction between 1a and 2a
was optimized with regard to solvent, base, the amount of base,
and the ratio of the starting materials (Table 1). It was found
that the transformation can be performed not only in 1,2-
dichloroethane but also in a number of other solvents including
tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide,
and o-dichlorobenzene (Table 1, entries 1−6). However, in no
case did the yield exceed that obtained in 1,2-dichloroethane
(Table 1, entry 2). It was also possible to replace K2CO3 by
other bases, such as K3PO4, Cs2CO3, C2H5ONa, and NaOH
(Table 1, entries 7−10). Again, the yields were always lower
B
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group of 2 can be disregarded as both electron-donating and
electron-withdrawing groups gave similar results. Furthermore, it
was established that the oxazole formation can also be performed
with bromomethyl 2-naphthyl ketone (2q) and bromomethyl
1-pyrenyl ketone (2r) as the substrates (Table 3, entries 10 and 11).
The reaction also tolerates the use of substituted nitrosonaphthols
such as 6-methoxy-1-nitroso-2-naphthol (1b) (Table 3, entry 12).
In another set of experiments it was studied whether the
bromomethyl aryl ketones can be replaced with other func-
tional groups (Table 4). The reactions of 1a with 1-bromo-
3-methyl-2-butene (2s) and 1-bromo-4-methyl-3-pentene-2-
one (2t) clearly demonstrated that allyl bromides as well as
bromomethyl vinyl ketones can be employed as substrates.
With both starting materials, the 2-vinylated naphthoxazole 3n
was isolated (Table 4, entries 1 and 2). The transformation with
bromo acetonitrile (2u) produces 3o in 75% and therefore is an
interesting alternative for the synthesis of 2-cyano oxazole
moieties (Table 4, entry 3). Finally, the transformations with the
α-bromoester 2v and the α-bromo ketoester 2w were studied.
It turned out that with both substrates the same product, namely,
the naphtho[1,2-d][1,3]oxazole-2-carboxylic acid ethyl ester (3p),
was formed exclusively (Table 4, entries 4 and 5).
With respect to the reaction mechanism, it is assumed that
the transformation starts with the reaction of 1a (in the form
of its o-quinone oxime tautomer) with the α-bromoketone 2a
to give the oxime ether 5. This is followed by rearrangement
of 5 to the corresponding nitrone 6, which after deprotonation
to 7 undergoes ring closure to the 3-benzoylated oxaziridine 8
(Scheme 3). Intramolecular nucleophilic 1,2-attack of the
phenolate on the CO double bond of 8 triggers the opening
of the oxaziridine ring to yield 9, which in turn results in the
formation of the 1,3-oxazetidine 11. The cleavage of formic
acid is the final step of the sequence (11 → 3a) and delivers the
2-phenylated naphthoxazole 3a.28
Table 2. Synthesis of 3a Using Different α-Functionalized
Acetophenones
a
entry
2
X
t (h)
yield of 3a (%)
b
1
2
3
4
b
c
Cl
5
60
c
OMs
OTs
OH
6.5
9
76
c
d
e
85
c
4
73
a
b
2 mmol of 1a was reacted with 1 mmol of 2. The reaction was
c
performed in 1,2-dichloroethane. The reaction was performed in
acetonitrile.
(Table 2, entries 2 and 3). Remarkably, α-hydroxy acetophenone
2e could also be used as starting material (Table 2, entry 4).
Despite the finding that with the α-tosyloxy ketone 2d the yield
of 3a was slightly better than with the α-bromo ketone 2a as the
substrate, all further reactions were performed with α-bromo-
functionalized compounds.
With optimized reaction conditions available, two control
reactions were performed. First, 1a was reacted with benzyl
bromide (2f) as the substrate to yield 3a as the only product
in 68% (Scheme 2). This result is in good agreement with the
Scheme 2. Two Control Experiments
So far, there is no proof for the reaction mechanism
presented. However, it is supported by a number of experi-
ments. First of all it seems that no radicals are involved as the
reaction of 1a with 2a in the presence of 1 equiv of the radical
scavenger 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic
acid under standard conditions resulted in the formation of
3a in 78%. Then, it was excluded that the α-functionalized
ketones 2 undergo decarbonylation under reaction conditions.
For this purpose, α-bromo acetophenone (2a) was treated with
3 equiv of K2CO3 in C2H4Cl2 in the absence of 1a. After 3 h
under reflux 92% of the starting material was recovered. This
result clearly demonstrates that 2a is stable under reaction
conditions. A similar observation was made with bromomethyl
phenyl diketone (2g): after treatment with 3 equiv of K2CO3 in
refluxing C2H4Cl2 for 3 h, 2g was reisolated with 95%.
To prove that the quinone oxime ether 5 can act as an inter-
mediate for the oxazole formation, we set out to synthesize the
compound. For this purpose, 1a and 2a were reacted in the
presence of 2.3 equiv of triethyl amine in dry methanol at room
temperature for 3 h (Scheme 4). Under these conditions,
the oxime ether 5 was formed with 76% yield. The structure
of 5 was confirmed by X-ray crystal structure analysis.29 The
exclusive formation of a quinone oxime ether is rather unusual
as the reaction between an o-quinone oxime and an alkylating
or benzylating agent is expected to produce the corresponding
nitrone as the main product.24c,30 When 5 was reacted under
the conditions of the oxazole formation, i.e., 3 equiv of K2CO3,
C2H4Cl2, reflux, 3 h, the oxazole 3a was formed with 75% yield
(Scheme 4). This experiment proves (a) that 5 can act as an
results of Yao and Hung.24a Next, 1a was reacted with
bromomethyl phenyl diketone (2g). It came as a big surprise to
us when again 3a was the only product formed, this time in
73% yield. This finding implies that the transformation with the
diketone proceeds with the formal loss of two CO groups.
As far as we know such loss of two CO groups has not been
reported before.
To evaluate the scope of the new transformation, the reac-
tion of 1 with several bromomethyl aryl ketones was conducted.
First, bromomethyl phenyl ketones 2h−p carrying different
substituents on the phenyl ring were studied. It was found that
a number of substituents, including methyl-, methoxy-, halo-,
cyano-, and methoxycarbonyl substituents, were tolerated (Table 3,
entries 1−9). The yields of 3b−j were in the range of 65−78%. It
seems that the electronic effects of the substituent(s) on the phenyl
C
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intermediate for the oxazole formation and (b) that the
decarbonylation takes place after the formation of 5.
and to react it under standard conditions. For this purpose,
2-phenacylpyridinium bromide 1231 was reacted with 1-nitroso-
2-naphthol (1a) according to the procedure of Lown and
Moser to give the desired material (Scheme 5).32 2-Benzoyl
To study the loss of the CO group in more detail, it was
decided to synthesize 2-benzoylnaphtho[1,2-d][1,3]oxazole (4a)
a
Table 3. Reaction of 1a,b with 2h−r for the Synthesis of 2-Aryl-Substituted Naphtho[1,2-d][1,3]oxazoles 3b−m
D
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Table 3. continued
a
2 mmol of 1 was reacted with 1 mmol of 2.
naphtho[1,2-d][1,3]oxazole (4a) was then treated with 3 equiv
of K2CO3 in C2H4Cl2. After reflux for 3 h, the starting material
4a was recovered in 95%. This experiment clearly demonstrates
that 4a cannot be considered as an intermediate in the for-
mation of 2-phenylnaphtho[1,2-d][1,3]oxazole (3a) from 1a and
2a. Even if the reaction mechanism for the unexpected formation
of decarbonylated 2-substituted naphtho[1,2-d][1,3]oxazoles
from the reaction of 1-nitroso-2-naphthols with α-functionalized
ketones and related compounds could not be elucidated in detail,
a number of experiments support the mechanism presented in
Scheme 3.
To find out whether the new transformation is restricted to
1-nitroso-2-naphthols 1, the regioisomer 2-nitroso-1-naphthol
(13) was also employed as a substrate (Scheme 6). Not unexpected,
the decarbonylated product, namely, 2-phenylnaphtho[2,1-d]-
[1,3]oxazole (14), was isolated in 45% yield.
spin systems: 6H, 7H, 8H, and 9H (ring A), 4H and 5H (ring B),
and 2′H−6′H (ring D). To assign the structure we used gHMBC
to fix the positions of the five quaternary carbon C-2, C-3a, C-5a,
C-9a, and C-9b, which link the three aromatic rings (A, B, and D).
It was shown by the gHMBC spectrum that ring D is attached
3
to ring C at carbon C-2 at δ = 162.3, which showed strong JCH
correlations to protons 2′-H and 6′-H. Ring B is linked to ring C
3
at C-5a and C-9a, which can be confirmed by the strong JCH
correlations from C-5a to protons 4-H, 7-H, and 9-H, as well as
from C-9a to protons 6-H and 8-H. Ring B is connected with ring
C via C-3a and C-9b, as shown by 3JCHcorrelations from C-3a to
the proton 5-H, whereas C-9b correlates to protons 4-H and 9-H
(Figure 2).
CONCLUSIONS
■
In summary, we have developed an efficient method for the
synthesis of 2-substituted naphtho[1,2-d][1,3]oxazoles by reaction
between 1-nitroso-2-naphthols and α-functionalized ketones, such
as α-bromo-, α-chloro-, α-mesyloxy-, α-tosyloxy-, and α-hydroxy
ketones, under basic conditions in a single synthetic operation.
The formation of naphtho[1,2-d][1,3]oxazoles also took place
The structures of all naphtho[1,2-d][1,3]oxazoles were
unambiguously elucidated by NMR spectroscopy and mass
spectrometry. Full assignment of the 1H and 13C chemical shifts
was achieved by evaluating their gCOSY, gHSQC, and gHMBC
1
spectra. For example, 3a has three scalar coupled aromatic H
E
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a
Table 4. Synthesis of Various 2-Substituted Naphtho[1,2-d][1,3]oxazoles
a
2 mmol of 1a was reacted with 1 mmol of 2.
in KMnO4 solution followed by heating. Products were purified by
flash chromatography on silica gel, 0.04−0.063 mm. Melting points
were obtained on a melting point apparatus with open capillary
tubes and are uncorrected. IR spectra were measured on a FT-IR
spectrometer. UV spectra were recorded with a spectrophotometer.
1H (13C) NMR spectra were recorded at 300 (75) and 500 (125)
MHz using CDCl3 as the solvent. The 1H and 13C chemical shifts were
referenced to residual solvent signals at δ H/C 7.26/77.00 (CDCl3)
relative to TMS as internal standard. HSQC, HMBC, NOESY,
ROESY, HSQMBC, and COSY spectra were recorded on a NMR
spectrometer at 500 or 300 MHz. Coupling constants J [Hz] were
directly taken from the spectra and are not averaged. Splitting patterns
are designated as s (singlet), d (doublet), t (triplet), q (quartet), quin
(quintet), m (multiplet), and br (broad). 1D and 2D homonuclear
NMR spectra were measured with standard pulse sequences. Low-
resolution electron impact mass spectra (MS) and exact mass electron
impact mass spectra (HRMS) were obtained at 70 eV using a double-
focusing sector field mass spectrometer. Intensities are reported as
percentages relative to the base peak (I = 100%).
with aryl bromides, allyl bromides, α-bromo diketones, α-bromo
cyanides, α-bromoesters, and α-bromo ketoesters as substrates.
The product formation was accompanied by the unexpected loss
of the CO group when α-functionalized ketones, α-function-
alized diketones, and α-bromo ketoesters were used as starting
materials. The method not only provides an efficient and reliable
access to numerous 2-substituted annulated oxazoles but also
is one of the few examples of a metal -free decarbonylation of
ketones.
EXPERIMENTAL SECTION
■
General Remarks. All commercially available reagents were used
without further purification. Glassware was dried for 4 h at 140 °C.
Solvents used in reactions were distilled over appropriate drying agents
prior to use. Solvents used for extraction and purification were distilled
prior to use. Reaction temperatures are reported as bath temperatures.
Thin-layer chromatography (TLC) was performed on TLC silica gel
60 F254. Compounds were visualized with UV light (λ = 254 nm)
and/or by immersion in an ethanolic vanillin solution or by immersion
General Procedure I for the Preparation of Compounds 3a−m.
A mixture of the 1-nitroso-2-naphthol 1 (2 mmol), the bromomethyl
F
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Scheme 3. Proposed Reaction Mechanism for the Formation of 2-Substituted Naphtho[1,2-d][1,3]oxazoles
General Procedure II for the Preparation of Compounds
3n−p. A mixture of 1-nitroso-2-naphthol (1a) (346 mg, 2 mmol),
substrate 2 (1 mmol), and K2CO3 (417 mg, 3 mmol) in dry CH3CN
(5 mL) was refluxed under argon until the starting material 2 was
consumed (TLC). After cooling to room temperature, the reaction
mixture was poured into water and extracted with ether (3 × 30 mL).
The combined organic extracts were washed with brine (30 mL). After
drying over anhydrous MgSO4 and concentration in vacuo the resulting
residue was purified by flash chromatography over silica gel to afford the
desired product.
Scheme 4. Synthesis of the Proposed Intermediate 5 and Its
Cyclization to 3a
Synthesis of Starting Materials. α-Tosyloxy acetophenone,33
α-mesyloxy acetophenone,34 bromomethyl phenyl diketone,35 1-bromo-
4-methyl-3-pentene-2-one,36 6-methoxy-1-nitroso-2-naphthol,37 methyl
4-(2-bromoacetyl)benzoate,38 and bromomethyl 1-pyrenyl ketone39
were prepared according to the literature.
Synthesis of 2-Substituted Naphtho[1,2-d][1,3]oxazoles 3.
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a).16b
According to the general procedure I, a mixture of 1-nitroso-2-naphthol
(1a) (346 mg, 2 mmol), 2-bromo acetophenone (2a) (199 mg, 1 mmol),
and K2CO3 (417 mg, 3 mmol) in dry 1,2-dichloroethane (5 mL) was
refluxed under argon for 3 h. Flash chromatography over silica gel
(cyclohexane/EtOAc = 20:1) gave 3a as a yellow solid in 80% yield
(196 mg, 0.80 mmol): mp 135136 °C (lit.16b mp 133135 °C); Rf =
0.56 (cyclohexane/EtOAc = 3:1); UV (MeCN) λmax (log ε) 343 (4.25),
330 (4.29), 302 (4.20), 291 (4.21) nm; 1H NMR (300 MHz, CDCl3) δ
7.54 (partially overlapped, 3H, 3′-H, 4′-H and 5′-H), 7.56 (partially
overlapped, 1H, 7-H), 7.69 (ddd, 4J (6-H, 8-H) = 1.2 Hz, 3J (7-H, 8-H) =
aryl ketone 2 (1 mmol), and K2CO3 (417 mg, 3 mmol) in dry
1,2-dichloroethane (5 mL) was refluxed under argon until the
starting material 2 was consumed (TLC). After cooling to room
temperature, the reaction mixture was poured into water and
extracted with ether (3 × 30 mL). The combined organic extracts
were washed with brine (30 mL). After drying over anhydrous
MgSO4 and concentration in vacuo the resulting residue was puri-
fied by flash chromatography over silica gel to afford the desired
product.
3
3
7.0 Hz, J (8-H, 9-H) = 8.0 Hz, 1H, 8-H), 7.74 (d, J (4-H, 5-H) =
3
8.9 Hz, 1H, 4-H), 7.81 (brd, J (4-H, 5-H) = 8.9 Hz, 1H, 5-H), 7.98
G
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Scheme 5. Synthesis of 2-Benzoylnaphtho[1,2-d][1,3]oxazole (4a) and Its Behavior under Standard Conditions
110.8, 122.3, 124.8, 125.3, 125.7, 126.5, 126.9, 127.3, 128.5, 129.6,
131.2, 137.7, 141.5, 147.9, 162.6.
Scheme 6. Synthesis of 2-Phenylnaphtho[2,1-d][1,3]oxazole
(13)
Synthesis of 2-(2-Methoxyphenyl)naphtho[1,2-d][1,3]oxazole
(3c).16b
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), 2-bromo-2′-methoxyaceto-
phenone (2i) (230 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol)
in dry 1,2-dichloroethane (5 mL) was refluxed under argon for 4.5
h. Flash chromatography over silica gel (cyclohexane/EtOAc =
10:1) gave 3c as a yellow solid in 76% yield (210 mg, 0.76 mmol):
mp 103104 °C (lit.16b mp 102 °C); Rf = 0.26 (cyclohexane/
1
EtOAc = 3:1); H NMR (300 MHz, CDCl3) δ 4.05 (s, 3H),
7.087.16 (m, 2H), 7.477.57 (m, 2H), 7.67 (ddd, 4J = 0.9 Hz,
3J = 7.2 Hz, 3J = 7.8 Hz, 1H), 7.76 (d, 3J = 8.9 Hz, 1H), 7.81 (d,
3J = 8.9 Hz, 1H), 7.97 (d, 3J = 8.2 Hz, 1H), 8.22 (dd, 4J = 1.6 Hz,
3J = 7.8 Hz, 1H), 8.63 (d, 3J = 8.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 56.2, 110.9, 112.1, 116.7, 120.8, 122.4, 125.2, 125.8,
126.6, 126.8, 128.5, 131.1, 131.3, 132.4, 137.4, 147.9, 158.2, 161.1.
Synthesis of 2-(4-Methoxyphenyl)naphtho[1,2-d][1,3]oxazole
(3d).16b
Figure 2. Important gHMBC correlations (H→C) of 3a (green arrow:
3J gHMBC).
3
(brd, J (6-H, 7-H) = 7.9 Hz, 1H, 6-H), 8.318.38 (m, 2H, 2′-H and
3
6′-H), 8.61 (brd, J (8-H, 9-H) = 8.4 Hz, 1H, 9-H); 13C NMR (75
MHz, CDCl3) δ 110.8 (C-4), 122.3 (C-9), 125.4 (C-7), 126.0 (C-5),
126.6 (C-9a), 126.9 (C-8), 127.3 (C-2′), 127.5 (C-1′), 128.6 (C-6),
128.9 (C-3′), 131.0 (C-4′), 131.2 (C-5a), 137.6 (C-9b), 148.0 (C-3a),
162.3 (C-2).
Synthesis of 2-(4-Methylphenyl)naphtho[1,2-d][1,3]oxazole
(3b).16b
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), 2-bromo-4′-methoxyacetophenone
(2j) (230 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 4.5 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave 3d
as a yellow solid in 78% yield (215 mg, 0.78 mmol): mp 116117 °C
(lit.16b mp 116118 °C); Rf = 0.36 (cyclohexane/EtOAc = 3:1);
1H NMR (300 MHz, CDCl3) δ 3.89 (s, 3H), 7.037.06
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), 2-bromo-4′-methylacetophenone
(2h) (213 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 4 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave 3b
as a yellow solid in 74% yield (192 mg, 0.74 mmol): mp 167169 °C
4
3
3
(m, 2H), 7.54 (ddd, J = 0.9 Hz, J = 7.0 Hz, J = 7.9 Hz, 1H),
(lit.16b mp 168170 °C); Rf = 0.58 (cyclohexane/EtOAc = 3:1); H
1
3
3
7.647.68 (m, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.7 Hz,
3
NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 7.35 (d, J = 8.1 Hz, 2H),
3
4
3
3
4
1H), 7.96 (d, 3J = 8.2 Hz, 1H), 8.258.28 (m, 2H), 8.58 (d, J = 8.2
7.55 (ddd, J = 1.0 Hz, J = 7.0 Hz, J = 8.1 Hz, 1H), 7.67 (ddd, J =
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 55.4, 110.7, 114.3, 120.1,
122.2, 125.2, 125.4, 126.4, 126.8, 128.5, 129.0, 131.2, 137.7, 147.8,
162.0, 162.5.
3
3
3
0.9 Hz, J = 7.3 Hz, J = 8.2 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.80
3
3
3
(d, J = 8.9 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 8.2 Hz,
2H), 8.59 (d, J = 8.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 21.6,
3
H
dx.doi.org/10.1021/jo3022956 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Synthesis of 2-(3-Bromophenyl)naphtho[1,2-d][1,3]oxazole
(5 mL) was refluxed under argon for 5 h. Flash chromatography over
silica gel (cyclohexane/EtOAc = 20:1) gave 3g as a yellow solid in
69% yield (193 mg, 0.69 mmol): mp 189190 °C (lit.41 mp 188
189 °C); Rf = 0.50 (cyclohexane/EtOAc = 3:1); 1H NMR (300 MHz,
(3e).16b
3
CDCl3) δ 7.507.58 (m, 3H), 7.68 (d, J = 7.4 Hz, 1H), 7.72 (d,
3J = 8.9 Hz, 1H), 7.82 (d, 3J = 8.9 Hz, 1H), 7.98 (d, 3J = 8.1 Hz, 1H),
3
3
8.26 (d, J = 8.6 Hz, 2H), 8.57 (d, J = 8.1 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 110.7, 122.2, 125.5, 126.0, 126.3, 126.5, 127.1,
128.55, 128.59, 129.2, 131.2, 137.2, 137.6, 148.1, 161.3.
Synthesis of 2-(3,4-Dichlorophenyl)naphtho[1,2-d][1,3]oxazole
(3h).
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), 2-bromo-3′-bromoacetophenone
(2k) (278 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 4.5 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave 3e
as a yellow solid in 66% yield (214 mg, 0.66 mmol): mp 199200 °C
(lit.16b mp 199 °C); Rf = 0.49 (cyclohexane/EtOAc = 3:1); H NMR
1
3
4
(300 MHz, CDCl3) δ 7.41 (dt, J = 7.9 Hz, 1H), 7.57 (ddd, J = 0.9
Hz, 3J = 7.0 Hz, 3J = 7.9 Hz, 1H), 7.65 (d, 3J = 8.2 Hz, 1 H), 7.70 (d,
3J = 7.6 Hz, 1H), 7.73 (d, 3J = 8.9 Hz, 1H), 7.83 (d, 3J = 8.9 Hz, 1H),
According to the general procedure I, a mixture of 1-nitroso-2-naphthol
(1a) (346 mg, 2 mmol), 2-bromo-3′,4′-dichloroacetophenone (2n) (268
mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-dichloroethane
(5 mL) was refluxed under argon for 5 h. Flash chromatography over
silica gel (cyclohexane/EtOAc = 20:1) gave 3h as a yellow solid in 65%
yield (205 mg, 0.65 mmol): mp 167168 °C; Rf = 0.56 (cyclohexane/
3
3
7.98 (d, J = 8.2 Hz, 2H), 8.26 (d, J = 7.8 Hz, 1H), 8.49 (brs, 1H),
8.58 (d, 3J = 8.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 110.8, 122.2,
123.0, 125.5, 125.8, 126.5, 126.6, 127.2, 128.6, 129.4, 130.2, 130.4,
131.3, 133.9, 137.5, 148.2, 160.7.
Synthesis of 2-(4-Fluorophenyl)naphtho[1,2-d][1,3]oxazole
(3f).40
EtOAc = 3:1); IR (ATR) ν
̃
1465 (CN), 1377, 1232 (C−O), 1137,
1091, 1060, 1028, 879, 812, 798, 760, 741, 722 cm−1; UV (MeCN) λmax
1
(log ε) 337 (4.41), 306 (4.22), 295 (1.50), 291 (4.19) nm; H NMR
(300 MHz, CDCl3) δ 7.57 (ddd, 4J (7-H, 9-H) = 1.3 Hz, 3J (7-H, 8-H) =
7.0 Hz, 3J (6-H, 7-H) = 8.3 Hz, 1H, 7-H), 7.62 (d, 3J (5′-H, 6′-H) =
8.5 Hz, 1H, 5′-H), 7.69 (ddd, 4J (6-H, 8-H) = 1.2 Hz, 3J (7-H,
8-H) = 6.9 Hz, 3J (8-H, 9-H) = 8.2 Hz, 1H, 8-H), 7.72 (d, 3J (4-H, 5-
H) = 8.9 Hz, 1H, 4-H), 7.84 (brd, 3J (4-H,5-H) = 8.9 Hz, 1H, 5-H),
3
4
7.98 (brd, J (6-H, 7-H) = 8.3 Hz, 1H, 6-H), 8.15 (dd, J (2′-H, 6′-
3
4
H) = 2.1 Hz, J (5′-H, 6′-H) = 8.5 Hz, 1H, 6′-H), 8.42 (d, J (2′-H,
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), 2-bromo-4′-fluoroacetophenone
(2l) (217 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 4.5 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave 3f as
a yellow solid in 68% yield (178 mg, 0.68 mmol): mp 168169 °C
(lit.40 mp 170171.5 °C); Rf = 0.65 (cyclohexane/EtOAc = 3:1); IR
3
6′-H) = 2.0 Hz, 1H, 2′-H), 8.56 (brd, J (8-H, 9-H) = 8.2 Hz, 1H,
9-H); 13C NMR (75 MHz, CDCl3) δ 110.7 (C-4), 122.2 (C-9),
125.7 (C-7), 126.3 (C-6′), 126.5 (C-9a), 126.7 (C-5), 127.3 (C-8),
127.4 (C-1′), 128.6 (C-6), 129.0 (C-2′), 131.0 (C-5′), 131.3 (C-5a),
133.5 (C-3′), 135.3 (C-9b), 137.5 (C-4′), 148.2 (C-3a), 160.1 (C-2);
MS (EI, 70 eV) m/z 313 (16) [M+], 278 (6) [M  Cl]+ 250 (4),
214 (3), 156 (5), 114 (23), 88 (4); HRMS (EI, M+) calcd for
C17H9Cl2NO (313.0061), found 313.0044.
(ATR) ν
̃
1465 (CN), 1227 (C−O), 1151, 1007, 1060, 799, 732,
715 cm−1; UV (MeCN) λmax (log ε) 343 (4.30), 329 (4.33), 302
1
Synthesis of 2-(4-Cyanophenyl)naphtho[1,2-d][1,3]oxazole (3i).
(4.26), 291 (4.25) nm; H NMR (300 MHz, CDCl3) δ 7.207.26
(m, 2H, 2′-H and 6′-H), 7.55 (ddd, 4J (7-H, 9-H) = 0.8 Hz, 3J (7-H, 8-
H) = 7.0 Hz, 3J (6-H, 7-H) = 8.1 Hz, 1H, 7-H), 7.67 (brd, 3J (7-H, 8-
3
H) = 7.3 Hz, 1H, 8-H), 7.72 (brd J (4-H, 5-H) = 8.9 Hz, 1H, 4-H),
7.80 (brd, 3J (4-H, 5-H) = 8.9 Hz, 1H, 5-H), 7.97 (d, 3J (6-H, 7-H) =
8.2 Hz, 1H, 6-H), 8.308.35 (m, 2H, 3′-H and 5′-H), 8.57 (brd,
3J (8-H, 9-H) = 8.2 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3) δ
110.7 (C-4), 116.1 (d, J (19F, 13C) = 22.0 Hz, C-3′), 122.2 (C-9),
2
123.7 (d, 4J (19F, 13C) = 3.3 Hz, C-1′), 125.4 (C-7), 126.0 (C-5), 126.5
(C-9a), 127.0 (C-8), 128.6 (C-6), 129.5 (d, 3J (19F, 13C) = 8.9 Hz, C-
2′), 131.2 (C-5a), 137.6 (C-9b), 148.0 (C-3a), 161.4 (C-2), 164.5 (d,
1J (19F, 13C) = 251 Hz, C-4′); MS (EI, 70 eV) m/z 263 (100) [M+],
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), 4′-(2-bromoacetyl)benzonitrile
(2o) (224 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 5.5 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 10:1) gave 3i as
a yellow solid in 71% yield (193 mg, 0.71 mmol): mp 221222 °C;
235 (4); HRMS (EI, M+) calcd for C17H10FNO (263.0746), found
263.0744.
Synthesis of 2-(4-Chlorophenyl)naphtho[1,2-d][1,3]oxazole
(3g).41
Rf = 0.35 (cyclohexane/EtOAc = 3:1); IR (ATR) ν
̃
2232 (CN),
1492 (CN), 1372, 1237 (C−O), 1090, 1053, 1008, 878, 848, 817,
749, 736 cm−1; UV (MeCN) λmax (log ε) 347 (4.29), 309 (3.99), 299
(4.00) nm; 1H NMR (300 MHz, CDCl3) δ 7.59 (ddd, 4J (7-H, 9-H) =
1.2 Hz, 3J (7-H, 8-H) = 6.9 Hz, 3J (6-H, 7-H) = 8.2 Hz, 1H, 7-H), 7.71
(ddd, 4J (6-H, 8-H) = 1.2 Hz, 3J (7-H, 8-H) = 7.0 Hz, 3J (8-H, 9-H) =
8.2 Hz, 1H, 8-H), 7.74 (d, 3J (4-H, 5-H) = 9.0 Hz, 1H, 4-H), 7.82 (d-
like, 3J (2′-H, 3′-H) = 8.5 Hz, 2H, 3′-H and 5′-H), 7.86 (brd, 3J (4-H,
5-H) = 9.1 Hz, 1H, 5-H), 7.99 (brd, 3J (6-H, 7-H) = 8.2 Hz, 1H, 6-H),
3
According to the general procedure I, a mixture of 1-nitroso-2-naphthol
(1a) (346 mg, 2 mmol), 2-bromo-4′-chloroacetophenone (2m) (233 mg,
1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-dichloroethane
8.41 (d-like, J (2′-H, 3′-H) = 8.5, 2H, 2′-H and 6′-H), 8.57 (brd,
3J (8-H, 9-H) = 8.3 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3) δ
110.8 (C-4), 114.2 (C-4′), 118.3 (CN), 122.2 (C-9), 125.8 (C-7),
I
dx.doi.org/10.1021/jo3022956 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
126.6 (C-9a), 127.3 (C-5), 127.4 (C-8), 127.6 (C-2′), 128.7 (C-6),
131.34 (C-5a), 131.38 (C-1′), 132.7 (C-3′), 137.6 (C-9b), 148.4
(C-3a), 160.1 (C-2); MS (EI, 70 eV) m/z 270 (100) [M+], 242
(3) [M  CO]+, 121 (4), 114 (17); HRMS (EI; M+) calcd for
C18H10N2O (270.0793), found 270.0803.
1,2-dichloroethane (5 mL) was refluxed under argon for 10 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave 3l as
a blue solid in 71% yield (261 mg, 0.71 mmol): mp 149150 °C;
Rf = 0.45 (cyclohexane/EtOAc = 3:1); IR (ATR) ν
̃
1524 (CN),
1226 (C−O), 1109, 1073, 1008, 832, 792, 704 cm−1; UV (MeCN)
Synthesis of 4-Naphtho[1,2-d][1,3]oxazol-2-yl-benzoic Acid
λmax (log ε) 573 (2.97), 413 (4.25), 393 (4.41), 289 (4.38), 238 (4.53)
Methyl Ester (3j).24a
1
4
nm; H NMR (500 MHz, CDCl3) δ 7.59 (ddd, J (7-H, 9-H) = 1.1
3
3
Hz, J (7-H, 8-H) = 6.8 Hz, J (6-H, 7-H) = 8.3 Hz, 1H, 7-H), 7.74
(brdd, 3J (8-H, 9-H) = 6.0 Hz, 3J (7-H, 8-H) = 7.1 Hz, 1H, 8-H), 7.80
(d, 3J (4-H, 5-H) = 8.6 Hz, 1H, 4-H), 7.83 (d, 3J (4-H, 5-H) = 8.6 Hz,
3
1H, 5-H), 8.01 (brd, J (6-H, 7-H) = 8.6 Hz, 1H, 6-H), 8.04 (dd,
3J (6′-H, 7′-H) = 6.8 Hz, 3J (7′-H, 8′-H) = 8.3 Hz 1H, 7′-H), 8.07 (d,
3J (4′-H, 5′-H) = 8.5 Hz, 1H, 4′-H), 8.14 (d, 3J (4′-H, 5′-H) = 8.5 Hz,
3
1H, 5′-H), 8.22 (d, J (6′-H, 7′-H) = 8.8 Hz, 1H, 6′-H), 8.23 (d,
3J (2′-H, 3′-H) = 7.6 Hz, 1H, 3′-H), 8.27 (d, 3J (7′-H, 8′-H) = 9.2 Hz,
3
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), methyl 4′-(2-bromoacetyl)benzoate
(2p) (258 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 5.5 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 10:1) gave 3j as
a yellow solid in 71% yield (215 mg, 0.71 mmol): mp 202203 °C;
Rf = 0.36 (cyclohexane/EtOAc = 3:1); 1H NMR (300 MHz, CDCl3) δ
3.97 (s, 3H), 7.57 (ddd, 4J = 1.3 Hz, 3J = 7.0 Hz, 3J = 7.9 Hz, 1H), 7.68
1H, 8′-H), 8.31 (d, J (9′-H, 10′-H) = 9.7 Hz, 1H, 9′-H), 8.76 (d,
3J (8-H, 9-H) = 7.9 Hz, 1H, 9-H), 8.89 (d, J (2′-H, 3′-H) = 8.5 Hz,
3
1H, 2′-H), 9.93 (d, 3J (9′-H, 10′-H) = 9.2 Hz, 1H, 10′-H); 13C NMR
(125 MHz, CDCl3) δ 110.8 (C-4), 120.5 (C-1′), 122.5 (C-9), 124.4
(C-10′c), 124.7 (C-3′), 125.1 (C-10′b), 125.4 (C-7), 125.5 (C-10′),
125.9 (C-8′), 126.1 (C-6′), 126.3 (C-7′), 126.7 (C-9a), 127.0
(C-8), 127.2 (C-4′), 127.3 (C-2′), 128.6 (C-6), 129.1 (C-5′), 129.4
(C-9′), 129.6 (C-10′a), 130.7 (C-8′a), 131.20 (C-5′a), 131.23 (C-5a),
133.2 (C-3′a), 138.0 (C-9b), 147.7 (C-3a), 162.7 (C-2); MS (EI,
70 eV) m/z 369 (100) [M+], 313 (3), 227 (12), 200 (4), 154 (6),
114 (8); HRMS (EI; M+) calcd for C27H15NO (369.1154), found
369.1159.
3
3
3
(d, J = 7.3 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 8.9 Hz,
1H), 7.98 (d, 3J = 8.1 Hz, 1H), 8.20 (d, 3J = 8.4 Hz, 2H), 8.39 (d, 3J =
8.4 Hz, 2H), 8.60 (d, 3J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
52.4, 110.8, 122.2, 125.6, 126.6, 126.8, 127.1, 127.2, 128.6, 130.1,
131.28, 131.34, 132.0, 137.7, 148.3, 161.2, 166.4.
Synthesis of 7-Methoxy-2-phenylnaphtho[1,2-d][1,3]oxazole
(3m).
Synthesis of 2-(Naphth-2-yl)naphtho[1,2-d][1,3]oxazole (3k).42
According to the general procedure I, a mixture of 6-methoxy-1-
nitroso-2-naphthol (1b) (408 mg, 2 mmol), 2-bromo acetophenone
(2a) (199 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 4 h. Flash chro-
matography over silica gel (cyclohexane/EtOAc = 20:1) gave 3m as a
yellow solid in 78% yield (216 mg, 0.78 mmol): mp 138139 °C;
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), bromomethyl 2-naphthyl ketone
(2q) (249 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 5 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave 3k
as a yellow solid in 70% yield (207 mg, 0.70 mmol): mp 153154 °C
Rf = 0.45 (cyclohexane/EtOAc = 3:1); IR (ATR) ν
̃
1595, 1530 (CN),
(lit.42 mp 154 °C); Rf = 0.54 (cyclohexane/EtOAc = 3:1); H NMR
1
1467, 1447, 1367 (C−O), 1272, 1232 (C−O), 1155, 1056, 1045,
1006, 937, 818, 776, 705 cm−1; UV (MeCN) λmax (log ε) 356 (4.19),
342 (4.13), 307 (4.19), 297 (4.26) nm; 1H NMR (300 MHz, CDCl3)
δ 3.96 (s, 3H, CH3), 7.30 (brd, 3J (6-H, 8-H) = 2.3 Hz, 1H, 6-H), 7.34
(dd, 4J (6-H, 8-H) = 2.5 Hz, 3J (8-H, 9-H) = 8.8 Hz, 1H, 8-H), 7.42
7.53 (m, 1H, 4′-H), 7.537.60 (m, 2H, 3′-H and 5′-H), 7.70 (s, 2H,
(500 MHz, CDCl3) δ 7.547.59 (m, 3H, 6′-H, 7′-H and 7-H), 7.70
(ddd, 4J (6-H, 8-H) = 1.3 Hz, 3J (7-H, 8-H) = 6.9 Hz, 3J (8-H, 9-H) =
8.1 Hz, 1H, 8-H), 7.78 (d, 3J (4-H, 5-H) = 8.9 Hz, 1H, 4-H), 7.84 (d,
3J (4-H, 5-H) = 8.9 Hz, 1H, 5-H), 7.877.91 (m, 1H, 5′-H), 7.97 (d,
3
3J (6-H, 7-H) = 8.2 Hz, 1H, 6-H), 7.98 (d, J (3′-H, 4′-H) = 8.7 Hz,
3
4
4-H and 5-H), 8.298.36 (m, 2H, 2′-H and 6′-H), 8.50 (d, J (8-H,
1H, 4′-H), 7.998.02 (m, 1H, 8′-H), 8.40 (dd, J (1′-H, 3′-H) = 1.7
9-H) = 8.9 Hz, 1H, 9-H); 13C NMR (75 MHz, CDCl3) δ 55.4 (CH3),
107.3 (C-6), 111.2 (C-4), 119.1 (C-8), 121.6 (C-9a), 123.8 (C-9),
124.7 (C-5), 127.3 (C-2′), 127.6 (C-1′), 128.9 (C-3′), 131.0 (C-4′),
132.5 (C-5a), 137.9 (C-9b), 146.9 (C-3a), 157.4 (C-7), 162.3 (C-2);
MS (EI, 70 eV) m/z 275 (100) [M+], 260 (8) [M  CH3]+, 232 (43),
138 (6), 101 (4); HRMS (EI; M+) calcd for C18H13NO2 (275.0946),
found 275.0949.
Hz, 3J (3′-H, 4′-H) = 8.5 Hz, 1H, 3′-H), 8.65 (brd, 3J (8-H, 9-H) = 8.1
Hz, 1H, 9-H), 8.84 (brs, 1H, 1′-H); 13C NMR (125 MHz, CDCl3) δ
110.7 (C-4), 122.3 (C-9), 123.9 (C-3′), 124.7 (C-2′), 125.3 (C-7),
126.0 (C-5), 126.5 (C-9a), 126.8 (C-7′), 126.9 (C-8), 127.48 (C-1′),
127.49 (C-6′), 127.9 (C-5′), 128.6 (C-6), 128.7 (C-4′), 128.8 (C-8′),
131.2 (C-5a), 133.0 (C-8′a), 134.5 (C-4′a), 137.7 (C-9b), 148.1
(C-3a), 162.4 (C-2).
Synthesis of 2-Prenylnaphtho[1,2-d][1,3]oxazole (3n).
Synthesis of 2-(Pyren-1-yl)naphtho[1,2-d][1,3]oxazole (3l).
According to the general procedure II, a mixture of 1-nitroso-
2-naphthol (1a) (346 mg, 2 mmol), prenyl bromide (2s) (149 mg,
1 mmol), and K2CO3 (417 mg, 3 mmol) in dry CH3CN (5 mL) was
refluxed under argon for 4 h. Flash chromatography over silica gel
(cyclohexane/EtOAc = 20:1) gave 3n as a colorless oil in 63% yield
According to the general procedure I, a mixture of 1-nitroso-2-
naphthol (1a) (346 mg, 2 mmol), bromomethyl 1-prenyl ketone
(2r) (324 mg, 1 mmol), and K2CO3 (209 mg, 1.5 mmol) in dry
J
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The Journal of Organic Chemistry
Article
(138 mg, 0.63 mmol): Rf = 0.35 (cyclohexane/EtOAc = 3:1); IR
111.1 (C-4), 122.4 (C-9), 126.3 (C-7), 126.9 (C-9a), 127.9 (C-8),
128.7 (C-6), 129.7 (C-5), 131.5 (C-5a), 136.5 (C-9b), 148.8 (C-3a),
151.9 (C-2), 156.5 (C-1′); MS (EI, 70 eV) m/z 241 (100) [M+], 196
(12) [M  OCH2CH3]+, 182 (13), 170 (12), 169 (80), 141 (18), 140
(12), 114 (11); HRMS (EI; M+) calcd for C14H11NO3 (241.0739),
found 241.0720.
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a) from 2-
Chloro Acetophenone (2b). According to the general procedure I,
a mixture of 1-nitroso-2-naphthol (1a) (346 mg, 2 mmol), 2-chloro
acetophenone (2b) (155 mg, 1 mmol), and K2CO3 (417 mg,
3 mmol) in dry 1,2-dichloroethane (5 mL) was refluxed under
argon for 5 h. Flash chromatography over silica gel (cyclohexane/
EtOAc = 20:1) gave 3a as a yellow solid in 60% yield (147 mg,
0.60 mmol).
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a) from 2-
Mesyloxy Acetophenone (2c). According to the general procedure
II, a mixture of 1-nitroso-2-naphthol (1a) (346 mg, 2 mmol),
2-mesyloxy acetophenone (2c) (214 mg, 1 mmol), and K2CO3
(417 mg, 3 mmol) in dry CH3CN (5 mL) was refluxed under
argon for 6.5 h. Flash chromatography over silica gel (cyclohexane/
EtOAc = 20:1) gave 3a as a yellow solid in 76% yield (186 mg,
0.76 mmol).
(ATR) ν
̃
3050 (alkene C−H), 2973, 1659 (alkene CC), 1514 (CN),
1434, 1374, 1335, 1314 (C−O), 1271, 1234 (C−O), 1202
(C−O), 1182, 1084, 1057, 1006, 931, 847, 795, 785, 744, 716 cm−1;
UV (MeCN) λmax (log ε) 341 (4.35), 326 (4.29), 300 (4.18), 289
1
(4.28) nm; H NMR (300 MHz, CDCl3) δ 2.07 (s, 3H, 3′-H), 2.43
4
(s, 3H, 4′-H), 6.38 (s, 1H, 1′-H), 7.52 (ddd, J (6-H, 8-H) = 1.1 Hz,
3J (7-H, 8-H) = 7.1 Hz, J (8-H, 9-H) = 7.9 Hz, 1H, 8-H), 7.61
3
3
(partially overlapped, 1H, 7-H), 7.65 (d, J (4-H, 5-H) = 8.6 Hz, 1H,
4-H), 7.75 (brd, 3J (4-H, 5-H) = 8.9 Hz, 1H, 5-H), 7.95 (brd, 3J (6-H,
7-H) = 8.2 Hz, 1H, 6-H), 8.51 (brd, 3J (8-H, 9-H) = 8.2 Hz, 1H, 9-H);
13C NMR (75 MHz, CDCl3) δ 21.0 (C-4′), 27.6 (C-3′), 110.7 (C-4),
112.0 (C-1′), 122.2 (C-9), 125.1 (C-8), 125.3 (C-5), 126.4 (C-9a),
126.7 (C-7), 128.5 (C-6), 131.1 (C-5a), 137.2 (C-9b), 146.9 (C-3a),
149.2 (C-2′), 162.3 (C-2); MS (EI, 70 eV) m/z 223 (100) [M+], 208
(28) [M  CH3]+, 152 (6), 114 (12); HRMS (EI; M+) calcd for
C15H13NO (223.0997), found 223.0996.
Synthesis of 2-Cyanonaphtho[1,2-d][1,3]oxazole (3o).
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a) from 2-
Tosyloxy Acetophenone (2d). According to the general procedure
II, a mixture of 1-nitroso-2-naphthol (1a) (346 mg, 2 mmol),
2-tosyloxy acetophenone (2d) (290 mg, 1 mmol), and K2CO3
(417 mg, 3 mmol) in dry CH3CN (5 mL) was refluxed under
argon for 9 h. Flash chromatography over silica gel (cyclohexane/
EtOAc = 20:1) gave 3a as a yellow solid in 85% yield (209 mg,
0.85 mmol).
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a) from 2-
Hydroxy Acetophenone (2e). According to the general procedure
II, a mixture of 1-nitroso-2-naphthol (1a) (346 mg, 2 mmol),
2-hydroxy acetophenone (2e) (136 mg, 1 mmol), and K2CO3
(417 mg, 3 mmol) in dry CH3CN (5 mL) was refluxed under argon
for 4 h. Flash chromatography over silica gel (cyclohexane/
EtOAc = 20:1) gave 3a as a yellow solid in 73% yield (179 mg,
0.73 mmol).
According to the general procedure II, a mixture of 1-nitroso-
2-naphthol (1a) (246 mg, 1 mmol), bromoacetonitrile (2u) (119 mg,
1 mmol), and K2CO3 (417 mg, 3 mmol) in dry CH3CN (5 mL) was
refluxed under argon for 3 h. Flash chromatography over silica gel
(cyclohexane/EtOAc = 8:1) gave 3o as a colorless solid in 75% yield
(145 mg, 0.75 mmol): mp 163164 °C; Rf = 0.45 (cyclohexane/
EtOAc = 3:1); IR (ATR) ν
̃
2241 (CN), 1579, 1518 (CN), 1287
(C−O), 1273, 1084, 1051, 1005, 959, 804, 786, 754, 697 cm−1; UV
1
(MeCN) λmax (log ε) 336 (4.10), 324 (4.08), 299 (4.01) nm; H
NMR (300 MHz, CDCl3) δ 7.66 (ddd, 4J (7-H, 9-H) = 1.3 Hz,
3
3J (7-H, 8-H) = 7.1 Hz, J (6-H, 7-H) = 7.9 Hz, 1H, 7-H), 7.72 (d,
3J (4-H, 5-H) = 8.9 Hz, 1H, 4-H), 7.77 (ddd, 4J (6-H, 8-H) = 1.2 Hz,
3
3J (7-H, 8-H) = 6.9 Hz, J (8-H, 9-H) = 8.0 Hz, 1H, 8-H), 8.01
3
3
(brd, J (6-H, 7-H) = 7.6 Hz, 1H, 6-H), 8.02 (brd, J (4-H, 5-H) =
8.9 Hz, 1H, 5-H), 8.52 (brd, J (8-H, 9-H) = 8.2 Hz, 1H, 9-H); 13C
3
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a) from
Benzyl Bromide (2f). According to the general procedure I, a mixture
of 1-nitroso-2-naphthol (1a) (346 mg, 2 mmol), benzylbromide (2f)
(171 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry 1,2-
dichloroethane (5 mL) was refluxed under argon for 6 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave 3a
as a yellow solid in 68% yield (167 mg, 0.68 mmol).
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a) from
Bromomethyl Phenyl Diketone (2g). According to the general
procedure I, a mixture of 1-nitroso-2-naphthol (1a) (346 mg, 2
mmol), bromomethyl phenyl diketone (2g) (227 mg, 1 mmol), and
K2CO3 (417 mg, 3 mmol) in dry 1,2-dichloroethane (5 mL) was
refluxed under argon for 10 h. Flash chromatography over silica gel
(cyclohexane/EtOAc = 20:1) gave 3a as a yellow solid in 73% yield
(178 mg, 0.73 mmol).
Synthesis of 2-Prenylnaphtho[1,2-d][1,3]oxazole (3n) from 1-
Bromo-4-methyl-3-pentene-2-one (2t). According to the general
procedure II, a mixture of 1-nitroso-2-naphthol (1a) (346 mg,
2 mmol), 1-bromo-4-methyl-3-pentene-2-one (2t) (177 mg, 1 mmol),
and K2CO3 (417 mg, 3 mmol) in dry CH3CN (5 mL) was refluxed
under argon for 8 h. Flash chromatography over silica gel (cyclohexane/
EtOAc = 20:1) gave 3n as a colorless liquid in 62% yield (139 mg,
0.62 mmol).
Synthesis of 4-Naphtho[1,2-d][1,3]oxazol-2-carboxylic Acid Ethyl
Ester (3p) from Ethyl Bromopyruvate (2w). According to the general
procedure II, a mixture of 1-nitroso-2-naphthol (1a) (346 mg,
2 mmol), ethyl bromopyruvate (2w) (195 mg, 1.0 mmol), and
K2CO3 (417 mg, 3.0 mmol) in dry CH3CN (5 mL) was refluxed
under argon for 12 h. Flash chromatography over silica gel
(cyclohexane/EtOAc = 8:1) gave 3p as a white solid in 52% yield
(125 mg, 0.52 mmol).
NMR (75 MHz, CDCl3) δ 109.4 (CN), 110.6 (C-4), 122.2 (C-9),
126.3 (C-9a), 126.9 (C-7), 128.5 (C-8), 128.8 (C-6), 130.7
(C-5), 131.7 (C-5a), 135.7 (C-9b), 136.1 (C-2), 148.7 (C-3a); MS
(EI, 70 eV) m/z 194 (100) [M+], 166 (6) [M  CO]+, 139 (4),
88 (4); HRMS (EI; M+) calcd for C12H6N2O (194.0480), found
194.0472.
Synthesis of 4-Naphtho[1,2-d][1,3]oxazol-2-carboxylic Acid Ethyl
Ester (3p).
According to the general procedure II, a mixture of 1-nitroso-
2-naphthol (1a) (346 mg, 1 mmol), ethyl bromoacetate (2v) (172 mg,
1 mmol), and K2CO3 (417 mg, 3 mmol) in dry CH3CN (5 mL) was
refluxed under argon for 6 h. Flash chromatography over silica gel
(cyclohexane/EtOAc = 8:1) gave 3p as a white solid in 56% yield (134
mg, 0.56 mmol): mp 107108 °C; Rf = 0.36 (cyclohexane/EtOAC =
3:1); IR (ATR) ν
̃
1736 (CO), 1537 (CN), 1444 (alkane C−H),
1330, 1275 (ester C−O), 1240 (C−O), 1190, 1172 (C−O), 1150,
1087, 1023, 810, 779, 761, 744 cm−1; UV−vis (MeCN) λmax (log ε)
335 (4.26), 325 (4.25), 298 (3.90) nm; 1H NMR (300 MHz, CDCl3)
δ 1.52 (t, 3J = 7.1 Hz, 3H, 3′-H), 4.61 (q, 3J = 7.1 Hz, 2H, 2′-H), 7.60
(ddd, 4J (7-H, 9-H) = 1.2 Hz, 3J (7-H, 8-H) = 7.1 Hz, 3J (6-H, 7-H) =
8.2 Hz, 1H, 7-H), 7.71 (ddd, J (6-H, 8-H) = 1.3 Hz, 3J (7-H, 8-H) =
4
7.1 Hz, 3J (8-H, 9-H) = 8.2 Hz, 1H, 8-H), 7.74 (d, 3J (4-H, 5-H) = 9.4
3
Hz, 1H, 4-H), 7.95 (brd, J (4-H, 5-H) = 9.4 Hz, 1H, 5-H), 7.98 (d,
3J (6-H, 7-H) = 8.4 Hz, 1H, 6-H), 8.64 (brd, J (8-H, 9-H) = 8.4 Hz,
3
1H, 9-H); 13C NMR (75 MHz, CDCl3) δ 14.2 (C-3′), 63.2 (C-2′),
K
dx.doi.org/10.1021/jo3022956 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Synthesis and Reaction of [1,2]Naphthoquinone 2-(O-
Benzoyloxime) (5). Synthesis of [1,2]Naphthoquinone 2-(O-
Benzoyloxime) (5).
Synthesis of 2-Phenylnaphtho[2,1-d][1,3]oxazole (14).24b
According to the general procedure II, a mixture of 2-nitroso-
1-naphthol (13) (346 mg, 2 mmol), 2-bromo acetophenone (2a)
(199 mg, 1 mmol), and K2CO3 (417 mg, 3 mmol) in dry acetonitrile
(5 mL) was refluxed under argon for 3 h. Flash chromatography over
silica gel (cyclohexane/EtOAc = 20:1) gave 14 as a yellow solid in 45%
yield (100 mg, 0.18 mmol): mp 8990 °C (lit.24b mp 7888 °C);
Rf = 0.45 (cyclohexane/EtOAc = 3:1); 1H NMR (300 MHz, CDCl3) δ
A solution of 1-nitroso-2-naphthol (1a) (177 mg, 1 mmol), 2-bromo
acetophenone (2a) (199 mg, 1 mmol), and triethylamine (254 mg,
2.3 mmol) in dry methanol (5 mL) was stirred under argon at room
temperature for 3 h. The reaction mixture was filtered on a sintered
Buchner funnel, and the solid obtained was recrystallized using
dichloromethane to give 5 as yellow crystals in 76% yield (220 mg,
0.76 mmol): mp 163165 °C; Rf = 0.32 (cyclohexane/EtOAc = 2:1);
3
7.527.60 (m, 4H), 7.627.69 (m, 1H), 7.80 (d, J = 8.8 Hz, 1H),
3
3
7.87 (d, J = 8.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 8.298.39 (m,
3H); 13C NMR (75 MHz, CDCl3) δ 118.5, 120.2, 120.4, 125.5, 125.7,
126.9, 127.29, 127.35, 128.7, 129.0, 131.3, 131.7, 138.4, 146.4, 162.4.
ASSOCIATED CONTENT
■
IR (ATR) ν
̃
1692 (CO), 1658 (CO), 1598, 1450, 1403, 1364,
1230, 1218, 920, 841, 751, 721, 685 cm−1; UV (MeCN) λmax (log ε)
S
* Supporting Information
1
NMR spectra for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
342 (2.10) nm; H NMR (300 MHz, CDCl3) δ 5.85 (s, 2H, 1′-H),
6.39 (d, 3J (3-H, 4-H) = 10.0 Hz, 1H, 3-H), 7.347.39 (m, 1H, 5-H),
7.397.45 (m, 1H, 4-H), 7.467.54 (m, 4H, 5′-H, 6-H, 7-H and
7′-H), 7.587.66 (m, 1H, 6′-H), 7.94 (dd, 4J (4′-H, 6′-H) = 2.0 Hz,
3J (4′-H, 5′-H) = 7.9 Hz, 2H, 4′-H and 8′-H), 8.94 (dd, 4J (6-H, 8-H)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ubeifuss@uni-hohenheim.de.
3
= 2.0 Hz, J (7-H, 8-H) = 8.9 Hz, 1H, 8-H); 13C NMR (75 MHz,
CDCl3) δ 79.0 (C-1′), 126.8 (C-8a), 127.3 (C-3), 127.7 (C-4′),
128.9 (C-5′), 129.9 (C-5), 130.5 (C-6), 131.2 (C-7), 131.3 (C-4a),
132.8 (C-8), 133.9 (C-6′), 134.3 (C-3′), 144.9 (C-4), 146.3 (C-1),
184.4 (C-2), 193.3 (C-2′); MS (EI, 70 eV) m/z 291 (24) [M+], 273
(12) [M  H2O]+, 261 (16), 245 (68), 233 (15), 186 (12), 169
(48), 156 (44); HRMS (EI; M+) calcd for C18H13NO3 (291.0895),
found 291.0878.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Ms. Sabine Mika for recording of NMR spectra and
Dr. Alevtina Baskakova, Dr. Heiko Leutbecher and Dipl.-Chem.
Hans-Georg Imrich for recording of mass spectra.
Synthesis of 2-Phenylnaphtho[1,2-d][1,3]oxazole (3a) from
[1,2]Naphthoquinone 2-(O-Benzoyloxime) (5). According to the
general procedure I, a mixture of [1,2]naphthoquinone 2-(O-benzoylox-
ime) (5) (146 mg, 0.5 mmol) and K2CO3 (208 mg, 3 mmol) in dry 1,2-
dichloroethane (3 mL) was refluxed under argon for 3 h. Flash
chromatography over silica gel (cyclohexane/EtOAc = 20:1) gave
3a as a yellow solid in 75% yield (92 mg, 0.38 mmol).
REFERENCES
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Synthesis of 2-Benzoylnaphtho[1,2-d][1,3]oxazole (4a).32
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2-Benzoylnaphtho[1,2-d][1,3]oxazole (4a) was prepared according to
the method of Lown and Moser32 by reaction of 1-nitroso-2-naphthol
(1a) (692 mg, 4 mmol) and phenacyl pyridinium bromide (12)31
(1108 mg, 4 mmol) in 87% yield (950 mg, 3.48 mmol): mp 124
125 °C (lit.32 mp 123 °C); Rf = 0.50 (cyclohexane/EtOAc = 3:1); IR
(ATR) ν
̃
1652 (CO), 1596, 1777, 1508, 1446, 1326, 1234, 1157,
1
962, 911, 812, 753, 725, 685 cm−1; H NMR (300 MHz, CDCl3) δ
7.577.67 (m, 3H), 7.687.73 (m, 1H), 7.747.78 (m, 1H), 7.81
3
3
3
(d, J = 8.9 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 7.6 Hz,
1H), 8.628.71 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 113.3,
122.3, 126.3, 127.3, 127.9, 128.6, 128.9, 130.1, 131.2, 131.6, 134.1,
135.2, 136.8, 148.6, 156.7, 179.9; MS (EI, 70 eV) m/z 273 (88) [M+],
245 (4) [M  CO]+, 214 (4).
Treatment of 2-Benzoylnaphtho[1,2-d][1,3]oxazole (4a) under
Reaction Condtions. A solution of 2-benzoylnaphtho[1,2-d][1,3]-
oxazole (4a) and K2CO3 (417 mg, 3 mmol) in dry 1,2-dichloroethane
(5 mL) was refluxed under argon for 3 h. After workup 95% of 4a were
recovered.
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L
dx.doi.org/10.1021/jo3022956 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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