A Five-Step Cascade for the Modular and Regiodefined Synthesis of Naphth[2,1-d]oxazoles

Article abstract of DOI:10.1055/s-0035-1561376

The reaction of 3-nucleofugal phthalides with 2-amidoacrylates is shown to provide a synthesis of densely substituted naphth[2,1-d]oxazoles in good yields. It is proposed to proceed via a five-step cascade which includes phthalide annulation, demethoxycarbonylation, and heterocyclization. The methodology is free from regiochemical ambiguity of the products. In certain cases, the corresponding 2-amidonaphthoquinones are directly formed.

Full text of DOI:10.1055/s-0035-1561376

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, A–K
paper
A
B. K. Dinda et al.
Paper
Synthesis
A Five-Step Cascade for the Modular and Regiodefined Synthesis
of Naphth[2,1-d]oxazoles
Bidyut Kumar Dindaa,b,◊
OH
Shyam Basaka,◊
Bidhan Ghosha,◊
Dipakranjan Mal*a
CN
O
Y
Y
LiHMDS, THF
X
+
X
–78 °C to r.t.
42–75%
MeO2C
NHCOMe
N
O
a Department of Chemistry, Indian Institute of Technology,
Kharagpur 721302, India
O
dmal@chem.iitkgp.ernet.in
b Present address: Department of Pharmaceutical Sciences, Wayne
State University, Detroit, MI 48202-3489, USA
X = H, Me, Br, OMe, o-phenylene
Y = H, Cl, OMe, NO2
11 examples
◊ These authors have contributed equally to this work.
Received: 30.09.2015
Accepted after revision: 14.01.2016
Published online: 16.02.2016
vergolide D17 show antibacterial and anticancer activities
(Figure 1). Jadomycin B (12)18 is an important natural prod-
uct of the angucycline family consisting of the unusual 8H-
benz[b]oxazolo[3,3-f]phenanthridine ring system. It dis-
DOI: 10.1055/s-0035-1561376; Art ID: ss-2015-z0573-op
Abstract The reaction of 3-nucleofugal phthalides with 2-amidoacry-
lates is shown to provide a synthesis of densely substituted naphth[2,1-
d]oxazoles in good yields. It is proposed to proceed via a five-step cas-
cade which includes phthalide annulation, demethoxycarbonylation,
and heterocyclization. The methodology is free from regiochemical am-
biguity of the products. In certain cases, the corresponding 2-ami-
donaphthoquinones are directly formed.
O
R
N
O
N
N
H
O
HO
HO
H
OH
MeO2C
O
Key words demethoxycarbonylative annulation, naphth[2,1-d]oxaz-
oles, phthalides, cascade, heterocycles
14
pseudopteroxazole
R = CH2OAc: 312d,e
R = Ph: 412d,e
(2)12
R
N
N
O
The naphthoxazole framework consists of a naphtha-
lene ring fused to an oxazole ring.1 Compounds with a
naphthoxazole moiety exhibit various biological activities
such as immune complex inhibition,2 anticancer (prostate
cancer),3 antioxidant (e.g. 1–5, Figure 1),4 and bacteriostat-
ic5 activities, cysteine protease inhibition (cathepsin inhibi-
tors),6 trypanocidal (Chagas disease) activity,7 topoisomer-
ase II inhibition,8 PTP-1B (protein tyrosine phosphatase-1B)
inhibition,9 lysophosphatidic acid acyltransferase-β inhibi-
tion,10 inhibition of Mycobacterium tuberculosis H37Rv,11
and cytotoxicity.4,12 The traditional Chinese medicine ‘Dan-
shen’ (TCM) containing salviamine A–F (see 6–9, Figure 1)
has been used worldwide in folk medicine since ancient
times.13a It is used for the treatment of menstrual disorders,
menostasis, menorrhalgia, insomnia, arthritis, and coro-
nary heart diseases, particularly angina pectoris and myo-
cardial infarction.13 Naphthoxazoles, regarded as masked 2-
aminonaphthoquinones, are important synthetic precur-
sors of biologically and pharmacologically active 2-amino-
naphthoquinones. 2-Aminonaphthoquinone frameworks
are widespread among the members of the ansamycin fam-
ily. Some of them are also marketed as important drugs, e.g.
rifabutin and rifapentine.14,15 Some other important ansa-
mycins, e.g. hygrocin B (10),16,17 divergolide C (11),17 and di-
O
N
O
O
O
HO
O
O
OH
OH
O
herqueioxazole (5)12f
salviamine A (6)13a R = H: salviamine B (7)13a
R = Me: salviamine C (8)13a
R = CH2CH2CO2Me:
salviamine D (9)13a
O
O
O
HO
H
O
N
HO
H
N
O
O
O
OH
O
O
O
OH
O
O
*
HO
Et
R
jadomycin B (12)18
R = Me: hygrocine B (10)16
R = CH=CMe2:
divergolide C (11)16,17
Figure 1 Representative naphthoxazole and aminonaphthoquinone
natural products
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

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B. K. Dinda et al.
Paper
Synthesis
CO2Et
NHAc
CO2Et
LiHMDS, THF
–78 °C to r.t.
+
+
O
O
NHAc
NHAc
O
OH
15 (20%)
O
13
14a
16 (50%, dr = 1:1)
Scheme 1 Reaction between phthalide (13) and ethyl 2-acetamidoacrylate (14a)
plays antitumor, antimicrobial, and antiviral activities.
Therefore, the development of practical and flexible syn-
thetic methods for 2-aminonaphthoquinones19 and naph-
thoxazoles9,20 is always in demand.
The literature syntheses of 2-amino-1,4-naphthoqui-
nones encompass three types of reactions, namely (a)
Diels–Alder reactions,19a–c (b) direct 1,4-type addition of
amines to naphthoquinones,19d–f and (c) nucleophilic dis-
placement of the halogens with amines.19g Considering the
Table 1 Screening of Bases for the Annulation of 3-(Phenylsulfa-
nyl)phthalide with Ethyl 2-Acetamidoacrylate (14a)
O
SPh
O
base, THF
+ EtO2C
NHAc
NHAc
O
O
17a
14a
18
Entry
Base
Temp
Yield (%)
regiochemical issues, we explored the use of [4+2] benzan-
nulation of phthalides with 2-azidoacrylates.21 Quite inter-
estingly, the reactions produced benzazepinones instead of
the desired 2-azido-1-naphthols.22 Alternatively, demeth-
oxycarbonylative annulation with α-acylaminoacrylates for
the synthesis of 2-amino-1-naphthols was envisaged,
which forms the subject of the present report. Although the
reactivities of amidoacrylates are well established, their an-
nulation behavior is less explored.23 To test the reactivity of
amidoacrylates in anionic annulation, the reaction of
phthalide (13) with ethyl 2-acetamidoacrylate (14a)24 was
attempted first in the presence of LiHMDS as the base in
THF at –78 °C (Scheme 1). The reaction produced the de-
sired product, 2-acetamido-1-naphthol (15)25 in 20% yield
along with the Michael addition adduct 16 (50%) as a 1:1 di-
astereomeric mixture. Use of LDA as the base in the reac-
tion furnished similar results and did not improve the out-
come of the annulation. However, the partial success of the
annulation encouraged us to scrutinize the reactions of 14a
with 3-nucleofugal phthalides (e.g., 17) for the synthesis of
the title compounds.
1
2
3
t-BuOLi
LiHMDS
LDA
–60 °C to r.t.
–78 °C to r.t.
–78 °C to r.t.
0
10
trace
We first attempted the reactions of 3-(phenylsulfa-
nyl)phthalide (17a)26a and 3-(phenylsulfonyl)phthalide
(17b)26b with ethyl 2-acetamidoacrylate (14a),24 owing to
their ready accessibility. The reaction of 17a with 14a was
examined in the presence of t-BuOLi, LiHMDS, and LDA in
THF at low temperature. As shown in Table 1, the reaction
in the presence of t-BuOLi in THF at –60 °C produced an in-
tractable mixture of products (entry 1). Interestingly, the
same reaction in the presence of LiHMDS in THF at –78 °C
furnished naphthoquinone 18 in 10% yield (entry 2).27 Use
of LDA as the base in the reaction provided a trace amount
of the product 18 (entry 3).
O
SPh
O
SPh
SPh
LiHMDS
O
N(SiMe3)2
OEt
NHAc
O
+
O
CO2Et
NHAc
EtO2C
NHAc
LiSPh
O
O
O
O
17a
19
20
14a
21
O
OLi
O
O
H3O/air [O]
LiHMDS
NHAc
NHAc
NHAc
OLi
OLi
22
23
Scheme 2 Probable mechanism for the formation of 2-acetamidonaphthoquinone (18)
18
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

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B. K. Dinda et al.
Paper
Synthesis
Formation of 2-acetamidonaphthoquinone (18) can be
explained by the speculative mechanism shown in Scheme
2. At low temperature, the incipient phthalide anion 19
adds to the amidoacrylate 14a in Michael addition mode to
form new anion 20. This anion further attacks at the car-
bonyl group of the phthalide, resulting in the removal of
lithium phenylthiolate to produce dihydronaphthoquinone
21. Attack of LiHMDS at the ester carbonyl produces 22 via
deethoxycarbonylation. Intermediate 22 then undergoes
enolization to produce 23. Acidic workup followed by aerial
oxidation of 23 produces 18.
Initially, we reasoned that the deprotonation of the NH
hydrogen was responsible for the low yields. Later, we
thought of experimenting with different nucleofuges in 17,
because such a tactic is reported in the literature.21 Accord-
ingly, we investigated the reaction of 3-(phenylsulfo-
nyl)phthalide (17b, Table 2, entry 2). Its reaction with 14a
in the presence of LiHMDS in THF at –78 °C was quite inter-
esting. A mixture of 2-(ethoxycarboxamido)naphthoqui-
none (24) (20%) and phenylsulfonyl-substituted naphthox-
azole 25 (20%) was produced. Mechanistic interpretation of
the formation of 24 and 25 is presented in the Supporting
Information (SI).
Table 2 [4+2] Benzannulation of 2-Amidoacrylates with 3-Cyanophthalidesa
Entry
Phthalide 17
Amidoacrylate 14
Products
Yield (%)
O
SPh
O
1
10
EtO2C
NHAc
NHAc
14a
O
O
O
17a
18
OH
O
SO2Ph
SO2Ph
20 (24)
20 (25)
O
O
2
14a
N
NHCO2Et
O
O
17b
24
25
OMe
O
3
4
14a
14a
30
75
NHAc
NHAc
O
O
O
17c
17d
18
18
CN
O
O
O
OR
CN
O
5
70 (31)
N
MeO2C
14b
NHAc
O
O
17d
31 R = H → 32 R = Me 95%b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

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B. K. Dinda et al.
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Synthesis
Table 2 (continued)
Entry
Phthalide 17
Amidoacrylate 14
Products
Yield (%)
Cl
OH
CN
O
Cl
6
72
N
MeO2C
14c
NHAc
O
O
17d
33
OMe
OH
OMe
CN
O
7
50d
N
MeO2C
14d
NHAc
O
O
17d
34
OH
CN
O
NO2
NO2
8
50
N
MeO2C
14e
NHAc
O
O
17d
17d
17d
36
OH
CN
O
9
68
MeO2C
14f
NHAc
N
O
O
37
OH
CN
O
10
55d
N
MeO2C
14g
NHCOPh
O
O
Ph
38
OH
CN
O
11
50c
NH
MeO2C
NHCOPh
O
OMe
14g
CN
Ph
O
OMe
17e
40
O
CN
O
12
57
NH
MeO2C
NHCOPh
O
14g
O
O
Ph
17f
46
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

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B. K. Dinda et al.
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Synthesis
Table 2 (continued)
Entry
Phthalide 17
Amidoacrylate 14
Products
Yield (%)
OMe
OH
O
CN
O
OMe
13
52d
N
MeO2C
14d
NHAc
O
17g
47
OMe
OH
OMe
CN
Br
Br
O
14
42
N
MeO2C
14d
NHAc
O
O
17h
49
a Reaction conditions: phthalide 17 (1.0 mmol), amidoacrylate 14 (1.0 mmol), LiHMDS (3.5 mmol), THF (15 mL), –78 °C to r.t.
b Reaction conditions: K2CO3, MeI, acetone, r.t. Yield of 32 for the one step from 31.
c Yields of dihydronaphthoxazoles.
d Side products of the annulation are reported in the SI.
The outcome of the annulations of 17a and 17b with
14a (Table 2, entries 1 and 2) prompted us to explore the
reactivities of a few other 3-nucleofugal phthalides (e.g.,
17c and 17d). With 3-methoxyphthalide (17c),28 the
Michael addition of the resulting methoxide ion was antici-
pated to be less likely than that of lithium benzenesulfinate
(18→29; see Scheme 3 in the SI). When donor 17c was
treated with 14a in the presence of LiHMDS in THF at
–78 °C, the reaction produced 18 exclusively in an improved
yield (30%) (Table 2, entry 3). In seeking further improve-
ment in the yield, we utilized 3-cyanophthalide (17d)29 in
the annulation reaction. That the cyanide group is a better
electron-withdrawing group as well as a better leaving
group compared to the methoxy group is well known in the
literature.30 The annulation of 17d with 14a in the presence
of LiHMDS in THF at –78 °C produced 18 in 75% yield (entry
4). This result was exciting with respect to both yield and
selectivity. Enthused by the success (entry 4), we carried
out the annulations of 3-cyanophthalide (17d) with differ-
ent 3-aryl-2-acetamidoacrylates 14b–e (entries 5–8).31
When the reaction of 17d was carried out with 14b in
the presence of LiHMDS in THF at –78 °C (Table 2, entry 5),
it produced 2-methyl-4-phenylnaphth[2,1-d]oxazol-5-ol
(31) in 70% yield. It was characterized by its NMR data. The
characteristic peak for the C2 methyl protons appeared at
δ = 2.71 ppm as a sharp singlet. For further confirmation of
the structure, the hydroxy group of 31 was O-methylated
by the treatment of 31 with K2CO3 and MeI in acetone to
produce methoxy derivative 32 (entry 5). NMR data of the
compound conformed to the structure of 32. Protons of the
methyl group appeared at δ = 2.73 ppm and those of the
methoxy group at δ = 3.60 ppm. Finally, the structure of 32
was confirmed by analysis of its X-ray crystal data (see SI).
From the ORTEP diagram of 32, it is obvious that the phenyl
ring and the naphthalene ring are not coplanar. This orien-
tation conforms to the low chemical shift value of the aro-
matic methoxy group (δ = 3.60 ppm) that arises from the
anisotropic effect of phenyl ring.
Next, we submitted 2-acetamido-3-(4-chlorophenyl)ac-
rylate 14c31 to the reaction with 17d in the presence of
LiHMDS in THF at –78 °C (Table 2, entry 6). This reaction
produced naphthoxazole 33 in 72% yield. Similarly, the re-
action of 17d with 2-acetamido-3-(4-methoxyphenyl)acry-
late 14d under the same reaction conditions furnished (4-
methoxyphenyl)-substituted naphthoxazole 34 in 50% yield
(entry 7). In addition to 34, a side product was also isolated
from the reaction mixture. On analysis of its spectral data
(NMR, IR, and HRMS), it was assigned as the 2-cyano-2-
methyl derivative of 34, structure 35 (see SI). The formation
of 35 can be explained by addition of cyanide to the imine
bond of naphthoxazole 34.
To increase the scope of the annulation, the reaction of
17d with nitro group containing acceptor 14e was attempt-
ed (Table 2, entry 8). The reaction produced naphthoxazole
36 in 50% yield. The reaction was not accompanied by any
dihydronaphthoxazole derivative of 36. Relatively low solu-
bility of 14e in THF was presumed to be responsible for the
lower yield. The results of entries 5–8 showed that the an-
nulation of 17d was compatible with a variety of 3-aryl-2-
acetamidoacrylates to produce arylnaphthoxazoles. To
check the reaction compatibility of 3-alkyl-substituted 2-
acetamidoacrylate, we examined the reactivity of com-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

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B. K. Dinda et al.
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Synthesis
pound 14f (entry 9).32 The reaction of 14f with 17d in the
presence of LiHMDS in THF at –78 °C exclusively produced
naphthoxazole 37 in 68% yield (entry 9). It shows that 3-al-
kyl substitution of the amidoacrylate 14f has little adverse
effect on the outcome of the annulation. Our next target
was to investigate the reaction of 17d with benzamido ac-
rylate 14g33 to ascertain if the benzoyl group is tolerated in
the annulation (entry 10). The reaction in the presence of
LiHMDS in THF at –78 °C produced naphthoxazole 38 in
55% yield (entry 10) with a minor amount of dihydronaph-
thoxazole 39 (15%) (see SI). Hence, entries 5–10 show that
various amidoacrylates are compatible in the annulation
with 17d to produce naphthoxazoles. Our next objective
was to check the reactivity of a substituted 3-cyanophtha-
lide. For this, we chose cyano(methoxy)phthalide 17e29 to
react with 14g in the presence of LiHMDS in THF at –78 °C
(entry 11). The reaction produced cyanonaphthoxazole 40
in 50% yield. No other side product was found in the reac-
tion mixture. Hence, the methodology is also compatible
with methoxy-substituted cyanophthalide.
As a model study on the synthesis of salviamines (e.g.,
Figure 1, 6–9), annulation of an angular phthalide was
planned. To this end, we chose cyanonaphthofuranone 17f
to employ in the annulation (Table 2, entry 12). The reac-
tion of 17f with 14g was carried out under the established
conditions, in the presence of LiHMDS in THF at –78 °C. The
reaction produced phenanthrenedione 46 in 57% yield (en-
try 12) via an aerial oxidation of the initial annulated hy-
droxy precursor. The quinone 46 was characterized by its
spectral data. Thus, the reaction is also compatible with an
angular cyanophthalide. The failure to obtain the corre-
sponding oxazole may be attributed to the peri effect. To
further generalize the reaction, substituted cyanophtha-
lides 17g35 and 17h35 were submitted to the annulation
with the acceptor 14d (entries 13 and 14). Expectedly, the
naphthoxazoles 47 and 49 were obtained in 52% and 42%
yields, respectively.
prior to use. The products were purified by column chromatography
on silica gel. Columns were prepared with silica gel (60–120 or 230–
400 mesh). 1H and 13C NMR spectra for all compounds were recorded
at 200/400/600 and 50/100/150 MHz (Bruker Avance 200, Bruker
Avance II 400, Bruker Ascend 600), respectively, and are referenced to
the signal of CHCl3 at 7.26 ppm (1H) and 77.23 ppm (13C) for CDCl3.
Sometimes DMSO-d6 (2.50 ppm for 1H, 39.51 ppm for 13C) was used as
solvent for recording NMR data. IR spectra were recorded with a
Perkin–Elmer FTIR instrument by using KBr pellets. Melting points
are uncorrected. High-resolution mass spectra were recorded with a
mass spectrometer in positive ion mode. The phrase ‘usual workup’
or ‘worked up in the usual manner’ refers to washing of the organic
phase with H2O (2 × 1/3 of the volume of the organic phase) and brine
(1 × 1/4 of the volume of the organic phase), drying (Na2SO4), filtra-
tion, and concentration under reduced pressure. Solvents used for
column chromatography were EtOAc and n-hexane. All the known
compounds were characterized by comparison with the 1H NMR data
reported in the literature. Substrates 14a,24 14b–e,31 14g,33 7a,26a
17b,26b 17c,28 17d,29 17e,29 and 4234 were prepared according to litera-
ture procedures.
Annulation Reaction in Presence of LiHMDS; General Procedure
A solution of 3-functionalized phthalide 17 (1.0 mmol) in THF (5 mL)
was added to a stirred solution of LiHMDS (3.5 mmol) in THF (15 mL)
at –78 °C under an inert gas. The resulting red/yellow solution was
stirred at –78 °C for 30 min and then a solution of 2-amidoacrylate 14
(1.0 mmol) in THF (5 mL) was slowly added. The cooling bath was re-
moved after approximately 30 min, and the reaction mixture was al-
lowed to reach r.t. over a period of 1–2 h, and then stirred at r.t. for 6–
7 h. Upon completion of the reaction (monitored by TLC), 3 N HCl (15
mL) was added, and the resulting solution was concentrated under
reduced pressure. The residue was extracted with EtOAc (3 × 50 mL),
and the organic layer was washed with H2O (3 × 20 mL). The resulting
organic layer was washed with brine (2 × 20 mL), and the combined
organic part was dried (Na2SO4) and concentrated. The residue was
purified by column chromatography on silica gel.
(Z)-Methyl 2-Acetamidobut-2-enoate (14f)32
To a stirred solution of thionyl chloride (0.584 mL, 8.05 mmol) in an-
hydrous MeOH (10 mL) was added L-threonine (960 mg, 8.05 mmol)
at 0 °C. After stirring at the same temperature for 30 min, the reaction
mixture was allowed to reach r.t. and stirred for 24 h. Then the reac-
tion mixture was evaporated under reduced pressure and the residue
was triturated with petroleum ether (3 × 20 mL) to provide the inter-
mediate ester compound. The ester without further purification was
dissolved in triethylamine (8.65 mL, 62 mmol) and the reaction mix-
ture was stirred at 0 °C for 30 min. Then acetic anhydride (1.91 mL,
20.2 mmol) was added and the reaction mixture was allowed to stir
at r.t. for 24 h. Then anhydrous MeOH (50 mL) was added and the
mixture was heated at 60 °C for 24 h. Solvent was evaporated and the
crude residue was dissolved in EtOAc (120 mL) and then washed with
10% aq NaHCO3 solution (3 × 30 mL). Usual workup of the EtOAc part
followed by chromatographic purification produced amidoacrylate
14f as a semisolid (55% overall yield). The compound was character-
ized by comparing its 1H NMR data with the reported values.32b
In summary, we have shown that the reaction between
3-cyanophthalides and acetamidoacrylates provides a di-
rect and general regiodefined synthesis of 5-hydroxy-
naphth[2,1-d]oxazoles via tandem demethoxycarbonylative
benzannulation and heterocyclization. It is direct and regio-
specific by virtue of the initial Michael addition and subse-
quent domino steps. The methodology is compatible with a
variety of substrates. Two important trends emerged from
this study. The heterocyclization, i.e. the formation of the
oxazole ring, is driven by a β-substituent in the acrylate ac-
ceptors and inhibited by a peri effect. Studies on the poten-
tial of the method in the total synthesis of natural products
such as jadomycines and salviamines are underway.
N-(1-Hydroxynaphthalen-2-yl)acetamide (15)25
All reactions involving moisture sensitive reagents were performed
under inert atmosphere. Solvents were dried prior to use, according
to the standard protocols. General chemicals were used after purifica-
tion. Reactions were monitored by TLC carried out on 0.25 mm silica
gel plates (60-F254). All solvents for chromatography were distilled
It was obtained as a side product with compound 16. Yellow solid.
Yield: 30 mg (20%).
IR (KBr): 3303, 1651, 1525, 1387, 1295, 771 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

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B. K. Dinda et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 9.58 (br s, 1 H), 8.39 (d, J = 8.8 Hz, 1 H),
7.75 (d, J = 7.2 Hz, 1 H), 7.54–7.45 (m, 3 H), 7.35 (d, J = 8.8 Hz, 1 H),
6.96 (d, J = 8.8 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.7 (CO), 144.6, 133.0, 127.7, 127.3
(CH), 126.5 (CH), 126.0 (CH), 123.4 (CH), 121.2 (CH), 120.5 (CH),
119.2, 24.0 (CH3).
3-Chloronaphtho[1,2-c]furan-1(3H)-one (17f′)
It was obtained as a side product with compound 17f. White solid.
Yield: 11 mg, 0.05 mmol (10%); Rf = 0.6 (EtOAc–n-hexane, 1:7.5); mp
139–140 °C.
IR (KBr): 1778, 1319, 1175, 1096, 1003, 772 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.88 (d, J = 8.0 Hz, 1 H), 8.21 (d, J = 8.4
Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.76 (t, J = 7.6 Hz, 1 H), 7.68 (t, J = 7.6
Hz, 1 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.14 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 167.8 (CO), 149.0, 137.0 (CH), 134.4,
129.9 (CH), 128.9 (CH), 128.8, 128.6 (CH), 123.9 (CH), 119.6, 119.3
(CH), 85.3 (CH).
.
Ethyl 2-Acetamido-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)pro-
panoate (16)
It was obtained as a diasteromeric mixture by the reaction of phtha-
lide (13; 134 mg, 1 mmol) and compound 14a (157 mg, 1 mmol) in
the presence of LiHMDS (3.2 equiv) following the general procedure
for annulation. Yellowish semisolid (dr = 1:1). Yield: 109 mg (50%).
N-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)acetamide (18)27
IR (KBr): 3457, 1751, 1654, 1636, 1544, 1375, 742 cm–1
.
According to the general procedure for annulation, the condensation
of 17d (95 mg, 0.60 mmol) with 14a (94 mg, 0.60 mmol) in the pres-
ence of LiHMDS (2.10 mL, 2.10 mmol) produced 2-acetamidonaph-
thoquinone 18 as a yellow solid.
1H NMR (200 MHz, CDCl3): δ = 7.93–7.87 (m, 2 H), 7.74–7.66 (m, 2 H),
7.58–7.44 (m, 4 H), 6.54 (unresolved d, 1 H), 6.26 (unresolved d, 1 H),
5.53 (unresolved dt, 2 H), 4.83–4.74 (m, 2 H), 4.27 (unresolved q, 4 H),
2.73–2.58 (m, 2 H), 2.30–2.16 (m, 2 H), 2.10 (s, 3 H), 1.96 (s, 3 H), 1.28
(unresolved t, 6 H)
13C NMR (50 MHz, CDCl3): δ = 171.5 (CO), 170.7 (CO), 170.5 (CO),
170.1 (CO), 149.3 (CO), 149.1 (CO), 134.4 (2 CH), 129.6 (CH), 129.5
(CH), 125.9 (CH), 125.8 (CH), 125.7, 125.6, 122.2 (CH), 122.0 (CH),
78.4 (CH), 77.8 (CH), 62.2 (CH2), 62.0 (CH2), 50.2 (CH), 50.0 (CH), 37.0
(CH2), 36.5 (CH2), 23.1 (CH3), 23.0 (CH3), 14.2 (CH3), 14.1 (CH3).
Yield: 97 mg, 0.45 mmol (75%); Rf = 0.3 (EtOAc–n-hexane, 1:3).
1H NMR (400 MHz, CDCl3): δ = 8.36 (br s, 1 H), 8.09 (dd, J = 7.6, 0.8 Hz,
2 H), 7.84 (s, 1 H), 7.77 (t, J = 7.4 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 2.28
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 185.4 (CO), 181.2 (CO), 169.6 (CO),
140.1, 135.2 (CH), 133.5 (CH), 132.4, 130.1, 126.9 (CH), 126.6 (CH),
117.4 (CH), 25.2 (CH3).
HRMS (ESI): m/z calcd for C15H18NO5 [M + H]+: 292.1185; found:
292.1225.
Ethyl 1,4-Dioxo-1,4-dihydronaphthalen-2-ylcarbamate (24)
According to the general procedure for annulation, the condensation
of 17b (274 mg, 1.0 mmol) with 14a (157 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced 2-amidonaphthoqui-
none 24 as a white solid.
1-Oxo-1,3-dihydronaphtho[1,2-c]furan-3-carbonitrile (17f)
To a stirred suspension of 3-hydroxy-3H-naphtho[1,2-c]furan-1-one
(100 mg, 0.50 mmol) in H2O (6 mL) was added KCN (91 mg, 1.40
mmol) in portions, and the mixture was allowed to stir at r.t. for 10
min. The reaction mixture was then cooled to 0 °C and treated with
concd HCl (1.5 mL) and again stirred at r.t. for another 5 h. Then the
reaction mixture was kept in a deep freeze overnight without stirring.
The mixture was then extracted with EtOAc (3 × 20 mL), and the com-
bined extracts were subjected to usual workup to get a semisolid
compound (cyanohydrin 45). A solution of this cyanohydrin 45 in
MeCN (4 mL), without further purification, was added to a solution of
Vilsmeier reagent, prepared from anhydrous DMF (0.30 mL, 4.13
mmol) and oxalyl chloride (0.30 mL, 3.31 mmol) in MeCN (2 mL) at
–20 °C (CCl4/liq N2). After 15 min, pyridine (0.60 mL, 7.8 mmol) was
added and the mixture was stirred for an additional 30 min at the
same temperature. The reaction was quenched with 3 N HCl (4 mL)
and the mixture was extracted with EtOAc (3 × 20 mL). After usual
workup and column chromatographic purification, compound 17f
was isolated as a white solid.
Yield: 49 mg, 0.20 mmol (20%); Rf = 0.3 (EtOAc–n-hexane, 1:3); mp
145 °C.
IR (KBr): 1719, 1642, 1613, 1444, 1317, 1268, 1130, 895 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.09 (dd, J = 7.6, 1.2 Hz, 2 H), 7.85 (br s,
1 H), 7.77 (td, J = 7.5, 1.5 Hz, 1 H), 7.70 (td, J = 7.5, 1.3 Hz, 1 H), 7.50 (s,
1 H), 4.28 (q, J = 7.2 Hz, 2 H), 1.34 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 184.9 (CO), 180.8 (CO), 152.5 (CO),
141.0, 135.1 (CH), 133.4 (CH), 132.4, 130.3, 126.9 (CH), 126.6 (CH),
115.5 (CH), 62.7 (CH2), 14.6 (CH3).
HRMS (ESI): m/z calcd for C13H12NO4 [M + H]+: 246.0766; found:
246.0804.
2-Methyl-4-(phenylsulfonyl)naphth[2,1-d]oxazol-5-ol (25)
It was obtained as a side product with 2-amidonaphthoquinone 24 as
Yield: 68 mg, 0.33 mmol (66%); Rf = 0.4 (EtOAc–n-hexane, 1:2); mp
a light yellow solid.
202–204 °C.
IR (KBr): 1775, 1176, 1097, 773 cm–1
Yield: 65 mg, 0.20 mmol (20%); Rf = 0.2 (EtOAc–n-hexane, 1:3); mp
decomposed over 150 °C.
.
1H NMR (400 MHz, CDCl3): δ = 8.94 (d, J = 8.4 Hz, 1 H), 8.30 (d, J = 8.4
Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.81 (t, J = 7.4 Hz, 1 H), 7.74 (t, J = 7.6
Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 6.16 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 168.0 (CO), 143.4, 137.5 (CH), 134.5,
130.3 (CH), 129.1, 129.0 (CH), 128.9 (CH), 123.7 (CH), 119.6, 118.3
(CH), 114.0, 65.6 (CH).
IR (KBr): 1740, 1628, 1559, 1457, 1384, 1271, 1062 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.97 (s, 1 H), 8.50 (d, J = 8.4 Hz, 1 H),
8.27 (d, J = 7.6 Hz, 2 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.75–7.71 (m, 1 H),
7.59–7.49 (m, 4 H), 2.67 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.0, 153.2, 141.8, 141.0, 134.0 (CH),
133.4, 130.9 (CH), 129.2 (CH), 128.1 (CH), 126.1 (CH), 125.6 (CH),
123.5, 123.3, 120.0 (CH), 107.6, 15.1 (CH3).
HRMS (ESI): m/z calcd for C13H8NO2 [M + H]+: 210.0555; found:
210.0563.
HRMS (ESI): m/z calcd for C18H14NO4S [M + H]+: 340.0644; found:
340.0659.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

H
B. K. Dinda et al.
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Synthesis
2-Methyl-4-phenylnaphth[2,1-d]oxazol-5-ol (31)
4-(4-Methoxyphenyl)-2-methylnaphth[2,1-d]oxazol-5-ol (34)
According to the general procedure for annulation, the condensation
of 17d (159 mg, 1.0 mmol) with 14b (219 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced naphthoxazole 31 as a
yellow solid.
According to the general procedure for annulation, the condensation
of 17d (159 mg, 1.0 mmol) with 14d (249 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced naphthoxazole 34 as a
brown solid.
Yield: 193 mg, 0.70 mmol (70%); Rf = 0.15 (EtOAc–n-hexane, 1:3); mp
Yield: 153 mg, 0.50 mmol (50%); Rf = 0.3 (EtOAc–n-hexane, 1:2); mp
168–170 °C.
166–168 °C.
IR (KBr): 1735, 1671, 1653, 1522, 1459, 1058, 726 cm–1
.
IR (KBr): 1561, 1510, 1291, 1248, 1034, 820 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.38 (d, J = 8.4 Hz, 1 H), 8.15 (d, J = 8.4
Hz, 1 H), 7.66–7.52 (m, 6 H), 7.47 (t, J = 7.0 Hz, 1 H), 2.71 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.4, 145.5, 141.3, 136.8, 132.9,
130.6 (CH), 130.0 (CH), 128.8 (CH), 127.5 (CH), 125.2 (CH), 124.0 (CH),
122.7, 120.1, 119.9 (CH), 113.7, 15.1 (CH3).
1H NMR (400 MHz, CDCl3): δ = 8.37 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.0
Hz, 1 H), 7.65–7.52 (m, 4 H), 7.11 (d, J = 8.0 Hz, 2 H), 5.86 (s, 1 H), 3.87
(s, 3 H), 2.70 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.3, 159.9, 145.4, 141.2, 137.2,
131.7 (CH), 131.5, 127.3 (CH), 125.1 (CH), 124.8, 123.9 (CH), 122.6,
119.9 (CH), 115.4 (CH), 113.5, 55.6 (OCH3), 14.9 (CH3).
HRMS (ESI): m/z calcd for C18H14NO2 [M + H]+: 276.1025; found:
276.1044.
HRMS (ESI): m/z calcd for C19H16NO3 [M + H]+: 306.1130; found:
306.1140.
5-Methoxy-2-methyl-4-phenylnaphth[2,1-d]oxazole (32)
5-Hydroxy-4-(4-methoxyphenyl)-2-methyl-2,3-dihydro-
naphth[2,1-d]oxazole-2-carbonitrile (35)
To a stirred solution of 31 (138 mg, 0.50 mmol) in anhydrous acetone
(15 mL) was added K2CO3 (207 mg, 1.50 mmol) and MeI (0.16 mL,
2.50 mmol) at r.t. and the mixture was allowed to stir at the same
temperature for 6 h. The solvent was evaporated and the crude resi-
due was diluted with H2O (20 mL) and extracted with EtOAc (3 × 40
mL). After usual workup, the solid crude was purified by column
chromatography to produce naphthoxazole 32 as a white solid.
It was obtained as a side product with naphthoxazole 34 as a white
solid.
Yield: 100 mg, 0.30 mmol (30%); Rf = 0.1 (EtOAc–n-hexane, 1:2); mp
208–210 °C.
IR (KBr): 2224, 1656, 1574, 1514, 1289, 1251, 1172, 1032, 773 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 10.68 (br s, 1 H), 9.11 (s, 1 H), 8.31
(d, J = 8.4 Hz, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 7.77 (t, J = 7.4 Hz, 1 H), 7.64
(t, J = 7.6 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 3.81
(s, 3 H), 1.77 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 170.8, 159.8, 154.9, 147.4, 132.8,
131.0 (CH), 129.9 (CH), 128.7, 126.9 (CH), 124.7 (CH), 124.4, 123.8
(CH), 118.3, 118.1, 113.9 (CH), 99.6, 55.6 (OCH3), 23.3 (CH3).
.
Yield: 137 mg, 0.48 mmol (95%); Rf = 0.4 (EtOAc–n-hexane, 1:3); mp
132–134 °C.
IR (KBr): 1701, 1653, 1560, 1542, 1458, 1260, 1108 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 8.4
Hz, 1 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.65–7.61 (m, 1 H), 7.60–7.51 (m, 3
H), 7.45–7.27 (m, 1 H), 3.60 (s, 3 H), 2.73 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.4, 150.5, 143.4, 137.3, 134.0,
130.8 (CH), 128.5 (CH), 127.9 (CH), 127.2 (CH), 126.5, 125.8 (CH),
123.9 (CH), 123.3, 120.3 (CH), 120.1, 61.8 (OCH3), 15.0 (CH3).
HRMS (ESI): m/z calcd for C20H17N2O3 [M + H]+: 333.1239; found:
333.1265.
HRMS (ESI): m/z calcd for C19H16NO2 [M + H]+: 290.1181; found:
290.1208.
2-Methyl-4-(3-nitrophenyl)naphth[2,1-d]oxazol-5-ol (36)
According to the general procedure for annulation, the condensation
of 17d (159 mg, 1.0 mmol) with 14e (264 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced naphthoxazole 36 as a
light yellow solid.
4-(4-Chlorophenyl)-2-methylnaphth[2,1-d]oxazol-5-ol (33)
According to the general procedure for annulation, the condensation
of 17d (159 mg, 1.0 mmol) with 14c (254 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced naphthoxazole 33 as a
light yellow solid.
Yield: 160 mg, 0.50 mmol (50%); Rf = 0.2 (EtOAc–n-hexane, 1:2); mp
decomposed over 160 °C.
Yield: 223 mg, 0.72 mmol (72%); Rf = 0.4 (EtOAc–n-hexane, 1:5); mp
221–222 °C.
IR (KBr): 1711, 1650, 1560, 1545, 1463, 1257, 1110 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.58 (s, 1 H), 8.58 (m, 1 H), 8.39 (d,
J = 8.4 Hz, 1 H), 8.25–8.22 (m, 1 H), 8.20–8.18 (m, 1 H), 8.12 (d, J = 8.4
Hz, 1 H), 7.81–7.77 (m, 1 H), 7.72–7.68 (m, 1 H), 7.61–7.57 (m, 1 H),
2.66 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 163.8, 148.1, 147.2, 140.8, 138.3
(CH), 136.9, 136.5, 129.9 (CH), 128.4 (CH), 126.0 (CH), 125.7 (CH),
124.6 (CH), 124.5, 122.4 (CH), 120.1 (CH), 120.0, 114.1, 14.8 (CH3).
IR (KBr): 1709, 1650, 1556, 1542, 1265, 1100 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 9.29 (s, 1 H), 8.38 (d, J = 9 Hz, 1 H),
8.12 (d, J = 7.8 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 2 H), 7.73–7.68 (m, 1 H),
7.60–7.57 (m, 1 H), 7.56 (d, J = 7.8 Hz, 2 H), 2.66 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 163.4, 146.6, 140.7, 137.2, 133.6,
133.2, 132.2, 128.3, 128.0, 125.4, 124.6, 124.5, 119.9, 119.6, 115.3,
14.7.
HRMS (ESI): m/z calcd for C18H13N2O4 [M + H]+: 321.0875; found:
321.0878.
HRMS (ESI): m/z calcd for C18H13NO2Cl [M + H]+: 310.0635; found:
310.0637.
2,4-Dimethylnaphth[2,1-d]oxazol-5-ol (37)
According to the general procedure for annulation, the condensation
of 17d (159 mg, 1.0 mmol) with 14f (157 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced naphthoxazole 37 as a
white solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

I
B. K. Dinda et al.
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Synthesis
Yield: 145 mg, 0.68 mmol (68%); Rf = 0.3 (EtOAc–n-hexane, 1:3); mp
110 °C.
1H NMR (400 MHz, CDCl3): δ = 10.23 (s, 1 H, D2O exchangeable), 7.98
(d, J = 7.2 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.59–7.50 (m, 5 H, one
proton is D2O exchangeable), 6.88 (d, J = 7.6 Hz, 1 H), 4.08 (s, 3 H), 3.07
(q, J = 7.6 Hz, 2 H), 1.31 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.7, 156.5, 154.6, 150.4, 135.6,
134.3, 132.2 (CH), 129.1 (CH), 129.0 (CH), 127.7 (CH), 119.2 (CH),
118.4, 117.7, 113.7, 105.4 (CH), 100.3, 56.8 (OCH3), 25.7 (CH2), 14.8
(CH3).
IR (KBr): 1654, 1560, 1401, 1242, 1073, 774 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 8.8 Hz, 1 H), 8.09 (d, J = 8.4
Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1 H), 2.74 (CH3),
2.61 (CH3).
13C NMR (100 MHz, CDCl3): δ = 163.1, 146.0, 141.1, 138.1, 126.5 (CH),
125.0 (CH), 123.0, 122.7 (CH), 120.0 (CH), 119.0, 109.5, 14.9 (CH3),
10.4 (CH3).
HRMS (ESI): m/z calcd for C21H19N2O3 [M + H]+: 347.1396; found:
347.1391.
HRMS (ESI): m/z calcd for C13H12NO2 [M + H]+: 214.0868; found:
214.0893.
N-(2-Ethyl-1,4-dioxo-1,4-dihydrophenanthren-3-yl)benzamide
(46)
4-Ethyl-2-phenylnaphth[2,1-d]oxazol-5-ol (38)
According to the general procedure for annulation, the condensation
of 17f (105 mg, 0.50 mmol) with 14g (117 mg, 0.50 mmol) in the
presence of LiHMDS (1.75 mL, 1.75 mmol) produced compound 46 as
a yellow solid.
According to the general procedure for annulation, the condensation
of 17d (159 mg, 1.0 mmol) with 14g (233 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced naphthoxazole 38 as a
white solid.
Yield: 101 mg, 0.285 mmol (57%); Rf = 0.5 (EtOAc–n-hexane, 1:3); mp
decomposed at high temperature.
Yield: 145 mg, 0.55 mmol (55%); Rf = 0.5 (EtOAc–n-hexane, 1:2); mp
154 °C.
IR (KBr): 2923, 1701, 1458, 1277, 1120, 772 cm–1
.
IR (KBr): 1645, 1500, 1476, 1285, 1256, 723 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.46 (d, J = 8.8 Hz, 1 H), 8.66 (br s, 1 H),
8.23 (dd, J = 23.4, 8.6 Hz, 2 H), 8.01 (d, J = 7.2 Hz, 2 H), 7.91 (d, J = 7.6
Hz, 1 H), 7.72 (t, J = 7.2 Hz, 1 H), 7.66–7.62 (m, 2 H), 7.56 (t, J = 7.8 Hz,
2 H), 2.76 (q, J = 7.2 Hz, 2 H), 1.23 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 185.6 (CO), 185.3 (CO), 165.6 (CO),
138.4, 137.7, 136.4, 136.0 (CH), 133.9, 133.6, 133.0 (CH), 130.5 (CH),
130.0, 129.2 (CH), 129.1 (CH), 128.7 (CH), 128.0 (CH), 127.8 (CH),
125.9, 122.6 (CH), 21.5 (CH2), 12.4 (CH3).
1H NMR (400 MHz, CDCl3): δ = 8.46 (br s, 1 H), 8.15 (dd, J = 7.4, 1.4 Hz,
1 H), 8.08 (dd, J = 7.4, 1.4 Hz, 1 H), 7.97–7.95 (m, 2 H), 7.76 (td, J = 7.5,
1.5 Hz, 1 H), 7.71 (td, J = 7.5, 1.5 Hz, 1 H), 7.62–7.60 (m, 1 H), 7.55–
7.51 (m, 2 H), 2.75 (q, J = 7.5 Hz, 2 H), 1.20 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 184.7, 182.6, 165.5, 140.9, 137.6,
134.7 (CH), 133.8, 133.6 (CH), 133.0 (CH), 130.8, 129.2 (CH), 128.1
(CH), 127.0 (CH), 126.5 (CH), 21.9 (CH2), 12.4 (CH3) (one quaternary C
peak overlaps with another peak).
HRMS (ESI): m/z calcd for C23H18NO3 [M + H]+: 356.1287; found:
356.1292.
HRMS (ESI): m/z calcd for C19H16NO2 [M + H]+: 290.1181; found:
290.1173.
4-(4-Methoxyphenyl)-2,7-dimethylnaphtho[2,1-d]oxazol-5-ol (47)
4-Ethyl-5-hydroxy-2-phenyl-2,3-dihydronaphth[2,1-d]oxazole-2-
carbonitrile (39)
According to the general procedure for annulation, the condensation
of 17g (87 mg, 0.50 mmol) with 14d (125 mg, 0.50 mmol) in the pres-
ence of LiHMDS (1.75 mL, 1.75 mmol) produced compound 47 as a
white solid.
It was obtained as the side product with naphthoxazole 38 as a
brown solid.
Yield: 47 mg, 0.15 mmol (15%); Rf = 0.2 (EtOAc–n-hexane, 1:2); mp
246–248 °C.
Yield: 83 mg, 0.26 mmol (52%); Rf = 0.5 (EtOAc–n-hexane, 1:3); mp
242 °C.
IR (KBr): 3446, 2343, 1636, 1507, 1235, 1026, 772 cm–1
.
IR (KBr): 3241, 2928, 1560, 1509, 1423, 1402, 1290, 1244, 1172, 1033
1H NMR (400 MHz, DMSO-d6): δ = 10.84 (br s, 1 H), 9.88 (s, 1 H), 8.28
(d, J = 8.0 Hz, 1 H), 8.05–7.98 (m, 3 H), 7.74 (t, J = 7.2 Hz, 1 H), 7.61–
7.53 (m, 4 H), 2.85 (m, 2 H), 1.16 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 167.3, 155.3, 150.2, 134.7, 133.0,
132.1 (CH), 129.8 (CH), 128.7 (CH), 128.4 (CH), 126.4 (CH), 124.3 (CH),
124.2, 123.9 (CH), 118.7, 117.8, 98.3, 25.6 (CH2), 14.8 (CH3).
cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 8.90 (s, 1 H), 8.14 (s, 1 H), 8.00 (d,
J = 8.4 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.07 (d,
J = 8.4 Hz, 2 H), 3.84 (s, 3 H), 2.64 (s, 3 H), 2.54 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 162.7, 158.8, 145.7, 140.8, 136.8,
134.5, 132.6, 129.4, 126.9, 124.9, 123.4, 119.9, 117.4, 116.5, 113.8,
55.6, 22.1, 14.7.
HRMS (ESI): m/z calcd for C20H17N2O2 [M + H]+: 317.1290; found:
317.1325.
HRMS (ESI): m/z calcd for C20H17NO3 [M + H]+: 320.1287; found:
320.1293.
4-Ethyl-5-hydroxy-9-methoxy-2-phenyl-2,3-dihydronaphth[2,1-
d]oxazole-2-carbonitrile (40)
5-Hydroxy-4-(4-methoxyphenyl)-2,7-dimethyl-2,3-dihydronaph-
According to the general procedure for annulation, the condensation
of 17e (189 mg, 1.0 mmol) with 14g (233 mg, 1.0 mmol) in the pres-
ence of LiHMDS (3.5 mL, 3.5 mmol) produced naphthoxazole 40 as a
greenish semisolid.
tho[2,1-d]oxazole-2-carbonitrile (48)
Obtained as a side product with naphthoxazole 47 as a yellow solid.
Yield: 48 mg, 0.14 mmol (28%); Rf = 0.1 (EtOAc–n-hexane, 1:3); mp
254 °C.
1H NMR (600 MHz, DMSO-d6): δ = 10.60 (s, 1 H), 9.08 (s, 1 H), 8.23 (d,
J = 9 Hz, 1 H), 7.82 (s, 1 H), 7.50 (d, J = 9 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 2
H), 7.04 (d, J = 9 Hz, 2 H), 3.83 (s, 3 H), 2.56 (s, 3 H), 1.79 (s, 3 H).
Yield: 173 mg, 0.50 mmol (50%); Rf = 0.4 (EtOAc–n-hexane, 1:1).
IR (KBr): 3310, 2924, 2211, 1781, 1648, 1484, 1399, 1301, 1078, 769
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, A–K

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B. K. Dinda et al.
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Synthesis
13C NMR (150 MHz, DMSO-d6): δ = 170.8, 159.8, 155.0, 147.4, 139.8,
133.1, 131.0, 128.9, 128.8, 123.8, 123.6, 122.6, 118.2, 117.7, 113.8,
98.9, 55.6, 23.3, 22.0.
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HRMS (ESI): m/z calcd for C21H18N2O3 [M + H]+: 347.1396; found:
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Org. Chem. 2009, 5321. (b) Ooyama, Y.; Egawa, H.; Yoshida, K.
Eur. J. Org. Chem. 2008, 5239. (c) Ooyama, Y.; Kagawa, Y.;
Harima, Y. Eur. J. Org. Chem. 2007, 3613. (d) Mayer, C. R.; Dumas,
E.; Sécheresse, F. Chem. Commun. 2005, 345. (e) Taki, M.;
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Lett. 1999, 1, 527. (b) Rodríguez, I. I.; Rodríguez, A. D. J. Nat.
Prod. 2003, 66, 855. (c) McCulloch, M. W. B.; Berrue, F.; Haltli,
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347.1412.
7-Bromo-4-(4-methoxyphenyl)-2-methylnaphtho[2,1-d]oxazol-5-
ol (49)
According to the general procedure for annulation, the condensation
of 17h (119 mg, 0.50 mmol) with 14d (125 mg, 0.50 mmol) in the
presence of LiHMDS (1.75 mL, 1.75 mmol) produced compound 49 as
a white solid.
Yield: 81 mg, 0.21 mmol (42%); Rf = 0.4 (EtOAc–n-hexane, 1:3); mp
>280 °C.
IR (KBr): 3395, 3330, 3240, 1752, 1651, 1556, 1506, 1420, 1395, 1246
cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 9.22 (s, 1 H), 8.52 (s, 1 H), 8.07 (d,
J = 9 Hz, 1 H), 7.78 (d, J = 9 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.08 (d, J =
9 Hz, 2 H), 3.84 (s, 3 H), 2.66 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 163.8, 159.0, 145.4, 140.5, 138.2,
132.6, 130.3, 126.5, 126.3, 125.9, 122.3, 118.5, 118.0, 117.6, 113.9,
55.6, 14.7.
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Acknowledgment
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Hertweck, C. Angew. Chem. Int. Ed. 2011, 50, 1630.
We gratefully acknowledge financial support of CSIR and DST, New
Delhi. B.D., S.B., and B.G. thank CSIR, New Delhi for research fellow-
ships and contingency grant. We thank Dr. Ganesan Mani for assis-
tance in solving an X-ray structure.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561376.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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