Unexpected reaction of 2-amino-1,4-naphthoquinone with aldehydes: New synthesis of naphtho[2,1-d]oxazole compounds

Article abstract of DOI:10.1016/j.tet.2010.10.082

Treatment of 3-substituted 2-amino-1,4-naphthoquinones 3 with an aldehyde in a solution of hydrobromic acid in acetic acid led to 2,4-disubstituted naphtho[2,1-d]oxazol-5-ols. The outcome of this simple conversion is even more remarkable in view of the very similar reactions reported in literature, which all give rise to completely different products. Furthermore, the acquired naphthoxazoles 5-11 could be oxidatively ring opened by means of PIFA or CAN into a series of N-acylated 2-amino-1,4-naphthoquinones. A synthetic pathway towards 2-substituted naphtho[2,3-d]oxazole-4,9-diones was also disclosed as the outcome of CAN mediated oxidation of a 4-chloronaphtho[2,1-d]oxazol-5-ol. Copyright

Full text of DOI:10.1016/j.tet.2010.10.082

Tetrahedron 67 (2011) 512e517
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Unexpected reaction of 2-amino-1,4-naphthoquinone with aldehydes: new
synthesis of naphtho[2,1-d]oxazole compounds
Sam Van Aeken a, Jurgen Deblander a, Johan De Houwer b, Timothy Mosselmans a,
,b,
Kourosch Abbaspour Tehrani a
*
a Laboratory of Organic Chemistry, Department of Applied Biological Sciences and Engineering, Faculty of Science and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2,
B-1050 Brussels, Belgium
b Organic Synthesis, Faculty of Sciences, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2010
Received in revised form 21 October 2010
Accepted 27 October 2010
Available online 12 November 2010
Treatment of 3-substituted 2-amino-1,4-naphthoquinones 3 with an aldehyde in a solution of hydro-
bromic acid in acetic acid led to 2,4-disubstituted naphtho[2,1-d]oxazol-5-ols. The outcome of this
simple conversion is even more remarkable in view of the very similar reactions reported in literature,
which all give rise to completely different products. Furthermore, the acquired naphthoxazoles 5e11
could be oxidatively ring opened by means of PIFA or CAN into a series of N-acylated 2-amino-
1,4-naphthoquinones. A synthetic pathway towards 2-substituted naphtho[2,3-d]oxazole-4,9-diones was
also disclosed as the outcome of CAN mediated oxidation of a 4-chloronaphtho[2,1-d]oxazol-5-ol.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Oxazoles
Quinones
2-Amino-1
4-naphthoquinone
N-Acylation
1. Introduction
diones,8e11 1H-1-azaanthracene-9,10-diones12 and 1,2,3,4-tetrahyd-
robenzo[g]quinazoline-5,10-diones.13 The reactions of 2-amino-
Quinone and naphthoquinone moieties are prevalent motifs in
various natural products, which are associated with diverse
biological activities.1 Among the naphthoquinones, 2-amino-1,4-
naphthoquinone derivatives are interesting molecules because of
their molluscicidal,2 cytotoxic,3 anti-tumor4 and antibacterial5
activities. The 2-amino-1,4-naphthoquinone moiety can be even
found in natural products, such as echinamines A (1) and B (2)6
from the sea urchin Scaphechinus mirabilis and hygrocins A and B7
from Streptomyces hygroscopicus (Fig. 1).
1,4-naphthoquinone (3a) as nucleophile have received only little
attention, which is presumably due to the amide like character of the
amino group in 3a. An example of the bidendate nucleophilic char-
acter of 2-amino-1,4-naphthoquinone (3a) can be found in the
reaction of 3a with electrophiles such as methyleniminium salts. The
N-aminomethyl compounds initially formed by kinetic control are
subsequently converted to the thermodynamically more stable
C-Mannich reaction products.13 In some cases the nucleophilicity of
the amino group is greater than may be expected from a vinylogous
amide. For example, 2-amino-1,4-naphthoquinone (3a), reacts as an
N-nucleophile with b-ketoesters bis-dielectrophiles giving rise to
anilides that can be cyclized to 2-oxo-lH-1-azaanthraquinones.12
C-Alkylated 2-amino quinone derivatives are obtained by reaction
2-amino-1,4-naphthoquinone with dimethylacetylene dicarbox-
ylate14 or copper(I) bromide catalyzed Michael addition reaction
with methyl vinyl ketone and 2-propenal.15
Fig. 1.
As a result of their importance in medicinal chemistry, a large
number of quinone derivatives and related compounds have
been synthesized in order to explore for novel bioactive agents
with enhanced pharmacological properties. In continuation of
our interest on new syntheses16 of 1,4-naphthoquinones we wish
to report on a new methodology for the reaction of 2-amino-
1,4-naphthoquinones 3 with aldehydes.
Besides, 2-amino-1,4-naphthoquinone may serve as a synthetic
precursor for benzo[b]acridine-6,11-diones,8e10 benzo[f]indole-4,9-
* Corresponding author. E-mail address: Kourosch.Abbaspourtehrani@ua.ac.be
(K. Abbaspour Tehrani).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.082

S. Van Aeken et al. / Tetrahedron 67 (2011) 512e517
513
2. Results and discussion
acetic acid at room temperature. The 2,4-disubstituted 5-hydrox-
ynaphtho[2,1-d]oxazoles 9e11 were obtained in 80e97% yields and
did not require further purification (Scheme 1).
In the course of our research towards new azaanthraquinones we
needed 2-amino-3-alkenyl-1,4-naphthoquinones 4. Inspired by the
synthesis of 2-hydroxy-3-(prop-2-enyl)-1,4-naphthoquinone from
2-hydroxy-1,4-naphthoquinone,17 2-amino-1,4-naphthoquinone (3a)
was reacted with 5 equiv of propanal in the presence of a 0.23 M
hydrogen bromide solution in acetic acid at 75e80 ꢀC. After acid base
workup and extraction with diethyl ether a white-grey powder
was obtained. 1H NMR-analysis of this product indicated the absence
of typical olefinic protons in the 5e7 ppm region, and suggested the
formation of another compound other than the expected naph-
thoquinone 4. Complete spectral investigation of this compound by
means of both 1-D (1H NMR, 13C NMR) and 2-D (HMBC and HMQC)
NMR allowed us to assign the structure as 2-ethyl-5-hydroxynaphtho
[2,1-d]oxazole (5). The reaction of 3a with 1 equiv of propanal in
0.23 M hydrogen bromide solution in acetic acid at room temperature
and a simplification of the workup procedure allowed an improve-
ment of the yield from 50 to 74%. Since the purity of the reaction
product was higher when using an excess of aldehyde all the following
annulations of 2-aminonaphthoquinone were performed with 5 equiv
of aldehyde. The treatment of 3a with substituted aliphatic aldehydes
and benzaldehyde, gave rise to 2-substituted 5-hydroxynaphtho
[2,1-d]oxazoles 5e8 in moderate yields (Scheme 1). In general, these
hydroxynaphtho[2,1-d]oxazoles could be simply purified by high
vacuum evaporation to remove traces of aldehydes, leaving the
products in purities of over 95%. The reaction of 2-amino-
naphthoquinone (3a) with acetaldehyde however, only led to starting
material. Most likely the volatility of acetaldehyde is the reason for
this. Next, 3-substituted 2-amino-1,4-naphthoquinones 3bed were
reacted with pivaldehyde in a 0.23 M hydrogen bromide solution in
Some closely related naphthoxazoles, like neosalvianen 1218 and
salviamines BeD 1319 have been isolated from several medicinal
Salvia species. Several other 5-oxygenated naphtho[1,2-d]oxazoles,
e.g.,14, derivatives of lapachol, display trypanocidal activity (Fig. 2).20
Fig. 2.
The formation of these naphtho[2,1-d]oxazoles was completely
unexpected since a previously reported reaction of 2-amino-
naphthoquinone with butanal or benzaldehyde in an excess of TFA
leads to 6,13-dihydro-6-azapentacene-5,7,12,14-tetraones 15 in
low yields. According to the literature, by changing the acid to
sulfuric acid, 2,4-diphenyl-1H-2,4-dihydronaphtho[2,3-d]1,3-oxa-
zine-5,10-dione (16) was formed.21 Under neutral conditions
2-amino-1,4-naphthoquinone (3a) reacts with aldehydes to give
N-(alkenyl)aminoquinones 17 in 47e56% yield, while a catalytic
amount of trifluoroacetic acid generates a diastereomeric mixture
of 2,4-dialkyl-1H-2,4-dihydronaphtho[2,3-d]1,3-oxazine-5,10-dio-
nes 18 (Scheme 2).22 Compounds 15 and 16, though in very low
Scheme 1.
Scheme 2.

514
S. Van Aeken et al. / Tetrahedron 67 (2011) 512e517
yields, were produced under very concentrated reaction conditions
(approximately 1 mmol of quinone/ml solvent), which might ex-
plain the fact that 2 mol of aldehyde were incorporated in 16 and
2 mol of quinone in 15.
Clearlythemechanismofformationof thenaphtho[2,1-d]oxazoles
5e11 is different from that of the related reactions in Scheme 2. Most
likely, a hemi-aminal 19 is formed, which upon a 5-exo-trig attack of
the hydroxyl group to the C1]O carbonyl resulted in an oxazolidine
ring 20. A subsequent electron delocalisation towards C4]O (com-
pound 21) followed by an elimination of water gave the oxazole
could be separated from two unknown compounds by means of
flash chromatography and was obtained in 35% yield (Scheme 5).
Compound 9, which can be regarded as a hydroquinone monoalkyl
ether will undergo an initial one-electron oxidation leading to
the electrophilic cation-radical 24, which eventually is attacked
by a molecule of water to give the hydrate (not shown). A second
one-electron oxidation leads to a cation, which is attacked by
water to give 25.25 Ring opening of 25 gives the 2-acylamino-
naphthoquinone 22b, which upon Lewis acid catalysis by Ce(IV)26
will undergo an intramolecular 1,4-addition of the amide oxygen
ring annulated to the
a-naphthol as the characteristic structural fea-
to the a,b-unsaturated enone. Elimination of HCl in 27 finally
ture of 5e11 (Scheme 3). The reaction of 2-aminonaphthoquinone
with 2-butanone in 0.23 M hydrogen bromide solution in acetic acid
at room temperature only afforded starting material.
yields the naphtho[2,3-d]oxazole-4,9-dione 23. In case of the
CAN oxidation of compound 7 also an intramolecular nucleophilic
attack on the enone system occurs, but instead of HCl elimination
the aromatic oxazole is formed by air oxidation.
Scheme 3.
Next, the oxidation reaction of 7 with different oxidising agents
was investigated. The reaction of 7 (R1¼H, R2¼tBu) with 1e3 equiv
of cerium(IV) ammonium nitrate (CAN) in aqueous acetonitrile at
0
ꢀC afforded a tarry reaction mixture containing varying ratio’s
of 2-(pivaloylamino)-1,4-naphthoquinone 22a, a rearranged oxa-
zole 23 and an unknown compound. The formation of 22a and
this unknown compound could be avoided by using a large excess
of 10 equiv of CAN under dilute conditions. After flash chroma-
tography, 2-tert-butylnaphtho[2,3-d]oxazole-4,9-dione (23) could
be isolated in only 10% yield (Scheme 4).
Scheme 5.
Scheme 4.
Hypervalent iodine reagents, e.g., [bis(trifluoroacetoxy)iodo]
benzene (PIFA) are frequently used to oxidize phenols,23 because of
the mild reaction conditions, good oxidation performances and low
toxicity.24 Indeed, the reaction of 7 with 1.5 equiv of PIFA in aqueous
acetonitrile led to an 18/1 (LC-MS) mixture of 2-(pivaloylamino)-
1,4-naphthoquinone (22a) and 2-tert-butylnaphtho[2,3-d]oxazole-
4,9-dione (23) (Scheme 4). Increasing the amount of PIFA to
2.5 equiv did not lead to further conversion of 22a into 23.
On the other hand, by the oxidation of 9 with 1.5 equiv of
PIFA 3-chloro-2-(pivaloylamino)-1,4-naphthoquinone (22b) was
isolated as the sole product in excellent yield after flash chro-
matography (Scheme 6). The mechanism of the PIFA oxidation
presumably involves initial ligand exchange at the iodine(III)
center of PIFA.27 This intermediate 28 is then trapped by a wa-
ter molecule and after reductive elimination of iodobenzene
leads to the product 25, which finally ring opens to give 22b. In
this case the absence of a Lewis acid prevents the further
intramolecular nucleophilic attack of oxygen on the enone
system.
2-tert-Butylnaphtho[2,3-d]oxazole-4,9-dione (23) could be
prepared in a more convenient way by treating 9 (R1¼Cl, R2¼tBu)
with 3 equiv of CAN in aqueous acetonitrile at 0 ꢀC. Compound 23

S. Van Aeken et al. / Tetrahedron 67 (2011) 512e517
515
importance. Furthermore, the acquired naphthoxazoles could be
oxidatively ring opened by means of PIFA or CAN into a series of
N-acylated 2-amino-1,4-naphthoquinones 22. A synthetic pathway
towards 2-substituted naphtho[2,3-d]oxazole-4,9-diones 23 was
also disclosed as the outcome of CAN mediated oxidation of
a 4-chloronaphtho[2,1-d]oxazol-5-ol 9.
4. Experimental section
4.1. General experimental methods
1H NMR spectra were recorded on a Bruker Avance DRX 250
spectrometer at 250 MHz or a Bruker Avance II 500 spectrometer at
500 MHz with internalstandard TMS.13C NMR spectrawere recorded
on a Bruker Avance DRX 250 spectrometer at 63 MHz, Bruker Avance
II 500 spectrometer at 125 MHz with internal standard CDCl3 (
d¼77).
13C NMR assignments were made using DEPT spectra. Melting points
€
were determined on a Buchi melting point apparatus B-540 and
are uncorrected. GCeMS analyses were performed using an Inter-
sience GC 8000 series gas chromatograph with an ECÔ-5 column
(length: 30 m, internal diameter: 0.32 mm, film thickness: 0.25 mm).
Scheme 6.
Products were injected in a split injector (250 ꢀC); the inert carrier
gas is helium. The mass spectrometer was a Fisons Instruments MD
800 using electron impact (70 eV) as ionization method. HRMS
was measured with a VGQuattro II mass spectrometer. Infrared
spectra were recorded with an Avatar 370 FT-IR apparatus (Thermo
Nicolet), using the attenuated total reflection technology. Column
chromatography was performed using Merck silica (diameter
Encouraged by this result 10 (R1¼Me, R2¼tBu) was also reacted
with 3 equiv of CAN, but this led to a complex reaction mixture,
which could not be further elucidated. The milder reaction of 10
and 11 with 1.5 equiv of PIFA furnished 3-methyl-2-(pivaloylamino)
naphthoquinone 22c and 22d as the only products in an excellent
crude yield (83e87%, 90% purity by HPLC). After flash chromatog-
raphy on silica gel the yields dropped drastically to 49% and
51%, respectively. The 4-methoxycarbonylnaphtho[2,1-d]oxazole
11, could also be completely converted into the N-acylated 2-ami-
nonaphthoquinone 22d upon treatment with CAN. Because of the
rather large drop in yield (56%) after flash chromatography on
silica gel, an alternative purification of 14d on neutral alumina
was attempted, but quantitative hydrolysis of the amide occurred,
furnishing the initial starting product 3d in 31% yield (Scheme 7).
40e63
mm). TLC-analysis was performed on glass-backed plates
(Merck) coated with 0.2 mm silica 60F254. Amino naphthoquinones
3a,28 3c28 and 3d29 were prepared according to literature procedures.
4.2. Reaction of 2-amino-1,4-naphthoquinones with
aldehydes: general procedure
2-Amino-1,4-naphthoquinone 3a (100 mg, 0.56 mmol) was dis-
solved in acetic acid (2 mL), after which a 33% solution of HBr in
acetic acid (0.1 mL) and the aldehyde (2.8 mmol) were added drop-
wise. It is important to prevent evaporation of the aldehyde by means
of a reflux condenser. The reaction mixture was stirred at room
temperature from 24 h to 48 h and followed to completion by TLC
(Petroleum ether/EtOAc, 2/1). After completion the reaction mixture
was diluted with water and extracted with diethyl ether. The com-
bined organic extracts were washed with aqueous sodium
bicarbonate, aqueous sodium sulphite and brine. Drying over
MgSO4, followed by filtration and concentration in vacuo gave the
corresponding product in moderate to good yield and more than
95% purity (HPLC). Eventually recrystallisation may be performed in
Et2O/heptane.
4.2.1. 2-Ethyl-5-hydroxynaphtho[2,1-d]oxazole (5). Yield: 74%. Light
brown powder, mp 208.3e208.7 ꢀC. 1H NMR (250 MHz, DMSO):
d
1.39 (3H, t, J¼7.5 Hz, CH2CH3), 3.01 (2H, q, J¼7.5 Hz, CH2CH3), 7.10
(1H, s, 4-CH), 7.49 (1H, ddd, J¼1.3, 7.0, 8.4 Hz, 7-CH), 7.64 (1H, ddd,
J¼1.3, 6.9, 8.2 Hz, 8-CH), 8.05 (1H, d, J¼8.1 Hz, 9-CH), 8.23 (1H, d,
J¼8.1 Hz, 6-CH), 10.26 (1H, s, OH). 13C NMR (62.90 MHz, DMSO):
Scheme 7.
3. Conclusions
d 10.9 (CH3), 21.5 (CH2), 99.2 (4-C), 119.3 (9-C), 119.7 (5a-C), 122.6
(9a-C), 123.4 (6-C), 124.2 (8-C), 127.4 (7-C), 137.5 (3a-C), 139.2 (9b-
A versatile procedure was discovered towards 2,4-disubsti-
tuted naphtho[2,1-d]oxazol-5-ols 5e11 and consisted in treating
3-substituted 2-amino-1,4-naphthoquinones 3 with an aldehyde in
a solution of hydrobromic acid in acetic acid. The outcome of
this simple reaction is even more remarkable in view of the very
similar reactions reported in literature, which all give rise to
completely different products. Apparently the type of acid and the
concentration of reagents used in this condensation are of prime
C), 150.7 (5-C), 167.0 (2-C). IR (KBr, cmꢁ1):
n 1586, 1639, 3157. MS
(70 eV, m/z (%)): 214 ([Mþ1]þ, 46), 213 ([M]þ, 100), 212 (93), 130
(54), 105 (47), 102 (91), 101 (67), 76 (54), 75 (48). HRMS (ESI): m/z
calcd for C13H11NO2þHþ: 214.0863; found 214.0856.
4.2.2. 2-Isopropyl-5-hydroxynaphtho[2,1-d]oxazole (6). Yield: 50%.
Dark red powder, mp 171.7e172.3 ꢀC. 1H NMR (400 MHz, DMSO):
d
1.43 (6H, d, J¼6.9 Hz, CH(CH3)2), 3.33 (1H, septet, J¼6.9 Hz, CH

516
S. Van Aeken et al. / Tetrahedron 67 (2011) 512e517
(CH3)2), 7.11 (1H, s, 4-CH), 7.50 (1H, ddd, J¼1.2, 7.0, 8.3 Hz, 7-CH),
7.64 (1H, ddd, J¼1.1, 7.0, 8.1 Hz, 8-CH), 8.06 (1H, d, J¼8.0 Hz, 9-CH),
8.26 (1H, d, J¼8.0 Hz, 6-CH), 10.25 (1H, s, OH). 13C NMR
CHarom.), 8.20 (1H, d, J¼8.1 Hz, CHarom.), 8.43 (1H, d, J¼8.4 Hz, CHarom.),
12.5 (1H, s, OH).13C NMR (62.90 MHz, CDCl3):
28.7 (C(CH3)3), 34.5 (C
d
(CH3)3), 52.9 (OCH3), 99.0 (Cquat.), 119.8 (CHarom.), 122.8 (Cquat.), 123.3
(Cquat.), 125.2 (CHarom.), 125.4 (CHarom.), 125.8 (Cquat.), 130.3 (CHarom.),
130.8 (Cquat.),134.2 (Cquat.),160.0 (5-C),171.6 (2-C or CO), 173.2 (CO or
(100.60 MHz, DMSO):
d 20.3 (CH(CH3)2), 28.2 (CH(CH3)2), 99.2
(4-C), 119.3 (9-C), 119.7 (5a-C), 122.6 (9a-C), 123.4 (6-C), 124.2 (8-C),
127.3 (7-C), 137.3 (3a-C), 139.1 (9b-C), 150.7 (5-C), 170.0 (2-C). IR
2-C). IR (ATR, cmꢁ1):
n 706, 757, 803, 1049, 1142, 1253, 1349, 1439,
(ATR, cmꢁ1):
n
1580, 1643. MS (70 eV, m/z (%)): 228 ([Mþ1]þ, 13),
1556,1647, 2971. MS (ES) m/z (%): 300 (MþHþ, 100). HRMS (ESI): m/z
227 ([M]þ, 99), 226 (37), 212 (100), 185 (10), 105 (22), 102 (44), 101
(20), 77 (17), 76 (19), 75 (16).
calcd for C17H17NO4þHþ: 300.1230; found 300.1221.
4.3. CAN oxidationdgeneral procedure
4.2.3. 2-tert-Butyl-5-hydroxynaphtho[2,1-d]oxazole (7). Yield: 79%.
Light brown powder, mp 203.5e204.1 ꢀC. 1H NMR (250 MHz,
The oxazole (0.2 mmol) was suspended in an acetonitrile/water
(3:1) (2 mL) mixture and cooled to 0 ꢀC, after which cerium am-
monium nitrate (0.6 mmol) was added. The reaction mixture was
stirred for 1 h at 0 ꢀC and subsequently quenched with water and
extracted with ethyl acetate. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The obtained residue
was if needed purified by flash chromatography on silica gel.
DMSO):
d 1.49 (9H, s, C(CH3)3), 7.10 (1H, s, 4-CH), 7.50 (1H, ddd,
J¼1.3, 7.0, 8.4 Hz, 7-CH), 7.64 (1H, ddd,¼1.2, 6.9, 8.2 Hz, 8-CH), 8.10
(1H, d, J¼7.9 Hz, 9-CH), 8.35 (1H, d, J¼8.3 Hz, 6-CH), 10.25 (1H, s,
OH). 13C NMR (62.90 MHz, DMSO):
d 28.3 (C(CH3)3), 33.8 (C(CH3)3),
99.2 (4-C), 119.3 (9-C), 119.7 (5a-C), 122.6 (9a-C), 123.4 (6-C), 124.2
(8-C), 127.3 (7-C), 136.7 (3a-C), 139.1 (9b-C), 150.5 (5-C), 172.0 (2-C).
IR (ATR, cmꢁ1): 1582, 1644. MS (70 eV, m/z (%)): 242 ([Mþ1]þ, 39),
n
241 ([M]þ, 82), 227 (40), 226 (85), 185 (100), 130 (64), 105 (55), 102
(70), 101 (49), 77 (42), 57 (58). HRMS (ESI): m/z calcd for
C15H15NO2þHþ: 242.1176; found 242.1183.
4.3.1. 2-tert-Butylnaphtho[2,3-d]oxazole-4,9-dione
(23). This
compound has been prepared before.30 Complete spectral data are
given here.
Rf¼0.05 (petroleum ether/EtOAc: 6/1). Yield: 35%. Yellow powder,
4.2.4. 2-Phenyl-5-hydroxynaphtho[2,1-d]oxazole (8). Yield: 65%.
Dark brown powder, mp (decomp.) 181.2e181.6 ꢀC. 1H NMR
mp 135e136 ꢀC. 1H NMR (250 MHz, CDCl3):
d 1.50 (9H, s, CH3), 7.54
(1H, ddd, J¼3.2, 5.6, 7.7 Hz, CHarom.), 7.73e7.70 (2H, m, CHarom.), 8.14
(250 MHz, DMSO):
7.92e7.95 (2H, m, CHarom.), 8.22e8.30 (2H, m, CHarom.), 10.41 (2H, s,
OH). 13C NMR (62.90 MHz, DMSO):
99.6 (CHarom.), 120.2 (CHarom.),
d
7.19 (1H, s, 4-CH), 7.46e7.75 (5H, m, CHarom.),
(1H, dd, J¼1.7, 7.7 Hz, CHarom.). 13C NMR (62.90 MHz, CDCl3):
d 28.4 (C
(CH3)), 34.4 (C(CH3)), 87.4 (Cquat.), 122.9 (CHarom.), 126.2 (Cquat.), 129.3
(Cquat.), 131.0 (2ꢂCHarom.), 135.4 (CHarom.), 158.8 (Cquat.), 173.5 (Cquat.),
d
124.1 (CHarom.), 125.3 (Cquat.), 127.3 (CHarom.), 128.2 (CHarom.), 129.0
(2ꢂCHar), 129.7 (CHarom.), 129.8 (CHarom.), 131.8 (Cquat.), 133.3
(CHarom.), 138.9 (Cquat.), 140.0 (Cquat.), 151.9 (5-C), 162.1 (Cquat.), 167.8
180.0 (CO), 184.2 (CO). IR (ATR, cmꢁ1):
n 695, 784, 906, 1103, 1201,
1569, 1585, 1680, 2974. MS (ESþ) m/z (%): 256 (MþHþ, 100). HRMS
(ESI): m/z calcd for C15H13NO3þHþ: 256.0968; found 256.0958.
(2-C). IR (ATR, cmꢁ1):
n 1583, 1597, 1683. MS (70 eV, m/z (%)): 263
([Mþ2]þ, 2), 262 ([Mþ1]þ, 19), 261 ([M]þ, 100), 130 (39), 104 (22),
102 (74), 77 (16), 76 (20), 75 (14), 73 (13). HRMS (ESI): m/z calcd for
C17H11NO2þHþ: 262.0863; found 262.0852.
4.3.2. 2-Methoxycarbonyl-3-(pivaloylamino)-1,4-naphthoquinone
(22d). Rf¼0.33 (petroleum ether/EtOAc: 2/1). Yield: 56%, mp
113.1e113.9 ꢀC. 1H NMR (250 MHz, CDCl3):
d 1.34 (9H, s, C(CH3)3),
3.95 (3H, s, OCH3), 7.78 (2H, ddd, J¼1.6, 7.0, 8.7 Hz, 6-CH and 7-CH),
4.2.5. 2-tert-Butyl-4-chloro-5-hydroxynaphtho[2,1-d]oxazole
8.11 (2H, ddd, J¼1.5, 6.0, 8.1 Hz, 5-CH and 8-CH). 13C NMR
(9). Yield: 97%. Orange-brown powder, mp 127.8e128.8 ꢀC. 1H
(62.90 MHz, CDCl3): d 27.1 (C(CH3)), 40.5 (C(CH3)3), 52.7 (OCH3),
NMR (250 MHz, CDCl3):
d
1.57 (9H, s, CH3), 5.97 (1H, s, OH), 7.54
121.9 (Cquat.), 126.7 (CHarom.), 126.9 (CHarom.), 129.4 (Cquat.), 131.7
(Cquat.), 133.7 (CHarom.), 135.6 (CHarom.), 136.1 (Cquat.), 164.0 (CO),
(1H, ddd, J¼1.4, 7.0, 8.4 Hz, CHarom.), 7.64 (1H, ddd, J¼1.3, 6.8, 8.2 Hz,
CHarom.), 8.14 (1H, dd, J¼1.1, 9.0 Hz, CHarom.), 8.32 (1H, dd, J¼1.3,
176.5 (CO), 181.4 (CO), 181.6 (CO). IR (ATR, cmꢁ1):
n 713, 743, 789,
8.2 Hz, CHarom.). 13C NMR (62.90 MHz, CDCl3):
d
28.8 (C(CH3)), 34.6
953, 971, 1118, 1157, 1286, 1488, 1661, 1704, 1734, 3355. MS (ES) m/z
(%): 316 (MþHþ, 100). HRMS (ESI): m/z calcd for C17H17NO5þHþ:
316.1179; found 316.1168.
(C(CH3)3), 104.8 (Cquat.), 119.1 (Cquat.), 119.9 (CHarom.), 122.3 (Cquat.),
123.3 (CHarom.), 125.4 (CHarom.), 127.4 (CHarom.), 134.8 (Cquat.), 141.0
(Cquat.),145.1 (5-C), 173.6 (2-C). IR (ATR, cmꢁ1):
n 758, 846, 914,1014,
1142, 1203, 1418, 1450, 1544, 2969. MS (ES) m/z (%): 276 (MþHþ,
100), 278 (Mþ3). HRMS (ESI): m/z calcd for C15H14ClNO2þHþ:
276.0786; found 276.0781.
4.4. PIFA oxidationdgeneral procedure
The oxazole (0.42 mmol) was dissolved in a mixture of aceto-
nitrile/water (2:1) (21 mL), with some MeOH (175 ml, 2.5 v/vH2O %).
4.2.6. 2-tert-Butyl-5-hydroxy-4-methylnaphtho[2,1-d]oxazole
1.5 equiv of PIFA was added and the reaction mixture was allowed
to stir for the indicated amount of time at room temperature. After
completion, the reaction mixture was diluted with water and
extracted with ethyl acetate. The combined organic phases were
dried over MgSO4 and concentrated in vacuo. The collected residue
was further purified by flash chromatography on silica gel.
(10). Yield: 80%. Dark red powder, mp 122.4e123.7 ꢀC. 1H NMR
(250 MHz, CDCl3): d 1.49 (9H, s, C(CH3)3), 2.48 (3H, s, CH3), 5.11 (1H,
s, OH), 7.49 (1H, ddd, J¼1.4, 6.9, 8.3 Hz, CHarom.), 7.56 (1H, ddd,
J¼1.2, 6.9, 8.0 Hz, CHarom.), 7.93 (1H, dd J¼0.6, 8.8 Hz, CHarom.), 8.18
(1H, dd, J¼0.4, 9.1, Hz, CHarom.). 13C NMR (62.90 MHz, CDCl3):
d 10.9
(CH3), 28.8 (C(CH3)3), 35.8 (C(CH3)3), 110.5 (Cquat.), 119.8 (Cquat.),
120.4 (CHarom.), 124.3 (CHarom.), 125.8 (Cquat.), 126.2 (CHarom.), 127.7
(CHarom.), 136.2 (Cquat.), 141.2 (Cquat.), 149.1 (5-C), 174.4 (2-C). IR
4.4.1. 2-(Pivaloylamino)-1,4-naphthoquinone (22a). Rf¼0.13 (petro-
leum ether/EtOAc: 4/1). Yield: 73%. Yellow powder, mp
(ATR, cmꢁ1):
n
755, 960, 1065, 1354, 1546, 2973. MS (ES) m/z (%):
199.3e199.9 ꢀC. 1H NMR (250 MHz, CDCl3):
d 1.35 (9H, s, C(CH3)3),
256 (MþHþ, 100). HRMS (ESI): m/z calcd for C16H17NO2þHþ:
7.72 (1H, dꢂpseudo t, J¼1.5, 7.5 Hz, 6-CH or 7-CH), 7.79 (1H,
dꢂpseudo t, J¼1.6, 7.6 Hz, 7-CH or 6-CH), 7.86 (1H, s, 2-CH), 8.11 (2H,
dd, J¼1.8, 7.3 Hz, 5-CH and 8-CH), 8.73 (1H, broad s, NH). 13C NMR
256.1332; found 256.1339.
4.2.7. 2-tert-Butyl-5-hydroxy-4-methoxycarbonylnaphtho[2,1-d]ox-
(62.90 MHz, CDCl3): d 27.3 (C(CH3)3), 40.6 (C(CH3)3), 116.9 (CHarom.),
azole (11). Yield: 86%. White powder, mp 150.3e151.1 ꢀC. 1H NMR
119.3 (Cquat.), 126.4 (CHarom.), 126.6 (CHarom.), 132.2 (Cquat.), 133.2
(CHarom.), 135.0 (CHarom.), 140.0 (Cquat.), 177.9 (CO), 181.5 (CO), 185.2
(250 MHz, CDCl3):
d 1.57 (9H, s, C(CH3)3), 4.14 (1H, s, OCH3), 7.53
(1H, ddd, J¼1.2, 7.1, 8.4 Hz, CHarom.), 7.72 (1H, ddd, J¼1.2, 7.0, 8.2 Hz,
(CO). IR (ATR, cmꢁ1):
n 724, 789, 886,1105,1201,1297,1336,1477,1497,

S. Van Aeken et al. / Tetrahedron 67 (2011) 512e517
517
1644, 1704, 2964, 2983, 3374. MS (ESþ) m/z (%): 258 (MþHþ, 100).
HRMS (ESI): m/z calcd for C15H15NO3þHþ: 258.1125; found 258.1132.
2. Barbosa, T. C.; Camara, C. A.; Silva, T. M. S.; Martins, R. M.; Pinto, A. C.; Vargas,
M. D. Bioorg. Med. Chem. 2005, 13, 6464e6469.
3. Del Corral, J. M. M.; Castro, M. A.; Gordaliza, M.; Martõn, M. L.; Gualberto, S. A.;
ꢀ
Gamito, A. M.; Vuevas, C.; San Feliciano, A. Bioorg. Med. Chem. 2005, 13,
631e644.
4. (a) Moret, E. E.; de Boer, M.; Hilbers, H. W.; Tollenaere, J. P.; Janssen, L. H. M.;
Holthuis, J. J. M.; Driebergen, R. J.; Verboom, W.; Reinhoudt, D. N. J. Med. Chem.
1996, 39, 720e728; (b) Bakare, O.; Ashendel, C. L.; Peng, H.; Zalkow, L. H.;
Burgess, E. M. Bioorg. Med. Chem. 2003, 11, 3165e3170.
4.4.2. 2-Chloro-3-(pivaloylamino)-1,4-naphthoquinone
(22b). Rf¼0.15 (petroleum ether/EtOAc: 4/1). Yield: 80%. Yellow
powder, mp 140.6e141.4 ꢀC. 1H NMR (250 MHz, CDCl3):
d 1.38 (9H,
s, C(CH3)), 7.75 (1H, dꢂpseudo t, J¼1.9, 7.0 Hz, 6-CH or 7-CH), 7.79
(1H, dꢂpseudo t, J¼1.9, 7.0 Hz, 7-CH or 6-CH), 7.92 (1H, broad s,
NH), 8.09e8.13 and 8.18e8.20 (2ꢂ1H, 2ꢂm, 5-CH and 8-CH). 13C
5. Oliveira, C. G. T.; Mˇ iranda, F. F.; Ferreira, V. F.; Freitas, C. C.; Rabello, R.; Car-
ballido, J. M.; Correa, L. C. D. J. Braz. Chem. Soc. 2001, 12, 339e345.
6. (a) Mischenko, N. P.; Fedoreyev, S. A.; Pokhilo, N. D.; Anufriev, V. Ph.; Deni-
senko, V. A.; Glazunov, V. P. J. Nat. Prod. 2005, 68, 1390e1393; (b) Pokhilo, N. D.;
Shuvalova, M. I.; Lebedko, M. V.; Sopelnyak, G. I.; Yakubovskaya, A. Ya.;
Mischenko, N. P.; Fedoreyev, S. A.; Anufriev, V. Ph. J. Nat. Prod. 2005, 69,
1125e1129.
NMR (62.90 MHz, CDCl3):
d 27.4 (C(CH3)), 40.5 (C(CH3)), 127.0
(CHarom.), 127.5 (CHarom.), 130.3 (Cquat.), 131.6 (Cquat.), 134.1 (CHarom.),
134.8 (CHarom.), 139.6 (Cquat.), 175.2 (CO), 177.7 (CO), 180.1 (CO). IR
(ATR, cmꢁ1):
n 714, 787, 1104, 1464, 1483, 1590, 1661, 1704, 1969,
7. Cai, P.; Kong, F.; Ruppen, M. E.; Glasier, G.; Carter, G. T. J. Nat. Prod. 2005, 68,
1736e1742.
3333. MS (ES) m/z (%): 292 (MþHþ, 100), 294 (Mþ3, 20). HRMS
8. Jiang, M.-C.; Chuang, C.-P. J. Org. Chem. 2000, 65, 5409e5412.
9. Chuang, C.-P.; Wu, Y.-L.; Jiang, M.-C. Tetrahedron 1999, 55, 11229e11236.
10. Chuang, C.-P.; Wang, S.-F. Heterocycles 1999, 50, 489e497.
11. (a) Wu, Y.-L.; Chuang, C.-P.; Lin, P.-Y. Tetrahedron 2001, 57, 5543e5549;
(b) Chuang, C.-P.; Wang, S.-F. Tetrahedron 1998, 54, 10043e10052.
(ESI): m/z calcd for C15H14ClNO3þHþ: 292.0735; found 292.0731.
4.4.3. 2-Methyl-3-(pivaloylamino)-1,4-naphthoquinone
(22c). Rf¼0.28 (petroleum ether/EtOAc: 4/1). Yield: 49%. Yellow
~
12. Marcos, A.; Pedregal, C.; Avendano, C. Tetrahedron 1994, 50, 12941e12952.
powder, mp 109.6e110.8 ꢀC. 1H NMR (500 MHz, CDCl3):
d 1.37
€
€
13. Mohrle, H.; Herbruggen, G. S. Arch. Pharm. 1991, 324, 165e171.
14. Pinto, A. V.; Ferreira, V. F.; Pinto, M. C. F. R.; Mayer, L. U. Synth. Commun. 1985, 15,
1181e1189.
(9H, s, C(CH3)3), 2.06 (3H, s, CH3), 7.69 (1H, dꢂpseudo t, J¼1.1,
7.4 Hz, 6-CH or 7-CH), 7.73 (1H, dꢂpseudo t, J¼1.2, 7.4 Hz, 7-CH or
6-CH), 8.05 (1H, dd, J¼0.9, 7.4 Hz, 5-CH or 8-CH), 8.11 (2H, d,
J¼7.6 Hz, 8-CH or 5-CH and NH overlap). 13C NMR (126 MHz,
15. Tapia, R. A.; Venegas, J.; Cantuarias, L. B. Synth. Commun. 2010, 40, 151e156.
16. (a) Jacobs, J.; Deblander, J.; Kesteleyn, B.; Abbaspour Tehrani, K.; De Kimpe, N.
Tetrahedron 2008, 64, 5345e5353; (b) Claessens, S.; Jacobs, J.; Van Aeken, S.;
Abbaspour Tehrani, K.; De Kimpe, N. J. Org. Chem. 2008, 73, 7555e7559; (c)
Deblander, J.; Van Aeken, S.; Jacobs, J.; De Kimpe, N.; Abbaspour Tehrani, K. Eur.
J. Org. Chem. 2009, 4882e4892; (d) Shinkevich, E.; Deblander, J.; Matthijs, S.;
Jacobs, J.; De Kimpe, N.; Abbaspour Tehrani, K. Org. Biomol. Chem., doi:10.1039/
C0OB00391C.
17. Hooker, S. C. J. Am. Chem. Soc. 1936, 58, 1163e1167. 2-Hydroxy-1,4-
naphthoquinone was reacted with with propanal in hot glacial acetic
acid and concentrated hydrochloric acid. The final concentration of HCl was
0.65 M.
CDCl3):
d 14.5 (CH3), 27.5 (C(CH3)), 40.3 (C(CH3)3), 126.2 (CHarom.),
126.7 (CHarom.), 130.5 (Cquat.), 132.5 (Cquat.), 133.3 (CHarom.), 134.4
(CHarom.), 135.3 (Cquat.), 138.1 (Cquat.), 176.4 (CO), 182.2 (CO), 184.8
(CO). IR (ATR, cmꢁ1):
n 714, 793, 1137, 1196, 1293, 1458, 1478,
1654, 1692 cmꢁ1. MS (ESþ) m/z (%): 272 (MþHþ, 100). HRMS (ESI):
m/z calcd for C16H17NO3þHþ: 272.1281; found 272.1289.
18. Don, M.-J.; Shen, C.-C.; Lin, Y.-L.; Syu, W., Jr.; Ding, Y.-H.; Sun, C.-M. J. Nat. Prod.
2005, 68, 1066e1070.
Acknowledgements
19. Lin, F.-W.; Damu, A. G.; Wu, T.-S. J. Nat. Prod. 2006, 69, 93e96.
20. (a) De Moura, K. C. G.; Emery, F. S.; Neves-Pinto, C.; Pinto, M. C. F. R.; Dantas, A.
We gratefully acknowledge the Research FoundationdFlanders
(FWO-Vlaanderen) and the IWT for financial support of this research.
~
P.; Salomao, K.; de Castro, S. L.; Pinto, A. V. J. Braz. Chem. Soc. 2001, 12, 325e338;
ꢀ
(b) Malta, V. R. S.; Pinto, A. V.; Molfetta, F. A.; Honorio, K. M.; de Simone, C. A.;
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21. Marcos, A.; Pedregal, C.; Avendano, C. Tetrahedron 1995, 51, 6565e6572.
Supplementary data
~
22. Hamdan, A. J.; Al-Jaroudi, S. Arabian J. Sci. Eng. 2003, 28, 51e60.
23. (a) Barret, R.; Daudon, M. Tetrahedron Lett. 1990, 31, 4871e4872; (b) Pelter, A.;
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Copies of 1H NMR and 13C NMR spectra for compounds 5e11,
22aed and 23 are included in the Supplementary data. Supplemen-
tary data related to this article can be found online at doi:10.1016/
j.tet.2010.10.082. These data include MOL files and InChIKeys of the
most important compounds described in this article.
25. Krohn, K.; Vitz, J. J. Prakt. Chem. 2000, 342, 825e827.
ꢀ
26. For examples where CAN acts as a Lewis acid see: Sridharan, V.; Menendez, J. C.
Chem. Rev. 2010, 110, 3805e3849.
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