Copper-mediated addition of ethanolamine affording 2-hydroxymethyl naphtho[2,1-d]oxazoles from 2-naphthols

Article abstract of DOI:10.1002/jhet.1666

A new and mild synthetic approach was presented for the synthesis of naphtho[2,1-d]oxazoles. In the presence of copper (II)-ethanolamine, 2-hydroxymethyl naphtho[2,1-d]oxazoles were one-pot synthesized in moderate to good yields through copper-mediated oxidation of 2-naphthols followed with the addition of ethanolamine in acetonitrile.

Full text of DOI:10.1002/jhet.1666

Month 2013
Copper-Mediated Addition of Ethanolamine Affording 2-Hydroxymethyl
Naphtho[2,1-d]oxazoles from 2-Naphthols
Xiuzhen Wang,* Baoyun Yang, and Rui Li
College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, People’s Republic of China
*
E-mail: wxzqq1234@163.com
Received January 13, 2012
DOI 10.1002/jhet.1666
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A new and mild synthetic approach was presented for the synthesis of naphtho[2,1-d]oxazoles. In the
presence of copper (II)-ethanolamine, 2-hydroxymethyl naphtho[2,1-d]oxazoles were one-pot synthesized
in moderate to good yields through copper-mediated oxidation of 2-naphthols followed with the addition
of ethanolamine in acetonitrile.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
was poor with only 16%. In order to enhance the yield, the
reaction conditions were optimized by changing the
solvent, temperature, and reaction atmosphere. The results
were summarized in Table 1. It was found that solvents
played a significant role in improving the yields (Table 1,
entries 1–6). As seen from Table 1, the yield was as high
as 57% with acetonitrile. Additionally, we screened the
impact of temperature and reaction atmosphere on the
Aryloxazoles are often found in naturally occurring
compounds that exhibit multiple and strong biological
activities, such as inhibitors of immune complex [1],
bacteriostatic agents [2], and cysteine protease inhibiters
[
3]. These compounds have been studied for extensively ever
since Fisher et al. synthesized 2-methylnaphthoxaz-ole
in 1906 [4]. Many useful synthetic approaches have been
developed, including the oxidation of 6-hydroxyindole with
primary amines [5], the reaction of a-nitroso-b-naphthol
with a pyridinium betaine to give oxazoles [6], the reactions
of quinone monoximes with alkyl halides [7], the coupling
of aminonaphthols with carboxylic acid derivatives [8],
photolysis of naphthoxazinone to afford 2-phylnaphthoxa-
zole [9], or photochemical synthesis from 5-(phenyl/hetero-
arylenthenyl)oxazoles [10]. However, copper-mediated
synthesis of naphthoxazole has not been reported so far.
Copper is an important oxidation catalysts element for
laboratory and industrial use. Another, copper-containing
oxidases play a crucial role in metalloproteins bio-oxidation
catalytic reactions.
ꢀ
yields. The highest yield of 52% was obtained at 60 C
and the reaction time was shorten to 10 h (Table 1, entry
ꢀ
8
). At the temperature of 90 C, the low yield was
observed. To elucidate if oxygen is necessary to the reaction,
the experiment was performed under N , no desired product
2
was found (Table 1, entry 9), but the reaction yield was not
improved under O atmosphere compared with under air, it
2
showed that the quantity of O in air was enough for the
2
reaction. (Table 1, entry 10).
The optimal condition for these reactions was the
copper-amine complex formed by two equiv of CuCl2
with four equiv of ethanolamine in 10–15 mL acetonitrile,
ꢀ
stirred for 10–15 h at 60 C in air. Under this optimiza-
tion, the substrate scope was investigated in detail. We
found that 1-naphthol 1g was oxidized to provide para-1,
Herein, we disclose a new synthetic route for oxidation of
2
-naphthols 1a–1f by the CuCl -ethanolamine complex, then
2
4
-naphthoquin-one 2g rather than corresponding naphthoxa-
with an addition of ethanolamine to generate corresponding
-hydroxymethyl naphtho[2,1-d]oxazoles 2a–2f. The inter-
est of the reaction focuses on using ethanolamine from
copper-amine complex as a nucleophile to take part in the
cyclization of 2-naphthols (Scheme 1).
zole(Table 2, entry 7). However, when substrates were
2
2-naphthols 1a–1f, 2-hydroxymethyl naphtho[2,1-d]oxazoles
2a–2f were obtained in moderate to good yield, which are
shown in Table 2.
It is well known that there are two isomeric structures of
naphthoxazole, one is N atom at C-1 and O atom at C-2
position of naphthyl ring that is formulated as naphtho
RESULTS AND DISCUSSION
[1,2-d]oxazole [11], another enantiomer is naphtho[2,1-d]
We took the synthesis of 2a as a sample. The initial
experiment was carried out by oxidation of 2-naphthol 1a
oxazole [12]. In this paper, we obtained X-ray crystallogra-
phy of compound 2a [13], the structure of naphthoxazole is
the latter. An ORTEP drawing of the cation with the
atomic numbering scheme is depicted in Figure 1. In this
under CuCl -ethanolamine complex in DMF. An annulated
2
naphthoxazole 2a resulted from the substrate, but the yield
©
2013 HeteroCorporation

X. Wang, B. Yang, and R. Li
Vol 000
Scheme 1
readily available starting materials and extends those
previously reported for the synthesis of naphthoxazoles.
EXPERIMENTAL
Microanalysis (C, H, and N) was carried out with a Perkin-
Elmer 240Q elemental analyzer (PerkinElmer Inc., Waltham,
MA). Fast atom bombardment (FAB) mass spectra were recorded
on a VG ZAB-HS spectrometer (VG Scientific Ltd, Cornwall,
England) in a 3-nitrobenzyl alcohol matrix. Electrospray mass
spectra were recorded on a LCQ system (Finnigan MAT, USA)
structure, N atom locates at b-position and oxygen atom at
a-position in naphthyl cycle.
During the course of reaction, a red intermediate was
found by thin-layer chromatography (TLC), which was
confirmed to be ortho-1,2-naphthoquinone. Therefore, we
deduced the possible reaction mechanism as following:
1
13
using methanol as mobile phase. H NMR spectra and
C
NMR spectra were recorded on a Varian-300 spectrometer (Var-
ian Medical Systems Inc. Palo Alto, CA). All chemical shifts
were given relative to tetramethylsilane. Infrared spectra were
taken on a Galaxy series FTIR 7000 (Thermo Nicolet, USA) in
2
-naphthol reactant was firstly oxidized to radical (i) by
potassium bromide pellets.
Common reagent-grade chemicals are either commercially
CuCl -ethanolamine complex and oxygen; this radical
2
available and were used without further purification or prepared by
standard literature procedures. Reactions were monitored by TLC.
All yields reported refer to isolated material. Column chromatogra-
phy purifications were carried out using silica gel (100–200mesh).
General experimental procedure for the synthesis of 2-
hydroxymethyl naphtho[2,1-d]oxazole. To a stirred solution
was also occurred oxidant reaction to form intermediate 1,
2-naphthoquinone (ii). Then, ethanolamine as a nucleophile
reacted with naphthoquinone (ii) to provide enamine (iii),
followed by intramolecular rearrange to obtain (iv). Finally,
compound (iv) was annulated to form 2-hydroxymethyl
naphtho[2,1-d]oxazoles through oxidative cyclization. The
plausible mechanism of this reaction is outlined in the
succeeding text (Scheme 2).
In summary, we have developed a new methodology for
the synthesis of 2-hydroxymethyl naphtho[2,1-d]oxazoles
by copper-mediated oxidation and the addition of ethanol-
amine from 2-naphthol and derivatives. The reaction utilizes
of CuCl
(0.350 g, 2 mmols) and ethanolamine (0.240 g,
2
4
mmols) in 15 mL MeCN were added 2-naphthols 1 (0.5 mmol)
ꢀ
at 60 C. The mixture was stirred for 15 h, the reaction was
quenched with 5% NH O, and the mixture was extracted
with EtOAc. The organic extract was washed with water and
dried over anhydrous Na SO . The solvent was evaporated and
3
ÁH
2
2
4
purification by silica gel chromatography (EtOAc-petroleum
ether 1:2), and the solid of naphtho[2,1-d]-oxazole was obtained.
Table 1
Optimization of reaction condition.
a
ꢀ
b
Entry
Solvent
DMSO
CH COOH
3
DMF
Reaction atmosphere
Temp ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
in air
in air
in air
in air
in air
in air
in air
in air
25
25
25
25
25
5
25
60
60
60
72
72
48
48
20
72
20
10
72
10
—
—
16
23
30
40
57
52
—
43
THF
Acetone
CH
CH
CH
CH
CH
3
3
3
3
3
CN
CN
CN
CN
CN
in N
in O
2
10
2
a
2
Unless otherwise specified, all the reactions were carried out in presence of 1 mmol of 1a, 2 mmol of CuCl , 4 mmol of ethanolamine in 10–15mL of solvent.
Isolated yield after column chromatography.
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Copper-Mediated Addition of Ethanolamine Affording 2-Hydroxymethyl
Naphtho[2,1-d]oxazoles from 2-Naphthols
Table 2
a
Copper-catalyzed synthesis of naphthoxazoles.
b
Entry
1
Reactants
Products
Yield (%)
57
2
62
3
4
44
68
5
76
40
6
7
92
a
ꢀ
Reagents and conditions: 2 mmol CuCl
Isolated yield after column chromatography.
2
and 4 mmol ethanolamine to form copper-amine complex in 10–15 mL MeCN, heated at 60 C in air.
b
2
-Hydroxymethyl naphtho[2,1-d]oxazole (2a). This compound
9-Acetylamino-2-hydroxymethyl naphtho[2,1-d]oxazole
1
1
was obtained as colorless needle crystal. H NMR (300 MHz,
Acetone-d ) d: 4.95(d, J = 5.4 Hz, 2H), 7.58 (t, J = 7.5 Hz, 1H),
.68 (t, J = 7.5 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.87 (d,
J = 8.7 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 8.21 (dd, J = 8.1Hz,
.6 Hz, 1H). C NMR (75 MHz, Acetone-d ) d: 58.0, 119.4,
20.6, 121.2, 126.0, 126.6, 127.9, 129.6, 132.6, 138.4, 147.2,
(2b).
This compound was obtained as white solid. H NMR
6
6
(300 MHz, Acetone-d ) d: 2.23 (s, 3H), 4.81 (d, J = 3.0, 2H), 5.97
7
(t, J = 6.0 Hz, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.67 (d, J = 7.2 Hz,
1H), 7,86 (d, J = 8.7 Hz, 1H), 7.96 (t, J = 8.4 Hz, 1H), 9.97
1
3
13
0
1
1
(s, 1H). C NMR (75 MHz, Acetone-d ) d: 23.45, 56.50, 116.89,
6
6
118.78, 123.87, 125.54, 125.58, 126.14, 130.92, 132.31, 137.95,
+
À
66.0 ppm. FAB-MS: m/z = 200 (100 [M + H] ), 182 (36
144.61, 165.10, 169.44 ppm. ESI-MS: m/z = 256.9 ([M+ H] ). IR
+
À1
[
M─OH] ). IR (KBr): 3254, 1599, 1270, 1084, 801 cm
Anal. Calcd for C12 NO (199): C, 72.35%; H, 4.55%; N,
.03%. Found: C 72.28%; H 4.63%; N 7.01%.
.
(KBr): 3270, 1662, 1554, 1399, 1281, 1142, 1089, 816,
À1
H
9
2
693 cm . Anal. Calcd for C14
H N O
12 2 3
(256): C, 65.62%; H,
7
4.72%; N, 10.93%. Found: C 65.99%; H 4.72%; N 10.62%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X. Wang, B. Yang, and R. Li
Vol 000
Scheme 2 Proposed mechanism for the formation of naphthoxazole 2.
5,6-Oxodimethylene-2-hydroxymethyl naphtho[2,1-d]oxazole
2e). This compound was obtained as yellow solid. H NMR
1
(
(
6
300 MHz, Acetone-d ) d: 4.91 (s, 2H), 5.06 (s, 2H), 5.10
(
s, 2H), 7.34 (d, J = 6.6 Hz, 1H), 7.55 (s, 1H), 7.64 (t, J = 8.1 Hz,
H), 8.06 (d, J = 8.1 Hz, 1H). C NMR (75 MHz, Acetone-d ) d:
6
13
1
5
1
6.5, 68.2, 68.6, 112.8, 118.1, 119.1, 120.3, 124.4, 126.9, 129.9,
À
34.1, 136.5, 144.5, 165.2 ppm. ESI-MS: m/z = 240 ([M À H] ).
IR (KBr): 3214, 2946, 2830, 1564, 1448, 1365, 1176, 1111,
1
4
À1
046 cm . Anal. Calcd for C14
H
11NO
3
(241): C, 69.70%; H,
.60%; N, 5.81%. Found: C 69.55%; H 4.60%; N 5.60%.
-Hydroxyethyamino-2,4-dihydroxymethyl naphtho[2,1-d]
5
1
oxazole (2f). This compound was obtained as yellow solid. H
NMR (300 MHz, Acetone-d ) d: 3.43 (t, J = 4.8 Hz, 1H), 3.73
t, J = 4.8 Hz, 1H), 4.87 (s, 2H), 5.12 (s, 2H), 7.52 (t, J = 7.5 Hz,
6
(
1
13
H), 7.62 (t, J = 7.5 Hz, 1H), 8.35 (d, J = 9.0 Hz, 2H). C NMR
(
75 MHz, Acetone-d ) d: 53.3, 55.5, 57.1, 61.3, 115.7, 121.9,
6
1
1
2
22.6, 124.4, 125.2, 126.7, 126.9, 130.8, 143.8, 147.8,
+
63.4 ppm. FAB-MS: m/z = 288 ([M] ). IR (KBr): 3315, 3074,
-1
907, 2854, 1638, 1589, 1401, 1339, 1215, 1083 cm .
Acknowledgment. We thank Guangdong Province Department
of Education (Nos. 1057310015) for providing funds for this
project. We also thank Yong Chen (Guangdong Institute of
Analysis) for the help with the NMR spectrometers.
REFERENCES AND NOTES
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1
2
1
988, 31, 1719.
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[
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[
[
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[
[
6] Krohnke, F. Angew Chem Int Ed Engl 1963, 2, 380.
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2
-Hydroxymethyl-8-hydroxyl naphtho[2,1-d]oxazole (2c). This
1
[8] (a) Osman, A. M.; Bassiouni, I. J Org Chem 1961, 27, 558;
compound was obtained as pale white solid. H NMR (300 MHz,
Acetone-d ) d: 4.75 (s, 2H), 7.10 (dd, J=9.0, 2.4 Hz, 1H), 7.34 (s,
H), 7.54 (d, J= 8.7 Hz, 1H), 7.73 (d, J= 8.7 Hz, 1H), 7.92 (d,
J= 8.7 Hz, 1H), 10.16 (s, 1H). C NMR (75 MHz, Acetone-d
9.9, 104.3, 117.9, 120.4, 124.4, 127.6, 129.1, 133.3, 140.6, 148.4,
(
(
b) Brunner, H.; Olschewski, G.; Nuber, B. Synthesis 1999, 3, 429;
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6
1
Hadi, G.; Tor, K.; Mark, R. P. Tetrahedron Lett 2003, 44, 175;
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S. Y. Inor. Chem. 2008, 47, 1476; (e) Li, H.; Wu, Y. Appl. Org.
Chem. 2008, 22, 233.
[9] Nonell, S.; Ferreras, L. R.; Canete, A.; Lemp, E.; Günther, G.;
Pizarro, N.; Zanocco, A. L. J Org Chem 2008, 73, 5371.
13
6
) d:
5
1
3
C
À
À1
59.2, 167.4 ppm. ESI-MS: m/z = 214 ([M À H] ). IR (KBr): 3262,
105, 2827, 1649, 1599, 1451, 1221, 1044 cm . Anal. Calcd for
12
H
9
NO
6.00%; H 4.24%; N 6.50%.
-Bromo-2-hydroxymethyl naphtho[2,1-d]oxazole (2d). This
3
(215): C, 66.97%; H, 4.22%; N, 6.51%. Found: C
[10] Sagud, I.; Faraguna, F.; Marini, Z.; Kulyk, M. S. J Org Chem
6
2011, 76, 2904.
7
[11] Katritzky, A. R.; Akhmedov, N. G.; Wang, Z. Q.; Roznyatovsky,
1
compound was obtained as off white solid. H NMR (300 MHz,
Acetone-d ) d: 4.61 (s, 2H), 6.88 (d, J = 9.0 Hz, 1H), 6.91 (s, 2H),
.26 (d, J = 9.0 Hz, 1H), 7.36 (s, 1H). C NMR (75 MHz,
Acetone-d ) d: 56.5, 118.2, 118.8, 119.9, 121.9, 124.5, 130.2,
30.7, 132.3, 137.5, 145.5, 165.6 ppm. FAB-MS: m/z = 278
[M + H] ). IR (KBr): 3256, 2922, 2852, 1587, 1359, 1157,
V. A.; Shestopalov, A. A.; Hall, C. D. Magn Reson Chem 2003, 41, 908.
[12] Aeken, S. V.; Deblander, J.; Houwer, J. D.; Mosselmans, T.;
Tehrani, K. A. Tetrahedron 2011, 67, 512.
6
1
3
7
[13] Note: Crystallographic data (excluding structure factors) for
6
the structures reported in this work have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
No. CCDC-839716. Copies of the data can be obtained free of charge on
application via www.ccdc.cam.ac.uk/data_request/cif or email (depos-
it@ccdc.cam.ac.uk).
1
(
1
2
+
À1
042 cm . Anal. Calcd for C12
.90%; N, 5.04%. Found: C 51.90%; H 3.04%; N 4.92%.
H NBrO
8
2
(278): C, 51.83%; H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet