Synthesis of novel aryl-1,2-oxazoles from ortho-hydroxyaryloximes

Article abstract of DOI:10.1016/j.tetlet.2009.08.086

The reaction of ortho-hydroxyaryloximes with p-toluenesulfonyl chloride in the presence of an amine base efficiently generates the corresponding aryl-1,2-oxazole. Investigations revealed that solvent polarity greatly affected the rate of the reaction with

Full text of DOI:10.1016/j.tetlet.2009.08.086

Tetrahedron Letters 50 (2009) 6173–6175
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Tetrahedron Letters
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Synthesis of novel aryl-1,2-oxazoles from ortho-hydroxyaryloximes
*
Trevor J. Dale, Aaron C. Sather, Julius Rebek Jr.
The Skaggs Institute for Chemical Biology and The Department of Chemistry, The Scripps Research Institute, Mail MB-26, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of ortho-hydroxyaryloximes with p-toluenesulfonyl chloride in the presence of an amine
base efficiently generates the corresponding aryl-1,2-oxazole. Investigations revealed that solvent polar-
ity greatly affected the rate of the reaction with faster rates observed in more polar solvents. The reaction
proceeds to completion in only a few minutes in acetonitrile at room temperature, and the synthesis of
four novel aryl-1,2-oxazoles is presented.
Received 13 August 2009
Revised 24 August 2009
Accepted 25 August 2009
Available online 29 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Aryl-1,2-oxazole-containing compounds have displayed some
promising biological activity1, and a number of useful synthetic
methods for the conversion of ortho-hydroxyaryloximes to the cor-
responding aryloxazoles have been employed.2 An elegant method
employing triphenylphosphine and DDQ was reported recently by
Iranpoor et al. to produce the desired heterocycles in high yields.3
As a supplement to these works, we describe here simple yet rapid
cyclization conditions for the efficient synthesis of novel aryl-1,2-
oxazoles.
During the course of an investigation into oxime reactivity, a
surprisingly mild and efficient synthesis of 1,2-aryloxazoles was
encountered. Starting from ortho-hydroxyaryloximes, reaction
with p-toluenesulfonyl chloride (TsCl) in organic solvents in the
presence of a tertiary amine base (iPr2NEt or Et3N) efficiently gen-
erated the corresponding aryloxazole. This appears to occur via a
cyclization reaction at the sp2 nitrogen of the oxime by the pheno-
lic oxygen (Scheme 1).
Initially we investigated the conversion using the simple sub-
strate 2-hydroxy-naphthalene-1-carbaldehyde oxime, 2 (Scheme
2). To this end, commercially available 2-hydroxy-1-naphthalde-
hyde 1 was converted to the desired ortho-hydroxyaryloxime 2
by heating in the presence of hydroxylamine hydrochloride. Cycli-
zation to naphtho[1,2-d]oxazole 3 proceeded quickly at room tem-
perature upon the addition of both the amine base and TsCl.
The cyclization reaction was easily monitored by a change in
absorbance since the long wavelength kmax of aryloxazole 3 was
greatly blue-shifted from the initial oxime 2 (Fig. 1). The reaction
proceeded cleanly through an isosbestic point indicating that the
initial tosylation reaction was the rate-limiting step in the 2-step
reaction scheme. Additional evidence for this was obtained upon
further analysis: the reaction rate was found to be dependent upon
the concentration of TsCl present and the reaction rate was re-
tarded when weaker electrophiles (e.g., p-toluenesulfonyl fluoride
or diethylchlorophosphate) were employed.
Additional investigations revealed that the rate of naphthoxaz-
ole 3 formation was highly solvent dependent and the reaction
proceeded at a greater rate as the polarity of the solvent was in-
creased.4 The slowest rate was measured in THF while the fastest
rate was measured in acetonitrile (Table 1).
After completing these initial studies, the synthesis of addi-
tional aryloxazoles was attempted using the developed conditions.
The aryloxazole of pyridoxal, 6, was synthesized as shown in
Scheme 3. Commercially available pyridoxal hydrochloride 4 was
converted to the ortho-hydroxyloxime 5 with hydroxylamine
hydrochloride in ethanol at room temperature. As anticipated,
cyclization to the corresponding aryloxazole 6 occurred rapidly
in acetonitrile with TsCl and iPr2NEt. The reaction yielded the
desired aryloxazole quantitatively in only a few minutes.
Toexpandthereactiontoamoregeneralstartingmaterial,thegoal
was to construct aryloxazoles from phenol compounds with a vacant
ortho site. Aromatic formylation of the open site followed by oxime
formation and cyclization produces the desired aryloxazole. Two no-
vel fluorescent analogues were subsequently constructed using this
methodology: coumarinoxazole 9 and pyreneoxazole 14.
Coumarinoxazole 9 was synthesized as shown in Scheme 4.
Compound 7,6 synthesized according to a literature procedure
from 7-hydroxycoumarin and employing a Duff reaction,7 was con-
verted to aryloxime 8 with hydroxylamine hydrochloride in EtOH.
Application of the cyclization reaction conditions produced the de-
sired 1,2-oxazole 9 in 90% yield in less than 5 min.
Pyreneoxazole 14 was synthesized as shown in Scheme 5. Com-
mercially available 1-hydroxypyrene was protected as the
methoxymethyl (MOM) ether with chloromethyl methyl ether
(MOMCl) in DMF. Ether 11 was selectively lithiated with n-butyl-
lithium using the ortho-directing MOM group8 and quenched with
DMF to install the formyl group and afford 1-methoxymethoxy-2-
pyrene carboxaldehyde 12. Conversion of the aldehyde to
aryloxime 13 was accomplished by heating in the presence of
* Corresponding author. Fax: +1 858 784 2876.
E-mail address: jrebek@scripps.edu (J. Rebek Jr.).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.086

6174
T. J. Dale et al. / Tetrahedron Letters 50 (2009) 6173–6175
OH
NOH
OH
O
TsCl, R3N
Ar
Ar
Ar
N
NOTs
H
H
Scheme 1. Reaction of an ortho-hydroxyaryloxime with TsCl in the presence of an amine base generates the corresponding aryloxazole.
H
NOH
OH
N
O
CHO
.
NH2OH HCl
OH
TsCl, Et3N
CH2Cl2
rt, 15 min
74%
EtOH
65 ºC, 18 h
82%
1
2
3
Scheme 2. Synthesis of naphthoxazole 3.
Table 1
Relative rates of naphthoxazole formation in organic solvents of varying polarities
Entry
Solvent
Relative rate
ET(30)a
1
2
3
4
5
Tetrahydrofuran
Toluene
Dichloromethane
Benzonitrile
Acetonitrile
1.0
6.6
270
810
6300
37.4
33.9
40.7
41.5
45.6
a
Empirical measure of solvent polarity derived from solvachromic betaine dyes.5
The developed reaction conditions again proved effective in gener-
ating the desired oxazole 14, although THF was employed as a sol-
vent in this case for solubility purposes and subsequently the
cyclization required additional reaction time (see Table 1).
In summary, four novel 1,2-aryloxazoles were synthesized
quickly and in high yields from ortho-hydroxyaryloximes via an
intramolecular cyclization upon reaction with p-toluenesulfonyl
chloride in the presence of an amine base. Initial tosylation of
Figure 1. Absorbance spectra for the naphthalene-based oxime 2 and oxazole 3.
Concentration = 3 Â 10À5 M in CH2Cl2.
hydroxylamine hydrochloride which also served to remove the
protecting group ether and afford 1-hydroxy-2-pyrenealdoxime.
H
NOH
OH
N
O
CHO
.
TsCl, iPr2NEt
NH2OH HCl
OH
HO
HO
HO
CH3CN
rt, 30 min
quant.
EtOH
rt, 30 min
61%
N
H
N
N
Cl–
4
5
6
Scheme 3. Synthesis of pyridyloxazole 6.
NOH
OH
H
TsCl, iPr2NEt
rt, 5 min
N
O
CHO
.
NH2OH HCl
O
O
OH
O
O
O
O
CH3CN
90%
EtOH, rt, 13 h
94%
8
9
7
Scheme 4. Synthesis of coumarinoxazole 9.
H
NOH
OH
N
O
CHO
OH
OMOM
OMOM
1. n-BuLi, TMEDA
Et2O
.
NH2OH HCl
MOMCl, iPr2NEt
TsCl, iPr2NEt
–20 ºC, 1 h
DMF
rt, 3 h
92%
2. DMF
THF, rt, 5 h
89%
EtOH
65 ºC, 18 h
90%
–20 ºC to rt, 1 h
64%
10
11
12
13
14
Scheme 5. Synthesis of pyreneoxazole 14.

T. J. Dale et al. / Tetrahedron Letters 50 (2009) 6173–6175
6175
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Acknowledgments
We thank the Skaggs Institute for Chemical Biology for financial
support. T.J.D. and A.C.S. are Skaggs postdoctoral and predoctoral
fellows, respectively.
Supplementary data
4. Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 3rd ed.; Wiley-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.08.086.
VCH, 2003.
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