Synthesis of 2-arylbenzoxazoles via DDQ promoted oxidative cyclization of phenolic Schiff bases - A solution-phase strategy for library synthesis

Article abstract of DOI:10.1016/S0040-4039(01)02302-4

The Schiff base derived from the condensation of o-aminophenol with benzaldehydes was induced to undergo oxidative cyclization in the presence of DDQ. The resulting 2-arylbenzoxazoles were separated from the reduced DDQ by product by treatment of reaction mixture with a strongly basic ion-exchange resin. The applicability of this chemistry to spatially separate library synthesis is demonstrated by the preparation of a 352-member library.

Full text of DOI:10.1016/S0040-4039(01)02302-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 951–954
Synthesis of 2-arylbenzoxazoles via DDQ promoted oxidative
cyclization of phenolic Schiff bases—a solution-phase strategy
for library synthesis
Junbiao Chang,a Kang Zhaob,* and Shifeng Pana,*
aGenomics Institute of Novartis Research Foundation, 3115 Merryfield Row, San Diego, CA 92121, USA
bCollege of Pharmaceuticals and Biotechnology, Tianjin University 300072, China
Received 26 October 2001; revised 27 November 2001; accepted 28 November 2001
Abstract—The Schiff base derived from the condensation of o-aminophenol with benzaldehydes was induced to undergo oxidative
cyclization in the presence of DDQ. The resulting 2-arylbenzoxazoles were separated from the reduced DDQ byproduct by
treatment of reaction mixture with a strongly basic ion-exchange resin. The applicability of this chemistry to spatially separate
library synthesis is demonstrated by the preparation of a 352-member library. © 2002 Elsevier Science Ltd. All rights reserved.
2-Arylbenzoxazoles posses the important biaryl phar-
macophore and have exhibited a variety of biological
activities, including antimicrobial and antitumor prop-
erties.1 For example, a 2-arylbenzoxazole, AJI9561, was
recently isolated as a cytotoxic metabolite from the
extract of Streptomyces sp.2 The two most popular
methods for synthesizing 2-substituted benzoxazoles
are: (1) coupling of carboxylic acids with 2-aminophe-
nols by dehydration catalyzed by a strong acid;3 and (2)
the oxidative cyclization of phenolic Schiff bases,
derived from the condensation of 2-aminophenols and
aldehydes, using various oxidants such as PhI(OAc)2,4
Recently, both solution- and solid-phase methods for
the synthesis of combinatorial libraries have gained
tremendous popularity in pharmaceutical and academic
institutions.10,11 The preparation of compound libraries
requires the development of superb methods for both
the synthesis and purification in order to final products
in a form suitable for biological testing. Although there
have been several reports describing the solid-phase
synthesis of benzoxazoles,12 there have yet to appear
any publications describing solution-phase libraries of
benzoxazoles presumably due to the lack of any robust
procedure for synthesis and purification. Herein, we
will describe a mild and efficient protocol for the syn-
thesis of 2-arylbenzoxazoles and the application to the
synthesis of a 352-member compound library.
− 6
Mn(OAc)3,5 Th+ClO4 , Ba(MnO4)2,7 NiO2,8 and
Pb(OAc)4.9 The first method has been used for making
large quantities of pharmaceutical intermediates but
typically requires activation of carboxylic acids under
strongly acidic conditions at high temperature. The
second method usually involves the use of transition
metals that require purification by filtration or aqueous
treatments to remove the metal byproducts.
A solution-phase library approach is an attractive
choice if reactions can be found that are high yielding
and that generate byproducts that can be readily
removed. Schiff base formation between 2-aminophe-
OH
OH
O
O
DDQ
CH2Cl2
ArCHO 2
R
Ar
R
R
R
Ar
MeOH, 45 oC
N
H
N
NH2
N
Ar
1
3
4
5
Scheme 1.
Keywords: 2-arylbenzoxazoles; DDQ; oxidation; ion-exchange resin; solution phase; library.
* Corresponding authors. Tel.: (858) 812-1621; fax: (858) 812-1584; e-mail: pan@gnf.org
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02302-4

952
J. Chang et al. / Tetrahedron Letters 43 (2002) 951–954
nols and aldehydes generates only water as a byproduct
and conversion to the final products can be achieved
with the appropriate selection of oxidants. 2,3-
Furthermore, we expected that 4,5-dichloro-3,6-dihy-
droxy-phthalonitrile (DDP), the reduced product of
DDQ, could be easily removed from the reaction mix-
ture by basic ion-exchange resins thereby enabling the
solution-phase synthesis of the desired library.
Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is
a
versatile reagent for the oxidation of alcohols and
selected amino groups. DDQ has also been described
for the synthesis of benzoimidazoles from correspond-
ing o-phenylenediamines and aldehydes.13 Li and co-
workers have also reported the DDQ oxidation of
hydroxylamine groups to the corresponding isoxazoli-
nes.14 We envisioned that DDQ would also be an
efficient reagent for the oxidative cyclization of pheno-
lic Schiff bases to produce 2-substituted benzoxazoles.
We first examined whether 2-arylbenzoxazoles would
result from the treatment of the phenolic Schiff bases 3,
preformed via the condensation of 2-aminophenols 1
and aromatic aldehydes 2 in methanol, with 1.1 equiv.
DDQ in CH2Cl2 (Scheme 1). As shown in Table 1,
2-arylbenzoxazoles were produced in high to excellent
yields by this method (Isolation A).15 The desired oxi-
Table 1. Results of DDQ-promoted synthesis of 2-arylbenzoxazoles

J. Chang et al. / Tetrahedron Letters 43 (2002) 951–954
953
dation presumably occurred after the cyclization of
phenolic Schiff bases with the phenol hydroxy moiety
to give the corresponding oxazolines 4. The 2-
aminophenols with electron-withdrawing groups, which
were predicted to be less reactive toward aldehydes,
gave comparable results (entries 5–6, 10–11). It is note-
worthy that the nitro compound needs higher reaction
temperature (reflux in ethanol) for the formation of
Schiff base to fulfill the final products in excellent
yields. This method can employ aldehydes with both
electron-donating (entries 3, 6 and 11) and electron-
withdrawing groups (entries 2, 5 and 8). In addition,
heterocyclic aldehydes can also be used for efficient
preparation of various 2-heterocyclic substituted ben-
zoxazoles (entries 4, and 11–12). These results have
shown that DDQ is an efficient oxidation agent for the
one-pot synthesis of benzoxazole-containing biaryl
structures.
mL of DCE was added to each well. The plates were
clamped and rotated slowly for 2 h before filtering the
solution into collection plates. The higher freezing tem-
perature of DCE allowed the reaction solutions to be
frozen so that possible leakage during the transfer was
avoided. The final removal of solvents using a plate
rotatory evaporator gave the desired compounds in the
collection plates.
The library was characterized by LC–MS. The purity of
the individual compound was determined by LC inte-
gration without calibration. As a result, 73% of the
library showed purity greater than 80%, while 9% of the
compounds with purities less than 50%.
In summary, the preparation of 2-arylbenzoxazoles was
efficiently achieved by the condensation arylaldehydes
with 2-aminophenols and subsequent DDQ-promoted
oxidative cyclization reactions. This one-pot procedure
is mild and efficient for producing individual arylbenz-
oxazole compounds. Moreover, the combination of
this procedure with the use of basic ion-exchange resin
allows for the combinatorial library synthesis. The cur-
rent method represents the first example for benzoxa-
zole library synthesis by a solution-phase strategy.
Encouraged by these preliminary results, we continued
to explore the possibility of generating a library of this
class of biaryl compounds. One prerequisite is to
remove the DDP in a highthroughput format. Among
various purification methods available for solution-
phase combinatorial synthesis, the treatment of reaction
solutions with ion exchange resins has proven effective
in the removal of some acidic or basic byproducts,16
and there is a recent report demonstrating applicability
to a 96-well format.17 We assumed that basic ion-
exchange resins could be a good option to neutralize
and absorb acidic DDP. Amberlite® IRA-900, which is
a macroreticular resin with benzyltrialkylammonium
functionality, proved to be the most efficient in this
respect. The results are summarized in Table 1 as
Isolation B.18 Thus, 4 g of the aforementioned resin was
freshly washed by methanol and used for the purifica-
tion of each reaction on a 0.2 mmol scale, and this
simple treatment gave the desired products in excellent
purities. Since we used exactly equal amount of DDQ
in the reaction leading to the comparable results as
aforementioned 1.1 equiv. of DDQ being used, there
was no need to use a polymer-bound scavenger resin
for removing DDQ from the reaction solutions.19
Acknowledgements
We thank Dr. Nathanael S. Gray for his valuable
suggestions in the preparation of this manuscript.
Funding was provided by the Novartis Research
Foundation.
References
1. For recent examples, see: (a) Temiz, O.; Rren, I.; Sener,
E.; Yalcin, I.; Ucarturk, N. Farmaco 1998, 53, 337; (b)
Aotsuka, T.; Wagatsuma, N.; Kato, H.; Ashizawa, N.
PCT Int. Appl. WO 98 46,594, 1998; (c) Sato, Y.;
Yamada, M.; Kobayashi, K.; Iwamatsu, K.; Konno, F.;
Shudo, K. Eur. Pat. Appl. EP 806, 419, 1997; (d) Deluca,
M. R.; Kerwin, S. M. Tetrahedron Lett. 1997, 38, 199.
2. Sato, S.; Kajiura, T.; Noguchi, M.; Takehana, K.;
Kobayashi, T.; Tsuji, T. J. Antibiot. 2001, 54, 102.
3. Terashima, M.; Ishii, M. Synthesis 1982, 1484 and refer-
ences cited therein.
A 352-member library was then prepared by this solu-
tion-phase strategy. Thus, 8 2-aminophenols and 44
arylaldehydes were prepared as 0.1 M stock solutions in
methanol. They were then mixed in four 2 mL 96
(8×12) deep-well plates (0.2 mL of 2-aminophenol and
0.2 mL of aldehyde in each well). The resulting plates
were heated in a oven at 45°C for 12 h. The methanol
was then removed by a plate rotatory evaporator and
the resulting residue was redissolved in 0.2 mL of
1,2-dichloroethane (DCE) in each well which was sub-
sequently treated with 0.2 mL of 0.1 M DDQ in 10%
THF in DCE. It was noteworthy that exactly equal
amount of DDQ was used in order to facilitate subse-
quent purification. The addition of THF is to increase
the solubility of DDQ. The reaction plates were agi-
tated at room temperature for 2 h before the solutions
were transferred to the corresponding filter bottom
plates loaded with 0.4 g of freshly washed (MeOH) and
dried Amberlite® IRA-900 in each well. Additional 0.4
4. Varma, R. S.; Saini, R. K.; Prakash, O. Tetrahedron Lett.
1997, 38, 2621.
5. Varma, R. S.; Kumar, D. J. Heterocyclic Chem. 1998, 35,
1539.
6. Park, K. H.; Jun, K.; Shin, S. R.; Oh, S. W. Tetrahedron
Lett. 1996, 37, 8869.
7. Srivastava, R. G.; Venkataramani, P. S. Synth. Commun.
1988, 18, 1537.
8. Nakagawa, K.; Onoue, H.; Sugita, J. Chem. Pharm. Bull.
1964, 12, 1135.
9. Stephens, F. F.; Bower, J. D. J. Chem. Soc. 1949, 2971.
10. For selected reviews, see: (a) Thompson, L. A.; Ellman, J.
A. Chem. Rev. 1996, 96, 555; (b) Balkenhohl, R.; Buss-
che-Hu¨nnefeld, C. v. d.; Lansky, A.; Zechel, C. Angew.

954
J. Chang et al. / Tetrahedron Letters 43 (2002) 951–954
Chem., Int. Ed. Engl. 1996, 35, 2288; (c) Hermkens, P. H.
was purified by flash column chromatography (10%
H.; Ottenheijm, H. C. J.; Rees, D. B. Tetrahedron 1996,
52, 4527.
EtOAc in hexane) to afford the desired product (0.187 g,
83%). H NMR (400 MHz, CDCl3) l 3.91 (s, 3H), 7.05
1
11. Baldino, C. M. J. Comb. Chem. 2000, 2, 89 and references
cited therein.
12. Wang, F.; Hauske, J. R. Tetrahedron Lett. 1997, 38,
6529.
13. Vanden Eynde, J. J.; Delfosse, F.; Lor, P.; Van Haver-
beke, Y. Tetrahedron 1995, 51, 5813.
14. Li, P.; Gi, H.-J.; Sun, L.; Zhao, K. J. Org. Chem. 1998,
63, 366.
15. Representative experimental procedure: To a solution of
2-aminophenol (0.109 g, 1.0 mmol) in MeOH (5 mL) was
added p-anisaldehyde (0.136 g, 1.0 mmol). The resulting
mixture was heated at 45°C for 12 h. After concentration
under reduced pressure, the residue was dissolved in
CH2Cl2 (10 mL) and DDQ (0.250 g, 1.1 mmol) was then
added. After stirring at room temperature for 30 min, the
resulting mixture was diluted with additional CH2Cl2 (10
mL) and washed sequentially with saturated Na2CO3 (10
mL×2) and brine (10 mL). The organic layer was dried
over anhydrous Na2SO4. After evaporation, the crude
(d, 2H, J=9.0 Hz), 7.34 (m, 2H), 7.58 (d, 1H, 9.1 Hz),
7.76 (d, 1H, 9.0 Hz), 8.22 (d, 2H, 9.0 Hz). 13C NMR (400
MHz, CDCl3) l 55.9, 110.8, 114.8, 120.0, 120.1, 124.8,
125.0, 129.8, 142.7, 152.6, 162.8, 164.0.
16. For examples, see: (a) Kulkarni, B. A.; Ganesan, A.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2454; (b) Siegel,
M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.;
Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997,
38, 3357.
17. Bookser, B. C.; Zhu, S. J. Comb. Chem. 2001, 3, 205.
18. The material loss, as indicated by crude yields in Table 1,
was mainly due to the binding of the product to the resin.
In order to keep the same protocol as used in the final
library synthesis, we did not use excessive solvent, which
was limited by the volume of the collection plate, to wash
the resin to improve the yields.
19. Deegan, T. L.; Gooding, O. W.; Baudart, S.; Porco, J. A.
Tetrahedron Lett. 1997, 38, 4973.