Rapid One-pot Solid-phase Synthesis of 1,2,4-Oxadiazolines

Article abstract of DOI:10.1246/cl.2003.842

The first solid phase synthesis of 1,2,4-oxadiazolines via 1,3-dipolar cycloaddition of nitrile oxide generated in situ on solid support with a variety of imines is described. The synthetic sequences were performed in parallel one-pot fashion. Cleavage from the support under two different mild conditions afforded a library of 1,2,4-oxadiazolines in good yields and purity.

Full text of DOI:10.1246/cl.2003.842

842
Chemistry Letters Vol.32, No.9 (2003)
Rapid One-pot Solid-phase Synthesis of 1,2,4-Oxadiazolines
Xu-Feng Lin, Sun-Liang Cui, and Yan-Guang Wangꢀ
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
(Received June 3, 2003; CL-030489)
The first solid phase synthesis of 1,2,4-oxadiazolines via
1,3-dipolar cycloaddition of nitrile oxide generated in situ on
solid support with a variety of imines is described. The synthet-
ic sequences were performed in parallel one-pot fashion. Cleav-
age from the support under two different mild conditions afford-
ed a library of 1,2,4-oxadiazolines in good yields and purity.
CsOOC
CHO
O
O
1
NH2OH.HCl
Cl
CHO
Merrifield Resin
Et3N
r.t.
DMF
2
Cl
O
O
O
5
NCS
r.t.
Et3N
r.t.
O
N
N
OH
O
N
OH
3
4
The polymer-supported synthesis of small heterocyclic
molecules is the subject of intense research activity,1 since it
represents one of the most promising ways to generate small
molecular libraries in the field of combinatorial chemistry.2
Substituted heterocyclic compounds offer a high degree of
structural diversity and have proven to be broadly useful as ther-
apeutic agents.3 As a result, an increasing range and number of
pharmaceutically useful heterocyclic compounds recently have
been prepared using solid phase methodology.4 This approach
permits the rapid synthesis of large numbers of individual com-
pounds, as well as mixture-based combinatorial libraries in a
short time period and facilitates their use in high-throughput
screening.5
O
CH3ONa
CH3OH/THFr.t.
N
O
H3CO
O
R1
O
R1
N
R3
N
6
R
2 Cleveage Method A
7
R2
R3
70%EtNH2/THF
Cleveage Method B
R3
N
N
O
EtHN
O
R1
R2
R3 NH2
R1
O
molecular sieves
N
R1
R2
8
r.t.
R2
R3
5
Scheme 1.
Nitrile oxides undergo [3 þ 2] cycoladditions withimines
to provide 1,2,4-oxadiazolines in solution phase synthesis.6
These products have proven to be very important in medicinal
chemistry.7 The major limitations of this chemistry are the pro-
pensity of nitrile oxide undergoing rapid dimerization to furo-
xan N-oxide8 and the slow synthesis of large organic compound
collections. Solid-phase organic synthesis can overcome these
limitations. Accordingly, our plan was to anchor a nitrile oxide
precursor onto the solid support, and then generate the reactive
species in the presence of multifold excess of imines, preferably
all in one pot. Finally, washing off all of the surplus reagents
followed by cleavage would provide the cycloadducts. Our ef-
forts to obtain a representative library of 1,2,4-oxadiazolines,
which exploited four sites of chemical diversity are presented
below.
dried to provide resin-bound 1,2,4-oxadiazolines 6. It is worthy
to note that imines, prepared by incubating the aldehyde and the
amine in dichoromethane overnight at room temperature in the
ꢀ
presence of activated 4 A molecular sieves, was directly used
without further purification. This is a crucial method for rapid
solid phase synthesis to provide large numbers of 1,2,4-oxadia-
zolines.
The cycloadducts were cleaved off the resin with two dif-
ferent methods to give a 20-member library of 1,2,4-oxadiazo-
lines 7 and 8. Method A: The target compounds 7 were released
from the resin by treatment of the resin 6 with0.5 M MeONa in
MeOH/THF (1:4) at room temperature for 12 h. Method B:
Cleavage of the product from the resin was readily achieved
with ethylamine (70% ethylamine in water and THF (1:1) at
40 ꢁC overnight, providing the ethyl amides 8.
As show in Scheme 1, cesium salt of 4-formylbenzoic acid
1 was attached on Merrifield resin in standard conditions.9 The
aldehyde functionality of resin 2 was converted to aldoxime by
treating with excess hydroxylamine hydrochloride in the pres-
ence of triethylamine in MeOH/CH2Cl2 at room temperature,
monitored by Infrared spectroscopy for the disappearance of
the aldehyde stretch at 1702 cmÀ1. The reaction went to com-
pletion over 48 h and gave a high yield of the corresponding al-
doxime resin 3.10 After washing and drying, reaction of the al-
doxime resin 3 withexcess N-chlorosuccinimide (NCS) in
CH2Cl2 for 6 hto afford chlorooxime resin 4, which is a precur-
sor to the nitrile oxide. To this was added directly ten folds ex-
cess of imines 5 as a methylene chloride solution before gener-
ating the nitrile oxide by slow addition of triethylamine. This is
one pot procedure. The resulting mixture was shaken at room
temperature for 36 h. The resin was then filtered, washed, and
A variety of imines reacted well withteh resin-bound
chlorooxime under similar reaction conditions to afford the cor-
responding 1,2,4-oxadiazolines in good yields and purity. The
ready availability of aldehydes and amines from commercial
sources allows the preparation of large heterocyclic compound
libraries. Table 1 summarizes some of the initial results we have
obtained by application of the above methodology.11
In summary, we have first demonstrated that solid-phase
methodology can be applied efficiently in parallel synthesis of
the 1,2,4-oxadiazoline libraries, which exploited four sites of
chemical diversity. This method of synthesis is versatile and
produces compounds with known pharmacophoric scaffolds,
and which are thus ideally suited for combinatorial library gen-
eration. This application to the synthesis of large 1,2,4-oxadia-
zoline libraries is presently under investigation.
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.9 (2003)
843
Table 1. One pot solid phase synthesis of 1,2,4-oxadiazolines
Rev., 96, 555 (1996). d) V. Krcnak and M. W. Holladay,
Chem. Rev., 102, 61 (2002).
A. Nefzi, J. M. Otresh, and R. A. Houghten, Chem. Rev., 97,
449 (1997).
Cleavage
Product
A
7
Cleavage
Product 8
Yield (Purity)%a
B
Carbony
compound
Amine
Entry
2
Yield (Purity)%a
CHO
NH2
NH2
80 (95)
96 (92)
87 (90)
a
3
4
G. F. Robert, J. Comb. Chem., 2, 195 (2000).
a) B. A. Bunin and J. A. Ellman, J. Am. Chem. Soc., 114,
10997 (1992). b) M. M. Murphy, J. R. Schullek, E. M.
Gordon, and M. A. Gallop, J. Am. Chem. Soc., 117, 7029
(1995). c) J. M. Ostresh, C. C. Schoner, V. T. Hamashin,
A. Nefzi, J. P. Meyer, and R. A. Houghten, J. Org. Chem.,
63, 8622 (1998). d) Y. P. Yu, J. M. Otresh, and R. A.
Houghten, Tetrahedron Lett., 44, 2569 (2003). e) Y. Chen,
Y. L. Lam, and Y. H. Lai, Org. Lett., 5, 1067 (2003).
R. A. Houghten, C. Pinilla, J. R. Appel, S. E. Blondelle, C.
T. Dooley, J. Eichler, A. Nefzi, and J. M. Ostresh, J. Med.
Chem., 42, 3743 (1999).
a) R. Lenaers and F. Eloy, Helv. Chim. Acta, 46, 1067
(1963). b) S. Morocchi, A. Ricca, and L. Velo, Chim.
Ind., 49, 168 (1967).
A. Chimirri, S. Grasso, A. M. Monforte, P. Monforte, Z. M.
Appala, and A. Carotti, Chem. Pharm. Bull., 28, 3296
(1980).
CHO
CHO
b
85 (92)
Me
F
NH2
NH2
c
91 (85)
95 (77)
73 (85)
68 (85)
NO2
CHO
d
NH2
NH2
NH2
CHO
CHO
CHO
CHO
CHO
e
f
77 (90)
81 (80)
93 (89)
80 (88)
MeO
5
6
7
Me
F
79 (87)
g
h
i
71 (97)
87 (96)
O
NH2
92 (88)
83 (89)
O
O
64 (89)
83 (86)
NH2
O
8
9
R. A. Whitney and E. S. Nicholas, Tetrahedron Lett., 35,
3371 (1981).
B. F. Gisin, Helv. Chim. Acta, 56, 1476 (1973).
NH2
j
90 (83)
F
aYields refer to crude chemical yields and purity
was determined by LC-MS analysis.
10 B. B. Shankar, D. Y. Yang, S. Girton, and A. K. Ganguly,
Tetrahedron Lett., 39, 2447 (1998).
11 All the compounds listed in Table 1 give satisfactory 1H
NMR, FT-IR, MS and HRMS data. For compound 8a is
as follows: 1H NMR (500 MHz, CDCl3): ꢀ 1.24 (t,
J ¼ 7:2 Hz, 3H), 3.48 (q, J ¼ 7:2 Hz, 2H), 6.35(br, 1H),
6.54 (s, 1H), 6.77(d, J ¼ 7:5 Hz, 2H), 7.11–7.18(m, 3H),
7.45 (m, 3H), 7.58–7.64 (m, 4H), 7.72 (d, J ¼ 8:3 Hz,
2H); FT–IR (KBr): 1642 (C=O), 1592 (C=N) cmÀ1; ESI–
MS (þ): 372.3 ([M + H]þ), 394.3 ([M + Na]þ); HRMS
calcd for C23H21N3O2 ([M + H]þ): 372.1634, found:
372.1645.
Authors would like to thank for the National Natural Sci-
ence Foundation of China (No. 20272051) as well as the Teach-
ing and ResearchAward Program for Outstanding Young
Teachers in Higher Education Institutions of MOE, P. R. China.
References and Notes
1
a) J. S. Fruchtel and G. Jung, Angew. Chem., Int. Ed. Engl.,
¨
35, 17 (1996). b) S. M. Allin and P. K. Sharma, Synthesis,
1997, 1217. c) L. A. Thompson and J. A. Ellmann, Chem.
Published on the web (Advance View) August 11, 2003; DOI 10.1246/cl.2003.842