A preferred synthesis of 1,2,4-oxadiazoles

Article abstract of DOI:10.1081/SCC-120034169

An efficient and high-yielding one-pot synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes is described. Activation of the carboxylic acid using hydroxybenzotriazole (HOBt) and EDC/HCl followed by reaction with an amidoxime generates an oxime ester. Without isolation, the oxime ester is dehydrated to give the oxadiazole ring.

Full text of DOI:10.1081/SCC-120034169

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A Preferred Synthesis of 1,2,4‐Oxadiazoles
Brenda Pipik a , Guo‐Jie Ho a , J. Michael Williams a & David A. Conlon a
a Department of Process Research , Merck Research Laboratories , P.O. Box 2000,
Rahway, New Jersey, 07065, USA
Published online: 20 Aug 2006.
To cite this article: Brenda Pipik , Guo‐Jie Ho , J. Michael Williams & David A. Conlon (2004) A Preferred Synthesis of
1,2,4‐Oxadiazoles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 34:10, 1863-1870, DOI: 10.1081/SCC-120034169
To link to this article: http://dx.doi.org/10.1081/SCC-120034169
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 10, pp. 1863–1870, 2004
A Preferred Synthesis of 1,2,4-Oxadiazoles
*
Brenda Pipik, Guo-Jie Ho, J. Michael Williams, and
David A. Conlon
Department of Process Research, Merck Research Laboratories,
Rahway, New Jersey, USA
ABSTRACT
An efficient and high-yielding one-pot synthesis of 1,2,4-oxadiazoles
from carboxylic acids and amidoximes is described. Activation of the car-
boxylic acid using hydroxybenzotriazole (HOBt) and EDC/HCl followed
by reaction with an amidoxime generates an oxime ester. Without
isolation, the oxime ester is dehydrated to give the oxadiazole ring.
Key Words: 1,2,4-Oxadiazoles; Carboxylic acids; Hydroxybenzotri-
azole; High-yielding synthesis.
INTRODUCTION
Substituted 1,2,4-oxadiazoles are important pharmacophores found in
pharmaceutical candidates, which are often used to replace ester or amide
*
Correspondence: Brenda Pipik, Department of Process Research, Merck Research
Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA; E-mail: brenda_pipik@
merck.com.
1863
DOI: 10.1081/SCC-120034169
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Pipik et al.
functions. Starting from acid (I), an efficient and high-yielding synthesis
of 3-methyl-5-[4-(methylsulfonyl)benzyl]-1,2,4-oxadiazole[1] suitable for
large-scale production was required (Sch. 1). Several different approaches
starting from the carboxylic acid and using a variety of peptide coupling
reagents were explored. These methods included carbonyl activation using
CDI,[2] DCC,[3] formation of an acid chloride,[4] or anhydride.[5] None of these
approaches were applicable to large-scale synthesis, because, most were low
yielding or required isolation by chromatography to afford product with accep-
table purity. An optimized procedure was developed which involved activation
of 4-(methylsulfonyl)phenylacetic acid using standard peptide coupling
reagents EDC/HCl and hydroxybenzotriazole (HOBt)[6] followed by displace-
ment with methylamidoxime.[7] Cyclization and dehydration took place upon
heating, without the addition of other reagents. Compound 3 was produced
on a 30kg scale in 90% yield employing this method.
We report herein the results from our studies on the application of this
procedure using these peptide-coupling reagents to form a wide range of oxa-
diazoles. A series of carboxylic acids (Table 1) was successfully activated
using a combination of HOBt and EDC/HCl. Displacement of HOBt from
the ester intermediate by methylamidoxime or commercially available 4-fluoro-
benzamidoxime occurred readily at room temperature in acetonitrile. It was
critical to ensure that the active ester formation was complete before addition
of the amidoxime. Low conversion of the starting carboxylic acid was
observed when all the reagents were charged at once, possibly due to the reac-
tion of the amidoxime with EDC/HCl. Other peptide coupling reagents such
as 2-isobutoxy-1-isobutoxycarbonyl-1,2-dihydroquinoline (IIDQ) and 2-ethoxy-
1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) were not effective even
when used in excess (greater than 2 equiv.), and generated impurities due to
side reactions.
The Z-isomer of the O-acylated intermediate II was isolated for structural
confirmation by NMR, and was found to be consistent with previously
reported structures.[3,4] Cyclodehydration of II to form the oxadiazole
occurred on heating. In some cases, water removal was necessary to avoid
the competing hydrolysis of the oxime ester which regenerates the starting
carboxylic acid. On laboratory scale, water removal was accomplished by
heating to reflux and returning the condensate through a bed of molecular
sieves which were contained in an addition funnel.a Aromatic compounds con-
taining an electron donating group para to the carboxylic acid were more
sensitive to hydrolysis compared to those containing an electron withdrawing
group such as cyano. The compounds containing an electron donating group
aA Soxhlet apparatus was not as efficient in water removal.

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Synthesis of 1,2,4-Oxadiazoles
1865

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Table 1. Yields of 1,2,4-oxadiazoles.
Isolated
Lit. yield
(%)
Entry
1
Oxadiazole
Methoda
yield (%)
A
70
68,[8] 53[2]
2
3
B
A
88
90
60[2]
—
4
5
B
B
76
70
—
—
6
7
B
A
69
60
—
51[2]
8
9
B
A
93
78
63[2]
—
(continued)

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Synthesis of 1,2,4-Oxadiazoles
1867
Table 1. Continued.
Isolated
yield (%)
Lit. yield
(%)
Entry
10
Oxadiazole
Methoda
B
93
76
—
11
12
B
B
—
73
—
aMethod A: In acetonitrile, the mixture was heated to reflux and the condensate dried
over a bed of sieves. Method B: Reaction mixture was solvent switched from aceto-
nitrile to diethoxyethane after formation of the oxime ester.
also required a longer reaction time for cyclization, thus, making the uncy-
clized intermediate available for hydrolysis in the presence of water generated
during cyclization. In such cases, we found that switching the solvent from
acetonitrile to a higher boiling solvent such as diethoxyethane or toluene com-
pensated for this rate decrease. The poor solubility of EDC/HCl in diethox-
yethane and toluene precluded the use of these solvents in the initial stage
of the reaction, because, a gummy material formed in the mixture so that reac-
tion in these solvents was not conducive to scale-up. Therefore, the formation
of the oxime ester was carried out in acetonitrile and then the reaction solvent
was switched to toluene or diethoxyethane. For those substrates containing an
electron withdrawing group, the entire reaction sequence was carried out in
acetonitrile and the cyclization went to completion cleanly and in high yield
(Table 1).
Excellent stereochemical retention was also demonstrated starting from an
amino acid with this method. When the oxadiazole was formed from CBZ-L-
serine and methylamidoxime, the product was obtained in .95% ee. In the
case of CBZ-L-serine and 4-fluorobenzamidoxime, there was complete reten-
tion of stereochemistry.
In conclusion, this communication describes an optimized, high-yielding
synthesis of 1,2,4-oxadiazoles. The process is easily scalable, as wasdemonstrated
on 30 kg and is suitable for use in preparation of a wide variety of substrates.

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EXPERIMENTAL
Overall yields were determined by evaporation to dryness and were
corrected based on quantitative assay by HPLC against a standard of known
1
purity. Yields were reproducible and structures were confirmed by H and
13C NMR spectroscopy, HPLC and elemental analysis. NMR spectra were
recorded on a Bruker DPX 400.
Typical Procedures
Method A: A carboxylic acid (20 mmol) and HOBt (24 mmol) are slurried
in dry acetonitrile (50 mL). Addition of EDC/HCl (23 mmol) to this mixture
at room temperature generates the HOBt ester. Methylamidoxime or 4-fluoro-
benzamidoxime is added and the mixture is heated to reflux. The condensate is
returned through a bed of molecular sieves, which are contained in an addi-
tion funnel. After concentration of the reaction mixture, the oxadiazole is
isolated by partitioning with ethyl acetate and aqueous bicarbonate solution.
Concentration of the separated organics is followed by crystallization of the
oxadiazole from isopropanol or isopropanol/hexane.
Method B: Ester formation as above. In cases where hydrolysis of the
HOBt ester occurs readily, the reaction mixture solvent is switched at this
point from acetonitrile to a higher boiling solvent such as diethoxyethane
and the resulting solution is heated to reflux. When using this procedure,
the reaction goes to completion in 4–6 hr without the use of sieves to remove
water. The reaction workup is the same as above.
3-Methyl-5-[4-(methylsulfonyl)benzyl]-1,2,4-oxadiazole (3). 1H-NMR
(CDCl3) d 7.90 (m, 2H), 7.52 (m, 2H), 4.27 (s, 2H), 3.02 (s, 3H), 2.35 (s, 3H);
13C-NMR (CDCl3) d 176.3, 167.4, 139.9, 139.6, 129.9, 127.9, 44.4, 32.6, 11.4.
Analytical Calculated: C, 52.37; H, 4.79; N, 11.10. Found: C, 52.34; H, 4.69;
N, 11.00; mp 90–918C (dec).
1
Benzyl[1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate (4). H-NMR
(CDCl3) d 7.31 (m, 5H), 5.56 (d, J ¼ 6.4, 1H), 5.13 (m, 3H), 2.37 (s, 3H),
1.57 (d, J ¼ 7.2, 3H); 13C-NMR (CDCl3) d 179.5, 167.2, 155.5, 136.1,
128.6, 128.3, 128.2, 67.3, 44.6, 19.9, 11.5. Analytical Calculated: C, 59.76;
H, 5.79; N, 16.08. Found: C, 59.64; H, 5.83; N, 16.25.
Benzyl[2-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)propyl]carbamate (5).
1H-NMR (CDCl3) d 7.36 (m, 5H), 5.47 (d, J ¼ 9.2, 1H), 5.15, 5.11 (AB quartet,
J ¼ 12.2, 2H), 4.97 (dd, J ¼ 9.2, J ¼ 5.9, 1H), 2.39 (s, 3H), 2.25 (m, 1H), 0.96
(d, J ¼ 7.2, 6H); 13C-NMR (CDCl3) d 178.4, 167.0, 155.9, 136.0, 128.5, 128.3,
128.2, 67.3, 54.0, 32.5, 18.6, 17.8, 11.5. Analytical Calculated: C, 62.27;
H, 6.62; N, 14.52. Found: C, 62.57; H, 6.63; N, 14.35; mp.

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Synthesis of 1,2,4-Oxadiazoles
1869
Benzyl[2-hydroxy-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]carbamate (6).
1H-NMR (CDCl3) d 7.34 (m, 5H), 6.05 (d, J ¼ 8.6, 1H), 5.12 (m, 3H), 4.06
(dd, J ¼ 11.3, 3.1, 1H), 3.95 (dd, J ¼ 11.3, 4.0, 1H), 2.97 (br s, 1H), 2.36
(s, 3H); 13C-NMR (CDCl3) d 177.1, 167.1, 156.0, 135.8, 128.6, 128.3,
128.2, 67.5, 63.2, 50.5, 11.4. Analytical Calculated: C, 56.31; H, 5.45; N,
15.15. Found: C, 56.44; H, 5.33; N, 15.05; mp 116–1178C (dec).
3-(4-Fluorophenyl)-5-[4-(methylsulfonyl)benzyl]-1,2,4-oxadiazole (9).
1H-NMR (CDCl3) d 8.08 (m, 2H), 7.97 (m, 2H), 7.45 (m, 2H), 7.18 (m, 2H),
4.40 (s, 2H), 3.06 (s, 3H); 13C-NMR (CDCl3) d 176.8, 167.8, 164.6
(d, J ¼ 251.7), 140.1, 139.6, 130.1, 129.6 (d, J ¼ 8.8), 128.1, 122.7
(d, J ¼ 3.1), 116.1 (d, J ¼ 22.0), 44.5, 32.8. Analytical Calculated: C,
57.82; H, 3.94; N, 8.43. Found: C, 57.87, H, 3.80, N, 8.46; mp 129–1308C
(dec).
Benzylf1-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethylgcarbamate (10).
1H-NMR (CDCl3) d 8.07 (m, 5H), 7.38 (m, 2H), 7.17 (m, 2H), 5.51
(d, J ¼ 7.4, 1H), 5.24 (m, 1H), 5.17, 5.15 (AB quartet, J ¼ 12.5, 2H), 1.66
(d, J ¼ 7.2, 3H); 13C-NMR (CDCl3) d 179.8, 167.6, 164.7 (d, J ¼ 251.8),
155.5, 136.0, 129.8 (d, J ¼ 8.8), 128.7, 128.4, 128.3, 122.8 (d, J ¼ 3.2), 116.1
(d, J ¼ 21.7), 67.4, 44.8, 20.1. Analytical Calculated: C, 63.34; H, 4.72; N,
12.31. Found: C, 63.30; H, 4.58; N, 12.30; mp 110–1118C (dec).
Benzylf1-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-methylpropylg
carbamate (11). 1H-NMR (CDCl3) d 8.08 (m, 2H), 7.38 (m, 5H), 7.17
(m, 2H), 5.47 (d, J ¼ 8.9, 1H), 5.17, 5.15 (AB quartet, J ¼ 12.5, 2H), 5.07
(dd, J ¼ 8.9, 5.85, 1H), 2.32 (m, 1H), 1.01 (d, J ¼ 6.8, 6H); 13C-NMR
(CDCl3) d 178.8, 167.4, 164.7 (d, J ¼ 251.8), 156.0, 136.1, 129.8
(d, J ¼ 8.7), 128.7, 128.4, 128.3, 122.9 (d, J ¼ 3.2), 116.1 (d, J ¼ 22.0),
67.5, 54.3, 32.7, 18.7, 17.9. Analytical Calculated: C, 65.03; H, 5.46; N,
11.38. Found: C, 64.90; H, 5.19; N, 11.29; mp 82–848C (dec).
Benzylf1-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-2-hydroxyethylg
carbamate (12). 1H-NMR (CDCl3) d 8.04 (m, 2H), 7.36 (m, 5H), 7.15
(m, 2H), 6.0 (d, J ¼ 8.8, 1H), 5.23 (m, 1H), 5.16 (s, 2H), 4.17 (dd,
J ¼ 11.2, 2.8, 1H), 4.05 (dd, J ¼ 11.2, 3.6, 1H), 2.59 (br s, 1H); 13C-NMR
(CDCl3) d 177.4, 167.5, 164.7 (d, J ¼ 252.2), 155.9, 135.8, 129.7
(d, J ¼ 8.8), 128.6, 128.4, 128.2, 122.4 (d, J ¼ 3.2), 116.1 (d, J ¼ 22.3),
67.6, 63.4, 50.6. Analytical Calculated: C, 60.50; H, 4.51; N, 11.76. Found:
C, 60.55; H, 4.31; N, 11.77; mp 104–1058C (dec).
ACKNOWLEDGMENTS
We thank Dr. Raymond Cvetovich and Dr. E.J.J. Grabowski for
helpful discussions. Thanks to Lisa DiMichele and Bob Reamer for NMR

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Pipik et al.
confirmations and Mirlinda Biba for SFC chiral separations for the
oxadiazoles prepared from serine.
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Received in the USA January 6, 2004

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