A novel convenient synthesis of 1,3,4-oxadiazol-2-ones and -thiones from N-tert-butyldiacylhydrazines

Article abstract of DOI:10.1055/s-2001-17703

An attractive, novel, convenient process for the preparation of 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and -thiones from the reaction of various equivalent and non-equivalent N-tertbutyldiacylhydrazines with potassium tert-butoxide followed by treatment with phosgene or thiophosgene, respectively, has been discovered. The 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and -thiones are confirmed both analytically and chemically. Various equivalent and non-equivalent N-tert-butyldiacylhydrazines are conveniently synthesized from the reaction of tert-butylhydrazine hydrochloride in the presence of i-Pr₂NEt, with acid chloride #1 followed by subsequent treatment with acid chloride #2. Both the syntheses of 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and -thiones, as well as N-tert-butyldiacylhydrazines, are easily performed on multigram scales.

Full text of DOI:10.1055/s-2001-17703

PAPER
1965
A Novel Convenient Synthesis of 1,3,4-Oxadiazol-2-ones and -thiones from N-
tert-Butyldiacylhydrazines
S
ynthesis of 1,3,4-Oxa
a
diazol-2-on
r
es
a
nd -
k
Rohm and Haas Company, 727 Norristown Road, Spring House, Pennsylvania, 19477, USA
Fax +1(914)3453565; E-mail: mark.mulvihill@osip.com
Received 4 May 2001; revised 17 July 2001
Abstract: An attractive, novel, convenient process for the prepara-
tion of 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and -thiones
O
O
N
C(=X)Cl2
R2
R1
N
N
R2
from the reaction of various equivalent and non-equivalent N-tert-
butyldiacylhydrazines with potassium tert-butoxide followed by
treatment with phosgene or thiophosgene, respectively, has been
discovered. The 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and
-thiones are confirmed both analytically and chemically. Various
equivalent and non-equivalent N-tert-butyldiacylhydrazines are
conveniently synthesized from the reaction of tert-butylhydrazine
hydrochloride in the presence of i-Pr2NEt, with acid chloride #1
followed by subsequent treatment with acid chloride #2. Both
the syntheses of 3,5-disubstituted-3H-[1,3,4]-oxadiazol-2-ones and
-thiones, as well as N-tert-butyldiacylhydrazines, are easily per-
formed on multigram scales.
R1
N
3a, X = O
3b, X = S
O
M
O
X
4 (X = O)
5 (X = S)
1 (M = H)
2 (M = K)
t-BuOK
THF
Scheme 1 1,3,4-Oxadiazol-2-ones 4 and -thiones 5 from N’-tert-bu-
tyldiacylhydrazines 1
forded 1,3,4-oxadiazol-2-thione 5a in 80% yield
(Scheme 1 and Table 1).
Key words: cyclization, heterocycles, regioselectivity, hydrazine,
phosgene
Understanding from literature precedence that 3-benzoyl-
5-phenyl-3H-[1,3,4]-oxadiazol-2-one readily underwent
cleavage at the 3-benzoyl position when subjected to
aniline to afford N-phenylbenzamide and 5-phenyl-3H-
[1,3,4]-oxadiazol-2-one,6b we decided to react our 3-(4-
ethylbenozyl)-5-(3,5-dimethylphenyl)-3H-[1,3,4]-oxadi-
azol-2-one (4a) under the same conditions. We found that
subjection of 3-(4-ethylbenozyl)-5-(3,5-dimethylphenyl)-
3H-[1,3,4]-oxadiazol-2-one (4a) to aniline in THF
smoothly afforded both expected products, 4-ethyl-N-
phenylbenzamide (6) and 5-(3,5-dimethylphenyl)-3H-
[1,3,4]-oxadiazol-2-one (7) (Scheme 2).8
N-tert-Butyldiacylhydrazines 1 such as tebufenozide
(1a),1 methoxyfenozide (1b),2 and halofenozide (1c)3 are
an important class of insecticidal compounds serving as
environmentally safe, extremely selective insect growth
regulators (Table 1).4 1,3,4-Oxadiazole derivatives 4 and
5 are also an important class of heterocyclic compounds
displaying a wide range of biological activities.5 Several
novel and efficient routes toward their syntheses have
been reported.5–7 Normally, one would not necessarily as-
sume a relationship between the two classes of com-
pounds, however, this paper reports the novel cyclization
reaction of N-tert-butyldiacylhydrazines 1 with phosgene
as well as thiophosgene to afford 1,3,4-oxadiazol-2-ones
and -thiones 4 and 5, respectively, with loss of the tert-bu-
tyl moiety.
O
N
aniline
N
+
O
N
O
O
HN
PhHN
O
O
4a
In studies, directed toward the synthesis of more insecti-
cidally active N-tert-butyldiacylhydrazines, we discov-
ered that 1,3,4-oxadiazol-2-one 4a (where R1 = 4-
ethylphenyl, R2 = 3,5-dimethylphenyl, and X = O) is pro-
duced in 95% yield. This is achieved when diacylhydra-
zine 1a (where R1 = 4-ethylphenyl and R2 = 3,5-
dimethylphenyl), is converted to its potassium salt 2a, via
treatment with potassium tert-butoxide, followed by reac-
tion with phosgene (3a, X = O) at –78 °C. Similar reaction
of potassium salt 2a with thiophosgene (3b, X = S) af-
6
7
Scheme 2 Reaction of 1,3,4-oxadiazol-2-one 4a with aniline to af-
ford benzamide 6 and 3H-[1,3,4]-oxadiazol-2-one 7
After analytically and chemically establishing the struc-
ture of 5-(3,5-dimethylphenyl)-3-(4-ethylbenozyl)-3H-
[1,3,4]-oxadiazol-2-one (4a) via both the Gogoi8 and Sae-
gusa method (Scheme 2), we began contemplating the
mechanism for such a cyclization. We envisioned that the
mechanism for the transformation of N-tert-butyldiacyl-
hydrazine salt 2 to 1,3,4-oxadiazol-2-one 4 via reaction
with phosgene involved N-acylation of N-tert-butyldia-
cylhydrazine 2 to afford the acyl adduct 8, which after cy-
clization via attack of the R2 carbonyl to give 9 and
subsequent loss of tert-butyl afforded 1,3,4-oxadiazol-2-
one 4 (Scheme 3).
Synthesis 2001, No. 13, 08 10 2001. Article Identifier:
1437-210X,E;2001,0,13,1965,1970,ftx,en;M02201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1966
M. J. Mulvihill et al.
PAPER
Table 1 1,3,4-Oxadiazol-2-ones 4 and -thiones 5 from N-tert-Butyldiacylhydrazines 1
Entry
1
N-tert-Butyldiacylhydrazines 1a
1,3,4-Oxadiazol-2-ones 4 and -thiones 5d
Yield (%)
95
mp (°C)
134–135
O
O
N
N
N
N
O
O
H
O
4a
1a
2
95
152–153
O
O
O
O
N
N
N
N
H
O
O
O
1b
4b
3
4
60
95
138–139
O
Cl
O
N
N
N
N
H
O
O
O
Cl
1c
4c
82–84
O
N
O
N
N
N
H
O
O
O
1d
4d
5
6
92
90
Oil
O
N
O
N
N
N
H
O
O
O
4e
1e
134–136b
O
N
O
N
N
N
H
O
O
O
1f
4f
7
80
Oil
O
O
N
N
N
N
H
O
O
O
1g
4g
Synthesis 2001, No. 13, 1965–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,3,4-Oxadiazol-2-ones and -thiones
1967
Table 1 1,3,4-Oxadiazol-2-ones 4 and -thiones 5 from N-tert-Butyldiacylhydrazines 1 (continued)
Entry
8
N-tert-Butyldiacylhydrazines 1a
1,3,4-Oxadiazol-2-ones 4 and -thiones 5d
Yield (%)
80
mp (°C)
142–144
O
O
N
N
N
N
S
O
H
O
5a
1a
9
75
166–168
O
O
O
O
N
N
N
N
H
S
O
O
1b
5b
10
70
135–136c
O
O
N
N
N
N
H
S
O
O
1f
5f
a N-tert-Butyldiacylhydrazines 1a, 1b, and 1c are commercially available or can be prepared according to known procedures.1–3
b Lit.6b mp 136–137 °C.
c Lit.6b mp 136–137 °C.
d Reaction of N-tert-butyldiacylhydrazines 1c, 1d, 1e, and 1g with thiophosgene did not give satisfactory results.
In order to further test the scope of this process for the forded 3-benzoyl-5-iso-propyl-3H-[1,3,4]-oxadiazol-2-
general preparation of 3,5-disubstituted-3H-[1,3,4]-oxa- one (4e), while treatment of benzoic acid N-tert-butyl-N’-
diazol-2-ones 4 and -thiones 5 from N’-tert-butyldiacyl- iso-butyrylhydrazide (1d) under identical conditions af-
hydrazines 1, we prepared
a series of N’-tert- forded 3-iso-butyryl-5-phenyl-3H-[1,3,4]-oxadiazol-2-
butyldiacylhydrazines 1a–g and subjected them to potas- one (4d) (Scheme 4).
sium tert-butoxide in THF at –78 °C followed by treat-
In conclusion, we have developed a novel, convenient,
ment with phosgene or thiophosgene. The results are
reported in Table 1 and the spectral data of compounds
prepared are listed in Table 2. It should be noted that tert-
butylhydrazine offers the versatility of a one-pot, two step
regioselective diacylation process. This is due to the ster-
ics associated with the tert-butyl moiety.9 For example,
benzoic acid N’-tert-butyl-N’-iso-butyrylhydrazide (1e)
can be prepared from the reaction of tert-butylhydrazine
hydrochloride salt (10) with 2 equivalents of i-Pr2NEt and
1 equivalent of benzoyl chloride, followed by the addition
of a third equivalent of i-Pr2NEt and 1 equivalent of iso-
butyryl chloride. On the other hand, benzoic acid N-tert-
butyl-N’-iso-butyrylhydrazide (1d) can be prepared by re-
versing the order of addition of the acid chlorides to first
charging the reaction with iso-butyryl chloride followed
by benzoyl chloride. Further reaction of benzoic acid N’-
tert-butyl-N’-iso-butyrylhydrazide (1e) with potassium
tert-butoxide followed by treatment with phosgene af-
and scaleable process toward the synthesis of 3,5-disubsti-
tuted-3H-[1,3,4]-oxadiazol-2-ones 4a–g and -thiones
5a,b,f by reacting N-tert-butyldiacylhydrazines 1a–g with
potassium tert-butoxide followed by the addition of phos-
gene 3a or thiophosgene 3b. We also determined the
structure of 5-(3,5-dimethylphenyl)-3-(4-ethylbenozyl)-
3H-[1,3,4]-oxadiazol-2-one (4a) not only through analyt-
O
O
Cl
R2
N
O
R2
COCl2
KCl
N
R1
N
R1
N
2
4
O
O
Cl
- t-Bu
O
9
8
Scheme 3 Proposed mechanism for the transformation of diacylhy-
drazine 2 to 1,3,4-oxadiazol-2-one 4
Synthesis 2001, No. 13, 1965–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

1968
M. J. Mulvihill et al.
PAPER
Table 2 Selected Spectra Data of Compounds 1d–g, 4a–g, 5a, 5b, 5f, 6, and 7
Producta
1H NMR (300 MHz, CDCl3) , J (Hz)
13C NMR (75 MHz, CDCl3)
IR (cm–1)
1d
0.45 (d, 3 H, J = 6.6), 0.89 (d, 3 H, J = 6.6), 1.50 (s, 18.7, 19.2, 28.0, 33.3, 61.4, 126.6, 128.1, 129.6,
9 H), 1.95 (m, 1 H), 7.21–7.34 (m, 5 H), 8.41 (br s, 138.4, 174.2, 175.9
1 H)
2900, 1706, 1684,
1637
1e
1.07 (d, 3 H, J = 6.0), 1.08 (d, 3 H, J = 6.0), 1.50 (s, 19.2, 20.1, 28.1, 31.9, 61.3, 127.2, 129.0, 132.1,
2919, 1666, 1643
9 H), 2.80 (m, 1 H), 7.48 (m, 2 H), 7.56 (m, 1 H),
132.6, 167.3, 179.4
7.80 (d, 2 H, J = 6.0), 8.33 (s, 1 H)
1f
1.60 (s, 9 H), 7.26–7.45 (m, 10 H), 7.85 (br s, 1 H) 28.1, 61.9, 126.6, 127.3, 128.2, 128.7, 129.6, 132.1, 1666, 1638
132.6, 138.1, 167.9, 174.2
1g
1.04 (t, 6 H, J = 6.6), 1.18 (t, 6 H, J = 6.6), 1.43 (s, 19.7, 20.3, 28.2, 32.0, 33.4, 61.2, 177.4, 179.9
3283, 2910, 1689
9 H), 2.57–2.67 (m, 1 H), 2.71–2.80 (m, 1 H), 9.11
(br s, 1 H)
4a
1.30 (t, 3 H, J = 7.5), 2.38 (s, 6 H), 2.75 (q, 2 H, J = 15.0, 21.2, 29.1, 122.4, 124.3, 127.9, 128.0, 130.9,
7.5), 7.18 (s, 1 H), 7.32 (d, 2 H, J = 8.1), 7.56 (s, 2 134.6, 139.0, 149.9, 150.9, 154.1, 164.2
H), 7.92 (d, 2 H, J = 8.4)
2927, 1831, 1703,
1301
4b
4c
4d
2.27 (s, 3 H), 2.36 (s, 6 H), 3.89 (s, 3 H), 7.05 (m, 2 13.0, 21.1, 55.7, 112. 9, 119.7. 122.2, 124.5, 125.8,
H), 7.19 (s, 1 H), 7.26–7.30 (m, 1 H), 7.54 (s, 2 H) 126.6, 133.0, 134.7, 138.9, 149.1, 154.8, 157.8. 164.9 1291
2931, 1822, 1726,
7.50–7.61 (m, 5 H), 7.92–7.97 (m, 4 H)
122.4, 126.6, 128.7, 129.0, 129.2, 132.0, 133.0,
140.3, 149.4, 153.9, 163.3
2926, 2891, 1850,
1728
1.30 (d, 3 H, J = 6.6), 1.32 (d, 3 H, J = 6.6), 3.53– 18.4, 33.4, 122.6, 126.6, 129.2, 133.9, 149.2, 154.0, 1849, 1824, 1725
3.63 (m, 1 H), 7.49–7.61 (m, 3 H), 7.94 (d, 2 H, J = 172.9
7.5)
4e
4f
1.34 (d, 6 H, J = 6.0), 2.94 (m, 1 H), 7.49 (m, 2 H), 18.6, 27.1, 128.2, 130.4, 130.8, 133.6, 150.1, 161.2, 1833, 1805, 1711,
7.63 (m, 1 H), 7.92 (d, 2 H, J = 6.0)
164.3
1307
7.49–7.66 (m, 6 H), 7.93 (d, 2 H, J = 6.0), 7.99 (d, 122.5, 126.6, 128.3, 129.2, 130.5, 130.7, 132.9,
2 H, J = 6.0) 133.7, 149.6, 153.8, 164.3
2916, 1821, 1701,
1293
4g
5a
1.26 (d, 6 H, J = 6.0), 1.33 (d, 6 H, J = 6.0), 2.92 (m, 18.4, 18.6, 27.1, 33.2, 149.8, 161.4, 172.8
1 H), 3.51 (m, 1 H)
1835, 1802, 1744,
1271
1.32 (t, 3 H, J = 7.5), 2.38 (s, 6 H), 2.77 (q, 2 H, J = 15.0, 21.2, 29.1, 121.3, 124.7, 128.0, 128.1, 131.4,
7.5), 7.22 (s, 1 H), 7.36 (d, 2 H, J = 8.1), 7.59 (s, 2 134.9, 139.1, 151.4, 158.3, 164.7, 175.0
H), 7.94 (d, 2 H, J = 8.1)
2940, 1713, 1607,
1279
5b
2.27 (s, 3 H), 2.36 (s, 6 H), 3.90 (s, 3 H), 7.04–7.10 13.0, 21.1, 55.7, 113.1, 120.2, 121.2, 124.8, 126.3,
2903, 1733, 1461,
(m, 2 H), 7.21 (s, 1 H), 7.26–7.31 (m, 1 H), 7.55 (s, 126.7, 133.3, 134.9, 139.1, 157.9, 158.6, 165.7, 174.2 1309
2 H)
5f
7b
6c
7.50–7.68 (m, 6 H), 7.96–8.01 (m, 4 H)
121.6, 127.1, 128.4, 129.3, 130.8, 130.9, 133.2,
134.0, 158.0, 164.9, 174.8
2925, 1727, 1625,
1287
2.37 (s, 6 H), 7.15 (s, 1 H), 7.48 (s, 2 H), 9.58 (br s, 21.2, 123.48, 123.53, 133.5, 138.8, 154.9, 155.7
1 H)
2932, 2906, 1777,
1734
1.26 (t, 3 H, J = 9.0), 2.72 (q, 2 H, J = 9.0), 7.14 (t, 15.3, 28.8, 120.1, 124.4, 127.1, 128.3, 129.1, 132.3, 3303, 2908, 1648
1 H, J = 9), 7.28–7.39 (m, 4 H), 7.64 (d, 2 H, J =
6.0), 7.79 (d, 2 H, J = 6.0), 7.85 (br s, 1 H)
138.0, 148.6, 165.7.
a Satisfactory microanalyses obtained: C 0.30, H 0.24, N 0. 29.
b Compound 7, mp 182–183 °C.
c Compound 6, mp 120–122 °C.
ical methods, but also through chemical means utilizing easily synthesized in a one-pot, two step regioselective
the methods of Gogoi and Saegusa as shown in Schemes 2 acylation procedure involving the reaction of tert-butyl-
and Ref.8 to synthesize both 4a and 5-(3,5-dimethylphe- hydrazine hydrochloride in the presence of i-Pr2NEt with
nyl)-3H-[1,3,4]-oxadiazol-2-one (7). We also demonstrat- R1COCl followed subsequently by R2COCl. Also, it
ed that various N-tert-butyldiacylhydrazines 1, equivalent should be noted that the tert-butyl moiety, which is incon-
and non-equivalent in nature of their acyl groups, could be spicuously removed in situ during the cyclization process,
Synthesis 2001, No. 13, 1965–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,3,4-Oxadiazol-2-ones and -thiones
1969
H2O (2 80 mL) and then with brine (80 mL). The EtOAc layer was
dried (MgSO4), filtered and concentrated in vacuo to afford 7.5 g
(90%) of the desired product 1d as a white solid which was recrys-
tallized from Et2O (Table 1); mp 156–157 °C.
t-Bu-NHNH2-HCl
1) EtOH/CH2Cl2,
PhCOCl,
DIEA
1) EtOH/CH2Cl2,
(CH3)2CHCOCl,
DIEA
10
2) (CH3)2CHCOCl,
DIEA
2) PhCOCl,DIEA
Benzoic Acid N’-tert-Butyl-N’-iso-butyrylhydrazide (1e)
Compound 1e was prepared in 80% yield according to the typical
procedure above except for charging the reaction first with benzoyl
chloride followed by iso-butyryl chloride; mp 180–181 °C.
O
O
N
N
Ph
N
N
Ph
Benzoic Acid N’-Benzoyl-N-tert-butylhydrazide (1f)
Compound 1f was prepared in 93% yield according to the typical
procedure above except benzoyl chloride was used instead of iso-
butyryl chloride; mp 172–173 °C.
H
H
O
O
1d
1e
1) t-BuOK
1) t-BuOK
2) COCl2
2) COCl2
iso-Butyric Acid N-tert-Butyl-N’-iso-butyrylhydrazide (1g)
Compound 1g was prepared in 90% yield according to the typical
procedure above except for the addition of iso-butyryl chloride in-
stead of benzoyl chloride; mp 151–152 °C.
O
O
N
N
N
N
Ph
Ph
O
O
O
3,5-Disubstituted-3H-[1,3,4]-oxadiazol-2-ones 4a–g and -
thiones 5a, 5b, and 5f; 5-(3,5-Dimethylphenyl)-3-(4-
ethylbenzoyl)-3H-[1,3,4]-oxadiazol-2-one (4a); Typical
Procedure
O
4d
4e
To a THF solution (30 mL) of 1a (500 mg, 1.42 mmol) under N2
was added KOBu-t (159 mg, 1.42 mmol). The resulting mixture was
allowed to stir at r.t. for 1 h at which time the solution was cooled
in a dry ice/acetone bath to –78 °C. Phosgene (2.2 M in EtOAc, 0.75
mL, 1.62 mmol) was then added in one portion and the resulting
mixture was allowed to stir at –78 °C for 0.5 h. The solution was
then concentrated in vacuo, redissolved into CH2Cl2 (30 mL),
washed with H2O (2 20 mL) and then with brine (20 mL). The
CH2Cl2 layer was dried (MgSO4), filtered, and concentrated in vac-
uo to afford 434 mg (95%) of 4a as a white solid, which was recrys-
tallized from EtOAc–hexanes.
Scheme 4 Selective diacylation of tert-butylhydrazine 10 to afford
iso-butyryl/benzoylhydrazine isomers 1d and 1e, respectively follo-
wed by cyclization to afford 1,3,4-oxadiazol-2-ones 4d and 4e
is especially attractive as it creatively serves a dual pur-
pose in directing both the regioselective diacylation reac-
tion as well as the subsequent cyclization reaction.
Reagents and solvents were used as received from commercial
sources. TLC was performed on 4 8 cm, SIL 6UV/254, Lot
111989 silica gel plates with fluorescent indicator available from
Alltech Associates, Inc. TLC plates were visualized with UV light.
Column chromatography was performed on silica gel (Merck, 70–
230 mesh). 1H and 13C NMR spectra were obtained in CDCl3 on a
Bruker 300 MHz spectrometer. All 1H NMR spectra are reported in
ppm relative to TMS. All 13C NMR spectra are reported in ppm rel-
ative to the central line of the triplet for CDCl3 at 77.00 ppm. Melt-
ing points were obtained on a Thomas Hoover capillary melting
point apparatus and are uncorrected. IR spectra were obtained by
dissolving the compound in CHCl3 and then applying the solution
to a polyethylene film plate and spectra were obtained on a Mattson
Genesis II FT-IR spectrophotometer and reported in cm–1. Elemen-
tal analyses were performed by Robertson Microlit Laboratories,
Inc., 29 Samson Avenue, P.O. Box 927, Madison, New Jersey
07940.
5-(3,5-Dimethylphenyl)-3-(3-methoxy-2-methylbenzoyl)-3H-
[1,3,4]-oxadiazol-2-one (4b)
Compound 4b was prepared according to the typical procedure
above except for the substitution of hydrazide 1b for 1a.
3-(4-Chlorobenzoyl)-5-phenyl-3H-[1,3,4]-oxadiazol-2-one (4c)
Compound 4c was prepared according to the typical procedure
above except for the substitution of hydrazide 1c for 1a.
3-iso-Butyryl-5-phenyl-3H-[1,3,4]-oxadiazol-2-one (4d)
Compound 4d was prepared according to the typical procedure
above except for the substitution of hydrazide 1d for 1a.
3-Benzoyl-5-iso-propyl-3H-[1,3,4]-oxadiazol-2-one (4e)
Compound 4e was prepared according to the typical procedure
above except for the substitution of hydrazide 1e for 1a.
N-tert-Butyldiacylhydrazines 1d–g; Benzoic Acid N-tert-Butyl-
N’-iso-butyrylhydrazide (1d); Typical Procedure
3-Benzoyl-5-phenyl-3H-[1,3,4]-oxadiazol-2-one (4f)
Compound 4f was prepared according to the typical procedure
above except for the substitution of hydrazide 1f for 1a.
To a solution of tert-butylhydrazine hydrochloride (4.0 g, 32.0
mmol) in a mixture of CH2Cl2 (75 mL) and EtOH (75 mL) was add-
ed i-Pr2NEt (11.2 mL, 64.0 mmol). The solution was cooled to 5 °C
in an ice-water bath and then charged with iso-butyryl chloride (3.3
mL, 32.0 mmol) at once and allowed to warm to r.t. After stirring
for 4 h, the solution was cooled to 5 °C in an ice bath, charged with
i-Pr2NEt (5.6 mL, 32.0 mmol) followed by benzoyl chloride (3.7
mL, 32.0 mmol) and then allowed to warm to r.t. After stirring for
4 h, the solvent was removed in vacuo and the solids were dissolved
in EtOAc (100 mL) and washed with 5% HCl solution (80 mL),
3-iso-Butyryl-5-iso-propyl-3H-[1,3,4]-oxadiazol-2-one (4g)
Compound 4g was prepared according to the typical procedure
above except for the substitution of hydrazide 1g for 1a.
3-(4-Ethylbenzoyl)-5-(3,5-dimethylphenyl)-3H-[1,3,4]-
oxadiazol-2-thione (5a)
Compound 5a was prepared according to the typical procedure
above except for the substitution of thiophosgene for phosgene.
Synthesis 2001, No. 13, 1965–1970 ISSN 0039-7881 © Thieme Stuttgart · New York

1970
M. J. Mulvihill et al.
PAPER
3-(3-Methoxy-2-methylbenzoyl)-5-(3,5-dimethylphenyl)- 3H-
[1,3,4]-oxadiazol-2-thione (5b)
Compound 5b was prepared according to the typical procedure
above except for the substitution of hydrazide 1b for 1a and the sub-
stitution of thiophosgene for phosgene.
(4) Thomson, W. T. Agricultural Chemicals, Book 1,
Insecticides; Thomson Publications: Fresno, CA, 1998, 14th
ed., 142–144.
(5) (a) Huang, L. J.; Kuo, S. C.; Wang, J. P.; Ishii, K.;
Nakamura, H. Chem. Pharm. Bull. 1994, 41, 2036.
(b) Hazarika, J.; Kataky, J. C. S. Ind. J. Heterocycl. Chem.
1997, 7, 47. (c) Musser, J. H.; Brown, R. E.; Loev, B.;
Bailey, K.; Jones, H.; Kahen, R.; Huang, F.; Khandwala, A.;
Leibowitz, M. J. Med. Chem. 1984, 27, 121.
3-Benzoyl-5-phenyl-3H-[1,3,4]-oxadiazol-2-thione (5f)
Compound 5f was prepared according to the typical procedure
above except for the substitution of hydrazide 1f for 1a and the sub-
stitution of thiophosgene for phosgene.
(d) Khandwala, A.; Coutts, S.; Dally-Meade, V.; Jariwala,
N.; Musser, J.; Brown, R.; Jones, H.; Loev, B.; Weinryb, I.
Biochem. Pharmacol. 1983, 32, 3325. (e) Singh, H.; Yadav,
L. D. S.; Bhattacharya, B. K. J. Ind. Chem. Soc. 1980, 57,
1006. (f) Meyer, R. F.; Cummings, B. L. J. Heterocycl.
Chem. 1964, 1, 186.
4-Ethyl-N-phenylbenzamide (6) and 5-(3,5-Dimethylphenyl)-
3H-[1,3,4]-oxadiazol-2-one (7)
A solution of 4a (500 mg, 1.55 mmol) in THF (8 mL) was charged
with aniline (144 mg, 1.55 mmol) and stirred for 4 h, upon which
time the reaction was deemed complete by TLC analysis. The THF
was removed in vacuo, and the crude product was purified by silica
gel column chromatography (EtOAc–hexanes, 1:1) to afford 300
mg (85%) of 6 and 250 mg (85%) of 7. The analytical data of com-
pound 7 was identical to that of 7 prepared via the Gogoi method.8
(6) (a) Squillacote, M.; Felippis, J. D. J. Org. Chem. 1994, 59,
3564. (b) Saegusa, Y.; Nakamura, S.; Chau, N.; Iwakura, Y.
J. Polym. Sci. 1983, 21, 637.
(7) Gogoi, P. C.; Kataky, J. C. S. Heterocycles 1991, 32, 237.
(8) We decided to further chemically validate the structure of 4a
utilizing Gogoi’s method7 for the synthesis of 3,5-disubsti-
tuted-3H-[1,3,4]-oxadiazol-2-ones. We synthesized N’-(3,5-
dimethylbenzoyl)hydrazinecarboxylic acid ethyl ester from
the reaction of a CH2Cl2 solution of ethyl carbazate with 3,5-
dimethylbenzoyl chloride in the presence of i-Pr2NEt.
Reaction of N’-(3,5-dimethylbenzoyl)hydrazinecarboxylic
acid ethyl ester with POCl3 afforded 5-(3,5-
Acknowledgement
We thank Kristen M. Mulvihill for her help in the preparation of this
manuscript.
dimethylphenyl)-3H-[1,3,4]-oxadiazol-2-one (7), which
was analytically identical to compound 7 synthesized via
Scheme 2 (Table 2). Benzoylation of 7 with 4-ethylbenzoyl
chloride afforded 5-(3,5-dimethylphenyl)-3-(4-
ethylbenozyl)-3H-[1,3,4]-oxadiazol-2-one (4a), which was
identical in all respects to 4a synthesized via our phosgene/
N-tert-butyldiacylhydrazine route.
References
(1) Tebufenozide (1a) is commercially available.
(2) (a) Lidert, Z.; Le, D. P.; Hormann, R. E.; Opie, T. R. US
Patent 5530028, 1996. (b) Chem. Abstr. 1996, 125, 161132.
(3) (a) James, W. N. Jr.; Aller, H. E. US Patent 5358966, 1994.
(b) Chem. Abstr. 1994, 122, 3593.
(9) (a) Kelley, M. J.; Budenz, A. M. US Patent 5675037, 1998.
(b) Chem. Abstr. 1998, 129, 54190.
Synthesis 2001, No. 13, 1965–1970 ISSN 0039-7881 © Thieme Stuttgart · New York