A mild and efficient one pot synthesis of 1,3,4-oxadiazoles from carboxylic acids and acyl hydrazides

Article abstract of DOI:10.1016/j.tetlet.2006.05.051

A convenient one pot method for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from acids and acyl hydrazides is reported. Acid activation with CDI, followed by coupling with the desired acylhydrazide and dehydration in the same pot with Ph₃P and CBr₄ affords the corresponding 1,3,4-oxadiazoles in good yield. The scope of the acid and acylhydrazide components is presented.

Full text of DOI:10.1016/j.tetlet.2006.05.051

Tetrahedron Letters 47 (2006) 4827–4830
A mild and efficient one pot synthesis of 1,3,4-oxadiazoles
from carboxylic acids and acyl hydrazides
Hemaka A. Rajapakse,* Hong Zhu, Mary Beth Young and Bryan T. Mott
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
Received 18 April 2006; revised 8 May 2006; accepted 9 May 2006
Abstract—A convenient one pot method for the synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from acids and acyl hydrazides is
reported. Acid activation with CDI, followed by coupling with the desired acylhydrazide and dehydration in the same pot with Ph3P
and CBr4 affords the corresponding 1,3,4-oxadiazoles in good yield. The scope of the acid and acylhydrazide components is
presented.
Ó 2006 Elsevier Ltd. All rights reserved.
Oxadiazoles are nonnaturally occurring five-membered
aromatic heterocycles with utility in synthetic and
medicinal chemistry. Cycloaddition of 1,3,4-oxadiazoles
with alkynes are known to provide furans following the
extrusion of nitrogen gas.1 In the field of medicinal
chemistry, oxadiazoles are utilized as ester or amide sur-
rogates. Biologically relevant entities containing the
1,3,4-oxadiazole motif include the HIV integrase inhibi-
tor 1 and the angiogenesis inhibitor 2 (Fig. 1).2,3
F
N
OH
N
O
N
O
F3C
N
N N
2
N
HN
1
OH
O
N
H
Figure 1. Biologically active compounds with the 1,3,5-oxadiazole
motif.
To the best of our knowledge, limited methodology
exists for the synthesis of 1,3,4-oxadiazoles. Typically,
a two step protocol is utilized where the acylhydrazide
and carboxylic acid partners are coupled under amide
bond forming conditions and the resulting product is
sistently observed under these conditions. Hence we
focused on performing the coupling of the acid and acyl
hydrazide partners under conditions compatible with
our preferred cyclodehydrating reagents.
isolated and dehydrated using standard reagents.4–6
A
few one pot methods have been reported in the litera-
ture, but these often require activated acids or forcing
conditions and are limited in substrate scope.7–9 We
wished to develop a more general and convenient
one pot method for the synthesis of these useful
heterocycles.
Gratifyingly, activation of N-Boc-(L)-Phe-OH with car-
bonyl diimidazole (CDI), followed by the addition of
benzoyl hydrazide provided the pivotal bis-acylhydr-
azide adduct by LC/MS. With the addition of CBr4 and
Ph3P, the dehydration proceeded smoothly to provide
the desired oxadiazole 3 in high yield (Table 1).10,11
Strictly anhydrous conditions were not required for this
transformation, and the product mixture was purified
directly by normal phase chromatography without the
need for an aqueous workup.12 The entire sequence
could be performed at 0 °C or room temperature, and
the formation of the bis-acylhydrazide intermediate
could be readily monitored by LC/MS or TLC. Polymer
supported Ph3P could be utilized for the dehydration
step with only a small loss in yield. This reaction
sequence displayed a surprising solvent dependence, as
Our previous experience accrued from the dehydration
of diacylated hydrazides toward the synthesis of 2,5-
disubstituted 1,3,4-oxadiazoles showed that CBr4 and
Ph3P were the optimal reagents for this transformation.
High yields and good substrate compatibility were con-
Keywords: 1,3,4-Oxadiazole; Synthesis; One pot.
*
Corresponding author. Tel.: +1 215 6525629; fax: +1 215 6523971;
e-mail: hemaka_rajapakse@merck.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.051

4828
H. A. Rajapakse et al. / Tetrahedron Letters 47 (2006) 4827–4830
Table 3. Scope of acid coupling partner
Table 1. Solvent and temperature scope
O
O
NH2
NH2
NHBoc
Ph
Ph
N
H
Ph
N
H
+
O
CDI
O
CDI
Ph
R
Ph
+
O
then Ph3P, CBr4
CH2Cl2
N N
O
N N
then Ph3P, CBr4
NHBoc
3
HO
HO
R
Yielda
(%)
Ph
Acid
Product
Solvent
Temperature (°C)
Yielda (%)
O
CH2Cl2
CH2Cl2
CH2Cl2
THF
0
RT
0!RT
0!RT
RT
83
87
75
50
0
O
Bn
N
Ph
52
66
N
HO
HO
b
Bn
N N
8
DMF
NHBoc
O
O
a Isolated yield.
b Polymer supported Ph3P was used in this example.
Ph
NHBoc
Ph
N N
Ph
9
Me
Me
Me
O
O
the coupling and dehydration proceeded very sluggishly
in THF. Incomplete coupling was observed with DMF,
and none of the desired product 3 was detected by LC/
MS after the addition of Ph3P and CBr4.
O
Ph
Me
Me
73
HO
HO
N N
Me
10
O
Ph
Ph
Ph
23b
We then surveyed this one pot methodology with respect
to the scope of nitrogen protecting groups (Table 2).
Cbz and acetamide also proved to be compatible with
this sequence, providing heterocycles 4 and 5, respec-
tively, with high yields. The base sensitive Fmoc and
TFA functionalities also proved to be compatible with
these conditions and provided oxadiazoles 6 and 7 in
good yield.
N N
11
Ph
O
O
NHBoc
NHBoc
O
N
HO
HO
0c
N N
12
N
NHBoc
NHBoc
O
OH
Ph
The reactions of a diverse set of acids with benzoyl
hydrazide are shown in Table 3. The basic amine moiety
of N-benzyl-Pro-OH was tolerated to provide 8 with
reasonable efficiency. Epimerization prone N-Boc pro-
tected phenylglycine provided 9 with minimal racemiza-
tion.13 Our methodology was compatible with sterically
hindered acids, as demonstrated by the synthesis of
oxadiazole 10 in good yield. Conjugation of the acid
with p-functionality proved to be detrimental, providing
the corresponding oxadiazole 11 in only 23% yield. We
suspect that this is primarily due to the sluggishness of
0c
N N
13
OH
a Isolated yield.
b The coupling of the activated acid with benzoyl hydrazide was heated
to 40 °C.
c The diacylhydrazide coupling intermediate was not detected by LC/
MS.
the coupling step, as heating was required to obtain
any diacylated hydrazide adduct. The dehydration pro-
cess appeared to be unaffected by this type of substitu-
tion, as the diacylated hydrazide was converted to the
desired oxadiazole at room temperature. Incorporation
of nucleophilic functionality on the acid partner was
not feasible as both N-Boc-4-pyridylalanine and N-
Boc-4-tyrosine did not provide oxadiazoles 12 and 13,
as determined by LC/MS analysis. We speculate that
this is due to the undesired reaction of the activated acid
with the nucleophilic functionality embedded within the
coupling partner.
Table 2. N-Protecting group compatibility
O
NH2
CDI
NHPG
Ph
Ph
N
H
+
O
then Ph3P, CBr4
Ph
O
N N
CH2Cl2
NHPG
Ph
0 oC
HO
PG
Product
Yielda (%)
The acylhydrazide component proved to be tolerant of a
variety of functional groups in this one pot sequence
(Table 4). Phenolic, aniline, and tertiary hydroxyl bear-
ing acyl hydrazides coupled effectively with activated
acids and cyclodehydrated to provide oxadiazoles 14,
17, and 18 in reasonable yields. The presence of the elec-
Boc
Cbz
Ac
Fmoc
TFA
3
4
5
6
7
83
81
75
73
57
a Isolated yield.

H. A. Rajapakse et al. / Tetrahedron Letters 47 (2006) 4827–4830
4829
Table 4. Acyl hydrazide compatibility
O
NH2
O
CDI, 70 oC
then
t-Bu
N
Me
Me
Ph
H
NH2
O
R1
N
t-Bu
H
+
O
CDI
R1
R2
N N
O
Ph3P, CBr4, RT
ClCH2CH2Cl
+
O
Ph
Me Me
19
then Ph3P, CBr4
CH2Cl2
N N
HO
62%
Scheme 1. Coupling of sterically demanding partners.
HO
R2
Hydrazide
Product
Yielda
(%)
In summary, we have developed a mild and convenient
one pot method for the synthesis of 2,5-disubstituted
1,3,4-oxadiazoles that is compatible with functionality
on both the acid and acyl hydrazide coupling partners.
Strictly anhydrous conditions are not required, and the
product mixture can be loaded directly onto a silica
gel column for purification, obviating the need for an
aqueous workup. The only functional group incompati-
bility that we observed was the presence of nucleophilic
functionality on the acid partner. Overall, the efficiency
of this process is mostly limited by the coupling step, as
once the diacylhydrazide is generated, dehydration pro-
ceeded without exception. The use of unsaturated car-
boxylic acids may require longer reaction times or
heating to induce reasonable conversion. We expect this
methodology to be useful in the context of both single
compound and library synthesis.
R2 = t-Bu
CbzHN
NH2
O
O
t-Bu
CbzHN
N
H
N N
90
75
14
HO
OH
O
O2N
O
NH2
t-Bu
15
N
H
N N
O2N
R2 = Ph
O
O
O2N
H2N
O
NH2
Ph
16
N
H
54b
N N
O2N
Acknowledgements
We thank Scott Kuduk for helpful discussions, and
Joan Murphy, for mass spectral data.
O
NH2
37b
Ph
17
N
H
N N
H2N
O
HO
Me
References and notes
O
N N
62c
HO
N
NH2
Ph
Me
Me
H
1. Wolkenberg, S. E.; Boger, D. L. J. Org. Chem. 2002, 67,
7361, and references cited therein.
18
Me
2. Johns, B. A. PCT Int Appl. WO 2004101512.
3. Piatnitski, E.; Kiselyov, A.; Doody, J.; Hadari, Y.;
Ouyang, S.; Chen, X. PCT Int Appl. WO 2004052280.
4. Brown, P.; Best, D. J.; Broom, N. J. P.; Cassels, R.;
O’Hanlon, P. J.; Mitchell, T. J.; Osborne, N. F.; Wilson, J.
M. J. Med. Chem. 1997, 40, 2563 (Ph3P/CCl4/Et3N).
5. Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J.
Tetrahedron Lett. 1999, 40, 3275 (polymer supported
Burgess reagent).
6. Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius,
L.; Luthman, K. J. Med. Chem. 1999, 42, 4331 (SOCl2).
7. Mashrqui, S. H.; Ghandigaonkar, S. G.; Kenny, R. S.
Synth. Commun. 2003, 33, 2541.
a Isolated yield.
b The coupling of the activated acid with the respective acylhydrazide
was heated to 40 °C.
c The coupling reaction proceeded at room temperature over 15 h.
tron withdrawing nitro group on the benzoyl hydrazide
moiety proved to be compatible with our conditions as
the reaction proceeds at room temperature with pivalic
acid to give 15 in good yield. When the identical hydra-
zide is coupled with benzoic acid, heating is required for
good conversion and oxadiazole 16 is produced in lower
yield, again illustrating the problematic nature of conju-
gated acids in this reaction sequence.
8. Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6989.
9. Wang, Y.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett.
2006, 47, 105.
10. Representative procedure: To a solution of N-Boc-(L)-Phe-
OH (58 mg, 0.22 mmol) in 2 mL CH2Cl2 at 0 °C was
added CDI (36 mg, 0.23 mmol). After 30 min, benzoyl
hydrazide (30 mg, 0.22 mmol) was added. The coupling
was allowed to proceed at 0 °C for 45 min then CBr4
(146 mg, 0.441 mmol) and Ph3P (116 mg, 0.441 mmol)
were added in one portion. The dehydration step was
allowed to proceed at 0 °C for 2 h and the reaction was
poured onto a silica gel column for purification via normal
phase chromatography (40 g silica, 30 mL/min, 5!50%
As a further demonstration of the utility of this method-
ology, the coupling/dehydration of two sterically
demanding partners to provide the corresponding
1,3,4-oxadiazole is depicted in Scheme 1. The activation
of a,a-dimethylphenylacetic acid and coupling with
pivaloyl hydrazide proceeded at 70 °C to cleanly afford
the coupled adduct as observed by LC/MS. Addition
of CBr4 and Ph3P and subsequent dehydration at room
temperature provided oxadiazole 19 in 62% yield.

4830
H. A. Rajapakse et al. / Tetrahedron Letters 47 (2006) 4827–4830
EtOAc/hex) to afford the desired product 3 (66 mg,
0.18 mmol, yield 83%) as a white solid.
11. In comparison, coupling N-Boc-(L)-Phe-OH and benzoyl
hydrazide with EDC, isolating the bis-acyl hydrazide and
dehydrating under identical conditions provided 3 in 92%
yield.
13. This reaction proceeded with ꢀ4% racemization as con-
firmed by chiral HPLC analysis (ChiralPak AD column,
60% EtOH/hex with 1 mL/L added diethylamine) of the
individual enantiomers of 9. For a review detailing the
challenges in the synthesis of and late stage manipulations
involving aryl glycines, see: Nicolaou, K. C.; Boddy, C. N.
C.; Brase, S.; Wissinger, N. Angew. Chem., Int. Ed. 1999,
38, 2096.
12. The reactions could be run in undried glassware under
ambient atmosphere.