Rapid, microwave accelerated synthesis of [1,2,4]triazolo[3,4-b][1,3,4]oxadiazoles from 4-acylamino-1,2,4-triazoles

Article abstract of DOI:10.1016/j.tetlet.2016.07.082

1,2,4-Triazoles and 1,3,4-oxadiazoles are prevalent moieties in pharmaceutical agents, yet fused [1,2,4]triazolo[3,4-b][1,3,4]oxadiazoles are surprisingly under-represented for both synthesis and biological application. We report a rapid, two-step synthes

Full text of DOI:10.1016/j.tetlet.2016.07.082

Accepted Manuscript
Rapid, Microwave Accelerated Synthesis of [1,2,4]Triazolo[3,4-b][1,3,4]oxa-
diazoles from 4-Acylamino-1,2,4-Triazoles
Stephanie L. Breunig, Margaret E. Olson, Daniel A. Harki
PII:
S0040-4039(16)30950-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.082
TETL 47944
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 June 2016
19 July 2016
27 July 2016
Please cite this article as: Breunig, S.L., Olson, M.E., Harki, D.A., Rapid, Microwave Accelerated Synthesis of
[1,2,4]Triazolo[3,4-b][1,3,4]oxadiazoles from 4-Acylamino-1,2,4-Triazoles, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.07.082
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Graphical Abstract
Rapid, Microwave Accelerated Synthesis of
[1,2,4]Triazolo[3,4-b][1,3,4]oxadiazoles from
4-Acylamino-1,2,4-Triazoles
Leave this area blank for abstract info.
Stephanie L. Breunig, Margaret E. Olson, Daniel A. Harki
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA

1
Tetrahedron Letters
Rapid, Microwave Accelerated Synthesis of [1,2,4]Triazolo[3,4-b][1,3,4]oxadiazoles
from 4-Acylamino-1,2,4-Triazoles
Stephanie L. Breunig, Margaret E. Olson, and Daniel A. Harki
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
1,2,4-Triazoles and 1,3,4-oxadiazoles are prevalent moieties in pharmaceutical agents, yet fused
[1,2,4]-triazolo[3,4-b][1,2,4]oxadiazoles are surprisingly under-represented for both synthesis
and biological application. We report a rapid, two-step synthesis of [1,2,4]-triazolo[3,4-
b][1,2,4]oxadiazoles from commercial 4-amino-1,2,4-triazoles that is highlighted by
a
Available online
microwave accelerated intramolecular cyclization to generate the fused ring system. Our efforts
to optimize reaction conditions and elucidate reaction mechanism are also described.
Keywords:
1,2,4-Triazole
2009 Elsevier Ltd. All rights reserved.
1,3,4-Oxadiazole
[1,2,4]Triazolo[3,4-b][1,3,4]oxadiazole
Microwave Chemistry
Intramolecular Cyclization
———
 Corresponding author. Tel.: +1-612-625-8687; fax: +1-612-625-4749; e-mail: daharki@umn.edu

2
Tetrahedron Letters
Introduction
1,2,4-Triazoles are represented in diverse molecules
with antimicrobial,1-2 antitubercular,3 anticancer,4
analgesic,5 and anticonvulsant6 activities. Notably, the
antiviral drug ribavirin and antifungal drugs
fluconazole, itraconazole, and voriconazole possess a
1,2,4-triazole. In a similar vein, 1,3,4-oxadiazoles, are
present in compounds bearing antimicrobial,7-8
antifungal,9
anxiolytic,10
antidepressant,11
antiproliferative,12-17 hypoglycemic,18 and antiviral
activities. Raltegravir, an FDA-approved HIV-1
integrase inhibitor, incorporates a 1,3,4-oxadiazole.
However, [1,2,4]triazolo[3,4-b][1,3,4]oxadiazoles (1)
are surprisingly under-investigated. In the few assays
executed, compounds containing this moiety exhibited
antibacterial activity similar to that of streptomycin,19
herbicidal activity comparable to the commercially
available 2,4-dichlorophenoxyacetic acid (2,4-D), and
fungicidal activity akin to the commercial Dithane M-
45.20 Furthermore, in a library of oxadiazole derivatives
screened for antimicrobial activity, the triazolo-
oxadiazole was considered the most active.21
The
[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole
heterocycle, 1, was first suggested in 1961;22 and since
then, multiple synthetic approaches have been reported
(Figure 1A). In nearly all approaches to 1 the
oxadiazole is first prepared and the triazole is formed in
the final step. For instance, 1,3,4-oxadiazoles
functionalized at the 2-position with acylhydrazines
(2),19,23-25 hydrazones (3),26-27 and unsubstituted
hydrazines (4)20,28-29 can be directly converted to 1 via
triazole cyclization. The triazole has also been formed
by reacting hydrazine hydrate with either EtOH and
amino oxadiazoles (5),21 N-substituted oxadiazolines
(6),30 or N-acylated oxadiazolones (7).31 Butler et al.
found that hydrazonyl bromides (8) could be cyclized
via nucleophilic attack of the oxadiazole.32 Bypassing
the formation of 8, Scott et al. found that tribromo-
diazobutadienes (9) could afford 1 when refluxed with
benzhydrazine and Et3N.33 Conversely, only two reports
of [1,2,4]triazolo[3,4-b][1,3,4]oxadiazole formation via
late-stage generation of the oxadiazole ring have been
reported. Tsuge et al. observed the formation of 1 when
carbamoyl chloride (10) was treated with anhydrous
sodium azide, and proposed the reaction proceeded via a
triazolone intermediate able to react with a second
equivalent of 10.34 They, along with Milcent et al., also
formed 1 from a pre-functionalized triazole (11) using
Figure 1. (A) Previously reported methods for the preparation of
heterocycles represented by 1. (B) Our strategy for the synthesis of 1 from
readily accessible precursors, such as 12.
previous studies by our laboratory, we found that
substituted
4-amino-1,2,4-triazole-3-thiols
inhibit
APOBEC3G (A3G) DNA cytosine-to-uracil deaminase
activity by covalently engaging A3G Cys321, a critical
residue proximal to the active site.36 As thiols are
inherently reactive functional groups, we sought to
replace this moiety on our inhibitor with a nitrile,
compound 15, to achieve a more drug-like scaffold with
tuneable reactivity. The nitrile functional group has
gained significant attention as an electrophile for
reversible covalent inhibition of therapeutic targets due
to its weak reactivity with nucleophiles in solution. For
instance, when appropriately positioned in an enzyme, a
34
Na2CO3 or POCl3,35 respectively. Herein, we report a
rapid, microwave accelerated synthesis of 1 from readily
synthesized 4-acylamino-1,2,4-triazoles (12) that are
iodinated in situ (Figure 1b).
In an effort to synthesize reversible covalent
inhibitors of APOBEC3 DNA cytosine-to-uracil
deaminases, we discovered the [1,2,4]triazolo[3,4-
b][1,3,4]oxadiazole synthesis presented herein. In
Scheme 1. Attempted synthesis of nitrile 15 via 14 under previously
published conditions38 for direct cyanation of heterocycles and isolated
16. (a) Benzoyl chloride, 1,4-dioxane, reflux, 24 h, 60-79% (b) CuCN
(0.7 equiv.), NaCN (1.2 equiv.), I2 (1.5 equiv.), tBuOLi (1.2 equiv.),
1,10-phenanthroline (1.0 equiv.), m-xylene, 1,4-dioxane, MW 125 oC,
18%.

3
solubility was poor when dioxane and xylene were used
as co-solvents, both DMF and methanol were also
utilized to enhance solubility. However, despite the fact
that a homogenous solution was obtained in both
instances, these solvent changes appeared to have little
effect on the transformation. Finally, it appeared that
Table 1. Initial studies to determine necessary reagents for
conversion of 14 to 16 based on previously reported38 direct
cyanation conditions.a,b
Temp
(°C)
Time
(min)
Reagents
Solvent(s)
% Yieldc
o
CuCN, tBuOLi, I2,
NaCN,
Phenanthroline
elevated temperatures (125 C) were required for the
1,4-dioxane/
m-xylene
125
30
18
transformation, as I2, CuCN, and tBuOLi were unable to
confer 16 at 50 oC, and only amide starting material was
recovered under these conditions. At this juncture, we
envisioned possible metal-catalyzed cross-couplings or
SNAr intramolecular cyclizations to yield 16, and
devised a series of experiments to probe the reaction
mechanism (Table 2).
1,4-dioxane/
m-xylene
CuCN, tBuOLi, I2
CuCN, tBuOLi
125
125
30
30
12
1,4-dioxane/
m-xylene
N/Ad
1,4-dioxane/
m-xylene
CuCN, tBuOLi, I2
CuCN, tBuOLi, I2
125
125
5
13
16
Our previous studies suggested that 16 may result
from a CuI-catalyzed cross coupling between the
benzamide oxygen and the 3-position of the triazole,
either via an iodinated intermediate or C-H activation.
To determine if other metal catalysts could afford 16,
we screened Pd(OAc)2, Pd(PPh3)4, and Pd(PPh3)2Cl2
under identical conditions as that used for CuCN.
However, little-to-no 16 was observed. Recently, the
synthesis of 2-arylbenzoxazoles through oxidative C-O
coupling with Cu(OTf)2 under an O2 atmosphere has
been reported,39 which lead us to evaluate if similar
conditions can be employed to deliver 16 from 14 using
either CuCN or Cu(OTf)2 as catalysts. In both instances
no increase in yield was observed for the transformation
of 14 to 16, and the condition in which I2 was omitted,
Cu(OTf)2 as catalyst, resulted in no product formation.
Additionally, a similar iodine-mediated oxadiazole
formation using Oxone, NaOH, and I2 has been
reported;40 however, no cyclization occurred when these
published conditions were applied to our system. We
further found that nucleophilic iodine sources (e.g., KI)
were insufficient to promote cyclization, whereas
electrophilic iodine sources (e.g., I2) resulted in product
formation. These results, taken with the fact that
cycliza
DMF
30
CuCN, tBuOLi, I2
CuCN, tBuOLi, I2
MeOH
MeOH
125
50
30
30
12
N/A
aReactions were typically performed on 0.4 mmol scale (for 14)
bMicrowave conditions, 200 W maximum
cIsolated yields
dN/A = No product observed
nitrile can undergo nucleophilic attack from a cysteine
residue, forming a transient thioimidate adduct that is
stabilized by hydrogen bonding with the enzyme.37
Accordingly, we acylated the commercially
available 4-amino-4H-1,2,4-triazole (13) with benzoyl
chloride, then attempted direct triazole cyanation of the
resulting amide 14. Direct heterocycle cyanation
conditions with CuCN, NaCN, I2, tBuOLi, and 1,10-
o
phenanthroline in m-xylene and 1,4-dioxane at 110 C
have been reported38 and similar conditions were
attempted with our system. However, the presence of
the pendant amide carbonyl instead promoted
cyclization into the triazole to yield the
[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole 16, as opposed to
target compound 15 (Scheme 1). Given the synthetic
ease of elaborating a simple triazole, such as 13, into a
substituted triazolo-oxadiazole such as 16, especially in
comparison to other methods that require more
transformations (see Figure 1), we instead turned our
attention to optimizing this reaction and examining its
mechanism.
tion
was
also
observ
ed
when
only
tBuOL
i
I2
and
Results and Discussion
Our initial efforts focused on determining which
reagents were necessary to promote cyclization of 14 to
16 based on the direct cyanation conditions published by
Do and Daugulis.38 Systematic removal of the various
reaction components revealed that neither 1,10-
phenanthroline nor NaCN were necessary to achieve 16
(Table 1). However, when I2 was omitted, no
cyclization occurred and only the amide starting
material was recovered. Because starting material
were
utilize
d
(Table
2),
sugges
Scheme 2. Two-step synthesis of 16 leads to a proposed mechanism of
[1,2,4]triazolo[3,4-b][1,3,4]oxadiazole formation via 17. (a) NIS, MeCN,
MW, 70 °C, 20 min, 36%. (b) MeCN, MW, 125 °C, 10 min, 32-35%. (c)
NIS, MeCN, MW, 125 °C, 10 min, 29%
ted
a
mecha
nism

4
Tetrahedron Letters
alternative to metal-catalyzed cross-coupling, and
inspired us to investigate I2-mediated intramolecular
cyclization.
In an attempt to explore a step-wise synthesis of 16
– iodination followed by cyclization – we aimed to
synthesize the mono-iodinated 17 using previously
reported conditions.41 To our surprise, subjecting 14 to
N-iodosuccinimide (NIS) in THF at 70 °C not only
resulted in the target molecule 17 (Scheme 2a), but was
also sufficient to promote cyclization to 16. Replacing
THF with MeCN as solvent increased the solubility of
14, and together with an increased microwave
temperature of 125 °C, conferred 16 in a 29% isolated
yield. Importantly, 17 was not observed at these higher
temperatures.
Table 2. Alternative conditions to assess conversion of 14 to
16.a
Heat
Temp
(°C)
Reagents
Solvent(s)
DMF
Time
30 min
30 min
% Yieldc
Sourceb
Pd(OAc)2, I2,
tBuOLi
MW
MW
MW
125
125
125
4
Pd(PPh3)4, I2,
tBuOLi
1,4-dioxane/
m-xylene
N/Ad
1
Pd(PPh3)2Cl2,
I2, tBuOLi
MeOH
DMF
30 min
23 h
CuCN, I2,
tBuOLi,
O2 (1 atm)
To probe the mechanism of the cyclization, purified
17 was simply dissolved in MeCN and subjected to
microwave irradiation at 125 °C. 16 was isolated from
this reaction mixture in 32-35% yield (Scheme 2).
These results led us to propose the following
mechanism: NIS or I2 mediates the formation of
Oil
bath
125
9
Cu(OTf)2,
O2 (1 atm)
Oil
bath
o-xylene
140
r.t.
40 h
43 h
N/A
N/A
Oxone, I2,
NaOH
MeOH
-
iodinated
intermediate
17,
which
undergoes
intramolecular cyclization through the amide oxygen via
a SNAr mechanism to form 16. Our data suggests that
microwave irradiation at 70 °C is sufficient for
iodination to occur, but higher temperatures (125 °C)
are required for 17 to cyclize completely to 16. It is also
possible that a second mechanism involving an
iodonium species across the C-N double bond of 14
followed by cyclization and elimination of HI is
involved in the formation of 16; however, no
experimental evidence has yet been found to support
this pathway.
CuCN, KI,
tBuOLi
1,4-dioxane/
m-xylene
MW
MW
125
125
30 min
10 min
N/A
11
tBuOLi, I2
MeCN
aReactions were typically performed on 0.4 mmol scale (for 14)
bMW = Microwave heating, 200 W maximum. Oil bath = conventional heating.
cIsolated yields
dN/A = No product observed
Interestingly, the addition of base (tBuOLi) to the
NIS-mediated reaction did not enhance the formation of
the cyclized product (Table 3), suggesting that
succinimide, ambient water, or the iodide anion released
after substitution is sufficiently basic for proton
abstraction and re-aromatization. Additionally, 14
heated at reflux overnight in MeCN using conventional
heating methods (i.e. an oil bath) did allow for
cyclization to 16 to occur, but in much lower yield (~9%
isolated yield) compared to optimized microwave
Scheme 3: Synthesis and subsequent cyclization of the 3-methyl analogue
20. (a) benzoyl chloride, 1,4-dioxane, reflux, 24 h, 61-72%. (b) NIS, MeCN,
MW 125 °C, 10 min, 49-60%.
Figure 2. Isolated byproduct 18 (yields are shown in Table 3).
conditions (29% yield) that require only 10 min reaction
times.

5
Table 3. Optimization of NIS-mediated cyclization of 14 to 16.a,b
Reagent(s)
Temp. (°C)
Time (min)
% Yieldc (16)
% Yieldc (18)
% Recoveredc (14)
NIS (1.0 eq.), tBuOLi (1.2 eq.)d
125
125
125
125
125
125
125
125
125
95
10
10
10
10
10
10
10
10
30
10
10
13
23
25
29
18
22
22
18
9
1
0
66
34
26
18
11
31
2
NIS (0.9 eq.)
NIS (1.0 eq.)e
NIS (1.1 eq.)
0
7
NIS (1.2 eq.)
1
NIS (1.3 eq.)
9
NIS (2.0 eq.)
25
37
1
NIS (4.0 eq.)
0
NIS (1.0 eq.)
24
34
10
NIS (1.0 eq.)d
NIS (1.0 eq.)d
19
27
1
140
1
aReactions were typically performed on 0.4 mmol scale (for 14)
bMicrowave conditions, 200 W maximum. Performed in duplicate in MeCN. Mean yields are shown.
cIsolated yields
dSingle measurement
eTriplicate measurements
One explanation for the modest yield is the
Conclusions
observation and isolation of the iodinated byproduct 18
with m/z = 312.9579 (calc’d = 312.9581, Figure 2). To
In conclusion, we report a rapid, microwave
accelerated method for the synthesis of
push the reaction towards completion while avoiding
over-iodination, we screened various equivalents of
NIS, as well as varying reaction times and temperatures;
however, of the conditions tested, none resulted in a
significant improvement in yield (Table 3). Because
both the byproduct 18 and starting material 14 could be
isolated from the reaction mixture during optimization
studies, this competing reaction, namely the formation
of 18, likely plays a role in low reaction yield. When the
reaction mixture was treated with excess (4 eq.) of NIS,
for instance, all starting material was consumed;
however, recovery of the desired product 16 declined
(18% yield) as the formation of the iodinated product 18
was promoted (37% yield). We found that 1.1
equivalents of NIS in MeCN heated to 125 °C for 10
min using microwave irradiation conferred the best
yield of 16 (29% yield).
[1,2,4]triazolo[3,4-b][1,3,4]-oxadiazoles from readily
available commercial building blocks. This method,
despite modest yields, offers an alternative approach for
synthesizing this interesting heterocycle in only two
synthetic steps. We believe our method expands the
synthetic accessibility of this heterocycle, which may
enable its evaluation for a variety of biological
applications.
Acknowledgments
We gratefully acknowledge funding by the National
Institutes of Health (R01-GM110129) and the
University of Minnesota, Office of the Vice President
for Research (Equipment Grant-in-Aid to purchase the
CEM Discover SP Microwave Synthesizer). S.L.B.
thanks the University of Minnesota, Undergraduate
Research Opportunities Program (UROP) and the
Department of Chemistry Heisig/Gleysteen Summer
Undergraduate Research Fellowship Program for
financial support. M.E.O. acknowledges the National
Institutes of Health for a Ruth L. Kirschstein NRSA
This limitation in transformation efficiency can be
corrected by blocking the site of additional iodination by
employing mono-substituted triazoles (e.g., 3-methyl;
19) as starting materials. Acylation of 19 to amide 20,
followed by treatment with an excess (4.0 equiv.) of
NIS under our established microwave conditions results
in formation of 21 in reasonable yields (49-60%;
Scheme 3). The substituted [1,2,4]triazolo[3,4-
b][1,3,4]oxadiazole 21 was synthesized from the triazole
19 in a 30-43% yield over two steps.
Predoctoral
Fellowship
(F31-CA18324).
Mass
spectrometry was performed at the Analytical
Biochemistry Core Facility of the Masonic Cancer
Center (University of Minnesota), which is supported in
part by the National Institutes of Health (P30-
CA77598).

6
Tetrahedron Letters
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*Highlights
Highlights
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[1,2,4]triazolo[3,4-b][1,3,4]oxadiazoles were synthesized in two steps
10-min microwave-accelerated cyclization forms the oxadiazole ring
3-substituted 1,2,4-triazoles cyclize in higher yields without byproduct
formation