Study of oxidative cyclization using PhI(OAc)2 in the formation of benzo[4,5]thiazolo[2,3- C ][1,2,4]triazoles and related heterocycles - Scope and limitations

Article abstract of DOI:10.1055/s-0033-1341159

A one-pot, two-step reaction for the synthesis of benzo[4,5]thiazolo[2,3-c] [1,2,4]triazoles and related heterocycles under mild conditions was herein developed. The key step of this transformation is an oxidative cyclization employing PhI(OAc)₂

Full text of DOI:10.1055/s-0033-1341159

LETTER
▌1279
lSettteur dy of Oxidative Cyclization Using PhI(OAc)2 in the Formation of Benzo-
[4,5]thiazolo[2,3-c][1,2,4]triazoles and Related Heterocycles – Scope and
Limitations
Synthesis of Benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles
Charles S. Demmer,*a,b Morten Jørgensen,a Jan Kehler,a Lennart Bunchb
a
Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, 2500 Valby, Denmark
b
Chemical Neuroscience Group, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of
Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
E-mail: charles.demmer@sund.ku.dk; E-mail: cdemmer15@gmail.com
Received: 14.03.2014; Accepted: 19.03.2014
the synthesis of benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles
Abstract: A one-pot, two-step reaction for the synthesis of ben-
by first forming the hydrazone followed by the oxidative
zo[4,5]thiazolo[2,3-c][1,2,4]triazoles and related heterocycles un-
cyclization at room temperature (Scheme 1).
der mild conditions was herein developed. The key step of this
transformation is an oxidative cyclization employing PhI(OAc)2 as
reagent. Scope and limitations (group functionality tolerance and
sterics) were studied showing the robustness of the present method-
(overnight and 2 h, respectively) and the desired product
ology which can be used as potential access to new fused heterocy-
cle libraries.
Benzaldehyde was employed as the standard reagent in
the study. Full conversion for both steps was observed
isolated in moderate yield after flash column chromatog-
raphy (49%, Table 1, entry 1).
Key words: cyclization, heterocycles, fused-ring systems, substitu-
A plausible mechanism for the cyclization step is de-
scribed in Scheme 2. Firstly, the most nucleophilic lone
pair, which resides on the double-bonded nitrogen of the
hydrazone, attacks the acetoxy(phenyl)iodonium cation
leading to intermediate 4. Then, favorable orbital overlap
of the aromatic lone pair of the nitrogen and the sp2-
hybridized carbon of the hydrazone allows for ring forma-
tion. Deprotonation is facilitated by the acetate anion giv-
ing intermediate 6. Elimination of the hypervalent iodine
moiety is aided by the nitrogen lone pair from the thiazole
ring and subsequent rearomatization of 7 by abstraction of
a proton leads to the desired benzo[4,5]thiazolo[2,3-
c][1,2,4]triazoles 3.
ent effects, condensation
Fused aromatic heterocycles are key components in me-
dicinal chemistry research and often found as fragments in
drugs.1 Thus, new and efficient synthetic routes to access
such scaffolds is an ongoing topic of research in the our
research group.2 The benzo[4,5]thiazolo[2,3-c][1,2,4]tri-
azole heterocycle has recently gained interest in medicinal
chemistry studies3 notably because of its antifungal,4 anti-
oxidant,5 and antimicrobial6 properties. An exhaustive
literature survey concluded that formation of ben-
zo[4,5]thiazolo[2,3-c][1,2,4]triazoles requires harsh con-
ditions such as refluxing with anhydrides7 or acids8 or
A set of aldehydes was studied to establish the scope and
limitations of the reaction. As shown in Table 1, an elec-
tron-withdrawing substituent in the 4-position, 4-formyl-
benzonitrile, gave the corresponding benzo[4,5]-
thiazolo[2,3-c][1,2,4]triazole 3b in comparable yield (Ta-
ble 1, entry 2). However, reaction with p-anisaldehyde led
to the desired product 3c in low yield (18%, Table 1, entry
3) together with formation of a major side product, which
molecular mass was determined by LC–MS to be an ace-
9
environmentally hazardous reagents such as Tl(OAc)3 or
Pb(OAc)4.10 Consequently, milder reaction conditions are
appreciated for the synthesis of this heterocycle.
Previously, a PhI(OAc)2-mediated oxidative cyclization
has been reported for the preparation of triazoloquinoxa-
lines,11 triazolopyridines,12 and triazolopyrimidines13 in
dichloromethane at room temperature or by heating. Our
idea was then to develop a one-pot, two-step procedure for
O
R
S
N
NH2
NH
S
N
1
PhI(OAc)2
2 h
R
N
N
N
S
N
CH2Cl2, r.t.
overnight
NH
R
2
3
Scheme 1 One-pot, two-step procedure for the construction of benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles and related heterocycles
SYNLETT 2014, 25, 1279–1282
Advanced online publication: 28.04.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341159; Art ID: ST-2014-D0227-L
© Georg Thieme Verlag Stuttgart · New York

1280
C. S. Demmer et al.
LETTER
O
Me
O
Me
Table 1 Synthesis of Benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles 1–6
Ph
N
Ph
N
Entry Aldehyde
Product
Isolated
yield (%)
AcO
S
I
N
4
AcO
S
I
N
8
S
N
N
N
H
H
N
N
O
1
2
3a R = H
3b R = CN
49
45
O
Me
O
Me
3
3c R = OMe 18
R
N
S
N
R
N
S
N
OAc
N
OAc
N
S
N
Cl
O
N
N
9
10
4
3d
67
Scheme 3 Possible mechanism for the side-product formation 10
Cl
N
Cl
Cl
Increasing the steric bulkiness of the aldehyde nicely gave
the desired product 3d in good yield (Table 1, entry 4).
This demonstrates that the cyclization is not stalled by ste-
rics. Turning to aliphatic aldehydes, ethyl aldehyde was
successfully carried on and the desired product 3e was ob-
tained in high yield (Table 1, entry 5). In the search for the
limitations of the present methodology, the reaction con-
ditions were applied to an acroleic aldehyde to give the
desired product 3f in 34% (Table 1, entry 6).
N
S
N
N
O
O
N
5
6
3e
3f
78
34
S
N
N
N
To further demonstrate the synthetic utility of the method-
ology, the synthesis of other heterocycles was pursued. A
literature study showed that PhI(OAc)2 has already been
applied for the synthesis of thiazolo[2,3-c][1,2,4]triazoles
but the reported procedure employs harsher conditions
and only few examples were disclosed.14 In order to ex-
pand it, 2-hydrazinyl-4-phenylthiazole was submitted to a
set of aldehydes using our one-pot reaction, and the results
are summarized in Table 2.
Pr
Pr
tate adduct. A mechanism for its formation is presented in
Scheme 3.
Stabilization of intermediate 4 by delocalization of the
methoxy lone pair leads to resonance structure 8, which
allows for an E2 elimination of the hypervalent iodine
moiety. Intermediate 9 is then attacked by the acetate an-
ion at its most electrophilic site giving side product 10.
Benzaldehyde led to thiazolo[2,3-c][1,2,4]triazole 11a in
56% which is similar to the results obtained for compound
3a (Table 1, entry 1). m-Anisaldehyde successfully gave
the desired product 11b in moderate yield (Table 2, entry
2) without sign of side-product formation (acetate ad-
duct). A free aryl boronic acid was not compatible with
these conditions and led to a complex mixture (Table 2,
entry 3). But interestingly, the free carboxylic acid provid-
ed the target compound 11d in 45% and thus represents an
additional attractive feature of our methodology. To the
best of our knowledge, this is the first example of oxida-
tive cyclization with a free carboxilic acid using
PhI(OAc)2. Picolinaldehyde gave only the corresponding
product 11e in moderate yield (Table 2, entry 5). On the
other hand, 2-furfural and 1H-indole-3-carbaldehyde
were unsuccessful resulting in the formation of a complex
product mixture and degradation, respectively.
OAc
R
N
H
R
N
H
OAc
AcO
OAc
I
I
OAc
Ph
Ph
S
N
Ph
I
S
N
N
N
2
4
S
S
N
H
••
N
H
N
OAc
N
N
OAc
N
OAc
I
I
R
R
Ph
Ph
5
S
S
N
S
N
N
N
N
••
N
N
The related heterocycles 2-hydrazinylbenzo[d]oxazole
and protected 2-hydrazinyl-benzo[d]imidazole were also
investigated, and the results are summarized in Table 3
and Table 4.
OAc
N
N
I
R
7
R
6
R
H
Ph
3
OAc
Scheme 2 Plausible mechanism for the formation of benzo[4,5]thi-
azolo[2,3-c][1,2,4]triazoles
Synlett 2014, 25, 1279–1282
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles
1281
tion process (Table 4, entry 3). Phenylglyoxal and malo-
nate were tried and both led to complex mixtures despite
full conversion into the hydrazones.
Table 2 Synthesis Thiazolo[2,3-c][1,2,4]triazoles 7–11
Entry Aldehyde
Product
Isolated
yield (%)
In summary, a simple, mild, and efficient one-pot protocol
for the synthesis of various benzo[4,5]thiazolo[2,3-
c][1,2,4]triazoles and related heterocycles was developed.
The study of scope and limitations including group-func-
tionality tolerances and sterics proved the robustness of
the methodology. Overall the presented method offers a
substantial improvement compared to reported synthetic
routes and can easily be applied to the construction of
compound libraries, medicinal chemistry, as well as find-
ing applications in diversity-oriented synthesis.
S
O
N
N
N
Ph
1
2
3
11a R = H
56
11b R = OMea 42
11c R = B(OH)2
0
R
R
S
N
N
N
O
Ph
Table 4 Synthesis of Benzo[4,5]imidazo[2,1-c][1,2,4]triazoles
4
11d
45
Entry Aldehyde
Product
Isolated yield (%)
HO2C
HO2C
F
S
N
N
N
O
O
Ph
N
1
13a 82
5
11e
41
N
N
Ph
N
N
N
Ph
a Hydrazone was formed under MW irradiation at 70 °C for 5 h.
F
Table 3 Synthesis of Benzo[4,5]oxazolo[2,3-c][1,2,4]triazoles
O
Entry Aldehyde
Product
Isolated yield (%)
2
13b 39
N
N
TBDMSO
N
O
N
N
O
N
N
1
12a
12b
56
TBDMSO
F
Ph
Ph
O
N
N
O
O
N
N
N
2
52
3
13c 79
N
N
First, 2-hydrazinylbenzo[d]oxazole was submitted to
benzaldehyde and dimethylbenzaldehyde, which pleas-
antly afforded the desired benzo[4,5]oxazolo[2,3-
c][1,2,4]triazoles 12a and 12b in moderate yields (Table Typical Experimental Procedure
To a solution of the hydrazine compound (100 mg) in CH2Cl2 (0.12
M) was added the corresponding aldehyde (1.1 equiv). The reaction
mixture was stirred overnight at r.t. unless otherwise mentioned and
then PhI(OAc)2 (1.2 equiv) was added portionwise. The reaction
was stirred for additional 2 h at r.t. and if still in solution, it was di-
rectly applied to a prepacked silica column. If it resulted in a sus-
pension it was dissolved in CH2Cl2 and adsorbed on Celite before it
was purified by CombiFlashRf using EtOAc and heptane as sol-
vents.
3, entries 1 and 2). Furthermore, the benzo[4,5]imid-
azo[2,1-c][1,2,4]triazole 13a was formed in high yield
(82%) (Table 4, entry 1). The higher nucleophilic charac-
ter of benzo[d]imidazole appears to facilitate the oxidative
cyclization. Use of (tert-butyldimethylsilyloxy)acetaldehyde
resulted in the formation of product 13b in 39% (Table 4,
entry 2) but also acetate adduct (side product). Reaction
carried out with pivalaldehyde, the most hindered aliphat-
ic aldehyde, afforded the desired product in high yield
showing once again that sterics does not stall the cycliza-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1279–1282

1282
C. S. Demmer et al.
LETTER
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