I2-TBHP-catalyzed one-pot highly efficient synthesis of 4,3-fused 1,2,4-triazoles from: N -tosylhydrazones and aromatic N-heterocycles via intermolecular formal 1,3-dipolar cycloaddition

Article abstract of DOI:10.1039/c6ob01926a

I₂-TBHP-catalyzed azomethine imine generation and subsequent regioselective 1,3-dipolar cycloaddition (DC) with aromatic N-heterocycles was developed to afford various 4,3-fused 1,2,4-triazoles in excellent yields. The method is operationally simple and highly efficient with broad functional group tolerance.

Full text of DOI:10.1039/c6ob01926a

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DOI: 10.1039/C6OB01926A
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I2–TBHP-catalyzed one-pot highly efficient synthesis of 4,3-fused
1,2,4-triazoles from N-tosylhydrazones and aromatic N-
heterocycles via intermolecular formal 1,3-dipolar cycloaddition†
Surendra Babu Inturi,a,b Biswajit Kalita*a and A. Jafar Ahamed*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
I2–TBHP-catalyzed azomethine imine generation and its pyridylhydrazones respectively followed by their cyclizations.
regioselective 1,3-dipolar cycloaddition (DC) reaction with These methods, although diverse, involve multi-step
aromatic N-heterocycles is developed to afford various 4,3-fused synthesis process. Moreover, despite being successful, the
1,2,4-triazoles in excellent yields. The method is operationally transition metal catalyzed methods impose general
simple and highly efficient with broad functional group limitation to substrate scopes particularly with aryl halides.
a
a
tolerability.
In 2010, Maiti et al. reported iodosobenzene (PhIO)
mediated reaction between N-tosylhydrazones and N-
heterocycles to synthesize fused triazoles.10 However, this
method needed super-stoichiometric amount of PhIO (2 equiv)
which is highly hazardous and explosive, and was applied only
to a limited set of para-substituted pyridine and unsubstituted
quinoline substrates. This led us to investigate a robust
methodology as economically and ecologically benign
alternative to the existing methods to synthesize this class of
fused triazoles with broad substrate scope.
The [1,2,4]triazolo[4,3-a]pyridine and related 4,3-fused 1,2,4-
triazoles constitute one of the most important structural
templates present in a variety of molecules with biological
importances. Many novel examples of this class of compounds
have been demonstrated in multiple therapeutic areas and
target classes.1─3 Because of their importances and usefulness,
construction of 4,3-fused 1,2,4-triazoles have attracted
interest of synthetic organic and medicinal chemists for several
years and hence development of efficient synthetic strategies
to construct this motif is highly desirable.
Within the context of non-metal based catalysts, readily
available molecular iodine has enabled
a
significant
Several methods have been devised to synthesize 4,3-fused
1,2,4-triazoles systems over the years. These methods in
general involve palladium catalyzed reactions of 2-
halopyridines with aryl hydrazides4 or aryl hydrazines5 to
development by virtue of its ability to generate reactive iodine
species with diverse redox potential.11─12 In continuation to
our efforts in developing metal free methodologies,13 we
sought to develop a catalytic method for the synthesis of 4,3-
fused 1,2,4-triazoles. Toward this approach we chose to use
molecular iodine as a catalyst in presence of TBHP to generate
azomethine imine ylides from a variety of N-tosylhydrazones
and their regioselective intermolecular formal [3+2]-
cycloaddition with aromatic N-heterocycles, which to best of
our knowledge has never been reported (Scheme 1).
generate
2-pyridylhydrazides
or
2-pyridylhydrazones
respectively which are then converted to the triazolopyridines
by a thermal6 or an oxidative cyclization7 reaction. Another
approach involves conversion of 2-halopyridines to 2-
pyridylhydrazines by SNAr or a palladium catalyzed coupling
reaction. This was then converted to triazolopyridines by a CDI
mediated tandem reaction with appropriate carboxylic acids.8
The triazolopyridines have also been successfully synthesized
from the 2-pyridylhydrazines by reactions with carboxylic
acids9 or aldehydes7 to synthesize 2-pyridylhydrazides or 2-
"[3+2]-cycloaddition"
Ts
I
2 (20 mol%)
TBHP
HN
N
n
Y
(2 equiv)
n
Y
+
X
rt
CH2Cl2
,
X
N
N
R
N
a.Medicinal Chemistry Division, Jubilant Biosys Ltd, #96, Industrial Suburb, 2nd
Stage, Yeshwanthpur, Bangalore 560022, Karnataka, India. E-mail:
biswajit_kalita@jubilantbiosys.com
+
+
+
+
+
A amount
catalytic
Green oxidant
I
of
2
N
=
=
or
or
1
X
Y
N
NMe
CH
CH
0
R
or
S
n = or
High regioselectivity
b.Post Graduate and Research Department of Chemistry, Jamal Mohamed College
(Autonomous),affiliated to Bharathidasan University, Tiruchirappalli - 620020,
Tamil Nadu, India.
=
R
Broad substrate
Scalable
scope
aryl, heteroaryl, alkyl,
benzyl, carbocyclic
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 I2–TBHP-catalyzed synthesis of 4,3-fused 1,2,4-triazoles.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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a
A thorough optimization of the reaction conditions,14 the
Reaction conditions: 1 (0.5 mmol), 2a–r (1.0 mmol), I2 (20 mol%), TBHP (1.0 mmol) in
View Article Online
b
CH2Cl2 (3.0 mL), rt (24–25 °C), time (3.5–24 h). This reaction was performed on 1.0 g
scale. In Parenthesis: isolated yields and reaction time.
DOI: 10.1039/C6OB01926A
optimized catalytic system was established as:
1 (1 equiv), 2g
(2 equiv), I2 (20 mol%), tert-Butyl hydroperoxide [TBHP (5–6 M)
in decane] (2 equiv) in DCM at room temperature. The desired
product 3g was achieved in 85% yield with complete
To further explore the synthetic potential of this
methodology, several quinoline and isoquinoline based
substrates (Table 2, 4a–j) were investigated under the
regioselectivity shown in eqn (1).
Ts
optimized reaction condition. Unsubstituted quinoline (4a) and
isoquinoline (4g) were converted to their corresponding
products 5a and 5g respectively in high yields (80% and 87%).
Both the two classes of heterocycles as reactants bearing EWG
(-CO2Me and -NO2) afforded moderate yields of 5c and 5j while
NH
I
2 (20 mol%)
TBHP
N
(2 equiv)
rt
N
N
+
(1)
H
CH2Cl2
,
N
N
85%
1
3g,
2g
EDG (Me) on quinoline substrates (4b, 4d and 4f) led to higher
product yields (86–96%). Notably, a halogen substitution (-Br)
on the isoquinoline ring gave desired products in good yields
With the optimized condition in hand, we decided to
evaluate the scope of the reagent system with various
aromatic N-heterocycles. As shown in Table 1, it was evident
that the in-situ formed azomethine amine ylide reactivity
varied based on the substituents on the N-heteroaryls. It was
found that aldehyde, ketone, ester, halogen and cyano groups
were tolerated under the reaction conditions which can be
utilized for further modifications. Strong electron withdrawing
groups (EWG, -CF3 and -CN) gave relatively low to moderate
yields (Table 1, 3e–f) while the electron donating groups (EDG,
Me and Et) and halogen substituted substrates (2h–j) could
react smoothly to offer the desired products in higher yields. It
is noteworthy to mention that in case of the meta substituted
pyridine substrates (2g–l), the 1,3-DC happened in a complete
regioselective way as confirmed by single crystal X-ray
5h and 5i, however a moderate yield with quinoline (5e
)
possibly because of a favourable electronic influence in
isoquinoline over quinoline.
Table 2 The substrate scope of quinoline and isoquinoline substratesa
Ts
I
2 (20 mol%)
NH
TBHP
(2 equiv)
N
+
rt
CH2Cl2
,
N
N
N
Ph
N
1
4a-j
5a-j
Ph
Br
R
N
N
N
N
diffraction analysis of 3h 15
proceed at all with the ortho substituted pyridine derivatives
3m–n). It was interesting to note that the pyridazine
.
Surprisingly, the reaction did not
N
N
N
N
N
N
N
N
Ph
Ph
5d
Ph
Ph
(
=
5
5f
9
5a R
8
,
5e
12
h)
R
H,
(96%, h)
(86%, h)
(80%, h)
12
Me,
(90%,
(57%,
=
5b R
,
substrates (2o–p) were very well tolerated under the reaction
condition; whereas 5-membered heterocycles (2q–r) could
react only moderately to afford the desired products in low
yields. The catalytic transformation performed in 1 g scale with
h)
16
Br
=
5c R CO2
,
Me,
(56%,
h)
N
N
N
Ph
Ph
Ph
N
N
1
was reproducible and yielded 82% of 3g.
N
N
N
4
N
12
h)
=
=
5i R
3
,
Br,
(84%, h)
(65%, h)
Table 1 The substrate scope of aromatic N-heterocyclesa
5h
5g (87%, h)
(88%,
R
4
NO2
,
,
5j
R
a
Y
Reaction conditions: 1 (0.5 mmol), 4a–j (1.0 mmol), I2 (20 mol%), TBHP (1.0 mmol) in
CH2Cl2 (3.0 mL), rt (24–25 °C), time (3–16 h). In Parenthesis: isolated yields and reaction
time.
Ts
I
R
2 (20 mol%)
TBHP
Y
NH
X
(2 equiv)
rt
N
N
N
N
+
N
X
CH2Cl2
,
N
N
N
N
Ph
Ph
Ph
1
2q-r
NMe
2a-p
Next, we tested the compatibility and generality of the 1,3-
DC catalyzed by I2–TBHP system in a reaction using 3-
methylpyridine (2g) and a variety of N-tosylhydrazones derived
3q-r
3a-p
=
or
=
or
X
N
Y
CH
S
R
R
N
=
R
6 h
b 6 h
,
Me, 85%,
82%,
3g
=
=
=
=
=
=
3a R
3b R
3c R
3d R
6 h
,
,
,
,
H, 85%,
Et, 87%,
CHO, 89%,
from diversely substituted aldehydes (Table 3, 1a
results of our studies were summarized in Table 3. Aromatic
and hetero-aromatic aldehyde derived N-tosylhydrazones (1a
and 1u) gave excellent yields of the desired fused
heterocycles (6a and 6u) with complete regioselectivity as
confirmed by single crystal X-ray diffraction analysis of 6k 15
N-
tosylhydrazones ( ) where was an aryl ring bearing EWG (1e
1g and 1h) or a hetroaryl ring (1k ) afforded the desired
products within a shorter reaction time (2 h) compared to
electron rich aryl rings (1c 1f and 1i). Also other heterocycles
like N-methyl pyrazole (1m), furan (1n) and thiophene (1o) at
–u). The
3.5 h
=
3h R
,
16 h
F, 65%,
16 h
24 h
N
11 h
N
=
3i R
,
Ac, 92%,
16 h
Cl, 68%,
=
Br, 71%,
=
N
–
3e R CF3
,
,
46%,
N
R
16 h
,
3j
N
3a-f
o
R
16 h
3f
,
Ph
CN, 41%,
R
Ph
R
3g-l
3k R CO
,
16 h
2Me, 68%,
–
o
=
3l R
,
12 h
OAc, 73%,
.
S
N
N
1
R
,
N
N
N
N
N
N
–l
N
N
N
N
N
Ph
R
Ph
R
3o-p
3m-n
N
Ph
=
=
3q
3o
3p
21 h
,
,
,
3m
16 h
,
H, 73%,
Me, 0%,
Ph 3r
24
h)
=
=
R
24 h
(32%,
16
(<10%, h)
3n
R
16 h
,
R
Me, 69%,
F, 0%,
2 | J. Name., 2012, 00, 1-3
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were very well tolerated to give the desired products (6m
in excellent yields 75–83%. It was noteworthy to mention that the N-tosylhydrazones was avoided. WeDinOiIt:i1a0l.l1y03e9x/aCm6OinBe0d19t2h6eA
the N-tosylhydrazones derived from aliphatic aldehydes (1p method by heptanal (Table 4, 7c equiv) with 4-
also offered the target fused heterocycles in moderate to good methylbenzenesulfonohydrazide ( , 1 equiv) in DCM (3.0 mL)
–
o)
limitation, we slightly modified the protocol wherVeieiwsoArltaictleioOnnlionef
–
s)
, 1
8
yields (6p
–
s
).
stirred at room temperature for 1 h followed by addition of 3-
methylpyridine (2g, 2 equiv), TBHP (2 equiv) and I2 (20 mol%)
stirred for another 2 h. Surprisingly, the desired compound
was isolated in 59% yield (Table 4, 6x). This protocol was
further extended to propanal (7a) and pentanal (7b) to give
the corresponding fused triazoles 6v and 6w. The results were
summarized in Table 4.
Table 3 The substrate scope of N-tosyl aldohydrazonesa
Ts
I
2 (20 mol%)
TBHP
NH
(2 equiv)
rt
N
+
N
N
CH2Cl2
,
N
N
R
6k
R
1a-u
2g
6a-u
Controlled reactions were performed to gain mechanistic
insights into the catalytic pathway. As illustrated in Scheme 2,
6a R1
6b R1
6c R1
6d R1 4-CO
6 h
R1
R1
5 h
87%,
=
=
=
=
,
6f,
4-F, 82%,
3-Me,
=
=
6 h
2 h
75%,
,
,
3-CF ,
the intermediate
time point which finally degraded into the desired product 3q
However, the reaction with the bisarylhydrazone could
produce only 9, thereby proving the necessity of the formation
of intermediate (Scheme 3) and hence supports the
7 could be trapped in LCMS arbitrarily at 12 h
4-Cl, 84%,
6g
6h R1
N
3
N
6 h
5.5 h 6i R1
2 h
,
,
4-OMe, 90%,
3-CN, 73%,
.
N
=
=
,
,
6.5 h
2Me, 74%,
2-Me,
92%,
8
6e R1 4-NO2
2 h
R1
5 h
=
=
,
,
,
62%,
2-F, 87%,
6j
R1
E
proposed catalytic cycle.
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
a
( )
N
Ts
S
S
I
mol
2 (20
%)
N
N
S
NH
+
TBHP
N
6o
6m
6n
(2 equiv)
6l
6k
O
N
S
Ts
N
N
N
N
N
+
2
4
5
(85%, h)
5
(77%, h)
12 h
rt,
CH2Cl2
,
(75%, h)
(83%, h)
2.5
N
(80%,
h)
N
N
b 2
Ph
(84%,
h)
1
Ph
Ph
2q
7
3q
LCMS observations:
detected
LCMS
(+H)
by
12 h: 7 and
24 h:
3q
N
N
=
M
358.0
N
R
N
only 3q
N
N
N
N
N
b
( )
N
N
N
O
Ph
6t
Ph
=
R
i
-Pr,
2.5
-Bu,
2.5
,
6p
I
mol
2 (20 %)
6u
1
(30%, h)
X
(50%,
h)
h)
O
NH
+
6
TBHP
(82%, h)
(2 equiv)
=
R
t
,
N
Ph
6q
=
=
2.5 h
N
6r X CH2
,
,
,
47%,
1 h
N
(60%,
16
h
CH2Cl2
,
rt,
6s X
O, 40%,
N
N
Ph
Ph
8
9
2g
a Reaction conditions: 1a–u (0.5 mmol), 2g (1.0 mmol), I2 (20 mol%), TBHP (1.0 mmol) in
CH2Cl2 (3.0 mL), rt (24–25 °C), time (1–6.5 h). This reaction was performed on 1.0 g
detected
by
=
286.1
LCMS
b
M
(-H)
scale. In Parenthesis: isolated yields and reaction time.
Scheme 2 Control experiments.
TBHP
t-BuOH+H2O
Table 4 One-pot reaction of linear chain aldehydes to triazolopyridinesa
O
CH Cl
1 h
,
H
N
rt,
(i)
2
2
+
H2N
Ts
H
m
R1
N
n
H N
-CH3-C5
N
(ii)
(2g)
4
HI
I
2 (20 mol%)
N
7a-c
8
N
Ts
N
Ts
I2
TBHP
rt,
(2 equiv)
2 h
n
n = or or
5
1
3
N
NH
N
6v-x
R
E
A
R
-TsH
N
N
N
N
N
N
R1
-HI
Ts
N
N
N
I
R1
N
N
N
Ts
6v
6w
N
I
6x
(45%)
(52%)
(59%)
H
N
N
N
R
R
B
N
a Reaction conditions: 7a–c (0.5 mmol), 8 (0.5 mmol), in CH2Cl2 (3.0 mL), rt, 1 h, 2g (1.0
mmol), I2 (20 mol%), TBHP (1.0 mmol), rt (24–25 °C), 2 h. In Parenthesis: isolated yields.
D
R
F
R1
N
C
While attempting to introduce various linear alkyl groups at
R
of 1 (Table 3), the isolation of the corresponding N-
Scheme 3 Proposed catalytic cycle.
tosylhydrazones was not successful. In order to overcome this
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(a) K. T. Potts and H. R. Burton, J. Org. Chem., 19V6ie6w,A3rt1ic,le2O5n1li;ne
6
7
Based on our results, a plausible mechanism for the I2–TBHP-
catalyzed regiocontrolled cycloaddition was proposed as
shown in Scheme 3. Iodine acts as a strong Lewis acid to
coordinate with the nitrogen atom of the N-tosyl
(b) J. J. Li, J. J. Li, J. Li, A. K. Trehan, H. SD. OWI:o1n0g.1,0S3.9/C6OB01926A
Krishnananthan, L. J. Kennedy, Q. Gao, A. Ng, J. A. Robl, B.
Balasubramanian and B.-C. Chen, Org. Lett., 2008, 10, 2897;
(c) J. Y. Roberge, G. Pei, M. Mikkilineni, X. Wu, Y. Zhu, R. M.
aldohydrazone
dipolar complex
intermolecular formal [3+2]-cycloaddition between the dipolar
complex and dipolarophile ended up with fused
cycloadduct followed by reductive elimination of HI to
generate the fused triazoline intermediate . The eliminated HI
was oxidized to I2 in the presence of TBHP and the catalytic
cycle was regenerated.16 Finally loss of TsH from
afforded the
fused triazole product
A
leading to the formation of azomethine imine
Lawrence and W. R. Ewing, ARKIVOC, 2007, 7, 132 and
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B
by elimination of HI. Then the unidirectional
B
C
D
E
E
8
9
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F
.
In summary, we have developed a highly efficient one-pot
methodology to synthesize structurally diverse 4,3-fused 1,2,4-
triazole derivatives using the catalytic system comprising of I2–
TBHP. The reactions proceeded under mild and metal-free
conditions using readily available starting substrates and gave
high yields, regioselectivity and wide functional group
tolerance which clearly demonstrates the unparalleled and
unique reactivity of the I2–TBHP system.
10 D. K. Maiti, N. Chatterjee, P. Pandit and S. K. Hota, Chem.
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Authors sincerely thank the Senior Management of Jubilant
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work.
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14 For the details on the reaction condition optimization, see
the ESI†.
15 The X-ray crystallographic structures for 3h and 6k have been
deposited at the Cambridge Crystallographic Data Centre
(CCDC), under deposition numbers CCDC 1487670 and
1487669, respectively.
Notes and references
1
(a) R. W. Carling, K. W. Moore, L. J. Street, D. Wild, C. Isted,
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB01926A
Table of contents
I2–TBHP-catalyzed azomethine imine generation and its regioselective formal 1,3-dipolar cycloaddition reaction
with aromatic N-heterocycles is reported.