Base free regioselective synthesis of α-triazolylazine derivatives

Article abstract of DOI:10.1039/c6ra10452e

A regioselective α-heteroarylation followed by deoxygenation towards the synthesis of variety of azine triazole from simple azine N-oxides derivatives and N-tosyl-1,2,3-triazoles has been described. The reaction is metal free and base free with shorter reaction time, high yields and a broad substrate scope.

Full text of DOI:10.1039/c6ra10452e

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: M. B. Harisha, M.
Nagaraj, S. Muthusubramanian and N. Bhuvanesh, RSC Adv., 2016, DOI: 10.1039/C6RA10452E.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 8
View Article Online
DOI: 10.1039/C6RA10452E
Journal Name
ARTICLE
Base free regioselective synthesis of α-triazolylazine derivatives
Mysore Bhyrappa Harisha,a,b Muthupandi Nagaraj,a Shanmugam Muthusubramanian*a and
Nattamai Bhuvaneshc
Received 00th January 20xx,
Accepted 00th January 20xx
A regioselective α-heteroarylation followed by deoxygenation towards the synthesis of variety of azine triazole from
simple azine N-oxides derivatives and N-tosyl-1,2,3-triazoles has been described. The reaction is metal free and base free
with lesser reaction time, high yields and a broad substrate scope.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Results and discussion
(Hetero)aryl substituted azines have wide range of medicinal
properties. Pyridotriazoles and quinolinotriazoles1 are
particularly interesting, as they exhibit significant biological
properties including control of arthropod tests,2 substance-
related disorders,3 ATP-competitive inhibition of vascular
endothelial growth factor receptors I and II4 and other
biological activities.5 A number of derivatives of 1-(pyridin-2-
yl)-1,2,3-triazole have been used as ligands.6 In recent years,
direct (hetero)arylation has emerged as an attractive
alternative to the commonly employed cross coupling
reactions as it avoids the preliminary preparation of the
metallated or halogenated arene. Several reviews highlight the
broad scope of this strategy involving high functional group
tolerance, atom economy and mild reaction conditions.7
It has been planned to investigate the reactivity of tosyl
substituted triazole with pyridine-N-oxide in the presence of
rhodium catalyst anticipating a [3+3] addition reaction. It can
be noticed that such additions are popular towards the
construction of six membered rings.12 Tosyl azide is well
known to generate active carbene in presence of Rh complex,
which can undergo [3+3] addition reactions.13 With this idea,
tosyl triazole was made to react with pyridine-N-oxide
1 in the
presence metal catalyst. The selected substrates 1a-y were
prepared by the oxidation of various pyridine with m-
chloroperbenzoic
acid
under basic
conditions
in
dichloromethane.14 The sulfonyl triazole
2
was synthesised by
the reaction of 1 eq of tosyl azide and 1.2 eq of phenyl
acetylene in the presence of cuprous oxide in water at room
temperature.15 The investigation was started with the reaction
between pyridine-N-oxide 1a and sulfonyl triazole 2a with the
hope of getting 3-phenylpyrido[1,2-b][1,2,4]oxadiazine moiety
via formal [3+3] cycloaddition of pyridine 1a with the sulfonyl
Functionalized azines are to be designed due to their biological
importance and though there are significant progress has been
achieved in the development of catalytic alkylation,
alkenylation and acylation reactions at the pyridine nucleus,8
the arylation/heteroarylation9 and alkenylation10 at pyridine N-
oxides could be achieved only with transition metal catalysts.
The regioselective arylation of azines has been achieved
through Pd-catalyzed direct arylation of the corresponding
N-oxides and N-iminopyridinium-ylides.11 New metal free
methods of arylation with regiocontrol are thus invaluable. We
report a new C-N bond forming reaction via regioselective
α-heteroarylation followed by deoxygenation towards the
synthesis of variety of azine triazole from simple azine
triazole 2, but the reaction did not proceed in the expected
pathway. The unexpected product 2-(4-phenyl-1H-1,2,3-
triazol-1-yl)pyridine, 4a was obtained in 55% yield along with a
by-product
5 in 25% yield (Scheme 1). The by-product was
identified as 4-phenyl-1H-1,2,3-triazole.
N-oxides derivatives and N-tosyl-1,2,3-triazole
.
a. Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj
University, Madurai - 625 021, Tamil Nadu, India
b.Advinus Therapeutics Limited, A TATA Enterprise, Bangalore - 560 058, India
c. X-ray Diffraction Laboratory, Department of Chemistry, Texas A & M University,
College Station, TX 77842, USA
Email: muthumanian2001@yahoo.com (Shanmugam Muthusubramanian)
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 8
View Article Online
DOI: 10.1039/C6RA10452E
ARTICLE
Journal Name
Base
t
time
(h)
Catalyst
(mol%)
Yield of
Entry
Solvent
(°C)
4a (%)
O
N
1
2
3
4
CHCl3
DCE
Rh2(Cod)4 (20)
Rh2(OAc)4 (20)
Rh2(OAc)4 (20)
Rh2(OAc)4 (20)
90
90
90
rt
1.5
7
55
43
52
<2
Rh2(Cod)4
Ts
N
O
N
CHCl3
DCE
2.5
18
N
N
N
5
6
7
8
9
THF
DCE
Toluene
Dioxane
DCM
Ni(COD)2 (20)
CuI (20)
90
90
110
100
50
18
12
6
12
12
NRb
8
1a
2
3
c
-
-
-
68
<10
48
10
11
12
13
14
15
16
ACN
Xylene
DMF
-
-
80
130
140
150
80
12
12
20
20
8
54
10
NRb
NRb
58
-
N
N
N
DMSO
CHCl3
THF
-
N
N
N
-
HN
--
-
65
18
5
<5
82d
DCE
95
4a (55%)
5 (25%)
17
18
DCE
DCE
-
-
rt
90
18
12
<2
<5
DIPA
Scheme 1. Attempted reaction of pyridine 1a and sulfonyltriazole 2a under
catalyst condition
19
DCE
-
DIPEA
90
12
<5
20
21
22
23
DCE
DIPA
DIPEA
Et3N
-
-
-
-
Et3N
90
95
95
95
12
8
<2
62
58
20
Puzzled by this, the reaction conditions were optimized (Table
1) and it is found under no circumstances, the six membered
ring is generated. It was also realized that the presence of
metal catalyst or base is not necessary for the reaction to yield
8
8
a
reagent and conditions: pyridine N-oxide 1a (1 mmol), sulfonyltriazole 2a (1
mmol), solvents (2 mL). No reaction. c reactions carried out without catalyst.
b
d
4. It is found that this is the first report of the α-
Isolated yield.
heteroarylation with simultaneous deoxygenative reaction
without a catalyst or a base. It should be mentioned that
previously stronger bases were employed for the related
conversion studied. Nevertheless, this protocol is a new
method of preparing triazole at the 2-position of pyridine ring.
The advantages of the present method are that it is free from
metal catalyst and base with reduced reaction time and high
yields. The substrate scope is broadened in the present
investigation.
The reaction has led to the formation of a single product
many cases. It must be mentioned that it is certain that the
product formed is triazole connected to the pyridine ring at 2
position, but the regiochemistry in the triazole ring has to be
established unambiguously. Previously mixture of
4 in
4
a
regioisomers have been obtained while constructing these
skeletons.16 The NMR features have been analyzed carefully in
these cases. A NOESY spectrum of 4c has also been recorded
which gives stronger contour between the triazole ring singlet
and the ortho-hydrogens of the aryl substituent. All the three
Table 1. Optimization of reaction conditions a
isomers
A, B and C (Figure 1) will show such contour. A, B and
C
are quite possible as the reaction is supposed to take place
after the generation of free triazolyl anion, which may be
resonating between different forms. However, if the
regiochemistry of the starting tosyl triazole is to be taken into
account, by memory effect and the stability of the triazolyl
anion, the isomer
A
may be the favourable one.
B
is sterically
could
hindered and hence its formation is not quite feasible.
C
be the other regioismer that might have been formed in low
yield in some cases.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 3 of 8
View Article Online
DOI: 10.1039/C6RA10452E
Journal Name
ARTICLE
methylpyrid-2-yl triazole. In contrast, in 4g, the coupling has
occurred para to acetyl and not ortho to acetyl (two singlets
and two doublets in the 1H NMR spectrum apart from the
singlet of triazole ring). Inductive electron withdrawing could
have assisted to have more electron deficiency in the carbon
alpha to methyl (4f), while mesomeric electron withdrawing
would have telling effect at the para to acetyl group (4g),
avoiding the steric conjunction, if entered at ortho to acetyl.
With 4h, it seems to be a mixture (81:19). Considerable
amount of another regioisomer has been formed and it could
not be possible to separate that from the major one. The
major isomer has the triazolyl ring hydrogen at 9.4 ppm as in
the case of 4a to 4g. The minor isomer has the triazolyl singlet
appearing at 8.8 ppm. The structure of this minor isomer may
Figure 1. Possible isomers for
4
be
C, 2-pyridyl-4-phenyl-2H-1,2,3-triazole. This is confirmed
with the related isomer 4ja (vide infra).
In the major/only isomer of
4 prepared in the present
In 4f and 4i, the triazolyl ring hydrogen is appearing slightly
shielded at 9.1 ppm. The presence of ortho substituent would
have made the triazole ring to go out plane with the pyridyl
ring and the deshielding ring current effect may be reduced.
With 3-fluoro-4-chloropyridine-N-oxide, the course is different.
Here two isomers have been obtained in relatively good yield
(38:20) labelled as 4j and 4ja. With 4j, the triazole ring
hydrogen comes at 9.4 ppm as with other cases, suggesting
investigation, the triazole hydrogen appears at 9.30 ppm
(DMSO-d6). This hydrogen is said to have observed at 8.88 in
CDCl3 and 9.37 in DMF for the structure A 17
. Hence the above
compounds have been said to assume the structure where the
2-pyridyl ring is 1 position and the aryl at 4 position. This is
confirmed by two dimensional NMR studies (Figure 2 shows
correct assignment based on 2D connectivities for 4c) and
single crystal X-ray analysis of 4d (Figure 3).
the structure to be
hydrogen appears at 8.8 ppm suggesting the structure to be
different. It is found to be , 2-pyridyl-4-aryl-2H-1,2,3-triazole.
A. In the case of 4ja, the triazole ring
Br
7.87, dd, J = 1.5, 5.2 Hz
127.5
135.1
C
8.55, d, J = 5.3 Hz
150.5
8.39, d, J = 1.5 Hz
117
It is possible to grow a single crystal in this case and the single
crystal X-ray data confirm the structure (Figure 4).
N
149.6
N
9.4, s, 1H
119
N
147
N
130.2
8.0, d, J = 7.1 Hz
126.0
7.41, t, J = 7.4 Hz
128.9
7.51, t, J = 7.4Hz
129.4
4c (A)
Figure 2 NMR assignments for 4c (DMSO-d6)
Figure 4. ORTEP diagram of 4ja (CCDC Number 1475932)
With 4k, the isomer is found to be 4,5-dimethylpyrid-2-yl
triazole and not 3,4-dimethylpyrid-2-yltriazole. There are three
one hydrogen singlets in the 1H NMR spectrum proving that
the compound is the former and not the latter with the
triazole group getting bonded to pyridine at para to the methyl
at 3 position and not at ortho to that methyl group. This is
surprising as 2-methylpyridine-N-oxide has behaved differently
giving 4f, where the triazole group is attached to the C-2
position of the pyridyl ring.
Figure 3 ORTEP diagram of 4d (CCDC number 1475885)
After varying the substitutents in pyridine-N-oxide, the scope
is extended to fused pyridine ring. With 5-nitroisoquinoline
oxide, the reaction goes succesfully coupling with the triazole
ring in the 1-position of isoquinoilne and not at the 3-position
giving 4l (four doublets and one triplet). This is not surprising
Interestingly in 4f, the coupling has occurred ortho to methyl
in the pyridyl ring and not para to methyl (no one hydrogen
1
singlet in the H NMR spectrum), though it is sterically placed.
Thus the product is 3-methylpyrid-2-yl triazole and not 5-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 8
View Article Online
DOI: 10.1039/C6RA10452E
ARTICLE
Journal Name
as the nucleophilicity of C-1 position is more compared C-3
position, in spite of the peri interaction.17 Obviously, due to
peri interaction, the triazole ring goes out of plane feeling an
upfield shift for the triazolyl hydrogen, appearing at 8.8 ppm
(cf: 4f and 4i).
R
N
O
1
N
N
N
O
S
N
N
N
O
O
S
R1
O
O
R1
N
2
The reaction takes with equal ease in quinoline system as well
I
(
4m). The substrate scope has also been extended by
introducing the substituents in the 4-aryl ring of triazole (4o
and 4p). The starting triazole sulphonyl compounds for 4q and
4r have been prepared by reported procedure.18
O
N
O
S
N
O
N
N
N
S
O
OH
HN
O
Scheme 2 Scope of the substrates (4a-4r)
N
R1
R1
N
R1
II
N
N
N
N
N
N
O
N
R
O
N
DCE
S
R
95 °C, 5 h
R1
4
III
R
O
6
4
2
1
N
N
N
N
N
N
N
N
N
N
Br
N
N
Conclusions
We have presented a new C-N bond forming reaction via
regioselective α-heteroarylation followed by deoxygenation
towards the synthesis of variety of azinetriazole from simple
azine N-oxides derivatives and N-tosyl-1,2,3-triazoles. The
reaction is metal free and base free with lesser reaction time,
Br
4c, 75%
4b, 79%
4a, 82%
N
N
N
N
N
N
Cl
N
N
N
O
N
N
N
4d, 80%
4e, 81%
4f, 73%
high yields and
a broad substrate scope. Out of the
N
N
N
N
N
N
N
N
NC
N
N
synthesised compounds, 4b, 4c, 4e-n & 4q are new.
N
N
Br
Br
O
4g, 70%
4h, 81%
4i, 69%
Experimental section
N
N
N
N
N
N
N
N
N
N
N
N
General consideration
F
F
The melting points reported in the work are uncorrected.
Unless stated otherwise, solvents and chemicals were
obtained from commercial sources and used without further
purification. The 1H and 13CNMR spectra of the new
compounds were measured at 400 MHz or 300 MHz and 100
MHz or 75 MHz (mentioned in respective NMR data itself)
respectively using Bruker NMR instrument in DMSO-d6 or
CDCl3. Chemical shifts are reported in parts per million (δ),
coupling constants (J values) are reported in Hertz (Hz) relative
to tetramethylsilane. Spin multiplicities are indicated by the
following symbols: s (singlet), d (doublet), t (triplet), m
(multiplet) dd (doublet of doublets), bs (broad singlet).
Infrared spectra were recorded on a FT-IR instrument and only
major peaks are reported in cm.-1 Column chromatography
was carried out in silica gel (60−120 mesh) using petroleum
ether-ethyl acetate as eluent.
Cl
Cl
4j, 38%
4ja, 35%
4k, 81%
N
N
N
N
OH
N
N
N
N
N
N
N
O2N
N
4l, 69%
4m, 72%
4n, 70%
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
OMe
Cl
4o, 74%
4p, 78%
4q, 79%
4r, 78%
aReaction conditions: 1 (1mmol), 2 (1mmol), DCE (2 mL), 95 ºC, 5 h. Isolated
yields refer to 1
The plausible mechanism of the reaction is provided in Scheme
3. It must be admitted that the reaction is not taking place with
alkyl azides.
General procedure for the preparation of 4
Scheme 3 Plausible mechanism for α-heteroarylation of pyridine N-oxide
To
a
solution of pyridine-N-oxide
1
(1 mmol) in 1,2-
(1 mmol).
dichloroethane (2 mL) was added sulfonyl triazole
2
The reaction was stirred magnetically reflux at 95 °C for the
indicated time (Table 1). After completion of the reaction
(monitored by TLC), the product was extracted with ethyl
acetate (15 mL) and purified by column chromatography (silica
gel) using ethyl acetate/petroleum ether mixture as a gradient
elution to afford product (4a-r).
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 5 of 8
View Article Online
DOI: 10.1039/C6RA10452E
Journal Name
ARTICLE
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)pyridine 4a 1,6f,199
Isolated yield 0.16 g (73%); off white solid; M.pt. 148-150⁰
C; 1H
Isolated yield 0.19 g (82%); off white solid; M.pt. 128-130⁰C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.39 (t, J = 7.6 Hz, 1H), 7.50 (t, J
= 7.2 Hz, 2H), 7.56 - 7.59 (m, 1H), 8.04 (d, J = 7.2 Hz, 2H), 8.12 -
8.19 (m, 2H), 8.63 (d, J = 7.6 Hz, 1H), 9.32 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δC: 114.2, 118.7, 124.8, 126.1, 128.9, 129.4,
NMR (400 MHz, DMSO-d6): δH: 2.44 (s, 3H), 7.40 (t, J = 3.8 Hz,
1H), 7.51 (t, J = 7.6 Hz, 2H), 7.56 - 7.59 (m, 1H), 8.00 - 8.05 (m,
3H), 8.51 - 8.52 (m, 1H), 9.14 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δC: 18.5, 122.1, 125.5, 125.9, 128.2, 128.7, 129.5,
130.7, 142.3, 146.6, 147.0, 148.2; IR (ATR KBr cell, cm-1) 1476,
1537, 2998, 3120; LC-MS calcd. m/z 236, found 237 [(M+1)]+.
Anal. Calcd for C14H12N4: C, 71.17; H, 5.12; N, 23.71; Found: C,
71.12; H, 5.09; N, 23.64.
1
130.4, 140.6, 147.9, 149.0, 149.5; H NMR (300 MHz, CDCl3):
δH: 7.35 - 7.40 (m, 2H), 7.49 ( t, J = 7.2 Hz), 7.94 - 7.97 (m, 3H),
8.26 ( d, J = 8.4 Hz, 1H), 8.53 - 8.54 (m, 1H), 8.82 (s, 1H); 13C
NMR (75 MHz, CDCl3) δC: 113.8, 116.8, 123.5, 125.9, 128.4, 1-(6-(4-Phenyl-1H-1,2,3-triazol-1-yl)pyridin-3-yl)ethanone 4g
128.9, 130.3, 139.1, 148.1, 148.5, 149.3; IR (ATR KBr cell, cm-1)
Isolated yield 0.13 g (70%); off white solid; M.pt. 198-200
⁰
C; 1H
1053, 1560, 3078, 3125.
NMR (400 MHz, DMSO-d6): δH: 2.69 (s, 3H), 7.51 - 7.56 (m, 3H),
8.05 - 8.23 (m, 3H), 8.58 - 8.81 (m, 2H), 9.16 (s, 1H); 13C NMR
(100 MHz, DMSO-d6) δC: 27.5, 114.0, 126.8, 129.4, 129.7,
130.1, 131.8, 136.2, 139.8, 150.2, 150.5, 152.6, 196.7; IR (ATR
KBr cell, cm-1) 1402, 1570, 1645, 2384, 3042; LC-MS calcd. m/z
264, found 265[(M+1)]+. Anal. Calcd for C15H12N4O: C, 68.17; H,
4.58; N, 21.20; Found: C, 68.11; H, 4.55; N, 21.15.
2-Bromo-6-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4b
Isolated yield 0.14 g (79%); off white solid; M.pt. 180-182⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.40 (t, J = 7.2 Hz, 1H), 7.50 (t, J
= 7.2 Hz, 2H), 7.83 (d, J = 7.6 Hz, 1H), 8.05 - 8.10 (m, 3H), 8.20
(d, J = 8 Hz, 1H), 9.33 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δC:
113.6, 118.9, 126.1, 128.8, 128.9, 129.4, 130.2, 140.2, 143.3,
147.8, 148.8; IR (ATR KBr cell, cm-1) 550, 1280, 3042, 3145. LC-
MS calcd. m/z 301, found 302 [(M+1)]+. Anal. Calcd for
C13H9BrN4: C, 51.85; H, 3.01; N, 18.60; Found: C, 51.80; H, 2.98;
N, 18.54.
6-(4-Phenyl-1H-1,2,3-triazol-1-yl)picolinonitrile 4h
Isolated yield 0.17 g (81%); off white solid; M.pt. 176-178⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.39 (t, J = 7.2 Hz, 1H), 7.46 -
7.53 (m, 2H), 8.03 - 8.06 (m, 2H), 8.19 (d, J = 7.6 Hz, 1H), 8.35 -
8.41 (m, 1H), 8.49 (d, J = 8.4 Hz, 1H), 9.43 (s, 1H); 13C NMR (75
MHz, DMSO-d6) δC: 116.5, 118.2, 125.9, 126.5, 128.6, 129.0,
129.9, 131.6, 135.4, 141.9, 148.0, 149.5; IR (ATR KBr cell, cm-1)
1570, 2928, 3042; LC-MS calcd.m/z 247, found 248 [(M+1)]+.
Anal. Calcd for C14H9N5: C, 68.01; H, 3.67; N, 28.32; Found: C,
67.99; H, 3.60; N, 28.27.
4-Bromo-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4c
Isolated yield 0.13 g (75%); off white solid; M.pt.118-120⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.41 (t, J = 7.4 Hz, 1H), 7.51 (t, J
= 7.44 Hz, 2H), 7.87 (dd, J = 1.48 Hz, 5.2 Hz, 1H), 8.04 (d, J =
7.36 Hz, 2H), 8.39 (d, J = 1.48 Hz, 1H), 8.55 (d, J = 5.32 Hz, 1H),
9.40 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δC: 117.2, 119.0,
126.1, 127.8, 128.9, 129.4, 130.2, 135.2, 147.8, 149.6, 150.5; IR
(ATR KBr cell, cm-1) 570, 1280, 3100, 3126. LC-MS calcd. m/z
301, found 302 [(M+1)]+. Anal. Calcd for C13H9BrN4: C, 51.85; H,
3.01; N, 18.60; Found: C, 51.80; H, 2.94; N, 18.53.
3,5-Dibromo-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4i
Isolated yield 0.10 g (69%); off white solid; M.pt. 128-130⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.41 (t, J = 7.6 Hz, 1H), 7.51 (t, J
= 7.2 Hz, 2H), 7.96 (d, J = 7.2 Hz, 2H), 8.86-8.89 (m, 2H), 9.12 (s,
1H); 13C NMR (100 MHz, DMSO-d6) δC: 116.7, 122.3, 122.9,
126.0, 128.9, 129.5, 130.3, 146.1, 146.6, 146.9, 149.5; IR (ATR
KBr cell, cm-1) 557, 1462, 1552, 1949, 3129. LC-MS calcd. m/z
380, found 381 [(M+1)]+. Anal. Calcd for C13H8Br2N4: C, 41.09;
H, 2.12; N, 14.74; Found: C, 41.02; H, 2.09; N, 14.70.
2-Chloro-6-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4d 6f
Isolated yield 0.16 g (80%); off white solid; M.pt.136-138⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.40 (t, J = 7.2 Hz, 1H), 7.49 (t, J
= 7.2 Hz, 2H), 7.69 (dd, J = 1.6 Hz, 6.8 Hz, 1H), 8.06 (d, J = 8.4
Hz, 2H), 8.15 - 8.21 (m, 2H), 9.32 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δC: 113.3, 119.0, 125.0, 126.1, 129.0, 129.4, 130.2,
143.8, 147.9, 148.7, 149.5; IR (ATR KBr cell, cm-1) 682, 733,
1474, 1593, 3131.
4-Chloro-5-fluoro-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4j
Isolated yield 0.07 g (38%); off white solid; M.pt. 158-160⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.40 (t, J = 7.2 Hz, 1H), 7.50 (t, J
= 7.6 Hz, 2H), 8.02 (d, J = 7.6 Hz, 2H), 8.44 (d, J = 5.2 Hz, 1H),
8.83 (s, 1H), 9.35 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δC:
116.3, 126.7, 129.1, 129.7, 131.1, 132.5, 135.6, 137.9, 147.2,
150.1, 154.5; IR (ATR KBr cell, cm-1) 1128, 1570, 3071; LC-MS
calcd. m/z 274, found 275 [(M+1)]+. Anal. Calcd for C13H8ClFN4:
C, 56.84; H, 2.94; N, 20.40; Found: C, 56.78; H, 2.91; N, 20.35.
4-(Benzyloxy)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4e
Isolated yield 0.13g (81%); off white solid; M.pt. 155-157⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 5.36 (s, 2H), 7.20 - 7.22 (m, 1H),
7.37 - 7.52 (m, 8H), 7.74 (d, J = 2 Hz, 1H), 8.03 (d, J = 7.2 Hz,
2H), 8.44 (d, J = 5.6 Hz, 1H), 9.33 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δC: 70.5, 100.3, 112.3, 119.0, 126.0, 128.5, 128.8,
128.9, 129.1, 129.4, 130.4, 136.1, 147.6, 150.5, 150.6, 167.2; IR
(ATR KBr cell, cm-1) 1580, 3080, 3125; LC-MS calcd. m/z 328,
found 329 [(M+1)]+. Anal. Calcd for C20H16N4O: C, 73.15; H,
4.91; N, 17.06; Found: C, 73.11; H, 4.84; N, 17.03.
4-Chloro-5-fluoro-2-(4-phenyl-2H-1,2,3-triazol-2-yl)pyridine 4ja
Isolated yield 0.03 g (20%); off white solid; M.pt. 170-172⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 7.47 (t, J = 7.2 Hz, 1H), 7.54 (t, J
= 7.2 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H), 8.34 (d, J = 5.2 Hz, 1H),
8.73 (s, 1H), 8.76 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δC:
116.4, 119.2, 126.1, 129.0, 129.5, 130.2, 133.0, 138.2, 145.6,
3-Methyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4f
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 8
View Article Online
DOI: 10.1039/C6RA10452E
ARTICLE
Journal Name
147.2, 154.8; IR (ATR KBr cell, cm-1) 700, 1135, 1499, 3012; LC- 131.4, 132.6, 134.3, 140.6, 146.3, 148.9, 149.4; IR (ATR KBr
MS calcd. m/z 274, found 275 [(M+1)]+. Anal. Calcd for cell, cm-1) 774, 1400, 1590, 3108.
C13H8ClFN4: C, 56.84; H, 2.94; N, 20.40; Found: C, 56.80; H,
2-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)pyridine 4p 6f
2.92; N, 20.36.
Isolated yield 0.21 g (78%); off white solid; M.pt. 110-112⁰
C; 1H
NMR (400 MHz, DMSO-d6): δH: 3.82 (s, 3H), 7.06 (t, J = 8.8 Hz,
C; 1H 2H), 7.56 - 7.59 (m, 1H), 7.97 (t, J = 8.4 Hz, 2H), 8.12 - 8.19 (m,
4,5-Dimethyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine 4k
Isolated yield 0.16 g (81%); off white solid; M.pt. 148-150
⁰
NMR (400 MHz, DMSO-d6): δH: 2.31 (s, 3H), 2.41 (s, 3H), 7.39 2H), 8.64 (t, J = 4.8 Hz, 1H), 9.27 (s, 1H); 13C NMR (100 MHz,
(t, J = 7.2 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.99 (s, 1H), 8.03 (d, J DMSO-d6) δC: 55.7, 114.2, 114.8, 117.7, 123.0, 124.7, 127.5,
= 7.2 Hz, 2H), 8.35 (s, 1H), 9.32 (s, 1H); 13C NMR (100 MHz, 140.6, 147.6, 149.1, 149.4, 159.9; IR (ATR KBr cell, cm-1) 1437,
DMSO-d6) δC: 16.1, 19.6, 114.4, 118.6, 126.0, 128.8, 129.4, 1476, 1645, 3085.
130.6, 133.7, 147.4, 147.5, 148.5, 150.4; IR (ATR KBr cell, cm-1)
1-(Pyridin-2-yl)-1H-benzo[d][1,2,3]triazole 4q
1041, 1466, 1601, 3173; LC-MS calcd. m/z 250, found 251
[(M+1)]+. Anal. Calcd for C15H14N4: C, 71.98; H, 5.64; N, 22.38; Isolated yield 0.16 g (79%); off white solid; M.pt. 108-110
⁰
NMR (400 MHz, DMSO-d6): δH: 7.53 - 7.58 (m, 2H), 7.70 - 7.74
C; 1H
Found: C, 71.93; H, 5.60; N, 22.31.
(m, 1H), 8.17 (td, J = 1.6 Hz, 7.2 Hz, 1H), 8.21 (d, J = 8 Hz, 1H),
8.26 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.70 - 8.72 (m,
5-Nitro-1-(4-phenyl-1H-1,2,3-triazol-1-yl)isoquinoline 4l
Isolated yield 0.12g (69%); off white solid; M.pt.188-190⁰
C; H 1H); 13C NMR (100 MHz, DMSO-d6) δC: 114.8, 114.9, 120.1,
1
NMR (400 MHz, DMSO-d6): δH: 7.49 (t, J = 7.2 Hz, 1H), 7.56 (t, J 123.6, 125.8, 129.7, 131.3, 140.4, 146.5, 149.2, 151.2; IR (ATR
= 7.2 Hz, 2H), 7.99 (d, J = 8 Hz, 1H), 8.04 (t, J = 8.4 Hz, 2H), 8.52 KBr cell, cm-1) 1579, 2380, 3141. LC-MS calcd. m/z 196, found
(d, J = 7.6 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.75 (d, J = 6.8 Hz, 197 [(M+1)]+. Anal. Calcd for C11H8N4: C, 67.34; H, 4.11; N,
1H), 8.79 (d, J = 6 Hz, 1H), 8.87 (s, 1H); 13C NMR (100 MHz, 28.55; Found: C, 67.29; H, 4.08; N, 28.51.
DMSO-d6) δC: 118.0, 122.7, 126.7, 128.6, 129.5, 129.6, 129.7,
2-(1H-1,2,4-Triazol-1-yl)pyridine 4r 16
129.9, 130.5, 132.7, 135.2, 144.4, 145.4, 149.7, 149.9; IR (ATR
KBr cell, cm-1) 1520, 1625, 3106. LC-MS calcd.m/z 317, found Isolated yield 0.12g (78%); off white solid; M.pt.84-86 C; 1H
⁰
318 [(M+1)]+. Anal. Calcd for C17H11N5O2: C, 64.35; H, 3.49; N, NMR (400 MHz, DMSO-d6): δH: 7.49 (t, J = 5.2 Hz, 1H), 7.87 (d, J
22.07; Found: C, 64.31; H, 3.41; N, 22.01.
= 8 Hz, 1H), 8.09 (t, J = 7.2 Hz, 1H), 8.29 (s, 1H), 8.54 (d, J = 4.4
Hz, 1H), 8.36 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δC: 113.3,
124.1, 140.5, 142.4, 149.1, 149.3, 153.4; IR (ATR KBr cell, cm-1)
2-(4-Phenyl-1H-1,2,3-triazol-1-yl)quinolin-8-ol 4m
Isolated yield 0.13 g (72%); off white solid; M.pt. 156-158⁰
C; 1H 1448, 1556, 3121.
NMR (400 MHz, DMSO-d6): δH: 7.49 (t, J = 7.2 Hz, 1H), 7.56 (t, J
= 7.2 Hz, 2H), 7.99 (d, J = 8 Hz, 2H), 8.04 (t, J = 8.4 Hz, 2H), 8.52
(d, J = 7.6 Hz, 1H), 8.69 (d, J = 8.4 Hz, 1H), 8.75 (d, J = 6.8 Hz,
1H), 8.79 (d, J = 6 Hz, 1H), 8.87 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) δC: 112.6, 113.3, 118.4, 119.3, 122.8, 123.7, 125.9,
129.0, 129.6, 130.5, 136.5, 144.0, 146.1, 147.7, 153.5; IR (ATR
KBr cell, cm-1) 1598, 3045, 3200. LC-MS calcd. m/z 288, found
289 [(M+1)]+. Anal. Calcd for C17H12N4O: C, 70.82; H, 4.20; N,
19.43; Found: C, 70.79; H, 4.14; N, 19.40.
Acknowledgements
M. B. H. is grateful to Advinus Therapeutics Limited, Bangalore
for support. S. M. thanks CSIR, New Delhi for the financial
assistance under a major research project.
Notes and references
1
B. Chattopadhyay, C. I. R. Vera, S. Chuprakov and V.
Gevorgyan, Org. Lett, 2010, 12, 2166.
T. Bretschneider, E-M. Franken, U. Goergens, M. Fuesslein,
A. Hense, J. Kluth, H -G. Schwarz, A. Koehler, O. Malsam and
A. Voerste, PCT Int. Appl, 2010, WO 2010006713 A2
20100121.
V. Garzya and S. P. Watson, PCT Int. Appl, 2009, WO
2009115486 A1 20090924.
A. S. Kiselyov, M. Semenova and V. V. Semenov, Bioorg. Med.
Chem. Lett, 2009, 19, 1344.
(a) M. F. Gordeev, Z. Yuan and J. Liu, PCT Int. Appl, 2008, WO
2008108988 A1 20080912; (b) I. L. Knox and R. B. Rogers,
U.S. Patent 4, 775,762, 1988; (c) B. Japelj, S. Recnik, P.
Cebasek, B. Stanovnik and J. Svete, J. Heterocycl. Chem,
2005, 42, 1167; (d) S. Ito, A. Satoh, Y. Nagatomi, Y. Hirata, G.
Suzuki, T. Kimura, A. Satow, S. Maehara, H. Hikichi, M. Hata ,
3-Methyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)quinoline 4n
Isolated yield 0.13 g (70%); off white solid; M.pt. 148-150⁰
C; 1H
2
NMR (400 MHz, DMSO-d6): δH: 2.58 (s, 3H), 7.41 (t, J = 7.2 Hz,
1H), 7.52 (t, J = 7.2 Hz, 2H), 7.73 (t, J = 8.4 Hz, 1H), 7.85 (t, J = 8
Hz, 1H), 8.06 (t, J = 7.6 Hz, 4H), 8.58 (s, 1H), 9.27 (s, 1H); 13C
NMR (100 MHz, DMSO-d6) δC: 19.2, 122.3, 126.0, 126.1, 127.8,
128.4, 128.5, 128.7, 128.8, 129.5, 130.6, 130.8, 141.2, 145.0,
146.6, 148.2; IR (ATR KBr cell, cm-1) 1496, 1599, 2923. LC-MS
calcd. m/z 286, found 287 [(M+1)]+. Anal. Calcd for C18H14N4: C,
75.50; H, 4.93; N, 19.57; Found: C, 75.46; H, 4.86; N, 19.53.
3
4
5
2-(4-(3-Chlorophenyl)-1H-1,2,3-triazol-1-yl)pyridine 4o 6f
Isolated yield 0.20 g (74%); off white solid; M.pt. 138-140⁰
C; 1H
H. Kawamoto, and H. Ohta, Bioorg. Med. Chem, 2008, 16
,
NMR (400 MHz, DMSO-d6): δH: 7.44 (d, J = 8 Hz, 1H), 7.53 (t, J =
7.6 Hz, 1H), 7.57 - 7.60 (m, 1H), 8.02 (d, J = 7.6 Hz, 1H), 8.11 -
8.18 (m, 2H), 8.64 (d, J = 4.4 Hz, 1H), 9.50 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δC: 114.3, 119.6, 124.6, 125.0, 125.7, 128.6,
9817; (e) J. Roppe, N. D. Smith, D. H. Huang, L. Tehrani, B. W.
Wang, J. Anderson, J. Brodkin, J. Chung, X. H. Jiang, C. King,
B. Munoz, M. A. Varney, P. Prasit and N. D. P. Cosford, J.
Med. Chem, 2004, 47, 4645; (f) A. R. Ellanki, A. Islam, V. S.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 7 of 8
View Article Online
DOI: 10.1039/C6RA10452E
Journal Name
ARTICLE
Rama, R. P. Pulipati, D. Rambabu, G. R. Krishna, C. M. Reddy, 14 H. P. Kokatla, P. F. Thomson, S. Bae, V. R. Doddi and M. K.
K. Mukkanti, G. R. Vanaja, A. M. Kalle, K. S. Kumar and M. Lashman, J. Org. Chem, 2011, 76, 7842.
Pal, Bioorg. Med. Chem. Lett, 2012, 22, 3455; (g) S. V. 15 K. Wang, X. Bi, S. Xing, P. Liao, Z. Fang, X. Meng Q. Zhang, Q.
Chapyshev and A. V. Chernyak, Synthesis, 2012, 3158; (h) T. Liu and Y. Ji, Green Chem, 2011, 13, 562.
Merckx, P. Verwilst and W. Dehaen, Tetrahedron Lett, 2013, 16 J. M. Keith. J. Org. Chem, 2010, 75, 2722.
54, 4237; (i) Y. Okumura, Y. Maya, Y. Shoyama and T. Onishi, 17 V. Balasubramanian, Chem. Rev. 1966, 66, 567.
Patent WO2012176587 A1, 2012; (j) F. Li, Y. J. Park, J-M. Hah 18 (a) A. R. Katritzky, T. Kurtz, S. Zhang, M. Voronkov, P. J. Steel,
and J-S. Ryu, Bioorg. Med. Chem. Lett, 2013, 23, 1083; (k) C.
HirthDietrich, P. Sandner, J-P. Stasch, M. Hahn and M.
Follmann, Eur. Pat. Appl, 2594270, 2013; (l) F. Li, Y. J. Park, J-
M. Hah, J-S. Ryu, Bioorg. Med. Chem. Lett, 2013, 23, 1083.
(a) Y. J. Li, J. C. Huffman and A. H. Flood, Chem. Commun,
2007, 2692; (b) S. J. Gu, H. Xu, N. Zhang, W. Z. Chen, Chem.-
Heterocycles, 2001, 55, 1703; (b) H. Law, I. Baussanne, J. M.
G. Fernandez and J. Defaye, Carbohydrate research, 2003,
338, 451.
19 W. K. C. Lo, G. S. Huff, J. R. Cubanski, A. D.W. Kennedy, C. J.
McAdam, K. C. Gordon and . D. Crowley, Inorg. Chem, 2015,
54, 1572.
6
Asian J, 2010,
5, 1677; (c) I. Stengel, A. Mishra, N.
Pootrakulchote, S-J. Moon, S. M. Zakeeruddin, M. Graetzel
and P. Baeuerle, J. Mater. Chem, 2011, 21, 3726; (d) A. Bolje
and J. Kosmrlj, Org. Lett, 2013, 15, 5084; (e) J. Sudarat, K.
Teerachanan, P. Thongkam, S. Kiatisevi, T. Khamnaen, P.
Phiriyawirut, S. Charoenchaidet, T. Sooksimuang, P.
Kongsaeree and P. Sangtrirutnugul, J. Organomet. Chem,
2014, 750, 35; (f) R. Sun, H. Wang, J. Hu, J. Zhao and H.
Zhang, Org. Biomol. Chem, 2014, 12, 5954. and references
cited therein.
7
(a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev, 2007,
107, 174; (b) L.-C. Campeau, D. R. Stuart, K. Fagnou,
Aldrichimica Acta 2007, 40, 35; (c) D. R. Stuart and K. Fagnou,
Science 2007, 316, 1172; (d) F. Kakiuchi and N. Chatani, Adv.
Synth. Catal, 2003, 354, 1077; (e) J. A. Lablinger and J. E.
Bercaw, Nature 2002, 417, 507; (f) V. Ritleng, C. Sirlin and M.
Pfeffer, Chem. Rev, 2002, 102, 1731; (g) M. Miura and M.
Nomura, Top. Curr. Chem, 2002, 219, 211; (h) Y. Fujiwara and
J. Chengguo, Pure Appl. Chem, 2001, 73, 319; (i) G. Dyker,
Angew. Chem. Int. Ed, 1999, 38, 1698; (j) A. Shilov and G.
Shulpin, Chem. Rev, 1997, 97, 2879.
8
9
(a) R. F. Jordan and D. F. Taylor, J. Am. Chem. Soc, 1989, 111,
778; (b) E. J. Moore, W. Pretzer, T. J. O’Connell, J. Harris, L.
LaBounty, L. Chou and S. S. Grimmer, J. Am. Chem. Soc, 1992,
114, 5888; (c) T. Fukuyama, N. Chatani, J. Tatsumi, F.
Kakiuchi and S. Murai, J. Am. Chem. Soc, 1998, 120, 11522;
(d) M. Murakami and S. Hori, J. Am. Chem. Soc, 2003, 125
4720.
,
(a) L. Lutz Ackermann and S. Fenner, Chem. Commun, 2011,
47, 430 and references cited therein; (b) F. Gosselin, S-J.
Savage, N. Blaquiere and S. T. Staben, Org. Lett, 2014, 14
862.
,
10 K. S. Kanyiva, Y. Nakao and T. Hiyama, Angew. Chem. Int. Ed,
2007, 46, 8872.
11 For direct arylation of azine N-oxides, see: (a) L-C. Campeau,
S. Rousseaux and K. Fagnou, J. Am. Chem. Soc, 2005, 127
,
18020; (b) L-C. Campeau, D. R. Stuart, J-P. Leclerc, M.
Bertrand-Laperle, E. Villemure, H-Y. Sun, S. Lasserre, N.
Guimond, M. Lecavallier and K. Fagnou, J. Am. Chem. Soc,
2009, 131, 3291; (c) L-C. Campeau, D. J. Schipper and K.
Fagnou, J. Am. Chem. Soc, 2008, 130, 3266; (d) D. J. Schipper,
L-C. Campeau and K. Fagnou, Tetrahedron 2009, 65, 3155;
For direct arylation of N-iminopyridiniumylides, see: (e) A.
Larivee, J. J. Mousseau and A. B. Charette, J. Am. Chem. Soc,
2008, 130, 52; (f) D. Alberico, M. E. Scott and M. Lautens,
Chem. Rev, 2007, 107, 174
12 (a) A. Padwa and P. D. Stull, Tetrahedron Lett, 1987, 28
,
5407; (b) R. M. Savizky and D. J. Austin, 2005, Rhodium(II)-
Catalyzed 1,3-Dipolar Cycloaddition Reactions, in Modern
Rhodium-Catalyzed Organic Reactions (ed P. A. Evans),
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, FRG. doi:
10.1002/3527604693.ch19; (c) Q-Q. Cheng, Y. Qian, P. Y.
Zavalij and M. P. Doyle, Org. Lett, 2015, 17, 3568
13 see recent review. H. M. L. Davies and J. S. Alford, Chem. Soc.
Rev, 2014, 43, 5151.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

RSC Advances
Page 8 of 8
View Article Online
DOI: 10.1039/C6RA10452E
Base free regioselective synthesis of αꢀtriazolylazine derivatives
Mysore Bhyrappa Harisha,a,b Muthupandi Nagaraj,a Shanmugam Muthusubramanian*a and
Nattamai Bhuvaneshc
aDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai - 625 021,
Tamil Nadu, India
bAdvinus Therapeutics Limited, A TATA Enterprise, Bangalore - 560 058, India
cX-ray Diffraction Laboratory, Department of Chemistry, Texas A & M University, College Station, TX 77842,
USA
Graphical abstract