An unprecedented intramolecular to intermolecular mechanistic switch in 1,1-diaminoazines leading to differential product formation during the I2-induced tandem oxidative transformation

Article abstract of DOI:10.1039/c9ob00610a

The tautomeric preference of guanylhydrazones towards the azine form induces an unprecedented intramolecular to intermolecular mechanistic switch during the I₂-catalyzed oxidative transformation leading to 4,5-disubstituted-3-amino-1,2,4-triazoles in contrast to the reaction of semicarbazones and thiosemicarbazones to form 1,3,4-oxa/thiadiazoles. This intramolecular to intermolecular cyclization shift was established through control experiments and was attributed to the high energy demand (～22 kcal mol^-1) for the azine tautomer to adopt the s-cis conformation which is essential for the intramolecular reaction. An I₂ induced protocol for an efficient and straightforward synthesis of 4,5-disubstituted-3-amino-1,2,4-triazoles has been developed via tandem oxidative transformation of guanylhydrazones (in its preferentially existing azine tautomeric form) with distinct advantages such as wide substrate scope, use of substoichiometric amounts of iodine, no requirement of external oxidizing agents, base free reaction conditions, short reaction time and moderate to good yields. The role of silver salt in improving the yield and shortening of reaction time was also highlighted.

Full text of DOI:10.1039/c9ob00610a

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Gupta, S. S. Chourasiya, S. C. sahoo, U. Beifuss, A. K. Chakraborti and P. V. Bharatam, Org. Biomol. Chem.,
2019, DOI: 10.1039/C9OB00610A.
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00610A
ARTICLE
An Unprecedented Intramolecular to Intermolecular
Mechanistic Switch in 1,1-diaminoazines Leading to
Differential Product Formation during the I2-Induced
Tandem Oxidative Transformation
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Deepika Kathuria,a Pankaj Gupta,a Sumit S. Chourasiya,a Subash C. Sahoo,b Uwe Beifuss,c Asit K.
Chakraborti,*a and Prasad V. Bharatam*a
The tautomeric preference of guanylhydrazones towards the azine form induces an unprecedented intramolecular to
intermolecular mechanistic switch during the I2-catalyzed oxidative transformation leading to 4,5-disubstituted-3-amino-
1,2,4-triazoles in contrast to the reaction of semicarbazones and thiosemicarbazones to form 1,3,4-oxa/thiadiazoles. This
intramolecular to intermolecular cyclization shift was established through control experiments and was attributed due to
the high energy demand (~22 kcal/mol) for the azine tautomer to adopt the s-cis conformation which is essential for
intramolecular reaction. An I2 induced protocol for an efficient and straight forward synthesis of 4,5-disubstituted-3-
amino-1,2,4-triazoles has been developed via tandem oxidative transformation of guanylhydrazones (in its preferentially
existing azine tautomeric form) with the distinct advantages such as wide substrate scope, use of substoichiometric
amount of iodine, no requirement of external oxidizing agents, base free reaction condition, short reaction time and
moderate to good yield. The role of silver salt in improving the yield and shortening of reaction time was also highlighted.
activation12 to form N-heterocycles. The hydrazone to azine
tautomeric shift results in better drug-receptor interaction
Introduction
Prototropic tautomerism is an important chemical
phenomenon and draws attraction due to its implications in
computer-aided drug design,1 drug delivery,2 understanding
the interactions of the drug molecules with the biological
targets3 and solid state structural property such as
polymorphism.4 Recently we have demonstrated that
prototropic tautomerism is exhibited by guanylhydrazones
which exist preferentially in the azine form.5 Azines are the
2,3-diaza analogues of 1,3-butadiene and have been
recognised as important class of compounds with interesting
structural,6 chemical,7 and biological properties8 and synthetic
applicability as feed stocks for the construction of diverse
heterocyclic scaffolds.9 Symmetrical acyclic azines undergo 1,3-
suggesting the azine tautomer to be the bioactive form of
guanylhydrazone class of drugs.13 Thus, while the implication
of prototropic tautomerism on biological activity
is well documented there has been no report on tautomerism
induced change in chemical reactivity.
We were attracted by the recent reports on the I2-
catalyzed
transformation
of
semicarbazones/thiosemicarbazones to form 2-amino-1,3,4-
oxa/thiadiazoles.14 In these cases, the heterocyclic ring
construction in the final product is governed by the propensity
of intramolecular cyclization through nucleophilic attack by the
acyl/thioacyl O/S atom on the I2-induced electrophilically
activated
-C=N
functionality
of
the
dipolar
cycloaddition,10
oxidative
intramolecular
semicarbazone/thiosemicarbazone (Scheme 1A).
cyclocondensation,11 and oxidative C-H and N-N bond
Scheme 1. The I2-Induced Cyclization of Semicarbazones/Thiosemicarbazones Vs
1,1-diaminoazines
a.D. Kathuria, P. Gupta, S.S. Chourasiya, Prof. Dr. A. K. Chakraborti, P. V. Bharatam
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research (NIPER) Sector 67, S.A.S. Nagar - 160 062, Punjab (India)
E-mail: pvbharatam@niper.ac.in; akchakraborti@niper.ac.in
b.Dr. Subash C. Sahoo
Department of Chemistry, Panjab University, Chandigarh – 160014, India.
c. Prof. Dr. U. Beifuss, Bioorganische Chemie, Institut für Chemie, Universität
Hohenheim, Garbenstraße 30, D-70599 Stuttgart, Germany.
† 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
A) Previous Works (Ref 14): Hydrazones undergoing Intramolecular Cyclization
H
I2, K2CO3,
N
N
N
NH2
R
N
1,4 - dioxane, 80 °C
R
NH2
X
X
X = O/S
B) This Work: Azines undergoing Intermolecular Cyclization
N
NH2
NH2
I2
N
R
R
N
N
1,4 - dioxane, 80 °C
N
N
NH2
R
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ARTICLE
This prompted us to explore the feasibility of the formation of
Journal Name
After confirming the product, we started optimizing the
View Article Online
DOI: 10.1039/C9OB00610A
5-substituted-3-amino-1,2,4-triazoles through the I2-catalyzed reaction condition in order to improve the yield of 5a, the
reaction of guanylhydrazones (Scheme 1B) that are isosteric to treatment of 1a with I2 was carried out under various conditions
the semicarbazones/thiosemicarbazones in that the C=O/S such as using variable amounts of I2 and K2CO3, different reaction
group is replaced by C=NH keeping in view the fact that time and temperature, Cs2CO3 and K3PO4 as the base in place of
guanylhydrazones exist preferentially in the azine tautomeric K2CO3, different oxidants such as NIS, NCS, NBS, KI, TBAI,
form (Figure 1).5,13
PhI(OAc)2, various Lewis acids such as InCl3, In(OTf)3, Pd(OAc)2
Herein, we report for the first time that the structural in place of I2 and different solvents etc. (Table 1). The best
preference in the azine tautomeric form influences the course result (72% yield of 5a) was obtained in performing the
of the chemical reaction of guanylhydrazones triggering a reaction with 0.5 equivalent of I2 in 1,4-dioxane at 80 °C for 3 h
mechanistic switch towards an unprecedented intermolecular in the absence of any base (Table 1, entry 7).
nucleophilic attack in the azine tautomer during I2-induced
Table 1. The Oxidative Intermolecular Cyclocondensation of 1a under Various
oxidative cyclization leading to different product.
Conditions to form 5a [a]
.
Results and Discussion
In a model study, 1a (prepared from the condensation of 2a
with aminoguanidine hydrochloride
3 following the literature
procedure),5 was subjected to the treatment with I2 (1.5 equiv)
in the presence of K2CO3 (3 equiv) in 1,4-dioxane at 80°C
(Scheme 2).
En
try
1
Oxidant (equiv)
Base
(equiv)
K2CO3 (3.0)
K2CO3 (1.5)
Cs2CO3 1.5)
K3PO4 (1.5)
Solvent
Time
(h)
3
Yield
(%)[b]
10
30
traces
traces
60
66
72[c]
60
58
52
40
32
0
traces
traces
10
48
35
60
52
0
I2 (1.5)
I2 (1.5)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMSO
DMF
MeCN
toluene
EtOAc
DCE
THF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Scheme 2. The I2-Induced Reaction of 1a
.
2
3
3
4
5
6
7
8
9
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.0)
I2 (0.5)
I2 (0.3)
I2 (0.25)
I2 (0.2)
I2 (0.1)
I2 (0.05)
-
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
4
4
3
3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
3
10
10
10
10
10
10
10
10
10
10
10
3
10
10
10
10
10
10
10
10
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
However, instead of observing the expected formation of
the 5-substituted 3-amino-1,2,4-triazole 4a via the
intramolecular oxidative cyclization (Scheme 2) the formation
of (E)-4-(4-chlorophenylideneamino)-5-(4-chlorophenyl)-3-
amino-1,2,4-triazole (5a), was observed presumably via the
intermolecular cyclization involving two molecules of 1a
(
)
,
(Table 1, entry 1). The structure of 5a was established through
spectrometric [NMR: 1H, 13C, Distortionless Enhancement by
Polarization Transfer-135 (DEPT-135), Heteronuclear Single
Quantum Correlation (HSQC), and Heteronuclear Multiple
Bond Correlation (HMBC) and High Resolution Mass
Spectrometry (HRMS): m/z 331.0392 (MH+)] data. The final
proof of concept can was obtained by recording the single
crystal XRD. However, as it was difficult to obtain a single
crystal of 5a, the corresponding fluoro analogue (E)-4-((4-
fluorobenzylidene)amino)-5-(4-fluorophenyl)-4H-1,2,4-triazol-
3-amine (5k) as a white needle shape crystal was subjected to
XRD analysis15 that clearly established its structure (Figure 2).
KI (0.5)
KI (1.5)
0
0
0
5
TBAI (0.5)
TBAI (1.5)
NBS (0.5)
NCS (0.5)
NIS (0.5)
NIS (1.5)
PhI(OAc)2 (0.5)
PhI(OAc)2 (1.5)
InCl3 (0.1)
In(OTf)3 (0.1)
Pd(OAc)2 (0.1)
8
10
20
0
0
0
10
10
10
10
10
0
0
[a] 1a (0.5 mmol), obtained by reacting 2a with one molar equivalent of 3 in aq
NaOH followed by filtration, was treated with I2 (0.25 mmol, 0.5 equiv) and the
base (as applicable) in the solvent (2 mL) at 80 ˚C. *b+ Isolated yield of 5a. *c+ 5a
was formed in 8, 51, 72, and 68 % yields at rt, 60, 80, and 100 °C, respectively.
Figure 2. ORTEP diagram of 5k with 50% thermal probability ellipsoids.18
2 | J. Name., 2012, 00, 1-3
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It was felt that the I2-assisted electrophilic activation of the oxidizing agent for removal of the ring -CH hydrogen atom as
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DOI: 10.1039/C9OB00610A
-C=N group in the azine I to generate the N-iodo intermediate the product yield is unaffected in performing the reaction
II should be facilitated by use of Ag-salt as an activator of I2. under anaerobic condition (under nitrogen).
Thus, the intermolecular cyclocondensation of 1a to form 5a
Scheme 3. Substrate Scope for the Synthesis of 4,5-Disubstituted-3-Amino-1,2,4-
Triazoles via I2-Induced Intermolecular Cyclocondensation of 1,1-Diaminoazines.
was performed in the presence of various Ag-salts (Table 2).
Distinct advantages in terms of the reduction of the reaction
time (Table 2, entry 2) and the amount of I2 (Table 2, entry 6)
was observed.
Table 2. The Effect of Various Ag-Salts as Activators of I2 During the Intermolecular
Cyclocondensation of 1a to From 5a.[a]
Activator
(equiv)
Time
(h)
3
1
3
3
3
3
3
3
4
3
3
Yield
(%)[b]
70
Entry
I2 (equiv)
1
2
3
4
5
6
7
8
9
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.25)
I2 (0.5)
I2 (0.5)
I2 (0.5)
I2 (0.5)
-
AgNO3 (0.5)
AgOTf (0.5)
AgOAc (0.5)
AgNO3 (0.25)
AgOTf (0.25)
AgOTf (0.25)
AgOAc (0.25)
AgNO3 (0.1)
AgOTf (0.1)
AgOAc (0.1)
AgOTf (0.25)
74b
32
58
70
65
54
40
62
58
NR
10
11
[a] The mixture of 1a (0.5 mmol), prepared from the reaction of 2a with one
molar equivalent of 3 in aqueous NaOH followed by filtration, I2 (0.25 mmol, 0.5
equiv), I2 in 1,4-dioxane (2 mL) was treated at 80 °C in the presence of the Ag-salt
for the indicated time period. [b] Isolated yield of 5a.
In order to assess the generality of the reaction, various
substituted 1,1-diaminoazines were subjected to the I2-
promoted tandem intermolecular nucleophile attack/
cyclocondensation/aromatization to form the corresponding 4-
arylideneamino-5-aryl-3-amino-1,2,4-triazoles (Scheme 3). The
reaction was amenable to a large variety of substituted
aromatic aldehydes (alkyl, halogen, electron donating and
withdrawing groups) in 42-72% yields. Wherein yields were
moderate (40-58%) a significant improvement of the product
yield could be achieved by using AgOTf as the activator of
iodine. The optimized reaction conditions were not found to
be suitable for the cyclization of aliphatic aldehydes.
aMethod A: 1a-v (0.5 mmol), prepared by reacting the aldehyde with one molar
equiv of 3 in aq NaOH followed by filtration, were treated with I2 (0.25 mmol, 0.5
equiv) in 1,4-dioxane (2 mL) at 80 °C. bMethod B: 1a,d,m,o-v (0.5 mmol),
prepared by reacting the aldehyde with one molar equiv of 3 in aq NaOH
followed by filtration, was treated with I2 (0.125 mmol, 0.25 equiv) in 1,4-dioxane
(2 mL) at 80 °C in the presence of AgOTf (0.25 equiv) at 80 °C
A mechanistic understanding of the progress of this I2-
promoted intermolecular cyclocondensation reaction is
depicted in Scheme 4. The iminic (CH=N) C4 carbon of
1, which
preferably exists in the azine tautomeric form , undergoes
I
electrophilic activation by the I2 through coordination with the
iminic nitrogen (N3) as it can be substantiated by increase in
the NBO charge at C4 from 0.246 to 0.312 (Figure-SI-3)
triggering nucleophilic attack by the N2 of another molecule of
Scheme 4. Proposed mechanism for I2-promoted cyclocondensation of 1 to 5.
1
(in the azine form) followed by elimination of HI and
generates the N-iodo species II. Intramolecular nucleophilic
displacement of the iodo group by the terminal NH2 group in II
with concomitant removal of one molecule of HI results in the
formation of the intermediate III. It appears that attaining
aromatic character of the central heterocyclic ring in III is the
driving force for the formation of the final product
5 from III.
Thus, the overall outcome of this tandem reaction is not
dependent on the presence of any external/additional
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J. Name., 2013, 00, 1-3 | 3
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The intermolecular nature of the reaction could be further cyclization proceeds intermolecularly. The quantVuiemw AcrthicelemOniclinael
realised by the fact that the reaction of equimolar mixture of calculation was carried out to compare the
DOI: 10.1039/Ce9nOeBr0g0e6t1i0cAs
1k and 1l resulted in the formation of four products that involved. The azines generally exist in their s-trans
resulted from the intermolecular reactions involving (i) two 1l conformation. For the intramolecular cyclization to take place,
molecules, (ii) two 1k molecules, (iii) one molecule of 1l as the an azine should adopt the s-cis stereoiosmeric structure (1A'
electrophilic partner and one molecule of 1k as the Figure 3) so that the terminal nucleophilic NH2 group can
nucleophilic partner, and iv) one molecule of 1k as the attack at the electrophilic iminic carbon (C4) of the azine 1A
electrophilic partner and one molecule of 1l as the nucleophilic Thus, the azine form (1A) needs to attain the desired s-cis
,
.
partner (Scheme 5).
conformation 1A' through rotation across N2-N3 bond.
Scheme 5. Intermolecular cyclization between two different azines (1k and 1l).
Figure 3. Energetics for the conversion of the semicarbazone, thiosemicarbazone, and
azine from their s-trans form to the s-cis form via rotation around the N2-N3 bond.
For more convincing evidence in support of the proposed
mechanistic pathway mass-spectrometric ion-fishing technique
was adopted as it has been a recognized tool for establishing
organic reaction mechanism.16 The involvement/formation of
the intermediate III (Scheme 4) could be established by the
presence of the ion peak at m/z 391.06 (MH+) (Ar = 4-
chlorophenyl) in the ESI-MS of the crude reaction mixture
obtained at different time interval (15 and 45 min) for the
model reaction (Figure-SI-1).
The energy calculation indicates that the conformer 1A' is
energetically disfavoured17 by 21.57 kcal/mol and thus an
intramolecular nucleophilic attack is not feasible for the azine
form. Whereas, the energy required to undergo
conformational change around the N-N bond in the
semicarbazone and the thiosemicarbazone is very less (0.66
kcal/mol and 1.48 kcal/mol respectively) and thus
intramolecular cyclization becomes feasible in these cases.
We observed that there is no straightforward method for
the synthesis of 4,5-disubstituted-3-amino-1,2,4-triazoles. The
limited literature reports to obtained this heterocyclic scaffold
involves the (i) treatment of robenidine free base with I2 and
H2O2,18 which contains one lone example of the target
heterocyclic compound, and (ii) imine formation with 5-aryl-
3,4-diamino-1,2,4-triazole, synthesized through a multistep
procedure.19
To further support the mechanism, additional control
experiments were carried out (Scheme 6). When 4-fluoro
substituted azine (1k) was treated with 4-fluoro/methoxy
benzaldehyde (2k/2l), in the presence (or absence) of iodine,
the triazole 5k was obtained; in both the cases, the 4-
fluoro/methoxy benzaldehyde remained unreacted (and was
isolated from the reaction mixture). This suggests that the
iminic moiety in the product triazole comes from the azine 1k
itself not from any external or in situ generated aldehyde and
supports the tandem intermolecular cyclization involving two
azine molecules (Scheme 6).
Conclusions
Scheme 6. Control experiments to support the intermolecular mechanism.
In conclusions, this work demonstrates an unprecedented
intramolecular to intermolecular mechanistic switch during the
I2-induced oxidative cyclization of guanylhydrazones that exist
perferably in the 1,1-diaminoazine from leading to the
synthesis of 4,5-disubstituted-3-amino-1,2,4-triazoles. In
contrast, the semicarbazones and thiosemicarbazones are
reported to from the corresponding 1,3,4-oxa/thiadiazoles
under similar treatment via an intramolecular mode of
cyclization.. This transition metal free protocol offers a
convenient and straight forward synthesis of 4,5-disubstituted-
3-amino-1,2,4-triazoles. The ease in the generation of the
strating azines, wider substrate scope, use of the
substoichiometric amount of iodine, lack of requirement of
external oxidizing agents, base free reaction condition and
Finally, we became interested to investigate that why the
semicarbazone
and
thiosemicarbazone
undergo
intramolecular cyclization whereas in case of the azine the
4 | J. Name., 2012, 00, 1-3
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short reaction time of this intermolecular oxidative cyclization
mark the distinct advantages.
NMR (101 MHz, DMSO-d6) δ 161.8, 138.7, 134.4, V1ie3w1A.9rti,cl1e2O9nl.i9ne,
129.3, 127.4, 127.1; LC-MS (ESI) m/z: [M+H] Calcd for
+
DOI: 10.1039/C9OB00610A
C8H10ClN4 197.0584; Found 197.01.
Methods
(E)-(3-chlorophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1c
)
Computational Methods
Yellow solid (134 mg, 96 %); 1H NMR (400 MHz, DMSO-d6) δ
The quantum chemical calculations were performed using the 7.95 (s, 1H), 7.81 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.8
Gaussian 0920 suite of programs. Geometry optimization of Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.02 (br s, 2H), 5.57 (br s, 2H).
compounds was performed by DFT21 using B3LYP22 method. 13C NMR (101 MHz, DMSO-d6) δ 161.5, 141.7, 139.9, 133.8,
The basis set used was 6-311++G(d,p). The frequency 130.6, 127.5, 125.6, 125.4; HRMS (ESI-TOF) m/z: [M+H]+
calculations were carried out on all the structures to verify Calcd for C8H10ClN4 197.0584; Found 197.0598.
stationary point with zero negative frequency. The NBO
charges were calculated.23
(E)-(2-Nitrophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1d)
24
1
White solid (131 mg, 95 %); H NMR (400 MHz, DMSO-d6) δ
8.29 (d, J = 8 Hz, 1H), 8.25 (s, 1H), 7.88 (d, J = 8 Hz, 1H), 7.62
(t, J = 8 Hz, 2H), 7.44 (t, J = 8 Hz, 2H), 6.10 (br s, 2H), 5.84
(br s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 162.2, 147.7,
137.2, 134.0, 132.9, 131.2, 128.2, 124.5; LC-MS (ESI) m/z
Chemistry
The reagents and chemicals required for the study were
procured and all the reagents were used as such without
further purification unless otherwise mentioned. The progress
of the reaction was monitored by Thin Layer Chromatography
(TLC) performed on silica gel aluminium plates and
visualization was done by UV light. 1H NMR and 13C NMR
spectra were recorded at 400 MHz and 100 MHz respectively,
[M+H]+ Calcd for C8H10N5O2
: 208.0824; Found: 208.01.
(E)-(3-Nitrophenyl)-1,1-diamino-2,3-diazabuta-1,3diene (1e
)
Yellow solid (128 mg, 93 %); 1H NMR (400 MHz, DMSO-d6) δ
8.46 (s, 1H), 8.13 (d, J = 7.7 Hz, 1H), 8.10 (s, 1H), 8.06 (d, J =
7.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 6.11 (br s, 2H), 5.70 (br s,
2H). 13C NMR (101 MHz, DMSO-d6) δ 161.8, 148.7, 140.9,
139.6, 132.5, 130.2, 122.1, 120.5; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C8H10N5O2 208.0824; Found 208.0830.
with TMS as an internal standard. The H NMR and 13C NMR
spectra were recorded for DMSO-d6 at 2.50 ppm and 39.51
ppm respectively. Chemical shift () are reported in part per
million (ppm). Coupling constants (J) were reported in hertz
(Hz). The abbreviations used to characterize the signals are as
follows: s = singlet, m = multiplet, d = doublet, br. s. = broad
singlet, dd = doublet of doublet, t = triplet. High resolution
mass spectra were recorded using ESI-TOF method. Melting
points were determined by using the melting point apparatus.
1
(E)-(4-nitrophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1f
)
Brick Red solid (129 mg, 94 %); 1H NMR (400 MHz, DMSO-d6)
δ 8.16 (d, J = 8.7 Hz, 2H), 8.06 (s, 1H), 7.92 (d, J = 8.7 Hz, 2H),
6.21 (br s, 2H), 5.87 (br s, 2H). 13C NMR (101 MHz, DMSO-d6) δ
162.4, 146.2, 144.6, 140.5, 126.9, 124.2; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C8H10N5O2 208.0824; Found 208.0831.
Experimental Section
General Procedure for the Preparation of
1
(E)-(2-bromophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1g
)
Yellow solid (124 mg, 95 %); 1H NMR (400 MHz, DMSO-d6) δ
8.13 (s, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H),
7.28 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H). 13C NMR
(101MHz, DMSO-d6) δ 161.7, 141.3, 135.7, 133.2, 129.6,
127.9, 127.5, 122.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C8H10BrN4 241.0078; Found 241.0077.
To a solution of aminoguanidine hydrochloride
3
(96 mg, 1.2
mmol) in water (2 mL), p-chlorobenzaldehyde 2a (100 mg, 1
mmol) and 1N NaOH was added, and the reaction mixture was
stirred at room temperature for 30 min. The white precipitate
was formed and the resultant precipitate was filtered and
dried to afford the 1a in 99 % yield. This representative
procedure was employed for the synthesis of 1a-v.
(E)-(3-bromophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1h
)
Off-white solid (120 mg, 92 %); 1H NMR (400 MHz, DMSO-d6)
δ 7.95 (s, 2H), 7.61 (s, 1H), 7.34 (m, 2H), 6.02 (br s, 2H), 5.57
(br s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.5, 141.6, 140.2,
130.9, 130.4, 128.5, 125.8, 122.51; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C8H10BrN4 241.0078; Found 241.0080.
(E)-(4-chlorophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1a
)
White solid (139 mg, 99 %); 1H NMR (400 MHz, DMSO-d6) δ
7.97 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H),
5.95 (br s, 2H), 5.53 (br s, 2H). 13C NMR (101 MHz, DMSO-d6) δ
161.3, 142.0, 136.5, 132.2, 128.8, 128.2; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C8H10ClN4 197.0584; Found 197.0587.
(E)-(4-bromophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1i
)
Yellow solid (128 mg, 98 %); 1H NMR (400 MHz, DMSO-d6) δ
8.28 (d, J = 7.6 Hz, 1H), 8.22 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H),
7.62 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 6.13 (br s, 2H),
5.87 (br s, 2H); 13C NMR (101 MHz, DMSO) δ 162.3, 147.6,
(E)-(2-chloroophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene
24
(1b)
Brown solid (137 mg, 98 %); 1H NMR (400 MHz, DMSO-d6) δ
8.27 (s, 1H), 8.15 (dd, J = 7.4, 2.1 Hz, 1H), 7.40 (dd, J = 7.5, 1.7
Hz, 1H), 7.29 – 7.24 (m, 2H), 6.07 (br s, 2H), 5.70 (br s, 2H). 13C
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137.1, 132.9, 131.2, 128.2, 124.5; HRMS (ESI-TOF) m/z: White solid (129 mg, 94 %); 1H NMR (400 MHz,VDiewMASrtOicl-edO6n)linδe
[M+H]+ Calcd for C8H10BrN4 241.0078; Found 241.0073.
(E)-(2-fluorophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1j
7.94 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 6.D88OI:(d10,.1J0=398/C.29OHBz0,0621H0)A,
5.82 (br s, 2H), 5.38 (br s, 2H), 4.03 (q, J = 6.7 Hz, 2H), 1.33 (t, J
)
Off-white solid (137 mg, 94 %); 1H NMR (400 MHz, DMSO-d6) = 6.9 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.5, 158.9,
δ
8.12 (s, 1H), 8.07 (td, J = 7.7, 1.5 Hz, 1H), 7.32-7.26 (m, 1H), 143.7, 130.0, 128.0, 114.7, 63.5, 15.1; HRMS (ESI-TOF) m/z:
7.21-7.06 (m, 2H), 6.02 (br s, 1H), 5.65 (br s, 1H); 13C NMR [M+H]+ Calcd for C10H15N4O 207.1235; Found 207.1255.
(101 MHz, DMSO) δ 161.5, 160.3 (d, 1JC-F = 253 Hz), 135.2,
129.5 (d, 3JC-F = 8 Hz), 126.7 (d, 4JC-F = 3 Hz), 124.8 (d, (E)-(3-nitro-4-chlorophenyl)-1,1-diamino-2,3-diazabuta-1,3-
3JC-F = 10 Hz), 124.7 (d, 4JC-F = 4 Hz), 115.9 (d, 2JC-F = 21 diene (1q
Hz)
19F NMR (376 MHz, DMSO-d6) δ –122.9. HRMS (ESI- Yellow solid (120 mg, 92 %); 1H NMR (400 MHz, DMSO-d6) δ
TOF) m/z: [M+H]+ Calcd for C8H10FN4 181.0879; Found 8.40 (d, J = 1.2 Hz, 1H), 8.00 (s, 1H), 7.92 (dd, J = 8.4, 1.3 Hz,
)
;
181.0887.
1H), 7.68 (d, J = 8.4 Hz, 1H), 6.19 (br s, 2H), 5.73 (br s, 2H). 13
C
NMR (101 MHz, DMSO-d6) δ 162.1, 148.7, 139.3, 138.7, 131.7,
(E)-(4-fluorophenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1k
)
130.9, 122.5, 121.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
Yellow solid (142 mg, 97 %); 1H NMR (400 MHz, DMSO-d6) δ C8H9ClN5O2 242.0434; Found 242.0452.
7.96 (s, 1H), 7.70 (dd, J = 8.6, 5.8 Hz, 2H), 7.15 (t, J = 8.9 Hz,
2H). 13C NMR (101 MHz, DMSO-d6) δ 162.2 (d, 1JC-F = 243 (E)-(3-nitro-4-methyl-phenyl)-1,1-diamino-2,3-diazabuta-1,3-
Hz), 161.5, 141.61, 134.3, 128.2 (d, 3JC-F = 8 Hz), 115.6 (d, diene (1r
)
2JC-F = 21 Hz);
19F NMR (376 MHz, DMSO-d6) δ –114.2. Yellow solid (123 mg, 92 %); 1H NMR (400 MHz, DMSO-d6) δ
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H10FN4 181.0879
Found 181.0889.
;
8.22 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.0
Hz, 1H), 6.11 (br s, 2H), 5.65 (br s, 2H), 2.48 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 161.7, 149.9, 140.7, 137.3, 133.1,
131.3, 130.6, 121.4, 19.6; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C9H12N5O2 222.0981; Found 222.0995.
(E)-(4-methoxyphenyl)-1,1-diamino-2,3-diazabuta-1,3-diene
(1l)
White solid (139 mg, 98 %); 1H NMR (400 MHz, DMSO-d6) δ
7.95 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), (E)-(2-nitro-4-dimethylaminophenyl)-1,1-diamino-2,3-
5.83 (br s, 2H), 5.39 (br s, 2H), 3.76 (s, 3H); 13C NMR (101 MHz, diazabuta-1,3-diene (1s
)
DMSO-d6) δ 160.5, 159.6 143.6, 130.1, 128.0, 114.3, 55.6; Brick Red solid (118 mg, 92 %); 1H NMR (400 MHz, DMSO-d6)
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C9H13N4O 193.1079
Found 193.1097.
;
δ 8.07 (s, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H),
6.97 (dd, J = 9.0, 2.4 Hz, 1H), 5.86 (br s, 2H), 5.52 (br s, 2H),
2.99 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 161.0, 150.0,
149.3, 138.4, 129.1, 117.7, 116.4, 105.8, 40.2; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C10H15N6O2 251.1246; Found
(E)-(2-methylphenyl)-1,1-diamino-2,3-diazabuta-1,3-diene
(1m)
White solid (136 mg, 92 %); 1H NMR (400 MHz, DMSO-d6) δ 251.1254.
8.22 (s, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 2.5 Hz, 3H),
2.38 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.9, 142.1, (E)-(4-benzyloxyphenyl)-1,1-diamino-2,3-diazabuta-1,3-diene
135.4, 135.1, 130.9, 127.8, 126.1, 126.1, 19.9; HRMS (ESI-
(1t)
TOF) m/z: [M+H]+ Calcd for C9H13N4 177.1130; Found Yellow solid (118 mg, 94 %); 1H NMR (400 MHz, DMSO-d6) δ
177.1136.
7.89 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H),
7.40 (t, J = 8 Hz, 2H), 7.35 – 7.31 (m, 1H), 6.97 (d, J = 8.7 Hz,
2H), 5.11 (s, 2H); 13C NMR (101 MHz, DMSO-d6) δ 161.4,
(E)-(4-methylphenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1n
)
Yellow solid (139 mg, 94 %) 1H NMR (400 MHz, DMSO-d6) δ 158.4, 142.1, 137.5, 131.0, 130.7, 130.7, 128.9, 128.3, 128.2,
7.96 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 127.7, 115.2, 69.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
5.88 (br s, 2H), 5.48 (br s, 2H), 2.30 (s, 3H); 13C NMR (101 MHz, C15H17N4O 269.1392; Found 269.1399.
DMSO-d6) 160.8, 143.7, 137.5, 134.72, 129.4, 126.6, 21.4;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C9H13N4 177.1130; (E)-(1-napthyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1u
)
Found 177.1136.
Yellow solid (125 mg, 92 %); 1H NMR (400 MHz, DMSO-d6) δ
8.74 (s, 1H), 8.67 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 7.2 Hz, 1H),
7.94 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.54 (m, J =
17.2, 7.2 Hz, 3H), 5.95 (br s, 2H), 5.61 (br s, 2H). 13C NMR (101
(E)-(4-dimethylaminophenyl)-1,1-diamino-2,3-diazabuta-1,3-
diene (1o
)
Yellow solid (128 mg, 93 %); 1H NMR (400 MHz, DMSO-d6) δ MHz, DMSO-d6) δ 161.1, 142.5, 134.0, 132.6, 130.7, 128.9,
7.86 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 6.68 (d, J = 8.6 Hz, 2H), 128.3, 126.9, 126.2, 126.0, 125.4, 124.5; HRMS (ESI-TOF)
2.91 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 160.5, 150.5, m/z: [M+H]+ Calcd for C12H13N4 213.1130; Found 213.1141.
143.6, 127.6, 125.7, 112.5, 40.6; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C10H16N5 206.1395; Found 206.1397.
(E)-(2-napthyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1v)
Yellow solid (126 mg, 93%); 1H NMR (400 MHz, DMSO-d6) δ
(E)-(4-ethoxyphenyl)-1,1-diamino-2,3-diazabuta-1,3-diene (1p
)
8.16 (s, 1H), 8.09 (dd, J = 8.6, 1.0 Hz, 1H), 7.94 (s, 1H), 7.88-
6 | J. Name., 2012, 00, 1-3
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ARTICLE
1
7.83 (m, 3H), 7.51-7.44 (m, 2H), 6.02 (br s, 2H), 5.59 (br s, Grey solid (57 mg, yield: 68%), mp 184−186 °C; H NMR (400
View Article Online
2H); 13C NMR (101 MHz, DMSO-d6) δ 161.2, 143.6, 135.4, MHz, DMSO-d6): δ 8.80 (s, 1H), 7.82 (d , J = 8 Hz, 2H), 7.81 (s,
DOI: 10.1039/C9OB00610A
133.7, 133.3, 128.2, 128.1, 126.7, 126.6, 126.2, 124.0; HRMS 1H), 7.72-7.67 (m, 2H), 7.59 (t, J = 8 Hz, 1H), 7.50- 7.49 (m, 2H),
(ESI-TOF) m/z: [M+H]+ Calcd for C12H13N4 213.1130; Found 6.35 (s, 2H, -NH2); 13C NMR (101 MHz, DMSO-d6): δ 163.4,
213.1136.
152.3, 145.6, 135.1, 134.2, 133.7, 132.5, 131.4, 131.1, 130.0,
129.2, 128.5, 127.7, 127.2, 126.1; FTIR (cm-1) ν 3311, 3127,
2921, 2852, 1658, 1561, 1476, 1242; HRMS (ESI-TOF) m/z:
General procedure for the preparation of 5 (Method A)
The reactions were carried out by treating of 1a (100 mg, 0.5 [M+H]+ Calcd for C15H12Cl2N5 332.0459; Found 332.0484.
mmol, 1 equiv) with I2 (32mg, 0.25 mmol, 0.5 equiv) in 1,4-
dioxane at 80 ˚C for 3 h. The progress of the reaction was (E)-4-((2-nitrobenzylidene)amino)-5-(2-nitrophenyl)-4H-1,2,4-
monitored by TLC. After the completion of reaction, the triazol-3-amine (5d
)
solvent was evaporated under reduced pressure and the I2 was Yellow solid (Method A: 49 mg, 58%; Method B: 54 mg, 64%),
1
quenched by aq. solution of Na2S2O8. 5H2O and the aqueous mp 216−218 °C; H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H),
part was extracted with EtOAc (3 × 15 mL). The combined 8.42 – 7.30 (m, 8H), 6.28 (s, 2H); 13C NMR (101 MHz, DMSO-
EtOAc extracts were dried (anh. Na2SO4), filtered, d6): δ 163.7, 159.5, 158.5, 151.7, 144.9, 132.0, 131.6, 131.3,
concentrated under vacuo, and the residue was subjected to 131.0, 130.5, 129.0, 126.6, 126.1, 122.3, 122.2; FTIR (cm-1) ν
column chromatography (eluent MeOH/DCM = 10:90) to 3331, 3153, 2921, 1655, 1589, 1474, 1071; HRMS (ESI-TOF)
obtain 5a in 72 % yield. This representative procedure was m/z: [M+H]+ Calcd for C15H12N7O4 354.0940; Found 354.0964.
employed for the synthesis of 5a-v.
(E)-4-((3-nitrobenzylidene)amino)-5-(3-nitrophenyl)-4H-1,2,4-
General procedure for preparation of
5
(Method B)
triazol-3-amine (5e)
Yellow solid (50 mg, 59%), mp 211−213 °C; H NMR (400 MHz,
1
The reactions were carried out by treating 1a
,d,
m
,o-
v
(0.5 DMSO-d6): δ 9.06 (s, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.44 (d, J =
mmol) with I2 (0.125 mmol, 0.25 equiv) and AgOTf (0.125 8 Hz, 1H), 8.35 (d, J = 8 Hz, 1H), 8.29- 8.25 (m, 2H), 7.86 (t, J =
mmol, 0.25 equiv) in 1,4-dioxane at 80 ˚C for 2-6 h. The 8, 1H), 7.77 (t, J = 8, 1H), 6.54 (s, 2H, -NH2); 13C NMR (101 MHz,
progress of reaction was monitored by TLC. After the DMSO-d6): δ 162.4, 152.3, 148.6, 148.3, 145.5, 134.7, 134.6,
completion of reaction, the solvent was evaporated under 133.5, 131.2, 130.8, 129.4, 128.2, 127.1, 123.9, 121.9; FTIR
reduced pressure and the I2 was quenched by aq solution of (cm-1) ν 3096, 1698, 1613, 1571, 1530, 1347; HRMS (ESI-TOF)
Na2S2O8. 5H2O and the aqueous part was extracted with EtOAc m/z: [M+H]+ Calcd for C15H12N7O4 354.0940; Found 354.0947.
(3 × 10 mL). The combined EtOAc extracts were dried (anh
Na2SO4), filtered, concentrated under vacuo, and the residue (E)-4-((4-nitrobenzylidene)amino)-5-(4-nitrophenyl)-4H-1,2,4-
was subjected to column chromatography (eluent MeOH/DCM triazol-3-amine (5f
)
1
= 10:90) to obtain 5a
,
d,
m,
o-
v.
Yellow solid (51mg, 60%), mp 220−223 °C; H NMR (400 MHz,
DMSO-d6): δ 9.03 (s, 1H), 8.39 (d, J = 8 Hz, 2H), 8.32 (d, J = 8
Hz, 2H), 8.17 (d, J = 8 Hz, 2H), 8.08 (d, J = 8 Hz, 2H), 6.61 (s, 2H,
-NH2); 13C NMR (101 MHz, DMSO-d6): δ 162.5, 152.5, 149.8,
(E)-4-((4-chlorobenzylidene)amino)-5-(4-chlorophenyl)-4H-
1,2,4-triazol-3-amine (5a
)
White solid (Method A: 61 mg, 72%; Method B: 63 mg, 74%), 147.6, 145.9, 138.8, 133.9, 130.4, 128.4, 124.5, 124.4; FTIR
1
mp 181−183 °C; H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), (cm-1) ν 3426, 2922, 2851, 1643, 1560, 1510, 1341; HRMS (ESI-
7.89 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H), 7.63 (d, J = 8 Hz, TOF) m/z: [M+H]+ Calcd for C15H12N7O4 354.0940; Found
2H), 7.53 (d, J = 8 Hz, 2H), 6.27 (s, 2H, -NH2); 13C NMR (101 354.0967.
MHz, DMSO-d6): δ 163.9, 152.2, 146.1, 137.5, 134.0, 131.9,
130.8, 129.6, 129.3, 129.2, 126.9; FTIR (cm-1) ν 3122, 2923, (E)-4-((2-bromobenzylidene)amino)-5-(2-bromophenyl)-4H-
2855, 1652, 1593, 1480, 1433; HRMS (ESI-TOF) m/z: [M+H]+ 1,2,4-triazol-3-amine (5g
)
1
Calcd for C15H12Cl2N5 332.0459; Found 332.0487.
Brown solid (57 mg, 65%), mp 172−174 °C; H NMR (400 MHz,
DMSO-d6): δ 8.35 (s, 1H), 8.27 (dd, J = 1.7, 7.7 Hz, 1H), 7.81 (d,
J = 8 Hz, 1H), 7.66 (t, J = 8 Hz , 1H), 7.64-7.57 (m, 2H), 7.52-7.46
(m, 2H), 7.45-7.40 (m, 1H), 6.45 (s, 2H, -NH2); 13C NMR (101
(E)-4-((2-chlorobenzylidene)amino)-5-(2-chlorophenyl)-4H-
1,2,4-triazol-3-amine (5b
)
Yellow solid (55 mg, 65%), mp 179−181 °C; 1H NMR (400 MHz, MHz, DMSO-d6): δ 154.2, 153.3, 143.4, 134.0, 133.7, 133.6,
DMSO-d6): δ 8.40 (s, 1H), 8.26 (d, J = 8Hz, 1H), 7.69-7.43 (m, 133.3, 132.6, 131.8, 130.5, 129.0, 128.8, 128.6, 124.9, 123.7;
7H), 6.45 (s, 2H, -NH2); 13C NMR (101 MHz, DMSO-d6): δ 154.1, FTIR (cm-1) ν 3402, 3148, 3031, 1661, 1622, 1562, 1462, 1319;
151.9, 142.4, 134.7, 133.9, 133.1, 132.5, 131.1, 130.3, 130.4, HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H12Br2N5 421.9429;
130.2, 128.5, 128.4, 128.2, 128.1; FTIR (cm-1) ν 3403, 3064, Found 421.9448.
1731, 1625, 1590, 1466, 1434, 1325; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C15H12Cl2N5 332.0459; Found 332.0487.
(E)-4-((3-bromobenzylidene)amino)-5-(3-bromophenyl)-4H-
1,2,4-triazol-3-amine (5h
Brown solid (53 mg, 61%), mp 179−181 °C; H NMR (400 MHz,
DMSO-d6): δ 8.80 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.86 (d, J =
)
1
(E)-4-((3-chlorobenzylidene)amino)-5-(3-chlorophenyl)-4H-
1,2,4-triazol-3-amine (5c
)
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8Hz, 1H), 7.80 (d, J = 8 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.63 (d, J
= 8 Hz, 1H), 7.52 (t, J = 8 Hz, 1H), 7.43 (t, J = 8 Hz, 1H), 6.36 (s, (E)-4-((2-methylbenzylidene)amino)-5-(oD-tOoIl:y1l0)-.140H3-91/C,29,O4B-00610A
2H, -NH2); 13C NMR (101 MHz, DMSO-d6): δ 163.3, 152.3, triazol-3-amine (5m
View Article Online
)
145.5, 135.4, 135.3, 132.0. 131.6, 131.4, 131.3, 130.2, 130.1, White solid (Method A: 51 mg, 62%; Method B: 55 mg, 67%),
1
128.1, 126.4, 122.6, 122.2; FTIR (cm-1) ν 3301, 3125, 2916, mp 165−167 °C; H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H),
1626, 1556, 1473, 1345; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for 7.99 (d, J = 8Hz, 1H), 7.43-7.40 (m, 2H), 7.36-7.31 (m, 3H), 7.27
C15H12Br2N5 421.9429; Found 421.9449.
(t, J = 8Hz, 1H), 7.18 (d, J = 8Hz, 1H), 6.20 (s, 2H, -NH2), 2.15 (s,
3H), 1.88 (s, 3H); 13C NMR (101 MHz, DMSO-d6): δ 159.0,
153.2, 144.5, 143.0, 139.0, 137.5, 132.2, 131.3, 131.0, 130.9,
130.8, 130.1, 128.5, 127.2, 126.7, 19.8, 18.5; FTIR (cm-1) ν
(E)-4-((4-bromobenzylidene)amino)-5-(4-bromophenyl)-4H-
1,2,4-triazol-3-amine (5i
)
1
Brown solid (58 mg, 67%), mp 186−188 °C; H NMR (400 MHz, 3397, 3154, 2922, 2852, 1623, 1565, 1476, 1455, 1259; HRMS
DMSO-d6): δ 8.84 (s, 1H), 8.20 (d, J = 8H, 1H), 8.12 (d, J = 8H, (ESI-TOF) m/z: [M+H]+ Calcd for C17H18N5 292.1552; Found
2H), 8.09 – 7.75 (m, 5H), 6.50 (s, 2H, -NH2); 13C NMR (101 292.1576.
MHz, DMSO-d6): δ 154.8, 152.9, 149.0, 148.5, 143.5, 134.8,
134.5, 133.1, 133.0, 132.0, 129.2, 127.4, 125.4, 125.3, 122.6; (E)-4-((4-methylbenzylidene)amino)-5-(p-tolyl)-4H-1,2,4-
FTIR (cm-1) ν 3443, 3284, 2922, 2852, 1621, 1519, 1341; HRMS triazol-3-amine (5n
)
1
(ESI-TOF) m/z: [M+H]+ Calcd for C15H12Br2N5 421.9429; Found White solid (51 mg, 62%), mp 161−163 °C; H NMR (400 MHz,
421.9446.
DMSO-d6): δ 8.70 (s, 1H), 7.75 (d, J = 8 Hz, 2H), 7.61 (d, J = 8
Hz, 2H), 7.65 (d, J = 8 Hz, 2H), 7.24 (d, J = 8 Hz, 2H), 6.09 (s, 2H,
-NH2), 2.38 (s, 3H), 2.32 (s, 3H); 13C NMR (101 MHz, DMSO-d6):
δ 165.3, 152.1, 146.8, 143.2, 138.8, 130.3, 130.0, 129.6, 129.2,
(E)-4-((2-fluorobenzylidene)amino)-5-(2-fluorophenyl)-4H-
1,2,4-triazol-3-amine (5j
)
White solid (54 mg, 65%), mp 177−179 °C; H NMR (400 MHz, 127.6, 125.5, 21.7, 21.3; FTIR (cm-1) ν 3116 , 1627, 1603, 1563,
DMSO-d6): δ 8.57 (s, 1H), 8.06 (t, J = 8Hz, 1H), 7.67-7.63 (m, 1489, 1275, 1177; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
1H), 7.62-7.56 (m, 2H), 7.39-7.27 (m, 4H), 6.37 (s, 2H, -NH2); C17H18N5 292.1552; Found 292.1577.
13C NMR (101 MHz, DMSO-d6): δ 164.3, 161.8 (d, 1JC-F = 251
1
Hz), 158.1, 153.3, 152.9 (d, 4JC-F = 4 Hz), 141.5, 134.8 (d, 3JC-F (E)-4-((4-(dimethylamino)benzylidene)amino)-5-(4-
= 8 Hz), 132.7 (d, 3JC-F = 8 Hz), 132.0 (d, 4JC-F = 3 Hz), 128.0, (dimethylamino)phenyl)-4H-1,2,4-triazol-3-amine (5o
)
125.5, 120.6 (d, 3JC-F = 9 Hz), 116.66 (d, 2JC-F = 20 Hz), 116.65, Brown solid (Method A: 48 mg, 56%; Method B: 52 mg, 61%),
116.5 (d, 2JC-F = 21 Hz); FTIR (cm-1) ν 3109, 2922, 1638, 1610, mp 159−161 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H),
1567, 1455, 1225; 19F NMR (376 MHz, DMSO-d6) δ –113.3, – 7.68 (d, J = 8 Hz, 2H), 7.56 (d, J = 8 Hz, 2H), 6.79 (d, J = 8 Hz,
118.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H12F2N5 2H), 6.72 (d, J = 8 Hz, 2H), 5.78 (s, 2H, -NH2), 3.02 (s, 6H), 2.91
300.1050; Found 300.1076.
(s, 6H); 13C NMR (101 MHz, DMSO-d6): δ 166.6, 153.5, 151.8,
150.7, 146.9, 130.9, 128.3, 119.8, 115.8, 112.1, 111.9, 40.2;
FTIR (cm-1) ν 3312, 2923, 2853, 1687, 1611, 1586, 1529, 1364,
1179; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C19H24N7
(E)-4-((4-fluorobenzylidene)amino)-5-(4-fluorophenyl)-4H-
1,2,4-triazol-3-amine (5k
)
1
Yellow solid (56 mg, 68%), mp 172−174 °C; H NMR (400 MHz, 350.2083; Found 350.2101.
DMSO-d6): δ 8.79 (s, 1H), 7.96-7.92 (m, 2H), 7.81-7.77 (m,
2H), 7.39 (t, J = 8 Hz, 2H), 7.30 (t, J = 8 Hz, 2H), 6.19 (s, 2H, - (E)-4-((4-ethoxybenzylidene)amino)-5-(4-ethoxyphenyl)-4H-
NH2); 13C NMR (101 MHz, DMSO-d6): δ 164.9 (d, 1JC-F = 249 1,2,4-triazol-3-amine (5p
)
Hz), 164.1, 162.7 (d, 1JC-F = 239 Hz), 152.1, 146. 2, 131.7 (d, White solid (Method A: 46 mg, 54%; Method B: 53 mg, 62%),
1
3JC-F = 9 Hz), 129.9 (d, 3JC-F = 9 Hz), 129.6 (d, 4JC-F = 3 Hz), mp 146−148 °C; H NMR (400 MHz, d6-DMSO): δ 8.64 (s, 1H),
124.7 (d, 4JC-F = 4 Hz), 116.6 (d, 2JC-F = 22 Hz), 116.1 (d, 2JC-F 7.81 (d, J = 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H), 7.07 (d, J = 8 Hz,
= 22 Hz); FTIR (cm-1) ν 3122, 2922, 2853, 1658, 1601, 1584, 2H), 6.98 (d, J = 8 Hz, 2H), 5.99 (s, 2H, -NH2), 4.12 (q, J = 8 Hz,
1488, 1232; 19F NMR (376 MHz, DMSO-d6) δ –106.8, –112.1; 2H), 4.04 (q, J = 8 Hz, 2H), 1.37-1.30 (m. 6H); 13C NMR (101
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H12F2N5 300.1050; MHz, d6-DMSO): δ 165.4, 162.4, 159.3, 131.2, 129.0, 125.34,
Found 300.1076.
125.33, 120.6, 120.5, 115.3, 114.9, 63.9, 63.6, 15.0, 14.9; FTIR
(cm-1) ν 3070, 2979, 2925, 1604, 1574, 1493, 1247; HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C19H22N5O2 352.1763; Found
352.1781.
(E)-4-((4-methoxybenzylidene)amino)-5-(4-methoxyphenyl)-
4H-1,2,4-triazol-3-amine (5l
Yellow solid (51 mg, yield: 61%), mp 158−160 °C; H NMR (400
MHz, DMSO-d6): δ 8.67 (s, 1H), 7.83 (d, J = 8 Hz, 2H), 7.67 (d, (E)-4-((4-chloro-3-nitrobenzylidene)amino)-5-(4-chloro-3-
)
1
J = 8 Hz, 2H), 7.09 (d, J = 8 Hz, 2H), 7.00 (d, J = 8 Hz, 2H), 6.01 nitrophenyl)-4H-1,2,4-triazol-3-amine (5q
)
(s, 2H, -NH2), 3.84 (s, 3H), 3.77 (s, 3H); 13C NMR (101 MHz, Brown solid (Method A: 53 mg, 51%; Method B: 60 mg, 58%),
DMSO-d6): δ 165.3, 163.1, 160.0, 152, 146.6, 131.1, 129.1, mp 179−181 °C; 1H NMR (400 MHz, d6-DMSO): δ 8.96 (s, 1H),
125.5, 120.7, 114.9, 114.5, 56.0, 55.7; FTIR (cm-1) ν 3306, 3077, 8.57 (s, 1H), 8.49 (s, 1H), 8.19 (d, J = 6.4 Hz, 1H), 8.09 (d, J = 6
2839, 1653, 1603, 1564, 1490, 1249; HRMS (ESI-TOF) m/z: Hz, 1H), 7.98 (d, J = 8 Hz, 1H), 7.86 (d, J = 8 Hz, 1H), 6.59 (s, 2H,
[M+H]+ Calcd for C17H18N5O2 324.1450; Found 324.1457.
-NH2); 13C NMR (101 MHz, d6-DMSO): δ 161.1, 152.4, 148.3,
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
Journal Name
ARTICLE
147.9, 144.7, 133.5, 133.4, 132.9, 132.6, 132.3, 128.8, 127.9, (E)-5-(naphthalen-2-yl)-4-((naphthalen-2-ylmethylVeineweA)artmicleinOonl)in-e
125.8, 125.7, 124.3; FTIR (cm-1) ν 3084, 1604, 1531, 1471, 4H-1,2,4-triazol-3-amine (5v
)
DOI: 10.1039/C9OB00610A
1346, 1048; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for White solid (Method A: 36 mg, 42%; Method B: 41 mg, 48%),
1
C15H10Cl2N7O4 422.0161; Found 422.0179.
mp 162−164 °C; H NMR (400 MHz, d6-DMSO): δ 8.97 (s, 1H),
8.35 (d, J = 12Hz, 2H), 8.14 (d, J = 8Hz, 1H), 8.07 (d, J = 8Hz,
2H), 8.03-7.98 (m, 2H), 7.94-7.93 (m, 3H), 7.68-7.59 (m, 2H),
7.57-7.53 (m, 2H), 6.30 (s, 2H, -NH2); 13C NMR (101 MHz, d6-
(E)-4-((4-methyl-3-nitrobenzylidene)amino)-5-(4-methyl-3-
nitrophenyl)-4H-1,2,4-triazol-3-amine (5r
)
Yellow solid (Method A: 45 mg, 53%; Method B: 51 mg, 60%), DMSO): δ 165.0, 152.5, 146.8, 135.2, 133.2, 133.1, 132.9,
1
mp 174−176 °C; H NMR (400 MHz, d6-DMSO): δ 8.96 (s, 1H), 132.5, 130.7, 129.3, 129.2, 128.8, 128.7, 128.6, 128.3, 128.1,
8.48-8.42 (m, 2H), 8.13 (t, J = 8Hz, 1H), 8.04 (d, J = 8Hz, 1H), 127.6, 127.3, 127.2, 126.9, 125.7, 125.2, 123.3; FTIR (cm-1) ν
7.70 (d, J = 8Hz, 1H), 7.60 (d, J = 8Hz, 1H), 6.45 (s, 2H, -NH2), 3315, 2922, 2854, 1630, 1468, 1263, 1020; HRMS (ESI-TOF)
2.61 (s, 3H). 2.56 (s, 3H); 13C NMR (101 MHz, d6-DMSO): δ m/z: [M+H]+ Calcd for C23H18N5 364.1552; Found 364.1571.
162.3, 152.2, 151.5, 149.6, 149.3, 145.3, 137.4, 134.1, 133.9,
133.8, 132.5, 132.3, 131.7, 127.0, 125.1, 123.1, 20.1; FTIR (cm-
Acknowledgements
1) ν 3118, 2923, 2855, 1613, 1532, 1342, 1249; HRMS (ESI-TOF)
The author DK acknowledges financial support from the INSPIRE
m/z: [M+H]+ Calcd for C17H16N7O4 382.1253; Found 382.1280.
program of Department of Science and Technology (DST), New
Delhi. Author’s also acknowledges the support from DST and DAAD.
(E)-4-((4-(dimethylamino)-2-nitrobenzylidene)amino)-5-(4-
(dimethylamino)-2-nitrophenyl)-4H-1,2,4-triazol-3-amine (5s
)
Supporting Information
Yellow solid (Method A: 46 mg, 52%; Method B: 50.5 mg,
57%), mp 181−183 °C; 1H NMR (400 MHz, d6-DMSO): δ 8.60 (s,
1H), 7.91(d, J = 8Hz, 1H), 7.46 (d, J = 2Hz, 1H), 7.27 (s, 1H), 7.14
(s, 1H), 7.07 (t, J = 8 Hz, 2H), 6.17 (s, 2H, -NH2), 3.06 (s, 6H),
3.04 (s, 6H); 13C NMR (101 MHz, d6-DMSO): δ 155.3, 152.6,
152.2, 151.7, 151.3, 149.8, 144.2, 133.2, 129.4, 116.3, 115.8,
112.1, 108.9, 106.9, 106.2, 40.2; FTIR (cm-1) ν 3424, 2921,
2852, 1615, 1505, 1524, 1338, 1277; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C19H22N9O4 440.1784; Found 440.1798.
Scanned spectra (1H NMR, 13C NMR and HRMS) for all the new
compounds, complete crystallographic data of 5k (CCDC No.
1828789) (CIF), compSSutational data and mechanistic studies. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Conflicts of interest
“There are no conflicts to declare”.
(E)-4-(5-amino-4-((4-(benzoyloxy)benzylidene)amino)-4H-
1,2,4-triazol-3-yl)phenyl benzoate (5t
)
References
White solid (Method A: 43 mg, 48%; Method B: 49 mg, 55%),
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mp 161−163 °C; H NMR (400 MHz, d6-DMSO): δ 8.88 (s, 1H),
8.13 (d, J = 8Hz, 1H), 8.05-8.02 (m, 2H), 7.97 (d, J = 8Hz, 1H),
7.92 (d, J = 8Hz, 1H), 7.90-7.87 (m, 1H), 7.78 (d, J = 8 Hz, 1H),
7.66 (t, J = 8Hz, 1H), 7.56-7.47 (m, 4H), 7.43 (d, J = 8Hz, 1H),
7.30 (t, J = 8Hz, 1H), 6.37 (s, 2H, -NH2); 13C NMR (101 MHz, d6-
DMSO): δ 160.5, 153.2, 144.7, 133.8, 133.5, 132.9, 131.3,
130.7, 130.4, 129.6, 129.2, 129.0, 128.9, 128.2, 127.7, 127.0,
126.8, 126.0, 125.9, 125.8, 125.7, 123.5; FTIR (cm-1) ν 3307,
2923, 2853, 1630, 1464, 1259, 1016; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C23H18N5 364.1552; Found 364.1557.
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This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
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ARTICLE
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15 Crystal data for 5k: C15H11F2N5, M = 299.28, Monoclinic,
space group I2/a, a = 25.282(2) Å, b = 3.7619(2) Å, c =
35.085(3) Å, α = 90°, β = 92.481(7)°, γ = 90°, V = 3333.7(4)
Å3, Z = 8, Dc =1.1925 g/cm3,
 (Mo-K) = 0.091 mm-1, T =
293 K, 11768 reflections collected. Refinement of 1166
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1828789.
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Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00610A
Table of Content
Intermolecular Cyclization
N
NH2
Ar
N
N
Ar
N
NH2
N
NH2
NH2
N
Ar
N
N
I2, 1,4-dioxane
NH2
Azine
Ar
Formation of 4,5-disubstituted-3-amino-1,2,4-triazoles via the intermolecular cyclization of 1,1-diaminoazine