Substrate Controlled Synthesis of Benzisoxazole and Benzisothiazole Derivatives via PhI(OAc)2-Mediated Oxidation Followed by Intramolecular Oxidative O-N/S-N Bond Formation

Article abstract of DOI:10.1021/acs.joc.5b02276

A phenyliodine(III) diacetate (PIDA)-mediated, highly efficient and tandem approach for the synthesis of aryldiazenylisoxazolo(isothiazolo)arenes from simple 2-amino-N′-arylbenzohydrazides has been developed. The reaction proceeds via formation of (E)-(2-aminoaryl)(aryldiazenyl)methanone as the key intermediate, followed by intramolecular oxidative O-N/S-N bond formation in one pot at room temperature. The quiet different reactivity of the substrate is due to the formation of a diazo intermediate which encounters a nucleophilic attack by carbonyl oxygen on the electrophilic amine to produce isoxazole products, as compared to the previous reportsa,b,4 in which an N-acylnitrenium ion intermediate is intramolecularly trapped by an amine group.

Full text of DOI:10.1021/acs.joc.5b02276

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Article
Substrate Controlled Synthesis of Benzisoxazole and
Benzisothiazole derivatives via PhI(OAc)2-Mediated Oxidation
followed by Intramolecular Oxidative O-N/S-N Bond Formation
Devireddy Anand, Om P. S. Patel, Rahul Kumar Maurya, Ruchir Kant, and Prem Prakash Yadav
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02276 • Publication Date (Web): 13 Nov 2015
Downloaded from http://pubs.acs.org on November 14, 2015
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Substrate Controlled Synthesis of Benzisoxazole and Benzisothiazole
derivatives via PhI(OAc)2ꢀMediated Oxidation followed by Intramolecular
Oxidative OꢀN/SꢀN Bond Formation
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Devireddy Anand,†,§ Om P. S. Patel,†,§ Rahul K. Maurya,† Ruchir Kant,‡ Prem P. Yadav*, †
†Medicinal and Process Chemistry Division; CSIRꢀCentral Drug Research Institute,
Lucknowꢀ226031, India
Eꢀmail: pp_yadav@cdri.res.in, ppy_cdri@yahoo.co.in
‡Molecular and Structural Biology Division, CSIRꢀCentral Drug Research Institute, Lucknowꢀ
226031, India
ABSTRACT: A phenyliodine(III) diacetate (PIDA)ꢀmediated, highly efficient and tandem
approach for the synthesis of aryldiazenylisoxazolo(isothiazolo)arenes from simple 2ꢀaminoꢀN´ꢀ
arylbenzohydrazides has been developed. The reaction proceeds via formation of (E)ꢀ(2ꢀ
aminoaryl)(aryldiazenyl)methanone as the key intermediate followed by intramolecular oxidative
OꢀN/SꢀN bond formation in one pot at room temperature. The quiet different reactivity of the
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substrate is due to the formation of diazo intermediate which encounters a nucleophilic attack by
carbonyl oxygen on elctrophilic amine to produce isoxazole products as compare to the previous
reports1a,1b,4 in which Nꢀacylnitrenium ion intermediate is intramolecularly trapped by amine
group.
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INTRODUCTION
Direct construction of NꢀX (X = N, O, S) bond is an interesting approach for the synthesis of
diverse heterocyclic compounds.1ꢀ5 NꢀX bond formations are relatively less explored as
compared to CꢀC and CꢀX bond formations. Various metalꢀcatalyzed approaches are reported for
the formation of NꢀX bond,2,3aꢀ3c,5 however, in view of cost and environmental concerns of metal
usage, the development of ecoꢀfriendly protocols are still highly desirable. Metalꢀfree approaches
for the construction of NꢀX bond has attracted a great attention due to their practical applicability
and green chemistry aspects.1,3d,4 Recently, environmentally benign iodine(III) reagents6
emerged as inexpensive and efficient oxidizing agents which were successfully used for various
intramolecular oxidative cyclizations.4,7 Tellitu et al., reported the synthesis of indazolone and
benzisothiazolone derivatives by using iodine(III) reagent via direct construction of
intramolecular oxidative NꢀN/NꢀS bond formation from anthranilamide and 2ꢀmercaptoamide
derivatives as the starting substrates via formation of an Nꢀacylnitrenium ion intermediate,1a,1b,4
which is stabilized by electronꢀdonating effect of a proper neighbouring groups.1a When we
conducted the experiment with 2ꢀaminoꢀN´ꢀphenylbenzohydrazides (1a) instead of
anthranilamide the course of reaction was changed and finally delivered the corresponding
benzisoxazole (2a)8 as product (Scheme 1) and laid the foundation of present work.
In line with the initial observations and continuation to our research on the development of
mild and ecoꢀfriendly protocols,9 we herein present an unprecedented, tandem approach for the
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synthesis of aryldiazenylisoxazolo(isothiazolo)arenes from 2ꢀaminoꢀN´ꢀarylarylhydrazides by
using PIDA as an external oxidant in an industrially acceptable and recommended green solvent
i.e. ethyl acetate (EtOAc)10 at room temperature.
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Previous Reports
Ref: 1a,1b
PhI(OCOCF3)2
O
O
R1
N
N R1
H
N
NHR
DCM, TFA, 0 °C
R
R = Alkyl, Aryl
R1 = OMe, Alkyl, Aryl
O
Ref: 4
O
R
N
PhI(OCOCF3)2
DCM, TFA, 0 °C
H
N R
S
SH
R = Alkyl, Aryl
Ar
Present Approach
N
N
PhI(OAc)2
EtOAc, rt
O
O
H
N
X
N
N
H
Ar
Ar
N
N
X
NH2
1. Lawesson's Reagent
THF, rt
X = C, N
S
2. PhI(OAc)2, EtOAc, rt
N
O
* Multiple operations in one pot
* No ligand and base
* Good yields at rt
N NH
N
Ar
* Under air
H
Scheme1. Direct NꢀX (X = N, S, O) bond annulation strategies to access heterocyclic compounds
Benzisoxazoles and benzisothiazoles are very prominent scaffolds found in various
biologically active compounds and drugs (Fig 1).11 On the other hand, aromatic azo compounds
have broad applications in the field of technical devices such as nonꢀlinear optical devices,
chemosensors, protein probes and molecular machines.12 Moreover, the azo group is also utilized
as the directing group for ortho CꢀH functionalization of organic compounds.13 The biological
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applications of these scaffolds as well as synthetic utility of azo compounds prompted us to
further investigate and optimize the synthetic methodology.
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O
O
N
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NH
N
O
O
O
Cl
N
N
N
SO2NH2
N
F
F
N
N
N
N
O
O
O
S
Risperidone
(antipsychotic)
Iloperidone
(antipsychotic)
Zonisamide
(anticonvulsant)
Ziprasidone
(antipsychotic)
Fig. 1: Representative compounds of biological significance.
RESULTS AND DISCUSSION
We initiated our studies by choosing 2ꢀaminoꢀN´ꢀphenylbenzohydrazide (1a) as a model
substrate. Based on the previous methodologies,1a,1b,4 we carried out the reaction of 1a in
dichloromethane (DCM) by using PIFA (Phenyliodotrifluoroacetate) (1.5 equiv., 0.01 M) as an
oxidant and trifluoroacetic acid (3 equiv.) as an additive at 0 °C. The reaction failed to give the
expected indazolone product. When we carried the same reaction without TFA at room
temperature, surprisingly, (E)ꢀ(2ꢀaminophenyl)(phenyldiazenyl)methanone (4a) was formed in
20% yield (Table 1, entry 2). When we used the 3 equiv of PIFA (0.01 M), the reaction delivered
the unexpected (E)ꢀ3ꢀ(phenyldiazenyl)benzo[c]isoxazole (2a) in 15% yield along with 4a (Table
1, entry 3). This interesting result motivated us to optimize the reaction condition to improve the
yield of annulated product 2a. When we switched the oxidant from PIFA to PIDA
(phenyliodoacetate) (3 equiv., 0.01 M), the yield of the benzisoxazole product 2a and the diazo
product 4a increased to 35% and 40% yields respectively (Table 1, entry 4). We performed the
same reaction in DCM with 0.1 M dilution of PIDA (3 equiv.), no change in the yield of 2a and
4a were observed (Table 1, entry 5). Next, we started optimization of solvents by keeping PIDA
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(3 equiv., 0.1 M) as an oxidant. We screened the reaction in various solvents such as DCE, IPA,
THF, ACN and EtOAc (Table 1, entries 6ꢀ10). Interestingly, EtOAc was found to be the best
solvent and furnished the product 2a in 80% yield with complete conversion of the intermediate
product 4a (entry 10). Other oxidants like PhI(OPiv)2, PhIO and I2 were also screened (Table 1,
entries 11ꢀ13), however, they failed to improve the yield of 2a. By decreasing the amount of
PIDA (1.5 equiv., 0.1 M) in the reaction, only oxidized intermediate 4a was formed in 90% yield
(entry 14).
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Table 1. Optimization of reaction conditions for 1a.a
Oxidant (X)
Solvent (Y)
O
O
N
N
H
N
N
N
N
H
O
+
NH2
4a
N
RT, 6h
NH2
1a
2a
Entry
Oxidant (X)
Solvent Yieldb
(equiv., Conc.)
(Y)
DCM
DCM
DCM
DCM
DCM
DCE
(%)
2a/4a
0/0
1
2
PIFA (1.5, 0.01 M)c
PIFA (1.5, 0.01 M)
PIFA (3.0, 0.01 M)
PIDA (3.0, 0.01 M)
PIDA (3.0, 0.1 M)
PIDA (3.0, 0.1 M)
PIDA (3.0, 0.1 M)
PIDA (3.0, 0.1 M)
PIDA (3.0, 0.1 M)
PIDA (3.0, 0.1 M)
0/20
15/20
35/40
35/40
30/50
32/41
65/10
70/10
80/0
3
4
5
6
7
IPA
8
THF
9
ACN
EtOAc
EtOAc
EtOAc
EtOAc
10
11
12
13
PhI(OPiv)2 (3.0, 0.1 M)
PhIO (3.0, 0.1 M)
I2 (3.0, 0. M)
35/40
0/20
0/0
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PIDA (1.5, 0.1 M)
EtOAc
0/90
5
6
a Reaction conditions: 1a (1 equiv.), oxidant (X) (equiv., Conc.) at RT, 6 h, under air. b Isolated
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c
d
yields. Reaction carried out at 0˚ C by using trifluoroaceticacid (TFA) (3 equiv.) as additive.
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Abbreviations used in the table: PIFA = Phenyliodine(III) bis(trifluoroacetate); PIDA =
Phenyliodine(III) diacetate; DCM = Dichloromethane; DCE = Dichloroethane; THF =
Tetrahydrofuran; IPA = Isopropylalcohol; ACN = Acetonitrile
With the optimal conditions (Table 1, entry 10) in hand, we next probed the scope and generality
of this intramolecular oxidative OꢀN bond formation approach to a variety of 2ꢀaminoꢀN´ꢀ
arylarylhydrazides. The arylhydrazides containing electron withdrawing groups (3ꢀF, 3ꢀCl, 4ꢀCl,
4ꢀBr, 2,4ꢀdichloro, and 3,4ꢀdichloro) underwent a smooth reaction and yielded the corresponding
products in good yields (Table 2, 2bꢀ2h). The structure of 2c was confirmed by Xꢀray diffraction
analysis14 (see supporting information). Similarly, the arylhydrazides bearing electronꢀdonating
groups (CH3, and OCH3) are well tolerated in the reaction and afforded the desired products in
excellent yields (2iꢀ2l). Next we demonstrated the reaction by using different substituents such as
Cl, Br and I on the aryl ring of arylhydrazides (derived from isatoic anhydride) (1mꢀ1x; see
experimental section) and they successfully furnished the desired products in good yields (2mꢀ
2x).
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Table 2. Synthesis of aryldiazenylisoxazoloarenes under the optimum reaction conditions.a,b
Ar
O
N
H
N
PIDA (3 equiv )
N
N
Ar
H
O
EtOAC, RT
6 h
X
NH2
N
X
R
R
1
X = C or N
2
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Cl
Cl
Cl
Br
F
Cl
N
F
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
N
O
O
O
O
N
O
N
N
N
N
N
2h,
68%
2e,
70%
2g, 68%
2b,
2d, 76%
2f, 71%
70%
2c,
x-ray of 2c15
CH3
76%
F
Cl
CH3
O
H3C
CH3
H3C
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
N
O
O
N
O
N
N
N
Cl
Cl
N
N
Cl
2m,
2o, 69%
78%
2j,
2n, 70%
2i, 80%
81%
2k,
81%
2l,
83%
Cl
CH3
CH3
Cl
Cl
N
H3C
N
N
N
N
N
N
N
N
N
N
N
N
N
I
I
O
O
O
O
O
O
O
N
N
N
N
N
N
N
Br
Br
Cl
Br
Cl
2p, 64%
2s,
2q,
71%
80%
2r,
2v,
65%
79%
2t,
75%
2u,
75%
Br
Cl
CH3
O
H3C
CH3
H3C
CH3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
I
I
O
O
O
O
O
N
O
O
N
N
N
N
N
N
N
N
N
N
N
2a ,
2x,
63%
78%
2w,
78%
2b ,
62%
2c , 62%
2d ,
65%
2e ,
67%
a
b
Reaction conditions: 1 (1 equiv.), PIDA (3 equiv., 0.1 M) at RT, 6 h, under air. Isolated
yields.
To expand the scope of present approach, we studied the reaction of 2ꢀaminoꢀN'ꢀ
phenylnicotinohydrazide (1aʹ) (derived from 2ꢀaminonicotinic acid and phenylhydrazine; see the
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supporting information) as diversified substrates under identical reaction conditions. Pleasingly,
the corresponding product (E)ꢀ3ꢀ(phenyldiazenyl)isoxazolo[3,4ꢀb]pyridine (2aʹ) was formed in
63% yield. Likewise, various electronꢀwithdrawing and electronꢀdonating groups such as Cl, Br,
CH3, and OCH3 containing nicotinohydrazides are employed in the reaction and afforded the
respective products in moderate to good yields (Table 2, 2bʹꢀ 2eʹ).
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Table 3. Synthesis of aryldiazenylbenzoisothiazoles under the optimum reaction
conditions.a,b
Ar
O
H
N
(I) Lawesson's reagent (1.0 equiv.)
THF, RT, N2 atm, 12 h
Ar
N
N
N
H
S
(II) PIDA (3 equiv.)
NH2
R
N
EtOAc, RT, 3 h
R
1
3
"One Pot"
R = Br, I
Cl
Cl
N
N
N
N
N
N
N
N
S
S
N
S
S
N
N
N
Br
Br
3a
, 70%
3b, 66%
3c, 60%
3d, 58%
Cl
H3C
H3C
Cl
CH3
CH3
N
N
N
N
N
N
I
S
S
N
S
N
N
3e
, 57%
3f, 68%
3g, 65%
a
Reaction conditions: (A) 1 (1 equiv.), Lawesson’s Reagent (1 equiv.), THF, RT, N2 atm, 12 h;
(B) PIDA (3 equiv., 0.1 M) , EtOAc, RT, 3 h, under air. b Isolated yields.
Additionally, in order to check the versatility of the reaction, the present method was extended
for the synthesis of biologically significant aryldiazenylbenzisothiazole scaffold from the
reaction of 2ꢀaminoꢀN´ꢀarylarylhydrazides. In this transformation, benzohydrazides were
converted to benzothiohydrazides by using Lawesson’s reagent (1 equiv.) in THF under N2
atmosphere at room temperature. After removal of THF under vacuum, the reaction mixture was
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directly subjected to oxidative intramolecular SꢀN bond formation by using standard reaction
conditions and yielded the respective aryldiazenylbenzoisothiazoles in moderate to good yields
(Table 3, 3aꢀ3g). Notably, to the best of our knowledge this is the first approach to synthesize
aryldiazenylbenzisothiazoles from arylhydrazides in one pot proving the practical application of
the methodology.
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Furthermore, in order to investigate the reaction mechanism, few control experiments were
performed (Scheme 2). The reaction of intermediate 4a with PIDA (1.5 equiv.) under similar
conditions produced the desired product 2a in 82% yield within 3 h (Scheme 2, eqn (1)). It is
evident that the reaction proceeds via formation of intermediate 4a. When the reaction was
carried out by using 2ꢀ(methylamino)ꢀN'ꢀphenylbenzohydrazide (1y) under identical reaction
conditions, only oxidized product 5a was formed in 85% yield (Scheme 2, eqn (2)). Moreover,
when the reaction of 1a was performed in the presence of radical inhibitor such as TEMPO
(2,2,6,6ꢀtetramethylpiperdine 1ꢀoxy) under similar conditions, no significant effect was observed
on the yield of desired product (Scheme 2, eqn (3)), which indicates the absence of radical
mechanism. These results collectively suggest that the formation of 4a is a prerequisite to getting
the oxidative annulated product (2a). The set of experiments also justified the importance of
oxidant and its stoichiometric amount in present methodology.
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Scheme 2. Controlled experiments.
Ph
O
N
N
N
PIDA (1.5 equiv.,0.1 M)
N
Ph
Ph
(1)
7
8
9
O
NH2
O
EtOAc
N
82%
2a
O
4a
1y
1a
RT, 3 h
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H
N
N
N
Ph
PIDA (3 equiv., 0.1 M)
N
H
NH
(2)
NH
CH3
85 %
5a
EtOAc
CH3
RT, 12 h
Ph
O
N
N
H
N
PIDA (3 equiv., 0.1 M)
N
H
NH2
Ph
(3)
O
TEMPO (3 equiv.)
EtOAc
RT, 4 h
N
80 %
2a
Based on the control experiments and previous literature reports,1c,14 a presumptive mechanism is
proposed (Scheme 3). Initially, the reaction of 1a with PhI(OCOCH3)2 (PIDA) gives the
iodinated intermediate A with the removal of acetic acid. The intermediate A is further converted
into an azo intermediate 4a via removal of iodobenzene and acetic acid. The reaction of 4a with
another mole of PIDA gives the iodinated intermediate B with the removal of acetic acid, which
upon subsequent oxidative OꢀN bond forming annulation with the loss of iodobenzene and acetic
acid delivered the desired benzisoxazole product (2a).
Ph
AcO
I
AcO
O
Ph
Ph
O
I
OAc
O
H
N
N
N
N
Ph
N
N
Ph
H
H
NH2
AcOH
PhI
NH2
NH2
AcOH
4a
AcO
1a
A
Ph
I
OAc
AcOH
Ph
N
Ph
Ph
N
N
N
N
N
O
O
N
H
O
N
AcOH
PhI, OAc
NH
B
2a
I
C
AcO
Ph
Scheme 3. Plausible reaction mechanism
In summary, we have developed a practical, mild and efficient protocol for the synthesis of
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aryldiazenylisoxazoloarenes from the reaction of 2ꢀaminoꢀN´ꢀarylarylhydrazides. Additionally,
we also demonstrated the synthesis of aryldiazenylbenzisothiazoles in one pot by using suitable
thiation agent (Lawesson’s reagent) followed by our standard reaction conditions. The present
work offers an efficient method to access highly interesting diazo group containing
arylisoxazoles and benzisothiazoles in good yields. Multiple operations in one pot by using mild
reaction conditions at room temperature under aerobic condition are the attractive feature of the
present methodology. Further, diazo directed CꢀH functionalization of these compounds is
underway in our laboratory.
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Experimental section
General Information. Melting points were determined on a capillary melting point apparatus
1
and are uncorrected. All the compounds were fully characterized by H, 13C, IR, and HRMS
1
analysis. H NMR spectra were recorded on 400 MHz in CDCl3/ DMSOꢀd6 and 13C NMR
spectra were recorded on 100 MHz in CDCl3/ DMSOꢀd6 using TMS as internal standard.
Multiplicities are reported as follows: singlet (s), doublet (d), broad singlet (br s), doublet of
doublets (dd), triplet (t), doublet of doublet of doublet (ddd), doublet of triplet (dt) and multiplet
(m). Chemical shift and coupling constants are reported in parts per million (ppm) relative to
residual signal of TMS in deuterated solvents and Hertz, respectively. IR spectra were recorded
using FTꢀIR spectrophotometer and values reported in cmꢀ1. HRMS were recorded using QꢀTOF
mass spectrometer. Column chromatography was performed over silica gel (60−120 Mesh) and
EtOAcꢀhexane as eluent. All chemicals and reagents were purchased from commercial sources
and used without further purification.
General experimental procedure for the preparation of 1d, 1e, 1g, 1h, 1j, 1k, 1l, 1nꢀ1q, and
1sꢀ1x and 1aʹꢀ1eʹ
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2ꢀaminoꢀNʹꢀarylbenzohydrazides 1a, 1b, 1c, 1f, 1i, 1m, 1r and 1y were known and they were
prepared by known literature procedure.16a The substrates 1d, 1e, 1g, 1h, 1j, 1k, 1l, 1nꢀ1q, 1sꢀ1x
and 1aʹꢀ1eʹ were unknown and prepared from known literature procedure16 as given below.
In a 50 mL roundꢀbottom flask, a suspension of isatoic anhydride (1.0 equiv.) in THF (20 mL)
was treated by slow addition of 1.2 equiv of phenylhydrazines. The reaction mixture was
refluxed overnight (12 h). The completion of the reaction was monitored by TLC. After
completion of the reaction, the mixture was cooled to room temperature and concentrated under
vacuum. 2ꢀAminoꢀN′ꢀarylbenzohydrazides (1) were obtained as solids after being crystallized
from ethanol.
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Experimental procedure for the preparation of 1aʹꢀ1eʹ:
To a solution of 2ꢀaminonicotinic acid (1 equiv.) in dry THF (20 mL) at 0 ˚C placed into a 50
mL of round bottom flask, 1,1ʹꢀcarbonyldiimidazole (CDI)(1.1 equiv.) was added. The
suspension was stirred for 2 h at room temperature. Eventually, the precipitate thinned out and
N,Nʹꢀdiisopropylethylamine (DIPEA)(1.2 equiv.) was added, which caused the precipitate to
fully dissolve, followed by the addition of phenylhydrazines. The mixture was stirred at rt for 24
h. The reaction was carefully quenched with water (20 mL) and extracted with EtOAc (3x20
mL). The organic layer was dried over anhydrous Na2SO4. The organic solvent was removed
under reduced pressure and crude residue was crystallized from ethanol to give the desired
products (1aʹꢀ1eʹ).
Experimental
procedure
for
the
synthesis
of
(E)ꢀ(2ꢀ
aminophenyl)(phenyldiazenyl)methanone intermediate(4a):
To a well stirred solution of phenyliodine(III) diacetate (PIDA) (637 mg, 1.5 equiv., 0.1 M) in
ethylacetate (20 mL), 2ꢀaminoꢀNʹꢀphenylbenzohydrazide (1a) (300 mg, 1.0 equiv) was added at
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room temperature. The resulting mixture was allowed to stir for 30 min. After completion of the
reaction (monitored by TLC), EtOAc was evaporated under reduced pressure and residue was
purified by column chromatography on silica gel (60ꢀ120 mesh) eluting with hexane: EtOAc (97:
3) to afford the red colour solid product 4a (90%).
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Experimental procedure for the synthesis of aryldiazenylisoxazoloarenes (2aꢀ2x and 2aʹ ꢀ
2eʹ):
To a well stirred solution of PIDA (3.0 equiv., 0.1 M) in ethylacetate (40 mL), 2ꢀaminoꢀNʹꢀ
arylbenzohydrazides (1) (1.0 equiv.) was added at room temperature. The resulting mixture was
allowed to stir for 6 h. The completion of the reaction was monitored by TLC. The reaction
mixture was quenched with water and extracted with EtOAc. The organic layer was washed with
brine and dried over anhydrous Na2SO4. Evaporation of solvent under reduced pressure gave a
crude product which was purified by silica gel (60ꢀ120 mesh) column chromatography by using
hexane: EtOAc (98: 2) as an eluent to afford the red colour solid products (2aꢀ2x and 2aʹ ꢀ2eʹ).
Experimental procedure for the synthesis of aryldiazenylbenzisothiazoles (3aꢀ3g):
To a solution of 1 (1 equiv.) in THF (25 mL) was added the lawesson’s reagent (1 equiv.) and
the reaction mixture was stirred for 24 h at rt under N2 ballon. After complete conversion of 1,
the solvent was evaporated under reduced pressure and the crude residue was directly subjected
for similar experimental procedure as mentioned above. The completion of the reaction was
monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc
(20x3 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4.
Evaporation of the solvent under reduced pressure gave a crude product which was purified by
silica gel (60ꢀ120 mesh) column chromatography by using hexane: EtOAc (99: 1) as an eluent to
afford the red colour solid products (3aꢀ3g).
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2ꢀaminoꢀN'ꢀ(4ꢀbromophenyl)benzohydrazide (1d): White solid (314 mg, 56%); mp 198ꢀ200 oC; FTꢀIR (KBr,
νmax/cmꢀ1) 3391, 3019, 1669, 1422, 1289, 1215, 1065, 758, 668; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.09 (s,
1H), 7.97 (s, 1H), 7.64 (d, 1H, J = 7.60 Hz), 7.29 (d, 2H, J = 8.56 Hz), 7.20ꢀ7.16 (m, 1H), 6.74ꢀ6.71 (m, 3H), 6.56ꢀ
6.52 (m, 1H), 6.36 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.8, 149.9 (C), 149.20 (C), 132.2 (CH),
131.3 (2xCH), 127.9 (CH), 116.4 (CH), 114.7 (CH), 114.2 (2xCH), 112.5 (C), 109.2 (C) ppm; HRMS (ESI): calcd
for C13H12BrN3O [M+H]+ 306.0242, found: 306.0242.
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2ꢀaminoꢀN'ꢀ(3ꢀfluorophenyl)benzohydrazide (1e): White solid (225 mg, 50%); mp 164ꢀ166 oC; FTꢀIR (KBr,
νmax/cmꢀ1) 3399, 3019, 1634, 1403, 1216, 1067, 770, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.09 (s, 1H), 8.07
(s, 1H), 7.65 (d, 1H, J = 7.44 Hz), 7.21ꢀ7.13 (m, 2H), 6.73 (d, 1H, J = 7.76 Hz), 6.61 (d, 1H, J = 7.78 Hz), 6.55 (t,
1H, J = 7.95 Hz), 6.51ꢀ6.45 (m, 2H), 6.38 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.8, 163.1 (d, J =
238.72 Hz, C), 152.1 (d, J = 10.20 Hz, C), 149.9 (C), 132.2 (CH), 130.3 (d, J = 9.88 Hz, CH), 128.0 (CH), 116.4
(CH), 114.7 (CH), 112.5 (C), 108.2 (CH), 104.5 (d, J = 21.20 Hz, CH), 98.6 (d J = 25.46 Hz, CH) ppm; HRMS
(ESI): calcd for C13H12FN3O [M+H]+ 246.1043, found: 246.1040.
o
2ꢀaminoꢀN'ꢀ(2,4ꢀdichlorophenyl)benzohydrazide (1g): White solid (271 mg, 50%); mp 197ꢀ200 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3399, 3019, 1639, 1384, 1215, 1155, 1068, 770, 668; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.23 (s, 1H),
7.67ꢀ7.65 (m, 2H), 7.43 (d, 1H, J = 2.32 Hz), 7.23ꢀ7.17 (m, 2H), 6.86ꢀ6.78 (m, 1H), 6.73 (d, 1H, J = 7.76), 6.55 (t,
1H, J = 7.18 Hz), 6.40 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.6, 150.0 (C), 144.3 (C), 132.4
(CH), 128.3 (CH), 128.0 (CH), 127.7 (CH), 121.9 (C), 117.7 (C), 116.4 (CH), 114.6 (CH), 114.0 (CH), 112.1 (C)
ppm; HRMS (ESI): calcd for C13H11Cl2N3O [M+H]+ 296.0357, found: 296.0346.
o
2ꢀaminoꢀN'ꢀ(3,4ꢀdichlorophenyl)benzohydrazide (1h): White solid (271 mg, 50%); mp 171ꢀ173 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3390, 3019, 1646, 1404, 1215, 1065, 770, 668; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.14 (s, 1H), 8.21
(s, 1H), 7.64 (dd, 1H, J = 7.88, 1.15 Hz), 7.36 (d, 1H, J = 8.72 Hz), 7.21ꢀ7.17 (m, 1H), 6.91 (d, 1H, J = 2.61 Hz),
6.77ꢀ6.72 (m, 2H), 6.57ꢀ6.53 (m, 1H), 6.39 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ =168.8, 150.07 (C),
150.00 (C), 132.4 (CH), 131.1 (C), 130.6 (CH), 128.0 (CH), 119.2 (C), 116.4 (CH), 114.7 (CH), 113.1 (CH), 112.5
(CH), 112.2 (C) ppm; HRMS (ESI): calcd for C13H11Cl2N3O [M+H]+ 296.0357, found: 296.0346.
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2ꢀaminoꢀN'ꢀ(3,4ꢀdimethylphenyl)benzohydrazide (1j): White solid (281 mg, 60%); mp 188ꢀ190 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3389, 3019, 1634, 1403, 1215, 1155, 1068, 758, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.02 (s, 1H),
7.65 (d, 1H, J = 7.8 Hz), 7.48 (s, 1H), 7.19ꢀ7.15 (m, 1H), 6.90 (d, 1H, J = 7.8 Hz), 6.72 (d, 1H, J = 8.24 Hz), 6.60 (s,
1H), 6.56ꢀ6.52 (m, 2H), 6.35 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.7, 149.8 (C), 147.8 (C),
136.0 (C), 132.0 (CH), 129.6 (CH), 127.9 (CH), 126.0 (C), 116.3 (CH), 114.7 (CH), 114.0 (CH), 112.9 (C), 110.0
(CH), 19.7 (CH3), 18.4 (CH3) ppm; HRMS (ESI): calcd for C15H17N3O [M+H]+ 256.1450, found: 256.1449.
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2ꢀaminoꢀN'ꢀ(2,5ꢀdimethylphenyl)benzohydrazide (1k): White solid (281 mg, 60%); mp 164ꢀ166 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3425, 1618, 1584, 1404, 1216, 1066, 764, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.08 (s, 1H), 7.68
(dd, 1H, J = 7.92, 1.2 Hz), 7.21ꢀ7.16 (m, 1H), 7.04 (br s, 1H), 6.89 (d, 1H, J = 7.48 Hz), 6.73 (dd, 1H, J = 8.24, 0.84
Hz), 6.58ꢀ6.53 (m, 2H), 6.49 (d, 1H, J = 7.28 Hz), 6.39 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.6,
149.9 (C), 146.9 (C), 135.2 (C), 132.1 (CH), 129.9 (CH), 127.9 (CH), 119.4 (CH), 119.0 (C), 116.4 (CH), 114.7
(CH), 112.8 (C), 111.8 (CH), 21.1 (CH3), 16.8 (CH3) ppm; HRMS (ESI): calcd for C15H17N3O [M+H]+ 256.1450;
found: 256.1438.
o
2ꢀaminoꢀN'ꢀ(4ꢀmethoxyphenyl)benzohydrazide (1l): White solid (307 mg, 65%); mp 150ꢀ152 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3378, 3019, 2932, 1634, 1585, 1508, 1404, 1215, 1156, 1068, 1030, 757, 668; H NMR (400 MHz,
1
DMSOꢀd6): δ = 10.06 (d, 1H, J = 2.6 Hz), 7.64 (d, 1H, J = 7.12 Hz), 7.44 (d, 1H, J = 2.84 Hz), 7.19ꢀ7.15 (m, 1H),
6.79ꢀ6.74 (m, 4H), 6.72ꢀ6.70 (m, 1H), 6.54 (t, 1H, J = 7.8 Hz), 6.35 (br s, 2H), 3.66 (s, 3H) ppm; 13C NMR (100
MHz, DMSOꢀd6) δ = 166.8, 152.7 (C), 149.8 (C), 143.6 (C), 132.1 (CH), 127.9 (CH), 116.3 (CH), 114.7 (CH),
114.2 (2xCH), 113.8 (2xCH), 112.9 (C), 55.2 ppm; HRMS (ESI): calcd for C14H15N3O2 [M+H]+ 258.1243, found:
258.1225.
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2ꢀaminoꢀ4ꢀchloroꢀN'ꢀ(4ꢀfluorophenyl)benzohydrazide (1n): White solid (212 mg, 50%); mp 160ꢀ162 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3378, 1636, 1507, 1403, 1218, 1065, 771; H NMR (400 MHz, DMSOꢀd6): δ = 10.15 (s, 1H),
1
7.75 (s, 1H), 7.65 (d, 1H, J = 8.46 Hz), 7.00ꢀ6.96 (m, 2H), 6.79ꢀ6.76 (m, 3H), 6.62 (s, 2H) 6.56 (dd, 1H, J = 8.41,
2.01Hz) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.1, 155.9 (d, J = 232 Hz, C), 151.1 (C), 146.1 (C), 136.7 (C),
129.8 (CH), 115.2 (d, J = 10.38 Hz, 2xCH), 115.0 (CH), 114.3 (CH), 113.5 (d, J = 7.50 Hz, 2xCH), 111.4 (C) ppm;
HRMS (ESI): calcd for C13H11ClFN3O [M+H]+ 280.0653; found: 280.0653.
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2ꢀaminoꢀ4ꢀchloroꢀN'ꢀ(4ꢀchlorophenyl)benzohydrazide (1o): White solid (251 mg, 56%); mp 172ꢀ174 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3377, 3019, 1631, 1385, 1215, 1155, 1068, 927, 758, 669; H NMR (400 MHz, DMSOꢀd6): δ =
1
6
7
8
9
10.17 (s, 1H), 7.97 (s, 1H), 7.66 (d, 1H, J = 8.32 Hz), 7.17 (d, 2H, J = 8.30), 6.79ꢀ6.76 (m, 3H), 6.63 (br s, 2H), 6.56
(d, 1H, J = 7.66 Hz) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.0, 151.2 (C), 148.6 (C), 136.8 (C), 129.8 (CH),
128.5 (2xCH), 121.8 (C), 115.1 (CH), 114.3 (CH), 113.7 (2xCH), 111.3 (C) ppm; HRMS (ESI): calcd for
C13H11Cl2N3O [M+H]+ 296.0357, found: 296.0346.
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2ꢀaminoꢀ4ꢀchloroꢀN'ꢀ(3ꢀchlorophenyl)benzohydrazide (1p): White solid ( 246 mg, 55%); mp 200ꢀ202 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3366, 3019, 1625, 1404, 1215, 1066, 849, 769, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.17 (s,
1H), 8.09 (s, 1H), 7.66 (d, 1H, J = 8.44 Hz), 7.15 (t, 1H, J = 7.90Hz), 6.80 (d, 1H, J = 1.30 Hz), 6.73ꢀ6.71 (m, 3H),
6.64 (br s, 2H), 6.57 (d, 1H, J = 7.90 Hz) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.0, 151.2 (2xC), 136.8 (C),
133.4 (C), 130.4 (CH), 129.8 (CH), 118.0 (CH), 115.2 (CH), 114.4 (CH), 111.5 (CH), 111.1 (C), 110.8 (CH) ppm;
HRMS (ESI): calcd for C13H11Cl2N3O [M+H] + 296.0357; found: 296.0346.
o
2ꢀaminoꢀ4ꢀchloroꢀN'ꢀ(3,4ꢀdimethylphenyl)benzohydrazide (1q): White solid (263 mg, 60%); mp 187ꢀ189 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3385, 3019, 1613, 1492, 1404, 1215, 1154, 1068, 769, 669; 1H NMR (400 MHz, DMSOꢀd6): δ =
10.10 (d, 1H, J = 2.03 Hz), 7.65 (d, 1H, J = 8.38 Hz), 7.50 (d, 1H, J = 2.03 Hz), 6.89 (d, 1H, J = 7.94 Hz), 6.78 (d,
1H, J = 1.77 Hz), 6.61 (br s, 2H), 6.59ꢀ6.50 (m, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.0, 151.1 (C),
147.7 (C), 136.6 (C), 136.1 (C), 129.8 (CH), 129.6 (CH), 126.1 (C), 115.1 (CH), 114.4 (CH), 114.0 (CH), 111.6 (C),
110.0 (CH), 19.7 (CH3), 18.4 (CH3) ppm; HRMS (ESI): calcd for C15H16ClN3O [M+H]+ 290.1060; found: 290.1053.
o
2ꢀaminoꢀ4ꢀbromoꢀN'ꢀ(4ꢀchlorophenyl)benzohydrazide (1s): White solid (229 mg, 55%); mp 185ꢀ187 C; FTꢀIR
1
(KBr, νmax/cmꢀ1) 3379, 3019, 1636, 1403, 1215, 1066, 758, 669; H NMR (400 MHz, DMSOꢀd6): δ = 10.17 (s,
1H), 7.97 (s, 1H), 7.57 (d, 1H, J = 8.44 Hz), 7.17 (d, 2H, J = 8.64 Hz), 6.96 (d, 1H, J = 1.24 Hz), 6.77 (d, 2H, J =
8.64 Hz), 6.69 (d, 1H, J = 8.28 Hz), 6.60 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.7, 151.4 (C),
148.8 (C), 130.3 (CH), 128.9 (2xCH), 126.3 (C), 122.5 (C), 118.6 (CH), 117.9 (CH), 114.2 (2xCH), 112.1 (C) ppm;
HRMS (ESI): calcd for C13H11BrClN3O [M+H]+ 339.9852, found: 339.9848.
2ꢀaminoꢀ4ꢀbromoꢀN'ꢀpꢀtolylbenzohydrazide (1t): White solid (224 mg, 57%); mp 189ꢀ191 oC; FTꢀIR (KBr,
νmax/cmꢀ1) 3449, 3390, 3354, 3287, 3021, 1654, 1607, 1492, 1216, 1062, 907, 761, 669; 1H NMR (400 MHz,
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DMSOꢀd6): δ = 10.11 (s, 1H), 7.59ꢀ7.56 (m, 2H), 6.96ꢀ6.94 (m, 3H), 6.69ꢀ6.67 (m, 3H), 6.58 (br s, 2H), 2.17 (s, 3H)
ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.2 (C), 151.2 (C), 147.4 (C), 129.9 (CH), 129.2 (2xCH), 127.4 (C),
125.7 (C), 118.2 (CH), 117.4 (CH), 112.7 (2xCH), 112.1 (C), 20.2 (CH3) ppm; HRMS (ESI): calcd for C14H14BrN3O
[M+H]+ 320.0398, found: 320.0389.
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2ꢀaminoꢀ5ꢀiodoꢀN'ꢀphenylbenzohydrazide (1u): White solid (210 mg, 58%); mp 218ꢀ220 C; IR FTꢀIR (KBr,
νmax/cmꢀ1) 3402, 1638, 1403, 1217, 1155, 1068, 771, 668; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.16 (s, 1H), 7.93
(d, 1H, J = 1.92 Hz), 7.75 (br s, 1H), 7.44 (dd, 1H, J = 8.68, 1.96 Hz), 7.16ꢀ7.12 (m, 2H), 6.76 (d, 2H, J = 7.68 Hz),
6.72ꢀ6.69 (m, 1H), 6.59 (d, 1H, J = 8.72 Hz), 6.51 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 168.0,
149.7 (C), 149.6 (C), 140.6 (CH), 136.1 (CH), 129.2 (2xCH), 119.4 (CH), 119.3 (CH), 115.7 (C), 112.7 (2xCH),
75.2 (C) ppm; HRMS (ESI): calcd for C13H12IN3O [M+H]+ 354.0103, found: 354.0102.
2ꢀaminoꢀN'ꢀ(4ꢀchlorophenyl)ꢀ5ꢀiodobenzohydrazide (1v): White solid (219 mg, 55%); mp 178ꢀ180 oC; FTꢀIR (KBr,
νmax/cmꢀ1) 3399, 1650, 1403, 1216, 1066, 770, 669; H NMR (400 MHz, DMSOꢀd6): δ = 10.18 (s, 1H), 7.95ꢀ7.92
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(m, 2H), 7.44 (dd, 1H, J = 8.68, 1.40 Hz), 7.18 (d, 2H, J = 8.68 Hz), 6.77 (d, 2H, J = 8.68 Hz), 6.59 (d, 1H, J = 8.72
Hz), 6.52 (br s, 2H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 167.5, 149.4 (C), 148.5 (C), 140.2 (CH), 135.7 (CH),
128.5 (2xCH), 121.8 (C), 118.9 (CH), 114.9 (C), 113.7 (2xCH), 74.7 (C) ppm; HRMS (ESI): calcd for
C13H11ClIN3O [M+H]+ 387.9714, found: 387.9711.
2ꢀaminoꢀ5ꢀiodoꢀN'ꢀpꢀtolylbenzohydrazide (1w): White solid (219 mg, 58%); mp 176ꢀ178 oC; FTꢀIR (KBr, νmax/cmꢀ
1) 3847, 3744, 3738, 3669, 3391, 1654, 1403, 1217, 1063, 771, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.13 (s,
1H), 7.91 (s, 1H), 7.57 (s, 1H), 7.43 (d, 1H, J = 7.64 Hz), 6.96 (d, 2H, J = 7.96 Hz), 6.68 (d, 2H, J = 8.00 Hz), 6.58
(d, 1H, J = 8.64 Hz), 6.50 (br s, 2H), 2.17 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 167.5, 149.3 (C), 147.3
(C), 140.1 (CH), 135.7 (CH), 129.1 (2xCH), 127.3 (C), 118.9 (CH), 115.3 (C), 112.6 (2xCH), 74.8 (C), 20.1 (CH3)
ppm; HRMS (ESI): calcd for C14H14IN3O [M+H]+ 368.0260, found: 368.0244.
2ꢀaminoꢀN'ꢀ(2,5ꢀdimethylphenyl)ꢀ5ꢀiodobenzohydrazide (1x): White solid (235 mg, 60%); mp 172ꢀ174oC; FTꢀIR
(KBr, νmax/cmꢀ1) 3398, 2927, 1637, 1403, 1218, 1067, 771, 669; H NMR (400 MHz, DMSOꢀd6): δ = 10.18 (s,
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1H), 7.96 (s, 1H), 7.44 (d, 1H, J = 8.60 Hz), 7.04 (s, 1H), 6.89 (d, 1H, J = 7.24 Hz), 6.61ꢀ6.48 (m, 5H), 2.17 (s, 3H),
2.14 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 167.4, 149.4 (C), 146.7 (C), 140.1 (C), 135.7 (CH), 135.3
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(CH), 129.9 (CH), 119.5 (CH), 119.0 (C), 119.0 (CH), 115.2 (C), 111.7 (CH), 74.8 (C), 21.2 (CH3), 16.8 (CH3)
ppm; HRMS (ESI): calcd for C15H16IN3O [M+H]+ 382.0416, found: 382.0410.
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2ꢀaminoꢀN'ꢀphenylnicotinohydrazide(1aʹ): White solid (272 mg, 55%); mp 158ꢀ160 C; FTꢀIR (KBr, νmax/cmꢀ1)
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3398, 1639, 1403, 1219, 1065, 771; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.27 (d, 1H, J = 1.88 Hz), 8.12ꢀ8.05 (m,
2H), 7.83 (d, 1H, J = 2.08 Hz), 7.15 (t, 2H, J = 8.12 Hz), 7.00 (br s, 2H), 6.78 (d, 2H, J = 7.76 Hz), 6.72 (t, 1H, J =
7.28 Hz), 6.63 (dd, 1H, J = 7.64, 4.8 Hz) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 167.6, 158.8 (C), 151.7 (CH),
149.5 (C), 136.4 (CH), 128.7 (2xCH), 118.7 (CH), 112.3 (2xCH), 111.4 (CH), 107.8 (C) ppm; HRMS (ESI): calcd
for C12H12N4O [M+H]+ 229.1089, found: 229.1088.
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2ꢀaminoꢀN'ꢀ(4ꢀchlorophenyl)nicotinohydrazide(1bʹ): White solid (295 mg, 52%); mp 220ꢀ222 C; FTꢀIR (KBr,
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νmax/cmꢀ1) 3401, 1637, 1403, 1216, 1068, 771, 668; H NMR (400 MHz, DMSOꢀd6): δ = 10.30 (d, 1H, J = 2.28
Hz), 8.12 (dd, 1H, J = 4.76, 1.72 Hz), 8.06ꢀ8.02 (m, 2H), 7.20ꢀ7.16 (m, 2H), 7.00 (br s, 2H), 6.80ꢀ6.76 (m, 2H), 6.62
(dd, 1H, J = 7.68, 4.76 Hz) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 167.6, 158.8 (C), 151.9 (CH), 148.5 (C),
136.4 (CH), 128.5 (2xCH), 121.9 (C), 113.7 (2xCH), 111.4 (CH), 107.6 (C) ppm; HRMS (ESI): calcd for
C12H11ClN4O [M+H]+ 263.0700, found: 263.0690.
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2ꢀaminoꢀN'ꢀ(4ꢀbromophenyl)nicotinohydrazide(1cʹ): White solid (345 mg, 52%); mp 216ꢀ218 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3400, 3019, 1639, 1404, 1215, 1063, 928, 757, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.29 (d, 1H, J
= 2.40 Hz), 8.12 (dd, 1H, J = 4.76. 1.72 Hz), 8.05ꢀ8.03 (m, 2H), 7.30ꢀ7.28 (m, 2H), 6.99 (br s, 2H), 6.74ꢀ6.72 (m,
2H), 6.62 (dd, 1H, J = 7.72, 4.8 Hz) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 167.6, 158.8 (C), 151.9 (CH), 148.9
(C), 136.4 (CH), 131.3 (2xCH), 114.3 (2xCH), 114.4 (CH), 109.4 (C), 107.6 (C) ppm; HRMS (ESI): calcd for
C12H11BrN4O [M+H]+ 307.0194, found: 307.0191.
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2ꢀaminoꢀN'ꢀ(4ꢀmethoxyphenyl)nicotinohydrazide (1eʹ ): White solid (337 mg, 60%); mp 149ꢀ151 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3745, 3393, 3019, 1633, 1403, 1215, 1155, 1068, 769, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 10.26
(d, 1H, J = 3.04 Hz), 8.11 (dd, 1H, J = 4.72, 1.60 Hz), 8.04 (dd, 1H, J = 7.68, 1.52 Hz), 7.52 (d, 1H, J = 3.16 Hz),
6.99 (br s, 2H), 6.79ꢀ6.74 (m, 4H), 6.61 (dd, 1H, J = 7.68, 4.80 Hz), 3.65 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀ
d6) δ = 167.6, 158.7 (C), 152.8 (CH), 151.6 (C), 143.3 (CH), 136.3 (C), 114.2 (2xCH), 113.8 (2xCH), 111.4 (CH),
107.9 (C), 55.2 ppm; HRMS (ESI): calcd for C13H14N4O2 [M+H]+ 259.1195; found: 259.1191.
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(E)ꢀ3ꢀ(phenyldiazenyl)benzo[c]isoxazole (2a): Red solid (235 mg, 80%); mp 90ꢀ92 C; FTꢀIR (KBr, νmax/cmꢀ1)
3401, 3018, 1654, 1384, 1216, 1084, 770, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 8.10ꢀ8.04 (m, 3H), 7.78 (d, 1H,
J = 9.00 Hz), 7.67ꢀ7.66 (m, 3H), 7.59ꢀ7.55 (m, 1H), 7.43ꢀ7.40 (m, 1H) ppm; 13C NMR (100 MHz, DMSOꢀd6): δ =
166.9 (C), 157.9 (C), 152.7 (C), 133.6 (CH), 132.3 (CH), 129.7 (2xCH), 129.5 (CH), 123.3 (2xCH), 121.4 (CH),
115.5 (CH), 108.7 (C) ppm; HRMS (ESI): calcd for C13H9N3O [M+H]+ 224.0824, found: 224.0824.
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(E)ꢀ3ꢀ((4ꢀfluorophenyl)diazenyl)benzo[c]isoxazole (2b): Red solid (205 mg, 70%); mp 158ꢀ159 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3400, 3019, 2400, 1592, 1496, 1384, 1215, 1070, 929, 846, 757, 669 ; 1H NMR (400 MHz, CDCl3): δ =
8.02ꢀ7.96 (m, 3H), 7.59 (d, 1H, J = 8.92 Hz), 7.36ꢀ7.32 (m, 1H), 7.21ꢀ7.15 (m, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ = 167.4 (C), 165.7 (d, J = 254.57 Hz) (C), 158.5 (C), 150.1 (C), 131.6 (CH), 128.6 (CH), 125.9 (d, J =
9.03 Hz, 2xCH), 121.8 (CH), 116.7 (d, J = 23.09 Hz, 2xCH), 116.0 (CH), 109.8 (C) ppm; HRMS (ESI): calcd for
C13H8FN3O [M+H]+ 242.0730, found: 242.0726.
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(E)ꢀ3ꢀ((4ꢀchlorophenyl)diazenyl)benzo[c]isoxazole (2c): Red solid (224 mg, 76%); mp 140ꢀ141 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3746, 3686, 3400, 3019, 2400, 1614, 1385, 1215, 1085, 929, 757, 669; 1H NMR (400 MHz, CDCl3): δ =
8.04ꢀ7.97 (m, 3H), 7.66 (d, 1H, J = 8.96 Hz), 7.52 (d, 2H, J = 10.56 Hz), 7.43ꢀ7.39 (m, 1H), 7.29ꢀ7.25 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ = 167.4 (C), 158.5 (C), 151.8 (C), 139.3 (C), 131.6 (CH), 129.8 (2xCH), 128.8
(CH), 124.8 (2xCH), 121.8 (CH), 116.1 (CH), 110.0 (C) ppm; HRMS (ESI): calcd for C13H8ClN3O [M+H]+
258.0434, found: 258.0434.
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(E)ꢀ3ꢀ((4ꢀbromophenyl)diazenyl)benzo[c]isoxazole (2d): Red solid (224 mg, 76%); mp 156ꢀ158 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3400, 3019, 1614, 1385, 1215, 1067, 758, 669; 1H NMR (400 MHz, CDCl3): δ = 7.99 (d, 1H, J = 7.68
Hz), 7.86 (d, 2H, J = 6.72 Hz), 7.65ꢀ7.64 (m, 3H), 7.37 (s, 1H), 7.25ꢀ7.23 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ = 167.4 (C), 158.6 (C), 152.1 (C), 132.8 (2xCH), 131.6 (CH), 128.9 (CH), 127.9 (CH), 125 (2xCH), 121.8
(CH), 116.1 (CH), 110.0 (C) ppm; HRMS (ESI): calcd for C13H8BrN3O [M+H]+ 301.9929, found: 301.9923.
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(E)ꢀ3ꢀ((3ꢀfluorophenyl)diazenyl)benzo[c]isoxazole (2e): Red solid (206 mg, 70%); mp 135ꢀ137 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3392, 1619, 1387, 1068, 770; 1H NMR (400 MHz, DMSOꢀd6): δ = 8.13 (d, 1H, J = 8.72 Hz), 7.98ꢀ7.95
(m, 1H), 7.85ꢀ7.80 (m, 2H), 7.75ꢀ7.69 (m, 1H), 7.62ꢀ7.51 (m, 2H), 7.48ꢀ7.44 (m, 1H) ppm; 13C NMR (100 MHz,
DMSOꢀd6) δ = 166.7 (C), 162.7 (d, J = 247.37 Hz, C), 158.0 (C), 154.1 (d, J = 8.89 Hz, C), 132.5 (2xCH), 131.6 (d,
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J = 8.57 Hz, CH), 130.0 (CH), 121.3 (d, J = 11.03 Hz, CH), 120.2 (d, J = 22.09 Hz, CH), 115.7 (CH), 109.5 (C),
108.2 (d, J = 22.93 Hz, CH) ppm; HRMS (ESI): calcd for C13H8FN3O [M+H]+ 242.0730, found: 242.0726.
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(E)ꢀ3ꢀ((3ꢀchlorophenyl)diazenyl)benzo[c]isoxazole (2f): Red solid (206 mg, 71%); mp 155ꢀ156 C; FTꢀIR (KBr,
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νmax/cmꢀ1) 3401, 3019, 1613, 1385, 1215,1068, 930, 757, 669; 1H NMR (400 MHz, CDCl3): δ = 8.06ꢀ8.02 (m, 2H),
7.96ꢀ7.93 (m, 1H), 7.68 (d, 1H, J = 9.04 Hz), 7.53ꢀ7.48 (m, 2H), 7.45ꢀ7.41 (m, 1H), 7.31ꢀ7.26 (m, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 167.3 (C), 158.6 (C), 154.1 (C), 135.7 (C), 132.6 (CH), 131.7 (CH), 130.5 (CH), 129.1
(CH), 123.1 (CH), 122.5 (CH), 121.7, 116.2 (CH), 110.2 (C) ppm; HRMS (ESI): calcd for C13H8ClN3O [M+H]+
258.0434, found: 258.0433.
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(E)ꢀ3ꢀ((2,4ꢀdichlorophenyl)diazenyl)benzo[c]isoxazole (2g): Red solid (201 mg, 68%); mp 174ꢀ176 C; FTꢀIR
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(KBr, νmax/cmꢀ1) 3400, 1636, 1403, 1217, 1068, 840, 771, 669; H NMR (400 MHz, CDCl3): δ = 8.13 (m, 1H),
7.88 (d, 1H, J = 8.8 Hz), 7.69 (d, 1H, J = 9.00 Hz), 7.63 (d, 1H, J = 2.16 Hz), 7.46ꢀ7.42 (m, 1H), 7.37ꢀ7.31 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ = 168.6 (C), 158.6 (C), 147.9 (C), 139.6 (C), 138.5 (C), 131.8 (CH), 131.0
(CH), 129.9 (CH), 128.2 (CH), 122.5 (CH), 117.7 (CH), 116.1 (CH), 108.3 (C) ppm; HRMS (ESI): calcd for
C13H7Cl2N3O [M+H]+ 292.0044 ; found: 292.0042.
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(E)ꢀ3ꢀ((3,4ꢀdichlorophenyl)diazenyl)benzo[c]isoxazole (2h): Red solid (201 mg, 68%); mp 158ꢀ160 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3853, 3745, 3400, 3019, 2400, 1615, 1385, 1215, 1083, 758, 669; 1H NMR (400 MHz, CDCl3): δ
= 8.13 (d, 1H, J = 2.12 Hz), 8.03 (d, 1H, J = 8.68 Hz), 7.90 (dd, 1H, J = 8.56, 2.16 Hz), 7.68 (d, 1H, J = 9.04 Hz),
7.63 (d, 1H, J = 8.56 Hz), 7.45ꢀ7.41 (m, 1H), 7.32ꢀ7.28 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ =167.2 (C),
158.6 (C), 152.3 (C), 137.1 (C), 134.1 (C), 131.7 (CH), 131.3 (CH), 129.4 (CH), 124.6 (CH), 123.2 (CH), 121.7
(CH), 116.3 (CH), 110.5 (C) ppm; HRMS (ESI): calcd for C13H7Cl2 N3O [M+H]+ 292.0044, found: 292.0045.
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(E)ꢀ3ꢀ(pꢀtolyldiazenyl)benzo[c]isoxazole (2i): Red solid (236 mg, 80%); mp 130ꢀ132 C; FTꢀIR (KBr, νmax/cmꢀ1)
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3400, 3019, 1600, 1385, 1215, 1070, 757, 669; H NMR (400 MHz, CDCl3): δ = 8.06 (dt, 1H, J = 8.72, 1.0 Hz),
7.95 (d, 2H, J = 8.32 Hz), 7.65 (dd, 1H, J = 9.04, 0.72 Hz ), 7.40 (ddd, 1H, J = 10.2, 6.44, 1.0 Hz), 7.35 (d, 2H, J =
8.08 Hz), 7.26ꢀ7.22 (m, 1H), 2.46 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 167.8 (C), 158.5 (C), 151.8 (C),
144.4 (C), 131.5 (CH), 130.2 (2xCH), 128.2 (CH), 123.8 (2xCH), 122.0 (CH), 115.9 (CH), 109.5 (C), 21.9 (CH3)
ppm; HRMS (ESI): calcd for C14H11N3O [M+H]+ 238.0980, found: 238.0975.
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(E)ꢀ3ꢀ((3,4ꢀdimethylphenyl)diazenyl)benzo[c]isoxazole (2j): Red solid (237 mg, 81%); mp 154ꢀ155 oC; FTꢀIR (KBr,
νmax/cmꢀ1) 3395, 1613, 1388, 1073, 760; 1H NMR (400 MHz, CDCl3): δ = 8.09 (d, 1H, J = 8.64 Hz), 7.85 (s, 1H),
7.82 (d, 1H, J = 8.12 Hz), 7.65 (d, 1H, J = 8.96 Hz), 7.42ꢀ7.39 (m, 1H), 7.32 (d, 1H, J = 7.96 Hz), 7.26ꢀ7.22 (m,
1H), 2.38 (s, 3H), 2.37 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ = 167.2 (C), 157.9 (C), 151.3 (C), 143.7 (C),
138.1 (C), 132.3 (CH), 130.8 (CH), 129.1 (CH), 123.9 (CH), 121.5 (CH), 121.4 (CH), 115.4 (CH), 108.3 (C), 19.7
(CH3), 19.3 (CH3) ppm; HRMS (ESI): calcd for C15H13N3O [M+H]+ 252.1137, found: 252.1135.
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(E)ꢀ3ꢀ((2,5ꢀdimethylphenyl)diazenyl)benzo[c]isoxazole (2k): Red solid (237 mg, 81%); mp 148ꢀ150 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3417, 1639, 1403, 1069, 757; 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, 1H, J = 8.68 Hz), 7.68 (d,
2H, J = 8.72 Hz), 7.43 (ddd, 1H, J = 9.0, 6.48, 0.92 Hz), 7.29ꢀ7.27 (m, 3H), 2.77 (s, 3H), 2.40 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ = 168.6 (C), 158.5 (C), 151.5 (C), 138.0 (C), 136.6 (C), 134.5 (CH), 131.5 (CH), 131.4
(CH), 128.5 (CH), 122.1 (CH), 115.9 (CH), 115.1 (CH), 107.9 (C), 21.0 (CH3), 17.6 (CH3) ppm; HRMS (ESI):
calcd for C15H13N3O [M+H] + 252.1137, found: 252.1132.
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(E)ꢀ3ꢀ((4ꢀmethoxyphenyl)diazenyl)benzo[c]isoxazole (2l): Red solid (243 mg, 83%); mp 120ꢀ122 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3409, 1638, 1403, 1068, 760; 1H NMR (400 MHz, CDCl3): δ = 8.07ꢀ8.03 (m, 3H), 7.63 (d, 1H, J = 9.05
Hz), 7.41ꢀ7.37 (m, 1H), 7.24ꢀ7.18 (m, 1H), 7.07ꢀ7.03 (m, 2H), 3.93 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ =
167.9 (C), 164.1 (C), 158.6 (C), 148.2 (C), 131.5 (CH), 127.8 (CH), 126.1 (2xCH), 122.1 (CH), 115.8 (CH), 114.8
(2xCH), 109.4 (C), 55.9 ppm; HRMS (ESI): calcd for C14H11N3O2 [M+H] 254.0930, found: 254.0915.
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(E)ꢀ6ꢀchloroꢀ3ꢀ(phenyldiazenyl)benzo[c]isoxazole (2m): Red solid (230 mg, 78%); mp 119ꢀ121 C; FTꢀIR (KBr,
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νmax/cmꢀ1) 3401, 1643, 1403, 1069, 770; H NMR (400 MHz, CDCl3): δ = 8.05ꢀ8.00 (m, 3H), 7.66 (dd, 1H, J =
1.36, 0.8 Hz), 7.60ꢀ7.54 (m, 3H), 7.17 (dd, 1H, J = 9.12, 1.56 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.0 (C),
158.6 (C), 153.4 (C), 137.9 (C), 133.6 (CH), 130.2 (CH), 129.6 (2xCH), 123.9 (2xCH), 123.3 (CH), 114.5 (CH),
107.3 (C) ppm; HRMS (ESI): calcd for C13H8ClN3O [M+H] + 258.0434, found: 258.0428.
(E)ꢀ6ꢀchloroꢀ3ꢀ((4ꢀfluorophenyl)diazenyl)benzo[c]isoxazole (2n): Red solid (206 mg, 70%); mp 170ꢀ172 oC; FTꢀIR
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(KBr, νmax/cmꢀ1) 3403, 2922, 2314, 1642, 1402, 1069, 766; H NMR (400 MHz, CDCl3): δ = 8.10ꢀ8.07 (m, 2H),
8.00 (d, 1H, J = 9.04 Hz), 7.67 (s, 1H), 7.26 (br t, 2H), 7.18 (dd, 1H, J = 9.08, 1.44 Hz) ppm; 13C NMR (100 MHz,
CDCl3) δ = 167.8 (C), 167.3 (C), 158.6 (C), 150.1 (C), 138.0 (C), 130.2 (CH), 126.2 (d, J = 8.98 Hz, 2xCH), 123.1
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(CH), 116.8 (d, J = 23.0 Hz, 2xCH), 114.6 (CH), 107.8 (C) ppm; HRMS (ESI): calcd for C13H7ClFN3O [M+H] +
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(E)ꢀ6ꢀchloroꢀ3ꢀ((4ꢀchlorophenyl)diazenyl)benzo[c]isoxazole (2o): Red solid (203 mg, 69%); mp 165ꢀ166 oC; FTꢀIR
(KBr, νmax/cmꢀ1) 3400, 3019, 2399, 1613, 1385, 1215, 1084, 928, 757, 669; 1H NMR (400 MHz, CDCl3): δ = 7.99
(d, 3H, J = 8.8 Hz), 7.67 (s, 1H), 7.54 (d, 2H, J = 8.8 Hz), 7.19 (dd, 1H, J = 9.12, 1.36 Hz) ppm; 13C NMR (100
MHz, CDCl3) δ = 167.8 (C), 158.6 (C), 151.7 (C), 139.9 (C), 138.0 (C), 130.5 (CH), 130.0 (2xCH), 125.0 (2xCH),
123.1 (CH), 114.6 (CH), 108.0 (C) ppm; HRMS (ESI): calcd for C13H7Cl2N3O [M+H]+ 292.0044, found: 292.0044.
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(E)ꢀ6ꢀchloroꢀ3ꢀ((3ꢀchlorophenyl)diazenyl)benzo[c]isoxazole (2p): Red solid (188 mg, 64%); mp 175ꢀ176 oC; FTꢀIR
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(KBr, νmax/cmꢀ1) 3401, 2922, 1644, 1403, 1068, 840, 767; H NMR (400 MHz, CDCl3): δ = 8.04ꢀ7.96 (m, 3H),
7.70 (d, 1H, J = 0.64 Hz), 7.56ꢀ7.50 (m, 2H), 7.22 (dd, 1H, J = 9.08, 1.48 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ
= 167.7 (C), 158.7 (C), 154.1 (C), 138.1 (C), 135.8 (C), 133.1 (CH), 130.8 (CH), 130.6 (CH), 123.2 (CH), 123.0
(CH), 122.7 (CH), 114.7 (CH), 108.3 (C) ppm; HRMS (ESI): calcd for C13H7Cl2N3O [M+H] + 292.0044; found:
292.0041
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(E)ꢀ6ꢀchloroꢀ3ꢀ((3,4ꢀdimethylphenyl)diazenyl)benzo[c]isoxazole (2q): Red solid (234 mg, 80%); mp 158ꢀ160 C;
FTꢀIR (KBr, νmax/cmꢀ1) 3394, 1619, 1386, 1300, 1045, 776; 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, 1H, J = 9.12
Hz), 7.78ꢀ7.75 (m, 2H), 7.61 (s, 1H), 7.28 (d, 1H, J = 8.00 Hz), 7.11 (dd, 1H, J = 9.08, 1.48 Hz) ppm; 13C NMR
(100 MHz, CDCl3) δ = 168.2 (C), 158.5 (C), 152.0 (C), 143.9 (C), 138.1 (C), 137.8 (C), 130.8 (CH), 129.7 (CH),
124.4 (CH), 123.5 (CH), 122.1 (CH), 114.3 (CH), 107.3 (C), 20.3 (CH3), 19.9 (CH3) ppm; HRMS (ESI): calcd for
C15H12ClN3O [M+H]+ 286.0747, found: 286.0734
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(E)ꢀ6ꢀbromoꢀ3ꢀ(phenyldiazenyl)benzo[c]isoxazole (2r): Red solid (233 mg, 79%); mp 120ꢀ122 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3409, 1634, 1403, 1216, 1069, 770, 669; 1H NMR (400 MHz, CDCl3): δ = 8.07ꢀ8.03 (m, 2H), 7.95 (dd,
1H, J = 9.08, 0.72 Hz), 7.88 (br t, 1H), 7.60ꢀ7.54 (m, 3H), 7.31 (dd, 1H, J = 9.08, 1.44 Hz) ppm; 13C NMR (100
MHz, CDCl3) δ = 168.1 (C), 159.0 (C), 153.4 (C), 133.7 (CH), 132.5 (CH), 129.6 (2xCH), 126.4 (C), 123.9 (2xCH),
123.2 (CH), 118.1 (CH), 107.8 (C) ppm; HRMS (ESI): calcd for C13H8BrN3O [M+H] + 301.9929, found: 301.9922.
(E)ꢀ6ꢀbromoꢀ3ꢀ((4ꢀchlorophenyl)diazenyl)benzo[c]isoxazole(2s): Red solid (209 mg, 71%); mp 210ꢀ212oC; FTꢀIR
(KBr, νmax/cmꢀ1) 3409, 1639, 1403, 1216, 1091, 840, 771, 669; 1H NMR (400 MHz, CDCl3): δ = 7.98 (dt, 2H, J =
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9.48, 2.6 Hz), 7.91 (dd, 1H, J = 9.08, 0.72 Hz), 7.88 (br t, 1H), 7.53 (dt, 2H, J = 9.48, 2.60 Hz), 7.31 (dd, 1H, J =
9.08, 1.4 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ = 167.9 (C), 159.0 (C), 151.7 (C), 139.9 (C), 132.7 (CH), 130.0
(2xCH), 126.5 (C), 125.0 (2xCH), 123.0 (CH), 118.1 (CH), 108.1 (C) ppm; HRMS (ESI): calcd for C13H7BrClN3O
[M+H] + 335.9539, found: 335.9546.
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(E)ꢀ6ꢀbromoꢀ3ꢀ(pꢀtolyldiazenyl)benzo[c]isoxazole (2t): Red solid (221 mg, 75%); mp 138ꢀ140 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3401, 1636, 1403, 1069, 768; 1H NMR (400 MHz, CDCl3): δ = 7.95ꢀ7.92 (m, 3H), 7.85 (s, 1H), 7.35 (d,
2H, J = 8.2 Hz), 7.27 (dd, 1H, J = 9.08, 1.32 Hz), 2.47 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.3 (C),
158.9 (C), 151.7 (C), 145.1 (C), 132.0 (CH), 130.3 (2xCH), 126.3 (C), 124.0 (2xCH), 123.4 (CH), 117.9 (CH),
107.6 (C), 21.9 (CH3) ppm; HRMS (ESI): calcd for C14H10BrN3O [M+H]+ 316.0085, found: 316.0072.
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(E)ꢀ5ꢀiodoꢀ3ꢀ(phenyldiazenyl)benzo[c]isoxazole (2u): Red solid (222 mg, 75%); mp 138ꢀ140 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3401, 1642, 1401, 1217, 1071, 769; 1H NMR (400 MHz, CDCl3): δ = 8.54 (br t, 1H), 8.09ꢀ8.04 (m, 2H),
7.63ꢀ7.54 (m, 4H), 7.43 (dd, 1H, J = 9.32, 0.8 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ = 166.4 (C), 156.9 (C),
153.5 (C), 140.3 (CH), 133.6 (CH), 131.0 (CH), 129.6 (2xCH), 123.9 (2xCH), 117.3 (CH), 110.8 (C), 94.2 (C) ppm;
HRMS (ESI): calcd for C13H8IN3O [M+H]+ 349.9790, found: 349.9795.
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(E)ꢀ3ꢀ((4ꢀchlorophenyl)diazenyl)ꢀ5ꢀiodobenzo[c]isoxazole (2v): Red solid (191 mg, 65%); mp 185ꢀ187 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3401, 1637, 1403, 1068, 841, 760; 1H NMR (400 MHz, CDCl3): δ = 8.52 (s, 1H), 8.02 (dt, 2H, J
= 9.44, 2.64 Hz), 7.63 (dd, 1H, J = 9.32, 1.48 Hz), 7.54 (dt, 2H, J = 9.48, 2.64 Hz), 7.44 (dd, 1H, J = 9.32, 0.8 Hz)
ppm; 13C NMR (100 MHz, CDCl3) δ = 166.2 (C), 157.0 (C), 151.9 (C), 140.4 (CH), 139.8 (C), 130.9 (CH), 130.0
(2xCH), 125.0 (2xCH), 117.4 (CH), 111.0 (C), 94.6 (C) ppm; HRMS (ESI): calcd for C13H7ClIN3O [M+H]+
383.9401, found: 383.9402.
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(E)ꢀ5ꢀiodoꢀ3ꢀ(pꢀtolyldiazenyl)benzo[c]isoxazole (2w): Red solid (229 mg, 78%); mp 142ꢀ144 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3400, 1644, 1403, 1068, 760; 1H NMR (400 MHz, CDCl3): δ = 8.52 (s, 1H), 7.96 (d, 2H, J = 8.32 Hz),
7.60 (dd, 1H, J = 9.32, 1.44 Hz), 7.41 (dd, 1H, J = 9.32, 0.76 Hz), 7.35 (d, 2H, J = 8.16 Hz), 2.46 (s, 3H) ppm; 13
C
NMR (100 MHz, CDCl3) δ = 166.6 (C), 156.9 (C), 151.8 (C), 145.0 (C), 140.2 (CH), 131.1 (CH), 130.3 (2xCH),
124.0 (2xCH), 117.3 (CH), 110.6 (C), 93.7 (C), 22.0 (CH3) ppm; HRMS (ESI): calcd for C14H10IN3O [M+H]+
363.9947, found: 363.9939.
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(E)ꢀ3ꢀ((2,5ꢀdimethylphenyl)diazenyl)ꢀ5ꢀiodobenzo[c]isoxazole (2x): Red solid (229 mg, 78%); mp 190ꢀ192 C; FTꢀ
IR (KBr, νmax/cmꢀ1) 3409, 1640, 1403, 1219, 1068, 771; H NMR (400 MHz, CDCl3): δ = 8.49 (s, 1H), 7.66 (s,
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1H), 7.61 (dd, 1H, J = 9.28, 1.4 Hz), 7.43 (d, 1H, J = 9.28 Hz), 7.29 (Br s, 2H), 2.74 (s, 3H), 2.39 (s, 3H) ppm; 13
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NMR (100 MHz, CDCl3) δ = 167.3 (C), 156.9 (C), 151.6 (C), 140.2 (CH), 138.4 (C), 136.7 (C), 135.0 (CH), 131.7
(CH), 131.3 (CH), 117.3 (CH), 115.2 (CH), 109.8 (C), 94.0 (C), 21.1 (CH3), 17.7 (CH3) ppm; HRMS (ESI): calcd
for C15H12IN3O [M+H]+ 378.0103, found: 378.0103.
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(E)ꢀ3ꢀ(phenyldiazenyl)isoxazolo[3,4ꢀb]pyridine (2aʹ ): Red solid (184 mg, 63%); mp 120ꢀ122 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3410, 1633, 1404, 1217, 1070, 771; 1H NMR (400 MHz, CDCl3): δ = 8.88 (dd, 1H, J = 3.88, 1.76 Hz),
8.43 (dd, 1H, J = 8.64, 1.72 Hz), 8.08ꢀ8.04 (m, 2H), 7.62ꢀ7.55 (m, 3H), 7.23 (dd, 1H, J = 8.60, 3.90 Hz) ppm; 13C
NMR (100 MHz, CDCl3) δ = 168.2 (C), 166.3 (C), 158.6 (CH), 153.2 (C), 134.0 (CH), 131.7 (CH), 129.6 (2xCH),
124.0 (2xCH), 123.8 (CH), 101.9 (C) ppm; HRMS (ESI): calcd for C12H8N4O [M+H]+ 225.0776, found: 225.0772.
(E)ꢀ3ꢀ((4ꢀchlorophenyl)diazenyl)isoxazolo[3,4ꢀb]pyridine (2bʹ ): Red solid (182 mg, 62%); mp 179ꢀ181oC; FTꢀIR
(KBr, νmax/cmꢀ1) 3401, 2922, 1644, 1403, 1068, 835, 771; 1H NMR (400 MHz, CDCl3): δ = 8.90 (dd, 1H, J = 3.72,
1.56 Hz), 8.42 (dd, 1H, J = 8.64, 1.6 Hz), 8.02 (d, 2H, J = 8.72 Hz), 7.56 (dd, 2H, J = 8.72 Hz), 7.26ꢀ7.23 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ = 168.1 (C), 166.4 (C), 158.6 (CH), 151.7 (C), 140.3 (C), 131.6 (CH), 130.1
(2xCH), 125.2 (2xCH), 124.0 (CH), 102.3 (C) ppm; HRMS (ESI): calcd for C12H7ClN4O [M+H]+ 259.0387, found:
259.0395.
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(E)ꢀ3ꢀ((4ꢀbromophenyl)diazenyl)isoxazolo[3,4ꢀb]pyridine (2cʹ ): Red solid (181 mg, 62%); mp 180ꢀ182 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3401, 1644, 1403, 1068, 838, 770; 1H NMR (400 MHz, CDCl3): δ = 8.89 (dd, 1H, J = 3.88, 1.72
Hz), 8.41 (dd, 1H, J = 8.64, 1.72 Hz), 7.95ꢀ7.91 (m, 2H), 7.74ꢀ7.70 (m, 2H), 7.26ꢀ7.22 (m, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ = 168.1 (C), 166.4 (C), 158.7 (CH), 152.0 (C), 133.1 (2xCH), 131.6 (CH), 129.1 (C), 125.3 (2xCH),
124.0 (CH), 102.3 (C) ppm; HRMS (ESI): calcd for C12H7BrN4O [M+H]+ 302.9881, found: 302.9873.
(E)ꢀ3ꢀ((2,5ꢀdimethylphenyl)diazenyl)isoxazolo[3,4ꢀb]pyridine (2dʹ ): Red solid (192 mg, 65%); mp 165ꢀ167 oC; FTꢀ
IR (KBr, νmax/cmꢀ1) 3400, 1636, 1403, 1217, 1068, 840, 771, 669; 1H NMR (400 MHz, CDCl3): δ = 8.87 (dd, 1H, J
= 3.88, 1.72 Hz), 8.34 (dd, 1H, J = 8.6, 1.72 Hz), 7.68 (s, 1H), 7.33ꢀ7.28 (m, 2H), 7.21 (dd, 1H, J = 8.6, 3.92 Hz),
2.74 (s, 3H), 2.38 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 169.1 (C), 166.3 (C), 158.4 (CH), 151.4 (C), 138.7
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(C), 136.8 (C), 135.5 (CH), 131.8 (CH), 131.7 (CH), 123.7 (CH), 115.2 ( CH), 100.9 (C), 21.0 (CH3), 17.6 (CH3)
ppm; HRMS (ESI): calcd for C14H12N4O [M+H]+ 253.1089, found: 253.1086.
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(E)ꢀ3ꢀ((4ꢀmethoxyphenyl)diazenyl)isoxazolo[3,4ꢀb]pyridine (2eʹ ): Red solid (198 mg, 67%); mp 165ꢀ167 oC; FTꢀIR
(KBr, νmax/cmꢀ1) 3399, 1637, 1403, 1217, 1069, 771; 1H NMR (400 MHz, CDCl3): δ = 8.85 (dd, 1H, J = 3.88, 1.72
Hz), 8.41 (dd, 1H, J = 8.6, 1.72 Hz), 8.05 (dt, 2H, J = 10.2, 3.16 Hz ), 7.16 (dd, 1H, J = 8.64, 3.92 Hz), 7.07ꢀ7.03
(m, 2H), 3.94 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ = 168.7 (C), 166.3 (C), 164.8 (C), 158.4 (CH), 148.0 (C),
132.1 (CH), 126.5 (2xCH), 123.0 (CH), 115.0 (2xCH), 101.5 (C), 56.0 ppm; HRMS (ESI): calcd for C13H10N4O2
[M+H]+ 255.0882, found: 255.0878
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(E)ꢀ3ꢀ(phenyldiazenyl)benzo[c]isothiazole (3a): Red solid (220 mg, 70%); mp 96ꢀ98 C; FTꢀIR (KBr, νmax/cmꢀ1)
3399, 2923, 1639, 1385, 1219, 1154, 1068, 771; 1H NMR (400 MHz, CDCl3): δ = 8.28ꢀ8.26 (m, 1H), 8.02ꢀ7.99 (m,
2H), 7.78 (d, 1H, J = 8.96 Hz), 7.58ꢀ7.52 (m, 3H), 7.51ꢀ7.46 (m, 1H), 7.40ꢀ7.36 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 173.2 (C), 162.8 (C), 152.6 (C), 132.5 (CH), 131.6 (C), 129.6 (CH), 129.4 (2xCH), 126.7 (CH), 123.6
(2xCH), 122.8 (CH), 121.2 (CH) ppm; HRMS (ESI): calcd for C13H9N3S [M+H]+ 240.0595; found: 240.0582.
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(E)ꢀ6ꢀbromoꢀ3ꢀ(phenyldiazenyl)benzo[c]isothiazole (3b): Red solid (205 mg, 66%); mp 116ꢀ118 C; FTꢀIR (KBr,
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νmax/cmꢀ1) 3399, 2922, 1638, 1385, 1218, 1153, 1068, 771; H NMR (400 MHz, CDCl3): δ = 8.11 (dd, 1H, J =
9.04, 0.36 Hz), 8.00ꢀ7.98 (m, 3H), 7.56ꢀ7.54 (m, 3H), 7.44 (dd, 1H, J = 9.04, 1.56 Hz) ppm; 13C NMR (100 MHz,
CDCl3) δ = 174.0 (C), 162.6 (C), 152.4 (C), 132.9 (CH), 130.3 (CH), 129.9 (C), 129.5 (2xCH), 124.9 (CH), 123.7
(2xCH), 121.9 (CH) ppm; HRMS (ESI): calcd for C13H8BrN3S [M+H]+ 317.9701; found: 317.9687.
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(E)ꢀ3ꢀ((4ꢀchlorophenyl)diazenyl)benzo[c]isothiazole (3c): Red solid (186 mg, 60%); mp 135ꢀ138 C; FTꢀIR (KBr,
νmax/cmꢀ1) 3400, 2921, 1639, 1385, 1218, 1153, 1068, 772; 1H NMR (400 MHz, CDCl3): δ = 8.24 (d, 1H, J =8.56
Hz), 7.96ꢀ7.94 (m, 2H), 7.78 (d, 1H, J = 8.92 Hz), 7.52ꢀ7.48 (m, 3H), 7.42ꢀ7.37 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ = 172.9 (C), 162.8 (C), 150.9 (C), 138.5 (C), 131.7 (C), 129.8 (2xCH), 129.7 (CH), 127.0 (CH), 124.7
(2xCH), 122.9 (CH), 121.1 (CH) ppm; HRMS (ESI): calcd for C13H8ClN3S [M+H]+ 274.0206, found: 274.0199.
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(E)ꢀ6ꢀbromoꢀ3ꢀ((4ꢀchlorophenyl)diazenyl)benzo[c]isothiazole (3d): Red solid (179 mg, 58%); mp 162ꢀ168 C; FTꢀ
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(dd, 1H, J = 9.04, 0.48 Hz), 7.99 (d, 1H, J = 1.00 Hz), 7.95ꢀ7.92 (m, 2H), 7.53ꢀ7.50 (m, 2H), 7.45 (dd, 1H, J = 9.04,
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1.56 Hz) ppm; 13C NMR (100 MHz, CDCl3) δ = 173.7 (C), 162.6 (C), 150.8 (C), 139.0 (C), 130.5 (CH), 129.8
(2xCH), 129.3 (C), 127.5 (C), 125.0 (CH), 124.9 (2xCH), 121.8 (CH) ppm; HRMS (ESI): calcd for C13H7BrClN3S
[M+H]+ 351.9311; found: 351.9303.
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(E)ꢀ3ꢀ((3,4ꢀdichlorophenyl)diazenyl)benzo[c]isothiazole (3e): Red solid (176 mg, 57%); mp 150ꢀ152 C; FTꢀIR
(KBr, νmax/cmꢀ1) 3396, 3019, 2920, 1638, 1385, 1216, 1154, 1067, 771, 669; 1H NMR (400 MHz, CDCl3): δ = 8.25
(d, 1H, J = 8.56 Hz), 8.10 (d, 1H, J = 2.2 Hz), 7.86 (dd, 1H, J = 8.56, 2.24 Hz), 7.79 (d, 1H, J = 8.92 Hz), 7.63 (d,
1H, J = 8.56 Hz), 7.53ꢀ7.48 (m, 1H), 7.44ꢀ7.40 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ =172.4 (C), 162.9 (C),
151.4 (C), 136.4 (C), 134.0 (C), 131.9 (C), 131.3 (CH), 129.8 (CH), 127.4 (CH), 124.2 (CH), 123.4 (CH), 122.9
(CH), 121.1 (CH) ppm; HRMS (ESI): calcd for C13H7Cl2 N3S [M+H]+ 307.9816; found: 307.9807.
o
(E)ꢀ3ꢀ((2,5ꢀdimethylphenyl)diazenyl)benzo[c]isothiazole (3f): Red solid (212 mg, 68%); mp 124ꢀ126 C; FTꢀIR
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(KBr, νmax/cmꢀ1) 3847, 3744, 3669, 3392, 2923, 1638, 1385, 1218, 1155, 1068, 772, 669; H NMR (400 MHz,
CDCl3): δ = 8.30ꢀ8.27 (m, 1H), 7.76 (d, 1H, J = 8.96 Hz), 7.67 (br s, 1H), 7.49ꢀ7.45 (m, 1H), 7.38ꢀ7.34 (m, 1H),
7.24 (s, 2H), 2.67 (s, 3H), 2.40 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 174.2 (C), 162.9 (C), 150.4 (C),
137.0 (C), 136.4 (C), 133.7 (CH), 131.5 (CH), 131.1 (C), 129.5 (CH), 126.5 (CH), 122.7 (CH), 121.3 (CH), 116.2
(CH), 21.1 (CH3), 17.2 (CH3) ppm; HRMS (ESI): calcd for C15H13N3S [M+H]+ 268.0908; found: 268.0902.
o
(E)ꢀ3ꢀ((2,5ꢀdimethylphenyl)diazenyl)ꢀ5ꢀiodobenzo[c]isothiazole (3g): Red solid (199 mg, 65%); mp 197ꢀ199 C;
1
FTꢀIR (KBr, νmax/cmꢀ1) 3400, 3019, 2344, 1638, 1385, 1216, 1068, 769, 668; H NMR (400 MHz, CDCl3): δ =
8.75 (s, 1H), 7.70ꢀ7.68 (m, 2H), 7.51 (d, 1H, J = 9.24 Hz), 7.28 (s, 2H), 2.69 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 173.3 (C), 161.1 (C), 150.4 (C), 138.1 (CH), 137.4 (C), 136.5 (C), 134.1 (CH), 132.4 (C),
131.6 (CH), 130.4 (CH), 123.8 (CH), 116.2 (CH), 93.1 (C), 21.1 (CH3), 17.2 (CH3) ppm; HRMS (ESI): calcd for
C15H12IN3S [M+H]+ 393.9875; found: 393.9867.
(E)ꢀ(2ꢀaminophenyl)(phenyldiazenyl)methanone (4a): Red solid (267 mg, 90%); mp 90ꢀ92 oC; FTꢀIR (KBr,
νmax/cmꢀ1) 3372, 3018, 2925, 2856, 1617, 1389, 1216, 1072, 669; 1H NMR (400 MHz, DMSOꢀd6): δ = 7.96 (dt, 2H,
J = 6.5, 1.26 Hz), 7.72ꢀ7.64 (m, 3H), 7.40ꢀ7.35 (m, 2H), 7.31 (br s, 2H), 6.92 (d,1H, J = 8.35 Hz), 6.54ꢀ6.50 (m, 1H)
ppm; 13C NMR (100 MHz, DMSOꢀd6): δ = 182.9, 153.0 (C), 151.4 (C), 136.0 (CH), 133.3 (CH), 131.5 (CH), 129.7
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(2xCH), 122.9 (2xCH), 116.9 (CH), 114.6 (CH), 109.1 (C) ppm; HRMS (ESI): calcd for C13H11N3O [M+H]+
226.0980, found: 226.0972
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(E)ꢀ(2ꢀ(methylamino)phenyl)(phenyldiazenyl)methanone (5a): Red solid (266 mg, 90%); mp 85ꢀ87 oC; FTꢀIR (KBr,
νmax/cmꢀ1) 3407, 2938, 2088, 1723, 1638, 1593, 1404, 1385, 1238, 1217, 1149, 1069, 917, 668, 599; 1H NMR (400
MHz, CDCl3): δ = 8.41 (br s, 1H), 8.01ꢀ7.98 (m, 2H), 7.79 (dd, 1H, J = 8.12, 1.56 Hz), 7.60ꢀ7.53 (m, 3H), 7.48ꢀ
7.44 (m,1H), 6.77 (d, 1H, J = 8.56 Hz), 6.60ꢀ6.56 (m, 1H), 3.01 (d, 3H, J = 5.08 Hz) ppm; 13C NMR (100 MHz,
CDCl3): δ = 183.0, 153.6 (C), 152.3 (C), 136.7 (CH), 133.2 (CH), 133.1 (CH), 129.4 (3xCH), 123.7 (CH), 114.3
(CH), 111.5 (C), 111.3 (CH), 29.6 (CH3) ppm; HRMS (ESI): calcd for C14H13N3O [M+H]+ 240.1137, found:
240.1133.
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ASSOCIATED CONTENT
Supporting Information
1H and 13C spectra of all compounds and Xꢀray crystallographic data for compound 2c. This
material is available free of charge via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: pp_yadav@cdri.res.in, ppy_cdri@yahoo.co.in
Author Contribution
§D. A. and O. P. S. P. contributed equally to this work.
Notes
The authors declare no competing financial interest.
Acknowledgement
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D. A. and R. K. M. are thankful to CSIR, New Delhi, and O. P. S. P. is thankful to UGC, New
Delhi for financial assistance. The authors are thankful to Mr. Anoop K. Srivastava for technical
support and SAIFꢀCDRI, Lucknow, India for providing spectral and analytical data. We are also
thankful to Dr. Tejender S. Thakur (Molecular and Structural Biology Division, CSIRꢀCDRI,
India) for supervising the Xꢀray analysis of compound (2c). This work was supported by CSIR
network project “HOPE” (BSC0114). This is CDRI communication no. 9101.
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