Iodine-catalyzed diazenylation with arylhydrazine hydrochlorides in air

Article abstract of DOI:10.1021/acs.joc.7b03149

A mild approach to diazenylation of active methylene compounds and N-heterocyclic compounds with arylhydrazine hydrochlorides in the presence of iodine under basic aerobic conditions was developed. The reaction could be executed either under heating or in the presence of blue LED light, though the latter condition was found to be relatively efficient. Presumably, the aryldiazene produced by oxidation of arylhydrazine hydrochloride acts as a nitrogen scavenger of the radical intermediate generated from the active methylene compound in the presence of iodine to produce the diazo compounds. The scope and limitations of the protocol are presented.

Full text of DOI:10.1021/acs.joc.7b03149

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Article
Iodine-catalyzed Diazenylation with Arylhydrazine hydrochlorides in air
Dinesh Singh Barak, Shashikant U. Dighe, Ilesha Avasthi, and Sanjay Batra
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03149 • Publication Date (Web): 27 Feb 2018
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The Journal of Organic Chemistry
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Iodineꢀcatalyzed Diazenylation with Arylhydrazine
hydrochlorides in air
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Dinesh S. Barak,†,‡ Shashikant U. Dighe,†, ‡, ¥ Ilesha Avasthi⊥ and Sanjay Batra†,§*
†Medicinal and Process Chemistry Division, CSIRꢀCentral Drug Research Institute, Sector 10,
Jankipuram extension, Sitapur Road, Lucknow 226031, India.
⊥Department of Chemistry, Indian Institute of Technology, Kanpur, Kalyanpur, Kanpur 228016, India
§Academy of Scientific and Innovative Research, New Delhi, 110025, India
batra_san@yahoo.co.uk (SB); s_batra@cdri.res.in
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT. A mild approach to diazenylation of active methylene compounds and Nꢀheterocyclic
compounds with arylhydrazine hydrochlorides in the presence of iodine under basic aerobic conditions
was developed. The reaction could be executed either under heating or in the presence of blue LED
light, though later condition was found to be relatively efficient. Presumably, the aryldiazene produced
by oxidation of arylhydrazine hydrochloride acts as nitrogen scavenger of the radical intermediate
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generated from the active methylene compound in the presence of iodine to produce the diazo
compounds. Scope and limitations of the protocol are presented.
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KEYWORDS. Diazo compound, Iodine, diazenylation, Arylhydrazine hydrochloride, diazene, air,
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Introduction
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Azo compounds are of profound importance due to their applications in organic synthesis, chemical
industry and biological systems.1,2 They are used as radical reaction initiator, as ligands of metal
complexes, dyes and pigments, therapeutic agents, materials, metalloꢀassemblies and sensors, food
additives and in textiles. In addition, the potential of azo compounds to act as drug carrier for site
specific delivery particularly to colon wherein bacterial extracellular azoreductase catalyzes the
reduction to produce the therapeutically active amine is reported too.3 Given such significance, their
chemistry has received immense attention. Often, the synthesis of diazo compounds is realized by
coupling of the diazo salts, Wills coupling of nitroso and nitro compounds with aromatic amines and
Wallach rearrangement of azoxy derivatives.4 Some of the recently reported methods also include
catalytic reduction of aromatic nitro compounds,5 oxidation of anilines,6 and dehydrogenation of
arylhydrazine.7 Notably however, to overcome the limitations of the reported strategies and avoid
excessive use of diazonium salts, innovative milder options for diazenylations have been reported
recently. Luo and coꢀworkers8 disclosed Sc(OTf)3ꢀcatalyzed diazenylation of 1,3ꢀcarbonyls using
triazene whereas Cao et al. and Zhang et al. achieved diazenylation of indole and pyrazole, respectively
with triazene in the presence of ionic liquids (Fig. 1).9ꢀ10 Very recently, Jiang et al. disclosed silver saltꢀ
mediated gemꢀdifluoromethylenation of the nitrogen center of aryldiazonium salts for preparing
diazenyl derivatives.11 Remarkably all these methods proceeded via the intermediacy of aryldiazonium
ions which are also known to serve as precursors to arylhydrazines via reduction.12 Heinrich et al.
disclosed that the aryldiazonum salt under the influence of SnCl2 in HCl leads to aryldiazene which
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Figure 1. Strategies for diazenylation
disproportionate to arylhydrazine hydrochloride.13 Conversely, the oxidation of phenylhydrazine results
into phenyl radical via unstable phenyldiazene intermediate14 which has the potential to act as nitrogen
radical scavenger to effect diazenylation. Heinrich et al. even accomplished carbodiazenylation of olefin
by phenylhydrazine in the presence of CAN albiet in 12% yield.15 Recently, Zhu and coꢀworkers
reported that the visible light photoredox catalysisꢀpromoted oxidation of methylhydrazine furnished
diazene which added to Michael acceptors for obtaining pyrazoles but phenylhydrazine under identical
conditions gave benzophenone.16 Perhaps, lack of attempts to use arylhydrazine for diazenylation may
be attributed to its unstable nature in air. In contrast, the air stable arylhydrazine hydrochloride via
oxygenꢀmediated oxidation afforded the aryldiazene which is immediately transformed to the aryl
radical under basic medium.15 With this background and in our interest in iodineꢀmediated reactions,17
we sought to investigate the potential of arylhydrazine hydrochlorides as the aryldiazene source for
diazenylation of active methylene compounds in the presence of iodine under air. We reasoned that the
radical intermediate B generated from the active methylene compound in the presence of iodine
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Scheme 1. Proposed route for diazenylation of active methylene compounds via arylhydrazine
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hydrochloride
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could be scavenged by the aryldiazene cation radical C to furnish D as outlined in Scheme 1.18
However, the possibility of reaction proceeding via JappꢀKlingenmann type ionic process to yield
identical compound cannot be ruled out.19
Results and Discussion
To probe the envisaged objective, in a pilot experiment we examined the reaction between
benzoylacetonitrile 1a and phenylhydrazine hydrochloride 2a in the presence of iodine (100 mol%),
o
K2CO3 (2.0 equiv) and hydrogen peroxide (2.0 equiv) in DMSO as medium under heating at 90 C. The
reaction was completed in 8 h to offer a complex mixture of product from which the major product
isolated in 35 % yield was established to be the desired azo compound 3aa (see Table 1). The melting
point and spectral data of 3aa was in alignment with the literature.20 Hence we considered optimizing
the reaction to obtain 3aa in superior yield. Further evaluation demonstrated that though performing the
reaction in the presence of TBHP enhanced the yield to 42%, carrying out the reaction in the absence of
any external oxidant and under air gave 3aa in 55% yield. Screening different amounts of K2CO3
revealed that 2.5 equiv. gave the product in best yield of 64%. Subsequently, the reaction was
investigated in the presence of alternative iodine source including NIS, TBAI but herein 3aa was
isolated in relatively lower yields. Titrating the amount of iodine in the reaction revealed that 50 mol%
of iodine was optimal to produce 3aa in 82% yield. The reaction failed when performed in the absence
of iodine inferring that it is necessary for the reaction. The reaction was unsuccessful under nitrogen
atmosphere suggesting that aerobic conditions are required for the success of this reaction. Since the
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Table 1. Optimization of the Reaction Conditions for diazenylaion with phenylhydrazine hydrochloridea
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entry reagent
(mol%)
solvent
base (equiv)/ oxidant temp.
(equiv) or light
(oC)
time (h) 3aa
yield
(%)b
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I2 (100)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K2CO3 (2.0)/ H2O2 (2.0) 90
K2CO3 (2.0)/ TBHP (2.0) 90
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57c
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I2 (100)
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I2 (100)
K2CO3 (2.0)
K2CO3 (2.5)
K2CO3 (3.0)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
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90
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I2 (100)
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I2 (100)
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NIS (100)
NBS (100)
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TBAI (100) DMSO
CuBr2 (10) DMSO
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13c,d
14d
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16 d
17 d
18 d
19 d
I2 (50)
I2 (30)
I2 (0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
EtOAc
MeCN
DMSO
DMSO
10
10
8
No reaction
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
I2 (50)
0
K2CO3 (2.5)/ white light rt
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trace
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K2CO3 (2.5)/ blue LED
K2CO3 (2.5)/ blue LED
K2CO3 (2.5)/ blue LED
Cs2CO3 (2.5)/ blue LED
KOH (2.5)/ blue LED
rt
rt
rt
rt
rt
aAll reactions were carried out using 1a (0.1 g, 1.26 mmol), 2a (0.095 g, 1.2 equiv), DMSO (3 mL) in
b
c
air. Isolated yields after column chromatography. Reaction performed under nitrogen atmosphere.
dStarting 1a was recovered from the reaction mixture
visible light promotes homolytic carbonꢀiodine bond fission resulting into radical species,21 we
investigated the reaction in the presence of visible light. Although white light failed to initiate the
reaction, we were delighted to note that under blue light (λ = 455 nm) the reaction was completed in 10
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h to furnish 3aa was in 88% isolated yield. Changing the solvent to MeCN or EtOAc, however was
found to be detrimental to the formation of the product. Replacing K2CO3 with either Cs2CO3 or KOH
gave 3aa in lower yields. Therefore, the optimized condition identified from the study was treating 1a
with 2a in the presence of iodine (50 mol%) and K2CO3 (2.5 equiv) in DMSO as medium either under
heating at 90 oC or in blue light at room temperature under air.
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With the optimized conditions in hand we tested the generality of protocol by employing different
active methylene compounds and arylhydrazine hydrochlorides and the results are summarized in
Scheme 2. In the first set of reaction the benzoylacetonitrile 1a was treated with several substituted
Scheme 2. Scope of diazenylation of active methylene compounds with arylhydrazine hydrochlorides
aAll reactions were carried out at 0.1 g scale. Yields in bracket are the ones from reaction under blue
LED.
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The Journal of Organic Chemistry
phenylhydrazine hydrochlorides under heating and we discovered that nearly all substrates, except for
2,4ꢀdinitrophenylhydrazine hydrochloride (2k), afforded the corresponding azoꢀcompounds 3ab-3aj in
77ꢀ90% yields. As evident from the NMR spectral data recorded in CDCl3 all products displayed azoꢀ
hydrazone tautomerism.8 Nonetheless, the structure of the products was unambiguously secured by the
Xꢀray diffraction analysis of 3ai. For the reaction with 2,4ꢀdinitrophenylhydrazine hydrochloride instead
of isolating the expected azo derivative 3ak, we isolated 1ꢀiodoꢀ2,4ꢀdinitrobenzene suggesting that
nitrogen was eliminated from the diazene leading to 2,4ꢀdinitrophenyl radical. Subsequently we
evaluated these reactions under the blue light and found that all reactions smoothly furnished 3ab-3aj in
identical or better yields. Next reactions of 3ꢀ(4ꢀchlorophenyl)ꢀ3ꢀoxopropanenitrile (1b) with different
hydrazine hydrochlorides (2a-d,i,n,o) were probed under heating and light and the respective products
(3a-d,i,n,o) were isolated in excellent yields. Alternatively, reactions of ethylcyanoacetate (3c) and
malononitrile (3d) with different hydrazine hydrochlorides were successful resulting into the
corresponding azoꢀderivatives. However, the reactions of ethyl 3ꢀoxoꢀ3ꢀphenylpropanoate (3e) and ethyl
nitroacetate (3f) with phenylhydrazine hydrochloride were unsuccessful. Perhaps the respective radical
species formed from these substrates are less stable leading to the failure of the protocol.22 Moreover,
treating 2ꢀbenzoylpentꢀ4ꢀenenitrile (3g) with phenylhydrazine hydrochloride under the optimized
condition was also unsuccessful to give the desired product. Finally, the scalability of the protocol was
evaluated by treating 1.0 g of 1a with 2g to obtain the product 3ag in 76% yield.
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Having studied the scope of the protocol with active methylene substrates, we turned our attention
towards investigating the suitability of the protocol for Nꢀheterocyclic compounds (4a-b). Treating 2ꢀ
methylindole (4a) with different phenyl hydrazine hydrochlorides (2a-h,j) under heating afforded the
respective products 5aa-5ah,5aj in 61ꢀ72% yields but when identical reactions were performed under
blue light, 5aa-5ah,5aj were isolated in improved yield (Scheme 3). Likewise, reactions of 4b and 4c
with 2g and 2h gave the corresponding azoꢀderivative 5bg and 5ch, respectively both under heating and
blue light. The scalability of the protocol was investigated by subjecting 1.0 g 4a to reaction with 4ꢀ
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bromophenylhydrazine hydrochloride (2h) under heating, which resulted into the corresponding product
5ah without any attenuation of yield.
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Scheme 3. Scope of diazenylation of Nꢀheterocyclic compounds with arylhydrazine hydrochloridesa
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R3
R3
Ar
N
R2
+
I2 (50 mol%)
N
R2
Ar NHNH2.HCl
N
K2CO3, DMSO, air
90 oC, 8 h or
N
R1
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R1
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blue LED, rt, 10 h
Br
Cl
N
N
N
N
HN
HN
HN
Ph
N
N
Me
Me
Me
5ac 68% (69%)
5ab 63% (65%)
5aa 71% (76%)
F
Me
N
N
N
N
N
F
HN
HN
HN
N
Me
Me
Me
5af 71% (74%)
5ad 65% (68%)
5ae 64% (66%)
Cl
Br
N
N
Cl
N
N
N
N
HN
HN
HN
Me
Cl
Me
Me
5aj 61% (63%)
5ag 70% (72%)
5ah 72% (78%)
N
Cl
N
N
N
Br
N
5bg, 69% (71%)
Me
N
Me
5ch 65% (65%)
Me
aAll reactions were performed at 0.1 g scale.
As stated earlier, the reaction following an ionic process via intermediacy of diazonium ion generated
upon oxidation of phenyl hydrazine hydrochloride under the influence of iodine is possible too. The
diazonum ion would attack the nucleophlic centre in benzoylacetonitrile to furnish the observed product.
Therefore, to investigate the plausible mechanism, several control experiments were performed. The
reactions between 1a and 2a and 4a and 2h were evaluated under the optimized conditions in the
presence of TEMPO which gave the product 3aa and 5ah in 18% and 14% isolated yields, respectively
thereby suggesting a radical pathway (Scheme 4). Next the reaction of 4ꢀbromophenylhydrazine
hydrochloride (2h) was carried out with 1b and 4a, respectively in the presence of TEMPO and the
products were analyzed via LCMS. Although we could not detect the presence of the radical generated
from 1b via LCMS, the presence of the adduct of TEMPO with the radical generated from 4a was
observed during the analysis (see SI). Conversely, when 2h was independently treated with TEMPO
under the optimized conditions, the adduct of TEMPO with 4ꢀbromophenyl radical was observed during
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The Journal of Organic Chemistry
Scheme 4. Control experiments
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the LCMS analysis. Based on the NMR experiment using trimethoxybenzene as internal standard the
yield of this adduct was calculated to be 27%. Next, to study the ionic process a reaction between the
diazonium salt (6) and benzoylacetonitrile was performed under the optimized conditions which
afforded 3aa in 86% yield.11,23 Notably, this reaction was completed in 2 h as compared to 10 h required
with phenylhydrazine hydrochloride. Repeating this reaction in the absence of iodine too offered 3aa in
identical yield ascertaining the progress of this reaction via an ionic route. In another control
experiment, treating 1e with 6 resulted into the corresponding product 3ea (71%) which was not formed
during the reaction of 1e and 2a. Finally, for verifying the presence of aryldiazonium ion in the
developed protocol if any, βꢀnaphthol was added to the reaction of 1a with 2a under the optimized
conditions.23 However, we failed to detect the azoꢀcoupling product 1ꢀphenylazonaphthalenꢀ2ꢀol in the
reaction mixture. These control experiments suggested that diazenylation with diazonium salt follow the
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traditional ionic route while phenylhydrazine hydrochloride produced the azo derivatives via the
intermediacy of diazene.
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To demonstrate the utility of the protocol, we transformed a sulfathiazole drug 7 into its hydrazine
hydrochloride salt 8 and treated it with 1b and 1d independently to afford 10 and 11 in 62 and 69%
yields, respectively (Scheme 5). Compounds 10 and 11 were obtained in relatively improved yields,
when the reactions were performed under blue LED light. To ascertain the structure of the isolated
Scheme 5. Synthetic utility of protocol with hydrazine hydrochloride salt of sulfathiazole product
unambiguously, we transformed 7 into its tetrafluoroborate salt 9 and treated it with 1b and 1d in the
presence of a base both under heating and in the presence of blue light source. The products 10 and 11,
respectively isolated were identical to the products obtained from the hydrazine hydrochloride 8.
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Finally, we investigated the compatibility of aliphatic hydrazine salt with the protocol by treating
methylhydrazine sulphate with 1a under the optimized conditions but the reaction was unsuccessful.
Conclusions
In summary, we have illustrated a mild approach to diazenylation of active methylene compounds and
Nꢀheterocyclic compounds with arylhydrazine hydrochloride in the presence of iodine and base under
aerobic conditions. It is proposed that the reaction proceed via the intermediacy of diazene rather than
the ionic mechanism and therefore it provides a new alternative to diazenylation reaction. The protocol
was however found to be limited to active methylene compounds bearing at least one nitrile group.
Nonetheless, commercially available cheap starting materials, simple reaction conditions in the presence
of air make it an attractive option for diazenylation.
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Experimental
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General. Unless otherwise stated all reactions were performed in nonꢀdry glassware under an air
atmosphere and were monitored by thin layer chromatography (TLC). TLC was performed on preꢀ
coated silica gel plates. After elution, plate was visualized under UV illumination at 254 nm for UV
active materials. The melting points were recorded on a hot stage apparatus and are uncorrected. IR
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spectra were recorded using a FTIR spectrophotometer. H NMR and C NMR spectra were recorded
on 400 or 500 MHz spectrometers with CDCl3 or DMSOꢀd6 as solvent, using TMS as an internal
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standard (chemical shifts in δ ppm). Peak multiplicities of HꢀNMR signals were designated as s
(singlet), brs (broad singlet), d (doublet), dd (doublet of doublet), t (triplet), q (quartet), m (multiplet)
etc. Coupling constants (J) are in Hz. The LCꢀESIꢀMS were recorded on triple quadrupole Mass
spectrometer. Column chromatography was performed using silica gel (100ꢀ200 mesh). Analytical
grade solvents for the column chromatography were used as received. Commercial grade reagents and
solvents were purchased from different commercial sources and used without further purification. The
yields were calculated based on the nitriles or Nꢀheterocycles as the starting material. The yields within
the bracket are the ones from the reaction performed via Method B. The products originating from
substrate 1a and 1b exist in azoꢀhydrazo (ketoꢀenol) tautomeric forms and in the solution equilibrium is
tilted to enol form (major tautomer, 70%) and therefore the NMR characterization data is in the enol
form.
General procedure for the synthesis of azo derivatives 3,5,10-11 as exemplified for the synthesis
of 3aa.
Method A. To a stirred solution of 3ꢀoxoꢀ3ꢀphenylpropanenitrile 1a (0.1 g, 0.69 mmol) in DMSO (3
mL) was added I2 (0.09 g, 0.34 mmol) at room temperature. After a delay of 15 minutes, phenyl
hydrazine hydrochloride 2a (0.12 g, 0.83 mmol) and K2CO3 (0.24 g, 1.72 mmol) were added and the
o
resulting mixture was heated at 90 C for 8 h under aerobic condition. After completion of the reaction
(as monitored by TLC), the solvent was removed under vacuum and the reaction was quenched with
saturated thiosuphate solution (25 mL) and subsequently extracted with EtOAc (2 x 20 mL). The
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organic layers were pooled, dried over anhyd. Na2SO4 and evaporated to yield the crude material that
was purified via silica gel column chromatography using hexanes/ EtOAc (9:1, v/v) as eluent to afford
2a (0.140 g, 82%) as a yellow solid.
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Method B. To a solution of 1a (0.1 g, 0.69 mmol) in DMSO (3 mL) were added I2 (0.09 g, 0.34
mmol), phenyl hydrazine hydrochloride (0.12 g, 0.83 mmol) and K2CO3 (0.24 g, 1.72 mmol) and the
reaction was continued for 10 h under the blue LED (λ = 455 nm) light at room temperature. After
completion of the reaction mixture was processed as stated above to furnish 0.150 g (88%) of 2a as a
yellow solid.
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(E)-2-Oxo-N',2-diphenylacetohydrazonoyl cyanide (3aa).20 Mp: 136ꢀ138 oC [Lit. 134ꢀ136 oC]; Rf =
0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 1695, 2224, 3251 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ
= 7.39 (d, J = 7.7 Hz, 1H), 7.48ꢀ7.58 (m, 4H), 7.66 (d, J = 7.0 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 8.00ꢀ
8.06 (m, 3H), 15.29 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 110.7, 115.3, 116.8, 117.9, 121.4, 123.3,
125.8, 127.2, 127.4, 128.3, 128.7, 129.0, 129.3, 129.4, 129.8, 130.1, 132.9, 133.3, 135.7, 136.0, 138.1,
140.5, 140.6, 186.1, 187.7 ppm. MS (ESI+): m/z = 250.1 ESIꢀHRꢀMS calcd. for C15H12N3O (M++H):
250.0980, found: 250.0982.
1H NMR (400 MHz, DMSOꢀd6): δ = 7.39 (d, J = 4.0 Hz, 4H), 7.55 (d, J = 7.7 Hz, 2H), 7.64 (d, J= 7.2
Hz, 2H), 7.88 (d, J = 7.5 Hz, 2H), 12.37 (s, 1H).
(E)-N'-(2-Chlorophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3ab). Yield: 84% (84%)
o
(0.163 g from 0.1 g); a yellow solid; mp: 125ꢀ127 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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νmax: 1685, 2217, 3260 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.12 (d, J = 8.8 Hz, 1H), 7.26ꢀ7.35 (m,
3H), 7.43ꢀ7.48 (m, 2H), 7.52ꢀ7.58 (m, 1H), 7.91 (m, 2H), 15.09 (s, 1H); 13C NMR (100 MHz, CDCl3): δ
= 109.9, 110.6, 111.8, 112.2, 116.9, 117.5, 117.6, 126.2, 127.7, 128.3, 128.7, 129.0, 129.2, 130.1, 133.1,
133.1, 133.1, 133.6, 135.4., 135.81, 137.5, 138.7, 185.7, 188.3 ppm. MS (ESI+): m/z = 284.0. ESIꢀHRꢀ
MS calcd. for C15H11ClN3O (M++H): 284.0591, found: 284.0594.
(E)-N'-(2-Bromophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3ac). Yield: 88% (89%)
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(0.198 g from 0.1 g); a yellow solid, mp: 124ꢀ126 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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νmax: 1689, 2210, 3281 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.02ꢀ7.10 (m, 1H), 7.30ꢀ7.38 (m, 2H),
7.42ꢀ7.45 (m, 2H), 7.52ꢀ7.55 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 15.19 (s, 1H) ;
13C NMR (100 MHz, CDCl3): δ = 116.9, 117.6, 127.9, 128.7, 129.1, 130.2, 131.5, 133.1 ppm. MS
(ESI+): m/z = 328.0. ESIꢀHRꢀMS calcd. for C15H11BrN3O (M++H): 328.0085, found: 328.0085.
(E)-2-Oxo-2-phenyl-N'-o-tolylacetohydrazonoyl cyanide (3ad). Yield: 78% (82%) (0.141 g from
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0.1 g); a yellow solid, mp: 136ꢀ138 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 1679,
2231, 3273 cmꢀ1. 1H NMR (400 MHz, , CDCl3): δ = 2.39 (s, 3H), 7.10ꢀ7.18 (m, 2H), 7.24ꢀ7.33 (m, 1H),
7.42ꢀ7.47 (m, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.92ꢀ7.97 (m, 2H), 15.38 (s, 1H);
13C NMR (100 MHz, CDCl3): δ = 16.9, 111.3, 115.8, 118.0, 125.1, 127.0, 127.8, 128.3, 128.6, 128.7,
130.1, 131.1, 133.3, 136.1, 138.9, 188.7 ppm. MS (ESI+): m/z = 264.1. ESIꢀHRꢀMS calcd. for
C16H14N3O (M++H): 264.1137, found: 264.1138.
(E)-N'-(3-Fluorophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3ae). Yield: 90% (90%)
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(0.165 g from 0.1 g); a yellow solid, mp: 140ꢀ142 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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max: 1683, 2227, 3249 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 6.80ꢀ6.96 (m, 2H), 7.19ꢀ7.35 (m, 2H),
7.44ꢀ7.58 (m, 3H) 7.92 (d, J = 7.5 Hz, 2H), 15.98 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 103.3,
103.5, 103.9, 104.1, 110.1, 111.4, 111.6, 111.7, 112.5 (d, J = 21 Hz), 113.9 (d, J = 21.7 Hz), 116.0,
117.5, 128.3, 128.6, 128.7, 130.1, 131.1, 131.2, 131.2, 131.3, 133.4 (d, J = 48 Hz), 135.6 (d, J = 31.14
Hz), 142.13, 142.2, 142.3, 163.7 (d, J = 247.3 Hz), 186.0, 188.8 ppm. MS (ESI+): m/z = 268.1. ESIꢀHRꢀ
MS calcd. for C15H11FN3O (M++H): 268.0886, found: 268.0889.
(E)-N'-(4-Fluorophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3af). Yield: 81% (85%) (0.149
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g from 0.1 g); a yellow solid, mp: 145ꢀ147 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v) IR (KBr) νmax
:
1695, 2233, 3256 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 7.00ꢀ7.10 (m, 2H), 7.38ꢀ7.56 (m, 5H), 7.92 (d,
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J = 7.4 Hz, 2H), 15.19 (s, 1H); C NMR (100 MHz, CDCl3): δ = 110.4, 110.8, 115.7 (d, J = 22.6 Hz),
116.6, 116.7, 116.9, 116.9, 117.4, 117.5, 117.8, 118.4, 118.5, 122.29 (d, J = 7 Hz), 127.0, 128.3, 128.5,
128.7, 128.8, 130.1, 131.9, 132.9, 133.79 (d, J = 54 Hz), 134.7, 135.7, 135.9, 136.9, 137.0, 159.2, 160.2,
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161.4 (d, J = 247.4 Hz), 165.8, 186.1, 188.1 ppm. MS (ESI+): m/z = 268.1. ESIꢀHRꢀMS calcd. for
C15H11FN3O (M++H): 268.0886, found: 268.0888.
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(E)-N'-(4-Chlorophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3ag). Yield: 77% (79%)
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(0.150 g from 0.1 g); a yellow solid, mp: 168ꢀ170 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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νmax: 1682, 2221, 3248 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.16ꢀ7.25 (m, 1H), 7.40ꢀ7.48 (m, 2H),
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7.53ꢀ7.58 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 8.03ꢀ8.06 (m, 2H), 15.34 (s, 1H);
13C NMR (100 MHz, CDCl3): δ = 117.0, 117.1, 117.9, 127.2, 128.3, 128.4, 128.6, 128.7, 130.0, 133.5,
135.8. ppm. MS (ESI+): m/z = 284.1. ESIꢀHRꢀMS calcd. for C15H11ClN3O (M++H): 284.0591, found:
284.0593.
(E)-N'-(4-Bromophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3ah). Yield: 90% (90%)
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(0.202 g from 0.1 g); a yellow solid, mp: 173ꢀ175 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
ν
max: 1691, 2229, 3279 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 7.16 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 8.9
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Hz, 1H), 7.52ꢀ7.60 (m, 4H), 7.65 (t, J = 7.4 Hz, 1H), 8.00ꢀ8.02 (m, 2H), 15.16 (s, 1H); C NMR (100
MHz, CDCl3): δ = 117.3, 117.6, 118.2, 120.3, 128.3, 128.6, 128.7, 130.1, 132.9, 133.0, 133.1, 133.5,
135.8, 139.7, 188.8 ppm. MS (ESI+): m/z = 328.0. ESIꢀHRꢀMS calcd. for C15H11BrN3O (M++H):
328.0085, found: 328.0088.
(E)-2-Oxo-2-phenyl-N'-p-tolylacetohydrazonoyl cyanide (3ai). Yield: 87% (87%) (0.150 g from
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0.1 g); a yellow solid, mp: 153ꢀ155 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 1688,
2232, 3266 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 2.39 (d, J = 12.53 Hz, 3H), 7.18ꢀ7.28 (m, 3H), 7.40 (d,
J = 8.3 Hz, 1H), 7.51ꢀ7.65 (m, 3H), 8.01 (t, J = 8.5 Hz 2H), 15.30 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 20.9, 21.13, 110.2, 110.5, 114.8, 116.8, 118.1, 128.2, 128.5, 128.6, 130.1, 130.4, 130.4,
132.8, 133.2, 135.8, 136.1, 137.5, 138.2, 138.4, 186.1, 188.6 ppm. MS (ESI+): m/z = 264.1. ESIꢀHRꢀ
MS calcd. for C16H14N3O (M++H): 264.1137, found: 264.1138.
(E)-N'-(2,4-Dichlorophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3aj). Yield: 86% (87%)
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(0.187 g from 0.1 g); a yellow solid, mp: 159ꢀ161 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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max: 1691, 2213, 3274 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 7.8 Hz, 1H), 7.39ꢀ7.57 (m,
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4H), 7.76 (d, J = 8.8 Hz, 1H), 7.91ꢀ7.96 (m, 2H), 15.20 (s, 1H); 13C NMR (100 MHz, CDCl3): δ =
117.5, 117.9, 122.7, 128.4, 128.7, 128.7, 128.8, 129.6, 130.1, 132.1, 133.7, 135.6 ppm. MS (ESI+): m/z
= 318.0. ESIꢀHRꢀMS calcd. for C15H10Cl2N3O (M++H): 318.0201, found: 318.0202.
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(E)-N'-(2,6-Difluorophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3al). Yield: 92% (92%)
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(0.180 g from 0.1 g); a yellow solid, mp: 135ꢀ137 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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max: 1687, 2219, 3242 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 6.97ꢀ7.06 (m, 2H), 7.56 (t, J = 7.8 Hz,
2H), 7.64ꢀ7.68 (m, 1H),7.83ꢀ7.89 (m, 1H), 8.00ꢀ8.04 (m, 2H) 15.22 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 104.4, 104.6, 104.6, 104.8, 109.6, 112.3, 112.8 (d, J = 23.0 Hz), 112.9 (d, J = 23.0 Hz),
117.4, 118.2 (d, J = 8 Hz), 126.0, 128.3, 128.6, 128.7, 130.1, 133.4 (d, J = 45 Hz), 135.4, 135.7, 151.9
(d, J = 262.8 Hz), 153.2, 160.7 (d, J = 262.4 Hz) 161.9, 162.0, 185.6, 188.6 ppm. MS (ESI+): m/z =
286.1. ESIꢀHRꢀMS calcd. for C15H10F2N3O (M++H): 286.0792, found: 286.0794
(E)-N'-(2,6-Dichlorophenyl)-2-oxo-2-phenylacetohydrazonoyl cyanide (3am). Yield: 89% (89%)
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(0.194 g from 0.1 g); a yellow solid, mp: 158ꢀ160 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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max: 1688, 2215, 3268 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.09ꢀ7.14 (m, 1H), 7.33ꢀ7.40 (m, 3H),
7.45ꢀ7.59 (m, 2H), 7.97ꢀ8.04 (m, 2H), 14.76 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 109.4, 112.3,
117.1, 118.9, 128.0, 128.1, 128.1, 128.5, 128.6, 128.7, 128.8, 129.5, 129.7, 130.3, 133.7, 134.0, 134.6,
134.8, 135.6, 185.3, 188.5 ppm. MS (ESI+): m/z = 318.0. ESIꢀHRꢀMS calcd. for C15H10Cl2N3O
(M++H): 318.0201, found: 318.0201.
(E)-2-(4-Chlorophenyl)-2-oxo-N'-phenylacetohydrazonoyl cyanide (3ba). Yield: 78% (81%)
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(0.123g from 0.1 g); a yellow solid, mp: 181ꢀ183 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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max: 1681, 2229, 3278 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.12ꢀ7.19 (m, 1H), 7.29ꢀ7.35 (m, 3H),
7.46 (s, 2H), 7.55 (d, J = 6.9 Hz, 1H), 7.82ꢀ7.96 (m, 2H), 15.24 (s, 1H); 13C NMR (100 MHz, CDCl3): δ
= 111.9, 115.1, 116.0, 116.9, 118.6, 120.6, 121.7, 125.1, 128.5, 129.0, 129.2, 129.8, 129.9, 130.0, 130.2,
130.5, 131.5, 135.1, 137.6, 142.1, 146.4, ppm. MS (ESI+): m/z = 284.0. ESIꢀHRꢀMS calcd. for
C15H11ClN3O (M++H): 284.0591, found: 284.0589.
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(E)-N'-(2-Chlorophenyl)-2-(4-chlorophenyl)-2-oxoacetohydrazonoyl cyanide (3bb). Yield: 80%
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(83%) (0.141 g from 0.1 g); a yellow solid; mp: 148ꢀ150 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR
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(KBr) νmax: 1689, 2224, 3264 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.08ꢀ7.19 (m, 1H), 7.26ꢀ7.45 (m,
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4H), 7.81ꢀ7.93 (m, 3H), 15.23 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 109.6, 111.9, 116.6, 117.2,
117.5, 121.2, 122.5, 126.0, 127.5, 128.4, 128.6, 129.1, 129.9, 130.0, 130.1, 131.5, 133.7, 134.0, 136.4,
137.4, 139.7, 140.2, 184.4, 186.9 ppm. MS (ESI+): m/z = 318.0. ESIꢀHRꢀMS calcd. for C15H10Cl2N3O
(M++H): 318.0201, found: 318.0202.
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(E)-N'-(2-Bromophenyl)-2-(4-chlorophenyl)-2-oxoacetohydrazonoyl cyanide (3bc). Yield: 85%
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(89%) (0.170 g from 0.1 g); a yellow solid, mp: 139ꢀ141 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR
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(KBr) νmax: 1695, 2237, 3259 cmꢀ1. H NMR (400 MHz CDCl3): δ = 7.08ꢀ7.17 (m, 1H), 7.37ꢀ7.41 (m,
1H), 7.49ꢀ7.53 (m, 2H), 7.59ꢀ7.62 (m, 1H), 7.79 (dd, J1 = 6.9 Hz, J2 = 1.3 Hz, 1H), 7.96ꢀ8.01 (m, 2H),
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15.25 (s, 1H); C NMR (400 MHz CDCl3): δ = 109.7, 110.7, 111.8, 111.9, 115.7, 116.9, 117.5, 117.6,
119.4, 126.4, 127.9, 128.3, 128.7, 129.05, 129.1, 129.2, 130.2, 131.5, 133.1, 133.2, 133.7, 134.1, 137.0,
138.6, 139.7, 140.2, 184.4, 186.8 ppm. MS (ESI+): m/z = 361.8. ESIꢀHRꢀMS calcd. for C15H10BrClN3O
(M++H): 361.9696, found: 361.9698.
(E)-2-(4-Chlorophenyl)-N'-(2-fluorophenyl)-2-oxoacetohydrazonoyl cyanide (3bn). Yield: 75%
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(82%) (0.126 g from 0.1 g); a yellow solid; mp: 142ꢀ144 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v) IR
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(KBr) νmax: 1676, 2219, 3273 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 7.09ꢀ7.20 (m, 3H), 7.43 (dd, J1 =
8.5 Hz, J2 = 2.4, Hz 2H), 7.75ꢀ7.79 (m, 1H), 7.90 (dd, J1 = 8.6 Hz, J2 = 2.3 Hz, 2H), 15.10 (s, 1H); 13C
NMR (100 MHz, CDCl3): δ = 109.5, 111.8, 116.0, 116.1, 116.1, 116.3, 116.8, 117.4 (d, J = 23 Hz),
125.5, 125.5, 125.6, 126.1, 127.6, 127.6, 128.7, 128.7, 129.1, 130.1, 131.5, 133.8 (d, J = 36.1 Hz),
139.7, 140.2, 150.2, 151.8 (d, J = 248.4 Hz) 152.7, 184.4, 187.1 ppm. MS (ESI+): m/z = 302.0. ESIꢀHRꢀ
MS calcd. for C15H10ClFN3O (M++H): 302.0496, found: 302.0494..
(E)-2-(4-Chlorophenyl)-2-oxo-N'-o-tolylacetohydrazonoyl cyanide (3bd). Yield: 89% (89%)
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(0.147g from 0.1 g); a yellow solid, mp: 163ꢀ165 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr)
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max: 1684, 2221, 3271 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3H), 7.16 (t, J = 7.4 Hz, 1H),
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7.25ꢀ7.27 (m, 1H), 7.30ꢀ7.40 (m, 2H), 7.50ꢀ7054 (m, 2H), 8.00 (t, J = 8.5 Hz, 2H), 15.23 (s, 1H); C
NMR (100 MHz, CDCl3): δ = 110.0, 110.9, 115.7, 115.9, 117.9, 124.4, 125.7, 126.1, 127.2, 127.9,
128.0, 128.6, 129.0, 130.0, 131.1, 131.5, 131.5, 133.9, 134.3, 138.1, 138.8, 139.5, 139.9, 184.5, 187.2
ppm. MS (ESI+): m/z = 298.1. ESIꢀHRꢀMS calcd. for C16H13ClN3O (M++H): 298.0747, found:
298.0745.
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(E)-2-(4-Chlorophenyl)-2-oxo-N'-p-tolylacetohydrazonoyl cyanide (3bi). Yield: 78% (80%) (0.129
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g from 0.1 g); a yellow solid, mp: 180ꢀ182 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax
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1673, 2235, 3251 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 2.27ꢀ2.32 (m, 3H), 7.06ꢀ7.19 (m, 2H), 7.31 (d,
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J = 8.5Hz, 1H), 7.39ꢀ7.43 (m, 3H), 7.86ꢀ7.90 (m, 2H), 15.20 (s, 1H); C NMR (100 MHz, CDCl3): δ =
21.0, 21.1, 109.8, 110.3, 114.7, 115.9, 116.9, 118.0, 120.4, 123.8, 128.5, 128.6, 128.7, 129.0, 129.6,
129.8, 130.0, 130.3, 130.4, 130.5, 130.8, 131.5, 134.1, 134.4, 134.50, 136.1, 137.8, 138.1, 138.3, 139.2,
139.7, 184.8, 187.2 ppm. MS (ESI+): m/z = 298.1. ESIꢀHRꢀMS calcd. for C16H13ClN3O (M++H):
298.0747, found: 298.0745.
(E)-2-(4-Chlorophenyl)-N'-(2,4-dimethylphenyl)-2-oxoacetohydrazonoyl cyanide (3bo). Yield:
84% (84%) (0.145 g from 0.1 g); a yellow solid; mp: 173ꢀ175 oC; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v);
IR (KBr) νmax: 1689, 2218, 3268 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 2.28 (s, 3H), 2.35 (s, 3H), 6.98ꢀ
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7.03 (m, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.88ꢀ7.92 (m, 2H), 15.47 (s, 1H); C
NMR (100 MHz, CDCl3): δ = 16.8, 21.1, 110.4, 115.8, 116.0, 118.1, 126.1, 128.6, 129.0, 130.0, 131.5,
131.7, 132.0, 134.4, 136.5, 137.6, 139.7, 187.2 ppm. MS (ESI+): m/z = 312.1. ESIꢀHRꢀMS calcd. for
C17H15ClN3O (M++H): 312.0904, found: 312.0902.
(E)-Ethyl 2-(2-(2-chlorophenyl)hydrazono)-2-cyanoacetate (3cb). Yield: 80% (82%) (0.177 g from
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0.1 g); a yellow solid, mp: 139ꢀ141 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 1716,
2236, 3261 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ =1.44 (t, J =7.3 Hz, 3H), 4.44 (q, J =7.2 Hz, 2H), 7.31ꢀ
7.17 (m, 1H), 7.36 (dd, J1 =7.9 Hz, J2 = 0.5 Hz 1H), 7.41 (dd, J1 =7.4 Hz, J2 = 1.2 Hz 1H), 7.75 (dd, J1
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=8.3 Hz, J2 = 1.1 Hz 1H), 13.47 (s, 1H); C NMR (100 MHz, CDCl3): δ = 14.1, 62.7, 106.6, 114.9,
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116.3, 121.4, 126.1, 128.3, 129.7, 137.5, 162.0 ppm. MS (ESI+): m/z =252.1. ESIꢀHRꢀMS calcd. for
C11H11ClN3O2 (M++H): 252.0540, found: 252.0543.
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(E)-Ethyl 2-(2-(2-bromophenyl)hydrazono)-2-cyanoacetate (3cc). Yield: 87% (87%) (0.181g from
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0.1 g); a yellow solid, mp: 138ꢀ140 C; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 1734,
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2224, 3246 cmꢀ1. H NMR (400 MHz, CDCl3): δ = 1.35 (t, J =7.1 Hz, 3H), 4.34 (q, J =7.14Hz, 2H),
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6.99 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H),
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13.35 (s, 1H); C NMR (100 MHz, CDCl3): δ = 14.1, 62.7, 106.5, 110.7, 115.0, 116.6, 126.5, 128.9,
132.9, 138.6, 161.9 ppm. MS (ESI+): m/z = 296.0. ESIꢀHRꢀMS calcd. for C11H11BrN3O2 (M++H):
296.0035, found: 296.0032.
(E)-Ethyl 2-cyano-2-(2-(2,4-dichlorophenyl)hydrazono)acetate (3cj). Yield: 84% (86%) (0.237 g
from 0.1 g); a yellow solid, mp: 176ꢀ178 oC; Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 1729,
2238, 3258 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J =7.1 Hz, 3H), 4.43 (q, J =7.1 Hz, 2H), 7.33
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(dd, J1 =8.8 Hz, J2 = 2.1 Hz 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 13.47 (s, 1H); C
NMR (100 MHz, CDCl3): δ = 14.1, 62.9, 107.2, 114.7, 117.1, 121.7, 128.7, 129.4, 130.9, 136.3, 161.9
ppm. MS (ESI+): m/z = 286.0. ESIꢀHRꢀMS calcd. for C11H10Cl2N3O2 (M++H): 286.0150, found:
286.0146.
Phenylcarbonohydrazonoyl dicyanide (3da). Yield: 64% (71%) (0.164 g from 0.1 g); a yellow
solid, mp: 140ꢀ142 oC; Rf = 0.45 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 2231, 3278 cmꢀ1. 1H NMR
(400 MHz, CDCl3): δ = 7.24ꢀ7.28 (m, 1H), 7.32 (d, J = 7.7 Hz, 2H), 7.43 (dd, J1 = 8.4 Hz, J2 = 0.9 Hz,
2H), 9.92 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 86.5, 108.4, 112.3, 116.1, 126.8, 129.9, 139.8 ppm.
MS (ESI+): m/z =171.1. ESIꢀHRꢀMS calcd. for C9H7N4 (M++H): 171.0671, found: 171.0668.
(4-Bromophenyl)carbonohydrazonoyl dicyanide (3dh). Yield: 70% (75%) (0.261 g from 0.1 g); a
yellow solid, mp: 173ꢀ175 oC; Rf = 0.45 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 2246, 3267 cmꢀ1. 1H
NMR (400 MHz, DMSOꢀd6): δ = 7.41 (d, J = 7.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.87, 13.05 (s, 1H);
13C NMR (100 MHz, DMSOꢀd6): δ = 90.6, 115.1, 119.5, 123.1, 123.7, 137.6, 146.1 ppm. MS (ESI+):
m/z = 248.7. ESIꢀHRꢀMS calcd. for C9H6BrN4 (M++H): 248.9776, found: 248.9775.
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p-Tolylcarbonohydrazonoyl dicyanide (3di). Yield: 65% (72%) (0.181 g from 0.1 g); a yellow
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solid, mp: 168ꢀ170 oC; Rf = 0.45 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 2238, 3251 cmꢀ1. 1H NMR
(400 MHz, DMSOꢀd6): δ = 2.29 (s, 3H), 7.23 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 13.47 (s,
1H); 13C NMR (100 MHz, DMSOꢀd6): δ = 20.9, 84.2, 110.5, 115.0, 116.9, 130.4, 135.9, 139.7 ppm. MS
(ESI+): m/z =185.1. ESIꢀHRꢀMS calcd. for C10H9N4 (M++H): 185.0827, found: 185.0825.
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(E)-2-Methyl-3-(phenyldiazenyl)-1H-indole (5aa).9 Yield: 71% (76%) (0.127 g from 0.1 g); a
yellow solid; mp: 173ꢀ175 oC; Rf = 0.49 (Hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 2128, 3339 cmꢀ1. 1H
NMR (400 MHz, CDCl3): δ = 2.71 (s, 3H), 7.19ꢀ7.23 (m, 3H), 7.33 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.5
Hz, 2H), 7.87 (d, J = 7.4 Hz, 2H) 8.21(s, 1H), 8.52 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
= 11.51, 110.8, 119.5, 121.6, 122.5, 122.9, 123.6, 128.6, 128.9, 132.8, 135.2, 143.7, 153.9 ppm. MS
(ESI+): m/z = 236.1. ESIꢀHRꢀMS calcd. for C15H14N3 (M++H): 236.1188, found: 236.1186.
(E)-3-((2-Chlorophenyl)diazenyl)-2-methyl-1H-indole (5ab). Yield: 63% (65%) (0.129 g from 0.1
g); a yellow solid; mp: 134ꢀ136 oC Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2121, 3329 cmꢀ
1. 1H NMR (400 MHz, CDCl3): δ = 2.81 (s, 3H), 7.24ꢀ7.32 (m, 5H), 7.53 (d, J = 7.6 Hz, 1H), 7.80 (d, J
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= 7.7 Hz, 1H), 8.27(s, 1H), 8.62 (d, J = 7.6 Hz, 1H); C NMR (100 MHz, CDCl3): δ = 11.6, 110.5,
116.9, 119.5, 122.8, 123.5, 123.9, 127.1, 129.2, 130.4, 133.8, 134.1, 135.0, 143.8, 150.0 ppm. MS
(ESI+): m/z = 270.0. ESIꢀHRꢀMS calcd. for C15H13ClN3 (M++H): 270.0798, found: 270.0794.
(E)-3-((2-Bromophenyl)diazenyl)-2-methyl-1H-indole (5ac). Yield: 68% (69%) (0.162 g from 0.1
g); a yellow solid; mp: 178ꢀ180 oC Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2125, 3327 cmꢀ
1. 1H NMR (400 MHz, CDCl3): δ = 2.82 (s, 3H), 7.18ꢀ7.38 (m, 5H), 7.72 (d, J = 7.8 Hz, 1H), 7.78 (d, J
= 6.9 Hz, 1H), 8.30(s, 1H), 8.68 (d, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 11.6, 110.4,
117.2, 118.4, 119.0, 119.4, 120.7, 123.0, 123.5, 123.9, 127.7, 129.5, 133.4, 143.9, 151.0 ppm. MS
(ESI+): m/z = 314.0. ESIꢀHRꢀMS calcd. for C15H13BrN3 (M++H): 314.0293, found: 314.0289.
(E)-2-Methyl-3-(o-tolyldiazenyl)-1H-indole (5ad). Yield: 65% (68%) (0.123 g from 0.1 g); a yellow
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solid; mp: 119ꢀ121 C Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2118, 3322 cmꢀ1. 1H NMR
(400 MHz, CDCl3): δ = 2.76 (s, 3H), 2.81 (s, 3H), 7.23ꢀ7.33 (m, 6H), 7.69ꢀ7.71 (m, 1H), 8.21(s, 1H),
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8.46 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 11.6, 18.2, 110.6, 114.9, 119.5, 122.3, 122.9,
123.5, 126.3, 128.6, 131.0, 133.6, 135.1, 136.2, 152.2 ppm. MS (ESI+): m/z = 250.1. ESIꢀHRꢀMS calcd.
for C16H16N3 (M++H): 250.1344, found: 250.1341.
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(E)-3-((3-Fluorophenyl)diazenyl)-2-methyl-1H-indole (5ae). Yield: 64% (66%) (0.123 g from 0.1
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g); a yellow solid; mp: 109ꢀ 111 C Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2120, 3324
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cmꢀ1. H NMR (400 MHz, CDCl3): δ = 2.81 (s, 3H), 7.01ꢀ7.06 (m, 1H), 7.23ꢀ7.30 (m, 3H), 7.40ꢀ7.45
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(m, 1H), 7.56ꢀ7.59 (m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 8.28(s, 1H), 8.49ꢀ8.51 (m, 1H); C NMR (100
MHz, CDCl3): δ = 11.6, 106.7 (d, J = 22.6 Hz), 110.6, 115.1 (d, J = 22.2 Hz), 119.4, 122.5, 123.1,
123.8, 129.9 (d, J = 8.7 Hz), 132.9, 135.1, 143.7, 155.9 (d, J = 6.8 Hz), 162.3, 164.7 ppm. MS (ESI+):
m/z = 254.1. ESIꢀHRꢀMS calcd. for C15H13FN3 (M++H): 254.1094, found: 254.1089.
(E)-3-((4-Fuorophenyl)diazenyl)-2-methyl-1H-indole (5af). Yield: 71% (74%) (0.137 g from 0.1
g); a yellow solid; mp: 117ꢀ119 oC Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2118, 3326 cmꢀ
1. 1H NMR (400 MHz, CDCl3): δ = 2.79 (s, 3H), 7.15 (t, J = 8.4 Hz, 2H) , 7.23ꢀ7.26 (m, 3H), 7.86ꢀ7.89
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(m, 2H), 8.24 (s, 1H), 8.42 (d, J = 7.19 Hz, 1H); C NMR (100 MHz, CDCl3): δ = 11.5, 110.0, 110.5,
115.5, 115.8, 118.7 (d, J = 61.0 Hz), 120.2 (d, J = 117.6 Hz), 122.4, 122.9, 123.3 (d, J = 8.5 Hz), 123.5,
135.0, 150.7, 161.7, 164.3 ppm. MS (ESI+): m/z = 254.1. ESIꢀHRꢀMS calcd. for C15H13FN3 (M++H):
254.1094, found: 254.1091.
(E)-3-((4-Chlorophenyl)diazenyl)-2-methyl-1H-indole (5ag). Yield: 70% (72%) (0.143 g from 0.1
g); a yellow solid; mp: 162ꢀ164 oC Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2117, 3322 cmꢀ
1. 1H NMR (400 MHz, CDCl3): δ = 2.80 (s, 3H), 7.23ꢀ7.28 (m, 3H), 7.43 (d, J = 8.7 Hz, 2H), 7.82 (d, J
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= 8.7 Hz, 2H), 8.40(s, 1H), 8.49 (d, J = 6.4 Hz, 1H); C NMR (100 MHz, CDCl3): δ = 11.6, 110.6,
116.3, 119.5, 122.9, 123.0, 123.7, 129.0, 129.1, 132.9, 134.0, 135.1, 143.4, 152.7 ppm. MS (ESI+): m/z
= 270.0. ESIꢀHRꢀMS calcd. for C15H13ClN3 (M++H): 270.0798, found: 270.0795.
(E)-3-((4-Bromophenyl)diazenyl)-2-methyl-1H-indole (5ah). Yield: 72% (78%) (0.171 g from 0.1
g); a yellow solid; mp: 198ꢀ200 oC Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2119, 3321 cmꢀ
1. 1H NMR (400 MHz, CDCl3): δ = 2.73 (s, 3H), 7.14ꢀ7.20 (m, 3H), 7.51 (d, J = 8.4 Hz, 2H), 7.68 (d, J
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= 8.4 Hz, 2H), 8.23(s, 1H), 8.42 (d, J = 7.0 Hz, 1H); C NMR (100 MHz, CDCl3): δ = 11.6, 110.6,
116.7, 119.5, 122.3, 122.5, 123.0, 123.2, 123.7, 132.0, 133.0, 135.1, 143.4, 153.0 ppm. MS (ESI+): m/z
= 314.0. ESIꢀHRꢀMS calcd. for C15H13BrN3 (M++H): 314.0293, found: 314.0292.
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(E)-3-((2,4-Dichlorophenyl)diazenyl)-2-methyl-1H-indole (5aj). Yield: 61% (63%) (0.140 g from
0.1 g); a yellow solid; mp: 188ꢀ 190oC Rf = 0.49 (Hexanes: EtOAc, 6:4, v/v); IR (KBr) νmax: 2119, 3323
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cmꢀ1. H NMR (400 MHz, CDCl3): δ = 2.82 (s, 3H), 7.25ꢀ7.31 (m, 4H), 7.55 (d, J = 2.2 Hz, 1H), 7.75
(d, J = 8.7 Hz, 1H), 8.31(s, 1H), 8.58 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ = 11.6, 110.5,
117.7, 119.4, 122.8, 123.7, 124.0, 127.4, 130.0, 134.0, 134.2, 134.3, 135.1, 144.2, 148.6 ppm. MS
(ESI+): m/z = 304.0. ESIꢀHRꢀMS calcd. for C15H12Cl2N3 (M++H): 304.0408, found: 304.0411.
(E)-3-((4-Chlorophenyl)diazenyl)-1,2-dimethyl-1H-indole (5bg). Yield: 69% (71%) (0.134 g from
0.1 g); a yellow solid; mp: 136ꢀ138 oC; Rf = 0.49 (Hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax: 2128, cmꢀ1.
1H NMR (400 MHz, CDCl3): δ = 2.78 (s, 3H), 3.72 (s, 3H), 7.24ꢀ7.29 (m, 3H), 7.41 (d, J = 8.6 Hz, 2H),
7.80 (d, J = 8.6 Hz, 2H), 8.51ꢀ8.53 (m, 1H); 13C NMR (100 MHz, CDCl3): 10.2, 29.9, 108.9, 119.0,
122.5, 122.8, 123.0, 123.3, 129.0, 132.5, 133.6, 136.9, 145.3, 152.8 ppm. MS (ESI+): m/z = 284.1 ESIꢀ
HRꢀMS calculated for C16H15ClN3 (M++H): 284.0955, found: 284.0951.
(E)-2-((4-Bromophenyl)diazenyl)-1-methyl-1H-pyrrole (5ch). Yield: 65% (65%) (0.210 g from 0.1
g); a red oil; Rf = 0.59 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 2233 cmꢀ1. H NMR (400 MHz,
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CDCl3): δ = 3.96 (s, 3H), 6.30 (dd, J1 = 4.2 Hz, J2 = 2.6 Hz, 1H), 6.72 (dd, J1 = 4.2 Hz, J2 = 1.6 Hz,
1H), 6.96 (s, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ =
33.4, 100.6, 110.5, 123.5, 127.4, 131.6, 132.1, 146.8, 152.9 ppm. MS (ESI+): m/z = 264.0. ESIꢀHRꢀMS
calcd. for C11H11BrN3 (M++H): 264.0136, found: 264.0133.
(E)-2-Oxo-2-phenyl-N'-(4-(N-thiazol-2-ylsulfamoyl)phenyl)acetohydrazonoylcyanide (10). Yield:
65% (68%) (0.161 g from 0.1 g); a yellow solid, mp: 262ꢀ264 oC; Rf = 0.48 (Hexanes: EtOAc, 7:3, v/v);
IR (KBr) νmax: 1085, 1676, 2229, 3262, 2217 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 6.83 (d, J = 4.5
Hz, 1H), 7.25 (d, J = 4.5 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.5 Hz,
2H), 7.92 (d, J = 8.4 Hz, 2H), 12.71 (s, 2H); C NMR (100 MHz, DMSOꢀd6): δ = 108.7, 111.5, 115.3,
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116.9, 128.1, 128.9, 132.3, 135.1, 137.9, 138.3, 138.5, 145.1, 186.5 ppm. MS (ESI+): m/z = 446.0. ESIꢀ
HRꢀMS calcd. for C18H13ClN5O3S2 (M++H): 446.0148, found: 446.0148.
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(4-(N-Thiazol-2-ylsulfamoyl)phenyl)carbonohydrazonoyl dicyanide (11). Yield: 62% (65%)
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(0.311 g from 0.1 g); a yellow solid, mp: >300oC; Rf = 0.49 (Hexanes: EtOAc, 7:3, v/v); IR (KBr) νmax
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1071, 1683, 2219, 3277, 2217 cmꢀ1. 1H NMR (400 MHz, DMSOꢀd6): δ = 6.84 (d, J = 4.5 Hz, 1H), 7.26
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(d, J = 4.5 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 12.76 (s, 2H); C NMR (100
MHz, DMSOꢀd6): δ = 87.1, 108.8, 110.1, 114.6, 117.0, 125.0, 128.0, 139.2, 144.7, 169.3 ppm. MS
(ESI+): m/z = 333.0. ESIꢀHRꢀMS calcd. for C12H9N6O2S2 (M++H): 333.0228, found: 333.0229.
Typical procedure for the synthesis of 824
o
Sulfathiazole (7) (0.5 g, 1.95 mmol) was dissolved in HCl (2 mL) at 0 C maintained by an ice bath.
NaNO2 (0.1 g, 1.95 mmol) was dissolved in water (2 mL) and added dropwise in to the reaction mixture
under stirring. The reaction was continued for 1h after which a solution of SnCl2.2H2O (0.9 g, 3.91
mmol) in 3 mL HCl was added dropwise at 0 oC. The reaction was continued for another 2 h after which
it was extracted with 30 mL EtOAc and organic layer was discarded. The solution was basified with
NaOH until it pH 7 and then extracted with EtOAc (3 X 20 mL). The organic layers were pooled, dried
over anhyd. Na2SO4 and evaporated to obtain the crude product 8 (0.5 g, 82%) as a yellow solid.
4-Hydrazinyl-N-(thiazol-2-yl)benzenesulfonamide (8). Yield: 82% (0.5 g from 0.5 g); a yellow
solid, mp: 228ꢀ230 C; H NMR (400 MHz, DMSOꢀd6): δ = 6.56 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 4.6
Hz, 1H), 7.18 (d, J = 4.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 2H), 9.51 (s, 1H), 10.18 (s, 2H), 12.41 (s, 1H);
13C NMR (100 MHz, DMSOꢀd6): δ = 107.9, 119.0, 128.5, 137.8, 141.3, 142.9, 170.1 ppm. MS (ESI+):
m/z = 271.0. ESIꢀHRꢀMS calcd. for C9H11N4O2S2 (M++H): 271.0323, found: 271.0327.
General procedure for the synthesis of 3aa, 3ea, 10, 11 from diazonium salt as exemplified for
the synthesis of 3ea
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To a stirred solution of ethyl 3ꢀoxoꢀ3ꢀphenylpropanoate 1e (0.1 g, 0.52 mmol) in DMSO (3 mL),
phenyldiazonium salt 6 (0.24 g, 0.78 mmol) and K2CO3 (0.06 g, 0.62 mmol) were added to the reaction
o
mixture and the reaction was heated at 90 C for 2 h. After completion (as monitored by TLC), the
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reaction was quenched with water (30 mL) and extracted with EtOAc (3 x 20 mL). The organic layers
were pooled, dried over Na2SO4 and evaporated to obtain a residue. This residue was purified by
column chromatography over silica gel using hexanes/ EtOAc (9:1, v/v) as eluent to afford the desired
product 3ea (0.11 g, 71%) as a yellow solid.
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(Z)-Ethyl 3-oxo-3-phenyl-2-(2-phenylhydrazono)propanoate (3ea). Mp: 63ꢀ65 oC [Lit. 63ꢀ65 oC]4b
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Rf = 0.49 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 1673, 1738, 3251 cmꢀ1. H NMR (400 MHz,
CDCl3): δ = 1.35 (t, J = 7.1 Hz, 3H), 4.36 (q, J = 7.1 Hz, 2H), 7.05ꢀ7.09 (m, 1H), 7.15ꢀ7.17 (m, 2H),
7.27ꢀ7.31 (m, 2H), 7.42ꢀ7.47 (m, 2H), 7.53ꢀ7.57 (m, 1H), 7.92ꢀ7.94 (m, 2H), 12.72 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ = 14.1, 61.4, 115.3, 124.4, 127.9, 129.5, 130.4, 132.4, 137.8, 141.9, 164.1, 189.5
ppm. MS (ESI+): m/z = 297.1. ESIꢀHRꢀMS calcd. for C17H17N2O3 (M++H): 297.1239, found: 297.1233.
(E)-Ethyl 2-nitro-2-(2-phenylhydrazono)acetate (3fa). Yield: 73% (0.130 g from 0.1 g); a yellow
solid; mp: 65ꢀ67 C; Rf = 0.47 (Hexanes: EtOAc, 9:1, v/v); IR (KBr) νmax: 2135, cmꢀ1. H NMR (400
o
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MHz, CDCl3): δ = 1.41 (t, J = 7.1 Hz, 3H), 4.43 (q, J = 7.13 Hz, 2H), 7.17ꢀ7.26 (m, 1H), 7.34ꢀ7.43 (m,
13
4H), 12.03 (s, 1H); C NMR (100 MHz, CDCl3): 14.1, 62.9, 116.3, 125.8, 126.5, 129.7, 140.6, 159.4
ppm. MS (ESI+): m/z = 238.1 ESIꢀHRꢀMS calculated for C10H12N3O4 (M++H): 238.0828, found:
238.0831.
‡These authors contributed equally.
Corresponding Author
* (Sanjay Batra, e mail; batra_san@yahoo.co.uk, s_batra@cdri.res.in; Tel. +91ꢀ522ꢀ2772450 xtn
4727.
Author Contributions
§ DSB and SUD contributed equally to this work.
Present Addresses
¥SUD, Postdoctoral Researcher (SBC Group), Center for Catalytic Hydrocarbon Functionalization,
Institute for Basic Science (IBS) and Dept. of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), 291 Daehakꢀro, Yuseongꢀgu, Daejeonꢀ34141, South Korea.
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ACKNOWLEDGMENT. Two of the authors DSB and SUD acknowledge CSIR, New Delhi whereas
IA acknowledge MHRD, New Delhi for the financial assistance in the form of fellowships. Authors
acknowledge SAIF Division of CDRI for providing the spectroscopic data. Authors also acknowledge
Prof. Sandeep Verma, IIT Kanpur for helping to acquire the Xꢀray diffraction data of 3ai. Authors
acknowledge the technical assistance by Mr. S. Samanta, project assistant (2015ꢀ2016) in the group for
optimization the protocol initially.
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This is CDRI Communication No. 12/2018/SB.
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SUPPORTING INFORMATION. Xꢀray analysis data of 3ai and copies of H and CꢀNMR data are
provided. The CIF for 3ai is also included. The Supporting Information is available free of charge on
the ACS Publications website.
SBꢀJOCꢀSIꢀDiazenylation (PDF); SBꢀ3ai (cif).
REFERENCES
1. (a) Hunger, K. Industrial Dyes: Chemistry, Properties, Applications; WileyꢀVCH: Weinheim, 2003.
(b) Zhao, Y.; Ikeka, T. In Smart Light Responsive Materials: AzobenzeneꢀContaining Polymers and
Liquid Crystals; Wiley: Chichester, 2009. (c) Kumar, G. S.; Neckers, D. C. Chem. Rev. 1989, 89, 1915.
(d) Ikeda, T. J. Mater. Chem. 2003, 13, 2037. (e) Fehrentz, T.; Schӧnberger, M.; Trauner, D. Angew.
Chem., Int. Ed. 2011, 50, 12156. (f) Beharry, A. A.; Woolley, G. A. Chem. Soc. Rev. 2011, 40, 4422. (g)
Bandyopadhyay, A.; Higuchi, M. Eur. Polym. J. 2013, 49, 1688. (h) Su, X.; Aprahamian I. Chem. Soc.
Rev. 2014, 43, 1963.
2. For selected examples, see: (a) Ikeda, T.; Tsutsumi, O. Science 1995, 268, 1873. (b) Natansohn, A.;
Rochon, P. Chem. Rev. 2002, 102, 4139. (c) Yu, Y.; Nakano, M.; Ikeda, T. Nature 2003, 425, 145. (d)
Venkataramani, S.; Jana, U.; Dommaschk, M.; Sönnichsen, F. D.; Tuczek, F.; Herges, R. Science 2011,
331, 445. (e) Szymański, W.; Beierle, J. M.; Kistemaker, H. A. V.; Velema, W. A.; Feringa, B. L.
Chem. Rev. 2013, 113, 6114. (f) Aljamali, N. M. Biochem. Anal. Biochem. 2015, 4, 169. (g) Dong, M.;
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Page 25 of 28
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Babalhavaeji, A.; Samanta, S.; Beharry, A. A.; Woolley, G. A. Acc. Chem. Res. 2015, 48, 2662. (h)
Nebel, N.; Strauch, B.; Maschauer, S.; Lasch, R.; Rampp, H.; Fehler, S. K.; Bock, L. R.; Hübner, H.;
Gmeiner, P.; Heinrich, M. R.; Prante, O. ACS Omega 2017, 2, 8649.
1
2
3
4
5
6
7
8
9
3. (a) Roldo, M.; Barbu, E.; Brown, J. F.; Laight, D. W.; Smart, J. D.; Tsibouklis, J. Expert Opin.
Drug Delivery 2007, 4, 547. (b) Dhaneshwar, S. S.; Gairola, N.; Kandpal, M.; Vadnerkar, G.; Bhatt, L.;
Rathi, B.; Kadam, S. S. Eur. J. Med. Chem. 2009, 44, 3922. (c) Cassano, R.; Trombino, S.; Cilea, A.;
Ferrarelli, T.; Muzzalupo, R.; Picci, N. Chem. Pharm. Bull. 2010, 58, 103. (d) Kennedy, D. A.; Vembu,
N.; Fronczek, F. R.; Devocelle, M. J. Org. Chem. 2011, 76, 9641.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. For diazo salts (a) Bulow, C.; Neber, P. Ber. 1912, 46, 3732. (b) Bolhofer, W. A. J. Am. Chem. Soc.
1952, 74, 5459. (c) (Boyer, J. H. In The Chemistry of the Nitro and Nitroso Groups; Interscience: New
York, 1969; Part 1. (d) Buncel, E. Acc. Chem. Res. 1975, 8, 132. (e) Szele, I.; Zollinger, H. Top. Curr.
Chem. 1983, 112, 1. (f) Zollinger, H. In Diazo Chemistry I: Aromatic and Heteroaromatic Compounds;
WileyꢀVCH: Weinheim, 1994. Zollinger H. Color Chemistry. Syntheses, Properties, Application of
Organic Dyes and Pigments. Third revised edition. WileyꢀVCH. 2003. For recent reviews, see: (g)
Hamon, F.; DjedainiꢀPilard, F.; Barbot, F.; Len, C. Tetrahedron 2009, 65, 10105. (h) Merino, E. Chem.
Soc. Rev. 2011, 40, 3835.
5. (a) Grirrane, A.; Corma, A.; García, H. Science 2008, 322, 1661. (b) Zhu, H.; Ke, X.; Yang, X.;
Sarina, S.; Liu, H. Angew. Chem., Int. Ed. 2010, 49, 9657. (c) Guo, X.; Hao, C.; Jin, G.; Zhu, H.ꢀY.;
Guo, X. Angew. Chem., Int. Ed. 2014, 53, 1973. (d) Liu, X.; Li, H.ꢀQ.; Ye, S.; Liu, Y.ꢀM.; He, H.ꢀY.;
Cao, Y. Angew. Chem., Int. Ed. 2014, 53, 7624.
6. (a) Lu, W.; Xi, C. Tetrahedron Lett. 2008, 49, 4011. (b) Grirrane, A.; Corma, A.; Garcia, H. Nat.
Protoc. 2010, 5, 429. (c) Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 6174. (d) Zhu, Y.; Shi, Y.
Org. Lett. 2013, 15, 1942. (e) Jiang, B.; Ning, Y.; Fan, W.; Tu, S.ꢀJ.; Li, G. J. Org. Chem. 2014, 79,
4018.
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7. (a) Shi, L.; Pan, F.; Jia, X.; Wang, Y. Synth. Commun. 2001, 31, 1691. (b) Drug, E.; Gozin, M. J.
Am. Chem. Soc. 2007, 129, 13784. (c) Gao, W.; He, Z.; Qian, Y.; Zhao, J.; Huang, Y. Chem. Sci. 2012,
3, 883. (d) Bai, L.ꢀS.; Gao, X.ꢀM.; Zhang, X.; Sun, F.ꢀF.; Ma, N. Tetrahedron Lett. 2014, 55, 4545. (e)
Singh, S.; Chauhan, P.; Ravi. M.; Taneja, I.; Wahajuddin; Yadav, P. P. RSC Adv. 2015, 5, 61876. (f)
Wang, L.; Ishida, A.; Hashidoko, Y.; Hashimoto, M. Angew. Chem., Int. Ed. 2017, 56, 870.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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32
33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8. Liu, C.; Lv, J.; Luo, S.; Cheng, J.ꢀP. Org. Lett. 2014, 16, 5458.
9. Cao, D.; Zhang, Y.; Liu, C.; Wang, B.; Sun, Y.; Abdukadera, A.; Hu, H.; Liu, Q. Org. Lett. 2016,
18, 2000.
10. Zhang, Y.; Hu, H.; Liu, C. –J.; Cao, D.; Wang, B.; Sun, Y.; Abdukader, A. Asian J. Org. Chem.
2017, 6, 102.
11. Jiang, H.; Chen, Y.; Chen, B.; Xu, H.; Wan, W.; Deng, H.; Ma, K.; Wu, S.; Hao, J. Org. Lett.
2017, 19, 2406.
12. For selected citations see (a) Blatcher, P.; Carter, M.; Hornby, R.; Owen, M. WO Patent
95/091166, 1995. (b) Baker, R.; Matassa, V. G.; Street, L. J. U.S. Patent 5,298,520, 1994. (c) Koilpillai,
J. P.; Subramanian, M.; Mallela, U.; Boddu, V. B; Dandala, R.; Meenakshisunderam, S. WO Patent
2008/075163, 2008. (d) Voslar, M.; Zatopkova, M.; Ridvan, L.; Pekarek, T. A. London, WO Patent
2008/ 104134, 2008. (e) Browne, D. L., Baxendale, I. R.; Ley, S. V. Tetrahedron 2011, 67, 10296. (f)
Ray, C. P.; Medikonduri, S.; Ramanjaneyulu, G. S. US Patent 20110313171, 2011. (g) For synthesis of
phenylhydrazines through reduction of phenyldiazonium salts with tin(II) chloride, see: “Methods of
Molecular Transformations” Science of Synthesis, Thieme, Stuttgart, 2007, pp. 1775
13. Fehler, S. K.; Pratsch, G.; Heinrich, M. R. Angew. Chem. Int. Ed. 2014, 53, 11361.
14. For selected examples see (a) Huang, P. C.; Kosower, E. M. J. Am. Chem. Soc. 1967, 89, 3910. (b)
Huang, P. C.; Kosower, E. M. J. Am. Chem. Soc. 1968, 90, 2367. (c) Kosower, E. M.; Huang, P. C.;
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Tsuji, T. J. Am. Chem. Soc. 1969, 91, 2325. (d) Myers, A. G.; Movassaghi, M.; Zheng, B. Tetrahedron
Lett. 1997, 38, 6569. (e) Misra, H. P.; Fridovich, I. Biochem 1976, 15, 681. (f) Hill, H. A. O.;
Thornalley, P. J. FEBS Lett. 1981, 125, 235. (g) Jasch, H.; Scheumann, J.; Heinrich, M. R. J. Org.
Chem. 2012, 77, 10699.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15. Hofmann, J.; Jasch, H.; Heinrich, M. R. J. Org. Chem. 2014, 79, 2314 and references cited therein.
16. Ding, Y.; Zhang, T.; Chen, Q.ꢀY.; Zhu, C. Org. Lett. 2016, 18, 4206.
17. For selected recent examples. (a) Dighe, S. U.; Samanta, S.; Kolle, S.; Batra. S. Tetrahedron 2017,
73, 2455ꢀ2467. (b) Dighe, S. U.; Mukhopadhyaya, S.; Kumari, P.; Batra. S. Org. Lett. 2016, 18, 4190.
(c) Mukhopadhyaya, S.; Dighe, S. U.; Kolle, S.; Shukla, P. K.; Batra. S. Eur. J. Org. Chem. 2016, 3836.
(d) Dighe, S. U.; Batra. S. Adv. Synth. Cat. 2016, 358, 500.
18. (a) Kawai, H.; Okusu, S.; Yuan, Z.; Tokunaga, E.; Yamano, A.; Shiro, M.; Shibata, N. Angew.
Chem. Int. Ed. 2013, 52, 2221. (b) Ravi, M.; Chauhan, P.; Kant, R.; Shukla, S. K.; Yadav, P. P. J. Org.
Chem. 2015, 80, 5369.
19. (a) Japp, F. R.; Klingemann, F. Ber. Dtsch. Chem. Ges. 1887, 20, 2942. (b) Japp, F. R.;
Klingemann, F. Ber. Dtsch. Chem. Ges. 1887, 20, 3284. (c) Japp, F. R.; Klingemann, F. Ber. Dtsch.
Chem. Ges. 1887, 20, 3398. (d) Japp, F. R.; Klingemann, F. Justus Liebigs Ann. Chem. 1888, 247, 190.
(e) Phillips, R. R. The JappꢀKlingemann Reaction. In Organic Reactions. John Wiley & Sons, Inc.
2011, p143.
20. (a) AbdelꢀKhalik, M. M.; Agamy, S. M.; Elnagdi, M. H. Z. Naturforsch. 2000, 55b, 1211. (b) Alꢀ
Mousawi, S.; Elassar, A.ꢀZ.; ElꢀApasery, M. A. Phosphorus Sulfur 2006, 181, 1755.
21. Usami, K.; Nagasawa, Y.; Yamaguchi, E.; Tada, N.; Itoh, A. Org. Lett., 2016, 18, 8.
22. (a) Blank, O.; Heinrich, M. R. Eur. J. Org. Chem. 2006, 4331. (b) Curran, D. P.; Bosch, E.;
Kaplan, J.; Newcomb, M. J. Org. Chem. 1989, 54, 1826.
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23. Heinrich, M. R.; Blank, O.; Wetzel, A. J. Org. Chem. 2007, 72, 476 and references cited therein.
1
2
3
4
24. Habib, N. S.; Hazza, A. A. B. Sci. Pharm. 1981, 49, 246.
5
6
7
8
9
10
11
12
13
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21
22
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