KOt-Bu promoted homocoupling and decomposition of N'-aryl acylhydrazines: synthesis of unsymmetric N',N'-diaryl acylhydrazines

Article abstract of DOI:10.1016/j.tet.2015.10.023

The KOt-Bu promoted homocoupling and decomposition of N'-aryl acylhydrazines has been achieved. The method allows for a novel and efficient synthesis of unsymmetric N',N'-diaryl acylhydrazines under mild reaction conditions. The reaction probably proceeds via the generation of N'-centered acylhydrazine radicals and the subsequent homolytic aromatic substitution.

Full text of DOI:10.1016/j.tet.2015.10.023

Tetrahedron 71 (2015) 9073e9080
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Tetrahedron
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KOt-Bu promoted homocoupling and decomposition of N0-aryl
acylhydrazines: synthesis of unsymmetric N0,N0-diaryl
acylhydrazines
*
*
Wei-juan Wang, Ting Zhang, Li-jun Duan, Xue-jing Zhang , Ming Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
The KOt-Bu promoted homocoupling and decomposition of N0-aryl acylhydrazines has been achieved.
The method allows for a novel and efficient synthesis of unsymmetric N0,N0-diaryl acylhydrazines under
mild reaction conditions. The reaction probably proceeds via the generation of N0-centered acylhydrazine
radicals and the subsequent homolytic aromatic substitution.
Article history:
Received 28 August 2015
Received in revised form 6 October 2015
Accepted 8 October 2015
Available online 14 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Nitrogen radical
Acylhydrazine
Homocoupling
Homolytic aromatic substitution
1. Introduction
acylhydrazine radicals have never been reported.5 Herein, we re-
port the KOt-Bu promoted homocoupling and decomposition of N0-
The nitrogen radicals are useful intermediates for the synthesis
of various amines and nitrogen heterocycles.1,2 However, their
synthetic applications are still limited comparing with carbon
radicals. There are two general approaches for generating nitrogen
radicals: (1) the scission of a weak NeX bond (X is a halogen, a ni-
trogen, an oxygen, or a sulfur); (2) the break of a NeH bond in the
presence of oxidants. Acylhydrazine radicals can be generated in
the presence of bases and oxidants.3,4 They are reported to be N-
centered (the unpaired electron is localized at the nitrogen atom
connected to the acyl group). Most acylhydrazine radicals are easily
oxidized to diazenes, which decompose to give the corresponding
carbon radicals. Bowman and co-workers reported Ag(I)-catalyzed
oxidation reaction of acylhydrazines. The N-centered acylhydrazine
radicals were suggested to be the intermediates. Mason and co-
workers observed the existence of short-lived acylhydrazine radi-
cals via the fast-flow technique by electron paramagnetic reso-
nance (EPR) spectroscopy.4 To the best of our knowledge, the direct
addition or substitution reactions via N-centered or N0-centered
aryl acylhydrazines. A series of unsymmetric N0,N0-diaryl acylhy-
drazines were prepared in good yields. The experiment evidences
approve a reaction mechanism involving the generation of N0-
centered acylhydrazine radicals and consequent homolytic aro-
matic substitution.6
Recently we found that KOt-Bu/DMF promotes inter- and
intramolecular additions of
a
-aryl substituted amides to alkenes
(Scheme 1, eq. 1).7 The formation of
a-amido alkyl radicals was
proposed based on the experiment evidences. We speculate that
the structurally analogues acylhydrazine can generate the acylhy-
drazine radicals under the similar reaction conditions. The sub-
sequent intramolecular addition with alkenes will provide
diazepinone derivatives. Initially, we examined the reaction of
acylhydrazide 1 in KOt-Bu/DMF at 90 ꢀC. Diazepinone and 2-
(phenylamino)-dihydroisoquinolinone were obtained with a ratio
of about 2/1. When the reaction was carried out at room temper-
ature, almost no diazepinone and 2-(phenylamino)-dihy-
droisoquinolinone were obtained. Unexpectedly we got N0,N0-
diphenyl benzohydrazide 2 in 20% yield (Scheme 1, eq. 2). The yield
could be increased to 62% while THF was used as the solvent. The
result uncovered a new synthetic pathway of N0,N0-diaryl acylhy-
drazines from N0-aryl acylhydrazines.8
* Corresponding authors. Tel.: þ86 2039943051; fax: þ862039943051 (X.Z.);
e-mail address: zhangxj33@mail.sysu.edu.cn (X.-jing Zhang).
http://dx.doi.org/10.1016/j.tet.2015.10.023
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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W.-juan Wang et al. / Tetrahedron 71 (2015) 9073e9080
Table 1
Optimization of reaction conditionsa
Entry
Base (equiv.)
Solvent
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
KOt-Bu (3.0)
NaOt-Bu (3.0)
LiOt-Bu (3.0)
KOMe (3.0)
K2CO3 (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (3.0)
KOt-Bu (1.5)
KOt-Bu (1.0)
KOt-Bu (1.5)
KOt-Bu (1.5)
KOt-Bu (1.5)
THF
THF
THF
THF
25
25
25
25
25
25
25
25
25
90
0
Reflux
25
25
25
25
25
99
45
0
52
0
86
86
79
53
0
60
31
99
40
99
0
Scheme 1. Previous study of amides and reaction of N0-aryl acylhydrazine 1 with KOt-
Bu.
We then examined the reaction of N0-phenyl-benzohydrazide 3a
in KOt-Bu/THF. The expected product 4a was obtained in a moder-
ate yield (Scheme 2, eq. 1). However, the reaction of 3,4-dichloro-
N0-(4-methoxyphenyl)-benzohydrazide 3b provided the product
4b in an almost quantitative yield (Scheme 2, eq. 2). Interestingly,
the substituted position of methoxyl group on the two phenyl
group was found to be different. Recently, Li, Lu and co-workers
reported copper (II)-catalyzed reaction of N0-aryl acylhydrazines,
respectively.9 Symmetric N0,N0-diaryl acylhydrazines were obtained
in good yields. The diazenes were proposed to be the intermediates
in the reactions. The generation of unsymmetric N0,N0-diaryl acyl-
hydrazine 4b implicated the existence of a different reaction
pathway in our study.
THF
DMF
DMSO
Dioxane
Toluene
HOt-Bu
THF
THF
THF
THF
THF
9
10
11
12
13
14
15c
16d
17e
THF
THF
6
a
Reaction conditions: 3b (0.3 mmol), base, solvent (1.5 mL), in a 20 mL Radleys
reaction tube at the indicated temperature for 24 h.
b
Isolated yields of 4b after column chromatography.
KOt-Bu (>99.99% purity, 0.45 mmol) was used.
The reaction was carried out with the strict exclusion of O2.
The reaction was carried out with an O2 balloon.
c
d
e
Scheme 2. Reaction of N0-aryl acylhydrazines 3aeb in KOt-Bu/THF.
Fig. 1. Influence of O2 concentration.
2. Results and discussion
found to be about 2% (v/v). The higher O2 concentration led to
a significant loss of the yield. The successful reaction in the Radleys
reaction tube could be ascribed to the slow penetration of O2
through the septum.10
When the reaction of 3b was stopped in 12 h, a homocoupling
compound 5 was isolated and characterized (Scheme 3). The
treatment of 5 under the reaction conditions gave the product 4b in
almost quantitative yield. The result indicated that compound 5 is
the primary product in the reaction.
Using 3b as the substrate, the effect of bases, solvents, and
temperature was examined. The reactions were carried out in the
Radleys reaction tube under a nitrogen atmosphere and the results
are summarized in Table 1. Other base such as NaOt-Bu, LiOt-Bu,
KOMe, K2CO3 were less effective (Table 1, entries 2e5). The reaction
in DMF, DMSO, dioxane and toluene provided lower yields (Table 1,
entries 6e9). Protonic solvent such as HOt-Bu was incompatible
(Table 1, entry 10). Lower reaction temperature (0 ꢀC) or higher
reaction temperature (reflux) resulted in lower yields (Table 1,
entries 11e12). The loading of KOt-Bu could be decreased to
1.5 equiv without eroding the yield, but the further decrease of the
loading lead to the significant loss of the yield (Table 1, entries
13e14). The ultra-pure KOt-Bu (>99.99% purity) was also exam-
ined, and the same yield of 4b was obtained. The result confirmed
that the residual transition metal in KOt-Bu did not exert the crucial
effect on the reaction (Table 1, entry 15).
The O2 concentration was found to exert the amazing effect on
the reaction. No product 4b was obtained with the strict exclusion
of O2 (Table 1, entry 16). On the other hand, the reaction with an O2
balloon gave only trace amount of 4b (Table 1, entry 17). A close
examination of the influence of O2 concentration was carried out
and the results are listed in Fig. 1. The optimal O2 concentration was
Scheme 3. Isolation and decomposition of homocoupling compound.

W.-juan Wang et al. / Tetrahedron 71 (2015) 9073e9080
9075
To explore the reaction mechanism, the control experiments
with free radical scavengers were examined (Scheme 4). The re-
action was found to be inhibited by hydroquinone and DPPH (1,1-
diphenyl-2-picrylhydrazyl).
phenyl with alkyl, methoxyl and halogen were well tolerated. Ex-
cellent yields were obtained for 4-tert-butyl and 4-methoxyl
substituted substrates 3de3e. The 4-trifluoromethyl substituted
substrate 3i was unreactive. Comparing with the electronic prop-
erty of the substituent, the steric effect is more significant. 3,5-
Dimethyl substituted substrate 3j gave low yield of the product
4j. 2-Methoxyl substituted substrate 3k provided only 14% yield.
More sterically demanding N0-naphthyl-N-benzohydrazide 3l was
completely unreactive. When the N0-aryl group was changed to N0-
tert-butyl, no expected reaction occurred.
Scheme 4. Controlled experiments with free radical scavengers.
The electron paramagnetic resonance (EPR) spectra of substrate
3b and 3e in KOt-Bu/THF were detected. The strong EPR signals
were observed in both solutions. The data suggested the generation
of acylhydrazine radicals (see Fig. 2).
Fig. 2. EPR spectra (X band, 9.875 GHz) of 3b and 3e in KOt-Bu/THF at room
temperature.
Based on the experiment data, a reaction mechanism was pro-
posed in Scheme 5. Firstly, an anion A is generated after the
deprotonation of the substrate 3b with KOt-Bu. The N-centered
acylhydrazine radical B is formed via a single-electron-transfer
(SET) to O2. After a 1,2-hydrogen migration, the N0-centered acyl-
hydrazine radical C is produced. The addition of C to 3b gives an aryl
radical D. Homocoupling product 5 is generated via a PCET (proton
coupled electron transfer) step. Again, O2 works as a single-
electron-transfer acceptor. Such a reaction can be ascribed to
a homolytic aromatic substitution (HAS) involving nitrogen radi-
cal.6 5 is further oxidized to a diazene E. The decomposition of E
provides product 4b and dichlorobenzoic acid, which was detected
by a GCeMS analysis.
Scheme 6. Reaction of N0-aryl acylhydrazinesa,b
.
aReaction conditions: N0-aryl acylhydrazines 3 (0.3 mmol), KOt-Bu (0.45 mmol), THF
(1.5 mL), 25 ꢀC, in a 20 mL Radleys reaction tube, stirred under a nitrogen atmosphere
for 24 h.
b
Isolated yields after column chromatography.
We also explored the influence of acyl group. Both the sub-
stitutions with alkyl, alkoxyl and halogen (4neq) provided the
products in good yields. The re-placement of benzoyl group with
a naphthoyl group (3r) also led to a good yield. However, the
substrate 3v with a nitro group provided only trace amount of the
Scheme 5. Tentative reaction mechanism.
The substrate scope of the reaction was then examined and the
results are summarized in Scheme 6. The 4-substitutions on N0-

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W.-juan Wang et al. / Tetrahedron 71 (2015) 9073e9080
product. A series of heteroaryl substituted substrates 3wey were
also examined. Furan-carbohydrazide and N-methyl-pyrrole-car-
bohydrazide (3w and 3y) gave the products in moderate yields.
Thiophene-carbohydrazide 3x gave a mixture of 4x and 4x0. Piv-
alohydrazide 3z is also applicable. The product 4z was obtained in
a low yield. The reaction of toluenesulfonohydrazide 6 was un-
successful. Although the complete consumption of the substrate
was observed, no expected product was obtained.
3035, 1650, 993, 912, 750, 710. HRMS (ESI) calculated for C15H15N2O
(MþH)þ: 239.1179, found: 239.1168.
4.2.2. 3,4-Dichloro-N0-(4-methoxyphenyl)benzohydrazide (3b). Off-
white solid (933.5 mg, 60%), mp 143.5e146.2 ꢀC. 1H NMR (400 MHz,
DMSO):
1H), 7.79 (d, J¼8.4 Hz, 1H), 7.65 (s, 1H), 6.74e6.80 (m, 4H), 3.65 (s,
3H). 13C NMR (100 MHz, DMSO):
164.6, 153.3, 143.5, 134.9, 133.9,
131.9, 131.4, 129.7, 128.0, 114.7, 114.4, 55.7. IR (KBr)
/cmꢁ1: 3253,
d
10.52 (s, 1H), 8.13 (d, J¼2.0 Hz, 1H), 7.87 (dd, J¼8.4, 2.0 Hz,
d
n
3. Conclusions
3055, 1660, 2960, 2870, 1650, 1490, 850, 750.7, 1510. HRMS (ESI)
calculated for
333.0159.
C
14H12Cl2N2NaO2 (MþNa)þ: 333.0168, found:
In conclusion, we have developed KOt-Bu promoted homocou-
pling and decomposition of N0-aryl acylhydrazines. A variety of
unsymmetric N0,N0-diaryl acylhydrazines were prepared in mod-
erate to excellent yields. The O2 concentration was found to exert
the crucial effect on the reaction. The experiment data approve
a reaction mechanism involving the generation of nitrogen radical
and a homolytic aromatic substitution. The finding provides a new
strategy for the generation and reaction of N0-centered acylhy-
drazine radicals.
4.2.3. N0-(4-(tert-Butyl)Phenyl)benzohydrazide (3d). White solid
(872.2 mg, 65%), mp 149.6e150.9 ꢀC. 1H NMR (400 MHz, DMSO):
d
10.36 (d, J¼3.0 Hz,1H), 7.91 (d, J¼7.4 Hz, 2H), 7.76 (d, J¼3.0 Hz,1H),
7.57 (d, J¼7.2 Hz, 1H), 7.50 (t, J¼7.5 Hz, 2H), 7.17 (d, J¼8.5 Hz, 2H),
6.72 (d, J¼8.5 Hz, 2H), 1.23 (s, 9H). 13C NMR (100 MHz, DMSO):
d
166.8, 147.7, 141.4, 133.6, 132.1, 128.9, 127.7, 125.8, 112.7, 34.1, 31.9.
IR (KBr) n
/cmꢁ1: 3263, 3055, 2960, 2870, 1647, 1514, 1255, 1285,
850, 692, 752. HRMS (ESI) calculated for C17H21N2O (MþH)þ:
4. Experimental section
4.1. General
269.1648, found: 269.1635.
4.2.4. N0-(4-(Trifluoromethyl)phenyl)benzohydrazide
solid (700.6 mg, 50%), mp 142.1e142.6 ꢀC. 1H NMR (400 MHz,
(3i). White
1H NMR and 13C NMR spectra were recorded on a 400 MHz
spectrometer. Chemical shifts of protons are reported in parts per
million downfield from tetramethylsilane. Chemical shifts of car-
bon are referenced to the carbon resonances of the solvent (CDCl3:
DMSO):
d
10.51 (s, 1H), 8.59 (s, 1H), 7.93 (d, J¼7.4 Hz, 2H), 7.60 (t,
J¼7.3 Hz, 1H), 7.48e7.54 (m, 4H), 6.88 (d, J¼8.5 Hz, 2H). 13C NMR
(100 MHz, DMSO):
d
166.8, 153.1, 133.1, 132.3, 129.5 (J¼270 Hz),
129.0, 127.8, 126.7 (J¼4 Hz), 119.2 (J¼32 Hz), 112.1. IR (KBr)
n :
/cmꢁ1
d
77.0). Peaks are labeled as single (s), broad singlet (br), doublet
3242, 3043, 1653, 1525, 835, 748, 696. HRMS (ESI) calculated for
(d), triplet (t), double doublet (dd), multiplet (m). Melting points
were determined with a commercially available melting point ap-
paratus. The IR spectra were recorded as thin films with KBr and
reported in wavenumbers (cmꢁ1). High-resolution mass spectra
(HRMS) were acquired using an electron spray ionization time-of-
flight (ESI-TOF) mass spectrometer in positive mode. Copies of
their 1H NMR and 13C NMR spectra were provided. EPR spectra
were recorded on a X-band spectrometer. The samples were taken
out by a capillary (borosilicate glass, 3 mm), and then recorded by
EPR spectrometer at indicated temperature and parameters. All
reagents were used without further purification as received from
commercial suppliers unless otherwise noted. All solvents were
dried and distilled prior to use according to the standard protocols.
C
14H11F3N2NaO (MþNa)þ: 303.0716, found: 303.0702.
4.2.5. 3,
(3j). White solid (773.0 mg, 50%), mp 203.7e205.1 ꢀC. 1H NMR
4-Dichloro-N0-(3,5-dimethylphenyl)benzohydrazide
(400 MHz, DMSO):
d
10.50 (s, 1H), 8.15 (s, 1H), 7.89 (d, J¼8.4 Hz, 1H),
7.80 (d, J¼8.3 Hz, 2H), 6.39 (s, 2H), 6.37 (s, 1H), 2.16 (s, 6H). 13C NMR
(100 MHz, DMSO):
d 164.5, 149.7, 138.2, 135.0, 133.8, 131.9, 131.4,
129.7, 128.1, 121.2, 110.7, 39.5, 21.7. IR (KBr) n
/cmꢁ1: 3263, 3055,
2960, 2870, 1647, 1514, 1255, 1285, 850, 752. HRMS (ESI) calculated
for C15H15N2OCl2 (MþH)þ: 309.0556, found: 309.0557.
4.2.6. N0-(Naphthalen-2-yl)benzohydrazide
(786.9 mg, 60%), mp 185.8e186.6 ꢀC. 1H NMR (400 MHz, DMSO):
(3l). White
solid
d
10.57 (d, J¼1.5 Hz, 1H), 8.48 (d, J¼1.4 Hz, 1H), 8.29e8.30 (m, 1H),
4.2. General procedure for the preparation of substrates (1,
8.00 (d, J¼7.3 Hz, 2H), 7.83e7.86 (m, 1H), 7.61 (t, J¼7.2 Hz, 1H), 7.54
(t, J¼7.5 Hz, 2H), 7.49 (dd, J¼9.2, 5.3 Hz, 2H), 7.31 (d, J¼4.3 Hz, 2H),
3aez)11
6.77 (t, J¼4.3 Hz, 1H). 13C NMR (100 MHz, DMSO):
d 166.8, 144.7,
To a solution of benzoic acid (610.6 mg, 5 mmol) and phenyl-
hydrazine hydrochloride (723.0 mg, 5 mmol) in DMF (10.0 mL) was
added HCTU (5-Chloro-1-[bis(dimethylamino)methylene]-1H-
benzotriazolium 3-oxide hexafluorophosphate) (2275.3 mg,
5.5 mmol) and Et3N (2085.0 mL, 15 mmol). The reaction mixture
was stirred at room temperature for overnight. Then the reaction
mixture was washed with saturated NH4Cl (aq), NaHCO3 (aq) and
brine. The organic layer was dried over MgSO4 and the solvent was
removed under reduced pressure. The residue was purified by
column chromatography to give 1a as a white solid (955.2 mg, 90%).
134.3, 133.5, 132.2, 129.0, 128.5, 127.8, 126.8, 126.3, 125.0, 122.7,
122.2, 119.0, 105.5. IR (KBr) n
/cmꢁ1: 3260, 3118, 2954, 2865, 1655,
1508, 1245, 1298, 852. HRMS (ESI) calculated for C17H14N2NaO
(MþNa)þ: 285.0998, found: 285.0994.
4.2.7. 4-Methyl-N0-phenylbenzohydrazide
(1006.9 mg, 89%), mp 180.8e181.6 ꢀC. 1H NMR (400 MHz, DMSO):
10.29 (s, 1H), 7.87 (d, J¼2.2 Hz, 1H), 7.83 (d, J¼8.2 Hz, 2H), 7.31 (d,
(3n). White
solid
d
J¼8.0 Hz, 2H), 7.15 (dd, J¼8.4, 7.4 Hz, 2H), 6.77e6.79 (m, 2H), 6.71 (t,
J¼7.3 Hz, 1H), 2.37 (s, 3H). 13C NMR (100 MHz, DMSO):
d 166.2,
149.6, 141.5, 130.2, 129.0, 128.7, 127.3, 118.6, 112.3, 21.0. IR (KBr) n/
4.2.1. N0-Phenyl-2-vinylbenzohydrazide (1). White solid (953.2 mg,
cmꢁ1: 3284, 3028, 2960, 2870,1649,1497,1380,1305, 902, 690, 750.
80% yield), mp 130.1e131.6 ꢀC. 1H NMR (400 MHz, DMSO):
d
10.13
HRMS (ESI) calculated for
found: 249.0984.
C
14H14N2NaO (MþNa)þ: 249.0998,
(d, J¼2.7 Hz,1H), 7.94 (d, J¼2.9 Hz,1H), 7.75 (d, J¼7.6 Hz,1H), 7.49 (t,
J¼7.4 Hz, 2H), 7.38e7.42 (m, 1H), 7.19 (dd, J¼8.4, 7.4 Hz, 2H), 6.98
(dd, J¼17.6,11.1 Hz,1H), 6.83 (dd, J¼8.5, 0.9 Hz, 2H), 6.74 (dd, J¼10.4,
4.1 Hz, 1H), 5.86 (dd, J¼17.6, 1.0 Hz, 1H), 5.34 (dd, J¼11.1, 0.9 Hz, 1H).
4.2.8. 4-(tert-Butyl)-N0-phenylbenzohydrazide (3p). White solid
(1207.6 mg, 90%), mp 220.6e221.7 ꢀC. 1H NMR (400 MHz, DMSO):
13C NMR (100 MHz, DMSO):
128.8, 127.6, 127.5, 125.2, 118.6, 116.2, 112.2. IR (KBr)
d
168.5, 149.4, 135.2, 134.4, 133.7, 129.9,
/cmꢁ1: 3280,
d
10.30 (d, J¼2.9 Hz, 1H), 7.88 (dd, J¼7.8, 5.7 Hz, 3H), 7.52 (d,
n
J¼8.5 Hz, 2H), 7.15 (dd, J¼8.3, 7.5 Hz, 2H), 6.78 (d, J¼7.7 Hz, 2H), 6.71

W.-juan Wang et al. / Tetrahedron 71 (2015) 9073e9080
9077
(t, J¼7.3 Hz, 1H), 1.31 (s, 9H). 13C NMR (100 MHz, DMSO):
d
166.2,
6.77 (d, J¼9.0 Hz, 2H), 6.71 (d, J¼9.0 Hz, 2H), 6.65 (dd, J¼3.4, 1.7 Hz,
1H), 3.65 (s, 3H). 13C NMR (100 MHz, DMSO):
158.0, 152.7, 146.6,
145.4, 143.1, 114.2, 113.8, 113.7, 111.7, 55.2. IR (KBr)
/cmꢁ1: 3225,
154.4, 149.6, 130.2, 128.7, 127.1, 125.2, 118.5, 112.3, 34.6, 30.9. IR
d
(KBr)
n
/cmꢁ1: 3251, 3155, 2964, 2870, 1649, 1496, 1395, 1365, 748,
n
688. HRMS (ESI) calculated for C17H19N2O (MꢁH)ꢁ: 267.1503,
3080, 2960, 2810, 1630, 1505, 1247, 820. HRMS (ESI) calculated for
found: 267.1508.
C
12H12N2NaO3 (MþNa)þ: 255.0740, found: 255.0726.
4.2.9. 4-Chloro-N0-phenylbenzohydrazide
(1048.4 mg, 85%), mp 140.5e141.6 ꢀC. 1H NMR (400 MHz, DMSO):
10.44 (d, J¼2.7 Hz, 1H), 7.95 (d, J¼1.8 Hz, 1H), 7.93 (d, J¼2.6 Hz,
(3q). White
solid
4.2.16. N0-(4-Methoxyphenyl)thiophene-2-carbohydrazide
(3x). Yellow solid (682.8 mg, 55%), mp 178.2e179.2 ꢀC. 1H NMR
d
(400 MHz, DMSO):
d
10.37 (d, J¼2.4 Hz, 1H), 7.88 (d, J¼3.4 Hz, 1H),
2H), 7.57e7.60 (m, 2H), 7.15 (t, J¼7.9 Hz, 2H), 6.79 (d, J¼7.7 Hz, 2H),
7.82 (d, J¼4.9 Hz, 1H), 7.64 (d, J¼2.5 Hz, 1H), 7.19 (t, J¼4.2 Hz, 1H),
6.72 (t, J¼7.3 Hz, 1H). 13C NMR (100 MHz, DMSO):
d
165.3, 149.3,
/cmꢁ1: 3238,
6.78 (d, J¼8.7 Hz, 2H), 6.73 (d, J¼8.8 Hz, 2H), 3.65 (s, 3H). 13C NMR
136.5, 131.7, 129.2, 128.7, 128.6, 118.7, 112.3. IR (KBr)
n
(100 MHz, DMSO): d 161.8, 153.2, 143.7, 138.4, 131.7, 128.8, 128.6,
3047, 1649, 1490, 852, 750, 700. HRMS (ESI) calculated for
114.7, 114.2, 55.7. IR (KBr) n
/cmꢁ1: 3224, 3079, 2960, 2870, 1635,
C
13H12ClN2O (MþH)þ: 247.0633, found: 247.0633.
1506, 1245, 825. HRMS (ESI) calculated for C12H12N2O2S (MþNa)þ:
271.0512, found: 271.0491.
4.2.10. N0-Phenyl-1-naphthohydrazide
(1049.2 mg, 80%), mp 192.9e193.4 ꢀC. 1H NMR (400 MHz, DMSO):
(3r). White
solid
4.2.17. N0-(4-Methoxyphenyl)-1-methyl-1H-pyrrole-2-
d
10.34 (d, J¼2.9 Hz, 1H), 8.20e8.23 (m, 1H), 8.07e8.09 (m, 2H),
carbohydrazide (3y). White solid (735.8 mg, 60%), mp
8.00e8.03 (m, 1H), 7.78 (dd, J¼7.0, 1.1 Hz, 1H), 7.57e7.63 (m, 3H),
7.22 (dd, J¼8.4, 7.4 Hz, 2H), 6.90 (d, J¼7.6 Hz, 2H), 6.77 (t, J¼7.3 Hz,
127.1e127.9 ꢀC. 1H NMR (400 MHz, DMSO):
d
9.81 (s, 1H), 7.39 (s,
1H), 6.91 (d, J¼2.8 Hz, 2H), 6.70 (q, J¼9.0 Hz, 4H), 6.00 (t, J¼2.8 Hz,
1H), 3.76 (s, 3H), 3.61 (s, 3H). 13C NMR (100 MHz, DMSO):
162.0,
153.0, 144.3, 128.7, 124.2, 114.7, 114.1, 113.1, 107.3, 55.7, 36.6. IR (KBr)
1H). 13C NMR (100 MHz, DMSO):
d
168.9, 149.9, 133.6, 133.2, 130.8,
d
130.4, 129.3128.8, 127.4, 126.8, 126.1, 125.5, 125.4, 119.1, 112.7. IR
(KBr)
n
/cmꢁ1: 3246, 3049, 3107, 1637, 1484, 1311, 912, 770, 779.
n
/cmꢁ1: 3236, 3055, 2956, 1635, 1510, 1329, 1246, 1032, 825. HRMS
HRMS (ESI) calculated for C17H14N2NaO (MþNa)þ: 285.0998, found:
(ESI) calculated for C13H15N3NaO2 (MþNa)þ: 268.1056, found:
285.0982.
268.1035.
4.2.11. 4-Fluoro-N0-(4-methoxyphenyl)benzohydrazide (3s). White
solid (650.7 mg, 50%), mp 150.6e151.7 ꢀC. 1H NMR (400 MHz,
4.2.18. N0-(4-Methoxyphenyl)pivalohydrazide (3z). White solid
(666.8 mg, 60%), mp 140.7e141.6 ꢀC. 1H NMR (400 MHz, DMSO):
DMSO):
d
10.38 (s, 1H), 7.80e7.96 (m, 2H), 7.60 (s, 1H), 7.34 (t,
d
9.45 (d, J¼3.7 Hz, 1H), 7.23 (d, J¼3.7 Hz, 1H), 6.74e6.77 (m, 2H),
J¼8.2 Hz, 2H), 6.77 (s, 4H), 3.66 (s, 3H). 13C NMR (100 MHz, DMSO):
6.65e6.68 (m, 2H), 3.65 (s, 3H), 1.16 (s, 9H). 13C NMR (100 MHz,
d
165.8 (J¼247 Hz), 165.7, 153.2, 143.8, 130.4 (J¼9 Hz), 130.0, 116.0
DMSO): d 177.0, 152.5, 143.7, 114.1, 113.6, 55.2, 37.4, 27.2. IR (KBr) n/
(J¼22 Hz), 114.7, 114.3, 55.7. IR (KBr)
n
/cmꢁ1: 3282, 3133, 2953,
cmꢁ1: 3280, 3109, 2960, 1657, 1510, 1395, 1365, 1294, 1243, 1035,
831. HRMS (ESI) calculated for C12H18N2NaO2 (MþNa)þ: 245.1260,
found: 245.1244.
2868, 3030, 1650, 1520, 1245, 1298, 840. HRMS (ESI) calculated for
C
14H13FN2NaO2 (MþNa)þ: 283.0853, found: 283.0844.
4.2.12. 4-Bromo-N0-(4-methoxyphenyl)benzohydrazide (3t). White
solid (802.9 mg, 50%), mp 159.1e159.8 ꢀC. 1H NMR (400 MHz,
4.3. General procedure for the preparation of substrates (2,
4aez)
DMSO):
J¼8.4 Hz, 2H), 7.63 (d, J¼3.4 Hz, 1H), 6.74e6.79 (m, 4H), 3.66 (s, 3H).
13C NMR (100 MHz, DMSO):
165.9, 153.2, 143.7, 132.67, 132.0,
129.8, 125.8, 114.7114.3, 55.7. IR (KBr)
/cmꢁ1: 3226, 3110, 2960,
d
10.44 (d, J¼3.4 Hz, 1H), 7.85 (d, J¼8.5 Hz, 2H), 7.72 (d,
To a dried 20 mL Radleys reaction tube was added 3a (63.7 mg,
0.3 mmol), KOt-Bu (50.5 mg, 0.45 mmol) and THF (1.5 mL). The
reaction mixture was stirred at 25 ꢀC for 24 h. The solvent was
removed under reduced pressure and the residue was purified by
column chromatography to give 4a as a white solid (22.5 mg, 52%).
d
n
2870, 1633, 1510, 1247, 1032, 831. HRMS (ESI) calculated for
C
14H12N2O2Br (MꢁH)ꢁ: 319.0088, found: 319.0078.
4.2.13. N0-(4-Methoxyphenyl)-4-(trifluoromethyl)benzohydrazide
(3u). White solid (775.7 mg, 50%), mp 169.4e170.6 ꢀC. 1H NMR
4.3.1. N0,N0-diphenyl-2-vinylbenzohydrazide
(29.3 mg, 62%), mp 120.5e121.69 ꢀC. 1H NMR (400 MHz, DMSO):
(2). White
solid
(400 MHz, DMSO):
d
10.58 (s, 1H), 8.10 (d, J¼8.1 Hz, 2H), 7.89 (d,
d
11.02 (s, 1H), 7.76 (d, J¼7.7 Hz, 1H), 7.52 (dd, J¼13.9, 7.5 Hz, 2H),
J¼8.2 Hz, 2H), 7.69 (s, 1H), 6.78 (s, 4H), 3.66 (s, 3H). 13C NMR
7.42 (t, J¼7.4 Hz, 1H), 7.34 (t, J¼7.5 Hz, 4H), 7.20 (d, J¼8.0 Hz, 4H),
7.03 (t, J¼7.1 Hz, 2H), 6.91 (dd, J¼17.4, 11.0 Hz, 1H), 5.84 (d,
J¼17.6 Hz, 1H), 5.32 (d, J¼11.1 Hz, 1H). 13C NMR (100 MHz, DMSO):
(100 MHz, DMSO):
d
165.6, 153.3, 143.5, 137.4, 132.1 (J¼32 Hz),
128.7, 126.0 (J¼4 Hz), 125.7 (J¼272 Hz), 114.7, 114.4, 55.7. IR (KBr)
n/
cmꢁ1: 3244, 3097, 2999, 1647, 1510, 1331, 1238, 831. HRMS (ESI)
d 168.0, 145.7, 135.5, 133.6, 133.4, 130.3, 129.1, 127.7, 127.4, 125.4,
calculated for
333.0799.
C
15H13F3N2NaO2 (MþNa)þ: 333.0821, found:
122.3, 118.8, 116.6.
4.3.2. N0,N0-Diphenylbenzohydrazide (4a). White solid (22.5 mg,
4.2.14. N0-(4-Methoxyphenyl)-4-nitrobenzohydrazide (3v). Yellow
solid (718.2 mg, 50%), mp 209.6e210.5 ꢀC. 1H NMR (400 MHz,
52%), mp 159.7e160.9 ꢀC. 1H NMR (400 MHz, DMSO):
d 11.22 (s,1H),
7.95 (dd, J¼5.2, 3.3 Hz, 2H), 7.59e7.63 (m, 1H), 7.52 (dd, J¼10.3,
DMSO):
7.71 (s, 1H), 6.78 (s, 4H), 3.66 (s, 3H). 13C NMR (100 MHz, DMSO):
164.7, 152.9, 149.2, 142.9, 138.8, 128.8, 123.6, 114.3, 113.9, 55.2. IR
d
10.66 (s, 1H), 8.34 (d, J¼8.8 Hz, 2H), 8.12e8.14 (m, 2H),
4.6 Hz, 2H), 7.28e7.32 (m, 4H), 7.17 (dd, J¼8.6, 1.0 Hz, 4H), 6.99 (dd,
J¼10.5, 4.1 Hz, 2H). 13C NMR (100 MHz, DMSO):
d 166.3,146.2,132.9,
d
132.5, 129.5, 129.1, 127.9, 122.6, 119.2. This is a known compound
and the spectral data are identical to those reported in the
literature.9b
(KBr) n
/cmꢁ1: 3296, 3025, 2999, 2833, 1643, 1520, 1340, 1232, 1033,
831. HRMS (ESI) calculated for C14H12N3O4 (MꢁH)ꢁ: 286.0833,
found: 286.0839.
4.3.3. 3,4-Dichloro-N0-(3-methoxyphenyl)-N0-(4-methoxyphenyl)
4.2.15. N0-(4-Methoxyphenyl)furan-2-carbohydrazide (3w). White
solid (580.6 mg, 50%), mp 140.4e142.6 ꢀC. 1H NMR (400 MHz,
benzohydrazide (4b). Off-white solid (62.6 mg, quant), mp
158.3e159.4 ꢀC. 1H NMR (400 MHz, CDCl3):
d
8.41 (s, 1H), 7.89 (s,
DMSO):
d
10.23 (s, 1H), 7.88 (d, J¼1.0 Hz, 1H), 7.22 (d, J¼3.4 Hz, 1H),
1H), 7.61 (d, J¼8.3 Hz, 1H), 7.45 (d, J¼8.3 Hz, 1H), 7.29 (d, J¼8.7 Hz,

9078
W.-juan Wang et al. / Tetrahedron 71 (2015) 9073e9080
2H), 7.11 (t, J¼8.1 Hz, 1H), 6.85 (d, J¼8.6 Hz, 2H), 6.46 (t, J¼7.7 Hz,
(400 MHz, DMSO): d 11.34 (s, 1H), 7.92e7.94 (m, 2H), 7.61 (d,
2H), 6.42 (s, 1H), 3.80 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz,
J¼7.4 Hz, 1H), 7.49e7.53 (m, 4H), 7.22e7.27 (m, 2H), 7.11e7.18 (m,
CDCl3):
d
164.7, 160.4, 157.5, 148.3, 138.1, 136.6, 133.2, 132.1, 130.7,
4H). HRMS (ESI) calculated for
C
19H14Br2N2NaO (MþNa)þ:
129.9,129.5,126.4,126.1,114.7,107.9,105.6,101.7, 55.5, 55.2. IR (KBr)
466.9365, found: 466.9339. 13C NMR (100 MHz, DMSO):
d 166.3,
n
/cmꢁ1: 3207, 3113, 2953, 2833, 1660, 1508, 1250, 1032, 839, 690.
147.5, 144.8, 132.8, 132.6, 132.4, 131.6, 129.2, 128.0, 125.3, 122.5,
HRMS (ESI) calculated for C21H18Cl2N2NaO3 (MþNa)þ: 439.0587,
122.2, 120.8, 117.6, 115.2. IR (KBr)
n
/cmꢁ1: 3260, 3080, 1659, 1510,
found: 439.0564.
1260, 835, 755, 705. HRMS (ESI) calculated for C19H14Br2N2NaO
(MþNa)þ: 466.9365, found: 466.9339.
4.3.4. N0-(3-Tolyl)-N0-(4-tolyl)benzohydrazide (4c). White solid
(28.5 mg, 60%), mp 179.7.1e180.9 ꢀC. 1H NMR (400 MHz, CDCl3):
4.3.10. 3,4-Dichloro-N0-(2, 4-dimethylphenyl)-N0-(3,5-
d
8.28 (s, 1H), 7.84 (d, J¼7.7 Hz, 2H), 7.54 (d, J¼7.3 Hz, 1H), 7.45 (t,
dimethylphenyl)benzohydrazide (4j). White solid (26.7 mg, 43%),
J¼7.5 Hz, 2H), 7.15 (t, J¼6.6 Hz, 3H), 7.10 (d, J¼8.5 Hz, 2H), 6.90e6.93
mp 199.1e120.3 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.57 (s, 1H), 7.81
(m, 2H), 6.79 (d, J¼7.4 Hz, 1H), 2.31 (s, 3H), 2.27 (s, 3H). 13C NMR
(s, 1H), 7.50 (d, J¼8.3 Hz, 1H), 7.28 (d, J¼8.3 Hz, 1H), 7.23 (d,
J¼7.6 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J¼8.2 Hz, 1H), 6.49 (s, 1H), 6.26
(s, 2H), 2.32 (s, 4H), 2.22 (s, 4H), 2.17 (s, 6H). 13C NMR (100 MHz,
(100 MHz, CDCl3):
d 166.4, 146.3, 143.4, 139.0, 133.4, 132.6, 132.2,
129.9, 129.0, 128.8, 127.3, 123.1, 121.1, 118.7, 115.2, 21.6, 20.9. IR (KBr)
n
/cmꢁ1: 3267, 3110, 2920, 1657, 1510, 1305, 690, 602. HRMS (ESI)
CDCl3):
d 164.5, 147.2, 140.8, 138.9, 136.9, 136.4, 136.0, 133.2, 132.4,
calculated for C21H21N2O (MþH)þ: 317.1648, found: 317.1626.
132.0, 130.7, 129.4, 128.0, 126.7, 126.4, 122.3, 111.7, 21.6, 21.1, 18.2. IR
(KBr) n
/cmꢁ1: 3250, 3082, 2960, 2870, 1660, 1509, 810, 755. HRMS
4.3.5. N0-(3-(tert-Butyl)phenyl)-N0-(4-(tert-butyl)phenyl)benzohy-
(ESI) calculated for
411.1032.
C
23H21N2OCl2 (MꢁH)ꢁ: 411.1036, found:
drazide (4d). White solid (58.9 mg, 98%), mp 207.8e208.4 ꢀC. 1H
NMR (400 MHz, CDCl3):
d
8.25 (s, 1H), 7.85 (d, J¼7.8 Hz, 2H), 7.54 (d,
J¼7.2 Hz, 1H), 7.46 (t, J¼7.5 Hz, 2H), 7.27e7.31 (m, 3H), 7.21 (t,
J¼7.9 Hz, 1H), 7.14 (d, J¼8.4 Hz, 2H), 7.06 (d, J¼7.7 Hz, 1H), 7.00 (d,
J¼7.8 Hz, 1H), 1.30 (s, 9H), 1.27 (s, 9H). 13C NMR (100 MHz, CDCl3):
4.3.11. N0-(2-Methoxyphenyl)-N0-(3-methoxyphenyl)benzohydrazide
(4k). White solid (7.4 mg, 14%), mp 202.6e202.9 ꢀC. 1H NMR
(400 MHz, CDCl3):
d
8.57 (s, 1H), 7.82 (d, J¼7.2 Hz, 2H), 7.66 (dd,
d
166.5, 152.3, 145.8, 145.7, 143.5, 132.8, 132.2, 128.9, 128.8, 127.2,
J¼7.7, 1.4 Hz, 1H), 7.52 (d, J¼7.4 Hz, 1H), 7.44 (t, J¼7.5 Hz, 2H), 7.29
(dd, J¼7.9, 1.3 Hz, 1H), 7.09 (t, J¼8.1 Hz, 1H), 7.02 (dd, J¼13.3, 7.4 Hz,
2H), 6.40 (dd, J¼13.8, 5.1 Hz, 2H), 6.35e6.42 (m, 1H), 3.83 (s, 3H),
126.1, 120.1, 119.1, 116.7, 116.4, 34.8, 34.3, 31.4, 31.3. IR (KBr) n :
/cmꢁ1
3278, 3113, 2960, 2870, 1659, 1514, 1309, 1279, 800, 775, 696. HRMS
(ESI) calculated for C27H33N2O (MþH)þ: 401.2587, found: 401.2573.
3.71 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 166.4, 160.5, 155.7, 149.9,
133.0, 132.3132.0, 130.8, 129.7, 128.8, 128.7, 127.3, 121.4112.4, 106.1,
4.3.6. N0-(3-Methoxyphenyl)-N0-(4-methoxyphenyl)benzohydrazide
104.7, 99.8, 55.8, 55.2. IR (KBr)
n
/cmꢁ1: 3236, 3113, 2926, 2865,
(4e). White solid (50.7 mg, 97%), mp 201.5e202.3 ꢀC. 1H NMR
1659, 1510, 1244, 1030, 845, 750, 700. HRMS (ESI) calculated for
(400 MHz, CDCl3):
d
8.33 (s, 1H), 7.81e7.83 (m, 2H), 7.54 (t, J¼7.4 Hz,
C
21H21N2O3 (MþH)þ: 349.1547, found: 349.1554.
1H), 7.43 (t, J¼7.6 Hz, 2H), 7.32e7.36 (m, 2H), 7.12 (t, J¼8.1 Hz, 1H),
6.85e6.89 (m, 2H), 6.53e6.54 (m, 1H), 6.49 (t, J¼2.2 Hz, 1H), 6.45
(dd, J¼8.1, 1.9 Hz, 1H), 3.80 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz,
4.3.12. 4-Methyl-N0,N0-diphenylbenzohydrazide (4n). White solid
(25.4 mg, 56%), mp 183.7e184.6 ꢀC. 1H NMR (400 MHz, CDCl3):
CDCl3):
d
166.4, 160.5, 157.4, 148.6, 138.5, 132.6, 132.2, 129.9, 128.8,
d
8.32 (s, 1H), 7.74 (d, J¼7.7 Hz, 2H), 7.26e7.28 (m, 5H), 7.21 (t,
127.3, 126.1, 114.7, 108.0, 105.7, 101.7, 55.5, 55.2. IR (KBr)
3236, 3113, 2926, 2865, 1659, 1510, 1244, 1030, 845, 735, 688. HRMS
(ESI) calculated for
349.1554.
n
/cmꢁ1
:
J¼8.8 Hz, 5H), 7.02 (t, J¼7.1 Hz, 2H), 2.41 (s, 3H). 13C NMR (100 MHz,
CDCl3):
(KBr) n
d 166.4, 145.8, 142.9, 129.5, 129.2, 127.3, 123.0, 119.5, 21.6. IR
C
21H21N2O3 (MþH)þ: 349.1547, found:
/cmꢁ1: 3280, 3030, 2960, 2870, 1660, 1515, 1380, 830, 750,
700. HRMS (ESI) calculated for C20H18N2NaO (MþNa)þ: 325.1311,
found: 325.1297.
4.3.7. N0-(3-Fluorophenyl)-N0-(4-fluorophenyl)benzohydrazide
(4f). White solid, 31.7 mg, 65% yield, mp 185.7e186.1 ꢀC. 1H NMR
4.3.13. 4-Methoxy-N0,N0-diphenylbenzohydrazide (4o). White solid
(35.4 mg, 74%), mp 197.7e198.6 ꢀC. 1H NMR (400 MHz, DMSO):
(400 MHz, CDCl3):
d
8.56 (s, 1H), 7.81 (d, J¼7.4 Hz, 2H), 7.55 (t,
J¼7.4 Hz, 1H), 7.42 (t, J¼7.6 Hz, 2H), 7.32 (dd, J¼8.8, 4.8 Hz, 2H), 7.14
d
10.22 (s,1H), 7.92 (d, J¼2.0 Hz,1H), 7.90 (d, J¼2.8 Hz,1H), 7.13e7.17
(dd, J¼14.8, 7.9 Hz, 1H), 7.01 (t, J¼8.6 Hz, 2H), 6.69 (d, J¼8.1 Hz, 1H),
(m, 2H), 7.04 (d, J¼1.9 Hz, 1H), 7.02 (d, J¼2.8 Hz, 1H), 6.79 (d,
J¼1.0 Hz, 1H), 6.77 (d, J¼0.9 Hz, 1H), 6.70e6.73 (m, 1H), 3.82 (s, 3H).
6.62 (dd, J¼16.0, 9.7 Hz, 2H). 13C NMR (100 MHz, DMSO):
d 166.2,
166.1, 164.6 (J¼242 Hz), 160.7 (J¼242 Hz), 149.1 (J¼10 Hz), 141.6,
132.6 (J¼5 Hz), 131.2 (J¼10 Hz), 129.1, 128.0, 125.3 (J¼9 Hz), 116.7
13C NMR (100 MHz, DMSO):
d 165.8, 161.9, 149.7, 129.1, 128.7, 125.1,
118.5, 113.7, 112.3, 55.4. This is a known compound and the spectral
(J¼23 Hz), 111.8, 107.4 (J¼21 Hz), 102.7 (J¼26 Hz). IR (KBr)
n :
/cmꢁ1
data are identical to those reported in the literature.9b
3257, 3116, 3062, 1659, 1504, 1269, 1169, 1169, 833, 712. HRMS (ESI)
calculated for
347.0945.
C
19H14F2N2NaO (MþNa)þ: 347.0966, found:
4.3.14. 4-(tert-Butyl)-N0,N0-diphenylbenzohydrazide
solid (41.9 mg, 81%), mp 250.0e250.5 ꢀC. 1H NMR (400 MHz,
CDCl3):
8.42 (s, 1H), 7.80 (d, J¼8.0 Hz, 2H), 7.45 (d, J¼8.0 Hz, 2H),
7.27 (t, J¼7.1 Hz, 4H), 7.20 (d, J¼8.0 Hz, 4H), 7.03 (d, J¼7.1 Hz, 2H).
13C NMR (100 MHz, CDCl3):
166.3, 155.9, 145.9, 129.5, 129.2, 127.2,
125.8, 123.0, 119.5, 35.1, 31.2. IR (KBr)
/cmꢁ1: 3273, 3113, 2962,
(4p). White
d
4.3.8. N0-(3-Chlorophenyl)-N0-(4-chlorophenyl)benzohydrazide
(4g). White solid (35.9 mg, 67%), mp 192.7e193.4 ꢀC. 1H NMR
d
(400 MHz, DMSO):
d
11.36 (s, 1H), 7.94 (d, J¼7.4 Hz, 2H), 7.63 (t,
n
J¼7.3 Hz, 1H), 7.54 (t, J¼7.6 Hz, 2H), 7.40 (d, J¼8.8 Hz, 2H), 7.32 (t,
2873, 1657, 1497, 1396, 1362, 850, 746, 700. HRMS (ESI) calculated
J¼8.4 Hz, 1H), 7.24 (d, J¼8.8 Hz, 2H), 7.02e7.07 (m, 3H). 13C NMR
for C23H24N2NaO (MþNa)þ: 367.1781, found: 367.1786.
(100 MHz, DMSO):
d 166.3, 147.5, 144.3, 134.1, 132.8, 132.4, 131.3,
129.7, 129.2, 128.0, 127.5, 122.2, 122.1, 117.5, 116.8. IR (KBr)
n
/cmꢁ1
:
4.3.15. 4-Chloro-N0,N0-diphenylbenzohydrazide (4q). White solid
(40.7 mg, 84%), mp 175.5e178.6 ꢀC. 1H NMR (400 MHz, DMSO):
3267, 3055, 3103, 1659, 1485, 1255, 1093, 827, 773, 683. HRMS (ESI)
calculated for C19H14Cl2N2NaO (MþNa)þ: 379.0375, found: 379.0357.
d 11.29 (s, 1H), 7.94e7.97 (m, 2H), 7.60e7.63 (m, 2H), 7.28e7.32 (m,
4H), 7.15 (dd, J¼8.6, 1.0 Hz, 4H), 6.99 (dd, J¼10.5, 4.1 Hz, 2H). 13C
4.3.9. N0-(3-Bromophenyl)-N0-(4-bromophenyl)benzohydrazide
NMR (100 MHz, DMSO):
128.7, 122.2,118.7. IR (KBr)
d
164.8, 145.6, 136.9, 131.2, 129.4, 129.1,
(4h). White solid (52.2 mg, 78%), mp 220.2e222.3 ꢀC. 1H NMR
n
/cmꢁ1: 3246, 3041, 1655,1494, 897, 746,

W.-juan Wang et al. / Tetrahedron 71 (2015) 9073e9080
9079
692. HRMS (ESI) calculated for C19H15ClN2NaO (MþNa)þ: 345.0765,
1H), 6.65 (s, 1H), 6.58 (d, J¼8.0 Hz, 1H), 6.52 (d, J¼8.2 Hz, 1H), 6.48
(s, 1H), 6.44 (d, J¼8.1 Hz, 1H), 3.79 (s, 6H), 3.74 (s, 3H), 3.71 (s, 3H).
found: 345.0744.
13C NMR (100 MHz, CDCl3):
d 164.8, 161.0, 160.5, 157.5, 149.1, 148.6,
4.3.16. N0,N0-Diphenyl-1-naphthohydrazide
(48.4 mg, 83%), mp 175.5e178.6 ꢀC. 1H NMR (400 MHz, DMSO):
11.22 (s, 1H), 8.10e8.15 (m, 2H), 8.01e8.04 (m, 1H), 7.82 (d,
(4r). White
solid
139.7, 138.4, 136.0, 135.4, 133.7, 131.3, 130.8, 130.0, 129.9, 129.4,
127.9, 126.8, 126.2, 124.3, 114.7, 110.4, 108.0, 107.9, 105.7, 104.1, 101.7,
d
55.5, 55.3, 55.2. IR (KBr) n
/cmꢁ1: 3235, 3083, 2958, 2840, 1665,
J¼7.0 Hz, 1H), 7.59e7.65 (m, 3H), 7.37 (t, J¼7.7 Hz, 4H), 7.26 (d,
1509, 1312, 1250, 830. HRMS (ESI) calculated for C19H18N2NaO3S
J¼8.2 Hz, 4H), 7.04 (t, J¼7.2 Hz, 2H). 13C NMR (100 MHz, DMSO):
(MþNa)þ: 377.0930, found: 377.0919.
d
168.4, 146.2, 133.7, 132.4, 131.2, 130.4, 129.7, 128.9, 127.7, 127.0,
126.2, 125.5, 125.3, 122.8, 119.2. IR (KBr)
n
/cmꢁ1: 3250, 3050, 3106,
4.3.22. N0-(3-Methoxyphenyl)-N0-(4-methoxyphenyl)-1-methyl-1H-
1650, 1490, 750, 700. HRMS (ESI) calculated for C23H18N2NaO
pyrrole-2-carbohydrazide (4y). White solid (33.8 mg, 64%), mp
(MþNa)þ: 361.1311, found: 361.1285.
153.8e154.6 ꢀC. 1H NMR (400 MHz, CDCl3):
d 7.99 (s, 1H), 7.32 (d,
J¼8.0 Hz, 2H), 7.11 (t, J¼8.1 Hz, 1H), 6.87 (d, J¼8.4 Hz, 2H), 6.78 (s,
1H), 6.70 (s,1H), 6.55 (d, J¼8.2 Hz,1H), 6.51 (s,1H), 6.43 (d, J¼7.8 Hz,
1H), 6.10 (s, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.71 (s, 3H). 13C NMR
4.3.17. 4-Fluoro-N0-(3-methoxyphenyl)-N0-(4-methoxyphenyl)ben-
zohydrazide (4s). White solid (38.5 mg, 81%), mp 182.6e183.6 ꢀC.
1H NMR (400 MHz, CDCl3):
d
8.56 (s,1H), 7.81 (dd, J¼7.5, 5.6 Hz, 2H),
(100 MHz, CDCl3):
d 160.8, 160.5, 157.2, 148.8, 138.7, 129.8, 129.0,
7.29 (d, J¼8.4 Hz, 2H), 7.10 (t, J¼8.2 Hz, 1H), 7.04 (t, J¼8.3 Hz, 2H),
6.83 (d, J¼8.4 Hz, 2H), 6.47 (dd, J¼18.6, 7.8 Hz, 3H), 3.79 (s, 3H), 3.70
125.5,123.2,114.6,112.2,108.0,107.6,105.6,101.6, 55.5, 55.2, 36.8. IR
(KBr) n
/cmꢁ1: 3259, 3091, 2966, 2933, 1655, 1603, 1489, 1240, 1031,
(s, 3H). 13C NMR (100 MHz, CDCl3):
d
166.4 (J¼251 Hz), 165.55,
833. HRMS (ESI) calculated for C20H21N3NaO3 (MþNa)þ: 374.1475,
160.5, 157.5, 148.6, 138.4, 129.9, 129.8 (J¼9 Hz), 128.6, 126.1, 116.0
found: 374.1463.
(J¼22 Hz), 114.7, 107.9, 105.5, 101.7, 55.5, 55.2. IR (KBr)
n
/cmꢁ1
:
3260, 3118, 2954, 2865, 1655, 1508, 1245, 1298, 852. HRMS (ESI)
4.3.23. N0-(3-Methoxyphenyl)-N0-(4-methoxyphenyl)pivalohy-
calculated for
389.1255.
C
21H19FN2NaO3 (MþNa)þ: 389.1272, found:
drazide (4z). White solid (16.3 mg, 33%), mp 185.6e186.5 ꢀC. 1H
NMR (400 MHz, CDCl3):
J¼8.0 Hz,1H), 6.86 (d, J¼8.6 Hz, 2H), 6.40e6.44 (m, 3H), 3.80 (s, 3H),
3.72 (s, 3H), 1.28 (s, 9H). 13C NMR (100 MHz, CDCl3):
176.6, 160.4,
157.1, 148.6, 138.6, 129.8, 125.5, 114.6, 107.8, 105.6, 101.4, 55.5, 55.2,
d
7.80 (s, 1H), 7.25 (d, J¼9.0 Hz, 2H), 7.10 (t,
4.3.18. 4-Bromo-N0-(3-methoxyphenyl)-N0-(4-methoxyphenyl)ben-
d
zohydrazide (4t). White solid (52.6 mg, 82%), mp 152.6e153.7 ꢀC.
1H NMR (400 MHz, CDCl3):
d
8.50 (s, 1H), 7.66 (d, J¼8.1 Hz, 2H), 7.50
38.3, 27.5. IR (KBr) n
/cmꢁ1: 3244, 3107, 2954,1664, 1491, 1395, 1365,
(d, J¼8.2 Hz, 2H), 7.29 (d, J¼8.6 Hz, 2H), 7.11 (t, J¼8.3 Hz, 1H), 6.84
1228, 1101, 832. HRMS (ESI) calculated for C19H25N2O3 (MþH)þ:
(d, J¼8.7 Hz, 2H), 6.46 (dd, J¼13.0, 7.5 Hz, 3H), 3.79 (s, 3H), 3.71 (s,
329.1860, found: 329.1847.
3H). 13C NMR (100 MHz, CDCl3):
d 165.6, 160.5, 157.5, 148.5, 138.3,
132.0, 131.3, 129.9, 128.9, 127.0, 126.1, 114.7, 107.9, 105.6, 101.7, 55.5,
4.3.24. 3,4-Dichloro-N0-(2-(2-(3,4-dichlorobenzoyl)hydrazinyl)-5-
methoxyphenyl)-N0-(4-methoxyphenyl)benzohydrazide (5). White
solid (36.3 mg, 39%), mp 146.6e147.6 ꢀC. 1H NMR (400 MHz,
55.2. IR (KBr)
n
/cmꢁ1: 3253, 3111, 2953, 2863, 1657, 1508, 1245,
1299, 1035, 892. HRMS (ESI) calculated for
C21H19BrN2NaO3
(MþNa)þ: 449.0471, found: 449.0466.
DMSO):
d
11.08 (s, 1H), 10.64 (d, J¼3.5 Hz, 1H), 8.18 (d, J¼2.0 Hz, 1H),
8.11 (d, J¼2.0 Hz, 1H), 7.91 (dd, J¼8.4, 2.0 Hz, 1H), 7.85 (td, J¼5.1,
2.5 Hz, 2H), 7.79 (d, J¼8.4 Hz, 1H), 7.67 (d, J¼3.4 Hz, 1H), 6.85e6.88
(m, 3H), 6.83 (d, J¼2.2 Hz, 2H), 6.70e6.74 (m, 2H), 3.69 (s, 3H), 3.65
4.3.19. N0-(3-Methoxyphenyl)-N0-(4-methoxyphenyl)-4-(tri-
fluoromethyl)benzohydrazide (4u). White solid (58.8 mg, 94%), mp
181.9e182.7 ꢀC. 1H NMR (400 MHz, CDCl3):
d
8.58 (s, 1H), 7.91 (d,
(s, 3H). 13C NMR (100 MHz, DMSO):
d 164.5,163.9,153.5,153.1,141.2,
J¼8.0 Hz, 2H), 7.64 (d, J¼8.0 Hz, 2H), 7.31 (d, J¼8.6 Hz, 2H), 7.12 (t,
140.4, 134.8, 134.5, 133.2, 132.7, 132.4, 131.5, 131.4, 131.0, 130.9,
129.4, 129.2, 127.9, 127.5, 115.6, 114.3, 114.1, 113.7, 55.4, 55.3. IR (KBr)
J¼8.1 Hz, 1H), 6.85 (d, J¼8.6 Hz, 2H), 6.48 (dd, J¼13.0, 7.8 Hz, 3H),
3.80 (s, 3H), 3.71 (s, 3H). 13C NMR (100 MHz, DMSO):
d
164.6, 160.0,
n
/cmꢁ1: 3250, 3084, 2960, 2870, 1644, 1506, 1242, 1033, 758, 700.
156.6, 148.5, 138.1, 136.4, 132.2 (J¼32 Hz), 129.8, 128.4, 127.9
HRMS (ESI) calculated for C28H21Cl4N4O4 (MꢁH)ꢁ: 617.0322, found:
(J¼272 Hz), 125.6 (J¼7 Hz), 125.3, 114.5, 107.4, 104.8, 100.9, 55.2,
617.0300.
54.9. IR (KBr)
n
/cmꢁ1: 3255, 3010, 2998, 1650, 1509, 1237, 835.
HRMS (ESI) calculated for C22H19F3N2NaO3 (MþNa)þ: 439.1240,
Acknowledgement
found: 439.1226.
We thank the National Natural Science Foundation of China
(Nos. 21202208, 21172270, 21472248), Guangdong Engineering
Research Center of Chiral Drugs for the financial supports of this
study.
4.3.20. N0-(3-Methoxyphenyl)-N0-(4-methoxyphenyl)furan-2-
carbohydrazide (4w). White solid (27.5 mg, 54%), mp
155.9e156.5 ꢀC. 1H NMR (400 MHz, CDCl3):
d 8.58 (s, 1H), 7.42 (s,
1H), 7.32 (d, J¼8.9 Hz, 2H), 7.16 (d, J¼3.4 Hz, 1H), 7.10 (t, J¼8.1 Hz,
1H), 6.85 (d, J¼8.9 Hz, 2H), 6.42e6.52 (m, 4H), 3.78 (s, 3H), 3.70 (s,
3H). 13C NMR (100 MHz, CDCl3):
d 160.5, 157.6, 157.3, 148.7, 146.6,
Supplementary data
144.5, 138.5, 129.8, 126.3, 116.0, 114.7, 112.3, 108.0, 105.7, 101.8, 55.5,
55.2. IR (KBr) n
/cmꢁ1: 3225, 3080, 2960, 2810,1630,1505,1247, 820.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.10.023.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
HRMS (ESI) calculated for
found: 361.1135.
C
19H18N2NaO4 (MþNa)þ: 361.1159,
4.3.21. N0-(3-methoxyphenyl)-N0-(4-methoxyphenyl)thiophene-2-
carbohydrazide (4x) and N0-(2-methoxyphenyl)-N0-(4-
methoxyphenyl)thiophene-2-carbohydrazide (4x0). Off-white solid
(47.9 mg, 90%), mp 152.0e152.6 ꢀC. 1H NMR (400 MHz, CDCl3):
References and notes
1. For the reviews of nitrogen radicals, see: (a) Alsfassi, Z. B. N-Centered Radicals;
Wiley: New York, NY, 1998; (b) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603; (c)
Minozzi, M.; Nanni, D.; Spagnolo, P. Chem.dEur. J. 2009, 15, 7830; (d) Hofling, S.
B.; Heinrich, M. R. Synthesis 2011, 173; (e) Reek, J. N. H.; van der Vlugt, J. I.; de
Bruin, B. Angew. Chem., Int. Ed. 2013, 52, 12510.
d
8.32 (s, 1H), 8.05 (d, J¼2.3 Hz, 1H), 7.66 (d, J¼2.3 Hz, 1H), 7.52 (d,
J¼4.8 Hz, 2H), 7.48 (s, 1H), 7.34 (d, J¼8.4 Hz, 2H), 7.20 (dd, J¼19.5,
8.4 Hz, 3H), 7.07e7.13 (m, 3H), 6.69e6.88 (m, 4H), 6.68 (d, J¼8.3 Hz,

9080
W.-juan Wang et al. / Tetrahedron 71 (2015) 9073e9080
2. For the selected recent reports of nitrogen radicals: (a) Foo, K.; Sella, E.; Thome,
I.; Eastgate, M. D.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 5279; (b) Song, L.;
Zhang, L.; Luo, S. Z.; Cheng, J. P. Chem.dEur. J. 2014, 20, 14231; (c) Zheng, G. F.;
Li, Y.; Han, J. J.; Xiong, T.; Zhang, Q. Nat. Commun. 2015, 6, 7011; (d) Jiang, H.; An,
X. D.; Tong, K.; Zheng, T. Y.; Zhang, Y.; Yu, S. Y. Angew. Chem., Int. Ed. 2015, 54,
4055; (e) Greulich, T. W.; Daniliuc, C. G.; Studer, A. Org. Lett. 2015, 17, 254; (f)
Qin, Q. X.; Yu, S. Y. Org. Lett. 2015, 17, 1894; (g) Wang, W. X.; Zhang, Q. Z.; Zhang,
T. Q.; Li, Z. S.; Zhang, W.; Yu, W. Adv. Synth. Catal. 2015, 357, 221.
7. Wang, W. J.; Zhao, X.; Tong, L.; Chen, J. H.; Zhang, X. J.; Yan, M. J. Org. Chem.
2014, 79, 8557.
8. For the applications of N0,N0-diaryl acylhydrazines, see: (a) Elliott, A. J.; Gibson,
M. S. J. Org. Chem. 1980, 45, 3677; (b) Waldrep, T. W.; Rieder, B. J.; Thibault, T. D.;
Canada, E. J. J. Agric. Food Chem. 1991, 39, 392; (c) Hong, S. S.; Bavadekar, S. A.;
Lee, S. I.; Patil, P. N.; Lalchandani, S. G.; Feller, D. R.; Miller, D. D. Bioorg. Med.
Chem. Lett. 2005, 15, 4691; (d) Sasikumar, T. K.; Burnett, D. A.; Zhang, H.; Smith-
Torhan, A.; Fawzi, A.; Lachowicz, J. E. Bioorg. Med. Chem. Lett. 2006, 16, 4543; (e)
Su, J.; Tang, H. Q.; McKittrick, B. A.; Burnett, D. A.; Zhang, H. T.; Smith-Torhan,
A.; Fawzi, A.; Lachowicz, J. Bioorg. Med. Chem. Lett. 2006, 16, 4548.
9. (a) Yu, J.; Wang, S. G.; Wen, J. M.; Wang, J.; Li, J. H. Synlett 2015, 1121; (b) Zhang,
J. Q.; Huang, G. B.; Weng, J.; Lu, G.; Chan, A. S. C. Org. Biomol. Chem. 2015, 13,
2055.
3. N0,N0-Diphenylbenzohydrazide (4a) was also formed via a different pathway as
a minor by-product in the following reference Bowman, W. R.; Forshaw, J. A.;
Hall, K. P.; Kitchin, J. P.; Mott, A. W. Tetrahedron 1996, 52, 3961.
4. Sipe, H. J.; Jaszewski, A. R.; Mason, R. P. Chem. Res. Toxicol. 2004, 17, 226.
5. For the selected recent reports of N-centered amidyl radicals: (a) Biechy, A.;
Hachisu, S.; Quiclet-Sire, B.; Ricard, L.; Zard, S. Z. Tetrahedron 2009, 65, 6730; (b)
Choi, G. J.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 9226.
6. For the reviews of HAS reactions, see: (a) Bowman, W. R.; Storey, J. M. D. Chem.
Soc. Rev. 2007, 36, 1803; (b) Sun, C. L.; Shi, Z. J. Chem. Rev. 2014, 114, 9219; (c)
Louillat-Habermeyer, M. L.; Jin, R. W.; Patureau, F. W. Angew. Chem., Int. Ed.
2015, 54, 4102.
10. The Radleys reaction tube is specially designed and used for Radleys Carousel
12 Plus Reaction Station. The tube is equipped with a Teflon cap containing
a small silicone septum. See http://www.radleys.com/products/our-products/
parallel-reaction-stations/carousel-12-plus-reaction-station for more details.
11. Lindquist, C.; Tedebark, U.; Ersoy, O.; Somfai, P. Synth. Commun. 2003, 33, 2257.
́