N-Aminations of Benzylamines and Alicyclic Amines with Nitrosoarenes to Hydrazones and Hydrazides

Article abstract of DOI:10.1055/s-0037-1610701

Unlike other alkylamines, benzylamines upon reaction with a nitrosoarene undergo oxidation to the corresponding imines. A direct amination of benzylamines, which was difficult to achieve due to its facile oxidation, to the corresponding hydrazones is reported. A wide variety of benzylamines and N-heterocycles were reacted with nitrosoarenes to provide structurally diverse hydrazones and hydrazides, respectively. Moreover, the direct N-amination reaction was applied to the one-pot synthesis of triazoles.

Full text of DOI:10.1055/s-0037-1610701

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
special topic
A
en
A. Purkait, C. K. Jana
Special Topic
Synthesis
N-Aminations of Benzylamines and Alicyclic Amines with
Nitrosoarenes to Hydrazones and Hydrazides
Anisha Purkait
O
H
N
O
Ar
N
Chandan K. Jana*
0
0
0
0-0
0
0
2-6
2
9
6-1
2
4
0
N
Ar
or
N
Ar'
NH2
or
Ar'
H+
N
NH
45–52%
40–71%
H
Ar
Department of Chemistry, Indian Institute of Technology
Guwahati, Guwahati 781039, India
ckjana@iitg.ac.in
Published as part of the Special Topic Amination Reactions in
Organic Synthesis
Received: 13.02.2019
Accepted after revision: 12.03.2019
Published online: 17.04.2019
nitrosoarene to provide the observed azoxyarene. We antic-
ipated that developing reaction conditions that facilitate
the dehydration of N-hydroxyhydrazine derivative II in-
stead of elimination of N-arylhydroxylamine would provide
the possibility of forming the corresponding azo com-
pounds or their tautomers. To our surprise, to the best our
knowledge, there are no previous reports of the reaction of
nitrosoarenes and benzylamines providing a benzyl-aryl
azo compounds or their tautomers. Herein, we report the
first example of Brønsted acid mediated direct N-amination
of benzylamines using nitrosoarenes to provide the corre-
sponding hydrazones. Similar N-amination of N-heterocy-
cles provided corresponding hydrazide derivatives (Scheme 1c).
DOI: 10.1055/s-0037-1610701; Art ID: ss-2019-c0091-st
Abstract Unlike other alkylamines, benzylamines upon reaction with a
nitrosoarene undergo oxidation to the corresponding imines. A direct
amination of benzylamines, which was difficult to achieve due to its fac-
ile oxidation, to the corresponding hydrazones is reported. A wide vari-
ety of benzylamines and N-heterocycles were reacted with nitro-
soarenes to provide structurally diverse hydrazones and hydrazides,
respectively. Moreover, the direct N-amination reaction was applied to
the one-pot synthesis of triazoles.
Key words N-amination, hydrazones, nitrosoarenes, triazoles, benzyl-
amines
(a) Reactions with alkyl and aryl amines
Nitrosoarenes are widely used in organic synthesis to
incorporate the amine functionality into molecules.1 The
nitroso group participates in various C–N bond-forming
process, such as N-nitroso aldol reactions,2 annulation reac-
tions,3 cycloaddition reactions,4 and nitroso-ene reactions.5
Furthermore, the nitroso functionality has recently been ef-
ficiently reacted with donor–acceptor cyclopropanes to
provide different heterocycles.6 In addition to these C–N
bond forming reactions, nitrosoarenes react with alkyl- and
arylamines to provide the corresponding azo derivatives
forming a N=N bond (Scheme 1a).1a,7,8 Interestingly, a simi-
lar reaction of nitrosoarenes with benzylamines does not
provide the desired azo derivative;7a the reaction produces
azoxy derivatives and the corresponding aldehyde. A careful
analysis of the mechanistic rationalization revealed that the
elimination of water involving N–H cleavage of initial N-hy-
droxyhydrazine derivative I provide the azo compound for
alkyl- or arylamines (Scheme 1b). In contrast, elimination
of hydroxylamine occurs (from II) involving the cleavage of
the activated benzylic C–H bond of the benzylamine to pro-
vide the corresponding imine derivative. Then the imine on
subsequent reaction with water or another molecule of
benzylamine produces an aldehyde and/or imine, respec-
tively. Hydroxylamine also reacts with another molecule of
OH
O
N
N
R
R
R
Ar
Ar
Ar
N
N
N
+
NH2
– H2O
H
I
R = alkyl and Aryl
(b) Reactions with benzylamines to imines and azoxybenzenes
O
N
Ar
Ar
N
+
Ar'
N
Ar
Ar'
+
N
O
Ar'
NH2
Ar'
NH2
HN
ArNO
+
OH
N
OH
Ar'
N
Ar
N
Ar'
Ar
H
H
II
(c) This work: benzylamines to hydrazones and N-heterocycles to hydrazides
H
27 examples
40–71%
N
Ar
N
Ar'
NH2
Ar'
O
H+
or
or
Ar
N
+
4 examples
45–52%
direct N-aminations
no oxidation to imines
O
N
H
N
NH
Ar
Scheme 1 Reaction of amines with nitrosoarenes
The hydrazones are an important class of compounds
that find application in organic synthesis, medicinal chem-
istry, and supramolecular chemistry including metal and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

B
A. Purkait, C. K. Jana
Special Topic
Synthesis
covalent organic frameworks.9 Hydrazone derivatives are
also found as a key unit of fluorescent chemosensors.10 The
classical condensation of arylhydrazines with an aldehyde
and coupling of hydrazines with an alcohol are mainly used
for the synthesis of hydrazone derivatives.11 However, the
synthetic utility of these methods are greatly restricted be-
cause of the limited availability of arylhydrazines due to
their inherent instability issues and difficulties in their syn-
thesis.12 Therefore, the development of an alternative meth-
od for the synthesis of arylhydrazones from readily avail-
able starting material is essential.13
Based on our hypothesis, nitrosobenzene was reacted
with benzylamine in the presence of 2,4-dichlorobenzoic
acid (DCBA), which is used to facilitate dehydration (Table 1,
entry 1). As expected the desired hydrazone 2a was formed
in 20% yield along with the oxidized product 3 and azoxy-
benzene 4. With this initial result in hand, further experi-
ments were carried out to optimize the reaction conditions
towards better yields of the hydrazone. The yield of the re-
action improved slightly when the reaction was carried out
in the presence of acetic acid (entry 2). The reaction at a
lower temperature in refluxing dichloromethane gave a
similar yield (entry 3). However, the yield of the product
significantly increases with increasing reaction time (entry
7). The poor yields were obtained when the reaction was
carried out either in the absence of acid or in the presence
of higher amount of acetic acid (2 equiv) (entries 9 and 10).
Next, we investigated the substrate scope of this reac-
tion using the optimal reaction condition. Reactions of ben-
zylamine with various nitrosoarenes were studied first
(Scheme 2). Nitrosoarenes containing both electron-donat-
ing and electron-withdrawing groups participated in the N-
amination reaction with benzylamines to give the corre-
sponding hydrazones 2a–aa in moderate to good yields. The
reaction with halogen-substituted nitrosoarenes provided
the better yields of the desired hydrazones 2c–e as com-
pared to the hydrazone 2b that is obtained from the reac-
tion with methyl-substituted nitrosoarene. The reactions of
various benzylamines with nitrosobenzene were investigat-
ed next. The studies revealed that the benzylamines con-
taining Me, OMe, Cl, F, etc. gave the desired products in
good yields.
H
AcOH
(0.5 equiv)
N
NO
NH2
N
R′
R′
R
R
+
DCM, reflux
18 h
1
5
2a–aa
H
N
H
N
2a, R = H, 60%
2b, R = Me, 40%
2c, R = F, 60%
2d, R = Cl, 56%
2e, R = Br, 51%
R
Ph
N
Ph
N
R
2f,R = Cl, 59%
2g,R = Br, 48%
H
H
N
N
N
N
2h, R = Cl, 55%
2i, R = Br, 44%
N
Ph
R
R
H
N
2m, R = Me, 57%
2n, R = F, 60%
2o, R = Cl, 55%
R
2j, R = F, 58%
2k, R = Cl, 51%
2l, R = Br, 48%
Table 1 Optimization of Reaction Conditionsa
2p, R = OMe, 63%
O
O
Ph
H
N
O
O
N
H
N
NH2
H
N
R
N
N
Ph
N
Ph
Ph
+
+
2q, R = H, 65%
2r, R = F, 71%
2s, R = Cl, 55%
2t, R = Br, 61%
N
Ph
N
Ph
Ph
N
Ph
conditions
R
2a
3
4
1
2u, R = Cl, 66%
2v, R = Br, 50%
Entry Conditions
2ab (%)
3c (%)
4c (%)
H
N
R
H
N
N
1d
2d
3e
4e
5
DCBA (0.6 equiv), toluene, reflux, 8 h
AcOH (0.6 equiv), toluene, reflux, 8 h
AcOH (0.6 equiv), DCM, reflux, 8 h
AcOH (0.6 equiv), DCM, reflux, 15 h
AcOH (0.6 equiv), DCM, reflux, 15 h
AcOH (0.5 equiv), DCM, reflux, 15 h
AcOH (0.5 equiv), DCM, reflux, 18 h
AcOH (0.5 equiv), DCM, reflux, 18 h
DCM, reflux, 18 h
20
30
38
41
53
56
60
55
36
47
27
24
36
33
nd
nd
9
21
20
17
16
nd
nd
11
nd
nd
nd
N
O
2w, R = F, 64%
2x, R = Cl, 56%
2y, R = Br, 50%
O
R
2z, R = Cl, 49%
2aa, R = Br, 45%
Scheme 2 Substrate scope of the N-amination reaction
6
The electron-donating group in the benzylamine makes
it more nucleophilic and an electron-withdrawing group
makes the nitrosoarene more electrophilic. Therefore, ben-
zylamines with electron-donating groups (Me, OMe) react-
ed efficiently with the nitrosoarene having electron-with-
drawing groups (Cl, F, Br, etc.) to provide the desired hydra-
zones 2h–aa in good yields.
The reactions of alicyclic amines with the nitrosoarene
were tested next. Accordingly, pyrrolidine was reacted with
an nitrosoarene under standard conditions. Surprisingly,
the reaction of pyrrolidine with various nitrosoarenes pro-
vided hydrazide derivatives 7a–d in 45–52% yields (Scheme
3). The structure of the 7b was confirmed from the X-ray
7
8f
9
nd
nd
nd
10
AcOH (2.0 equiv), DCM, reflux, 18 h
a Reaction conditions: benzylamine (0.37 mmol), nitrosobenzene (0.37
mmol), solvent (3.0 mL), unless otherwise stated.
b Isolated yield calculated with respect to nitrosobenzene.
c Isolated yield of 3 and 4 were calculated with respect to benzylamine and
nitrosobenzene, respectively, considering maximum possible yield as 50%;
nd = not determined.
d Benzylamine (4 equiv) was used.
e Benzylamine (2 equiv) was used.
f Nitrosobenzene (1.5 equiv) was used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

C
A. Purkait, C. K. Jana
Special Topic
Synthesis
structure (Figure 1). A similar result was also observed for
the tetrahydroisoquinoline, which gave the corresponding
hydrazide 9 in 50% yield.
for hydrazones
NO
OH
R'
R'
N
5
NH2
N
R
H
R
– H2O
H
1
10
NO
H
H
N
O
N
H
DCBA, toluene
R'
R'
N
isomerization
+
7a, R = 4-iPr, 52%
7b, R = 3-Me, 45%
7c, R = 3-Br, 46%
7d, R = 4-Cl, 48%
NH
N
N
R
reflux, 10 h
R
N
H
R
2
11
5
6
7a–d
R
for hydrazides
OH
O
H2O
O
ArNO
H+
PhNO
N
N
N
N
NH
N
H
NH
NH
NH
DCBA, toluene
reflux, 12 h
N
Ar
H
Ar
Ar
O
9, 50%
6
12
13
7
8
Scheme 4 Proposed mechanism of N-amination reaction
Scheme 3 N-Amination of N-heterocycles to hydrazides
Ph
N
N
R2
1. AcOH, DCM, reflux
O
N
NH2
N
R1
+
R2
NH2
Ph
2. I2, TBHP
MeCN
R1
(one pot)
14a-d
5
1
14a, R1 = H, R2 = Et, 45%
14b, R1 = H, R2 = Pr, 41%
14c, R1 = Me, R2 = Pr, 32%
14d, R1 = H, R2 = nonyl, 30%
Scheme 5 Direct synthesis of triazoles starting from nitrosoarenes and
amines
the corresponding triazoles 14a–d with acceptable yields
(Scheme 5).
Figure 1 ORTEP diagram of 7b (with ellipsoid contour 35%)
In summary, we have developed an unprecedented N-
amination reaction of benzylamines and N-heterocycles
with the nitrosoarenes to provide hydrazones and hydra-
zides, respectively. The use of Brønsted acid facilitated de-
hydration reaction in comparison to undesired hydroxyl-
amine elimination to achieve the difficult N-amination of
benzylamines. A wide range of benzylamines and N-hetero-
cycles reacted efficiently with the readily available nitro-
soarenes to provide the corresponding hydrazone and hy-
drazide derivatives, respectively. This unconventional
method for hydrazone synthesis does not involve hydra-
zines and thus issues relating to the preparation and the
stability of hydrazines can be avoided. Moreover, this N-
amination reaction was successfully applied in a one-pot
synthesis of triazoles.
A plausible mechanism for the formation of hydrazones
and hydrazides is presented in Scheme 4. Analogous to the
reaction of amines with carbonyl compounds, nucleophilic
addition of amines 1 to the nitrosoarenes 5 occurs to pro-
vide hydroxylamine derivative 10.1a,7a Acid-mediated dehy-
dration of 10 produces the corresponding arylazoalkanes
derivative 11, which isomerizes readily to provide the ob-
served hydrazone 2.14 A similar intermediate 12 is formed
from the reaction of nitrosoarene and N-heterocycles. The
iminium intermediate 12 is trapped by H2O to provide the
corresponding hemiaminal 13 which upon subsequent oxi-
dation gives the hydrazide 7.15
Hydrazones are reacted with primary amines in the
presence of iodine and tert-butyl hydroperoxide (TBHP) for
the synthesis of triazoles;16 they are an important scaffold
in biological, pharmaceuticals, and medicinal chemistry.17
Therefore, we wanted to employ our N-amination reaction
for the synthesis of triazoles directly starting from amines
and nitrosoarenes. Accordingly, benzylamines were N-ami-
nated under standard conditions to give the corresponding
hydrazones that were further reacted with alkylamines in
the presence of iodine and TBHP in the same pot to provide
All reactions involving air- or moisture-sensitive reagents or interme-
diates were carried out in oven-dried glassware under an argon atmo-
sphere. Dichloromethane (DCM) was freshly distilled from P2O5. Com-
mercial grade xylene, benzene, and toluene were distilled over CaH2
before use. All other solvents and reagents were purified according to
standard procedures or were used as received from Aldrich, Acros,
Merck, and Spectrochem. 1H and 13C NMR spectroscopy: Varian Mer-
cury plus 400 MHz, Bruker 600 MHz (at 298 K), and reported relative
to TMS  = 0 (1H),  = 0 (13C), which was used as the inner reference.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

D
A. Purkait, C. K. Jana
Special Topic
Synthesis
Otherwise the solvents residual proton resonance and carbon reso-
nance (CHCl3,  (1H) = 7.26,  (13C) = 77.23) were used for calibration.
Column chromatography: Merck or Spectrochem silica gel 60–120
under gravity. IR: spectra were recorded on a Perkin Elmer Instru-
ment at r.t. as a KBr pellet (IR Grade). MS (ESI-HRMS): mass spectra
were recorded on an Agilent Accurate-Mass Q-TOF LC/MS 6520, and
peaks are given in m/z (% of basis peak). Nitrosoarenes are prepared
according to the known procedures.
(E)-1-Benzylidene-2-(3-chlorophenyl)hydrazine (2d)18c
According to GP I: 1-chloro-3-nitrosobenzene3h (53 mg, 0.37 mmol),
benzylamine (40 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2d (48 mg, 56%) as a
white solid.
FTIR (KBr): 3323, 2958, 2918, 1592, 1508, 1483, 1300, 1129, 1091,
991, 852, 694 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.67–7.66 (m, 3 H), 7.40–7.38 (m, 2 H),
7.34–7.31 (m, 1 H), 7.19–7.16 (m, 2 H), 6.92–6.90 (m, 1 H), 6.83 (d, J =
7.8 Hz, 1 H).
13C NMR (151 MHz, CDCl3):  = 145.9, 138.5, 135.4, 135.0, 130.5,
129.0, 128.9 (2 C), 126.5 (2 C), 120.1, 112.9, 111.1.
Hydrazone Derivatives 2; General Procedure I
Freshly prepared nitrosoarene 5 (1 equiv) and AcOH (0.5 equiv) were
successively added to a solution of benzylamine 1 (1 equiv) in DCM
(3–4 mL); the mixture was refluxed for 15–24 h under an argon atmo-
sphere. The solvent was evaporated under reduced pressure and the
crude mixture was subjected to column chromatography (silica gel)
to afford analytically pure products.
HRMS: m/z [M + H]+ calcd for C13H12N2Cl: 231.0684; found: 231.0684.
(E)-1-Benzylidene-2-(3-bromophenyl)hydrazine (2e)18d
(E)-1-Benzylidene-2-phenylhydrazine (2a)13c
According to GP I: 1-bromo-3-nitrosobenzene3h (69 mg, 0.37 mmol),
benzylamine (40 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2e (52 mg, 51%) as a
white solid.
According to GP I: nitrosobenzene (40 mg, 0.37 mmol), benzylamine
(40 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in DCM (3 mL)
were refluxed for 18 h. Column chromatography of crude product (sil-
ica gel, EtOAc/hexane, 1:15) gave 2a (44 mg, 60%) as a white solid.
1H NMR (600 MHz, CDCl3):  = 7.68–7.66 (m, 3 H), 7.40–7.37 (m, 2 H),
7.33–7.28 (m, 3 H), 7.13 (d, J = 7.8 Hz, 2 H), 6.89 (t, J = 7.2 Hz, 1 H).
FTIR (KBr): 3322, 2956, 2923, 2855, 1589, 1567, 1478, 1287, 1240,
1131, 984, 776, 694 cm–1
.
13C NMR (151 MHz, CDCl3):  = 144.8, 137.5, 135.5, 129.5 (2 C), 128.8
1H NMR (600 MHz, CDCl3):  = 7.67–7.66 (m, 3 H), 7.60 (s, 1 H), 7.40–
(2 C), 128.6, 126.4 (2 C), 120.3, 112.9 (2 C).
7.38 (m, 2 H), 7.35–7.32 (m, 2 H), 7.13–7.10 (m, 1 H), 6.99–6.95 (m, 2
H).
13C NMR (151 MHz, CDCl3):  = 146.0, 138.6, 135.0, 130.7, 129.0, 128.9
(E)-1-Benzylidene-2-(m-tolyl)hydrazine (2b)
According to GP I: 1-methyl-3-nitrosobenzene18a (45 mg, 0.37 mmol),
benzylamine (40 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2b (31 mg, 40%) as a yel-
low gum.
(2 C), 126.6 (2 C), 123.5, 123.0, 115.8, 111.5.
HRMS: m/z [M + H]+ calcd for C13H12N2Br: 275.0178; found: 275.0178.
(E)-1-Benzylidene-2-(4-chlorophenyl)hydrazine (2f)13c
According to GP I: 1-chloro-4-nitrosobenzene3h (53 mg, 0.37 mmol),
benzylamine (40 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2f (50 mg, 59%) as a
white solid.
1H NMR (400 MHz, CDCl3):  = 7.69 (s, 1 H), 7.65 (d, J = 7.2 Hz, 2 H),
7.40–7.36 (m, 2 H), 7.33–7.29 (m, 1 H), 7.23 (d, J = 8.8 Hz, 2 H), 7.05
(d, J = 8.0 Hz, 2 H).
FTIR (KBr): 2956, 2924, 2854, 1587, 1490, 1464, 1376, 1262, 1209,
1097, 1020, 802, 691 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.67 (s, 1 H), 7.66 (s, 2 H), 7.38 (t, J = 7.8
Hz, 2 H), 7.32–7.29 (m, 1 H), 7.17 (t, J = 7.8, Hz, 1 H), 6.98 (s, 1 H), 6.91
(d, J = 7.8 Hz, 1 H), 6.71 (d, J = 7.2 Hz, 1 H), 2.36 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 144.8, 139.4, 137.3, 135.5, 129.4, 128.8
(2 C), 128.6, 126.4 (2 C), 121.2, 113.6, 110.2, 21.9.
HRMS: m/z [M + H]+ calcd for C14H15N2: 211.1230; found: 211.1230.
HRMS: m/z [M + H]+ calcd for C13H12N2Cl: 231.0684; found: 231.0684.
(E)-1-Benzylidene-2-(3-fluorophenyl)hydrazine (2c)
(E)-1-Benzylidene-2-(4-bromophenyl)hydrazine (2g)
According to GP I: 1-fluoro-3-nitrosobenzene18b (46 mg, 0.37 mmol),
benzylamine (40 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2c (48 mg, 60%) as white
solid; mp 113–114 °C.
According to GP I: 1-bromo-4-nitrosobenzene3h (69 mg, 0.37 mmol),
benzylamine (40 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2g (49 mg, 48%) as a
white solid; mp 125 °C.
FTIR (KBr): 3317, 2960, 2924, 1615, 1518, 1490, 1443, 1263, 1070,
FTIR (KBr): 3339, 2962, 2923, 2853, 1650, 1484, 1401, 1257, 1067,
798, 679 cm–1
.
1027, 812, 691 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.70 (s, 1 H), 7.67–7.66 (m, 2 H), 7.40–
7.37 (m, 2 H), 7.33–7.31 (m, 1 H), 7.21–7.18 (m, 1 H), 6.96–6.93 (m, 1
H), 6.78–6.77 (m, 1 H), 6.57–6.54 (m, 1 H).
13C NMR (151 MHz, CDCl3):  = 165.0, 163.4, 146.6, 146.5, 138.3,
135.1, 130.63, 130.57, 129.0, 128.9 (2 C), 126.5 (2 C), 108.43, 108.41,
106.8, 106.7, 100.3, 100.2.
1H NMR (600 MHz, CDCl3):  = 7.69 (s, 1 H), 7.65 (d, J = 7.2 Hz, 2 H),
7.39–7.35 (m, 4 H), 7.33–7.30 (m, 1 H), 7.00 (d, J = 9.0 Hz, 2 H).
13C NMR (151 MHz, CDCl3):  = 143.9, 138.2, 135.2, 132.3 (2 C),
128.91, 128.86 (2 C), 126.5 (2 C), 114.5 (2 C), 112.0.
HRMS: m/z [M + H]+ calcd for C13H12N2Br: 275.0178; found: 275.0167.
HRMS: m/z [M + H]+ calcd for C13H12N2F: 215.0979; found: 215.0979.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

E
A. Purkait, C. K. Jana
Special Topic
Synthesis
(E)-1-(4-Chlorophenyl)-2-(4-methylbenzylidene)hydrazine (2h)
HRMS: m/z [M + H]+ calcd for C14H14N2Cl: 245.0840; found: 245.0840.
(E)-1-(3-Bromophenyl)-2-(4-methylbenzylidene)hydrazine (2l)
According to GP I: 1-chloro-4-nitrosobenzene ( 53 mg, 0.37 mmol), 4-
methylbenzylamine (45 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:15) gave 2h (50 mg,
55%) as a white solid; mp 155–156 °C.
According to GP I: 1-bromo-3-nitrosobenzene ( 69 mg, 0.37 mmol), 4-
methylbenzylamine (45 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:15) gave 2l (51 mg,
48%) as a white solid; mp 116–118 °C.
FTIR (KBr): 3320, 2960, 2923, 2856, 1598, 1500, 1408, 1253, 1092,
827 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.65 (s, 1 H), 7.54 (d, J = 8.4 Hz, 2 H),
7.22 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 7.8 Hz, 2 H), 7.03 (d, J = 8.4 Hz, 2 H),
2.37 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 143.6, 139.0, 138.4, 132.4, 129.6 (3 C),
129.4, 126.4 (3 C), 124.6, 114.0, 21.6.
FTIR (KBr): 3313, 3029, 2950, 2912, 1589, 1497, 1238, 1130, 1063,
988, 817, 682 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.65 (s, 1 H), 7.55 (d, J = 8.0 Hz, 2 H),
7.33 (t, J = 2.0 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.10 (t, J = 8.0 Hz, 1 H),
6.98–6.93 (m, 2 H), 2.38 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 146.2, 139.2, 138.9, 132.3, 130.7, 129.6
HRMS: m/z [M + H]+ calcd for C14H14N2Cl: 245.0840; found: 245.0840.
(2 C), 126.6 (2 C), 123.5, 122.9, 115.8, 111.5, 21.6.
(E)-1-(4-Bromophenyl)-2-(4-methylbenzylidene)hydrazine (2i)
HRMS: m/z [M + H]+ calcd for C14H14N2Br: 289.0335; found: 289.0337.
According to GP I: 1-bromo-4-nitrosobenzene ( 69 mg, 0.37 mmol), 4-
methylbenzylamine (45 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:15) gave 2i (47 mg,
44%) as a white solid; mp 160–162 °C.
(E)-1-(4-Methylbenzylidene)-2-phenylhydrazine (2m)13c
According to GP I: nitrosobenzene (40 mg, 0.37 mmol), 4-methylben-
zylamine (45 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in DCM
(3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2m (44 mg, 57%) as a
white solid.
1H NMR (600 MHz, CDCl3):  = 7.68 (s, 1 H), 7.56 (d, J = 7.8 Hz, 2 H),
7.28 (d, J = 7.8 Hz, 2 H), 7.18 (d, J = 7.8 Hz, 2 H), 7.11 (d, J = 7.8 Hz, 2 H),
6.86 (t, J = 7.2 Hz, 1 H), 2.37 (s, 3 H).
FTIR (KBr): 2923, 2854, 1592, 1501, 1402, 1248, 1068, 820 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.67 (s, 1 H), 7.54 (d, J = 8.0 Hz, 2 H),
7.35 (d, J = 8.8 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.8 Hz, 2 H),
2.37 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 144.0, 139.0, 138.5, 132.4, 132.2 (2 C),
129.6 (2 C), 126.4 (2 C), 114.5 (2 C), 111.8, 21.6.
13C NMR (151 MHz, CDCl3):  = 145.0, 138.7, 137.7, 132.7, 129.54 (2
C), 129.49 (2 C), 126.4 (2 C), 120.1, 112.9 (2 C), 21.6.
HRMS: m/z [M + H]+ calcd for C14H14N2Br: 289.0335; found: 289.0333.
(E)-1-(4-Fluorobenzylidene)-2-phenylhydrazine (2n)13c
(E)-1-(3-Fluorophenyl)-2-(4-methylbenzylidene)hydrazine (2j)
According to GP I: nitrosobenzene (40 mg, 0.37 mmol), 4-fluoroben-
zylamine (46 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in DCM
(3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2n (47 mg, 60%) as a
white solid.
1H NMR (600 MHz, CDCl3):  = 7.67–7.62 (m, 3 H), 7.30–7.27 (m, 2 H),
7.11 (d, J = 7.8 Hz, 2 H), 7.08–7.05 (m, 2 H), 6.90–6.87 (m, 1 H).
According to GP I: 1-fluoro-3-nitrosobenzene ( 46 mg, 0.37 mmol), 4-
methylbenzylamine (45 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:15) gave 2j (49 mg,
58%) as a white solid; mp 111–113 °C.
FTIR (KBr): 3319, 2960, 1613, 1589, 1490, 1257, 1140, 764, 515 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.68 (s, 1 H), 7.55 (d, J = 8.4 Hz, 2 H),
7.21–7.15 (m, 3 H), 6.95–6.91 (m, 1 H), 6.77–6.75 (m, 1 H), 6.56–6.51
(m, 1 H), 2.37 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 164.3, 161.8, 144.8, 136.3, 131.7, 129.5
(2 C), 128.0, 127.9, 120.4, 116.0, 115.8, 112.9 (2 C).
13C NMR (101 MHz, CDCl3):  = 146.9, 146.7, 139.1, 138.7, 132.4,
130.6, 130.5, 129.6 (2 C), 126.5 (2 C), 108.43, 108.41, 106.7, 106.5,
100.4, 100.1, 21.6.
(E)-1-(4-Chlorobenzylidene)-2-phenylhydrazine (2o)13c
According to GP I: nitrosobenzene (40 mg, 0.37 mmol), 4-chloroben-
zylamine (53 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in DCM
(3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:15) gave 2o (47 mg, 55%) as a
white solid.
HRMS: m/z [M + H]+ calcd for C14H14N2F: 229.1136; found: 229.1147.
(E)-1-(3-Chlorophenyl)-2-(4-methylbenzylidene)hydrazine (2k)
According to GP I: 1-chloro-3-nitrosobenzene (53 mg, 0.37 mmol), 4-
methylbenzylamine (45 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:15) gave 2k (46 mg,
51%) as a white solid; mp 116–118 °C.
1H NMR (600 MHz, CDCl3):  = 7.64 (s, 1 H), 7.59 (d, J = 8.4 Hz, 2 H),
7.34 (d, J = 9.0 Hz, 2 H), 7.30–7.27 (m, 2 H), 7.11 (d, J = 7.8 Hz, 2 H),
6.90–6.88 (m, 1 H).
13C NMR (151 MHz, CDCl3):  = 144.6, 136.0, 134.2, 134.0, 129.5 (2 C),
129.0 (2 C), 127.5 (2 C), 120.6, 113.0 (2 C).
FTIR (KBr): 3312, 2924, 2854, 1592, 1501, 1482, 1241, 1131, 1090,
991, 856, 684 cm–1
.
(E)-1-(4-Methoxybenzylidene)-2-phenylhydrazine (2p)13c
1H NMR (400 MHz, CDCl3):  = 7.62 (s, 1 H), 7.55 (d, J = 8.0 Hz, 2 H),
7.50 (s, 1 H), 7.21–7.15 (m, 4 H), 6.91–6.89 (m, 1 H), 6.84–6.82 (m, 1
H), 2.39 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 146.1, 139.1, 138.9, 135.3, 132.4,
130.4, 129.6 (2 C), 126.5 (2 C), 120.0, 112.9, 111.1, 21.6.
According to GP I: nitrosobenzene (40 mg, 0.37 mmol), 4-methoxy-
benzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:10) gave 2p (53 mg, 63%) as a
white solid.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

F
A. Purkait, C. K. Jana
Special Topic
Synthesis
1H NMR (600 MHz, CDCl3):  = 7.63 (s, 1 H), 7.60 (d, J = 8.4 Hz, 2 H),
7.28 (t, J = 7.8 Hz, 2 H), 7.10 (d, J = 7.8 Hz, 2 H), 6.91 (d, J = 9.0 Hz, 2 H),
6.86 (t, J = 7.2 Hz, 1 H), 3.84 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.2, 145.2, 137.6, 129.5 (2 C), 128.3,
127.8 (2 C), 120.0, 114.3 (2 C), 112.9 (2 C), 55.5.
FTIR (KBr): 2960, 2916, 2848, 1639, 1598, 1466, 1249, 1103, 1022,
753, 674 cm–1
.
1H NMR (600 MHz, CDCl3):  = 8.12 (s, 1 H), 7.99–7.98 (m, 1 H), 7.33
(t, J = 1.8 Hz, 1 H), 7.31–7.28 (m, 1 H), 7.11–7.08 (m, 1 H), 7.01–6.99
(m, 1 H), 6.96–6.93 (m, 2 H), 6.90 (d, J = 8.4 Hz, 1 H), 3.86 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 157.2, 146.3, 134.7, 130.7, 130.1,
126.1, 123.6, 123.5, 122.8, 121.2, 115.7, 111.4, 111.1, 55.7.
(E)-1-(2-Methoxybenzylidene)-2-phenylhydrazine (2q)18e
HRMS: m/z [M + H]+ calcd for C14H14BrN2O: 305.0284; found:
305.0279.
According to GP I: nitrosobenzene (40 mg, 0.37 mmol), 2-methoxy-
benzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19 mmol) in
DCM (3 mL) were refluxed for 18 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:10) gave 2q (54 mg, 65%) as a yel-
low gum.
1H NMR (400 MHz, CDCl3):  = 8.13 (s, 1 H), 8.00–7.98 (m, 1 H), 7.30–
7.27 (m, 3 H), 7.11 (d, J = 7.6 Hz, 2 H), 6.99 (t, J = 7.6 Hz, 1 H), 6.91–
6.85 (m, 2 H), 3.87 (s, 3 H).
(E)-1-(4-Chlorophenyl)-2-(2-methoxybenzylidene)hydrazine (2u)
According to GP I: 1-chloro-4-nitrosobenzene (53 mg, 0.37 mmol), 2-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2u (64 mg,
66%) as a yellow gum.
13C NMR (101 MHz, CDCl3):  = 157.2, 145.0, 133.7, 129.8, 129.5 (2 C),
126.1, 124.0, 121.2, 120.2, 113.0 (2 C), 111.2, 55.6.
FTIR (KBr): 3080, 2960, 2924, 2852, 1599, 1490, 1437, 1242, 1092,
1019, 822, 756, 606 cm–1
.
(E)-1-(3-Fluorophenyl)-2-(2-methoxybenzylidene)hydrazine (2r)
1H NMR (600 MHz, CDCl3):  = 8.11 (s, 1 H), 7.98–7.96 (m, 1 H), 7.30–
7.27 (m, 1 H), 7.22–7.19 (m, 2 H), 7.04–7.02 (m, 2 H), 7.00–6.98 (m, 1
H), 6.90–6.88 (m, 1 H), 3.86 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 157.1, 143.7, 134.2, 130.0, 129.3 (2 C),
125.9, 124.5, 123.7, 121.1, 113.9 (2 C), 111.1, 55.7.
According to GP I: 1-fluoro-3-nitrosobenzene (46 mg, 0.37 mmol), 2-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol mmol) in DCM (4 mL) were refluxed for 18 h. Column chroma-
tography of crude product (silica gel, EtOAc/hexane, 1:10) gave 2r (64
mg, 71%) as a yellow gum.
HRMS: m/z [M
+
H]+ calcd for C14H14ClN2O: 261.0789; found:
FTIR (KBr): 2926, 2847, 1613, 1601, 1518, 1486, 1288, 1248, 1139,
261.0787.
1023, 756, 683 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.12 (s, 1 H), 8.00–7.98 (m, 1 H), 7.67
(s, 1 H), 7.32–7.28 (m, 1 H), 7.21–7.15 (m, 1 H), 7.00 (t, J = 7.2 Hz, 1 H),
6.95–6.92 (m, 1 H), 6.90 (d, J = 8.4 Hz, 1 H), 6.77–6.75 (m, 1 H), 6.56–
6.51 (m, 1 H), 3.86 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 165.5, 163.0, 157.2, 146.9, 146.8,
134.5, 130.6, 130.5, 130.0, 126.1, 123.7, 121.2, 111.2, 108.40, 108.38,
106.6, 106.3, 100.3, 100.0, 55.7.
(E)-1-(4-Bromophenyl)-2-(2-methoxybenzylidene)hydrazine (2v)
According to GP I: 1-bromo-4-nitrosobenzene (69 mg, 0.37 mmol), 2-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2v (56 mg,
50%) as a yellow gum.
FTIR (KBr): 2958, 2924, 2849, 1598, 1488, 1437, 1243, 1070, 1020,
HRMS: m/z [M
+
H]+ calcd for C14H14FN2O: 245.1085; found:
822, 755, 606 cm–1
.
245.1100.
1H NMR (400 MHz, CDCl3):  = 8.11 (s, 1 H), 7.98–7.95 (m, 1 H), 7.36–
7.33 (m, 2 H), 7.31–7.27 (m, 1 H), 7.01–6.97 (m, 3 H), 6.89 (d, J = 8.4
Hz, 1 H), 3.86 (s, 3 H).
(E)-1-(3-Chlorophenyl)-2-(2-methoxybenzylidene)hydrazine (2s)
According to GP I: 1-chloro-3-nitrosobenzene (53 mg, 0.37 mmol), 2-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2s (53 mg,
55%) as a yellow gum.
13C NMR (101 MHz, CDCl3):  = 157.2, 144.2, 134.4, 132.2 (2 C), 130.0,
126.0, 123.8, 121.2, 114.5 (2 C), 111.8, 111.2, 55.78.
HRMS: m/z [M + H]+ calcd for C14H14BrN2O: 305.0284; found:
305.0293.
FTIR (KBr): 3068, 2956, 2924, 2849, 1597, 1518, 1478, 1326, 1241,
(E)-1-(3-Fluorophenyl)-2-(4-methoxybenzylidene)hydrazine (2w)
1095, 1020, 853, 756, 606 cm–1
.
According to GP I: 1-fluoro-3-nitrosobenzene (46 mg, 0.37 mmol), 4-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2w (58 mg,
64%) as a white solid; mp 120–122 °C.
1H NMR (400 MHz, CDCl3):  = 8.12 (s, 1 H), 8.00–7.97 (m, 1 H), 7.32–
7.27 (m, 1 H), 7.18–7.14 (m, 2 H), 7.02–6.98 (m, 1 H), 6.90 (d, J = 8.4
Hz, 2 H), 6.82–6.80 (m, 1 H), 3.86 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 157.3, 146.2, 135.4, 134.7, 130.4,
130.1, 126.1, 123.7, 121.2, 119.9, 112.9, 111.2, 111.0, 55.8.
FTIR (KBr): 3310, 2964, 2921, 2837, 1614, 1495, 1413, 1261, 1175,
HRMS: m/z [M
+
H]+ calcd for C14H14ClN2O: 261.0789; found:
917, 840, 687 cm–1
.
261.0788.
1H NMR (600 MHz, CDCl3):  = 7.65 (s, 1 H), 7.60 (d, J = 9.0 Hz, 2 H),
7.20–7.16 (m, 1 H), 6.92 (d, J = 9.0 Hz, 3 H), 6.75–6.74 (m, 1 H), 6.55–
6.52 (m, 1 H), 3.84 (s, 3 H).
(E)-1-(3-Bromophenyl)-2-(2-methoxybenzylidene)hydrazine (2t)
According to GP I: 1-bromo-3-nitrosobenzene (69 mg, 0.37 mmol), 2-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2t (69 mg,
61%) as a yellow gum.
13C NMR (151 MHz, CDCl3):  = 165.0, 163.4, 160.4, 146.9, 146.8,
138.4, 130.6, 130.5, 127.94 (2 C), 127.90, 114.3 (2 C), 108.31, 108.29,
106.5, 106.3, 100.2, 100.0, 55.6.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

G
A. Purkait, C. K. Jana
Special Topic
Synthesis
HRMS: m/z [M
245.1085.
+
H]+ calcd for C14H14FN2O: 245.1085; found:
FTIR (KBr): 3307, 2962, 2928, 2829, 1604, 1505, 1486, 1407, 1252,
1172, 1024, 818, 642 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.62 (s, 1 H), 7.58 (d, J = 8.8 Hz, 2 H),
7.46 (s, 1 H), 7.34 (d, J = 8.8 Hz, 2 H), 6.97 (d, J = 8.8 Hz, 2 H), 6.91 (d,
J = 8.8 Hz, 2 H), 3.83 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 160.4, 144.2, 138.3, 132.2 (2 C), 128.0,
127.9 (2 C), 114.43 (2 C), 114.37 (2 C), 111.7, 55.6.
(E)-1-(3-Chlorophenyl)-2-(4-methoxybenzylidene)hydrazine (2x)
According to GP I: 1-chloro-3-nitrosobenzene (53 mg, 0.37 mmol), 4-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2x (54 mg,
56%) as a white solid; mp 132–133 °C.
HRMS: m/z [M + H]+ calcd for C14H14BrN2O: 305.0284; found:
305.0292.
FTIR (KBr): 3313, 2964, 2922, 2831, 1594, 1485, 1295, 1251, 1172,
1026, 917, 767, 684 cm–1
.
Hydrazide Derivatives 7 and 9; General Procedure II
1H NMR (400 MHz, CDCl3):  = 7.60–7.57 (m, 3 H), 7.18–7.14 (m, 2 H),
6.93–6.90 (m, 2 H), 6.90–6.87 (m, 1 H), 6.83–6.80 (m, 1 H), 3.84 (s, 3
H).
13C NMR (101 MHz, CDCl3):  = 160.5, 146.3, 138.7, 135.3, 130.4, 128.0
(2 C), 127.9, 119.8, 114.4 (2 C), 112.8, 111.0, 55.5.
Freshly prepared nitrosoarene 5 (1 equiv) and 2,4-dichlorobenzoic
acid (0.5 equiv) were successively added to a solution of cyclic sec-
ondary amine 6 or 8 (4 equiv) in toluene (3 mL). The mixture was re-
fluxed for 10–12 h under an argon atmosphere. The solvent was evap-
orated under reduced pressure and crude mixture was subjected to
column chromatography (silica gel) to afford analytically pure prod-
ucts.
HRMS: m/z [M
+
H]+ calcd for C14H14ClN2O: 261.0789; found:
261.0788.
1-[(4-Isopropylphenyl)amino]pyrrolidin-2-one (7a)
(E)-1-(3-Bromophenyl)-2-(4-methoxybenzylidene)hydrazine (2y)
According to GP II: 1-isopropyl-4-nitrosobenzene (37 mg, 0.25
mmol), pyrrolidine (82 L, 1.00 mmol), and DCBA (24 mg, 0.12 mmol)
in toluene (3 mL) were refluxed for 10 h. Column chromatography of
crude product (silica gel, EtOAc/hexane, 1:3) gave 7a (29 mg, 52%) as a
brown gum.
According to GP I: 1-bromo-3-nitrosobenzene (69 mg, 0.37 mmol), 4-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (4 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2y (56 mg,
50%) as a white solid; mp 132–133 °C.
FTIR (KBr): 2962, 2924, 2853, 1696, 1589, 1514, 1455, 210, 1099, 803,
FTIR (KBr): 3300, 2960, 2926, 2839, 1592, 1500, 1415, 1290, 1170,
608 cm–1
.
1023, 840, 675 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.10 (d, J = 8.4 Hz, 2 H), 6.71 (d, J = 8.8
Hz, 2 H), 6.04 (s, 1 H), 3.63–3.60 (m, 2 H), 2.87–2.80 (m, 1 H), 2.48 (t,
J = 8.0 Hz, 2 H), 2.18–2.11 (m, 2 H), 1.20 (d, J = 6.8 Hz, 6 H).
13C NMR (101 MHz, CDCl3):  = 174.1, 144.1, 142.5, 127.5 (2 C), 114.2
(2 C), 48.5, 33.6, 29.2, 24.4 (2 C), 16.7.
1H NMR (400 MHz, CDCl3):  = 7.61 (s, 1 H), 7.60–7.57 (m, 2 H), 7.31
(t, J = 2.0 Hz, 1 H), 7.09 (t, J = 8.0 Hz, 1 H), 6.97–6.90 (m, 4 H), 3.84 (s, 3
H).
13C NMR (101 MHz, CDCl3):  = 160.5, 146.4, 138.7, 130.7, 128.0 (2 C),
127.9, 123.5, 122.7, 115.7, 114.4 (2 C), 111.4, 55.6.
HRMS: m/z [M + H]+ calcd for C14H14BrN2O: 305.0284; found:
HRMS: m/z [M + H]+ calcd for C13H19N2O: 219.1492; found: 219.1502.
305.0280.
1-(m-Tolylamino)pyrrolidin-2-one (7b)
According to GP II: 1-methyl-3-nitrosobenzene (30 mg, 0.25 mmol),
pyrrolidine (82 L, 1.00 mmol), and DCBA (24 mg, 0.12 mmol) in tolu-
ene (3 mL) were refluxed for 10 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:3) gave 7b (21 mg, 45%) as a
white solid; mp 123–125 °C.
(E)-1-(4-Chlorophenyl)-2-(4-methoxybenzylidene)hydrazine
(2z)18f
According to GP I: 1-chloro-4-nitrosobenzene (53 mg, 0.37 mmol), 4-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2z (47 mg,
49%) as a white solid.
FTIR (KBr): 2956, 2923, 2854, 1697, 1609, 1490, 1415, 1264, 1381,
1019, 777, 541 cm–1
.
FTIR (KBr): 3310, 2958, 2925, 2839, 1606, 1488, 1459, 1411, 1252,
1H NMR (400 MHz, CDCl3):  = 7.14–7.10 (m, 1 H), 6.73 (d, J = 7.6 Hz, 1
H), 6.57–6.55 (m, 2 H), 6.03 (s, 1 H), 3.63–3.60 (m, 2 H), 2.49 (t, J = 8.0
Hz, 2 H), 2.29 (s, 3 H), 2.19–2.12 (m, 2 H).
13C NMR (101 MHz, CDCl3):  = 174.2, 146.3, 139.5, 129.4, 122.6,
114.6, 111.0, 48.5, 29.1, 21.8, 16.7.
1171, 1092, 915, 818, 646 cm–1
.
1H NMR (600 MHz, CDCl3):  = 7.66 (s, 1 H), 7.59 (d, J = 8.4 Hz, 2 H),
7.21 (d, J = 9.0 Hz, 2 H), 7.02 (d, J = 7.8 Hz, 2 H), 6.91 (d, J = 8.4 Hz, 2 H),
3.84 (s, 3 H).
HRMS: m/z [M
+
H]+ calcd for C14H14ClN2O: 261.0789; found:
HRMS: m/z [M + H]+ calcd for C11H15N2O: 191.1179; found: 191.1179.
261.0788.
1-[(3-Bromophenyl)amino]pyrrolidin-2-one (7c)
(E)-1-(4-Bromophenyl)-2-(4-methoxybenzylidene)hydrazine
According to GP II: 1-bromo-3-nitrosobenzene (46 mg, 0.25 mmol),
pyrrolidine (82 L, 1.00 mmol), and DCBA (24 mg, 0.12 mmol) in tolu-
ene (3 mL) were refluxed for 10 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:3) gave 7c (29 mg, 46%) as a light
yellow gum.
(2aa)18f
According to GP I: 1-bromo-4-nitrosobenzene (69 mg, 0.37 mmol), 4-
methoxybenzylamine (51 mg, 0.37 mmol), and AcOH (11 L, 0.19
mmol) in DCM (3 mL) were refluxed for 18 h. Column chromatogra-
phy of crude product (silica gel, EtOAc/hexane, 1:10) gave 2aa (51 mg,
45%) as a white solid.
FTIR (KBr): 2963, 2925, 2851, 1699, 1595, 1524, 1476, 1294, 1262,
1096, 1021, 801, 682 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

H
A. Purkait, C. K. Jana
Special Topic
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.08 (t, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.0
Hz, 1 H), 6.85 (s, 1 H), 6.66 (d, J = 8.8 Hz, 1 H), 6.25 (s, 1 H), 3.62–3.58
(m, 2 H), 2.52–2.47 (m, 2 H), 2.21–2.13 (m, 2 H).
13C NMR (151 MHz, CDCl3):  = 174.4, 147.8, 130.9, 124.4, 123.5,
116.4, 112.4, 48.4, 29.0, 16.6.
diluted with MeCN (2 mL). PrNH2 (83 mg, 1.41 mmol), I2 (24 mg,
0.094 mmol), and aq TBHP (127 mg, 1.41 mmol) were added and the
mixture was heated at 90 °C for an additional 4 h. The crude product
was purifying by column chromatography (silica gel, EtOAc/hexane,
1:10) to give 14a (53 mg, 45%) as a yellow gum.
1H NMR (400 MHz, CDCl3):  = 8.19–8.16 (m, 2 H), 7.52–7.36 (m, 8 H),
2.87–2.82 (m, 2 H), 1.35 (t, J = 7.6 Hz, 3 H).
HRMS: m/z [M + H]+ calcd for C10H12N2BrO: 255.0128; found:
255.0124.
13C NMR (101 MHz, CDCl3):  = 161.5, 158.0, 137.7, 131.1, 129.5 (2 C),
129.3, 129.0, 128.6 (2 C), 126.5 (2 C), 125.2 (2 C), 20.3, 12.5.
1-[(4-Chlorophenyl)amino]pyrrolidin-2-one (7d)
According to GP II: 1-chloro-4-nitrosobenzene (35 mg, 0.25 mmol),
pyrrolidine (82 L, 1.00 mmol), and DCBA (24 mg, 0.12 mmol) in tolu-
ene (3 mL) were refluxed for 10 h. Column chromatography of crude
product (silica gel, EtOAc/hexane, 1:3) gave 7d (25 mg, 48%) as a light
yellow gum.
1,3-Diphenyl-5-propyl-1H-1,2,4-triazole (14b)16
According to GP III: nitrosobenzene (50 mg, 0.47 mmol), benzylamine
(50 mg, 0.47 mmol), and AcOH (14 L, 0.24 mmol) in DCM (4 mL)
were refluxed for 18 h. The mixture was evaporated to dryness and
diluted with MeCN (2 mL). BuNH2 (0.10 g, 1.41 mmol), I2 (24 mg,
0.094 mmol), and aq TBHP (127 mg, 1.41 mmol) were added and the
mixture was heated at 90 °C for an additional 4 h. The crude product
was purifying by column chromatography (silica gel, EtOAc/hexane,
1:10) to give 14b (51 mg, 41%) as a yellow gum.
1H NMR (400 MHz, CDCl3):  = 8.19–8.17 (m, 2 H), 7.52–7.36 (m, 8 H),
2.80 (t, J = 7.6 Hz, 2 H), 1.86–1.77 (m, 2 H), 0.98–0.94 (m, 3 H).
13C NMR (101 MHz, CDCl3):  = 161.5, 157.0, 137.7, 131.1, 129.5 (2 C),
FTIR (KBr): 2960, 2924, 2853, 1696, 1596, 1491, 1417, 1261, 1091,
1020, 822, 630 cm–1
.
1H NMR (400 MHz, CDCl3):  = 7.19 (d, J = 8.8 Hz, 2 H), 6.69 (d, J = 8.8
Hz, 2 H), 6.12 (s, 1 H), 3.62–3.58 (m, 2 H), 2.51–2.47 (m, 2 H), 2.22–
2.12 (m, 2 H).
13C NMR (151 MHz, CDCl3):  = 174.3, 145.0, 129.5 (2 C), 126.5, 115.1
(2 C), 48.4, 29.0, 16.7.
HRMS: m/z [M
+
H]+ calcd for C10H12N2ClO: 211.0633; found:
129.3, 129.0, 128.6 (2 C), 126.5 (2 C), 125.3 (2 C), 28.6, 21.5, 13.9.
211.0634.
1-Phenyl-5-propyl-3-(p-tolyl)-1H-1,2,4-triazole (14c)
2-(Phenylamino)-3,4-dihydroisoquinolin-1(2H)-one (9)
According to GP III: nitrosobenzene (50 mg, 0.47 mmol), 4-methyl-
benzylamine (57 mg, 0.47 mmol), and AcOH (14 L, 0.24 mmol) in
DCM (4 mL) were refluxed for 18 h. The mixture was evaporated to
dryness and diluted with MeCN (2 mL). BuNH2 (0.10 g, 1.41 mmol), I2
(24 mg, 0.094 mmol), and aq TBHP (127 mg, 1.41 mmol) were added
and the mixture was heated at 90 °C for an additional 4 h. The crude
product was purifying by column chromatography (silica gel, EtO-
Ac/hexane, 1:10) to give 14c (42 mg, 32%) as a yellow gum.
According to GP II: nitrosobenzene (27 mg, 0.25 mmol), tetrahy-
droisoquinoline (0.13 mL, 1.00 mmol), and DCBA (24 mg, 0.12 mmol)
in toluene (3 mL) were refluxed for 12 h. Column chromatography of
crude product (silica gel, EtOAc/hexane, 1:3) gave 9 (30 mg, 50%) as a
white solid; mp 155–156 °C.
FTIR (KBr): 2956, 2925, 2854, 1599, 1464, 1211, 1071, 1019, 719, 606
cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.11 (d, J = 7.6 Hz, 1 H), 7.49–7.46 (m, 1
H), 7.37 (t, J = 7.6 Hz, 1 H), 7.28 (s, 1 H), 7.24 (s, 1 H), 7.00 (s, 1 H),
6.96–6.91 (m, 3 H), 3.87 (t, J = 6.8 Hz, 2 H), 3.26–3.23 (m, 2 H).
13C NMR (151 MHz, CDCl3):  = 165.1, 147.1, 138.2, 132.5, 129.5 (2 C),
128.7, 128.6, 127.5, 127.4, 121.9, 114.4 (2 C), 49.8, 28.6.
FTIR (KBr): 2960, 2926, 2854, 1639, 1598, 1501, 1468, 1347, 1111,
1020, 831, 751, 692 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.04 (d, J = 8.0 Hz, 2 H), 7.54–7.44 (m, 5
H), 7.24 (d, J = 8.0 Hz, 2 H), 2.82–2.78 (m, 2 H), 2.39 (s, 3 H), 1.86–1.77
(m, 2 H), 0.98–0.94 (m, 3 H).
HRMS: m/z [M + H]+ calcd for C15H15N2O: 239.1179; found: 239.1178.
13C NMR (101 MHz, CDCl3):  = 161.7, 157.0, 139.3, 137.88, 129.6 (2
C), 129.4 (2 C), 129.1, 128.4, 126.6 (2 C), 125.5 (2 C), 28.7, 21.7, 21.6,
14.0.
One-Pot Synthesis of Triazoles 14; General Procedure III
Freshly prepared nitrosoarenes (1 equiv), and AcOH were successively
added to a solution of benzylamines (1 equiv) in DCM (3–4 mL). The
mixture was refluxed for 18 h under an argon atmosphere. The mix-
ture was evaporated to dryness, and MeCN (2 mL) was added. Next,
primary amine (3 equiv), molecular I2 (20 mol%), and aq TBHP (3
equiv) were added successively and the mixture was refluxed at 90 °C
for an additional 4 h. The mixture was cooled to r.t., water (15 mL)
was added to the mixture, and it was extracted with DCM (3 × 30 mL).
The combined organic layers were washed with 10% Na2S2O3 solution,
dried (anhyd Na2SO4), and concentrated in vacuo to provide crude
product that was purified by column chromatography (silica gel) to
give analytically pure product.
HRMS: m/z [M + H]+ calcd for C18H20N3: 278.1651; found: 278.1656.
5-Nonyl-1,3-diphenyl-1H-1,2,4-triazole (14d)
According to GP III: nitrosobenzene (50 mg, 0.47 mmol), benzylamine
(50 mg, 0.47 mmol), and AcOH (14 L, 0.24 mmol) in DCM (4 mL)
were refluxed for 18 h. The mixture was evaporated to dryness and
diluted with MeCN (2 mL). Decylamine (0.22 g, 1.41 mmol), I2 (24 mg,
0.094 mmol), and aq TBHP (127 mg, 1.41 mmol) were added and the
mixture was heated at 90 °C for an additional 4 h. The crude product
was purifying by column chromatography (silica gel, EtOAc/hexane,
1:15) to give 14d (49 mg, 30%) as a yellow gum.
FTIR (KBr): 3066, 2954, 2925, 2854, 1645, 1599, 1500, 1466, 1354,
1173, 1070, 1022, 763, 694 cm–1
.
5-Ethyl-1,3-diphenyl-1H-1,2,4-triazole (14a)16
1H NMR (400 MHz, CDCl3):  = 8.18–8.15 (m, 2 H), 7.54–7.37 (m, 8 H),
2.84–2.80 (m, 2 H), 1.81–1.74 (m, 2 H), 1.35–1.23 (m, 12 H), 0.87 (t, J =
6.8 Hz, 3 H).
According to GP III: nitrosobenzene (50 mg, 0.47 mmol), benzylamine
(50 mg, 0.47 mmol), and AcOH (14 L, 0.24 mmol) in DCM (4 mL)
were refluxed for 18 h. The mixture was evaporated to dryness and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

I
A. Purkait, C. K. Jana
Special Topic
Synthesis
13C NMR (101 MHz, CDCl3):  = 161.6, 157.3, 137.8, 131.2, 129.6 (2 C),
129.3, 129.1, 128.7 (2 C), 126.6 (2 C), 125.4 (2 C), 32.0, 29.5, 29.38,
29.36, 29.3, 28.2, 26.8, 22.8, 14.3.
2009, 15, 9078. (g) Carosso, S.; Miller, M. J. Org. Biomol. Chem.
2014, 12, 7445. (h) Maji, B.; Yamamoto, H. J. Am. Chem. Soc.
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(b) Atkinson, D.; Kabeshov, M. A.; Edgar, M.; Malkov, A. V. Adv.
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HRMS: m/z [M + H]+ calcd for C23H30N3: 348.2434; found: 348.2434.
(6) (a) Chidley, T.; Vemula, N.; Carson, C. A.; Kerr, M. A.; Pagenkopf,
B. L. Org. Lett. 2016, 18, 2922. (b) Das, S.; Daniliuc, C. G.; Studer,
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Funding Information
We acknowledge financial support from Science and Engineering Re-
search Board (SERB).()
(7) (a) Wu, Y. M.; Ho, L. Y.; Cheng, C. H. J. Org. Chem. 1985, 50, 392.
(b) Zhao, R.; Tan, C.; Xie, Y.; Gao, C.; Liu, H.; Jiang, Y. Tetrahedron
Lett. 2011, 52, 3805. (c) Wróbel, Z.; Stachowska, K.; Kwast, A.
Eur. J. Org. Chem. 2014, 7721. (d) Ramakumar, K.; Tunge, J. A.
Chem. Commun. 2014, 50, 13056. (e) Li, J.; Zhou, H.; Zhang, J.;
Yang, H.; Jiang, G. Chem. Commun. 2016, 52, 9589. (f) Nguyen, T.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610701. X-ray data and copies of
NMR spectra are included.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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Special Topic
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J