Cs2CO3-mediated decomposition of N-tosylhydrazones for the synthesis of azines under mild conditions

Article abstract of DOI:10.1007/s11164-016-2688-3

Abstract: A facile, environmentally and efficient Cs₂CO₃-mediated decomposition of N-tosylhydrazones reaction has been developed for the synthesis of functionalized azines under mild conditions. This method offers broad substrate scope, occurs as additive-free, without strong base conditions, utilizes readily available reactants, and forms products in good to high yields. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2688-3

Res Chem Intermed
DOI 10.1007/s11164-016-2688-3
Cs2CO3-mediated decomposition of N-tosylhydrazones
for the synthesis of azines under mild conditions
Zai-Gang Luo1 Peng Liu2 Yu-Yu Fang1
•
•
•
Xue-Mei Xu1 Cheng-Tao Feng1 Zhong Li1
Xiao-Mei Zhang1 Jie He1
•
•
•
•
Received: 26 May 2016 / Accepted: 1 August 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A facile, environmentally and efficient Cs2CO3-mediated decomposition of
N-tosylhydrazones reaction has been developed for the synthesis of functionalized azines
under mild conditions. This method offers broad substrate scope, occurs as additive-free,
without strong base conditions, utilizes readily available reactants, and forms products in
good to high yields.
Graphical Abstract
H
N
Ts
R2
N
R1
N
Cs2CO3 (2 equiv)
MeCN, 100°C, 6h
N
R2
R1
2
R1
R2
24 examples
up to 92% isolated yield
R1 = H, Me, MeO, CF3, NO2, F, Cl, Br
R2 = H, Me, Ph, Benzyl
Without strong base
Additive-free
Broad substrate scope
Mild conditions
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2688-3)
contains supplementary material, which is available to authorized users.
&
&
1
Zai-Gang Luo
luozi139@163.com
Jie He
aust_jhe@163.com
College of Chemical Engineering, Anhui University of Science and Technology,
Huainan 232001, China
2
Guang Zhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
Guangzhou 510530, China
123

Z.-G. Luo et al.
Keywords Decomposition Á N-Tosylhydrazones Á Cs2CO3 Á Azines
Introduction
Azines, N–N linked diimines, which exhibit interesting biological [1–3], conductive
[4–6], and optical [7–9] properties and are extensively used as synthetic
intermediates [10–14], have received increasing attention in recent years. Generally,
azines are prepared by the condensation of aldehydes or ketones with hydrazine
hydrate in solution under refluxing conditions or with promoters such as iodine or
acid [15–17]. These reactions proceed rapidly but often generate large amounts of
unwanted byproducts. Very recently, Peltier et al. [18] reported the first examples of
copper-catalyzed hydrohydrazination of terminal alkynes with hydrazine hydrate for
the synthesis of symmetrical and unsymmetrical azines. However, hydrazine
hydrate is a volatile liquid, which is extremely hazardous with risks of handling and
transportation. In 2011, Lee et al. [19] demonstrated that the synthesized solid
hydrazine can be a very valuable alternative for the toxic liquid hydrazine. Solid
hydrazine is remarkably stable but is as reactive as liquid hydrazine even in the
absence of solvents for the synthesis of azines. Although many of these methods
provide an efficient route to azines they require toxic liquid hydrazine or
synthesized solid hydrazine as a reactant, relatively harsh reaction conditions, and
a tedious workup procedure. Thus, the development of a novel reaction system
under mild reaction conditions is required.
N-Tosylhydrazones, derived from the corresponding aldehydes or ketones, have
been extensively utilized as the precursors of diazo compounds or carbenes [20, 21].
In recent years, rapid progress has been made in tosylhydrazone-participated
transition-metal-catalyzed or metal-free cross-coupling reactions [22–27]. For
example, in the presence of PPh3 and t-BuOLi, asymmetrical azines were formed
in good yields by the metal-free cross-coupling reaction of tosylhydrazones with
aldehydes [25]. In addition, these reactions reported in the literature were usually
carried out in basic conditions. Decomposition of tosylhydrazones toward byprod-
ucts such as azines or N-substituted hydrazones usually took place [28–31].
Therefore, the transition-metal-catalyzed or metal-free decomposition of tosylhy-
drazones provides an attractive alternative to the reported methods for the synthesis
of azines. In 2011, Fe-catalyzed or t-BuOLi-mediated decomposition of tosylhy-
drazone affording azine was reported by Barluenga et al. [30] (Scheme 1a).
Recently, a similar transformation promoted by NaOH and CH3NO2 was reported
by Sha and Wei [31] (Scheme 1b). The past developments are still far from being
considered as environmentally benign since the use of a metal catalyst, strong base
and toxic reagents restrict their applicability. Hence, the study of new procedures
that are less hazardous to human health and the environment has received extensive
attention. Considering the wide applications of azines, a mild base and solvent-
controlled metal- and additive-free decomposition pathway toward azines using
aldehyde tosylhydrazones and ketone tosylhydrazones as substrates is reported here
(Scheme 1c).
123

Cs2CO3-mediated decomposition of N-tosylhydrazones for…
é
(a) Barluenga and Vald s's work
H
N
Ts
N
[Fe]/t-BuOLi
N
N
or t-BuOLi (3 equiv)
2
(b)
Wei's work
H
N
Ts
.
R2
N
R1
N
N
NaOH (3 equiv)
MeNO2 (5 equiv)
N
R2
R1
2
R1
R2
(c) This work
H
N
Ts
R2
N
R1
Cs2CO3 (2 equiv)
N
R2
R1
2
R1
R2
Scheme 1 Synthesis of azines from N-tosylhydrazones
Experimental
Unless otherwise noted, all materials were obtained from commercial suppliers and
dried and purified by standard procedures. The melting point was measured on a
SGW X-4 monocular microscope melting point apparatus with thermometer
1
unadjusted. H NMR and 13C NMR spectra were acquired on a Bruker Avance III
400 MHz spectrometer with CDCl3 as the solvent and tetramethylsilane (TMS) as
the internal standard. Mass spectra (MS) data were obtained using an Esquire 6000
Mass Spectrometer. Column chromatography was performed with silica gel
(200*300 mesh; Qingdao Haiyang Chemical, China). Petroleum ether used for
column-chromatography has a boiling range of 60–90 °C. Various N-tosylhydra-
zones 1a–x were prepared according to the related literature [30, 31].
General procedure for the synthesis of azines 2a–x
A 25-mL Schlenk tube was charged with various N-tosylhydrazones (1) (0.5 mmol),
Cs2CO3 (1 mmol) and CH3CN (2 mL). The tube was sealed, and then the mixture
was stirred under air at 100 °C for 6 h. The reaction mixture was then allowed to cool
to ambient temperature. After concentration in vacuo, the crude product was purified
by column chromatography on silica gel (petroleum ether:ethyl acetate = 10:1–6:1).
1,2-bis(1-phenylethylidene)hydrazine (2a) [11, 31] White solid, 54.3 mg, 92%
1
yield. mp 123–125 °C. H NMR (400 MHz, CDCl3, ppm) d: 7.93–7.90 (m, 4H),
123

Z.-G. Luo et al.
7.43–7.42 (m, 6H), 2.32 (s, 6H); 13C NMR (100 MHz, CDCl3, ppm) d: 157.8,
140.9, 131.6, 128.1, 124.0, 20.8. MS (ESI) m/z: 258.9 [M ? Na]?, 495.1
[2M ? Na]?.
1,2-bis(1-(p-tolyl)ethylidene)hydrazine (2b) [11, 12] White solid, 53.5 mg, 81 %
1
yield. mp 152–154 °C. H NMR (400 MHz, CDCl3, ppm) d: 7.86 (d, J = 8.0 Hz,
4H), 7.30 (d, J = 8.0 Hz, 4H), 2.45 (s, 6H), 2.35 (s, 6H); 13C NMR (100 MHz,
CDCl3, ppm) d: 157.7, 139.7, 129.1, 126.6, 21.4, 15.0. MS (ESI) m/z: 286.9
[M ? Na]?, 550.9 [2M ? Na]?.
1,2-bis(1-(4-methoxyphenyl)ethylidene)hydrazine (2c) [11] White solid, 65.9 mg,
89% yield. mp 169–171 °C. 1H NMR (400 MHz, CDCl3, ppm) d: 7.93 (d,
J = 4.0 Hz, 4H), 6.99 (d, J = 4.0 Hz, 4H), 3.90 (s, 6H), 2.37 (s, 6H); 13C NMR
(100 MHz, CDCl3, ppm) d: 160.9, 157.8, 131.4, 128.1, 113.7, 55.4, 14.8. MS (ESI)
m/z: 319.0 [M ? Na]?, 615.1 [2M ? Na]?.
1,2-bis(1-(3-methoxyphenyl)ethylidene)hydrazine (2d) [11] White solid, 66.6 mg,
1
90% yield. mp 163–165 °C. H NMR (400 MHz, CDCl3, ppm) d: 7.80–7.77 (m,
4H), 7.52–7.50 (m, 2H), 7.04–7.01 (m, 2H), 3.96 (s, 6H), 2.66 (s, 6H). 13C NMR
(100 MHz, CDCl3, ppm) d: 158.9, 133.6, 130.4, 128.4, 120.6, 111.6, 55.5, 31.8. MS
(ESI) m/z: 319.1 [M ? Na]?, 615.1 [2M ? Na]?.
1,2-bis(1-(2-methoxyphenyl)ethylidene)hydrazine (2e) [12] White solid, 64.4 mg,
87% yield. mp 155–157°C. 1H NMR (400 MHz, CDCl3, ppm) d: 7.78 (d,
J = 4.0 Hz, 2H), 7.52 (t, J = 6.0 Hz, 2H), 7.06–7.01 (m, 4H), 3.96 (s, 6H), 2.66 (s,
6H). 13C NMR (100 MHz, CDCl3, ppm) d: 158.9, 133.6, 130.4, 128.4, 120.6, 111.6,
55.5, 31.8. MS (ESI) m/z: 319.1 [M ? Na]?, 615.2 [M ? Na]?.
4,40-hydrazine-1,2-diylidenebis(ethan-1-yl-1-ylidene))dianiline (2f) [9] White
1
solid, 59.2 mg, 89% yield. mp 162–164 °C. H NMR (400 MHz, CDCl3, ppm) d:
8.21 (d, J = 8.0 Hz, 4H), 7.42 (d, J = 4.0 Hz, 4H), 4.79 (s, 4H), 2.51 (s, 6H). 13C
NMR (100 MHz, CDCl3, ppm) d: 147.9, 131.6, 130.4, 129.4, 123.2, 22.1. MS (ESI)
m/z: 265.0 [M - H]-.
1,2-bis(1-(4-(trifluoromethyl)phenyl)ethylidene)hydrazine (2g) [32] White solid,
84.6 mg, 91% yield. mp 134–136 °C. 1H NMR (400 MHz, CDCl3, ppm) d: 8.07 (d,
J = 4.0 Hz, 4H), 7.74 (d, J = 4.0 Hz, 4H), 2.38 (s, 6H). 13C NMR (100 MHz,
CDCl3, ppm) d: 156.9, 141.4, 131.7, 131.4, 127.0, 125.42, 125.39, 125.36, 125.33,
122.98, 15.1. MS (ESI) m/z: 372.8 [M ? H]?.
1,2-bis(1-(4-nitrophenyl)ethylidene)hydrazine (2h) [31] Yellow solid, 75.8 mg,
93% yield. mp 165–167 °C. 1H NMR (400 MHz, CDCl3, ppm) d: 7.86 (d,
J = 8.0 Hz, 4H), 7.29 (d, J = 8.0 Hz, 4H), 2.45 (s, 6H). 13C NMR (100 MHz,
CDCl3, ppm) d: 145.9, 134.0, 130.1, 128.6, 21.8. MS (ESI) m/z: 325.6 [M - H]-.
1,2-bis(1-(3-nitrophenyl)ethylidene)hydrazine (2i) [19] Yellow solid, 73.4 mg,
1
90% yield. mp 161–163 °C. H NMR (400 MHz, CDCl3, ppm) d: 8.81–8.80 (m,
2H), 8.35–8.32 (m, 4H), 7.69–7.66 (m, 2H) 2.45 (s, 6H). 13C NMR (100 MHz,
123

Cs2CO3-mediated decomposition of N-tosylhydrazones for…
CDCl3, ppm) d: 145.9, 140.0, 130.5, 130.1, 128.6, 124.0, 21.8. MS (ESI) m/z: 325.4
[M - H]-.
1,2-bis(1-(2-nitrophenyl)ethylidene)hydrazine (2j) [33] Yellow solid, 71.7 mg,
88% yield. mp 155–157 °C. 1H NMR (400 MHz, CDCl3, ppm) d: 8.15 (d,
J = 8.0 Hz, 2H), 7.78–7.75 (m, 2H), 7.66–7.63 (m, 2H), 7.49–7.47 (m, 2H), 2.60 (s,
6H). 13C NMR (100 MHz, CDCl3, ppm) d: 152.9, 128.6, 128.5, 123.3, 115.4, 115.2,
15.0. MS (ESI) m/z: 325.4 [M - H]-.
1,2-bis(1-(4-fluorophenyl)ethylidene)hydrazine (2k) [11, 12] White solid,
53.0 mg, 78% yield. mp 158–160 °C. 1H NMR (400 MHz, CDCl3, ppm) d:
7.93–7.90 (m, 4H), 7.43–7.42 (m, 4H), 2.32 (s, 6H). 13C NMR (100 MHz, CDCl3,
ppm) d: 145.6, 128.9, 128.2, 123.9, 123.4, 18.3. MS (ESI) m/z: 294.9 [M ? Na]?,
567.0 [2M ? Na]?.
1,2-bis(1-(4-bromophenyl)ethylidene)hydrazine (2l) [12] White solid, 76.8 mg,
78% yield. mp 153–155 °C. 1H NMR (400 MHz, CDCl3, ppm) d: 7.27 (d,
J = 4.0 Hz, 4H), 6.86 (d, J = 4.0 Hz, 4H) 2.16 (s, 6H). 13C NMR (100 MHz,
CDCl3, ppm) d: 139.2, 132.0, 130.7, 129.4, 126.9, 30.7. MS (ESI) m/z: 394.9
[M ? H]?.
1,2-bis(1-(3-chlorophenyl)ethylidene)hydrazine (2m) [11] White solid, 61.8 mg,
1
81% yield. mp 158–160 °C. H NMR (400 MHz, CDCl3, ppm) d: 7.79–7.77 (m,
2H), 7.53–7.49 (m, 2H), 7.06–7.01 (m, 4H), 2.66 (s, 6H). 13C NMR (100 MHz,
CDCl3, ppm) d: 158.9, 133.6, 130.4, 128.4, 125.8, 120.6, 111.6, 21.2. MS (ESI): m/
z = 304.1 [M ? H]?.
1,2-bis(1-(naphthalen-2-yl)ethylidene)hydrazine (2n) [34] Yellow solid, 73.9 mg,
1
88% yield. mp 189–191°C. H NMR (400 MHz, CDCl3, ppm) d: 8.52 (s, 1H),
8.10–8.08 (m, 1H), 8.03–8.01 (m, 1H) 7.95 -7.92 (m, 2H), 7.67–7.59 (m, 2H), 2.78
(s, 3H). 13C NMR (100 MHz, CDCl3, ppm) d: 136.6, 133.6, 131.4, 129.4, 128.8,
127.9, 127.6, 26.8. MS (ESI) m/z: 358.9 [M ? Na]?, 695.0 [2M ? Na]?.
1,2-dibenzylidenehydrazine (2o) [31] White solid, 44.2 mg, 85% yield. mp
1
125–127°C. H NMR (400 MHz, CDCl3, ppm) d: 8.72 (s, 2H), 7.90–7.89 (m,
4H), 7.51–7.50 (m, 6H); 13C NMR (100 MHz, CDCl3, ppm) d: 162.1, 131.2, 128.8,
128.6, 128.0. MS (ESI) m/z: 231.8 [M ? Na]?, 440.9 [2M ? Na]?.
1,2-bis(2-methoxybenzylidene)hydrazine (2p) [35] White solid, 54.3 mg, 81%
1
yield. mp 234–236°C. H NMR (400 MHz, CDCl3, ppm) d: 8.20 (s, 2H), 7.86 (d,
J = 8.0 Hz, 2H), 7.38–7.34 (m, 2H), 6.98–6.95 (m, 2H), 6.89 (d, J = 8.0 Hz, 2H).
13C NMR (100 MHz, CDCl3, ppm) d: 158.0, 133.2, 131.9, 129.0, 128.0, 120.9,
111.0, 55.6. MS (ESI) m/z: 292.9 [M ? Na]?, 563.0 [2M ? Na]?.
1,2-bis(4-nitrobenzylidene)hydrazine (2q) [16, 19] Yellow solid, 66.3 mg, 89%
yield. mp 260–262 °C. 1H NMR (400 MHz, CDCl3, ppm) d: 10.19 (s, 2H), 8.43 (d,
J = 8.0 Hz, 4H), 8.11 (d, J = 8.0 Hz, 4H). 13C NMR (100 MHz, CDCl3, ppm) d:
156.6, 148.2, 140.5, 129.4, 128.7, 128.0. MS (ESI) m/z: 319.0 [M ? Na]?, 615.1
[2M ? Na]?.
123

Z.-G. Luo et al.
1,2-bis(3-nitrobenzylidene)hydrazine (2r) [16, 19] Yellow solid, 63.3 mg, 85%
1
yield. mp 248–250°C. H NMR (400 MHz, CDCl3, ppm) d: 10.16 (s, 2H), 8.21 (d,
J = 8.0 Hz, 2H), 7.98–7.94 (m, 2H), 7.60–7.57 (m, 2H), 7.48–7.46 (m, 2H). 13C
NMR (100 MHz, CDCl3, ppm) d: 148.2, 146.9, 136.0, 134.2, 129.4, 127.9, 123.9.
MS (ESI) m/z: 323.0 [M ? Na]?, 623.1 [2M ? Na]?.
Dimethyl 4,40-(hydrazine-1,2-diylidenebis(methanylylidene))dibenzoate (2s) [36] White
solid, 68.0 mg, 84% yield. mp 200–202°C. 1H NMR (400 MHz, CDCl3, ppm) d: 10.12
(s, 2H), 7.99 (d, J = 8.0 Hz, 4H), 7.59 (d, J = 8.0 Hz, 4H). 13C NMR (100 MHz,
CDCl3, ppm) d: 166.5, 164.4, 136.4, 133.9, 131.5, 129.7, 52.2. MS (ESI) m/z: 347.0
[M ? Na]?, 671.1 [2M ? Na]?.
1,2-bis(4-chlorobenzylidene)hydrazine (2t) [16, 19] White solid, 56.8 mg, 82%
yield. mp 145–147°C. 1H NMR (400 MHz, CDCl3, ppm) d: 8.21 (s, 2H), 8.06–8.03
(m, 4H), 7.60–7.57 (m, 4H). 13C NMR (100 MHz, CDCl3, ppm) d: 143.8, 133.4,
131.4, 129.8, 129.1, 128.0. MS (ESI) m/z: 300.9 [M ? Na]?, 579.1 [2M ? Na]?.
1,2-bis(3-chlorobenzylidene)hydrazine (2u) [1] White solid, 55.4 mg, 80% yield.
1
mp 146–148°C. H NMR (400 MHz, CDCl3, ppm) d: 8.21 (s, 2H), 7.97–7.95 (m,
2H), 7.67–7.64 (m, 2H), 7.59–7.31 (m, 6H). 13C NMR (100 MHz, CDCl3, ppm) d:
154.6, 135.3, 134.2, 129.1, 128.6, 123.5. MS (ESI) m/z: 276.4 [M - H]-.
1,2-bis(naphthalen-1-ylmethylene)hydrazine (2v) [37] Blown solid, 70.1 mg, 91%
1
yield. mp 232–234°C. H NMR (400 MHz, CDCl3, ppm) d: 10.46 (s, 2H), 9.31 (d,
J = 4.0 Hz, 2H), 8.17 (d, J = 8.0 Hz, 2H) 8.06 (d, J = 4.0 Hz, 2H), 7.99 (d,
J = 8.0 Hz, 2H) 7.77–7.73 (m, 2H), 7.69–7.31 (m,4H). 13C NMR (100 MHz,
CDCl3, ppm) d: 147.8, 134.5, 131.7, 131.5, 129.7, 128.7, 128.1, 126.4, 125.9, 124.5.
MS (ESI) m/z: 332.8 [M ? Na]?, 642.9 [2M ? Na]?.
1,2-bis(1,2-diphenylethylidene)hydrazine (2w) [38] Brown oil, 74.7 mg, 77%
1
yield. H NMR (400 MHz, CDCl3, ppm) d: 7.56–7.54 (m, 8H), 7.36–7.33 (m, 8H),
7.31–7.27 (m, 4H), 3.16 (s, 4H). 13C NMR (100 MHz, CDCl3, ppm) d: 136.3, 135.4,
131.5, 131.3, 129.8, 129.7, 128.9, 45.8. MS (ESI) m/z: 411.0 [M ? Na]?, 799.1
[2M ? Na]?.
1,2-bis(diphenylmethylene)hydrazine (2x) [11] White solid, 65.7 mg, 73% yield.
mp 220–222°C. 1H NMR (400 MHz, CDCl3, ppm) d: 8.14–8.12 (m, 8H), 7.73–7.70
(m, 4H), 7.58–7.55 (m, 8H). 13C NMR (100 MHz, CDCl3, ppm) d: 163.1, 134.3,
129.8, 128.9, 125.7. MS (ESI) m/z: 382.9 [M ? Na]?, 743.0 [2M ? Na]?.
Results and discussion
We initiated the present study with N-tosylhydrazone 1a as the model substrate for
optimizing the reaction conditions, and various bases, solvents, and temperatures
were then screened (Table 1). First, we chose Li2CO3 (2 equiv) as the base in
CH3CN at 100 °C for 6 h, and the desired product 2a was obtained in 46 % yield
(Table 1, entry 1). Next, a range of bases such as Na2CO3, K2CO3, Cs2CO3,
123

Cs2CO3-mediated decomposition of N-tosylhydrazones for…
Table 1 Optimization of the
reaction conditions
H
N
Ts
N
N
N
Base
solvent,t°C
2
1a
2a
Entry Base (eq)
Solvent
T (°C) Time (h) Yield (%)a
1
Li2CO3 (2)
MeCN
MeCN
MeCN
MeCN
100
100
100
100
100
100
100
100
100
100
100
100
100
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
46
45
67
92
35
33
47
49
58
75
79
80
79
26
40
52
29
42
n.d.
77
82
2
Na2CO3 (2)
K2CO3 (2)
Cs2CO3 (2)
3
4
5
NaHCO3 (2) MeCN
KH2PO3 (2) MeCN
6
7
NaOH (2)
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
8
KOH (2)
9
t-BuOK (2)
Cs2CO3 (1)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
10
11
12
13
14
15
16
17
18
19
20
21
DMSO
CH3OH 100
CHCl3
DMA
100
100
a
Acetone 100
Reaction conditions: 1a
(0.5 mmol), solvent (2 mL),
DCE
100
100
90
90–110 °C, 6 h
H2O
b
Isolated yield
MeCN
MeCN
Bold values indicate the optimal
reaction conditions
110
NaHCO3, KH2PO4, NaOH, KOH and t-BuOK were then screened, and Cs2CO3 was
found to be the most suitable base (Table 1, entries 2–9). Raising or decreasing the
loading of Cs2CO3 did not deliver an improvement in the yield of product 2a
(Table 1, entry 10–11). Then, various solvents were screened and evaluated. The
identical reaction performed in DMF, DMSO, CH3OH, CHCl3, N,N-dimethylac-
etamide (DMA), acetone and 1,2-dichloroethane (DCE) lowered the yield of the
product 2a (Table 1, entries 12–18), while no target compound 2a was detected
when H2O was used as the solvent (Table 1, entry 19). Finally, a diminished
chemical yield was observed when the reaction temperature was dropped to 90 °C
or elevated to 110 °C (Table 1, entries 20–21). Therefore, the optimal reaction
conditions were selected as shown in entry 4.
With these optimized conditions in hand, the scope of both aldehyde tosylhydra-
zones and ketone tosylhydrazones were established and the results are presented in
123

Z.-G. Luo et al.
Table 2 Cs2CO3-mediated synthesis of azines
R1
H
R2
N
N
Ts
N
N
Cs2CO3 (2 equiv)
CH3CN, 100°C, 6h
R2
2
R1
R2
R1
2
1
R1 = H, 2a, 92%
2b
R1 = 4-Me, , 81%
R1 = 4-MeO, 2c, 89%
R1
R
1 = 3-MeO, 2d, 90%
2e
R1 = 2-MeO, , 87%
1 = 4-NH2, 2f, 89%
R1 = 4-CF3, 2g, 91%
N
R
N
N
N
2h
R
R
R
R
R
1 = 4-NO2, , 93%
R1
1 = 3-NO2, 2i, 90%
1 = 2-NO2, 2j, 88%
1 = 4-F, , 78%
2n
2a-m
, 88%
2k
1 = 4-Br, 2l, 78%
R1 = 3-Cl, 2m, 81%
H
N
R1 = H, 2o, 85%
R1
2p
R
R
1 = 2-MeO, , 81%
N
H
H
N
1 = 4-NO2, 2q, 89%
N
R1 = 3-NO2, 2r, 85%
2s
R
1 = 4-MeOCO, , 84%
R1 = 4-Cl, 2t, 82%
1 = 3-Cl, 2u, 80%
H
2v
R1
, 91%
R
2o-u
N
N
N
N
2w
, 77%
2x
, 73%
Reaction conditions: N-tosylhydrazones 1 (0.5 mmol), CH3CN (2 ml). Isolated yield
Table 2. First, when R2 was the methyl group and the phenyl ring with electron-
withdrawing substituents (p-CF3, p-NO2, m-NO2, o-NO2,) or electron-donating
substituents (p-Me, p-MeO, m-MeO, o-MeO, p-NH2), as well as the para-, ortho- and
meta-substituted groups, all of the substrates 1a–j gave the desired products in good to
excellent yields (2a–j), showing no obvious electronic effect in this transformation.
The para- and meta-substituted halogen atoms such as fluorine, bromine and chlorine
were well tolerated, affording the corresponding products in good yields (2k–m).
Notably, 2-acetonaphthone tosylhydrazone 1n was also a suitable substrate for this
reaction, which reacted smoothly to give the expected products in good yields (2n,
88 %). Similarly, when R2 was a hydrogen atom, the substrates 1o–u bearing different
kinds of functional groups on the phenyl ring, such as methoxyl, nitro, methoxycar-
bonyl and chloro groups, all reacted smoothly to afford the desired azines in good
123

Cs2CO3-mediated decomposition of N-tosylhydrazones for…
Ts
NH
Ts
N
N2
N
N
Cs2CO3
R2
R2
R2
R1
R1
R1
Ts
B
A
1
Ts
N
N
R2
N2
R1
A
R1
R1
R1
R2
R2
N
R2
N
N
N
N
Cs2CO3
N
Ts
Ts
R2
R2
R2
R1
R1
Ts
R1
C
2
D
Scheme 2 Proposed reaction mechanism
yields (2o–2u). It was observed that 1-naphthaldehyde tosylhydrazone 1v converted to
azine 2v in excellent yields (91%). Next, the reaction efficiency affected by steric
effects was also considered. Gratifyingly, under the standard conditions, when R2 was
a benzyl or phenyl group, N-tosylhydrazones 1w and 1x could be smoothly
transformed into azines 2w and 2x in 77 and 73 % yields, respectively. Obviously,
the above results indicate that the reaction was insensitive to the sterically hindered
substrates. In addition, we tried to synthesize the asymmetrical azines from the two
different N-tosylhydrazones, such as 1a and 1c; however, the reaction system was
messy and no main products could be isolated and obtained.
In the light of the nature of N-tosylhydrazones and based on previous reports
[27, 31], a plausible mechanism is proposed (Scheme 2). Initially, the intermediate
anion A was formed in the presence of the base via removal of a proton on the
nitrogen of tosylhydrazones 1. Subsequently, intermediate A is converted in situ to
the corresponding diazo compound B with concomitant elimination of the Ts group
[27]. Next, decomposition of B by interaction with A afforded the intermediate
C. Eventually, symmetrical azines 2 were then obtained by base-catalyzed
elimination of TsH from intermediate C.
Conclusions
In conclusion, we have developed a simple, mild, and efficient protocol for the
synthesis of symmetrical azines from N-tosylhydrazones in the Cs2CO3 and CH3CN
reaction system. The method offers broad substrate scope, occurs as additive-free,
123

Z.-G. Luo et al.
without strong base conditions, utilizing readily available reactants, and forms
products in good to high yields, which represents an environmentally and efficient
access to the C–N bond construction.
Acknowledgments The authors gratefully acknowledge the financial support from the National Natural
Science Foundation of China (21102003) and the Natural Science Foundation of Anhui Province
(1608085MB38).
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