Solid-state and solvent-free synthesis of azines, pyrazoles, and pyridazinones using solid hydrazine

Article abstract of DOI:10.1016/j.tetlet.2012.12.106

Azines, pyrazoles, and pyridazinones were isolated as the sole products in high yields (>97%) by grinding solid hydrazine (H₃N ⁺NHCO₂^-) with di-carbonyl compounds or by their reaction in the absence of solvent. Neither catalysts nor additives were needed to promote the reactions. The solid-state and solvent-free reactions proceeded under ambient conditions and did not produce any wastes other than water and carbon dioxide. They are operationally easy, environmentally safe, and readily scalable, allowing for highly selective synthesis of compounds containing the hydrazine motif. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.106

Tetrahedron Letters 54 (2013) 1384–1388
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solid-state and solvent-free synthesis of azines, pyrazoles, and pyridazinones
using solid hydrazine
Byeongno Lee a, Philjun Kang a, Kyu Hyung Lee a, Jaeheung Cho b, Wonwoo Nam c, Won Koo Lee a,
,
⇑
Nam Hwi Hur a,
⇑
a Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
b Department of Emerging Materials Science, DGIST, Daegu 711-873, Republic of Korea
c Department of Bioinspired Science, Department of Chemistry and Nano Science, Ewha Womans University, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Azines, pyrazoles, and pyridazinones were isolated as the sole products in high yields (>97%) by grinding
solid hydrazine (H3N+NHCO2ꢀ) with di-carbonyl compounds or by their reaction in the absence of sol-
vent. Neither catalysts nor additives were needed to promote the reactions. The solid-state and sol-
vent-free reactions proceeded under ambient conditions and did not produce any wastes other than
water and carbon dioxide. They are operationally easy, environmentally safe, and readily scalable, allow-
ing for highly selective synthesis of compounds containing the hydrazine motif.
Received 20 November 2012
Revised 24 December 2012
Accepted 26 December 2012
Available online 5 January 2013
Keywords:
Solid state reaction
Azines
Ó 2012 Elsevier Ltd. All rights reserved.
Pyrazoles
Pyridazinones
Solvent-free conditions
Organic reactions are typically carried out in the presence of
solvent. Therefore, isolation of the pure products requires separa-
tion and purification steps, which result in a substantial decrease
in yield and can be environmentally hazardous processes. In sol-
vent-based reactions, the weight ratio of waste to product, which
is known as the E factor,1,2 is inevitably high. A simple and efficient
way to increase yields and reduce environmental impact is to con-
duct the reaction in the absence of solvent, which includes solvent-
free or solid-state reactions. Compared to conventional organic
reaction, they have several advantages that include high reaction
rate, cost savings, considerable process reduction, and minimal im-
pact on the environment.3–5
Thus far, numerous efforts have been directed toward the
development of novel solvent-free or solid-state reaction for
the synthesis of a wide range of organic materials in high
yields.3–9 Wang and Qin reported the synthesis of pyrazole
derivatives by solvent-free reactions of diketones with hydrazine
hydrate.6 The solid-state-grinding method has been directly ap-
plied to aldol condensation reactions between aldehydes and ke-
tones in the solid state, which smoothly proceeded at ambient
conditions in the absence of solvent.7 Kaupp and Schmeyers dis-
covered the solid-state reactivity of hydrazine–hydroquinone
complex toward carbonyl compounds and also investigated the
reaction mechanism on the solid surface by atomic force
microscopy.8
Thus far, numerous green strategies have been developed as
potential solutions to alleviate the problems associated with
solvent-based reactions, suggesting that highly reactive and stable
molecular precursors are necessary to make the routes syntheti-
cally efficient and environmentally benign.
We have recently isolated
a
hydrazinium carboxylate
(H3N+NHCO2ꢀ, 1a) as a crystalline powder by reacting aqueous
hydrazine with supercritical CO2, which exhibited excellent reac-
tivity toward aldehydes in the solid state at ambient conditions,
producing only water and CO2 as waste.9 The solid hydrazine
(1a) proved to be a synthetic alternative to toxic liquid hydra-
zine (H2NNH2).10 Thus, we reasoned that 1a should be effective
for the synthesis of other compounds containing the hydrazine
motif through an efficient and green route. Herein, we report so-
lid-state and solvent-free reactions between 1a and di-carbonyl
compounds including
a-, b-, and c-keto derivatives. The reac-
tions afford azines, pyrazoles, and pyridazinones in high yields
with excellent selectivities (Scheme 1). These findings are signif-
icant because the reactions not only proceed at ambient condi-
tions without solvents, but they also do not generate toxic
waste.
⇑
Corresponding authors.
E-mail addresses: wonkoo@sogang.ac.kr (W.K. Lee), nhhur@sogang.ac.kr
We initially focused on the solid-state reactivity of 1a toward
a-keto acid. A mixture of 1a and benzoylformic acid (2a) with a
(N.H. Hur).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.106

B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388
1385
O
temperature. At 50 °C, the reaction took longer and was complete
in 24 h. The products of the reaction after 3, 6, 12, and 24 h were
characterized by XRD and 1H NMR spectroscopy. The yields of 3a,
determined from the 1H NMR spectra of the reaction mixture, grad-
ually increased with increasing time, as shown in Figure 1. No
byproducts were detected by XRD or 1H NMR spectroscopy.
In contrast to the excellent reactivity of 1a with 2a, inferior
results were obtained when hydrazine hydrate (H2NNH2ꢁH2O,
1b) was used as the source of hydrazine. The solvent-free reac-
tion of 1b with 2a performed at 90 °C for 3 h afforded about
50% yield to 3a (Table 1, entry 2) along with unidentified
byproducts. Similar results were obtained when the same reac-
tion was performed in the presence of THF, resulting in low con-
version (ꢂ57%) even under reflux conditions (Table 1, entry 3).
The low selectivity and low conversion in the two reactions
might be due to the presence of water in 1b. Solid hydrazine
1a clearly showed better conversion and higher selectivity than
1b for the formation of 3a. This remarkable reactivity is presum-
ably ascribed to the facile production of anhydrous hydrazine
and evolution of CO2 gas upon reaction of 1a. To further evaluate
the solid-state reactivity of 1a, the substrate scope was extended
OR'
R
R'O
R
H
O
N
O
H
H
O
N+
O
N
N
O-
- CO2, - 2H2O
OR'
R
H
Azine
1a
O
O
R
R''
R'
O
R''
OH
- CO2
R
H
- 2H2O
R'
O
N
N
R''
- CO2
- 2H2O
R
R'
H
N
Pyrazole
N
R
O
R'
R''
Pyridazinone
to other
a-keto compounds. Under similar reaction conditions,
a
-keto esters containing phenyl (2b) and methyl (2c) substitu-
Scheme 1. Formation of azines, pyrazoles, and pyridazinones via reactions of 1a
with di-carbonyl compounds in the absence of solvent.
ents resulted in the formation of the corresponding azines as
the sole products (entries 4 and 5, Table 1).
Analysis by single crystal X-ray diffraction was conducted to
confirm the solid-state structure of 3a. We obtained single crystals
of the resulting powder by slow evaporation of a CH3OH/CHCl3
(1:1) solution of 3a over a period of about 7 days. The ORTEP dia-
gram of 3a is illustrated in Figure 2, showing a (Z,Z)-configuration
with respect to the two C@N double bonds. The N1–N1 bond
length (1.398 Å) of 3a is shorter than that of 1a (1.438 Å),9a but is
similar to those of other azine compounds.11 The distance between
C5 and N1 is 1.281 Å and the bond has a double bond character,
which is similar to the C@N double bonds.9b,11 The C8–O1 bond
length is 1.305 Å, which is close to the single C–O bond distance
(1.315 Å). Details of the crystal structure of 3a including bond
lengths and angles are given in Tables S1–S3.
molar ratio of 1:2 was ground using a mortar and pestle at room
temperature and then allowed to react in a vial. The reaction of
1a with 2a proceeded smoothly in the solid state to yield
(2Z,20Z)-2,20-(hydrazine-1,2-diylidene)bis(2-phenylacetic
acid)
(3a). Although the solid-state reaction proceeded even at 25 °C,
an increased temperature was needed for the reaction to reach
completion in a few hours. Complete conversion to 3a was
achieved at 90 °C within 3 h (see Table 1, entry 1). The product
was obtained as pure, single phase as judged by both powder X-
ray diffraction (XRD) and 1H NMR spectroscopy. The solid-state
reactivity of 1a toward 2a was strongly dependent on the reaction
Table 1
Reactions of solid hydrazine (1a) and liquid hydrazine (1b) with a
-keto derivativesa
Entry
Reactant (mp, °C)
Hydrazine
Product (mp, °C)
Time (h)
Temp (°C)
Yieldb (%)
Remark
O
OH
O
N
N
OH
O
1
1a
3
90
>96
Grinding
HO
O
2a (66)
3a (157-158)
2
3
2a
2a
1b
1b
3a
3a
3
3
90
Reflux
50c (unknown ꢂ50)
53d (unknown ꢂ4.5)
Neat (no grinding)
THF
O
N
O
O
N
O
O
4
5
1a
1a
0.5
0.5
70
70
97
97
Neat (no grinding)
Neat (no grinding)
O
O
O
e
2b
(-)
3b (138-140)
O
O
O
O
N
N
O
O
2c (-)e
(196)
3c
a
b
c
Hydrazinium carboxylate 1a (5.2 mmol);
Isolated yield based on di-carbonyl compounds.
a-keto acid 2 (10.0 mmol).
Not isolated, unknown compound(s): ꢂ50% at 100% conversion based on 1H NMR (see Fig. S3 in Supplementary data).
Not isolated, unknown compound(s): ꢂ8% at 57% conversion based on 1H NMR (see Fig. S4 in Supplementary data).
Liquid at 25 °C.
d
e

1386
B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388
than 97% conversion to 3,4,5-trimethyl-1H-pyrazole (5a). The
solvent-free reaction was accomplished at 70 °C within 2 h without
producing any byproducts other than CO2 and water (Table 2, entry
1). When hydrazine hydrate (1b) was used as the source of hydra-
zine, however, the same reaction produced 5a in 77% yield along
with unidentified byproducts (Table 2, entry 2). Unknown byprod-
ucts were also obtained when the same reaction was performed in
the presence of THF (Table 2, entry 3). To confirm the reactivity of
1a toward other b-keto derivatives, a range of b-keto compounds
were treated with 1a in the absence of solvent or in the solid state
(Table 2, entries 4–7). All the reactions gave over 97% conversions
to the corresponding pyrazoles. It is evident that solid hydrazine 1a
proved to be the most effective reagent for the synthesis of
pyrazoles.
It is worth mentioning that pyrazole motifs are essential com-
ponents of many agrochemicals and pharmaceuticals.12–14 They
are typically synthesized by the condensation of 1,3-diketones
with hydrazine derivatives in the presence of solvents and
acid.5,11–13 However, the solvent-based reactions afford moderate
yields of pyrazoles along with unknown byproducts. Thus, separa-
tion and purification steps are necessary to obtain the pure prod-
ucts. The additional processes lead to a substantial decrease in
the yields of the pyrazole products and are environmentally haz-
ardous processes. In contrast, our method based on solid hydrazine
1a gave pyrazoles as the sole products with excellent yields, and
the method is found to be an effective and environmentally benign
process.
The scope of the reaction of 1a was further investigated using
c-keto acids as di-carbonyl substrates. Grinding c-keto acids
with one molar equivalent of 1a led to the formation of pyridaz-
inones in the solid state, even at 25 °C. A long reaction time or
high reaction temperature was necessary for the reactions to
reach completion. Almost complete conversions were accom-
plished at 90 °C within 3 h and the reactions gave excellent
yields (Table 3, entries 1–5). Clearly, our solvent-free reaction
based on solid hydrazine constitutes a simple one-pot alternative
to existing complicated methodologies15,16 for the preparation of
pyridazinones.
In summary, solid hydrazine played a major role in the devel-
opment of the environmentally benign methodology described
herein, and it reacted efficiently with a range of di-carbonyl
compounds under solvent-free conditions. The resulting prod-
ucts, including azines, pyrazoles, and pyridazinones, which are
not readily synthesized by conventional solvent-based reactions
were obtained in high yields with excellent selectivities. In par-
ticular, pyrazoles are not easily synthesized using the solution-
phase methodology. Moreover, the reactions proceeded without
the need for any additives such as catalysts and did not produce
any toxic waste. These advantages make this simple methodol-
ogy based on solid hydrazine attractive for industrial applica-
tions and provide the opportunity to synthesize a wide range
of organic materials with excellent selectivity in a much greener
way.
Figure 1. (a) Powder XRD patterns of the products synthesized in solid-state
reactions of 1a and 2a at 50 °C at intervals of 3, 6, 12, and 24 h. The vertical bars at
the bottom of the XRD patterns correspond to the theoretical diffraction peaks of
3a. (b) Yields of 3a as
spectroscopy.
a
function of reaction time determined by 1H NMR
Experimental section
Instrumentation
Figure 2. ORTEP plot of 3a at the 30% probability level of the thermal ellipsoids.
Selected bond lengths (Å): O1–C8 1.305(1), O2–C8 1.211(1), N1–C5 1.281(1), N1–
N1i 1.398(2), and C5–C8 1.516(1). Selected bond angles (°): C5–N1–N1i 111.5(1),
N1–C5–C4 120.50(9), and N1–C5–C8 120.50(9). Red, pale blue, and gray ellipsoids
represent O, N, and C atoms, respectively. Small open circles represent H atoms.
A Thermo Scientific Nicolet 205 spectrometer was used to
measure infrared spectra. Absorption spectra were recorded on
an Agilent 8453 UV–visible spectrophotometer. Melting points
were measured with a Barnstead IA9100 Digital Melting Point
Apparatus. GC/MS data were recorded on an Agilent 5973 N
The reactivity of 1a was further explored using b-keto deriva-
tives as di-carbonyl substrates. The reaction of 3-methylpentane-
2,4-dione (4a) with 1a in the absence of solvent afforded greater
and elemental analyses were conducted using
EA1180 at the Organic Chemistry Research Center at Sogang
a Carlo Erba

B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388
1387
Table 2
Reactions of solid hydrazine (1a) and liquid hydrazine (1b) with b-keto derivativesa
Entry
Reactant (mp, °C)
Hydrazine
Product (mp, °C)
Time (h)
Temp (°C)
Yieldb (%)
Remark
O
O
H
N
N
1
1a
2
70
96
Neat (no grinding)
c
4a
(-)
5a
(130-131)
2
3
4a (—)c
4a (—)c
O
1b
1b
5a
5a
H
2
2
70
Reflux
77d (unknown ꢂ23%)
90d (unknown ꢂ10%)
Neat (no grinding)
THF
O
N
N
4
5
1a
1a
0.3
1
70
70
99
Neat (no grinding)
Neat (no grinding)
4b (-)c
5b
(107-108)
O
O
H
N
N
97
c
4c
(-)
5c (-)c
O
O
O
H
N
N
6
7
1a
1a
3
5
90
90
98
98
Grinding
Grinding
4d
(57)
5d (121-122)
O
H
N
N
4e (78)
5e (202-203)
a
b
c
Solid hydrazine (1a, 5.2 mmol); b-diketone 5 (5.0 mmol).
Isolated yield based on di-carbonyl compounds.
Liquid at 25 °C.
d
Not isolated, based on 1H NMR (see Figs. S14 and S15 in Supplementary data).
University. High resolution mass spectra were recorded on a
4.7 Tesla Ion Spec ESI-TOFMS and a JEOL (JMS-700). The 1H
NMR and 13C NMR spectra were recorded in solution on a Varian
hours. Water and CO2 were produced during the reaction. Note:
a 1:1 molar ratio was used for the reactions of b-diketones
(5.0 mmol) or
c-keto acids (5.0 mmol) with 1a (5.2 mmol). All
l
400-MHz Gemini operating at 400 MHz for H and 100 MHz for
products were initially characterized by 1H and 13C NMR spec-
troscopy. Both yields and selectivities were determined by 1H
NMR spectroscopy.
l3C. Some NMR spectra were also recorded on a Varian UNITY
l
INOVA 500 at 500 MHz for H and 125 MHz for l3C. All chemical
shifts were referenced to tetramethylsilane. Single crystal X-ray
diffraction data were collected using a Bruker SMART AXS dif-
Acknowledgments
fractometer equipped with a monochromator with a Mo K
a
(k = 0.71073 Å) incident beam.
N.H.H. thanks the Korea CCS R&D centre grant (20120008890)
and the Converging Research Centre Program (2012K001486)
funded by the Ministry of Education, Science, and Technology
through the National Research Foundation of Korea. W.K.L.
acknowledges the financial support (NRF-2010-0005538 and
NRF-2009-0081956) funded by the Ministry of Education, Science,
and Technology through the National Research Foundation of
General procedure
Both solid and liquid compounds were used as di-carbonyl
substrates. Typical procedures are as follows. For solid substrate,
a mixture of solid
a-keto acid (10.0 mmol, entry 1 in Table 1)
Korea.
B.L.
thanks
the
Research
Fellow
Program
and 1a (5.2 mmol) was ground using a pestle and a mortar.
Although the solid-state reaction proceeded at 25 °C without
any agitation, heating was necessary to achieve complete con-
version within a few hours. Therefore, the ground powder was
placed in a vial and heated in an oil bath. The reaction temper-
ature was adjusted depending on the nature of the di-carbonyl
compound. For liquid substrate, a 5.2 mmol of 1a was added to
(2012R1A12043256) funded by the Ministry of Education, Science,
and Technology through the National Research Foundation of
Korea.
Supplementary data
a neat solution of
The neat reaction also proceeded smoothly at 25 °C but heating
was necessary to achieve complete conversion within a few
a-keto acid (10.0 mmol, entry 2 in Table 1).
Supplementary data (X-ray crystallographic data and NMR
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.12.106.

1388
B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388
Table 3
Solid state reactions of solid hydrazine (1a) with
c
-keto derivativesa
Product (mp, °C)
Entry
Reactant (mp, °C)
Time (h)
1.5
Temp (°C)
Yieldb (%)
98
Remark
O
N
NH
OH
1
90
Grinding
O
O 6a
O
7a
(103)
(30-33)
O
O
N
HO
NH
HO
OH
2
3
3
3
90
90
99
97
Grinding
Grinding
O
O
6b (116)
7b (196)
O
N
NH
OH
O
6c (O118)
7c (226)
O
O
O
OH
4
5
3
3
90
90
98
98
Grinding
Grinding
N
O
N
O
H
6d
(149)
7d
(150-151)
O
O
OHO
N NH
7e
(241-243)
6e
(128)
a
Hydrazinium carboxylate 1a (5.2 mmol),
Isolated yield based on di-carbonyl compounds.
c
-keto acid 6 (5.0 mmol).
b
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