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Tetrahedron Letters 54 (2013) 1384–1388
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier .com/ locate / tet let
Solid-state and solvent-free synthesis of azines, pyrazoles, and
pyridazinonesusing 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 Koreab
Department of Emerging Materials Science, DGIST, Daegu 711-873,
Republic of Koreac 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
Article history:Received 20 November 2012Revised 24 December
2012Accepted 26 December 2012Available online 5 January 2013
Keywords:Solid state
reactionAzinesPyrazolesPyridazinonesSolvent-free conditions
0040-4039/$ - see front matter � 2012 Elsevier Ltd.
Ahttp://dx.doi.org/10.1016/j.tetlet.2012.12.106
⇑ Corresponding authors.E-mail addresses: [email protected]
(W.K
(N.H. Hur).
a b s t r a c t
Azines, pyrazoles, and pyridazinones were isolated as the sole
products in high yields (>97%) by grindingsolid hydrazine
(H3N+NHCO2�) 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 thanwater and carbon dioxide. They are operationally easy,
environmentally safe, and readily scalable, allow-ing for highly
selective synthesis of compounds containing the hydrazine
motif.
� 2012 Elsevier Ltd. All rights reserved.
Organic reactions are typically carried out in the presence
ofsolvent. Therefore, isolation of the pure products requires
separa-tion and purification steps, which result in a substantial
decreasein yield and can be environmentally hazardous processes. In
sol-vent-based reactions, the weight ratio of waste to product,
whichis known as the E factor,1,2 is inevitably high. A simple and
efficientway 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
organicreaction, they have several advantages that include high
reactionrate, cost savings, considerable process reduction, and
minimal im-pact on the environment.3–5
Thus far, numerous efforts have been directed toward
thedevelopment of novel solvent-free or solid-state reaction forthe
synthesis of a wide range of organic materials in highyields.3–9
Wang and Qin reported the synthesis of pyrazolederivatives by
solvent-free reactions of diketones with hydrazinehydrate.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 ambientconditions in the absence
of solvent.7 Kaupp and Schmeyers dis-covered the solid-state
reactivity of hydrazine–hydroquinone
ll rights reserved.
. Lee), [email protected]
complex toward carbonyl compounds and also investigated
thereaction mechanism on the solid surface by atomic
forcemicroscopy.8
Thus far, numerous green strategies have been developed
aspotential solutions to alleviate the problems associated
withsolvent-based reactions, suggesting that highly reactive and
stablemolecular precursors are necessary to make the routes
syntheti-cally efficient and environmentally benign.
We have recently isolated a hydrazinium carboxylate(H3N+NHCO2�,
1a) as a crystalline powder by reacting aqueoushydrazine 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 effectivefor the synthesis of other
compounds containing the hydrazinemotif through an efficient and
green route. Herein, we report so-lid-state and solvent-free
reactions between 1a and di-carbonylcompounds including a-, b-, and
c-keto derivatives. The reac-tions afford azines, pyrazoles, and
pyridazinones in high yieldswith 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 toxicwaste.
We initially focused on the solid-state reactivity of 1a
towarda-keto acid. A mixture of 1a and benzoylformic acid (2a) with
a
http://dx.doi.org/10.1016/j.tetlet.2012.12.106mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.tetlet.2012.12.106http://www.sciencedirect.com/science/journal/00404039http://www.elsevier.com/locate/tetlet
-
HN+
N O-
HH O R
OR'O
O
- CO2, - 2H2O
R
N
N
R
O
OR'
O
R'O
NN
RR'
R''
1a
- CO2- 2H2O
ROH
O
OR'
R''
R R''
O O
R'
- CO2- 2H2O
NNOR
R' R''
HAzine
Pyrazole
Pyridazinone
H
H
Scheme 1. Formation of azines, pyrazoles, and pyridazinones via
reactions of 1awith di-carbonyl compounds in the absence of
solvent.
B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388 1385
molar ratio of 1:2 was ground using a mortar and pestle at
roomtemperature and then allowed to react in a vial. The reaction
of1a 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
reachcompletion in a few hours. Complete conversion to 3a
wasachieved at 90 �C within 3 h (see Table 1, entry 1). The
productwas obtained as pure, single phase as judged by both powder
X-ray diffraction (XRD) and 1H NMR spectroscopy. The
solid-statereactivity of 1a toward 2a was strongly dependent on the
reaction
Table 1Reactions of solid hydrazine (1a) and liquid hydrazine
(1b) with a-keto derivativesa
Entry Reactant (mp, �C) Hydrazine Product (mp, �C)
1 O
OH
O
2a (66)
1a
NN
OHO
O OH
3a (157-158)2 2a 1b 3a3 2a 1b 3a
4 O
O
O
2b (-)e
1a
NN
OO
O O
3b (138-140)
5
O
O
O
2c (-)e
1a
O
O
NN
O
O
3c (196)
a Hydrazinium carboxylate 1a (5.2 mmol); a-keto acid 2 (10.0
mmol).b Isolated yield based on di-carbonyl compounds.c Not
isolated, unknown compound(s): �50% at 100% conversion based on 1H
NMR (sd Not isolated, unknown compound(s): �8% at 57% conversion
based on 1H NMR (seee Liquid at 25 �C.
temperature. At 50 �C, the reaction took longer and was
completein 24 h. The products of the reaction after 3, 6, 12, and
24 h werecharacterized 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.
Nobyproducts were detected by XRD or 1H NMR spectroscopy.
In contrast to the excellent reactivity of 1a with 2a,
inferiorresults were obtained when hydrazine hydrate
(H2NNH2�H2O,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 about50% yield to 3a (Table 1, entry 2) along with
unidentifiedbyproducts. Similar results were obtained when the same
reac-tion was performed in the presence of THF, resulting in low
con-version (�57%) even under reflux conditions (Table 1, entry
3).The low selectivity and low conversion in the two reactionsmight
be due to the presence of water in 1b. Solid hydrazine1a clearly
showed better conversion and higher selectivity than1b for the
formation of 3a. This remarkable reactivity is presum-ably ascribed
to the facile production of anhydrous hydrazineand evolution of CO2
gas upon reaction of 1a. To further evaluatethe solid-state
reactivity of 1a, the substrate scope was extendedto other a-keto
compounds. Under similar reaction conditions,a-keto esters
containing phenyl (2b) and methyl (2c) substitu-ents resulted in
the formation of the corresponding azines asthe sole products
(entries 4 and 5, Table 1).
Analysis by single crystal X-ray diffraction was conducted
toconfirm the solid-state structure of 3a. We obtained single
crystalsof 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)-configurationwith respect to the two C@N double bonds. The
N1–N1 bondlength (1.398 Å) of 3a is shorter than that of 1a (1.438
Å),9a but issimilar to those of other azine compounds.11 The
distance betweenC5 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
bondlength 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
bondlengths and angles are given in Tables S1–S3.
Time (h) Temp (�C) Yieldb (%) Remark
3 90 >96 Grinding
3 90 50c (unknown �50) Neat (no grinding)3 Reflux 53d (unknown
�4.5) THF
0.5 70 97 Neat (no grinding)
0.5 70 97 Neat (no grinding)
ee Fig. S3 in Supplementary data).Fig. S4 in Supplementary
data).
-
Figure 1. (a) Powder XRD patterns of the products synthesized in
solid-statereactions of 1a and 2a at 50 �C at intervals of 3, 6,
12, and 24 h. The vertical bars atthe bottom of the XRD patterns
correspond to the theoretical diffraction peaks of3a. (b) Yields of
3a as a function of reaction time determined by 1H
NMRspectroscopy.
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
ellipsoidsrepresent O, N, and C atoms, respectively. Small open
circles represent H atoms.
1386 B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388
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
than 97% conversion to 3,4,5-trimethyl-1H-pyrazole (5a).
Thesolvent-free reaction was accomplished at 70 �C within 2 h
withoutproducing any byproducts other than CO2 and water (Table 2,
entry1). When hydrazine hydrate (1b) was used as the source of
hydra-zine, however, the same reaction produced 5a in 77% yield
alongwith unidentified byproducts (Table 2, entry 2). Unknown
byprod-ucts were also obtained when the same reaction was performed
inthe presence of THF (Table 2, entry 3). To confirm the reactivity
of1a toward other b-keto derivatives, a range of b-keto
compoundswere treated with 1a in the absence of solvent or in the
solid state(Table 2, entries 4–7). All the reactions gave over 97%
conversionsto the corresponding pyrazoles. It is evident that solid
hydrazine 1aproved to be the most effective reagent for the
synthesis ofpyrazoles.
It is worth mentioning that pyrazole motifs are essential
com-ponents of many agrochemicals and pharmaceuticals.12–14 Theyare
typically synthesized by the condensation of 1,3-diketoneswith
hydrazine derivatives in the presence of solvents andacid.5,11–13
However, the solvent-based reactions afford moderateyields 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 inthe yields of
the pyrazole products and are environmentally haz-ardous processes.
In contrast, our method based on solid hydrazine1a gave pyrazoles
as the sole products with excellent yields, andthe method is found
to be an effective and environmentally benignprocess.
The scope of the reaction of 1a was further investigated
usingc-keto acids as di-carbonyl substrates. Grinding c-keto
acidswith one molar equivalent of 1a led to the formation of
pyridaz-inones in the solid state, even at 25 �C. A long reaction
time orhigh reaction temperature was necessary for the reactions
toreach completion. Almost complete conversions were accom-plished
at 90 �C within 3 h and the reactions gave excellentyields (Table
3, entries 1–5). Clearly, our solvent-free reactionbased on solid
hydrazine constitutes a simple one-pot alternativeto existing
complicated methodologies15,16 for the preparation
ofpyridazinones.
In summary, solid hydrazine played a major role in the
devel-opment of the environmentally benign methodology
describedherein, and it reacted efficiently with a range of
di-carbonylcompounds under solvent-free conditions. The resulting
prod-ucts, including azines, pyrazoles, and pyridazinones, which
arenot readily synthesized by conventional solvent-based
reactionswere obtained in high yields with excellent selectivities.
In par-ticular, pyrazoles are not easily synthesized using the
solution-phase methodology. Moreover, the reactions proceeded
withoutthe need for any additives such as catalysts and did not
produceany 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
rangeof organic materials with excellent selectivity in a much
greenerway.
Experimental section
Instrumentation
A Thermo Scientific Nicolet 205 spectrometer was used tomeasure
infrared spectra. Absorption spectra were recorded onan Agilent
8453 UV–visible spectrophotometer. Melting pointswere measured with
a Barnstead IA9100 Digital Melting PointApparatus. GC/MS data were
recorded on an Agilent 5973 Nand elemental analyses were conducted
using a Carlo ErbaEA1180 at the Organic Chemistry Research Center
at Sogang
-
Table 2Reactions 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
1
OO
4a (-)c1a
NHN
5a (130-131)
2 70 96 Neat (no grinding)
2 4a (—)c 1b 5a 2 70 77d (unknown �23%) Neat (no grinding)3 4a
(—)c 1b 5a 2 Reflux 90d (unknown �10%) THF
4
OO
4b (-)c1a
NHN
5b (107-108)
0.3 70 99 Neat (no grinding)
5
OO
4c (-)c1a
NHN
5c (-)c
1 70 97 Neat (no grinding)
6
OO
4d (57)
1a
NHN
5d (121-122)
3 90 98 Grinding
7
O O
4e (78)
1a
NHN
5e (202-203)
5 90 98 Grinding
a Solid hydrazine (1a, 5.2 mmol); b-diketone 5 (5.0 mmol).b
Isolated yield based on di-carbonyl compounds.c Liquid at 25 �C.d
Not isolated, based on 1H NMR (see Figs. S14 and S15 in
Supplementary data).
B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388 1387
University. High resolution mass spectra were recorded on a4.7
Tesla Ion Spec ESI-TOFMS and a JEOL (JMS-700). The 1HNMR and 13C
NMR spectra were recorded in solution on a Varian400-MHz Gemini
operating at 400 MHz for lH and 100 MHz forl3C. Some NMR spectra
were also recorded on a Varian UNITYINOVA 500 at 500 MHz for lH and
125 MHz for l3C. All chemicalshifts were referenced to
tetramethylsilane. Single crystal X-raydiffraction data were
collected using a Bruker SMART AXS dif-fractometer equipped with a
monochromator with a Mo Ka(k = 0.71073 Å) incident beam.
General procedure
Both solid and liquid compounds were used as
di-carbonylsubstrates. Typical procedures are as follows. For solid
substrate,a mixture of solid a-keto acid (10.0 mmol, entry 1 in
Table 1)and 1a (5.2 mmol) was ground using a pestle and a
mortar.Although the solid-state reaction proceeded at 25 �C
withoutany agitation, heating was necessary to achieve complete
con-version within a few hours. Therefore, the ground powder
wasplaced in a vial and heated in an oil bath. The reaction
temper-ature was adjusted depending on the nature of the
di-carbonylcompound. For liquid substrate, a 5.2 mmol of 1a was
added toa neat solution of a-keto acid (10.0 mmol, entry 2 in Table
1).The neat reaction also proceeded smoothly at 25 �C but
heatingwas necessary to achieve complete conversion within a
few
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). Allproducts were
initially characterized by 1H and 13C NMR spec-troscopy. Both
yields and selectivities were determined by 1HNMR spectroscopy.
Acknowledgments
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
Technologythrough the National Research Foundation of Korea.
W.K.L.acknowledges the financial support (NRF-2010-0005538
andNRF-2009-0081956) funded by the Ministry of Education,
Science,and Technology through the National Research Foundation
ofKorea. B.L. thanks the Research Fellow Program(2012R1A12043256)
funded by the Ministry of Education, Science,and Technology through
the National Research Foundation ofKorea.
Supplementary data
Supplementary data (X-ray crystallographic data and NMRdata)
associated with this article can be found, in the online ver-sion,
at http://dx.doi.org/10.1016/j.tetlet.2012.12.106.
http://dx.doi.org/10.1016/j.tetlet.2012.12.106
-
Table 3Solid state reactions of solid hydrazine (1a) with c-keto
derivativesa
Entry Reactant (mp, �C) Product (mp, �C) Time (h) Temp (�C)
Yieldb (%) Remark
1
6a (30-33)O
OH
ONH
N
O
7a (103)
1.5 90 98 Grinding
2HO
OOH
OO
6b (116)
NHN
HO
O
O
7b (196)
3 90 99 Grinding
3
O
OH
O
6c (118)
NH
N
O
7c (226)
3 90 97 Grinding
4
O
OOH
O
6d (149)
O
NNH
O
7d (150-151)
3 90 98 Grinding
5OHO
O
6e (128)
N NHO
7e (241-243)
3 90 98 Grinding
a Hydrazinium carboxylate 1a (5.2 mmol), c-keto acid 6 (5.0
mmol).b Isolated yield based on di-carbonyl compounds.
1388 B. Lee et al. / Tetrahedron Letters 54 (2013) 1384–1388
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Solid-state and solvent-free synthesis of azines, pyrazoles, and
pyridazinones using solid hydrazineExperimental
sectionInstrumentationGeneral procedure
AcknowledgmentsSupplementary dataReferences and notes