Tetrahedron Letters 54 (2013) 1384–1388

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Tetrahedron Letters

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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: wonkoo@sogang.ac.kr (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), nhhur@sogang.ac.kr

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:wonkoo@sogang.ac.krmailto:nhhur@sogang.ac.krhttp://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