Chemistry of Heterocyclic Compounds

INDEX

LIST OF ABBREVIATIONS.

CHAPTER 1: PYRAZOLINES.
1.1. INTRODUCTION..
1.2. SYNTHESIS OF 2-PYRAZOLINES.
1.2.1. Reaction of α,b-unsaturated esters with diazoalkanes.
1.2.2. 1,3-Dipolar cycloaddition of α, b -enones and diazoalkanes.
1.2.3. Cycloaddition of nitrile imines with α, b -enones.
1.2.4. Reaction of α, b -unsaturated aldehydes and ketones with hydrazines.
1.2.5. Synthesis of 2-pyrazolines and pyrazoles via hydrohydrazination.
1.3. CONCLUSION..
REFERENCES.

CHAPTER 2: PYRIDAZINONES.
2.1. INTRODUCTION..
2.2. CHEMICAL SYNTHESES.
2.2.1. Ring closure of acyclic compounds.
2.2.2. Modification of pyridazine derivatives.
2.3. CONCLUSION..
REFERENCES.

CHAPTER 3: SULPHONYLUREAS AND THIOUREAS.
3.1.INTRODUCTION..
3.2. CHEMICAL SYNTHESES.
3.2.1. Synthesis from sulfonyl isocyanates by interaction with amines.
3.2.2. Synthesis from sulfonamides.
3.2.3. Synthesis from sulfonyl cyanamides.
3.2.4. Synthesis from sulfonyl chlorides.
3.3. CONCLUSION..
REFERENCES.

CHAPTER 4: ISOXAZOLINES.
4.1. INTRODUCTION..
4.2. CHEMICAL SYNTHESES.
4.2.1. From α, β-unsaturated ketones and hydroxylamine.
4.2.2. From β -chloroketones and hydroxylamine.
4.2.3. From isoxazoline N -oxides.
4.2.4. From quaternary salts.
4.2.5. From 1,3-dipolar cycloaddition of nitrile oxide to achiral allylic alcohol
REFERENCES.

List of Abbreviations

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CHAPTER 1: PYRAZOLINES

1.1. Introduction

Pyrazole is a p-excessive heterocycle and contains two nitrogen atoms at the position-1 and -2. Pyrazole exist in three partially reduced forms with different positions of double bond i.e. 1-Pyrazoline, 2-Pyrazoline and 3-Pyrazoline. Pyrazole ring is incorporated into many of the commercially available pharmaceuticals. Antipyrine (R=H) was the first synthetic drug, which was introduced in 1887 for the reduction of fever. Propylphenazone (R= -CH(CH3)2), ampyrone (R= NH2) and isopyrine (R= -NH-CH(CH3)2) are the other important examples which have been used as analgesics, antipyretic and anti-inflammatory agents.

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Substituted pyrazolines are important biological agents and tremendous research has been done on the ring system, owing to its ease of synthesis and pharmacological range. Various pyrazoline derivatives were found to possess important biological and pharmaceutical activities which stimulated research activity in the field of these nitrogen containing heterocyclic compounds. Some examples of their most important effects include antibacterial (Nauduri, and Reddy, 1998), antidepressant (Johnson, et al, 2007) and anticancer (Oezdemir, et al, 2007), antiinflammatory, analgesic activities.

1.2. SYNTHESIS OF 2-PYRAZOLINES

It was in the late nineteenth century that Fischer and Knovenagel described the reaction of acrolein with phenylhydrazine (Fischer and Knovenagel, 1887) to provide a pyrazoline type compound. Their experiment seems to be the first example of pyrazoline formation by the reaction of an α, b-enone with a hydrazine derivative. Later Auwers et al. (1908, 1925) corroborated that the product of this reaction was 1-phenyl-2-pyrazolines. During the last century, after these pioneering studies, numerous 2-pyrazolines were synthesized by various methods. The most important procedures developed for the preparation of 2-pyrazolines are summarized below.

1.2.1. Reaction of α,b-unsaturated esters with diazoalkanes

The diazomethane gave a pyrazoline type compound on its reaction with dimethyl fumarate (Pechmann, 1894). Later, it was corroborated (Auwers, 1929) that Pechmann correctly anticipated the mechanism of this reaction. The primary product of this 1,3-dipolar cycloaddition is 1-pyrazoline (Cpd-1), which spontaneously isomerizes into its thermodynamically more stable 2-pyrazoline isomer (Cpd-2) by a 1,3-H shift (Scheme-1).

Reaction of α,b-unsaturated carboxylic acid esters and diazomethane have been thoroughly studied by Auwers et al. (1929, 1933). The reaction of acrylic acid and b-substituted acrylic acid esters (Cpd-3) provided 4-substituted 2-pyrazoline-3-carboxylic acid esters (Cpd-4) (Scheme- 2).

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Source: Pechmann, 1894

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Source: Auwers et al.1929, 1933

2-Pyrazoline dicarboxylic acid esters have been synthesized by the reaction of unsaturated dicarboxylic acid esters with diazoalkanes (Auwers and Koinig, 1932; Jones, 1959; Anken and Rinehart, 1962). When dimethyl fumarate or maleate was allowed to react with diazoalkanes 3,4-dicarbomethyl-2-pyrazolines (Cpd-4) were obtained (Scheme-3).

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Source: Jones, 1959; Auwers and Konig, 1932

Thermal denitrogenation of the pyrazoline carboxylic acid derivatives affording cyclopropanes has also been thoroughly investigated by several research groups (Jones et al., 1963, Anken and Rinehart, 1962; Auwers and Konig, 1932). This reaction proved to be a simple and convenient procedure for the preparation of cyclopropane derivatives.

Galley et al. (1995) synthesized optically active 2-pyrazoline derivative (Cpd-6) by a stereoselective 1,3-dipolar cycloaddition of the optically active ester (Cpd-5) with diazomethane (Scheme- 4). However, this synthetic method itself is not new since the starting material can be considered to be a b-substituted acrylic acid ester, the cycloaddition of which with diazoalkanes is a well-established procedure for the synthesis of pyrazolines.

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Galley et al., 1995

Barluenga et al (1997) also synthesized the optically active 2-pyrazoline derivative (Cpd-8) (Scheme-5).

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Source: Barluenga et al 1997

1.2.2. 1,3-Dipolar cycloaddition of α,b-enones and diazoalkanes

Reaction of chalcones and related α, b -unsaturated ketones with diazomethane

Preparation of 3-acetyl-4-phenyl-2-pyrazoline (Cpd-10) by the reaction of benzylideneacetone (Cpd-9) with diazomethane (Scheme-6) is probably the first example of the synthesis of a pyrazoline from the reaction of an α, b-unsaturated ketone and diazomethane and was published by Azzarello in 1906. Later, this reaction was reinvestigated by Smith and Howard (1943) and by Raju and Rao (1989) and assumptions made by Azzarello (1906) were corroborated.

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Source: Azzarello, 1906

Also in the early twentieth century the reaction of chalcone (Cpd-11) and the ethyl diazoacetate was performed by Kohler and Steele in 1919. The obtained pyrazoline (Cpd-12) was supposed to yield a cyclopropane derivative (Cpd-13) and pyrone (Cpd-14) on thermal denitrogenation (Scheme-7).

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Source: Kohler and Steele, 1919

1,3-dipolar cycloaddition of chalcones (Cpd-11) and diazomethane was first investigated by Smith and Pings (1937) and 3-benzoyl-4-phenyl-1-pyrazoline (Cpd-15) was prepared as a primary product, which was then isomerized into the 3-benzoyl-4-phenyl-2-pyrazoline (Cpd-16) on gentle heating. Substance (Cpd-16) yielded b-methylchalcone (Cpd-17) on thermal denitrogenation, which proves that the cycloaddition of the chalcone and the diazomethane is regioselective (Scheme-8).

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Source: Smith and Pings, 1937

Reaction of variously substituted chalcones (Cpd-18) and diazomethane has been studied by Mustafa and Fleifel (1959) as well as Sayed and Kjosen (1980), but probably because of a misinterpretation of the 1H NMR spectra, formation of 5-benzoyl-4-phehyl-2-pyrazoline (Cpd-19) was misdescribed by both research groups (Scheme-9).

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Source: Sayed and Kjosen, 1980

Aleksandrova et al. (1978) prepared 4-aryl-3-(2-furyl)-2-pyrazolines (Cpd-21) by the cycloaddition of 2-furyl analogues of chalcones (Cpd-20) and diazomethane without the detection or isolation of the appropriate 1-pyrazoline isomers (Scheme-10).

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Source: Aleksandrova et al., 1978

The above examples unequivocally prove that there were several conflicting data concerning the structure of pyrazolines formed by the 1,3-dipolar cycloaddition of α,b-enones with diazomethane. The reaction of substituted chalcones and related α, b-unsaturated ketones (Cpd-22) with diazomethane were reinvestigated in order to establish unequivocally the structure of the resulting pyrazolines (Tokes et al., 1983; Levai, 1995; Levai, et al., 1996). UV, IR, 1H and 13C NMR spectroscopic investigations unambiguously proved that synthesized products were the 3-aryl-2-pyrazolines (Cpd-23) in each case (Scheme-11) (Tokes et al., 1983; Levai, 1995; Levai et al., 1996).

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Source: Tokes et al., 1983; Levai, 1995; Levai et al., 1996

The thermal denitrogenation of the pyrazolines gave Cpd-24 when unequivocally prove that the methylene part of the diazomethane attacked the b-carbon atom of the α,b-enone in the course of the cycloaddition (Scheme-11) (Levai, 1995).

The reaction of E- 2-styrylchromones (Cpd-25) were allowed to react with diazomethane in a mixture of anhydrous diethyl ether and chloroform at room temperature gave 4-aryl-3-(2-chromonyl)-2-pyrazolines (Cpd-26) were obtained as major products. A minor component was also detected and identified as 3-aryl-4-(2-chromonyl)-1-pyrazolines (T-71) on spectroscopic structure elucidation. It can be concluded from these results that the cycloaddition of the 2-styrylchromones and diazomethane is highly regioselective. The most part of the initially formed 4-aryl-3-(2-chromonyl)-1-pyrazolines spontaneously rearrange into their 2-pyrazoline isomers (Cpd-26) which was isolated as the major product of the reaction. However, 1-pyrazolines as minor components (Cpd-27) was also been isolated (Scheme-12) (Pinto et al., 1999).

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Source: Pinto et al., 1999

Reaction of exocyclic α, b -unsaturated ketones with diazoalkanes

The reaction of 2-arylidene-3-pheny-1-indanones (Cpd-28) with diazomethane performed by Mustafa and Hilmy in 1951 can be considered as the first example of pyrazoline formation by the cycloaddition of an exocyclic α,b-unsaturated ketone and a diazoalkane. However, the authors were unable to establish whether their compounds were 1-pyrazolines (Cpd-29) or 2-pyrazolines (Cpd-30) (Scheme-13).

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Sourece: Mustafa and Hilmy, 1951

1.2.3. Cycloaddition of nitrile imines with α,b-enones

The synthesis of tricyclic 2-pyrazolines by an intramolecular 1,3-dipolar cycloaddition of nitrile imines is well documented in the literature (Fusco et al., 1974; Garanti et al., 1977; Meir and Heimgartner, 1985; Padwa et al., 1978; Shimizu et al., 1984). 2,3,3a,4-Tetrahydro-2-aryl-[1]benzopyrano[4,3-c]pyrazoles (Cpd-33) have been prepared by the intramolecular 1,3-dipolar cycloaddition of nitrile imines generated either from 1-(o- allyloxyphenyl)- N -(arylhydrazidoyl)chloride (Cpd-31) on treatment with triethylamine or by the irradiation of 2-aryl-5-(o -allyloxyphenyl)tetrazole (Cpd-32) (Scheme-14) (Smith and Luade, 1978; Padwa et al., 1978; Meier and Heimgartner, 1985). Various 2,3-disubstituted 2,3,3a, 4-tetrahydro[1]benzopyrano[4,3-c]pyrazoles have also been synthesized by the utilization of nitrile imine intermediates (Shimizu et al., 1984).

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Source: Smith and Luade, 1978; Padwa et al., 1978; Meier and Heimgartner, 1985

1.2.4. Reaction of α,b-unsaturated aldehydes and ketones with hydrazines

Reaction of α, b -unsaturated aldehydes with hydrazines

In the late nineteenth century and in the first decades of the twentieth century the first reaction of α,b-enones and hydrazine derivatives have been conducted. (Auwers and Muller, 1908; Auwers and Kreuder, 1925; Raiford and Entrikin, 1933; Auwers and Voss, 1909; Auwers and Heimke, 1927). α,b-Unsaturated aldehydes (Cpd-35) afforded hydrazones (Cpd-36) on reaction with hydrazines (Cpd-34) (Scheme-15). These aldehyde hydrazones (Cpd-36) yielded 2-pyrazolines (Cpd-37) on the acid catalyzed ring closure (Scheme-15). The addition of NH moiety to the C=C double bond of hydrazones (Cpd-36) is supposed to be a rate controlling step in the formation of 2-pyrazolines (Cpd-37) (Scheme-15). Electronic structure, stereochemistry and solubility of the hydrazones may influence the ring closure reaction affording 2-pyrazolines (Cpd-37).

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Source: Auwers and Muller, 1908

Reaction of chalcones and related α, b -unsaturated ketones with hydrazines

The reaction of chalcones and related α,b-unsaturated ketones (Cpd-38) with hydrazines (Cpd-34) is probably the most popular procedure for the synthesis of 2-pyrazolines (Cpd-39) (Scheme-16). This reaction can be conducted under various conditions.

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Source: Raiford and Entrikin, 1933

The most commonly used method is the reaction of compounds (Cpd-34) and (Cpd-38) in acetic acid solution to prepare 2-pyrazolines (Cpd-39) in high yield (Scheme-16) (Raiford and Entrikin, 1933; Auwers and Lammerhirt, 1921; Reid and Dankert, 1957; Baroni et al., 1960; Sachchar and Singh, 1985). This method is used either with or without the isolation of the hydrazone intermediate. Another opportunity for the reaction of α,b-unsaturated ketones (Cpd-38) and hydrazines (Cpd-32) under acid catalyzed conditions is the use of hydrazine hydrochloride in hot alcoholic or dimethylformamide solution (Mishriky et al., 1996, Amir et al., 2008). Synthesis of 2-pyrazolines (Cpd-39) can also be achieved under alkaline conditions by using pyridine as catalyst in ethanolic solution (Anjaneyulu et al., 1995) or as solvent (Sammour, 1964). In some cases the two reactants were refluxed in alcoholic solution without catalyst to provide 2-pyrazolines (Cpd-39) (Habib et al., 1986; Ferres and Jackson, 1969).

2-pyrazolines (Cpd-42) were also synthesized by the reaction of chalcones (Cpd 40) with 4-hydrazinobenzenesulfonamide hydrochloride (Cpd 41) in ethanolic solution (Rathish et al., 2009) (Scheme-17).

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Source: Rathish et al., 2009

Reaction of chromanone and chromone derivatives with hydrazines

Reaction of 2-phenylchromanones (flavanones) (Cpd-43) and hydrazines has been thoroughly studied by Kallay et al. (1973) and in other laboratories (Sammour and Elkasaby, 1969; Joshi and Wadidkar, 1981). The experimental results accumulated to date prove that, among the different nitrogen containing reaction products, 2-pyrazolines (Cpd-45) may also be present depending on the choice of reaction conditions (Cpd-32). An alkaline medium has proved to be beneficial for pyrazoline formation. According to the assumption of Kallay et al. (1973), pyrazoline formation may proceed through the corresponding flavanone hydrazone (Cpd-44) or via the hydrazinolysis of the hetero-ring of the flavanones (Scheme-18). However,since 2-pyrazolines obtained in this way are identical to those synthesized by the reaction of hydrazines with 2'-hydroxychalcones, the precursor of the synthesis of the appropriate flavanones, this procedure cannot be considered as an efficient method for the preparation of 2-pyrazolines.

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Source: Kallay et al., 1973

1.2.5. Synthesis of 2-pyrazolines and pyrazoles via hydrohydrazination

An intermolecular zinc-mediated and catalyzed hydrohydrazination reaction of alkynes, allows a general synthesis of substituted indoles (Cpd-48) (Alex, et al., 2008). Following these investigations, we discovered that the reaction of phenylhydrazine (Cpd-46) with 3-butynol (Cpd-47) in the presence of a stoichiometric amount of zinc chloride did not result in the expected indole motif. Instead, the formation of the pyrazoline (Cpd-48) occurred via hydrohydrazination of the alkyne and condensation reaction (Alex, et al. , 2008) (Scheme 19).

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Source: Alex, et al. , 2008

Conclusion

Thus, it could be concluded that pyrazolines are five menbered nitrogen heterocycle containing nitrogen atoms at 1, 2- positions, which have extensively researched upon. Pyrazoline ring is very stable and inspired many researchers to carry out various strutural variations in the ring. The structure of pyrazolines, their biological properties and the different method of chemical syntheses of pyrazolines as reported by various researchers are illustrated in this chapter.

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