E-Book, Englisch, 500 Seiten, ePub
E-Book, Englisch, 500 Seiten, ePub
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12.1.5 Pyrazoles (Update 2017)
A. C. Götzinger and T. J. J. Müller General Introduction
Pyrazole chemistry has developed rapidly since the publication of the last review of pyrazoles in Science of Synthesis (Section 12.1), which covers literature up to around the beginning of this millennium. Since then, more than 600 papers have been published relating to the synthesis and properties of pyrazole derivatives. Improvements have been made in regioselective synthesis, which constitutes a problem to be solved, especially with the most frequent disconnection, which is the formation of two N—C bonds between 1,3-dicarbonyl compounds or their analogues and hydrazine derivatives. The regioselectivity depends strongly on the substituents on the hydrazine as well as on the three-carbon fragment and can be improved by the choice of reaction conditions.[1] Other than that, milder reaction conditions, a larger scope, and a number of new disconnections have been made possible. Several review articles have been published in the meantime, focusing on advances in synthesis,[2] regioselectivity,[1] pharmacological and technical applications,[3] and biological activities.[4] Although extensive research on pyrazoles as ligands in coordination chemistry has also been reported,[5] this will not be covered in the context of this survey. Metal complexes are only included as intermediates and can be found in the respective sections. This chapter focuses on the synthesis of aromatic 1H-pyrazoles whereas the other possible tautomers are only of synthetic interest as intermediates in ring-closure reactions. Fused pyrazole-containing ring systems are not touched upon. For information on 1H- and 2H-indazoles see Section 12.2. The numbering of the pyrazole core is shown in ? Scheme 1. Scheme 1 Numbering of the Pyrazole Core The structure of this review is modeled on that of the original section. The aforementioned newly developed disconnections, however, made it necessary to include additional chapters. The development of multicomponent reactions has led to a huge increase in publications on ring closure by formation of several bonds in a single reaction, which led to new sections on the formation of one N—N and two N—C bonds (? Section 12.1.5.1.7), one C—C and two N—C bonds (? Section 12.1.5.1.8), one C—C, one N—N, one N—C bond (? Section 12.1.5.1.9), and the formation of four new bonds, namely two N—C and two C—C bonds (? Section 12.1.5.1.12). The current disconnection strategies available for pyrazole synthesis by ring closure are shown in ? Scheme 2. Scheme 2 Current Disconnection Strategies Available for Pyrazole Synthesis by Ring Closure In the section on ring transformations, most progress has been made in the field of cross-coupling reactions of pyrazole derivatives. The section on cross-coupling reactions (? Section 12.1.5.4.4) covers the reaction of metalated pyrazole derivatives as well as reactions with metalated coupling partners, including the introduction of substituents by C—H activation. Although this review cannot be exhaustive, we have tried to present a clear overview of the developments in the synthesis of pyrazoles over the last 15 years and we hope this will be a help and inspiration for researchers in the field. 12.1.5.1 Synthesis by Ring-Closure Reactions
12.1.5.1.1 By Formation of One N—C and Two C—C Bonds
12.1.5.1.1.1 Fragments N—N—C, C, and C 12.1.5.1.1.1.1 Method 1: One-Pot Synthesis of Phosphonyl- and Sulfonylpyrazoles from Aldehydes and a Bestmann–Ohira Reagent The Bestmann–Ohira reagent diethyl (1-diazo-2-oxopropyl) phosphonate can play a double role in a one-pot reaction with aldehydes, first converting them into the respective terminal alkynes 1 and then functioning as an N—N—C fragment for a subsequent cycloaddition reaction to give 3-phosphonylpyrazoles 2 (? Scheme 3). When the Bestmann–Ohira reagent is employed only in the first step and a diazomethyl sulfone in the second, 3-sulfonylpyrazoles are obtained instead.[6] Scheme 3 Synthesis of Phosphonylpyrazoles from Aldehydes and a Bestmann–Ohira Reagent[6] R1 Time (h) Yield (%) Ref 4-O2NC6H4 6 81 [6] 4-F3CC6H4 26 75 [6] 4-FC6H4 24 70 [6] 3-BrC6H4 24 68 [6] 1-naphthyl 29 58 [6] 28 71 [6] 3,4-(MeO)2C6H3 36 55 [6] 2-furyl 28 60 [6] 2-thienyl 26 62 [6] 3-thienyl 32 66 [6] Diethyl [5-(4-Nitrophenyl)-1H-pyrazol-3-yl]phosphonate (2,R1 =4-O2NC6H4); Typical Procedure:[6] To a stirred soln of 4-nitrobenzaldehyde (76 mg, 0.50 mmol) and diethyl (1-diazo-2-oxopropyl) phosphonate (275 mg, 1.25 mmol) in anhyd EtOH (10 mL) was added Cs2CO3 (480 mg, 1.5 mmol) at 0 °C, and the resulting mixture was stirred until complete consumption of the aldehyde was observed (monitored by TLC). To the mixture containing the alkyne 1 (R1 =4-O2NC6H4) were then added CuI (19 mg, 0.10 mmol), diethyl (1-diazo-2-oxopropyl) phosphonate (165 mg, 0.75 mmol), and KOH (56 mg, 1.0 mmol) and stirring was continued until all the alkyne had been consumed (monitored by TLC). The mixture was concentrated under reduced pressure and the crude residue was directly subjected to column chromatography (silica gel, hexane/EtOAc 3:7) to afford the pure product; yield: 81%. 12.1.5.1.1.1.2 Method 2: Synthesis from Aldehydes, 1,3-Dicarbonyls or Analogues, and Diazo Compounds Aldehydes react with dicarbonyl compounds in a solvent-free, piperidinium acetate catalyzed Knoevenagel condensation toward the respective 2-alkylidene-1,3-dicarbonyl compounds. These are reacted with diazoacetates or tosylhydrazones in a one-pot fashion to give trisubstituted pyrazole derivatives.[7] Phosphonylpyrazoles 3 can also be prepared in good to excellent yields in a three-component reaction (? Scheme 4). In this case, aldehydes react with cyanoacetic acid derivatives instead of dicarbonyls and the Bestmann–Ohira reagent dimethyl (1-diazo-2-oxopropyl) phosphonate as diazo compound. The reaction proceeds without a catalyst under mild conditions.[8] Scheme 4 One-Pot, Three-Component Synthesis of Phosphonylpyrazoles[8] R1 R2 Yield (%) Ref 4-BrC6H4 CN 95 [8] 4-BrC6H4 CO2Me 83 [8] Ph CN 91 [8] Ph CO2Me 68 [8] Ph CONH2 73 [8] Ph CONHBn 75 [8] 4-HOC6H4 CN 85 [8] 4-MeOC6H4 CN 92 [8] 2-O2NC6H4 CN 91 [8] 4-O2NC6H4 CN 90 [8] 2,4-Cl2C6H3 CN 87 [8] pyren-1-yl CN 82 [8] 2-(HO)2BC6H4 CN 79 [8] Fc CN 78 [8] 2-thienyl CN 88 [8] 2-thienyl CONH2 85 [8] cycloundecyl CN 78 [8] (E)-CH-CH(CH2)4Me CN 85 [8] CO2Me 78 [8] 5-Phosphonylpyrazoles 3; General Procedure:[8] To a stirred soln of an aldehyde (1.0 mmol), a cyanoacetic acid derivative (1.2 mmol), and dimethyl (1-diazo-2-oxopropyl) phosphonate (1.5 mmol) in distilled MeOH (4 mL) was added molecular sieves, followed by the addition of powdered KOH...
