Science of Synthesis Knowledge Updates 2017 Vol. 3 E-Book

• Herausgeber: Thieme
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 962

Veröffentlichungsjahr: 2017

Beschreibung

The Science of Synthesis Editorial Board, together with the volume editors and authors, is constantly reviewing the whole field of synthetic organic chemistry as presented in Science of Synthesis and evaluating significant developments in synthetic methodology. Several annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.

Leseprobe

Science of Synthesis

Science of Synthesis is the authoritative and comprehensive reference work for the entire field of organic and organometallic synthesis.

Science of Synthesis presents the important synthetic methods for all classes of compounds and includes:

Methods critically evaluated by leading scientists

Background information and detailed experimental procedures

Schemes and tables which illustrate the reaction scope

Preface

As the pace and breadth of research intensifies, organic synthesis is playing an increasingly central role in the discovery process within all imaginable areas of science: from pharmaceuticals, agrochemicals, and materials science to areas of biology and physics, the most impactful investigations are becoming more and more molecular. As an enabling science, synthetic organic chemistry is uniquely poised to provide access to compounds with exciting and valuable new properties. Organic molecules of extreme complexity can, given expert knowledge, be prepared with exquisite efficiency and selectivity, allowing virtually any phenomenon to be probed at levels never before imagined. With ready access to materials of remarkable structural diversity, critical studies can be conducted that reveal the intimate workings of chemical, biological, or physical processes with stunning detail.

The sheer variety of chemical structural space required for these investigations and the design elements necessary to assemble molecular targets of increasing intricacy place extraordinary demands on the individual synthetic methods used. They must be robust and provide reliably high yields on both small and large scales, have broad applicability, and exhibit high selectivity. Increasingly, synthetic approaches to organic molecules must take into account environmental sustainability. Thus, atom economy and the overall environmental impact of the transformations are taking on increased importance.

The need to provide a dependable source of information on evaluated synthetic methods in organic chemistry embracing these characteristics was first acknowledged over 100 years ago, when the highly regarded reference source Houben–Weyl Methoden der Organischen Chemie was first introduced. Recognizing the necessity to provide a modernized, comprehensive, and critical assessment of synthetic organic chemistry, in 2000 Thieme launched Science of Synthesis, Houben–Weyl Methods of Molecular Transformations. This effort, assembled by almost 1000 leading experts from both industry and academia, provides a balanced and critical analysis of the entire literature from the early 1800s until the year of publication. The accompanying online version of Science of Synthesis provides text, structure, substructure, and reaction searching capabilities by a powerful, yet easy-to-use, intuitive interface.

From 2010 onward, Science of Synthesis is being updated quarterly with high-quality content via Science of Synthesis Knowledge Updates. The goal of the Science of Synthesis Knowledge Updates is to provide a continuous review of the field of synthetic organic chemistry, with an eye toward evaluating and analyzing significant new developments in synthetic methods. A list of stringent criteria for inclusion of each synthetic transformation ensures that only the best and most reliable synthetic methods are incorporated. These efforts guarantee that Science of Synthesis will continue to be the most up-to-date electronic database available for the documentation of validated synthetic methods.

Also from 2010, Science of Synthesis includes the Science of Synthesis Reference Library, comprising volumes covering special topics of organic chemistry in a modular fashion, with six main classifications: (1) Classical, (2) Advances, (3) Transformations, (4) Applications, (5) Structures, and (6) Techniques. Titles will include Stereoselective Synthesis, Water in Organic Synthesis, and Asymmetric Organocatalysis, among others. With expertevaluated content focusing on subjects of particular current interest, the Science of Synthesis Reference Library complements the Science of Synthesis Knowledge Updates, to make Science of Synthesis the complete information source for the modern synthetic chemist.

The overarching goal of the Science of Synthesis Editorial Board is to make the suite of Science of Synthesis resources the first and foremost focal point for critically evaluated information on chemical transformations for those individuals involved in the design and construction of organic molecules.

Throughout the years, the chemical community has benefited tremendously from the outstanding contribution of hundreds of highly dedicated expert authors who have devoted their energies and intellectual capital to these projects. We thank all of these individuals for the heroic efforts they have made throughout the entire publication process to make Science of Synthesis a reference work of the highest integrity and quality.

The Editorial Board

July 2010

E. M. Carreira (Zurich, Switzerland)

C. P. Decicco (Princeton, USA)

A. Fuerstner (Muelheim, Germany)

G. Koch (Basel, Switzerland)

G. A. Molander (Philadelphia, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

M. Shibasaki (Tokyo, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Abstracts

12.1.5 Pyrazoles

A. C. Götzinger and T. J. J. Müller

This review presents an overview of the developments in pyrazole synthesis since the beginning of the 21st century. It includes the synthesis of the pyrazole core by ring-closing reactions, ring expansion or contraction, and aromatization. The introduction of substituents onto the pyrazole ring is also covered. Novel synthetic methods that have been developed since the original Science of Synthesis review on pyrazoles (Section 12.1) include various multicomponent approaches in which multiple bonds are formed, cross coupling, and C—H activation reactions of pyrazole derivatives.

Keywords: pyrazoles • nitrogen heterocycles • ring-closing reactions • condensation reactions • multicomponent reactions • ring expansion • ring contraction • aromatization • regioselectivity • 1,3-dicarbonyl compounds • hydrazines • hydrazones • diazo compounds • cross-coupling reactions • C—H activation

32.5.3.2 Enol Ethers

F. Bartels, R. Zimmer, and M. Christmann

In this chapter, recent methods for the preparation and elaboration of enol ethers are summarized. In addition to updates on classical methods, recently developed metal-catalyzed procedures are presented. The relevance of these methods is also demonstrated in the context of natural product synthesis.

Keywords: enol ethers • alkoxyallenes • metathesis • Julia alkenation • Wittig alkenation • Suzuki coupling • heterogeneous catalysis • Diels–Alder cycloaddition • cyclization

40.1.1.5.2.4 The Mannich Reaction

C. Schneider and M. Sickert

The Mannich reaction, one of the most fundamental C—C bond-forming reactions, is more than 100 years old and yet is still fascinating. This chapter is an update to the earlier Science of Synthesis contribution (Section 40.1.1.5.2) describing methods for the asymmetric synthesis of highly versatile β-amino carbonyl compounds and derivatives via Mannich reaction. This review predominantly focuses on recent developments in catalytic enantioselective and diastereoselective processes of direct, indirect, and vinylogous Mannich reactions using both metal-based catalysts as well as organocatalysts.

Keywords: asymmetric Mannich reaction • asymmetric aminoalkylation • Mannich bases • metal catalysis • organocatalysis • enamine catalysis • Brønsted acid catalysis • hydrogen-bond catalysis • N-heterocyclic carbene catalysis • phase-transfer catalysis • aldimines • ketimines • hydrazones • imine surrogates • enamines • enols • enolates • dienols • dienolates • direct Mannich reaction • indirect Mannich reaction • vinylogous Mannich reaction • Mukaiyama–Mannich reaction • C—C bond formation

Science of Synthesis Knowledge Updates 2017/3

Preface

Abstracts

Table of Contents

12.1.5 Pyrazoles (Update 2017)

A. C. Götzinger and T. J. J. Müller

32.5.3.2 Enol Ethers (Update 2017)

F. Bartels, R. Zimmer, and M. Christmann

40.1.1.5.2.4 The Mannich Reaction (Update 2017)

C. Schneider and M. Sickert

Author Index

Abbreviations

Table of Contents

Volume 12: Five-Membered Hetarenes with Two Nitrogen or Phosphorus Atoms

12.1 Product Class 1: Pyrazoles

12.1.5 Pyrazoles

A. C. Götzinger and T. J. J. Müller

12.1.5 Pyrazoles

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

12.1.5.1.1.1.2 Method 2: Synthesis from Aldehydes, 1,3-Dicarbonyls or Analogues, and Diazo Compounds

12.1.5.1.2 By Formation of Two N—C Bonds

12.1.5.1.2.1 Fragments C—C—C and N—N

12.1.5.1.2.1.1 From 1,3-Dicarbonyl Compounds (and Synthetic Equivalents) and Hydrazines

12.1.5.1.2.1.1.1 Method 1: Synthesis from Alk-2-en-1-ones with a Leaving Group in Position 3 and Hydrazines

12.1.5.1.2.1.1.1.1 Variation 1: From Haloalkenones or Sulfonylalkenones and Hydrazines

12.1.5.1.2.1.1.1.2 Variation 2: From Enaminones and Hydrazines

12.1.5.1.2.1.1.1.3 Variation 3: From α,β-Unsaturated-β-alkoxy Ketones and Hydrazines

12.1.5.1.2.1.1.1.4 Variation 4: From α,β-Unsaturated-β-(alkylsulfanyl) Ketones and Hydrazines

12.1.5.1.2.1.1.2 Method 2: Synthesis from Alk-2-en-1-ones and Hydrazines Followed by Dehydrogenation

12.1.5.1.2.1.1.3 Method 3: Synthesis from Alk-2-en-1-ones and Tosylhydrazine Followed by Elimination

12.1.5.1.2.1.1.4 Method 4: Synthesis from β,γ-Unsaturated α-Oxo Esters and Hydrazones

12.1.5.1.2.1.1.5 Method 5: Synthesis from Propargylic Aldehydes and Hydrazines

12.1.5.1.2.1.1.5.1 Variation 1: From 3-Ferrocenylpropynal

12.1.5.1.2.1.1.5.2 Variation 2: From (Het)aryl Iodides, Propynal Diethyl Acetal, and Hydrazine

12.1.5.1.2.1.1.6 Method 6: Synthesis from Alk-2-yn-1-ones and Hydrazines

12.1.5.1.2.1.1.7 Method 7: Synthesis from Dialkyl Acetylenedicarboxylates, Phenylhydrazine, and Aroyl Chlorides

12.1.5.1.2.1.1.8 Method 8: Synthesis from Alk-3-yn-1-ones and Hydrazines

12.1.5.1.2.1.1.9 Method 9: Synthesis from 1,3-Diketones and Hydrazines

12.1.5.1.2.1.1.9.1 Variation 1: From Dioxo Oximes and Hydrazine Hydrate

12.1.5.1.2.1.1.9.2 Variation 2: From 1,3-Diketones, Allyltrimethylsilanes, and Hydrazines

12.1.5.1.2.1.1.9.3 Variation 3: From 1,3-Diketones and Sulfonylhydrazines

12.1.5.1.2.1.1.9.4 Variation 4: From Acetylacetone, Adamantyl Diazirine, and Arylmetal Species

12.1.5.1.2.1.1.10 Method 10: Synthesis from 1,3-Diketones and Arylhydrazones

12.1.5.1.2.1.1.11 Method 11: Synthesis from β-Oxo Esters and Hydrazine Hydrochloride

12.1.5.1.2.1.1.12 Method 12: Synthesis from 1,3-Dicarbonyls, Aryl Halides or Arylboronic Acids, and Di-tert-butyl Azodicarboxylate

12.1.5.1.2.1.1.13 Method 13: Synthesis from β-Oxo Amides and Hydrazines in the Presence of Lawesson's Reagent

12.1.5.1.2.1.1.14 Method 14: Synthesis from β-Oxo Acylsilanes and Hydrazines

12.1.5.1.2.1.1.15 Method 15: Synthesis from 1,3-Diaryl-3-thioxopropan-1-ones or 1,3-Diaryl-3-(methylsulfanyl) prop-2-en-1-ones and Arylhydrazines

12.1.5.1.2.1.1.16 Method 16: Synthesis from β-Oxo Dithioesters or β-Oxo Thioesters and Hydrazines

12.1.5.1.2.1.1.17 Method 17: Synthesis from Sodium Acetylacetonate Hydrate, Aryl Isothiocyanates, and Hydrazine Hydrate

12.1.5.1.2.1.1.18 Method 18: Synthesis from Allenic Ketones and Hydrazines

12.1.5.1.2.1.1.19 Method 19: Synthesis from 3-Chloroenals and Hydrazines

12.1.5.1.2.1.1.19.1 Variation 1: One-Pot Synthesis from Aryl Halides, α-Bromocinnamaldehyde, and Tosylhydrazine

12.1.5.1.2.1.1.20 Method 20: Synthesis from Propargylic Alcohols and Tosylhydrazine or N-Acetyl-N-tosylhydrazine

12.1.5.1.2.1.1.21 Method 21: Synthesis from Enynes or Diynes and Hydrazine

12.1.5.1.2.1.1.22 Method 22: Synthesis from α-Cyano Ketones and Hydrazines

12.1.5.1.2.1.1.23 Method 23: Synthesis from Vinamidinium Salts and Arylhydrazines

12.1.5.1.2.1.1.24 Method 24: Synthesis from Morita–Baylis–Hillman Adducts and Hydrazines

12.1.5.1.2.1.1.25 Method 25: Synthesis from α-Cyanoalkenes Bearing a Leaving Group and Hydrazines

12.1.5.1.2.1.1.26 Method 26: Synthesis from α,β-Bis (tosyloxy) Ketones and Phenylhydrazine

12.1.5.1.2.1.1.27 Method 27: Synthesis from 2-(1,3-Dithian-2-yl) 1,3-Diketones and Hydrazine

12.1.5.1.2.1.1.28 Method 28: Synthesis from α-Epoxy Ketones and Semicarbazide or Hydrazines

12.1.5.1.2.1.1.29 Method 29: Synthesis from Ethyl 3-[(Dimethylamino) methylene]pyruvate or Diethyl 3-[(Dimethylamino) methylene]-2-oxosuccinate and Hydrazines

12.1.5.1.2.1.1.30 Method 30: Synthesis from Alk-3-en-1-ones and Phenylhydrazine

12.1.5.1.2.1.2 From Other Compounds and Hydrazine

12.1.5.1.2.1.2.1 Method 1: Synthesis from But-3-yn-1-ol and Arylhydrazines

12.1.5.1.2.1.2.2 Method 2: Synthesis from Nitroallylic Acetates and Tosylhydrazine

12.1.5.1.2.1.2.3 Method 3: Synthesis from 1-Aryl-2-tosyldiazenes and Allylic Carbonates

12.1.5.1.2.1.2.4 Method 4: Synthesis from 1,3-Diols and Hydrazines

12.1.5.1.2.1.2.5 Method 5: Synthesis from Enaminones and Arenediazonium Salts

12.1.5.1.2.1.2.6 Method 6: Synthesis from Allyl Aryl Ketones, Arenediazonium Salts, and Sodium Trifluoromethanesulfonate

12.1.5.1.3 By Formation of One N—C and One C—C Bond

12.1.5.1.3.1 Fragments N—N—C and C—C

12.1.5.1.3.1.1 Method 1: Synthesis from Diazo Compounds and Alkynes, Allenes, or Alkenes

12.1.5.1.3.1.1.1 Variation 1: From Tosylhydrazones and Alkynes

12.1.5.1.3.1.2 Method 2: Synthesis from Diazoacetates and Carbonyl Compounds

12.1.5.1.3.1.3 Method 3: Synthesis from Hydrazones and Alkenes

12.1.5.1.3.1.4 Method 4: Synthesis from Hydrazones and Alkynes

12.1.5.1.3.1.5 Method 5: Synthesis from Trichloroacetylhydrazones and β-Oxo Esters

12.1.5.1.3.1.6 Method 6: Synthesis from Hydrazones and Vicinal Diols

12.1.5.1.3.1.7 Method 7: Synthesis from Hydrazonoyl Halides and Alkynes or Alkenes with a Leaving Group

12.1.5.1.3.1.8 Method 8: Synthesis from Hydrazonoyl Halides and Carbonyl Compounds

12.1.5.1.3.1.9 Method 9: Synthesis from Enol Diazoacetates and Donor–Acceptor Substituted Hydrazones

12.1.5.1.3.1.10 Method 10: Synthesis from a Bestmann–Ohira Reagent and Alkenes or Alkynes

12.1.5.1.3.1.10.1 Variation 1: From Bestmann–Ohira Reagent and α,β-Unsaturated Aldehydes

12.1.5.1.3.1.11 Method 11: Synthesis from Ugi Adducts

12.1.5.1.3.1.12 Method 12: Synthesis from Dialkyl Azodicarboxylates and Allenic Esters

12.1.5.1.3.1.13 Method 13: Synthesis from N-Propargylhydrazones by Rearrangement

12.1.5.1.3.2 Fragments N—N—C—C and C

12.1.5.1.3.2.1 Method 1: Synthesis from Hydrazones under Vilsmeier Conditions

12.1.5.1.3.2.2 Method 2: Synthesis from Hydrazones, Dimethylformamide, and Cyanuric Chloride

12.1.5.1.3.2.3 Method 3: Synthesis from Hydrazones by Acylation

12.1.5.1.3.2.4 Method 4: Synthesis from α-Halo Ketone Hydrazones and Isocyanides

12.1.5.1.3.2.5 Method 5: Synthesis from Acetophenone Hydrazones and Aldehydes

12.1.5.1.3.2.6 Method 6: Synthesis from α-Halo Hydrazones and Enals

12.1.5.1.4 By Formation of One N—N Bond

12.1.5.1.4.1 Fragment N—C—C—C—N

12.1.5.1.4.1.1 Method 1: Pyrazole 2-Oxides from β-Nitro Hydrazones

12.1.5.1.4.1.2 Method 2: Synthesis from Cyclopropyl Oximes

12.1.5.1.5 By Formation of One N—C Bond

12.1.5.1.5.1 Fragment N—N—C—C—C

12.1.5.1.5.1.1 Method 1: Synthesis from Acetylene- or Allene-Bearing Hydrazones

12.1.5.1.5.1.2 Method 2: Synthesis from α,β-Unsaturated Hydrazones

12.1.5.1.5.1.3 Method 3: Synthesis from β-Oxo or β-Carboxy Hydrazones

12.1.5.1.5.1.4 Method 4: Synthesis from Semicarbazones formed by Reaction of 3-Siloxy-1,3-dienes with 1,2-Diazabuta-1,3-dienes

12.1.5.1.5.1.5 Method 5: Synthesis from Acetylenic Nitrosoamines

12.1.5.1.5.1.6 Method 6: Synthesis from Propargylic Hydrazides

12.1.5.1.5.1.7 Method 7: Synthesis from Vinyl Diazo Compounds and Arenediazonium Salts

12.1.5.1.5.1.8 Method 8: Synthesis from 1-Chloro-3-hydrazonopropan-2-ones

12.1.5.1.5.1.9 Method 9: Synthesis from (Difluoroalkenyl) tosylhydrazines

12.1.5.1.5.1.10 Method 10: Synthesis from β-Azo Hydrazones

12.1.5.1.6 By Formation of One N—C and One N—N Bond

12.1.5.1.6.1 Fragments N—C—C—C and N

12.1.5.1.6.1.1 Method 1: Synthesis from 3-Azidopropenals and Arylamines

12.1.5.1.6.1.2 Method 2: Synthesis from α-(1,3-Dithian-2-yl) Enamine Ketones and Primary Amines

12.1.5.1.6.1.3 Method 3: Synthesis from β-Formyl Enamides and Hydroxylamine

12.1.5.1.7 By Formation of One N—N and Two N—C Bonds

12.1.5.1.7.1 Fragments C—C—C, N, and N

12.1.5.1.7.1.1 Method 1: Synthesis from an Oxaziridine, Primary Amines, and Heptane-3,5-dione

12.1.5.1.8 By Formation of One C—C and Two N—C Bonds

12.1.5.1.8.1 Fragments C—C, C, and N—N

12.1.5.1.8.1.1 Method 1: Synthesis from Acyl Chlorides, Terminal Alkynes, and Hydrazines

12.1.5.1.8.1.1.1 Variation 1: Tetrasubstituted Pyrazoles from Acyl Chlorides, Terminal Alkynes, and Hydrazines with Subsequent Halogenation/Suzuki Coupling

12.1.5.1.8.1.1.2 Variation 2: Biaryl-Substituted Pyrazoles from Acyl Chlorides, Terminal Alkynes, and Hydrazines with Subsequent Suzuki Coupling

12.1.5.1.8.1.1.3 Variation 3: From Glyoxylic Acids, Alkynes, and Hydrazines by In Situ Activation

12.1.5.1.8.1.2 Method 2: Synthesis from Arylglyoxal Monohydrates, Tosylhydrazine, and Alkenes

12.1.5.1.8.1.3 Method 3: Synthesis from Terminal Alkynes, Carbon Monoxide, Aryl Iodides, and Hydrazines

12.1.5.1.8.1.4 Method 4: Synthesis from Phthalimides, Lithium Arylacetylides, and Hydrazines

12.1.5.1.8.1.5 Method 5: Synthesis from Aryl Bromides, Carbon Monoxide, Vinyl Ethers, and Hydrazines

12.1.5.1.8.1.6 Method 6: Synthesis from N-Hydroxyimidoyl Chlorides, Terminal Alkynes, and Hydrazines

12.1.5.1.8.1.7 Method 7: Synthesis from Aldehydes, Terminal Alkynes or Allenes, and Hydrazines

12.1.5.1.8.1.8 Method 8: Synthesis from Aldehydes, 1,3-Dicarbonyl Compounds, and Hydrazines

12.1.5.1.8.1.8.1 Variation 1: From Dimethylformamide Dimethyl Acetal, 1,3-Dicarbonyls, and Hydrazines

12.1.5.1.8.1.9 Method 9: Synthesis from Aldehydes, Malono Derivatives, and Arylhydrazines

12.1.5.1.8.1.10 Method 10: Synthesis from Aldehydes, 1,1-Bis (methylsulfanyl)-2-nitroethene, and Hydrazine

12.1.5.1.8.1.11 Method 11: Synthesis from Aldehydes, Dimethyl Acetylenedicarboxylate, and Arylhydrazines

12.1.5.1.8.1.12 Method 12: Synthesis from Aldehydes, Hydrazines, and Nitroalkenes or Enols

12.1.5.1.8.1.13 Method 13: Synthesis from Alkynes, Isocyanides, Amines, and Hydrazines

12.1.5.1.8.1.13.1 Variation 1: From Alkynes, Isocyanides, and Hydrazines

12.1.5.1.8.1.14 Method 14: Synthesis from Dialkyl Acetylenedicarboxylates, Isocyanides, and Hydrazine Carboxamides

12.1.5.1.8.1.15 Method 15: Synthesis from Aldehydes, Vinyl Azides, and Tosylhydrazine

12.1.5.1.8.1.16 Method 16: Synthesis from Ketone Enolates, Acid Chlorides, and Hydrazines

12.1.5.1.8.1.17 Method 17: Synthesis from Ketones, Diethyl Oxalate, and Hydrazines

12.1.5.1.8.1.18 Method 18: Synthesis from Terminal Alkynes, Carbon Dioxide and Hydrazines

12.1.5.1.8.1.19 Method 19: Synthesis from β-Oxo Esters, 1,1,2,2-Tetrafluoroethyl-N, N- dimethylamine, and Hydrazines

12.1.5.1.9 By Formation of One C—C, One N—N, and One N—C Bond

12.1.5.1.9.1 Fragments C—C, C—N, and N

12.1.5.1.9.1.1 Method 1: Synthesis from Allenoates, Amines, and Nitriles

12.1.5.1.9.2 Fragments C—C—N, C, and N

12.1.5.1.9.2.1 Method 1: Synthesis from Oxime Acetates, Anilines, and Paraformaldehyde

12.1.5.1.10 By Formation of One C—C and One N—N Bond

12.1.5.1.10.1 Fragments N—C—C and C—N

12.1.5.1.10.1.1 Method 1: Synthesis from Enamines and Nitriles

12.1.5.1.11 By Formation of One C—C Bond

12.1.5.1.11.1 Fragment C—N—N—C—C

12.1.5.1.11.1.1 Method 1: Synthesis from N,N-Disubstituted Hydrazones

12.1.5.1.12 By Formation of Two N—C and Two C—C Bonds

12.1.5.1.12.1 Fragments C, C, C, and N—N

12.1.5.1.12.1.1 Method 1: Synthesis from Aldehydes, Arylglyoxal Monohydrates, and Tosylhydrazine

12.1.5.2 Synthesis by Ring Transformation

12.1.5.2.1 Ring Enlargement

12.1.5.2.1.1 From Three-Membered Carbocycles

12.1.5.2.1.1.1 Method 1: Synthesis from trans-1-Acyl-2-arylcyclopropanes

12.1.5.2.1.2 From Four-Membered Carbocycles

12.1.5.2.1.2.1 Method 1: Synthesis from 3-Ethoxycyclobutanones and Hydrazines

12.1.5.2.2 Retention of Ring Size

12.1.5.2.2.1 Method 1: Synthesis from 1,2,3-Oxadiazolium-5-olates (Sydnones)

12.1.5.2.2.1.1 Variation 1: From Sydnones and Alkynes

12.1.5.2.2.1.2 Variation 2: From Sydnones and Chalcones

12.1.5.2.2.1.3 Variation 3: From Sydnones and Dihaloalkenes

12.1.5.2.2.2 Method 2: Synthesis from Isoxazoles

12.1.5.2.2.3 Method 3: Synthesis from Isothiazoles

12.1.5.2.3 Ring Contraction

12.1.5.2.3.1 From Six-Membered Rings

12.1.5.2.3.1.1 Method 1: Synthesis from Triazines and α-Chloro Carbanions

12.1.5.2.3.1.2 Method 2: Synthesis from 4-Chloroquinolines and Hydrazine

12.1.5.2.3.1.3 Method 3: From Cyclic Alkenones and Hydrazine

12.1.5.2.4 From One Four- and One Six-Membered Ring

12.1.5.2.4.1 Method 1: Synthesis from Thietanones and 1,2,4,5-Tetrazines

12.1.5.3 Aromatization

12.1.5.3.1 By Dehydrogenation

12.1.5.3.1.1 Method 1: Oxidation of Dihydropyrazoles

12.1.5.3.1.2 Method 2: Synthesis of 3-Benzoyl-4-styryl-4,5-dihydropyrazoles and Oxidation to the Corresponding Pyrazoles

12.1.5.3.1.3 Method 3: Synthesis of 5-(Pyrazol-4-yl)-4,5-dihydropyrazoles and Oxidation to the Corresponding Bipyrazoles

12.1.5.3.2 By Elimination

12.1.5.3.2.1 Method 1: 1-Acyl-4-iodo-1H-pyrazoles by Iodine Monochloride Induced Dehydration/Iodination

12.1.5.3.2.2 Method 2: Synthesis from 4-(Benzotriazol-1-yl)-4,5-dihydropyrazoles

12.1.5.3.3 By Addition

12.1.5.3.3.1 Method 1: Conjugate Addition of Diarylphosphine Oxides to 4-Alkylidene-2,4-dihydro-3H-pyrazol-3-ones

12.1.5.4 Synthesis by Substituent Modification

12.1.5.4.1 Substitution of Existing Substituents

12.1.5.4.1.1 Of Hydrogen

12.1.5.4.1.1.1 Method 1: C-Acylation, C-Alkylation, and C-Allylation

12.1.5.4.1.1.1.1 Variation 1: C-Acylation with Carboxylic Acid Anhydrides

12.1.5.4.1.1.1.2 Variation 2: C-Alkylation

12.1.5.4.1.1.1.3 Variation 3: ortho-Allylation of (Phenylsulfinyl) pyrazoles

12.1.5.4.1.1.2 Method 2: Halogenation

12.1.5.4.1.1.3 Method 3: Nitration

12.1.5.4.1.1.4 Method 4: Full Substitution via Regioselective Metalation

12.1.5.4.1.2 Of Carbon Functionalities

12.1.5.4.1.2.1 Method 1: Deformylation or Decarboxylation

12.1.5.4.1.3 Of Heteroatoms

12.1.5.4.1.3.1 Substitution of Halogen

12.1.5.4.1.3.1.1 Method 1: Nitrodeiodination

12.1.5.4.1.3.1.2 Method 2: Nucleophilic Substitution of Chloropyrazoles

12.1.5.4.1.3.1.3 Method 3: Preparation of 3-Substituted Pyrazoles via Bromine–Lithium Exchange

12.1.5.4.1.3.1.4 Method 4: Palladium-Catalyzed Dehalogenation of Halopyrazoles

12.1.5.4.1.3.1.5 Method 5: Pyrazole-4-boronic Acids from 4-Bromopyrazoles

12.1.5.4.1.3.2 Substitution of Nitrogen Functional Groups

12.1.5.4.1.3.2.1 Method 1: Nucleophilic Substitution of 3,4,5-Trinitro-1H-pyrazoles

12.1.5.4.2 Addition Reactions

12.1.5.4.2.1 Addition of Organic Groups

12.1.5.4.2.1.1 Method 1: N-Alkylation

12.1.5.4.2.1.2 Method 2: N-Arylation

12.1.5.4.3 Modification of Substituents

12.1.5.4.3.1 Method 1: C—H Activation of the ortho-Position in N-Arylpyrazoles

12.1.5.4.3.2 Method 2: Pyrazole-Substituted Chalcones from Pyrazole-4-carbaldehydes

12.1.5.4.3.3 Method 3: Synthesis of 4-(Arylmethyl) pyrazoles from (Pyrazol-4-yl) methanol Derivatives

12.1.5.4.3.4 Method 4: Conversion of (Trifluoromethyl) pyrazoles into Pyrazolecarboxylic Acids or Pyrazolecarbonitriles

12.1.5.4.3.5 Method 5: Hydrovinylation of Alkynes with 1-Vinylpyrazoles

12.1.5.4.4 Cross-Coupling Reactions

12.1.5.4.4.1 Cross-Coupling Reactions at Position 1

12.1.5.4.4.2 Cross-Coupling Reactions at Position 3

12.1.5.4.4.2.1 Method 1: Of Pyrazol-3-yl Trifluoromethanesulfonates, Nonafluorobutanesulfonates, or Iodides

12.1.5.4.4.2.2 Method 2: 1-(Arylmethyl)-3-hetarylpyrazoles by Suzuki Coupling

12.1.5.4.4.3 Cross-Coupling Reactions at Position 4

12.1.5.4.4.3.1 Method 1: C—H Activation

12.1.5.4.4.3.2 Method 2: Cross Coupling of 4-Metalated Pyrazole Derivatives

12.1.5.4.4.3.3 Method 3: Cross Coupling of 4-Halopyrazoles with Arylmetal Species

12.1.5.4.4.4 Cross-Coupling Reactions at Position 5

12.1.5.4.4.4.1 Method 1: C—H Activation

12.1.5.4.4.4.2 Method 2: Suzuki Coupling of Pyrazol-5-yl Trifluoromethanesulfonates

12.1.5.4.4.4.3 Method 3: Cross Coupling of 5-Metalated Pyrazole Derivatives

12.1.5.4.4.5 Multiple Substitution

12.1.5.4.4.5.1 Method 1: C—H Activation

12.1.5.4.4.5.2 Method 2: Regioselective Metalation of Pyrazole N-Oxides

12.1.5.4.4.5.3 Method 3: Regioselective Metalation Using a Switchable Metal-Directing Group

12.1.5.4.4.5.4 Method 4: Tetraaryl-Substituted Pyrazoles by SNAr Reaction/Suzuki Coupling/C—H Arylation

12.1.5.4.4.5.5 Method 5: Direct Diarylation with Aryl Bromides

12.1.5.4.4.5.6 Method 6: Synthesis of C3-, C4-, and C5-Phosphonylated Pyrazoles

32.5 Product Class 5: (Organooxy) alkenes

32.5.3.2 Enol Ethers

F. Bartels, R. Zimmer, and M. Christmann

32.5.3.2 Enol Ethers

32.5.3.2.1 Functionalization of the Enol Ether Oxygen Atom

32.5.3.2.1.1 Method 1: Reactions of 1,3-Dicarbonyl Compounds with Alcohols

32.5.3.2.1.1.1 Variation 1: Heterogeneous/Immobilized Catalysts

32.5.3.2.1.1.2 Variation 2: Homogeneous Condensation of 1,3-Dicarbonyl Compounds and Alcohols

32.5.3.2.1.2 Method 2: Reaction of 2-Hydroxy-1H-indole-3-carbaldehydes with Alcohols

32.5.3.2.1.3 Method 3: Enolate Methylation

32.5.3.2.1.4 Method 4: O-Methylation of α-Trifluoromethylsulfonyl Ketones

32.5.3.2.1.5 Method 5: O-Allylation of 1,3 Diketones

32.5.3.2.1.6 Method 6: Anaerobic Oxidative Free-Radical Cyclization

32.5.3.2.1.7 Method 7: Reaction of 1,3-Dicarbonyl Compounds with Difluorocarbene

32.5.3.2.1.8 Method 8: Reaction of 1,3-Dicarbonyl Compounds with Diaryliodonium Salts

32.5.3.2.2 Formation of the α-C—O Bond

32.5.3.2.2.1 Method 1: Reactions of Alkenyl Halides or Alkenyl Boronates with Alcohols or Phenols

32.5.3.2.2.1.1 Variation 1: Conjugate Addition/Elimination

32.5.3.2.2.1.2 Variation 2: Copper-Mediated C—O Bond Forming Reactions

32.5.3.2.2.2 Method 2: Alkoxylation Reactions

32.5.3.2.2.3 Method 3: Additions to Alkynes

32.5.3.2.2.3.1 Variation 1: Additions of Alcohols to Alkynes under Basic Conditions

32.5.3.2.2.3.2 Variation 2: Metal-Catalyzed Additions of Alcohols or Phenols to Alkynes

32.5.3.2.2.3.3 Variation 3: Intramolecular Additions of Hydroxyalkyl-Substituted Alkynes

32.5.3.2.3 Substitution at the α-Carbon Atom

32.5.3.2.3.1 Method 1: Palladium-Catalyzed Synthesis of Enol Ethers

32.5.3.2.3.1.1 Variation 1: Continuous-Flow Heck Reaction

32.5.3.2.3.1.2 Variation 2: Oxidative Heck Reaction

32.5.3.2.3.1.3 Variation 3: Suzuki–Miyaura Cross Coupling

32.5.3.2.3.1.4 Variation 4: Stille Cross Coupling

32.5.3.2.3.2 Method 2: Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling Reaction

32.5.3.2.3.3 Method 3: Lithiation of Enol Ethers and Reaction with Electrophiles

32.5.3.2.3.3.1 Variation 1:α-Formylation of Enol Ethers

32.5.3.2.3.3.2 Variation 2:α-Alkylamino Functionalization of Enol Ethers

32.5.3.2.4 Substitution at the β-Carbon Atom

32.5.3.2.4.1 Method 1: Heck Reaction

32.5.3.2.4.2 Method 2: Acylation of Enol Ethers

32.5.3.2.5 Formation of the Enol Ether C═C Bond by Condensation Reactions

32.5.3.2.5.1 Method 1: Julia Alkenation

32.5.3.2.5.1.1 Variation 1: Reaction of Lactones with Sulfones

32.5.3.2.5.1.2 Variation 2: Reaction of Lactones with Fluoroalkyl-Substituted Sulfones

32.5.3.2.5.1.3 Variation 3: Reaction of Alkoxyalkyl-Substituted Sulfones with Aldehydes

32.5.3.2.5.2 Method 2: Wittig Reaction

32.5.3.2.5.2.1 Variation 1: Reaction of Ketones with (Methoxymethylene) triphenylphosphorane

32.5.3.2.5.2.2 Variation 2: Reaction of Aldehydes with Phosphonium Salts

32.5.3.2.5.2.3 Variation 3: Wittig–Horner Reaction

32.5.3.2.5.3 Method 3: Direct Conversion of Lactones into Enol Ethers Using Organotitanium Reagents

32.5.3.2.5.3.1 Variation 1: Using the Tebbe Reagent

32.5.3.2.5.3.2 Variation 2: Using the Petasis Reagent

32.5.3.2.5.4 Method 4: Other Condensation Reactions

32.5.3.2.6 Enol Ether Formation by Metathesis Reaction

32.5.3.2.6.1 Method 1: Formation of Acyclic Enol Ethers

32.5.3.2.6.1.1 Variation 1: Molybdenum- and Ruthenium-Catalyzed Cross Metathesis

32.5.3.2.6.1.2 Variation 2: Catalytic Enantioselective Ring-Opening Cross Metathesis Using Molybdenum Catalysts

32.5.3.2.6.1.3 Variation 3: Ruthenium-Catalyzed Ring-Opening Cross Metathesis

32.5.3.2.6.1.4 Variation 4: Enantioselective Ruthenium-Catalyzed Ring-Opening Cross Metathesis

32.5.3.2.6.2 Method 2: Synthesis of Cyclic Enol Ethers Using a Suzuki–Miyaura Cross Coupling/Ring-Closing Metathesis Sequence

32.5.3.2.7 Thermolysis and Pyrolysis

32.5.3.2.7.1 Method 1: Thermolysis of Bis (allenes)

32.5.3.2.7.2 Method 2: Pyrolysis of Azetidinones and Their Thio Analogues

32.5.3.2.8 Formation of the C═C Bond by Reduction

32.5.3.2.8.1 Method 1: Hydrogenation of Alkynyl Ethers

32.5.3.2.8.2 Method 2: Hydride Reduction of Alkynyl Ethers

32.5.3.2.8.3 Method 3: Cross-Dehydrogenative C—C Bond Forming Reaction of Alkynyl Ethers

32.5.3.2.8.4 Method 4: Palladium-Catalyzed Cross Addition of Alkynes to Alkynyl Ethers

32.5.3.2.9 Formation of Enol Ethers through Cycloaddition and Cyclization Reactions

32.5.3.2.9.1 Method 1: Cycloaddition Reactions

32.5.3.2.9.1.1 Variation 1: [4 + 2] Cycloaddition

32.5.3.2.9.1.2 Variation 2: Hetero Diels–Alder Reaction

32.5.3.2.9.2 Method 2: Cyclization Reactions

32.5.3.2.9.2.1 Variation 1: Gold-Catalyzed Cyclization

32.5.3.2.9.2.2 Variation 2: Oxidation-Induced Cyclization

32.5.3.2.10 Transformation of sp-Hybridized β-Carbon into sp2-Hybridized β-Carbon

32.5.3.2.10.1 Method 1: Cycloadditions with Alkoxyallenes

32.5.3.2.10.1.1 Variation 1: Gold-Catalyzed [4 + 2] Cycloaddition

32.5.3.2.10.1.2 Variation 2: Gold-Catalyzed [2 + 2] Cycloaddition

32.5.3.2.10.2 Method 2: Additions to Alkoxyallenes

32.5.3.2.10.2.1 Variation 1: Samarium (II) Iodide Mediated Additions to Methoxyallene

32.5.3.2.10.2.2 Variation 2: Additions of Perfluoroalkanesulfinyl Chlorides to Alkoxyallenes

32.5.3.2.10.3 Method 3: Ring Closure/Ring Opening Sequence of Alkoxyallene Derivatives

32.5.3.2.10.3.1 Variation 1: Via Dihydrofurans

32.5.3.2.10.3.2 Variation 2: Via 1,2-Oxazines

32.5.3.2.10.4 Method 4: Intramolecular Pauson–Khand Reaction of Alkynyl-Substituted Alkoxyallenes

Volume 40: Amines, Ammonium Salts, Amine N-Oxides, Haloamines, Hydroxylamines and Sulfur Analogues, and Hydrazines

40.1 Product Class 1: Amino Compounds

40.1.1.5.2.4 The Mannich Reaction

C. Schneider and M. Sickert

40.1.1.5.2.4 The Mannich Reaction

40.1.1.5.2.4.1 Metal-Catalyzed Mannich Reactions

40.1.1.5.2.4.1.1 Method 1: Direct Metal-Catalyzed Mannich Reactions

40.1.1.5.2.4.1.1.1 Variation 1: Reaction with Aldimines

40.1.1.5.2.4.1.1.2 Variation 2: Reaction with Ketimines

40.1.1.5.2.4.1.2 Method 2: Direct Vinylogous Metal-Catalyzed Mannich Reactions

40.1.1.5.2.4.1.2.1 Variation 1: Reaction with Aldimines

40.1.1.5.2.4.1.2.2 Variation 2: Reaction with Ketimines

40.1.1.5.2.4.1.3 Method 3: Indirect Metal-Catalyzed Mannich Reactions

40.1.1.5.2.4.1.3.1 Variation 1: Reaction with Aldimines

40.1.1.5.2.4.1.3.2 Variation 2: Reaction with Ketimines

40.1.1.5.2.4.1.4 Method 4: Metal-Catalyzed Vinylogous Mukaiyama–Mannich Reactions

40.1.1.5.2.4.1.4.1 Variation 1: Reaction with Aldimines

40.1.1.5.2.4.1.4.2 Variation 2: Reaction with Ketimines

40.1.1.5.2.4.2 Direct Organocatalyzed Stereoselective Mannich Reactions

40.1.1.5.2.4.2.1 Method 1: Reactions with Aldimines

40.1.1.5.2.4.2.1.1 Variation 1: syn-Selective Mannich Reactions of Ketones Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.1.2 Variation 2: syn-Selective Mannich Reaction of Aldehydes Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.1.3 Variation 3: anti-Selective Mannich Reaction of Ketones Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.1.4 Variation 4: anti-Selective Mannich Reaction of Aldehydes Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.1.5 Variation 5: Mannich Reaction of Acetaldehydes Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.1.6 Variation 6: Mannich Reaction Catalyzed by Chiral Guanidine Derivatives

40.1.1.5.2.4.2.1.7 Variation 7: Mannich Reactions Catalyzed by Chiral Phosphoric, Sulfonic, and Carboxylic Acids and Derivatives

40.1.1.5.2.4.2.1.8 Variation 8: Mannich Reaction Catalyzed by Bifunctional Chiral Catalysts Based on Urea and Thiourea Motifs

40.1.1.5.2.4.2.1.9 Variation 9: Mannich Reaction Catalyzed by Cinchona Alkaloid Derivatives

40.1.1.5.2.4.2.1.10 Variation 10: Mannich Reaction Catalyzed by Phase-Transfer and Ion-Pair Catalysts

40.1.1.5.2.4.2.1.11 Variation 11: Mannich Reaction Catalyzed by N-Heterocyclic Carbenes

40.1.1.5.2.4.2.2 Method 2: Reaction with Ketimines

40.1.1.5.2.4.2.2.1 Variation 1: Mannich Reaction of Ketimines with Ketones Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.2.2 Variation 2: Mannich Reaction of Ketimines with Aldehydes Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.3 Method 3: Three-Component Reactions

40.1.1.5.2.4.2.3.1 Variation 1: Three-Component Reaction of Ketones, Amines, and Aldehydes via Enamine Catalysis

40.1.1.5.2.4.2.3.2 Variation 2: Three-Component Mannich Reactions Catalyzed by Chiral Phosphoric Acids and Derivatives

40.1.1.5.2.4.2.3.3 Variation 3: Mannich Reaction Catalyzed by Bifunctional Chiral Catalysts Based on (Thio) Urea Motifs

40.1.1.5.2.4.2.3.4 Variation 4: Mannich Reaction Catalyzed by Enzymes

40.1.1.5.2.4.2.4 Method 4: Reaction with Imine Surrogates

40.1.1.5.2.4.2.4.1 Variation 1: Mannich Reaction of Imine Surrogates Catalyzed by Chiral Amines via Enamine Catalysis

40.1.1.5.2.4.2.4.2 Variation 2: Mannich Reaction of Imine Surrogates Catalyzed by Bifunctional Thioureas

40.1.1.5.2.4.2.4.3 Variation 3: Mannich Reaction of Imine Surrogates Catalyzed by Phase-Transfer Catalysts

40.1.1.5.2.4.2.5 Method 5: Reaction with Hydrazones

40.1.1.5.2.4.2.5.1 Variation 1: Mannich Reaction of Hydrazones Catalyzed by Bifunctional Amine Thioureas

40.1.1.5.2.4.3 Indirect Organocatalyzed Stereoselective Mannich Reactions

40.1.1.5.2.4.3.1 Method 1: Reaction with Aldimines

40.1.1.5.2.4.3.1.1 Variation 1: Indirect Mannich Reaction Catalyzed by Bifunctional Amine Thioureas

40.1.1.5.2.4.3.1.2 Variation 2: Indirect Mannich Reaction Catalyzed by Chiral Phosphoric Acids

40.1.1.5.2.4.3.2 Method 2: Indirect Mannich Reaction of Imine Surrogates

40.1.1.5.2.4.3.2.1 Variation 1: Indirect Mannich Reaction Catalyzed by Chiral Phosphoric Acids and Analogues

40.1.1.5.2.4.4 Direct Organocatalyzed Stereoselective Vinylogous Mannich Reactions

40.1.1.5.2.4.4.1 Method 1: Reaction with Aldimines

40.1.1.5.2.4.4.1.1 Variation 1: Vinylogous Mannich Reactions Catalyzed by Bifunctional Thioureas

40.1.1.5.2.4.4.1.2 Variation 2: Vinylogous Mannich Reactions Catalyzed by Cinchona Alkaloids

40.1.1.5.2.4.4.2 Method 2: Reaction with Ketimines

40.1.1.5.2.4.4.2.1 Variation 1: Vinylogous Mannich Reactions Catalyzed by Cinchona-Based Alkaloids

40.1.1.5.2.4.4.3 Method 3: Reactions with Imine Surrogates

40.1.1.5.2.4.4.3.1 Variation 1: Vinylogous Mannich Reactions Mediated by Phase-Transfer Catalysts

40.1.1.5.2.4.5 Indirect Organocatalyzed Stereoselective Vinylogous Mannich Reactions

40.1.1.5.2.4.5.1 Method 1: Reaction with Aldimines

40.1.1.5.2.4.5.1.1 Variation 1: Indirect Vinylogous Mannich Reactions Catalyzed by Chiral Phosphoric Acids

40.1.1.5.2.4.5.1.2 Variation 2: Indirect Vinylogous Mannich Reactions Catalyzed by Disulfonimides

40.1.1.5.2.4.5.2 Method 2: Three-Component Reactions

40.1.1.5.2.4.5.2.1 Variation 1: Indirect Vinylogous Mannich Reactions Catalyzed by Chiral Phosphoric Acids

Author Index

Abbreviations

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]

R

1

Time (h)

Yield (%)

Ref

4-O

2

NC

6

H

4

6

81

[

6

]

4-F

3

CC

6

H

4

26

75

[

6

]

4-FC

6

H

4

24

70

[

6

]

3-BrC

6

H

4

24

68

[

6

]

1-naphthyl

29

58

[

6

]

28

71

[

6

]

3,4-(MeO)

2

C

6

H

3

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]

R

1

R

2

Yield (%)

Ref

4-BrC

6

H

4

CN

95

[

8

]

4-BrC

6

H

4

CO

2

Me

83

[

8

]

Ph

CN

91

[

8

]

Ph

CO

2

Me

68

[

8

]

Ph

CONH

2

73

[

8

]

Ph

CONHBn

75

[

8

]

4-HOC

6

H

4

CN

85

[

8

]

4-MeOC

6

H

4

CN

92

[

8

]

2-O

2

NC

6

H

4

CN

91

[

8

]

4-O

2

NC

6

H

4

CN

90

[

8

]

2,4-Cl

2

C

6

H

3

CN

87

[

8

]

pyren-1-yl

CN

82

[

8

]

2-(HO)

2

BC

6

H

4

CN

79

[

8

]

Fc

CN

78

[

8

]

2-thienyl

CN

88

[

8

]

2-thienyl

CONH

2

85

[

8

]

cycloundecyl

CN

78

[

8

]

(

E

)-CH═CH(CH

2

)

4

Me

CN

85

[

8

]

CO

2

Me

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 (2.0 mmol), and the mixture was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), MeOH was distilled off under reduced pressure. The crude residue was dissolved in EtOAc (50 mL) and the soln was washed with sat. aq NH4Cl (2 × 20 mL) and sat. brine (20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (CH2Cl2 to acetone/CH2Cl2 3:7).

12.1.5.1.2 By Formation of Two N—C Bonds

12.1.5.1.2.1 Fragments C—C—C and N—N

12.1.5.1.2.1.1 From 1,3-Dicarbonyl Compounds (and Synthetic Equivalents) and Hydrazines

For previously published information, see Section 12.1.1.2.1.1.

12.1.5.1.2.1.1.1 Method 1: Synthesis from Alk-2-en-1-ones with a Leaving Group in Position 3 and Hydrazines

For previously published information, see Section 12.1.1.2.1.1.13. Alk-2-en-1-ones with a leaving group in position 3 react with hydrazine derivatives and aromatization occurs by elimination.

12.1.5.1.2.1.1.1.1 Variation 1: From Haloalkenones or Sulfonylalkenones and Hydrazines

Chloro- or bromovinyl ketones react with 1,1-dimethylhydrazine in anhydrous hexane at ambient temperature to form the corresponding 3-substituted 1-methylpyrazoles after elimination of halomethane,[9,10] whereas 3-(trifluoromethyl) pyrazoles are obtained from 3-fluoro-3-(trifluoromethyl) alk-2-en-1-ones and methyl- or phenylhydrazine.[11] 4-Fluoro-5-(perfluoroalkyl) pyrazoles are prepared regioselectively from the corresponding 1-alkyl-1-(trialkylsiloxy) perfluoroalk-1-enes and hydrazines at ambient temperature in diethyl ether.[12] Cyclization can also be achieved by a palladium-catalyzed cross-coupling reaction of in situ formed arylhydrazones derived from 2-bromobenzaldehydes or (2-bromovinyl) aldehydes and hydrazines, the former leading to fused pyrazole systems.[13] 1,1-Dichloro-4-haloalk-1-en-3-ones can be cyclized with hydrazines to give the corresponding 3-alkenyl-5-chloropyrazoles 5 after dehalogenation of the crude 5-chloro-3-(1-haloalkyl) pyrazoles 4 (▶ Scheme 5).[14] Instead of a halide as a leaving group, a 4-toluenesulfonate group can be employed in a solid-phase synthesis using polymer-supported vinyl sulfones.[15]

Scheme 5 Synthesis of 3-Alkenyl-5-chloropyrazoles from 1,1-Dichloro-4-haloalk-1-en-3-ones and Hydrazines[14]

R

1

R

2

X

Yield

a

(%)

Ref

H

Me

Cl

72

[

14

]

H

Et

Cl

70

[

14

]

H

Bn

Cl

72

[

14

]

Me

Bn

Br

78

[

14

]

a

Over 2 steps.

β,β-Dibromo enones can be employed in a one-pot procedure initiated by cyclization with 1,1-dimethylhydrazine, followed by Suzuki–Miyaura coupling of the resulting 5-bromopyrazoles 6 to give 5-arylpyrazoles 7 (▶ Scheme 6). Cyclization with methylhydrazine is also possible, but in this case the palladium-catalyzed coupling is inhibited.[16]

Scheme 6 One-Pot Cyclization and Suzuki Coupling of β,β-Dibromo Enones[16]

R

1

Yield (%)

Ref

Ph

76

[

16

]

4-MeOC

6

H

4

66

[

16

]

4-O

2

NC

6

H

4

68

[

16

]

1-naphthyl

63

[

16

]

2-thienyl

76

[

16

]

59

[

16

]

76

[

16

]

5-Chloro-3-(1-haloalkyl)-1H-pyrazoles 4; General Procedure:[14]

A hydrazine (50 mmol) and Et3N (5.1 g, 50 mmol) were added dropwise to a soln of a dichlorovinyl ketone (50 mmol) in Et2O (150 mL) over 20 min [in the synthesis of N-methyl-1H-pyrazoles, 1,1-dimethylhydrazine (2.0 equiv) was used instead of Et3N]. On completion of the exothermic process, the mixture was stirred for 5 h and then poured into H2O (150 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3 × 50 mL). The organic layer was combined with the extract, dried (CaCl2), and filtered. Et2O was evaporated, and the crude products obtained were usable for further purposes without additional purification.

3-Alkenyl-5-chloro-1H-pyrazoles 5; General Procedure:[14]

A soln of a 5-chloro-3-(1-haloalkyl) pyrazole 4 (50 mmol) in DMF (20 mL) was exposed to microwave irradiation (800 W) for 10–30 min. The mixture was diluted with H2O (200 mL) and extracted with Et2O (3 × 50 mL). The extract was dried (MgSO4) and filtered. Et2O was evaporated and the product was distilled under reduced pressure or recrystallized.

A 10-mL round-bottomed flask equipped with an argon inlet, a condenser, and a magnetic stirrer bar was charged with 1,1-dimethylhydrazine (20 mg, 0.34 mmol) and THF (1 mL). A soln of 3,3-dibromo-1-phenylprop-2-en-1-one (50 mg, 0.17 mmol) in THF (1 mL) was then added, followed by Pd (PPh3)4 (9.8 mg, 8.5 μmol), PhB (OH)2 (42 mg, 0.34 mmol), and powdered K3PO4 (108 mg, 0.51 mmol). The stirred mixture was heated at reflux for 18 h, allowed to cool to rt, and filtered through a small plug of silica gel, rinsing with EtOAc (50 mL). The filtrate was concentrated under reduced pressure, and the oily residue was preadsorbed on silica gel and purified by flash column chromatography (silica gel, petroleum ether/EtOAc 9:1) to afford the product as a pale-yellow solid; yield: 76%.

12.1.5.1.2.1.1.1.2 Variation 2: From Enaminones and Hydrazines

Enaminones react with hydrazine derivatives to give the corresponding pyrazoles 8 and/or 9 by elimination of the respective amine (▶ Scheme 7). The reaction can be catalyzed by acids[17,18] or ionic liquids,[19,20] and conducted under microwave[21,22] or ultrasound[23] irradiation. Reactions can also be conducted by grinding[24] or in a ball mill,[25] or on a solid phase using a germanium-based linker,[26] a Rink amide,[27] or Wang resin.[28] Pyrazole-3-,[29] -4-,[30–33], and -5-carboxylates,[34] or 4,5-dicarboxylates,[35] as well as 4-acylpyrazoles, can also be generated.[36] Pyrazole-5-carboxylates can be obtained from the regiospecific reaction of unsymmetrical enamino diketones.[34] Utilization of chiral enaminones leads to the corresponding chirally substituted pyrazole derivatives,[37] whereas trifluoromethyl enaminones give 3- or 4-(trifluoromethyl) pyrazoles, depending on the nature of the substituent on the hydrazine.[38] Trifluoromethoxy substituents are also tolerated.[39] The synthesis of fluoroalkyl-substituted pyrazole-4-carboxylic acids can be achieved in methanol in the absence of a catalyst on a multigram scale.[40] 3-(Dihalomethyl) pyrazole-4-carboxylates can be generated by the regioselective reaction of 2-(dihaloacyl)-3-aminoacrylic esters with hydrazines.[41] Silylated pyrazoles 8 or 9 are synthesized from the corresponding silylated enaminones, which are in turn generated from the corresponding isoxazoles by catalytic hydrogenation. The regioselectivity depends on the nature of the silyl group.[42]

Scheme 7 Synthesis of Pyrazoles from Enaminones and Hydrazines[30,34,38,42]

A soln of ethyl 3-benzoyl-4-(dimethylamino)-2-oxobut-3-enoate (5 mmol) and H2NNHCO2Me (0.540 g, 6 mmol) in anhyd EtOH (20 mL) was stirred at rt for 1 h. Then, the product was collected by filtration, washed with EtOH, and dried under reduced pressure; yield: 75%.

CAUTION:

Methylhydrazine is highly flammable and may self-ignite in air. It is corrosive to skin, eyes, and mucous membranes.

A mixture of a silylated enaminone (2.0 mmol) and free methylhydrazine or ethylhydrazine oxalate (3.0 mmol) in anhyd EtOH (8 mL) was stirred at rt or heated at reflux. After the reaction was complete (monitored by TLC), the solvent was evaporated under reduced pressure and the residue was partitioned between CH2Cl2 and H2O. The organic layer was dried, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, CH2Cl2/Et2O 20:1 to 10:1).

12.1.5.1.2.1.1.1.3 Variation 3: From α,β-Unsaturated-β-alkoxy Ketones and Hydrazines

Scheme 8 Synthesis of Pyrazoles from α,β-Unsaturated-β-alkoxy Ketones and Hydrazines[43,50,52]

R

1

R

2

R

3

R

4

R

5

Conditions

Ratio (

10

/

11

)

Yield (%)

Ref

4-MeOC

6

H

4

C≡CTMS

4-O

2

NC

6

H

4

H

Et

EtOH, rt, 3–4 h

0:1

98

[

43

]

Ph

C≡CTMS

4-MeOC

6

H

4

H

Et

EtOH, 80 °C, 3–4 h

1:10

63

[

43

]

Bn

C≡CTMS

4-O

2

NC

6

H

4

H

Et

EtOH, rt, 1–2 h

1.4:1

79

[

43

]

Ph

CF

3

H

Me

Me

microwave, 150 °C, 6 min

1:3

92

[

50

]

Ph

CF

3

H

Ph

Me

microwave, 150 °C, 6 min

0:1

90

[

50

]

(CH

2

)

2

OH

CF

3

H

H

Et

microwave, 50 °C, 2 min

1:0

75

[

50

]

Ph

4-Tol

Bt

Ph

Et

EtOH, reflux

1:0

79

[

52

]

[2-(Trimethylsilyl) ethynyl]-1H-pyrazoles 10 and/or 11 (R2 =C≡ CTMS); General Procedure:[43]

The enynone (1.7 mmol) was dissolved in EtOH (15 mL) in a screw-cap vial. The corresponding hydrazine (2.5 mmol) was added to this soln and the mixture was stirred at rt or at 80 °C for 1–4 h (monitored by TLC). When the hydrazine was used as a hydrochloride salt, an equivalent amount of Et3N (0.35 mL, 0.25 g, 2.5 mmol) was added to the mixture. After the reaction was complete, the solvent was removed under reduced pressure and the residue was purified by column chromatography.

(Trifluoromethyl)-1H-pyrazoles 10 and/or 11 (R2 =CF3); General Procedure:[50]

A 10-mL microwave vessel equipped with a standard cap (vessel commercially furnished by CEM Discover) was filled with an enone (1.0 mmol) and a hydrazine (1.2 mmol). After the vessel was sealed, the sample was irradiated with microwaves at the specified temperature for the time indicated, which was plotted in Synergies Version 3.5.9 software applying the power of 200 W as the maximum level of irradiation and a maximum level of internal vessel pressure of 250 psi. The irradiation power was in the range of 1–95 W for reactions at 50–100 °C, with simultaneous cooling, and 30–190 W for reactions at 150–200 °C, without simultaneous cooling. The mixture was subsequently cooled to 50 °C by compressed air. CHCl3 (5 mL) was added and the mixture was washed with H2O (3 × 5 mL). CHCl3 was evaporated under reduced pressure to give the pure products.

12.1.5.1.2.1.1.1.4 Variation 4: From α,β-Unsaturated-β-(alkylsulfanyl) Ketones and Hydrazines

α,β-Unsaturated-β-(alkylsulfanyl) ketones react with hydrazines to give the corresponding pyrazoles 12 or 13 (▶ Scheme 9).[57] The regioselectivity of the reaction depends on the conditions.[58] If ketene dithioacetals are employed in water as a solvent, (alkylsulfanyl) pyrazoles are obtained, which can be further functionalized by oxidation to the corresponding sulfones[59] or hydrogenated to give 5-unsubstituted derivatives.[60] A one-pot reaction starting with Liebeskind–Srogl coupling of α-oxo ketene dithioacetals is also possible.[57] A preceding reaction of aroyl formyl ketene dithioacetals with ammonium acetate gives 3-amino-2-aroyl-3-(methylsulfanyl) prop-2-enals, which are converted into the corresponding aroyl pyrazolamines.[61] The employment of 1,3-dithietane derivatives leads to pyrazoles bearing a free thiol group at position 3 or 5.[62]

Scheme 9 Synthesis of Pyrazoles from α,β-Unsaturated-β-(alkylsulfanyl) Ketones or Ketene Dithioacetals and Hydrazines[57–59]

R

1

R

2

R

3

R

4

R

5

Product

Conditions

Yield (%)

Ref

Ph

Me

H

Ph

Et

12

t

-BuOK,

t

-BuOH, reflux, 7–16 h

78

[

57

]

Bn

Me

H

Ph

Et

13

AcOH,

t

-BuOH, reflux, 5–9 h

96

[

57

]

H

2-furyl

H

Ph

Et

–

AcOH,

t

-BuOH, reflux, 5–9 h

83

[

57

]

Ph

4-MeOC

6

H

4

H

piperidin-1-yl

Me

12

NaH, DMF, benzene, 90 °C, 12 h

67

[

58

]

Ph

Ph

H

morpholino

Me

12

NaH, DMF, benzene, 90 °C, 12 h

74

[

58

]

Ph

4-MeOC

6

H

4

H

piperidin-1-yl

Me

13

DABCO,

t

-BuOH, reflux, 12–16 h

64

[

58

]

Ph

Ph

H

morpholino

Me

13

DABCO,

t

-BuOH, reflux, 12–16 h

70

[

58

]

H

Me

CONHPh

SMe

Me

–

H

2

O, reflux, 3 h

97

[

59

]

H

Me

2-MeOC

6

H

4

NHCO

SMe

Me

–

H

2

O, reflux, 2.9 h

92

[

59

]

H

Me

4-O

2

NC

6

H

4

NHCO

SMe

Me

–

H

2

O, reflux, 2.5 h

91

[

59

]

CAUTION:

Phenylhydrazine is a potent skin sensitizer, and may damage the liver and kidneys.

A soln of the respective N, S-acetal (5.0 mmol) and an arylhydrazine (6.0 mmol) in benzene (50 mL) (CAUTION:carcinogen) was added to a suspension of NaH (0.24 g, 6.0 mmol) in DMF (10 mL) at rt over a period of 0.5 h. The mixture was heated at 90 °C with constant stirring for 12 h (monitored by TLC), cooled, and poured into sat. NH4Cl (50 mL), and extracted with benzene (2 × 25 mL). The combined benzene layer was washed with H2O (3 × 50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexane/EtOAc 10:1).

CAUTION:

Phenylhydrazine is a potent skin sensitizer, and may damage the liver and kidneys.

A soln of the respective N, S-acetal (5.0 mmol), an arylhydrazine (6.0 mmol), and DABCO (0.67 g, 6.0 mmol) in t-BuOH (50 mL) was heated at reflux for 12–16 h with constant stirring (monitored by TLC). The mixture was concentrated under reduced pressure and poured into ice-cold water, extracted with CH2Cl2 (3 × 50 mL), washed with H2O (2 × 50 mL) and brine (1 × 50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EtOAc 10:1).

CAUTION:

Hydrazine hydrate is toxic. It is a severe skin and mucous membrane irritant and a possible human carcinogen.

80% H2NNH2•H2O (1 mL, 20 mmol) was added to a suspension of an α-acylketene dithioacetal (10 mmol) in H2O (25 mL), and the mixture was heated at reflux for the appropriate time with constant stirring. After completion of the reaction, the mixture was cooled to rt and cold H2O (50 mL) was added. The separated solid was collected by filtration, washed with H2O (2 × 50 mL), dried, and crystallized (MeOH) to afford the analytically pure product, which was used for the next step without further purification.

12.1.5.1.2.1.1.2 Method 2: Synthesis from Alk-2-en-1-ones and Hydrazines Followed by Dehydrogenation

Alkenones not carrying a leaving group can react with hydrazines to give dihydropyrazole derivatives 14. Subsequent oxidation leads to the corresponding pyrazoles 15 (▶ Scheme 10). Oxidation can be achieved by molecular oxygen,[63] molecular iodine,[64] air in the presence of copper (II) trifluoromethanesulfonate,[65] 3,4-dihydro-2H-pyran under air,[66] sulfur under microwave irradiation,[67] sodium persulfate under ball milling,[68] or a solid-phase bifunctional Pd/C/K-10 catalyst that also catalyzes the cyclization reaction.[69] The reaction can also be mediated by molecular iodine.[70] Sugar chalcones undergo cyclization with hydrazines, followed by self-oxidation to give sugar pyrazole derivatives.[71]

Scheme 10 Synthesis of Pyrazoles from Alkenones and Hydrazines Followed by Dehydrogenation[63,67,69]

R

1

R

2

R

3

R

4

Conditions

Yield (%)

Ref

Ph

Ph

H

Ph

1,2-dichlorobenzene, 130 °C, O

2

(balloon), 5 h

87

[

63

]

4-MeOC

6

H

4

Ph

H

Ph

1,2-dichlorobenzene, 130 °C, O

2

(balloon), 5h

80

[

63

]

Ph

Ph

H

1,2-dichlorobenzene, 130 °C, O

2

(balloon), 5 h

84

[

63

]

Ph

4-O

2

NC

6

H

4

H

1,2-dichlorobenzene, 130 °C, O

2

(balloon), 5 h

88

[

63

]

Ph

Ph

Ph

Ph

1,2-dichlorobenzene, 130 °C, O

2

(balloon), 4 d

76

[

63

]

H

4-MeOC

6

H

4

H

4-FC

6

H

4

S, EtOH, microwave, 150 °C, 2 h

82

[

67

]

H

4-O

2

NC

6

H

4

H

4-O

2

NC

6

H

4

S, EtOH, microwave, 150 °C, 2 h

63

[

67

]

Me

Ph

H

Ph

Pd/C/K-10,

a

microwave, 160 °C, 30 min

98

[

69

]

Ph

Ph

H

4-MeOC

6

H

4

Pd/C/K-10,

a

microwave, 160 °C, 30 min

86

[

69

]

3-F

3

CC

6

H

4

4-FC

6

H

4

H

4-FC

6

H

4

Pd/C/K-10,

a

microwave, 160 °C, 30 min

85

[

69

]

a

Mechanical mixture of 5% Pd/C and K-10 montmorillonite clay.

CAUTION:

Phenylhydrazine is a potent skin sensitizer, and may damage the liver and kidneys.

A mixture of 1,3-diphenylprop-2-en-1-one (208 mg, 1.0 mmol) and phenylhydrazine hydrochloride (173 mg, 1.2 mmol) in 1,2-dichlorobenzene (2.0 mL) was heated to 130 °C under O2 balloon atmosphere for 5 h. 1,2-Dichlorobenzene was removed and the residue was purified by column chromatography (hexanes/Et2O 12:1) to give the product as a pale yellow solid; yield: 87%.

CAUTION:

Hydrazine hydrate is toxic. It is a severe skin and mucous membrane irritant and a possible human carcinogen.

CAUTION:

Hydrogen sulfide is extremely flammable and at higher levels causes respiratory paralysis and asphyxia.

A mixture of a chalcone (20 mmol), sulfur (30 mmol), and H2NNH2•H2O (40 mmol) in EtOH (20 mL) was introduced into a fluoropolymer cylindrical flask placed in a MARS5 XP-1500 PLUS CEM multimode microwave reactor and irradiated (300 W) for 2 h at 150 °C under pressure. The mixture was cooled and the solvent was evaporated under reduced pressure. The hydrogen sulfide was trapped using liq N2. The residue was treated with EtOH or EtOAc and filtered to remove the excess of sulfur. The solid compound was collected by filtration and dried (as reported).

1H-Pyrazoles 15; General Procedure Using Pd/C/K-10:[69]

CAUTION:

Phenylhydrazine is a potent skin sensitizer, and may damage the liver and kidneys.

A mixture of a chalcone (1.0 mmol) and phenylhydrazine (1.5 mmol) was dissolved in CH2Cl2 (3 mL) in a round-bottomed flask. The mechanically premixed combination of 5% Pd/C (21 mg) and K-10 montmorillonite (500 mg) was added and the mixture was stirred for 10 min. The solvent was evaporated under reduced pressure. The dry mixture was placed into a reaction vial and irradiated in the microwave reactor (CEM Discover Benchmate, 160 °C). During optimization the reaction was monitored by TLC and GC/MS. When the reaction was complete, CH2Cl2 was added to the cold mixture, which was stirred for 10 min, and the catalyst was removed by filtration. The products were purified by flash chromatography.

12.1.5.1.2.1.1.3 Method 3: Synthesis from Alk-2-en-1-ones and Tosylhydrazine Followed by Elimination

Tosylhydrazine reacts with alkenones and α,β-unsaturated aldehydes not carrying a leaving group with elimination of the tosyl group and formation of the respective NH pyrazoles 16. The reaction can be carried out in water using sodium hydroxide and tetrabutylammonium bromide (▶ Scheme 11).[72] A one-pot reaction with subsequent deprotonation and nucleophilic substitution at the pyrazole NH group gives the corresponding substituted pyrazoles, with the regioselectivity reversed compared to the classical Knorr condensation since, in the case shown in ▶ Scheme 11, pyrazoles with the sterically more demanding substituent at position 3 are formed preferentially.[73]

Scheme 11 Condensation of Alkenones with Tosylhydrazine and Elimination of the Tosyl Group[72]

R

1

R

2

R

3

Yield (%)

Ref

Me

H

Ph

94

[

72

]

Me

H

4-MeOC

6

H

4

87

[

72

]

Me

H

4-O

2

NC

6

H

4

82

[

72

]

Me

H

2-HOC

6

H

4

69

[

72

]

Me

H

3-pyridyl

99

[

72

]

Me

H

2-furyl

97

[

72

]

H

Et

Ph

92

[

72

]

H

Me

Ph

98

[

72

]

1H-Pyrazoles 16; General Procedure:[72]

A Schlenk tube equipped with a magnetic stirrer bar was charged with an α,β-unsaturated carbonyl compound (0.50 mmol, 1.0 equiv), tosylhydrazine (0.60 mmol, 1.2 equiv), NaOH (1.5 equiv), and TBAB (1.5 equiv). The reaction vessel was placed in an oil bath at 80 °C, and the mixture was stirred at this temperature for 10 h, allowed to cool to rt, diluted with EtOAc (20 mL), and washed with brine (15 mL) and H2O (15 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography.

12.1.5.1.2.1.1.4 Method 4: Synthesis from β,γ-Unsaturated α-Oxo Esters and Hydrazones

β,γ-Unsaturated α-oxo esters react in a cycloaddition reaction with hydrazones to give pyrazole-3-carboxylates 17. As hydrazones are in a higher oxidation state than hydrazines, no extra oxidation step is required (▶ Scheme 12).[74]

Scheme 12 Synthesis of Pyrazoles from β,γ-Unsaturated α-Oxo Esters and Hydrazones[74]

R

1

R

2

R

3

Yield (%)

Ref

Ph

Me

CO

2

Et

76

[

74

]

4-MeOC

6

H

4

Me

CO

2

Et

63

[

74

]

3-BrC

6

H

4

Me

CO

2

Et

69

[

74

]

2-FC

6

H

4

Me

CO

2

Et

72

[

74

]

(

E

)-CH═CHPh

Me

CO

2

Et

68

[

74

]

4-Tol

Ph

Bz

57

[

74

]

3-MeOC

6

H

4

Ph

Bz

55

[

74

]

3-FC

6

H

4

Ph

Bz

74

[

74

]

2-BrC

6

H

4

Ph

Bz

56

[

74

]

(

E

)-CH═CHPh

Ph

Bz

62

[

74

]

Methyl 1H-Pyrazole-3-carboxylates 17; General Procedure:[74]

A soln of a β,γ-unsaturated α-oxo ester (0.50 mmol) and a hydrazone (0.60 mmol) in DMSO (2 mL) was stirred at 100 °C until the reaction was complete (TLC monitoring). The mixture was diluted with H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated, and the crude product was purified by flash column chromatography (silica gel, petroleum ether/EtOAc 5:1).

12.1.5.1.2.1.1.5 Method 5: Synthesis from Propargylic Aldehydes and Hydrazines

12.1.5.1.2.1.1.5.1 Variation 1: From 3-Ferrocenylpropynal

3-Ferrocenylpropynal reacts with hydrazine derivatives to give the 1,5- and/or 1,3-disubstituted ferrocenylpyrazoles 18 and/or 19. The reaction can either be performed in dioxane or in methanol at the respective reflux temperature. Which set of reaction conditions gives better yield and selectivity depends on the nature of the hydrazine (▶ Scheme 13).[75]

Scheme 13 Synthesis of Ferrocenylpyrazoles from 3-Ferrocenylpropynal and Hydrazines[75]

R

1

x

Conditions

Yield (%)

Ref

18

19

H

2

1,4-dioxane, reflux, 8 h

47

–

[

75

]

H

2

MeOH, reflux, 5 h

70

–

[

75

]

Ph

1

1,4-dioxane, reflux, 8 h

45

14

[

75

]

Ph

1

MeOH, reflux, 5 h

70

20

[

75

]

(CH

2

)

2

OH

2

1,4-dioxane, reflux, 8 h

6

19

[

75

]

(CH

2

)

2

OH

2

MeOH, reflux, 5 h

31

25

[

75

]

Bn

2

1,4-dioxane,reflux, 8h

63

0

[

75

]

Bn

2

MeOH, reflux, 5 h

46

30

[

75

]

Ferrocenyl-1H-pyrazoles 18 and/or 19; General Procedure:[75]

To a soln of 3-ferrocenylpropynal (100 mg, 0.42 mmol) in 1,4-dioxane or MeOH (10 mL) under argon was added the respective hydrazine derivative (1.3 mmol). The resulting mixture was then heated at reflux for 8 or 5 h. After the reaction was complete, the mixture was cooled to 25 °C, and the solvent was removed on a rotary evaporator. The residue was dissolved in H2O (20 mL) and the soln was extracted with CH2Cl2 (3 × 30 mL). The combined CH2Cl2 layers were dried (MgSO4), filtered, and concentrated on a rotary evaporator. The residue was purified by flash chromatography (silica gel, hexane/EtOAc from 19:1 to 1:1).

12.1.5.1.2.1.1.5.2 Variation 2: From (Het) aryl Iodides, Propynal Diethyl Acetal, and Hydrazine

3-(Het) aryl-1H-pyrazoles 21 can be synthesized in a one-pot, three-component reaction starting with a room temperature Sonogashira arylation of 3,3-diethoxyprop-1-yne, which is used as a propynal synthetic equivalent. The resulting intermediate 20 can undergo acetal cleavage with water, followed by cyclocondensation with hydrazine hydro-chloride to give pyrazoles 21. The excess of triethylamine is quenched by adding a stoichiometric amount of 4-toluenesulfonic acid. Electron-rich and electron-poor substituents as well as unprotected phenol derivatives are tolerated (▶ Scheme 14).[76]

Scheme 14 Three-Component Synthesis of 3-(Het) aryl-1-H-pyrazoles Using 3,3-Diethoxyprop-1-yne[76]

Ar

1

Yield (%)

Ref

4-MeOC

6

H

4

56

[

76

]

3,4,5-(MeO)

3

C

6

H

2

63

[

76

]

2-HOC

6

H

4

47

[

76

]

3-HOC

6

H

4

61

[

76

]

4-FC

6

H

4

53

[

76

]

4-ClC

6

H

4

34

[

76

]

4-F

3

CC

6

H

4

57

[

76

]

4-NCC

6

H

4

27

[

76

]

3-O

2

NC

6

H

4

55

[

76

]

2-thienyl

50

[

76

]

CAUTION:

Hydrazine is flammable and its reaction with oxidants is violent. It is a severe skin and mucous membrane irritant and a possible human carcinogen.

PdCl2(PPh3)2 (28 mg, 40 μmol) and CuI (16 mg, 80 μmol) were tempered in a screw-cap Schlenk tube, and 1-iodo-3,4,5-trimethoxybenzene (600 mg, 2.0 mmol), 3,3-diethoxyprop-1-yne (0.32 mL, 2.2 mmol), degassed anhyd 1,4-dioxane (5.0 mL), and Et3N (0.55 mL, 4.0 mmol) were successively added under argon. The mixture was stirred for 2 h at rt (water bath) until complete conversion (monitored by TLC). Then, H2NNH2•HCl (280 mg, 4.0 mmol), deionized H2O (5.0 mL), and TsOH•H2O (390 mg, 2.0 mmol) were added. The mixture was stirred at 80 °C (preheated oil bath) until complete conversion (monitored by TLC), and extracted with CH2Cl2 (10 × 10 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated under reduced pressure. The crude mixture was purified by chromatography (silica gel, CH2Cl2/MeOH/aq NH3) to give the product as an orange solid; yield: 63%.

12.1.5.1.2.1.1.6 Method 6: Synthesis from Alk-2-yn-1-ones and Hydrazines

For previously published information, see Section 12.1.1.2.1.1.17.

Alk-2-yn-1-ones react with hydrazine derivatives to give the corresponding pyrazole derivatives 22 and/or 23 (▶ Scheme 15).[77–79] The regioselectivity of the reaction depends on the electronic and steric nature of the substituent on the hydrazine as well as on the alkynone, as the first nucleophilic attack can occur on the carbonyl group or on the Michael system. Regioselectivity can also be influenced by the reaction conditions.[77] If phenylhydrazine is employed, the selectivity is inversed compared to alkylhydrazines and harsher reaction conditions are necessary due to the lower nucleophilicity of the hydrazine nitrogen.[77,80,81] Typically, the reaction is performed in alcoholic solvents at room temperature, under conventional heating, or under microwave irradiation. It is also possible to employ acid additives. Alkynyl ferrocenyl ketones, synthesized from ferrocenyl iodide and terminal alkynes in a carbonylative Sonogashira coupling, give ferrocenylpyrazoles in a regioselective manner.[80] Pyrazolyl trifluoroborates, which can be employed in cross-coupling reactions, are generated regioselectively from the corresponding ynone trifluoroborates,[81] whereas di- and trifluoromethyl α,β-ynones give the respective di- or trifluoromethylpyrazoles.[82] 1,1-Diethoxy-5-hydroxyalk-3-yn-2-ones can also be employed and lead to the corresponding 5-(diethoxymethyl)-3-(1-hydroxyalkyl)-1H-pyrazoles.[83]

Scheme 15 Synthesis of Pyrazoles from Alk-2-ynones and Hydrazine[77,80,81]

R

1

R

2

R

3

Conditions

Ratio (

22

/

23

)

Yield (%)

Ref

Ph

4-Tol

Me

EtOH, rt, 1 h

94:6

82

[

77

]

4-Tol

Ph

Me

EtOH, rt, 1 h

93:7

78

[

77

]

4-O

2

NC

6

H

4

Ph

Me

EtOH, rt, 1 h

93:7

79

[

77

]

Ph

4-Tol

Ph

EtOH, reflux, 3–4 h

2:98

82

[

77

]

Fc

Ph

Me

EtOH, rt, 4 h

>99:1

90

[

80

]

Fc

t

-Bu

Me

EtOH, rt, 4 h

>99:1

56

[

80

]

Fc

Ph

Ph

EtOH, reflux, 8 h

4:96

78

[

80

]

4-MeOC

6

H

4

BF

3

K

H

EtOH, rt, 2 h

–

96

[

81

]

t

-Bu

BF

3

K

H

EtOH, rt, 2 h

–

48

[

81

]

4-MeOC

6

H

4

BF

3

K

Me

EtOH,rt, 2h

7:1

63

[

81

]

2-MeOC

6

H

4

BF

3

K

Me

EtOH, rt, 3 h

>98:2

92

[

81

]

Ph

BF

3

K

Ph

EtOH, 40 °C, 19 h

<2:98

88

[

81

]

The method can also be employed to synthesize pyrazoles that are subsequently modified by side-chain-functionalization and then used as ligands.[84] (2-Tosylethyl) hydrazine can be used as a novel access to pyrazoles with a free NH group as deprotection can be achieved under mild conditions in acetic acid at 65 °C.[85] Diacetylenic ketones carrying an ester group, obtained via ortho ester derivatives, can be employed to give the corresponding acetylenic pyrazoles. Coordination leads to a regioselective reaction of only the triple bond next to the ester. A mixture of products is, however, obtained when phenylhydrazine is used instead of hydrazine hydrate.[86,87] See also ▶ Sections 12.1.5.1.8.1.1 and 12.1.5.1.8.1.3 for one-pot reactions with in situ generation of alkynones.

CAUTION:

Methylhydrazine is highly flammable and may self-ignite in air. It is corrosive to skin, eyes, and mucous membranes.

To a soln of 1-phenyl-3-(4-tolyl)-prop-2-yn-1-one (997 mg, 4.50 mmol) in EtOH (10 mL) at rt was added methylhydrazine (0.26 mL, 5.00 mmol). The reaction was left for 1 h at rt. EtOH was removed under reduced pressure to afford an orange oil, which was purified by column chromatography (EtOAc/hexane 5:95); yield: 82%.

CAUTION:

Phenylhydrazine is a potent skin sensitizer, and may damage the liver and kidneys.

Phenylhydrazine (0.120 mL, 1.20 mol) was added to a soln of 1-phenyl-3-(4-tolyl)-prop-2-yn-1-one (193 mg, 0.880 mmol) in EtOH (2 mL) at rt under N2. The soln was heated at reflux for 3–4 h and EtOH was removed under reduced pressure. The residual orange oil was purified by column chromatography (EtOAc/hexane 1:99); yield: 82%.

CAUTION:

Methylhydrazine is highly flammable and may self-ignite in air. It is corrosive to skin, eyes, and mucous membranes.

CAUTION:

Phenylhydrazine is a potent skin sensitizer, and may damage the liver and kidneys.

An alkynyl ferrocenyl ketone (0.20 mmol) was reacted with methylhydrazine or phenylhydrazine (0.30 mmol) in EtOH (2 mL) at rt or at reflux, respectively, for the time indicated. The solvent was evaporated and the residue was purified by column chromatography (silica gel, toluene/EtOAc 8:1).

1H-Pyrazolyl Trifluoroborate Salts 22 or 23 (R2 =BF3K); General Procedure:[81]

To a soln of an ynone trifluoroborate (1.0 mmol) in EtOH (2 mL) was added a hydrazine (1.2 mmol). The soln was stirred at rt under N2 until the reaction was judged complete by 19F NMR spectroscopy. The solvent was removed under reduced pressure and the crude material was purified by recrystallization (acetone/Et2O).

12.1.5.1.2.1.1.7 Method 7: Synthesis from Dialkyl Acetylenedicarboxylates, Phenylhydrazine, and Aroyl Chlorides

Dialkyl acetylenedicarboxylates react with phenylhydrazine and aroyl chlorides in a onepot fashion to give the respective 5-(aroyloxy)-1H-pyrazole-3-carboxylates 24 (▶ Scheme 16).[88]

Scheme 16 Synthesis of 5-(Aroyloxy)-1H