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.

July 2010

The Editorial Board

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

1.3.6 Organometallic Complexes of Platinum

A. Nomoto and A. Ogawa

This chapter is an update to the earlier Science of Synthesis contribution (Section 1.3) describing methods for the synthesis of organometallic complexes of platinum and related applications in catalytic reactions using organoplatinum complexes. Recently, organometallic complexes of platinum have been used in many areas, including as medical or luminescent materials.

Keywords: Diels–Alder cycloaddition · allene complexes · dinuclear complexes · anticancer agents · allyl complexes · metallacycles · alkyne complexes · catalytic reactions · selenaplatinacycles · dicationic complexes

1.6.9 Organometallic Complexes of Iridium

H. Li and C. Mazet

This chapter is an update to the earlier Science of Synthesis contribution (Section 1.6) that covers literature from 1999 to the first half of 2013. While Section 1.6 provided a fantastic overview of the different types of organometallic complexes of iridium and their preparation, this contribution aims at focusing more on their applications in homogeneous catalysis.

Keywords: iridium complexes · catalysis · borylation · oxidation · hydroamination · dehydrogenative coupling · hydrogenation · transfer hydrogenative coupling · transfer hydrogenation · allylic substitution · isomerization · oligomerization

13.13.6 1,2,3-Triazoles

A. C. Tomé

This chapter is an update to the earlier Science of Synthesis contribution (Section 13.13) describing methods for the synthesis of 1,2,3-triazoles. Recent interest in this area has mainly been generated by the discovery that copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and ruthenium (II)-catalyzed azide–alkyne cycloaddition (RuAAC) regioselectively afford 1,4- or 1,5-disubstituted 1,2,3-triazoles in high yields under mild conditions. This review focuses on the contributions published between 2002 and 2013.

Keywords: 1,2,3-triazoles · azides · alkynes · click chemistry · Huisgen reaction · 1,3-dipolar cycloadditions · copper catalysts · ruthenium catalysts

16.10.5 Phthalazines

T. J. Hagen and T. R. Helgren

This chapter is an update to the earlier Science of Synthesis contribution (Section 16.10) concerning the synthesis and reactions of phthalazines. Literature from 2004 to early 2014 has been considered. The major focus since the initial publication involves phthalazine substituent modification rather than the synthesis of phthalazine rings.

Keywords: phthalazines · 2,3-dihydrophthalazine-1,4-diones · multicomponent reactions · cyclization · heteroarylation · cross coupling · hypervalent iodine

16.13.5 Quinazolines

F.-A. Kang and S.-M. Yang

This chapter is an update to the earlier Science of Synthesis contribution (Section 16.13) describing methods for the synthesis of quinazolines. It summarizes new technologies and surveys the literature published in the period 2002–2012.

Keywords: quinazolines · quinazolinones · quinazolinediones · nitriles · isocyanides · annulation · rearrangement · multicomponent condensation · cyclization · ionic liquids · copper(I) iodide · solid-phase synthesis · C—H insertion · carbon dioxide fixation · solvent free

24.4.2.3 1-(Organooxy) alk-1-ynes and 1-(Heterooxy) alk-1-ynes

M. H. Larsen, M. Cacciarini, and M. Brøndsted Nielsen

This manuscript is an update to the earlier Science of Synthesis contribution (Section 24.4.2) describing methods for the synthesis of 1-(organooxy) alk-1-ynes and 1-(heterooxy) alk-1-ynes. The original contribution describes the synthesis of six subgroups: alk-1-ynyl N, N-dialkylcarbamates, carboxylates, ethers, sulfonates, and dialkyl phosphonates as well as 1-siloxyalk-1-ynes. However, during the period covered in this update (2005–2014), new contributions have only been made in the field of alk-1-ynyl ethers and 1-siloxyalk-1-ynes. These methodologies, primarily methods centering on elimination reactions, are covered in this chapter, along with a short description of the applications of these two types of compound.

Keywords: alkynyl ethers · siloxyalkynes · elimination · Meyer–Schuster rearrangement · metal catalysis

24.4.4.4 1-Nitrogen-Functionalized Alk-1-ynes

K. Banert

This chapter is an update of the earlier Science of Synthesis contributions (Sections 24.4.4.1–24.4.4.3) describing methods for the synthesis of ynamines, and especially those alk-1-yn-1-amines that bear electron-withdrawing units such as N-acyl and N-sulfonyl groups. Compounds with C☰C bonds directly connected to azido or nitro functionalities are likewise updated, whereas the chemistry of N-alk-1-ynyl-substituted sulfoximines and isocyanates is described for the first time. The update focuses on new developments published in the period 2004–2014.

Keywords: alkynes · alkynylation · amines · azides · carboxamides · copper catalysis · dehydrohalogenation · isocyanates · nitro compounds · oxazolidinones · sulfonamides · sulfoximines

24.4.5.3 1-Phosphorus-Functionalized Alk-1-ynes

M. Cacciarini, M. H. Larsen, and M. Brøndsted Nielsen

This chapter is an update to the earlier Science of Synthesis contribution (Section 24.4.5) describing methods for the synthesis of 1-phosphorus-functionalized alk-1-ynes. The focus is on the literature published in the period 2006–2014.

Keywords: alkynylation · oxidative coupling · metal catalysis · (alk-1-ynyl) benziodoxolone reagents · alkynyl protecting groups

33.4.2.3 1-Nitrosoalkenes

H.-U. Reissig and R. Zimmer

This chapter deals with the generation of nitrosoalkenes from suitable precursors and their application as synthetically useful key intermediates in organic synthesis, including the synthesis of natural products and biologically active compounds. This is an update to Section 33.4.2, covering selected relevant literature that has been reported since 2007.

Keywords: nitrosoalkenes · dehydrohalogenation · halooximes · nitroalkene reduction · [4 + 2] cycloaddition · [3 + 2] cycloaddition · hetero-Diels–Alder · N-hydroxypyrroles · natural products

33.5.7.2 1,2-Dihydrophosphetes and Derivatives

Gy. Keglevich and A. Grün

This chapter is an update to the earlier Science of Synthesis contribution (Section 33.5.7) describing methods for the synthesis of 1,2-dihydrophosphetes. It focuses on the literature published in the period 2004–2015.

Keywords: vinyl compounds · titanium complexes · phosphorus heterocycles · phosphine oxides · metallacycles

33.5.8.2 2,3-Dihydro-1H-phospholes and Derivatives

Gy. Keglevich and A. Grün

This chapter is an update to the earlier Science of Synthesis contribution (Section 33.5.8) describing methods for the synthesis of 2,3-dihydro-1H-phospholes. It focuses on the literature published in the period 2004–2015.

Keywords: zirconium complexes · phosphorus heterocycles · phosphines · metallacycles · metathesis

33.5.9.2 1,2,3,4-Tetrahydrophosphinines and Derivatives

Gy. Keglevich and A. Grün

This chapter is an update to the earlier Science of Synthesis contribution (Section 33.5.9) describing methods for the synthesis of 1,2,3,4-tetrahydrophosphinines. It focuses on the literature published in the period 2004–2015.

Keywords: enamines · bromine compounds · phosphorus heterocycles · phosphonium salts · cyclization

33.5.10.2 1,4-Dihydrophosphinines and Derivatives

Gy. Keglevich and A. Grün

This chapter is an update to the earlier Science of Synthesis contribution (Section 33.5.10) describing methods for the synthesis of 1,4-dihydrophosphinines. It focuses on the literature published in the period 2004–2015.

Keywords: phosphorus heterocycles · phosphinic acids · unsaturated compounds · ring expansion · carbenes

35.1.1.1.9 Synthesis by Substitution of Hydrogen

J. Iskra and S. S. Murphree

This chapter is an update to the earlier Science of Synthesis contribution (Section 35.1.1.1) summarizing methodology for the chlorination of non-activated C—H bonds, with a particular focus on regioselectivity.

Keywords: chlorination · halogenation · chlorine compounds · halo compounds · chlorides · halides · alkanes · carbon—halogen bonds

35.2.1.1.8 Synthesis by Substitution of Hydrogen

J. Iskra

This chapter is an update to the earlier Science of Synthesis contribution (Section 35.2.1.1) summarizing methodology for the bromination of non-activated C—H bonds, with a particular focus on regioselectivity.

Keywords: bromination · halogenation · bromine compounds · halo compounds · bromides · halides · alkanes · carbon—halogen bonds

35.3.1.1.6 Synthesis by Substitution of Hydrogen

J. Iskra

This chapter is an update to the earlier Science of Synthesis contribution (Section 35.3.1.1) summarizing methodology for the iodination of non-activated C—H bonds, with a particular focus on regioselectivity.

Keywords: iodination · halogenation · iodine compounds · halo compounds · iodides · halides · alkanes · carbon—halogen bonds

35.3.1.2.7 Synthesis by Substitution of Metals

M. C. Elliott and B. A. Saleh

This chapter is an update to the earlier Science of Synthesis contribution (Section 35.3.1.2) describing methods for the synthesis of alkyl iodides from organometallic reagents, generally by addition of iodine, although other iodide sources have been used. It focuses on the literature published in the period 2005–2014.

Keywords: iodoalkanes · alkyl iodides · iodination · organometallic · organomercury · organozinc · organotin

35.3.1.3.8 Synthesis by Substitution of Carbon Functionalities

B. A. Saleh and M. C. Elliott

This chapter is an update to the earlier Science of Synthesis contribution (Section 35.3.1.3) describing methods for the synthesis of alkyl iodides from carboxylic acids and related compounds. It focuses on the literature published in the period 2005–2014.

Keywords: iodoalkanes · alkyl iodides · iodination · decarboxylation · hypervalent iodine

35.3.1.4.6 Synthesis by Substitution of Other Halogens

F. V. Singh and T. Wirth

Iodoalkanes are versatile reagents and precursors in a variety of organic reactions such as nucleophilic substitution, elimination, and metal-catalyzed C—C bond-forming reactions. In this chapter, various halogen-exchange approaches for the synthesis of iodoalkanes from other haloalkanes are described. The methods described cover the literature published in the period 2007–2014.

Keywords: halogen-exchange reaction · iodoalkanes · bromoalkanes · chloroalkanes · sodium iodide · phase-transfer catalyst

35.3.1.5.7 Synthesis by Substitution of Oxygen Functionalities

F. V. Singh and T. Wirth

Iodoalkanes are important synthetic intermediates in organic chemistry. These compounds undergo various reactions such as nucleophilic substitution, elimination, and metal-catalyzed C—C bond-forming reactions. This chapter describes various synthetic approaches available for the generation of C—I bonds from different oxygen functionalities and covers the literature published in the period 2007–2014.

Keywords: iodoalkanes · iodination · ionic liquids · silicaphosphine · polymethylhydrosiloxane · iodotrimethylsilane · alcohols · ethers · phosphate esters · sulfonate esters · microwave irradiation

35.3.1.8.7 Synthesis by Addition to π-Type C—C Bonds

U. Hennecke

This chapter is an update to the earlier Science of Synthesis contribution (Section 35.3.1.8) describing methods for the synthesis of iodoalkanes by addition reactions to π-type C—C bonds (mostly alkenes). It focuses mainly on the literature published in the period 2007– 2014.

Keywords: alkyl iodides · carbocyclization · carbocyclic compounds · carboiodination · electrophilic additions · iodo compounds

35.3.5.1.5 Synthesis by Addition across C═C Bonds

U. Hennecke

This chapter is an update to the earlier Science of Synthesis contribution (Section 35.3.5.1) describing methods for the synthesis of 1-iodo-2-heteroatom-substituted alkanes by addition reactions across C═C bonds. The chapter also covers the synthesis of 1-iodo-3-heteroatom-substituted alkanes including saturated 3-iodo-substituted heterocycles. It focuses mainly on the literature published in the period 2007–2014.

Keywords: alkyl iodides · electrophilic additions · iodination · iodo compounds · iodohydrins · iodolactonization · piperidines · Prins reaction

Science of Synthesis Knowledge Updates 2015/2

Preface

Abstracts

Table of Contents

1.3.6 Organometallic Complexes of Platinum (Update 2015)

A. Nomoto and A. Ogawa

1.6.9 Organometallic Complexes of Iridium (Update 2015)

H. Li and C. Mazet

13.13.6 1,2,3-Triazoles (Update 2015)

A. C. Tomé

16.10.5 Phthalazines (Update 2015)

T. J. Hagen and T. R. Helgren

16.13.5 Quinazolines (Update 2015)

F.-A. Kang and S.-M. Yang

24.4.2.3 1-(Organooxy) alk-1-ynes and 1-(Heterooxy) alk-1-ynes (Update 2015)

M. H. Larsen, M. Cacciarini, and M. Brøndsted Nielsen

24.4.4.4 1-Nitrogen-Functionalized Alk-1-ynes (Update 2015)

K. Banert

24.4.5.3 1-Phosphorus-Functionalized Alk-1-ynes (Update 2015)

M. Cacciarini, M. H. Larsen, and M. Brøndsted Nielsen

33.4.2.3 1-Nitrosoalkenes (Update 2015)

H.-U. Reissig and R. Zimmer

33.5.7.2 1,2-Dihydrophosphetes and Derivatives (Update 2015)

Gy. Keglevich and A. Grün

33.5.8.2 2,3-Dihydro-1H-phospholes and Derivatives (Update 2015)

Gy. Keglevich and A. Grün

33.5.9.2 1,2,3,4-Tetrahydrophosphinines and Derivatives (Update 2015)

Gy. Keglevich and A. Grün

33.5.10.2 1,4-Dihydrophosphinines and Derivatives (Update 2015)

Gy. Keglevich and A. Grün

35.1.1.1.9 Synthesis by Substitution of Hydrogen (Update 2015)

J. Iskra and S. S. Murphree

35.2.1.1.8 Synthesis by Substitution of Hydrogen (Update 2015)

J. Iskra

35.3.1.1.6 Synthesis by Substitution of Hydrogen (Update 2015)

J. Iskra

35.3.1.2.7 Synthesis by Substitution of Metals (Update 2015)

M. C. Elliott and B. A. Saleh

35.3.1.3.8 Synthesis by Substitution of Carbon Functionalities (Update 2015)

B. A. Saleh and M. C. Elliott

35.3.1.4.6 Synthesis by Substitution of Other Halogens (Update 2015)

F. V. Singh and T. Wirth

35.3.1.5.7 Synthesis by Substitution of Oxygen Functionalities (Update 2015)

F. V. Singh and T. Wirth

35.3.1.8.7 Synthesis by Addition to π -Type C— C Bonds (Update 2015)

U. Hennecke

35.3.5.1.5 Synthesis by Addition across C═ C Bonds (Update 2015)

U. Hennecke

Author Index

Abbreviations

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