Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200400655

Controlled microwave heating in modern organic synthesis.

Since the discovery of organic azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich molecules have been developed. In more recent times in particular, completely new perspectives have been developed for their use in peptide chemistry, combinatorial chemistry, and heterocyclic synthesis. Organic azides have assumed an important position at the interface between chemistry, biology, medicine, and materials science. In this Review, the fundamental characteristics of azide chemistry and current developments are presented. The focus will be placed on cycloadditions (Huisgen reaction), aza ylide chemistry, and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chemistry.

Organic Azides: An Exploding Diversity of a Unique Class of Compounds

Asymmetric 1,3-Dipolar Cycloaddition Reactions

The Diels-Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule construction, the Diels-Alder cycloaddition has afforded numerous and unparalleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder's birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized.

https://www.ch.ic.ac.uk/local/organic/pericyclic/DA.pdf

The Diels--Alder reaction in total synthesis.

Introduction Cationic domino reactions Anionic domino reactions Radical domino reactions Pericyclic domino reactions Photochemically induced domino processes Transition metal catalysis Domino reactions initiated by oxidation or reduction Enzymes in domino reactions Multicomponent reactions Special techniques in domino reactions

Domino Reactions in Organic Synthesis

Geometrical isomers of a bridgehead imine: (E)- and (Z)-2-azabicyclo[3.2.1]oct-1-ene, and 2-azabicyclo[2.2.2]oct-1-ene

Flash vacuum thermolysis (FVT) of 1-(dimethylamino)pyrrole-2,3-diones 5 causes extrusion of CO with formation of transient hydrazonoketenes 7. The transient ketenes 7 are observable in the form of weak bands at 2130 (7a) or 2115 cm−1
(7b) in the Ar matrix IR spectra resulting from either FVT or photolysis of either 5 or 1,1-dimethylpyrazolium-5-oxides 8, and these absorptions are in excellent agreement with B3LYP/6-31G* frequency calculations. Under FVT conditions the ketenes 7 cyclize to pyrazolium oxides 8, which undergo 1,4-migration of a methyl group to yield 1,4-dimethyl-3-phenylpyrazole-5(4H)-one 9a and 1,4,4-trimethyl-3-phenylpyrazole-5(4H)-one 9b. All three tautomers of 9a have been characterized, viz. the CH form 9a
(most stable form in the gas phase, the solid state and solvents of low polarity), the OH form 9a′
(metastable solid at room temperature) and the NH form 9a″
(stable in aprotic dipolar solvents). The isomeric 1,4-dimethyl-5-phenylpyrazole-3(2H)-one 12 tautomerizes to the 3-hydroxypyrazole 12′. The crystal structure of the hydrochloride 14 of 9a′/9a″ is reported, representing the first structurally characterised example of a protonated 5-hydroxypyrazole.

N-Aminopyrroledione–hydrazonoketene–pyrazolium oxide–pyrazolone rearrangements and pyrazolone tautomerism

Carbenes are molecules with a carbon atom bound to just two other atoms. These species are usually transient intermediates. In his Perspective, [Wentrup][1] charts recent progress in the synthesis of stable carbenes. He highlights the report by [ SolA© et al .][2], who have succeeded in synthesizing an unusually stable carbene that retains its reactivity. Such species may find future application as catalysts.

 [1]: http://www.sciencemag.org/cgi/content/full/292/5523/1846
 [2]: http://www.sciencemag.org/cgi/content/short/292/5523/1901

Fleeting Molecules Extend Their Stay

Thermolysis of tetrazolopyrazine (1) in organic solvents gives pyrazinylnitrene (2) which undergoes ring contraction to 1-cyanoimidazole (3). 7-Methyl-5-methylthio-tetrazolo[1,5-c]pyrimidine (4) likewise gives 1-cyano-2-methylthio-4-methyl-imidazole (6). The two tetrazoles also undergo ring contraction to 1-cyanoimidazoles by gas chromatography, and 1 gives a low yield of 3 by photolysis. Thermolysis of 1 and 4 in cyclohexane gives aminopyrazine (7) and 6-amino-4-methyl-2-methylthio-pyrimidine (8), respectively. Tetrazolo[1,5-a]pyrimidines (9) give only 2-aminopyrimidines (10).



1-Cyanoimidazole, formed by thermolysis of 1 in acetic acid, reacts further to give 1-acetylimidazole, which with more acetic acid gives imidazole and acetic anhydride. An earlier report [2] of ring expansion of pyrazinylnitrene in acetic acid is discredited.



In protic deuteriated solvents (D3O, CH3OD), tetrazolopyrazine reacts as an enamine, specifically exchanging HC(6) for deuterium.

Hetarylnitrenes V. Reactions of Tetrazolopyrazine Ring Contraction of Nitrenodiazines in Solution. Preliminary communication

o-Tolylacetylene 5 is obtained by flash vacuum pyrolysis (FVP) of the isoxazolone 13a at 800 °C/10–4 hPa. At 900–1000 °C the acetylene 5 isomerizes to indene 1, which reacts further by elimination of a hydrogen atom and dimerization of the 1-indenyl radical 9 to 1,1′-biindenyl 10. The latter undergoes partial isomerization to 3,3′-biindenyl 16, and further pyrolysis of the biindenyls yields higher polycyclic aromatic hydrocarbons (PAHs), particularly chrysene 2. C–H bond breakage in indene, which occurs with an activation energy of 80 ± 5 kcal/mol with formation of the 1-indenyl radical 9, has been the subject of much investigation in relation to hydrocarbon combustion, in particular the formation of chrysene and other PAHs from indene, which itself is formed in the combustion of toluene and other hydrocarbons. However, C–C bond breakage also needs to be considered. Calculations at the B3LYP/6-311+G(d,p) level indicate that key C–C bond breakages in indene have free energies of activation of ca. 80 kcal/m...

Curt Wentrup

Papers

Geometrical isomers of a bridgehead imine: (E)- and (Z)-2-azabicyclo[3.2.1]oct-1-ene, and 2-azabicyclo[2.2.2]oct-1-ene

N-Aminopyrroledione–hydrazonoketene–pyrazolium oxide–pyrazolone rearrangements and pyrazolone tautomerism

Fleeting Molecules Extend Their Stay

Hetarylnitrenes V. Reactions of Tetrazolopyrazine Ring Contraction of Nitrenodiazines in Solution. Preliminary communication

C9H8 Pyrolysis. o-Tolylacetylene, Indene, 1-Indenyl, and Biindenyls and the Mechanism of Indene Pyrolysis