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 The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction.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

Several tetrazolo[1,5-a]pyridines/2-azidopyridines undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes (7,10,13,16,19,22) as well as ring cleavage to cyanovinylketenimines (8,17,20b) in low temperature Ar matrices. 6,8-Dichlorotetrazolo[1,5-a]pyridine/2-azido-3,5-dichloropridine 6 undergoes ready exchange of the chlorine in position 8 (3) with ROH/RONa. 8-Chloro-6-trifluoromethyltetrazolo[1,5-a]pyridine 15 undergoes solvolysis of the CF3 group to afford 8-chloro-6-methoxycarbonyltetrazolo[1,5-a]pyridine 18. Several tetrazolopyridines/2-azidopyridines afford 1H- or 5H-1,3-diazepines in good yields on photolysis in the presence of alcohols or amines (11,14,23,25). 5-Chlorotetrazolo[1,5-a]pyridines/2-azido-6-chloropyridines 21 and 38 undergo a rearrangement to 1H- and 3H-3-cyanopyrroles 27 and 45, respectively. The mechanism of this rearrangement was investigated by 15N-labelling and takes place via transient 1,3-diazepines. The structures of 6,8-dichloro-tetrazolo[1,5-a]pyridine 6T, 6-chloro-8-ethoxytetrazolo[1,5-a]pyridine 9Tb, dipyrrolylmethane 28, and 2-isopropoxy-4-dimethylamino-5H-1,3-diazepine 25b were determined by X-ray crystallography. In the latter case, this represents the first reported X-ray crystal structure of a 5H-1,3-diazepine.

Synthesis of 1,3-diazepines and ring contraction to cyanopyrroles.

1,2-Didehydro-1,3-diazepines 4D, 5D, 4,6D and 5,6D are identified as unique products of both photolysis and thermolysis of azido-/tetrazolo-pyridines; the ultimate thermolysis products are trifluoromethylpyrrolecarbonitriles (7–9, 11–13 and 16–18).

Trifluoromethyl-substituted dehydrodiazepines and cyanopyrroles from azido-/tetrazolo-pyridines

As the prototype Curtius rearrangement reaction, carbamoyl azide decomposes into aminoisocyanate and molecular nitrogen. However, the key intermediate carbamoylnitrene was previously undetected, even though the decomposition of carbamoyl azides has been studied frequently since its discovery in the 1890s. Upon ArF laser (λ=193 nm) photolysis, the stepwise decomposition of the two simplest carbamoyl azides H2NC(O)N3and Me2NC(O)N3,isolated in solid noble gas matrices, occurs with the formation of the corresponding carbamoylnitrenes H2NC(O)N and Me2NC(O)N. Both triplet species are characterized for the first time by combining matrix-isolation IR spectroscopy and quantum-chemical calculations. Subsequent visible-light irradiations cause efficient rearrangement of these nitrenes into the respective aminoisocyanates. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Direct Observation of Carbamoylnitrenes.

NNS is produced by flash vacuum pyrolysis of 5-aryl-1,2,3,4-thiatriazoles 1, 3, 5, and 7 and 5-phenoxy-1,2,3,4-thiatriazole (9). The Ar matrix infrared spectrum shows nu(NN) at 2039 cm-1 and nu(NS) at 752 cm-1. The experimental data are compared with high-level ab initio as well as semiempirical (MNDO) calculated structural and vibrational data. NNS is destroyed photochemically or on heating to 160 K.

Infrared spectrum of dinitrogen sulfide

The photolysis of 2-azido-1,4-naphthoquinone (1) in argon matrices at 8 K results in the corresponding triplet vinylnitrene 32, which was detected directly by IR spectroscopy. Vinylnitrene 32 is stable in argon matrices but forms 2-cyanoindane-1,3-dione (3) upon further irradiation. Similarly, the irradiation of azide 1 in 2-methyltetrahydrofuran (MTHF) matrices at 5 K resulted in the ESR spectrum of vinylnitrene 32, which is stable up to at least 100 K. The zero-field splitting parameters for nitrene 32, D/hc = 0.7292 cm–1 and E/hc = 0.0048 cm–1, verify that it has significant 1,3-biradical character. Vinylnitrene 32 (λmax ∼ 460 nm, τ = 22 μs) is also observed directly in solution at ambient temperature with laser flash photolysis of 1. Density functional theory (DFT) calculations support the characterization of vinylnitrene 32 and the proposed mechanism for its formation. Because vinylnitrene 32 is relatively stable, it has potential use as a building-block for high-spin assemblies.

Curt Wentrup

Papers

Synthesis of 1,3-diazepines and ring contraction to cyanopyrroles.

Trifluoromethyl-substituted dehydrodiazepines and cyanopyrroles from azido-/tetrazolo-pyridines

Direct Observation of Carbamoylnitrenes.

Infrared spectrum of dinitrogen sulfide

Direct detection of a triplet vinylnitrene, 1,4-naphthoquinone-2-ylnitrene, in solution and cryogenic matrices.