Gregory B. Dudley

Correspondence on Microwave Effects in Organic Synthesis

Angewandte Chemie recently published an unusual Essay by Prof. C. Oliver Kappe and co-workers entitled, “Microwave Effects in Organic Synthesis—Myth or Reality?” The major point of discussion is an Edge Article we published last year in the RSC journal Chemical Science entitled, “On the Rational Design of Microwave-Actuated Organic Reactions.” The Angewandte Essay is unusual in its inclusion of 38 pages of experimental details in the Supporting Information, 30 of which describe unpublished data from original experiments pertaining to our work. These data are interpreted as conflicting with our report. We reject their alternative interpretations of our experiments, and we discuss here how the new data from their experiments in fact align with our conclusions. In our article, we provided an example of a microwave (MW)-actuated reaction system, which we define as one for which MW irradiation provides a synthetic advantage over conventional heating at the same temperature. We designed an extreme reaction system—an ionic benzyl-transfer reagent in a nonpolar aromatic solvent—and subjected it to extreme conditions: constant MW irradiation at high power (300 W). Our design of this chemical system was predicated on the concept of selective heat storage in the domains existing around microwave-absorbing solutes in nonabsorbing media at fixed (and typically high) applied microwave powers. The design rationale aligns with an understanding of selective microwave heating obtained from fundamental dielectric relaxation studies carried out by Richert and Huang. In such a system, the selective absorption of microwave energy by the solute will result in localized energy in the solvation domain (i.e. effective temperature) that is higher than the surrounding medium. The solute then acts as a molecular radiator, transferring thermal energy to the bulk solution. If convective heat transfer out of the domains is slow compared to the build-up of thermal energy within the solute domains, then the thermal energy of the solute will exceed what would be predicted based on the measured temperature of the bulk solution. As an extension of that work, one can hypothesize that a microwave-absorbing reactant in a nonabsorbing medium can potentially realize product formation at rates in excess of what would be expected from conventional heating at the same measured bulk temperature. Indeed, we observed reactivity enhancements under MW heating compared to conventional oil-bath heating in a benzylation of [D10]pxylene (Figure 1).

On the rational design of microwave-actuated organic reactions

Microwave-actuated organic reactions are defined herein as chemical reaction systems for which microwave irradiation provides a clear benefit over conventional heating to the same temperature. This study is focused on a rationally designed, microwave-actuated reaction (thermal Friedel–Crafts benzylation), in which a microwave-absorbing ionic solute reacts in a non-polar and largely microwave-transparent solvent. Steady-state microwave irradiation (ssMWi) induces observed levels of reactivity from the solute that cannot be duplicated by conventional heating of the homogeneous solution to similar temperatures. This observation is qualitatively consistent with the Arrhenius [k = Ae(−Ea/RT)] relationship between rate and molecular collisions (k ∝ A at constant T). A new paradigm for designing microwave-actuated organic reactions for microwave-assisted organic synthesis emerges from this study.

Stereocontrol of 5,5-Spiroketals in the Synthesis of Cephalosporolide H Epimers

A blueprint for controlling the stereochemistry of oxygenated 5,5-spiroketals using chelation effects is provided. Chelation specifically of zinc salts (other protic and Lewis acids were less effective) between the spiroketal oxygen and an appropriately positioned alcohol group overrides normal biases in the preparation of 5,5-spiroketals, as illustrated by the stereocontrolled synthesis of epimeric cephalosporolide H isomers. This study provides new and valuable information for prescribing the chirality of the stereogenic core of 5,5-spiroketals.

Remarkable stereoselectivity in the alkylation of a hydroazulenone: progress towards the total synthesis of guanacastepene

Abstract exo-Methylene ketone 6 serves as a vehicle for elaboration of the C8 quaternary center en route to guanacastepene via a conjugate addition–alkylation sequence. Methylation of the cycloheptadienolate derived from 7 is highly selective for the desired relative stereochemistry, as determined by NMR and crystallographic analysis.

Parameters Affecting the Microwave-Specific Acceleration of a Chemical Reaction

Under appropriate conditions, significant microwave-specific enhancement of the reaction rate of an organic chemical reaction can be observed. Specifically, the unimolecular Claisen rearrangement of allyl p-nitrophenyl ether (ApNE) dissolved in naphthalene was studied under microwave heating and conventional convective (thermal) heating. Under constant microwave power, reaching a temperature of 185 °C, a 4-fold rate enhancement was observed in the microwave over that using convective heating; this means that the microwave reaction was proceeding at an effective temperature of 202 °C. Conversely, under constant temperature microwave conditions (200 °C), a negligible (∼1.5-fold) microwave-specific rate enhancement was observed. The largest microwave-specific rate enhancement was observed when a series of 300 W pulses, programmed for 145-175 °C and 85-155 °C cycles, where 2- and 9-fold rate enhancements, over what would be predicted by conventional thermal heating, was observed, respectively. The postulated origins of the microwave-specific effect are purely thermal and arise from selective heating of ApNE, a microwave-absorbing reactant in a nonabsorbing solvent. Under these conditions, excess heat is accumulated in the domains around the ApNE solute so that it experiences a higher effective temperature than the measured temperature of the bulk medium, resulting in an accelerated unimolecular rearrangement.

Strain-promoted azide-alkyne cycloadditions of benzocyclononynes.

Preliminary studies related to the design and development of new cycloalkyne reagents for metal-free click coupling are reported. Cyclononynes are more stable than cyclooctynes, and the robust benzocyclononyne platform offers spontaneous reactivity toward azides at rates competitive with other azidophiles that have been employed for metal-free click coupling. Benzocyclononynes (e.g., 1) provide valuable insight into the design of new cycloalkynes for strain-promoted azide-alkyne cycloaddition (SPAAC) couplings for applications in which side reactions and decomposition of the reagent must be kept to a minimum.

A gold-catalyzed alkyne-diol cycloisomerization for the synthesis of oxygenated 5,5-spiroketals

Summary A highly efficient synthesis of oxygenated 5,5-spiroketals was performed towards the synthesis of the cephalosporolides. Gold(I) chloride in methanol induced the cycloisomerization of a protected alkyne triol with concomitant deprotection to give a strategically hydroxylated 5,5-spiroketal, despite the potential for regiochemical complications and elimination to furan. Other late transition metal Lewis acids were less effective. The use of methanol as solvent helped suppress the formation of the undesired furan by-product. This study provides yet another example of the advantages of gold catalysis in the activation of alkyne π-systems.

Generation of medium-ring cycloalkynes by ring expansion of vinylogous acyl triflates.

Reductive cyclization of aryl and vinyl iodides tethered to vinylogous acyl triflates (VATs) induces a ring-expanding fragmentation to provide cyclic alkynyl ketones, including strained nine-membered cycloalkynes, in fair to excellent yield. The tandem cyclization/C-C bond-cleavage is initiated under carefully optimized conditions by halogen-metal exchange in the presence of carbonyl and vinyl triflate functionality. A modified protocol for alkylation of 1,3-cyclohexanedione is described for preparing the relevant VAT substrates.

Ring Opening of Cyclic Vinylogous Acyl Triflates Using Stabilized Carbanion Nucleophiles: Claisen Condensation Linked to Carbon−Carbon Bond Cleavage

Addition of stabilized carbanionic nucleophiles to cyclic vinylogous acyl triflates (VATs) triggers a ring-opening fragmentation to give acyclic beta-keto ester and related products, much like those observed traditionally in the Claisen condensation. Unlike in the classical Claisen condensation, however, the VAT-Claisen reaction described herein is rendered irreversible by C-C bond cleavage, not by deprotonation of the activated methylene product. Full details of this original reaction methodology are disclosed herein, including how subtle differences between the various nucleophiles impact the proper choice of reaction conditions for making 1,3-diketones, beta-keto esters, and beta-keto phosphonates.

[1,2]-Anionic rearrangement of 2-benzyloxypyridine and related pyridyl ethers.

An anionic rearrangement of 2-benzyloxypyridine is described. Pyridine-directed metalation of the benzylic carbon leads to 1,2-migration of pyridine via a postulated associative mechanism (addition/elimination). Several aryl pyridyl carbinols were obtained in high yields. A formal synthesis of carbinoxamine, an antihistamine drug used for the treatment of seasonal allergies and hay fever, emerges from this methodology.