James Sanderson

Organolithiums have passed the test! Previously considered too reactive and unstable, organolithiums have been tamed and can now participate successfully in palladium-catalysed cross-coupling with aryl/vinyl bromides and triflates.

The metal-catalysed hydrofunctionalisation of alkenes and alkynes provides a convenient and atom-economic route to diversely functionalised products with control of regio-, chemo- and stereoselectivity. As one of the most abundant elements on earth, iron offers a level of sustainable and long-term availability that is uncommon for most transition metals. Although iron is commonly found in the oxidation states of +2 and +3, the use of redox-active ligands has allowed the synthesis and application of low oxidation state iron complexes in catalysis. A broad range of hydrofunctionalisation reactions have been developed by using iron catalysts in a wide variety of oxidation states. Intense development over the past decade has resulted in the development of iron-catalysed hydroamination, hydroalkoxylation, hydrocarboxylation, hydrothiolation, hydrovinylation, hydrosilylation, hydroboration, hydrophosphination, hydromagnesiation and carbonylation reactions, amongst others. With the field still in its infancy, there is great potential for further developments in the mechanistic understanding and synthetic and industrial applicability of these processes.

Adding up the values: The hydrofunctionalisation of alkenes and alkynes provides a convenient and atom-economic route to functionalised, “value-added” products. There has been rapid expansion in the use of iron catalysts for these hydrofunctionalisation reactions. A variety of approaches have been developed that exploit the various redox states of iron complexes to give functionalised products with control of chemo-, regio- and stereoselectivity.

A highly practical, one-step, facile synthesis of aromatic, heteroaromatic, allylic and aliphatic nitriles from primary alcohols catalyzed by ferric nitrate [Fe(NO₃)₃⋅9H₂O] in the presence of TEMPO, aqueous ammonia and air at room temperature is described.

Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.

The synthesis of plantazolicin A, which exhibits desirable selective activity against the causative agent of anthrax toxicity, and its biosynthetic precursor plantazolicin B is reported. The syntheses were achieved through an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles, and the mild synthesis of thiazoles from natural amino acids.

A convenient and efficient iron-catalyzed nucleophilic addition of simple alkenes to isochroman acetals has been established for the synthesis of 1-alkenyl isochromans. In the presence of 5–20 mol % iron(III) p-toluenesulfonate, the alkenyl functionalized isochromans were prepared in moderate to excellent yields. This transformation provides a novel methodology for the synthesis of 1-alkenyl isochromans from simple alkenes and isochroman acetals.

Isn't it ironic? A convenient and efficient alkenylation method for synthesis of 1-alkenyl isochromans is established by the iron-catalyzed nucleophilic addition of simple alkenes to isochroman acetals. This new transformation proceeds very well in the presence of an inexpensive iron-catalyst under redox-neutral conditions. R=H, CH₃, Cl, Br or aryl , R¹=H, aryl or heteroaryl , R²=H, aryl or heteroaryl , Ts=tosyl.

A direct Pd-catalyzed CH functionalization of benzoquinone (BQ) can be controlled to give either mono- or disubstituted BQ, including the installation of two different groups in a one-pot procedure. BQ can now be directly functionalized with aryl, heteroaryl, cycloalkyl, and cycloalkene groups and, moreover, the reaction is conducted in environmentally benign water or acetone as solvents.

Direct CH functionalization of benzoquinone in water or acetone is now possible with Pd catalysis. The reaction can be controlled to afford either the mono- or the disubstituted product, and the difunctionalization includes the installation of two different groups in a one-pot procedure. 2,6-DCBQ=2,6-dichloro-1,4-benzoquinone, EDG=electron-donating group, EWG=electron-withdrawing group.

The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an average productivity 20 % lower than that of batch, whereas three-layer reactors were 20 % more productive. Finally, the utility of flow chemistry was demonstrated in the scale-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.

Spot the difference! By careful matching of reaction parameters, the performance of 13 different photochemical reactions were compared in both batch and flow reactors. Surprisingly, the yields obtained in the different reactor modes were essentially identical. Similarly, the productivity differences between the two reactor modes, under the same time scales, were relatively small (see figure).

A series of new, easily activated NHC–Pd^II precatalysts featuring a trans-oriented morpholine ligand were prepared and evaluated for activity in carbon-sulfur cross-coupling chemistry. [(IPent)PdCl₂(morpholine)] (IPent=1,3-bis(2,6-di(3-pentyl)phenyl)imidazol-2-ylidene) was identified as the most active precatalyst and was shown to effectively couple a wide variety of deactivated aryl halides with both aryl and alkyl thiols at or near ambient temperature, without the need for additives, external activators, or pre-activation steps. Mechanistic studies revealed that, in contrast to other common NHC–Pd^II precatalysts, these complexes are rapidly reduced to the active NHC–Pd⁰ species at ambient temperature in the presence of KOtBu, thus avoiding the formation of deleterious off-cycle Pd^II–thiolate resting states.

Sulfin' safari: A series of new, easily activated [(NHC)PdCl₂(morpholine)] complexes were prepared and evaluated for activity in the sulfination of aryl halides. [(IPent)PdCl₂(morpholine)] (1) was identified as the most active, effectively coupling a variety of deactivated aryl halides with aryl, alkyl, and silyl thiols at ambient temperature. Rapid reduction to the active NHC–Pd⁰ species obviates the need for additives, external activators, or cumbersome pre-activation steps.

The first examples of catalytic Wittig reactions with semistabilized and nonstabilized ylides are reported. These reactions were enabled by utilization of a masked base, sodium tert-butyl carbonate, and/or ylide tuning. The acidity of the ylide-forming proton was tuned by varying the electron density at the phosphorus center in the precatalyst, thus facilitating the use of relatively mild bases. Steric modification of the precatalyst structure resulted in significant enhancement of E selectivity up to >95:5, E/Z.

Time for a tune up: Catalytic Wittig reactions with semi- and nonstabilized ylides were enabled by use of a masked base (NaOCO₂tBu) and/or ylide tuning. The acidity of the ylide-forming proton was tuned by varying the electron density at the P center in the precatalyst, thus facilitating the use of relatively mild bases. Steric modification of the precatalyst structure resulted in significant enhancement of E selectivity.

A wide range of air-stable, solid, polyfunctional aryl and heteroarylzinc pivalates were efficiently prepared by either magnesium insertion or Hal/Mg exchange followed by transmetalation with Zn(OPiv)₂ (OPiv=pivalate). By reducing the amount of LiCl the air stability could be significantly enhanced compared with previously prepared reagents. An alternative route is directed magnesiation using TMPMgCl⋅LiCl (TMP=2,2,6,6-tetramethylpiperidyl) followed by transmetalation with Zn(OPiv)₂ or, for very sensitive substrates, direct zincation by using TMPZnOPiv. These zinc reagents not only show excellent stability towards air, but they also undergo a broad range of CC bond-formation reactions, such as allylation and carbocupration reactions, as well as addition to aldehydes and 1,4-addition reactions. Acylation reactions can be performed by using an excess of TMSCl to overcome side reactions of the omnipresent pivalate anion.

Reactive but stable: The preparation of polyfunctional, air-stable, solid aryl and heteroaryl organozinc pivalates by either Mg insertion or Hal–Mg (Hal=Br, I) exchange, followed by transmetalation with Zn(OPiv)₂ (OPiv=pivalate) or alternatively by directed metalation is described. The zinc reagents show excellent stability in air (up to 4 h at 25 °C) and undergo a range of reactions including allylation, acylation, and carbocupration reactions, additions to aldehydes, and 1,4-addition reactions (see scheme).