The Kornblum DeLaMare rearrangement in natural product synthesis: 25 years of innovation.

Covering: 1998 up to the end of 2023Since its initial disclosure in 1951, the Kornblum DeLaMare rearrangement has proved an important synthetic transformation and has been widely adopted as a biomimetic step in natural product synthesis. Utilising the base catalysed decomposition of alkyl peroxides to yield a ketone and alcohol has found use in many syntheses as well as a key strategic step, including the unmasking of furans, as a biomimetic synthetic tool, and the use of the rearrangement to install oxygen enantioselectively. Since ca. 1998, its impact as a synthetic transformation has grown significantly, especially given the frequency of use in natural product syntheses, therefore this 25 year time period will be the focus of the review.

High-Productivity Single-Pass Electrochemical Birch Reduction of Naphthalenes in a Continuous Flow Electrochemical Taylor Vortex Reactor.

We report the development of a single-pass electrochemical Birch reduction carried out in a small footprint electrochemical Taylor vortex reactor with projected productivities of >80 g day-1 (based on 32.2 mmol h-1), using a modified version of our previously reported reactor [Org. Process Res. Dev. 2021, 25, 7, 1619-1627], consisting of a static outer electrode and a rapidly rotating cylindrical inner electrode. In this study, we used an aluminum tube as the sacrificial outer electrode and stainless steel as the rotating inner electrode. We have established the viability of using a sacrificial aluminum anode for the electrochemical reduction of naphthalene, and by varying the current, we can switch between high selectivity (>90%) for either the single ring reduction or double ring reduction with >80 g day-1 projected productivity for either product. The concentration of LiBr in solution changes the fluid dynamics of the reaction mixture investigated by computational fluid dynamics, and this affects equilibration time, monitored using Fourier transform infrared spectroscopy. We show that the concentrations of electrolyte (LiBr) and proton source (dimethylurea) can be reduced while maintaining high reaction efficiency. We also report the reduction of 1-aminonaphthalene, which has been used as a precursor to the API Ropinirole. We find that our methodology produces the corresponding dihydronaphthalene with excellent selectivity and 88% isolated yield in an uninterrupted run of >8 h with a projected productivity of >100 g day-1.

Continuous Photo-Oxidation in a Vortex Reactor: Efficient Operations Using Air Drawn from the Laboratory.

We report the construction and use of a vortex reactor which uses a rapidly rotating cylinder to generate Taylor vortices for continuous flow thermal and photochemical reactions. The reactor is designed to operate under conditions required for vortex generation. The flow pattern of the vortices has been represented using computational fluid dynamics, and the presence of the vortices can be easily visualized by observing streams of bubbles within the reactor. This approach presents certain advantages for reactions with added gases. For reactions with oxygen, the reactor offers an alternative to traditional setups as it efficiently draws in air from the lab without the need specifically to pressurize with oxygen. The rapid mixing generated by the vortices enables rapid mass transfer between the gas and the liquid phases allowing for a high efficiency dissolution of gases. The reactor has been applied to several photochemical reactions involving singlet oxygen (1O2) including the photo-oxidations of α-terpinene and furfuryl alcohol and the photodeborylation of phenyl boronic acid. The rotation speed of the cylinder proved to be key for reaction efficiency, and in the operation we found that the uptake of air was highest at 4000 rpm. The reactor has also been successfully applied to the synthesis of artemisinin, a potent antimalarial compound; and this three-step synthesis involving a Schenk-ene reaction with 1O2, Hock cleavage with H+, and an oxidative cyclization cascade with triplet oxygen (3O2), from dihydroartemisinic acid was carried out as a single process in the vortex reactor.

Continuous N-alkylation reactions of amino alcohols using γ-Al2O3 and supercritical CO2: unexpected formation of cyclic ureas and urethanes by reaction with CO2.

The use of γ-Al2O3 as a heterogeneous catalyst in scCO2 has been successfully applied to the amination of alcohols for the synthesis of N-alkylated heterocycles. The optimal reaction conditions (temperature and substrate flow rate) were determined using an automated self-optimising reactor, resulting in moderate to high yields of the target products. Carrying out the reaction in scCO2 was shown to be beneficial, as higher yields were obtained in the presence of CO2 than in its absence. A surprising discovery is that, in addition to cyclic amines, cyclic ureas and urethanes could be synthesised by incorporation of CO2 from the supercritical solvent into the product.

Efficient Preparation of TMSCCl2 Br and Its Use in Dichlorocyclopropanation of Electron-Deficient Alkenes.

The reaction of excess TMSCl and LiCCl2 Br at low temperature is a technically simple high yield route to TMSCCl2 Br. The latter is a stable source of the dichlorobromomethide carbanion, which undergoes 1,4-addition with cyclic nitroalkenes and (E)-fumarates leading to dichlorocyclopropanes after bromide expulsion. For nitrostyrenes the reaction arrests at the 1,4-addition product. Low temperature NMR spectroscopy studies and DFT calculations suggest the formation of an "ate" species [(nitronate)SiFMe3 ](-) which, upon boil-off of TMSF at 10-20 °C, yields the cyclopropane. DFT calculations also support the experimental differences between fluoride and acetate as promotors.

Vanadium(V) Oxo and imido calix[8]arene complexes: synthesis, structural studies, and ethylene homo/copolymerisation capability.

Interaction of p-tert-butylcalix[8]areneH8 (L(8) H8 ) with [NaVO(OtBu)4 ] (formed in situ from VOCl3 ) afforded the complex [Na(NCMe)5 ][(VO)2 L(8) H]⋅4 MeCN (1⋅4 MeCN). Increasing [NaVO(OtBu)4 ] to 4 equiv led to [Na(NCMe)6 ]2 [(Na(VO)4 L(8) )(Na(NCMe))3 ]2 ⋅10 MeCN (2⋅10 MeCN). With adventitious oxygen, reaction of 4 equiv of [VO(OtBu)3 ] with L(8) H8 afforded the alkali-metal-free complex [(VO)4 L(8) (µ(3) -O)2 ] (3); solvates 3⋅3 MeCN and 3⋅3 CH2 Cl2 were isolated. For the lithium analogue, the order of addition had to be reversed such that lithium tert-butoxide was added to L(8) H8 and then treated with 2 equiv of VOCl3 ; crystallisation afforded [(VO2 )2 Li6 [L(8) ](thf)2 (OtBu)2 (Et2 O)2 ]⋅Et2 O (4⋅Et2 O). Upon extraction into acetonitrile, [Li(NCMe)4 ][(VO)2 L(8) H]⋅8 MeCN (5⋅8 MeCN) was formed. Use of the imido precursors [V(NtBu)(OtBu)3 ] and [V(Np-tolyl)(OtBu)3 ] and L(8) H8 , afforded [tBuNH3 ][{V(p-tolylN)}2 L(8) H]⋅3 1/2 MeCN (6⋅3 1/2 MeCN). The molecular structures of 1 to 6 are reported. Complexes 1, 3, and 4 were screened as precatalysts for the polymerisation of ethylene in the presence of cocatalysts at various temperatures and for the copolymerisation of ethylene with propylene. Activities as high as 136 000 g (mmol(V) h)(-1) were sometimes achieved; higher molecular weight polymers could be obtained versus the benchmark [VO(OEt)Cl2 ]. For copolymerisation, incorporation of propylene was 7.1-10.9 mol % (compare 10 mol % for [VO(OEt)Cl2 ]), although catalytic activities were lower than [VO(OEt)Cl2 ].

Palladium-catalyzed stereoselective intramolecular oxidative amidation of alkenes in the synthesis of 1,3- and 1,4-amino alcohols and 1,3-diamines.

An efficient and practical Pd-catalyzed intramolecular oxidative allylic amidation provides facile access to derivatives of 1,3- and 1,4-amino alcohols and 1,3-diamines. The method operates under mild reaction conditions (RT) with molecular oxygen (1 atm) as the sole reoxidant of Pd. Excellent diastereoselectivities were attained with substrates bearing a secondary stereogenic center.

Two related lithium calixarene complexes, [p-tert-butylcalix[4]arene(OMe)(OH)2(OLi)](2).4MeCN and {p-tert-butylcalix[4]arene(OH)2(OLi)[OLi(NCMe)2]}(2).8MeCN, determined using synchrotron radiation.

The crystal structures of acetonitrile solvates of two related lithium calixarene complexes have been determined by low-temperature single-crystal X-ray diffraction using synchrotron radiation. Bis(mu-5,11,17,23-tetra-tert-butyl-26,28-dihydroxy-25-methoxy-27-oxidocalix[4]arene)dilithium(I) acetonitrile tetrasolvate, [Li2(C45H57O4)2].4C2H3N or [p-tert-butylcalix[4]arene(OMe)(OH)2(OLi)](2).4MeCN, (I), crystallizes with the complex across a centre of symmetry and with four molecules of unbound acetonitrile of crystallization per complex. Tetraacetonitrilebis(mu-5,11,17,23-tetra-tert-butyl-26,28-dihydroxy-25,27-dioxidocalix[4]arene)tetralithium(I) acetonitrile octasolvate, [Li4(C44H54O4)2(C2H3N)4].8C2H3N or {p-tert-butylcalix[4]arene(OH)2(OLi)[OLi(NCMe)2]}(2).8MeCN, (II), also crystallizes with the complex lying across a centre of symmetry and contains eight molecules of unbound acetonitrile per complex plus four more directly bound to two of the lithium ions, two on each ion. The cores of both complexes are partially supported by O-H...O hydrogen bonds. The methoxy methyl groups in (I) prevent the binding of any more than two Li+ ions, while the corresponding two O-atom sites in (II) bind an extra Li(+) ion each, making four in total. The calixarene cone adopts an undistorted cone conformation in (I), but an elliptical one in (II).