Arbeitsgruppe Hartung


B) Vanadium-catalyzed Oxidation

cis-2,6-Bis-(methanolate)-piperidine Oxovanadium(V) Complexes as Catalysts for Oxidative Alkenol Cyclization by tert-Butyl Hydroperoxide

1. Keywords:

Alkenol; Alkyl hydroperoxide; Catalysis; Epoxidation; Ligand substitution; Oxepane; Oxidation; Stereoselective synthesis; Tetrahydrofuran; Tetrahydropyran; Vanadium.


2. Summary:

cis-2,6-Bis-(methanolate)-piperidine oxovanadium(V) complexes are Lewis-acids able to catalyze oxidative cyclization of alkenols by tert-butyl hydroperoxide (TBHP). Terminal dimethyl-substituted (prenyl-type) 4-pentenols bearing an alkyl or a phenyl group in position 1 afford under such conditions 2,5-cis-derivatives of 2-(tetrahydrofuran-2-yl)-2-propanols as major and tetrahydropyran-3-ols as minor products (four examples). Oxidizing a prenyl-type 5-hexenol yields a 75/25-mixture of 2-(tetrahydropyran-2-yl)-2-propanol and oxepan-3-ol, while 2-propenols give epoxides in up to 94% yield. Epoxidizing geraniol by TBHP in the presence of a vanadium catalyst prepared from (2S,6R)-2-diphenylmethanol-6-hydroxymethylpiperidine occurs enantioselectively. Highfield shifts of vanadium-51 resonances upon adding alkyl hydroperoxides to solutions of cis-2,6-bis-(methanolate)-piperidine vanadium(V) complexes point to vanadium(V)-binding as key step for activating peroxides.


3. Introduction and outline:

Oxovanadium(V) compounds are Lewis-acids, able to activate alkyl hydroperoxides for selectively converting prochiral alkenols into epoxides, tetrahydrofurans, or tetrahydropyrans (Scheme 1). These target compounds are subunits of several natural products and used as building blocks for preparing secondary metabolites, artificial ionophores, molecular devices, receptors, and other functional molecules.

The most important alkyl hydroperoxide used in science and engineering for oxidizing alkenols is tert-butyl hydroperoxide (TBHP). TBHP dissolves in polar and non-polar organic solvents and is stable unless heated, photolyzed, protonated, or treated with a reductant. TBHP is a nucleophile, converting alkyl vanadates at room temperature into vanadyl(V) peresters. The d0-metal center in peroxy vanadium(V) compounds withdraws electrons from the peroxide functional group, causing the peroxide entity to become an electrophile and thus able to oxidize p-bonds of alkenols. Oxidations by TBHP afford tert-butanol as by-product, which has a sufficiently low boiling point (bp 83 °C) for being evaporated from reaction mixtures and possibly used to prepare tert-butyl ethers or -esters serving as additives, reagents, or solvents.

Scheme 1. Products of alkenol oxidation by tert-butyl hydroperoxide ([O] = tert-butyl hydroperoxide catalyzed by an oxovanadium(V) complex (vide infra); ○, ● = hydrogen, methyl, or aryl; R = hydrogen, alkyl, or aryl).


Almost all vanadium compounds for activating TBHP in use today are O-esters of ortho-vanadic acid, having one or two alkoxy groups replaced by a chelate ligand, binding via oxygen and nitrogen donor atoms to the metal. Auxiliaries of this kind alter electron population and steric demand at vanadium, improving chemoselectivity and directing stereoselectivity in alkenol oxidation. The most effective auxiliaries for controlling selectivity in vanadium(V)-catalyzed oxidation by TBHP are bishydroxamates for epoxidation of 2-propenols (allylic alcohols), 3-butenols (homoallylic alcohols), and Schiff base-derived iminodiolates for oxidatively cyclizing 4-pentenols into (tetrahydrofuran-2-yl)-methanols.

Our interest in transition metal-catalyzed oxidation started with the quest for controlling regio- (exo/endo) and stereoselectivity (cis/trans) in synthesis of a medium-sized ether from terpenol- and acetogenin-derived alkenols using peroxides as terminal oxidants (Scheme 1). Medium sized ethers (Figure 1) frequently exhibit attractive physiological effects, motivating us to develop selective syntheses of this product class. For many years, vanadium-catalyzed oxidation contributed to advances in the field of oxidative alkenol cyclizations, based on otherwise unmatched 2,5-cis- and 2,4-trans-selectivity for tetrahydrofuran synthesis from terminal dimethyl-substituted (prenyl-type) 4-pentenols.

Figure 1. Natural products from an exo-cyclized 4-pentenol (left) and endo-cyclized alkenols (center and right).


In the course of an ongoing project, we increasingly faced the problem of declining chemoselectivity, as reaction times extended to several days, and additional TBHP had to be added for attaining quantitative alkenol oxidation in reactions catalyzed by oxovanadium(V) iminodiolate complexes. To solve the chemoselectivity problem, we searched for new oxidation catalysts. The most important results from the project show that cis-2,6-bis-(methanolate)-piperidine vanadium(V) complexes (Scheme 1, Figure 1) are valuable Lewis-acids for activating alkyl hydroperoxides with improved chemoselectivity (Schemes 2 and 3). Prenyl-type 4-pentenols, a 5-hexenol, and 2-propenols furnish products of oxidative cyclization in usefield yields with noteworthy selectivity. Epoxidizing geraniol by TBHP in the presence of a vanadium catalyst prepared from (2S,6R)-2-diphenylmethanol-6-hydroxymethylpiperidine occurs enantioselectively (Scheme 4). Highfield shifts of vanadium-51 resonances upon adding alkyl hydroperoxides to solutions of cis-2,6-bis-(methanolate)-piperidine vanadium(V) complexes point to vanadium(V)-binding as key step for activating peroxides.


4. Results:

Scheme 1. General method for preparing oxovanadium(V) complexes 2ad VO(Ln)(OEt) from tridentate auxiliaries H2Ln (1ad) and triethyl vanadate [n = 1–4, vide infra; protons substituted by vanadium(V) are printed in bold; VO(L4)(OEt) crystallizes as EtOH-adduct from a solution of ethanol].

Figure 1. Ellipsoid graphic (50 % probability) of piperidine-derived oxovanadium complexes 2b (left) and 2c (right, ethyl part of the ethoxo-group is disordered over two positions with site occupancies of 0.6 and 0.4) in the solid state (150 K; vanadium is depicted in orange, oxygen in red, nitrogen in blue, and carbon in black; hydrogen is drawn as a circle of an arbitrary radius).

Scheme 2. Yields of purified products obtained from oxidation of alkenols by TBHP, catalyzed by piperidine-derived vanadium complexes 2a and 2c.

Scheme 3. Products of 6-methyl-1-phenylhept-5-en-1-ol oxidation by TBHP in vanadium-catalyzed reaction.

Scheme 4. Products of 6-methyl-1-phenylhept-5-en-1-ol oxidation by TBHP in vanadium-catalyzed reaction.



5. Concluding remarks:

Piperidine-2,6-bismethanol-derived oxovanadium(V) complexes 2ac are valuable Lewis-acids, able to chemoselectively activate alkyl hydroperoxides for preparing 2-(tetrahydrofuran-2-yl)-2-propanols, 2-(tetrahydropyran-2-yl)-2-propanols, oxepan-3-ols, and epoxides from alkenols. Major advantages for using the new family of oxidation catalysts relate to improved chemical inertness of the saturated tridentate auxiliary, enhanced reactivity, and improved chemoselectivity, compared to oxidations catalyzed by iminodiol-derived Schiff-base complex 2d.

Summarizing the chemical progress made in synthesis of hydroxyl-substituted cyclic ethers from alkenols, we consider cis-2,6-bis-(hydroxymethyl)-piperidine complexes of oxovanadium(V) as promising leads for solving the standing problem on controlling stereoselectivity for oxidative tetrahydrofuran synthesis from alkenols. Chirality transfer according to the concept pursued in this project relies on C1-symmetry for auxiliary 1c with the aim to control configuration in vanadium complex 2c and all other vanadium compounds involved in selectivity determining steps . So far we have no structural evidence other than the solid state structure of 2c showing a stereochemical relation between configuration of the auxiliary and the metal atom. We are not aware of reports on configurational stability of stereotopic oxovanadium entities. Racemization of chiral oxovanadium compounds in the solid state occurs by interconverting configuration at the metal center in the solid state. The data on enantioselective geraniol epoxidation and oxidation of further prochiral alkenols in this study point a stereochemical leak along a sequence of steps involved with stereocontrol in carbon-oxygen bond formation, beginning with the solution structure of catalyst 2c, including derived tert-butyl peroxy vanadate and the adduct formed by binding a prochiral alkenol to a chiral tert-butylperoxy vanadate.


6. Cooperation:

Dr. Harald Kelm, TU Kaiserslautern.

Prof. Dr. Markus Gerhards, TU Kaiserslautern.


7. Leading References:

Formation of 3-Acyloxy-g-butyrolactones from 4-Pentenols in Vanadium-Catalyzed Oxidations. M. Amberg, M. Dönges, G. Stapf, J. Hartung, Tetrahedron 2014, 70, 5321–5331; DOI: 10.1016/j.tet.2014.05.011.


Oxovanadium(V) Complexes of 2,6-Bishydroxymethyl-substituted Piperidines for Selectively Oxidizing Alkenols by Alkyl Hydroperoxides. M. Dönges, M. Amberg, G. Stapf, U. Bergsträßer, J. Hartung, Inorg. Chim. Acta, 2014, 420, 120–134;  DOI:10.1016/j.ica.2014.02.007.


8. Funding:

Deutsche Forschunggemeinschaft, Land Rheinland-Pfalz, NanoKat.



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