OA11237A - Homogeneous oxidation catalysis using metal complexes - Google Patents

Abstract

The present method provides a method of transferring oxygen to at least one oxidizable site on a target compound. The method includes the steps of selectively oxidizing an oxidizable site on a target compound by reacting in solution: the target compound, a source of oxygen atoms, a source of a Lewis acid, such as a proton, alkali, alkaline earth, rare earth, transition metal or main group metal ion, and a catalyst. The catalyst has general structure (I) wherein Z is preferably N, but may include O and MO is a transition metal-oxo species. The Lewis acid binds to a bidentate secondary site on the Ch1 substituent to form a Lewis acid-catalyst complex.

Description

011237

TITLE

H0M0GENE0US OXIDATION CATALYSIS USING METAL COMPLEXES CROSS REFERENCE TO RELATED APPLICATIONNot Applicable

STATEMENT REGARDINQ FEDERALLY SPONSORED RESEARCH

This work was supported bÿ a grant from the National Institutes of Health.(5RO1GM55836). The U.S. Government has certain rights in this invention.

BACKGROUND OF THE INVENTION

The présent invention relates to the field of oxidation catalysts and caialysis.More particularly, the invention relates to the field of catalysts useful for theoxidation of olefins, in particular, the enantioselective oxidation of olefins.

Selectïvity in reactions» including chemoselectivity, regioselectivity, andstereoseleetivity, ïs of paramount significance both in chemistry and in biology.Sélection in réactions among or between different functional groups, such asalcohols, ketones, aldéhydes, carboxylic acids and others is referred to aschemoselectivity. Regioselectivity refers to the sélection of one orientation, orregioisomer, over any other that could be created or destroyed in a substrate alteredby the reaction. Stereoseleetivity encompasses the concepts of diastèreoselectivity(sélection among diastereomers, two Chemicals that hâve the same connectivity thatare nonsuperimposable nonmirror images) and enantioselectivity (sélection betweentwo possible entantiomers, two Chemicals that hâve the same connectivity that arenonsuperimposable mirror images). For example, in the production of varionsphaimaceuticals, it has been leamed, often with disastrous conséquences, that oneenantiomer has bénéficiai properties while the other enantiomer is hannful. To 2 011237 attain the desired degree and type of selectivity, chemists employ an array ofreagents that incorporete almost the entire periodic table; éléments are collectedfrom every accessible environment. Methods of using chiral transition métalcatalysts for enantioselectively epoxidizing a prochiral olefin and enantioselectivelyoxidizing a prochiral sulfïde are disclosed in Jacobsen et al., LJ.S. Patent No.5,637,739.

In contrast, Nature uses the relatively small number of éléments available ineach local environment and uses these within the limitations of solvent availabiiityand température accessïbility to practice the elaborate chemistry of life. Naturesucceeds with its selectivity objectives by accomplishing a reagent design and aSystems interoonnectedness that appear boundiess in sophistication; and through thisdesign complexity, Nature is able to use a small group of éléments in a much widerrange of structural and functional rôles than chemists hâve achieved for the same. Inthis strategie différence lies a root cause of much of the environmental damageattributable to chemistry, certainly to technological chemistry practiced withoutappropriate understanding or due care. By employing a diversity of éléments toattain selectivity, chemists are able to function within a comparatively simplisticdesign constellation. In the process, living things are confronted with éléments thatare unfamiliar and, consequently, often toxic. The preferred reagents that expand therange of reactivity of low toxicity trransition éléments, e.g, manganèse and iron, canlead to processes that are environmentally more désirable than currently exist.

Efforts toward the design of oxidatively robust chelating ligands to supportperoxide-activating catalysts of manganèse and iron hâve been reported in T. J,Collins, Accaunte of Chemical Research 27,279-285 (1994); and in F. C. Anscn, etal., J, Am. Chem. Soc, 106,4460-4472 (1984), A particularly robust tetradentateligand is disclosed in co-pending United States Patent Application, Serial No.08/681,237 of T. Collins et al. for “Long-Lived Homogenous Oxidation Catalysts”,which is hereby incorporated herein by référencé. The development of the firststable manganyls, i.e., Mnv-oxo complexes, were reported ίη T, J. Collins, S. W.Gordon-Wylie,J.^ Chem, Soc. 111,4511-13 (1989) and in T. J. Collins, R, D. 3 011237

Powell, C. Slebodnick, E. S. Uffelman, J. Am, Chem. Soc. 112,899-901 (1990); thecomplex described in the latter article is also stable in aqueous environments. Whilethe macrocyclic tetraamide ligands described in the aforementioned 1989 and 1990Collins et al. J. Am. Chem. Society articles are stable when coordinated to oxidizingmétal ions, these ligand-metal complexes and their analogues are not highly reactiveoxygen atom transfer agents. This contrasts with Systems employing dianionicporphyrin and salen tetradentate ligands, where Mnv and MnIV -oxo complexes arethe puiported reactive intermediates in a variety of O-atom transfer processes. See,E. Srinivasan, P. Michaud, J. K. Kochi, J. Am. Chem. Soc. 108,2309-2320 (1986); J. T. Groves, Μ. K. Stem, J, Am. Chem. Soc. 110,8628-8638 (1988); W. Zhang, J.L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am. Chem. Soc. 112,2801-2803(1990).

BRIEF SUMMARY OF THE INVENTION

It is believed that the muted reactivity of the prior tetraamide Mnv -oxocomplexes résulte from the hîgher négative charge and σ-donor capacities of thetetraamide ligands vis-a-vis the porphyrin or salen ligands. The présent inventionuses a new oxidatively and hydrolytically robust transition métal complex,containing metals such as iron or manganèse, where in its active form the oxo ligandspecies is reactive in O-atom transfer reactions to organic nucleophiles.

Significantly, the System of the présent invention also employs a second reaction toincrease the electrophilicity of the oxo ligand. Attachment of Lewis acidic speciesusually in the form of positively-charged ions in the immédiate vicinity of the métal-oxo moiety of a modified tetradentate ligand delîvers the targeted increase in O-electrophilicity and thereby résulta in effective métallo O-atom transfer agents, asshown schematically in Figure 1 for one embodiment of the catalysL

The présent invention provides a method of transferring oxygen to at least one oxidizable site în a target compound having a plurality of oxidizable sites or of transferring oxygen to an oxidizable site of a prochiral species. Oxidizable, as used herein, refers to any site that will accept an oxygen atom, such as, an olefin or an 4 011237 alkynyl site, or that is subject to another form of oxidation produced by the oxidizmgcatalyst Systems presented hereine. The case of compounds with a plurality ofoxidizable sites wiU be explained in detail. Oxidation of prochiral species toproduce chiral conipounds proceeds similarly except that only one oxidizable site 5 need be présent and the catalyst System must be one that possesses' chirality. Themethod comprises adding to a solution containing a target compound having aplurality of oxidizable sites therein, a source of oxygen atoms, a source of a Lewisacid species, most commonly a cationic species, and, a catalyst having the structure

Ch4 10 orwherein: Z is N or O and at least one and preferably four Zs are N species; MO is a transition métal -oxo species ;

Chi is selected from the group consisting of pyridine, pyrimidine, pyTazine, dicyano-pyrazine, mono- or di-, tri- or tetra- substituted benzene, 15 benzimidazôle, benzoquinone, di-imino-substituted benzene, indole, substituted crown dérivatives, cryptand ligands, EDTA dérivatives, fivemembered rings and five membered ring dérivatives, porphyrin dérivatives,metallated pthalocyanine based Systems, bipyridyl-based Systems,phenanthroline based Systems and salen based Systems; 5 011237

Cha and Cb3 each represent a unit joining the adjacent Z atomecomprisedof

wherein Rj, Rj, Rs, and It», pairwîse and cumulatively, are the same ordifferent and each is selected from the group consisting of hydrogen, alkyl,aryl, alkenyl, alkynyl, alkylaryl, cycloalkyl, cycloalkenyl, alkoxy, phenoxy,halogen, fluoroalkyl, perfluoroalkyl, fluoroalkenyl, perfluoroalkenyl, CïhCF3and CF3, or Ri, R2, R3 and R4 together form a substituted or an unsubstitutedbenzene ring, or the paired R substituent? of the R|, R2 or the R3, R4 pairstogether form a cycloalkyl or a cycloalkenyl ring; and,

Ch4 is a unit joining the' adjacent Z atoms selected from the group

and wherein Rj, Ré, are the same or different linked or nonlinked and areeach comprised of hydrogen, ketones, aldéhydes, carboxylic acids, esters,ethers, amines, imines, amides, nitro, sulphonyls, sulfates, phosphoryls,phosphates, silyl, siloxanes, alkyl, aryl, alkenyl, alkynyl, alkylaryl,cycloalkyl, cycloalkenyl, alkoxy, phenoxy, halo, CHCF3 or CF3, or thepaired R substituents of the Rj, R$ pair together form a cycloalkyl or acycloalkenyl ring; and allowing the oxidation reaction to proceed for a period of timesuffîcient to oxidïze the desired oxidizable site in the target compound.

Those skilled in the art will recognize that Lewis acids includecationic, neutral and anionic species, The use of the term catîon-catalyst 6 011237 complex as used herein is intended to encompass the use of ail such speciesas the entity thaï binds to the catalyst and changes its activity and is notlimited to cations.

The métal ions are any Lewis acid species, such as protons, alkali, 5 alkalinc earth, rare earth, transition métal or main group métal ions.

In a prçferred method for using the catalyst described above, die plurality of oxidizable sites in the target compound differ from each other inrelative reactivity and the cation added to the solution is selected toselectively activate the catalyst to oxidize one oxidizable site of the target 10 compound. The method of the invention therefore includes the steps of identifying à sériés of oxidizable sites on the target compound, eachoxidizable site in the sériés having sequential reactivities rangingsequentially from a beginhing oxidizable site having the highest relativereactivity of the séries of oxidizable sites to an ending oxidizable site having 15 the lowest relative reactivity of the oxidizable sites in the sériés of sites, adding to the solution a First cation for activatîng the catalyst to form a firstcation-catalyst complex having a first reactivity level sufficient to oxidize adesired first oxidizable site, such that a second oxidizable site in the sériés ofoxidizable sites then has the highest relative reactivity of the oxidizable sites 20 remaining in the sériés of sites of the target compound. Following the oxidation of each available beginning oxidizable site, the first cation isoptionally reraoved from the solution. Thereafter, a second cation foractivating the catalyst to form a second cation-catalyst complex is added tothe solution, the second cation-catalyst complex having a reactivity level 25 sufficient to oxidize the second oxidizable site on the target compound, and the oxidation reaction proceeds for a period of time sufficient to permit theoxidation of each second oxidizable site on the target compound such thatthe next oxidizable site in the sériés of oxidizable sites on the targetcompound bas the highest relative reactivity of the oxidizable sites remaining 30 in the sériés of sites. Following the oxidation, the second cation is 7 011237 optionally removed from the solution. The foregoing steps are repeated byadding cations to the solution, allowing the oxidation to proceed andoptionally removing the cation from the solution, each successive cationadded to the solution forming a cation-cataiyst compiex having aprogressively higher reactivity to effeet the séquentiel oxidation of theoxidizable sites in the sériés of oxidizable sites until each ending oxidizablesite is oxidized. Where the cations form strong bonds with the secondary siteor sites of the catalyst, removal of the cation and the cation-cataiyst compiexwill not be required. In addition, if removal of the cation is not necessary topermit subséquent added cations to activate the catalyst, cation removal willnot be necessary.

The method may fiirther include the enantioselective oxidation of atleast one prochiral oxidizable site on a taiget compound such targetedcompounds may hâve only one oxidizable site. The catalyst or cation- • catalyst compiex used in the enantioselective oxidation includes substituentsfor making the compiex asymmetric such that when reacting with theprochiral oxidizable site of the target compound, the cation-cataiyst compiexfavors the formation of one enantiomer over the other or in cases where thesubstrate already possesses chirality favors a sélection among diastereomericalternatives. The method may altematively functîon in kinetic resolutionapplications in which one enantiomer of a pair in a mixture is selectivelywinnowed from that mixture.g23 ERIEF DESCRIPTION OF THE DRAWINGSThe présent invention can be better understood by référencé to the figures which include the titles "compound 1 " and [LMnv »O]’as interchangeable terms forthe prefened embodiment of Figure 1. FIG, 1 is a schematic représentation of the catalytic cycle that the switchedoxidations of the présent invention are belîeved to follow. 8 011237 FIG. 2 is a molecular structure of the compound I : an ORTÈP drawing withnonhydrogen atoms drawn to encompass 50% of électron density wherein the Mnatom lies 0.579Â above the plane towards the oxo atom, and the coordinated oxygeais positioned symmetrically above the manganèse. Selected bond iengths [A]: Mn- 5 0(1), 1.549(3); Mn - N(l), 1.884(4); Mn - N(2), 1.873(3); Μη - N<3), 1.881(3); Mn - N(4), 1.885(3). FIGS. 3A and 3B illustrate, in A) the UV/Vis spectia of compound 1 (9.71 x10's M, 3 mL sample size) wherein aliquots of LifOSOaCFs) in acetonitri le wereadded (0.06 gmol in 2 pL in initial additions); and in B) the mole ratio plot corrected 0 for dilution. FIG. 4 représenta the infiared spectra (polyethylene film) of compound 1(light line) and of Uthiated compound 1 (heavy line) showing the 15 cm’1 increase inthe v(Mns,80) band associated with lithiation of the switching site. The Li* bindinginduces a substantial drop in donor capacity of the macrocydic tetraamido-N ligand, 5 a drop that is compensated for by an increase in the binding energy of the oxo ligand. FIGS, 5 A and 5B represent, in A) rates of change of the UV/Vis absorptionof compound 1 at 396 nm in the presence of triphenylphosphine and differentswitching ions. Noimalized observed rate constants; experiment number, number ofequiv of cation, cation, relative rate ± standard déviation of minimum of three runs: ) 1, no cation, 0,1; 2a, 5, Na*, 2,7 ± 0.1; 3a, 5, Ba2*, 4.8 ± 0.5; 3b, 60, Ba2*, 5.7 ± 0.1; 4a, 5, Mg2*, 7.0 ± 0.4; 4b, 60, Mg2*, 7.2 ± 0.8; 5a, 5, Li*, 13.5 ± 2.0; 6a, 5. Zn2*, 24.5 ±1 ; 6b, 60, Zn3*, 24.1 i 0.8; 5b, 60 Li+, 25.0 ± 0.5; 2b, 60, Na*, 506.4 ± 7.0; 7a, 5, Sc3*, 1246.0 ± 206.1 ; 7b, 60, Sc3*, 1577.6 ± 290.0; and in B) the expansion ofthe time scale showing the fastest oxidations. > FIG. 6 schematically illustrâtes the ligand synthesis. FIG. 7 schematically illustrâtes the métal insertion, for manganèse. FIG, 8 is the lHNMR spectrum of the species, [LMnv=O]’. The low symmetry resulting from the presence of the pyridine-N and the Mn(O) is reflectedin the observation of four methyl résonances, cc'dd1. 9 011237 FIGS. 9A and B illustrât© the UVZVis study of Na+ binding to [LMnvsO]’forvarious molar équivalents of Na+, 0.0 (shown by the longer dashed line, 25(shown by the shorter dashed line, —), and 60 (shown by the darkest solid line). Themole ratio plot indicates tbat there are two binding processes. One is Na* bindinginto the switching site and the other binding event is believed to occur at one of theamide oxygens. FIGS. 10A, B, C and D illustrate the UVZVis and IR study of Zx?* binding to[LMnv=O]' for various molar équivalents of Zn2+, 0.0 (shown by the longer dashed line,----), 0.23 (shown by the shorter dashed Unes, —) and 0.69 (shown by the darkest solid line). FIGS. HA, B, C and D illustrate the UVZVis study of Mg2* binding to[LMnv=O]‘ for various molar équivalents of Mg2* with 0.0 being shown by longerdashed lines, 0.30 shown by shorter dashed lines and 1.06 shown by the darkest solidline. FIGS. 12A and B illustrate the UVZVis study of Ça? binding to [LMnV£O]'for various molar équivalents of Ca2*. FIGS. 13A and B illustrate the UVZVis study of Ba*+ binding to [LMnvsO]'for various molar équivalents of Baî+. FIGS. 14A and B illustrate the UVZVis study of Se3* binding to [LMnv=O]'for various molar équivalents of Sc3+. The Sc3+ exhibits complex binding behavior,however, only one équivalent is required to reach the endpoint. FIGS. 15A-F illustrate the O · atom reactivity studies of [LMnveO]‘ andtetramethylethylene monitored by 13C-NMR; growth on the résonances of the carbonproduct over tirae are shown in a progression front light to dark tracés.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The preferred embodiment of the catalyst used in the method of the presentinvention contributés to the “greening” of chemistry by invoking the prînciple thatreagents should be composed of low toxicity éléments. Among the green designéléments considered to be important are the following. Preferably, the métal is one 10 011237 of the low toxicity éléments, i.e., iron or manganèse. The supporting ligand Systemis preferably comprised of carbon, hydrogen, nitrogen, oxygen and other biologicallycommon éléments. It is preferred that the primaiy oxidantis one found widely inNature, such as oxygen or one of its reduced dérivatives, especially hydrogenperoxide. This reasoning constitutes a significant environmental case for advancingligand design to afford nontoxic, long-lived iron and manganèse catalysts fçractivating peroxides and oxygen for a wide range of homogeneous oxidations.

The catalysts found to be useful for the methods of the présent inventionhâve the general structure:

v/herein: Z is N or O and at least one Z, and preferably four Zs are N; MO is a transition métal -oxo species ;

Chi is selected fiora the group consisting of pyridine, pyrimidine, pyrazine, dicyano-pyrazine, mono- di- tri- or tetra- substituted benzene,benzimidazole, benzoquinone, dimino-substituted benzene, indole,substituted crown dérivatives, cryptand ligands, EDTA dérivatives, fivemembered rings and five membered ring dérivatives, poiphyrin dérivatives,raetallated pthalocyanine based Systems, bipyridyl-based-systeras,phenanthroline based Systems and salen based Systems, in accordance withthe représentations for such substituents as set forth in Table I herein ;

11

Ch2 and Ch3 each represent a unit joining the adjacent Z atomscomprised of

/ \ wherein Ri, R2, Ra, and &amp;♦, pairwise and cumulatively, are the same ordifferent and each is selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, alkylaryl, cycloalkyl, cycloalkenyl, alkoxy, phenoxy,halogen, CH:CF3 and CF3, or Rb Rj, Rj and R4 together form a substituted or an unsubstituted benzene ring, or the paired R substituents of the Ri, R2 orthe R3, R4 pairs together form a cycloalkyl or a cycloalkenyl ring; and, CE» is a unit joining the adjacent Z atoms selected from the groupconsisting of and wherein Rs, and R$, are the same or different, linked or nonlinked,and each is comprised of hydrogen, ketones, aldéhydes, carboxylic acids,esters, ethers, amines, imines, amides, nitro, sulphonyls, sulfates,phosphoryls, phosphates, silyl, siloxanes, alkyl, aryl, alkenyl, alkynyl,alkylaryl, cycloalkyl, cycloalkenyl, alkoxy, phenoxy, halo, CHCF3 or CF3,or the paired R substituents of the R5, R4 pair together form a cycloalkyl or acycloalkenyl ring, A preferred embodiment of the catalyst is the tetraamido ligand shown inFigure 1, referred to herein as compound 1. The catalyst used in the method of theinvention contains a bidentate secondary site which in compound 1 is comprised ofthe pyridine nitrogen and the adjacent amide oxygen, The electronîc influence ofbinding a secondary ion is transmftted to the Mn(O) moiety via a combination of σ 12 011237 and π perturbations. Such a binding increases the electrophilicîty of the oxo ligand,thereby increasing its O-atom transfer reactivity. The secondary binding is referredto herein as a 'switching' event, an event whereby a secondary reaction is arranged inlime to cause a primary reaction to proceed to deliver a targeted reactivity andselectivity at an acceptable rate.

In the method of the présent invention, switching processes are used toactivate compound 1 such that it performs useful oxidations on convenient timescales, By raanipulating the Lewis acid or cation that binds to the secondary site, therelative reactivity of the catalyst can be controlled. Using this technique, asexplained in more detail below, the chemo- and regio-selectivity and sequence ofoxidation reactions at desired sites in a larger compound having a plurality ofpossible oxidation sites can be controlled. In addition, the introduction of chirality atdesired prochiral sites can be controlled, by synthetically modîfying the environmentsurrounding the active site of the catalyst to introduce asymmetry or by bringingasymmetry to the cation catalyst complex via groupe attached to the switchingcation. The size and shape of the complex can be altered to hâve it favor contactwith one side of the desired oxidation site, for example, an olefin, in préférence tothe other side. A cationic ligand(L)-metal(M)-oxo(O)-speçies {[LM~O]+} has been used asthe active oxidant in métal catalyzed olefin oxidations similar to those of the présentinvention, generally as follows: [LM]+ + [O] -* {[LM = O]+} + olefin [LM]+ + epoxide (or otheroxidation product)

The macrocyclic tetraamides 13 011237

give stable anionic (LM « O)' species, such as [LMnv - O]‘. These anionicmanganyl species are not very active as O-atom transfer agents. Alteration of theanionic species to provide neutral or cationic species was found to enhance thecatalyzing ability of the manganèse species in oxidation reactions. In one method ofthe présent invention, a bidentate secondary ion binding site was added to themacrocycle

to permit tuning of the charge, modification of the donor capacity of theamides and alteration the kinetics and thermodynamics of the axial ligand binding tothe métal. The [LMnv s O]' complex was titrated with triflate-fSOsCFj] salts ofreprésentative alkali, alkaline earth, or transition métal cations. The changes werefollowcd by UV/Vis spectroscopy. Mole ratio plots were generated and interpretedfor understanding of the binding process. An example is shown in Fig. 3 using Lfas the cation where K-9.0 x 104 -1.2 x 10s and pK=4.95 - 5.08. The mole ratio plotindicates that there is only one binding process.

The changes in the Mnv band in the UV/Vis spectrum were also monitoredfor Na+, Zn2+, Mg24, Ca2+, Ba2+ and Sc3+. See, Figs. 9-14, Cation-catalystcomplexes having transition métal ions Rn and Rh hâve been prepared and hâvesuccessfulîy catalyzed oxidations. •14 011237

As shown in Fig. 5, in an initial test réaction, the [LMnv*OJ ’ switchingcomplex was reacted with PPha to produce PhaP-Q in the absence and in thepresence of the switching ions. The decay of the Mnv band in the UV/Vis spectrumwas monitored.

The resuits demonstrate that the presence of switching ions dramaticallyenhances the O-atom itransfer reactivity, The rate can be controlied by the choice ofthe secondary ion. The successful catalytic O-atom transfer to tetramethylethylene(see Fig. 15) together.with the abîlity to control the rate of the reaction by sélectivemanipulation of the secondary ion demonstrates that the oxidation catalysts of theprésent invention are usefül in the oxidation of a variety of substrates, includingolefins.

Refening to Fig. 15, for example, the sélective oxidation raethod of theprésent invention maÿproceed as follows: the oxo cataiyst [LMnv ·Ο]’ and asource of the desired alkaline, alkaline earth or transition métal .cation, main groupmetalion and a source of oxygen atoms, such as a peroxy compound or oxidant, aremixed at room température in a solution containing a solvent and a target compoundhaving a pluraiity of olefin sites. If necessary to produce a reaction atan acceptablerate, the solution is heated. The réaction produces an oxidation at the most réactivéolefin site or sites and any others that the reactivity of the cation-catalyst complexwill accommodate.

[LMnvsO]’ + switches or cations + olefin or target compound + [O]oxidized product or an epoxide at one or .more selected sites of the olefin A spécifie reaction is shown in Fig, 15.

To control the oxidation so that only one site, or only sites having a certainreactivity are oxidized, the first cation used is one that yields the cation-catalystcomplex of the lowest reactivity. The low-reactivity cation-catalyst complexproduced upon binding with the cation will oxidize only the most reactive olefinsites on the substrate, or target compound. In this manner, a sériés of olefin sitesfrom the most reactive to the least reactive can be oxidized respectively, by catalysisbeginning with the cation bound to the secondary binding site of the oxo-tetraamido 15 011237 ligand that yields the least reactive cation-catalyst complex, [LM(O)f andproceeding to the most reactive cation-catalyst complex. A typical sequence for atarget compound having a plurality of olefin sites, a, b, c, d, e, f, g, etc., is to add asource of a first cation, one yielding the least réactivé cation-catalyst complex, to thereaction mixture described above. The cation will bind to the secondary binding siteof the oxo catalyst. The cation-catalyst complex will initiate the oxidation of themost reactive olefin site, the first olefin site a, on the target compound. The reactionwill stop and the first cation optionally will be removed, if neccssary. A source of asecond cation will be added to the reaction mixture and will bind to the secondarybinding site of the oxo catalyst which will in tum initiate the oxidation of the mostreactive remaining olefin site, a second olefin site b, on the target compound, (themost réactivé site originally présent having been previously oxidized), Then thesecond cation will be removed, if necessary from the réaction mixture and a thirdcation will be added to bind to the secondary binding site of the oxo-catalystwhereupon the catalyst will initiate the oxidation of the most reactive remainingolefin site, a third olefin site c, on the target compound. The process can continueto effect the sequential oxidation of different olefin sites, d, e, f, g, etc., on the targetcompound. Séquentiel reactivity can also be obtained wiîh one cation whereby thetempérature is the controlling factor. Thus, the cation/catalyst complex oxidizes theleast reactive site at a température chosen so that only this site reacts. On raising thetempérature, a température can be found where the two mostt reactive sites reactselectively compared to the others, etc. The foregoing is an example ofchemoselectivity. In a compound where olefins are not identical, or where there aregroupings of olefins that are identical and groupings of olefins that are not identicalin the same compound, one of the olefins or one grouping of olefins will be morereactive than the other olefins or groupa of olefins. Each olefin or olefin group willdifîer somewhat in reactivity. Because the reactivities of the various functionalgroups adjacent to or attached to the double bond of the olefin sites will be fcnown,sélection of oxidation at one functional group in préférence to oxidation at anotherfunctional group can be controlled. The reactivity of the oxo-catalyst can also be 011237 16 controlled by cbanging the métal ion, M, to another transition métal. Iron, for example, is vastly more reactive than manganèse in these catalyst Systems.

Manganèse is preferred for Systems where a mïld oxidation catalyst is called for.

The switching catalysts are useful for incorporating asymmetry into prochiralsubstrates. The enantioselectivity with regard to the prochiral sites on a targetcompound can be controlled by the presence of asymmetry in the cation-complex.The oxygen atom transfer site on the catalyst must be able to reach the olefin, orother oxidizable prochiral site of the target compound. Chirality can be built intothe oxo-catalyst or brought to it via the switching cation and groups attached thereto.By selecting the substituents on the catalyst, the size, shape and chiral character ofthe catalyst can be controlled. Numerous variations for substituent groups and themanner of making them are disclosed in the Collins et al. patent application citedabove and incorporated herein and in co-pending United States Patent Application,Serial No. 08/681,187 of S. Gordon-Wylie et al., for “Synthesis of MacrocyclicTetraamido N-Ligands”, the relevant portions of which are hereby incorporatedherein by référencé. Sirailariy, the. size and shape of the target compound and theposition of fimctional groups on the target compound, particulariy those nearest thedouble bond, will control which side of the olefin double bond the catalyst canapproach to effect oxygen atom transfer to the olefin, i.e., oxidation of the olefin site.Selectivity occurs where One enantiomer is created or destroyed in préférence to theother enantiomer that could hâve been created or destroyed. While there arecommercially available catalysts that can provide enantioselectivity, the best arelimited to 10 to 20 cycles or tum-overs of the oxidation catalyst. It has beenobserved that the catalyst System of the présent invention is véry long-lived andappears to regenerate in the presence of a source of oxiditing power preferablyoxygen or one of its reduced dérivatives many, many more times than thecommercially available catalysts.

The catalyst Systems of the présent invention can also induce chirality bytransferring sulfur compounds oxygen atoms from the switching catalyst to an 17 011237 organic or înorganic substrate. A prochiral phosphorous compound, for example,can be oxidized at phosphorys or sulfur so that chiral species resuit.

The pyridine-substituted macrocycle (Compound 1) shown in Figure ί can besynthesized by an adaptation of the multistep procedure for making macrocyclic 5 tetraamides discloséd in co-pending U. S. Patent Application, Serial No. 08/681,187of S. Gordon-Wylie et al., cited above and incorporated herein. The parent complexwithout the pyridine group was reported in T. J. Collins, R. D. Powell, C.

Slebodnick, E. S. Uffelman, J. Am. Chem. Soc, 113, 8419-8425 (1991).

The synthesis of the tetradentate ligand proceeds generally as follows. In the 10 first step, an amino carboxylic acid, preferably an a or û amino carboxylic acid, isdissolved in a supporting solvent and heated with an actîvated dérivative selectedfront the group consisting of oxalates and malonates, such as a substituted malonyldichloride in the presence of a base, to form an intennediate. Following completîonof the sélective double coupling reaction, a diamide dicarboxyl-containing

15 intermediate is isolated. In the second step, a diamine is added to the intennediate inthe presence of a solvent and a coupling agent. The diamine is one providing asecondary binding site, such as those selected from the group consisting of pyridine,pyrimidine, pyrazine, dicyano-pyrazine, mono- or di- substituted benzene,benzimidazole, indole, substituted crown dérivatives, cryptand ligands, EDTA 20 dérivatives, fîve membered rings and five membered ring dérivatives, porphyrindérivatives, metallated pthalocyanine based sÿstems, bi-pyridy 1 based Systems,phenanthroline based Systems and salen based Systems, such as those diaminesshown in Table I. The coupling agent is preferably a phosphorous halide compoundor pivaloyl chloride. The resulting mixture is heated and the reaction is allowed to 25 proceed for a period of time suffirent to produce the macrocyclic tetradentate compounds, usualiy 48-72 hours at reflux when pyridine is the solvent. Typically,stoichiometric amounts of the reactants are used.

The substituent groups on the amino carboxylic acids, the actîvated oxalateor malonate dérivatives and the diamines may ail be selectively varied so that the 18 011237 resulting tetradentate microcycle can be tailored to spécifie desired end uses.Variation in the substituents has Utile or no effect on the synthesis methodology.

Once the macrocyclic ligand has been prepared, the compound is complçxedwith a métal ion, preferably a transition métal ion from Groups 6 (Cr, Mo, W), 7(Mn, Te, Re), 8 (Fe, Ru, Os), 9 (Co, Rh, Ir), 10 (Ni, Pd, Pt), and 11 (Cu, Ag, Au) ofthe Periodic Table of the Eléments or those having oxidation States of I, II, III, IV, V,VI, VII or VIII, Because the preferred use of the catalyst Systems of the présentinvention is environmentally sound oxidations, those metals that are nontoxic arepreferred, with manganèse and iron being the most preferred.

If the resulting metallated complex is then combined with a strong O-atomtransfer oxidant, preferably aperoxide, suoh as hydrogen peroxide, t-butyl peroxide,or curoyl peroxide, a ligand métal oxo complex is formed. Any source of oxygenatoms can be used.

For particularly robust oxidation catalysts which are usefbl when the métal isiron, Ch» has the general structure

wherein: 2 is the métal complexing atom, preferably N; X is a functionality résistant to oxidation when the métal complex is in the présence of an oxidizing medium; and R' and R" are the same or different and each is selected from the groupconsisting of substituents which are unreactive, forra strong bonds intramolecularlywithin R’ and R" and with the cyclîc carbon to which they are bound, are stericallyhindered and are confoimationally hindered such that oxidative dégradation of themétal complex is restricted in the présence of an oxidizing medium. 19 0Ί1237 X is preferably oxygen or NR»; wherein Rj is methyl, phenyl, hydroxyl,oxylic, CFj and CH2CF3. R' and R" are each preferably hydrogen, methyl, halogen,CFs, and if linked, a.cycloalkyl such as cyclopentyl, cyclobutyl, cyclohexyl orcyclopropyl.

Altematively, when in milder oxîdation environments, for example when themétal is manganèse, R' and R” can be any one of the groups recited for Ch above oradditionally those chosen for R5 and R$ on page 11, Oxidatively robust oxîdationcatalysts are described in more detail in the T. Collins et al., U.S. Patent Application,Serial No. 08/6S1,237 filed July 22,1996 cited above and incorporated herein byréférencé.

Manganèse insertion into the macrocycle of compound 1 is complicated inthat both the primary'tetraamide and the secondary site readily bind manganèseunder basic aprotic conditions. Thus, manganèse must be removed from thesecondary site after the insertion into the primary site. In the case of manganèse, thisis achieved by basic aqueous workup conditions. A useful synthesis proceeded asfollows.

The ligand (425 mg, 1.05 x 10’3 mol), was dissolved in dry tetrahydrofuran(THF, 40 mL) under an inert atmosphère, and lithium [bis(trimethylsiIylamÎde)] (6.32 mL of 1,0M THF solution, 6,3 x 10'3 mol) was added. The mixture was stirred(5 mins) and manganic acetylacetonate, Mn (acac)3 (557 mg, 1,58 x 1 O*3 mol), wasthen added as an acetonîrile solution (10 mL). The reaction mixture was stirred (2hours) and the solution was then evaporated to dryness in air on a rotary evaporator.The solid residue was dissolved in minimal amount of water and filtered to removethe solid residue. The fîltrate was evaporated to dryness under reduced pressure andthe resulting solid, Li[LMnnÎJ, was dissolved in acetone and filtered. The fîltrate wastreated with excess rerf-butylhydroperoxide (TBHP) solution (0.586 mL, 5.25 x 10mol, 90% TBHP containing 5% teri-butyl alcohol and ,5% water). The ensuingreaction was monitored by a color change from a starting color of bright orange to afinal color of deep red-brown. Excess tetraphenylphosphonium chloride (2.0 g, 5.25

20 x 10'3 mol) dissolved in water (20 mL) was added to the product solution whichcontained Li[LMnv(O)), i.e. the lithium sait of compound 1 essentially inquantitative yield. The solvent volume of the mixture was reduced by rotaryévaporation giving a suspension of [Phæ]corapound 1 in water, Single crystals weregrown by vapor diffusion of pentane into an ethyl acetate solution of[PhjPjcompound 1 at room température; the résulte of an X-ray crystal structuredétermination are shown in Figure 2 for the compound 1 anion-(C&amp;Hs)4P[corapound 1]: Anal. Calcd for Ci^iMnNjOjP; C, 65.26; H, 5.60; N,8.65; P, 3.82. Found C, 65.42; H, 5,67; N, 8.85; P, 3.89- ’HNMR (chloroform-di):(See Fig. 8) (CfsHj),-P [compound 1] δ 8.58 (ra, 1 H), 8.10 (m, 1 H), 7.47-7.85 (m, 20 H), 6.86 (m, 1H), 2,05 (q, 2 H, J “ 7,3 Hz), 1,97 (q, 2H, J * 7.3 Hz), 1.86 (s, 3 H), 1.85 (s, 3 H), 1.81 (s, 3 H), 1.80 (s, 3 H), 0.83 (t, e H» J - 7.7 Hz), 0.55 (t, 3 H, J * 7.4 Hz). ESI-MS (négative ion): m/z 470.1, [compound l]1’ (100%);

Crystal Data; Single crystals are orthorhombic, space groupPècn, with a = 14.205(2) Â, b- 19.87(2) Â,c = 28.341(4) À, 7999(9)A3at-lOO’C,andZ-* 1 -355 g cm"3; μ e 4.24 cm'1. A total of 7895 unique reflections (2°<2θ<52.16°) were collected using ω scans with Zr-filtered Mo Kcc X-radiation.The structure was solved by direct methods using SHELXS [G. M. Sheldrick, ActaCryst,, A46, (1990), 467], and refined by full-matrix least-squares on F5 usingSHELXL93 [G.M, Sheldrick, SHELXL93, Program for Crystal StructureRefinement, University of Gôttingen, Fédéral Republic of Germany, 1993]. Thedistinction between C and N in the pyridine ring was made as follows: Since therewas no différence between the heights of the peaks in the différence map, or thelengths of the bonds to each atom, both atoms were included and refined as C atoms.One of the two [that subsequently labeled N(5)] displayed more asymmetric thermalparameters on anisotropîc refinement. The other [that labeled C(2)] was the onlyone to show a likely H atom position in a différence map. As ail other hydrogenatoms could be unarabiguously located in différence maps this was considered to besuffirent evidence, taken in conjunction with the température factor data, formaking the atoraic assignments, However, they are by no means certain, and these 21 011237 atoms might be interchangeable. Hydrogen atoms were refîned using the ridingmodcl with isotropie température factors set to 1.2 times that of the atom to whichthey were attached. Methyl hydrogens were refîned as rigid groups, The crystalstudied was.observed to contain a fractional water molécule of crystallization asindicated by the NMR spectrum. The refîned occupancy factor for this oxygen atomwas 0.38. Refïnement converged with Æj (based on F), “0,0564 for 4202 observedreflections [£>2σ(7)].

The réversible formation of secondary complexes of compound 1 wasmonitored in acetonitrile by UV/Vis spectroscopy employing a range of mono-, di-,and trivalent cations. The monocationic alkali sériés, Li+, Na+ and K+ (as the triflatesalis), exhibit a surprisingly large variation in the binding properties. Thus, Lfbinding exhibits isosbestic behavior (Figure 3) and a mole ratio plot indicates that2.5 équivalents of Lf are required for complété lithiation. Titrations were caxriedout in triplicate ([compound 1] - 0.30,0.27 and 0.14 mmol L*’, logKjs ^=5.(^0.06).In comparison, the mole ratio plot for Na+ binding (Figure 9) shows that there aretwo binding processes, as evidenced by a first plateau beginning at 8 équivalents ofNa* and a second plateau beginning at 47 équivalents. lt is beiieved that the firstbinding event occurs at the bidentate site and the second binding event occurs at amonodentate araide O-aXom. The UV/Vis spectrum does not change on addition ofK4, (up to 60 equiv). The UV/Vis changes nonisosbestically on addition of Ba2+(Figure 13) in such a .marner as to suggest that more than one compound 1 anion canbind to BaJ+; Baî+ binding is strong with the mole ratio plot indîcating that theendpoint is reached at 1.3 équivalents of the Ba2+. Similarly, S<?+ binding exhibitsnonisosbestic behavior, but only one équivalent is required to reach the endpoint(Figure 14). Unfortunately, the cyclic voltammetric behavior of the systemrepresented by compound 1 is not electrochemicalîy réversible for any switching ion.However, cyclic voltammetric studies of the planar, four-coordinate Co,n analogueof compound 1 show eleetrochemîcally réversible électron transfer properties for avariety of secondary ions. For example, under conditions of excess Co111 compiex, 011237 22 the dinuclôar, trinuclçar and tetranuclear species are ail observable with Ca2+. Fromthese and electrospray ionization MS studîes where the multinuclear ions are alsoobservable, one can çonclude that the Co111 analogue of compound 1 binds more thanonce to multiply-charged switching ions. The multiple binding of compound 1 tomultiple charged switching ions provides a cohérent rationalization for the absenceof isosbestic behavior in the UV/Vis binding studîes for Baz+/compound 1 andSc3+/compound 1. Cumulatively, these résulte suggest that both the bidentate andamide-0 binding sites express a significant sensiti vity to the chargeZsize ratio of thesecondary ion or ions.

Exemple Set 3

The susceptibility of the manganyl moiety of the compound 1 System tosecondary ion perturbation can be illustrated by the effect of Lf binding on thev(MnsO) band in the ÏR spectrum. To obtain an IR région free of macrocyclicligand bands, the 18O~labeled manganyl was examined; thls was produced by stirring[EtçN][compound 1] in a mixture of CH3CN/H2I!O (kl; 98¾ 18O) for three weeks atroom température, The v(Mnæ,8O) band for the Li+ free and Li+ bound species are t shown in Figure 4; v(Mns18Q) shifts from 939 cm'1 in the parent complex to 954 cm’1 in the Li+ complexed species. This blue shift of 15 cm’1 implies that Li+ bindinginduoes a substantial drop in the donor capacity of the macrocyclic tetraamido-Vligand, a drop thaï is compensated for by an increase in donation from the oxo ligandwith its associated increase in oxo binding energy. One can infer that theelectrophilicity of the oxo ligand should also increase significantly on secondarycation binding.

Exampie-Set-4

The effecte of the different switching ions on reactivity were first examinedby studying a proof of concept oxidation, namely the ûxidation oftriphenylphosphine to triphenylphosphine oxide. The réactions with differentswitching ions were monitored by UV/Vis spectroscopy at 15 °C in acetonitrileunder air employing one équivalent of compound I and 100 équivalents oftriphenylphosphine. Switching ions were added as the triflate salte (5 and 60 equiv); 23 011237 the reactions were performed at least in triplicate. Formation of the oxidationproduct, triphenylphosphine oxide, was demonstrated by ’H NMR spectroscopy andby IR spectroscopy in the v(P=O) région. The results are presented in Figure 5; therelative rates are normalized against the rate of oxidation of triphenylphosphine bythe parent compound 1 in the absence of a switching ion. As was found forsecondary cation binding to compound 1, the switching effect on the rate ofphosphine oxidation is strongly dépendent on the nature of added switching ion.Oxidation of triphenylphosphine to triphenylphosphine oxide under the conditions ofthe UVZVis experiment by unswitched compound 1 is slow; the réaction takesseveral thcusand seconds to reach completion. The rates relative to the unswitchedrate in the presence of fîve équivalents of various switching ions were found to bethe following: Na+=3, Ba2+=5, Mg2+=7,Li+=13, Zn2+=24, Sc3+-1244. Asnotedabove it was found that the Na+ ion is unique among the switching ions stùdied inpossessing an appréciable second binding to compound 1. The relative rates oftriphenyiphosphine oxidation by. compound I with different awitches reflect thisfinding. Thus, no increase in the rate of triphenylphosphine oxidation was foundupon an increase in the switching ion: compound I ratio from 5:1 to 60:1 for Mg*+or Zn2\ Small increases are found when this ratio increase is enacted for Ba2+ (1.2fold), Li+ (2 foid) and':Sc3+ (1.3 fold). In contrast, an increase in the Na+: compound1 ratio from 5:1 to 60:1 preduces a 169-fold increase in the rate of phosphineoxidation. Moreover, addition of K+ (up to 60 equiv) does not perturb the oxidationrate of the parent unswitched compound 1 reinforcing what was noted above that K+does not appear to bind to the switching site in a concentration régime that can bereadily studied, !

The oxo-transfer rate increases presented above for a trivial oxidation signalgenuinely useful properties. We hâve also investigated the reactivity of compound 1as an O-atom transfer agent for the electron-rich olefîn, tetramethylethylene. A mixture of [PhiPjcompound 1 (1 equiv), ZnTfs (4,5 equiv), 2,3-dimethyl-2-butene (tetramethylethylene, 132 equiv), and TBHP (90%, 266 equiv) in 24 011237 acetronitrîle-d3 was monitored at 50°C via l3C spectroscopy until ail of the olefinhad been consunied (48 hr). The only observable product was 2,3-dimethylbut-3-en-2-ol (>98%); the reaction was performed in triplicatç. I3C NMR (acetonitrile^):(See Figure 15) 2,3’dimethylbut-3-en-2‘ol; δ 19.5,29.3,73.3,108.7, 153.3. See, R.W. Murray, W. Kong; S. N. Rajadhyaksha, J. Org. Chem. 58,315-321 (1993). SeeFig. 15. j

The product solution was also analyzed by GCZMS which confirraed thepresence of 2,3-dimethylbut-3-en-2-ol as the only olefin-derived product. Theproduct/the generated ierr-butanol, and the remaining TBHP had the same relativeabundance indicating a very clean stoichiometric and sélective reaction.Significantiy, except for minor amounts of décomposition, the unemployed TBHPremained unconsumed and addition of further olefin resulted in therecommencement of the catalytic oxidation process. UV/Vis analysis of thecatalysis solution indiçated the quantitative presence of compound 1 throughout andafter the catalytic oxidation, While trace amounts of other products, apparentlyderived firom the TBHP, were détectable in the ,3C NMR spectra, a spent reactionsolution in acetone«d$ remained essentially unchanged upon standing in an NMRtube on the bench top for nine months; after this finie, it was found to contain 2,3-dimethylbut-S-en^-olJieri-butanol, TBHP and its acetone adduct in the samerelative ratios that were established at the end of the reaction and nothing else. Acontrol System without compound 1 consisting of ZnTfc (1 equiv), 2,3-dimethÿl-2-butene (30 equiv), and TBHP (90%, 64 equiv) in acetonitrile-d3 was also monitoredat 50°C for five days by l3C NMR spectroscopy; no change was observed. When theréaction conditions were changed by raising the température to 70° C and usingdeuteraied acetonitrile as the solvent, the same five characteristic peaks shown inFig, 15 for 2,3-dimethyibut-3-en’2-oI were présent, Thus, compound 1 présents araild, exceptionally sélective and extraordinarily stable catalytic O-atom transferSystem.

As part of Natures design, enzymes often arrange multiple réactionsprecisely in both time and space to achieve a targeted selectivity. While modem 25 chemistry incluses rich insighl into how to arrange reactions in space to achieveselectivity, the mastering of selecti vi ty by the deliberate arrangement of multiplereactions in time is noveî territory, Using the variations in reactivity, spatialorientation and size àfforded by the oxidation catalysts described herein, a ligandSystem can be designed for organizing in sequence and reaction site more than oneoxidation reaction toi achieve a targeted reactivity and selectivity. The ligandSystems of the présent invention are signifîcantly résistant to oxidativedécomposition such that they provide very long-Iived and reusable catalysts. Thesynthetic procedures'to produce numerous variations of compound 1 hâve beenrefined such that the ligand can be produced in a two-step procedure from the sériés

I of diamines shown ίή Table 1 accordîng to the procedures set forth in Gordon-Wylie et al., incorporated herein by référencé, as modifîed by the substitution of the ! diamines of Table I fpr the diamines described in the Gordon-Wylie synthèses. It isimportant to reaiize that the approach presented clearly expands the range ofreactivity achievable for the environmentally désirable transition metals, such asmanganèse, by allowing one to deliberately increase the reactivity of an otherwiseslow O-atom transfert agent or, more generally, reagents such as compound 1 and itsvariants which are designed to assemble more than one reaction to oxidation catalystachieve a reactivity objective may become essential in the greening of chemistry.They make possible the noveî methods of the présent invention for makingenvironmentally desiijable catalytic éléments perform al] the tasks necessary toreplace the environmentally undesirable éléments currently in use. The approach ofarranging multiple réactions in time holds enormous promise for deaiing withdifficult reactivity problems such as for obtaining otherwise inaccessible greenreagents, especially oxidants, and for achieving enantioselectivity andchemoselectivity in oxidations that hâve proven to be résistant to less ambitionsdevelopment approaches. 011237 26 TABLE!

Aza Aryl Substitutions NH2 nh2 nh2

The parent complex (pyridine-) pyridine-

pyrimidine- ; pyrazine- dicyano-pyrazine·

Simple Aromatic Substitutions

Ql = NH2, RNH, R2N, CO2H, SO3H, OH, SH

Ql = NH2, RNH, R2N, CO2H, SO3H, OH, SHQ2 = NH2, RNH, R2N, CO2H, SOjH. OH, SH

Other Switching Sübstituents

Benziniiüazole-

Indole- 27 IA3LEI Continugd

Substituted Crown Dérivatives

Qi*NH,NR, O,orSQ2 = NH,NR, 0, orSQ3 = NH, NR, G, or S substituted -beczo-9-crown-3-

Qi=NH, NR, O, or SQ2 - NH, NR, O, or SQ3 = NH,NR, O, or SQ4 - NH, NR, O, or SQs = NH, NR, O, or S substituted -benzo-15-crown-5-

Qi=NH, NR, O, or SQ2 = NH, NR, O, or SQ3-NH, NR, O, or SQ4 = NH, NR, O, or SQs = NH, NR, O, or SQô = NH,NR, O, or S substituted -benzo-i8-crown-6- 28 1ABLEI Continuer! Ο Ί 'ί r 7 '7 υ ι I ζ ό /

Other Cryptand Ligands

Qj - NH, NR, O, or SQ2 = NH,NR, O, or$Q3 = NH, NR, O, or SQ4 = NH, NR, O, or S /—\Q4 Qr nh2

nh2

Qj-NH.NR, O, or SQ2«NH,NR, 0, orS.Q3 = NH, NR, O.orSQ4-NH, NR, O, or S /"\ Qî Q4

Q2 Q

Qj = NH, NR.O, or SQ2-NH, NR, 0, or SQ3~NH, NR, 0, or SQ4 = NH, NR, 0, or S 1~λ ~\_/·νη2nh2

Qi =NH, NR, 0, or SQ2 = NH, NR, 0, or SQ3*NH, NR, 0, or SQ4 = NH, NR, 0, or S 29 011237 TABLE; T Cnntinued

Dérivatives of EDTA

30 011237 TABLE I Continued

Q = NH (pyirole-), S (thipphene-), O (furan-), CH2 (cyclopentadiene-),RCH (substituted cyclopéntadienyl witb R- alkyl, aryl) R, = H, Alkyl, Aryl, Alkenyl, HaloR2 = H, Alkyl, Axyl, Alkenyl, Halo

Five niembered ring dérivatives

Μ = V, Cr, Mn, Fe, Co, Ni, Ru, Os, Rh e,g. for M" Fe one obtains Ferrocene/Ferrocenium switched dérivatives R) = H, Alkyl, Aryl, Àlkpnyl, HaloR2 - H, Alkyl, Aryl, Alkenyl, HaloR3 = H, Alkyl, Aryl, Alkenyl, HaloR4 = H, Alkyl, Aryl, Alkenyl, Halo R5 = H, Alkyl, Aryl, Alkenyl, HaloR$ = H, Alkyl, Aryl, Alkenyl, HaloR7 » H, Alkyl, Aryl, Alkenyl, HaloR}j — H, Alkyl, Aryl, Alkenyl, Halo 31 011257 XÀÊI^lCûaîmuÊil

Porphyrîn Based Swltching

nh2

NH, NH,

Switching can be accomplished via metaîlation of the porphyrin, viaoxidation state change of the free base porphyrin or the metallated porphyrin,via change in the ax?al ligation of the métal porphyrin, opticaliy etc. 32 011237 TABLE I Gflniitmgd

33 01 1237

I ί TABLE I Contint,

Bi-Pyridyl Based Systems

NH2 34 011237 TABLE I Γοηΐίηη^

Phcnanthrolîne Based Systems

35 011237 XàBXE I Cantinued

Salen Based Swîtching Systems

I

*6 NH2

nh2

Claims (30)

1. 011237 36 i What we daim is·.

   1. A method of transferrmg oxygen to at least one oxidizable site on a targetcompound having a plurality of oxidizable sites, the method comprising; selectively oxidizihg an oxidizable site on a target compound having aplurality of oxidizable site$ therein by reacting in solution: the target compouhd;a source of oxygen atoms;a source of a Lewis acid; and,a catalyst having the structure

   wherein; Z is N or O and at ieast ope Z is N; MO is a transition metal-çxo species; I Ch! is selected frqm the group consisting of pyridine, pyrimidine, pyrazine,dicyano-pyrazine, mono-, di-, tri- or tetra· substituted benzene, benzimidazole,benzoquïnone, mono- or dj- iminobenzene, indole, substituted crown dérivatives,cryptand ligands, EDTA dérivatives, five-raembered rings and five-membered ringdérivatives, porphyrin dérivatives, metallated-pthalocyaniné based Systems, bi- pyridyl-based Systems, phenanthroline-based Systems and salen-based Systems i Chî and Ch3 each represent a unit joining the adjacent Z atoms comprised of 37

   wherein Ri, Rî, R3, anà R4 pairwise and cumulatively are the same or different andeach is selected from the group consisting of alkyl, aryl, alkenyi, alkynyl, alkylaryl, ΐ cyeloalkyl, cycloalkenyl, alkoxy, phenoxy, halogen,haloalkyl,pexhaloalkyl, CH2CP3 I and CF3 or R|, R2, Rj and R4 together form a suhstituted or an unsubstituted benzenering, or the paired R substituents of the Ri, R2 or the R3, R4 pairs together form a * I cyeloalkyl or a cycloalkenyl ring; and, Ch4 is a unit joining the adjacent Z atoms selected from the group consisting

   wherein Rs and Ri are fhe same or different, linked or nonlinked, and each is I coraprised of hydrogen, ketones, aldéhydes, carboxyliç acids, esters, ethers, amines, i imines, amides, nitro, suîphonyls, sulfates, phosphoryls, phosphates, silyl, siloxanes,alkyl, aiyl, alkenyi, alkyjtyl, alkylaiyl, cyeloalkyl, cycloalkenyl, alkoxy, phenoxy,halo, CH2CF3 or CF3, οχ the paired R substituents of the Rj, Rs pair together form a J cyeloalkyl or a cycloalkenyl ring; with substituents chosen as for unlinked R5, R$ and, I allowing the reaction to proceed for a period of tinte sufficient to oxidize atleast one oxidizable site of the target compound,
2. 2. The method recited In the daim 1 wherein the Lewis acid is selected from the i group consisting of proton, alkali, alkaline earth, rare earth or transition métal ormain group métal ions, i
3. 3. The method of claini 1 wherein the plurality of oxidizable sites in the target i compound differ froin each other in relative reactivity and the Lewis acid (is 38 011237 I I ί selected to selectively) activâtes the catalyst by forming a cation-catalyst » I complex for oxidizing one oxidizable site on the target compound.
4. 4, The method of claim 3 further including the steps of: î identifying a sériés of oxidizable sites on the target compound, having ! reactivities ranging sequentially from generally the highest relative reactivity for a i beginning set of oxidizable sites of the sériés of oxidizable sites to the lowest I relative reactivity for an ending set of oxidizable site of the oxidizable sites in the I sériés of sites; and, i (a) adding to thesolution a first cation for activating the catalyst to forrn afîrst cation-catalyst complex having a first reactivity, the first reactivity ofthe first cation-catalyst complex suffi ci ent to selectively oxidize the firstset of oxdizable sites in préférence to oxidizing other oxidizable sites inthe target compound; (b) allowing the bxidation reaction to proceed for a period of time sufficient i to oxidize eacjh beginning oxidizable site on the target compound such I that the secoijd set of oxidizable sites in the sériés has the highest relative t reactivity of the oxidizable sites remaining in the sériés of sites; i (c) optionally removing the first cation from the solution; (d) adding a second cation to the solution, the resulting cation-catalyst i complex having a second reactivity sufïicient to selectively oxidize the second set of oxidizable sites; I (e) allowing the oxidatlon reaction to proceed for a period of time sufficientto permit the Oxidation of the second set of oxidizable sites on the target i compound such that any next oxidizable sites in the sériés of oxidizablesites on the target compound has the highest relative reactivity of theoxidizable sit^s remaining in the sériés of sites; (f) optionally removing the second cation from the solution; I (g) repeating stepjs (d) to (f) for each successive oxizable site in the sériés of oxidizable sites on the target compound by sequentially adding selected

   39 011237 the selected cation from the solution before the next selected cation isadded, each successive cation added to the solution having progressive^higher reactivities to eiïect the sequential oxidation of the oxidizablesites in the sériés of oxidizable sites until the ending oxidizable site isoxidized.
5. 5. The method recited in claim 4 wherein the set of oxidizable sites includesone oxidizable site.
6. 6. The method recited in claim 4 wherein the set of oxidizable sites includesmore than one oxidizable site.
7. 7. The method recited in claim 1 wherein the target compound has at leastone prochiiial oxidizable site and the Lewis acid catalyst complex haschirality suçh that it catalyzes the enantioselective oxidation of said atleast one oxidizable site.
8. 8. The method recited in claim 7 wherein the oxidizable site is a prochiralphosphorous containing compound.
9. 9. The method recited in claim 1 wherein the oxidizable sites are olefîns
10. 10. The method recited in claim 7 wherein the oxidizable sites are alkynes.
11. 11. The method recited in claim 7 wherein the transition métal of the catalystis manganèse.
12. 12. The method of claim 7 wherein the transition métal of the catalyst is iron.
13. 13. The method of claim 7 wherein the transition métal is selected from thegroup consîstin'g of Groups 6,7, 8, 9,10, and 11 of the periodic table ofthe éléments or those having an oxidation State of I, II, III, IV, V, VI, Vil or VÏÏI. : .
14. 14. The method recited in daim 1 wherein the oxidizable sites are alkynes.
15. 15. The method recited in claim 1 wherein the oxidizable sites are olefîns.
16. 16. The method recited in claim 1 wherein the transition métal of the catalystis manganèse.
17. 17. The method of claim 1 wherein the transition métal of the catalyst is iron. 40 011237
18. 18. The method of claim 1 wherein the transition métal is selected front thegroup consisting of Groupa 6,7,8, 9,10, and 11 of the periodic table of the éléments or those having an oxidation State of I, II, III, IV, V, VI, Vil » or VIII. ί
19. 19. The method recited in claim 1 wherein the Lewis acid is selected fromthe group of atoms of the lanthanide sériés,
20. 20. The method recited in claim 1 wherein the Lewis acid is selected fromthe group of atoms of the actinide sériés.
21. 21. The method of claim 1 wherein the cation is selected from the groupconsisting of Li+, Na+, Zn2+, Mg2*, Caî+, Ba2+, Sc3+ Rh3+ and Ru2+,
22. 22. The method recited claim 1 wherein the métal of the metal-oxo species isan iron and'jChJs

    wherein: l Z is the métal coraplexing atom, preferably N; X is a functionality résistant to i oxidation when the métal complex is in the presence of an oxidizing medium; andR' and R" are thb same or different and each is selected from the group I consisting of substitueras which are unreactive, form strong bonds intramolecularly within R' and R” and. with the cyclic carbon to which they are bound, are sterically ί hindered and are confofmationally hindered such that oxidative dégradation of themétal complex is restricted in the presence of an oxidizing medium.
23. 23. The methodj recited in claim 22 wherein Rs and R$ are each selectedfrom the group consisting of hydrogen, halogen, methyl, Cfj, and if linked, cyclobutyl, cyclopentyljcyclopropyl, or cyclohexyl. î
24. 24. A method of transferring oxygen to an oxidizable site on a targetcompound comprising: i 41 011237 selectiveiy oxidizing an oxidizable site on a target compound having oneprochiral oxidizable site by reacting in solution: the target compound;a source of oxygen atoms;a source of a Lewis acid; and, I ’ a catalyst for forining a complex with the Lewis acid, said complex having I chirality and said caialysft having the structure

    Ch, wherein: 10 ZisNorOandatleastJoneZîsN;· MO is a transition metal-oxo spficies; Ch i îs selectcd from the group consisting of pyridine, pyrimidîne, pyrazine,dicyano-pyrazine, monos di-, tri- or tetra- substituted benzene, benzimidazole, I benzoquinone, di- iminobenzene, indole, substituted erown dérivatives, cryptand15 ligands, EDTA dérivatives, flve-membered rings and frve-membered ring dérivatives,porphyrin dérivatives, metallated pthalocyanine-based Systems, bi-pyridyl-based Systems, phenanthroline-based Systems and salen-based Systems; Chî and Chj each represent a unit joining the adjacent Z atoms comprised of

    or

    42 011237 wherein Rj, R&amp; Ra, and Rj pairwise and cumulatively are the same or different and i each is selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, alkylaryl,cycloalkyl, cycloalkenyl, alkoxy, phenoxy, halogen,haloalkyls perhaloalkyl, CH2CF3 and CF3 or R], R2, R3 anà R4 together form a substituted or an unsubstituted benzene i ring, or the paired R subsjituents of the Ri, R2 or the R3, R4 pairs together form acycloalkyl or a cycloalkenyl ring; and, I Ch4 is a unit joining the adjacent Z atoms selected from the group consisting of

    and ! wherein R$ and R$ are the same or different, linked or nonlinked, and each is i comprised of hydrogen, k'etones, aldéhydes, carboxylic acids, esters, ethers, amines,imines, amides, nitro, sulphonyls, sulfates, phosphoryls, phosphates, silyl, siioxanes,alkyl, aryl, alkenyl, alkynyl, alkylaryl, cycloalkyl, cycloalkenyl, alkoxy, phenoxy,halo, haloaJkyl, perhaloalkyl, CH2CF3 or CF3. or the paired R substituents of the Rs,R4 pair together form a cycloalkyl or a cycloalkenyl ring; and, ί wherein the Lewis acid-catalyst complex catalyzes the enantioselectiveoxidation of said oxidizable site of the target compound.
25. 25. The methpd recited in claîm 24 wherein the Lewis acid is selectedfrom the group consisting of proton, alkali, alkaline earth, rare earth or transition métal ions.26. olefin. 27. 28. The methùd recited in daim 24 wherein the oxidizable site is an The methpd recited in daim 24 wherein the oxidizable site an alkyne.The methpd recited in daim 24 wherein the oxidizable site is a I phosphorous containing Compound.
26. 29. The methpd recited in daim 24 wherein the transition métal of thecatalyst is manganèse. ! 43 011237
27. 30. The method recited in daim 24 wherein the transition métal of thecatalyst is iron. !
28. 31. The method of daim 24 wherein the transition métal of the metal-oxospecies is selected from the group consisting of Groups 6,7,8,9,10» and 11 of the 5 periodic table of the éléments or those having an oxidation State of I, II, III, IV, V,VI, VII or VIH. j
29. 32. The method recited in daim 24 wherein the Lewis acid is selected I from the group of atonis of the lanthanide sériés.
30. 33. The meihod recited in daim 24 wherein the Lewis acid is selected i 10 from the group of atonis of the actinide sériés. 1