Oxidation of oximes with hypervalent iodine reagents: opportunities, development, and applications

The paper reviews the oxidation of oximes to nitrile oxides with hypervalent iodine reagents, especially PhI(OAc) 2 , and the synthetic uses of such a transformation. Side reactions attending the process are also discussed.


Introduction
Hypervalent organoiodine compounds 1 have emerged as uniquely capable oxidants in a number of noteworthy transformations, some of which are all but unachievable by the use of alternative reagents.For instance, PhI(OCOCH 3 ) 2 (DIB), or occasionally PhI(OCOCF 3 ) 2 (PIFA), serve as exquisite promoters of the oxidative amidation of phenols, 2 a special case of oxidative dearomatization of phenols 3 exemplified in Scheme 1. 4 Low toxicity and environmentally benign nature amplify the practical value of such oxidants.

Scheme 1. The oxidative amidation of phenols.
Three modes of oxidative phenolic amidation are known at this time: the oxidative cyclization of phenolic oxazolines (1 → 2) 5 or sulfonamides (3 → 4), 6 both of which are intramolecular reactions, and the bimolecular Ritter-like amidation in the presence of nitriles (5 → 6). 7Investigations centering on the application of these transformations to the synthesis of certain natural products revealed the desirability of engaging the emerging dienones in a nitrile oxide cycloaddition ("INOC") reaction, 8 ideally, within the context of a tandem oxidative amidation / INOC sequence.A number of considerations induced us to focus on the oxidation of oximes with hypervalent iodine reagents as a means to generate nitrile oxides in a manner consonant with the foregoing objective.Research in that sense ultimately produced excellent solutions.In addition, it stimulated significant activity in other domains of chemical science, including bio-organic, main-group, and materials chemistry.The present contribution highlights key developments in these areas, and it covers literature published through June 2011.

Desymmetrization of Dienones obtained through Oxidative Amidation Reactions
The incentive for revisiting the oxidation of oximes with hypervalent iodine reagents emanated from a desire to create a tetrasubstituted, N-bearing stereogenic carbon of a specific configuration in connection with a particular synthetic objective (vide infra).The stereoselective assembly of such carbon centers is generally difficult, but the desymmetrization of a "locally symmetrical" dienones ensuing from an oxidative amidation reaction provides an effective and straightforward solution.As apparent from Scheme 2, this entails the selective addition of an.

Scheme 2. Desymmetrization of "locally symmetrical" dienones 7
Appropriate agent, X-Y, either to the pro-(R) or the pro-(S) double bond.The various methods that were devised to that end were inspired by the observation that conformational effects can elicit selective reactivity at a particular diastereotopic π bond of the dienone.For instance, spirolactam 10 undergoes highly stereoselective cyclization to 11 upon standing (Scheme 3).5b Evidently, welldocumented conformational effects direct the OH group selectively to the pro-(R)-double bond of 10. 9 This translates into a highly selective formation of the (R)-configuration of the spiro center in 11.

Scheme 3. Stereoselective Michael cyclization of 10.
On the basis of the foregoing observation, we charted a synthesis of (-)-cylindricine C and putative (+)-lepadiformine 6b-c that relied on dienone desymmetrization via a stereocontrolled Michael cyclization of the anion of mesylamide 12 (Scheme 4).When compound 12, P = TIPS, was deprotonated with KHMDS, products 13 and 14 were formed in a 7:1 ratio.The selectivity in favor of 13 increased to 14:1 when unprotected 12 (P = H) was treated with 2 equivalents of LHMDS.For TIPS-protected substrates, the stereochemical result may be explained by invoking preferential cyclization from conformer anti-15, in which the sulfonyl unit experiences a reduced degree of steric compression against the short side chain relative to conformer syn-15.In the unprotected series, cyclization is likely to proceed from a Li-chelate such as 16, wherein the anion of the sulfonamide is directed to add to the pro-(R) double bond of the dienone.
The reactions of Schemes 3-4 embody "nucleophilic" modes of dienone desymmetrization.A "pericyclic" variant of this process was recently demonstrated through intramolecular Diels-Alder (IMDA) chemistry.As detailed in Scheme 5, oxidative cyclization of sulfonamide 17 in trifluoroacetic acid (TFA) and in situ heating of the resultant 18 afforded an 8:1 mixture of products 20 (major, desired) and 21.Clearly, the IMDA step occurs preferentially from the less sterically congested conformer anti-18, leading to the desired 20.Interestingly, the primary adduct 19 underwent in situ acid-catalyzed epimerization of the stereocenter adjacent to the carbonyl group to produce the thermodynamically more favorable trans fusion between the two six-membered rings.Four stereogenic carbons, including a spiro center, are thus created stereoselectively in a single operation.Substance 20 is structurally related to the core of the unusual alkaloid, himandrine, albeit it possesses the antipodal configuration.

Tandem Oxidative Amidation /Intramolecular Nitrile Oxide Cycloaddition Reactions
The desirability of dienone desymmetrization via 1,3-dipolar cycloaddition reactions of nitrile oxides materialized in connection with an ongoing synthesis of tetrodotoxin, 22 ("TTX", Scheme 6). 11Simplification of the molecule leads to precursor 23, which could be obtained by bisdihydroxylation of diene 24, wherein the groups in parentheses represent expressed or latent forms of the CHO and COOH functionalities.In turn, 24 may derive from 25 by fragmentation of the isooxazoline ring and Wittig reaction.The assembly of 25 may proceed via oxidative amidation of phenol 28 and intramolecular nitrile oxide cycloaddition 12 of 26.Scheme 6. Approach to tetrodotoxin, 22.
Substituent (N) in 27-28 stands for a nitrogenous functionality suitable for the generation of a nitrile oxide, while G is a group that must fulfill a number of requirements.First, it must be sufficiently bulky to direct the nitrile oxide segment of 26 to the pro-(S) double bond, resulting in selective formation of the desired 25.Indeed, a sterically demanding G would preferentially reside outside the developing bowl-shaped tricyclic product, favoring cyclization through transition state 29, leading to the requisite 25 (Scheme 7).By contrast, transition state 30, which leads to the undesired regioisomer of the product, would force G within the developing bowl, creating severe congestion.Second, G must enable oxazoline fragmentation as well as the elaboration of the αhydroxyacid functionality found in intermediate 23.Finally, it should be such that the starting 28 is readily available in enantiopure form.Interestingly, if group (N) were amenable to conversion into a nitrile oxide under the same conditions employed for the oxidative amidation step (reaction with hypervalent iodine agents), then 28 could be advanced to 25 by a tandem oxidative amidation / INOC reaction.The only proviso is that the rate of oxidation of (N) to a nitrile oxide should be slower than that of the oxidative amidation, so that the dienone may already be in place by the time that the nitrile oxide begins to form.

Scheme 7. Stereoselective INOC cyclization directed by substituent G.
A logical choice for (N) appeared to be an aldoxime.Indeed, the literature records examples of oxidation of aldoximes to nitrile oxides with hypervalent iodine reagents, including PhICl 2 , 13 PhIO, 14 and, subsequent to the publication of the results we are about to describe, with PhI(OTs)OH (Koser's reagent). 15Especially relevant to our objectives was the pioneering work of Das, who had previously described the oxidation of aldoximes to nitrile oxides with DIB: the reagent of choice for the oxidative amidation of phenols. 16However, all such reactions employ conditions that are unsuitable for the conduct of a tandem oxidative amidation/INOC sequence.In particular, it was unclear whether the chemistry described in these reports would perform adequately in the solvents normally employed for oxidative amidation reactions, i.e. trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP, oxidative cyclization of oxazolines and some sulfonamides), or neat TFA (most sulfonamides), or acetonitrile containing a catalytic amount of TFA (bimolecular oxidative amidation).
We note that nitrile oxide formation occurs in a range of solvents, even nonpolar ones like toluene.A relevant example drawn from the work of Yang is shown in Scheme 8. 17 Our exploration of alternative media was dictated uniquely by a projected need to induce INOC reactions in tandem with oxidative amidation events and related transformations.It should also be emphasized that the feasibility of a tandem oxidative amidation / INOC reaction in protic solvents was not at all certain at the onset of the studies detailed below, because the action of DIB upon oximes may induce a number of side reactions. 18cheme 8. Oxidation of aromatic oximes to nitrile oxides with DIB in toluene.
Initial experiments ascertained that DIB smoothly oxidizes aldoximes to nitrile oxides in solvents compatible with oxidative amidation chemistry. 19This enabled the conduct of the tandem processes adumbrated in Scheme 9. Thus, exposure of 31 to DIB (2.2 equiv) in MeCN in the presence of TFA afforded 32 (71% yield after chromatography), the structure of which was ascertained by X-ray diffractometry.More importantly, (±)-tyrosine-derived 33, wherein the bulky N-benzyl tosylamide substituent functions now as group G in 28, was converted into (±)-34, single diastereomer, as the sole identifiable product in 44% chromatographed yield.A NOESY-2D experiment unveiled strong dipolar coupling between the indicated protons, confirming the relative configuration shown.The genesis of this particular diastereomer of the product is entirely consistent with the hypothesis formulated earlier in Scheme 7. We stress that a catalytic amount of TFA acts as an effective Bronsted acid promoter of oxime oxidation.In its absence, nitrile oxide formation may proceed inefficiently and side reactions are apt to occur, especially when operating in MeCN as the solvent.In that respect, Patel and collaborators have shown that the reaction of aldoximes with Koser's reagent or DIB in MeCN at 60 °C, without added TFA, can lead to hydroxamic acids or the corresponding O-acetyl derivatives (Scheme 10). 20hile the authors correctly suggest that 36 and 37 could originate from a nitrile oxide intermediate, alternative mechanisms for the formation of the observed products may also be envisaged, and cannot be excluded at this time.
Scheme 10.Oxidation of aldoximes to hydroxamic acids in MeCN without added TFA.

Other Processes Involving the Reactions of Oximes with Hypervalent Iodine Reagents
In the course of our investigations, we observed that methanol containing a catalytic amount of TFA is one of the best solvents for DIB-mediated nitrile oxide generation from oximes.It should be noted that MeOH is unsuitable for the conduct of oxidative amidation reactions, in that being nucleophilic, it will rapidly intercept electrophilic intermediates arising through DIB activation of phenols.In those cases where no oxidative phenolic amidation / alkoxylation steps are required prior to nitrile oxide generation, MeOH becomes a solvent of choice for DIB-mediated oxime oxidation.Pertinent examples appear in Scheme 13. 19 As in the previous cases, a catalytic amount of TFA is essential for maximum efficiency.An instructive example of what might happen in the absence of protonic catalysis emerges from the work of Wang, Hu, and collaborators, who found that the treatment of oxime 50 with DIB in methanol / catalytic TFA failed to produce the desired 51 (Scheme 14; decomposition of 50). 22It is likely that the basic amine neutralized the TFA, thereby denying protonic catalysis to the process and opening the door to side reactions.A limitation of the above methodology is that the formation of isoxazoles from terminal alkynes is inefficient.For instance, the reaction of benzaldoxime with DIB in MeOH / TFA and in the presence of phenylacetylene furnished 53 in only 50% yield, while an analogous reaction with 1hexyne provided 54 in a modest 16% yield (Scheme 15).In either case, much benzonitrile oxide dimer (3,4-diphenyl-1,2,5-oxadiazole-2-oxide) was formed, indicating that the poor yields were due to a side reaction that was subtracting the alkyne from the medium.All indications implicated a competing formation of reactive alkynyliodonium species, 23 which might then combine with various nucleophiles present in the medium, including MeOH, to form a host of different products.Interestingly, shortly after the appearance of our own work Hou described a method for the synthesis of α-acyloxy ketones (Scheme 16) by the reaction of terminal alkynes with DIB.A plausible mechanism indeed involves alkynyliodonium intermediates 56. 24heme 15.Unsatisfactory isoxazole formation from terminal alkynes.

Scheme 16. DIB-mediated conversion of terminal alkynes into α-acyloxyketones.
One may conclude from the foregoing that an internal alkyne should participate more efficiently in such DIB-mediated reactions; a surmise that finds confirmation in recent work by Boons and collaborators. 25Strained cycloalkynes such as 60 are especially effective trapping agents for nitrile oxides so generated (Scheme 17).No TFA is required in this case.Van Delft and coworkers subsequently discovered that PIFA in aqueous MeOH is superior to DIB for this general reaction (Scheme 18). 26Even terminal alkynes provide isoxazoles efficiently under the new conditions.Evidently, the rate of oxime oxidation by PIFA is so fast that side reactions such as the one outlined in Scheme 16 no longer compete.Furthermore, the examples listed in Scheme 19 indicate that the methodology is exceptionally tolerant of spectator functionality: even substrates incorporating basic (lysine and arginine) or acidic (aspartic acid) aminoacids, nucleotides, and aminopurines (e.g., adenine) react efficiently.These reactions embody a new form of "click" technology, and under this rubric, a noteworthy application of the Boons methodology 25  The foregoing developments encouraged us to broaden the scope of the reaction of oximes with hypervalent iodine reagents.A synthetically appealing opportunity materialized in the form of an oxidation of 75, leading to carbethoxyformonitrile oxide (CEFNO): 27 a useful (and safe) fulminic acid equivalent. 28Happily, methanolic DIB in the presence of TFA smoothly converted 75 into CEFNO, which was efficiently trapped in situ with norbornene and styrene (Scheme 21). 29nalogous reactions of oximinoacetone, 76 also proceeded in a satisfactory manner, albeit the yields of products 79-80 were lower than those obtained from 75.Regardless, the oxidation of oximes 75-76 nicely complements other methods for the generation of α-oxo-nitrile oxides. 30Contrary to an aldoxime, an ordinary ketoxime cannot produce a nitrile oxide directly upon oxidation.However, a nitrile oxide could form as a result of the oxidation of an α-oxo-ketoxime in a nucleophilic solvent such as MeOH, through solvolytic fragmentation of the carbonyl-imino C-C bond, perhaps through the mechanism depicted in Scheme 22.This is indeed the case.As seen in Scheme 23, the oxidation of representative α-oxo-ketoxime 85, 88, and 91 with DIB in methanol proceeded in a satisfactory manner, although consistently higher yields of cycloadducts were obtained when norbonene, rather than styrene, was employed as a trap.The reasons for this remain unclear.It should be noted that norbornene adducts of the type 89 have been employed as building blocks for the synthesis of prostaglandin analogs. 31The methodology outlined in Scheme 23 offers a particularly direct avenue to these materials.Also worthy of note is the fact that the nitrile oxide arising from camphor-derived 91 reacted with norbornene to yield an essentially 1:1 mixture of diastereomeric adducts 89 and 90, which arise from the two possible exo-topologies of the cycloaddition step, while its styrene adduct 94 emerged as a 1:1 mixture of diastereomers.Evidently, cyloaddition reactions of this chiral nitrile oxide proceed with no stereoinduction whatsoever.
A limitation of this chemistry is that α,α'-dioxoketoximes are generally poor substrates for solvolytic DIB oxidation (Scheme 24).To wit, oxime 95 yielded 78 as efficiently as did 76 (cf.Scheme 21), but 96 gave 77 in lower yield than 75, while the oxidations of 97 and 99 were no longer preparatively useful.As detailed elsewhere, 29 inductive, resonance, and steric effects conspire to retard the rate of oxidation of α,α'-dioxo substrates and of nucleophilic cleavage of the resulting reactive intermediates, hampering nitrile oxide formation and diminishing overall yields.Scheme 24.Generally unsatisfactory oxidation of α,α'-dioxo-ketoximes with methanolic DIB.

Conclusions
The oxidation of oximes to nitrile oxides by the use of hypervalent iodine reagents provides new tactical opportunities for the synthesis of nitrogenous substances, natural or otherwise.While the first examples of this reaction 13,14,17 predate our own contributions, the appearance of our 2009 paper 19 seems to have rekindled interest in this noteworthy transformation.Indeed, numerous applications in natural product, bio-organic, heterocyclic, and materials chemistry have been described since.The method complements existing avenues to nitrile oxides, the usefulness of which in preparative operations is likely to make this chemistry of interest to a broad cross section of synthetic and medicinal chemists.In closing, we would be remiss not to underscore that the incentive to research the reactions discussed herein originated exclusively from a perceived need for new synthetic technology: Synthesis is, and will always be, the engine that drives chemical invention.

Scheme 17 .Scheme 19 .
Scheme 17. Internal alkynes as traps for nitrile oxides obtained by DIB oxidation of oximes