Oxidative cyclizations of oximes using hypervalent iodine reagents

This account overviews oxidative cyclization reactions of aldoximes or ketoximes promoted by hypervalent iodine reagents. The oxidation of aldoximes by iodine(III) compounds generates nitrile oxides which can further react with appropriate substrates via intermolecular or intramolecular 1,3-dipolar cycloaddition reactions leading to a variety of nitrogen and oxygen heterocycles. Hypervalent iodine reagents can also react with ketoximes producing the corresponding heterocyclic products via intramolecular cyclization reactions. Recently

0][31] The oxidation of ketoximes initially generates oxonitrenium ions as active intermediate species, intramolecular cyclization of which forms the corresponding heterocycles (see Section 3).
Recently, the first catalytic procedures for the preparation of isoxazolines 8, isoxazoles 9, or oxadiazoles 10 have been developed.These procedures utilize catalytic hypervalent iodine species 15 generated in situ from iodoarenes 16 and appropriate terminal oxidants such as m-CPBA or Oxone (Scheme 3). 32,33The reaction mechanism of the catalytic synthesis of oxadiazoles 10 has been investigated by NMR spectroscopy and ESImass spectrometry (Section 4). 34heme 3. Catalytic cyclization of aldoximes 1 using in situ generated hypervalent iodine(III) species 15.
In the present account, the oxidative heterocyclization reactions of aldoximes or ketoximes using various organohypervalent iodine(III) reagents are overviewed, and recent developments in hypervalent iodine catalyzed cyclizations are summarized.

Reactions of aldoximes using hypervalent iodine reagents
Various aldoximes can be converted into the highly reactive, non-isolable nitrile oxides 3 (Scheme 1) by oxidation with organohypervalent iodine(III) reagents under mild conditions.6][37] When hypervalent iodine(III) reagents are used for oxidation of aldoximes, the generated nitrile oxides dimerize at room temperature to give the corresponding oxadiazole N-oxides. 38,39 Scheme 4. Formation of N-hydroxy-or N-acetoxy-amides in the reactions of aldoximes with HTIB or DIB.
The hypervalent iodine(III) mediated intramolecular nitrile oxide cycloaddition (INOC) represents a convenient approach to fused heterocyclic ring system.8][49][50] In particular, Yao and co-workers have demonstrated that the INOC reaction of 2-allyloxybenzaldoximes 26 using Koser's reagent in water gives the corresponding tricyclic isoxazoline derivatives 27 in moderate to good yields (Scheme 7). 49This is an environmentally friendly reaction, which can be easily handled in water without special care.Tricyclic compounds 27 are potentially important pharmaceutical products.
Among practically important INOC reactions, tandem oxidative inter-or intramolecular phenol dearomatization-INOC reactions have been developed.In these tandem reactions, the iodine(III) reagent serves as the oxidant for both phenol and aldoxime. 13,16,28,51,52Ciufolini and co-workers reported a practical approach to the tandem oxidative dearomatization-INOC reaction using (diacetoxyiodo)benzene (Scheme 8). 51n this procedure, the iodine(III) reagent is employed as the oxidant for the oxidative dearomatization reaction of phenolic compounds 28 to give the corresponding cyclohexadienone nitrile oxides 29, and then the intramolecular 1,3-dipolar reaction of 29 occurs to give the tricyclic products 30 in moderate to good yields.Another tandem oxidative intramolecular dearomatization-INOC reaction leading to the core skeleton of coristatins has been reported by Sorensen and co-workers.Das and co-workers have reported a simplified one-pot procedure for the synthesis of isoxazolines 33 from corresponding aldehydes 31 with hydroxylamine and alkenes 32 using iodosylbenzene in water in the presence of sodium dodecyl sulfate (SDS) as anionic surfactant (Scheme 9). 53This procedure has been performed with various functionalized aldehydes and alkenes, and it also can be used for the intramolecular heterocyclization of 2-allyloxybenzaldehyde.Scheme 9. One-pot synthesis of isoxazolines from aldehydes and alkenes.

Cycloaddition of aldoximes leading to isoxazoles
8][19] In particular, the reaction of various aldoximes with alkynes in the presence of organohypervalent iodine(III) reagents such as DIB, 48,51,54-57 BTI, 46,58,59 Koser's reagent, 49,60 or PhIO, 27,61 leads to oxidative heterocyclization yielding the corresponding isoxazoles.This procedure is applicable to various internal or terminal alkynes under mild condition.For example, the reaction of aromatic or aliphatic aldoximes with various alkynes using BTI affords the corresponding isoxazole products in good yields. 58The BTI induced heterocyclization has been used for the efficient synthesis of nucleoside-substituted isoxazoles 36 from aldoximes 34 and nucleoside 35 (Scheme 10).Several oxidative cycloaddition reactions of internal alkynes with aldoximes using iodine(III) reagents have been reported. 46,54,60][57][58] For example, the reaction of lactose oxime with dibenzocyclooctyne derivatives using DIB gives the corresponding isoxazoles in good yields. 56The obtained compound can be modified with the biotin tag, and can then be useful for an immobilization reaction to the surface of Streptavidin.Boons and co-workers reported the preparation of amphiphilic polymeric compounds 39 by using strain-promoted heterocyclization of polymer-supported aldoxime 37 and cyclooctyne derivatives 38 using DIB (Scheme 11). 57The polymers produced can form stable molecular assemblies in aqueous solution because of their hydrophilic-hydrophobic balance.These self-assembled products can further form nanoparticles potentially useful in materials or biomaterials sciences.Scheme 11.DIB mediated preparation of amphiphilic polymers.
The iodine(III)-mediated intramolecular cyclizations of aldoximes can be performed under conditions similar to the intermolecular reactions conditions. 49,53The intramolecular cyclization reaction of 2propargyloxybenzaldoximes using Koser's reagent in water gives the corresponding tricyclic isoxazole derivatives in good yields.Das and co-workers have also reported an efficient one-pot procedure for the preparation of tricyclic isoxazole product 41 from 2-propargyloxybenzaldehyde 40 and hydroxylamine using iodosylbenzene in the presence of anionic surfactant (Scheme 12).Alkynyliodonium salts are electron-deficient alkyne derivatives useful for heterocyclization reactions. 8,62,63In a specific example, Stang and Murch reported the reaction of alkynyliodonium salt 43 with nitrile oxide generated from aldoxime 42 using iodosylbenzene to give the corresponding isoxazoles 45 in moderate yields. 61This reaction probably involved the intermediate iodonium salt 44, formed in situ from aldoxime 42 and alkynyliodonium salts 43, followed by loss of the of a phenyliodonium moiety to give the isoxazole products 45 (Scheme 13).

Cycloaddition of aldoximes leading to other heterocycles
Oxidative heterocyclization reactions of aldoximes with nitriles or aldehydes using hypervalent iodine(III) reagents have also been reported. 27,34,64For example, treatment of aliphatic or aromatic aldoximes 46 with 2-[hydroxy(trifluoromethanesufonyloxy)]iodobenzoic acid 47 in acetonitrile solution affords the corresponding oxadiazoles 48 in moderate to good yields (Scheme 14). 34This reaction also proceeds smoothly in solutions of other nitriles under similar conditions affording 1,2,4-oxadiazoles 48 in moderate to good yields.

Reactions of ketoximes using hypervalent iodine reagents
Syntheses of various heterocyclic compounds using ketoximes as building blocks have been reported. 65,66rganohypervalent iodine(III) compounds are particularly effective reagents for the oxidation of ketoximes.Reaction of ketoximes 52 with iodine(III) reagents probably involves the initial formation of oxonitrenium species 53 followed by intramolecular cyclization to form heterocyclic products 54 (Scheme 16).8][69][70][71] Zefirov and co-workers reported an efficient conversion of oximes into the acetoxy nitroso compounds. 72This reaction involves initial generation of oxonitrenium intermediates from oximes using 4-bromo(diacetoxyiodo)benzene followed by their reaction with AcO -affording acetoxy nitroso compounds in good yields.
The cyclization reactions of oximes using hypervalent iodine(III) reagents can proceed with various nucleophiles, such as alkenes, [73][74][75][76] alcohols, [77][78][79][80][81] or amines, 67,82 within the molecule to produce the respective cyclic compounds.For example, Aggarwal and co-workers have reported an efficient synthesis of 2,3-diphenylquinoxaline-1-oxides 56 from benzyl--arylimino oximes 55 using DIB (Scheme 17). 76Products 56 are potentially important as angiotensin II receptor antagonists.8][79][80] Effective procedures for the preparation of various isoxazole N-oxides from ketoximes have been developed by several research groups.Yao and co-workers have reported the Koser's reagent-induced oxidative heterocyclization reactions of ketoximes in water or methanol producing the corresponding isoxazole N-oxides in good yields. 77The reaction of bisoxime 57 with Koser's reagent in water affords benzodiisoxazole di-N-oxide 58 as the sole product in good yield (Scheme 18).The analogous iodine(III)mediated reactions of ketoximes with amines as nucleophiles result in N-N bond formation producing the corresponding pyrazolin-5-one N-oxide derivatives. 67 Ciufolini and co-workers have reported the hypervalent iodine(III)-induced oxidation of -oxo-oximes to nitrile oxides. 83The oxidation of -oxo-ketoximes 59 with DIB in the presence of norbornene 60 in methanol gave the corresponding isoxazoline compounds 61 in moderate yields.The mechanism of this reaction starts from the generation of iodine(III) species 62 via ligand exchange followed by a methanol-promoted solvolytic fragmentation of 63 to form nitrile oxide 64.Finally, the nitrile oxide 64 reacts with norbornene 60 to give the final isoxazoline products 61 (Scheme 19).

Oxidative cyclization of aldoximes using catalytic hypervalent iodine species
87,88 In 2013, our group was the first to report the hypervalent iodineinduced catalytic cyclization of aldoximes. 32We have found that oxidative heterocyclization of various aldoximes 65 with alkenes 66 or alkynes 67 in the presence of catalytic aryl iodide and Oxone as the oxidant affords the corresponding isoxazolines 68 or isoxazoles 69 in moderate to good yields (Scheme 20).Later, Yan and co-workers reported a similar catalytic iodine(III)-mediated oxidative cycloaddition of aldoximes with alkenes or alkynes. 87,88OH Recently, we have reported the catalytic oxidative cyclization of aldoximes 70 with maleimides 71 using highly active hypervalent iodine(III) species producing the corresponding pyrrolo-isoxazoles 72 in moderate to good yields (Scheme 21). 33This catalytic reaction probably involves the highly reactive hydroxy(aryl)iodonium species generated from 2-iodobenzoic acid and m-chloroperoxybenzoic acid (m-CPBA) in the presence of trifluoromethanesulfonic acid.The presence of these active iodine(III) species in the reaction mixture was confirmed by 1 H NMR spectrocopy and ESI-mass spectrometry.Recently, the catalytic hypervalent iodine-mediated oxidative cyclization reactions of aldoximes with nitriles have been reported. 34,64This process also involves the hydroxy(aryl)iodonium species generated in situ from 2-iodobenzoic acid, m-CPBA and trifluoromethanesulfonic acid as confirmed by 1

Conclusions
This account demonstrates the active current interest and high research activity in oxidative heterocyclization reactions promoted by the environmentally sustainable organohypervalent iodine reagents.Oxidative cycloaddition reactions of aldoximes or ketoximes with appropriate dipolarophiles in the presence of common iodine(III) oxidants provide an efficient synthetic approach to various nitrogen and oxygen heterocycles.The oxidation of aldoximes generates nitrile oxides, which are efficient 1,3-dipolar reactants in intra-or intermolecular cycloadditions.Suitably functionalized ketoximes and hypervalent iodine(III) reagents have been utilized as efficient reactants in intramolecular heterocyclization reactions.Moreover, catalytic methodologies for aldoxime heterocyclization using various iodoarenes as precatalysts have been recently developed.We expect that this synthetically important area of hypervalent iodine chemistry will continue to attract significant research activity in the future.

Acknowledgements
This work was supported by a research grant from the NSF (CHE-1262479).