Phenyliodine(III) diacetate as a mild oxidant for aziridination of olefins and imination of sulfoxides with N -aminophthalimide

Phenyliodine(III) diacetate (PIDA) was found to promote facile nitrene transfer to olefins and sulfoxides giving aziridines and sulfoximines, respectively, in high isolated yields and with high selectivities. The reactions are tolerant for a range of functional groups and proceed under mild conditions. The feasibility of scale-up has been demonstrated


Introduction
Due to frequent occurrence of nitrogen atoms in the structures of biologically active compounds, chemoselective functionalization of organic molecules with nitrogen-containing groups is among the most important goals in organic synthesis.Recently, a great progress in this field has been achieved.Many amination protocols have been developed and their utilization in organic synthesis has been demonstrated. 1Our group recently reported electrochemical aziridination 2a of olefins and imination of sulfoxides with N-aminophthalimide.2b 1-Phthalimidoaziridines can also be obtained using lead tetraacetate(IV) (LTA) as an oxidant. 3Unfortunately, application of LTA is limited due to its high toxicity and difficulties associated with storage and handling. 4Thus, introduction of an alternative reagent, which would be stable, non-toxic (unlike LTA) and readily available (unlike electrochemical equipment) is of great interest.Herein we report aziridination of olefins and sulfoximination of sulfoxides with N-aminophthalimide and phenyliodine(III) diacetate (PIDA) as a mild oxidant.Scheme 1 Understanding the nature of the reactive intermediate and mechanism of the nitrene transfer led us to the assumption that a mild electrophilic oxidant such as PIDA can serve as an oxidant in the aziridination reaction.As in the case of phenol oxidation with PIDA, 7 the mechanism of generating the N-acetoxy nitrenium ion from N-aminophthalimide can be explained according to Scheme 2. The N-aminophthalimide is oxidized by PIDA producing intermediate 7. The phenyliodide group dissociates from 7 with the formation of the acetoxy nitrenium ion Nacetoxyaminophthalimide 2, the reactive intermediate of the olefin aziridination.The byproducts of this process are acetic acid and iodobenzene.In the case of certain olefins containing electron-withdrawing groups (such as dimethyl maleate and maleic acid anhydride) that do not react under these conditions or give products in small yields, substantial amounts of tetrazane 4 and tetrazene 5 were isolated.

Scheme 2
The reaction conditions were optimized for cyclohexene as a model substrate.Dichloromethane was found to be the best solvent (Table 1.Optimization of the reaction conditions, entry 4).In a typical run, PhthNH 2 gradually dissolves after addition of the oxidant within 2 minutes in CHCl 3 , 20-40 minutes in CH 2 Cl 2 , and 30 minutes in CH 3 CN.The reaction is complete within 2 hours in CH 2 Cl 2 (monitored by TLC), and after basic work-up aziridines were purified by column chromatography.At the end of the reaction, precipitation of the tetrazane and tetrazene by-products may be observed, depending on the solvent used and the nature of the olefin, which indicates the reduced yield of the product (unless the formed aziridine has a low solubility).*Procedure: PIDA (0.5mmol-0.75mmol)was dissolved in 4 ml solvent and gradually added to the mixture of 0.5mmol olefin and PhthNH 2 (0.5mmol-1mmol) in 1ml solvent.After 3-4h the reaction mixture was quenched with 5ml saturated NaHCO 3 and worked up.
The optimized reaction conditions were applied to a variety of olefins.Aliphatic olefins usually give good yields (Table 2, entry 1-3).The reaction tolerates a variety of functional groups such as an ester, a carbonyl function, a nitrile, a hydroxyl group and an amide (Table 2, entry 5-10), although the yield for the olefins with a primary hydroxyl group was found to be lower than for the acetylated ones (Table 2, entry 6,7).Some of the N-phthalimidoaziridines exist as mixtures of invertomers, which have distinctly different 1 H and 13 C NMR signals.The aromatic olefins such as chalcones and styrenes gave the best yields (Table 3).No oxidation of aromatic ring of electron rich chalcones has been observed (Table 3, entry 3, 4), although PIDA is a standard reagent for the oxidation of electron rich aromatics.Scale-up of the reaction for trans-4′-methoxychalcone (0.1mol scale) gave product in quantitative yield.Although dimethyl fumarate gives product in 47% yield (Table 4, entry 3), dimethyl maleate and maleic anhydride do not react at all.Surprisingly, N-methylmaleimide, which is structurally and electronically similar to maleic anhydrate, gives aziridine in 60% yield (Table 4, entry 4).Haloolefins give the corresponding aziridines only in moderate yields (Table 4, entry 5-8).The reaction with 3,3-dimethylallylbromide was scaled up without significant change in yield (Table 4, entry 5).As well, the aziridination reaction was found to be stereospecific: Z-1,2-dichloro-2butene gives cis-aziridine (Table 4, entry 7), whereas E-olefin gives only the trans-product (Table 4, entry 8).Among the challenging substrates, terminal olefins were found to give lower yields.Excess of olefin increased the yield of 3,3-dimethylbutane aziridine from 7 to 20% (Table 5, entry 2, 3).The use of fluorinated analog of PIDA (PIFA) did not improve the yield.Similar reaction conditions were applied to the imination of sulfoxides. 8A number of sulfoxides were converted to the corresponding sulfoximines in moderate to excellent yields (Table 6).In the case of vinylsulfoxide, no reaction at the carbon-carbon double bond has been observed (Table 6, entry 4).

Entry
Product Yield, % 1 The reaction with sulfides was found to be less effective.In the case of benzylphenyl sulfide, the corresponding sulfimine was isolated in small yield together with unreacted starting material.The low yield and efficiency of the reaction can be attributed to the unstable nature of sulfimines, which upon mild heating tend to decompose to the starting sulfides. 9

Scheme 3
In closing, we have found that PIDA/PhthNH 2 combination can be used for aziridination of olefins with a variety of functional groups.The reaction can be scaled up (up to 5 mol of olefin) without any substantial change in yield.Sulfoxides and sulfides can also be used as nucleophilic traps for the generated nitrenium ions.The non-toxic nature of PIDA together with the simplicity of the developed procedure will facilitate preparation and application of sulfoximines and aziridines, which is the subject of ongoing studies.

a
Ratio of invertomers was determined by 1 H NMR. b 0.1mol scale.

a
Ratio of invertomers was determined by 1 H NMR. b 0.1mol scale.

Table 1 .
Optimization of the reaction conditions

Table 2 .
Substrate scope: functional group compatibility