Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes

Iminoiodinanes comprise a class of hypervalent iodine reagents that is often encountered in nitrogen-group transfer (NGT) catalysis. In general, transition metal catalysts are required to effect efficient NGT to unactivated olefins because iminoiodinanes are insufficiently electrophilic to engage in direct aziridination chemistry. Here, we demonstrate that 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) activates N -arylsulfonamide-derived iminoiodinanes for the metal-free aziridination of unactivated olefins. 1 H NMR and cyclic voltammetry (CV) studies indicate that hydrogen-bonding between HFIP and the iminoiodinane generates an oxidant capable of direct NGT to unactivated olefins. Stereochemical scrambling during aziridination of 1,2-disubstituted olefins is observed and interpreted as evidence that aziridination proceeds via a carbocation intermediate that subsequently cyclizes. These results demonstrate a simple method for activating iminoiodinane reagents, provide analysis of the extent of activation achieved by H-bonding, and indicate the potential for chemical non-innocence of fluorinated alcohol solvents in NGT catalysis.


Introduction
Hypervalent iodine reagents find widespread application in selective oxidation chemistry due to the combination of synthetically tunable iodine-centered electrophilicity and the diversity of substrate functionalization mechanisms that can be accessed [1,2].Large families of iodine(III)-and iodine(V)-based reagents have been developed -including iodobenzene diacetate (PhI(OAc) 2 , PIDA), Koser's reagent (PhI(OH)OTs), Zhdankin's reagent (C 6 H 4 (o-COO)IN 3 , ABX), and Dess-Martin periodinane (DMP) -and find application in an array of synthetically important transformations including olefin difunctionalization, carbonyl desaturation, alcohol oxidation, and C-H functionalization [3,4].Iminoiodinanes (ArI=NR) are a subclass of hypervalent iodine reagents that function as nitrene equivalents in synthesis [5,6].The direct reaction of iminoiodinanes with olefins, which could be envisioned to give rise to aziridines directly, is typically not observed and thus Scheme 1: a) Lewis acid activation of hypervalent iodine reagents can enhance the reactivity of these reagents.b) Charge-tagged iminoiodinanes display enhanced reactivity in aziridination reactions with unactivated olefins (ref.[34]).c) Here, we demonstrate that H-bonding between fluorinated alcohol solvents and iminoiodinanes can enable direct metal-free aziridination of unactivated olefins with simple iminoiodinanes.
families of transition metal catalysts or photochemical procedures have been developed to enable this transformation [7][8][9].
We recently developed a metal-free aziridination of unactivated olefins via the intermediacy of an N-pyridinium iminoiodinane (Scheme 1b) [34].We rationalized the enhanced reactivity towards olefin aziridination as a result of charge-enhanced iodine-centered electrophilicity arising from the cationic N-pyridinium substituent.Based on those observations, we reasoned that similarly enhanced reactivity might be accessed by Lewis acid or H-bond activated iminoiodinanes.Here, we describe the HFIP-promoted aziridination of unactivated olefins with N-sulfonyl iminoiodinane reagents, which are among the most frequently encountered iminoiodinanes in NGT catalysis (Scheme 1c).This simple procedure afforded the formal transfer of various nitrogen groups, including those derived from complex amines, and is complementary to other metal-free aziridinations of unactivated olefins [35][36][37][38][39].
The impact of the iminoiodinane structure on the efficiency of HFIP-promoted direct aziridination was next investigated (Scheme 3).For this purpose, cyclopentene was selected as it underwent efficient aziridination with PhINTs.A family of iminoiodinanes 2 was synthesized from PIDA and the corresponding sulfonamide derivative.Reaction of phenylsulfonamide-derived iminoiodinane with cyclopentene afforded N-phenylsulfonylaziridine 6b in 45% yield, while N-(p-trifluoromethylsulfonyl)aziridine 6c was furnished in 47% yield.Similarly, 2,6-difluorosulfonyl-substituted iminoiodinane 2d afforded aziridine 6d in 52% yield.The aziridination procedure was tolerant of heterocyclic substituents on the iminoiodinane, N-(5-methylpyridin-2-ylsulfonyl)aziridine 6e could be obtained in 46% yield.The N-Tces group (Tces = trichloroethylsulfamate) could also be transferred to afford 6f in 39% yield.Finally, the iminoiodinane derived from celecoxib (2i) could be used to transfer this drug moiety to furnish aziridine 6i in 46% yield.In general, the efficiency of aziridination correlates with the stability of the relevant iminoiodinane reagent, with higher yields attributed to more electron-rich sulfonamide substitution such as 2a.Relatively electron-deficient iminoiodinanes are less efficient but are also more prone to decomposition (see Supporting Information File 1, Figure S2 for challenging iminoiodinanes).In situ preparation of the iminoiodinane intermediates is possible, and for those reagents that undergo facile decomposi- tion, aziridination is more efficient using these conditions (yields for in situ-generated iminoiodinanes are in parentheses in Scheme 3, with N-o-methyl (6g) and N-p-methoxysulfonyl (6h) aziridines obtained each in 22% yield; the drug topiramate could also be transferred to furnish aziridine 6j in 11% yield).
We carried out a series of experiments to clarify the origin of the observed reactivity enhancement of N-arylsulfonyliminoiodinanes in the presence of HFIP (Scheme 4).First, 1 H NMR was employed to examine the interaction between HFIP and iminoiodinane 2c in CD 3 CN (compound 2c was chosen over 2a due to its increased solubility in nonprotic solvents).In a sample of 2c with 4 equivalents of HFIP, a broad signal for O-H proton of HFIP was observed at 5.52 ppm with a FWHM = 56.6Hz (Scheme 4a).This resonance was broader and more downfield than that of free HFIP in CD 3 CN (5.41 ppm with FWHM = 5.0 Hz), suggesting a hydrogen bonding interaction between HFIP and 2c, and similar observations were also reported for the hydrogen bonding between HFIP and PIDA [30,33].During this experiment, a small amount of hydrolysis product 4-(trifluoromethyl)benzenesulfonamide was also observed (1.2 mM, signals at 8.0, 7.9, and 5.86 ppm), but this compound did not greatly contribute to the broadening of O-H proton signal of HFIP as a separate 4.0 mM sample of the sulfonamide resulted in O-H proton signal of HFIP being at 5.64 ppm with FWHM = 11.3Hz.Second, to evaluate the impact of HFIP on the redox chemistry of PhINTs, we collected cyclic voltammograms (CVs) of iminoiodinane 2c in MeCN in the presence of varying HFIP increments (Scheme 4b).The CV of 25 µL HFIP in MeCN showed no electrochemical events between −2.0-0 V.The CV of 2c in the absence of HFIP showed a reductive current (i p = −0.80mA) at peak potential (E pr ) of -1.72 V vs Fc + /Fc.Upon addition of 5.0 µL of HFIP (1.2 equiv with respect to 2c), the current increased to −1.22 mA, signaling the binding of HFIP to 2c enhanced the electron transfer kinetics between the hypervalent iodine reagent and the electrode [45].Further additions of HFIP further increased the current response and shifted the peak potential, with 10 µL and 15 µL of HFIP showing responses with E pr at −1.55 V and −1.52 V, respectively.The titration showed a saturation point at 25 µL of HFIP (6.0 equiv with respect to 2c), at which the CV of 2c showed an E pr = -1.47V and -1.52 mA current.Overall, the addition of HFIP results in a 250 mV shift in the reduction of 2c.The increased facility of reduction is consistent with H-bonding between HFIP and 2c, which results in a more potent oxidant and gives rise to the observed HFIP-promoted olefin aziridination chemistry.
A number of observations are relevant to the mechanism by which unactivated olefin aziridination is accomplished by the HFIP-activated iminoiodinanes: First, the reaction of PhINTs with either cis-or trans-β-methylstyrene (1n) in HFIP afforded aziridine 3n as a mixture of 2.0:1.0 cis/trans (from cis-1n) and 1.0:1.7 cis/trans (from trans-1n) (Scheme 4c).The formation of diastereomeric mixtures suggests that aziridination proceeds in a stepwise fashion.The dissimilarity of the diastereomeric ratios from cis-and trans-starting materials indicates that the potential intermediate is too short lived for complete ablation of the starting material stereochemistry.Second, the aziridination of cyclopentene by PhINTs in the presence of a radical trap N-tert-butyl-α-phenylnitrone (PBN) afforded the aziridine product 3b in 60% NMR yield (Scheme 4d), suggesting a radical pathway was unlikely to be operative.
An 1 H NMR experiment was carried out to probe the speciation of 2a in HFIP, and we observed that 2a underwent reversible ligand exchange with alcohol solvent to afford ArI(OR) 2 and TsNH 2 (Supporting Information File 1, Figure S3); similar solvolysis of PhIO in HFIP has been reported [10].Reaction between cyclohexene and PhIO (2 equiv) in HFIP delivered <10% of cyclohexene oxide; meanwhile, both cyclohexene and cyclohexene oxide were shown to be unreactive towards sulfonamide (Scheme 4e), suggesting that epoxidation is not on path to the observed aziridines.For discussion of side-products and reaction mass balance, see Figure S4 (Supporting Information File 1).Based on these observations, we favor a mechanism in which H-bond activated iminoiodinane reacts directly with the olefin to generate a short-lived alkyl-bound iodinane 7 or iodonium species 8 (Scheme 4f).Ligand coupling from 7 or extrusion of iodobenzene from 8 would furnish a carbocation intermediate 9 which could undergo C-C bond rotation prior to ring closure to form the aziridine product.Such a process would account for the simultaneous stereochemical scrambling observed and the lack of radical trapping noted.

Conclusion
In conclusion, we describe the activation of simple iminoiodinane reagents by fluorinated alcohols, such as HFIP.While most iminoiodinane reagents do not engage aliphatic olefins in the absence of transition metal catalysts, the addition of HFIP enables direct aziridination to be observed.The enhanced reactivity is rationalized as resulting from H-bonding between HFIP and the nitrogen center of the iminoiodinane reagents. 1H NMR data are consistent with such an association and electrochemical data collected in the presence of increasing HFIP concentrations are consistent with H-bonding affording an increasingly strong oxidant.These results demonstrate a simple method for activating iminoiodinane reagents and indicate the potential for chemical non-innocence of fluorinated alcohol solvents in NGT catalysis.

Supporting Information
Supporting Information File 1 Experimental procedures and characterization data, original spectra of new compounds, and optimization details.