Hypervalent iodine compounds for anti-Markovnikov-type iodo-oxyimidation of vinylarenes

The iodo-oxyimidation of styrenes with the N-hydroxyimide/I2/hypervalent iodine oxidant system was proposed. Among the examined hypervalent iodine oxidants (PIDA, PIFA, IBX, DMP) PhI(OAc)2 proved to be the most effective; yields of iodo-oxyimides are 34–91%. A plausible reaction pathway includes the addition of an imide-N-oxyl radical to the double C=C bond and trapping of the resultant benzylic radical by iodine. It was shown that the iodine atom in the prepared iodo-oxyimides can be substituted by various nucleophiles.


Introduction
The presented work opens a new chapter in the chemistry of N-hydroxyimides in combination with hypervalent iodine compounds with formation of imide-N-oxyl radicals. These radicals were used as reagents for the addition to a terminal position of the double bond of styrenes with subsequent iodination of the resulting benzylic radical.
In the present work imide-N-oxyl radicals were used for the addition to the C=C bonds of styrenes with subsequent functionalization of the resulting benzylic radicals.
Recently, the precursors of N-oxyl radicals, such as N-hydroxyphthalimide (NHPI), N-hydroxysuccinimide (NHSI), N-hydroxybenzotriazole (HOBt) and hydroxamic acids, have been used in the reactions of radical oxygenation of styrenes [45]. Growth of interest is observed concerning the reactions of styrenes with imide-N-oxyl radicals, in which the latter add to the terminal position of the double C=C bond with the forma-tion of stabilized benzyl radicals, which undergo the subsequent functionalization. In the presence of oxygen or tertbutyl hydroperoxide, oxidation proceeds to form the C-O [46][47][48][49][50][51] or the C=O [52][53][54][55] moiety. More complex reagents and reaction systems allows to form C-C [56,57] and C-N [58,59] bonds.
Among the above-mentioned methods, there are no examples of C-Hal bond formation despite the wide usage of organohalides in chemical syntheses. In the row of organohalides, iodides are the most reactive and versatile reagents for the following transformations [60].
One of the purposes of our work was to introduce iodine in the process of difunctionalization of styrenes with imide-N-oxyl radicals. Iodine atom in the product can act as a versatile leaving group for further transformations. The involvement of the iodine in the radical reactions of styrenes is complicated by the fact that unsaturated compounds readily undergo electrophilic iodination with the addition of an external nucleophile [61,62]. The oxidants used for the preparation of imide-N-oxyl radicals, in particular the hypervalent iodine compounds and peroxides [63][64][65][66][67][68][69][70][71][72][73], also generate electrophilic iodinating intermediates (Scheme 1).
For several decades, a number of papers on the electrophilic iodination of C=C bonds by iodine-containing oxidative systems with the addition of various nucleophiles have been published, all of these processes have common mechanism and the same regioselectivity. The free-radical approach developed in the present work affords the opposite (anti-Markovnikov) regioselectivity of the addition to the double bond.

Results and Discussion
In the present work, the reaction of styrenes 1a-k and N-hydroxyimides 2a,b with the formation of iodo-oxyimidated products 3aa-ka, 3ab-db, 3fb, 3hb and 3kb was carried out (Scheme 2).
The key feature of the developed process is the non-standard regioselectivity of the formation of C-I and C-O bonds, which implies the radical pathway of the reaction.
The iodo-oxyimidation of styrenes was studied in the model reaction of styrene (1a) with N-hydroxyphthalimide (2a). During the optimization, the oxidant and the iodine source, as well as the nature of the solvent and the reaction time were varied (Table 1).
Dichloromethane proved to be the best solvent for the reaction, as carrying out the reaction in other solvents led to a decrease in the yield of 3aa (Table 1, entries 5-7). Increasing the amount of PhI(OAc) 2 from 0.6 mmol to 1.5 mmol (Table 1, entry 4) leads to a decrease in the yield of 3aa presumably due to the enhancing the role of side oxidation processes. The optimal reaction time was 10 min, a reaction of 5 min resulted in a significant decrease in the yield of the desired product (Table 1, entry 1). Prolongation of the reaction time to 24 h led to a slight decrease in the yield of 3aa (Table 1, entry 3) due to its instability under the reaction conditions.
The possibility of using iodide salts (NaI and TBAI) was shown in Entries 8 and 9, however, the yield of 3aa in that cases is lower than in the case of molecular iodine.
In the optimized reaction conditions (Table 1, entry 2) iodooxyimidation of various vinylarenes were performed in order to study the scope of the developed method ( Figure 1).
Structures of the iodo-oxyimides 3aa-ka, 3ab-db, 3fb, 3hb and 3kb were confirmed by 1D and 2D NMR spectroscopy, IR spectroscopy, high-resolution mass spectrometry and elemental analysis. An additional confirmation of the structure of 3ca was made using X-ray crystallographic analysis ( Figure 2). Details of the data collection and refinement are provided in Supporting Information File 1 and can be obtained free of charge via the web at https://www.ccdc.cam.ac.uk/structures/ (CCDC-1845323).

Proposed mechanism of the iodo-oxyimidation
Based on the literature data describing the formation of the phthalimide-N-oxyl radical (PINO) from NHPI under the action of PhI(OAc) 2 [34,55,59,76,77], and based on information about the reaction of the PINO radical with styrenes [45] and interac- tion of benzyl radicals with iodine [78,79], a mechanism for the reaction of iodo-oxyimidation of styrenes under the action of the NHPI/I 2 /PhI(OAc) 2 system was proposed (Scheme 3).
On the first step, NHPI (2a) is oxidized by PhI(OAc) 2

Electrochemical studies
Cyclic voltammetry (CV) experiments on a working glassy-carbon electrode were carried out for deeper understanding of the plausible reaction mechanism. As CH 2 Cl 2 is not suitable as a solvent due to the poor solubility of NHPI, thus MeCN was used. Tetrabutylammonium tetrafluoroborate, which cannot be oxidized in such experimental conditions [80], was chosen as a supporting electrolyte. Cyclic voltammograms of styrene (1a), NHPI (2a), I 2 and PhI(OAc) 2 in MeCN solution were registered ( Figure 3).

Scheme 3:
The proposed mechanism of iodo-oxyimidation of styrene (1a) using the NHPI/I 2 /PhI(OAc) 2 system with the formation of product 3aa.

Scheme 4:
Gram-scale synthesis of compound 3aa. The NHPI oxidation peak is observed at +2.18 V, whereas iodine is oxidized at slightly higher potential (+2.27 V), and styrene oxidation peak is not so pronounced. Therefore, we can conclude that under experimental conditions NHPI is oxidized preferentially over iodine providing PINO radicals that leads to the observed regioselectivity. The contribution of the oxidation of styrene to the overall process is unlikely.

Practical application of the iodo-oxyimidation
The applicability of the developed method for the gram-scale preparation was demonstrated by the synthesis of 3aa (3.1 g, 79%) without column chromatography (Scheme 4).
The synthetic utility of the obtained products 3aa and 3ab was demonstrated by the substitution of the iodine atom with O-(methanol), S-(benzenesulfinate) and N-(azide) nucleophiles (Scheme 5).
It is noteworthy that the reaction of compound 3aa with sodium benzenesulfinate results in the nucleophilic substitution of both the iodine atom and the oxyphthalimide moiety to form a vicinal disulfone 4b.

Conclusion
Iodo-oxyimidation of vinylarenes using N-hydroxyphthalimide and N-hydroxysuccinimide was developed. PhI(OAc) 2 was the best oxidant for the synthesis of the target products (yields up to 91%). In contrast to previous studies in which oxidants promote the electrophilic addition of iodine to the C=C bond, radical addition predominates in the discovered process. Radical pathway starts from the attack of imide-N-oxyl radicals on the double C=C bond, which allows for anti-Markovnikov type regioselectivity of C-O and C-I bond formation. Electrochemical mechanistic studies based on cyclic voltammetry (CV) data confirm proposed reaction mechanism. Possible ways of using the obtained iodo-oxyimidated products via substitution of iodine atom were demonstrated.
Iodo-oxyimides 3aa-ka, 3ab-db, 3fb, 3hb and 3kb should be stored in a freezer and handled with minimal heat due to their instability at elevated temperatures.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization data, copies of 1 H, 13 C and 19 F NMR spectra, copies of HRMS and FT-IR spectra and the ORTEP diagram and X-ray data for compound 3ca.