C−N Axial Chiral Hypervalent Iodine Reagents: Catalytic Stereoselective α‐Oxytosylation of Ketones

Abstract A simple synthesis of a library of novel C−N axially chiral iodoarenes is achieved in a three‐step synthesis from commercially available aniline derivatives. C−N axial chiral iodine reagents are rarely investigated in the hypervalent iodine arena. The potential of the novel chiral iodoarenes as organocatalysts for stereoselective oxidative transformations is assessed using the well explored, but challenging stereoselective α‐oxytosylation of ketones. All investigated reagents catalyse the stereoselective oxidation of propiophenone to the corresponding chiral α‐oxytosylated products with good stereochemical control. Using the optimised reaction conditions a wide range of products was obtained in generally good to excellent yields and with good enantioselectivities.

Abstract: As imple synthesis of al ibrary of novel CÀNa xially chiral iodoarenes is achievedi nathree-step synthesis from commerciallya vailable aniline derivatives. CÀNa xial chiral iodine reagents are rarely investigated in the hypervalent iodinea rena. The potential of the novel chiral iodoarenes as organocatalysts for stereoselective oxidative transformations is assessed using the well explored,b ut challenging stereoselective a-oxytosylation of ketones. All investigated reagents catalyset he stereoselective oxidation of propiophenonet ot he corresponding chiral a-oxytosylated products with good stereochemical control. Using the optimised reactionc onditions aw ider ange of products was obtained in generally good to excellent yields and with good enantioselectivities.
Hypervalent iodine compounds are very attractive in modern synthetic chemistry as they are environmentally and economically viable alternatives to transition metal reagents. [1] Althought he history of chiral hypervalent iodine reagents can be tracedback to the seminal work by Pribram published in 1907, [2] it took almostacenturyt ill they became active players in stereoselective synthesis. [3] Nowadays, chiral hypervalent iodine reagents are widely used in aw ide range of stereoselective transformations, including, but not limited to, stereoselective difunctionalisation of alkenes, [4] a-functionalisation of carbonyl compounds, [5] oxidation of sulfur compounds, [6] phenol dearomatisation, [7] and oxidative rearrangements. [8] In addition they are gaining an increasedi nterest as redox-activem ediators in oxidative electrochemical transformations. [9] Among the wides pectrum of chiral hypervalent iodine reagents and chiral iodoarene catalysts, axial chiral iodine-containings caffolds are very promising from structurala nd synthetic perspectives. Numerous enantioselective oxidative transformationsh ave been achieved with high levels of stereocontrol using axial chiralh ypervalent iodine reagents under stoichiometric and catalytic reaction conditions. [3] The majority of axial chiralh ypervalent iodine reagents and their iodoarene precursors contain ac hiral CÀCa xis such as biphenyls 1, [10] binaphthyls 2 [11] or spiroindanes 3 [12] (Figure 1). On the other hand,a xial chiral iodoarenes containing ac hiral CÀNa xis such as 4 are rarely investigated in the context of hypervalent iodinec hemistry.H ence, the synthesis of such compounds with ac hiral CÀNa xis and the investigation of their potential in stereoselective oxidative transformations is of great interest. To the bestofo ur knowledge,only one report on the synthesis and reactivity of C-N axial chiral hypervalenti odine reagents emerged during the final preparation of this work. [13] Herein, we report as imple synthesis of as mall library of novelC ÀNa xial chiral iodoarenes, starting from commercially availablea niline derivativesa nd investigate their potentiala s chiralo rganocatalysts using the extensively studied-yet challenging-hypervalenti odine mediateds tereoselective a-oxytosylation of ketones as am odel reaction. [5c-d, 14] In contrast to axial chiral biaryl systems, the methods available fort he stereoselective construction of CÀNa xial chiral compounds are limited. As we are interested to develop a facile and rapid access to the targetm olecules, we want to avoid the use of specialised and/or complex or expensive catalysts and reagents. Therefore,o ur synthesis relies on chiral resolutiont ok eep the syntheticr oute simple and to access optically active target molecules from simple and cheap commer-   cially available chemicals. In addition, chiral resolution would enable access to diastereomers of each compound enabling a rapid construction of the target library of chiraliodoarenes. The synthesis commencesw ith the electrophilici odination of anilinesu sing molecular iodine [8f] to give the corresponding iodoanilines 5a and 5b in 88 %a nd 40 %y ield, respectively. Racemic iodosulfonamides 6a-d were obtained in good yields by treatment of iodoanilines 5 with the sulfonyl chloride derivatives,n amely, p-tosyl chloride (TsCl), p-nosyl chloride (NsCl) and p-anisylsulfonyl chloride (AnCl). Reaction of the racemic mixtures 6a-d with (S)-lactate esters under Mitsunobu reaction conditions [8f] led to the formation of the corresponding diastereomeric mixtures of 7 that were easily separated by crystallisation or column chromatography.T he reactionl ed to the formation of the S C-N diastereomera sm ajor isomer and the R C-N diastereomer as the minor isomer in all cases with the de ranging from 10 %t o3 0%.A sar esult,ten novel optically active CÀ Na xial chiral iodoarenes (7a-j)w ere synthesised in satisfactory yields over three simple chemical steps (Scheme 1).
The absolute configuration of the iodoarenes 7 were assigned through analysiso ft he X-ray crystallographic structures. [15] The3 Ds tructures of the diastereomers 7a and 7b are shown in Figure2while other X-ray structures (7d, 7e, 7h)a re found in the supportingi nformation.
After the library synthesis of CÀNa xial chiral iodoarenes, their potential as organocatalysts for the stereoselective a-oxytosylation of ketones was initially probed using propiophenone 8a as am odel substrate, m-chloroperbenzoic acid (mCPBA, 3equiv) as the terminal oxidanta nd p-toluenesulfonic acid (TSA, 3equiv) as nucleophile,a ccording to al iterature procedure. [14b] The result of the catalyst screening (Table 1) shows that catalytic amounts (10 mol %) of all iodoarenes 7 led to the formation of the desired product 9a in good to excellent yields and only with pre-catalyst 7j (entry 10) al ow yield was obtained.T he enantiomeric excess of the resulted a-tosyloxy ketone 9a was moderate to good (31-67 % ee)i na ll cases except for pre-catalysts 7i (9 % ee,e ntry 9) and 7g (21 % ee, entry 7). The bestr esultsw ere obtained using pre-catalyst 7d (entry 4) where (S)-9a was formed in excellent yield (96 %) and with good enantioselectivity (67 % ee). On the other hand, precatalyst 7c gave the best results fort he opposite enantiomer (R)-9a.I mportantly,t he configuration of the stereogenic centre of 9a seems solely depending on the configuration of the chiral CÀNa xis where the R C-N configuration alwaysf orms 9a with (S)-configuration. This proves that the stereochemical inductioni sm ainly controlled by the chiral axis and not by the stereocentre in the lactate moiety.
Using pre-catalyst 7d,t he influence of other reactionp arameters, such as solvent, stoichiometries of the terminal oxidant and p-toluenesulfonic acid, and temperature were studied ( Table 2). Performing the reaction at 0 8C( entry 2) lead to a slight increaseine nantioselectivity (70 % ee)b ut was accompanied by as ignificant reduction in yield (26 %). On the other hand, increasing the reactiont emperature to 50 8C( entry 3) Scheme1.Synthesis of novel C-N axial chiral iodoarenes 7a-j.T s: 4-toluenesulfonyl;Ns: 3-nitrobenzenesulfonyl;An: 4-methoxybenzenesulfonyl.  did not show asignificant change in the reaction outcome. Decreasingt he amount of mCPBA and p-toluenesulfonic acid from 3t o2equivalents (entry 4) did not affect the yield, but led to ar educed ee of 52 %w hile using 5equivalents (entry 5) had no effect. Subsequent results show that the most effective reactionp arameter is the solvent. The reactionp erformed in ethyl acetate did not perform well (entry 8), but with dichloromethanea nd diethyle ther an improved enantioselectivity of 73 %a nd 76 % ee was observed albeit with much smaller yields (entries 6, 7). Using mixtures of acetonitrile and dichloromethane (entries 9-11) was more efficient compared to using any of the two solvents on their own.T he best result,9 4% yield and 75 % ee of 9a was obtained using a1 :1 mixture. On the other hand, the best results for using the diastereomericp recatalyst 7c [(R)-9a:72% yield, 75 % ee,e ntry 12] were obtained with a1 :1 mixture of EtOAc and CH 2 Cl 2 (see supporting information, Table S1). With the optimised reactionc onditions for synthesising both enantiomers of 9a,t he scope of the substrates was investigated (Scheme 2). The reaction provided satisfactory to excellent yields (31-96 %) under both conditions A and B for most of the products. Onlyt he thiophene derivative 9m is formed in poor yields and 1-benzosuberone was not reactive under the reactionc onditions formingo nly trace amountso ft he product 9p.T he enantioselectivity was moderate to very good under both reaction conditions ranging from 48-80 %u nder condition A and from 60 %t o8 0% under condition B,e xcept the a-tetralone derivative 9o was formed in only 32 and 20 % ee,r espectively.Ac omparison of the enantioselectivity of the reactionu sing the conditions A and B with already reported protocols [5c, 14] using variousc lasses of chiral iodoarenes/h ypervalent iodine reagents shows ag ood improvement of the stereochemical induction of the reaction using the newly synthesised C-N axial chiral iodoarenes 7,e specially 7d and 7c and demonstrates their potential as organocatalysts in stereoselective oxidative transformations. Propiophenone derivatives with electron-withdrawing group attached to the aromatic ring (Cl, CF 3 ,N O 2 )g ave the products 9b, 9c, 9d and 9e in very good yields and with good enantioselectivities under both conditions, while the derivatives with electron-donating groups( Me, OMe, tBu) gave the corresponding products 9f, 9g and 9h in lower yields, but withoutb ig influence on the enantioselectivity.Also, the naphthyl derivative 9i was obtained in good enantioselectivity but with moderate yield. Changing the aliphatic a-carbon from methyl to ethyl lead to product 9j in excellent yields (> 90 %) and good stereoselectivities (77 %a nd 80 % ee) under both conditions A and B,r espectively,w hile introducing ap henyl group at the aliphatic a-carbon led to complete loss of stereoselectivity,g iving 9k in high yields but as ar acemate. Heterocyclic ketones containing furan and thiophene moieties providedt he corresponding products 9l and 9m in good (57 %) to high (80 %) enantiomeric excess and high yields for the furan derivative 9l.T he reactivity and selectivity of the reaction showedd ependence on the ring size of cyclic ketones. 1-Indanone afforded the corresponding product 9n in high yields and in moderate ee, a-tetralone gave 9o in lowc onversion and yield and poor ee while the seven-membered ring ketone 1-benzosuberone was not reactive at all. Changing the [a] Enantiomeric excesses were determined by chiral-phaseH PLC analysis.
sulfonica cid from p-toluenesulfonic acid to benzenesulfonic acid and methanesulfonic acid was successful under both reaction conditions and led to the formation of the propiophenone derivatives 9q and 9r in excellent yields and with reasonable enantioselectivity. The reactionm echanism was as ubjecto fv arious studies. [10a, 14c,d] The reaction has two possible mechanisticp athways Aa nd B( Scheme 3). Equilibration of Int-I and Int-II could lead to racemisationa nd account for the lower stereoselectivity of the reaction. Although, Beaulieu andLegault [14c] excluded pathway Ba nd demonstrated computationally that the reaction proceeds via pathway A, the formation of the product from Int-I through aS N 2' mechanism could also suffer from low stereoselectivity.
In conclusion, ten novel C-N axial chiral iodoarenes have been synthesised from simple aniline derivatives. Easily separable diastereomers were obtained via chiral resolutionu sing lactate esters, enabling rapid access to the target library of chiral iodoarene reagents avoiding the use of complex and/orexpensive reagents and catalysts.Their application in the stereoselective a-oxytosylation of ketones demonstrated their potential as efficient chiral organocatalysts as aw ide range of ketones could be transformed into the corresponding a-oxygenated products in generally good to excellent yields up to 96 %a nd with good to high enantioselectivity up to 80 % ee. Cyclic and aliphatic ketones remainc hallengings ubstrates giving unsatisfactory yields and/ore nantioselectivities. The stereochemical reactionisc ontrolled mainly by the axial chirality.

Experimental Section
Chiral iodine pre-catalyst 7c or 7d (0.027 mmol, 0.1 equiv), mCPBA (0.81 mmol, 3equiv), and RSO 3 H( 0.81 mmol, 3equiv) were dissolved in am ixture of MeCN and dichloromethane (1:1) or am ixture of EtOAc and dichloromethane (1:1) followed by the addition of the appropriate ketone 8 (0.27 mmol, 1equiv). The reaction mixture was stirred at room temperature for 72 h. After completion of the reaction, the mixture was washed with sat. aq. NaHCO 3 solution and sat. aq. Na 2 S 2 O 3 solution and extracted with dichloromethane (3 5mL). The combined organic layers were dried over MgSO 4 ,f iltered, and concentrated under reduced pressure. The crude products were purified by flash chromatography on silica gel (hexane/EtOAc) to afford pure products 9.