Enantioselective Oxidative Rearrangements with Chiral Hypervalent Iodine Reagents

Abstract A stereoselective hypervalent iodine‐promoted oxidative rearrangement of 1,1‐disubstituted alkenes has been developed. This practically simple protocol provides access to enantioenriched α‐arylated ketones without the use of transition metals from readily accessible alkenes.


Introduction
Rearrangements inducedb yi odine(III) reagents are very versatile protocols to induce complexity and new stereocentres into molecules. Hypervalent iodine reagentse xhibit attractive features of low cost, low toxicity and are environmentally benign. [1] Their highly electrophilicn ature [2] coupled with the ability of the aryliodine(III) moiety to act as an excellent leaving group have seen their employmenta sm uch safer alternatives to more toxic heavy metal-based oxidants, such as lead(IV) acetate, mercury(II)a nd thallium(III) salts. However, it remains ac hallenge to develop techniques to rival the synthetic utility of first-ands econd-row transition-metal catalysts. Great effort has been invested in the development of efficient methodsf or the synthesis of a-aryl carbonyl compounds, in part due to their importance to the pharmaceutical industry. [3] Driven primarily by the groupso fB uchwald, [4] Hartwig, [5] Miura [6] and Fu, [7] palladium(0) [8] and nickel(0) [9] -catalyzed intermolecular arylation andc ross-coupling methodsh ave emergeda sp owerful synthetic tools (Scheme 1a). [10] Increasing emphasis has recentlyb een placed on the use of copper(I) catalysis, [11] gold catalysis [12] and more sustainable routest oa-arylated ketones, such as metal-free intermolecular reactions [13] and rearrangements. [14] Results and Discussion Hypervalent iodiner eagents are knownf or their ability to promotee fficient oxidation reactions of unsaturated systems. Followingt he seminalr eport by Koser et al. describing the oxidative rearrangement of 1,1-diphenylethene with hydroxy-(tosyloxy)iodobenzene (1;F igure 1), [15] hypervalent iodine reagents have been utilisedt og eneratec ationic intermediates leadingt oo xidatives keletal rearrangements. [16] Ring-contrac-Scheme1.Asymmetric strategies to a-arylated ketones.   tion and ring-expansion reactions of cyclic alkenesh ave been demonstrated using 1, [17] and 1,2-aryl shifts of acrylamide derivatives, [18] arylalkenes [19] and 1,1-diphenylalkenes [20] have been performed in ar acemic fashion using 1 or its derivatives. Althoughchiral hypervalent iodine reagents in stereoselective reactions have received much attention, [21] their use in stereoselective rearrangements are still scarce. We recently reported the first highly stereoselective rearrangement of chalcones to a-aryl acetals promoted by hypervalent iodine reagent 2a [22] in the presence of trimethylsilyltriflate( TMSOTf;S cheme 1b). [23] As parto fo ur studies on asymmetric a-arylation strategies, herein, we report the transformation of aryl alkenes to a-aryl ketones (Scheme 1c). This transformation can also be performed using other reagents, [24] but the important progress described herein is the first use of chirali odine(III)d erivatives under base-free conditions to achieve the enantioselective synthesis of tertiary stereocenters of enolizable products. We initially investigated the reactiono f1 ,1-diphenylpentene 4a with reagent 2b [25] in dichloromethane/2,2,2-trifluoroethanol (TFE;1 0:1) in the presence of methanola sanucleophilic oxygen source. No reaction occurred in the absence of any activating agent. When p-toluenesulfonic acid monohydrate was added to 2b before addition of the alkene,k etone 7a resulting from an 1,2-aryl migration and concomitant oxidation was obtainedw ith good stereoselectivity albeit in moderate yield (Table 1, entry 2).
Addition of p-toluenesulfonic acid monohydrate to amixture of diacetate 2b and alkene at À78 8Ct og enerate reagent 2c in situ gave superiorr esults (Table 1, entry 3). The postulated enantiopure hydroxy(tosyloxy) derivative 2c could not be satisfactorily characterized by NMR spectroscopy due to its instability,b ut itsf ormation was evidenced by as hift in UV/Vis spectrum absorption maxima in the reactions olvents ystem (see the Supporting Information). In the absence of methanol, the reactionp roceeded satisfactorily,b ut required nine hours for completion (Table 1, entries 4a nd 11). Limiting the amount of methanol to three equivalents minimized methoxy addition across the double bond and furtheri mproved the yield. Under these conditions, iodoarene 2b gave the highest enantioselectivity (Table 1, entry 7). Triflic acid (TfOH) and trimethylsilyltriflate (TMSOTf) also provedt ob ep otent activators for 2b, althougha ddition of six equivalents of methanol wasr equired for these reactions to reach completion. It is assumed that rapid methanolysis of TMSOTf generates triflic acid in situ as the activating agent.A ttempts to furtheri mprove the enantioselectivity of this transformation employing chiral activators, such as (1R)-(À)-and (1S)-(+ +)-10-camphorsulfonic acid, didn ot improvet he outcome (Table 1, entries 12 and 13). Reaction of 6a with other chiral iodanes 4 and 5 gave the desired ketone with reduced enantioselectivities.R eagent 4 [26] led to the formationo f( S)-7a with 16 %e nantiomeric excess, whereas 44 % ee could be achieved by using iodane 5 [27] (Table 1, entries 14 and 15). In each reaction, the reduced iodoarene could be recovered (85-90 %) and was re-oxidized withoutl oss of enantiomeric purity.
Under the optimized reactionc onditions, ar ange of 1,1diphenyl alkenes (6b-i)g ave the corresponding a-phenyl ketones (7b-i) in good yields (Scheme2). [28] The absolute www.chemeurj.org configuration of 7b,kand o was determined by comparison of the optical rotationw ith known compounds (see the Supporting Information). Using the identical enantiopure reagent 2b,t he same direction of asymmetric induction is assumed in the other products 7.S terically hindered iso-propyls ubstituted styrene 6c rearrangedw ith only moderate enantioselectivity, which was not improved by the use of al ess sterically encumbered reagent 3, [29] which gave 7c in 88 %y ield, ando nly 39 % ee was obtained. It is noteworthy that access to ketone 7c is not possible by the intermolecular catalytic Negishic oupling protocolr eported by Lou and Fu. [7c] 1,2-Substituted styrenes 6j-r (used as am ixture of E and Z isomers) gave the expected rearranged ketones in good yields. It should be noted that in the case of 7k-p,p roductsr esulting from alkyl-group migration were not observed. In ther eactiono f7j,t races of an isopropylm igration product were observed in the 1 HNMR spectrum of the crude mixture, but not in sufficient quantities to allow characterization. When alkene 6n containing cyclopentyl ring was subjected to the rearrangement reactionc onditions, rearranged ketone 7n was obtained in good yield and high selectivity (87 % ee). Unfortunately,1 -cyclopropyl-2-methylstyrene bearingacyclopropylr ing as substituent, gave ac omplex reaction mixture. Furthermore, oxidation of (E/Z)-1-(but-2-en-2-yl)naphthalene (6p)w ith reagent 2b gave am ixture of 3-(naphthalene-1-yl)butan-2-one( 7p;8 9% ee)a nd 3-(naphthalene-2-yl)butan-2one with 85 % ee.
Ta king this evidencei nto account, ap lausible mechanistic pathway is proposed in Scheme4.E lectrophilic addition of iodine 2c to the alkene followed by ring openingw ith methanol would result in l 3 -iodane B.F ollowing bond rotationt oC, reductivee limination of the aryliodonio moiety gave a1 ,2-aryl migration with stereochemical inversiona tt his centre to give the observed product. However, it is not entirely clear why only conformer C is reactivea tl ower temperature. It is likely that relief of steric interactions between the Ar and Rg roups in C contribute to an increased propensity for this conformer to rearrange, providing the (Z)-aryl migration product.
Key intermediate in the proposed mechanism is the cyclic iodonium ion A,b ecause its restricted conformational space allows ar egio-and stereoselective nucleophilic attack, as was demonstrated by using methanol( Scheme 4). At the same time, it may serve as the startingp oint for the formation of an on-classical carbenium ion that could lead also to the major product observed (Scheme 5).
DFT calculations were employed to analyse the bonding situation and the stabilityo fA1 in comparison to the "open" Scheme3.Chemoselectivity of the oxidative rearrangement.
[a] Minor enantiomer was not detected.
Scheme4.Plausible reaction pathwaytoexplain the observed regio-and stereochemical outcome. Chem. Eur.J.2016, 22,4030 -4035 www.chemeurj.org form, (carbenium ion) and the nonclassical form A2.A lthough iodonium ions are usually preferred over carbeniumi ons in the addition of iodine electrophiles to alkenes, [31] the structures described herein with at least ap ronouncedc arbeniumi on character in the benzylic position could be possible intermediates ( Figure 2). To elucidate the relative energy of the cyclic and open cationic form, relaxed potential energy surface (PES) scans were performed [32] by driving the C1ÀIb ond (0.025 over 20 steps, two consecutive scans) starting from minimum A1 [33] (r(C1ÀI) 2.90 , r(C2ÀI) 2.70 ). The circled points were subjected to geometry optimization and frequency analysis; however, only A1 could be confirmed as ag round-state structure( Figure 2).
As was expected, the energy rises with increasing r(C1ÀI), but with 9.6 kcal mol À1 for af ull acyclicc arbenium ion (r(C1ÀI) 3.40 , r(C2ÀI) 2.73 ), the anticipatedb arrier for the processes of ring opening should be accessible at room temperature. However,t he associated structure could neither be characterized as at ransition state nor as ag round state on the free energy surface, leaving room for other mechanistic scenarios, as indicated in Scheme 5. As econd interesting feature of the PES scan plot is the shallow minimum at r(C1ÀI) 3.30 , r(C2ÀI) 2.69 ( Figure 2). Startingg eometry optimizations at this local minimum on the electronice nergy surfaced id not lead to as table minimumg eometry with more carbenium-ion character on the PES. On the contrary,t he optimized structures relaxed back to the structure A1.A lso, extensive search and optimizations under consideration of arene participation (A2)t o stabilizeamore carbenium-ion-like intermediate didn ot result in the identification of local minima (see the Supporting Information). To exclude that overbinding inherent to the M06-2X [34] functional due to the incorporation of dispersion corrections is biasing the geometry search, B3LYP [35] was used as a complementary method, because it hasn od ispersion correction. The obtained B3LYP-structures of A1-p,t houghl ooser (+ 7% for r(C1ÀI) and + 1% for r(C2ÀI) comparedt ot he M06-2X structure) and more asymmetric [36] in their CÀIb onds (r(C1ÀI) 3.10 , r(C2ÀI) 2.73 ) did not differ qualitatively. Consequently,t he proposed iodonium ion A1 is believed to be the most prevalent structure in the reaction mechanism.
An umber of commerciallya vailable symmetrical ketones was used to preparea lkenes 6u-bb to determine the effect of arene-substitutionp attern on the enantioselectivity of the rearrangement, as shown in Table 2. ortho-Substitution as in 6aa completely shuts down the migration pathway with 2b;e ven with PhI(OAc) 2 and TMSOTf upon heatinga tr eflux for six hours,o nly at race of the expected ketone was observed.

Figure 2.
Relaxed PES scan by sequentially changing the C1ÀIb ond length. Chem. Eur.J.2016, 22,4030 -4035 www.chemeurj.org iodine(I)!iodine(III) oxidation of chiral iodoarenes. Severalo xidants including oxone, selectfluor,s odium perborate, peracetic acid and tert-butyl hydroperoxidew ere investigated, and best results were obtained using meta-chloroperoxybenzoic acid (mCPBA) and 2a (20 mol %, employed as the iodine(I) compound leadingt oketone 7a in 34 %y ield with 74 % ee. The stereoselective rearrangementp rotocol described above was examined in ap harmaceutical context. Non-steroidal antiinflammatory drugs (NSAIDs) have found widespread clinical applicationf or their antipyretic, analgesic and anti-inflammatory effects. Of these, cyclooxygenase-2 (COX-2)-selective inhibitors have an established medicinale fficacy and have been the focus of recent studies to determine their therapeutic effects in tumour cell genesis and growth. [38] Racemic aryl ketone 8 (Scheme 6) has been identified as an analogue of the highly selectiveC OX-2 inhibitor lumiracoxib( 9;N ovartis). [39] From commercially availablem aterials, rac-8 can be efficiently synthesized (89 %y ield from methyl 5,5-diphenylpent-4-enoate) and (R)-8 can be synthesized with high enantioselectivity (89 % ee), as shown in Scheme 6. This methodology avoids the potentialt oxicity from contamination with trace amounts of transition metals, which otherwise would be required for its synthesis. The conditions fort he ester hydrolysis of 11 had to be carefully selected. Hydrolysis under basic conditions or with dilute hydrochloric acid led to unacceptable levels of racemization, but employing p-toluenesulfonic acid avoided racemizationa lmost completely.I na ddition, access to (S)-8 should be possible using the reagent ent-2b derived from commercially available(+ +)-methyl lactate.

Conclusion
We have developed ah ighly enantioselective oxidative rearrangement of various 1,1-disubstituted alkenese mploying chiral hypervalent iodine reagents. This method provides an attractive metal-free route to a-arylated ketones. The wider scope of such oxidative rearrangementsi sc urrently under investigation and will be reported in due course.