A Triazole‐Substituted Aryl Iodide with Omnipotent Reactivity in Enantioselective Oxidations†

Abstract A widely applicable triazole‐substituted chiral aryl iodide is described as catalyst for enantioselective oxidation reactions. The introduction of a substituent in ortho‐position to the iodide is key for its high reactivity and selectivity. Besides a robust and modular synthesis, the main advantage of this catalyst is the excellent performance in a plethora of mechanistically diverse enantioselective transformations, such as spirocyclizations, phenol dearomatizations, α‐oxygenations, and oxidative rearrangements. DFT‐calculations of in situ generated [hydroxy(tosyloxy)iodo]arene isomers give an initial rational for the observed reactivity.

Abstract: Aw idely applicable triazole-substituted chiral aryl iodide is described as catalyst for enantioselective oxidation reactions.The introduction of asubstituent in ortho-position to the iodide is key for its high reactivity and selectivity.B esides ar obust and modular synthesis,t he main advantage of this catalyst is the excellent performance in ap lethora of mechanistically diverse enantioselective transformations,s uch as spirocyclizations,p henol dearomatizations, a-oxygenations, and oxidative rearrangements.D FT-calculations of in situ generated [hydroxy(tosyloxy)iodo]arene isomers give an initial rational for the observed reactivity.
Hypervalentiodinecompoundsareversatileoxidantswhich have been utilized with great success in aplethora of oxidative coupling reactions [1] and in natural product synthesis. [2] In related enantioselective processes,achiral aryl iodide precursor can be used in catalytic amounts in combination with aterminal co-oxidant to generate achiral hypervalent iodine compound in situ. This chiral oxidant is subsequently capable of transferring its chirality onto the desired coupling products through diastereotopic transition states in the key oxidative C-X bond forming step. [3] Since the discovery of the first enantioselective transformation catalyzed by ac hiral aryl iodide in 2007 by Wirth and co-workers, [4] more than ad ozen highly diverse C1-and C2-symmetric chiral aryl iodides have been developed. [5] Successful catalysts,s uch as 1-4 (Figure 1), usually show ag ood reactivity and selectivity in only one distinct class of oxidative transformation. So far there is no omnipotent chiral aryl iodide available that performs well throughout the most important oxidative transformations and hence can be seen as broadly applicable catalyst for iodane-based enantioselective couplings.Our group is heavily interested in the development of N-heterocycle-stabilized iodanes (NHIs) as an ew class of stable and at the same time highly reactive hypervalent iodine compounds. [6,7] With the aim to design novel chiral aryl iodides which are robust to synthesize in amodular sequence and show ag ood performance throughout adiverse range of enantioselective oxidations,w erecently developed the novel triazole-substituted aryl iodide 5 ( Figure 2) and evaluated its reactivity in the Kita-spirocyclization of 1-naphthols. [8] Even though this "first-generation" catalyst gave the so far highest enantioselectivities in direct comparison to other C1-symmetric aryl iodides for this reaction, reactivities were low.W ell-established C2-symmetric aryl iodides,s uch as spirobiindanes developed by Kita or resorcinol ethers 1 developed by Uyanik and Ishihara, showed significantly higher stereoinduction and yielded the desired chiral lactones in better yields. [9] Due to the promising initial results with catalyst 5 and its highly modular and robust synthesis,w e further developed "second-generation" triazole catalysts 6 ( Figure 2) bearing as imple ortho-modification at the aryl iodide.W et herefore synthesized ortho-Cl, -Me,a nd -OMesubstituted derivatives 6a-c (Scheme 1). Their synthesis is   straightforward and was completed on ag ram scale for each chiral triazole starting from the iodinated carbaldehydes 7ac.A ddition of ethynylmagnesium bromide gave the racemic propargylic alcohols 8a-c,w hich were treated with the esterase CALB and isopropenyl acetate to give the enantiopure alcohols ent 8a-c in excellent selectivity.S ince both products of the kinetic resolution, the free alcohol and the enantiomeric acetate,can be separated effortlessly,this route gives an efficient access to both enantiomers of the final catalysts.Copper-mediated Huisgen 1,3-dipolar cycloaddition of the free alcohols with benzyl azide gives triazoles 9a-c.The final catalysts 6a-c were observed through final TIPS-protection.
Having these second-generation catalysts in hand, we investigated their performance in the Kita-spirocyclization of 1-naphthol carboxylic acid 10 (Table 1). In comparison to 5, the ortho-Cl-substituted catalyst 6a had ah igher reactivity yielding the spirolactone (R)-11 with improved yields after shorter reaction times but with aslightly lower enantioselectivity.O rtho-Me-substituted catalyst 6b was more reactive than 5 and 6a,w hich correlated with an increased enantioselectivity of 78 % ee. Theh ighest reactivity and enantioselectivity was observed with OMe-substituted catalyst 6c giving 11 in 81 %y ield and 82 % ee. We further optimized the reaction conditions and found that a1:1 mixture of DCM/ CHCl 3 and addition of ethanol increased the enantioselectivity of 11 to 99 % ee (Table 1, entry 6). These are the highest enantioselectivities ever observed in this representative model reaction. 6c even outperforms all of the well-established C2-symmetric chiral aryl iodides,s uch as the C2symmetric resorcinols 1a and 1b. [10] Surprised by the significantly increased reactivity based on this simple synthetic modification we wanted to evaluate the general applicability of 6cin other, more challenging,oxidative C-O bond forming reactions (Scheme 2). First, we investigated the oxidative dearomatization of 4-substituted phenols to para-quinols. Even with sterically highly demanding aryl iodide catalysts, this reaction gives low enantioselectivities due to the high distance between the phenolate,w hich is bound to the hypervalent iodine center, and the hydroxylated C4. Even the successful resorcinol-derived aryl iodides 1 give only moderate selectivity of up to 50 %. In 2018, Maruoka and coworkers introduced as pecially designed C1-symmetric indanol-based aryl iodide 2,which was so far the best performing catalyst for this reaction. [11] We were pleased to find that with 10 mol % 6c,2-bromo-4-methylphenol 12 could be efficiently dearomatized into the 2-bromo para-quinol 13 in 92 %y ield and 93 % ee,a gain an ovel best mark for this transformation (Scheme 2a).
We then investigated the intramolecular a-oxygenation of 5-oxo-5-phenylpentanoic acid 14 to 5-benzoyldihydrofuran-2(3H)one 15.H ere,t he C1-symmetric pseudoephedrine-substituted aryl iodide 3,a sd eveloped by Moran, gave the best results so far (47 %y ield and 51 % ee). [12] Again, 6c is as uperior catalyst for this transformation and yielded the desired lactone 15 in 88 %yield and 81 % ee (Scheme 2b). We then tested the performance of 6c in the a-tosyloxylation of propiophenone.This was the first oxygenation to be catalysed by achiral aryl iodide catalyst as developed by Wirth and coworkers in 2007. [4] However,even after more than adecade of this first enantioselective report, numerous efforts to design efficient chiral aryl iodide catalysts did not result in synthetically adequate enantioselectivities due to hard to control concurring S N 2-and S N 2'-based reaction pathways.I n2 017, Masson and co-workers developed the sulfone-containing aryl iodide 4 as the best performing catalyst for this reaction giving 17 in 67 % ee. [13] Again, 6c showed superior results in this transformation. Ac ombination of 10 mol % 6c and mCPBAa sc o-oxidant resulted in an efficient conversion of propiophenone 16 to 17 in 90 %y ield and 88 % ee (Scheme 2c). Apart from oxygenations,h ypervalent iodine compounds can be applied efficiently in enantioselective rearrangements. [14] Very recently,G ong and co-workers developed the oxidative rearrangement of allylic alcohols to boxygenated ketones with the lactic-acid-derived catalyst 1c. [15] We utilized this useful reaction as another benchmark for 6c (Scheme 2d). Tr eatment of the tertiary allyl Scheme 1. Catalyst synthesis. Reaction conditions: a) 7 (1 equiv), ethynylmagnesium bromide (1.25 equiv) at 0 8 8Cfor 2.5 h. b) 8 (1 equiv), CALB (6 mg/mmolo f8), isopropenyla cetate (1.5 equiv) in toluene at room temperaturef or 3days c) ent 8 (1 equiv), benzyl azide (1.3 equiv), TTMCuCl (0.005 equiv) in water at room temperature for 17 h. d) 9 (1 equiv), 2,6-lutidine( 2equiv), trialkylsilyl trifluoromethanesulfonate (1.2 equiv), in DCM at 0 8 8Cf or 6h.The starting aldehydes are known in the literature and commerciallya vailable.F or detailed synthetic procedures,s ee the SupportingInformation. alcohol 18 with 10 mol % 6c,S electfluor as co-oxidant, and benzyl alcohol, resulted in the formation of the rearranged boxygenated ketone 19 in 80 %y ield and 98 % ee.
After catalyst 6c showed this superior performance among av ariety of mechanistically diverse transformations, we decided to gain ab etter rational about the underlying structural aspects that cause the high reactivity of 6c,i n particular in direct comparison to the first-generation catalyst 5.
It was of particular interest, which secondary bonding interactions stabilize the oxidized hydroxy iodobenzene. After initial oxidation, the iodane can be further stabilized either by an oxygen lone pair of the TIPS-protected benzyl alcohol or by N3 of the triazole giving two potential isomers.
Both isomers could further react in distinct ligand exchange and oxidation pathways and this competition should result in diminished yields and enantioselectivities.T oc onfirm this finding for 6c and to verify the importance of an N-I interaction for the performance of this catalyst we synthesized the N-methyl triazolium tetrafluoroborate 6d by treatment of 6c with Meerwein salt (Scheme 3a). This catalyst was then used in the Kita-spirolactonization. Here we found that 6d has ad iminished reactivity compared to 6c giving the spirolactone in only 32 %y ield and 61 % ee (Scheme 3b). This poor reactivity is comparable to the reactivity of the firstgeneration catalyst 5.L egault and co-workers and our group recently demonstrated that as tabilization of cationic iodane species by covalently attached N,O-heterocycles,s uch as oxazoles and oxazolines,i sf avored through dative N-I bonding interactions as indicated by N-I distances being significantly shorter than O-I distances in calculated structures. [16] In solid-state structures only the N-bound intermediates were observed. [6] Even though the N-methylation experiment is afirst hint for an intramolecular N-I interaction in the active species of 6c,i td oes not explain the observed effect of the orthosubstituent. Besides the donor ligand, the angle between the plane of the iodoarene and the I-OH bond is an important structural feature which is heavily influenced by orthosubstituents,a sd escribed by Legault and co-workers. [17] Since all attempts to produce suitable crystals for X-ray analysis were not successful, DFT calculations were performed for ad eeper structural understanding of the catalyst structure and its reactivity. [18] Energy minima of oxidized [hydroxy(tosyloxy)iodo]arenes 5-OH and 6c-OH were searched by preoptimization with Grimmest ight-binding method GFN2-xTB [19] and further fine optimized on aPBEh-3c/ma-def2-SVP(O,N)/def2-TZVP(I) level of theory. [20] Single point energies were calculated with the double hybrid PWPB95-D3 functional together with ma-def2-TZVP-(O,N)/def2-TZVPP(I) basis sets. [21] Preoptimization with GFN2-xTB resulted in four distinct energy minima for each catalyst (Figure 3). In good agreement with theoretical investigations by Legault et al.,i nitial calculations based on dissociated species with as eparated tosylate anion and an iodonium cation revealed that the dissociation process is highly endergonic.( Supporting Information, Scheme S1). [22] Therefore,d issociated iodonium complexes were not further considered. Minimized structures of 5-OH are summarized in  These oxidized isomers are nearly equal in energy for 5-OH,w hereas for 6c-OH the N-bound isomer is favored by 3.81 kcal mol À1 .Inthese isomers the tosylate counterion (not shown) is usually bound in an apical position with typical TsO-I bond length of more than 2.6 .Inthe other observed isomers (5/6 c-OH-OTs1 and 5/6 c-OH-OTs2)the tosylate acts as the key ligand building the linear hypervalent bond in the oxidized state together with the OH group (TsO-I bond length of 2.19-2.25 ). In 5/6 c-OH-OTs1 the hydroxy group is located cis to the triazole ring and is engaged in hydrogen bonding with the N-heterocycle.For 6d this hydrogen bond is not operational and therefore this isomer would be destabilized. Furthermore,t he oxidation with mCPBAs hould be favored through an initial hydrogen bonding between the triazole and the transferred terminal hydroxy group of the peracid.
However,for isomer 5/6 c-OH-OTs2,the hydroxy ligand is located trans to the triazole ring and hence no further intramolecular secondary interactions can be observed. For 5-OH the TsO-bound isomers are significantly higher in energy (+ 1.97 and + 5.47 kcal mol À1 )c ompared to the triazolebound isomer 5-OH-N.I nc ontrast, the TsO-stabilized isomers of 6c are equal or slightly lower in energy compared to 6C-OH-N.I np articular,t he relatively high stability of 6c-OH-OTs1 is remarkable due to the high dihedral angle of 93.86 between C(1)/C(6) of the arene ring and the I-O bond. Usually,linear arrangements are preferred in which the arene is in plane with the hypervalent bond. This can be nearly found in 5-OH-O.This isomer has the smallest dihedral angle of 11.008 8.Ahigh dihedral angle between the arene ring and the hypervalent bond, defined by Legault and co-workers as "hypervalent twist", [16] together with the good leaving-group ability of the tosylate ligand as found in 6c-OH-OTs1 are crucial for further ligand exchange reactions with phenolic or enolic oxygens to initiate the discussed enantioselective coupling reactions.W ea re therefore confident that these calculations give agood initial rational for the high reactivity of catalyst 6c and are an ideal starting point for further catalyst improvements and theoretical investigations concerning the underlying mechanisms of each investigated enantioselective transformation.
In summary,t he triazole-substituted aryl iodide 6c is the most versatile chiral aryl iodide catalyst that has been developed so far for enantioselective reactions based on in situ generated hypervalent iodine compounds.T his single catalyst shows ar emarkable reactivity in the Kita-spirocyclizaton, the a-tosyloxylation of propiophenone,o xidative lactonizations,a nd in the oxidative rearrangement of allyl alcohols.T oo ur knowledge the observed enantioselectivity for every investigated reaction is the highest ever reported and hence this catalyst can be defined as omnipotent. The initial DFT calculations indicate as ignificant role of the triazole as as tabilizing donor both in ap otential N-bound state or as ah ydrogen-bond acceptor in a[ hydroxy-(tosyloxy)iodo]arene derivative.T his forces the geometry of the hypervalent iodine centre into ar eactive bent state with an unusual vertical alignment between the hypervalent bond and the arene.I n-depth theoretical investigations are now necessary for every investigated reaction to fully explain the observed omnipotence.W ith this information rational fine tuning of this highly modular catalyst for further enantioselective oxidations will be possible.