The development of iodine(III)-mediated synthetic transformations has received growing interest, in particular to mediate enantioselective processes. In this class, the α-tosyloxylation of ketone derivatives using iodine(III) is a particularly powerful one, as it yields α-tosyloxy ketones – versatile chiral precursors that enable rapid access to numerous α-chiral ketones through nucleophilic displacement. Despite years of research from numerous groups, the enantioselectivities for this transformation have remained modest. Using quantum chemical calculations, we have uncovered a possible rational for the lack of selectivity. With these computational insights, we have developed an alternative experimental strategy and achieved unprecedented levels of selectivities. Applying this newfound knowledge, we have recently developed a new method to access α-halo ketones from non-ketonic precursors.
Oxidative transformations are ubiquitous in synthetic chemistry. It is thus not surprising to see relentless efforts to further discover and improve such useful processes. The field of hypervalent iodine chemistry has been particularly active in this regard , , , , . Reagents based on hypervalent iodine tend to be eco-friendly and versatile oxidants, and have been found to be in some cases good alternative to toxic heavy metal-based reagents. While iodine(V) reagents have been recognized for common oxidation reactions such as alcohol to carbonyl conversion , iodine(III) reagents open access to a very diverse array of synthetic methodologies , , , , , . They have been used in the past 25 years in numerous relevant reactions, such as phenolic dearomatizations , , , , , , ,  and various other oxidative rearrangements , , . Numerous advances in the field of enantioselective chemistry, which has been particularly active, have also been reported , , , . One transformation that raised interest from numerous groups is the α-oxidation of carbonyl compounds. This strategy is complementary to the more classical enolate formation/electrophilic substitution strategy, as it enables the introduction of nucleophiles at the α position of carbonyl compounds (Scheme 1).
First reported by Koser et al. in 1982 , the α-tosyloxylation of ketones is particularly attractive as it yields α-tosyloxy ketones – versatile building blocks to access numerous α-substituted ketone derivatives (eq. 1). This method has much lower environmental impact compared to its Thallium-mediated variant . It was rendered even more attractive by Yamamoto and Togo , as they demonstrated that it could be mediated with a catalytic amount of an iodoaryl pre-catalyst and the presence of a co-oxidant (m-CPBA) in the reaction medium (eq. 2).
Considering all the potential advantages of this method, it is not surprising that numerous groups have worked to develop an enantioselective variant. The latter would allow the rapid synthesis of diverse chiral non racemic α-substituted ketones. Thomas Wirth has been a pionneer to develop chiral iodoarenes for both the stoichiometric , ,  and catalytic , ,  variants of the reaction. Despite much effort, the enantioselectivities have remained modest (<40% ee). Other groups, including our own, have also pursued this goal, with mixed results , , , , , , , , , , , , . The pre-catalysts illustrated in Scheme 2 have been the best reported by the different research groups for the α-tosyloxylation of propiophenone, under similar conditions. They have been reported between 1997 and 2015, some of them have been published either during of after the research described in this account was pursued.
Results and discussion
We initiated our research program in this field in 2010 with the objective to better understand the mechanism of the α-tosyloxylation reaction and with the long-term goal to tackle the selectivity issue and develop a highly enantioselective method to access chiral non racemic α-tosyloxy ketones. We initially investigated new iodoarene pre-catalysts bearing a group (X) ortho to the iodine that could coordinate the latter, in the conditions developed by Yamamoto and Togo , in order to better understand the requirements for reactivity (Scheme 3). The expectation was that a chiral coordinating group would ultimately lead to efficient stereoinduction.
We uncovered in the process that for iodoarenes bearing a strongly coordinating group, such as an amide or an oxazoline, additional steric hindrance was required next to the iodine atom to access good catalytic activity . This effect is reminiscent of the “hypervalent twist” effect reported by Su and Goddard for iodine(V) reagents , , . It enabled us to explore oxazolines as chiral sources next to the iodine center (eq. 3).
A structure/selectivity relationship study of the oxazoline moiety led to the discovery that a stereogenic center alpha to the oxazoline oxygen atom was required to obtain stereoinduction. We proposed that protonation of the oxazoline moiety under the catalytic reaction conditions forced the orientation of the oxazoline oxygen towards the positive iodine center in the reaction process . This proposal was supported by quantum chemical calculations. To the best of our knowledge, this is the only example of the use of a chiral oxazoline in which the stereoinduction process is controlled by the stereogenic center alpha to the oxygen. With this information in mind, we investigated iodoarene pre-catalysts bearing oxazolines derived from chiral ketones; no improvement in selectivity could be achieved .
Despite the effort of our group and others (Scheme 2), all the best pre-catalysts have yielded selectivities under 60% ee, regardless of the wide variety of chirality sources involved in these iodoarenes. This raised the question of the origin of the low enantioselectivities. It could arise from a simple lack of stereoinduction, which would be solved by better pre-catalyst design. On the other hand, the low selectivities could be due to a racemization process of an intermediate during the reaction, or multiple mechanistic pathways. In either case, an alternative route to the α-tosyloxy ketones would be necessary to achieve high selectivities. Experimentally, it was demonstrated that the final α-tosyloxy ketones did not racemize under the reaction conditions.
We thus investigated the mechanism of this transformation using quantum chemical (QM) calculations to rationalize the lack of selectivity, and possibly contribute a solution to this longstanding issue . The QM calculations strongly suggested that the reaction could proceed by two widely different mechanisms, as illustrated in Scheme 4. The mechanism that has been usually proposed in the literature, pathway B, involves reaction of the iodine(III) reagent with the enol tautomer of the ketone substrate, formed under acidic conditions. The enolization is thermodynamically disfavored, resulting in low effective concentration of the enol tautomer. The QM calculations suggest that under acidic conditions, direct reaction of the enol with HTIB is not favored, but instead a dissociative pathway is operative to access the iodonium intermediate Int-1. Again, due to the endergonicity of the formation of Int-1, it is in low effective concentration, greatly disfavoring the bimolecular process with the enol. For this reason, we concluded that the usually recognized mechanism, pathway B, involving the formation of a C-bound intermediate (Int-C) by reaction of the enol with the iodine(III) reagent would be improbable, or at least only partial. Instead it was found that Int-1 could act as a Lewis acid with the ketone substrate, present in high concentration. Formation of this adduct greatly enhances the acidity of the protons alpha to the carbonyl, enabling what we coined an iodine(III)-mediated enolization. This key step leads to the formation of an O-bound enol iodonium intermediate (Int-O). The latter then yields the final product through a SN2′-type addition on the enol pi-system and displacement of iodobenzene. Finally, an isomerization mechanism between the O-bound (Int-O) and C-bound (Int-C) intermediates could bridge the two pathways, but calculations suggest this process to be too high in energy to occur at room temperature. We concluded that the most probable cause for the low selectivities was difficult stereoinduction in the final SN2′ reaction of pathway A. Of course, competition of both pathways is not to be excluded as the origin of the issue.
Since in either case the source of the low selectivities could be the access to pathway A, we elected to find a strategy to prevent passage through the latter as a possible solution. The main issue arises from the low effective concentration of the enol tautomer, we thus envisioned that we could simply force the starting material into this tautomeric form by using enol surrogates. A few example of these substrates have been reported to react cleanly with iodine(III) reagents. In particular, Moriarty et al. have reported the direct conversion of silyl enol ethers to α-tosyloxy ketones using Koser reagent (eq. 4) . Additionnally, during the course of our research, Mizar and Wirth have reported the conversion of silyl enol ethers to chiral non racemic α-substitued ketones using chiral iodine(III) reagents (eq. 5) .
However, such enol ethers would be quite sensitive to acidic conditions and would not be compatible with the catalytic protocol presented in eq. 3. We envisioned that enol derivatives bearing electron-withdrawing groups on the oxygen would render them more resistant to ward hydrolysis and oxidation, and could make them viable substrates for catalytic conditions. We found that acetyl enol esters were substrates that could meet our requirements. Surprisingly, they had not been studied as enol surrogates in hypervalent iodine chemistry; we published the proof of concept and scope evaluation recently . For example, substrate 9 can be converted to the desired product 8 under both stoichiometric and catalytic conditions (Scheme 5).
We investigated the stereochemical aspects of both propiophenone (6) and enol ester 9 under catalytic conditions (Table 1) . The use of our best iodoaryloxazoline pre-catalyst (3) resulted unfortunately in the production of an almost racemic product from the enol ester 9 (entry 3). We thus evaluated a widely different pre-catalyst, the C2-symmetric iodoarene 10, developed by Ishihara for the dearomatizing spirolactonization of napthols , . To our surprise, this pre-catalyst resulted in an almost racemic product starting from propiophenone (entry 2), but yielded an unprecedented level of selectivity from the enol ester 9 (entry 4). These widely different and inverse stereoselectivity profiles are a good indication that both substrates do proceed through different mechanisms with distinctive stereochemistry-defining steps.
aProtocol A: Substrate 6, ArI (10 mol%), m-CPBA (3 equiv), TsOH·H2O (3 equiv), MeCN:CH2Cl2, r.t., 24 h; Protocol B: Substrate 9 (slow addition), ArI (20 mol%), m-CPBA (1.5 equiv), TsOH·H2O (1.0 equiv), MeCN, r.t., 13 h.
Further optimization of the pre-catalyst and reaction conditions resulted in even better levels of selectivities, under both stoichiometric (Scheme 6a) and catalytic conditions (Scheme 6b). The products can further be enantioenriched by recrystallization. For practical reasons, the scope of this reaction was done under the non-catalytic conditions illustrated in Scheme 6a. The results are illustrated in Scheme 7; the reaction times are reported beside the yields.
Under these conditions, most enol esters react fairly rapidly within 4 h. The length of the alkyl chain on styrene-type derivatives does not influence drastically the yields or selectivities (12a, b). The electronic properties of the aromatic moiety do have a strong effect on reactivity (12c–f). Reactions with substrates with an electron-rich aromatic (12d, e) are almost instantaneous, while an electron-poor aromatic (12g) drastically decreases the reaction rate.
Cyclic substrates, having an E-enol, suffer from low enantioselectivities (12h–j). Aliphatic substrates are compatible with the reaction conditions, but show some limitations in terms of tolerated steric hindrance (12k). Overall, these unprecedented selectivities are an indication of the large impact of the reaction mechanism and support our computationally-driven hypothesis.
In the case of ketones, the main pathway involves a prochiral O-bound intermediate. The large distance between the newly forming stereocenter and iodoarene chirality in the SN2′ transition structure could explain the difficulty to attain high enantioselectivities (Scheme 8a). In contrast, for enol esters, the stereochemistry-defining step will be the direct reaction of the iodonium intermediate with the substrates (Scheme 8b). A much more pronounced interaction between the chiral iodonium and substrate could explain the success to access higher selectivities. We can not rule out at the moment the possibility of concomitant pathways in the case of ketones.
This work highlighted the opportunity to synthesize the α-nucleofuge ketones building blocks from non ketonic substrates. To further test this idea, we envisioned that vinyl halides could also be proficient substrates, as they are also enol surrogates (Scheme 9). They could thus yield similar highly useful chiral building blocks for synthesis. We investigated the treatment of vinyl chlorides and bromides with HTIB and found they afford, in almost quantative yield, the corresponding α-chloro and α-bromo ketones, respectively (Scheme 10).
A small quantity of an internal aryl migration product was observed for vinyl chlorides. Addition of water prevented this side-reaction, and was attributed to facilitated solvation of the chloride anion during the reaction process. Decrease of yield with the addition of water in the case of vinyl bromides was found to be due to slow addition of the water on the resulting α-bromo ketone products. An initial scope of this new synthetic transformation was recently published . Finally, we demonstrated the first example of direct conversion of a prochiral vinyl chloride to a chiral non racemic α-chloro ketone using chiral iodoarene 11 (eq. 6). These latest developments highlighted the great potential of enol surrogates as substrates for hypervalent iodine chemistry .
This work illustrates how the development of synthetic methodologies can be greatly improved by joint computational/experimental interactions. From these studies, we found that a possible reason for the low selectivities in the α-tosyloxylation of ketones might be a reaction pathway involving an O-bound intermediate. This newfound knowledge led us to propose an alternative stragegy using enol esters. While the full scope and understanding of the whole process remains to be done, we have clearly demonstrated that these substrates solve the longstanding selectivity problem for the iodine(III)-mediated synthesis of chiral non racemic α-tosyloxy ketones.
A collection of invited papers based on presentations at the 23rd IUPAC Conference on Physical Organic Chemistry (ICPOC-23), Sydney, Australia, 3–8 July 2016.
This work was supported by the National Science and Engineering Research Council (NSERC) of Canada, the Canada Foundation for Innovation (CFI), the FRQNT (Nouveau Chercheur grant and Centre in Green Chemistry and Catalysis (CGCC)), and the Université de Sherbrooke. Computational resources were provided by Calcul Québec and Compute Canada. S.B. is grateful to NSERC for an Undergraduate Student Research Award (USRA). A.-A.G. is grateful to Hydro-Québec and FRQNT for postgraduate scholarships. Financial support in the form of a CNC/IUPAC travel award to present to ICPOC-23 is acknowledged.
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