A Journal of Accepted Article Title: α,α-Alkylation-Halogenation and Dihalogenation of Sulfoxonium Ylides. A Direct Preparation of Geminal Difunctionalized Ketones Authors: Rafael Gallo, Anees Ahmad, Gustavo Metzker, and Antonio Carlos Bender Burtoloso This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Eur. J. 10.1002/chem.201704609 Link to VoR: http://dx.doi.org/10.1002/chem.201704609 Supported by 10.1002/chem.201704609 Chemistry - A European Journal COMMUNICATION α,α-Alkylation-Halogenation and Dihalogenation of Sulfoxonium Ylides. A Direct Preparation of Geminal Difunctionalized Ketones Abstract: A one-pot alkylation-halogenation of ketosulfoxonium ylides in the presence of alkylhalides is described. The method furnishes several gem-difunctionalized haloketones (an alkyl and F, Cl, Br, or I) in good yields. Replacing alkyhalides with a mixture of electrophilic halogen species and various halide anions led to gemdihalogenated ketones containing a combination of the same or two different halogens. Kinetic isotopic effects as well as reaction kinetic experiments give insight to the mechanism of these reactions. Sulfur ylides were described in 1930 by Ingold and Jessop. 1 Although almost 90 years has passed, most applications involving these compounds are related to the pioneering work developed by Johnson and LaCount,2 Franzen,3 and Corey and Chaykovsky4 in the 1960s. For example, cyclopropanation, epoxidation, and aziridination reactions as well as [2,3] sigmatropic rearrangements are most commonly used. 5 New transformations employing sulfur ylides have been described in more recent years,5,6 but this has occurred less frequently than expected when compared to other classes of compounds. An interesting application of the chemistry of sulfur ylides that continues to receive little attention is the reaction of ketosulfoxonium ylides with HCl to prepare α-chloroketones.7 Protonation of the ylide generates a reactive sulfoxonium salt that upon heating is attacked by the acid counterion with displacement of DMSO. Recent efforts in our laboratory8 have demonstrated that sulfoxonium ylides can be protonated by acids other than HCl, such as arylthiols, to furnish ketothioethers without catalysis. Mechanistic studies also revealed the course of these reactions, suggesting that protonation is ratedetermining.8 Recognizing the importance of sulfur ylides in promoting both nucleophilic and electrophilic reactions, and inspired by these contributions,7,8 we chose to investigate in detail their reactivity in the presence of alkylhalides, aiming to directly prepare geminal alkylated haloketones (Figure 1b, Chart A). Moreover, by replacing alkylhalides with a mixture of electrophilic halogen species and halide salts, we considered whether geminal dihalogenated ketones (containing the same or different halogens at the same carbon) could be readily prepared (Figure 1b, Chart B). α-Haloketones9 have great importance in organic synthesis as bifunctional intermediates in that they undergo a vast array of useful transformations.9,10 Unfortunately, most preparatory methods11 remain limited to electrophilic halogenation of ketones and the use of hazardous and reactive reagents. Because these methods always employ enol, enolate, enamine, or silyl enol [a] Instituto de Química de São Carlos, Universidade de São Paulo, CEP 13560-970, São Carlos, SP, Brasil. E-mail: firstname.lastname@example.org Supporting information for this article is given via a link at the end of the document. ether intermediates, a mixture of products is often observed when nonsymmetrical mono-haloketones with two enolizable carbons are prepared.12 Worse yet are the methods used to prepare geminal dihalogenated ketones in a selective and onepot fashion. Few representative examples are known. 13-15 Although diazoketones have been the reagents of choice for that, in the majority of the cases, halogens are added individually by means of two separate reactions. Finally, to the best of our knowledge, the literature provides no direct method for attachment of both an alkyl group and a halogen atom α to a ketone, in order to synthesize more complex haloketones (Figure 1A). Therefore, and according to what we envisioned (illustrated in Figure 1b, Charts A and B), sulfoxonium ylides could be viable alternatives to preparing mono- and α,αdihaloketones (F, Cl, Br, or I) in a direct fashion. Moreover, sulfoxonium ylides are very stable crystalline solids, safe and can be easily prepared in kilogram quantities, 16 making them attractive for industrial applications. Figure 1. Preparation of halo- and geminal dihaloketones via (a) traditional methods and (b) a one-pot method using sulfoxonium ylides. We first evaluated the reaction of sulfoxonium ylide 1 and methyl iodide under various conditions (Table 1). Based on previous work,8 compound 1 and methyl iodide were mixed in equimolar amounts in acetonitrile (ACN) at 25 oC for 24 hours, and a 22% yield of 2 was achieved (entry 1). Using two equivalents of the electrophile, the yield almost doubled (entry 2). Prolonged reaction time (entry 3) provided 15% yield and several byproducts. Investigating solvents other than ACN (entries 4-10), tetrahydrofuran (THF) and chloroform were found to provide the best yields (48% and 44%, entries 8 and 10, respectively). These two, in addition to ACN, were selected for This article is protected by copyright. All rights reserved. Accepted Manuscript Rafael D. C. Gallo[a], Anees Ahmad[a], Gustavo Metzker[a] and Antonio C. B. Burtoloso*[a] 10.1002/chem.201704609 Chemistry - A European Journal COMMUNICATION Table 2. Scope studies between 1 and various alkyl halides. Product Yield. (%)[a] Entry R-X 1[b] EtI 42 2 All-I 43 3[c] BnI 60 4[d] iPr-I or Cy-I ___ RSM 5[d] EtBr or n-BuCl ___ RSM 6[e,f] BnBr 80[g] 7[h] BnCl 81[g] 8 BrCH2CO2Me 53[i] 9 MeI + TBACl 66 10 MeI + TBABr 63 11 MeI + TBAF 47 Table 1. Optimization Studies. Entry Solvent Temp (oC) Time MeI %Yield[a],[b],[c] 1 ACN rt 24h 1 equiv 22 2 ACN rt 24h 2 equiv 38 3 ACN rt 48h 2 equiv 15 4 Acetone rt 24h 2 equiv 32 5 DMSO rt 24h 2 equiv 33 6 MeOH rt 24h 2 equiv -7 AcOEt rt 24h 2 equiv 28 8 THF rt 24h 2 equiv 48 9 Dioxane rt 24h 2 equiv 33 10 CHCl3 rt 24h 2 equiv 44 11 THF 40 24h 2 equiv 62 12 CHCl3 40 24h 2 equiv 38 13 ACN 40 24h 2 equiv 51 14 THF 40 24h 1 equiv 41 15 THF 40 24h 3 equiv 63 16 THF 60 24h 2 equiv 50 17 THF 40 12h 2 equiv 46 18 THF 40 24h 2 equiv 39[d] 19 THF 40 24h 2 equiv 37[e] 20 THF 40 24h 3 equiv 56[f] 21 ACN-d3 40 24h 2 equiv 74[g] 22 THF 40 24h 2 equiv 71[h] [a] Isolated yield. [b] The reaction was performed on 0.3 mmol scale. [c] conc. 1 M. [d] conc. 0.5 M. [e] conc. 2 M. [f] 20 mol% KI. [g] Not isolated; Yield by NMR using 1,2,4,5 tetramethylbenzene as an internal standard. [h] Repetition of entry 11 in a larger scale (1.0 g of 1, 5.1 mmol scale). We next investigated the reaction between ylide 1 and various alkyl iodides, alkyl chlorides, and alkyl bromides to evaluate reaction scope. Reaction with ethyl iodide, allyl iodide, or benzyl iodide, using conditions in entry 11 of Table 1, furnished the alkylated iodoketones in 44-66% isolated yields (entries 1-3, Table 2). Reaction with a secondary alkyl iodide or with aliphatic alkyl chlorides or bromides yielded no reaction: only starting material was recovered (entries 4-5). Performing these reactions at higher temperatures, prolonged reaction times, or in other solvents did not change this result. However, reaction with more reactive benzyl bromide and benzyl chloride provided the alkylated-halogenated products in yields of 64% and 25%, respectively. Changing the solvent to ACN and increasing the temperature to 80 oC improved the yield to 7882% and 79-83%, respectively (entries 6-7). The reaction between ylide 1 and the reactive methyl bromoacetate also provided a good yield (entry 8). 12 BnCl or BnBr + KI 56 [a] Each reaction condition was performed three times. [b] In this reaction we also observed the formation of 16% of compound 2; [c] The reaction can also be performed at 25 oC, providing a 48% yield of the benzylated iodo ketone; [d] Different conditions from 40-80 oC, 24-48 h in THF or ACN; [e] 64% yield using the standard conditions (entry 11, Table 1); [f] 68-72% yield replacing THF by ACN in standard condition; [g] ACN at 80 oC; [h] 25% yield using the standard conditions (entry 11, Table 1); [i] 3:1 inseparable mixture of 8 and its β-elimination product. This article is protected by copyright. All rights reserved. Accepted Manuscript studies at 40 oC, and THF proved to be the best (62% yield, entry 11). By lowering the amount of methyl iodide, yield decreased to 41% (entry 14), and increasing it did not improve yields either (63%, entry 15). Other variations, such as increasing temperature, decreasing reaction time, changing concentrations, and adding potassium iodide (entries 16-20) did not improve yield. Interestingly, under the conditions shown in entry 13 using ACN-d3, the yield calculated directly by NMR (using an internal standard) was 74% (entry 21), indicating some loss or degradation during work-up and/or purification of the reactive and volatile haloketone 2. We also repeated entry 11 in a larger scale (1.0 g of 1), observing an isolated yield of 71%. 10.1002/chem.201704609 Chemistry - A European Journal COMMUNICATION After studying the scope of this alkylation-halogenation method in the presence of 1 and various alkyl halides, these reactions were performed in the presence of ten structurally different sulfoxonium ylides (Figure 2). Ylides 12-16 are derivatives of model ylide 1 containing electron-donating and electron-withdrawing groups. Ylides 17-21 are aliphatic, the former presenting a bulky pivaloyl group and the others enolizable CH2 groups. Ylide 20 is a derivative from an aminoacid and ylide 21 from malic acid. In practically all the cases, moderate to very good yields could be obtained with a broad of structurally different ylides (5 aromatics and 5 aliphatics). In the case of bulky ylides such as 14 (orto-chloro) and 17 (pivaloyl), no product and the elimination product 31 was observed, respectively. It is worth mentioning that for the aliphatic ylides, no byproducts containing the halogen or the alkyl group at the other carbon α to the carbonyl group was observed (a regiochemical problem always encountered in traditional alkylation and halogenating methods). To probe into the mechanism of this geminal alkylationhalogenation reaction, we employed kinetic isotope effect studies and revealed that the first step (ylide alkylation) is most likely rate limiting (Figure 3). Performing two sets of reactions using model ylide 1 in the presence of equal amounts of CH3I and CD3I showed a kH-to-kD ratio of 0.86 ± 0.01 (carefully determined using GC-MS in quintuplicate). This is a secondary kinetic effect that is characteristic for SN2 reactions. Beyond this kinetic isotope effect study, the fact that the second step does not discriminate between halide anions with different nucleophilicities (the one in higher concentration attacks the sulfoxonium first; see entries 9-12, Table 2) also corroborate a fast second step. According to the results depicted in Tables 2 and Figure 2, path A (Figure 3) is the primary path, but paths B and C can also compete depending on the type of ylide and alkyl halide employed. Detailed kinetic studies by NMR were also carried out for the reaction between 1 and methyl iodide (see SI for details), and they also suggested that the first step is rate limiting. This study furnished a rate constant value (k) of 3.3 x 10-5 L-mol-1-s-1 and revealed a global second-order reaction based on the concentration of both ylide and alkyl halide (Figure 4). The rate of this alkylation-halogenation reaction can be expressed as v = 3.3 x 10-5 [ylide 1][MeI]. Figure 2. Scope of the sulfoxonium ylide in the alkylation-halogenation reaction with methyl iodide and benzyl bromide. This article is protected by copyright. All rights reserved. Accepted Manuscript As depicted in entry 5 in Table 2, reaction with aliphatic alkyl chlorides and bromides failed to provide the respective alkylated chloro- and bromoketones. This problem was easily circumvented by using an excess of TBACl or TBABr (entries 9 and 10, Table 2). The same result was observed when preparing a fluoroketone, when an excess of TBAF was added (entry 11). For reactive alkyl bromides and chlorides such as BnCl and BnBr, addition of KI to the reaction vessel also furnished good yields of the alkylated iodide (entry 12) without use of the more expensive benzyl iodide. 10.1002/chem.201704609 Chemistry - A European Journal importance and challenges in preparing fluorinated compounds, we chose to perform these reactions in the presence of an electrophilic fluorinating agent and different halides salts (Figure 5). Reaction of ylide 1, 12, 15, 16 and 18 with Selectfluor in the presence of TBACl, KBr, and KI gave geminal dihalogenated fluoroketones in moderate yields 49-72%. The combination of the same halogen was also possible for Cl and Br, leading to compounds 47 and 48 in 80 and 77% yield respectively. However, all the attempts to combine two F atoms at the geminal position were fruitless and a complex mixture of products were obtained. The results depicted in Figure 5 show a new entry in the preparation of unsymmetrical geminal dihalogenated ketones and also open the possibility for an enantioselective version if chiral electrophilic halogen species are employed. Figure 3. Kinetic isotopic effects and a proposed mechanism for the alkylation-halogenation reaction. Figure 5. One-pot preparation of di-halogenated haloketones, containing the same or different halogens. Figure 4. kinetic studies of the alkylation-halogenation reaction. We next decided to investigate the possibility of extending this method to the preparation of dihalogenated ketones, especially those containing two different halides. Few methods can be found for synthesizing geminal dihaloketones, containing the same halogen, in a direct fashion. For the much more difficult preparation of geminal dihaloketones possessing two different halogens, except for employing diazoketones, 14 only stepwise methods are described. At this point, and knowing the In summary, we have disclosed a novel chemical transformation that permits attachment of an alkyl group and a halogen atom, or alternatively, the same or two different halogen atoms, onto sulfoxonium ylides. This can be performed in a single transformation and introduces a new entry for preparing gem-difunctionalized haloketones (an alkyl and F, Cl, Br, or I) or gem-dihalogenated haloketones (containing a combination of the same or two different halogens) in good yields. In the past, basically sequential transformations, adding these groups or atoms separately, have been reported. We have also provided insights into a detailed mechanism for these reactions based on kinetic isotopic effect studies and kinetics, and in doing so, determined the rate equation and rate constant values. Experimental setup is easy and consists of mixing all reagents at once. Moreover, the great stability of sulfoxonium ylides, in addition to the fact that they are solids, makes them very attractive in chemistry and for industrial applications. This article is protected by copyright. All rights reserved. Accepted Manuscript COMMUNICATION 10.1002/chem.201704609 Chemistry - A European Journal Acknowledgements We would thank FAPESP (Research Supporting Foundation of the State of Sao Paulo) for financial support (2013/18009-4). We also thank CNPq for fellowships. Keywords: haloketones • fluoroketones • sulfur ylides • disubstituted ketones       C. K. Ingold, J. A. Jessop, J. Chem. Soc. 1930, 713. A. W. Johnson, R. B. LaCount, J. Am. Chem. Soc. 1961, 83, 417. (a) V. Franzen, H. J. Schmidt, C. Mertz, Chem. Ber. 1961, 94, 2942; (b) V. Franzen, H. E. Driesen, Chem. Ber. 1963, 96, 1881. (a) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1962, 84, 3782; (b) E. J. Corey, M. Chaykovsky, J. Am. Chem. Soc. 1964, 86, 1640; (c) E. J. Corey, M. Chaykovsky, J. Am. Chem. 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Accepted Manuscript COMMUNICATION 10.1002/chem.201704609 Chemistry - A European Journal COMMUNICATION COMMUNICATION Rafael Gallo, Anees Ahmad, Gustavo Metzker and Antonio C B Burtoloso* Page No. – Page No. Accepted Manuscript Text for Table of Contents α,α-Alkylation-Halogenation and Dihalogenation of Sulfoxinium Ylides. A direct Preparation of Geminal Difunctionalized Ketones. This article is protected by copyright. All rights reserved.