Research Article Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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Peracetic Acid: An Atom-Economical Reagent for Pd-Catalyzed Acetoxylation of C−H Bonds Christopher J. Mulligan,† Sharanappa M. Bagale,† Oliver J. Newton,† Jeremy S. Parker,‡ and King Kuok Mimi Hii*,† †
Department of Chemistry, Imperial College London, Molecular Science Research Hub, 80 Wood Lane, London W12 0BZ, U.K. Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield SK10 2NA, U.K.
‡
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S Supporting Information *
ABSTRACT: Peracetic acid can be used universally as a source of acetate and an oxidant for the selective acetoxylation of C−H bonds in compounds containing ortho-directing groups, catalyzed by Pd(OAc)2. Compared to previous procedures, where persulfates and PhI(OAc)2 were used, the new protocol provides significant improvements in atom efficiency, product yield, substrate scope, cost, scalability, and environmental impact. KEYWORDS: Acetoxylation of C−H bonds, Palladium, Peracetic acid, Atom economy
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such as Cu,12,13 Ru,14,15 and even Co16 are known, Pd(II) catalysts, specifically Pd(OAc)2, remain the most versatile, as it can be directly employed without ligands in the acetoxylation of a myriad of substrates. One of the major issues, however, is the limited choice of effective oxidants. For Pd-catalyzed acetoxylation reactions, (diacetoxy-iodo)benzene, PhI(OAc)2 (DIB), is often employed as a source of acetate ions and an oxidant. The use of this hypervalent reagent generates a stoichiometric amount of iodobenzene, a high-molecular weight, halogenated byproduct that will require additional workup procedures for its removal from the product mixture, which effectively negate the green credentials of the original experimental design. For the acetoxylation of certain substrates, such as acetanilide, DIB was reported to be ineffective. In such cases, the potassium or ammonium salt of peroxodisulfate (S2O82−) is required for the reaction to proceed in good yields (Scheme 2).17,18 Compared to iodobenzene, the inorganic sulfate byproducts are easier to remove (by aqueous workup). However, because of their limited solubility in organic solvents,
INTRODUCTION Transition-metal-catalyzed C−H activation reactions can provide a considerable step- and atom-efficient replacement for tradition cross-coupling methods, obviating the need to preactivate the starting material and the subsequent generation of halide waste. 1−3 In the absence of a halide, the regioselectivity of the reactions can be controlled by the presence of certain functional (directing) groups on the arene substrates. In the early years, reactions were mostly limited to Pd(II)-catalyzed functionalization of arenes, particularly at the sp2 carbon adjacent (ortho) to the directing group. More recently, significant advances in the field, notably through the seminal work by Yu and co-workers,4−6 have shown that regioselectivity of the reaction can be controlled at distal positions using a “template” approach, presenting opportunities for extending molecular complexity through late-stage functionalization. Acylalkoxylation of a C−H bond of an aromatic ring (Scheme 1) is one of the earliest examples of Pd-catalyzed C− H activation reactions7 and is also one of the best exemplified.8−11 While reports of cheaper metal catalysts
Scheme 2. Precedents of Pd(II)-Catalyzed Acetoxylation of Acetanilides
Scheme 1. Classical versus Oxidative C−O Coupling Reactions
Received: October 17, 2018 Revised: December 4, 2018 Published: December 11, 2018 © XXXX American Chemical Society
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DOI: 10.1021/acssuschemeng.8b05370 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Research Article
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a solution of PAA to 1 at room temperature, whereupon an exothermic reaction occurred to generate 4a, which can be isolated in 50% yield (entry 5). To date, there is no literature precedent where peracetic acid is used in C−H acetoxylation reactions. The ability to employ this reagent is a highly attractive proposition; PAA can serve as both an oxidant and the source of acetate. However, it is a substantially “greener” oxidant than either DIB or persulfate, as only H2O is generated as a benign byproduct (Table 2). The
they were often employed in excess (2 equiv). The prolonged reaction time also limits the large-scale applications of these processes. In this work, we will report our discovery of peracetic acid as a more sustainable reagent for the acetoxylation of C−H bonds.
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RESULTS AND DISCUSSION The mechanism of the acetoxylation reaction is generally proposed to involve a Pd(II)−Pd(IV) redox cycle, initiating with the formation of a stable cyclometalated complex 1 from the reaction between Pd(OAc)2 and acetanilide 2a (Scheme 3). The role of the oxidant is believed to facilitate the
Table 2. Comparison of Different Oxidants for Acetoxylation Reactions
Scheme 3. Proposed Catalytic Cycle for the Acetoxylation of Anilides a
oxidant/reagent
byproduct(s)
combined Mw of byproduct(s)a
PhI(OAc)2 0.5 K2S2O8, AcOH AcOOH
PhI, AcOH KHSO4 H2O
264 136 18
Generated from the acetoxylation of each C−H bond.
favorable E-factor is further complemented by the availability and cost effectiveness of PAA (widely used as a disinfectant on an industrial scale),21 providing us with strong incentives to develop a method for performing catalytic acylalkoxylation reactions using this oxidant. Guided by related studies,22−24 reactions were performed in the presence of a substoichiometric amount of toluenesulfonic acid (25 mol %) to facilitate the C−H activation step. When acetic acid is employed as the solvent, the use of environmentally undesirable chlorinated solvents can be avoided. Initial investigations revealed that Pd(OAc)2 causes competitive decomposition of the oxidant, which hampers product formation (Table 3, entry 1). Subsequently, the reaction Table 3. Optimization of the Reaction Conditions for orthoAcetoxylation of Acetanilide formation of Pd intermediates of higher oxidation states, such as 3a and/or 3b, which are more labile and undergo reductive elimination to form the acetylated product 4a. The study originated from an empirical observation made during an earlier study of the redox properties of palladacycles,19 where a solution of complex 1 in 1,2-dichloroethane (DCE) was found to be inert to treatments with DIB or K2S2O8 (Table 1, entries 1 and 2). However, when the
oxidant (2 equiv)
solvent
T (°C)
yield of 4a (%)
1 2 3 4 5
PhI(OAc)2 K2S2O8 PhI(OAc)2 K2S2O8 AcOOH
DCE DCE DCE:AcOH (1:1) DCE:AcOH (1:1) DCE:AcOH (1:1)
80 80 80 80 r.t.
100 (HPLC) 100 (HPLC) 50 (isolated)
2a (equiv)
PAA (equiv)
addition time (h)
4aa (%)
1 2 3 4 5c
1 1 1 1.5 1.5
1 1 1.5 1 1
0 10b 10b 10b 10b
trace 62 57 88 78
a Isolated yield. bA solution of PAA in AcOH (0.1M) was added at a rate of 1 mL/h. cCatalyst loading of 1 mol %.
Table 1. Stoichiometric Reactions between Complex 1 and Oxidants entry
entry
protocol was adjusted, using a syringe pump to deliver the oxidant to the reaction mixture at a rate of 1 mL/h. Under these conditions, the product was obtained in 62% yield (entry 2), which can be improved to 88% by further adjustment of the reaction stoichiometry (entry 4). The conversion is lower (78%) at 1 mol % catalyst loading (entry 5), which is attributed to product inhibition, as the reaction mixture remained as a yellow homogeneous solution, so the formation of Pd black is not a significant process. The method was tested in the ortho-acetoxylation of several arenes with amide directing groups (Scheme 4); the results were compared with that reported previously using persulfate as the oxidant.17,18 In all cases, similar, if not better, yields were obtained using the peracid (e.g., 4a, 4c, 4f, and 4h) in a shorter reaction time. The reactivity pattern agrees with previous
experiments were repeated in a mixture of acetic acid-DCE, the formation of the acetate product 4a occurred spontaneously in quantitative yields at 80 °C (entries 3 and 4). The observation led us to speculate that the true oxidant might be peracetic acid (CH3CO3H, PAA), as it has been reported that peracids can be formed by the treatment of carboxylic acid with strong oxidants such as K2S2O8.20 This was verified by the addition of B
DOI: 10.1021/acssuschemeng.8b05370 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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hydroxyl product 4m in a moderate yield (52%). Such spontaneous deacetylation has been previously reported in other systems.28,29 The new methodology was further tested on further substrates containing O-methyl oxime as a directing group (Scheme 5). The acetoxylation of O-methyl oximes of
Scheme 4. Catalytic C−H Acetoxylation of Anilides Using PAA as the Oxidanta
Scheme 5. Acetoxylation of Oxime Derivatives
acetophenone (5a) and o-tolualdehyde (5b) had been reported previously by Sanford and co-workers using either DIB or Oxone (potassium monopersulfate) at 100 °C30 to afford 6a and 6b, respectively, as a 5:1 mixture of E/Z-isomers. In comparison, at ambient conditions, PAA afforded comparable yields of 67% and 73% for 6a and 6b, respectively. Significantly, the E-stereochemistry of the oxime ether was conserved during the reaction under the milder reaction conditions. Slow addition of the oxidant also allowed for more precise control of reaction stoichiometry, thus allowing the monoacetoxylaton of the oxime ether of p-tolualdehyde 5c to be achieved, affording the novel compound 6c in 62% yield. The protocol is also applicable to the acetoxylation of sp3 C−H bonds; the functionalization of camphor oxime 7 at the C-10 position was achieved in 68% yield, compared to 63 and 68% reported using Oxone and DIB, respectively.30 Given that the treatment of complex 1 with DIB afforded the expected product (Table 1, entry 2), we revisited earlier reports where it was found to be an ineffective acetoxylation reagent17,31 by performing the reaction using two different protocols: (1) Adding an equimolar of DIB to the reaction mixture at the beginning of the reaction afforded a low 28% yield of the product. (2) Slow addition of the oxidant led to a dramatic improvement to 73% yield (Scheme 6). This clearly demonstrates that the hypervalent iodine(III) reagent can be an equally effective oxidant, so long as its decomposition can be suppressed during the reaction.32
a
Conditions: 2a−n (1.5 mmol), PAA (1 mmol, 0.1 M in acetic acid, 10 mL), addition rate = 1 mL/h, Pd(OAc)2 (5 mol %, 0.05 mmol), TsOH·H2O (0.25 mmol), AcOH (10 mL). Unless otherwise indicated, isolated yields are reported. Values in parentheses correspond to reported yields achieved using K2S2O8, 100 °C, 48 h.17 [a] ortho/meta substitution = 4:1. [b] Yield was calculated from the 1H NMR spectrum, as the separation of product from 2l was not possible by column chromatography. [c] Reported yield obtained using (NH4)2S2O8, r.t., 48 h.18
observations: electron-rich substrates (2b−d, 2f−g) are more reactive toward C−H activation and furnished better yields than electron-deficient substrates (2e). For the para-anisidine derivative 2g, a mixture of ortho- and meta-regioisomers of 4g were obtained; the latter is likely due to a competitive uncatalyzed reaction.25,26 Replacing the acetyl group at nitrogen with sterically bulky benzoyl derivatives (2h−j), pivaloyl (2k), or the chelating 1,3dicarbonyl moiety (2l) did not significantly affect the reaction outcome. The corresponding ortho-acetoxylated products 4h−l were all obtained in good to excellent yields. It is interesting to note that for the substrates 2h−j, acetoxylation occurred exclusively on the N−Ar and not on the benzoyl ring. For the acetoxylation of cyclic amides, N-acetyl indoline (2m) and tetrahydroquinoline (2n) serve as model substrates to test the potential application of the methodology for late stage-functionalization reactions.27 Interestingly, while the reaction of the tetrahydroquinoline derivative produced the expected acetoxylated product 4n in good yields (74%), the reaction with the 5-membered indoline ring afforded the
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CONCLUSIONS In this work, we have identified peracetic acid (PAA) as the active oxidant involved in Pd-catalyzed C−H acetoxylation reactions. This discovery led us to develop a method where Scheme 6. Acetoxylation of Acetanilide Using DIB as an Oxidant at Ambient Conditions
C
DOI: 10.1021/acssuschemeng.8b05370 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
ACS Sustainable Chemistry & Engineering
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PAA can be employed as an atom-efficient replacement of conventional oxidants, as well as a source of acetate ions, in Pdcatalyzed acetoxylation reactions. The precise roles of the oxidants in these reactions are not clear. Given that the three different oxidants (persulfate, peracetic acid, and DIB) afforded similar yields (Scheme 5), it is likely that very similar reactive intermediates are involved. Finally, the green metrics of the different oxidants can be quantified for the acetoxylation of acetanilide by using the toolkit developed by the CHEM21 project (Table 4).33,34 The
reaction mass efficiency (RME) atom economy (AE) PMI (reaction) overall efficiency (OE) solvent reaction temperature reference
PAA
(NH4)2S2O8
K2S2O8
* Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.8b05370. Additional experimental procedures, characterization data for the acetoxylated products, and copies of NMR spectra (PDF)
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22%
21.9%
30.9%
91.4% 125.5 66.6% AcOH
53.2% 18.8 41.3% AcOH
42.2% 152.3 73% AcOH
r.t. this work
r.t. 18
47.6% 82.5 46% AcOHDCE 100 °C 17
*E-mail:
[email protected]. ORCID
Jeremy S. Parker: 0000-0002-4758-3181 King Kuok Mimi Hii: 0000-0002-1163-0505 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge EPSRC and AstraZeneca for a doctoraltraining grant, awarded to C.J.M. (EP/L50547X/1), and the Pharmacat Consortium for supporting O.J.N.
r.t. this work
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REFERENCES
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reaction performed with PAA is clearly superior in terms of mass efficiency, atom economy, and overall efficiency. The higher PMI is attributed to the amount of solvent required to enable a slow addition. It is envisaged that this can be improved by optimizing the dosing of the oxidant, e.g., slower addition of a more concentrated/neat solution, which can be more easily achievable on a large scale. From a process chemistry perspective, slow addition of the oxidant also allows more precise control of the reaction exotherm and product selectivity, thus allowing the process to be implemented safely in a sustainable way.
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AUTHOR INFORMATION
Corresponding Author
PhI(OAc)2
60.9%
ASSOCIATED CONTENT
S
Table 4. Comparison of Green Metrics (CHEM21) for the Acetoxylation of Acetanilide under Different Reaction Protocols metric
Research Article
EXPERIMENTAL SECTION
General Procedure for Catalytic Acetoxylation of Arenes Using PAA. Reactions were conducted in 50 mL round-bottom flasks with no special precautions taken to exclude moisture or air. Slow addition of peracetic acid was achieved using a syringe pump and a syringe fitted with a PTFE tube (Note: metal needles are to be avoided as they can cause degradation of peracetic acid). The requisite substrate (2a−n/5a−c/7, 1.5 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol %), and TsOH·H2O (47.5 mg, 0.25 mmol) were dissolved in acetic acid (10 mL), to which a solution of peracetic acid (0.1 M in acetic acid, 10 mL, 1 mmol) was slowly added over 10 h (1 mL/h). The reaction mixture was stirred for a further 8 h at ambient temperature (total reaction time 18 h) before the solvent was evaporated under reduced pressure. Purification of the products was achieved by silica gel column chromatography. Typical Procedure for Catalytic Acetoxylation Using DIB (Protocol 2, Scheme 6). Acetanilide 2a (135 mg, 1.0 mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol, 5 mol %), and TsOH·H2O (47.5 mg, 0.25 mmol) were dissolved in acetic acid (10 mL), and the mixture was warmed to 30 °C. Using a syringe pump, a solution of PhI(OAc)2 (322.1 mg, 1 mmol) in acetic acid (10 mL, 0.1 M) was added to this mixture over 10 h, at a rate of 1 mL/h. Stirring was continued at 30 °C for a further 8 h (18 h total). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate) providing 4a as a white solid (141 mg, 73%). D
DOI: 10.1021/acssuschemeng.8b05370 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Research Article
ACS Sustainable Chemistry & Engineering (15) Okada, T.; Nobushige, K.; Satoh, T.; Miura, M. Rutheniumcatalyzed regioselective C-H bond acetoxylation on carbazole and indole frameworks. Org. Lett. 2016, 18, 1150−1153. (16) Lan, J.; Xie, H.; Lu, X.; Deng, Y.; Jiang, H.; Zeng, W. Co(II)catalyzed regioselective cross-dehydrogenative coupling of aryl C-H bonds with carboxylic acids. Org. Lett. 2017, 19, 4279−4282. (17) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. Direct ortho-acetoxylation of anilides via palladium-catalyzed sp2 C-H bond oxidative activation. J. Org. Chem. 2008, 73, 4717−4720. (18) Yang, F.; Song, F.; Li, W.; Lan, J.; You, J. Palladium-catalyzed C-H activation of anilides at room temperature: ortho-arylation and acetoxylation. RSC Adv. 2013, 3, 9649−9652. (19) Nguyen, B. N.; Adrio, L. A.; Albrecht, T.; White, A. J. P.; Newton, M. A.; Nachtegaal, M.; Figueroa, S. J. A.; Hii, K. K. Electronic structures of cyclometalated palladium complexes in the higher oxidation states. Dalton Trans. 2015, 44, 16586−16591. (20) Pande, C. S.; Jain, N. Phase transfer catalyzed peroxidation of carboxylic acids with potassium persulfate. Synth. Commun. 1988, 18, 2123−2127. (21) Uhl, A.; Bitzer, M.; Wolf, H.; Hermann, D.; Gutewort, S.; Völkl, M.; Nagl, I. Peroxy Compounds, Organic. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2017. DOI: 10.1002/ 14356007.a19_199.pub2. (22) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. Selective Pd-catalyzed oxidative coupling of anilides with olefins through C−H bond activation at room temperature. J. Am. Chem. Soc. 2002, 124, 1586−1587. (23) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Mild C−H halogenation of anilides and the isolation of an unusual palladium(I)−palladium(II) species. Angew. Chem., Int. Ed. 2011, 50, 5524−5527. (24) Reay, A. J.; Hammarback, L. A.; Bray, J. T. W.; Sheridan, T.; Turnbull, D.; Whitwood, A. C.; Fairlamb, I. J. S. Mild and regioselective Pd(OAc)2-catalyzed C−H arylation of tryptophans by [ArN2]X, promoted by tosic acid. ACS Catal. 2017, 7, 5174−5179. (25) Barlin, G. B.; Riggs, N. V. The reaction of phenyl iodosoacetate with N-arylacetamides. J. Chem. Soc. 1954, 3125−3128. (26) Kokil, P. B.; Patil, S. D.; Ravindranathan, T.; Nair, P. M. Chemistry of trivalent iodine: Part II. Mechanism of action of phenyliodosoacetate on p-substituted acetanilides and N-alkylanilines. Tetrahedron Lett. 1979, 20, 989−992. (27) For example, see: White, K. L.; Movassaghi, M. Concise total syntheses of (+)-haplocidine and (+)-haplocine via late-stage oxidation of (+)-fendleridine derivatives. J. Am. Chem. Soc. 2016, 138, 11383−11389. (28) Banerjee, A.; Bera, A.; Guin, S.; Rout, S. K.; Patel, B. K. Regioselective ortho-hydroxylation of 2-arylbenzothiazole via substrate directed C-H activation. Tetrahedron 2013, 69, 2175−2183. (29) Bera, M.; Sahoo, S. K.; Maiti, D. Room-temperature metafunctionalization: Pd(II)-catalyzed synthesis of 1,3,5-trialkenyl arene and meta-hydroxylated olefin. ACS Catal. 2016, 6, 3575−3579. (30) Desai, L. V.; Malik, H. A.; Sanford, M. S. Oxone as an inexpensive, safe, and environmentally benign oxidant for C-H bond oxygenation. Org. Lett. 2006, 8, 1141−1144. (31) Shrestha, A.; Lee, M.; Dunn, A. L.; Sanford, M. S. Palladiumcatalyzed C−H bond acetoxylation via electrochemical oxidation. Org. Lett. 2018, 20, 204−207. (32) Because the use of the DIB is less attractive than PAA as a reagent, further application of the protocol was not pursued further in this work. (33) McElroy, C. R.; Constantinou, A.; Jones, L. C.; Summerton, L.; Clark, J. H. Towards a holistic approach to metrics for the 21st century pharmaceutical industry. Green Chem. 2015, 17, 3111−3121. (34) Copies of CHEM21 excel spreadsheet downloaded from: https://www.chem21.eu/project/metrics-toolkit/ (downloaded November 23, 2018).
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DOI: 10.1021/acssuschemeng.8b05370 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
