TEMPO-Catalyzed Aerobic

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Development of a Large-Scale Copper(I)/TEMPO-Catalyzed Aerobic Alcohol Oxidation for the Synthesis of LSD1 Inhibitor GSK2879552 Augustine Ochen,† Robert Whitten,† Helen E. Aylott,† Katie Ruffell,† Glynn D. Williams,† Fiona Slater,† Andrew Roberts,‡ Paul Evans,§ Janelle E. Steves,*,∥ and Mahesh J. Sanganee*,† API Chemistry, ‡Analytical Sciences and Development, and §Pilot Plant Operations, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom ∥ API Chemistry, GlaxoSmithKline, 1250 South Collegeville Rd., Collegeville, Pennsylvania 19426, United States Downloaded via UNIV OF SUNDERLAND on October 25, 2018 at 20:52:13 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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S Supporting Information *

ABSTRACT: An improved process to an aldehyde en route to an LSD1 inhibitor was developed using an aerobic oxidation with a CuI and TEMPO (2,2,6,6-tetramethylpiperdine 1-oxyl) catalyst system. In this report, kinetic information is utilized to understand the generation a of number of key byproducts that affect catalyst performance and aldehyde yield. Insight into factors affecting the formation of these byproducts is presented. This CuI/TEMPO catalyst facilitates rapid conversion of the starting aliphatic alcohol in 1−2 h with apparent zero-order kinetics unprecedented for this substrate class with this catalyst system. Process optimization of catalyst components and reaction solvent led to the successful 400 g scale-up of this oxidation with bubbling air in a batch reactor.

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INTRODUCTION Oxidation of alcohols to aldehydes or ketones is one of the most widely used transformations in organic chemistry.1 While well-established methods such as the Swern oxidation2 and protocols that utilize hypervalent iodide3 are frequently chosen for small-scale oxidations, these reagents are often not viable on a larger, manufacturing scale due to their requirement for cryogenic conditions and involvement of high-energy and sensitive intermediates. In the pharmaceutical industry, alcohol oxidation is carried out infrequently compared to other reaction classes.4 When it is utilized in a large-scale synthetic route to an active pharmaceutical ingredient (API),5 Parikh− Doering6 (SO3·pyr/DMSO, pyr = pyridine) and TEMPO/ NaOCl7 (TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl) methods provide robust and inexpensive access to these carbonyl compounds. In order to access LSD1 inhibitor GSK2879552 (LSD1 = Lysine-Specific Histone Demethylase 1), a compound targeted to treat acute myelogenous leukemia,8 we envisioned obtaining intermediate aldehyde 2 from the oxidation of 1 (Scheme 1). Avoiding complete isolation and purification of 2 would allow for its direct use in a subsequent aqueous resolution and reductive amination9 to produce 3. This telescoped protocol would enable us to avoid isolation of 2, a potentially unstable intermediate.10 Due to the sensitivity of the aqueous conditions, we needed to identify an alcohol oxidation method with reagents and solvents that could be carried into the aqueous reductive amination at residual levels without detriment to reaction efficiency. Moreover, it was critical to obtain a highly selective oxidation in order to avoid generation of significant byproducts which would require additional purification steps at the end of the synthesis. Screening a variety of traditional stoichiometric © XXXX American Chemical Society

Scheme 1. Proposed Route to Access Intermediate 3

oxidants (Table S1) including DMSO-based reagents with different mediators, TEMPO-based protocols with various terminal oxidants, Oppenauer11 conditions, and hydrogen peroxide, led us to discover that many of these methods failed to provide 2 in sufficient yield and purity for the reductive amination. However, we ultimately identified T3P/DMSOmediated oxidation conditions (T3P = propylphosphonic anhydride) as a fit-for-purpose robust oxidation method (Scheme 2).12 Unfortunately, several manufacturability issues made these conditions unsuitable for subsequent campaigns, including (a) the use of 2 equiv of T3P, a chemical weapons precursor Special Issue: The Roles of Organometallic Chemistry in Pharmaceutical Research and Development Received: July 31, 2018

A

DOI: 10.1021/acs.organomet.8b00546 Organometallics XXXX, XXX, XXX−XXX

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Organometallics Scheme 2. T3P/DMSO-Mediated Oxidation of 1

Scheme 3. Mechanism of Cu/Nitroxyl-Catalyzed Aerobic Alcohol Oxidation and Key Mechanistic Differences between Systems

requiring tight regulations over its use; (b) the production of dimethylsulfide as a byproduct, requiring extra precautions to ensure containment and proper reactor cleaning; and (c) the long time required to complete the reaction with laborintensive workup. Multiple phase separations and distillations contributed to an undesirable high process mass intensity (PMI),13 with 73 kg of reagents and solvents required for the oxidation and workup in order to deliver 1 kg of 2. Together, these limitations compelled us to search for alternative oxidation methods that would improve process efficiency, reduce reagent and solvent use, and maintain high yield and selectivity. Aerobic alcohol oxidation methods are attractive due to the use of O2, an inexpensive oxidant, and the production of H2O, a benign byproduct. We anticipated that these features would enable us to lower the oxidation PMI by reducing the amount of reagents used and simplifying reaction workup. Ample literature precedent describing the development of aerobic alcohol oxidation methods14 led us to consider these protocols as viable alternatives to the T3P/DMSO-mediated conditions. Copper-catalyzed aerobic alcohol oxidation methods are among the mildest and most versatile homogeneous catalytic systems for this transformation.15,16 Among the many conditions available, we identified the CuI/nitroxyl-catalyzed conditions developed by Stahl,16e,f Iwabuchi,16g,i and Muldoon16h as viable starting points since reactions are often performed at room temperature using ambient air as the terminal oxidant. Detailed mechanistic information reported for these CuI/nitroxyl catalysts17 and process versatility as demonstrated by Stahl gave us a number of options to explore; the CuI/nitroxyl systems perform well in more than one solvent with inexpensive CuI sources and ligands,18 and have been scaled up to 100 g in batch and flow reactors.19 These features would give us flexibility to identify conditions that could be telescoped into the aqueous resolution and reductive amination. Of the various nitroxyl radicals available leading to diverse reactivity and selectivity in these oxidations, we chose to focus on commercially available TEMPO derivatives and ABNO (ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl) to keep process cost low. Mechanistic insight from the literature significantly guided our optimization efforts. The catalytic cycle for CuI/nitroxylcatalyzed aerobic alcohol oxidation (Scheme 3) begins with oxidation of a CuI source to a binuclear CuII intermediate (step 1). Subsequent breakup of this intermediate by a hydroxylamine (step 2) yields an equivalent of CuI and a CuII−OH species, believed to act as a strong base for deprotonation of the alcohol (step 3). The CuII−alkoxide is then oxidized by a nitroxyl species, resulting in product formation and regeneration of CuI (step 4). Significant differences are observed in the rate, substrate scope, and selectivity of CuI/TEMPO and CuI/ABNO-

catalyzed aerobic alcohol oxidation reactions. Although the CuI/TEMPO catalyst system offers chemoselective oxidation of primary alcohols, sterically unhindered and electronically activated alcohols are oxidized at much faster rates than aliphatic alcohols, which can require longer reaction times and/or elevated temperatures.16e Stahl and co-workers established that catalyst oxidation is turnover-limiting for benzylic alcohols and that alcohol oxidation primarily controls the rate of oxidation of aliphatic alcohols.17a These findings are manifested in key differences in substrate kinetics: Benzylic alcohols are oxidized rapidly, with zero-order [alcohol] dependence, while aliphatic alcohols are oxidized at a slower rate and exhibit saturation dependence on [alcohol]. Changing the nitroxyl source to the less sterically hindered bicyclic nitroxyl, ABNO, increases the scope and efficiency of alcohol oxidation. Using ABNO broadens the substrate scope to both primary and secondary alcohols, with all substrate classes exhibiting fast, near-linear kinetics.16f,20 Herein, we discuss the adaptation of the CuI/TEMPO catalyst system for the efficient oxidation of an aliphatic alcohol under safe and scalable batch conditions. Optimization for large-scale pharmaceutical application led to unusual apparent zero-order kinetics for this aliphatic alcohol oxidation. Moreover, we observed a number of byproducts not previously reported for CuI/nitroxyl catalyst systems and discuss factors that affect their formation.

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RESULTS AND DISCUSSION In order to attain oxidation conditions suitable for large-scale application, we needed to avoid explosion hazards associated with O2 and flammable solvents, reduce process cost, decrease time required for the reaction and workup, minimize environmental impact, and ensure that residual oxidation reagents and solvents are tolerated in the aqueous resolution and reductive amination. Establishing the safety of the aerobic oxidation conditions was paramount. While different process modifications exist to ensure the safety of flammable oxygensolvent mixtures,18,21 we adopted the approach of operating at temperatures at least 25 °C below solvent flash point with bubbling air in a batch reactor. We anticipated that if a 25 °C gap was not initially viable, optimization of reaction conditions would enable us to lower temperature and meet this guideline. We also sought to reduce process cost and environmental impact with the judicious choice of inexpensive catalyst components18 and an increase in reaction concentration to >0.5 M. In addition, we aimed to reduce the number of workup steps required to obtain 2 in sufficient purity for the aqueous resolution and reductive amination. B

DOI: 10.1021/acs.organomet.8b00546 Organometallics XXXX, XXX, XXX−XXX

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Information for details). As a result, sulfolane was chosen as the reaction solvent for further studies. The byproducts observed during the solvent optimization process (Scheme 4) were identified by NMR spectroscopy and

Initially, we attempted the oxidation of 1 with modified conditions compared to those reported by Stahl16e using bubbling air as the O2 source (eq 1). On the basis of current mechanistic understanding of the oxidation17 (vide supra), we expected the CuI/TEMPO catalyzed aerobic oxidation of 1 to reach completion more slowly than that of an analogous benzylic substrate. Even with elevated temperature, aliphatic alcohols with this catalyst can take up to 24 h to reach completion. Therefore, we increased catalyst loading from 5 mol % (standard conditions)16e to 10 mol % and performed the reaction at 80 °C rather than at room temperature in order to improve reaction rate. Unexpectedly, the oxidation of 1 under these conditions afforded 2 in 85% yield after 1 h.

Scheme 4. Byproducts Characterized and Observed in Aerobic Oxidation of 1a

a

R = tert-butyl 4-methylbenzoate.

mass spectrometry and were independently synthesized. We obtained accurate quantitation of some of these byproducts by HPLC except 7 and 8, which were present in all reactions at levels up to 2 and 1%, respectively (see Figure S1). While carboxylic acid byproducts19a and lactones24 have been reported as products of aerobic alcohol oxidation, to our knowledge, this is the first report of byproducts with similar structures to 5−7, originating from CuI/nitroxyl-catalyzed aerobic alcohol oxidation. To gain insight into the formation of these byproducts, we monitored oxidation progress over time. Several observations can be made from the time course (Figure 1A). Linear growth of the aldehyde is observed, with the reaction reaching

With efficient initial conditions identified, we next examined six different copper salts, four nitroxyl radicals, three additives, and five nitrogenous ligands using DMSO as a high flash point solvent. These experiments identified bpy (2,2′-bipyridine) as the best ligand, CuI as the best low-cost copper source, TEMPO as the optimal nitroxyl,22 and NMI (N-methylimidazole) and DMAP (4-dimethylaminopyridine) as optimal additives (see Table S2). These results are consistent with literature precedent16e−i and met our requirements to reduce process cost. At this point, we elected to continue optimization with CuI, bpy, TEMPO, and NMI, and moved forward to assess other high flash point solvents in order to improve reactivity. Solvents with flash points of 87−177 °C that sufficiently dissolved 1 were subjected to catalytic aerobic oxidation conditions with bubbling air (Table 1). While high yields were obtained in most dipolar aprotic solvents, sulfolane afforded the highest yield of 2 and the lowest byproduct levels (Table 1, entry 6).23 Experimental analysis of the flash point of 2 in sulfolane demonstrated that the solution did not ignite up to the boiling point of sulfolane (189 °C, see the Supporting Table 1. Optimization of Reaction Solvent for Aerobic Oxidation of 1

entry

solventa

FP (°C)b

1

isosorbide methyl ether NEP NMP DMSO propylene carbonate sulfolane

2 3 4 5 6

1c

2c

4c

5c

6c

120

56

33

0

0.8

0.2

91 91 87 116

4 1 1 7

82 84 85 79

5 7 6 0.4

5 5 4 6

0.9 1 2 5

177

0.4

95

0.7

0.9

1

a

R = tert-butyl-4-methylbenzoate. NEP = N-ethylpyrrolidone; NMP = N-methylpyrrolidone. bFP = flash point. Solvent flash points were obtained from Sigma-Aldrich. cYields reported were determined by HPLC accounting for response factors of 1, 2, and 4. Yields for 5 and 6 were determined by analysis of their peak areas in comparison to total peak area.

Figure 1. R = tert-butyl 4-methylbenzoate. (A) Time course of aerobic alcohol oxidation of 1. HPLC yield accounting for response factors of 1, 2, and 4. Yields for 5 and 6 were determined by analysis of their peak areas in comparison to total peak area. (B) O2 uptake data for the 100 g (327 mmol) oxidation of 1. C

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Organometallics maximum conversion within 0.75 h and 2 degrading over time after reaction completion. This decrease in aldehyde yield over time correlates with an increase in the four byproducts quantified during reagent and solvent optimization. While quenching the catalyst quickly to minimize these byproducts is possible on a small scale, stopping the reaction on a large scale requires more time and could lead to a decreased yield of 2. A separate large-scale oxidation of 1 reveals linear O2 uptake for most of the reaction (Figure 1B), similar to the linear formation of 2 in Figure 1A. Total O2 consumed (Figure 1B) correlates well with the expected stoichiometric value.25 These apparent zero-order kinetics exemplified in the reaction time course and gas uptake experiment are not consistent with the results of previously reported studies of CuI/TEMPO-catalyzed aliphatic alcohol oxidation. The oxidation of aliphatic alcohols exhibits saturation kinetics under standard CuI/TEMPO-catalyzed conditions.16e We inferred from mechanistic precedent17a that linear consumption of 1 suggests that catalyst oxidation (Scheme 3) is the turnover-limiting step in this reaction, as has been established for benzylic alcohol oxidation with a CuI/TEMPO catalyst. The correlation between the formation of byproducts and decrease in concentration of 2 led us to believe that the byproducts originated from 2. To corroborate this hypothesis, we subjected aldehyde 2 to the reaction conditions and monitored levels of the byproducts over time (Figure 2). While we sought to understand how and when these byproducts formed, rigorous examination of the mechanistic origin of these impurities was out of the scope of our study. We found that 5−8 could be effectively removed in subsequent synthetic steps to access GSK2879552. Carboxylic acid 4, however, could not be eliminated and risked contaminating GSK2879552. Experiments in which 4 is spiked into an active alcohol oxidation show that the byproduct immediately stops productive alcohol conversion, possibly due to the coordination of 4 to a CuII species and/or protonation of the CuII−alkoxide, followed by subsequent dimerization of the CuII−OH intermediate (Scheme 3).26 Due to the potential of 4 to contaminate GSK2879552 and deactivate the alcohol oxidation catalyst, minimizing 4 was our primary concern. In the presence of copper and TEMPO, generation of 4 reaches a maximum level of 6% within 2 h (Figure 2A). Reaction conditions without TEMPO (Figure 2B) reveal slower buildup of 4, and conditions without copper (Figure 2C) do not promote its generation. Suspecting that the presence of water as a byproduct of aerobic oxidation may contribute to generation of 4, we spiked an additional 1.7 equiv of H2O into the oxidation (see Schemes S2 and S3). This increased water concentration did not affect formation of 4, but dilution of the reaction slowed the generation of this acid (vide infra). Early experiments studying the stability of 2 in DMSO at 20−25 °C showed disappearance of 2 and concomitant increase of 4 after 1 day. Similar experiments conducted in the presence of BHT (BHT = 2,6-ditert-butyl-4methylphenol), a radical inhibitor, resulted in reduced degradation of 2 and a significantly lower level of 4 after 19 days (see Scheme S1 and Table S3). On the basis of these data, we anticipate that 4 could be formed via a number of different pathways. The rapid formation of 4 observed under conditions with CuI/TEMPO (Figure 2A) could indicate an operative mechanism similar to the CuI/nitroxyl-catalyzed lactonization of diols,24 which likely proceeds through oxidation of a hemiacetal intermediate.

Figure 2. Time course experiments of degradation of 2. HPLC yield accounting for response factor of 4. Yields of 5 and 6 were determined by analysis of their peak areas in comparison to total peak area. R = tert-butyl 4-methylbenzoate. (A) Byproduct generation from aldehyde 2 under standard oxidation conditions. (B) Byproduct generation without TEMPO. (C) Byproduct generation without CuI.

Attack of H2O on a Cu-bound aldehyde followed by oxidation of a resulting hydrate could lead to the generation of acid 4. In the presence of copper without TEMPO (Figure 2B), 4 may be formed via a Fehling-type oxidation27 or a modified autoxidation pathway.28 Finally, the lack of generation of acid 4 in the presence of TEMPO and absence of copper (Figure 2C) corroborates results obtained from the assessment of the stability of 2 in DMSO; analogous to BHT, TEMPO likely inhibits autoxidation of 2 under aerobic conditions. Since 5 and 6 could be removed from the products of subsequent steps in our synthesis of GSK2879552, we conducted fewer experiments to determine their origins of formation. However, their changing concentrations under different catalytic conditions (Figure 2) convey factors that influence their production. Piperidone 5 reaches its highest level under conditions in which only copper is present (Figure 2B), while conditions that include TEMPO (Figure 2A,C) promote generation of 5 at lower overall rates. While similar D

DOI: 10.1021/acs.organomet.8b00546 Organometallics XXXX, XXX, XXX−XXX

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transfer limitations are operative under our conditions. Oxygen mass transfer effects in similar CuI/nitroxyl-catalyzed aerobic alcohol oxidation reactions have been reported by Muldoon and co-workers,16h and benzylic and aliphatic alcohols exhibit different reaction rates with an ABNO cocatalyst when these effects are removed. An assessment of the kinetic order30 of the oxidation in TEMPO suggests that the rate of oxidation of 1 is not dependent on TEMPO between 2.5 and 5 mol % loading (Figure 4D). A similar finding was reported for the CuI/ TEMPO-catalyzed oxidation of benzylic alcohols.17a This zeroorder dependence on TEMPO prompted us to reduce TEMPO loading to 1 mol %. We reasoned that if catalyst oxidation (Scheme 3) is the turnover-limiting step, we would observe similar reaction efficiency at a low TEMPO loading. However, a decrease in reaction rate and failure to reach complete conversion at 1 mol % TEMPO led us to believe that reduced reaction efficiency could be caused by two potential scenarios: (a) the involvement of TEMPO in the generation of byproducts and/or (b) O2 mass transfer limitations that mask the true TEMPO dependence for the oxidation of 1, which is anticipated to be first-order.17a With this information, the rate of air flow was increased to ensure sufficient mass transfer on a 400 g scale. While we observed an apparent zero-order dependence on TEMPO, the concentration of TEMPO was maintained at 5 mol % due to incomplete conversion of 1 observed at lower TEMPO levels. The optimized conditions (Scheme 5A) were performed successfully in triplicate on a 400 g scale, affording 86% yield of 2 within 2 h. Application of 2 to subsequent resolution and reductive amination yielded 3 in high yield and enantiopurity. As described by Stahl,16e,f the oxidation exhibits a vibrant color change from red-brown to green upon completion (Scheme 5B). Aqueous workup provided satisfactory removal of most catalytic components prior to treatment of 2 with reagents for the resolution and reductive amination.

products have been reported to originate from aldehyde autoxidation processes28 and catalytic photoredox reactions,29 we currently do not have enough evidence to propose a mechanism for the generation of 5. However, the presence of TEMPO clearly reduces growth of this byproduct. Conversely, enal 6 is not necessarily minimized in the presence of TEMPO. Standard catalytic conditions (Figure 2A) promote the formation of this byproduct up to 4%, while conditions in which TEMPO is present without copper (Figure 2C) do not increase the level of 6 observed. Due to the formation of 6 under conditions with copper in the absence of TEMPO (Figure 2B) and under standard catalytic conditions, we inferred that copper has a role in the generation of 6. On the basis of our analysis of the formation of 4−7, we sought to minimize levels of these byproducts by lowering copper, bpy, and TEMPO loading to 5−6 mol %. Loadings lower than 5 mol % of each of the catalytic components were detrimental to reaction efficiency and conversion of 1. Decreasing reaction temperature from 70 to 50 °C and diluting the reaction from 0.65 to 0.55 M slowed the formation of all impurities, resulting in reduced degradation of the aldehyde after reaction completion (Figure 3). While the time

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CONCLUSION In summary, we have developed a highly efficient CuI/ TEMPO-catalyzed aerobic oxidation protocol for an aliphatic alcohol. The use of sulfolane as a high flash point solvent, lowcost catalyst components, and reaction concentration of >0.5 M make this method amenable to safe large-scale application in a batch reactor. Monitoring reaction conversion, product formation, and byproduct generation over time guided optimization efforts to improve aldehyde yield and minimize byproducts. This analysis enabled us to identify some sideproducts not previously reported for CuI/nitroxyl-catalyzed aerobic alcohol oxidation. Our experimental investigation into the origin of these byproducts suggests unconventional pathways for their formation, and further analysis may improve the selectivity of these oxidation conditions. While process optimization allowed us to access a faster reaction for an aliphatic alcohol than has been previously reported with the CuI/TEMPO catalyst, these modified conditions prompted us to consider the influence of potential O2 mass transfer limitations on large scale reaction efficiency. We have not yet further investigated the nature of the apparent zero-order kinetics observed, but we speculate that increasing the overall reaction concentration from the lower concentrations used in previously reported batch methods may contribute to this phenomenon. The observation of these novel byproducts and kinetic behavior consistent with O2 mass transfer limitations reveals important implications for the future development of

Figure 3. Improved conditions for aerobic oxidation of 1 on a 100 g (327 mmol) scale. HPLC yield accounting for response factors of 1, 2, and 4. Yields for 5 and 6 were determined by analysis of their peak areas in comparison to total peak area. R = tert-butyl 4methylbenzoate.

to completion increased from 0.75 to 2 h at this reduced temperature, greater control over the byproducts formed encouraged us to adopt these modifications for scale up. Prior to scaling the oxidation of 1 to 400 g in a batch reactor, we wanted to ensure that the rate at which we could deliver O2 to the reaction would be sufficient to achieve full conversion. During the course of optimization of the alcohol oxidation conditions, we noticed a shift in apparent kinetic order of the reaction upon lowering catalyst loading (Figure 4A). At 5 mol % copper loading, the reaction exhibits linear kinetics, while at 2.5 mol % copper loading, the reaction rate is slower and the trace of aldehyde yield is no longer linear. Suspecting O2 mass transfer limitations, we conducted the oxidation of 1 at two different temperatures (Figure 4B) and two different bubbling rates (Figure 4C). An increase in air flow rate through the reaction improves agitation of the homogeneous liquid phase, similar to a stir rate dependence. The lack of reaction rate increase at 60 °C and the difference in reaction efficiency between two air bubbling rates may imply that O2 mass E

DOI: 10.1021/acs.organomet.8b00546 Organometallics XXXX, XXX, XXX−XXX

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Figure 4. R = tert-butyl 4-methylbenzoate. (A) 2.5−5 mol % bpy, 5 mol % TEMPO, 10 mol % NMI. 70 °C. (B) 5 mol % CuI, bpy, TEMPO, 10 mol % NMI. (C) 5 mol % CuI, bpy, 2.5 mol % TEMPO, 10 mol % NMI. 50 °C. (D) 5 mol % CuI, bpy, 10 mol % NMI. 50 °C.

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Scheme 5. Oxidation of 1a

EXPERIMENTAL SECTION

General Information. All solvents and reagents were obtained from commercial sources and were used as they were received. Ethylpiperidine-4-carboxylate, ethylpyridine-4-carboxylate, piperidin4-ylmethanol, and tert-butyl-4-(chloromethyl)benzoate were also purchased from commercial sources and used as received. All reactions were carried out in a jacketed lab reactor (JLR), Easymax, or oven-dried reaction vessels. Thin-layer chromatography (TLC) analysis was performed on silica gel TLC plates. Column chromatography was carried out on prepacked silica gel columns using a Biotage purification unit. 1H and 13C{1H} NMR spectra were recorded on 400, 600, and 700 MHz spectrometers, respectively, and are reported as chemical shifts (δ) in parts per million (ppm). Deuterated NMR solvent signals were used as a reference. Highresolution mass spectroscopy (HRMS) (m/z) was measured using a LTQ Discovery Orbitrap (Thermo) mass spectrometer equipped with a heated electrospray ionization (HESI) ion source. Low resolution mass spectroscopy (LRMS) (m/z) was measured using a Water Acquity SQD mass spectrometer on a Waters CSH column (C18, 30 mm × 2.1 mm, 1.7 μm particle size). High-pressure liquid chromatography (HPLC) was performed on an Agilent HP1200 instrument at 40 °C equipped with an Agilent Bonus RP column (150 mm × 4.6 mm, 3.5 μm). A gradient of 5−95% MeCN/H2O with 0.05% v/v trifluoroacetic acid over 20 min was used. Contents were monitored at 220 nm. Procedure for Synthesis of tert-Butyl 4-((4(hydroxymethyl)piperidin-1-yl)methyl)benzoate (1). To a stirred solution of tert-butyl 4-(chloromethyl)benzoate (500g, 2.21 mol, 1.00 equiv) in isopropyl acetate (3 L) was added potassium carbonate (426.8 g, 3.09 mol, 1.40 equiv, 325 mesh grade) followed by piperidin-4-ylmethanol (292 g, 2.54 mol, 1.15 equiv) and water (50 mL). The resultant slurry was stirred under nitrogen while heating to ca. 74 °C for at least 5.5 h. Once the reaction was judged to be complete by HPLC, the reaction mixture was cooled to ca. 20 °C, and water (1.5 L) was added to obtain a complete biphasic solution.

a

(A) Large-scale oxidation of 1 telescoped into aqueous resolution and reductive amination. (B) Photos of 400 g scale oxidation of 1.

large scale CuI/nitroxyl-catalyzed aerobic alcohol oxidation. Moreover, achieving rapid aerobic oxidation of a primary aliphatic alcohol with a CuI/nitroxyl catalyst in a batch reactor may no longer require ABNO or another sterically accessible nitroxyl radical. This adapted CuI/TEMPO catalyst highlights the versatility of CuI/nitroxyl-based aerobic alcohol oxidation catalysts and expands options for synthetic chemists to add this alcohol oxidation platform to their repertoire. F

DOI: 10.1021/acs.organomet.8b00546 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics

nitrogen atmosphere. The reaction was heated to 70 °C and held for 4 days. It was then cooled to ambient temperature, quenched with water (150 mL), and extracted with EtOAc (2 × 150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography using n-heptane/EtOAc (10:1 to 2:1) to give product as a white solid (23.0 g, 68.5% yield). 1H NMR (700 MHz, DMSO-d6, 300 K): δ 7.88 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 3.68, (s, 2H), 2.68 (t, J = 6.2 Hz, 4H), 2.35 (t, J = 6.2 Hz, 4H), 1.54 (s, 9H). 13C{1H} NMR (176 MHz, DMSO-d6, 300 K): δ 208.7, 165.3, 144.2, 130.6, 129.5, 129.2, 81.0, 60.6, 52.7, 41.1, 28.3. HRMS (ESI) m/z [M + H]+: molecular ion calculated for C17H24NO3: 290.1750, found 290.1751. Procedure for Synthesis of tert-Butyl-4-((4-formyl-5,6dihydropyridin-1(2H)-yl)methyl)benzoate (6). To a stirred solution of intermediate 15 (1.00 g, 2.77 mmol, 1.00 equiv) in THF (10 mL) at −70 °C was added DIBAL-H (8.32 mL, 1.0 M, 8.32 mmol, 3.00 equiv) under a nitrogen atmosphere. The reaction was stirred at −70 °C for 6 h. It was quenched with saturated aqueous ammonium chloride (20 mL) and saturated aqueous potassium sodium tartrate (20 mL). The mixture was stirred at 20 °C and then extracted with EtOAc (3 × 50 mL). The combined organic layers was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by silica column chromatography using n-heptane/EtOAc (20:1 to 10:1). The pure fractions were combined and concentrated under reduced pressure to give a light red oil (0.50 g, 59.8% yield). 1H NMR (700 MHz, DMSO-d6, 300 K): δ 9.45 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.95−6.93 (m, 1H), 3.68 (s, 2H), 3.24−3.22 (m, 2H), 2.53 (t, J = 5.6 Hz, 2H), 2.20−2.16 (m, 2H), 1.54 (s, 9H). 13C{1H} NMR (176 MHz, DMSO-d6, 300 K): δ 193.7, 165.3, 148.8, 143.9, 138.9, 130.6, 129.5, 129.2, 81.0, 61.1, 53.0, 48.6, 28.3, 22.5. HRMS (ESI) m/z [M + H]+: molecular ion calculated for C18H24NO3: 302.1751, found 302.1751. Procedure for Synthesis of tert-Butyl-4-((4-formyl-4((2,2,6,6-tetramethylpiperidin-1yl)oxy)piperidin-1-yl)methyl)benzoate (7). To a solution of 1 (500 mg, 1.64 mmol, 1.00 equiv) and TEMPO (1.28 g, 8.19 mmol, 5.00 equiv) in THF (5.00 mL) was added KBr (81.9 uL, 2.0 M, 0.16 mmol, 0.10 equiv). The reaction mixture was stirred vigorously and cooled to−10 °C. Sodium hypochlorite (1.80 mL, 1.0M, 1.8 mmol, 1.10 equiv) was then added slowly over 15−20 min. The mixture was heated to 70 °C and held for 24 h. The reaction was then cooled to ambient temperature, quenched with water (10 mL), and extracted with EtOAc (3 × 50 mL). It was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica column chromatography using n-heptane/ethyl acetate (20:1 to 10:1), and the pure fraction was concentrated under reduced pressure to give a light red oil (90 mg, 12.0% yield). 1H NMR (700 MHz, DMSO-d6, 300 K): δ 9.80 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 3.51 (s, 2H), 2.59−2.54 (m, 2H), 2.28−2.22 (m, 2H), 1.98− 1.93 (m, 2H), 1.91−1.86 (m, 2H), 1.54 (s, 9H), 1.52−1.48 (m, 3H), 1.39−1.33 (m, 2H), 1.29−1.24 (m, 1H), 1.09 (s, 6H), 1.08 (s, 6H). 13 C{1H} NMR (176 MHz, DMSO-d6, 300 K): δ 203.1, 165.4, 144.4, 130.5, 129.4, 129.1, 81.0 (2C), 61.7, 60.2, 49.8, 40.5, 34.2, 31.6, 28.3, 20.8, 16.9. MS (ESI) m/z [M + H]+: molecular ion calculated for C27H43N2O4: 459, found 459 (no accurate mass obtained). Procedure for Synthesis of (1-(4-(tert-Butoxycarbonyl)benzyl)piperidin-4-yl)methyl-1-(4-(tert-butoxycarbonyl)benzyl)piperidine-4-carboxylate (8). To a solution of 4 (20 g, 62.6 mmol, 1.00 equiv) and 1 (19.1 g, 62.6 mmol, 1.00 equiv) in DMF (200 mL) was added DIPEA (21.8 mL, 125 mmol, 2.00 equiv) and HATU (35.7 g, 93.9 mmol, 1.50 equiv). The reaction was stirred for 12 h at 30 °C. EDCI (18.0 g, 93.9 mmol, 1.50 equiv) and HOBt (12.7 g, 93.9 mmol, 1.50 equiv) were added, and the reaction was stirred at 30 °C for 12 h. Water (400 mL) was added, and the mixture was extracted with EtOAc (2 × 400 mL), dried over Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography eluted with n-hepane/EtOAc = 20:1 to 5:1 to afford 10.9 g of pure product and 6.1 g of crude product (17.0 g,

The phases were settled and separated. The aqueous phase was discarded. The organic phase was concentrated in vacuo under reduced pressure to a clear pale yellow solution of 1.25 L. Heptane (3 L) was added, and the mixture was reconcentrated back to 2 L, during which time the product crystallized. This suspension was adjusted to ca. 15 °C over 1 h and stirred for an additional 1 h. The solid was collected by vacuum filtration and washed with heptane (1 L). The material was transferred to a suitable container and dried overnight at 48−52 °C in vacuo to constant weight. The product was isolated as a white solid (628.1 g, 93.3%). 1H NMR (600 MHz, DMSO-d6, 300 K): δ 7.84 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 4.39 (t, J = 4.9 Hz, 1H), 3.47 (s, 2H), 3.23 (t, J = 5.5 Hz, 2H) 2.75 (dt, J = 11.5 Hz, 3.0 Hz, 2H), 1.88 (dt, J = 11.5 Hz, 2.2 Hz, 2H), 1.58−1.62 (m, 2H), 1.53 (s, 9H), 1.28−1.35 (m, 1H), 1.08−1.16 (m, 2H). 13C{1H} NMR (151 MHz, DMSO-d6, 300 K): δ 164.8, 144.2, 129.9, 128.9, 128.6, 80.4, 65.9, 62.0, 53.1, 38.3, 28.7, 27.8. MS (ESI) m/z [M + H]+: molecular ion calculated for C18H28NO3: 306, found 306 (no accurate mass obtained). Procedure for 400 g Scale Synthesis of 2-tert-Butyl 4-((4formylpiperidin-1-yl)methyl)benzoate (2). All reagent charges are based on 1.00 equiv of alcohol 1 charged. (1) To a 10 L jacketed glass reactor fitted with a stainless-steel sparger (2.1 cm length, 1.6 cm diameter, 1−5 μm pore size) and a mass flow controller were charged 1 (400 g, 1.31 mol, 1.00 equiv), TEMPO (10.24 g, 65.5 mmol, 0.05 equiv), 2,2′-bipyridine (12.28 g, 78.6 mmol, 0.06 equiv), copper(I) iodide (14.96 g, 78.6 mmol, 0.06 equiv), N-methylimidazole (9.4 mL, 117.9 mmol, 0.09 equiv), and sulfolane (2.4 L). The mixture was inerted with nitrogen (not required), stirred, and heated to 55 °C. The reaction mixture was then sparged continuously with air (1.4 L/ min) and monitored qualitatively by ReactIR until no further conversion was observed. This was further confirmed by HPLC analysis prior to quench. (2) Air was turned off, and the reaction mixture was inerted with nitrogen. The reaction was cooled to 20−25 °C. MTBE (5.76 L) was charged followed by sodium chloride (125.2 g) and water (2.88 L). The combined mixture was stirred for at least 0.50 h and was settled. The lower aqueous phase was separated, and the upper organic phase was washed three times with water (3 × 2.4 L). The lower aqueous phase was discarded each time. (3) The organic phase was concentrated under reduced pressure at 30−40 °C to ∼1.2 L. DMSO (2.0 L) was added, and the distillation was continued until the amount of MTBE was