NMI-Catalyzed Aerobic Alcohol

Article pubs.acs.org/OPRD

Process Development of CuI/ABNO/NMI-Catalyzed Aerobic Alcohol Oxidation Janelle E. Steves,† Yuliya Preger,‡ Joseph R. Martinelli,§ Christopher J. Welch,∥ Thatcher W. Root,*,‡ Joel M. Hawkins,*,⊥ and Shannon S. Stahl*,† †

Department of Chemistry, University of WisconsinMadison, Madison, Wisconsin 53706, United States Department of Chemical and Biological Engineering, University of WisconsinMadison, Madison, Wisconsin 53706, United States § Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States ∥ Department of Process & Analytical Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, United States ⊥ Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States

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‡

S Supporting Information *

ABSTRACT: An improved Cu/nitroxyl catalyst system for aerobic alcohol oxidation has been developed for the oxidation of functionalized primary and secondary alcohols to aldehydes and ketones, suitable for implementation in batch and flow processes. This catalyst, which has been demonstrated in a >50 g scale batch reaction, addresses a number of process limitations associated with a previously reported (MeObpy)CuI/ABNO/NMI catalyst system (MeObpy = 4,4′-dimethoxy-2,2′-bipyridine, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl, NMI = N-methylimidazole). Important catalyst modifications include the replacement of [Cu(MeCN)4]OTf with a lower-cost Cu source, CuI, reduction of the ABNO loading to 0.05−0.3 mol%, and use of NMI as the only ligand/additive (i.e., without a need for MeObpy). Use of a high flash point solvent, N-methylpyrrolidone, enables safe operation in batch reactions with air as the oxidant. For continuous-flow applications compatible with elevated gas pressures, better performance is observed with acetonitrile as the solvent.

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(Table 1),2g and both have been demonstrated in continuous flow.4a,b The latter applications achieved residence times as low as 1 min for diverse alcohols bearing a variety of functional groups. The Cu/TEMPO catalyst system is selective for primary alcohols and displays faster reaction rates with activated substrates, while Cu/ABNO exhibits fast reaction rates with both primary (1°) and secondary (2°) alcohols. These Cu/ nitroxyl systems tolerate functionalities such as thioethers, alkenes, internal alkynes, heterocycles, amines, and halogenated arenes. Despite the practical advantages that these Cu/nitroxyl protocols offer on laboratory scale (i.e., simple setup and workup, open to air, room temperature), they have features that could limit large-scale applications, such the cost of some of the catalyst components (e.g., bpy, ABNO). In addition, it would be preferred to avoid a requirement for continuous processing equipment, which may not be available at all manufacturing sites. Herein, we describe the development of less expensive Cu/ABNO-catalyzed aerobic alcohol oxidation methods that are more amenable to safe and scalable oxidation of functionalized 1° and 2° alcohols under both batch and flow conditions.

INTRODUCTION Alcohol oxidation to produce aldehydes and ketones is one of the most frequently encountered oxidation reactions in the synthesis of complex organic molecules. Despite the breadth of reagents available for this transformation,1 aerobic alcohol oxidation has been the focus of considerable attention due to its use of O2 as a near-ideal oxidant that typically forms only water as a stoichiometric byproduct.2 The application of many homogeneous and heterogeneous catalytic aerobic oxidation methods to production-scale pharmaceutical synthesis, however, has been constrained by safety concerns associated with the combination of flammable organic solvents with O2. In addition, the scope and selectivity of most previously reported aerobic methods do not compete with other viable, though less green, protocols for the oxidation of complex pharmaceutical intermediates (e.g., TEMPO/NaOCl, pyridine·SO3).3 Continuous-flow reaction methods are well equipped to address many of the safety issues associated with the combination of O2 and organic solvents: smaller reactor volume, effective and reproducible gas−liquid mixing, and the ability to operate at high gas pressures can promote faster aerobic oxidation on large scale.4−6 We recently reported two different Cu/nitroxyl catalyst systems for aerobic alcohol oxidation, composed of a CuI source, such as [Cu(MeCN)4]OTf; a 2,2′-bipyridyl (bpy) ligand; an organic nitroxyl, such as 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl (TEMPO) or 9azabicyclo[3.3.1]nonane N-oxyl (ABNO); and N-methylimidazole (NMI).7,8 The synthetic scope, selectivity, and functional group compatibility of these catalyst systems rival or surpass those of most traditional alcohol oxidation methods © 2015 American Chemical Society

Special Issue: Oxidation and Oxidative Reactions Received: June 4, 2015 Published: June 30, 2015 1548

DOI: 10.1021/acs.oprd.5b00179 Org. Process Res. Dev. 2015, 19, 1548−1553

Organic Process Research & Development

Article

Table 1. Representative Scope of Copper/TEMPO and Copper/ABNO-Catalyzed Aerobic Alcohol Oxidation

Scheme 1. Proposed Modifications for Cu/ABNO-Catalyzed Aerobic Alcohol Oxidation

Table 2. Optimization of Cu/ABNO-Catalyzed Alcohol Oxidationa

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RESULTS AND DISCUSSION Assessment of Process Challenges. The principal goal of this study was to identify a “process-friendly” catalyst system for Cu/nitroxyl-catalyzed aerobic oxidation of alcohols that could facilitate larger-scale applications. An ABNO-based catalyst system was of particular interest because of its broad substrate scope. The following benchmarks, summarized in Scheme 1, were identified as important criteria: 1. Copper source. [Cu(MeCN)4]OTf should be replaced with an inexpensive copper halide salt to lower the catalyst cost and avoid fluorine-containing waste from the triflate counterion. 2. Ligand. The MeObpy ligand should be replaced with a low-cost alternative, such as bpy or, preferably, a monodentate nitrogenous ligand. 3. ABNO loading. The ABNO loading should be reduced from 1 mol% to minimize operating costs. 4. Solvent and concentration. For batch reaction applications, acetonitrile should be replaced with a water-soluble, high flash point solvent to permit the use of air as the source of oxidant. As a starting point, reactions should be performed at least 25 °C below the solvent flash point under 1 atm of air, with the understanding that a full safety assessment would be required prior to scale-up.9 In addition, the reaction concentration should be increased from 0.1 M to ≥0.5 M to maximize throughput and minimize waste. Catalyst Optimization for Batch Reactions. The studies were initiated by examining NMI as ligand replacement for bpy on the basis of a promising lead result obtained in the course of developing the previous Cu/ABNO system7b (Table 2, entry 1). Bubbling air through the reaction with a gas dispersion tube (entry 2) afforded slightly higher yield. Employing a high flash point solvent (NMP = N-methylpyrrolidone, flash point = 90 °C) and switching from [Cu(MeCN)4]OTf to CuI halide salts provided lower product yields, with the exception of CuI (entry 5). Reducing the NMI loading to 5 mol% (entry 6) in NMP boosted reactivity, and increasing the temperature to 60 °C and ABNO loading to 0.3 mol% provided the best results for a 2° aliphatic alcohol (entry 9). Numerous other high flash point

entry

Cu salt

T (°C)

NMI (%)

nitroxyl (%)

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12

Cu(OTf) Cu(OTf) CuCl CuBr Cul Cul Cul Cul Cul none Cul Cul

22 22 22 22 22 22 60 60 60 60 60 60

20 20 20 20 20 5 5 5 5 5 0 5

1.0 1.0 0.2 0.2 0.2 0.2 0.2 0.3 0.3 0.3 0.3 0.0

20b,c 28b 10 13 19 32 68 82 89d 0d 24d 0d

a

Reactions were performed on a 0.5 mmol scale in 1 mL of NMP, unless otherwise noted. GC yields, internal standard = biphenyl. b Reaction performed with 0.1 mmol of substrate in 1 mL of MeCN. c Ambient air used as O2 source without bubbling. d10 mL/min air bubbling rate.

solvents were tested under the conditions in entry 6, such as DMF, DMA, dimethylimidazolidinone, and γ-valerolactone, but NMP was chosen for its good performance, excellent solubility of reaction components, and high potential operating temperature. Alternate solvents, such as DMF and DMA, also led to good product yields, but they have lower flashpoints that limit the available temperature for performing the reactions. Increasing the NMI loading to 20 mol% in propylene carbonate provided excellent results with a different substrate (see Supporting Information, Scheme S1), but again, NMP was chosen for further study due to the improved solubility of many substrates in this solvent. The reaction was ineffective when CuI, NMI, or ABNO was not present (entries 10−12). The CuII/ABNO/NMI conditions identified from these tests (i.e., entry 9) met most of the criteria we established (cf. Scheme 1) and provided the basis for subsequent investigation of other substrates. A variety of 1° and 2° benzylic and aliphatic alcohols underwent efficient oxidation on 10 mmol scale with the CuII/ ABNO/NMI system, and the functional group compatibility aligns with previous results obtained with the (MeObpy)CuI/ ABNO/NMI catalyst system7b (Table 3). The catalyst system also mediated efficient oxidation of the densely functionalized precursor to rosuvastatin (Scheme 2, 10 mmol scale).10 For electron-rich benzylic alcohols, ABNO can be lowered to 0.05 1549



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Table 3. Scope of (NMI)CuI/ABNO-Catalyzed Aerobic Alcohol Oxidationa

removal of ABNO from the product without using silica gel column chromatography are ongoing in our laboratory. Catalyst Optimization for Flow Reactors. Acetonitrile is the solvent of choice for many Cu/nitroxyl-catalyzed aerobic oxidation reactions,14 and can be safely employed by using a slug flow reactor4b with elevated pressures of dilute O2 (e.g., 9% in N215) or in a membrane reactor using elevated pressures of pure O2.4c,16 A direct comparison of MeCN and NMP as solvents showed that the CuII/ABNO/NMI-catalyzed aerobic alcohol oxidation performs better in MeCN (Figure 1). Since O2 solubility is slightly higher in NMP than in MeCN,17 the higher reaction rate in MeCN is attributed to a solvent effect on the reaction, rather than O2 solubility. Consequently, we elected to use MeCN as the solvent for testing the CuII/ ABNO/NMI catalyst system under continuous-flow conditions. The (bpy)Cu/TEMPO/NMI catalyst was demonstrated previously in a stainless steel slug flow reactor;4b however, the new CuI-based system led to noticeable stainless steel corrosion in less than 24 h when operated at representative reaction conditions (35 bar 9% O2 in N2 at 100 °C). As a result, a PTFE membrane reactor4c (Figure 2) was used to test the CuII/ABNO/NMI catalyst in flow. To avoid contact with stainless steel, a solution of CuII/ABNO/NMI in MeCN was stored in a PTFE loop and was delivered to the reactor using an HPLC pump that contained acetonitrile. A PTFE Luer lock attachment to the PTFE loop allowed for facile loading of the catalyst solution via gastight glass syringe. In the initial attempts to use the CuII/ABNO/NMI catalyst in flow, a solid precipitated from the stock solution of CuI, ABNO, and NMI in MeCN. The solid was not characterized but was presumed to consist of insoluble Cu species. Increasing the NMI loading threefold (i.e., 15 mol% under the reaction conditions) prevented solid formation in the catalyst solution. This catalyst system was then tested in the conversion of 1-Boc3-hydroxyazetidine to the corresponding ketone. A 6 min residence time provided the highest product yield (Figure 3A), and a steady state yield of ≥98% was maintained over a 3 h period, corresponding to the oxidation of 9 mmol of 1-Boc-3hydroxyazetidine (Figure 3B).

a

Isolated yields. All reactions were performed on a 10 mmol scale in 20 mL of NMP in purged reaction vessel, unless otherwise noted. b250 mmol scale in a 500 mL cylindrical vessel (see Experimental Section), air flow = 2.5 L/min, 1H NMR yield. c5 mol% bpy used instead of NMI. d>99% ee.

Scheme 2. Oxidation of a Rosuvastatin Precursor

mol% without loss of activity. More sterically hindered or electron-deficient benzylic alcohols and aliphatic substrates require ABNO loadings of 0.2−0.3 mol% in order to achieve quantitative conversion. In the case of a substrate with a basic functional group near the alcohol (cf. 2, Table 3), the use of bpy led to better performance than NMI (98% vs 28%, respectively). The bidentate ligand is believed to disfavor CuII chelation and deactivation by the substrate. This new process-friendly method proved to be scalable in batch mode. A 250 mmol (59 g) scale oxidation of 2iodobenzyl alcohol afforded the aldehyde in quantitative yield in under 2 h with 0.05 mol% ABNO. Isolation of the product on a 10 mmol scale was accomplished with aqueous extraction to remove CuI, NMI, and NMP. The product may be isolated from most of the catalytic components by partitioning the reaction between water and ethyl acetate, then washing the combined organic layers with sodium bisulfite or passing the layers through activated carbon to remove yellow color. Complete separation of NMP from the product required additional washing of the organic layer with water. Removal of ABNO from the product may be accomplished with silica gel column chromatography on the laboratory scale, or crystallization of the product or subsequent intermediates on a larger scale. (The presence of residual ABNO is unlikely to affect the performance of many subsequent reactions.11) Polymerimmobilized or other supported ABNO12 or water-soluble ABNO13 derivatives could facilitate separation of the nitroxyl from the product on a large scale, and efforts to achieve efficient

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CONCLUSION The results presented here showcase a new CuII/ABNO/NMI reaction system that exhibits many advantageous features for large-scale aerobic alcohol oxidation reactions. This catalyst appears to retain all of the favorable characteristics of the previously reported Cu/nitroxyl catalyst systems, including

Figure 1. Kinetic profiles of CuII/NMI/ABNO-catalyzed aerobic alcohol oxidation in NMP and MeCN. 1550



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Article

EXPERIMENTAL SECTION

General Considerations. 1H and 13C{1H} NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer. Chemical shifts (δ) are given in parts per million and are referenced to tetramethylsilane (all 1H NMR spectra) or residual solvent signal (all 13C NMR spectra). All coupling constants are reported in Hz. GC analyses were performed using a DB-Wax column installed on a Shimadzu GC-17 with FID. All commercial reagents were purchased from Aldrich and used as received. 4-(4-Fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidin-5-yl methanol was donated by DSM. CuI was purchased at 98% purity, NMP at ≥99% purity (Chromasolv Plus, for HPLC), and NMI at 99% purity (ReagentPlus). CH3CN was taken from a solvent system which passes the solvent through a column of activated molecular sieves, but no precautions to exclude water or air from the solvent or reaction mixtures were taken. Reactions were monitored by GC or 1H NMR spectroscopy. Representative Procedure for 10 mmol Scale Batch Reactions. A solution of ABNO (0.7−4.2 mg, 0.005−0.03 mmol) in NMP (1 mL) and a solution of CuI (95 mg, 0.5 mmol) and NMI (40 μL, 0.5 mmol) in NMP (4 mL) were added to a solution of the alcohol (10 mmol) in NMP (15 mL) in a 25 × 150 mm test tube with oval (15.9 × 6.35 mm) stirbar. The vessel was fitted with a rubber septum with a hole in the center holding a Tygon tube attached to an Ace glass gas dispersion tube (7 mm × 135 mm, 4−8 μm porosity; see Figure 4). A vent needle leading to a bubble meter (Supelco 25 mL manual bubble flow meter, standard version) was attached to the septum. Air was bubbled (120 mL/min) from a tank of compressed air and the reaction was stirred at 700 rpm and heated to 60 °C. Reactions were monitored by 1H NMR spectroscopy; aliquots (50 μL) were removed via syringe, diluted with EtOAc (1 mL), and filtered through SiO2 plugs in pipets. The plugs were flushed with additional EtOAc (3 mL), and the filtrate was concentrated in vacuo and taken up in CDCl3 for 1H NMR analysis. When the reaction was deemed complete by 1H NMR spectroscopy, the vessel was cooled to room temperature. The reaction was quenched with H2O (100 mL) and brine (50 mL), and the aqueous layer was extracted with EtOAc (3 × 150 mL). The organic layers were combined and washed with 10% aqueous Na2S2O3 (250 mL) to remove yellow color and water (3 × 300 mL) to remove NMP. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the corresponding aldehyde or ketone as the sole product.

Figure 2. Diagram of PTFE membrane flow reactor (BPR = back pressure regulator).

Figure 3. Flow reaction yields for aerobic oxidation of 1-Boc-3hydroxyazetidine with the Cu II/ABNO/NMI catalyst system. Residence-time scan (A) and yields obtained during continuous operation with a 6 min residence time (B). Yields determined by 1H NMR spectroscopy with biphenyl as an internal standard.

broad substrate scope with both benzylic and aliphatic alcohols as well as excellent functional group compatibility. Expensive CuI salts and bpy-based ligands have been replaced with CuII and NMI, respectively, and ABNO loadings as low as 0.05 mol% have been demonstrated successfully. Use of NMP as a high flash point solvent (flash point = 90 °C) provides the basis for the safe use of air as an oxidant under batch reaction conditions, while use of MeCN as the solvent provides optimal performance in continuous-flow applications under elevated gas pressures. Reactions performed in batch mode exhibited 1−6 h reaction times, and oxidation of an aliphatic substrate in flow mode was achieved with a residence time of 6 min. The low cost and flexible implementation of this catalyst are attractive features compared to our previous catalysts, and these results have important implications for implementation of large-scale aerobic alcohol oxidation reactions in the pharmaceutical and fine chemicals industries.

Figure 4. Representative reaction vessel for 10 mmol aerobic alcohol oxidation reactions. 1551



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pump flow rates were varied to identify the lowest residence time that led to the highest yield.

Isolation of 1-Boc-3-azetidinone. After washing with 10% aqueous Na2S2O3, the organic layer was washed with saturated aqueous NH4Cl (pH = 8) to remove blue color. The organic layer was then washed with water (2 × 300 mL) to remove NMP and dried over MgSO4. Solvent was removed in vacuo, yielding 1-Boc-3-azetidinone as the sole product. 250 mmol Scale Oxidation of 2-Iodobenzyl Alcohol. A solution of ABNO (17.5 mg, 0.125 mmol), CuI (2.38 g, 12.5 mmol), and NMI (996 μL, 12.5 mmol) in NMP (20 mL) was added to a solution of 2-iodobenzyl alcohol (58.5 g, 250 mmol) and biphenyl (internal standard; 19.3 g, 125 mmol) in NMP (480 mL) in a cylindrical vessel with gas dispersion tube and stir bar (19.1 × 9.5 mm, “+” shape; see Figure 5). The vessel was fitted to a compressed air tank and rotameter, and then was stirred and heated to 60 °C. Air was bubbled through the vessel (2.5 L/min). At 1.75 h, an aliquot was removed (200 μL), diluted with EtOAc (1 mL), and filtered through a pipet SiO2 plug. The plug was flushed with additional EtOAc (3 mL), and the filtrate was concentrated in vacuo. The residue was taken up in CDCl3 for 1H NMR analysis, and the acquired spectrum was consistent with 2-iodobenzaldehyde as the sole product (100% yield based on internal standard). Representative Procedure for Alcohol Oxidation in Flow. The substrate (15 mmol, 1 M) and biphenyl internal standard (7.5 mmol, 0.5 M) were prepared as a stock solution in MeCN. The solution was delivered to the reactor by a Hitachi L6200 HPLC pump. A Hamilton gastight syringe was used to inject the catalyst solution into a 30 mL PTFE sample loop filled with MeCN through a six way, two-position valve (in “load” position). A gastight syringe was then used to push MeCN through the sample loop, moving the green catalyst solution through the sample loop until it reached the end of the six-way valve. A clear boundary between the two phases was observed. The six-way valve was switched to the “run” position to connect the sample loop to the reactor and a Hitachi L6200 HPLC pump containing pure MeCN. The MeCN pump was used to push the catalyst solution through the loop and into the reactor, avoiding contact between the stainless steel pump and CuI. The oven was set to 100 °C and allowed to equilibrate at temperature for 1 h. The liquid back pressure regulator was set 3 atm higher than the gas pressure. The O2 tank was set to the 17 atm by a gas pressure regulator. The solutions were pumped through the system, with each HPLC pump providing half of the total flow. The EtOAc quench pump flow rate was maintained at 6 times the liquid feed flow rate from the reactor. The product (diluted with EtOAc) was collected at the exit of the liquid back pressure regulator. For the residence time scan,

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures and characterization data for all products. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.oprd.5b00179.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: joel.m.hawkins@pfizer.com. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to Dr. Paul Alsters (DSM) for supplying a sample of the rosuvastatin precursor. We thank Dr. David Mannel for insightful discussion, and Dr. Eric Cordi (Pfizer) for calculation of O2 solubility values in MeCN and NMP. Financial support for this work was provided by the ACS GCI Pharmaceutical Roundtable, a consortium of pharmaceutical companies (Eli Lilly, Pfizer, and Merck), and the NSF (predoctoral fellowship to J.E.S.). NMR spectroscopy facilities were partially supported by the NSF (CHE-9208463) and NIH (S10 RR08389).

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REFERENCES

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Figure 5. Representative reaction vessel for a 250 mmol aerobic alcohol oxidation reaction. 1552



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NOTE ADDED AFTER ASAP PUBLICATION An incomplete version of the Supporting Information was published with the article on July 15, 2015. The complete version was posted on August 26, 2015.

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NMI-Catalyzed Aerobic Alcohol

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