Safe and Scalable Aerobic Oxidation by 2-Azaadamantan-2-ol

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Safe and Scalable Aerobic Oxidation by 2‑Azaadamantan-2-ol (AZADOL)/NOx Catalysis: Large-Scale Preparation of Shi’s Catalyst

Yusuke Sasano,† Hikaru Sato,‡ Shinsuke Tadokoro,‡ Masami Kozawa,‡ and Yoshiharu Iwabuchi*,† †

Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan ‡ Chemical Research Laboratory, Nissan Chemical Corporation, 2-10-1 Tsuboi-nishi, Funabashi, Chiba 274-8507, Japan

Org. Process Res. Dev. Downloaded from pubs.acs.org by WEBSTER UNIV on 03/04/19. For personal use only.

S Supporting Information *

ABSTRACT: A method for safe and scalable aerobic alcohol oxidation using 2-azaadamantan-2-ol (AZADOL), an azaadamantane-type hydroxylamine catalyst, with a NOx cocatalyst in a conventional batch reactor has been developed. The use of 2 mol % AZADOL and 10 mol % NaNO2 was determined to promote aerobic alcohol oxidation quantitatively within a reasonable time (8 h). Safety is ensured by controlling the reaction temperature below the flash point of the acetic acid solvent. The robustness of the developed method is demonstrated by the 500 g scale oxidation of diacetone fructose into Shi’s catalyst for asymmetric epoxidation. KEYWORDS: aerobic oxidation, alcohol oxidation, nitroxyl radical, hydroxylamine, oxoammonium, NOx

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INTRODUCTION The oxidation of alcohols to their corresponding carbonyl compounds is a fundamental transformation in organic chemistry because alcohols are ubiquitous or rather readily accessible and because carbonyl groups are not only widely found both in natural and synthetic products but also amenable to versatile use in further synthetic transformations.1 Consequently, numerous reagents and methods have been developed to date and continuously investigated to achieve this oxidative transformation more selectively, efficiently, and economically in pioneering the frontiers of chemical sciences.2 This particular oxidation plays significant roles at the cutting edge of discovery-oriented research in both academia and industry. Unfortunately, however, the adoption of alcohol oxidation on a large scale is avoided because of safety concerns and environmental issues associated with the reagents employed.3 These issues often force process chemists to search for alternative routes that do not require the oxidation step, hampering the sustainable development of organic chemical industries. Catalytic aerobic oxidation of alcohols has been regarded as an ideal method because its bulk oxidant, molecular oxygen, is abundant and its byproduct is only water. This feature has spurred the development of various additional methods.4 Among various methods for catalytic aerobic alcohol oxidation, methods catalyzed by nitroxyl radicals, such as 2,2,6,6tetramethylpiperidine-N-oxyl (TEMPO), have been extensively investigated (Figure 1). Two mechanistically distinct catalytic systems have been developed,5 namely, (1) a nitroxyl

radical with Cu cocatalysis featuring the generation of copper(II) alkoxide coupled with a redox cycle of nitroxyl radical−hydroxylamine6 and (2) a nitroxyl radical with NOx cocatalysis featuring the generation of the corresponding oxoammonium salt.7 Catalytic aerobic alcohol oxidation using a nitroxyl radical with Cu cocatalysis was first introduced by Semmelhack and co-workers in 1984.8 Various crucial factors that enhance the catalytic performance have been identified. The use of 2,2′bipyridine (bpy)-type ligands reported by Sheldon9 and of the N-methylimidazole (NMI) base reported by Koskinen10 made critical contributions to the enhancement of the catalytic performance. Nitroxyl radical/Cu-catalyzed aerobic alcohol oxidation culminated in the establishment of a highly practical system consisting of TEMPO/CuOTf/bpy/NMI, as reported by Stahl,11 that enables chemoselective aerobic oxidation of benzylic, allylic, propargylic, and aliphatic alcohols in ambient air: this and related mild reaction conditions were compatible with numerous functional groups, including unprotected amino groups and electron-rich divalent sulfur functionalities.12 Recently, applications of this reaction to large-scale operations have been reported.13 Catalytic aerobic alcohol oxidation using a nitroxyl radical with NOx cocatalysis was first introduced in 2004, when Hu, Liang, and co-workers disclosed that Br2 and NOx mediate redox events between nitroxyl radicals and molecular oxygen.14 Subsequently, they and Studer’s group achieved TEMPOcatalyzed aerobic oxidation under halogen- and transitionmetal-free conditions (TEMPO/tert-butyl nitrite, TEMPO/ NH2OH).15 Special Issue: Japanese Society for Process Chemistry Received: December 28, 2018

Figure 1. Nitroxyl radicals and AZADOL. © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.8b00456 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Scheme 1. Aerobic Alcohol Oxidation by 5-F-AZADO/NOx Catalysis

Table 1. Optimization of the Reaction Conditions

entry

1 (g)

x/y

atmosphere

temp. (°C)a

conv. at 6 h (%)b

conv. at 24 h (%)b

conv/time (%)b

1 2 3c 4 5 6 7

1.0 1.0 1.0 1.0 10 10 10

1.0/10.0 1.0/5.0 1.0/5.0 1.0/5.0 1.0/5.0 2.0/10.0 2.0/10.0

air (balloon) air (balloon) air (balloon) O2 (balloon) ambient air + O2 (10 kPa) ambient air + O2 (10 kPa) ambient air + O2 (10 kPa)

22 22 22 22 22 22 27

50 50 45 94 88 98 −

96 100 100 100 100 − −

96/30 h − − − 91/8 h 100/8 h >99/5 h

a

The temperature of the reaction mixture was maintained at the indicated value. bDetermined by GC. cAZADO was used instead of AZADOL.

a value sufficiently lower than the flash point of acetic acid should prevent fire even in ambient air.20 (2) 2-Azaadamantan-2-ol (AZADOL), a hydroxylamine variant of AZADO, is a reasonable source of an AZADO-type catalyst for large-scale applications because of its good availability.21 However, AZADO itself, without an electron-withdrawing group, was previously shown to be deactivated during aerobic alcohol oxidation and not to completely oxidize menthol, whereas 5-F-AZADO completed this reaction.22 Therefore, reaction conditions that include AZADOL and realize quantitative conversion should be identified.

Our group has focused on the development of catalytic alcohol oxidation since we discovered 2-azaadamantane-N-oxyl (AZADO) (Figure 1), which shows much higher catalytic activity for alcohol oxidation than TEMPO.12a−c,16 The substrate applicability of AZADO-catalyzed alcohol oxidation was successfully expanded by developing a highly efficient aerobic alcohol oxidation reaction using AZADOs (5-FAZADO or Nor-AZADO) in combination with a NOx cocatalyst in acetic acid as the solvent (Scheme 1).16d,e This reaction realizes the oxidation of various benzylic, allylic, and even aliphatic alcohols in the presence of various functional groups, including 1,2-diols and nucleic acid bases in high yields. The usefulness of this reaction has been demonstrated by its applications to synthetic studies of natural products.17 Despite its economic and environmental superiority, aerobic oxidation innately poses the risk of fire, particularly in liquidphase oxidation using flammable organic solvents, causing process chemists to refrain from using aerobic oxidation. One promising way to promote the application of alcohol oxidation in process chemistry is to develop a flow reactor that diminishes the risk of fire;18,19 however, this approach requires special equipment. With our firm belief in the facile operation and wide substrate scope of the AZADO/NOx system for aerobic alcohol oxidation, we sought to apply this reaction to the largescale synthesis of a useful compound in a conventional batch reaction. At the outset, the following issues were considered to achieve safe and scalable aerobic alcohol oxidation by AZADO/NOx catalysis: (1) Safety should be secured for large-scale operation. Because the AZADO/NOx-catalyzed aerobic alcohol oxidation proceeds efficiently at room temperature in ambient air (balloon) and the flash point of acetic acid (39 °C; closed cup) is higher than room temperature, we assumed that controlling the reaction temperature at

Herein we describe a safe and scalable method for aerobic alcohol oxidation by AZADOL/NOx catalysis in a conventional batch reactor. Considering both reaction efficiency and ensuring safety, the optimum conditions have been identified as follows: AZADOL, 2.0 mol %; NaNO2, 10 mol %; acetic acid, 4.0× wt; O2 with air, 27.3% O2; O2 partial pressure, 30 kPa; 22 °C. The robustness of the developed method is demonstrated by the 500 g scale oxidation of diacetone fructose (1) into ketone 2, Shi’s catalyst for asymmetric epoxidation.23

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RESULTS AND DISCUSSION Optimization of the Reaction Conditions. We first investigated reaction conditions that included AZADOL and achieved quantitative oxidative conversion of 1. The conditions using 1.0 g of 1 with AZADOL (1.0 mol %), NaNO2 (10.0 mol %), AcOH (4.0× wt; 1.0 M), air (balloon), and 22 °C, which are equivalent to conditions reported in 2011,16d afforded 96% conversion in 24 h, which did not increase further over an extended time (Table 1, entry 1). To reduce nitric acid generated in situ, which is known to deactivate AZADO/ AZADOL,22 the amount of NaNO2 was reduced. As a result, B



Article

Figure 2. Heat flow of the reaction: (left) integration of heat flow for the initial 1 min; (right) integration of heat flow for the entire reaction time. The total weight of the reaction mixture was 50.80 g, and the specific gravity of the mixture was 1.084 g/mL. The specific heat of the reaction mass was 4.694 J g−1 K−1.

than the flash point of the acetic acid solvent (39 °C). These results indicate that removing heat is necessary to operate this reaction safely. The heat flow indicates that the required heatremoval capability to maintain the temperature of the reaction mixture is 33% of the total reaction calorie level per hour, namely, 57.16 kJ mol−1 h−1 or 15.88 W/mol. On the basis of this thermal analysis, control of the reaction temperature at a large scale was simulated. When aerobic alcohol oxidation is operated in a 1000 L GL reaction tank, 214.7 kg (824.8 mol) of 1 is oxidized in 1000 L of solution (4.0× wt AcOH). The required heat-removal capability is estimated as 13 098 W. By the use of general values for a GL reaction tank, namely, a heat transfer area (A) of 4.559 m2 and a heat transfer coefficient (U) of 200 W m−2 K−1,25 the difference between the reaction temperature (temperature inside the vessel) and the mean coolant temperature in the jacket (ΔT) is estimated as

quantitative conversion was achieved in 24 h (entry 2). AZADO showed almost the same reactivity as AZADOL (entry 3). When an O2 balloon was used instead of an air balloon, the reaction was accelerated, giving 94% conversion in 6 h (entry 4). Next, the amount of 1 was increased to 10 g. To maintain the partial pressure of O2 and prevent the leakage of NOx, a 10 kPa positive pressure of O2 was applied to a reaction flask filled with ambient air by bubbling during the reaction using a Mitos P-Pump (Dolomite Microfluidics) as a precise pressure regulator.24 The reaction apparatus is shown in Figures 5 and 6. The resulting partial pressure of O2 should be maintained at 30 kPa and the resulting concentration of O2 should be kept at 27%. The same amounts of catalysts as those in entry 2 [AZADOL (1.0 mol %), NaNO2 (5.0 mol %)] afforded quantitative conversion in 24 h; however, we considered that it would be better to finish the reaction more quickly to ensure a process-friendly reaction (entry 5). When the amounts of AZADOL and NaNO2 were increased to 2.0 mol % and 10.0 mol % respectively, the reaction was completed in 8 h (entry 6). Increasing the reaction temperature to 27 °C shortened the reaction time to 5 h (entry 7). Considering the margin between the reaction temperature and the flash point of acetic acid (39 °C), we identified the conditions at a lower temperature (22 °C) shown in entry 6 as optimum for process-scale operation.20 Thermal Analysis and Development of a Safe Procedure. Heat evolution in AZADOL/NaNO2-catalyzed aerobic alcohol oxidation was evaluated using a METTLERTOLEDO EasyMax 102 heat flow calorimeter. The same reaction conditions as those shown in Table 1, entry 6 were used for this experiment. The results of thermal analysis are shown in Figure 2. An instantaneous heat output of 114.7 J was observed when NaNO2 was added in one portion (Figure 2, left). This heat output arises from the reaction between NaNO2 and acetic acid to give HNO2 and NaOAc. The corresponding adiabatic temperature rise (ΔTad0) was 0.48 K. After this instantaneous heat output, a constant heat output was observed for 4 h, which is consistent with a constant reaction rate as observed by GC during the optimization study (Table 1, entry 6). The total reaction calorie level was 173.2 kJ/mol, and the adiabatic temperature rise (ΔTad) was 27.9 K (Figure 2, right). The maximum temperature of the synthesis reaction (MTSR) at this ΔTad was 49.9 °C, which is higher

13 098 W = UAΔT = (200 W m−2 K−1)(4.559 m 2)ΔT

which gives

ΔT = 14.4 K Therefore, a mean coolant temperature of 7.6 °C is estimated to be required to maintain the temperature of the reaction mixture at 22 °C for the safe operation of aerobic alcohol oxidation in a 1000 L GL reaction tank. The temperature should be maintained above the melting point of acetic acid (16−17 °C). It should be noted that an increase in the amount of the solvent decreases the MTSR below the flash point of acetic acid, ensuring the safety of aerobic alcohol oxidation, although the volume efficiency is lower. To find a method to prevent a runaway reaction, stopping the oxygen supply was examined. A reaction was run using 2.5 g of 1 with the optimized amounts of the catalysts and solvent under an O2 atmosphere at room temperature (without control of the temperature). The progress of the reaction was estimated by monitoring the reaction temperature (100% conversion in 3.5 h was confirmed by GC). An increase in temperature was observed after NaNO2 was added (0−0.27 h) (Figure 3). After the supply of O2 was stopped at 0.27 h, the reaction temperature decreased, which indicates slowing of the reaction. Resupplying O2 at 0.8 h caused the temperature to increase again, which indicates that the AZADOL/NOx C



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Table 2. Larger-Scale Operation and Determination of the Yields of 2

entry

1 (g)

conv. (%)a

yield (%)b

1 2

170 500

>99 >99

quant (84) 99.9

a

Determined by GC. bGC yields. An isolated yield is shown in parentheses.

Figure 3. Effect of stopping and restarting the supply of oxygen in alcohol oxidation. Conditions: 1 (2.5 g), AZADOL (2.0 mol %), NaNO2 (10 mol %), acetic acid (4.0× wt), O2 (balloon), rt (without control of temperature).

catalytic system survives during the period without oxygen. These results indicate that pulse feeding of oxygen can control the reaction rate and the exotherm. Measurement of the Concentration of NOx in the Gas Phase. Catalytic NO and NO2 are considered to play key roles in the developed method.16d They are nonflammable but support combustion.26 To evaluate their risk, the total amount of NO and NO2 in the gas phase of the reaction flask was measured using a GASTEC 11HA detector tube. The same reaction conditions as those shown in Table 1, entry 6 were used for this experiment. The reaction was performed in a 100 mL four-neck round-bottom flask (internal volume = 140 mL). The volume of the reaction mixture was 40 mL. The results are shown in Figure 4. When the reaction started, 1% (NO +

Figure 5. Reaction apparatus for the 500 g scale operation.

Figure 6. Diagram of the reaction apparatus.

Figure 4. Monitoring of the concentration of NO and NO2.

NO2) was observed in the gas phase. The concentration of (NO + NO2) decreased as the reaction proceeded. Little amounts of NO and NO2 were detected after the reaction was complete. Application of the Optimized Conditions to LargeScale Synthesis. With the optimum conditions ensuring safety determined, aerobic alcohol oxidation was carried out on a larger scale (Table 2 and Figures 5 and 6). The reaction temperature was controlled between 20 and 23 °C using an ethylene glycol/water bath (20.7−21.7 °C) (Figure 7). The reaction proceeded with >99% conversion in 8 h even when 500 g of 1 was used, and the yield of 2 was 99.9%. Compound

Figure 7. Monitoring of the bath and reaction temperatures for the 500 g scale operation.

2 was isolated using 170 g of 1. An 84% yield of 2 was obtained without column chromatography. The yield is higher than that D



Article

After confirmation by the use of potassium iodide−starch paper that no peracetic acid was generated the next day, the acetic acid was evaporated under reduced pressure (1.5 kPa) at a temperature below 30 °C. The residual solid was dissolved in EtOAc (680 g). The EtOAc solution was slowly (ca. 5 min) added to 11.5% aqueous Na2CO3 (116.60 g of Na2CO3 in 900 g of H2O) at a temperature below 30 °C. After the resulting mixture was stirred vigorously for 30 min, it was transferred to a 3 L separatory funnel, and the aqueous phase was removed. The organic phase was washed with H2O (85 g) and evaporated (99% by GC. The supply of O2 was stopped, and then the reaction mixture was stirred with N2 bubbling at 22 °C for 30 min while the reaction flask was purged with N2. At this point, the GC yield of ketone 2 was determined to be 101.9%. The mixture was allowed to stand at 22 °C overnight while the reaction flask was purged with N2.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00456. 1 H NMR spectrum of 2 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yusuke Sasano: 0000-0002-3852-8607 Yoshiharu Iwabuchi: 0000-0002-0679-939X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Professor Emeritus Kunio Ogasawara (Tohoku University) and Mr. Norio Tanaka (Nissan Chemical Corporation) for fruitful discussions and encouragement.

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REFERENCES

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of Alcohols to Carbonyl Compounds with Diisopropyl Azodicarboxylate Catalyzed by Nitroxyl Radicals. J. Org. Chem. 2012, 77, 3005. (c) Shibuya, M.; Sasano, Y.; Tomizawa, M.; Hamada, T.; Kozawa, M.; Nagahama, N.; Iwabuchi, Y. Practical Preparation Methods for Highly Active Azaadamantane-Nitroxyl-Radical-Type Oxidation Catalysts. Synthesis 2011, 2011, 3418. (d) Shibuya, M.; Osada, Y.; Sasano, Y.; Tomizawa, M.; Iwabuchi, Y. Highly Efficient, Organocatalytic Aerobic Alcohol Oxidation. J. Am. Chem. Soc. 2011, 133, 6497. (e) Hayashi, M.; Sasano, Y.; Nagasawa, S.; Shibuya, M.; Iwabuchi, Y. 9Azanoradamantane N-Oxyl (Nor-AZADO): A Highly Active Organocatalyst for Alcohol Oxidation. Chem. Pharm. Bull. 2011, 59, 1570. (f) Shibuya, M.; Tomizawa, M.; Sasano, Y.; Iwabuchi, Y. An Expeditious Entry to 9-Azabicyclo[3.3.1]nonane N-Oxyl (ABNO): Another Highly Active Organocatalyst for Oxidation of Alcohols. J. Org. Chem. 2009, 74, 4619. (g) Shibuya, M.; Sato, T.; Tomizawa, M.; Iwabuchi, Y. Oxoammonium salt/NaClO2: an expedient, catalytic system for one-pot oxidation of primary alcohols to carboxylic acids with broad substrate applicability. Chem. Commun. 2009, 1739. (h) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. 2azaadamantane N-oxyl (AZADO) and 1-Me-AZADO: Highly efficient organocatalysts for oxidation of alcohols. J. Am. Chem. Soc. 2006, 128, 8412. (17) (a) Sasano, Y.; Koyama, J.; Yoshikawa, K.; Kanoh, N.; Kwon, E.; Iwabuchi, Y. Stereocontrolled Construction of ABCD Tetracyclic Ring System with Vicinal All-Carbon Quaternary Stereogenic Centers of Calyciphylline A Type Alkaloids. Org. Lett. 2018, 20, 3053. (b) Morisaki, K.; Sasano, Y.; Koseki, T.; Shibuta, T.; Kanoh, N.; Chiou, W. H.; Iwabuchi, Y. Nazarov Cyclization Entry to Chiral Bicyclo[5.3.0]decanoid Building Blocks and Its Application to Formal Synthesis of (−)-Englerin A. Org. Lett. 2017, 19, 5142. (18) (a) Hone, C. A.; Kappe, C. O. The Use of Molecular Oxygen for Liquid Phase Aerobic Oxidations in Continuous Flow. Top. Curr. Chem. 2019, 377, 2. (b) Gemoets, H. P. L.; Su, Y. H.; Shang, M. J.; Hessel, V.; Luque, R.; Noël, T. Liquid phase oxidation chemistry in continuous-flow microreactors. Chem. Soc. Rev. 2016, 45, 83. (c) Gavriilidis, A.; Constantinou, A.; Hellgardt, K.; Hii, K. K.; Hutchings, G. J.; Brett, G. L.; Kuhn, S.; Marsden, S. P. Aerobic oxidations in flow: opportunities for the fine chemicals and pharmaceuticals industries. React. Chem. Eng. 2016, 1, 595. (d) Wiles, C.; Watts, P. Continuous flow reactors: a perspective. Green Chem. 2012, 14, 38. (19) Aerobic oxidation of 1 catalyzed by a nitroxyl radical with Cu cocatalysis using a flow reactor has been reported (see ref 18c). (20) A margin of 15 °C is generally accepted to be safe. See: Flammability: A safety guide for users. https://chemycal.com/dap/ files/Guidance/ESIG-flammability_guidance.pdf (accessed Feb 12, 2019). (21) (a) FUJIFILM Wako Pure Chemical Corporation. Hyperactive oxidation catalyst: AZADOL®. http://www.wako-chem.co.jp/ english/labchem/product/Org/AZADOL/index.htm#06 (accessed Jan 2, 2019). (b) Tokyo Chemical Industry Co., Ltd. 2-Hydroxy-2azaadamantane (1155843-79-0). https://www.tcichemicals.com/ eshop/en/jp/commodity/H1404/ (accessed Jan 2, 2019). (c) AZADOL is prepared on a kilogram scale by Nissan Chemical Corporation. Readers that want to use more than 100 g of AZADOL should contact the Custom Chemicals Department, Pharmaceuticals Division, Nissan Chemical Corporation (https://www.nissanchem.co. jp/eng/products/pharmaceuticals/finetech.html). (22) Shibuya, M.; Nagasawa, S.; Osada, Y.; Iwabuchi, Y. Mechanistic Insight into Aerobic Alcohol Oxidation Using NOx-Nitroxide Catalysis Based on Catalyst Structure-Activity Relationships. J. Org. Chem. 2014, 79, 10256. (23) Shi, Y. Organocatalytic asymmetric epoxidation of olefins by chiral ketones. Acc. Chem. Res. 2004, 37, 488. (24) The Mitos P-Pump was developed as a device that provides pulseless liquid flow with a precise pressure-driven pumping mechanism. In this experiment, it was used as a regulator that maintained the pressure in the flask at a constant positive pressure by supplying oxygen gas. The P-Pump controls the pressure more F



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precisely and makes it easier to detect a leak compared with a conventional regulator. (25) Carpenter, K. J. AGITATED VESSEL HEAT TRANSFER. http://www.thermopedia.com/content/547/ (accessed Dec 28, 2018). (26) Harbison, R. D.; Bourgeois, M. M.; Johnson, G. T. Hamilton and Hardy’s Industrial Toxicology, 6th ed.; John Wiley & Sons: Hoboken, NJ, 2015. (27) Ager, D. J.; Anderson, K.; Oblinger, E.; Shi, Y.; VanderRoest, J. An epoxidation approach to a chiral lactone: Application of the Shi epoxidation. Org. Process Res. Dev. 2007, 11, 44.

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Safe and Scalable Aerobic Oxidation by 2-Azaadamantan-2-ol

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