Toward the Synthesis of Noroxymorphone via Aerobic Palladium

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Towards the Synthesis of Noroxymorphone via Aerobic PalladiumCatalyzed Continuous Flow N-Demethylation Strategies Bernhard Gutmann, Petteri Elsner, D. Phillip Cox, Ulrich Weigl, Dominique M. Roberge, and C. Oliver Kappe ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/acssuschemeng.6b01371 • Publication Date (Web): 22 Jul 2016 Downloaded from http://pubs.acs.org on July 22, 2016

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Article

Towards the Synthesis of Noroxymorphone via Aerobic PalladiumCatalyzed Continuous Flow N-Demethylation Strategies Bernhard Gutmann,†,‡ Petteri Elsner,§ D. Phillip Cox,∥ Ulrich Weigl,¶ Dominique M. Roberge,*,§ and C. Oliver Kappe*,†,‡

†

Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria

‡

Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria §

Microreactor Technology, Lonza AG, CH-3930 Visp, Switzerland

∥ Noramco ¶

Inc., 503 Carr Rd, Suite 200, Wilmington DE 19809, USA

Cilag AG, Hochstrasse 201, 8200 Schaffhausen, Switzerland

* C. Oliver Kappe. E-mail: [email protected]

ACS Paragon Plus Environment


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ABSTRACT:

The

palladium-catalyzed

N-demethylation

of

the

opioid

alkaloids

oxymorphone 3,14-diacetate and 14-hydroxymorphinone 3,14-diacetate to their norderivatives with oxygen as the terminal oxidant has been investigated. Palladium(II) acetate forms colloidal palladium(0) particles upon heating in N,N-dimethylacetamide. The palladium(0) particles are effective catalysts for the aerobic N-demethylation of these opiate alkaloids. Demethylation of 14-hydroxymorphinone 3,14-diacetate with pure oxygen as oxidant in a continuous flow reactor provided the demethylated product with excellent selectivity after residence times of only 10 to 20 min with 2.5 to 5 mol% of palladium acetate as catalyst on a laboratory scale. Scale-up of the oxidation in a 100 mL flow reactor (combination of FlowPlate® A6 and coiled tube to enhance the gas-liquid mass transfer), hydrogenation in a packed bed reactor and subsequent hydrolysis afforded the desired noroxymorphone in high quality and good yield on a kg-scale. The reaction sequence consumes only oxygen, hydrogen and water as stoichiometric reagents.

KEYWORDS: Aerobic oxidation, N-Demethylation, Flow chemistry, Naltrexone, Naloxone, Process intensification


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INTRODUCTION Many naturally occurring alkaloids, including tropane alkaloids such as atropine, scopolamine, and cocaine, as well as opiate alkaloids like morphine, codeine, oripavine, and thebaine, contain a tertiary N-methylamine structure (Figure 1). Modification of the Nmethylamine group of these compounds has a profound effect on their pharmacological properties. In fact, a wide range of clinically relevant molecules are formally derived by replacing the N-methyl group of an alkaloid by another alkyl moiety.1 The syntheses of all opiate-type medicines in use today start from naturally occurring opiate alkaloids, isolated from Papaver somniferum (opium poppy). For example, thebaine and oripavine serve as synthetic precursors for oxycodone and oxymorphone, respectively (Figure 1). The introduction of an N-allyl or an N-cyclopropylmethyl group into the latter compound by Ndemethylation/N-alkylation generates the potent opioid receptor antagonists naloxone and naltrexone. Naloxone is on the World Health Organization's List of Essential Medicines. It is a potent pure opioid antagonist and is the first line of treatment for patients experiencing an opioid overdose.1 In many countries it is necessitated to be in place whenever opioids are administered to reverse the effects of the narcotic agonists. Naltrexone, on the other hand, is primarily used for the management of opioid and alcohol dependence. N-Demethylation is furthermore a crucial step in the synthesis of mixed opioid agonist–antagonists such as nalorphine, nalbuphine and buprenorphine (Figure 1). Longer N-alkyl groups typically restore agonist activity and N-phenethylnormorphine has a 10-fold greater potency than morphine itself.1

Figure 1. Naturally occurring morphine alkaloids and semi-synthetic derivatives.



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A number of methods to accomplish the N-demethylation of tertiary amines have been reported, but none of them are entirely satisfactory. Standard procedures for the removal of the N-methyl group involve the use of electrophilic reagents such as cyanogen bromide (von Braun reaction),2 or chloroformates.3 These reactions produce cyanamides and carbamates, respectively, which can be readily hydrolyzed to the corresponding amines. Even though these methods can afford the nor-derivatives in moderate to high yields, the use of highly toxic and corrosive reagents in stoichiometric amounts and the generation of stoichiometric amounts of waste products limits their wide practical use. Alternatively, the demethylation can be achieved starting from the N-oxides (Polonovski-type reactions).4-6 For Polonovskitype reactions, the N-demethylation is typically performed in two steps: oxidation of the alkaloid to the corresponding N-oxide and isolation of the N-oxide as the hydrochloride salt, followed by a subsequent activation and decomposition affords the demethylated product.6 In addition, photochemical7 and biochemical8,9 approaches for the demethylation of various alkaloids have been reported. In 2008 Hudlicky and co-workers developed the palladium-catalyzed oxidative demethylation of morphine-type alkaloids in the presence of air or molecular oxygen as oxidant.10-12 The reaction proceeded with oxymorphone 3,14-diacetate (1a) as substrate in dioxane as solvent within reaction times of 4 h at 80 °C.12 The demethylation was accompanied by intramolecular 14-O- to 17-N-acetyl migration to form noroxymorphone 3,17-diacetate (2a) as the product (Scheme 1).12 We recently demonstrated that the oxidation can be extended to unprotected 14-hydroxy morphine derivatives if palladium(0) is used as catalyst in dimethylacetamide (DMA) as solvent.13 Oxidation of the N-methyl group to an iminium cation and subsequent cyclization afforded an oxazolidine ring structure. Hydrolysis of the oxazolidine under reduced pressure followed by hydrogenation over palladium(0) as catalyst provided noroxymorphone (3) in good overall yield (Scheme 1). From an economic and ecological perspective, the catalytic demethylation with O2 as terminal oxidant is clearly preferable to existing demethylation techniques.14-16 O2 is the most abundant oxidant and is available at very little cost. Furthermore, aerobic oxidations generally generate only environmentally benign by-products (usually H2O). In the last decade, a broad variety of remarkably selective aerobic oxidation reactions have been developed. However, even though these oxidations have proven to be quite versatile and reliable on a laboratory scale, practical applications of these methods in the pharmaceutical industry are limited. The rather slow uptake is, at least partly, owed to the fact that conventional batch reactors are only poorly suited to address the distinct process challenges and safety risks associated with reactions with ACS Paragon Plus Environment

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molecular oxygen. Aerobic oxidation reactions are often dominated by mass transfer effects and even short periods of poor gas-liquid mixing can adversely affect reaction kinetics and selectivity, or lead to irreversible decomposition of a catalyst.17,18 Moreover, significant process challenges arise due to the formation of flammable mixtures of oxygen and solvent vapor. Generally, the oxygen concentration in any open space in the system needs to be kept below the flammability limit of the reaction mixture to ensure safe operation of aerobic oxidation reactions (typically around 8 vol% for organic materials).19 Recently, continuous processes using small-diameter tube- or plate-reactors have become popular for the laboratory and industrial synthesis of pharmaceuticals and fine chemicals.20-22 The characteristic features of these devices, i.e. their high mass- and heat transport capabilities, offer strong advantages particularly for multi-phase and highly exothermic reactions.20-22 Gaseous reagents can be easily and accurately dosed and mixed into the liquid phase using flow-based systems.23-25 Importantly, combustion and explosion hazards are reduced in these reactors and, consequently, reactions often can be performed under unusually harsh process conditions in a safe and controllable manner (i.e. high temperature/high pressure conditions).24,25 Indeed, over the past years, flow processes on various scales have been developed which rely on air or oxygen as oxidant to accomplish transformations of significance for pharmaceutical and fine chemical synthesis.24-28 Preliminary studies performed in our laboratories demonstrated that the oxidation of 14hydroxymorphinone proceeds efficiently on a gram scale under continuous flow conditions in an experimental flow reactor (Scheme 1).13 Herein we present our investigations towards the production of noroxymorphone (3) using 14-hydroxymorphinone 3,14-diacetate (1b) as substrate (Scheme 1). The present publication focuses on the development of a scalable and sustainable continuous flow protocol for the palladium-catalyzed N-demethylation with pure oxygen as oxidant, suitable for the production of noroxymorphone (3) on an industrial scale. The oxidation was explored and optimized in a benchtop flow reactor. Scale-up of the reaction was performed in a 100 mL stainless steel tubular flow reactor. Starting from 14hydroxymorphinone 3,14-diacetate (1b) the three step reaction sequence –oxidation, hydrogenation and hydrolysis- was performed on a kg-scale, affording the desired noroxymorphone (3) in high quality and excellent yield.



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Scheme 1. Synthetic strategies noroxymorphone (3).

RESULTS AND DISCUSSION Batch Optimization for the N-Demethylation of Oxymorphone 3,14-Diacetate (1a). Initial N-demethylation experiments were performed with oxymorphone 3,14-diacetate (1a) as the substrate under conditions close to those reported by Hudlicky et al (Scheme 2).12 Oxymorphone 3,14-diacetate (1a) can be synthesized by well-developed procedures starting from the naturally occurring opiates oripavine and thebaine.29,30 Hydroxylation of oripavine at position C14 provides 14-hydroxymorphinone, which in turn can be acetylated and hydrogenated to give the oxymorphone 3,14-diacetate (1a).29,30 The initial optimization for the N-demethylation of 1a was performed in a microwave batch reactor.31 For these reactions, 50 mg of the starting material (0.13 mmol), Pd(OAc)2 and 1 mL of solvent were filled into a 5 mL microwave vessel. The vessel was sealed with a septum, and O2 was flushed through the septum with a needle for several minutes (the ~4 mL headspace of the microwave vessel provides about 0.16 mmol or 1.25 equiv of O2). Using this procedure, full conversion of the substrate was obtained in dioxane as solvent after a reaction time of 80 min at 120 °C with 10 mol% of Pd(OAc)2 (Table S1 in the Supporting Information). As expected, the product was the N-acetyl derivative 2a, which is evidently formed by N-demethylation and subsequent intramolecular O- to N-acetyl migration (Scheme 2).12 At this reaction temperature, the catalyst loading can be reduced to 5 mol% Pd(OAc)2 without reducing the reaction rate appreciably (Table 1). The demethylation reaction was very clean with a selectivity of >90% for the desired product 2a (HPLC at 215 nm). The main side-products of this reaction were 14-hydroxymorphinone 3,14-diacetate (1b) and 14-hydroxy-normorphinone 3,17-diacetate


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(2b) (Scheme 2). The 14-hydroxymorphinone 1b is produced by a Pd(OAc)2-catalyzed aerobic dehydrogenation of the oxymorphone 3,14-diacetate (1a) to the corresponding enone.32,33 Compound 1b then underwent slow N-demethylation and concomitant acetyl migration to generate the unsaturated N-acetyl derivative 2b (Scheme 2). The noroxymorphone 3,17-diacetate (2a), on the other hand, was quite stable under the reaction conditions and is not oxidized further to the α,β-unsaturated ketone 2b, even after extended reaction times (Table S2 in the Supporting Information). Lower reaction temperatures reduced the reaction rate dramatically and furnished the dehydrogenated opioid 1b as the main product (conversions of ca. 7% were obtained after 90 min at 80 °C), while a further increase of the reaction temperature did not accelerate the reaction any further (Table S1 in the Supporting Information).

Scheme 2. Pd(OAc)2-Catalyzed Oxymorphone 3,14-Diacetate (1a).

Aerobic

N-Demethylation/Dehydrogenation

of

Table 1. N-Demethylation of Oxymorphone 3,14-Diacetate (1a) at 120 °C in Dioxane in a Microwave Reactor.a reaction time 1a 2a 1b 2b others [min] [%] [%] [%] [%] [%] 15 63 33 2 0 2 40 25 69 0 1 5 80 0 90 0 4 6 a

HPLC peak area integration at 215 nm. Conditions: 50 mg of 1a (0.13 mmol), 5 mol% of Pd(OAc)2 and 1 mL of dioxane were filled into a 5 mL Pyrex microwave vial. The vial was sealed with a Teflon septum, and O2 was flushed through the septum with a needle for several minutes. The mixture was then heated in a microwave reactor to 120 °C. After a reaction time of 15 min the vial was cooled to room temperature, the mixture analyzed by HPLC, the vial flushed again with O2 and subsequently heated again in the microwave reactor for 25 and finally 40 min.



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Stahl and co-workers reported that the palladium-catalyzed aerobic oxidation of alcohols to ketones requires pyridine as an additive.17 In its absence, the oxidation is only stoichiometric with respect to Pd(II) since the homogeneous Pd(0) intermediate irreversibly agglomerates to metallic palladium. For the N-methyl oxidation reactions described above, Pd(0) precipitated on the wall of the reaction vessel almost immediately after the reaction mixture was heated. Indeed, formation of a Pd(0) precipitate is crucial for the aerobic oxidation of the N-methyl group to occur.13 For instance, one equiv of pyridine (with respect to the substrate) stabilized Pd and no formation of Pd-black was observed during the reaction (Table 2, entry 2). However, no N-demethylation was observed under these conditions. Instead, oxymorphone 1a was slowly dehydrogenated to the 14-hydroxymorphinone 1b. Formation of a Pd precipitate was not completely suppressed upon reducing the amount of pyridine to 10 mol% (with respect to the substrate). Accordingly, the N-demethylation proceeded with reduced reaction rate and a mixture of the N-demethylated compound 2a and dehydrogenated products 1b and 2b was formed (Table 2, entry 3). Similarly, tetrabutylamonium bromide (TBAB), often used to stabilize Pd(0) in coupling reactions, suppressed the demethylation of the oxymorphone 1a and produced mixtures of demethylated and dehydrogenated products (Table 2, entry 4).

Table 2. N-Demethylation of Oxymorphone 3,14-Diacetate (1a) at 120 °C in the Presence of Additives (80 min Reaction Time).a entry additive 1a 2a 1b 2b others (equiv) [%] [%] [%] [%] [%] 1 none 0 84 0 8 8 2 Pyridine (1) 49 0 51 0 0 3 Pyridine (0.1) 73 10 12 4 1 4 TBAB (0.1) 80 2 12 6 0 a

HPLC peak area integration at 215 nm. Conditions: 50 mg of 1a (0.13 mmol), additive and 10 mol% of Pd(OAc)2 in 1 mL of dioxane after 80 min at a reaction temperature of 120 °C. The reactions were performed in a microwave reactor as described in the footnote of Table 1.

It is well documented, that palladium(II) complexes are unstable at elevated temperatures and they have the tendency to form palladium(0) colloids above about 120 °C.34 Recently we demonstrated that black solutions of finely dispersed Pd(0) particles can be formed by heating Pd(OAc)2 in DMA as solvent.13 The formation of the Pd(0) particles does not need an inert atmosphere or any additional reducing agent. With 14-hydroxymorphinone dissolved in the dark solution of colloidal Pd(0), a fast and selective oxidation of the N-methyl group took place.13 Interestingly, Pd(0) is not formed when Pd(OAc)2 is heated in the presence of unprotected 14-hydroxy opioids and no oxidation reaction proceeds.13 In contrast, solutions of ACS Paragon Plus Environment

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Pd(OAc)2 and the O-protected 14-hydroxy opioid 1a quickly turned black upon heating in DMA as solvent, indicating the formation of Pd(0) colloids, and a clean and fast demethylation reaction takes place. Importantly, the colloidal Pd remained dispersed in solution throughout the reaction and did not precipitate on the vessel wall. Several further protic and polar aprotic solvents were tested for the aerobic N-demethylation of 1a (Table S1 in the Supporting Information). Dimethylacetamide (DMA) provided the fastest reaction in microwave batch experiments with complete consumption of 1a after ~40 min at 120 °C. Unfortunately, the reaction rate decreased when the scale of the reaction was increased to 100 mg under otherwise identical conditions (120 min at 120 °C were required for full conversion; see Table S1 in the Supporting Information). However, the reaction rate was essentially restored on this scale, when the reaction was performed on a hot plate with O2 bubbled through the reaction solution. Indeed, with 100 mg oxymorphone 3,14-diacetate (1a) and only 5 mol% of Pd(OAc)2 in 1 mL DMA, full conversion of the substrate was obtained after around 40 min at 120 °C (89% selectivity according to HPLC). The reaction also can be performed with atmospheric oxygen (Table S2 in the Supporting Information). For these experiments, the reaction mixture was simply stirred in an open vial at 120 °C. The reaction was somewhat slower under these conditions, but the selectivity of the reaction was virtually the same for O2 and air oxidations. Finally, the influence of water on the reaction was studied. The reaction probably proceeds via an iminium cation as intermediate (cf. Figure 3).13 Hydrolysis of the iminium ion by water would form the secondary amine and formaldehyde. However, as can be seen from the results in Table 3, the presence of water decreases both reaction rate and selectivity of the demethylation reaction. Table 3. N-Demethylation of Oxymorphone 3,14-Diacetate (1a) in DMA at 120 °C in the Presence of Water (30 min Reaction Time).a H2O [µL] 0 10 50

1a [%] 8 57 72

2a [%] 74 21 10

1b [%] 0 13 14

2b [%] 12 9 4

a

others [%] 6 0 0

HPLC peak area integration at 215 nm. Conditions: 100 mg of 1a (0.26 mmol) and 5 mol% of Pd(OAc)2 in 1 mL of DMA at a reaction temperature of 120 °C. The reactions were performed on a hot-plate with O2 bubbled through the solution.



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Continuous Flow N-Demethylation of Oxymorphone 3,14-Diacetate (1a). For the continuous flow reactions, the reaction mixture was pumped by a HPLC pump into a mixing unit at room temperature. In the mixer the liquid stream was combined with O2, fed in from a gas cylinder, and the combined gas-liquid stream then went through a residence tube (RT), which was heated to the desired temperature in a GC-oven (Figure 2). The processed mixture was finally cooled in a short residence tube in a water bath (HE) and left the reactor through a back-pressure regulator (BPR). With back pressures of around 15 bar and flow rates of 0.5 mL/min and 5 mLN/min (gas flow at normal conditions, i.e. TN = 0 °C and pN = 1 atm) for the liquid and the gaseous feed, respectively, the oxygen was apparently completely dissolved in the liquid stream and no gas phase was visible at room temperature. At higher flow rates of the gas, discrete gas/liquid segments were formed in the residence tube. Several flow experiments were performed, using different mixer geometries and tube reactors made of either perfluoroalkoxy alkane (PFA) or stainless steel (SS) with residence volumes of 10, 20 or 25 mL. The reactions were executed in DMA or dimethylformamide (DMF) as solvent in a pressure range from atmospheric to about 20 bar and residence times varying between 8 to 40 min. As oxidant either synthetic air or oxygen was used with stoichiometries of the oxidant varied in the range from 0 to 17 equiv. Surprisingly, however, none of these experiments reproduced the results we have obtained under batch conditions and both conversions and selectivities were poor (for selected results see Table 4; for further results see Table S3 in the Supporting Information). In fact, regardless of process parameters such as residence time, pressure or stoichiometry of oxidant, for most of these experiments conversions were around 30 to 35% only, and the desired product 2a and the dehydrogenated α,β-unsaturated ketone 1b were formed in essentially equal amounts (Table S3 in the Supporting Information). Interestingly, formation of the dehydrogenated side products 1b and 2b was strongly reduced when the amount of O2 was reduced well below 1 equiv (Table 4, entry 3).


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Figure 2. Continuous-flow setup. PS=pressure sensor (Uniqsis Pump Module), MFC=mass flow controller (ThalesNano Gas module), BPR=back-pressure regulator.

The diacetyloxymorphone 1a and Pd(OAc)2 dissolve in DMA to give a yellowish to orange, homogeneous solution, but, as mentioned above, the mixture quickly turns black upon heating due to the formation of fine palladium(0) particles. In contrast, when the reaction was performed in the flow reactor, the processed reaction mixture kept its clear, orange appearance (the exceptions were experiments with < 0.5 equiv of O2, which resulted in black solutions during the reaction; Table 4, entry 3). Importantly, continuous flow reactions with the black solutions, obtained by heating the reaction mixture for ~2 min at 90 °C on a hot plate prior to the flow reaction, led to significantly better conversions (Table 4, entries 4-6). These results suggest that the catalytic cycle starts with a Pd(0) species, and a deficiency of oxygen is necessary for the catalytically active species to form from Pd(OAc)2. Under the highly oxidative conditions in the flow reactor, the active Pd(0) species is apparently not formed and the palladium remains in its Pd(II) state throughout the reaction. Indeed, the aerobic demethylation probably proceeds without an actual, stable Pd(II) intermediate.13

Table 4. N-Demethylation of Oxymorphone 3,14-Diacetate (1a) under Continuous Flow Conditions.a entry reactor/ solvent/flow gas/flow stoich. temp p RT 1a volume rate rate [°C] [bar] [min] [%] [mL] [mL/min] [mLN/min] 1 SS/20 DMF/0.5 O2/20 6.9 120 13 18 71 2 SS/20 DMF/0.5 O2/10 3.4 120 11 32 75 3 PFA/25 DMF/1.0 O2/0 0.0 120 9 22 82 4b SS/20 DMF/0.5 O2/10 3.4 120 11 24 52 5b SS/20 DMA/0.5 O2/6 2.1 130 11 21 17 b 6 SS/20 DMA/0.5 O2/6 2.1 140 10 23 0


2a 1b 2b [%] [%] [%] 13 18 16 39 61 73

13 4 2 3 2 0

3 1 0 5 17 22


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a

HPLC peak area integration at 215 nm. Conditions: Liquid feed: 200 mg of 1a (0.52 mmol), 5 mol% Pd(OAc)2 in 2 mL DMA or DMF; gaseous feed: O2 or air controlled by a mass flow controller (gas flow at normal conditions, i.e. Tn = 0 °C and pn = 1 atm); RT=residence time (determined with a stopwatch; see Experimental Section for details). b The reaction mixture was heated on a hot plate before the continuous flow reactions for ~ 2 min at 90 °C. For further results see Table S3 in the Supporting Information.

The dealkylation of tertiary amines in 0.7 M HCl with Pd(0) under an argon atmosphere was already described in 1979 (the reaction required many hours at 200 °C with 40 mol% of Pd(0) as catalyst).14 The authors suggest that the reaction starts with a reversible insertion of the low-valent Pd(0) into the carbon-hydrogen bond adjacent to the nitrogen (Figure 3). Hydrolysis of the iminium cation regenerates Pd(0) and releases the dealkylated secondary amine, aldehyde and H2. A similar mechanism has also been proposed for the palladiumcatalyzed aerobic demethylation.12,13 However, the aerobic demethylation proceeds under considerably milder conditions and without the release of hydrogen (Figure 3).

Figure 3. Pd(0) Catalyzed Oxidative N-Demethylation.12,13

Batch Optimization for the N-Demethylation of 14-Hydroxymorphinone 3,14-Diacetate (1b). Even though the continuous flow aerobic N-demethylation of oxymorphone 3,14diacetate (1a) was achieved with pre-heated reaction mixtures, the reaction formed large quantities of the α,β-unsaturated derivatives 1b and 2b as side products (Table 4). Since the oxymorphone 1a is prepared by hydrogenation of 14-hydroxymorphinone 1b in a preceding step, we explored the direct oxidative N-demethylation of 14-hydroxymorphinone 3,14diacetate (1b). Hydrogenation of the enone double bond of the nor-derivative 2b would then generate the noroxymorphone 3,17-diacetate (2a) (Scheme 2). ACS Paragon Plus Environment

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Scheme 2. Alternative Route to Noroxymorphone 3,17-Diacetate (2a).

14-Hydroxymorphinone 3,14-diacetate (1b) dissolves quite slowly in aprotic polar solvents such as DMF or DMA and black Pd(0) formed already before the starting material was completely dissolved. Batch reactions with 5 mol% of Pd(OAc)2 in either DMF or DMA as solvent gave virtually identical results (Table 5), while reactions in other solvents, such as dioxane, acetonitrile or i-PrOH were significantly slower (Table S4 in the Supporting Information). Interestingly, the demethylation reaction using hydroxymorphinone 1b as the substrate required considerably longer reaction times than the corresponding reactions with the saturated counterpart 1a. For example, while the reaction of oxymorphone 3,14-diacetate (1a) using air as oxidant and 5 mol% of Pd(OAc)2 as catalyst in DMA as solvent required 90 min at 120 °C for a complete demethylation, full demethylation of hydroxymorphinone 1b was not obtained even after 6 h at 120 °C. However, complete conversions were obtained after 90 min at 120 °C when O2 rather than air was used as the oxidant (Table 5). The reaction was remarkably clean and the only side-product formed in significant amounts was the Nformyl derivative 4b (Table 5). The N-formyl compound 4b is formed by a palladiumcatalyzed oxidation of the N-methylamine group to the formamide in a competing reaction, and it is not an intermediate in the main reaction path leading to the 14hydroxynormorphinone 2b.35 The N-formyl derivative 4b is formed to a lesser extent when air was used as the oxidant.

Table 5. N-Demethylation of 14-Hydroxymorphinone 3,14-Diacetate (1b) with Air or O2 as Oxidant at 120 °C (90 min Reaction Time).a



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entry

solvent

oxidant

1 2 3 4

DMF DMF DMA DMA

air O2 air O2

1b [%] 64 7 62 0

2b [%] 36 90 38 97

4b [%] 0 2 0 3

a

HPLC peak area integration at 215 nm. Conditions: 100 mg of 1b (0.26 mmol) and 5 mol% of Pd(OAc)2 in 1 mL solvent at a reaction temperature of 120 °C. The reactions were performed on a hotplate, either in an open vial (air) or with O2 bubbled through the solution.

As mentioned above, formation of Pd(0) appears to be required to initiate the aerobic Ndemethylation reaction. Indeed, reactions with palladium on charcoal (Pd/C) under batch conditions gave virtually identical results as reactions with Pd(OAc)2 as homogeneous precatalyst. With 5 mol% catalyst at 140 °C, the starting material 1b was virtually fully consumed after a reaction time of around 4 h (Figure 4). The desired 14hydroxynormorphinone 2b was the only product detected in the reaction mixture. Furthermore, platinum on charcoal (Pt/C) is an efficient catalyst for this reaction (see Table S5 in the Supporting Information). Not surprisingly, without a catalyst essentially no reaction was observed (Table S4 in the Supporting Information).

conversion [%]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

100 90 80 70 60 50 40 30 20 10 0

5 mol% Pd(OAc)2

DMA

5 mol% Pd/C (10%)

0

100

200

300

400

reaction time [min]

Figure 4. Reaction at 140 °C with either Pd(OAc)2 or Pd/C as (pre)-catalyst. Conditions: 100 mg of 1b (0.26 mmol) in 1 mL of DMA as solvent at a reaction temperature of 140 °C. The reaction mixtures were stirred in an open vial on a hot-plate.

Continuous Flow N-Demethylation of 14-Hydroxymorphinone 3,14-Diacetate (1b). The continuous flow reactions were performed in the same flow set-up as described above. The 14-hydroxymorphinone 3,14-diacetate (1b) and 5 mol% of Pd(OAc)2 were dissolved in the respective solvent and injected into the flow reactor. The best results were obtained in DMA as solvent. As mentioned above, 14-hydroxymorphinone 3,14-diacetate (1b) dissolves quite slowly in DMA and the mixtures were thus generally heated to about 50 °C to dissolve the substrates prior to the flow process. Upon heating, Pd(0) formed and the reaction mixture


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became black. All continuous flow reactions were performed with O2 as oxidant in a 20 mL stainless steel coil with a back pressure of ~10 bar or ~20 bar. ICPMS analysis of the processed reaction mixture revealed that some of the palladium is lost in the flow reactor.36 Interestingly, the deposited Pd(0) exhibited catalytic activity for the aerobic N-demethylation (Table S8 in the Supporting Information). As shown in Table 6, essentially complete conversion of the starting material 1b was obtained after reaction times of around 20 min at 140 °C with ~2 equiv of O2 (for further results see Table S6 in the Supporting Information). In accordance with the batch experiments, the only significant side product was the N-formyl derivative 4b. Notably, the reaction temperature could be increased to 160 °C without affecting the purity of the reaction (Table 6, entry 6). Oxygen pressure had no appreciable effect on the reaction rate or reaction selectivity, even though the residence time was significantly higher at higher back-pressures (compare entries 4 and 5 in Table 6). The amount of oxygen used in the flow experiments also had little effect (compare entries 3, 4 and 7 in Table 6). Reducing the amount of Pd(OAc)2 to 2.5 equiv at a temperature of 140 °C decreased the conversion to around 85%, without reducing the selectivity for the Ndemethylation reaction appreciably (Table 6, entry 8 and Table S6 in the Supporting Information). The product from an experiment on a 800 mg scale (5 mol% Pd(OAc)2, 1.7 equiv O2 at 145 °C) was isolated by chromatography on a silica column using CHCl3/MeOH as eluent. This provided 674 mg of the pure product 2b (87% isolated yield) in addition to 106 mg of the N-formyl derivative 4b (contaminated with small amounts of DMA). Table 6. N-Demethylation of 14-Hydroxymorphinone 3,14-Diacetate (1b) under Continuous Flow Conditions.a entry

solvent/flow rate [mL/min]

1 2 3 4b 5 6 7b 8

DMA/0.5 DMA/0.5 DMA/0.5 DMA/0.5 DMA/0.5 DMA/0.5 DMA/0.5 DMA/0.5

O2 flow stoich. Pd(OAc)2 temp p RT 1b rate [mol%] [°C] [bar] [min] [%] [mLN/min] 10 3.4 5 100 12 17 87 10 3.4 5 120 10 18 42 10 3.4 5 140 10 18 7 6 2.1 5 140 9 17 2 6 2.1 5 140 23 29 2 6 2.1 5 160 11 22 0 5 1.7 5 140 11 21 1 6 2.1 2.5 140 22 30 6

a

2b [%]

4b [%]

11 54 86 90 89 91 88 84

2 4 6 8 6 8 11 8

HPLC peak area integration at 215 nm. Conditions: liquid feed: 200 to 400 mg of 1b (0.52 to 1.04 mmol), 2.5 or 5 mol% Pd(OAc)2 in 2 to 4 mL solvent; gaseous feed: O2 controlled by a mass flow controller (gas flow at normal conditions, i.e. Tn = 0 °C and pn = 1 atm); RT=residence time (determined with a stop-watch; see Experimental Section for details). b average of 3 experiments (on 200 and 400 mg scales). For further results see Table S6 in the Supporting Information.



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The reaction initially proved difficult to reproduce with a second lot of the starting material. Even though the reaction worked well in batch reactions, the initial conversions after continuous flow reactions were low. Apparently the starting material contained trace amounts of an impurity which impeded the formation of Pd(0). For example, heating of a reaction mixture containing this substrate for 5 min at 70 °C on a hot plate did not result in the formation of the typical black solution. However, upon heating the reaction mixture to 140 °C, the catalytically active Pd(0) species was formed and the subsequent continuous flow reaction proceeded essentially as expected (entry 2 in Table 7). The reaction was further improved with AcOH as additive. Acetic acid stabilizes the colloidal Pd(0) and prevents its precipitation on the vessel walls (Figure S3 in the Supporting Information).13 With 4 equivalents of AcOH as additive the catalyst loading was reduced to 2.5 mol%, providing ~95% conversion of the hydroxymorphinone after a residence time of only ~12 min at 145 °C. Furthermore, formation of N-formyl derivative 4b was suppressed in the presence of AcOH (entry 6 in Table 7).

Table 7. N-Demethylation of 14-Hydroxymorphinone 3,14-Diacetate (1b) under Continuous Flow Conditions.a entry

1 2 3 4 5c 6 7

pre-heating T/t [°C]/[min] 70/5 140/2 140/2 140/2 140/2 140/2 140/2

colorb

orange black black black black black orange

AcOH flow rate p RT 1b [equiv] liquid/gas [bar] [min] [%] [mL/min] 0 0.5/5 16 26 77 0 0.5/5 18 28 19 0 1/10 14 12 34 2 1/10 17 12 11 2 1/10 17 12 11 4 1/10 10 12 5 10 1/10 14 13 53

2b [%]

4b [%]

17 70 62 87 87 93 47

1 7 4 2 2

Toward the Synthesis of Noroxymorphone via Aerobic Palladium

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