ppm Pd Nanoparticle Nitro Group

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Sustainable and Scalable Fe/ppm Pd Nanoparticle Nitro Group Reductions in Water at Room Temperature Christopher Michael Gabriel, Michael Parmentier, Christian Riegert, Marian Lanz, Sachin Handa, Bruce H. Lipshutz, and Fabrice Gallou Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00410 • Publication Date (Web): 27 Jan 2017 Downloaded from http://pubs.acs.org on January 27, 2017

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Organic Process Research & Development

Sustainable and Scalable Fe/ppm Pd Nanoparticle Nitro Group Reductions in Water at Room Temperature Christopher M. Gabriel†, Michael Parmentier‡, Christian Riegert‡, Marian Lanz‡, Sachin Handa§, Bruce H. Lipshutz†, and Fabrice Gallou*‡ †Department of Chemistry & Biochemistry, University of California, Santa Barbara 93106, United States ‡ Novartis Pharma AG, CH-4057 Basel, Switzerland § Department of Chemistry, University of Louisville, Louisville, Kentucky 40292, United States

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Table of Contents Graphic

ABSTRACT: An operationally simple and general process for the safe and selective reduction of nitro groups utilizing ppm Pd supported on Fe nanomaterials in aqueous solution of designer surfactant TPGS-750-M has been developed and successfully carried out at a 100 mmol scale. Preferred use of KBH4 as the hydride source, at ambient temperature and pressure, lends this process suitable for a standard reaction vessel alleviating the need for specialized hydrogenation equipment. Calorimetry data parallels that expected for a classical nitro group reduction when measuring the heat of reaction (-896 to -850 kJ/mol).

Keywords: green chemistry, KBH4, micellar catalysis, nanoparticles, reduction, chemistry in water.

INTRODUCTION

century,9 the need, especially at scale, for a safer, more environmentally responsible method remains.

The reduction of a nitro group to the corresponding amine represents one of the most widely utilized transformations in organic synthesis. With aromatic compounds, this transformation represents, by far, the most common procedure for the synthesis of aryl amines due to the ease, low cost, and predictability by which such aryl derivatives can be generated.1,2 Most often, hydrogenation conditions are employed utilizing a transition metal catalyst such as Pd/C,3 Rainey-Ni,4 or PtO25. Less expensive, alternative metals such as Fe,6 Zn,7 and Sn,8 have been widely employed for these reductions as well; however, they oftentimes require stoichiometric (or super stoichiometric) amounts of metals, and/or harsh reaction conditions. Moreover, such reduction methods may stop at intermediate stages, and/or go through accumulation of highly energetic intermediates. While this transformation has been ubiquitous in the synthesis of pharmaceuticals, dyes, explosives, agrochemicals, functional materials, and bioactive natural products for well over a

Recently, a new reagent has been developed that can be utilized under conditions that meet many of these concerns associated with the reduction of aromatic and heteroaromatic nitro compounds to their corresponding amines. Using nanoparticles (NPs) derived from FeCl3 that contain ppm levels Pd, along with NaBH4 as the source of hydrogen under aqueous micellar conditions at room temperature, reductions take place in good to exceptional yields (80-98% isolated) within short reaction times (typically 2-4 hours).10 These NPs and associated conditions have been found to be highly general, tolerating a variety of other potentially reducible functional groups, including aryl halides, alkenes, alkynes, esters, amides, nitriles, and ketones, as well as benzyl protected alcohols and amines which would otherwise be cleaved under Pd-catalyzed hydrogenation conditions.11 Encouraged by this success, development of a scale-up process for this method was pursued, as was a

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study of several other reaction parameters, the results from which are described herein. Our standard procedure for Fe/ppm Pd-catalyzed reduction of nitro compounds calls for generating Fe nanoparticles (≥80 ppm Pd) in a 2 wt % solution of designer surfactant TPGS-750-M in water (Figure 1).10 NaBH4 (1.5-3.0 equiv) is then transferred to the catalyst solution to arrive at the active nanomaterial catalyst (activation), as well as to charge the reaction mixture with the hydride source for the subsequent reductions. In a separate vessel, the nitro group-containing starting material is dispersed in 2 wt % TPGS750-M/H2O prior to its addition into the reaction mixture. Once added, the reaction is allowed to stir at room temperature until full conversion of starting material and intermediates is observed, as monitored by TLC. Amine isolation/purification is carried out via extraction with ethyl acetate or t-butyl methyl ether (MTBE) from the reaction mixture, followed by column chromatography or, more favorably (and feasible) via direct recrystallization as the corresponding HCl salt. O O O

O

O

O 16

1

Figure 1. Structure of TPGS-750-M

RESULTS AND DISCUSSION The reduction of 1-chloro-4-nitrobenzene (2) to 4-chloroaniline, 3, was investigated as the model system for scalable Fe/ppm Pd-catalyzed nitro group reductions. We began by considering the physical aspects of the system. Materials containing nitro functionality are typically highly crystalline solids, oftentimes unfavorable for reactions in which water is used as the reaction medium. While the use of surfactants at or above their critical micellar concentrations (CMC) can be used to stabilize a biphasic mixture as a microemulsion, this is often not sufficient to liberate material from its energetically more favorable crystalline state, especially at relatively high solute concentrations. As a result, heterogeneous mixtures containing undissolved solids can provide challenges on scale. For this reason, we sought to employ the use of a cosolvent that would aid in dissolving crystalline material and stabilize the starting material emulsion. Consistent with our previous efforts,10,12 THF was found to be the cosolvent of choice showing, for this specific transformation based on observations highlighted below, slightly better conversion on a 78 mg scale than literature conditions (Table 1). While PEG-200 was found to work equally as well, solubility of 2 in this solvent was poor resulting in an unstable emulsion. When a solution of 2 in THF was added directly to the reaction mixture, the progress of the reaction suffered significantly as only 18% product was observed after 18 hours (entry 6), showing that the dispersion of the nitro compound in surfactant solution is in fact necessary for high conversion. In forming an emulsion for a given starting material, it was found that dissolution in THF prior to addition to 2 wt % TPGS-750-M/H2O achieves the desired ‘milky’ appearance much faster than other addition sequences. This should be done at high stirring rates (>800 rpm). Water-miscible alcohols such as methanol and isopropanol were not considered as co-solvents due to their inability to dissolve 2 prior to addition of the aqueous surfactant solution.

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Table 1. Comparison of various co-solvents

We next focused on understanding the role of NaBH4 as the reductant. Upon addition of NaBH4 to the homogeneous catalyst solution, the iron(III) salt is quickly reduced, as it precipitates as fine black particles while the reaction mixture foams due to gas evolution. A hydrogenation study was done in order to assess whether NaBH4 acts as the direct hydride source or as an H2 precursor (Table 2). Consistent with the initial report,10 when NaBH4 is directly replaced with H2, only a negligible amount of product is detected even at a pressure of 2 bars (entry 3). Under hydrogenation conditions, no visual change in catalyst solution was observed, indicating that the catalyst was not activated. When only a catalytic amount of NaBH4 was added to the reaction for catalyst activation, the reduced Fe/Pd catalyst was readily observed. Even under 10 bar H2, only trace amounts of product was observed along with the appearance of condensation and dehalogenated by-products. Table 2. Fe/ppm Pd-catalyzed nitro group reduction of 1chloroaniline under hydrogenation conditions

At this stage, we envisioned that a more dissociated borohydride might impact the outcome of the reduction. When NaBH4 is replaced by other metal borohydride salts, a pronounced effect is observed depending on the nature of the counterion (Table 3). In comparison to NaBH4, KBH4 reacts far faster both in terms of starting material conversion and in the final slow step of the reduction; i.e., from hydroxylamine 5 to aniline 3 (Scheme 1).


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Table 3. Initial MBH4 screening

completion. Upon our second attempt, quantitative conversion to product was achieved by charging the reaction with 3.0 additional equivalents KBH4 prior to adding the second portion of starting material. We have found that portion-wise addition of materials can be continued up to at least ten additional times without effecting reaction conversion, however, precipitation of product leads to a decrease in homogeneity of the reaction mixture which may not be desirable for this process at a larger scale. These results translated well when the identical procedure was carried out on a 100 mmol scale affording 3 in 94% isolated yield (as its HCl salt).

It has been well studied that aromatic nitro reductions may be achieved via two pathways, both of which go through nitroso- and hydroxylamine intermediates (Scheme 1). In order to further understand this system, isolated intermediates and by-products were submitted to standard reaction conditions including the corresponding hydroxylamine 5, azoxy 6, and diazo compound 7 (Table 4). Complete conversion of 5 to 3 was achieved while only trace amounts of azoxy 6 were reduced to 7, and no conversion of 7 to 8 was detected rendering the condensation reaction pathway a dead end under our conditions. The condensation of 4 and 5 to 6 is not only a concern in terms of overall conversion to product, but also in terms of safety, as these by-products be both genotoxic and carcinogenic.13 Therefore, conditions were required for avoiding this pathway so as to ultimately arrive at a safer, more efficient process. Scheme 1. Reaction pathways for nitro group reductions

Reaction work-up via acidification of the mixture with HCl under air achieves the quenching of KBH4, deactivation and solubilization of the catalyst, as well as solubilization of the product amine in water. It should be investigated that all KBH4 has been decomposed before continuing further work-up and purification. Also, it should be noted that the catalyst will not be solubilized if the reaction quench is performed under oxygen-free conditions. At this point, extraction with a minimal amount of heptanes is used to remove impurities arising from the condensation pathway outlined in Scheme 1. Noteworthy is that isolation of all impurities associated with this pathway represented less than 0.1% of the total crude mass at the 100 mmol scale. Product isolation is then achieved via neutralization with aqueous NaOH solution, extraction of the product with i-PrOAc (isopropyl acetate), and passing the organic extracts through a plug of filter aide (Celite). After reducing the volume of filtrate with recovery of much of the solvent, recrystallization of the product as the corresponding HCl salt followed from the dropwise addition of 1 M HCl solution in ethyl acetate to afford 3 as white crystals. ICP analysis was carried out on the purified material revealing < 1 ppm of residual Pd content. Scheme 2. Conditions for avoiding the condensation pathway

Table 4. Intermediate and by-product formation under standard conditions

A careful kinetic study led us to a simple process that prevents formation of the unproductive by-products and minimizes accumulation of problematic intermediates. First, to increase reaction rate, we changed the nature of the hydride source from NaBH4 (1.5 equiv) to the more reactive KBH4, and increased its loading (3.0 equiv). Additionally, catalyst loading was increased to 200 ppm Pd loading. Next, we considered the entropic factor of condensation by diluting the system from 0.5 to 0.25 M. Within one hour, 100% conversion of 2 was achieved and by two hours the reaction had gone to completion free of by-products (Scheme 2). The reaction was then charged with an additional equivalent of starting material, and although full consumption of 2 was achieved, the remaining hydride in the system was not sufficient to bring the reaction to

In terms of the physical aspects characteristic of the system, it is apparent that the majority of gas evolved for all processes of this reaction occurs during catalyst activation upon addition the initial portion of KBH4. Foaming has been observed to increase the reaction volume up to four times the original solvent level during catalyst activation (for example, 200 mL of catalyst solution can generate ~600 mL of foam). This is a result of the high surface tension of the surfactant solution and gas generated in-situ. Investigations were conducted to counteract/diminish the amount of foam present during catalyst activation. Upon addition of the 1-chloro-4nitrobenzene emulsion, the foam will collapse completely, which can also be effected by the introduction of the solute 2 and THF, not merely THF alone. Addition of KBH4 that is charged to the system after the substrate is present will not lead to the generation of any significant amount of foam. In order to investigate the limitations of our conditions, catalyst loading was decreased (Table 5, entry 2), as were the equivalents of reductant (entry 3). The resulting rate of the reaction was



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slower from both modifications, and the undesired azoxy byproduct 6 was observed yet again. To further generalize this revised system, we also examined the effect of added KCl in the presence of other less reactive hydride sources, such as LiBH4 and NaBH4. While the reactivity of LiBH4 was only marginally affected, identical results to our optimized system were realized when NaBH4 (3 equiv) was used in the presence of 1.0 equivalent KCl salt (entry 6). Due to the lower cost of NaBH4 in comparison to other borohydride salts, use of KCl as additive may serve as a viable alternative to KBH4 on scale.14 Table 5. Limitations and effects of added KCl

Additional representative examples using this technology are illustrated in Table 6, with each being run in water at ambient temperature. These are meant to be suggestive of the functional group compatibility associated with this process, where an aryl bromide, a dihalocyclopropane, a protected acylhydrazine derivative, and an α,β-unsaturated ester all survive these conditions and afford the targeted anilines in good isolated yields.

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tude for classical nitro reduction per hydrogenation; the heat of reaction approximately after each addition being in the range of 896 to -850 kJ/mol. As expected, the heat of reaction in kJ/kg depends on the concentration of the nitro compound in the reaction mixture; the reaction is strongly exothermic [ca. -153 kJ/kg FRM (final reaction mass), corresponding to theoretical adiabatic temperature increase of about 37 °C] in the first portion and ca -115 kJ/kg FRM corresponding to theoretical adiabatic temperature increase of about 29 °C in the second portion. About 50% of the whole energy is accumulated at the end of the addition corresponding to a theoretical adiabatic temperature increase of about 18 °C to 15 °C. Even in a worst case scenario, in the case of an undetected loss of cooling, a maximum temperature of about 62 °C (IT + ΔTad = 25 + 37°C = 62 °C) could theoretically be reached. This is well below the boiling point of the solvent (water) and would not be safety matter; however, a potential increase in gas release can be expected. The dynamic SEDEX thermostability test of the reaction mixture after addition of the second portion of 2 at 20 °C within 10 minutes shows no significant exothermal decomposition reaction up to 160 °C.15 The expected H2 evolution based on a 3:1 stoichiometry of KBH4 to nitro compound is calculated at 36.7 L / kg FRM16 and much of the remaining KBH4 portion is decomposed upon workup. Potential accumulation of KBH4 should be evaluated as this may lead to potential higher gas release and the entire process should be performed under argon flow to ensure good conversion. This process alleviates the occurrence of pressure build-up which can be expected after several portion additions and eliminates the requirement for specialized equipment. • approximate heat of reaction from -896 to - 850 kJ/mol • 50% of the energy accumulated at the end of the addition • an undetected loss of cooling could result in an increase to only 62 °C • no significant exothermal decomposition reaction up to 160°C

Figure 2. Key results from a calorimetry study

SUMMARY & CONCLUSIONS

Table 6. Additional examples using KBH4

In conclusion, we have developed a safe scale-up process for the Fe/ppm Pd-catalyzed reduction of nitro compounds in water at room temperature. This process benefits from the use of an aqueous solution of TPGS-750-M as the gross reaction medium, minimal levels of palladium (80-200 ppm), and minimal by-product accumulation. Furthermore, this process allows for reductions which typically require high pressure equipment to be run in a standard reactor without significant safety concerns as determined by calorimetry studies. As the result of the aqueous nature of this process, reaction work up and product purification is operationally simple. In addition, we envision this process to be well suited for late stage reduction of aryl and heteroaryl nitro groups due to the to the high functional group tolerance of these conditions, as well as the low levels of residual metal catalyst in the final product.

EXPERIMENTAL SECTION

CALORIMETRY These results translated well when this procedure was carried out on a 40 mmol scale in a 0.5 L RC1 reactor by charging KBH4 and 2 stepwise and portion-wise; with each portion of KBH4 and 2 only being added once full conversion of the precedent portion was confirmed, considering each portion as a separate process. Calorimetric analysis measured the energy for each portion corresponding to the nitro reduction and the decomposition of KBH4. The measured heat of reaction in kJ/mol is in the same order of magni-

General. Unless otherwise noted, all reactions were performed under an atmosphere of argon. A solution of 2 wt % TPGS750-M/H2O solution was prepared by dissolving TPGS-750-M in degassed Millipore purified water. All commercially available reagents and solvents were used without further purification including TPGS-750-M (CAS-No. 1309573-60-1). Thin layer chromatography (TLC) was done using Silica Gel 60 F254 plates (Merck, 0.25 mm thick). The developed chromatogram was analyzed by UV


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lamp (254 nm). Flash chromatography was performed using a Biotage IsoleraTM Four using prepacked Biotage® SNAP Ultra cartridges. Hydrogenation experiments utilized Argonaut Technologies EndeavorTM Katalysator Screening system. 1H and 13C NMR were recorded at 297.8 K on a Bruker® 400 MHz spectrometer. The FID was processed using ACD Labs NMR analysis software. Chemical shifts in 1H NMR spectra are reported in parts per million (ppm) on the δ scale from an internal standard of residual CDCl3 (7.260 ppm) or the central peak of DMSO-d6 (2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet), and integration. Chemical shifts in 13C chemical spectra are reported in ppm on the δ scale from the central peak of residual CDCl3 (77.16 ppm) or the central peak of DMSO-d6 (39.51 ppm). ICP-OES measurements were conducted by Solvias AG. Reaction profile based on analysis of UPLC/MS data using Acquity HSS T3 1.8 µm 2.1 x 50 mm at 60°C with the following eluent system: (A: water + 0.05 % formic acid + 3.75 mM ammonium acetate; B: acetonitrile + 0.04% formic acid); gradient from 5 to 98 % B in 1.4 min; flow 1.0 mL/min.

Preparation of 4-chloroaniline hydrochloride (3). In a threeneck round bottom flask with overhead stirring at 200 rpm, 1.117 g Fe nanomaterial (11.4 μmol Pd) was dissolved in 200.0 mL 2 wt % TPGS-750-M/H2O. KBH4 (8.091 g, 150 mmol) was slowly charged to the catalyst solution resulting in catalyst precipitation as black solids, foaming, and gas evolution. In a separate 500 mL round bottom flask with Teflon coated stir bar, 1-chloro-4nitrobenzene 1 (15.76 g, 100 mmol), was dissolved in 40 mL THF followed by the slow addition of 100.0 mL 2 wt % TPGS-750M/H2O while stirring at 1000 rpm. A milky emulsion was achieved after stirring ca. 30 min. Chloro-4-nitrobenzene emulsion (70 mL) was then transferred dropwise (1 drop/sec) via addition funnel to the center of the reaction mixture. Upon reaction completion (as determined by TLC), the reaction was charged with an additional KBH4 (8.091 g, 150 mmol) followed by the remaining 70 mL of the chloro-4-nitrobenzene emulsion as described above. Upon completion ca. 11 h, the reaction was exposed to air and quenched with 37% HCl to pH = 3 and stirred for ca. 1 h. The quenched reaction mixture was then extracted with 50 mL n-heptane to remove condensation by-products. The aqueous phase was then separated, charged back into the reaction flask and neutralized with 11 M NaOH, precipitating 4-chloroaniline (3). The mixture was then extracted with 3 x 50 mL isopropyl acetate, the organic layers were combined, filtered through Celite into a 500 mL round bottom flask, concentrated under reduced pressure to ~75 mL and 75 mL n-heptane was charged into the flask. The flask was then charged with a Teflon coated stir bar and 1 M HCl solution in EtOAc (110 mL, 110 mmol) was transferred via addition funnel at a rate of 1 drop / sec while stirring at 200 rpm leading to the precipitation of 4-chloroaniline hydrochloride as white crystals. Stirring continued for an additional 1 h after complete addition of HCl solution, the solid was collected via vacuum filtration and dried at 45 °C and 0 torr for 18 h to afford 15.49 grams (94%). 1H NMR (500 MHz, DMSO-d6) δ 10.12 (brs, 3H), 7.53 (dt, 2H), 7.39 (dt, 2H). 13C NMR (125 MHz, DMSO-d6) δ 132.02, 131.66, 129.58, 124.68. Preparation of 5-bromopyridin-2-amine (9). A 50 mL round bottom flask with Teflon-coated stir bar was charged with 16 mg Fe nanomaterial (0.11 μmol Pd) and was suspended in 1.5 mL 2 wt % TPGS-750-M/H2O. KBH4 (162 mg, 3.0 mmol) was slowly charged to the catalyst solution resulting in catalyst precipitation as black solids, foaming, and gas evolution. A separate 8 mL dram vial with a

Teflon coated stir bar was charged with 5-bromo-2-nitropyridine (203 mg, 1.0 mmol), 0.4 mL THF, followed by the slow addition of 1.5 mL 2 wt % TPGS-750-M/H2O. The mixture was mixed via vortex and stirred at high speed (>1000 rpm) and approx. half of the mixture was transferred to the catalyst reaction. After ca. 4 h, the reaction was charged with KBH4 (162 mg, 3.0 mmol) and the remaining portion of the starting material mixture. After ca. 16 h (reaction time not optimized), the crude product was extracted with 3 x 3 mL EtOAc, dried over anhydrous Na2SO4, and purified via flash chromatography to yield 5-bromopyridin-2-amine as a yellow solid (157.6 mg, 91%). Spectroscopic data was in agreement with literature values.17 1H NMR (500 MHz, CDCl3) δ 7.85(dd, 1H, J = 2.60, 0.52 Hz), 7.21 (dd, 1H, J = 8.56, 0.52 Hz), 6.88 (dd, 1H J = 8.56, 3.11 Hz). 13C NMR (125 MHz, CDCl3) δ 142.06, 137.01, 129.48, 127.75, 124.68.

(2,2-Dibromo-3,3-dimethylcyclopropyl)methyl 4-aminobenzoate (10). Prepared as described for 5-bromopyridin-2-amine from (2,2-dibromo-3,3-dimethylcyclopropyl)methyl 4-nitrobenzoate (484.0 mg, 1.2 mmol) to yield the product as a white solid (400.5 mg, 88%). 1H NMR (500 MHz, CDCl3) δ 7.88 (dt, 2H), 6.66 (m, 2H), 4.38 (m, 2H), 4.12 (s, 2H), 1.78 (t, 1.78), 1.45 (s, 3H), 1.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.37, 151.02, 131.69, 119.24, 113.74, 103.67, 99.03, 63.20, 43.73, 37.25, 28.96, 27.12, 19.67. t-Butyl 2-(3-aminobenzoyl)hydrazine-1-carboxylate (11). Prepared as described for 5-bromopyridin-2-amine from t-butyl 2(3-nitrobenzoyl)hydrazine-1-carboxylate (281.3 mg, 1.0 mmol) to yield the product as a yellow solid (233.0 mg, 93%). 1H NMR (500 MHz, DMSO-d6) δ 9.91 (d, 1H, J = 1.30 Hz), 8.78 (s, 1H), 7.08 (t, 1H, J = 7.79 Hz), 7.03 (s, 1H), 6.95 (d, 1H, J = 7.53), 6.71 (ddd, 1H, J = 7.79, 2.34, 0.78 Hz), 5.29 (s, 2H), 1.42 (s, 9H). 13C NMR (125 MHz, DMSO-d6) δ 166.73, 155.45, 148.49, 133.49, 128.72, 116.97, 114.46, 113.05, 79.01, 28.11. ethyl (E)-3-(4-aminophenyl)acrylate (12). Prepared as described for 5-bromopyridin-2-amine from ethyl (E)-3-(4nitrophenyl)acrylate (221.2 mg, 1.0 mmol) to yield the product as a yellow oil as an inseparable mixture of 12 and the corresponding alkane (181.9 mg, 93%, 17:3 alkene:alkane). Spectroscopic data was in agreement with literature values.18 1H NMR (500 MHz, CDCl3) δ 7.60 (d, 1H, J = 16.09 Hz), 7.36 (m, 2H), 6.65 (m, 2H), 6.24 (d, 1H, J = 15.8 Hz), 4.25 (q, 2H), 1.33 (t, 3H). 13C NMR (125 MHz, CDCl3) δ 167.65, 148.60, 144.79, 129.82, 124.76, 114.80, 113.75, 60.13, 14.37.

ASSOCIATED CONTENT Supporting Information Experimental procedures, characterization data, 1H and 13C NMR spectra, and calorimetry data. This material is available free of charge via the internet at http://pubs.acs.org

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Author Contributions This work was performed in large measure at Novartis in Basel, carried out predominantly by Chris Gabriel. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.



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ACKNOWLEDGMENT Financial support provided by Novartis and the NSF (GOALI; SusChEM 1566212) is warmly acknowledged. The authors would like to thank Pascale Hoehn for compilation of the calorimetric report, and Darija Dedic for miscellaneous experimental support. (7)

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ppm Pd Nanoparticle Nitro Group

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