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Green Chemistry Highlights Cite This: Org. Process Res. Dev. 2019, 23, 1118−1133

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Green Chemistry Articles of Interest to the Pharmaceutical Industry 1. INTRODUCTION The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable (PR) was developed in 2005 to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The ACS GCI is a not-for-profit organization whose mission is to catalyze and enable the implementation of green and sustainable chemistry throughout the global chemistry enterprise. The ACS GCI PR is composed of pharmaceutical and biotechnology companies, including contract research/ manufacturing organizations, generic pharmaceuticals, and related companies, and was established to encourage innovation while catalyzing the integration of green chemistry and green engineering in the pharmaceutical industry.1 One of the strategic priorities of the Roundtable is to inform and influence the research agenda. Two of the first steps to achieve this objective were to publish a paper outlining key green chemistry research areas from a pharmaceutical perspective (Green Chem. 2007, 9, 411−420) and to establish annual ACS GCI PR research grants. Highlighted reaction classes follow on from the Green Chemistry paper and are largely based on the key research areas, though new sections have been added. The review period covers October 2017 to March 2018. These articles of interest represent the opinions of the authors and do not necessarily represent the views of the member companies. Some articles are included because, while not currently regarded as green, the chemistry has the potential to improve the current state of the art if developed further. The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures.

The peptide prepared using N-butylpyrrolidone (NBP) had the closest crude purity to that obtained with DMF (80% cf. 86%), tetramethylurea (TMU) and N,N-dimethyl-2-imidazolidinone (DMI) were next best (78%), and dimethyl sulfoxide (DMSO) (52%) and N,N-dimethylpropyleneurea (DMPU) (51%) gave poor results. The crude purity is related to the rate of the coupling reaction, which was run for a fixed time in the test. TMU (H360D) and DMI (H361) both have GHS reproductive toxicity hazard statements, leaving NBP as the best candidate. The higher viscosity of NBP compared with DMF, leading to slower flow through the peptide synthesizer, is suggested to be one of the reasons for the difference in product purity from the unoptimized reaction sequence. (Org. Process Res. Dev. 2018, 22, 494−503) In continuing studies on the use of sustainable solvents in ́ ́ lvarez et al. polar organometallic chemistry, Rodriguez-A reported the successful preparation of biaryl ketones through the addition of aryllithiums to benzonitriles using glycerol as the solvent. Glycerol is a widely available, sustainable solvent that is obtained as a byproduct of biodiesel manufacture. It has good safety properties, including a high boiling point, low volatility, and a flash point of >100 °C, allowing safe use in air to be considered. As a protic solvent, its successful use with aryllithium reagents would not be expected. However, addition of 2 equiv of phenyllithium to benzonitrile in glycerol at room temperature gave benzophenone imine in 85% yield. Treatment with aqueous HCl resulted in rapid hydrolysis, affording benzophenone in 83% overall yield. Benzonitrile is poorly soluble in glycerol, and further investigation led the authors to conclude the reaction occurs “on glycerol”, analogous to “on water” reactions. Also, water was shown to support the reaction during this work, affording benzophenone in 79% yield. Phenylmagnesium bromide did not react. A range of substituted benzonitriles and aryllithiums were evaluated on glycerol and water, and a relationship between the yield and (low) solubility of benzonitrile in the solvent was proposed. Glycerol could be used for inverse addition (benzonitrile to phenyllithium in glycerol), while the same reaction using water resulted in hydrolysis of the phenyllithium. Phenyllithium was successfully added to benzophenone (56%), acetophenone (62%), and trifluoromethyl acetophenone (80%) in glycerol to form the corresponding tertiary alcohols. Although the reactions were conducted in air, the use of the aryllithium in an ethereal solvent (e.g., butyl ether, flash point 25 °C) would require an inert atmosphere for safer scale-up. (Chem.Eur. J. 2018, 24, 1720−1725)

2. SOLVENTS Solid-phase peptide synthesis (SPPS) is one of the main approaches for the manufacture of therapeutic peptides. SPPS involves repeating cycles of carboxylate activation, coupling, deprotection, and washing until the peptide chain is complete, followed by release from the resin. The approach can be automated; however, it typically generates a large amount of solvent waste (e.g., the preparation of 1 kg of octreotide, a cyclic octapeptide, generates 2−3 tons of solvent waste). A drawback of the approach is the widespread use of reprotoxic dipolar aprotic solvents, in particular N,N-dimethylformamide (DMF), which is listed as a substance of very high concern under the EU REACH legislation. Lopez et al. conducted a systematic evaluation of 37 solvents to identify a less toxic alternative to DMF for SPPS using a polystyrene resin support. A series of experiments measuring resin swelling, solubility of the SPPS reagents, the rate of coupling using Oxyma/ diisopropylcarbodiimide activation, and FMOC protecting group cleavage reduced the number of solvents to five polar aprotic solvents, which were compared in a use test preparation of a linear octapeptide used in the manufacture of octreotide. © 2019 American Chemical Society

Published: May 23, 2019 1118

DOI: 10.1021/acs.oprd.9b00158 Org. Process Res. Dev. 2019, 23, 1118−1133

Organic Process Research & Development

Green Chemistry Highlights

3. AMIDE FORMATION Two reports that discuss use of more sustainable solvents in amidation reactions emerged in the period under review. Petchey et al. reported the use of predictive tools to enable judicious selection of the solvent in a series of K60-silicacatalyzed direct amidation reactions. Specifically, the authors used the Hansen Solubility Parameters in Practice (HSPiP) software package in conjunction with the Yalkowsky approximation to predict the solubilities of the amide products in a series of solvents at different temperatures, with the goal being to identify a suitable bio-based solvent not only to mediate the reaction but also to allow the direct isolation of high-purity product by filtration. Experimentally, they evaluated 13 acid/amine combinations under the standard conditions of toluene at reflux (111 °C), p-cymene (derived from D-limonene) at 111 °C, and p-cymene at reflux (177 °C). Although toluene performed better in many cases at the lower temperature, the authors noted a significant boost when the reaction was carried out at the higher temperature, and this was further enhanced by the fact that the amide solubilities were consistently lower in p-cymene. Use of this solvent in a continuous flow amidation process was also demonstrated. Despite the many advantages reported herein, research is required in order to make the bio-based production of pcymene more economically viable. (ACS Sustainable Chem. Eng. 2018, 6, 1550−1554) Wilson et al. reported on perhaps a more conventional strategy in replacing dipolar aprotic solvents (DMF, Nmethylpyrrolidone (NMP)) directly with the bio-based solvent Cyrene (two steps from cellulose) in the HATU-mediated coupling of acids and amines. Model studies on the reaction between p-toluic acid and aniline demonstrated the importance of rapid stirring to obtain reproducible results because of the viscous nature of Cyrene, which often led to suboptimal mixing at low stirring rates. However, variation in the excess of diisopropylethylamine (DIPEA) (2 to 3 equiv) was able to mitigate this to a large degree. Under the optimal conditions, a range of alkyl and aryl carboxylic acids and amines (primary, acyclic, and cyclic secondary) were successfully coupled, though in cases where low yields were encountered, the mass balance was found to be primarily composed of the unreacted activated ester. The conditions were extended to a series of peptide couplings (in which unprotected heteroaromatic residues were tolerated), and one of these was successfully demonstrated on a gram scale with the product isolated after a workup/trituration protocol. (Org. Biomol. Chem. 2018, 16, 2851−2854)

The challenges in promoting the direct amidation reaction of acids and amines (e.g., ammonium salt formation) have long been recognized, and though impressive advances have been made, especially with regard to catalysis, there are still significant breakthroughs remaining to be realized before this can truly be recognized as a general approach to amide bond formation. Dalu et al. reported a direct amidation reaction that is thermally driven using ethanol (recognized as a green solvent) as the reaction medium and generates only water and ethanol as the byproducts. The initial finding was somewhat fortuitous in that the authors were evaluating the reaction of oleic acid and oleylamine to cap metal oxide nanoparticles but then found out that the corresponding N-oleyloleamide was formed in 80% conversion even in the absence of the nanoparticles. Recognizing the importance of this finding, they carried out a systematic variation of the reaction parameters, which revealed that the highest conversion was realized at 160 °C, with an acid concentration of 1.05 M and a reaction time of 6 h. The ethyl ester of oleic acid was postulated as the reactive species under these conditions, and indeed, this material can be observed by NMR spectroscopy. Further experimentation highlighted the beneficial roles of acid and water in the process, wherein the former catalyzes the amide formation through protonation of the ester while the latter facilitates elimination of the leaving group in the nucleophilic acyl substitution. From a scope perspective, aliphatic and aromatic acids and amines were all shown to be successful substrates, though the yield drops precipitously in the cases of benzoic acids and anilines. The stereochemical integrity of both olefins and chiral centers is preserved in the process, and although no heterocyclic substrates have been demonstrated at this stage, the fact that an example was demonstrated on a multigram scale suggests that this solvothermal approach is worthy of further investigation. (Green Chem. 2018, 20, 375−381)

Often the rationale for using undesirable solvents such as DMF, N,N-dimethylacetamide (DMAC), and NMP in amide synthesis is increased solubility of a wide range of reagents as well as a stabilizing effect on charge-polarized transition states of a suitably activated acid and an amine. Surveying the vast number of examples within the literature describing the 1119




reaction of acid chlorides and amines to form amides, Otsuka et al. made the observation that for almost half of the cases carried out in DMAC, no additional base (e.g., DIPEA, Et3N) was added. This led to the hypothesis that perhaps in these instances the solvent itself served as a latent Brønsted base catalyst and thus acted as a reagent rather than a solvent. Evaluation of the reaction between 4-methoxybenzylamine and chloroacetyl chloride supported this, as good yields of the desired amide were obtained (and isolated by direct precipitation upon addition of water) when the reaction was run with as little as 2 equiv of DMAC. Of a number of other solvents evaluated (EtOAc, acetone, CH2Cl2), the reaction stalled at less than 50% conversion, though high yields could be realized in these solvents if DMAC (typically 2 equiv) was added (providing an alternative approach to amide synthesis herein using only stoichiometric quantities of this solvent). In addition, DMAC was shown to be a superior base compared with several others evaluated in this model system given its inability to deprotonate the α-position of the acid chloride. The use of the solvent as the base was extended for this reaction to a range of urea-based solvents, thus providing the opportunity for more environmentally acceptable solvents to be explored, though ease of isolation should be considered when evaluating a new process. Examination of the scope showed that in a somewhat counterintuitive manner, the combination of aromatic acid chlorides and anilines reacted fastest under the influence of DMAC catalysis, which provides some intriguing opportunities from a selective amidation perspective. (Synthesis 2018, 50, 2041−2057)

The major rise in the number of peptide-based products both on the market and in development pipelines has prompted a rise in interest in sustainable methods to access these compounds in an efficient manner. Although SPPS has represented the benchmark in peptide synthesis, the number of reagents, solvents, and water involved in this process, particularly on scale, creates a significant environmental burden. Muramatsu et al. reported a catalytic reaction for amide bond synthesis that in contrast to the majority of previous approaches is subject to “substrate” (as opposed to “reagent”) control. The starting materials for the reaction are the N-hydroxyimino esters (easily accessed through reaction of the pyruvate and NH2OH or reaction of the ester with nitroso reagents) and the hydrochloride salts of the t-Bu esterprotected amino acids (easily handled and stable for long-term storage). Model studies indicated that the use of Et3N as the base and a catalytic amount of Nb(OEt)5 enabled the desired amides to be obtained in quantitative yield under solvent-free conditions after 24 h. The reaction time could be significantly shortened using microwave irradiation and petroleum ether as the solvent with only a slight attrition in yield. The method was applied to a wide variety of protected amino acids, and although slightly lower yields were observed in cases in which a free OH group was present, the fact that the method tolerates a range of unprotected functional groups (such as a free indole) is an advantage. Mechanistic studies indicated that the rate of the amidation reaction is related to the geometric conformation of the N-hydroxyimino ester, with the typical racemization pathway of enolization of either the activated acid or the oxazolone precluded through the bulk of the t-Bu protecting group and the formation of an intermediate Nbbased chelate. To access the desired peptides, diastereoselective hydrogenation of the oxime functionality is carried out under Pd catalysis [Pd(OH)2/C] to give the new chiral carbon (S configuration), typically in high yield and diastereoselectivity (>99:1 dr). In cases in which diminished diastereoselectivity was obtained, it was possible to separate the diastereomers through a variety of conventional techniques (chromatography, etc.). (ACS Catal. 2018, 8, 2181−2187)

Métro et al. provided a brief perspective on the advantages, from a sustainability perspective, of utilizing 1,1′-carbonyldiimidazole (CDI) in combination with mechanochemistry (specifically ball-milling) to activate carboxylic acids. A range of practical examples is highlighted, including amidation to form the active pharmaceutical ingredient teriflunomide, which is indicated in the treatment of multiple sclerosis. Not only is the innocuous nature of the byproducts (imidazole, CO2) from CDI highlighted, but several benefits from their formation are also discussed. For example, imidazole can easily be removed by aqueous washes, can function as a base, and because of its relatively low melting point favors the formation of eutectics, which may explain why often these reactions do not require additional external liquid grinding assistants (though poly(ethylene glycol) derivatives are used in some studies). In addition to easy removal of CO2 because of its gaseous nature, CO2 release is also proposed to enhance the reaction rate (because it is not trapped in an organic solvent) and potentially to enhance mixing. (ACS Sustainable Chem. Eng. 2017, 5, 9599−9562) 1120




Two reports emerged that document the utility of commercially available silicon-based reagents to mediate simple amide bond formation reactions between carboxylic acids and amines. Sayes and Charette described the use of diphenylsilane as a coupling reagent, with the optimal reaction conditions for amide bond formation utilizing MeCN as the catalyst at 60 °C. In addition, they showed that concentrated reaction conditions favor higher yields of the desired product and proposed that the reaction proceeds through a chemical ligation pathway on the basis of the observation that both the acid and amine react individually with the silane catalyst. Because the intermediate with both species ligated to the silicon could not be observed, the authors also suggested that a competitive pathway involving initial acid activation might be in play. A range of benzylic, aromatic, and aliphatic acids were coupled with primary and secondary amines. In the case where a stereocenter was present in the acid, a slight degree of epimerization was observed, and the authors also noted that benzoic acids are more sluggish reactants. To extend the methodology of the peptide coupling, addition of both DMAP and DIPEA to the system was found to be necessary, though in these cases both the yield and in some cases the degree of epimerization were dictated by both sterics and product inhibition of the reaction. (Green Chem 2017, 19, 5060−5064) Braddock et al. reported the use of tetramethyl orthosilicate (TMOS) in toluene at reflux to mediate this transformation. The major advantage of this method appears to be the simple workup, in which base hydrolysis destroys the excess reagent, allowing essentially pure amide to be obtained through extractive workup. Again, a good scope was demonstrated, no epimerization was detected, and the approach was successfully applied to a series of pharmaceutically active scaffolds containing basic nitrogen atoms. From a mechanistic perspective, in this report only the acid activation as a silyl ester pathway was proposed for in situ evidence of this intermediate being observed by NMR spectroscopy. Attempts to scale a reaction to 1 mol at a concentration of 2 M did cause a significant retardation in rate, and this was attributed to retention of methanol in the reaction mixture. To overcome this, a procedure was developed in which methanol was removed throughout the process by fractional distillation to provide a 90% yield of the desired product after 12 h. The process mass intensity (PMI) of this reaction was calculated to be 43, which compares favorably with the more conventional methods for amide bond formation. (Org. Lett. 2018, 20, 950−953)

Investigations into the Ru-catalyzed oxidative amidation reaction between alcohols and amines are gaining popularity, and although several active well-defined Ru−NHC halide complexes have been identified for this transformation, typically they require initial preparation of the corresponding Ag−NHC complex (followed by transmetalation) as well as the presence of an additional ligand to facilitate isolation and purification. Cheng et al. reported a study of this oxidative amidation in which they screened the reaction between benzyl alcohol and benzylamine in the presence of a number of Nheterocyclic carbene (NHC) precursors (mono- and multidentate), [RuCl2(p-cymene)]2, and NaH (a strong base). These studies revealed that monodentate benzimidazole-based catalysts were by far the most effective, while further optimization studies with this system indicated that the amount of NaH (20 mol %) was crucial for success. The optimized system worked well for numerous benzylic alcohols, though it was somewhat sensitive to steric effects but surprisingly not the electronics of this component. For the amines, the reaction worked with both primary and secondary amines (in some cases, refluxing mesitylene was used instead of refluxing toluene as the reaction medium), though in the case of the weakly basic anilines, diminished yields were observed. Mechanistic studies were carried out by both NMR spectroscopy and high-resolution mass spectrometry, and it was hypothesized that the success of the benzimidazole system (specifically compared with the analogous imidazole) is due the ability of this ligand to enable the faster formation of the key Ru−H species in the presence of the alcohol. This is believed to be explicitly enabled by the benzimidazole-based NHC lowering the electron density at the Ru center, thus enabling ligand substitution of the halides (initially by alkoxide) to take place in a more facile manner. (Chem. Asian J. 2018, 13, 440−448)

Kolesnikov et al. have reported an atom-economical Rhcatalyzed reductive amidation reaction for the formation of amides, which not only employs CO as a deoxygenative agent, but also shows a remarkable solvent dependency for the 1121




4. OXIDATION Direct C−H oxidation of aliphatic amines can provide efficient access to valuable amino ketones. Taking advantage of the ability of the decatungstate anion to oxidize unbiased aliphatic alkanes, Schultz et al. developed a distal oxidation of aliphatic amines via amine protonation and decatungstate photocatalysis. The reaction is catalyzed by 1% sodium decatungstate (NaDT) in the presence of sulfuric acid and uses H2O2 as the terminal oxidant in batch mode. Various γ- and β-amino ketones can be obtained in moderate to good yields. This can also be performed in a continuous flow setup using oxygen as the terminal oxidant to enable the scale-up. Additionally, in situ light-emitting diode (LED) NMR spectroscopy was developed to monitor the kinetics of the reaction. (Angew. Chem., Int. Ed. 2017, 56, 15274−15278)

reaction outcome. Model studies on the reaction of benzamide with p-fluorobenzaldehyde indicated that Rh2(OAc)4 was the best catalyst with THF as the best solvent while the reaction temperature was shown to be substrate dependent (aliphatic amides working better at slightly lower temperatures than the aromatic counterparts). In addition, in demonstrating the scope of the new methodology, amidation of piracetam (the parent compound of the racetam family of drugs) was demonstrated, enabling facile late-stage N-functionalization at the amide function to probe biological activity which is known to be key for the compound’s pharmaceutical properties in this family. Interestingly, switching the solvent to MeOH, and employing a 3:1 ratio of aldehyde to amide, led to good yields of the tertiary amides. Although it is obvious herein that the central nitrogen must originate from the amide starting material, it is unclear how this reaction proceeds though mechanistic hypotheses based on previous observations and deuterium labeling studies are provided for both this and the reductive amidation protocol. (Org. Lett. 2017, 19, 5657−5660)

Laudadio et al. also reported C−H oxidation by decatungstate photocatalysis in flow. With tetrabutylammonium decatungstate (TBADT) as the hydrogen atom transfer photocatalyst and oxygen as the oxidant, a wide range of aliphatic alkanes such as cyclohexane can be oxidized to the corresponding ketones in moderate to good yields. Benzylic C−H oxidation also worked well to give aromatic ketones. The method can selectively oxidize natural scaffolds such as (−)-ambroxide, pregnenolone acetate, (+)-sclareolide, and artemisinin, demonstrating its potential application in latestage functionalization. (Angew. Chem., Int. Ed. 2018, 57, 4078−4082)

Nageswara Rao and co-workers reported two metal- and base-free oxidative amidation approaches, both mediated by the combination of I2 and tert-butyl hydroperoxide (TBHP). In the case of benzylamines, the model reaction utilizing Nmethylbenzylamine indicated that although 20 mol % I2 was optimal, it was key to find a balance between the amount of aqueous TBHP (an excess was required) and the temperature. Other oxidants and sources of iodide were shown to be less effective for the reaction. A range of examples of both primary and secondary amines were provided, though heteroaromatic derivatives led to diminished yields and tertiary amines gave only trace amounts of product. Applying these conditions in the presence of ammonia (or other amines) to the amidation of benzyl nitriles required some optimization of the reaction time to obtain complete conversion. Electron-donating and electron-withdrawing substituents were all tolerated, though again heteroaromatic compounds gave lower yields. Ammonia and primary and cyclic secondary amines could all be successfully employed, and initial mechanistic studies on both reaction paradigms indicated not only that a radicalbased mechanism is likely to be in operation but also that the reaction can potentially be exploited for selective monobenzylic oxidation. (J. Org. Chem. 2017, 82, 13632−13642)

Stoichiometric amounts of oxidants, often toxic, are typically required for oxidative cleavage of 1,2-diols. To enable this fundamental transformation under greener conditions, Zhou et al. developed a catalytic method using silver triflate and 1 atm O2 as the oxidant. The reaction proceeds at a mild temperature, although significantly above the flash point of the solvents used, and generally gives various aryl or alkyl carboxylic acids or ketones in high yields. (Angew. Chem., Int. Ed. 2018, 57, 2616−2620)

2,4-Dichloro-5-fluorobenzoic acid is an important intermediate for pharmaceuticals, pesticides, and antimicrobial agents, but the existing methods to prepare it from the acetophenone starting material in a batch process all suffer 1122




from adverse environmental impact. Leveraging the ability of a gas−liquid flow setup to handle highly exothermic reactions, Guo et al. developed a safer and greener method by using oxygen gas and a solvent mixture of nitric acid and acetic acid. The product crystallized out directly upon cooling in the collection tank and was isolated in >99% yield in a kilogramscale run with an output of 2.7 kg/h. The same reaction in batch mode gave a yield of only 81% with potential scale-up issues due to the large exotherm. (Org. Process Res. Dev. 2018, 22, 252−256)

Although iridium is a platinum group element with low earth abundance, Ir-based catalysts continue to prove to be invaluable for the asymmetric hydrogenation of unfunctionalized olefins. Müller et al. at the University of Basel reported the recovery and recycling of iridium phosphinopyridine hydrogenation catalysts. By the addition of cyclooctadiene (COD) to the dimeric Ir(III) dihydride complex that the catalyst forms once the reaction substrate has been consumed, a CODbearing precatalyst was regenerated. This species is stable toward oxygen and moisture and can be isolated with 60−70% recovery after filtration through a silica pad. The recovered catalyst displays the same reactivity and enantioselectivity as the original precatalyst, though readers should note that the reactions are performed in dichloromethane. Iridium catalysts that use phosphinooxazoline ligands irreversibly convert to catalytically inactive iridium clusters once the substrate has been consumed, indicating that the above procedure does not seem to work in general for such catalysts. (Adv. Synth. Catal. 2018, 360, 1340−1345)

Co-catalyzed C−H amination is known, but it usually requires stoichiometric amounts of silver or manganese oxidants. Gao et al. developed an electrochemical approach to this reaction that avoids the use of a chemical oxidant. With the quinolinylamide directing group, arenes and heteroarenes (furans and thiophenes) can be ortho-aminated by secondary alkylamines in moderate yields with a 20% loading of the cobalt catalyst in divided cells. Various functional groups are tolerated. A key step in the proposed catalytic cycle is the anode oxidation of Co(II) to Co(III) prior to C−H activation at the ortho position by Co(III). (J. Am. Chem. Soc. 2018, 140, 4195−4199)

5. ASYMMETRIC HYDROGENATION Jing et al. reported the encapsulation of a Noyori−Ikariya catalyst within hollow silica particles and the use of these structures for asymmetric transfer hydrogenation. The method involves the polymerization of a vinyl-bearing version of the parent diphenylethylenediamine ligand with styrene within the cavities of the silica particles. Subsequent exposure to a solution containing [Cp*RhCl2]2 allows the immobilized ligand to coordinate to the metal to form an encapsulated catalyst. The catalyst is described as acting as though it were “semifree” rather than genuinely heterogeneous. This may explain why the use of these structures for the asymmetric transfer hydrogenation of acetophenone structures produces a turnover frequency broadly similar to (actually, almost 40% higher than) that of the corresponding nonencapsulated catalyst, as well as a similar enantioselectivity. The silica particles were recovered at the end of the reaction by centrifugation. Recycling (demonstrated with a further three cycles) was shown not to affect the enantioselectivity, though the reaction time increased with each recycle, which was in part attributed to leaching of 5% rhodium from the particles with each cycle. The applicability of the method to substrates other than acetophenones was not discussed. (Catal. Sci. Technol. 2018, 8, 2304−2311)

Yamada et al. from Takeda and the ATTO Corporation developed an efficient hydrogenation as part of a set of processes used for the large-scale production of fasiglifam, a phase III clinical candidate for the treatment of diabetes. At the outset of process development, a 1% loading of a rhodium catalyst produced a telescoped product with 91.0% ee. Chiral chromatography was used to upgrade the enantiomeric excess in order to meet an acceptance criterion of ≥99.7%. Process optimization identified a cheaper ruthenium catalyst that provided an improvement in the substrate/catalyst ratio to 20 000. While these changes were detrimental to the ee (81− 83%), a diastereomeric salt resolution was used to control the level of the undesired stereoisomer. The crystallization used a mixture of solvents, including diisopropyl ether (CAUTION: risk of peroxide formation upon exposure to oxygen). The low catalyst loading necessitated prior purification of the starting material (in order to purge it of trace catalyst poisons) and control of the oxygen content of the methanol solvent to no more than 1 ppm. With these controls in place, the process was successfully used to process 2 tons of the product. (J. Synth. Org. Chem. Jpn. 2017, 75, 432−440) 1123




Finally, the addition of secondary amines was demonstrated in an analogous fashion. All examples were based on cyclic secondary amines (morpholine, piperidine, and piperazine) and were run in a similar way as for the alkyne chemistry (2 equiv of amine). The reactions were optimized with γvalerolactone (GVL), and the same cobalt catalyst and undivided electrochemical reactor setup were utilized. Longer reaction times (24 h) and increased temperature (40 °C) were required to achieve the desired conversions (55−83%). (Angew. Chem., Int. Ed. 2018, 57, 5090−5094)

6. C−H ACTIVATION Ackermann and co-workers have published several examples of electrochemical C−H activation of pyridine N-oxide benzamide systems. Each publication discusses the mechanistic understanding of the transformation, including the importance of the pyridine N-oxide directing group and cyclic voltammetry measurements to understand the catalytic cycle. By the use of this methodology, it was possible to generate new bicyclic systems by reaction with substituted alkynes. Conditions were optimized in an undivided cell with a reticulated vitreous carbon (RVC) anode and platinum cathode. Reaction screening quickly determined that a variety of other metal catalysts were all ineffective but cobalt at 10 mol % reliably produced the desired transformation. In each case, 2 equiv of base and 2 equiv of alkyne were required, but the reaction proceeded cleanly in methanol/water mixtures. Halides on the benzamide ring were well-tolerated, and while alcohol/water mixtures were preferred, the reaction proceeded in water alone, although in a slightly reduced yield (77 vs 51% as one example). Alkynes containing aromatic groups, alkyl halides, and even cyclopropyl groups were cleanly converted to the desired products in yields of 55−85%. (Angew. Chem., Int. Ed. 2018, 57, 2383−2387)

Wang and co-workers reported an annulation to form carbazoles from acetyl indoles and alkynes. The reaction is operationally simple, as a readily available metal-free catalyst (N-bromosuccinimide, NBS) promotes the reaction. The carbazole products are densely functionalized and can be further elaborated. A wide variety of substituted phenylacetylene derivatives undergo annulation in high yield (76− 99%) with excellent regioselectivity, and the reaction is tolerant of halogens, esters, and ethers. Unfortunately, internal alkynes and alkyl-substituted alkynes lead to much lower yields (12− 22%). The indole fragment can be varied across the ring with little change in reaction performance. In addition, N-H and Nalkyl indoles are both effective coupling partners. Acetyl indole requires an electron-withdrawing group to be present for the reaction to occur, and the authors show that nitriles, amides, esters, and ketones are effective substituents. Some drawbacks to the current methodology are the long reaction times and relatively high catalyst loading. (Org. Lett. 2017, 19, 6140−6143)

In a second publication, Ackermann and co-workers investigated incorporation of alcohols into similar benzamide systems. When these conditions were optimized, a divided cell provided slightly better yields, but the same cathode and anode setup was utilized. Cobalt remained the best metal for the desired transformations, and in the case of simple alcohols, the reactant could also be used as the solvent. Substitution on the starting benzamide was well-tolerated, and functional groups similar to those explored in the alkyne case were investigated. For more precious alcohols, the amount could be reduced by mixing with acetonitrile and phase transfer catalysts, but a significant excess was still required along with increased reaction temperature (60 °C). Additionally, several examples of incorporating alcohols into various trisubstituted alkenes were provided. (J. Am. Chem. Soc. 2017, 139, 18452−18455)

Preparatively useful C−H hydroxylation using an αketoglutarate (αKG)-dependent dioxygenase was demonstrated for the first time. Notably, the enzyme GriE shows excellent catalytic efficiency and substrate promiscuity, which allows for chemo- and stereoselective hydroxylation at the δposition of several unprotected α-amino acids. In all cases the products were formed with >99:1 dr. While most substrates produce alcohol products, double oxidation can occur for γmethyl-L-leucine (Mleu) and its derivatives, which allows for facile synthesis of proline derivatives. In addition, the power of this chemoenzymatic synthesis was highlighted in the five-step 1124




temperature and exhibits efficient direct hydrofluorination of alkenes due to the bifunctional role of KHSO4. The −O−K+ terminus is a strong hydrogen-bond acceptor for HF that condenses gaseous HF to a liquid solution and enhances the nucleophilicity of HF, and the −OH terminus is a strongly acidic group (pKa = 1.9) whose acidity is further enhanced by the HF hydrogen-bonding network. This reagent directly hydrofluorinated monosubstituted, disubstituted, and trisubstituted alkenes in a yield range of 31−94% (with most yields above 70%) within 2 h. Functional group tolerability was observed with ester, sulfonate, sulfonamide, alkyne, nitro, aldehyde, free hydroxyl, and heterocycle groups. Regioselectivity in favor of the double bond with higher HOMO electron density was also observed. Although substrate scope studies were carried out in environmentally unfriendly 1,2-dichloroethane,2 the authors showed that the reaction performed equally well in toluene. (J. Am. Chem. Soc. 2017, 139, 18202−18205)

formal synthesis of manzacidin. While the enzyme shows some reasonable promiscuity, D-amino acids and some common Lamino acids, such as L-valine and L-isoleucine, cannot be functionalized because they do not properly orient in the enzyme’s binding pocket. (J. Am. Chem. Soc. 2018, 140, 1165−1169)

7. FLUORINATION The use of difluoromethyl (CF2H) as a structural mimic of the hydroxymethyl group in bioactive molecules has attracted considerable attention. Available synthetic methods for introducing CF2H to arenes are radical approaches, crosscouplings of aryl halides with difluoromethyl metal reagents, and cross-couplings of arylmetal reagents with difluorocarbene sources. Coupling of arylmetals with XCF2H reagents has scarcely been reported when X is a halogen atom, presumably because of the low boiling points and limited accessibilities of these reagents, not to mention potential complications from undesired deprotonation. Miao et al. reported the first ironcatalyzed difluoromethylation of arylzincs using difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H), a bench-stable and costeffective reagent previously developed by the same group. The reported conditions are very mild, employing Ar2Zn (1.5 equiv), PySO2CF2H (1.0 equiv), Fe(acac)3 (0.2 equiv) as the catalyst, N,N,N′,N′-tetramethylethylenediamine (TMEDA) (2.0 equiv) as the ligand, and THF as the solvent over the temperature range from −40 °C to room temperature. These conditions converted a range of arylzincs to difluoromethylated arenes in 53−94% yield, including electron-neutral, -rich, and -poor arylzincs with meta or para substituents, arylzincs bearing an olefin or acetal group, and heteroarylzincs. An ortho-substituted arylzinc gave an inferior yield of 36%. On the basis of the results of radical inhibition experiments, the authors proposed a catalytic cycle involving a single-electron transfer between an in situ arylzinc-reduced iron species (LFe(n)Ar) and 2-PySO2CF2H to generate LFe(n+1)Ar and a radical anion of the latter. The radical anion fragments to form a difluoromethyl radical, recombination of which with LFe(n+1)Ar followed by reductive elimination delivers the product. (J. Am. Chem. Soc. 2018, 140, 880−883)

A number of halogen-exchange fluorination methods have been reported for allylic, primary, and secondary alkyl halides, but reports on fluorination of tert-alkyl halides are limited, most of which involve formation of carbocations and hence suffer from competing solvolysis, elimination, or rearrangement, narrowing the substrate scope to bridgehead halides. A copper-catalyzed fluorination of α-bromo-N-arylamides with CsF does not work for ordinary tertiary all-alkyl halides. Chen et al. reported a direct halogen-exchange fluorination of tertiary all-alkyl halides using Selectfluor, which is proposed to proceed through alkyl radicals and expands the substrate scope. Treatment of tert-alkyl bromides or iodides with 3 equiv of Selectfluor in acetonitrile at room temperature gives the corresponding fluorides in 12 h. Substrates bearing ether, ketone, ester, amide, imide, nitro, sulfone, or sulfonate functional groups were converted to the corresponding fluorides in 40−96% yield. tert-Alkyl bromides bearing a motif of primary, secondary, or tertiary chloride or primary, secondary, or dialkyl α-carbamoyl bromide all gave site-specific fluorination at the tertiary all-alkyl bromide with the other halide moieties intact. On the basis of a radical probing experiment and an isolation to determine the fate of Selectfluor, the authors proposed a radical pathway in which an aminium radical cation is generated via single-electron reduction of Selectfluor, presumably by tert-alkyl bromide. Extraction of a bromine atom from the substrate affords the tert-alkyl radical, which in turn extracts a fluorine atom from Selectfluor to generate the fluoride. The reaction with 1 equiv of Selectfluor proceeds but requires a longer reaction time (36 h) and therefore was not applied to substrate scope studies. (Angew. Chem., Int. Ed. 2017, 56, 15411−15415)

The direct hydrofluorination of alkenes using hydrogen fluoride is a challenging fundamental transformation because of the insufficient acidity of HF in the available complexed form, such as that with Et3N, pyridine, or DMPU. Previous reports using pyridine−HF or a HF-based superacid system (HF/ SbF5) have restricted substrate scope. Alternatively, a few formal hydrofluorinations have been developed using combinations of electrophilic fluorination reagents and reductants, mediated or catalyzed by transition metals. Lu et al. reported the development of a new-generation KHSO4-complexed HF reagent for direct hydrofluorination of alkenes. This reagent, in the form of KHSO4·13HF, is a stable liquid at room 1125




8. BIOCATALYSIS Imine reductases (IREDs) are a very promising group of enzymes used to catalyze the asymmetric reductive amination of ketones, resulting in the formation of secondary and tertiary amines. Borlinghause et al. showed that the substrate scope of these enzymes can be successfully extended to the preparation of a set of piperazine moieties. Initially three enantiocomplementary IREDs (R-IRED_Ms from Myxococcus stipitatus, RIRED_Sr from Streptosporangium roseum, and S-IRED_Pe from Paenibacillus elgii) were investigated in the reaction of 1,2diamines with 1,2-dicarbonyls, with product formation monitored by the depletion of NADPH. Piperazines were obtained with high enantiomeric excess (>99% ee). In addition, the enzymes appear to tolerate 1,2-diamines despite their known toxicity toward proteins. Furthermore, the specificity of R-IRED_Ms was assessed on 68 substrate combinations. The results showed that several alkyl and aryl groups are well-accepted; arylamines and carboxy- or esterfunctionalized diamines did not react. Several reactions occurred with regioselectivity or high diastereoselectivity when relevant. The practical utility of R-IRED_Ms was demonstrated by running several reactions at high substrate concentrations [50 mM (1,2-diamine) and 62.5 mM (1,2dicarbonyl)] which resulted in yields of up to 92%. (ACS Catal. 2018, 8, 3727−3732)

peroxygenase and a gold-loaded TiO2 plasmonic photocatalyst. As a proof of principle, ethylbenzene was used as a model substrate and oxidized to (R)-1-phenylethanol by the use of Au-loaded TiO2 as a methanol oxidation catalyst with a turnover number of approximately 71 000. Studies also showed that a steady concentration of hydrogen peroxide maintains the enzyme activity. The reaction was shown not to progress in the absence of the photocatalyst or when run in the dark. A systematic investigation of the effect of the methanol concentration was conducted, which showed that an increase in concentration has a positive influence on process robustness. Other parameters such as the photocatalyst and enzyme concentrations were also evaluated in addition to testing other alcohols such as ethanol or isopropanol, which proved to be less effective than methanol. When the substrate scope was investigated, a range of (cyclo)alkanes and alkyl arenes were successfully converted to the corresponding alcohols. (Angew. Chem., Int. Ed. 2017, 56, 15451−15455)

An acyl transferase from Mycobacterium smegmatis (MsAcT) was reported to perform the transesterification of alcohols in aqueous media. MsAcT is reported to have a very hydrophobic active site that allows the reaction to take place in the presence of water. In this paper, the authors showed transesterification of a range of primary and secondary alcohols in phosphate buffer (pH 7.5) using ethyl acetate or vinyl acetate as the acyl donor. Primary alcohols were converted in good yields (>90%) in less than an hour, but secondary alcohols required longer reaction times (up to 5 h). Hydrolysis of the ester product and acyl donor are the main side reactions, and a sharp pH drop is observed during the reaction. Kinetic resolution of cyanohydrins and alkynols was investigated, and opposite enantioselectivities were observed, most likely caused by the difference in polarity between nitrile and alkyne groups. Preparative kinetic resolution of 2-hydroxypentanenitrile and hex-1-yn-3-ol (3.5 mmol scale) was performed. (R)-1-Cyanobutyl acetate was isolated in 16% yield with 94% ee after column chromatography, and (S)-hex-1-yn-3-yl acetate was isolated in 38% yield with 90% ee. This methodology expands the enzyme toolbox for esterification reactions. (Adv. Synth. Catal. 2018, 360, 242−249)

Zhang et al. demonstrated the first use of a biocatalytic C−H functionalization for the synthesis of tambromycin. Retrosynthetic analysis identified C3-oxidized lysine as a useful intermediate that could be synthesized via a lysine hydroxylase, KDO1. The biocatalytic reaction using KDO1 suffered from several drawbacks, such as poor enzyme expression and reaction scalability, which were elegantly addressed by evaluating the relative expression level of KDO1 in different constructs as well as using chaperones. The reaction was scaled up to 4.1 g of L-Lys with >99% conversion to the hydroxylated product, resulting in a highly economical process. Attempts to run an enzymatic intramolecular cyclization starting from hydroxylated lysine using VioD, a PLP-dependent enzyme from the capreomycidine biosynthesis pathway, failed. (Angew. Chem., Int. Ed. 2018, 57, 5037−5041)

A one-pot, two-step approach using two laccases from the Trametes versicolor/2,2,6,6-tetramethylpiperidin-N-oxyl (TEMPO) system and enoate reductases (EREDs) to prepare saturated ketones from allylic alcohols was reported. The reactions were first optimized separately. A number of allylic sec-alcohols were treated with laccase/TEMPO, and >99% conversion to the unsaturated ketones in pH 5 citrate buffer was observed. Methyl tert-butyl ether (20% v/v) was added for hydrophobic compounds in order to drive the reaction to completion. The ERED-catalyzed bioreduction could also be run at pH 5, showing excellent conversion and selectivity for most examples. When the reaction was run in one pot, laccase/ TEMPO was found to be incompatible with the NADPH recycling system (glucose−GDH) used in the ERED-catalyzed

Selective C−H functionalization was successfully demonstrated by combining inorganic photocatalysts with biocatalysis. To achieve their goals, Zhang et al. employed rAaeUPO 1126




reaction, and therefore, the reactions had to be performed sequentially. This approach provides an alternative to the metal-catalyzed redox isomerization of this type of compound. (ACS Catal. 2018, 8, 2413−2419)

9. REDUCTION Brenna et al. reported a three-step approach for the preparation of chiral keto esters. In the first step, allylic C− H hydroxylation of cycloalkenecarboxylates was performed using calcium alginate-entrapped Rhizopus oryzae resting cells with >96% conversion after 3 days. In contrast to most traditional chemical methods, the oxidation showed very little or no formation of unsaturated keto esters or byproducts. Oxidation of the allylic alcohols was achieved using a laccase/ TEMPO system that led to the corresponding ketones in quantitative yield after 24 h in a sequential cascade. Finally, the enantioselective reduction of the unsaturated keto ester was studied using ERED from the old yellow family (OYE), affording either enantiomer with excellent conversion and very good selectivities. In contrast to the previous example, the laccase and ERED reactions were compatible upon removal of the dissolved oxygen via bubbling of nitrogen. The three-step procedure represents a sustainable and selective alternative to prepare cyclic γ-keto esters compared to traditional methods. In particular, the hydroxylation reaction was reported to occur with high regioselectivity and little byproduct formation and could be used for direct C−H hydroxylations. (Green Chem. 2017, 19, 5122−5130)

Kelly et al. reported a manganese catalyst with the ability to reduce aldehydes, ketones, esters, and tertiary amides at 25 °C. This follows on from previous work in the group whereby the corresponding iron system was used to reduce aldehydes, esters, and ketones. The catalyst features high-spin manganese(II) (S = 5/2) in a distorted trigonal-planar structure. Aldehydes, ketones, and esters were reduced in >90% yield with 1 mol % catalyst and PhSiH3 as reductant within 4 h at 25 °C. Only tertiary amides were successfully reduced, and there was generally a need for higher catalyst loadings (5 mol %) and temperatures to realize high yields. Some simple cases were shown to be accessible with 2 mol % catalyst at 25 °C. Some examples demonstrate potential limitations. A 2-thienylcarboxamide gave poor performance at 25 °C, while 1-benzyl-2piperidone gave no reaction at all. Substrates containing −NO2 or −CN also gave complex mixtures at elevated temperatures, suggesting that other reaction pathways become competitive. A further issue to be addressed was the solvent choice, since all of the reactions were conducted in benzene with no attempt to explore other options. (Angew. Chem., Int. Ed. 2017, 56, 15901−15904)

A three-step cascade approach for the preparation of secondary amines starting from cycloalkanes was described. The cascade makes use of a p450 monooxygenase (P450-BM3 mutant) followed by an alcohol dehydrogenase (TeSADH variant) and an imine reductase (AspRedAm). The authors used cyclohexane as a model substrate. The reductase domain of P450-BM3 was modified to increase its affinity for NADH cofactor and minimize the incompatibility between the P450 and the IRED. Initial experiments showed that the P450 activity was affected by the amine concentration. Additional experiments suggested that endogenous Escherichia coli enzymes competed for reducing equivalents (NADP +/ NADPH), and P450/IRED competition for NADPH was also observed. Therefore, the cascade was run as a two-step process. Considering the number of enzymes available in the literature and different substrate scopes, this strategy could be expanded to the general synthesis of amines from alkanes or unfunctionalized starting materials. (Org. Biomol. Chem. 2017, 15, 9790−9793)

Low-valent phosphorus species offer significant potential as green reductants. Sodium hypophosphite has been classified as nonhazardous for humans and the environment under the REACH Framework in the EU. Letort et al. reported investigations into the role of ultrasound on reduction of aliphatic nitro groups using this reagent in the presence of Pd/ C. Although the accelerating effect of ultrasound on this reaction had been reported, it was not clear how this occurs. A comparison of ultrasound- and vibromix-stimulated reactions clearly demonstrated that the effects were a consequence of dispersal of organics in the water/2-MeTHF (2:1) solvent system. Although hypophosphites are strong reducing agents, their low cost and stability in the absence of catalysts renders them attractive for industrial use. This report provides some basis to further explore this approach. (Green Chem. 2017, 19, 4583−4590) 1127




were low: in each case, palladium was present at 25 allylic azides, with yields typically ranging from 60 to 90%. Althoug the use of chloroform is a limitation, this strategy allows rapid access to valuable heterocycles. A number of chromanes and tetrahydroquinolines were synthesized in high yields and selectivities under mild conditions. Activating groups such as methyl or methoxy were tolerated, as were halogen substituents and polysubstitutions. Despite a lower yield (37%), the trifluoromethyl group was also found to be competent. The authors proposed a stereochemical model based on chairlike transition states in which the major diastereoisomer would arise when the vinyl group is in the pseudoequatorial position. (J. Am. Chem. Soc. 2018, 140, 1211−1214)

Handa et al. disclosed a ppm-level palladium-catalyzed Sonogashira coupling in water with a surfactant. The authors describe HandaPhos, a ligand designed to have high lipophilicity, thereby causing the Pd catalyst to reside within the micelle where the coupling takes place. As a result of the increased lifetime of the catalyst within the TPGS-750-M micelle, a lower temperature, catalyst loading, and ligand loading are possible. The authors demonstrated the coupling on a wide variety of substrates, including heteroaromatic aryl halides and heteroaryl, alkenyl, and aliphatic alkynes, with yields typically ranging from 70 to 90%. The authors also demonstrated that the aqueous medium containing the catalyst and surfactant can be recycled at least four times without a decrease in performance. (Org. Lett. 2018, 20, 542−545)

Another advance in the area of Friedel−Crafts alkylation is the use of trifluoroethanol (TFE) and hexafluoro-2-propanol (HFIP) as the hydrogen-bond donor and solvent. Tang et al. reported an efficient and clean alkylation of indoles and electron-rich arenes with β-nitroalkenes in HFIP. A variety of functional groups such as methoxy, N,N-dimethylamino, halides, and nitrile were tolerated. Aliphatic nitroalkenes were successfully transformed into the desired products in good yields under mild conditions. The desired products formed smoothly in short times at ambient temperature without any additional catalysts or reagents. Because of its low boiling point (59 °C) and low viscosity, HFIP can be recovered and reused. A one-pot Friedel−Crafts alkylation/ nitro reduction was also developed by adding zinc and HCl. (RSC Adv. 2018, 8, 10314−10317)

Ramakrishna et al. developed an imidazolium-based palladium(II) precatalyst for use in Suzuki−Miyaura couplings in water without the presence of a surfactant. Under ligand-free conditions or utilizing triphenylphosphine or XPhos, the authors demonstrated cross-couplings on >100 substrates using catalyst loadings as low as 0.5 mol %. Substrates include a range of aryl/heteroaryl boronates and aryl/heteroaryl halides, including sp2−sp3 couplings of benzyl halides and ketone synthesis via coupling of acid chlorides. The air-stable reaction conditions are operationally friendly. Products can typically be filtered from the reaction mixture without additional purification. (Eur. J. Org. Chem. 2017, 7238−7255)

12. CHEMISTRY IN WATER Vivancos et al. disclosed a catalytic hydrogenation of quinoline derivatives in water. In the presence of water-soluble iridium complexes bearing a triazoylidene-based ligand, water, and H2 as the stoichiometric reductant, substituted quinoline derivatives are reduced to tetrahydroquinolines. The authors 1130




tion was performed to generate isoindolinones. (Angew. Chem., Int. Ed. 2017, 56, 15446−15450)

Zhang et al. communicated a ruthenium-catalyzed carboxylic acid-directed ortho C−H functionalization of arenes in water. This research focused on the use of α,β-unsaturated electrophiles to generate a variety of β-aryl carbonyl products. Several unsaturated carbonyl substrates were demonstrated, including cyclic/acyclic ketones, amides, and carboxylic acids, with the latter requiring the use of CsF instead of Li3PO4 as the base. The authors found that the reaction had to be run under an inert atmosphere in order to avoid an undesired Heck reaction. Deuterium labeling studies were conducted by investigating a deuterated arene substrate and using D2O as the solvent in either the presence or absence of the electrophile. The use of D2O resulted in deuterium incorporation ortho to the carboxylic acid directing group as well as at various positions of the product, suggesting reversible C−H bond cleavage. A high kinetic isotope effect was observed with the deuterated arene substrate, indicating that C−H bond cleavage is the ratedetermining step. (Chem.Eur. J. 2018, 24, 4537−4541)

Several reports highlighted a unique flow reactor platform with enhanced mass transfer characteristics. Pye et al. designed a thin-film processing device that creates a thin film of liquid within a spinning tube by centrifugal force (termed a vortex fluidic device, or VFD). The thin-film characteristics are controlled by adjustments in the rotational speed, tilt angle, and available volume of the liquid. The effect is high micromixing with enhanced mass, flux, and heat transfer. Consequently, the efficiency of mass/flux-transfer-limited processes is enhanced.

13. CONTINUOUS PROCESSING Electrosynthesis is increasingly seen as a viable green alternative for oxidation/reduction reactions in which reactive radical ion intermediates are accessed without needing toxic or hazardous oxidizing or reducing agents. Although this approach is considered a potential green alternative to traditional oxidation/reduction procedures, some obstacles exist that hinder its application on scale: large distances between electrodes in batch electrochemical cells leads to current gradients, and traditional organic solvents typically have low conductivity, which requires the use of a supporting electrolyte, leading to increased waste. In many respects, adapting electrosynthesis to flow can potentially overcome these obstacles, as demonstrated by Werth et al. Their report describes a readily accessible reactor design in which each half of an aluminum or polymer (3D-printed) microreactor body is fitted with electrode plates that are then separated by a fluorinated ethylene propylene (FEP) film spacer in which channels are cut. The thickness of the film spacer defines the distance between electrodes (typically 100−500 μm). The short distances between electrodes eliminate current gradients and offer high surface-to-reactor volume ratios that improve mass transfer on the electrode surfaces, leading to more efficient and milder reaction conditions using little or no supporting electrolyte. A demonstration of its utility was presented in which N-centered radical intramolecular cycliza-

The authors demonstrated the advantages of this design through a series of oxidations using environmentally preferred oxidants that often suffer from mass transfer limitations. For example, oxidation using molecular oxygen is highly desirable from a sustainability perspective, but the rate of oxidation is mass-transfer-limited and poses flammability hazards when organic solvents are used. To demonstrate the utility of their reactor design, the authors described an example in which an aqueous solution of N-acetyl-L-cysteine (pH 9.6) was oxidized by oxygen by using the VFD. The results highlighted the increased efficiency that can be achieved under thin-film conditions (55% oxidation in 5 min using the VFD vs 3−5% oxidation over 1 h in batch mode). This was further improved by adjusting the pH to 11 to achieve full conversion and demonstrated in flow with a residence time of only 2.5 min.

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14. GENERAL GREEN CHEMISTRY Maertens and Plugge published a paper that reviews several data aggregation and analysis schemes to present toxicology data for common reagents used in synthesis. The authors advocate the use of newer data-driven methodologies to assess the “greenness” of a reagent through toxicology data that will allow for development of green chemistry procedures that have focused on every angle of development and propose a path forward to the continued development of comprehensive toxicology data assessments. (ACS Sustainable Chem. Eng. 2018, 6, 1999−2003) A recent review article by Veleva et al. calls into focus the existing gap between progress in benchmarking green metrics within the pharma industry and identification of future opportunities to ensure that green chemistry is equally applied to the entire supply chain. The three objectives of this publication are to benchmark adoption of green chemistry practices by “Big Pharma”, to examine the drivers and barriers to greater adoption of green chemistry, and to identify opportunities to advance wider adoption of green chemistry by the entire pharmaceutical supply chain. (ACS Sustainable Chem. Eng. 2018, 6, 2−14)

In another example, epoxidation of a hydrophobic alkene using aqueous hydrogen peroxide was achieved without the need for solvents, surfactants, or phase-transfer catalysts. Epoxidation in batch mode with magnetic stirring gave 75% conversion with a diastereoselectivity of 11:1, whereas the same reaction in the VFD offered 90% conversion and improved diastereoselectivity of 22:1. The improved conversion is attributed to the high micromixing of the VFD. The lower diastereoselectivity in batch mode is attributed to an uncontrolled exotherm that occurs when the reaction is run without external cooling (Trxn = 90 °C). The VFD conditions give more uniform heat dissipation and faster heat transfer compared with batch conditions (Trxn = 23 °C). Since no solvents, surfactants, or phase-transfer reagents are needed and the only byproduct of the reaction is innocuous water, the product can be isolated by simple phase separation, and the aqueous layer can be reused. (Green Chem. 2018, 20, 118−124)

Green Chemistry Articles of Interest are produced on behalf of The ACS GCI Pharmaceutical Roundtable.

Marie-Gabrielle Braun

In a separate report, the same research group explored plasma−liquid oxidation using the VFD. The VFD device was fitted with an internal electrode in the tube and an outer electrode opposite to generate a nonthermal plasma above the thin film. Like other flux-limited processes, high interfacial contact is important for the reaction rate. The VFD achieves this by dispersing the reaction medium across a large surface area as a thin film with high dynamic mixing. Parameters such as the rotation speed, tilt angle, and feed rate were studied to understand their influence on the fluid dynamics and profile within the system using the oxidation of methylene blue as a proof of concept. Although not synthetically useful, the oxidation of methylene blue demonstrated that plasma processing using a thin-film platform offers advantages beyond simply increasing the contact time, including improved flux penetration and dynamic mixing. (RSC Adv. 2017, 7, 47111−47115) The concept is thought to be applicable to other flux-driven chemistries such as electrochemistry and photochemistry. An example was offered in a separate report in which a Rose Bengal-photocatalyzed Ugi-type reaction was performed with a significantly reduced catalyst loading (10-fold reduction) compared with literature reports. (Chem.Eur. J. 2018, 24, 8869−8874)

Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States

Alba Díaz-Rodríguez GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.

Louis Diorazio AstraZeneca, Macclesfield SK10 2NA, U.K.

Zhongbo Fei Novartis Pharmaceuticals (China) Suzhou Operations, #18 Tonglian Road, Changshu, Jiangsu 215537, China

Kenneth Fraunhoffer Bristol-Myers Squibb Co., One Squibb Drive, New Brunswick, New Jersey 08903, United States

John Hayler* GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.

Matthew Hickey* Bristol-Myers Squibb Co., One Squibb Drive, New Brunswick, New Jersey 08903, United States

Mark McLaws Asymchem Inc., 600 Airport Boulevard, Suite 1000, Morrisville, North Carolina 27560, United States

Paul Richardson Pfizer Global Research and Development, 10578 Science Center Drive, La Jolla, California 92121, United States

Gheorghe-Doru Roiban GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.

Andrew T. Parsons Amgen, 360 Binney Street, Cambridge, Massachusetts 02139, United States

Alan Steven AstraZeneca, Macclesfield SK10 2NA, U.K.

Jack Terrett Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States 1132




Timothy White Eli Lilly and Company, Indianapolis, Indiana 46285, United States

Jingjun Yin

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Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Zhongbo Fei: 0000-0002-5980-4017 John Hayler: 0000-0003-3685-3139 Gheorghe-Doru Roiban: 0000-0002-5006-3240 Andrew T. Parsons: 0000-0002-0320-0919 Alan Steven: 0000-0002-0134-0918

■

ADDITIONAL NOTES For details of the current membership, see: https://www.acs. org/content/acs/en/greenchemistry/industry-business/ pharmaceutical.html. 2 See: https://www.ich.org/fileadmin/Public_Web_Site/ ICH_Products/Guidelines/Quality/Q3C/Q3C__R6___ Step_4.pdf. 3 See: https://echa.europa.eu/authorisation-list. 1

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