Green Chemistry Articles of Interest to the Pharmaceutical Industry

Green Chemistry Highlights Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Green Chemistry Articles of Interest to the Pharmaceutical Industry 1. INTRODUCTION The American Chemical Society’s (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 Roundtable currently has 19 member companies, compared with three in 2005. The membership scope has also broadened to include contract research/manufacturing organizations, generic pharmaceuticals, and related companies. Members currently include ACS GCI, AbbVie, Amgen, AstraZeneca, Asymchem, Inc., Biogen, Boehringer-Ingelheim, Bristol-Myers Squibb, Codexis, Eli Lilly and Company, FHoffmann-La Roche Ltd., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, Pharmaron, Pfizer, Inc., Sanofi, and WuXi AppTec, Co., Ltd. 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 GCIPR research grants. This document follows on from the Green Chemistry paper and is largely based on the key research areas, though new sections have been added. The review period covers October 2016 to March 2017. 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 being 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.

linked poly(ethylene glycol) resin (ChemMatrix) accommodated the requirements and was demonstrated to be applicable to the synthesis of bradykinin (Green Chem. 2017, 19, 1685−1691). In a special issue of Molecules dedicated to “Organic ́ Reactions in Green Solvents”, edited by Sperry and GarciaÁ lvarez, several remarkable specific examples of the replacement of traditional organic reaction media were discussed. Studies of halogenation, hydrosilylation, selenium chemistry, and the synthesis of specific scaffolds such as 3,4-dihydropyrimidin-2(1H)-ones and 2-aminoimidazoles were described. Different solvent systems were discussed, ranging from water to deep eutectic solvents and ionic liquids (Molecules 2016, 21, 1527 and subsequent articles). Alves Costa Pacheco et al. compare three approaches to the determination of solvent polarity properties to aid identification of suitable candidates for solvent substitution. Considering known and potential molecules derived from levoglucosenone, which is obtained from cellulose biomass, Hansen solubility parameters were calculated for 164 compounds, and the dipole parameter δp and hydrogen-bonding parameter δH were mapped. Fifteen potential replacements for dichloromethane and also for NMP were identified, whose numbers were further reduced by additional filters, including potential reactive functionality. The authors selected the Cygnet family of solvents [cyclic ketals derived from dihydrolevoglucosenone (Cyrene)] for further evaluation. They considered chemical potential plots calculated using the conductor-like screening model for realistic solvation (COSMO-RS), which models the strengths of electron-pair and hydrogen-bond donation of the solvent. The modeling approaches were augmented with experimental determination of the solvatochromic Kamlet− Abboud−Taft parameters, and differences between the relative mappings of the new solvents with known solvents by the different methodologies were discussed. The Cygnet solvents are the first bio-derived solvents to occupy an area of Kamlet− Abboud−Taft solvent space previously devoid of “green” solvents. Cygnet 0.0 was shown to be comparable to NMP in Heck and aryl fluorination reactions. The authors conclude with a discussion of the relevance of application in solvent selection with Cygnet 0.0 as a solid at room temperature (ChemSusChem 2016, 9, 3503−3512).

2. SOLVENTS Lawrenson et al. recently reported an approach employing either propylene carbonate or ethylene carbonate as a replacement for DMF and other polar aprotic solvents for use in both solution- and solid-phase peptide synthesis. In the case of the model solution-phase peptide coupling between Boc-Ala and phenylalanine benzyl ester, ethylene carbonate gave an increased yield versus that under the same coupling conditions performed in dichloromethane/DMF mixtures. For the reaction mixtures to remain liquid, the coupling had to be performed at 40 °C. Use of propylene carbonate allowed for a room-temperature reaction in yields that exceeded those for conventional polar aprotic solvent mixtures. Even when the reaction was carried out at 70 °C, there was no loss of stereochemical integrity in the couplings, and 99:1 enantiomeric purity was maintained. The application of propylene carbonate was extended further to solid-phase peptide synthesis of various tetrapeptides. Judicious choice of resin was required, however, as swelling of the resin in propylene carbonate was not as efficient for polystyrene-based resins. Use of a cross© XXXX American Chemical Society

Received: February 19, 2018 Revised: April 26, 2018 Accepted: April 30, 2018

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DOI: 10.1021/acs.oprd.8b00056 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Green Chemistry Highlights

3. AMIDE FORMATION Multicomponent reactions represent a means of generating molecular complexity with high efficiency, convergence, and atom efficiency and are also operationally simple to carry out. They often provide novel disconnections to biologically important molecules, as demonstrated by the work of Guo et al. in a report on the four-component (three-starting-material) reaction leading to pyrimidine carboxamides. DMF not only would be the solvent but also would serve as a dual fragment donor for the construction of the desired molecules. The initial reaction of DMF with styrene would provide an enamide, which could further react with an amidine and a one-carbonatom synthon (liberated from DMF) to provide the product. Model studies under oxidative Pd-mediated conditions demonstrated that the pyrimidine carboxamide could be formed in 71% yield using Pd(TFA)2Xantphos and 70% aqueous tert-butyl hydroperoxide (TBHP) as the oxidant in DMF at 120 °C over 24 h. Studies of the scope showed that both aliphatic and aromatic amidines were tolerated while molecules with electron-withdrawing substituents were less reactive. With regard to the styrene component, electrondeficient groups gave higher yields, and heteroaromatic styrenes were also tolerated. Isotope labeling of DMF proved that this provided C-6 of the pyrimidine (from a methyl group of DMF) as well as the amide unit. The authors also demonstrated that with DMA as the one-carbon-atom synthon, it was possible to vary the amide formed by utilizing different N,N-dialkylsubstituted formamides. Addition of a radical scavenger (e.g., TEMPO) halted the reaction, indicating that a radical pathway is in operation (Angew. Chem., Int. Ed. 2017, 56, 1289−1293).

enzyme than the FDA-approved HDAC inhibitor vorinostat (IC50 = 484 nM) (Org. Lett. 2016, 18, 5512−5515).

Yun et al. were also faced with an amidation challenge while working on the development of HDAC inhibitors, specifically the poor nucleophilicity of azaarene systems such as 3aminopyridine. From an atom-economy standpoint, the direct reaction of a carboxylic acid and an amine represents the most efficient manner to access an amide. Though numerous reports of this methodology have emerged, there are limited examples for azaarenes. In the cases known, low to moderate yields are obtained with harsh conditions, and excess noncommercial reagents are required to promote the desired reaction. The authors revisited the use of boric acid to catalyze the model reaction between 3-aminopyridine and 8-methoxy-8-oxooctanoic acid. They observed that addition of an equimolar (30 mol %) amount of N,N,N′,N′-tetramethylpropane-1,3-diamine greatly enhanced the reactivity, with an optimal yield of 82% being obtained at reflux in mesitylene after 7 h. The significant reactivity difference between the azaarene and a closely related (from an electronics perspective) aniline is highlighted. The scope with respect to the nucleophile indicates that the reaction can tolerate one deactivating substituent on the aromatic ring, but a second such substituent shuts down the reactivity. While quinolines are successful substrates, both pyrazines and pyrimidines failed to react. 4-Aminopyridines were also unsuccessful even with electron-releasing substituents, presumably because of tautomerization. The reaction was extended to a range of benzoic and cinnamic acids, benchmarked for azaarene substrates against previously reported methodology using excess B(OCH2CF3)3, and shown to be superior. Mechanistically, the reaction is hypothesized to proceed through a mixed acid anhydride, which is stabilized by the polyamine additive (Synthesis 2017, 49, 1583−1596).

Often intriguing biological activity associated with a series of compounds can inspire the development of new synthetic methods for both more facile access to the lead molecules and potential access to new chemical matter. Zhang and Chou have disclosed a metal-free direct amidation of naphthoquinones with hydroxamic acids in a program directed at the synthesis of novel HDAC6 inhibitors. Model studies of the reaction between 1,4-naphthoquinone and N-hydroxybenzamide indicated that a base was crucial for the reaction to proceed, with Hunig’s base proving to be the most effective. A variety of solvents were also successful, with acetonitrile being the best, and the optimal temperature was 70 °C. Strict exclusion of oxygen and moisture was not necessary. For the hydroxamic acid component, a range of aryl and alkyl substrates worked, though the yields in the latter cases were slightly lower. For the quinone, addition of an electron-deficient substituent at the 2position boosted the yields, except in cases in which this substituent possessed an ortho substituent. Lower yields were obtained, presumably as a result of steric hindrance. Mechanistic studies indicated that the reaction does not proceed through a radical pathway but does involve the intermediacy of an amide anion. The chemistry was extended to the synthesis of a novel HDAC6 inhibitor (IC50 = 6 nM), which was significantly more potent against the human recombinant

Kumar et al. have also developed a direct amidation methodology utilizing Montmorillonite K10 with 4 Å molecular sieves under microwave irradiation. Model studies showed that conducting the reaction at 130 °C in toluene with a slight excess of the amine provided the optimal yields. The examples provided show that both benzylic and cyclic secondary amines work well, while both aromatic and aliphatic acids are successful substrates. For the latter, heteroaromatics such as indoles are well-tolerated, while the reaction also tolerates substitution at the α-position. When either a trans- or cis-cinnamic acid is B




temperature represents an example of such a procedure. Patre et al. have disclosed that this reaction can be facilitated under enzyme-mediated conditions using a commercially available lipase acrylic resin from Candida antarctica (Novozyme 435 CALB). Model studies using benzylamine showed that when 20% w/w Novozyme 435 was used with 1.5 equiv of ethyl formate in THF at room temperature, the reaction was complete within 1 h and provided a 99% yield of the formylated product. In contrast, in the absence of the enzyme, the background reaction provided only ca. 8% conversion. From a scope perspective, aliphatic primary and secondary amines were successful substrates, though benzylic amines proved to be the best in terms of reactivity. Under the standard conditions with THF, anilines did not react, but running the reaction in neat ethyl formate gave the products in excellent yield. For anilines with electron-withdrawing groups, more modest conversions were observed. Chemoselectivity for an aliphatic amine over an aromatic one was also demonstrated. The enzyme resin could be recycled through 10 cycles without any loss in activity, though an increase in reaction time was observed for each cycle. Since lipases are well-established for the kinetic resolution of both racemic amines and alcohols, attempts were made to extend this reaction to a kinetic resolution protocol, though these have so far proven unsuccessful (Chem. Commun. 2017, 53, 2382−2385).

utilized, the more stable trans product is isolated, and both enantiopure amines and acids react without any loss of chiral integrity. Several reactions are demonstrated on gram-scale, and a mechanism is proposed that involves activation of the carbonyl group of the carboxylic acid on the Lewis acidic surface of the K10 clay (Asian J. Org. Chem. 2017, 6, 342−346).

Mechanochemistry of high-speed ball milling (HSBM) offers an alternative methodology utilizing a nontraditional energy source to promote reactions under solvent-free or liquidassisted grinding conditions. Landeros and Juaristi have reported on the synthesis of dipeptides using this technique while investigating the effect of hydrotalcite minerals (HTs) in promoting the transformation. HTs are commercially available, inexpensive anionic clays that have been utilized as replacements for classical inorganic bases. The study investigated the composition and structure of the commercial material (HT-S) and highlights the changes upon calcination to 450 °C (HT-C) and again after reconstruction through rehydration under a flow of water vapor (HT-R). Interestingly, HT-R resembles HT-S closely in both powder X-ray diffraction and FT-IR analyses, demonstrating the so-called “memory effect” in that the original layered structure is restored. Examination of a model reaction between N-Boc-L-leucine and L-alanine methyl ester hydrochloride demonstrated that both the type of reactor (stainless steel) and operating frequency (25 Hz) played a pivotal role, though the presence of HT-S as an activating base was crucial. In addition, HT-S was shown to be superior to a number of more conventional inorganic bases. Comparison across the subtypes of resin indicated that HT-C leads to a somewhat depressed yield, whereas HT-R and HT-S are comparable in their ability to mediate the reaction. From a scope perspective, a series of variously N-protected amino acids were successfully coupled in 70−89% yield. Attempts to reuse the HT-S resin proved possible, though a significant decrease in yield was observed after each cycle. However, full reactivity could be restored through calcination and rehydration to form HT-R. Finally, scale-up proved challenging because of the viscous nature of the reaction medium, though this challenge could be overcome by addition of a few drops (“minimal solvent”) of DMPU to the reaction medium (Eur. J. Org. Chem. 2017, 687−694).

Oxidative amidation of aldehydes represents an alternative, more atom-economical method for the synthesis of amides. In their investigations of the development of new potential antimicrobial agents, Guggilapu et al. have developed a new oxidative amidation methodology employing the nontoxic, stable frustrated Lewis acid [B(C6F5)3] as the catalyst. Model studies of the reaction between benzaldehyde and aniline indicated that 3 mol % was the optimum loading, and TBHP was shown to be the most efficient oxidant, while the reaction was best carried out in acetonitrile. For aromatic aldehydes, electron-withdrawing groups at the para position led to higher yields, while steric hindrance had a deleterious effect on the yields. Anilines and benzylic and cyclic secondary amines all worked well, whereas simple aliphatic amines led to dramatically reduced yields. N-Benzylanilines were also successful substrates provided that an excess of aldehyde was utilized. The reaction was subsequently demonstrated on a 10 g scale; a mechanism proceeding through a hemiaminal intermediate is proposed (New J. Chem. 2017, 41, 2328−2332).

4. OXIDATIONS In the synthesis of Merck’s drug elbasvir for the treatment of hepatitis C, oxidation of the chiral indoline intermediate (R = Ph) to the indole had to be carried out with KMnO4 as the oxidant because of ee erosion with most other oxidants. The reaction generates stoichiometric MnO2 as a byproduct that is very difficult to remove on manufacturing scale. To develop a greener oxidation, Peng et al. discovered the use of a catalytic

The synthesis of N-formyl derivatives of amines often requires the use of expensive organo- or metal catalysts, harsh conditions, arduous procedures, and extended reactions times. Direct formylation using neat ethyl formate at elevated C




amount of Cu(I) salt with tert-butylperoxy 2-ethylhexyl carbonate (TBPC) as the organic oxidant, which generates more benign byproducts. The reaction is carried out in only 3 volumes of MeCN, and the product is simply isolated via filtration at the end of the reaction, giving this step a very low process mass intensity (PMI). The mild conditions are applicable to a number of analogues and other indolines in good to excellent yields. The reaction likely proceeds via a tertbutoxy radical generated from TBPC and the Cu(I) catalyst (J. Org. Chem. 2016, 81, 10009−10015).

Wang et al. developed a transition-metal-free sp3 carbon oxidation of bis(hetero)aryl methanes to ketones. Potassium tert-butoxide was used in combination with 18-crown-6 as the promoter and air as the oxidant. The user-friendly conditions provide a large variety of diaryl ketones in good yields with tolerance of electron-donating and electron-withdrawing groups. It was readily scaled up to produce grams of ketone products. Preliminary mechanistic studies suggested the involvement of radical intermediates (Org. Lett. 2016, 18, 5680−5683).

Ding et al. discovered a novel bifunctional photocatalyst for the asymmetric oxidation of α-keto esters using air as the oxidant and visible light. The catalyst consists of Ni(acac)2 and a bifunctional ligand that was designed by tethering a triplet photosensitizer (thioxanthone) and a chiral bisoxazoline (BOX) ligand. The photosensitizer generates the active triplet state of O2, which more readily oxidizes the enolate in high yield with high ee under the stereocontrol of the chiral ligand. The synergetic effect of the bifunctional catalyst was confirmed by significantly lower conversion and ee when the photooxygenation reaction was performed with the untethered chiral BOX ligand and photosensitizer. Keto esters and keto amides in five- to seven-membered ring systems all give high yields and ee’s (J. Am. Chem. Soc. 2017, 139, 63−66).

5. ASYMMETRIC HYDROGENATIONS Lau et al. have expanded their interests in intramolecular hydroamination and transfer hydrogenation of ether-bearing aminoalkyne starting materials into a one-pot procedure for the asymmetric synthesis of 3-substituted morpholines. The reaction involves the asymmetric transfer hydrogenation of an imine intermediate arising from an initial hydroamination. Hydrogen-bonding interactions between the morpholine oxygen and the TsDPEN ligand of the Noyori−Ikariya catalyst are believed to stabilize the transition state for the reduction. This leads to useful levels of enantioselectivity and allows the absolute configuration of the product to be reliably predicted. However, replacing the morpholine oxygen atom leads to erosion of the yield and/or enantioselectivity. Purities of the morpholine products after an acid−base extractive workup are reported to be routinely above 95%. While a nitrile functionality is shown to interfere with the reduction, successful outcomes are achieved with a variety of alkyl substituents on the alkyne starting material. While limited to one example, heteroaromatic functionality seems to be tolerated in this substituent (J. Org. Chem. 2016, 81, 8696−8709).

Yu et al. discovered the use of a heterogeneous iron(III) catalyst for the aerobic oxidation of aldehydes in water. The catalyst is a single-sided triol-functionalized iron-centered Anderson polyoxometalate, [N(C4H9)4]3[FeMo6O18(OH)3 {(OCH2)3CNH2}] ([FeIIIMo6] complex), and only 0.1 mol % is required to convert a large variety of aldehydes to acids in high yields. Additionally, the heterogeneous catalyst can be recycled at least eight times without significant loss of activity (Angew. Chem., Int. Ed. 2017, 56, 3867−3871).

In a Perspective containing 77 references, Margarita and Andersson reviewed the recent history and prospects for the homogeneous asymmetric hydrogenation of olefins that lack coordinating functionality attached to the double bond. Such an approach is particularly powerful for the introduction of a stereogenic center on an alkyl region remote from coordinating functionality in the rest of a target molecule. While the Perspective predictably focuses on alkyl, aryl, and hydrogen substituents, it points out that the noncoordinating ability of silane, boronate, or halogen functionality presents similar challenges when these groups are directly attached to an olefin. Most attention is given to N,P-Ir catalysts, which have maintained their importance to the field since the first D




development of chiral versions of Crabtree catalysts. The few highlights achieved with iridium catalysts bearing P,S-, O,P- and C,N- (i.e., NHC) ligands are also described, as are recent breakthroughs using catalysts containing earth-abundant metals such as cobalt and iron. Challenges in the field that remain include the following: (i) the lack of substrate scope displayed by the most efficient catalysts; (ii) the dependence of stereochemical outcomes on the geometric purity of the olefin-bearing starting material; (iii) the hydrogenation of unfunctionalized tetrasubstituted olefins. (J. Am. Chem. Soc. 2017, 139, 1346−1356) Rasu et al. have developed a system for producing alcohols by hydrogenation of α-substituted amides using hydrogen at low pressures. The use of potassium tert-butoxide as an additive allows the dynamic kinetic resolution of racemic substrates such that the alcohol products are produced in high yields with high enantioselectivities. The displacement of the amine half of the amide functionality by tert-butoxide is observed as a side reaction. Replacing the α-aryloxy substituent with an alkoxy substituent has a negative effect on the yield and enantioselectivity, while replacing the α-methyl substituent was shown to negatively influence one of these reaction attributes (depending on the substituent). The presence of isopropanol in the reaction mixture was found to benefit the enantioselectivity (J. Am. Chem. Soc. 2017, 139, 3065−3071).

The study of a number of cationic ruthenium complexes of chiral monotosylated diamines has yielded phosphine-free conditions for the asymmetric hydrogenation of phenanthridines. Interestingly the enantioselectivity of the transformation was significantly influenced by the counterion. Substrate screening concentrated on assessing the impact of various substituted benzyl groups at the 6-position. The position of a substituent on the benzyl group was observed to have a larger effect on the enantioselectivity than its electronic properties. The conversion and enantioselectivity were found to be wellretained when one of the reactions was repeated at a gram scale. The parent phenanthridine with a phenyl ring attached to its 6position did not react at all, while a methyl or fluoro group at the 2-position of the phenanthridine nucleus was found to lower the enantioselectivity compared with the reaction where a substituent was missing at this position (Org. Lett. 2017, 19, 1458−1461).

Hou and co-workers have developed a system for the smooth enantioselective hydrogenation of cyclic imines employing an Ir−f-spiroPhos complex. The electron-donating properties of the spiroPhos ligand, together with its bulk and rigidity, were found to be critical for both the conversion and enantioselectivity of this transformation. Of the solvents screened, the use of 1,4-dioxane was optimal, though ethyl acetate, DME, THF, and toluene also produced impressive results. Substrate compatibility was explored by varying the ring size of the cyclic imine and the electronic and steric properties of its aryl substituent. In all cases, high yields (92−99%) were achieved, and the enantioselectivities were >90%. Replacing the aryl substituent with an alkyne was found to erode the enantioselectivity. Catalyst performance was found to be maintained when one example was extended to a gram scale. The utility of the method was demonstrated by its use in the synthesis of (+)-(6S,10bR)-McN-4612-Z, an inhibitor of neurotransmitter uptake (Org. Biomol. Chem. 2017, 15, 3006−3012).

Yu et al. developed a novel series of ferrocene-based tridentate amino−phosphine acid ligands (f-Ampha) for the asymmetric hydrogenation of substituted acetophenones. The f-Ampha ligands are air-stable and can be easily prepared by a simple one-pot procedure starting from (S)-N,N-dimethyl-1ferrocenylethylamine, which can be purchased in kilogram quantities. Of the bases screened, lithium tert-butoxide produced the best enantioselectivity. Increasing the size of the substituents on the phosphorus center also improved the enantioselectivity. The reported conditions were used largely with methyl ketones based on acetophenone. The electronic properties and position of substituents on the aryl ring of acetophenone had little to no effect on the conversion and enantioselectivity. The latter was typically reported to be >99%. This performance was retained when the catalyst loading was dropped to 0.0002 mol % and the reaction was performed on a decagram scale. Replacing the acetophenone aryl group with an E




alkyl group led to a decrease in enantioselectivity (Org. Lett. 2017, 19, 690−693).

Lee and Sanford reported a method for the oxygenation of remote C(sp3)−H bonds in the presence of protonated primary and secondary amines under aqueous conditions. The conditions were optimized on 4-methylpiperidine utilizing water as the solvent to avoid potential C−H activation of the solvent. The use of 2.2 equiv of sulfuric acid and only 2 equiv of K2S2O8 achieved the desired transformation at 80 °C after 2 h. Subsequent conversion to the amide with benzoyl chloride resulted in improved isolation of the product from the aqueous reaction system. A variety of cyclic and acyclic substrates resulted in yields ranging from 31 to 64%, with the highest yields observed for tertiary C−H bonds two or three carbons from the nitrogen. Several tertiary amines were also investigated and resulted in similar conversions. Finally, in benzylic systems where secondary C−H bonds were present, a mixture of the alcohol and ketone was generated. This ratio could be shifted toward the alcohol or ketone by adjusting the amount of oxidant (Org. Lett. 2017, 19, 572−575).

6. C−H ACTIVATION McManus and Nicewicz developed a direct C−H cyanation reaction to produce benzonitriles. The reaction is enabled by photoredox catalysis using 455 nm light from a light-emitting diode (LED) along with a 5 mol % loading of an acridinium photoredox catalyst. The chemistry is run under mild conditions (room temperature) and uses oxygen as the terminal oxidant. Notably, the reaction is highly regioselective, as benzylic cyanation is not observed and dicyanated products are not produced. The authors showcase several substrates, including some more complex arenes and heteroarenes, that provide the desired product as a single regioisomer. The reaction shows good functional group tolerance, as allyl groups, esters, amides, and tosylates do not interfere with the chemistry. One drawback is that for some substrates the ortho/para regioselectivity is modest (∼1:1), and the authors comment that the product distribution is consistent with the expected electrophilicity of electron-rich arene radical cations (J. Am. Chem. Soc. 2017, 139, 2880−2883).

A visible-light-photocatalyzed synthesis of substituted quinolones was disclosed by Yang et al.. They envisioned that photocatalytic conditions would result in conversion of a glycine ester to an iminium intermediate that could be trapped by an alkene. Screening of several photocatalysts and additives revealed that Ru(bpy)3Cl 2·6H2 O and Cu(OTf)2 under irradiation with a blue LED in the presence of air gave the best conversion to the quinolone system. Substitution on the alkene was well-tolerated for a wide variety of styrenes, with ortho, meta, and para substitutions all giving good yields. Alkenes without aromatic rings were reactive, but the yields were lower (18−44%). Disubstituted alkenes were also reactive, although the yields were lower and a higher loading of Cu(OTf)2 was required. Finally, the system was tolerant of electron-donating and -withdrawing groups at the para position of the glycine, and several ester groups were also demonstrated to react (J. Org. Chem. 2016, 81, 12433−12442).

A selective trifluoromethylthiolation of aliphatic C−H bonds was recently developed that utilizes photoredox-mediated hydrogen atom transfer catalysis. The reaction is conducted using LED-derived light with an iridium-based photocatalyst, sodium benzoate as the hydrogen atom transfer catalyst, and Phth-SCF3 as the trifluoromethylthiolating agent. The reaction is chemoselective for tertiary C−H bonds over secondary and primary C−H bonds. Heterocycles such as thiophenes, pyridines, and quinolines are well-tolerated under the reaction conditions. The reaction shows promise as a late-stage trifluoromethylthiolation method, as pregablin and steroid derivatives can be functionalized at the most electron-rich tertiary C−H bond. Simple secondary C−H bonds undergo the reaction very sluggishly, but more activated methylene C−H bonds that are adjacent to heteroatoms (e.g., ethers) can be efficiently trifluoromethylthiolated (J. Am. Chem. Soc. 2016, 138, 16200−16203).

7. GREENER FLUORINATION The current nucleophilic fluorination methods to prepare aryl and heteroaryl fluorides, including classical SNAr reaction, Pdcatalyzed fluorination of aryl bromides or triflates, and PhenoFluor-mediated deoxyfluorination of phenols, cannot fully meet the criteria of being cost-efficient, mild, and free from regioisomer formation. Schimler, Cismesia, and co-workers reported a new nucleophilic fluorination approach satisfying the aforementioned criteria while demonstrating a wide substrate scope. This approach transforms phenol derivatives to aryl fluorides in a stepwise manner by initial conversion of the F




thermostability (melting temperature of 83.5 °C). More than 20 substrates containing aliphatic, aromatic, or cyclic groups were tested. The paper also discusses challenges and further opportunities for this intriguing class of enzymes (ACS Catal. 2017, 7, 3204−3209).

phenols to aryl fluorosulfonates (ArOFs) using cheap sulfuryl fluoride (SO2F2) followed by nucleophilic fluorination using tetramethylammonium fluoride (NMe4F) or in a one-pot fashion by addition of all of the components at the beginning. In the stepwise approach, isolated fluorosulfonates bearing either electron-withdrawing or electron-donating substituents were fluorinated under mild conditions with variable yields depending on the electron density of the arene. No isomeric fluorides were formed. Heteroaryl fluorosulfonates, including pyridines, quinolines, carbazoles, and indoles, were also fluorinated without the formation of isomeric fluorides. When the one-pot approach was applied, phenol derivatives were fluorinated in comparable yields. These conditions were found to be compatible with aryl halides, non-enolizable esters, amides, and ketones and displayed selective substitution of FsO in the presence of potential leaving groups such as NO2 and Cl. Ab initio calculations revealed that this nucleophilic fluorination does not proceed through a discrete Meisenheimer intermediate. It starts with bonding of a fluoride to the sulfur of FsO to form a pentacoordinate intermediate, followed by concomitant cleavage of the C(sp2)−O bond and formation of the C(sp2)−F bond (J. Am. Chem. Soc. 2017, 139, 1452−1455).

Pesci et al. have shown an intriguing approach to produce the flavor compound 4-ethylguaiacol (4-EG) from biomass-derived ferulic acid via 4-vinylguaiacol (4-VG) using a chemoenzymatic two-step protocol with phenolic acid decarboxylase (PAD) and Pd/C. By the use of a biphasic system in the biocatalytic stage, the reaction could be directly telescoped into the hydrogenation step with the intermediate 4-VG partitioned into the hydrocarbon phase. The product was obtained in 70% isolated yield over the two steps combined in a 19 g/L process. Using an extraction/distillation recycling system allowed the substrate concentration to be increased to 33 g/L. Furthermore, the stability of the enzyme in the biphasic hexane/buffer system was shown to be 3-fold greater than that of the enzyme in buffer. The enzymatic reaction worked equally well in heptane. The authors compared the E-factors for their process with those for chemical approaches. The E-factor for the synthesis of 4-VG including downstream processing was found to be favorable compared with those for alternative routes. The Efactor for the synthesis of 4-EG is greater than those for other routes but could be significantly improved by using an enzyme that is able to act at higher substrate concentrations (Org. Process Res. Dev. 2017, 21, 85−93).

α-CF3-substituted carbonyls are versatile building blocks for preparing CF3-containing compounds. Su, Huang, and coworkers reported a mild radical approach for synthesizing αCF3-substituted ketones from the ketone-derived enol triflates. Under the developed conditions (AgNO3, (NH4)2S2O8, t BuOH/H2O, 30 °C), a CF3 radical was formed upon fragmentation of the triflate group and underwent addition to another enol triflate to generate the α-CF3-substituted ketone with release of another CF3 radical to allow radical chain propagation. These mild conditions regiospecifically converted a broad range of cyclic enol and linear and aromatic triflates to α-CF3-substituted ketones, mostly in 60−95% yield. The researchers also extended the method to the preparation of α-nonafluoroalkyl ketones from enol nonaflates in excellent yields (Angew. Chem., Int. Ed. 2017, 56, 1338−1341).

Amino acids have significant applicability in medicinal chemistry, where they are used primarily as building blocks for peptide and protein synthesis but also for the synthesis of chiral intermediates or as valuable active pharmaceutical ingredients (APIs). In this context, Hernandez et al. described the development of a one-pot stereoselective enzymatic cascade for the synthesis of homoserine enantiomers. The biocatalytic synthesis of (S)- and (R)-2-amino-4-hydroxybutanoic acid was accomplished by coupling a class II pyruvate aldolase from Escherichia coli with a pyridoxal phosphate-dependent transaminase. The aldolase involved in the aldol reaction was found to tolerate high levels of formaldehyde (up to 1.4 M), while the subsequent reductive amination using transaminase was performed in an enantioselective manner using (S)- or (R)alanine as an amine donor. The resulting sodium pyruvate was effectively recycled by the aldolase, which favored the equilibrium toward the formation of the product, allowing yields of >86% with excellent stereoselectivities (>99% ee) at

8. BIOCATALYSIS Amine dehydrogenases (AmDHs) are a very promising group of enzymes for asymmetric reductive aminations of ketones, using ammonia as the sole amino donor without the equilibrium challenges observed for widely applied transaminases. Pushpanath et al. have shown that using enzyme and reaction engineering on a phenylalanine dehydrogenase (PheDH) from Caldalkalibacillus thermarum afforded an AmDH that can be applied in a 70% (J. Am. Chem. Soc. 2017, 139, 2577−2580).

́ Garcia-Ferná ndez et al. reported a Cu(II)/DNA cocatalyzed Friedel−Crafts conjugate addition/enantioselective protonation reaction of indole derivatives in water to give α-substituted enones. This work builds on the authors’ previous report of an enantioselective Friedel−Crafts addition to β-substituted enones, wherein the enantiodetermining step was carbon− carbon bond formation between the indole and the Michael acceptor. Products were obtained in modest yields (30−87%) with moderate enantioselectivities (up to 84% ee). As a general trend, indoles containing electron-donating substituents at the 5-position performed best, providing yields above 80% with enantioselectivities ranging from 69 to 84% ee. The moderate enantioselectivity is all the more impressive when one considers that the chemistry is performed in an aqueous medium; nonenzymatic catalytic enantioselective protonation reactions tend to require rigorously dry conditions. The authors discovered a remarkable rate acceleration during kinetic studies in the presence of the DNA catalyst: reactions proceeded 700− 990-fold faster in the presence of DNA and Cu(II)−dmbipy compared with experiments performed with Cu(II)−dmbipy alone. The results from this study, coupled with recent spectroscopic data showing binding of Cu(II) and enone substrates to DNA, suggest that DNA acts as a pseudophase,

Celaje et al. developed a ruthenium catalyst for the monoalkylation of primary amines with benzylic alcohols, conducting the reaction solvent-free and without base or additive. Mechanistic studies showed rapid alcohol dehydrogenation, which is usually the rate-limiting step in the hydrogen borrowing mechanism. Reactions were run neat in a sealed tube, and a wide range of other functionality was tolerated. J




similar to more commonly used micellar aggregates in water (J. Am. Chem. Soc. 2016, 138, 16308−16314).

Kong et al. described a one-pot water-mediated approach to spiro[dihydroquinoline−naphthofuranone] compounds from readily available and inexpensive isatins, 2-naphthols, and 1,3d i c a r b o n y l s ub s t r a t e s . O v e r 5 0 d i ff e r e n t sp i r o [dihydroquinoline−naphthofuranone] compounds were prepared in yields that routinely exceeded 80%. Higher yields were observed upon addition of the anionic surfactant sodium dodecyl sulfate (SDS) to the aqueous solution. Experiments performed in D2O displayed slower kinetics and resulted in lower yields compared with H2O-mediated reactions. On the basis of these results, the authors hypothesized that the ability of H2O to hydrogen bond to the substrates promotes reactivity by enhancing the nucleophilicity of the 2-naphthol and the enol of the 1,3-dicarbonyl compound as well as the electrophilicity of the isatin. The authors demonstrated that the 10% SDS aqueous medium can be filtered and recycled up to five times with no appreciable loss in yield (ACS Sustainable Chem. Eng. 2017, 5, 3465−3470).

12. CONTINUOUS PROCESSING Although experimentation with immobilized catalysts has been conducted for decades, their adoption on commercial scale in pharmaceutical manufacturing has been slow. Issues with catalyst leaching, slower kinetics relative to their homogeneous counterparts, and deactivation can dilute the benefits immobilization may provide. Interest remains high given the clear advantages immobilization can realize in terms of recovery and reuse, in particular the prospects of using such catalysts in continuous flow processes. A number of reports from the group of Pericàs are highlighted in which asymmetric transformations were achieved using chiral organocatalysts immobilized through covalent bonding. Immobilization through covalent bonding generally provides greater stability, thus helping maintain activity through continued use. Wang et al. disclosed an immobilized Lewis base catalyst based on the chiral isothiourea scaffold first reported by Birman and Okamoto. This catalyst class has been shown to be a versatile catalyst in the promotion of a number of asymmetric transformations. In this report, the catalyst was used to promote an enantioselective formal [4 + 2] cycloaddition reaction between unsaturated heterocycles and arylacetic acids in both batch and flow mode. Good stereoselectivities and broad substrate scope were reported in batch mode, which could offer an attractive approach for rapid preparation of diversity-oriented libraries when adopted to flow. The catalyst was demonstrated in flow mode for 18 h to afford the product in 67% yield with 99% ee as a single diastereomer in one example. However, it was noted that the selectivity began to deteriorate after 18 h, highlighting the limitations of catalyst stability that hinder adoption on larger scale (ACS Catal. 2017, 7, 2780−2785).

β-Hydroxyamides are highly useful building blocks in synthesis, serving as versatile precursors to a variety of nitrogen-containing heterocycles. As such, a considerable amount of attention is being paid to new and efficient routes detailing their preparation. In this report, González-Fernández et al. described a ruthenium-catalyzed tandem hydration/ transfer hydrogenation sequence to access β-hydroxy amides from β-keto nitriles in water. This chemistry builds on a previous report by the authors involving Ru(II)-catalyzed hydration of β-keto nitriles to give β-keto amides in water. By taking advantage of the known ability of Ru(II) complexes to promote transfer hydrogenation of carbonyl compounds in the presence of sodium formate in water, the authors optimized a process to directly access β-hydroxy amides. The chemistry is performed at 100 °C using [RuCl2(η6-p-cymene){P(4C6H4F)2Cl}] catalyst and sodium formate. The reaction tolerates a wide variety of electronically differentiated aromatic ketones without any substantial change in reactivity. Sterically encumbered aliphatic ketones as well as β-keto nitriles containing substitution at the α-position are also well-tolerated; yields typically ranged from 70 to 88%. Transfer hydrogenation of the intermediate β-keto amide to the desired β-hydroxy amide was determined to be rate-limiting through a series of control experiments (Org. Lett. 2016, 18, 6164−6167).

In a separate report, the same group disclosed an immobilized catalyst based on Luo’s chiral vicinal diamines that promotes asymmetric Robinson annulations of cyclic 1,3diketones and methyl vinyl ketone. They also demonstrated a simple flow process to produce Wieland−Miescher ketone, a commercially important stock material for the production of a variety of terpenoids and steroids. The process was demonstrated over a 24 h period with a turnover number of 117. Interestingly, the immobilized catalyst proved more active K




than the homogeneous counterpart at elevated temperatures. The enhanced reactivity was postulated to be due to a beneficial effect of the nonpolar polystyrene environment around the active site of the supported catalyst. Catalyst deactivation was initially a problem because of competitive aza-Michael addition of methyl vinyl ketone to form alkylated derivatives of the catalyst. This was overcome in large part in the flow process by reacting the two starting materials to preform the mesotriketone intermediate before enantioselective annulation (ACS Catal. 2017, 7, 1383−1391).

Thaisrivongs et al. reported their experiences with adapting a Mannich-type addition of a lithiated sulfonamide to a chiral sulfinyl ketamine. The reaction was previously scaled successfully in batch mode to produce the API to support late-stage clinical trials. Although the batch process was deemed efficient, a flow process was investigated to address some deficiencies, namely, energy-intensive cryogenic temperatures (−60 °C) and competitive α-deprotonation of the sulfinyl ketamine. It was postulated that the latter was due to insufficient mixing in batch mode, which would result in exposure of unreacted sulfinyl ketamine to the lithium anion of the Mannich product. A flow process can provide extremely fast micromixing, which should minimize exposure of these two species. Additionally, improved heat transfer afforded by flow can permit operations at higher temperatures. Various types of mixers were evaluated, which confirmed that mixing was indeed critical. The best results were obtained using static mixers (∼100% conversion) as opposed to a simple T-connector (66% conversion). Fouling and clogging of flow pathways over extended process times are well-known issues for organolithium-mediated reactions, and the authors encountered this issue in their work. The issue was resolved by selecting a suitable mixer design and ensuring efficient heat removal. The optimized flow process provided improved yields (87−91% assay yield in flow vs 73% in batch) at a less energy-intensive temperature (−20 °C) (Org. Process Res. Dev. 2016, 20, 1997−2004).

In another communication, this group reported a supported BINOL-derived phosphoric acid Brønsted acid catalyst based on the popular 2,4,6-triisopropyl (TRIP) derivative for the asymmetric allylboration of aldehydes. Unlike the previously mentioned examples, the remarkable feature demonstrated by this catalyst was very high reusability. The activity remained unchanged through substrate scope studies except for a couple of examples, after which the activity was restored simply by washing the resin with a solution of HCl in EtOAc. The ability to regenerate the activity and the robustness of the catalyst make this catalyst a good candidate for scaled use (ACS Catal. 2016, 6, 7647−7651).

Llanes et al. leveraged immobilization to adapt an enantioselective cyclopropanation reaction using Jorgensen− Hayashi-type catalysts to a flow process. Modifying the reaction to continuous flow was done to avoid a competitive side reaction in batch mode in which ring opening of the newly formed cyclopropane ring occurs. By limiting exposure to the basic reaction environment through the shortened contact time and immediate quench, this ring-opened impurity could be minimized. This was accomplished by placing an aqueous ammonium chloride feed and a liquid−liquid separator after the packed bed reactor to wash away the base. In this report, microporous resins were compared with monoliths to arrive at a support that preserved adequate catalyst activity while providing sufficient mechanical stability. Evaluation of both types of supports showed that the catalyst activity was eventually lost using microporous resins as a result of mechanical degradation, whereas the catalyst supported on monoliths did not show any reduction of activity even after 12 months of use in substrate screening experiments (Org. Lett. 2016, 18, 6292−6295).

The antifungal drug flucytosine is listed as an essential medicine by the World Health Organization and recommended as part of a combination therapy for the first-line treatment of Cryptococcal meningitis, a disease of particular concern to patients with compromised immune systems. Its use in Africa and other parts of the world is limited by the cost of this essential medicine. Harsanyi et al. explored flow chemistry as a means to shorten the synthetic route to improve the economics of production through direct fluorination of inexpensive cytosine using fluorine gas. The current process requires four steps to achieve this otherwise simple transformation. Direct fluorination of cytosine in batch mode generates a major difluorinated byproduct and several other side products, making L




it unfeasible at scale. As highlighted in earlier examples, flow processing has far superior micromixing capabilities, which often dramatically suppress competitive side reactions. The authors were able to design, optimize, and scale a flow process to give flucytosine in 83% yield with 99.8% purity on a 58 g/h proof-of-concept run using a silicon carbide flow reactor system (Org. Process Res. Dev. 2017, 21, 273−276).

in which all of the associated functional units were considered, found that continuous processing was superior because of the disproportionate contribution equipment washing adds to the PMI of the batch process (the wash mass intensity was 38.9% of the cumulative mass intensity for batch compared to just 4.6% for continuous). Consequently, a more comprehensive LCA gave a cumulative mass intensity for the continuous process of 112 kg/kg compared with 160 kg/kg for the batch process. Improvements in the environmental impacts from cleaning, utilities, and waste management outweighed the increase in environmental impact from materials and processing. The report illustrates that a comprehensive assessment is sometimes needed to fully understand the benefits (or lack thereof) provided by flow manufacturing and offers details of how to appropriately compare the two modes of manufacturing (Org. Process Res. Dev. 2016, 20, 1937−1948).

13. GENERAL GREEN CHEMISTRY The year 2017 marked the 25th anniversary of the E-factor concept. Sheldon published a Perspective detailing the conception, evolution, and application of the E-factor since its appearance in 1992. The article also discusses the other metrics used to define “greenness” of chemical transformation processes and compares and contrasts the results of the application of these metrics versus the E-factor. In the conclusion, some future steps that can be taken to further drive process greenness and the “circular economy” are given (Green. Chem. 2017, 19, 18−42). Kreuder et al. reported a new method for assessing green metrics for chemical processes. In the introduction, the authors reviewed many of the green metrics currently available and their applications to evaluating chemical processes. The authors noted that many of these metrics do not provide a score for all 12 of the principles of green chemistry and often have limitations to their implementation. In particular, they may require a high level of effort to complete the metrics scoring, utilize data that are not readily available, or require access to specialized or proprietary data sets. Lack of transparency and difficulties in communication are other limitations that were identified. The authors set about providing a metrics system relying on publicly available data that can be readily applied with little effort and will produce robust green chemistry metrics that can be easily compared across different processes. The result was the green chemistry metric (GCM) approach, which when applied to a chemical process gives scores for all 12 principles of green chemistry, presented in three groups based on hazards, resource usage, and energy efficiency. The article concludes with a direct comparison of two routes of synthesis to 1-aminobenzotriazole. The results are organized in a table, and recommendations for applying the GCM approach are given (ACS Sustainable Chem. Eng. 2017, 5, 2927−2935). Lipshutz published a Perspective that reviews the course of work in his laboratory on moving away from the use of organic solvents. The Perspective starts with the observations collected during the work on coenzyme Q10 within his group. Development of a vitamin E-based surfactant was required to improve the bioavailability of this compound and ultimately presented questions about whether it or other custom surfactants could be synthetically useful. Initial successes with olefin metathesis, Heck, and Suzuki−Miyaura reactions led to characterization of the micellar systems involved and influenced the design of new custom surfactants. Applications to a wide

May et al. provide a detailed account of the design, development, and GMP piloting of a continuous iridiumcatalyzed homogeneous reductive amination for the production of an API in late-phase clinical trials to treat high-risk vascular disease. The process supporting earlier work used stoichiometric sodium triacetoxyborohydride in batch mode. Reaction parameters were first screened in batch mode in the lab to arrive at optimal conditions. These were then translated to a pipes-in-series reactor that could achieve the same reaction residence time, temperatures, and pressures, thus facilitating the transition. This account describes how development obstacles were overcome. In particular, the iridium catalyst was found to deposit on the surfaces of the reactor during initial flow runs. This was remediated by adding tetrabutylammonium iodide as a stabilizer and adjusting the order of addition to introduce the catalyst last. It is of interest that the authors provide useful discussions on GMP-related questions such as how to approach and respond to online analytical monitoring, how to define and manage operational parameters, and how to define lot genealogy (Org. Process Res. Dev. 2016, 20, 1870−1898). The advantages in accessing chemistries and conditions not amenable to batch processing using continuous flow are wellknown and present opportunities to lower costs of manufacturing and improve sustainability. However, when just the manufacturing is considered independently of other factors, the benefits may not be as apparent, and a more holistic life cycle assessment (LCA) is needed to fully understand the benefits of adapting an established batch process to flow. Lee et al. provided a useful example of a batch-versus-flow comparison for the production of 4-D-erythronolactone that illustrates this point. They used a modular approach in which the product life cycle was compartmentalized into modules representing various functional units (e.g., Inputs Module, Transportation Module, Process Module, etc.). Software-assisted evaluation of PMI and other LCA metrics showed that the Process Module for continuous processing had a higher PMI compared with batch processing (35 kg/kg batch vs 50 kg/kg flow) since the optimized flow process required more reagents and a higher dilution factor to keep the solutes in solution. Consequently, other metrics, such as global warming potential (GWP) were negatively impacted for the same reason. If just the metrics for manufacturing were considered independently, one would incorrectly conclude that the batch process was superior to the continuous process. However, a more holistic assessment, M




Gheorghe-Doru Roiban: 0000-0002-5006-3240 Alan Steven: 0000-0002-0134-0918

range of disparate chemistry types are discussed, and the scope has been extended considerably from the first three reaction types initially explored. The Perspective concludes with a discussion of the limitations of this approach to chemical transformations and hints at applications on scale (J. Org. Chem. 2017, 82, 2806−2816). Green Chemistry Articles of Interest are produced on behalf of The ACS GCI Pharmaceutical Roundtable.

Marian C. Bryan Genentech, Inc., 1 DNA Way, MS 18B, South San Francisco, California 94080, United States

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

Shaun Hughes AstraZeneca, Macclesfield SK10 2NA, U.K.

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.

Markus Schober GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.

Austin G. Smith Amgen, Thousand Oaks, California 91320, United States

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

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

Stijn Wuyts Janssen Pharmaceutical Companies of Johnson and Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium

Jingjun Yin

■

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

Marian C. Bryan: 0000-0002-3138-6888 Zhongbo Fei: 0000-0002-5980-4017 John Hayler: 0000-0003-3685-3139 N


Green Chemistry Articles of Interest to the Pharmaceutical Industry

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