Green Chemistry Articles of Interest to the Pharmaceutical Industry

Green Chemistry Highlights pubs.acs.org/OPRD

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 16 member companies as compared to 3 in 2005. The membership scope has also broadened to include contract research/manufacturing organizations, generic pharmaceuticals, and related companies. Members currently include ACS GCI, Amgen, AstraZeneca, Asymchem, Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Codexis, Eli Lilly and Company, F-Hoffmann-La Roche Ltd., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, 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. This review covers publications in print or online in the period October 2015 to March 2016. 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.

to ortho-lithiation/functionalization-type processes (Eur. J. Inorg. Chem. 2015, 5147−5157). Guajardo et al. have provided an overview of the use of DESs in the areas of organocatalysis and biotransformations. One of the advantages of the first field is that the DES serves not only as the solvent but also as the organocatalyst, and given the broad tunability of the solvent, either basic or acidic catalysis can easily be achieved. In biotransformations, the use of DESs as (co)solvents in both isolated enzyme and whole cell systems is illustrated as well as their utility as extractive agents. Finally, a tandem reaction featuring an initial biocatalysis step to generate reactive acetaldehyde in situ followed by an organocatalyzed asymmetric aldol-reaction in the same medium is demonstrated. This has an additional benefit in that the DES phase may act as an “immobilizing” agent for the organocatalyst thus compartmentalizing the two reaction steps (ChemCatChem 2016, 8, 1020−1027). Durand et al. have discussed the various classifications of low transition temperature mixtures (LTTM) and noted that there is often a degree of overlap between the various classes, which can lead to some confusion in the literature. The authors also make a strong case for the involvement of natural deep eutectic solvents (NADES) in a variety of biological processes such as enzymatic stabilization, and as an alternative to water and lipids in the biosynthesis and storage of nonwater-soluble metabolites and macromolecules (Biochimie 2016, 120, 119−123). NADES also form the subject of a review from Espino et al. highlighting the range of potential uses that they have in analytical chemistry. In particular, their use in sample preparation and extraction with reference to their high solubilization power of both polar and nonpolar compounds is highlighted (Trends Anal. Chem. 2016, 76, 126−136). With reference to the pharmaceutical field, Lu et al. have investigated a series of DESs as a potential liquid administration vehicle for a set of nonsteroidal anti-inflammatory compounds (NSAIDs). Initially, the DESs were prepared and evaluated for their stability and range of fluidity leading to 19 being selected for the solubilization of the drugs. Compared to pure water, it was found that the use of DES increased the solubility of the NSAIDs from 17- to 5477fold, and a number of the systems evaluated were composed of pharmaceutically acceptable excipients. Addition of water to the DES was shown to decrease solubility, though tuning the system in this manner led to a decrease in viscosity with the solubility still enhanced compared to pure water alone (Med. Chem. Commun. 2016, 7, 955−959). Shanab et al. have published the second part of an overview highlighting specific examples of green solvents utilized in organic synthesis. This section focuses on (1) 2-MeTHF demonstrating its capability as a solvent for biotransformations, (2) ethyl lactate with its ability to have its polarity tuned

2. SOLVENTS The growing interest in Deep Eutectic Solvents (DESs) is reflected not only by exponential growth in publications since their initial disclosure in 2003 but also in several articles focusing on specific applications of these novel solvents in the ́ ́ lvarez has reported on the period under review. Garcia-A employment of DESs in a series of metal-mediated organic transformations including Ru-catalyzed isomerizations, Au-catalyzed cycloisomerizations, click reactions, Pd-mediated cross-couplings, and Ru-mediated hydrogenations and hydroformylations. In many of the examples, a comparison with the classical solvent media is provided highlighting advantages of the DES-based systems in terms of catalyst activity, ease of product isolation, and potential catalyst recyclability. Additions of Grignard reagents and organolithiums to ketones are also demonstrated in choline chloride (ChCl)-based DESs and shown to take place almost instantaneously in high yield at room temperature under air. The enhanced reactivity and lack of competing hydrolysis are proposed to arise from the in situ formation of highly reactive magnesiates and lithiates in the presence of ChCl. For the organolithium reagents, the chemistry has been extended © 2017 American Chemical Society

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January 16, 2017 January 18, 2017 January 20, 2017 February 7, 2017 DOI: 10.1021/acs.oprd.7b00014 Org. Process Res. Dev. 2017, 21, 153−164

Organic Process Research & Development

Green Chemistry Highlights

2015, 51, 384−387). The reaction utilizes both PhI(OAc)2 as the optimal iodine source and NaHCO3 as the base and proceeds through cleavage of the alkyne. Labeling studies showed the amide oxygen originates from the water solvent. Sequential addition of the various reactants leads to the highest yields with an observable change in both the appearance and color of the reaction enabling it to be easily monitored. Substituted phenylacetylenes proved to be the best alkyne substrates reacting with a range of primary and secondary amines in excellent yields, whereas more moderate yields were obtained for aliphatic alkynes and aromatic amines as substrates. Variations of the reaction conditions enabled ketoesters to be isolated as the major products. A second report in the period under review from the same group focused on expanding the scope of the amide synthesis as well as developing a novel route to cyclic imides from 2-ethynylbenzaldehyde derivatives. In addition, a range of techniques were exploited (DFT, ReactIR) to identify intermediates in the reaction pathway and, thus, provide a mechanistic rationale for the transformation (RSC Adv. 2015, 5, 106633−106643).

through dilution with water, (3) CPME as a solvent for the Pinner reaction, (4) limonene and p-cymene looking at them as potential replacements for toluene in reactions requiring the azeotropic removal of water, and (5) solvent-free synthesis of heterocycles through simple grinding of the materials together (Curr. Org. Chem. 2016, 20, 1576−1583). Abou-Shehada et al. have presented a strategy to both minimize solvent use and, in a number of cases, expedite product separation and/or catalyst recovery through the use of “tunable solvents”. Tunable solvents are defined as solvents that have variable properties that are precisely controlled by the use, with the simplest example of a tunable solvent being a supercritical fluid. The authors note that, with this in mind, property tuning is more facile in sealed systems, and as such, the uptake of tunable solvents in industry will to a large extent be governed by the significant changes required not only to processes but also to the manufacturing plants in which they are run. The utility of tunable solvents is exemplified by a series of case scenarios in which they can be employed with several real examples of current use being provided. One such study highlights use of a gas expanded liquid (GXL) as an antisolvent for product isolation. In this case, a product is soluble in an organic solvent to which CO2 is added to expand the liquid phase. The product is insoluble in the GXL so formed and can be isolated, after which CO2 is removed by depressurization, and can be recycled along with the organic solvent (Chem. Eng. Process. 2016, 99, 88−96). Obregón et al. have reported on the synthesis of 2-methyltetrahydrofuran directly from levulinic acid (LA) in a one-pot process using Ni/Cu/Al2O3 as a catalyst. Given that LA is a solid at room temperature, investigation into a suitable solvent indicated that 2-PrOH was optimal with the hypothesis that given its behavior as a hydrogen-donor molecule, this solvent was key in its ability for the conversion of the stable γ-valerolactone (GVL) intermediate. A series of catalysts were evaluated, and it was found that the Ni and Cu perform synergistic roles, with the Ni being responsible for conversion to high levels of the product and the Cu responsible preventing side products being formed from breakdown of the 2-MeTHF under the reaction conditions. An optimum ratio of 23Ni− 12Cu was determined, and changes in the catalyst surface and microenvironments of the metallic particles were studied in depth in order to generate a mechanistic hypothesis for the overall transformation, which overall provides a maximum yield of 56% of 2-MeTHF (ChemSusChem 2015, 8, 3483−3488). There continues to be a debate as to the greenness of ionic liquids (ILs) as solvents, as although atmospheric pollution due to these chemicals is unlikely because of their low volatility, questions remain regarding their biodegradability and their potential impact on both terrestrial and aquatic environments. Amde et al. have published a comprehensive review, which collates all the known data with regard to this topic. Literature data on biodegradability are presented together with potential mechanisms. Of particular utility is a collation of trends based on both anion and cation properties correlated with increasing toxicity as well as a roadmap for the synthesis of less toxic and more biodegradable ILs (Environ. Sci. Technol. 2015, 49, 12611−12627).

The hydration of nitriles to form amides is often carried out under harsh conditions, which give rise to undesired side reactions such as formation of the corresponding acids as well as presenting issues with functional group tolerance in sensitive substrates. Veisi et al. have reported a mild chemoselective nitrile hydrolysis mediated by aqueous tetrabutylammonium hydroxide either under neat conditions if the substrate is suitably miscible or with the addition of EtOH as a cosolvent. The reaction is applicable to aliphatic, aromatic, and heteroaromatic nitriles with neither electronics nor steric hindrance of the substrates appearing to affect the reaction yield. The reaction also tolerates a range of functional groups including olefins, aldehydes, and oximes, and 1,4-dicyanobenzene can be hydrated selectively to either the mono- or bis-amide depending on the reaction time. The catalyst can be recovered and recycled using ion exchange resins. Coordination of the nitrile to the quaternary ammonium moiety is believed to be critical for the observed reactivity (RSC Adv. 2015, 5, 6365−6371).

From an environmental standpoint, the direct coupling of an amine with a carboxylic acid liberating only water as a byproduct is the most attractive reaction for the synthesis of amides. Basavaprabhu et al. have reported on this reaction mediated by 20 mol % FeCl3 in the presence of 0.5 equiv of glacial acetic acid. Refluxing toluene was the optimal solvent with the hypothesis that being a nonpolar solvent, the formation of the charged salt between the acid and amine is disfavored. The catalytic effect of FeCl3 was confirmed through testing the background reaction, and the Fe is proposed to activate the carbonyl group of the acid toward nucleophilic

3. AMIDE FORMATION Khamarui et al. have previously reported on a novel synthesis of amides from alkynes and amines under aqueous conditions mediated by a hypervalent iodine species (Chem. Commun. 154

DOI: 10.1021/acs.oprd.7b00014 Org. Process Res. Dev. 2017, 21, 153−164



and aliphatic amines. In addition, the GO could be recycled 6 times without any loss in reactivity. The reaction is postulated to proceed through the aldehyde, which is activated for nucleophilic attack by either hydroxyl or carboxyl groups on the surface of the GO (Ultrasonics Sonochemistry 2016, 32, 37−43).

attack by the amine. The reaction was demonstrated to work well for a range of anilines as well as bromoacetic acid and sterically hindered amino acids, although in the latter cases racemization was observed (New J. Chem. 2015, 39, 7746−7749).

Gu et al. have reported on an azide-aldehyde [3 + 2] cycloaddition to give a 1,2,3-triazoline followed by a rearrangement featuring the extrusion of nitrogen gas during the workup to provide the amide product. Model studies on the reaction between phenyl azide and cyclohexanecarboxaldehyde indicated that the reaction proceeded best in DMSO at mild temperatures and was catalyzed using the ionic liquid, 1-n-butyl-3-methylimidazolium hydroxide ([bmIm]OH), with an aqueous NH4Cl mediated workup giving the amide. From a scope perspective, electron-deficient aryl azides reacted more rapidly, and at lower temperatures than electron-rich substrates, and the sterics of the aryl azide appeared to have little effect. Heterocyclic aryl azides also worked well, although aliphatic and tosyl azides were unsuccessful coupling partners. A range of aldehydes were also demonstrated to couple successfully though model studies indicated that enolization (proposed to be mediated by [bmIm]OH) was key for the reaction to proceed (Green Chem. 2016, 18, 2604−2608).

Two groups have reported on the use of copper sources to mediate the reaction between amines and aldehydes to form amides. Saberi et al. utilized Cu(I) on charcoal (Cu/C), which was initially shown to catalyze the reaction between β-ketoesters and formamides to provide enol carbamates. The reaction between benzaldehyde and ammonium chloride was studied to extend use of this catalyst to the synthesis of amides, and model studies indicated that MeCN was the best solvent using aqueous TBHP as the oxidant at 60 °C. Meta and para substituents were well tolerated on the benzaldehyde though ortho-substitution shut down the reaction completely. Primary and secondary amine hydrochloride salts worked well, though anilines were poor substrates, and it was observed that the yields deteriorated if the free amine was used instead of the salt. The catalyst could be reused 5 times with minimal loss of reactivity (Tetrahedron Lett. 2016, 57, 95−99). Lu et al. described a similar system using CuCl and aqueous TBHP in water at 100 °C for the same transformation. Although the reaction proceeded in the absence of the Cu salt, addition of the latter almost doubled the conversion. In this system, aliphatic and aromatic (and heteroaromatic) aldehydes were successful, and in the aromatic cases, ortho-substitution was tolerated. Primary and secondary amines performed well though anilines were demonstrated to be unreactive (Tetrahedron Lett. 2016, 57, 633−636).

Several reports emerged in the period under review describing the oxidative amidation of alcohols to provide amides. Gu et al. describe a continuous flow method, which uses an initial tube reactor to carry out the alcohol to the aldehyde oxidation in line with a second reactor for subsequent addition to the amine in the presence of an oxidant to form the desired amide. Based on previous work, the initial oxidation was achieved using H2O2/NaBr/H+; however, although this system was able to carry out the hemiaminal oxidation as well, it was inferior to TBHP. The two reactors were maintained at 70 and 80 °C respectively, and residence times were optimized using the reaction between benzyl alcohol and morpholine. From a scope perspective a range of benzyl and heterocyclic alcohols were good substrates with the reactions proceeding with secondary amines. However, primary amines were unsuccessful substrates (RSC Adv. 2015, 5, 95014−95019). Mirza-Aghayan et al. have described the amidation of benzylic alcohols catalyzed by graphite oxide (GO) facilitated by ultrasonic irradiation. The synthesis of N-benzylbenzamide was chosen as the model reaction, which demonstrated that solvent (MeCN), temperature (50 °C), and the presence of molecular oxygen were critical for the reaction to proceed. For scope, a range of differentially substituted benzylic alcohols were successful substrates reacting with aromatic, heteroaromatic,

Liu et al. have described the use of carbamoylsilanes as an amide source in a C−H functionalization reaction, which is equivalent to an aminocarbonylation avoiding both the precious metal catalyst and the use of CO. A model reaction using 3-cyanopyridine with N,N-dimethylcarbamoyl(trimethyl)silane showed a significant solvent effect for the formation of the carbinolamine. Although benzene was the best solvent, toluene also performed in an adequate manner. The reaction was extended 155




efficiency as well as the sensitivity toward racemization utilizing these alternative solvents. In solution phase, 2-MeTHF provided better results than DMF in terms of coupling efficiency when used with DIC and most additives and showed a similar racemization profile. In addition, 2-MeTHF was superior to CPME, THF, and MeCN. With uronium/aminium-based methods, DMF was the solvent of choice though the performance of COMU in 2-MeTHF was acceptable. Moving to solid phase, and evaluating the synthesis of a pentapeptide under various conditions, 2-MeTHF gave excellent results (97% purity vs 43% for DMF under analogous conditions) when utilized as solvent in conjunction with DIC/OxymaPure. Based on the various studies reported, the authors recommend 2-MeTHF, DIC/OxymaPure and PS resin as the method of choice for greener solid-phase peptide synthesis (Amino Acids 2016, 48, 419−426).

to a range of electron-deficient aromatic systems with acetyl, isocyanate, nitro, and nitrile functionalities. In the case of several heterocyclic systems such as 2-chloro-5-nitropyridine, the amide product was obtained exclusively from the reaction. Several other heterocyclic systems and alternative carbamoylsilanes are also reported to give either the carbinolamines or amides in good to excellent yields (Tetrahedron Lett. 2016, 57, 937−941).

Supported reagents offer the opportunity for both recovery and recycling, and various supported benzotriazoles have been developed for amide couplings although they suffer from low loading capacities, poor swelling properties, and limited scope. Shakoor et al. have reported on an imidazolium-supported benzotriazole, which is easily accessed in four steps followed by anion exchange with KPF6 to tune the solubility properties. DSC indicates the exothermic decomposition temperature of the reagent initiates at 150 °C while TGA shows full degradation around 366 °C. The model reaction of benzoic acid with the reagent was screened to determine the optimum conditions for generating the activated acid with DCC in MeCN and catalytic DMAP at room temperature giving the highest yield. The DCU could easily be removed by washing with EtOAc with the desired product precipitated from MeOH. A number of aromatic and heteroaromatic carboxylic acids and even acetic acid were activated by the supported reagent. For the amidation, the reaction proceeded smoothly in H2O under microwave irradiation using DMAP as the base. In a similar manner, both sulfur and oxygen nucleophiles could be used under slightly modified conditions. The reagent could be easily recovered simply by washing the reaction mixture with EtOAc and drying the solid residue under high vacuum, and was used over 5 cycles with only a slight decrease in yield. Although a one-pot method was also developed, the stepwise sequence led to easier isolation of the final product, and this was demonstrated on gram scale for the preparation of paracetemol (RSC Adv. 2015, 5, 82199−82207).

4. OXIDATIONS Wang et al. reported a highly selective air-oxidation of primary alcohols with an Fe(NO3)3·9H2O/9-azabicyclo[3.3.1]nonan-Noxyl (ABNO) catalyst system. While an Fe−TEMPO system has been used for alcohol oxidations, it usually requires a halogenated solvent such as dichloromethane, 1,2-dichloroethane, and trifluorotoluene. It also suffers from moderate selectivity with primary alcohols due to overoxidation of the aldehyde product. Switching TEMPO to a less hindered nitroxyl radical ABNO not only improved the reactivity but also gave significantly higher selectivities (>90%). The oxidation is carried out in MeCN without any base or ligand and has a broad substrate scope, including secondary alcohols (J. Org. Chem. 2016, 81, 2189−2193).

Benzylic oxidation is a very useful reaction but has typically required expensive terminal oxidants in combination with a transition metal catalyst and/or expensive ligands. Zhang et al. developed a metal-free benzylic oxidation with a recyclable TEMPO derivative as the catalyst, HCl and NaNO2 as cocatalysts, and oxygen as the terminal oxidant. The reaction is run in MeCN with just 0.5% of the catalyst and gives efficient access to isochromanones and xanthones. The catalyst can be recycled by aqueous extraction due to its sulfonic acid salt chain (Org. Lett. 2015, 17, 5492−5495).

For a variety of reasons such as reagent solubility and resin swelling, DMF is considered to be the best solvent for solidphase peptide synthesis. Jad and co-workers have carried out a detailed analysis looking at both 2-MeTHF and CPME as potential green replacements in this area. Initial studies focused on the solubility of the protected amino acid building blocks, the coupling reagents, and the swelling of the various resins in these solvents. Utilizing these results, a series of comparative coupling reactions were analyzed to investigate the coupling

Conversion of aldehydes to nitriles via aerobic oxidation in the presence of an ammonium source is an attractive green method, but most of the approaches utilize a metal catalyst. Noh and Kim found that NHAc−TEMPO can catalyze the aerobic oxidative conversion of aldehydes to nitriles with 156




Catalysis using first row transition elements is attractive from the point of view of cost and sustainability. With an approach that relied heavily on high throughput experimentation, Shevlin et al. have disclosed the first homogeneous nickel-catalyzed asymmetric hydrogenation of α,β-unsaturated esters that uses hydrogen as the terminal reductant. The optimized conditions use nickel acetate as an air stable precatalyst. A catalytic amount of a tetrabutylammonium salt additive was found to increase both reactivity and enantioselectivity. The enantioselectivities observed (up to 96% ee) are notable given the relatively poor ability of ester substituents to function as directing groups through coordination to a transition metal catalyst. Job plots and kinetic studies were used to establish that a trimetallic complex, in equilibrium with other nickel complexes, is the active species for the hydrogenation. The reaction can tolerate a range of electron-donating and -withdrawing groups on the aryl ring (J. Am. Chem. Soc. 2016, 138, 3562−3569).

ammonium acetate and NaNO2 cocatalysts. Use of acetic acid as the solvent was important. Functional groups such as halides, nitro, ethers, and phenols are well tolerated (J. Org. Chem. 2015, 80, 11624−11628).

It should be noted that all three methods cited here operate under an air or oxygen atmosphere above the flash point of the solvent and will require appropriate engineering control for safe scale-up. Direct oxidation of amines to amides is a powerful reaction but has seen limited success. Cu, Ru, or Au catalyzed oxidations have been developed, but they are unreactive for simple, acyclic tertiary alkyl amines. Legacy et al. developed an iron catalyzed oxidation of tertiary alkyl amines with PhCO3tBu as the terminal oxidant. 2-Picolinic acid was found to be the best ligand, and a small amount of water was important to limit the elimination reaction that gives secondary amines. While the yields are moderate, this method provides a rapid access to such amides under mild conditions and was successfully applied to the synthesis of the amide metabolite of Lidocaine (Angew. Chem., Int. Ed. 2015, 54, 14907−14910).

Friedfeld et al. reported a cobalt-catalyzed enantioselective hydrogenation of minimally functionalized cyclic alkenes. The latest work uses a cobalt(II) complex bearing a redox-active bis(imino)pyridine ligand. For exocyclic alkenes, the manifold that involves exo- → endo- isomerization prior to hydrogen addition became increasingly facile as the size of the ring bearing the alkene was reduced, so much so that seven- and five-membered exocyclic alkenes produced stereodivergent outcomes. As might be expected, stereoselectivities are enhanced by the presence of a substituent ortho to the vinylic substituent on the aromatic ring of a substrate. While some of the reactions are run in diethyl ether, several examples use toluene or run the reactions under solvent-free conditions. A mechanism for the reaction is reported that is underpinned by a combination of deuterium labeling and kinetic studies (J. Am. Chem. Soc. 2016, 138, 3314−3324).

5. ASYMMETRIC HYDROGENATIONS The asymmetric hydrogenation of 2-substituted quinolines can be used to efficiently access the tetrahydroquinoline motif found in biologically active compounds such as torcetrapib, angustureine, and cuspareine. The use of a Hantzsch ester as the hydrogen source and a chiral phosphoric acid catalyst as the source of chirality renders the transformation transition metalfree. While such a transfer hydrogenation using benzene and diethyl ether as the reaction solvent has been reported previously, the use of diethyl carbonate has only recently been disclosed. Organic carbonates such as diethyl carbonate are useful solvents on account of their noncorrosive nature, low acute toxicity, biodegradability, and availability in bulk. Interestingly, the use of propylene carbonate produced a racemic product. Most of the substrates examined bore an aryl group at the 2-position of the quinoline (Tetrahedron: Asymmetry 2015, 26, 1174−1179).

Chen et al. from Zhejiang University have developed an oxazoline iminopyridine−cobalt complex for the asymmetric reduction of 1,1-diarylalkenes, a motif which features in a number of biologically active molecules. All of the 1,1-diarylalkenes examined had an ortho-substituent, typically chlorine, on one of the aryl rings, presumably to aid differentiation between the two faces of the alkene by the catalyst. The authors demonstrate that the ortho-chloro substituent can be readily removed, if necessary, with an ensuing transfer hydrogenation using Pd/C. A small number of α-alkylstyrenes were also 157




disclosed by Joe and Doyle. The reaction is conducted under mild conditions and uses relatively simple reagents to generate useful α-amino ketone products. A variety of cyclic and acyclic N-aryl amines work well in the reaction which exhibits selective functionalization at the less hindered C−H bond. Five-, six-, and seven-membered cyclic amines, as well as heterocyclic indolines and tetrahydroisoquinolines, all produce the desired product. Symmetric anhydrides as well as the more versatile 2-pyridylthioesters work well as the electrophilic component. The authors demonstrate the power of the new method by coupling the thioester derivatives of biotin and the steroid derivative TBS-lithocholic acid. One current limitation of the method is that aryl electrophiles do not work (Angew. Chem., Int. Ed. 2016, 55, 4040−4043).

examined and produced useful levels of selectivity (89−95% ee) without the need for the ortho-substituent (Org. Lett. 2016, 18, 1594−1597).

Vilhanová et al. have described a protocol for the enantioselective hydrogenation of olefins which uses achiral metal−organic framework (MOF) additives. The MOF absorbs a rhodium catalyst when the reaction is performed in toluene. This results in a heterogeneous reaction system, limiting the metal content of the reaction liquors and increasing the enantioselectivity versus the control without the MOF. The heterogeneous nature of this catalytic system is of particular interest due to its potential to simplify reaction workup operations. The enantioselectivity is enhanced during the recycling of the catalyst/MOF, though yields were observed to deteriorate under these circumstances. Although this methodology is in its infancy and only a limited number of substrates have been tested, this work makes a useful contribution to the development of heterogeneous enantioselective hydrogenations of alkenes (ChemCatChem 2016, 8, 308−312).

Hatano et al. have developed a method to generate chiral ethers from the corresponding vinyl ether and N-mesylamides. The catalyst of choice was a system using the chiral hydroxoiridium/Me-tfb* catalyst with loadings as low as 5 mol % with respect to iridium. A wide variety of ethers were utilized, and internal alkenes in the substrates were not reactive. Good yields were realized for all examples with chiral purity between 83 and 97% ee. Additional examples proceeded in similar yields and ee’s for a wide range of substitution patterns on the aryl mesylamide. However, N-mesylbenzamide showed significant levels of the dialkylation product. In addition to multiple examples of C−H activation in this article the authors outline the utility of transforming the N-mesylamide to the corresponding ester, alcohol, aldehyde, and amide (J. Am. Chem. Soc. 2016, 138, 4010−4013).

6. C−H ACTIVATION Masuda et al. have developed a light-promoted carboxylation of o-alkylphenyl ketones. The general protocol relies on light-driven energy and avoids the use of Grignard reagents or transition metal catalysts required for many common carboxylations. Simply irradiating a DMSO solution of the substrate using an LED lamp (365 nm) under atmospheric pressure of carbon dioxide produces o-acyl-phenylacetic acid products. Both alkyl o-tolyl ketones and aryl o-tolyl ketones undergo the reaction, and the reaction is tolerant of common functionality such as alcohols, aldehydes, and aryl chlorides. In one example, solar light drove the reaction to a 72% yield (89% yield using UV light). The authors provide evidence that photoirradiation of the substrate generates an o-quinodimethane. The o-quinodimethane intermediate then undergoes [4 + 2] cycloaddition with CO2 followed by ring opening to generate the product (J. Am. Chem. Soc. 2015, 137, 14063−14066).

Zhang et al. demonstrated the use of a catalytic amino acid to serve as a temporary directing group via imine formation with an aldehyde. Water was an important additive to ensure the imine intermediate was short-lived. Initial optimization with a variety of R1 and R3 substituents where R2 = H utilized 40 mol % glycine to achieve good yields of the desired product. For all these examples the aryl iodide was utilized. Multiple examples of both electron-donating and -withdrawing aryl iodides also performed well on ketone substrates and exhibited excellent syn diastereoselectivity for cyclic substrates. Finally, chiral amino acids could be utilized to impart enantioselectivity for examples when R2 is an alkyl group. 20 mol % L-tert-leucine resulted in greater than 90% ee for all examples that were reported (Science 2016, 351, 252−256).

A direct C−H functionalization of N-aryl amines by acyl electrophiles, enabled by nickel and photoredox catalysis, was 158




chloroquinoline, chloroisoquinoline, and chloropyridazine could be transformed to the desired SNAr fluorinated products at room temperature in excellent yields. Less reactive substrates, such as ortho- and para-chlorobenzonitrile, required elevated temperatures up to 80 °C and also gave excellent yields, while meta-chlorobenzonitrile gave a low yield even at 80 °C. The authors studied the effect of the leaving group on the reaction rates for 2-substituted benzonitriles with Cl, Br, I, NO2, and OTf as well as for the 2-substituted pyrimidine series, and found that the relative rate was substrate dependent but the nitro group showed the highest reactivity in both series. A cost analysis comparing NMe4F (anh) with CsF for large-scale SNAr fluorinations showed that NMe4F (anh) offers a significant cost advantage for three fluorinations studied (J. Org. Chem. 2015, 80, 12137−12145).

Finally, in addition to the articles discussed above a review article by Santoro et al. covers literature over the past decade focusing on recyclable heterogeneous catalysis for C−H activations (Green Chem. 2016, 18, 3471−3493).

7. GREENER FLUORINATION 1,1-Difluoroalkenes are structurally unique compounds often found both in the course of drug discovery efforts and in applications in general synthetic chemistry for functional group manipulations. One approach to access these compounds is via transition metal catalyzed gem-difluoroolefinations of diazo compounds with TMSCF3. Hu et al. reported a new metal-free approach that exploits the intrinsic nucleophilicity of the diazo substrate and the electrophilicity of in situ generated difluorocarbene. Two sets of conditions were developed based on different methods of generating the difluorocarbene species. The first used the combination of TMSCF3/NaI, and the second used the combination of TMSCF2Br/n-Bu4NBr. These two conditions converted a variety of α-diazo acetates to 1,1-difluoroalkenes with comparable yields in most cases. For diaryldiazomethanes, the first condition was preferred due to comparably lower reaction temperatures needed for difluorocarbene generation. For arylalkyldiazomethanes, which are even less stable and were generated in situ by thermal decomposition of diazirines, the second condition was preferred because the reaction temperatures were better matched at producing the two reactive partners at comparable rates, and minimizing cyclopropanation of the product (J. Am. Chem. Soc. 2015, 137, 14496−14501). Interestingly, Zhang et al. reported the TMSCF2Br/n-Bu4NBr approach shortly thereafter, widening the substrate scope. Alkylaryldiazomethanes were generated in situ from N-tosylhydrazones; however, all reactions were performed in 1,2-dichloroethane (Angew. Chem., Int. Ed. 2016, 55, 273−277).

The direct difluoromethylation of aryl halides is an underdeveloped area. Previous reported methods are limited to cross-couplings using either stoichiometric copper systems or a catalytic, but a complicated combination of palladium and silver. One restriction in this area is the lack of an efficient reagent to provide a good source of difluoromethyl. The most commonly employed reagent, Me3SiCF2H, requires either elevated temperatures or an exogenous base such as tertbutoxide to cleave the Si−CF2H bond. Xu and Vicic have reported the discovery of a new reagent and its application in the direct difluoromethylation of aryl halides using a catalytic nickel system at room temperature. The reagent, [(DMPU)2Zn(CF2H)2], prepared from reacting ICF2H with diethyl zinc in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), is an isolable, free-flowing solid and is stable under an inert atmosphere for months. Employing 1.2 equiv of this reagent, together with 15 mol % Ni(COD)2 and 15 mol % dppf in DMSO, allowed the difluoro-methylation to be successfully performed on a range of aryl/heteroaryl iodides, bromides, and triflates. It was found, however, that the reaction was sensitive to the electron density of aromatic rings. Substituted benzenes bearing electron-withdrawing groups afford good yields, while those with electron-donating groups such as alkyl or alkoxyl groups gave little or no desired product (J. Am. Chem. Soc. 2016, 138, 2536−2539).

Identification of an appropriate fluoride source is critical for practical nucleophilic aromatic fluorinations (SNAr). Challenges associated with this type of reaction are cost control, the need for dry conditions, and reactivity. Schimler et al. report the utilization of anhydrous tetramethylammonium fluoride (NMe4F) as a fluoride source to address these challenges. NMe4F can be prepared from inexpensive precursors such as NMe4Cl and KF and can be rigorously dried at elevated temperature (it is known that NBu4F is susceptible to Hoffman elimination upon heating). Unlike alkali metal fluorides which usually require high temperatures for SNAr fluorination due to poor solubility, NMe4F (anh) is soluble in organic solvents and can effect SNAr fluorinations at room temperature. Reactive substrates such as monochloro-picolinates, dichloropicolinates,

8. BIOCATALYSIS The C−H activation of organic compounds at nonactivated sites is of high value for synthetic organic chemistry. Cytochrome P450 enzymes are an ideal catalyst for this transformation since they often show excellent chemo-, stereo-, and regioselectivity while working under benign reaction conditions. However, the industrial application of these enzymes has often been limited by their poor performance under 159




technology to a wide range of substrates (Angew. Chem., Int. Ed. 2016, 55, 1511−1513).

industrially relevant process conditions. Kaluzna et al. were able to use a cytochrome P450 to produce kilogram quantities of hydroxylated (R)-hydroxyisophorone, a valuable intermediate that is difficult to obtain by chemical oxidation. After initial catalyst selection via screening in microtiter plates, the reaction with the most promising enzyme was gradually scaled up to a 100 L reaction. A systematic optimization of process parameters was conducted, and both scale dependent and independent process limitations were identified. Finally the group was able to report product concentrations >6 g/L and volumetric productivities of more than 1 g/L*h on a 100 L scale. The process development work presented in this report could be useful as a guideline for future industrial P450 processes (Org. Process Res. Dev. 2016, 20, 814−819).

Enoate reductases have shown to be potent catalysts for selective trans-hydrogenation of CC bonds. One drawback of these reactions is that they need equimolar amounts of sacrificial cosubstrates (e.g., glucose, formate, isopropanol) as reductants, decreasing their atom efficiency. Koeninger et al. have reported an alternative using cyanobacteria whole cells overexpressing the enoate reductase YqjM from Bacillus subtilis. The cyanobacteria are able to oxidize water in light-driven photosynthesis to regenerate the redox cofactor used by the enoate reductase, NADPH, thus removing the need for a cosubstrate such as isopropanol. Specific catalyst activities of 100 Ug1− were achieved with this system. The applicability of the process was shown by reducing 100 mg of 2-methylmaleimide to enantiopure (R)-2-methylsuccinimide (>99% ee, 81% isolated yield). Even though further development is necessary to obtain higher substrate concentrations required in industrial processes, the study presents an intriguing way to use photosynthesis to regenerate NADPH which could be applied for a wide range of NADPH dependent enzymes (Angew. Chem., Int. Ed. 2016, 55, 5582−5585).

Another group of enzymes that are able to conduct selective oxidation of allylic C−H bonds are Rieske nonheme iron oxygenases (ROs). Gally et al. have shown that these enzymes are also able to catalyze the stereoselective cis-dihydroxylation of a range of mono-, gem-di-, cis-di-, and trisubstituted alkenes. They were able to obtain conversions of up to 99% and >95% de by only modifying a single amino acid residue. Directed evolution was also applied to vary the selectivity for alkyl oxidation versus alkene dihydroxylation and additionally the regioselectivity of the dihydroxylation. A very impressive example of the latter was achieved for the selective dihydroxylation of styrene. By gradually decreasing the size of the side chain amino acid at position 232, a regioselectivity change from arene-1,2-dihydrodiol (a) to alkene-1,2-diol (b) was observed. While the WT enzyme showed clear preference (99.7:0.3, a:b), the change from methionine to alanine led to an almost complete change in selectivity (8:92, a:b). The study shows that ROs are able to conduct a wide range of regio- and stereoselective oxyfunctionalizations of organic molecules, some of which are hard to obtain by Sharpless AD or Riley oxidation (Angew. Chem., Int. Ed. 2015, 54, 12952−12956).

9. REDUCTIONS A paper from Ogiwara et al. shows the versatility of catalytic processes in biasing reaction outcomes. Phenylsilane (1 equiv) and an indium salt (1 mol %) were used to effect reductive amination, followed by intramolecular amidation of a large variety of anilines to give γ- and δ-lactams in good to excellent yields. During screening of indium salts, it was observed that InI3 preferentially led to over-reduced products, the yield of which could be optimized by using additional phenylsilane. Thus, essentially the same conditions could also provide the corresponding pyrrolidines/piperidines although the demonstrated functional scope was reduced for this extension. Nonetheless, such multitransformation processes offer a distinct advantage over traditional single step methodology and nicely demonstrate the control that a catalyst can apply (Angew. Chem., Int. Ed. 2016, 55, 1864−1867).

An intriguing approach to chiral amines has been shown by Both et al., conducting an enantioselective C−H amination via a four enzyme cascade in an E. coli cell. The single whole cell catalyst, consisting of an evolved chimeric self-sufficient P450 monooxygenase, two alcohol dehydrogenases, and a transaminase, was able to convert five benzylic substrates with up to 26% conversion and 97.5% ee. In the process the reaction only needs isopropylamine as the amine donor and molecular oxygen, as other cofactors are provided by the cell. Each of the enzymes expressed could easily be replaced by a different variant, which opens the door for the application of this 160




both successful application as well as current limitations. This work illustrated examples where alkylating agents could be avoided and multiple simple aliphatic alcohols were successfully employed. However, in the example shown below, the authors show that, while benzyl alcohol is a suitable substrate for reaction with the protected diamine (1) as it is known to work well in redox-neutral alkylations, coupling 1 with protected ethanolamine did not yield the desired product, as dehydrogenation of the amine is either preferred or a competing reaction over alcohol dehydrogenation. The authors highlight some shortcomings of the “borrowing hydrogen” strategy that are worthy for further exploration, including structural incompatibilities found in the complex polyfunctional molecules typified by pharmaceutical intermediates, catalyst incompatibilities with heteroatom-rich heterocyclic structures, and the need for more active and tolerant catalysts, capable of operating at low loadings and across a broad range of solvents (Org. Process Res. Dev. 2015, 19, 1400−1410).

A similar two-step outcome is reported by Mamillapalli and Sekar in the reduction of α-ketoamides. Using (EtO)3SiH as reductant and CuF2 as catalyst in the presence of the chiral ligand (S)-DTBM-SEGPHOS, they reported asymmetric reduction to the corresponding α-hydroxyamides in high yields and good to excellent stereoselectivities. If catalytic TBAF and further (EtO)3SiH were subsequently added, reduction of the amide occurred to provide the chiral β-aminoalcohol. Control experiments showed the expected ketone reduction occurred prior to the amide reduction and also that there was minimal racemization during amide reduction in contrast to earlier work on α-ketoesters (Chem.Eur. J. 2015, 21, 18584−18588).

Nitro reduction is a very common transformation due to the abundance of aniline substrates and intermediates in pharmaceuticals. Zhu et al. have reported coupling nitro reduction with hydroamination using bench-stable iron(III) catalysts in the presence of silanes. The bis-phenolate iron(III) catalyst gave excellent chemoselectivities for nitro reduction over aromatic substituents such as nitrile, ester, and halide irrespective of the substitution pattern relative to the nitro group. With the ability of the catalyst to also promote hydroamination taken into consideration, the combined process was conducted giving the alkylated aniline in yields ranging from 40% to 75% with catalyst loadings of 2 mol %. Significant tenability in the catalyst system was apparent. An isolated carbonyl group could be carried intact while an alkene bearing an appropriately sited carbonyl substituent underwent subsequent reductive amination with the aniline to give a piperidine on prolonged exposure. The selectivity of the reduction was very sensitive to both solvent and silane choice suggesting additional versatility in the catalyst system (Chem. Sci. 2016, 7, 3031−3035).

Hikawa and co-workers have also reported on hydrogen borrowing methodology for N-benzylation using a benzylpalladium system to promote the transformation in water. The scope of the reaction was limited to electron-donating or neutral groups on the benzyl alcohol and electron-withdrawing groups ortho to the amine on the aniline to give moderate to high yield of the monobenzylated product. The sole heteroaryl example was 2-aminopyridine, and neither phenethyl alcohol nor alcohols with electron-withdrawing groups at C4 provided the desired transformation. Still, the reaction conditions allow for efficient N-monobenzylation of electron-deficient anilines or 2-aminopyridine with unactivated benzylic alcohols under neutral conditions with a low catalyst loading (5 mol %) in water, and the authors speak to investigating the scope further with other nucleophiles (Adv. Synth. Catal. 2016, 358, 784−791).

Li et al. studied the direct alkylation of various amines including sulfonamides, arylamines, and heteroarylamines with aliphatic and benzylic alcohols under basic conditions. Of the alcohols screened, two examples featured substitution of the benzylic position, though no branched aliphatic alcohols were reported. Screening studies identified potassium hydroxide (0.5 mol %) as the most effective base when heated at 130 °C

10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT Leonard et al. relate a survey of the “borrowing hydrogen” approach to several intermediates at AstraZeneca, highlighting 161




80 °C for 24 h. Sequential alkylation of 1,3-diaminobenzene enabled the preparation of unsymmetrically alkylated products (Angew. Chem., Int. Ed. 2015, 54, 15046−15050).

under an argon atmosphere and monitored for amine consumption. The authors propose a “hemiaminal” model for the transformation and argue against aldehyde catalysis. The transition-metal-free process was used to couple benzylic alcohols in high yield and showed no erosion when either partner was heteroaryl. Aliphatic alcohols were coupled in more modest yield, and these transformations required the use of a stronger base, although discussions on improving the reaction for these types of substrates or the lack of branched aliphatic alcohols were not included (Org. Lett. 2015, 17, 5328−5331).

Zhang et al. have also used a cobalt catalyst in a base-free alkylation, using a different tridentate ligand and 4 Å molecular sieves in toluene at reflux. The reaction scope includes primary amines, although low level imine byproducts were observed in some reactions. A lower yield was obtained when the reaction was run in a smaller Schlenck tube with reduced headspace implying a possible role for oxygen in the reaction (Org. Lett. 2016, 18, 300−303). Kempe and co-workers present a multicomponent pyrimidine synthesis under catalytic Ir conditions. A variety of catalysts, precatalysts, bases, and solvents were screened prior to identification of the reaction conditions shown below for the three-component coupling: Ir precatalyst, potassium hydroxide as the base, and tert-amyl alcohol as the solvent under reflux. The fact that the reaction is run under reflux in a sealed tube while releasing water and hydrogen gas is a potential concern for the transformation on scale. When a four-component coupling was utilized, the solvent was changed to 1,4-dioxane for the first step of the coupling to form the R1/R2 coupling partner followed by coupling to the other alcohol and amidine (J. Am. Chem. Soc. 2015, 137, 12804−12807).

It should be noted that while cobalt is a more abundant metal, permitted daily exposure limits for cobalt in an API are lower than palladium. A number of cobalt(II) salts are carcinogenic and toxic for reproduction and are on the list of substances of very high concern proposed for authorization under the EU REACH legislation. Yan et al. have further developed the iron catalyzed preparation of benzylamines prepared via the amination of benzyl alcohols. This work complements their previous publication reporting alkylation of benzylamines using alcohols. The reaction follows the hydrogen autotransfer/hydrogen borrowing mechanism. Electron-rich and -poor benzyl alcohols, thiophene, and furan methanols are aminated with secondary amines in good yield; reaction with primary amines and anilines could also be achieved in lower yield. Different reactivity is obtained between primary and benzylic alcohols, enabling a one-pot preparation of unsymmetrical tertiary amines. The authors applied their methodology to the synthesis of an intermediate to potential muscarinic agonists with monoamination of 2,5-dihydroxymethylfuran, a bioderived building block (ACS Catal. 2016, 6, 381−388).

Hydrogen autotransfer alkylation is a very powerful approach but to date has been heavily dependent on platinum group metals as illustrated above. Catalysis using more abundant metals has started to emerge in recent years. Rösler et al. report the first application of cobalt catalysis in the monoalkylation of anilines and 3-aminopyridine with a range of benzyl and some primary alcohols. Reactions are conducted with 2.5 mol % catalyst and 1 equiv of potassium tert-butoxide in toluene at 162




the alcohol so it can be more readily displaced. The major challenge associated with the optimization of this reaction was avoiding the formation of the dialkyl ether. The optimum conditions were a 15 min residence time at 120 °C, using 2 to 3 equiv hydrochloric acid. Adding an in-line phase separator allowed the organic stream containing the halide to be combined directly for the subsequent displacement reaction of the halide. In this report, the nucleophiles of choice were nitrogen-containing heterocycles, such as morpholine and piperazine derivatives. Furthermore, the authors applied their successful technology to the synthesis of generic APIs such as cyclizine, buclizine, and meclizine in yields in excess of 90% (ChemSusChem 2016, 9, 67−74).

Elangovan et al. report the iron catalyzed alkylation of aryl alkyl ketones with benzyl alcohols. The reaction scope includes ortho and para electron-donating and -withdrawing substitution of the arene, 2-naphthyl, 4-pyridyl, and 1-tetralone, reacted with para-substituted benzyl alcohols, furan and thiophene methanols and primary alcohols. Reactions are run in the presence of 10 mol % cesium carbonate, in toluene at 140 °C for 24−48 h giving alkylated product in moderate to good yield. 2- and 2,3-substituted quinolones can be prepared from 2-aminobenzyl alcohol and potassium tert-butoxide as base in a modified Friedländer annulation to form 2,3-substituted quinolones, avoiding the use of 2-aminobenzaldehyde (Angew. Chem., Int. Ed. 2015, 54, 14483−14486).

Falß et al. have described utilization of the Buchwald− Hartwig amination using continuous flow techniques to prepare an intermediate to the pharmaceutical AR-A2 on microscale and gram scale. The key challenge to maintaining a flow approach to this type of transformation is to prevent clogging of the tubing due to precipitation of the inorganic salt byproduct formed in the reaction mixture. The authors describe in depth the development of the process and the implementation of continuous ultrasonication to prevent clogging. A separator is used to completely remove the desired product into the aqueous phase, allowing for reuse of the catalyst from the organic phase. Continuous flow approaches produced the product in >90% yield, and in purities of ≥92% at 1 L/h flow rates. In all cases the product stream contained less than 1 ppm palladium, as is desired for a pharmaceutical intermediate. Additionally a life cycle analysis is presented in comparison with the previously reported batch process (Org. Process Res. Dev. 2016, 20, 558−567).

Buonomo and Aldrich report the use of phospholane (2) as a precatalyst in a Mitsunobu reaction that is catalytic in phosphine. Phenylsilane was used to regenerate the phosphine, and 1.1 equiv of diisopropylazodicarboxylate (DIAD) was used as the coupling partner giving an optimized yield of 77% for the esterification of p-nitrobenzoic acid, compared to 84% with triphenylphosphine; substitution of chiral secondary alcohols proceeded with inversion in good enantiomer ratio. The authors combined their approach with a modification of the Taniguchi catalytic azo-carboxylate protocol {using iron(II) phthalocyanine [Fe(Pc)] and oxygen to regenerate the azocarboxylate; Angew Chem., Int. Ed. 2013, 52, 4613−4617} to demonstrate a Mitsunobu reaction that is catalytic in both reagents. Careful engineering will be required in order to safely scale-up the methodology which is run in boiling THF under an oxygen enriched atmosphere (Angew. Chem., Int. Ed. 2015, 54, 13041−13044).

Amann et al. report the use of continuous processing to avoid decomposition of a thermally unstable starting material and product. The Overman rearrangement has been used for stereospecific synthesis of protected amines from allylic amides. The authors wished to use this approach to synthesize an intermediate for a pharmaceutical compound, but were limited in batch mode processing due to thermal instabilities of both the starting amide and the product amine. The use of continuous processing is indicated under these conditions, since the heated zone of the reaction can be controlled such that the starting material and product are maintained at lower temperatures. By establishing a 2 min residence time at 220 °C, the product can be prepared in quantitative yield and purity sufficient for downstream processing. A slightly higher residence time of 3 min was used to process 95 kg of the starting amide,

11. CONTINUOUS PROCESSING Borukhova et al. have reported the use of continuous processing to overcome the challenges of direct displacement of an alcohol with chloride using hydrochloric acid. This is a very concise route to the synthesis of alkyl and benzylic halides that obviates the need for an activation step to activate 163




also monitored. The authors provide an interactive Web page (details in the Supporting Information) to allow further analysis of the data set (J. Med. Chem. 2016, 59, 3935−3952).

which produced a quantitative yield of the desired product in 81.6% purity by NMR assay (Org. Process Res. Dev. 2016, 20, 446−451).

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

12. GENERAL GREEN CHEMISTRY The use of CO2 as a feedstock for commodity chemical synthesis is an attractive way to reduce greenhouse gas emissions as well as a possible route to renewable synthetic fuels. Although CO2 reacts readily with carbon-centered nucleophiles, the main issue is that generation of these intermediates requires high energy reagents, which negate the environmental benefit gained from using CO2 as a substrate. Banerjee et al. have reported on a methodology to overcome these drawbacks and extended this to develop a scalable synthesis of the highly desirable biobased feedstock furan-2,5dicarboxylic acid (FDCA) from lignocellulose. Key to the success of this methodology is the ability of salts such as cesium carbonate to deprotonate weakly acidic bonds (pKa > 40) in the molten state (200−350 °C), and the intermediate anion is trapped by a flow of CO2 to form the carboxylate salt. For the synthesis of FDCA, 2-furoic acid is successfully carboxylated on 100 mmol scale under 1 bar of CO2 pressure at 260 °C in 71% yield in 48 h. 2-Furoic acid is obtained from furfural, which is obtained from lignocellulose on a 400 kiloton scale annually. Although these processes are not restricted to Cs salts, they tend to be preferred, as they typically have lower melting points. The chemistry was extended to thiophenes and benzoates, and methodology for conversion of the desired products to the corresponding esters is provided (Nature 2016, 531, 215−219). Metrics represent a cornerstone for evaluating green chemistry performance throughout the industry. With this in mind, Andraos has performed an evaluation of seven published algorithms designed to determine the material efficiency of chemical reactions and synthesis plans. The report not only provides an overview of each of the algorithms but also benchmarks them against each other in a series of case studies. The report further highlights common areas in which various parameters are either overlooked or misrepresented with guidance on how to incorporate the most accurate information particularly with regard to workups and chromatography. Gaps in the current algorithms specifically with biotransformations, and misconceptions regarding linear/convergent routes are also addressed (ACS Sustainable Chem. Eng. 2016, 4, 1917−1933). A number of publications in recent years have surveyed the types of reactions used by Medicinal Chemists and in the preparation of active pharmaceutical ingredients. Schneider et al. utilized data mining techniques to survey the reactions and products published in granted U.S. Patents and U.S. patent applications between 1976 and 2015. 1.3 million unique chemical reactions were extracted and classified; heteroatom alkylation and arylation have the highest frequency of use, followed by acylation and related processes, deprotection and C−C bond formation. The evolution of reaction classes was charted over time showing a marked increase in C−C bond formation. It was possible to obtain reaction yields for over 500 000 of the reactions and chart the progress of key reactions over time; the type of reaction product and properties were

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.

Luke Humphreys GlaxoSmithKline, Stevenage, Hertfordshire, SG1 2NY, U.K.

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

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

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

Timothy White Eli Lilly, 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

John Hayler: 0000-0003-3685-3139 Alan Steven: 0000-0002-0134-0918

164


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