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 15 member companies as compared to three in 2005. Membership scope includes contract research/manufacturing organizations, generic pharmaceuticals, and related companies. Current members are ACS GCI, Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Codexis, Dr Reddy’s, Eli Lilly and Company, F-Hoffmann-La Roche Ltd., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, Pfizer, Inc., and Sanofi. 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 period covers April to September 2015. 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.

solvents, DESs), though care must be exercised in modifications of the cation as even minor changes lead to a decrease in biodegradability. In summary, the authors note that prior to industrial utilization of an IL, a full eco(toxicity) life cycle assessment should be carried out to enable the hazard of using the IL to be weighed against the potential benefit (Chem. Soc. Rev. 2015, 44, 8200−8237). Pena-Pereira et al. have provided a perspective on the potential replacement of organic solvents in analytical methodologies with a view to utilizing more sustainable alternatives. An initial overview of the 12 principles of green analytical chemistry is followed by an overview on the continuing expanding role of both water and carbon dioxide (both natural and renewable solvents) in analytical extraction and separation processes. With a view to replacing solvents of concern, the authors provide an overview of several potential sources of greener solvents including those derived from renewable resources, ILs, and DESs. Whereas the promising nature of each class of solvent from an environmental perspective and replacement opportunities/initial studies are highlighted, the review also cites the numerous challenges involved in carrying out such a replacement. Intrinsic to these are implementation cost, acceptable solvent purity, deficient sensitivity, and inadequate accuracy and precision. In addition, further potential roadblocks are raised in that alternatives to conventional solvents with the required physicochemical properties might not be available, and it is also important to bear in mind that just because a material is derived from renewable resources does not necessarily mean that it is safe and benign as an alternative solvent (Green Chem. 2015, 17, 3687−3705). Farrán et al. have written a review on the expanding role that green solvents play in carbohydrate chemistry. The article is systematically organized focusing initially on an overview of the key roles that carbohydrates play in multiple industries as well as the critical importance of moving to more sustainable solvent media for the various operations involved in these. Subsequent sections then consider the application of greener reaction media in the solubilization, synthesis, extraction, separation, purification, and analysis of carbohydrates. Finally, the conversion of carbohydrate polymers into higher value feedstocks, integrated processes involving carbohydrates, and emerging applications such as carbohydrate-derived ILs are discussed (Chem. Rev. 2015, 115, 6811−6853). Pd−mediated C−C bond formation represents a highly utilized methodology for the formation of C−C bonds, and several reports have emerged on the direct arylation of varying heterocycles utilizing sulfonyl chlorides through a desulfitative pathway. Although later reports no longer required a Cu source, all the previous work has been carried out in either DMA or 1,4-dioxane. Hfaiedh et al. have demonstrated that either diethyl carbonate (DEC), cyclopentyl methyl ether (CPME), or solvent-free

2. SOLVENTS Bubalo et al. have published a mini-review providing a brief overview of ionic liquids (ILs), supercritical (CO2 and water), and subcritical (water) fluids, and solvents from natural and renewable resources as well as subsections on deep eutectic solvents (DESs) and glycerol and its derivatives. The overview of each focuses in particular on the properties, current applications, and the potential of each class to be adopted as a green industrial solvent. An overview of the literature from 2010−2014 shows that ionic liquids have dominated the publication landscape, though have not as yet established widespread commercial application. One of the hypotheses for this is the high cost of ILs, though there are also some concerns with the relatively poor biodegradability and persistency of some of the more commonly utilized ILs resulting in hazardous toxicity toward both aquatic and terrestrial organisms (J. Chem. Technol. Biotechnol. 2015, 90, 1631−1639). The degree of environmental impact is strongly linked to the structure of the IL, and Jordan et al. have published an extensive review collating biodegradation data enabling establishment of guidelines for designing “green” ILs. Of the readily biodegradable ILs synthesized to date, over 50% contain the cholinium cation and an organic acid anion (often described as deep eutectic © 2016 American Chemical Society

Received: Revised: Accepted: Published: 1118

May 16, 2016 June 1, 2016 June 3, 2016 June 23, 2016 DOI: 10.1021/acs.oprd.6b00174 Org. Process Res. Dev. 2016, 20, 1118−1132

Organic Process Research & Development

Green Chemistry Highlights

Both Kotha et al. and Wang et al. have reported on the direct oxidative amination of methylarenes with amines to form amides under iron catalysis. Model studies by Kotha on the reaction between piperidine and 4-methylanisole initially formed the N-chloroamine through reaction with NCS in MeCN, which was treated with Fe(OAc)2 and excess methylarene and TBHP (5−6 M in decane) at 80 °C to afford the amide in 95% yield. Selection of MeCN as the solvent was critical with no product formed in the other solvents evaluated probably due to the difficulty of forming the N-chloroamine in alternative media. Electron-rich methylarenes reacted more efficiently than electron-poor derivatives with the reactivity in these systems inversely correlating with the strength of the electron-withdrawing group. Steric bulk in the ortho-position of the methylarene was observed to inhibit the reaction. Primary, secondary, and even sterically encumbered-amines were effective substrates though anilines failed to react due to decreased nucleophilicity of the amine. The reaction was extended to the synthesis of the antiarrhythmic agent, N-acetylprocainamide, and initial mechanistic studies indicate that a radical mechanism is operating (Adv. Synth. Catal. 2015, 357, 1437−1445). Model studies by Wang on the reaction between toluene and n-butylamine indicated that the optimum conditions utilized FeCl3 as the catalyst, aqueous TBHP as the oxidant, and TBAI as an additive with the reaction being run in water at 60 °C in the presence of 4 Å molecular sieves. Again, both electron-donating and electron-withdrawing methylarenes are compatible with the former providing better yields, and chemoselective monoamidation was observed when multiple methyl groups were present in the substrate. A range of primary amines were successful substrates, though secondary amines all failed to react with the exception of morpholine. In cases when the amine salt was utilized, FeCl3 was replaced in the reaction by CaCO3. Preliminary mechanistic studies hypothesized that the initial oxidation of the methylarene is a radical process with the amidation proposed to proceed through a hemiaminal intermediate (Green Chem. 2015, 17, 2741−2744).

conditions can be utilized in these couplings specifically for the C−5 arylation of furans, the C−2 arylation of benzofurans, the C−2 arylation of pyrroles, and the C−3 arylation of (benzo)thiophenes. The reaction is chemoselective with C−X (where X = Cl, Br) bonds being shown not to participate in the transformation. Multiple examples are provided with the greener solvents demonstrated to perform in an equivalent manner to the more conventional alternative (in this case, 1,4-dioxane). In addition, enhanced reactivity leading to increased selectivity was observed in some cases under solvent-free conditions (ChemSusChem 2015, 8, 1794−1804).

3. AMIDE FORMATION The majority of amidation reactions are carried out in undesirable solvents such as DMF and CH2Cl2, and alternatives to these would highly attractive. Solvent-free synthesis is often hindered by mass transfer limitations, and although these can be overcome by mechanically induced agitation using ball mills, often recovery of the product from the milling jar is achieved using an organic solvent. Métro et al. have reported on a strategy that allows the complete elimination of organic solvents from the CDI-mediated acylation of carboxylic acids, and provided an analysis of product contamination resulting from the wear of the milling material over time. Initial optimization studies on the amidation reaction indicated that using 0.9 equiv amine hydrochloride salt led to the best yields although the filling ratio also influenced the yield to some extent. A variety of milling materials were evaluated both in terms of reaction efficiency and contamination, and extensive studies showed that although classic heavy materials such as stainless steel were effective, utilizing lighter grinding materials such as PTFE could also mediate the reaction, and were helpful in reducing the contaminant content of products from procedures using organic solvents for isolation. In addition, the amount of contamination increased with milling time indicating the importance of optimizing this parameter as well. A range of primary and secondary amines were successfully coupled with the majority of products simply isolated by taking advantage of their lack of solubility/immiscibility with water. In cases where the products showed appreciable water solubility, either direct distillation or extractive workup using ethyl acetate was employed. The protocol was extended to the synthesis of the active metabolite of leflunomide and terifluonomide as well as a range of O-, S-, and C-nucleophiles. Comparison of the ball-milling solventfree acylation with a range of other methodologies demonstrated the eco-friendly nature of the protocol (Chem.Eur. J. 2015, 21, 12787−12796).

Gabriel et al. have reported on an amide bond formation under aqueous conditions utilizing the surfactant TPGS-750-M, which on dissolution in water forms nanomicelles, which are capable of dissolving water-insoluble reagents. Model studies on the coupling of p-toluic acid with L-Leu-OEt·HCl indicated that using the oxime-based activator, COMU, in tandem with a pyridine base such as 2,6-lutidine led to quantitative yields and rapid reaction rates using 2−4% of the surfactant with a reaction concentration of 0.5 M. For peptide couplings, the reaction was demonstrated to

Utilizing renewable feedstocks for the synthesis of amides provides not only an advantage from a sustainability perspective but also potentially extends the scope of the possible products. 1119

DOI: 10.1021/acs.oprd.6b00174 Org. Process Res. Dev. 2016, 20, 1118−1132



tolerate a wide range of both N- and C-terminus protecting groups, and no epimerization was observed due to the mildly acidic to neutral conditions employed. A range of amides were also demonstrated though electron-rich benzoic acids proved challenging and required mild heating due to the reduced electrophilicity of the activated intermediate. Given the high aqueous solubility of the reagent byproducts, workup could be achieved by extraction with a minimal amount of organic solvent, and addition of additional reagents to the aqueous mixture allowed this to be recycled up to four times without any variation in yield (Org. Lett. 2015, 17, 3968−3971).

indicated that sterically accessible aliphatic esters were more favorable substrates, and both primary and secondary amines reacted well, though in the case of less reactive amines such as anilines, an increase in reaction temperature was required. However, this differential reactivity could be exploited with reaction of 4-aminobenzylamine taking place exclusively at the more reactive aliphatic NH2 (Tetrahedron 2015, 71, 5547−5553). Nguyen et al. observed that alkaline earth metal salts were able to catalyze the direct amidation of methyl butyrate with benzyl amine in boiling toluene with calcium salts proving optimum. The differential reactivities between the various salts could be correlated to their solubility under the reaction conditions. Calcium iodide was the preferred catalyst and was shown to mediate the reaction between a range of aliphatic and aromatic methyl and ethyl esters and a wide variety of primary amines. Secondary amines were not successful substrates, and unlike previously reported systems, CaI2 did not catalyze the amidation of either carboxylic acids or amides enabling chemoselective reactions to take place (RSC Adv. 2015, 5, 77658−77661).

Transamidation of amides with amines represents an underutilized approach to amides due to the high stability of amide groups and the corresponding harsh reaction conditions required to effect the uncatalyzed reaction. Srinivas et al. initially studied the reaction of aniline with acetamide and demonstrate that, in the presence of K2S2O8, good yields of the transamidated product could be obtained in a range of boiling solvents with water appearing to be the best. No product was observed in DMSO, and the presence of a stoichiometric amount of K2S2O8 as opposed to other peroxy-based reagents, was critical for the optimum yield. Either conventional or microwave heating was shown to promote the reaction, with the solvent-free variant being demonstrated under microwave conditions. Acetamide, formamide, and DMF (though not benzamide) were all demonstrated to react with a range of aryl and alkyl amines though heteroarylamines were unsuccessful substrates. The protocol was further extended for the conversion of phthalimides to the corresponding N-substituted derivatives, and the N-formylation of various alkyl and arylamines using either DMF or formamide. Several biologically relevant targets are also synthesized using this approach, and a mechanistic hypothesis is proposed based on the observation of several intermediates in a time-monitored experiment (Tetrahedron Lett. 2015, 56, 4775−4779).

Zhang et al. have described a novel base mediated amine acyl exchange reaction of aromatic aldehydes with N,N-disubstituted formamides to form aromatic amides. Optimization studies indicated that pretreatment of the formamide substrate with t-BuOK in THF at room temperature, followed by treatment with the aldehyde at 50 °C under air worked best. Both electronrich and electron-poor aromatic aldehydes performed well, though aliphatic aldehydes provided a complex mixture of products under the optimized conditions. A range of acyclic and cyclic formamides also worked well in the reaction, although yields deteriorated when sterically congested systems were employed. Further studies showed that alternative acyl donors such as acyl chlorides, unactivated esters, and acid anhydrides could also be employed in the reaction. Mechanistic studies demonstrate that, in the initial step, the formamide breaks down to provide the amine and CO, and labeling studies show that the carbonyl of the amide originates from the acyl donor employed (Adv. Synth. Catal. 2015, 357, 2855−2861).

From the perspective of both atom economy and benign byproduct formation, the catalytic transamidation of carboxylic esters represents one of the most attractive methods for the preparation of amides. In the period under review, two approaches for this transformation have been disclosed. Lenstra et al. screened a range of common transition metals and simple organocatalysts in a model reaction of methyl benzoate with benzylamine in boiling toluene, and showed that both Cp2HfCl2 and Cp2ZrCl2 were excellent catalysts. Given the cheaper cost, they probed the properties of the Zr-based catalyst and showed that both the size and electronics of the Cp-type ligand as well as the chlorine played an important role in catalytic activity. Studies on the scope of the reactions 1120




Catalytic oxidative amidation represents an attractive alternative to conventional amide bond formation reactions, and numerous examples have been reported employing homogeneous or heterogeneous transition metal catalysis. Alanthadka et al. have reported on the reaction mediated by N-heterocyclic carbene (NHC) organocatalysis. Model studies on the reaction between benzaldehyde and n-butylamine led to the determination of the optimal NHC as well as the observation that the ideal oxidant was NBS with organic bases providing better results than their inorganic counterparts. With acetonitrile as the reaction solvent, the scope was evaluated with electron-withdrawing substituents on the aromatic ring leading to better yields than substrates with electron-donating groups while steric factors were shown to have a minimal effect. Primary amines and secondary cyclic amines also worked well, though in the case of dibenzylamine, side reactions were observed from benzylic C−H oxidation. Chiral amino acid derivatives also performed admirably leading to high yields and no detection of racemization with the exception being (L)-phenylglycine. A mechanism is proposed based on experimental data, which suggests that the N-bromoamine is the pivotal intermediate in the reaction (Adv. Synth. Catal. 2015, 357, 1199−1203).

The combination of organic tertiary amines with chlorotriazine reagents for the activation of carboxylic acids in amidation reactions is well-established. Duangkamol et al. have demonstrated that triphenylphosphine is able to fulfill a similar role in amidation reactions mediated by either 2,4,6-trichloro-1,3,5-triazine (TCT) or 2,4-dichloro-6-methoxy-1,3,5-triazine (DMCT). Model studies on the reaction between benzylamine and benzoic acid revealed that an inorganic base such as cesium carbonate was required and that sonication considerably enhanced the reaction rate. Addition of the amine last was also critical for success. The scope of the reaction showed that aromatic acids were more effective substrates than aliphatic acids and that aromatic and sterically hindered amines led to lower conversions. The reaction could also be mediated by polymer-supported PPh3 (PS−PPh3), which could be recovered and reused up to six times with only a minor loss of yield. 31 P NMR studies were conducted to provide a mechanistic rationale involving a Meisenheimer complex with both the carboxyl and phosphonium moieties bound. One major drawback from an environmental standpoint is that the reported optimal solvent is CH2Cl2 though a full solvent screen was not disclosed with the only comment being that the reaction fails in either MeOH or H2O due to the reactivity of the triazine reagents (Tetrahedron Lett. 2015, 56, 4997−5001).

NHC-based ruthenium hydride complexes have also been reported to mediate the direct synthesis of amides from alcohols and amines under base-free conditions. Kim et al. studied the reaction of 3-phenyl-1-propylamine and 2-phenylethanol and showed that the catalytic activity of the Ru-NHC complex depends on the structure of the NHC with sterically bulky ligands providing the best yields. The optimal conditions utilized a slight excess of the alcohol, and were shown to be effective for a range of primary amines. For benzylic systems, electron-rich systems worked better than the corresponding electron-poor substrates, and anilines were poor coupling partners. Secondary amines required the addition of a base to provide acceptable yields indicating that the reaction might proceed through an alternative pathway involving the intermediacy of an ester (Tetrahedron 2015, 71, 4565−4569). Arefi et al. have described the use of superparamagnetic Fe-based nanoparticles to mediate the formation of amides in a similar manner from alcohols and amine-hydrochloride salts. The catalyst is reported to be easy to prepare and was fully characterized by a range of techniques. Model studies on the 0.5 mmol reaction between benzyl alcohol and benzylamine hydrochloride indicated that 20 mg of the catalyst using acetonitrile at 80 °C were the optimum conditions with addition of both CaCO3 as the base and TBHP (70% in water) as the oxidant required. A range of benzylic alcohols were successful substrates with again electron-donating groups giving higher yields, though simple aliphatic alcohols did not work. For the amine partner, good diversity was observed with the reaction yield being negatively impacted by increased steric hindrance on the amine. The catalyst could be easily recovered and recycled through six reactions with only minor losses in yield observed, and a radical mechanism is proposed for the transformation (ACS Combinatorial Sci. 2015, 17, 341−347).

4. OXIDATIONS Oxidation of alcohols by ketones is an attractive method that can be achieved with a metallic reagent such as Al(OiPr)3 in the Oppenauer oxidation. Kamijo et al. successfully demonstrated the same type of reaction under photo irradiation conditions. The key is the use of a near equal molar amount of 4-benzoylpyridine as the oxidant, which is much more efficient than benzophenone. A variety of solvents, including aprotic acetone, MeCN, CH2Cl2, PhCF3, benzene, and EtOAc, as well as protic t-BuOH can be used, and acetone was chosen as a green solvent. Dialkyl, alkyl−aryl, and diaryl-ketones are all reduced at room temperature in good yields. The reaction tolerates polar functionalities including benzoyl, silyl, and methoxymethyl alcohol protecting groups as well as tosyloxy, 1121




bromo, sulfonyl, carbamate, ester, and carboxylic acid units (Org. Lett. 2015, 17, 3326−3329).

1,2-Diols are readily accessible from biomass and synthetic methods, but their oxidation to α-hydroxy carboxylic acids, an important subunit in bioactive compounds, has been very challenging due to competitive oxidative C−C bond cleavage and oxidation of the secondary alcohol. Furukawa et al. found that use of catalytic TEMPO, NaOCl, and stoichiometric NaClO2 in MeCN resulted in poor selectivity of desired product vs oxidative cleavage. However, switching the solvent system to water immiscible toluene and a phosphate buffer at pH 6.8 resulted in excellent selectivities and gave desired hydroxy acids in high yields. The oxidation of the diol probably proceeds in the organic layer via a hydrophobic charge transfer complex (TEMPO−ClO2), and the high selectivities are due to the resultant product staying intact in the aqueous layer and avoiding over oxidation (Org. Lett. 2015, 17, 2282−2285).

Murray et al. reported the use of a synthetic flavin and alloxan dual-catalysts system for aerobic amine oxidation that mimics the flavoenzyme monoamine oxidase (MAO) B. Various benzylamines can be oxidized to homodimeric imines with the synthetic flavin catalyst A and a cocatalyst B, which was initially an impurity in the synthesis of A. Dimethylsulfide is also added as a charge transfer catalyst. A detailed mechanistic study showed the reaction proceeds through a charge-transfer-initiated substrate hydrogen radical abstraction. The reaction tolerates electron-withdrawing and donating groups as well as heterocyles (Angew. Chem., Int. Ed. 2015, 54, 8997−9000).

5. ASYMMETRIC HYDROGENATION N,P-tethered iridium catalysts have been employed in the asymmetric hydrogenation of two allylic fragments (S1 and S2) of aliskiren. These catalysts (C1 and C2) were found to be very effective to a high degree of enantioselectivity with excellent conversions (Ar in C1 is not disclosed and is assumed to be Ph or o-tol, based on reference 10c). The ligands for these catalysts were derived from imidazole and thiazole. The aliphatic nature of both of the substrates poses a great challenge to obtaining high enantiomeric excess during asymmetric catalytic hydrogenation. Asymmetric hydrogenation of substrate S1 using 1 mol % C1 catalyst afforded the corresponding product P1 in 99% yield with 97% ee whereas catalyst C2 gave 77% yield with 72% ee. However, asymmetric hydrogenation of substrate S2, using similar catalyst loading and reaction conditions, afforded P2 in 99% yield with 83% ee, whereas use of C2 resulted in 99% yield with 93% ee. Products P1 and P2 were used in a formal synthesis of aliskiren (Chem.Eur. J. 2015, 21, 7292−7296).

Dioxygenation of alkenes using abundant and environmentally benign source of oxygen is desirable but remains largely unexplored. To this end, Andia et al. reported copper(I)-catalyzed oxidations of alkenes with molecular oxygen and hydroxylamine derivatives, N-hydroxyphthalimide (NHPI) and N-hydroxybenzotriazole (HOBt), to form α-oxygenated ketones. Both styrenes and enynes can be oxidized efficiently with the Cu(I) catalyst in MeCN and an oxygen balloon. The reaction probably proceeds through a radical mechanism. The resulting oxygenated ketones, especially in the case of HOBt derivatives, can be readily converted to various functional groups, such as 1,2-diketones, vinyl phosphates, and α-haloketones (Org. Lett. 2015, 17, 2704−2707).

Yan et al. report an enantioselective hydrogenation of α,βunsaturated nitriles catalyzed by Rh-(R,R)-f-spiroPhos. The catalyst was found to be very versatile for the reduction of both (E)- and 1122




(Z)-isomers of alkyl and aryl substituted α,β-unsaturated nitriles to the corresponding chiral nitriles with excellent output. Hydrogenation at lower hydrogen pressure (5 atm) did not affect the conversion but gave lower enantioselectivity, however, at higher pressure (50 atm), both conversion and enantioselectivity were found to be excellent. Moreover, the role of solvent was also investigated; successful hydrogenation was achieved in most of the solvents examined (THF, CH2Cl2, toluene, dioxane and DME), but not in MeOH. CH2Cl2 and dioxane afforded comparable results. Mechanistically, the (E)−isomer of the substrate gave the (S) configured product, plausibly through coordination of the substrate with the metal from the Re-face, whereas the (Z)-isomer afforded the (R) product arising from coordination with the metal from the Si-face. Under optimized conditions, the catalyst using the spirobiindane-based chiral diphosphine [(R,R)-f-spiroPhos] ligand was applied to the synthesis of indatraline and several other bisabolane sesquiterpene family members. In the key step, the product was obtained in 99% yield with 99.8% ee using 1 mol % catalyst, hydrogenated at room temperature for 6 h (J. Am. Chem. Soc. 2015, 137, 10177−10181).

6. C−H ACTIVATION Beukeaw et al. have developed a metal-free, iodine-catalyzed oxidative cross-coupling of indoles and various azoles. The reaction is run in acetonitrile at ambient temperature and uses aqueous tert-butyl hydrogen peroxide as terminal oxidant. The authors propose that the combination of iodine and tertbutyl hydrogen peroxide generates an electrophilic iodonium species that is the active catalyst. The electronics of the indole coupling partner dramatically impact the transformation. Indole substrates with electron neutral and electron donating substituents work well for the chemistry; however, electronwithdrawing substituents at the C−3, C−5, and C−6 positions shut down the chemistry. Importantly, both N-methylated and free indole N−H substrates work equally well. A wide variety of azoles such as pyrazole, imidazole, triazole, benzimidazole, and benzotriazole undergo coupling; however, it is important to note that the reaction requires 2 equiv of azole (J. Org. Chem. 2015, 80, 3447−3454).

The pyridine moiety in the SpiroPAP catalyst system is critical for high reactivity and enantioselectivity in the hydrogenation of aromatic ketones and β-aryl-β-ketoesters. Hydrogenation of β-alkyl-β-ketoesters was less successful, and Bao et al. envisioned that the enantioselectivity of the hydrogenation could be enhanced by replacing the planar pyridine with a thioether moiety, allowing variation of the steric bulk in the complex. A range of new tridentate Spiro P−N−S, SpiroSAP, ligands were prepared and their application in the iridium-catalyzed asymmetric hydrogenation of β-alkyl-β-ketoesters evaluated. Introduction of the dithiane group was particularly effective at 0.1 mol % catalyst loading under 10 atm of hydrogen; lower catalyst loading could be achieved at higher pressure. β-alkyl-βketoamides were also reduced with slightly lower ee. The catalyst system was applied to the synthesis of a number of pharmaceutically relevant β-alkyl-β-hydroxyesters. For example, the (S)catalyst (0.002 mol %) was used in the reduction of the sitagliptin precursor affording the corresponding alcohol in 99% yield, 99% ee, on a 12 g scale (Angew. Chem., Int. Ed. 2015, 54, 8791−8794).

A synthesis of phthalides was developed based on rutheniumcatalyzed, copper-promoted oxidative C−H bond alkenylation of benzoic acids. The reaction is run in a nontoxic solvent system containing PEG-400 and water. Ortho-substituted benzoic acids were the best substrates for the reaction (76−95% yield). Substrates that do not contain an ortho substituent gave a lower 36−65% yield as there can be competing formation of regioisomeric or bis-alkenylation adducts. The authors demonstrate that acrylates and acrylonitrile are viable alkenes for the reaction; however, 2 equiv of alkene are required, and there was no product formation when acrylamide was used. The product can be extracted from the reaction mixture using organic solvent and the solvent mixture containing the catalyst and oxidant reused. The authors demonstrated the recycling protocol over six cycles, and there was no reduction in product yield and reaction rate (J. Org. Chem. 2015, 80, 8449−8855).

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demonstrated to be an efficient deoxy-fluorination reagent for a broad range of primary and secondary alcohols without affecting tertiary alcohol, carbonyl, carbamate, and amide functionalities, rendering it potentially applicable for late-stage introduction of fluorine in highly functionalized molecules. Fluorination of chiral secondary alcohols occurred with inversion. However, β-hydroxycarbonyl compounds underwent complete elimination instead of fluorination. Other limitations of this reagent are that reaction conditions are basic and that it requires 48 h reaction time at room temperature (J. Am. Chem. Soc. 2015, 137, 9571−9574).

Yan et al. have demonstrated metal and peroxide free conditions to generate quinazolines and quinazolinones. Extensive condition screening demonstrated that TMEDA was the best methylamine source to introduce the carbon into the ring, and ammonium chloride was the best nitrogen source for the synthesis of quinazolines from starting ketoaniline. Also, screening a variety of oxidants revealed that an oxygen atmosphere resulted in the same yield as the best peroxide conditions. The quinazoline synthesis was tolerant of electron withdrawing and electron donating aryl groups at R1. Quinazolinones were also readily synthesized with TMEDA and was best with phenyl at the R position with lower yields for alkyl groups and no reaction for the primary amide (J. Org. Chem. 2015, 80, 5581−5587).

Allylic fluorides are widely applied in medicinal, agricultural, and biological fields. To form the allylic carbon−fluorine bond in a regio- and stereoselective fashion is a challenging task. Zhang et al. have achieved this goal by an efficient dynamic kinetic asymmetric transformation process that converts racemic branched allylic trichloroacetimidates to enantiomerically enriched allylic fluorides with high regio-selectivities via iridium catalysis. The key factor to the success of this process is a combination of allylic substrates with trichloroacetimidate as leaving group and a preformed iridium catalyst containing a chiral diene ligand with a large bite angle. This ligand is rationalized to decrease the rate of the fluoride attack and increase the time allowed for interconversion of two diastereomeric π-allyliridium intermediates. The reaction conditions employ 2.5 mol % catalyst and 1.5 equiv of Et3N·HF in MTBE at 25 °C. A variety of allylic substrates bearing β-oxygen or nitrogen, or α-linear carbon groups were converted to the allylic fluorides with modest to good yields, mostly greater than 90% ee, and regio-selectivities greater than 20:1. Azido- and alkynyl-functional groups were tolerated, providing allylic fluorides which could serve as a handle for further biorthogonal conjugation. This approach is complementary to a previously reported approach, which gave poor enantioselectivities for α-linear allylic fluorides (J. Am. Chem. Soc. 2015, 137, 11912−11915).

A palladium catalyzed coupling of oxiranes and arenes was developed by Wang et al. Oxiranes without heteroatoms outside of the ring were unsuccessful but reaction with the phenoxymethyl substituted compound proceeded at room temperature. Overall, substitution was well-tolerated for a variety of substitutions at R1 and R2 along with directing groups other than pyridine and other heteroatom containing oxiranes. It was also noteworthy that isochromanones were generated directly by reaction of oxirane with N-methoxybenzamide with only a slight increase in catalyst loading to 10 mol %. Finally, results detailing gram scale synthesis and examples utilizing chiral oxiranes which resulted in excellent retention of chirality were described (J. Am. Chem. Soc. 2015, 137, 6140−6143).

7. GREENER FLUORINATION Direct conversion of aliphatic alcohol to fluoride is an attractive way to prepare aliphatic fluorides. Direct conversion can be achieved by applying deoxy-fluorination reagents such as DAST, Deoxo-Fluor, XtalFluoro, Fluolead, and PhenoFluor. Each of these reagents has limitations on cost, shelf-stability, and selectivity of desired substitution versus competing elimination. Nielsen et al. report a new deoxy-fluorination reagent, 2-pyridinesulfonyl fluoride (PyFluor), that is readily prepared from 2-mercaptopyridine and comparably superior to the aforementioned reagents. Optimal reaction conditions employ just 1.1 equiv of PyFluor and 2 equiv of base in common solvents such as toluene, cyclic ethers, and acetonitrile, typically at room temperature. PyFluor was

The ubiquitous carboxylic acid group has long been a targeted handle for introducing fluorine via decarboxylative fluorination. This reaction typically utilizes electrophilic fluorination reagents (F+) which are either too reactive, such as fluorine gas and XeF2, or too expensive such as Selecfluor. Huang et al. disclose a decarboxylative fluorination using fluoride ion for the first time. The optimized conditions use 2.5 mol % [Mn(tmp)]Cl as catalyst, 3.3 equiv of iodosylbenzene (PhIO) as oxidant, 1.2 equiv Et3N·HF as the fluoride ion source, and 0.5 equiv of benzoic acid as additive in dichloroethane as solvent. Mechanism studies support a radical process where decarboxylation via a carboxyl radical is believed to occur under the reaction conditions. This is 1124




followed by fluorine transfer from the concomitantly formed F−MnIV−F species. Fluorination of benzylic and aryloxy carboxylic acids utilizing this method provided fluorinated products in yields ranging from 50% to 80%, while other types of primary, secondary, and tertiary carboxylic acids resulted in yields below 40%. While moving away from electrophilic fluorination reagents, the reaction uses a high stoichiometry of oxidant and dichloroethane as solvent which are areas for improvement with respect to its sustainability (Angew. Chem. 2015, 127, 5330−5334).

An enantioselective Heck coupling between iodobenzene and 2,3-dihydrofuran using a synthetic metalloprotein has been reported by Filice et al. The hybrid catalyst was prepared by covalent attachment of a phosphonate palladium catalyst to a lipase from Candida antarctica B (CALB) through the serine residue. The immobilization strategy is important for a successful process with the metalloenzyme immobilized on different supports, which enabled the catalyst to be conveniently reused, and modification of the support surface to create a hydrophobic environment around the enzyme. The reaction was run in ethylene glycol and DMF and found to be better in DMF at high temperatures. The transformation is achieved with high stereo and enantioselectivity (Adv. Synth. Catal. 2015, 357, 2687−2696).

8. BIOCATALYSIS In the area of C−C bond formation, Busto et al. describe the direct condensation of phenols and pyruvate in the presence of ammonia leading to the corresponding p-vinylphenols. The transformation comprises a three-step biocatalytic cascade process starting with the C−C coupling catalyzed by a tyrosine phenyl lyase (TPL) to give a tyrosine derivative (with the amino acid nitrogen coming from the ammonia in the reaction mixture). Elimination of ammonia and decarboxylation then follow, catalyzed by an ammonia lyase (TAL) and a ferrulic acid decarboxylase (FAD), respectively. The process is highly regioselective giving p-vinylphenol derivatives with conversions >99% with CO2 and water generated as the only byproducts (Angew. Chem., Int. Ed. 2015, 54, 10899−10902).

Mutti et al. have reported a hydrogen borrowing amination cascade starting from primary and secondary alcohols using different alcohol dehydrogenases (Lbv-ADH, AA-ADH, or hT-ADH) and an amine dehydrogenase (PhAmDH or Ch1-AmDH) to obtain enantiopure (R)-configured amines. This is a redox neutral process that requires NH3 or NH4+ as nitrogen source and generates water as the sole byproduct. Only catalytic amounts of NAD+ are needed. The applicability of the method was demonstrated by performing amination of aromatic alcohols not only with inversion or retention of configuration but also starting from the corresponding racemic mixtures by using complementary ADHs. Moreover, the methodology was expanded to aliphatic and primary alcohols by selecting the appropriate pair of enzymes. This approach was carried out at preparative scale with a representative number of substrates with very good conversions in most of the cases (Science 2015, 349, 1525−1529).

Another complex C−C coupling transformation has been reported by Mazzaferro et al. with the preparation of chiral biaryls. A number of biaryl compounds display structural and biological properties, but their synthesis can be challenging. The authors have identified novel fungal P450 enzymes and demonstrated that they can catalyze the intermolecular coupling between phenolic compounds in a highly regio- and stereoselective manner. The P450 enzymes KtnC and DesC were isolated from the kotanin and desertorin A biosynthesis pathways, respectively. Both enzymes were expressed in Saccharomyces cerevisiae and their enzymatic activities tested. KtnC catalyzed the coupling of 7-demethylsiderin to P-orlandin by P-8,8′ coupling while the DesC produces M-desertorin A via M-6,8′ dimerization with excellent selectivity (J. Am. Chem. Soc. 2015, 137, 12289−12295).

During the past decade, the use of ω-transaminases has been demonstrated as a powerful method for the synthesis of enantiopure amines from the corresponding ketones. As a consequence, a number of transaminases with both (S)- and (R)- selectivity are available, however, the efficiency of these approaches relies upon the amine donor employed. Richter et al. have reported a remarkable recycling system when it is not possible to use 2-propylamine as the donor for (R)-selective transaminases. While L-alanine can be employed as an amine donor in a recycling system with (S)-selective transaminases, the corresponding D-alanine required for obtaining the (R)-configured amines is over 13 times more expensive making its use prohibitive. As an alternative, the authors used a racemase AlaR from Streptomyces coelicolor and L-alanine as donor. Moreover, the equivalents of the amine donor can be drastically reduced when using the AlaR recycling system. This approach results in a more economical and greener process since 1125




performed on its natural substrate, 7-carboxy-7-deazaguanine (CDG) but may be a good starting point for evolution to increase the substrate scope. In the process, the carboxylate form of CDG is activated by ATP leading to 7-amido-7-deazaguanine (ADG) after ammonia addition. Subsequently, a second equivalent of ATP activates the amide intermediate leading to the nitrile, 7-cyano-7-deazaguanine (preQ10) (Angew. Chem., Int. Ed. 2015, 54, 10627−10629).

both the cost of the amine donor and the E-factor is reduced. Finally, the AlaDH or LDH recycling system can be used to consume the pyruvate byproduct (Green Chem. 2015, 17, 2952−2958).

The oxidative decarboxylation of short and long chain fatty acids (FAs) to terminal alkenes has been reported by Denning et al. The preparation of 1-alkenes from FAs is a very attractive approach since FAs can be obtained from natural sources. The authors developed a biocatalytic system based on the employment of a P450 monoxygenase (OleT) and O2 as oxidant. An important factor in the process was the introduction of an efficient electron transfer system. In particular, putidaredoxin CamAB was found as the most effective system together with glucose, formate or phosphite as sacrificial substrates for the regeneration of the NAD(P)H. Using the described system, the oxidative decarboxylation gave titers of up to 0.93 g/L and total turnover numbers higher than 2000 (Angew. Chem., Int. Ed. 2015, 54, 8819−8822).

Martinez-Montero et al. have shown the laccase from Trametes versicolor/TEMPO pair to be an excellent system to deprotect N-benzylated primary amines. This method stands out from those previously described as the methodology uses oxygen as the terminal oxidant in aqueous buffer. The removal of the benzyl group was performed in a chemoselective manner with excellent yields even when secondary amines or alcohol moieties were present in the same molecule. Moreover, in order to demonstrate the environmental benefits of this aerobic oxidation, a simplified environmental impact analysis using the E-factor concept was evaluated. The laccase/TEMPO system was compared with two other efficient deprotection methods (H2-Pd/C and DIAD) and the laccase mediated oxidation was found to be more eco-friendly. The E factor value excluding solvents was improved in 17-fold (from values higher than 380 to 21.5) (Green Chem. 2015, 17, 2794−2798).

An essential approach to construct complex molecules is the modular assembly of simple and small percursors. Szekrenyi et al. capitalize on the stereocontrolled activity of several variants of D-fructose-6-phosphate aldolases (FSA) from Escherichia coli for the synthesis of aldose sugars and derivatives from simple achiral and unprotected substrates, e.g., glycolaldehyde and aldehyde surrogates. This process has been performed by tandem biocatalytic reactions using one or two FSA mutants with control of the sugar size and configuration. The engineering of the aldolase mutants was achieved by small modifications of their catalytic active site (Nature Chem. 2015, 7, 724−729).

9. REDUCTIONS While amide reduction can be readily achieved with reagents such as LiAlH4 and BH3·THF, these can pose safety issues with respect to processing and impurity formation due to their high reactivity. To this end, catalytic reduction of amides remains an area of intense activity. Lampland et al. have reported the use of the milder reagent, pinacolborane, as a reductant for secondary and tertiary amides in the presence of catalytic quantities of the magnesium complex, ToMMgMe. This allows reactions to proceed at ambient temperatures in the presence of potentially reducible groups such as aryl bromide, benzyl, nitro, cyano, and azo. At present, the highest yields for tertiary amides are obtained with a large excess (20 equiv) of pinacolborane. Although secondary amides are generally more challenging to reduce, these gave similar yields although only secondary formamides were attempted. Interestingly, reduction of secondary amides proceeded with much lower quantities of pinacolborane although this was at the expense of longer reaction times and higher catalyst loadings.

Nelp and Bandarian described an unprecedented biotransformation where for the first time a single enzyme, ToyM (from Streptomyces rimosus), catalyzed the transformation of a carboxylic acid into a nitrile. ToyM was reported to be an amide synthetase as well as nitrile synthetase and therefore capable of accepting both the acid and the amide compound. ToyM was shown to be ATP dependent and employed ammonia as the source of nitrogen making this process very attractive. The substrate scope is narrow since this transformation has been solely 1126




alkylated amines were prepared with most examples obtained between 50 and 80% yield. The approach was extended to the preparation of a chiral amino-alcohol from a monoprotected diol (J. Am. Chem. Soc. 2015, 137, 4944−4947).

The mechanism of the reaction was suggested to be a complex multistep pathway with a limiting step of C−O cleavage. The HBPin/ToMMgMe system has previously been shown to reduce esters, competition experiments in this report suggest a different pathway is operating between the two substrate classes with a dependence on the amount of pinacolborane employed (ACS Catal. 2015, 5, 4219−4226).

10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT Burnit et al. relate a Brønsted acid-catalyzed intramolecular nucleophilic substitution with transfer of chirality. The authors theorize that phosphinic acid plays a bifunctional role and promotes an SN2-type reaction. This transformation achieves direct substitution of the hydroxyl group in enantio-enriched alcohols with high degree of chirality transfer and in good-toexcellent yields. While the use of 1,2-dichloroethane as solvent is not desirable, only a subset of solvents were screened with cyclohexane providing comparable yield but lower transfer of chirality and toluene showing improved chiral transfer with lower yield. The hydroxyl group of benzyl, allyl, propargyl, and alkyl alcohols was substituted by O-, S-, and N-centered nucleophiles to generate enantiomerically enriched five-membered heterocyclic compounds. The 1,4-relationship between alcohol and nucleophile is crucial for a successful reaction as 3-, 4-, or 6-membered rings are not formed (J. Am. Chem. Soc. 2015, 137, 4646−4649).

Lu et al. studied the alkylation of variously substituted aminobenzenesulfonamides with aliphatic and benzylic alcohols. Screening studies identified 1 mol % [Cp*IrCl2]2 as the most effective catalyst when heated in tert-amyl alcohol in the presence of base (CsCO3) at 120 °C for 12 h. Exclusive alkylation was achieved on the sulfonamide nitrogen with benzyl, substituted benzyl, linear, and branched primary alcohols, typically in >80% isolated yield. Sterically hindered cyclohexanol and cyclopentanol required heating for 24 h at 150 °C to achieve 56−50% yield. Only trace amounts of alkylation at the aniline nitrogen was observed in all cases, and in some examples the product of alkylation on both nitrogens was obtained in up to 5% yield. The catalyst has previously been used to alkylate both anilines (1 mol % catalyst, NaHCO3 in toluene at 110 °C; Tetrahedron 2008, 64, 1943) and sulfonamides (1 mol % catalyst, tert-BuOK in boiling toluene or p-xylene; Org. Lett. 2010, 12, 1336). The authors propose coordination of one of the sulfonamide oxygens to iridium as a key intermediate in the classical hydrogen autotransfer (borrowing) mechanism. The utility of this reaction was demonstrated by the synthesis of the histone arginine methyltransferase PRMT1 inhibitor, C-7280948, which was obtained by heating the reaction mixture neat (5 equiv phenethylalcohol) in the presence of KOH (1 equiv) the product isolated in 80% yield after column chromatography (Org. Lett. 2015, 17, 2350−2353).

Rong et al. report the application of a chiral phosphoric acid (10 mol %) and iridium complex (5 mol %) toward a dynamic kinetic asymmetric amination of alcohols. Screening identified the preferred combination of phosphoric acid and iridium complex, which when heated with 3-phenylbutan-2-ol (1.2 equiv), aniline, and 4 Å molecular sieves in toluene at 110 °C for 24 h afforded predominantly a single product in high diastereomeric and enantiomeric ratios in 73% yield. Increasing the concentration to 0.4 M and reaction time to 60 h allowed use of an excess of aniline and increased the yield to 81%. The authors propose a hydrogen borrowing mechanism with oxidation to the intermediate ketone, condensation with aniline, and subsequent asymmetric transfer hydrogenation. Diastereoselectivity is achieved through asymmetric reduction of the preferred iminium intermediate, the two isomers interconverting through the enamine. A range of α-branched

Dang et al. reported both α-alkylation of ketones and N-alkylations of amines using alcohols and a silica supported palladium−NiXantphos complex. The catalyst accepted both secondary amines as well as alcohols and provided the desired product in modest to excellent yield. The scope allowed for heteroaryl ketones as well as aryl and alkyl amines. Furthermore, the authors showed that the catalyst recyclability could be 1127




improved by increasing the ligand to palladium ratio to give two additional catalysts showing minimal decrease in yield over up to four reactions (RSC Adv. 2015, 5, 42399−42406).

The first report of γ−butyrolactone synthesis from 1,2-diols and diethyl malonates using a ruthenium pincer-catalyst came recently from Pena-Lopez et al. A ruthenium catalyst system previously reported for amination reactions to give α-amino acid amides (Angew. Chem., Int. Ed. 2011, 50, 11197−11201) failed to promote lactone formation. However, when the catalyst was changed to Ru-MACHO-BH, the base to a carbonate and the solvent to t-amyl alcohol, lactone formation was seen in moderate yield with 2 mol % catalyst loading after heating at 150 °C. The authors propose a Ru catalyzed Knoevenagel reaction, via the hydrogen borrowing mechanism, followed by decarboxylation and intramolecular cyclization. In a variation, the reaction of cyclic diols with alkyl-substituted malonates resulted in the formation of α,β-unsaturated lactones; elimination of water takes place after decarboxylation, and the resulting tetra-substituted double bond is not reduced. Lower yields were observed in all cases for phenyl substituted substrates (Chem. Commun. 2015, 51, 13082−13085).

Continuing the theme of heterogeneous catalysis, Yang et al. report the use of activated carbon for reductive hydrogen transfer. The carbon catalysts were prepared by sol−gel polymerization of resorcinol and formaldehyde and the resulting wet gel mixed with base and heated at 800 °C under a flow of nitrogen, washing, and drying. A range of catalysts were prepared varying the nature and loading of the added base. The preferred catalyst was identified through screening the alkylation of aniline with benzyl alcohol with catalyst C−1, prepared from a 1:1 mixture of RFgel:KOH. Benzyl alcohol was used to monoalkylate a range of substituted anilines, benzylamines, and primary and secondary amines in moderate to good yield after chromatography. Similarly a range of substituted benzyl alcohols and pyridine- and thiophene-methanols were used to alkylate aniline. Reactions were performed in a sealed tube under argon at 130 °C for 24 h. The authors conducted a number of experiments to show that catalyst activity was not arising from precious metal contamination. The separated catalyst could be reused after washing with acetone and drying, at least 5 times. Hydrogen transfer reduction of nitrobenzenes and ketones using isopropanol as the hydrogen donor were also demonstrated (Nat. Commun. 2015, 6, 6478).

Koshizawa et al. found that bis(2,2,2-trifluoroethoxy)triphenylphosphorane was a superior stoichiometric reagent for conversion of benzyl alcohol (1) to thioether (2), a key intermediate in the synthesis of a GPR119 agonist. The previous synthesis required stepwise formation of the thioether through akylation of potassium ethanethioate with a benzyl bromide, hydrolysis, and alkylation with 2-(bromomethyl)pyridine; the route also required protection of the piperidine nitrogen. Variations on the Mitsunobu conditions applied to (1) resulted in low to moderate yields of the desired product whereas bis(2,2,2-trifluoroethoxy)-triphenylphosphorane gave clean conversion to the thioether, obtained in 98% yield after chromatography. The successful reaction was run on a small scale in dichloromethane, and a solvent screen is not reported (Tetrahedron 2015, 71, 3231−3236).

Mild, iridium-catalyzed conditions have recently been reported for the alkylation of amines with either amines or alcohols by Zou et al. Reactions were conducted at 1 mol % catalyst loading with 5 mol % base in a sealed tube. Of note is that the solvent trifluoroethanol was critical to reaction progression with greener solvents not being tolerated. Due to the mild conditions explored, a variety of secondary and tertiary amines were generated. The route allowed for a wide variety of functional groups including heterocycles and esters and reaction with multiple alcohols to form amine-containing heterocycles was also possible in moderate to high yield (Chem.Eur. J. 2015, 21, 9656−9661). 1128




Moderate to high yields at ambient or slightly elevated temperatures (up to 45 °C) were observed, and a diverse substrate scope with respect to thermal stability was established. The team additionally demonstrated the ability to recycle the water/micelle mixture by extracting the product with organic solvent. Recycling of the aqueous media resulted in improving the E-factor and reducing aqueous waste (Org. Lett. 2015, 17, 4734−4737).

11. FRIEDEL−CRAFTS CHEMISTRY Mo et al. has reported the use of a ferroceniumboronic acid hexafluoro-antimonate salt catalyst for the direct Friedel−Crafts alkylations of a variety of monohalogenated, neutral, and moderately activated arenes with stable and readily available primary and secondary benzyl alcohols. The catalyst is both air and moisture stable and the reaction proceeds under mild conditions via a proposed SN1 mechanism. The yields reported were high with moderate to high regioselectivity even for reaction of benzyl alcohols with electron-withdrawing groups. This catalyst was superior to those previously identified by the Hall lab employing tetrafluorophenylboronic acid catalyzed Friedel−Crafts allylations and benzylations of neutral arenes (Chem.Eur. J. 2015, 21, 4218−4223). Slightly deactivating substituents led to high yields, and the reaction was suitable for scale-up to gram scale, up to 1 M concentration, with catalyst recovery. Successful application of the strategy to heteroarenes, though, is not reported. The polar solvent for the reaction was optimized as a 4:1 mixture of hexafluoroisopropanol (HFIP) and nitromethane, consistent with previous work, although no other, potentially greener, solvents were evaluated (J. Am. Chem. Soc. 2015, 137, 9694−9703).

Wang et al. described the development of a copper-catalyzed hydroxylation of aryl halides in water. The syntheses of phenols generally require the use of energy intensive and/or harsh reaction conditions which can impact the substrate scope. This methodology utilized a hydroxylated phenanthroline ligand to improve solubility in water. Optimization of this method through screening resulted in the selection of copper(I) oxide (Cu2O) as the copper source and tetrabutyl-ammonium hydroxide (TBAOH) at 110 °C. The TBAOH was proposed to function as both phase transfer catalyst and nucleophile, resulting in high yields and excellent selectivity toward phenol versus biphenyl ether. The scope of this method with substituted aryl halides was demonstrated, affording excellent yields and high selectivity for para-substituted electron-rich and electrondeficient aryl bromides, as well as meta-substituted bromo-halides. Functional groups such as carboxyl and hydroxyl groups were also tolerated. The team additionally demonstrated a one-pot synthesis of either alkyl aryl ethers or benzofuran by trapping the in situ generated phenol with an alkyl bromide or through intramolecular cyclization (Green Chem. 2015, 17, 3910−3915).

Jung et al. reported the use of a continuous flow reactor to synthesize propargylamines in an atom economic fashion using stoichiometric quantities of reagents, water as solvent, and generating only CO2 and water as byproducts. The team exploited the use of a pressurized tube reactor to achieve temperatures above the boiling point of water, enabling excellent yields (≥88%) and reasonable residence time (2 h). This procedure improved the atom economy of previously reported methods for this transformation by eliminating the use of transition metal catalysts and excess of reagents. The substrate scope was demonstrated for multiple alkynyl carboxylic acids and secondary amines (Tetrahedron. Lett. 2015, 56, 4697−4700).

12. CHEMISTRY IN WATER Isley et al. reported the use of the nonionic amphiphile TPGS750-M (2 wt %) in water to facilitate nucleophilic aromatic substitution reactions (SNAr) with oxygen, nitrogen, and sulfur nucleophiles. The team eliminated the use of dipolar aprotic organic solvents traditionally required for SNAr reactions, such as dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), and N-methyl-2-pyrrolidone (NMP). 1129




Wang et al. reported the synthesis of an easily accessible diammonium functionalized Ru-alkylidene complex capable of ring-closing metathesis (RCM) and cross metathesis (CM) reactions in water. The NHBoc penultimate intermediate was isolated as an air-stable, nonhygroscopic Ru-alkylidene complex. Acidic cleavage of the Boc groups with trifluoroacetic acid (TFA) in dichloromethane generated the diammonium catalyst as a green solid after removal of volatiles under reduced pressure. The diammonium catalyst (5 mol %) achieved modest to high conversion to cyclic RCM products in D2O at ambient to elevated temperatures (up to 80 °C). Lowering the catalyst loading to 0.1 mol % established a turnover number (TON) of >900. Homocoupling of allyl alcohol and long chain alkenylammonium salts provided the desired diammonium cross products in high yield/conversion. Short chain alkenyl-ammonium salts were poor substrates for the CM reaction. Catalyst deactivation was attributed to the ammonium:free amine equilibration in water followed by Lewis basic nitrogen coordination to the Ru-center (Green Chem. 2015, 17, 3407−3414).

Bhowmick et al. published a review “Water: the most versatile and nature’s friendly media in asymmetric organocatalyzed direct aldol reactions”. This review addressed the various types of organocatalysts based on (1) L-proline, (2) 4-hydroxy-L-proline, (3) amino acid derivatives, (4) enzymes, and (5) other miscellaneous catalysts applied to the aldol reaction in aqueous media. In general, the intermolecular asymmetric aldol reaction has been shown to perform poorly in pure aqueous media and is typically performed in organic solvents such as DMF, DMSO, etc. However, structural modifications to L-proline and 4-hydroxy-Lproline have generated catalysts capable of asymmetric aldol reactions in aqueous media. Examples provided in this review highlight (a) instances of enhanced reactivity using water as a solvent, cosolvent, or additive, (b) formation of enzyme mimics that use hydrophobic forces to reinforce substrate/catalyst binding, (c) the use of aqueous media to interrogate proposed transition state geometries, and (d) the pH dependence of organocatalyzed aldol reactions. Limitations presented in the review include (a) substrate specific catalyst activities, (b) multistep/low-yielding synthesis of the organocatalysts, (c) slow catalysis rate in pure aqueous media, (d) high catalyst loading, and (e) poor to moderate selectivity (Tetrahedron: Asymmetry 2015, 26, 1215−1244).

The same research group additionally reported the divergent functionalization of L-tyrosine to generate a family of tyrosinederived Ru-alkylidene RCM catalysts. This common ligand precursor approach was utilized to successfully create not only a hydrophilic/water-soluble PEG Ru-alkylidene, but a hydrophobic alkane Ru-alkylidene for solvent-free catalysis and a solidphase supported Ru-alkylidene to access a potentially recyclable precatalyst system. The PEG Ru-alkylidene complex displayed poor solubility in water at 40 °C under ultrasonication, providing the desired model RCM product in only 25% conversion. >95% conversion was achieved by utilizing a 1:1 water−MeOH solvent system at 40 °C with 2.5 mol % catalyst loading. It was rationalized in the Green Chemistry report (vide supra) that functionalization of the benzylidene ligand to increase aqueous solubility may be problematic due to the dissociation of the labile ligand during the catalytic cycle, whereas functionalization of nondissociating NHC ligand could sustain the desired solubility throughout the reaction. The hydrophobic alkane Ru-alkylidene provided solvent-free RCM and CM products in high conversion. The solid-phase Ru-alkylidene also provided the desired RCM products in high conversion and demonstrated stable performance after multiple catalyst recovery/reuse operations. Sustained leaching of Ru metal into the reaction media was monitored and observed for the recycled solid-phase catalyst method. However, this iterative loss of metal did not negatively impact conversion (J. Org. Chem. 2015, 80, 7205−7211).

13. CONTINUOUS PROCESSING Correia et al. have published a three-step flow synthesis of racEffavirenz. This short synthetic route begins with cryogenic 1130




trifluoroacetylation of 1,4-dichlorobenzene. After quench and removal of morpholine using silica gel, this intermediate could either be isolated, or the product stream could be used directly in the next alkynylation step. Nucleophilic addition of lithium cyclopropylacetylide to the trifluoroacetate gave the propargyl alcohol intermediate in 90% yield in under 2 min residence time. This reaction was temperature-sensitive, and low temperatures were required to minimize decomposition. Again silica gel proved effective in the quench of the reaction. However, residual alkyne and other byproducts were difficult to remove. Thus, isolation of this intermediate was performed to minimize the impact of impurities on the final copper catalyzed cyanate installation/ cyclization step to afford Effavirenz. Optimization of this step in batch mode for both copper source and ligand identified Cu(NO3)2 and CyDMEDA in a 1:4 molar ratio (20 mol % and 80 mol %, respectively) produced the product in 60% yield. Adaptation of this procedure to flow conditions resulted in poor conversion due to slow in situ reduction of the Cu(II) to Cu(I). Thus, a packed bed reactor of NaOCN and Cu(0) was used. Under these conditions, the ligand and catalyst loading could be reduced without compromising yield. Due to solubility limitations of Cu(NO3)2, Cu(OTf)2 was used with CyDMEDA in 1:2 molar ratio (5 mol % and 10 mol % loading, respectively). Under these optimized conditions, rac-Effavirenz was obtained in 62% isolated yield in reaction time of 1 h. This three-step process provides 45% overall yield of rac-Effavirenz and represents the shortest synthesis of this HIV drug reported to date (Angew. Chem., Int. Ed. 2015, 54, 4945−4948).

14. GENERAL GREEN CHEMISTRY One of the common debates within Green Chemistry is how to evaluate how successful a process is not only in terms of reaction yield, but also in terms of sustainability. With this in mind, numerous simple metrics have been developed with the general understanding that within each of these, there are gaps with regard to capturing all the necessary data for a full evaluation. McElroy et al. at the University of York were tasked with carrying out an assessment of the various Green metrics with the goal of providing a recommendation to the CHEM21 project for the preferred method to measure sustainability. This led to the creation of a unified “Metrics Toolkit”, which not only takes into consideration the various parameters involved in a process, but also recognizes that the depth of analysis required is also contingent on the stage of development of the reaction. Given this, one is able to make a rapid evaluation of a screening reaction utilizing simple variables like yield, conversion, and nature of solvents, whereas when a reaction is ready for manufacturing, a deeper analysis involving a full energy investigation, recovery/ recycling, and waste generated is warranted. A simple overview of each of the criteria to be considered at each stage of the evaluation is provided in the article, as well as three new metrics being proposed to link several previously utilized criteria. These are optimum efficiency (OEdefined as reaction mass efficiency/ atom economy), renewable percentage (RPdefined as renewables intensity/process mass intensity), and waste percentage (WPdefined as waste intensity/process mass intensity) (Green Chem. 2015, 17, 3111−3121). Rakeshwar Bandichhor Dr. Reddy’s Laboratories Ltd., Innovation Plaza, IPDO, Bachupally, Hyderabad, A.P. 500072, India Apurba Bhattacharya Dr. Reddy’s Laboratories Ltd., Innovation Plaza, IPDO, Bachupally, Hyderabad, A.P. 500072, India Marian C. Bryan Genentech, Inc., 1 DNA Way, MS 18B, South San Francisco, California 94080, United States Andrew Cosbie Amgen, Thousand Oaks, California 91320, United States Alba Díaz-Rodríguez GlaxoSmithKline, Stevenage, Hertfordshire, SG1 2NY, U.K. Louis Diorazio AstraZeneca, Macclesfield, SK10 2NA, U.K. Zhongbo Fei Novartis Pharmaceuticals (China) Suzhou Operations, #18 Tonglian Road, Changshu, Jiangsu 215537, China Kenneth Fraunhoffer Bristol-Myers Squibb, Co., One Squibb Drive, New Brunswick, New Jersey 08903, United States John Hayler* GlaxoSmithKline, Stevenage, Hertfordshire, SG1 2NY, U.K. Matthew Hickey* Bristol-Myers Squibb, Co., One Squibb Drive, New Brunswick, New Jersey 08903, United States

Wang et al. developed a flow process that uses metal catalyzed hydrogenation of NAB (2-nitro-2′-hydroxy-5′-methylazobenzene) to BTA (2-(2′-hydroxy-5′-methylphenyl)benzotriazole), a commonly used ultraviolet absorber. The major challenge in this process was to optimize the reduction of the diazo functionality over the nitro group and control formation of over reduction side products. The initial screen of metals adsorbed onto a γ-Al2O3 support indicated Pd to be superior to the other metals and also confirmed that catalyst preparation plays an important role in selectivity. To better understand the characteristics of the supported metal catalyst systems, the best performing were analyzed by TEM, XRD, H2-TPR, and N2 adsorption−desorption. Finally, solvents and bases were screened ultimately arriving at the optimized conditions using toluene, 2 equiv n-butylamine over 1% Pd/Al2O3, which provided 90% yield BTA in process with 98% conversion. The process can run over 200 h without a decrease in performance (ACS Sustainable Chem. Eng. 2015, 3, 1890−1896). 1131




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

Scott Roberts Amgen, Thousand Oaks, California 91320, United States

Timothy White Eli Lilly, Indianapolis, Indiana 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].

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