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Green Chemistry Articles of Interest to the Pharmaceutical Industry 1. INTRODUCTION The American Chemical Society’s (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable (PR) was developed in 2005 to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The Roundtable currently has 16 member companies as compared to three in 2005. The membership scope has also broadened to include contract research/manufacturing organizations, generic pharmaceuticals, and related companies. Members currently include ACS GCI, Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Codexis, Cubist Pharmaceuticals, Dr. Reddy’s, DSM Pharmaceutical Products, 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. The review period covers October 2013 to April 2014. 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, whilst 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.

A publication by Ab Rani et al. reported volatile methyl siloxanes (VMS) as new solvents for synthetic applications and as more sustainable alternatives to the currently available nonpolar solvents. An evaluation and comparison on the EHS profiles is described together with the chemistries that can be applied in these VMS solvents (Green Chem. 2014, 16, 1282−1296). Skowerski et al. reported on an environmentally friendly solvent selection guide for olefin metathesis reactions. This is a type of reaction that is typically performed in environmentally detrimental aromatics and chlorinated solvents. A selection of 10 modern and most frequently used ruthenium catalysts were assessed in the most recommended green solvent for the different types of alkene metathesis reactions (Green Chem. 2014, 16, 1125−1130).

3. AMIDE FORMATION Lundberg et al. have published a comprehensive review on catalytic amide formation from nonactivated carboxylic acids and amines. The review is broken down into sections, which focus on biocatalysis, boron-based catalysts, metal catalysis, and miscellaneous catalysis with each section being further broken down to enable facile access to the most relevant methods if specific information is desired (e.g., primary vs secondary amides, homogeneous vs heterogeneous catalysis). As well as documenting detail in terms of synthetic utility, practicality, and scope for each of the methods presented, the sections also provide an overview in terms of the advantages, disadvantages, and future potential for each of the discrete methodologies with an emphasis on environmental benefits. Direct thermal amidation is briefly discussed though from a perspective of its impact as a background reaction enhancing product formation for the catalytic processes under review (Chem. Soc. Rev. 2014, 43, 2714−2742). Gaudino et al. have reported on the direct amidation of carboxylic acids mediated by commercially available TiO2 powder (Aeroxide). The optimized reaction takes place under solvent-free conditions at 100 °C for 20 min in a monomode microwave reactor. The reaction did proceed at lower temperatures (80 °C) though preactivation of the catalyst was required. The optimal catalyst loading was shown to be 33 wt %, with a slight excess of amine being utilized. The reaction did not proceed in solvents, and sequential addition of the acid and amine to the catalyst with two heating steps was also shown to be deleterious. The heterogeneous catalyst could easily be recovered, regenerated by heating to 450 °C in a muffle furnace, and reused over 5 cycles with minimal depreciation in performance. A range of aromatic and aliphatic acids were successful substrates with minimal effects of either sterics or electronics being observed. Primary amines worked well, whereas secondary amines were less reactive. No examples of

2. SOLVENTS Prat et al. from Sanofi-Aventis have published the Sanofi Solvent Selection guide. Solvents are divided into four rankings, recommended (green), substitution advisible (yellow), substitution requested (red), and banned. The ranking is derived from an evaluation of safety, heath, environmental, quality, and industrial considerations. The guide also gives cost information where methanol is given a cost of 1 and all other solvents are given a cost relative to methanol (RCM) so for example 2-methyl-THF is given an RCM of 18. Costs are rounded to the nearest integer to minimize the need to update the guide (Org. Process Res. Dev. 2013, 17, 1517−1525). Glycerol is a byproduct of biodiesel production and worldwide biodiesel production has increased almost 10-fold between 2004 and 2011. A review by Garcia et al. covers the synthesis, properties, and application of glycerol-based solvents (Green Chem. 2014, 16, 1007−1033). A review by Pollet et al. covers some neoteric solvents such as supercritical fluids, gas expanded liquids, and switchable solvents (Green Chem. 2014, 16, 1034−1055). © 2014 American Chemical Society

Received: November 3, 2014 Accepted: November 4, 2014 Published: December 19, 2014 1602

dx.doi.org/10.1021/op500345y | Org. Process Res. Dev. 2014, 18, 1602−1613

Organic Process Research & Development

Green Chemistry Highlights

heterocyclic substrates are provided. Mechanistic studies using IR indicate activation of the oxygen atoms of the carboxylate moiety through direct interaction with Ti4+ atoms, which act as Lewis acid centres, on the catalyst surface (Catal. Sci. Technol. 2014, 4, 1395−1399).

optimal solvent was shown to be 1,2-dichloroethane though other solvents such as acetonitrile were also effective. The reaction was observed to be sensitive to both steric and electronic effects with electron-withdrawing substituents retarding the reaction. Aliphatic aldehydes were also only converted with low yield. Simply increasing the amount of TBHP enabled benzylic alcohols to be utilized in this reaction. Subjecting an acetophenone to slightly modified reaction conditions lead to formation of the α-ketoamide in moderate yield. A radicalbased mechanism is proposed based on control experiments using radical scavengers (Org. Biomol. Chem. 2014, 12, 414−417). We suggest using caution when heating TBHP for extended periods as outlined in the reaction procedure (Proc. Eng. 2012, 45, 574−579). Vanjari et al. have utilized the reaction of N-chloroamines with aldehydes mediated by 20 mol % of AIBN for the formation of secondary and tertiary amides. The optimum conditions utilized two equivalents of the N-chloroamine in acetonitrile at 80 °C. A range of aromatic aldehydes were converted with the reaction showing minimal sensitivity to electronics, though it was observed that the reaction did not tolerate a free hydroxyl substituent. Aliphatic aldehydes were also successful substrates though slightly diminished yields were obtained. A radical based mechanism is proposed based on AIBN’s well-known role as a radical initiator and inhibition of the reaction in the presence of radical scavengers such as TEMPO (Green Chem. 2014, 16, 351−356).

Two groups have published on the direct amidation from alcohols and amines through a tandem oxidative process using heterogeneous gold catalysis. Soulé et al. have published a full account on their previously disclosed use of heterogeneouspolymer-incarcerated gold nanoparticles (PICB-Au) for this transformation. Full details of the preparation, stoichiometry, size and surface analysis, and morphologies of the various nanoparticles utilized are provided. Two different systems are optimized depending on whether the alcohol is activated and the nature of the amine. For activated alcohols reacting with primary amines, 1 mol % of a bimetallic PICB-Au/Co system is employed using NaOH as the base. Both the solvent system (THF/H2O, 19:1) and the concentration (0.75 M) are shown to be key parameters to obtain optimum yields with the reaction proceeding at ambient temperature under an oxygen (or air) atmosphere. Similar conditions are employed for unactivated alcohols or reactions using secondary amines with the major difference being the use of a monometallic PICB-Au catalyst. For both systems, a wide substrate scope is demonstrated with good functional group tolerance and no racemization observed in the case of enantiopure substrates. The differential selectivity of the two systems is demonstrated through selective amidation mediated by the bimetallic PICBAu/Co catalyst of an activated alcohol in the presence of an unactivated substrate. The catalysts can be successfully recycled through five reactions provided they are pretreated with a water wash and heated to 170 °C for 4 h prior to reuse. Mechanistic studies and a rationale for the activity of the two catalyst systems are also provided (Chem. Asian J. 2013, 8, 2614−2626). Wang et al. have reported on a similar reaction mediated by a hydroxyapatite-supported Au catalyst. Model studies demonstrated that the optimum conditions utilized NaOH as the base with 0.77 mol % of the catalyst with the reaction proceeding under an oxygen atmosphere in H2O at 40 °C. A range of aliphatic and aromatic alcohols and amines (in general an excess of the amine was used) were well-tolerated with ammonia also being successfully employed. Several heteroaromatic alcohols were also acceptable substrates. Electronwithdrawing groups and steric hindrance had a negative influence on the reaction with higher catalyst loadings being required to obtain good yields. The reaction has also been demonstrated on a gram scale. Attempts to recycle the catalyst were unsuccessful with structural characterization showing a particle size change after reaction. Mechanistic studies indicate initial alcohol adsorption followed by oxidation and the reaction proceeding through a hemiaminal intermediate (Tetrahedron Lett. 2014, 55, 124−127). Two groups have published on metal-free amidation processes utilizing aldehydes/alcohols as substrates, and both employ tert-butylhydroperoxide (TBHP) as the stoichiometric oxidant. Wang et al. have described the formation of primary amides from aldehydes using ammonium carbonate as the ammonia source and 10 mol % of Et4NI as a catalyst. The

Transamidation of amides with amines represents a potentially attractive alternative method to direct amide bond formation from carboxylic acids. Ayub Ali et al. have reported on a solvent free variant of this transformation using Fe3+-exchanged montmorillonite (Fe-mont) as an inexpensive and recyclable heterogeneous catalyst, which displays higher activity than previously disclosed catalyst systems, and a broad substrate scope. Model studies showed the optimum reaction temperature was 140 °C over a reaction time of 30 h with 1 mol % of catalyst being employed. A 1.1:1 ratio of amine to amide provided the best yields indicating a stronger interaction of the amide than the amine with the Fe3+ Lewis acidic active sites on the catalyst surface. A stoichiometric amount of ammonia is generated in the reaction of primary amides and primarily released into the gas phase. The catalyst was recycled over five reactions with minimal loss of activity by washing the product 1603




recover the catalyst. The catalyst recovered in this manner can be reused up to five times with only a minimal loss of activity being observed (Tetrahedron Lett. 2014, 55, 1136−1140).

away, centrifugation, and air drying. A wide scope of aromatic, heteroaromatic, and aliphatic amides are tolerated, as are both anilines and aliphatic amines. The authors compare the new method with a variety of previously reported heterogeneous and homogeneous catalysts for transamidation and show the current method to be superior with regard to both TOF and TON. Mechanistic studies using IR indicate the initial interaction of the amide carbonyl with Fe3+ sites on the catalyst surface resulting in an increase in electrophilicity of the amide (Tetrahedron Lett. 2014, 55, 1316−1319).

Ma et al. have reported on the hydrolysis of nitrile to primary amides using 10 mol % of sodium molybdate (VI) dihydrate and acetaldoxime (3 equiv) at reflux in water. A variety of structurally diverse nitriles were successfully converted though substrates bearing an electron-donating or sterically encumbered nitriles showed lower conversions and required longer reaction times and a larger excess of acetaldoxime. In contrast, substrates with electron-withdrawing substituents could be successfully hydrated at ambient temperature. Mechanistically, the reaction is proposed to occur through initial coordination of the nitrile to Mo(VI), which enhances the electrophilicity of the nitrile carbon, thus rendering it prone to nucleophilic attack by acetaldoxime (Synth. Commun. 2014, 44, 474−480).

Lebleu et al. have reported on a simple transamidation method for the formylation of amines using formamide. Solvent screening appeared to indicate that water played a unique role in promoting the reaction, but it was then found that running the reaction neat at 80 °C for 24 h provided the optimum yield. The reaction worked well for a range of aliphatic, aromatic, and heteroaromatic amines with only a stoichiometric amount of formamide being required though longer reaction times were required for sterically encumbered substrates. A one-pot procedure for the mono methylation of amines through formylation and reduction is also reported (Tetrahedron Lett. 2014, 55, 362−364).

4. OXIDATIONS Visible light photoredox catalysis has attracted a great deal of interest in organic synthesis due to the ability to activate organic molecules via single electron transfer (SET) processes. While heavy transition metals such as Ir and Ru are typically used, metal-free organic dyes are a greener alternative due to their lower costs and greater availability. Yadav et al. developed an eosin Y catalyzed oxidative cyclization for an efficient synthesis of 1,3,4-oxadiazoles from aldehydes and acylhydrazines. The oxidative cyclization of the acylhydrazone, which is generated in situ from the acylhydrazine and the aldehyde, is promoted with 2 mol % of eosin Y, green LED, air, and Hünig’s base at room temperature (Tetrahedron Lett. 2014, 55, 2065−2069).

Yadav et al. have reported a novel approach to a range of amides through the desulfurization of thioamides mediated by visible light. Optimization studies demonstrated that the reaction utilized 2 mol % of the organic dye eosin Y at room temperature under air and irradiation with green LEDs. A number of suitable solvents were identified as being viable for the reaction with DMF being the best. A range of alkyl, aryl, and heteroaryl substrates worked well in the reaction with good functional group tolerance being observed. However, due to dimerization, the reaction was not applicable to primary thioamides. A series of control experiments eliminated the intermediacy of singlet oxygen in the reaction, and a plausible mechanism is proposed involving the superoxide radical anion (New J. Chem. 2013, 37, 4119−4124).

Kaur et al. have described an efficient Beckmann rearrangement using dodecatungstophosphoric acid (DTPA) as a recyclable catalyst. Model studies using benzophenone oxime as the substrate indicated that the optimal conditions used 1 mol % of catalyst in refluxing acetonitrile. A variety of examples are provided with electron-withdrawing substituents shown to favor the reaction. The new method was also shown to compare favorably in terms of yield and mildness of the reaction conditions to a number of previously disclosed protocols. The catalyst can easily be recovered simply by the addition of water, filtering the product, and evaporating and drying the aqueous to

While various metals can catalyze the allylic oxidation with molecular oxygen, Z/E-isomerization of the C−C double bond is a major issue with Z-allylic alcohols. To overcome this problem, Liu and Ma developed a mild, Fe(NO3)3-TEMPOcatalyzed aerobic allylic alcohol oxidation with complete retention of the C−C double bond configuration. A catalytic amount of NaCl is also needed, possibly as a ligand to Fe; 1604




Bachman et al. have published a ruthenium catalyzed asymmetric hydrogenation of an α-aryl, β-alkyl substituted acrylic acid to prepare (1), an intermediate in the synthesis of a glucokinase activator. Screening of a wide range of catalysts derived from Ir, Rh, Ru, and commercially available ligands, identified a ruthenium MeOBIPHEP based system for scale-up. Optimum conditions were found to be in methanol at 50 °C and 50 bar hydrogen. Further study showed the importance of enantiomerically pure E-isomer on the stereoselectivity of the reduction. The desired intermediate was obtained with ∼99% ee in 62% yield after crystallization. This strategy compared favorably on cost when compared with the previous approach based on a resolution (Org. Process Res. Dev.. 2013, 17, 1451−1457).

unfortunately 1,2-dichloroethane was the only solvent evaluated (Org. Lett. 2013, 15, 5150−5153).

Wang et al. have reported a metal-free oxidative spirocyclization in the synthesis of spirooxindoles, a privileged structure in bioactive compounds. Reaction of 1,3-cyclohexadione with the hydroxymethylacrylamide results in cascade formation of two new C−C bonds and a C−O bond. It tolerates functional groups such as esters, halides, ethers, nitriles, and ketones. Without the need for a heavy metal as either a catalyst or reagent, K2S2O8 serves as the oxidant for the two formal C−H bond activation processes, the first being the radical formation of the diketone and the second the aromatization of the benzene radical from the cascade reaction (Org. Lett. 2013, 15, 5254−5257).

Precious metal catalysts (e.g., Ru, Rh, Pd, Pt) are mainly used in asymmetric hydrogenation. However, these metals are a finite resource and therefore it is warranted to develop methods involving nonprecious metals such as Fe. In this context, Zuo et al. have investigated partially saturated amine(imine)diphosphine ligands (P-NH−N-P) which activate iron to catalyze the asymmetric reduction of the ketones and imines to obtain corresponding alcohols and amines. Isopropanol was used as the hydrogen donor in this strategy. The proposed catalytic mechanism was verified by several spectroscopic techniques. A number of ketones and imines were reduced to alcohols and amines in high yields (80 to >99%) and ee (90 to >99%) by employing 0.016−1 mol % catalyst loading with turnover number in the order of 2000−6000 (Science 2013, 342, 1080−1083).

5. ASYMMETRIC HYDROGENATIONS Fang et al. have developed an asymmetric hydrogenation strategy to access 3,5-dihydroxycarboxylic acids. Asymmetric reduction of 2,2,-dimethyl-6-(2-oxoaryl)-1,3-dioxin-4-ones was explored by employing a known transfer hydrogenation catalyst and formic acid/triethylamine as the reducing agent. Addition of solvent was found to be advantageous, with DCM and acetonitrile affording the best results (93% yield and 98% ee for R = phenyl). The reaction rate at room temperature was slow; however, running the reaction at 50 °C facilitated full reduction in 10 h at an S/C ratio of up to 5000:1 without loss of enantioselectivity. The stereoselective outcome can be explained through a transition state geometry that signifies the π−CH interaction between catalyst and the aryl substituent, although steric effects also appear to play a significant role. The optimized conditions were employed in the synthesis of enantiomerically pure isomers of yashabushitriol >94% yield and >30:1 diastereoselectivity (Tetrahedron Lett. 2013, 54, 6834−6837).

A highly efficient asymmetric synthesis of chiral isochromenes has been developed using the nonprecious metal copper. This transformation involves a copper(II)/phosphate-catalyzed intramolecular cyclization/asymmetric transfer hydrogenation sequence of o-alkynylacetophenone derivatives. Hantzsch esters are used as the hydrogen source. Multisubstituted isochromenes 1605




enantioselective variant is ongoing (J. Am. Chem. Soc. 2013, 135, 16074−16077).

are prepared in high yields (79%) with good to excellent enantioselectivities (80−97%). A copper-containing carbonyl ylide is proposed as a reactive intermediate in the mechanism (Angew. Chem., Int. Ed. 2013, 52, 13284−13288).

A copper-catalyzed aerobic dehydrogenative cyclization has been developed which constructs imidazo[1,2-a]pyridines from simple pyridines and oxime esters. The reaction uses 20 mol % CuI and 20 mol % Li2CO3 with air as the stoichiometric oxidant. Many oximes derived from aryl methyl ketones react in good yield, including substituted phenyl, naphthyl, and heteroaryl groups (31−89%). Substitution of the pyridine at the C−3 and C−4 positions typically results in diminished yield (32−52%), and it is noteworthy that 3-substituted pyridines react at the more hindered C−2 position, whereas 2-substituted pyridines do not react at all. Isoquinoline is an effective substrate reacting with several different oximes (40−70%). One drawback of the method is that the reaction requires 3 equiv of the pyridine or isoquinoline fragment (Org. Lett. 2013, 15, 6254−6257).

Zhou et al. screened several diphosphine ligands for the asymmetric hydrogenation of nitro olefins, and TangPhos was found to be the ligand of choice. In this transformation solvent seems to be playing a critical role as a screen of a variety of solvents showed that trifluoroethanol (TFE) promoted the desired transformation in high yields and selectivity with 1 mol % catalyst. Substituent effects were also investigated revealing that aryl substituents alpha to the acylamino group were required for high enantioselectivity. The optimized conditions for reduction of nitro olefins employ 1 mol % Rh(COD)TangPhos/H2 (5 atm) at 25 °C and produce nitroalkanes in high yields (98%) and enantioselectivity (∼93% ee). These results have potential to inform alternate strategies for the synthesis of pharmaceutically relevant molecules such as clopidogrel, oseltamivir, GR-205171A, (+)-CP-99,994, CP690,550, and asimadoline (Org. Lett. 2013, 15, 5524−5527).

Fennewald and Lipshutz report a trifluoromethylation procedure developed with addressing the solvent selection, recycling, and waste minimization in mind. The reaction conditions developed utilize an aqueous system of NaSO2CF3 as the trifluoromethyl source, with the surfactant TPGS-750-M and t-butylhydroperoxide. Reaction conditions were optimized on 4-t-butylpyridine to utilize 2 wt % of the surfactant, 3 equiv of NaSO2CF3, and 5 equiv of the oxidizing agent in water as the solvent. The ability to run in water addresses the greener solvent choice, and after addition of ethyl acetate to remove the product, it was possible to reuse the aqueous layer in subsequent reactions which helps address both recycling and waste minimization. Several additional heterocycles were investigated and gave similar or better yields to previous literature conditions (43−84%). Unfortunately, yields dropped with each consecutive recycle due to the presence of t-butyl alcohol complicating removal of the product from the aqueous layer (Green Chem. 2014, 16, 1097−1100).

6. C−H ACTIVATION Evans et al. have developed a copper-catalyzed direct oxidative coupling between α-carbonyls and secondary aliphatic amines. The reaction uses 10 mol % CuBr2 to form an α-bromo carbonyl intermediate which undergoes C−N bond formation using 2−3 equiv of the amine. Air (in some cases 1 atm oxygen) is used as the stoichiometric oxidant. The carbonyl scope is broad as aldehydes, aryl and aliphatic ketones, and esters all react. Aliphatic ketones use a cocatalyst such as NiBr2 to help promote enolization. Both cyclic and acyclic dialkyl amines undergo coupling, with acyclic amines requiring sodium iodide additive. The authors demonstrate the power of the method through the synthesis of pharmaceuticals amfepramone and racemic Plavix. The authors note that work towards an

A copper acetate catalyzed benzylic oxidation in the presence of air has been developed by Jiang et al. The presence of a remote p-hydroxy group directed the oxidation, and a wide range of 2,6-disubstituted 4-cresols were investigated. Alkoxy and/or alkyl substitution at R2 and R3 was required, and over 30 examples resulted in yields ranging from 62 to 87% for the 1606




interesting selectivity for mono versus disubstitution (Org. Lett. 2014, 16, 1744−1747).

resulting ketones (when R1 was alkyl) and aldehydes when R1 was a proton. Substitution of one or both of the R2, R3 groups with halogens or nitriles resulted in poor conversion with recovery of significant amounts of starting material. Finally, when R1 is hydroxyl or alkoxy, the resulting aldehyde is generated under the same reaction conditions in yields ranging from 84−96%. Additional substrate scope is currently under investigation (Green Chem. 2014, 16, 1248−1254).

Rueda-Becerril et al. developed the first photoredox catalytic method for carbon−fluorine bond formation using Ru(bpy)3Cl2. The reaction proceeds through a photoredox pathway involving a key single electron transfer from the triplet metal-to-ligand charge transfer state of the ruthenium catalyst to Selectfluor that ultimately enables decarboxylative fluorination. Although the substrate scope is rather limited at this stage and yields are modest to good (from 51% to 92%), the methodology gives access to difficult products and opens up new opportunities for more selective transformations in the future (J. Am. Chem. Soc. 2014, 136, 2637−2641).

7. GREENER FLUORINATION Lee et al. reported a versatile and practical palladium-catalyzed nucleophilic fluorination of aryl bromides and iodides). The previous nucleophilic fluorination methods required aryl triflate substrates and the use of hindered biaryl phosphine ligands. The described work utilizes precatalyst 1 in 1−3 mol % loading, silver fluoride as the fluoride source and potassium fluoride as the base of choice. Despite harsh temperature conditions (90−150 °C), very low levels of reduction byproduct and goodto-high yields are observed (69−94% for the benzene ring systems, 51−96% for the heteroaromatic systems). The substrate scope appears promising, and is compatible with a wide range of functional groups including ketones, amides, esters, amines, nitriles, and heteroaromatic bromides. The paper includes insight on the identification of the proper (pre)catalyst and its synthesis, which should benefit future optimization. It will hopefully enable further development and allow an expanded substrate scope to encompass fivemembered ring systems and other heterocycles (J. Am. Chem. Soc. 2014, 136, 3792−3795).

8. BIOCATALYSIS Although mild, selective, and greener methods of oxidation are being developed, the chemical cleavage of alkenes to give aldehydes or ketones is still preferentially achieved through methods such as ozonolysis or with metal salts such as OsO4. Whilst progress has been made to make these processes run catalytically or in flow reactors, an alternative would be to carry out this transformation using enzymatic methods. Rajagopalan et al. have now identified and expressed an enzyme capable of this transformation. The enzyme (from fungus Trametes hirsuta) was expressed in E. coli and showed activity towards a number of benzylic substrates. The enzyme was found to require a MnIII ion for catalytic activity with oxygen as the terminal oxidant (ChemBioChem 2013, 14, 2427−2430).

Mormino et al. developed an operationally simple protocol for the perfluoroalkylation of heteroaryl bromides by addition of the corresponding phenanthroline copper-stabilized trifluoromethyl and pentafluoroethyl complexes. The methodology described is a rapid and attractive procedure for routine laboratory operations. It also opens up the opportunity for the introduction of longer perfluorinated side-chains. The methodology was demonstrated on a wide range of heteroaromatic systems and proceeded in good to high yields (50% − 99%) displaying remarkable functional group compatibility and

Alcohol dehydrogenases (ADHs) are currently one of the most used enzyme classes, typically for the preparation of chiral alcohols. β,β-Dihalogenated alcohols are an interesting class of synthetically useful intermediates and as analogues to αhydroxy aldehydes. Chemical methods of synthesis, such as reduction with chiral oxaborolidines, give only moderate selectivity (∼80% ee). However, Ked̨ ziora et al. have now reported the preparation of these compounds using ADHs. The 1607




bioreduction of a number of α,α-dichloroacetophenone derivatives was studied using six different ADHs with LBADH from Lactobacillus brevis shown to be the most versatile. The chiral alcohols were produced with good conversion and ee, and either enantiomer could be prepared by selecting the appropriate enzyme (ChemCatChem 2014, 6, 1066−1072).

Scheme 1

for the production of non-natural compounds. Wu et al. have reported such a cascade in E. coli using a monooxygenase and an epoxide hydrolase.

Regio- and stereoselective hydroxylation of nonactivated carbon atoms is a potentially useful although challenging reaction to carry out using chemical methods. In particular, the hydroxylation of alkane feedstocks has the potential to produce valuable synthetic intermediates. Monooxygenases offer a green solution to this problem using molecular oxygen as the terminal oxidant but often show poor selectivity and a narrow substrate range. Yang et al. show that through directed evolution the regioselectivity of P450pyr hydroxylase towards n-octane and propylbenzene could be increased dramatically. The selectivity of the wild type enzyme was improved from very low to >95% in six rounds of evolution (Angew. Chem., Int. Ed. 2014, 53, 3184−3188).

This process forms chiral diols from the corresponding alkenes under conditions which are milder and complementary to traditional metal catalyzed methods. Starting from either the cis or trans olefin a combination of styrene monooxygenase (SMO) and an appropriate epoxide hydrolase (either SpEH or StEH) gave access to all four diastereoisomer in very good yields and with high ee and de (ACS Catal. 2014, 4, 409−420).

Chiral amines are found widely in both natural products and pharmaceutical intermediates, which makes their synthesis from achiral building blocks highly desirable. O’Reilly et al. have reported the synthesis of trans-2,5-disubstituted pyrrolidines using both transaminase and monoamine oxidase enzymes together in a cascade reaction. Starting from an asymmetric diketone an (S) selective transaminase is used to set the first stereocenter at the methyl ketone and the amine produced cyclises onto the second ketone to form the pyrroline. This is reduced nonselectively with borane whilst the monoamine oxidase then oxidises one enantiomer back to the pyrroline. Using this approach, a single diastereoisomer of the pyrrolidine is formed. A range of pyrrolidines are formed in excellent conversion and de in one pot (Angew. Chem., Int. Ed. 2014, 53, 2447−2450) (Scheme 1). One pot cascades offer advantages over the equivalent number of single step processes by reducing unit operations, labour, energy and cycle time. Compared with chemical catalysis, cascade biocatalysis such as that above can be easily combined into one pot since enzymes typically require similar reaction conditions. Although this is elegantly demonstrated by metabolic pathways in cells, non-natural cascades are required

Significant effort can be required in order to achieve high yields in these processes. For example, the expression levels of the genes may require optimization by engineering and testing a number of expression cassettes. An additional factor which should be taken into account when planning a multistep enzyme cascade concerns the connection to the cell’s primary metabolism through redox cofactor regeneration. Placing too high a demand upon the cell to recycle cofactors may lead to a poor yield. To neatly illustrate this concept, Oberleitner et al. have recently published a multienzyme cascade in E. coli by creating a “mini” metabolic pathway capable of producing diverse compounds through differing reaction pathways. Three biocatalysts with broad substrate scopes [alcohol dehydrogenase (ADH), enoate reductase (Ered), and Baeyer−Villiger monooxygenase (BVMO)] were combined into an in vivo pathway with a partially self-sustaining cofactor RedOx system. Having established a toolbox of recombinantly expressed enzymes in the correct combination in a single cell, the methodology was then demonstrated for the conversion of (1S,5S)-carvol 1608




(η6-arene)iron complexes that are stabilised by bis(Nheterocyclic carbene) ligands and can be viewed as Fe(0) precatalysts. These species show good reactivity towards tertiary amides with loadings of 1 mol % when used in combination with Ph2SiH2. Although only 4 examples were presented, a variety of structural features were considered including cyclic amides that have often demonstrated reduced reactivity in other studies. All is not perfect, however, and the use of benzene in the preparation of the Fe precatalyst complex is undesirable from a green chemistry perspective (J. Am. Chem. Soc. 2012, 135, 18108−18120).

and 3-methylcyclohex-2-enol in good yield and with excellent ee and de.

By focusing on the functional groups, the design principle of this artificial pathway can be planned on the basis of a retrosynthetic approach in the same way as traditional organic synthesis. Combining reactions in this manner has clear sustainability benefits, and this report illustrates the potential power of this methodology (ChemCatChem 2013, 5, 3524−3528).

Werkmeister et al. have published a concise review of the catalytic hydrogenation of carboxylic amides, esters, and nitriles using homogeneous catalysts. Both C−N and C−O bond cleavage in amide reductions is considered as well as the reduction of esters to alcohols and selectivity in the reduction of nitriles to primary amines. The review highlights that, despite considerable progress in recent years, reaction conditions remain generally harsh, requiring high temperature, pressure, and the use of precious metal catalysts. The authors conclude with a discussion of future challenges in the field (Org. Process Res, Dev. 2014, 18, 289−302).

9. REDUCTIONS The reduction of amides to amines is a keen target for industrial application. A number of catalytic systems using base metals or metalloids have demonstrated this reactivity, but none have been able to do so for primary, secondary, and tertiary amides. Now Li et al. have reported results from screening various acid promoters that has identified boronic acids as effective catalysts for silane-mediated reduction of amides. Over 30 boronic acids were considered with 2-benzothiopheneboronic acid and 5-bromo-2-benzothiopheneboronic acid being most effective. Various silanes were considered with PhSiH3 and, to a lesser extent, Et3SiH being preferred. The order of amide reactivity was demonstrated to be tertiary > secondary > primary, and the reducing reactivity could be addressed through increasing temperature and catalyst loading. The catalyst system displayed good chemoselectivity with other potentially reducible groups (ester, cyano, nitro) unaffected (Angew. Chem., Int. Ed. 2013, 52, 11577−11580).

10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT Zhang et al. relate the development of methodology providing chiral amine products through the coupling of an alcohol and amine via a “borrowing hydrogen” process. Attempts at coupling their model system of 2-octanol with p-anisidine over molecular sieves employing Ru, Rh, and Ir catalysts provided only poor results. Examination of the reaction progression indicated the problem lay with the imine condensation which suggested the inclusion of phosphoric acids. This system was honed to a particular combination of chiral phosphoric acid and Ir catalyst with generally very good results for several substrate combinations and intramolecularly to form (S)-2-methyltetrahydroquinoline. Typical solvents were toluene or t-amyl alcohol (Angew. Chem., Int. Ed. 2014, 53, 1399−1403) (Scheme 2). Chan et al. report the catalytic methylation of aromatic and cyclopropylketones using methanol as the alkylating agent. Consideration of the byproducts formed in a scoping reaction resulted in selection of a rhodium catalyst which favors 1,4reduction of α,β-unsaturated ketones. The reaction proceeds with electron-poor and electron-rich aromatics and can be used to form α-branched products; double methylation of methyl ketones can be achieved, and the reaction also tolerates β-substitution on the alkyl chain. A one-pot sequential Ir catalysed ketone alkylation followed by Rh catalysed methylation was demonstrated, and the product could be converted to the corresponding aryl ester through a Baeyer−Villiger oxidation. Aspects of the method that are currently of concern

Iron species continue to be of interest in reduction processes although these are typically been based around in situ formation of Fe(II) complexes. Blom et al. have prepared 1609




The authors demonstrate recovery and reuse of the catalyst with the benchmark preparation of Pirbedil three times with no loss of activity. Preliminary studies also showed the feasibility of alkylation of methyl ketones in reasonable yields. The catalyst was also used in a column reactor in flow mode for benzylation of piperidine in 71% yield after reaching steady state. The yield was stable for 6 h before declining (ChemCatChem 2014, 6, 808−814).

Scheme 2

are both the use of 5 equiv of cesium carbonate and running the reaction at 65 °C under an oxygen atmosphere (Angew. Chem., Int. Ed. 2014, 53, 761−765).

A procedure for the coupling of in situ generated intermediate aldehydes reacting with thiols in the presence of Pd/MgO catalyst to form a variety of thioethers was investigated by Corma et al. The model reaction of benzyl alcohol with benzenethiol in trifluorotoluene (TFT) gave good conversion of the thiol primarily to the thioether along with a lesser amount of diphenyl disulfide. Lower temperature or radical scavengers led to higher conversion to the disulfides presenting the possibility that the dehydrogenation of benzyl alcohol to benzaldehyde proceeds through radical intermediates. Mechanistic pathways were discussed for the desired reaction postulating possible hemithioacetal/thioacetal intermediates. The scope of the reaction was investigated indicating that alkyl alcohols were inert to the reaction conditions and p-substituted aromatic alcohols (with the exception of methyl substitution) provided good conversion while other ring substitutions were deleterious (Chem.Eur. J. 2013, 19, 17464−17471).

The use of heterogeneous catalysis is desirable because of the ease of product/catalyst separation and the potential for catalyst reuse. The downside is the generally harsh reaction conditions required to achieve good conversion, conditions that may not be compatible with pharmaceutically relevant substrates. Reddy et al. report a nanosized zeolite beta as a heterogeneous catalyst for the N-alkylation of amines with benzyl alcohols via a SN1 reaction. The authors argue that the nanosized catalyst is more reactive because of the greater external surface area, reduced diffusion path lengths, and more exposed active sites. Reactions are run neat with 3 equiv of alcohol at 135 °C for up to 24 h achieving the benzylation of a range of anilines and some heterocyclic amines in moderate to good yields. Primary allylic alcohols are also reactive, as well as 1-hexanol, although the reactivity of higher aliphatic alcohols is significantly reduced. Halogenated benzyl alcohols are less reactive, and nitro-substituted benzyl alcohols afforded imines when reacted with anilines. The catalyst was recovered by filtration, recalcinated, and reused three times for the benzylation of aniline with no loss of yield (Green Chem. 2013, 15, 3474−3483).

Cui et al. use a CuAlOx catalyst for the methylation of primary and secondary amines using a mixture of carbon dioxide (3 MPa) and hydrogen (7 MPa) in hexane at 160−170 °C. The catalyst is prepared by addition of aqueous sodium carbonate into a solution of copper(II) and aluminum nitrates, isolation of the precipitate followed by washing, drying, calcination, and reduction under a hydrogen flow. Yields are generally >80%, and in addition, aromatic nitro compounds and nitriles can be dimethylated following reduction to the corresponding aniline or benzylamine. Mechanistic studies support reduction of a formamide intermediate in accordance with previous publications (Chem. Sci. 2014, 5, 649−655).

Shan et al. use a polymer supported ruthenium catalyst for the alkylation of primary and secondary amines with primary alcohols via the hydrogen borrowing mechanism. Screening found that triphenylphosphine supported by polystyrene through an ether linkage gave best results with a 1:6 Ru−P ratio optimum to minimize ruthenium leeching. Reactions are run in toluene in a sealed tube at 120−140 °C for up to 24−48 h.

An et al. have reviewed progress in the area of catalytic nucleophilic substitution reactions in particular the research of 1610




12. CHEMISTRY IN WATER

the Denton and Lambert groups using phosphorus and cyclopropenone catalysts. The review covers phosphorus-mediated catalytic SN2 reactions, including a redox neutral catalytic Appel reaction and advances in catalytic Mitsunobu reactions where the phosphorus component remains stoichiometric, but the azodicarboxylate partner may be catalytic. Cyclopropenone catalysis complements the catalytic halogenation achieved by the phosphorus approaches and extends the utility to cyclodehydration and a potential alternative Mitsunobu reaction through alcohol inversion with the methansulfonate ion. The authors conclude by discussing the requirements for the ideal catalytic SN2 substitution of a secondary alcohol (Org. Biomol. Chem. 2014, 12, 2993−3003).

Jia et al. report the first silver catalyzed hydrogenation of aldehydes in water. Up to quantitative yields of substituted benzyl alcohols are obtained with the homogeneous silver catalyst prepared in situ from 5 mol % of AgPF6 and 7.5 mol % of XPhos by hydrogenation at 10−40 bar H2 for 24 h at 100 °C. Heteroaryl and aliphatic aldehydes are also hydrogenated in good yield, but ketones are much less reactive (Angew. Chem., Int. Ed. 2013, 52, 11871−11874).

11. FRIEDEL−CRAFTS CHEMISTRY Jeffries and Cook have provided a method whereby unactivated secondary alcohols may be used directly in inter- or intramolecular Friedel−Crafts type alkylations utilizing a simple iron based catalyst. Investigation of the substrate scope showed that reactions followed the traditional electrophilic aromatic substitution trends. Moderate regioselectivity was identified in some cases, consistent with other Friedel−Crafts type reactions. These milder conditions also allowed good retention of chirality through an intramolecular ring closure reaction as opposed to total racemisation under standard Friedel−Crafts conditions. Unfortunately 1,2-dichloroethane was the only solvent studied for the reaction (Org. Lett. 2014, 16, 2026−2029).

A remarkable configurational switch from anti to syn-product in the asymmetric aldol reaction of ketones with substituted benzaldehydes has been observed by Gou and co-workers. When a simple, chiral N,N-dialkyl-1,2-diaminocyclohexane (10 mol %) is used as chiral organocatalyst, combined with TFA as auxiliary acid, the anti-selectivity in organic solvents (e.g., EtOH) changed to syn-selectivity in water. In particular, high syn-selectivity and improved yields were observed when the PTC catalyst TBAB (10 mol %) was added (Tetrahedron Lett. 2013, 54, 6358−6362).

Barbero et al. report the use of o-benzenedisulfonimide to catalyze Friedel−Crafts alkylations of activated arenes and heteroarenes with alcohols. Results of the study are explained on the basis of Professor Herbert Mayr’s nucleo- and electrophilicity scales. Reactions were performed neat with an excess of arene vs alcohol and 10 mol % of the catalyst. Most were performed at or near ambient temperature and required fairly brief reaction times to produce moderate-to-good product yields sometimes accompanied by dehydrative cross coupling of the alcohol. A wide range of substrates were tested and mechanistic considerations detailed (Tetrahedron 2014, 70, 1818−1826).

In addition, two reviews appeared on the (asymmetric) aldol reaction in aqueous media. The use of water-compatible Lewis acids, originally based on lanthanide triflates, in the Mukaiyama aldol reaction has been surveyed by Kitanosono and Kobayashi (Adv. Synth. Catal. 2013, 355, 3095−3118), while an update of the asymmetric aldol reaction in water over the last 5 years was published by Mlynarski and Baś (Chem. Soc. Rev. 2014, 43, 577−587). The use of heteropoly acids (HPAs) and polyoxometalates (POMs) as environmentally friendly solid acids in various acid-catalyzed organic reactions in water has been reviewed by Heravi et al. As an example, in the condensation reaction of anthranilamides with aldehydes to the corresponding 2,3dihydro-4(1H)-quinazolines the HPA H3PW12O30 (0.1 mol %) proved to be much more reactive in water than in organic solvents. Application of HPAs and POMs in various other condensation reactions, carbonylation reactions, hydrolysis and hydration reactions, oxidation reactions, and multicomponent reactions are presented (Green Chem. Lett. Rev. 2013, 6, 282−300). Khusnutidinova et al. describe the formation of lactams via dehydrogenation of cyclic amines in water with H2 liberation. 1611




water/organic compound interface. To test this hypothesis, Sela and Vigalok compared “on water” vs “on liquids” reactivity of three organic reactions: the Passerini reaction, epoxide ring opening with secondary amines, and the ene-reaction between isopropyl azodicarboxylate and β-pinene. As a measure, the yields of the reactions “on water” were compared with those under neat conditions, “on perfluorooctane”, “on perfluorohexane”, and even “on mercury” conditions. In general similar or even somewhat better yields were observed for the “on liquids” reactions than for the reaction “on water”. Similar yields were observed under neat reaction conditions. Based on this, the authors conclude that the observed behaviour is consistent with high concentrations of the reactants and not a result of a defined water surface. For one of the epoxide ring opening reactions the higher yield of the “on water” reaction was assumed to result from a specific stoichiometric interaction between the organic reactant(s) and water: In this case the addition of 1−3 equiv of water to the neat or “on perfluorooctane” reaction increased the yields substantially vs the level of the “on water” reaction (Org. Lett. 2014, 16, 1964−1967).

This reaction is catalyzed by the pincer Ru complex 2 and a catalytic amount of base, with water as the oxidant. The reactions are performed at 0.3 M concentration in water− dioxane mixtures in a pressure tube at 150 °C, using 1−5 mol % of Ru-catalyst and optionally 1.5−6 mol % of NaOH as a base. Depending on the amount of catalyst, yields are moderate to good. The cosolvent dioxane can be replaced by toluene or lutidine. A key role in this reaction is most likely played by the (stabilized) intermediate cyclic hemiaminal, formed by oxidation of the amine followed by hydration of the imine. Further dehydrogenation of the hemiaminal results in the formation of the lactam. For noncyclic and primary amines, deamination of the unstable hemiaminal resulted mainly in intermediate aldehyde formation, which is then either reduced back to the primary alcohol or further dehydrogenated to the corresponding carboxylic acid, even if the reaction is performed under NH3 (J. Am. Chem. Soc. 2014, 136, 2998−3001).

13. CONTINUOUS PROCESSING AND PROCESS INTENSIFICATION Hernandez-Perez and Collins reported a novel continuous photoredox synthesis of carbazoles through C−C bond formation in the presence of various oxidants using in situ formed Cu based [Cu(Xantphos)(dmp)]BF4 and Ru based {[Ru(bpy)3](PF6)2} sensitizers. Reactions under similar batch conditions in the presence of visible light gave a very slow formation of product, but changing to continuous processing significantly increased the exposure of the reaction mixture to ambient light, greatly enhancing the reaction rates (Angew. Chem., Int. Ed. 2013, 52, 12696−12700).

A related dehydrogenative oxidation occurs in the dirhodium(II)-catalyzed coupling reaction of arylboronic acids to aryl aldehydes in water as described by Kuang and Wang. The initially formed diaryl carbinol is further oxidized by water to the corresponding benzophenone. From previous work in organic solvents, i.e., using acetone as oxidant, this conversion is known to be of highly practical use. On the other hand, when catalyzed by dirhodium complexes of Rh2(OAc) 4 and phosphine or NHC ligands in organic solvents (DME/water 5:1 or toluene/water 5:1), this reaction results in formation of the carbinol. However, by replacing the organic solvent with pure water, in situ dehydrogenative oxidation of the carbinol to the ketone occurs without need of an additional oxidant (Eur. J. Org. Chem. 2014, 1163−1166).

Sedelmeier et al. reported the conversion of 3-halo-N-acyl anilines to corresponding benzoxazoles using a two-stage sequential flow process to avoid decomposition of unstable intermediates while maintaining good temperature control. In the first stage, ortho-lithiation followed by intramolecular cyclization is used to generate the unstable lithiated benzoxazole intermediate followed by sequential quenching by different electrophiles as required in the second stage (Org. Lett. 2013, 15, 5546−5549).

Mascia et al. reported the first example of an end-to-end integrated manufacturing plant for a pharmaceutical product involving API, aliskiren hemifumarate. The model plant combined chemical reactions, separations, crystallization, drying, and formulation to generate the final tablet, and had the flexibility to vary production volumes as required while quality was monitored and controlled by automated system (Angew. Chem., Int. Ed. 2013, 52, 12359−12363).

The rate acceleration of organic reactions under “on water” conditions is typically explained by hydrogen bonding at the 1612




Rakeshwar Bandichhor Dr. Reddy’s Laboratories Ltd., Innovation Plaza, IPDO, Bachupally, Hyderabad, A.P., India 500072

Apurba Bhattacharya Dr. Reddy’s Laboratories Ltd., Innovation Plaza, IPDO, Bachupally, Hyderabad, A.P., India 500072

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

Synthesis of cyclic carbonates from epoxides and CO2 in the presence of bromine as catalyst under continuous processing conditions was reported by Kozak et al. The addition of catalytic benzoylperoxide was found to significantly enhance the reaction rate (J. Am. Chem. Soc. 2013, 135, 18497−18501).

Peter Dunn Pfizer Global Research and Development, Ramsgate Road, Sandwich CT13 9NJ, U.K.

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

Fabrice Gallou NovartisPharma AG, Forum 1, Novartis Campus, 4056 Basel, Switzerland

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

14. GENERAL GREEN CHEMISTRY There is an interesting editorial which celebrates the first 15 years of the Green Chemistry journal with contributions from all of the editors and scientific editors of the journal: James Clark, Roger Sheldon, Colin Raston, Martyn Poliakoff, and Walter Leitner. The article charts the history of the journal with some of the early editors recalling how difficult it was to persuade academics to publish in a “fledgling” journal. Fast forward 15 years to a journal with a high impact factor and large article rejection rate: in many ways the development of the journal parallels the development of green chemistry as a research area (Green Chem. 2014, 16, 18−23). Dunn from Pfizer has published a survey of the time taken for regulatory review and approval for Pfizer Green Chemistry “second generation” process improvements. The article shows that major environmental benefits have been achieved through the implementation of several second generation processes, but that these benefits have been partially negated by the variable time taken for global regulatory review and approval. The survey covers FDA, EU, and ROW. For the FDA the median approval time for 8 second generation Green Chemistry processes was 136 days; however, in some markets review times of three years or more are known and often expected (Green Chem. 2013, 15, 3099−3104). Federsel from AstraZeneca has published a perspective covering the progress of Green Chemistry in the pharmaceutical industry over the past 20 years (Green Chem. 2013, 15, 3099−3104). De Soete et al. from the University of Ghent have published a paper based on a collaboration with Janssen Pharmaceutica using their Exergy Analysis and Exergy Life Cycle Analysis to compare a batch vs continuous wet granulation process for the pain medication Tramacet. Continuous technology was shown to have a lower environmental impact than the batch process for this particular product (Green Chem. 2013, 15, 3039−3048). Leseurre et al. from Chimex published a new visualization tool called Eco-footprint that is based on 10 indicators which get scored between 1 and 4 and are explained in depth in the article. The visual representation of the different indicators makes it possible to compare processes at a glance, and this is shown in the assessment of two industrial products (Green Chem. 2014, 16, 1139−1148).

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

Bill Hinkley GlaxoSmithKline, Research Triangle Park, North Carolina 27709, United States

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

Bernard Kaptein DSM Innovative Synthesis BV, P.O. Box 18, 6160 MD Geleen, The Netherlands

Suju Mathew Pfizer Global Research and Development, Ramsgate Road, Sandwich CT13 9NJ, U. K.

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

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].

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