Green Chemistry Articles of Interest to the Pharmaceutical Industry

Green Chemistry Highlights Cite This: Org. Process Res. Dev. 2018, 22, 1699−1711

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Green Chemistry Articles of Interest to the Pharmaceutical Industry

Org. Process Res. Dev. 2018.22:1699-1711. Downloaded from pubs.acs.org by OPEN UNIV OF HONG KONG on 01/23/19. For personal use only.

1. INTRODUCTION

3. AMIDE FORMATION The use of both precious transition metals and Brønsted acids to mediate the intramolecular hydrofunctionalization of unactivated alkenes is well-established, though the utility and generality of many methods is somewhat diminished by a range of drawbacks such as high catalyst loadings and the use of numerous additives (e.g., silver salts, bases), often in excess. Ferrand et al. carried out a systematic investigation into the use of niobium salts, which possess minimal toxicity and are cheap and readily available, to catalyze these processes. A range of Nb(III) and Nb(V) catalysts were initially studied in a model hydroalkoxylation reaction, and the cationic system NbCl5/ AgNTf2 (1:2) was shown to be the best, though one environmental drawback reported was the use of DCE as the optimal solvent. The reaction was extended to the formation of a range of cyclic structures [including tetrahydrofurans and pyrrolidines (provided that sulfonamide protection was used on the nitrogen atom)]. Competition studies indicated that in general hydroalkoxylation was the preferred pathway in molecules featuring both an alcohol and a protected amine. Extending the reaction to unsaturated carboxylic acids was also successful, though poor regioselectivities were observed in the case of nonterminal olefins. However, for the analogous unsaturated amides, no such issues arose, and the desired fivemembered-ring lactams formed smoothly in good to excellent yields. A mechanism involving direct interaction between the metallic species and the substrate is proposed on the basis of experiments utilizing a noncoordinative proton scavenger (Org. Lett. 2017, 19, 2062−2065).

The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable (PR) was developed in 2005 to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The Roundtable currently has 26 member companies, compared with three in 2005. The membership scope has also broadened to include contract research/manufacturing organizations, generic pharmaceuticals, and related companies. Members currently include AbbVie, ACS GCI, Amgen, AstraZeneca, Asymchem, Inc., Biogen, Boehringer-Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Codexis, Eli Lilly and Company, F-Hoffmann-La Roche Ltd., Gilead, GlaxoSmithKline, Hikal, Ipsen, Johnson & Johnson, Merck & Co., Inc., Neurocrine, Novartis, Novo Nordisk, Pharmaron, Pfizer, Inc., Sanofi, Takeda, and WuXi AppTec, Co., Ltd. One of the strategic priorities of the Roundtable is to inform and influence the research agenda. Two of the first steps to achieve this objective were to publish a paper outlining key green chemistry research areas from a pharmaceutical perspective (Green Chem. 2007, 9, 411−420) and to establish annual ACS GCI PR 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 April 2017 to September 2017. These articles of interest represent the opinions of the authors and do not necessarily represent the views of the member companies. Some articles are included because, while not currently 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.

There are several reports detailing the direct oxidative amidation of toluene (or related methyl arenes), though these often suffer from drawbacks such as the use of harsh reaction conditions, unstable amine derivatives, or undesirable oxidants. Yang et al. described a method that overcomes many of these issues utilizing Cu(OAc)2 as a catalyst with aqueous tert-butyl hydroperoxide (TBHP) to mediate the reaction between an in situ-generated N-chloroamine and the methyl arene. Model studies also indicated that acetonitrile was the best solvent, and 20 mol % tetrabutylammonium iodide (TBAI) was shown to be a beneficial additive. From a scope perspective, a range of functional groups were tolerated on the (hetero)aromatic methyl arene, though interestingly, in cases featuring two methyl groups only monoamidation was observed. A range of primary and secondary amines were effective substrates, and the methodology was extended to the synthesis of the antidepressant mocleobemide. Initial mechanistic studies indicated that the reaction proceeds through a radical pathway (RSC Adv. 2017, 7, 22797−22801).

2. SOLVENTS Byrne et al. reported the synthesis and properties of a nonpolar, non-peroxide-forming ether solvent, 2,2,5,5-tetramethyltetrahydrofuran (TMTHF), as a replacement for hydrocarbon solvents. The criteria used by the authors to investigate TMTHF as a solvent included limited peroxide formation, low mutagenicity, and low boiling point. Synthesis by continuous catalytic dehydration of 2,5-dimethylhexane-2,5-diol gave high yield and purity of the solvent. The solvent tested negative in the Ames mutagenicity test and was demonstrated to be effective in Fischer esterification, amidation, Grignard, and radical-initiated vinyl polymerization reactions. It is stable toward concentrated acids, both organic and mineral acids, is water-immiscible, and can be used for extractive workups. With a boiling point of 112 °C, the potential for recycling exists (Green Chem. 2017, 19, 3671−3678). © 2018 American Chemical Society

Published: December 7, 2018 1699

DOI: 10.1021/acs.oprd.8b00363 Org. Process Res. Dev. 2018, 22, 1699−1711

Organic Process Research & Development

Green Chemistry Highlights

Despite the numerous methods that exist for the synthesis of primary amides through the hydration of nitriles, challenges remain because of the use of strong acids/bases, high temperatures, and extended reaction times. Deng and Wang reported a mild method for this reaction that utilizes the oxidation of gallic acid in air to produce hydrogen peroxide, thus enabling the hydration to take place. Model studies on benzonitrile indicated that 2 equiv of gallic acid with a catalytic amount of an inorganic base (KOH was shown to be the most efficient) in aqueous ethanol at room temperature were the optimal conditions, with no reaction taking place when oxygen was rigorously excluded. From a scope perspective, aromatic, heteroaromatic, and aliphatic nitriles were all shown to be suitable, and the reaction was demonstrated on a gram scale for the synthesis of a precursor to a cathepsin K inhibitor. Mechanistically, two pathways were proposed in which H2O2 was produced either through a thermal (major) or photochemical (minor) route, and the reaction was also efficiently mediated using dry Galla chinensis extract from a local Chinese market, indicating that the other components of the extract had no effect on the process (ChemCatChem 2017, 9, 1349−1353).

The formation of secondary and tertiary amides through Pdcatalyzed carbonylation of aryl halides using primary and secondary amines, respectively, is well-established, though often it requires relatively forcing conditions that employ excess base, ligands, and organic solvents. Mane and Bhanage reported a novel Pd-mediated carbonylative synthesis of amides employing tertiary amines in which the required Ndealkylation proceeds in the absence of an oxidant. Model studies on the reaction of iodobenzene with Bu3N indicated that PdCl2 with no ligand was the best catalyst at 80 °C using a solvent system of PEG-400 [though other lengths of poly(ethylene glycol) were equally well tolerated] containing several drops of water. Replacement of the PEG with an ionic liquid interestingly led to the formation of the corresponding benzoic acid, while the use of a standard organic solvent provided only traces of the desired product. It was hypothesized that under the optimal reaction conditions the highly active catalyst is Pd nanoparticles formed in situ, and this was confirmed by a range of spectroscopic techniques as well as the use of presynthesized Pd nanoparticles in the reaction. The reaction performed well with a range of aryl iodides, though disappointingly, heterocyclic substrates failed to react, as did the corresponding bromides and chlorides. Symmetrical aliphatic tertiary amines were effective (though it should be noted that triphenylamine did not react under the optimal conditions), whereas the unsymmetrical derivatives furnished a mixture of products. However, alicyclic and heteroalicyclic tertiary amines all furnished a single product in high yield. Recycling of the catalyst system was also demonstrated, with five cycles being achieved without any deterioration in performance and only minimal leaching of the Pd. Mechanistic studies indicated the intermediacy of a Pd− iminium species that is hydrolyzed in situ to the secondary amine, thus explaining the beneficial effect of the water (Adv. Synth. Catal. 2017, 359, 2621−2629).

Often biological processes are used to inspire new modes of reactivity in organic chemistry, as demonstrated by the development of N-heterocyclic carbenes (NHCs) for reversing the reactivity (umpolung) of carbonyl groups. Although examples of the use of this approach are rare in systems other than aldehydes, Wang et al. reported an NHC-catalyzed synthesis of amides through reversal of the reactivity of unactivated imines under mild conditions. Model studies on this aerobic oxidative amidation not only enabled the optimal catalyst, base, and solvent to be determined but also demonstrated that the Lewis acid LiCl plays a critical role in the transformation. With the optimal conditions in hand, the scope was evaluated, and aldimines bearing aromatic, heteroaromatic, and enal moieties all were well-tolerated. A gram-scale reaction was also performed, and a one-pot method involving in situ formation of the aldimine further enhanced the utility of this methodology. Mechanistic studies demonstrated both the intermediacy of the Breslow intermediate, which could be isolated and fully characterized, and the fact that the oxygen of the product amides derived from air as opposed to the base or solvent. The key additive LiCl is hypothesized to activate the aldimine in the formation of the imine-derived Breslow intermediate (Org. Lett. 2017, 19, 3362−3365).

4. OXIDATIONS The oxidative cleavage of 1,2-diols to produce aldehydes or ketones is a very useful reaction in organic synthesis and recently in biomass valorization of renewable feedstock production. However, the existing methods that are highly selective require either highly toxic reagents or precious metal catalysts. Escande et al. developed the sodium−manganese oxide-catalyzed aerobic oxidative cleavage of 1,2-diols in 1butanol. The manganese layered mixed oxide (Mn LMO) catalyst is readily prepared from inexpensive reagents. Because 1700




of its heterogeneous nature, it can be easily recycled by simple filtration, and it maintains activity after at least six cycles. At least one aryl group is required as an activating group. The reaction is highly selective and gives a variety of aryl aldehydes and ketones in high yields. It should be noted that engineering controls will be required to safely run this reaction on scale, as it is heated above the flash point of butanol under oxygen (Angew. Chem., Int. Ed. 2017, 56, 9561−9565).

moderate 59% ee. One such reaction was scaled up to 1 mmol successfully (Org. Lett. 2017, 19, 2122−2125).

Liu et al. developed a general Wacker oxidation using an iron catalyst and air as the sole oxidant along with polymethylhydrosiloxane (PMHS) as the reductant. The new method has several advantages over the traditional Pd/Cu-catalyzed Wacker oxidation, such as no toxic oxidants, mild conditions, and the ability to oxidize internal olefins and styrenes. A number of terminal and internal olefins were oxidized to ketones in high yields. Very importantly, the mild conditions enabled exceptional tolerance of functional groups such as B(OH)2, SiMe3, OH, CHO, COOH, OAc, CO2R, NO2, PO(OEt)2, and halides, thus allowing for late-stage functionalization of many natural products. It should be noted that engineering controls will be required to safely run this reaction on scale, as it is heated in air above the flash point of ethanol (Angew. Chem., Int. Ed. 2017, 56, 12712−12717).

5. ASYMMETRIC HYDROGENATION Biosca et al. developed a catalyst system that hydrogenates minimally functionalized olefins as well as cyclic β-enamides in high conversion with useful levels of enantioselectivity. The catalyst is iridium(I)-based and uses phosphite-oxazoline ligands that are air-stable solids and can be made in two steps from substituted β-amino alcohols. While dichloromethane was used for most of the reported results, the authors quoted examples where it could be substituted with the more environmentally benign propylene carbonate with no effect on the reaction conversion or selectivity (Adv. Synth. Catal. 2017, 359, 2801−2814).

Aerobic radical chain autoxidation of toluene is the most important manufacturing process for benzaldehyde fragments in various industries. However, stopping the oxidation at benzaldehyde has been a great challenge because of the higher reactivity of benzaldehyde compared with toluene. Gaster et al. were able to solve the long-standing challenge and achieve high selectivity (up to 99/1 aldehyde/acid) with catalytic cobalt(II) acetate and N-hydroxyphthalimide (NHPI) in 1,1,1,3,3,3hexafluoropropan-2-ol (HFIP). The reaction gives high yields and tolerates a large number of functional groups such as a second methyl group, OMe, ester, ketone, acid, halogens, acetate, acetamide, etc. (Angew. Chem., Int. Ed. 2017, 56, 5912−5915).

6. C−H ACTIVATION A visible-light-promoted, metal-free, imidate-directed β-C−H amination was recently disclosed. The reaction sequence results in the net formation of 1,2-amino alcohols from alcohols. First, the alcohol is transformed into an imidate. In the second step, the imidate is converted to an sp2 N-centered radical, which undergoes 1,5-hydrogen atom transfer to form an oxazoline intermediate, and the oxazoline can be hydrolyzed in situ to form the 1,2-amino alcohol. Aside from 1,2-amino alcohols, the oxazoline intermediates can be isolated and converted to oxazoles, carbamates, and other amine-containing products. A variety of compounds containing benzylic and allylic C−H bonds were aminated in good to excellent yields (65−97% isolated yield after oxazoline hydrolysis) and diastereoselectivities (>20:1 dr) using a trichloroacetimidate intermediate. Aliphatic C−H bonds can also be aminated, but a benzimidate intermediate must be used. These more challenging substrates form the desired products in moderate to good yields for amination of secondary C−H bonds (45−

Fu et al. developed a catalytic asymmetric electrochemical oxidative coupling of tertiary amines and ketones. In such cross-dehydrogenative coupling (CDC) of two C−H components, most use a stoichiometric oxidant such as DDQ, TBHP, or IBX. In this work, the chemical oxidant was replaced with electrochemical oxidation, and in combination with a chiral primary amine catalyst to activate the ketone, this provided the CDC products in good yields and enantioselectivities. Cyclohexanone, cyclopentanone, and cycloheptanone were all good substrates, while acyclic benzylideneacetone gave a 1701




subsequent structure−activity relationship studies, and they reported several examples of halogens that were well-tolerated. Finally, to exemplify the utility of the continuous equipment, the reaction was run for 3.5 h to generate 545 mg of one of the more difficult substrates (Synthesis 2017, 49, 4978−4985).

85%), and the products formed after oxazoline hydrolysis are N-benzoylated amino alcohols. A tertiary C−H bond was completely racemized after undergoing amination, which suggests the presence of a radical or cationic intermediate. It should be noted that while the authors used chloroform for the aqueous workup, a greener solvent should be used for largerscale applications (J. Am. Chem. Soc. 2017, 139, 10204−10207).

The development of an asymmetric C−H alkylation of indoles was reported. Utilization of a p-methoxyaniline directing group masked the aldehyde until the C−H activation was complete. During optimization ligand substitution was investigated, and the importance of meta substitution with a 1adamantyl group to provide the best enantioselectivity and lowest ligand loading (10 mol %) was demonstrated. N,N,N′,N′-Tetramethylethylenediamine (TMEDA) and CyMgCl were both important to achieve optimal reactions, and [Fe(acac)3] was also charged at 10 mol %. Variation of the R′ and Ar groups was well-tolerated, as was substitution on the indole, with typical yields of 80−98% and >90:10 e.r. Finally, pyrrolopyridine also underwent effective alkylation, but the stereoselectivity was significantly reduced (Angew. Chem., Int. Ed. 2017, 56, 14197−14201).

A ruthenium-catalyzed C−H hydroxylation of nitrogencontaining molecules was recently developed. The reaction is run in aqueous acid using catalytic cis-[Ru(dtbpy)2Cl2] and works with a variety of oxidants and acid additives. A screen of these demonstrated periodic acid and triflic acid to be the optimal oxidant and acid additive, respectively. The catalyst can also be generated in situ from the metal and ligand, which can allow for further ligand screening for specific substrates, albeit with lower yields. The reaction is chemoselective for benzylic and tertiary sp3 C−H bonds and provides the products in moderate to high yields (29−88%) with good selectivity over secondary C−H bonds. In most cases the reaction mass balance is predominantly starting material, which can be recovered. The reaction is tolerant of common nitrogen-containing functionalities such as pyridines, piperidines, and piperazines, and even unprotected amino acid derivatives undergo chemoselective C−H oxidation since the acid additive blocks the amine from N-oxide formation. The reaction also works on substrates that do not contain nitrogen functionality, and for these reactions the triflic acid additive is not necessary. Notably, the hydroxylation reaction of optically pure tertiary C−H bonds proceeds with stereoretention (J. Am. Chem. Soc. 2017, 139, 9503−9506).

Finally, a review highlighting the research within the NSF CCI Center for Selective C−H Functionalization and tracking the collaborative progress toward catalytic C−H activations has been published (ACS Cent. Sci. 2017, 3, 936−943).

7. GREENER FLUORINATION The development of electrophilic trifluoromethylation reagents has allowed access to a number of trifluoromethylated compounds because of the abundance of nucleophilic substrates. Various electrophilic trifluoromethylation reagents have been developed, among which the most commonly utilized are Umemoto’s reagent and Togni’s reagent. While Togni’s reagent is reported to have an explosive nature, the original Umemoto’s reagent suffers from both multistep preparation and generation of a dibenzothiophene byproduct after trifluoromethylation reactions. Umemoto et al. reported the first practical one-pot preparation of fluorine-substituted Umemoto’s reagents from fluorobiphenyl starting materials and recycling of the formed fluorodibenzothiophenes by desulfurization to give the same fluorobiphenyl compounds after trifluoromethylation. These reagents demonstrate more powerful trifluoromethylating capabilities and higher thermal stability compared with the original Umemoto’s reagent. The ease of preparing the new reagent is due to the abnormal para activation of the fluorine substituent toward aromatic electrophilic C−S bond formation. The authors demonstrated the high efficiency of these reagents by trifluoromethylating a

A visible-light protocol for trifluoromethylation of arenes, heteroarenes, and benzo-fused heterocycles in continuous flow was recently reported. The optimal conditions were developed by first investigating luminescence quenching studies to determine the optimal photocatalyst for this transformation, [Ir{dF(CF3)ppy}2(dtbpy)]PF6. Caffeine was investigated to optimize the reaction conditions for reagent equivalents, time, and temperature in an off-the-shelf continuous photoreactor. Conversion to generate the desired product typically ranged from 28% to a high of 80% for pyrimidin-4(3H)-one. In most cases where more than one reactive site was present, mixtures of isomers were observed, however these isomers were readily separable. The authors were especially interested in trifluoromethylation of compounds containing halogens to allow 1702




8. BIOCATALYSIS Direct activation of alcohols to generate amines under mild conditions has been identified as an area of interest for synthetic chemists. An alcohol dehydrogenase (ADH) and reductive aminase from Aspergillus oryzae (AspRedAm) was reported by Montgomery et al. to catalyze the alkylation of amines with alcohols in a neutral cascade. This approach enabled the preparation of a variety of secondary amines through biocatalytic hydrogen borrowing. The use of chiral secondary alcohols permitted access to optically active amines in up to 84% conversion with ee up to >97%. This process was performed on a 100 mg scale to prepare N-allylcyclohexylamine in 61% isolated yield. The potential of reductive aminases is a new field of research for the preparation of enantiopure amines, and this example shows the advantages that the use of enzymes in a cascade or tandem fashion can bring (Angew. Chem., Int. Ed. 2017, 56, 10491−10494).

variety of nucleophiles, including aniline, keto esters, 1,3diketones, 3-methylindole, arenethiol, arylsulfinate, and diarylphosphine, and performing metal-catalyzed/mediated trifluoromethylations with styrene, acetylene, aryl halides, and a benzyl bromide (J. Org. Chem. 2017, 82, 7708−7719).

Fluoroform (HCF3) is a nontoxic but potent greenhouse gas that is produced as a byproduct of polytetrafluoroethylene manufacturing (over 0.5 million metric tons yearly) and incinerated. Geri and Szymczak reported the use of fluoroform as a CF3 feedstock to prepare nucleophilic trifluoromethylation reagents in the form of Lewis acid (LA)−CF3 adducts. Because of the instability of CF3− upon deprotonation of HCF3, an elegantly designed system of hexamethylborazine (as the LA) and base allowed the immediate formation of the stable hexamethylborazine−CF3 adduct upon introduction of HCF3 into the system. The hexamethylborazine−CF3 adduct was used as a nucleophilic trifluoromethylation reagent to easily react with benzophenone and also to make other CF3 transfer reagents including SiMe3CF3, KSO2CF3, and Togni I reagent. Following the CF3 transfer, the borazine can be recycled (J. Am. Chem. Soc. 2017, 139, 9811−9814).

Arnold and co-workers reported the directed evolution of a cytochrome P450 monooxygenase, P411CHA, for the enantioselective intermolecular amination of benzylic C−H bonds. Substrate scope investigations showed that whole cells overexpressing P411CHA achieve benzylic amination of a series of aromatic hydrocarbons with excellent enantioselectivity (>90% ee), making the enzymatic approach superior to previously reported metal-catalyzed examples. The amination reaction is typically performed at 2.5−5 mM concentration using TsN3 and anaerobic conditions. Amination of 4ethylanisole was achieved on a preparative scale (0.25 mmol) in 78% isolated yield (59.5 mg, turnover number = 610, >99% ee). Crystallography studies revealed that mutations introduced on the path to P411CHA can modulate the interactions with the azide and substrate in the active site. The ability to accelerate C−H insertion through mutagenesis opens the door to evolving P450s for reactions that are currently challenging for chemocatalysis (Nat. Chem. 2017, 9, 629−634).

Fluoroalkylthio groups can serve to increase the lipophilicity of compounds and have attracted great interest in medicinal chemistry. The direct incorporation of these groups is possible by developing an appropriate fluoroalkylthiolating reagent. Zhao et al. reported the preparation of an electrophilic monofluoromethylthiolating reagent, S-fluoromethyl benzenesulfonothioate (PhSO 2 SCH2 F), and its reactions with arylboronic acids and alkyl alkenes. The reagent is easily prepared from PhSO2SNa with CH2FI or CH2FCl via direct displacement and is shelf-stable. By application of this reagent, a variety of aryl monofluoromethyl thioethers were prepared via cross-coupling with arylboronic acids under very mild conditions (5 mol % CuSO4, 1.5 equiv of NaHCO3, methanol, room temperature). This reagent was also applied to prepare alkyl monofluoromethyl thioethers by reaction with alkyl alkenes under very mild conditions (10 mol % AgNO3, 1 equiv K2S2O8, N-methyl-2-pyrrolidone/water, 25 °C) (Angew. Chem., Int. Ed. 2017, 56, 11575−11578).

Roiban et al. reported the preparation of multigram quantities of (R)-2-butyl-2-ethyloxirane by kinetic resolution of the racemic epoxide using epoxide hydrolase from Agromyces mediolanus (EH 5) at a reaction concentration of 338 g/L. Process optimization studies identified potassium phosphate buffer (pH 7.4) at 30 °C using EH 5 lyophilized clarified lysate powder (9.5% w/w) to be the best conditions. Organic extraction and distillation afforded the diol in 20% yield with 99% ee. Additional experiments showed that the N240D EH 5 mutant gave a slight improvement in enantioselectivity and enzyme loading (E = 23 and 5−8% w/w, respectively) compared with wild-type EH 5 (E = 20 and 9.5% w/w, respectively). The authors also reported enantioselective resolution through hydrolysis of the R-configured epoxide with halohydrin dehalogenases. Interestingly, running the reaction using the epoxide hydrolase from Aspergillus niger to 1703




92% conversion yielded the S-configured diol via an enantioconvergent process, opening the (S)-epoxide at C1 with retention of chirality and the (R)-epoxide at C2 with inversion (Org. Process Res. Dev. 2017, 21, 1302−1310).

Wu et al. reported a biocatalytic anti-Markovnikov hydroamination and hydration providing access to terminal alcohols or amines. In both cases, a number of enzymes were simultaneously expressed in Escherichia coli cells and used without further purification of the biocatalyst. Both reactions proceed via styrene monooxygenase (SMO)-catalyzed epoxide formation followed by highly stereoselective isomerization to give the terminal aldehyde catalyzed by styrene oxide isomerase (SOI). The terminal aldehyde reacts further to give the amine [using NH3/NH4Cl and a transaminase (TA)] or alcohol [using an ADH or aldehyde reductase (AR)]. In the transaminase reaction, alanine dehydrogenase (AlaDH) was coexpressed to regenerate the alanine cosubstrate. Excellent conversion and regioselectivity were obtained for both hydroamination (45−99% conversion and >99:1 regioselectivity) and hydration (60−99% conversion and >99:1 regioselectivity) on 12 aryl alkenes examined. The biocatalytic reactions described provide an interesting option for the synthesis of terminal alcohols and amines under benign reaction conditions using cheap and nontoxic reagents (O2, NH3/NH4Cl, and glucose) and cells (biodegradable) (ACS Catal. 2017, 7, 5225−5233).

Another advance in the application of earth-abundant base metals in catalysis was demonstrated by Di Gregorio et al., who reported a “borrowing hydrogen” process in the synthesis of 3benzylated indoles through coupling of benzyl alcohols and indoles using an iron(II) phthalocyanine catalyst. A range of differentially substituted benzyl alcohols containing electrondonating and electron-withdrawing groups were coupled efficiently at C3 of the indole using Cs2CO3 (1.1 equiv) at elevated temperature (140 °C) without the need for prior alcohol activation. The Fe(II)Pc catalyst used in the transformation is not only inexpensive and commercially available but also air- and moisture-stable, enabling easy reaction setup. The utility of this transformation was further emphasized through a gram-scale reaction in which the reaction efficiency accomplished on a small scale was retained (J. Org. Chem. 2017, 82, 8769−8775).

A borrowing hydrogen process to enable a three-component coupling of two alcohols and a ketone was reported by Chakrabarti et al. Using a non-phosphine-based air- and moisture-stable ruthenium catalyst, the authors were able to construct α-methyl ketones using methanol as an alkylating agent. These products can be synthesized efficiently from methanol, benzyl alcohols, and acetophenones using a 1 mol % loading of the Ru catalyst and KOtBu at 110 °C. A range of differentially substituted benzyl alcohols and aryl methyl ketones were tolerated, as were aliphatic alcohols with slightly diminished efficiency. This approach improves upon current precedent by using lower catalyst loadings and avoiding the need for expensive phosphine-based ligands. This was further exemplified in the case of ketone α-methylation with methanol, where similar efficiency was achieved at a catalyst loading of 0.1 mol % when the reaction temperature was increased (Org. Lett. 2017, 19, 4750−4753).

9. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT Dehydrogenative coupling of alcohols and aryl diamines to form benzimidazoles is generally accomplished using ruthenium- or iridium-based catalyst systems in the presence of stoichiometric base. Daw et al. reported the synthesis of 2substituted benzimidazoles using cobalt pincer complexes under base-free conditions. In the presence of 5 mol % Co catalyst, 5 mol % NaBEt3H, 4 Å MS, and toluene at 150 °C, primary alcohols and 1,2-diaminobenzene can be coupled in yields of >70% for most substrates tested. Both aliphatic and aromatic primary alcohols can be employed, forming the corresponding 2-substituted benzimidazoles with H2 and H2O as the only byproducts. The reaction works in the absence of a hydride source, albeit in slightly lower yield, indicating that the Co(I) active species can be accessed by the alcohol and diamine alone (ACS Catal. 2017, 7, 7456−7460). 1704




which spontaneously formed in the reaction. Further studies of this enzyme class could expand the substrate scope beyond resorcinol derivatives, offering a mild and selective alternative to currently used chemical reactions (Angew. Chem., Int. Ed. 2017, 56, 7615−7619).

Wong et al. described C−N bond formation across a range of alcohol and amine substrates using an Ir(III) catalyst. The optimal reaction conditions utilized pentamethylcyclopentadienyliridium(III) complexes of bidentate carbene−triazole ligands as excellent homogeneous catalysts for the hydrogenborrowing-mediated coupling of aliphatic and benzylic alcohols. Reactions were performed at a low catalyst loading of 0.5 mol % and reached completion in 1−6 h at 100 °C with moderate to good yields (59−80%). These conditions are selective for primary alcohols over secondary alcohols, which did not react. A heterogeneous Ir(III) catalyst containing the bidentate carbene−triazole ligand was developed to exploit direct covalent attachment of the complex to a carbon surface. Despite not reaching complete conversion after 24 h, the catalyst performed well with high turnover numbers. Further studies showed that it was possible to recycle the catalyst three times in the reaction with only a slight decrease in conversion after the third cycle. This transformation represents the first report of a covalently linked heterogeneous iridium catalyst on carbon used for hydrogen borrowing (Green Chem. 2017, 19, 3142−3151).

Schmidt and Kroutil further reported the use of different acyl donors and the effect of added base with IPEA as the donor in the reaction using the ATase from Pseudomonas protegens (PpATaseCH). Ethyl acetate, isopropyl acetate, and acetanilide did not react, while acetic anhydride gave a low yield (5%) only in the presence of imidazole. Phenyl acetates, however, were very effective, with >99% product yield in the presence or absence of imidazole; para-substituted phenyl acetates with electron-withdrawing groups gave lower yields. The phenyl acetates were shown not to undergo the enzymecatalyzed Fries rearrangement in the absence of resorcinol. An investigation of amine additives with IPEA showed Nmethylimidazole and morpholine to be superior to imidazole, and 1,4-diazabicyclo[2.2.2]octane (DABCO) gave the highest conversion (32%) under the standardized conditions of the experiment while suppressing competing O-acylation. However, the higher pH of the DABCO reactions (9.85, cf. 8.3 for imidazole) led to a reduction in reaction rate after 6 h, presumably due to instability of the enzyme. A limited study of substituted resorcinols showed higher yields for substrates substituted at C4 (40−98%) than at C5 (2−29%) and different yields with DABCO and imidazole. This approach shows considerable promise compared with the classical chemocatalyzed Friedel−Crafts reaction (Eur. J. Org. Chem. 2017, 5865−5871).

10. FRIEDEL−CRAFTS CHEMISTRY Friedel−Crafts acylation is one of the most commonly applied C−C bond-forming methods and the standard method for the preparation of acylated phenols. However, applicability is often diminished by competing C-polysubstitution and/or Oacylation. Schmidt et al. identified a biocatalytic process using an acyltransferase (ATase) to enable acylation of resorcinols to give the corresponding aryl ketones. The reaction proceeds under mild reaction conditions (KPi buffer, 35 °C) and was shown to be selective for C-monoacylation with yields of >80% obtained for several substrates. The reaction was shown to work with 2,4-diacetylphloroglucinol (DAPG), the natural acyl donor of the reaction, as well as Nacetylimidazole (NAcIm), vinyl acetate, and isopropenyl acetate (IPEA). Conversions were significantly improved with both vinyl acetate and IPEA when they were used in the presence of equimolar imidazole. The authors demonstrated that the ATase was also able to catalyze a biocatalytic equivalent of the Fries reaction from 3-hydroxyphenyl acetate,

11. CHEMISTRY IN WATER Brals et al. reported the use of proline-based FI-750-M as a custom surfactant that is efficient in promoting the Pdcatalyzed sp2−sp3 α-arylation of nitroalkanes and aryl bromide electrophiles in water. Broad functional group tolerance was displayed with respect to the aryl bromide: electron- poor and electron-rich aryl bromides were well-tolerated, providing the products in yields of up to 92% when the chemistry was carried out with nitromethane or nitroethane as the nucleophile. In addition, ester, keto, and nitrile functional groups on the aryl 1705




corresponding imine substrates at room temperature in the presence of reagent-grade NaOCl or commercial bleach. The yields were nearly quantitative for this transformation using water, compared with low yields when acetonitrile, toluene, and hexane were used. Aromatic, heteroaromatic, and aliphatic amines were well-tolerated as part of the substrate scope. As a serendipitous discovery, the authors reported the synthesis of the corresponding amide products in this chemistry when excess NaOCl was used. Elevating the temperature to 80 °C led to a high-yielding amidation reaction, routinely providing product in >85% yield. By variation of the equivalents of the two amines employed, efficient heterocoupling oxidation to give the corresponding imine and amide products was possible. Mechanistic experiments confirmed that the amide product is derived from oxidation of the imine precursor, which in turn is derived from chlorination of the primary amine by NaOCl as detected by NMR spectroscopy (ACS Sustainable Chem. Eng. 2017, 5, 8439−8446).

bromide were unaffected in the coupling chemistry, despite the basic pH conditions. Dynamic light scattering experiments showed an increase in the average particle size upon addition of 2% nitroethane to FI-750-M, which supports the merging of smaller micelles and nitroethane into larger micelles. Catalyst screening experiments revealed the importance of a πallylpalladium species in the catalytic cycle in order to obtain high yields and conversions. The mild aqueous conditions described for the α-functionalization of nitroalkanes compare quite favorably with more traditional approaches to this chemistry, which use high catalyst loadings, undesirable polar organic solvents such as DMF and 1,4-dioxane, and stringently dry and inert conditions at high temperature (ACS Catal. 2017, 7, 7245−7250).

Fang et al. have disclosed a regioselective and direct orthoazidation of anilines using Cu(II) catalysis in water. In the presence of catalytic Cu(OAc)2, water-soluble NaN3, and benign H2O2 as the stoichiometric oxidant, direct C−H functionalization of anilines is possible, with the desired o-azide isolated as the sole regioisomer with no reported diazidation product formed. The authors displayed a broad substrate scope featuring >20 anilines, with yields typically ranging from 50 to 65%. In an effort to demonstrate the late-stage C−H functionalization potential of this methodology, the chemistry was extended to the aniline-containing drugs procaine, benzocaine, and aminogluthimide. Monoazidation occurred in 60−65% yield in each case. The C−H functionalization methodology was also extended to ortho-bromination and -iodination of anilines using KBr and KI, respectively, as halogenating reagents. Yields ranged from 27 to 55%. The authors proposed a radical-based mechanism for this process on the basis of several key control experiments. When the radical scavenger TEMPO was charged to the standard reaction mixture, no desired product was observed. In addition, when the radical acceptor 1,1-diphenylethylene was added to the reaction, the corresponding vinyl azide was observed as the sole product, suggesting that an azido radical is involved in the process (J. Org. Chem. 2017, 82, 11212−11217).

Fujita et al. communicated the discovery and development of a dicationic iridium complex that is capable of performing dehydrogenative oxidations of primary and secondary alcohols in aqueous media, generating stoichiometric H2 as the byproduct. Aromatic and aliphatic secondary alcohols are oxidized to the corresponding ketones in nearly quantitative yields when the chemistry is performed in refluxing water for 20 h. The iridium catalyst is bound to a newly designed ligand bearing an NHC and an α-hydroxypyridine moiety. A catalyst screen of alternative water-soluble iridium complexes demonstrated that both ligand functional groups are important for high catalyst activity. Test reactions with an iridium catalyst bearing only the NHC group, only the hydroxypyridine group, or both the NHC and an unsubstituted pyridine group showed little to no catalytic activity. The authors demonstrated that the water-soluble iridium catalyst could be reused in subsequent oxidation reactions by extracting the product from the first oxidation using hexane. The corresponding aqueous phase containing the catalyst could then be used up to three times in additional catalytic dehydrogenations with no decrease in catalytic activity (>93% yield in each case). The chemistry could also be extended to primary alcohol substrates. Benzylic primary alcohols, when heated in refluxing water in the presence of the dicationic iridium complex, were transformed to their corresponding carboxylic acids in good isolated yields ranging from 60 to 72% (ACS Catal. 2017, 7, 7226−7230).

An “on-water” approach to performing chemical reactions, wherein water-insoluble compounds are placed in an aqueous suspension rather than an organic solvent medium, has gained increasing attention as an alternative green medium for many organic reactions. de Souza et al. describe a metal-free oxidative coupling−amidation approach using primary amines with NaOCl as the oxidant and water as the reaction medium. Primary amines can be directly homocoupled into the 1706




magnetic field across the reactor to arrange and vibrate the catalyst in the reaction channel, as depicted in panel (b). Parameters such as the catalyst particle size, flow rate, magnetic field strength, and frequency were optimized to ensure retention of catalyst in the flow system. The authors demonstrated their flow system using a Sonogashira reaction in which the yield was low (12%) with a permanent magnet but improved to a more acceptable value (89%) with an alternating magnetic field (RSC Adv. 2017, 7, 37181−37184).

The Cu-catalyzed azide−alkyne cycloaddition (CuAAC) is a powerful method to access 1,4-disubstituted 1,2,3-triazoles. The chemistry features high-yielding reactions, broad functional group tolerance, mild conditions, and perfect atom economy and can be performed in aqueous media. In contrast, analogous cycloaddition methods to access 1,5-disubstituted 1,2,3-triazoles are less common and typically require highly inert conditions, free from water, which limit their applications in biochemical research. Kim et al. reported a 1,5-selective Nicatalyzed azide−alkyne cycloaddition (NiAAC) that can be performed in air at room temperature with water as the reaction medium. With Cp2Ni as the precatalyst, Xantphos as the ligand, and Cs2CO3 as the base, a high-yielding and moderately to highly selective cycloaddition reaction is possible, favoring the 1,5-disubstituted 1,2,3-triazole regioisomer. The selectivity for the 1,5-isomer over the 1,4isomer typically ranged from 11:1 to 99:1; moderate selectivity of approximately 4:1 was observed only when N-phenyl and Nadamantyl azides were used, which the authors attributed to increased steric congestion with these substrates and the bulky catalyst. The chemistry proved to be compatible with biomolecules such as carbohydrates and amino acids. Both O and N-linked sugars were well-tolerated as the azide coupling partner, providing products in 65−81% yield with regioselectivity typically >15:1 (J. Am. Chem. Soc. 2017, 139, 12121−12124).

Uozumi’s group expanded its amphiphilic polystyrene (PS)−PEG resin-supported catalysts to include one using copper. The supported catalyst was used to carry out Huisgen reactions on a variety of alkynes and azides under batch and continuous flow conditions to give triazoles in yields ranging from 88% to 99% (>20 examples). The active catalyst is thought to be Cu(I) or Cu(0) nanoparticles, which are generated in situ through reduction of complexed CuSO2 by sodium ascorbate buffer. The catalyst proved to be robust, showing no appreciable depletion of activity over 48 h of continuous use. Inductively coupled plasma analysis indicated that leaching of Cu is low (99.9% purity by GC analysis. The report offers a good example of a novel and highly effective purification technique that is adsorbent-free (Angew. Chem., Int. Ed. 2017, 56, 8742−8745).

Drug discovery efforts are responsible for as much as 2 million kg of waste during the preclinical process. One solution to minimize waste is through judicious choices of candidates to ensure that high-value targets are synthesized early in the process. In a review by Aliagas et al., several cheminformatics approaches to early drug discovery are summarized, including discovery strategies from hit to candidate identification (J. Med. Chem. 2017, 60, 5955−5968). Green Chemistry Articles of Interest are produced on behalf of The ACS GCI Pharmaceutical Roundtable.

Marie-Gabrielle Braun

13. GENERAL GREEN CHEMISTRY Photochemical approaches to synthesis have increased over the past few years. In addition to the photochemical transformations described above, two photochemical reactions using sunlight were reported during the review period. Zhou et al. described an iterative [3 + 2]/[4 + 2] annulation of o-alkynylaniline and α-bromoacetates that provides de novo access to bifunctional azabenzobicyclo[4.3.0] derivatives. While the authors initially explored the use of the photocatalyst fac-Ir(ppy)3, they observed that reactions run in the absence of catalyst also worked well. No reaction was observed when the mixtures were held in the dark. Other solvents were explored, and the performance was similar, suggesting that greener solvents based on the substrate of interest may be employed. While artificial light sources such as blue LEDs and 33 W compact fluorescent lamp (CFL) bulbs worked well to promote the reaction, sunlight was the optimum light source, producing a complete reaction within 3 h versus 16 h for artificial light. Substrates were limited to arylsulfonylsubstituted anilines as removal of this moiety led to no reaction (Chem. Commun. 2017, 53, 10707−10710).

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

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

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

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

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

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

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

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

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

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

Singh and co-workers reported a direct synthesis of dihydropyrano[2,3-c]pyrazoles via a multicomponent reaction using a 1:1:1:1 mixture of hydrazine hydrate, ethyl acetoacetate, an aromatic aldehyde, and malononitrile. While other conditions exist for this type of reaction, they typically employ metal catalysts, hazardous solvents, and high temperatures. On the basis of previous experience using visible-light catalysis, the reaction was conducted in various solvents at room temperature using 22 W CFL bulbs as the artificial light source. In the dark, the reaction conversion was very low, indicating that the light worked to mediate the reaction. The reaction proceeded in a number of solvents, and 1:2 ethanol/ water or neat conditions worked best (78% and 88% yield, respectively). The use of photocatalysts had little effect on the reaction outcome, and when run under daylight in the absence of catalyst, the reaction gave a modest yield of 39% (New J. Chem. 2017, 41, 11148−11154).

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

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

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

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

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

Jingjun Yin Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States 1710



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AUTHOR INFORMATION

Corresponding Authors

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

Zhongbo Fei: 0000-0002-5980-4017 John Hayler: 0000-0003-3685-3139 Alan Steven: 0000-0002-0134-0918

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Green Chemistry Articles of Interest to the Pharmaceutical Industry

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