Green Chemistry Articles of Interest to the Pharmaceutical Industry

Green Chemistry Highlights pubs.acs.org/OPRD

Green Chemistry Articles of Interest to the Pharmaceutical Industry 1. INTRODUCTION The American Chemical Society’s (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable (PR) was developed in 2005 to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The Roundtable currently has 15 member companies as compared to three in 2005. 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, Dr. Reddy’s, Eli Lilly and Company, F-Hoffmann-La Roche Ltd., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, Pfizer, Inc., and Sanofi. One of the strategic priorities of the Roundtable is to inform and influence the research agenda. Two of the first steps to achieve this objective were to publish a paper outlining key green chemistry research areas from a pharmaceutical perspective (Green Chem. 2007, 9, 411−420) and to establish annual ACS GCIPR research grants. This document follows on from the Green Chemistry paper and is largely based on the key research areas though new sections have been added. The review period covers April−September 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, while not currently being regarded as green, the chemistry has the potential to improve the current state of the art if developed further. The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures.

CHEM21 collaboration’s solvent guide which is currently under development (Green Chem. 2014, 16, 4546−4551). Parker et al. showed the use of organic cyclic carbonates like ethylene and propylene carbonate as viable greener solvents to use in Heck reactions. This offers a highly effective alternative to traditionally used and problematic dipolar aprotic solvents such as NMP, DMF, and DMAc. (Sustainable Chem. Eng. 2014, 2 (7), 1739−1742).

3. AMIDE FORMATION The synthesis of amides from alcohols and amines via catalytic, acceptorless dehydrogenation represents a potential solution to address the issues associated with traditional amide bond formation (harsh conditions, generation of stoichiometric amounts of waste). Oldenhuis et al. have reported on the ability of the PNP-type ruthenium(II) catalyst, {RuHCl(CO)[HN(CH2CH2PPh2)2]} (Ru-Macho) to mediate this transformation. Importantly, the catalyst precursor is commercially available, relatively inexpensive, and activation with base affords the active catalyst in situ. Model studies indicated that KOH was the optimal base in either dioxane or toluene as solvent with the reaction being carried out at reflux under a continuous flow of nitrogen to drive off the hydrogen formed. A range of both alcohols and amines were well-tolerated with no racemization observed when enantiopure amines were utilized. The current conditions were also demonstrated to work well for secondary amines to generate tertiary amides, though increased steric bulk on the secondary amine does lead to deterioration in yield. Utilization of secondary alcohols also led to isolation of secondary ketimines in moderate to high yield (Tetrahedron 2014, 70, 4213−4218).

2. SOLVENTS Peterson (Amgen) along with scientists from AstraZeneca, GSK, Merck, and Pfizer have published a perspective on sustainable chromatography. The article outlines a compound isolation decision tree giving a hierarchy of methods based upon sustainability. The article is primarily aimed at chemists working in medicinal chemistry with many practical suggestions which can be incorporated into the day to day work of a bench chemist. However, the article is useful to everyone involved in preparative synthetic organic chemistry (Green Chem. 2014, 16, 4060−4075). Prat et al. have published a survey of solvent selection guides which looks at areas of overlap and difference between the four published solvent guides GSK, Pfizer, Pharmaceutical Roundtable, and Sanofi and a fifth guide which is unpublished but was donated by AstraZeneca. Although overall there is good general agreement between the solvent guides, there are some differences, and of the 51 solvents considered only 34 could be ranked unequivocally. This survey will form the basis for the European Union, Innovative Medicines Initiative (IMI) © XXXX American Chemical Society

Han et al. have also employed Ru-Macho in the direct synthesis of amides from amines and esters. Screening studies on the model reaction between benzyl benzoate and benzylamine indicated that 20 mol % t-BuOK was the optimum initiator of the reaction. Toluene was shown to be the best solvent when 1 mol % of the Ru-Macho catalyst was employed. Both aromatic and aliphatic esters were effective substrates, with the former giving higher yields, while both primary and secondary amines were successfully employed. The reaction was subsequently scaled to 240 mmol with no observed deterioration in performance. One key requirement is the use of a symmetric ester, e.g., benzyl benzoate or ethyl acetate, in order to obtain a single product from the reaction. The reason for this is provided by the proposed mechanism, which affords an initial molecule of the amide through intermolecular Received: October 28, 2015

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DOI: 10.1021/acs.oprd.5b00344 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Green Chemistry Highlights

nucleophilic attack of a Ru-amine complex on the ester. The liberated alcohol from the ester then forms a Ru-alkoxy complex, which is oxidized through dehydrogenation to an aldehyde intermediate. Nucleophilic attack on this by a second molecule of amine followed by β-elimination provides a second molecule of the amide (Catal. Commun. 2014, 58, 85−88). Enzymatic approaches to generate amides are attractive in terms of their benign nature and the mild conditions employed. In their studies on the marinacarbolines (MCBs) natural products, Ji et al. have identified McbA as a new ATPdependent amide synthetase. Cloning, overexpression, and purification of the enzyme enabled synthetic studies to be carried out that revealed that the optimal conditions for enzyme activity were using pH 7.5 phosphate buffer at 37 °C with ATP crucial for reactivity. The substrate scope was also evaluated revealing a broad capability to catalyze the reaction between a β-carboline core and a range of β-phenethylamine and tryptamine derivatives of specific (1−4 carbon) chain lengths (Tetrahedron Lett. 2014, 55, 4901−4904).

Sindhuja et al. have prepared a series of Ru(II) thiocarboxamide complexes and evaluated their ability to mediate the direct synthesis of amides from alcohols and amines. The complexes were prepared by reaction of an aniline, Na2S, and 2-methylpyridine with the ruthenium precursor, [RuHCl(CO) (AsPh3)3], and isolated as air stable solids. The complexes were studied in a model reaction between benzyl alcohol and benzylamine, which showed that the optimum conditions used t-BuOH as solvent at a reaction temperature of 62 °C with a catalyst loading of 0.05 mol %. Variation of the aromatic backbone of the catalyst (through variation of the aniline) had relatively little impact on either reactivity or stability of the complex. From a substrate perspective, benzyl alcohols and a range of heterocyclic benzylic alcohols were shown to be effective. For the amine component, anilines (with a range of substituents), benzylic amines, and cyclic secondary amines were all successfully employed. The catalyst system could also be recovered and reused 5 times before a significant drop in activity was observed. In comparison to previously reported systems, lower temperatures are utilized, no additional base is required, and the reaction displays no sensitivity to air or moisture with oxygen purported to play in a key role in the proposed catalytic cycle (Organometallics 2014, 33, 4269−4278).

Dev et al. have reported on ethyl 2-cyano-2-(2nitrobenzenesulfonyloxyimino)acetate (o-NosylOXY) as a novel recyclable coupling reagent for amide synthesis. This Oxyma-based reagent is readily synthesized and shows good stability on being stored at 25 °C. Model studies indicated DCM to be the optimal solvent, but good yields of the amide could also be obtained in more favorable solvents such as ethyl acetate or MeCN. From a reactivity standpoint, o-NosylOXY compares favorably with more conventional coupling reagents (HATU, HBTU) and shows a minimal tendency for racemisation. The utility of the reagent is also demonstrated for the synthesis of complex peptides, hydroxamates, and esters as well as its applicability for solid phase peptide synthesis. The byproducts originating from the coupling reagent can be easily recovered after reaction and reprocessed to regenerate oNosylOXY (J. Org. Chem. 2014, 79, 5420−5431).

Alkylation of primary amides represents an alternative method for the synthesis of secondary amides. However, the utility of this reaction is limited due to poor yields being obtained with less reactive alkyl halides (e.g., secondary halides). Do et al. reported on a photoinduced mild alkylation using copper iodide as the catalyst with LiOtBu as the base. The reaction proceeds at room temperature in preferably a mixed solvent system of MeCN and DMF. A range of secondary alkyl bromides are successful electrophiles (including neopentyl bromide), and good functional group tolerance is observed. Numerous aliphatic primary amides (as well as a lactam and 2-oxazolidinone) are effective nucleophiles though for aromatic/heteroaromatic amides; it is necessary to employ alkyl iodides as the electrophile to obtain optimal yields. Initial mechanistic studies suggest an electron transfer/radical pathway featuring photoexcitation of a copper-amidate complex (J. Am. Chem. Soc. 2014, 136, 2162−2167).

Aminocarbonylation represents an alternative method for the synthesis of amides that is attractive in terms of atom-economy and cost-effectiveness. Mei et al. have reported on an efficient palladium-1,10-phenanthroline catalyst encapsulated in Yzeolite for the aminocarbonylation of aryl iodides. Recycling of the catalyst is demonstrated across 15 cycles with negligible loss of reactivity. A double-protection strategy is proposed to explain the minimal leaching observed with Pd both chemically B




coordinated to the phenanthroline ligand as well as physically caged within the Y-zeolite. Optimal conditions use 0.6 mol % of catalyst with triethylamine as base in DMA as solvent at 130 °C and 2 MPa CO pressure. The high reactivity of the catalyst is hypothesized to originate from its pseudohomogeneous nature and the facile reduction of Pd(II) to Pd(0) in the aminocarbonylation process, and experimental data is presented to support these assertions (Appl. Catal., A 2014, 475, 40−47).

Yaragorla et al. have described a Ca(II)-catalyzed Ritter reaction under aqueous conditions for amide synthesis. Model studies on the reaction between 1-phenylethanol and benzonitrile indicated that 5 mol % of both the catalyst Ca(OTf)2 and an additive Bu4NPF6 were crucial for reactivity with the reaction being optimally performed in the microwave at 140 °C. A range of benzylic, secondary, and tertiary alcohols were demonstrated to react with a diverse range of nitriles. The reaction is proposed to proceed through initial activation of the hydroxyl group by a combination of the catalyst and additive with protonation of hydroxyl regenerating the active catalyst (Tetrahedron Lett. 2014, 55, 4657−4660).

Sharif et al. have reported on a novel metal-free oxidative synthesis of amides from styrenes and amines. Using ammonia, a range of substituted aromatic and heteroaromatic styrenes were successfully converted to the corresponding benzamides using TBHP as the oxidant under reflux conditions. Aliphatic alkenes were inert to the reaction, which is believed to proceed through the aldehyde, which could be observed as an intermediate in the absence of ammonia, under radical-type conditions. Ammonia could be substituted by a number of simple primary amines to generate secondary amides though anilines did not work under the current conditions (Chem. Commun. 2014, 50, 4747−4750).

Kumari et al. have prepared and characterized a graphene oxide (GO) catalyst and exploited the nanosheets obtained to catalyze the synthesis of amides from aromatic aldehydes and secondary amines. Optimization studies revealed that a mixed solvent system of MeCN/H2O with 5% of GO catalyst at 100 °C were the best conditions. Electronic effects of substituents had a negligible effect on reactivity, though steric hindrance around the aldehyde was shown to adversely affect the yield. Primary amines were not successful substrates for the reaction. The catalyst could be recycled and reused for up to 3 cycles before a significant loss of efficiency was observed. The reaction is proposed to proceed through a superoxide radical intermediate, and evidence for this is provided by the reaction shutting down when carried out under an inert atmosphere (RSC Adv. 2014, 4, 41690−41695).

Heterogeneous catalysts derived from magnetic nanoparticles represent an attractive option in synthesis due to both the ease of separation and potential recyclability of the catalyst after the reaction. Two reports have emerged on the use of such catalyst systems for the synthesis of amides. Zhao et al. have reported and fully characterized a sulfamic acid immobilized on magnetic CoFe2O4 nanoparticles for use as an efficient catalyst for the Ritter reaction. Good yields are obtained for a range of benzylic, secondary, and tertiary alcohols at 80 °C under solvent-free conditions using 10 mol % of the catalyst. Primary alcohols are not effective substrates. Recycling studies showed the catalyst could be recovered and reused over 6 cycles, and comparison studies with other methods indicate that the solidsupported sulfamic acid is equal to or more efficient than other methods (Appl. Catal., A 2014, 482, 258−265). Saberi et al. have characterized a Cu(II)−acetylacetone based nanoparticle anchored to a maghemite-based support and exploited their use as catalysts for the oxidative amidation of carboxylic acids with formamides. Model studies indicated that TBHP at reflux under neat conditions were the optimal conditions with a number of benzoic, phenylacetic, and cinnamic acids being demonstrated as successful substrates. Recycling was demonstrated for up to five consecutive reactions without any loss in catalyst efficiency, and a radical-type mechanism is proposed for the reaction (J. Organomet. Chem. 2014, 772−773, 222−228).

Lukasik and Wagner-Wysiecka have published a review on the use of microwave organic synthesis in the preparation of amides. In particular, focus is placed on the advantages that this technology can have on the environmentally attractive synthetic approaches of direct amidation of carboxylic acids and esters (Curr. Org. Synth. 2014, 11, 592−604).

4. OXIDATIONS While nature has used metalloenzymes for selective oxidation with oxygen, biomimetic catalysts for ether oxidations with O2 have often encountered poor chemoselectivity and substrate scope and harsh conditions. Gonzalez-de-Castro et al. reported an iron catalyst to enable such oxidation under mild conditions with TON up to 1530. The key to the high reactivity and selectivity is the tridentate N-donar ligand, pyridine bisimidazoC




line (PyBidine) ligand. The reactions were run neat with hydrogen gas as the only byproduct. Mechanistic study showed evidence of the peroxobisether intermediate in the two-step oxidation sequence. γ-Butyrolactones, isochromanones, and phthalides with various functional groups were obtained with high TON and mass balance (J. Am. Chem. Soc. 2014, 136, 8350−8360).

Pd-catalyzed Wacker oxidation is a powerful approach to make methyl ketones. A large number of stoichiometric oxidants have been used. Fernandes and Chaudhari reported the use of Fe(III) sulfate as the terminal oxidant for a mild and benign Wacker oxidation. The reaction was completely regioselective with no aldehyde formation and tolerated various functional groups such as ether, ester, carboxylic acid, halide, and nitro. Homoallylic alcohol derivatives, typical difficult substrates due to side-reactions, also gave clean reactions. Practically, the Fe2(SO4)3 salt is soluble in the reaction medium, MeCN/water (7:1), making this reaction operationally simple (J. Org. Chem. 2014, 79, 5787−5793).

Water as a solvent provides a possibility for greener reactions. Use of commercially available designer surfactants enabled many organic reactions to be run in water due to the high concentrations of reactants in the lipophilic cores of the surfactant. Handa et al. recently expanded this concept to the use of oxygen for the oxidation of arylalkynes in water. Oxidative reaction of arylalkynes with sulfinic acid in air, in the presence of 2 wt % of TPGS-750-M surfactant and 2,6-lutidine base, provided β-ketosulfones in good yields at room temperature. Functional groups such as bromo, acetyl, cyano, and amide were well-tolerated. The product was recovered from water with a small amount of organic solvents, and the aqueous medium could be reused for the reaction twice more, albeit lower yields were obtained (Angew. Chem., Int. Ed. 2014, 53, 3432−3435).

Miao et al. reported milder and greener conditions by use of 0.5% of RuCl3 as catalyst, NaOCl as stoichiometric oxidant, and diethylcarbonate (DEC) as solvent. Functional groups such as ester, ether, cyano, ketone, halide, and nitro were well-tolerated (Eur. J. Org. Chem. 2014, 5071−5077).

5. ASYMMETRIC HYDROGENATIONS Bernasconi et al. have devised an iridium catalyzed asymmetric hydrogenation of dimethyl maleate and fumarate derivatives to give chiral 2-substituted succinates. A range of catalysts based on N,P ligands were screened with [Ir(cod)L]BArF, derived from a 2,6-difluorophenyl-substituted pyridine−phosphinite ligand, affording the conversion of a wide range of 2-alkyl and 2-arylmaleic acid diesters to the corresponding succinates in high yields and enantiomeric purity. It was also found that this strategy has excellent scope as cis/trans mixtures of substrates were successfully hydrogenated in an enantioconvergent manner with excellent output. In particular asymmetric hydrogenation of a mixture of E and Z isomers using 1 mol % [Ir(cod)L]BArF and H2 (50 bar) in DCM (0.2 M solution) afforded >99% yield and >95% ee after stirring for 18 h at room temperature. Screening to evaluate alternative solvents to dichloromethane is not reported (Angew. Chem., Int. Ed. 2014, 53, 5385−5388).

Moriyama et al. reported a transition metal-free, bromide anion catalyzed oxidation of alcohols under mild conditions. Various secondary alcohols were converted to ketones in high yields by oxone as the stoichiometric oxidant, catalyzed by potassium bromide, in MeCN−water at room temperature. Alternatively, H2O2 was also used as the stoichiometric oxidant in the presence of 10 mol % PhSO3H additive, but unfortunately dichloromethane was required for higher conversions. Under these conditions, primary alcohols were converted to carboxylic acids. In order to attenuate reactivity, 10 mol % of TEMPO was added to produce the corresponding aldehydes in high yields. Interestingly, if 1.2 equiv of KBr was used, p-methoxytoluene could selectively be brominated in high yield (J. Org. Chem. 2014, 79, 6094−6104). D




diastereoselectivity (5:1 to >20:1) for several valine and valinol derivatives containing two primary sp3 carbons. For phenylalanine derivatives which contain no primary sp3 C−H bonds, C−H borylation takes place on a sp2 C−H bond of the phenyl ring instead. The reaction is tolerant of common organic functionality such as esters and benzyl ethers, and the authors demonstrate selective functionalization of an estrone derivative. One current drawback of the method is the requirement for a high catalyst loading [20 mol % Pd(OAc)2] along with superstoichiometric amounts of borylating agent (4 equiv B2pin2) and additives (5 equiv iPr2S, 3 equiv LiF, 3 equiv Li2CO3, and 1 equiv NaHCO3) (Angew. Chem., Int. Ed. 2014, 53, 3899−3903).

Enantioselective hydrogenation of β-acylaminonitroolefins to chiral β-amino-nitroalkanes has been achieved in high yields and excellent enantioselectivities (up to 99.9% ee) using an Ir-fspiroPhos catalyst system (Chem. Commun. 2014, 50, 12870−12872).

Li et al. have built upon their previous work for the methylation of amines with CO2 and report the methylation of heteroarenes via C−H activation in the presence of CO2 and hydrogen. Reaction conditions were optimized with 2methylindole, which verified that a facial tridentate ligand and acid were necessary for a selective reaction with good yields. The reaction is believed to proceed through an acetal intermediate and efforts to observe this species are still ongoing. Substituted indoles with electron donating groups all provided good yields but indoles with halogens afforded less of the desired product. Substituted pyrroles provided lower selectivity when the optimized indole conditions were utilized, but very high yields could be achieved by replacing the MSA with diphenyl phosphate. Finally, electron-rich benzene substituents could also be mono and dimethylated depending on the substituents and the reaction conditions utilized (Angew. Chem., Int. Ed. 2014, 53, 10476−10480).

6. C−H ACTIVATION Xu et al. have developed a silver-catalyzed benzylic fluorination to generate difluoromethylated arenes. The reaction shows good chemoselectivity as ketones, esters, carboxylic acids, amides, and halogens are all well-tolerated. The best substrates for the reaction have carbonyl functionality ortho- to the benzylic center, which the authors propose may allow for metal chelation and intramolecular benzylic C−H abstraction. More general toluene and ethylbenzene derivatives work in the reaction but typically require 20 mol % catalyst and use of greater than 3.0 equiv of Selectfluor. Some heterocycles such as pyridine and isoquinoline are also viable substrates. The authors propose that sodium persulfate generates a Ag(II) species which promotes benzylic C−H abstraction. Selectfluor then fluorinates the substrate and reoxidizes Ag(I) to Ag(II). The cycle is repeated one more time on the monofluorinated compound to selectively generate the difluoromethylated compounds, producing less than 10% total mono- and trifluoromethylated compounds (Angew. Chem., Int. Ed. 2014, 53, 5955−5958).

Mo and Dong report a selective monoalkylation with terminal olefins at the least substituted site of substituted ketones. The Rh(coe)2 dimer in the presence of IMes, TsOH, and 7-azaindoline provides the necessary bicatalytic reactivity to activate both the C−H alpha to the carbonyl and the olefin C− H. Functionality at the R1 position is well tolerated and the diastereomeric ratio is moderate, ranging from 1.1 to 2 favoring the cis compound. When one enantiomer of an enolizable R1 group was examined, the chirality of that center remained intact due to the absence of strong base that is utilized in many alpha alkylation reactions. In examples where the olefin was a gas the reaction was run under 300 psi of pressure and the olefin was used as solvent in cases where the olefin is a liquid at room temperature. The reaction could be run up to 3.3 M, making scale-up more practical than some previously disclosed C−H activations (Science 2014, 345, 68−72).

A palladium-catalyzed, substrate-directed borylation of primary aliphatic C−H bonds that uses air as the stoichiometric oxidant has been developed by Zhang et al. The reaction requires a picolinyl-protected amine moiety to direct the metal to promote intramolecular C−H cleavage. The reaction is selective for primary sp3 C−H bonds over secondary sp3 C−H bonds, and the authors demonstrate moderate-to-excellent E




tion of an HF-DMPU complex that regioselectively fluorinates alkynes. The specificity of the methodology relies on the weakly coordinating hydrogen-bond acceptor character of DMPU, and its low basicity and nucleophilicity, that prevents it from interfering with transition-metal catalysts. This novel fluorinating agent is therefore compatible with cationic catalysts, such as gold, and promotes selective mono-or dihydrofluorination of alkynes, although the reaction is run in 1,2-dichloroethane (J. Am. Chem. Soc. 2014, 136, 14381−14384).

7. GREENER FLUORINATION Xiao et al. reported a first example of nickel-catalyzed difluoroalkylation of aryl boronic acids. Difluoroalkylated arenes can be obtained from the corresponding bromo or chlorodifluoroacetate derivatives in modest to good yields using nickel nitrate and bpy as an economically attractive catalytic system. Electron-rich and electron-deficient aryl boronic species exhibit sufficient reactivity under moderately activated conditions (80 °C in dioxane). Besides, the methodology is compatible with a wide range of additional functionality. The broad scope of boronic acids is complemented by that of bromo or chlorodifluoroalkyl arenes, ketones, and amides which only require slightly higher loading in catalyst and ligand and result in otherwise difficult to make substrates. The methodology however suffers from the use of dioxane which would need to be substituted for really environmentally interesting applications, and the need for excess boronic acid (Angew. Chem., Int. Ed. 2014, 53, 9909−9913).

8. BIOCATALYSIS Although mild, selective, and greener methods of oxidation are being developed, such methods can require the use of halogenated solvents and high temperatures. An alternative is to use a biocatalytic system involving a laccase enzyme in aqueous buffer solution at room temperature. Laccases are Cu2+ dependent oxidases and are used together with a mediator which shuttles electrons from the substrate to the enzyme. The terminal oxidant in this system is oxygen which is converted into water. Diaz-Rodriguez et al. have reported a laccase/ TEMPO system for the oxidation of diols and amino alcohols to give lactones and lactams. The laccase from Trametes versicolour was shown to produce the desired compounds in excellent conversion in a two phase system using aqueous buffer and tert-butylmethyl ether (Adv. Synth. Catal. 2014, 356, 2321−2329).

Gianatassio et al. developed a remarkable methodology to incorporate trifluoromethylcyclopropane into various scaffolds after C−H functionalization. The main benefit of the methodology is the convergency it allows to build on already functionalized substrates, compared to other methods that rely on elaboration of one or the other of the cyclopropane or trifluoromethyl groups. The method uses the corresponding sodium sulfinate salt in excess (3 equiv) and an excess of an oxidizing agent, TBHP (5 equiv), and proceeds within an hour at 90 °C to the corresponding cross-coupled product in moderate to good yields. It shows no sensitivity to air or water and proceeds in the absence of metal. Other fluorinated sidechains can be introduced as reported in the communication. The protocol is also compatible with a variety of other functionalities (Angew. Chem., Int. Ed. 2014, 53, 9851−9855).

Bechi et al. have demonstrated an oxidative approach to the synthesis of carboxyl derivatives using catalytic biochemo or biobio tandem oxidations to produce either amides or carboxylic acids. In the first example, a biocatalytic oxidation using either a laccase as above (or an alternate oxidase) produces an aldehyde which is then condensed with an amine and the resultant imine or hemiaminal is further oxidized to the amide using a chemical oxidant. To produce the corresponding carboxylic acid, the aldehyde formed from the first biocatalytic oxidation is further oxidized using xanthine dehydrogenase (XDH).

The direct use of HF as a fluorinating agent is the most desirable approach from an atom-economic standpoint. It is however rendered difficult by the complex handling required. Okoromoba et al. reported the development and implementaF




proteins. Green et al. report a new method of screening which utilizes an amine donor that both efficiently shifts the unfavorable equilibrium and provides a substrate independent colorimetric output to detect transaminase activity. The method was demonstrated on a range of ketones with a commercially available TA. When using commercially available ortho-xylylenediamine as the amine donor, the reaction byproduct spontaneously cyclizes to give an imine which undergoes a further tautomerisation to the more stable aromatic isoindole. This has the dual benefit of removing the byproduct from the system thus shifting the reaction equilibrium in the desired direction and giving a colored read-out due to the polymerization of the isoindole. In comparison, other amine donors gave far lower yields. This method could also be used to visibly screen for new catalysts, as colonies able to use the new amine donor become colored as the byproduct of the reaction accumulates (Angew. Chem., Int. Ed. 2014, 53, 10714−10717).

The amides were produced in moderate-to-excellent yields and the carboxylic acids with excellent conversions. The final cascade starts from the amine and through sequential oxidations using a monoamine oxidase (MAO-N) and XDH gives the amide as the final product with excellent conversion. Compared with chemical catalysis, cascade biocatalysis such as that reported can be easily combined into a one-pot process because enzymes typically require similar reaction conditions. These types of cascade have enormous synthetic potential for further development (Green Chem. 2014, 16, 4524−4529).

Wang et al. applied their method for the P450 monooxygenase catalyzed cyclopropanation in the formal synthesis of levomilnacipran, a selective serotonin reuptake inhibitor. By changing a proximal cysteine ligand, which coordinates to the heme in the enzyme’s active site, the redox potential of the protein can be increased making the FeIII-heme (inactive) to FeII-heme (active) reduction more efficient. In this case, mutating the cysteine residue to histidine gave the most active cyclopropanation catalyst although further mutations were required to increase the ee of the desired diastereoisomer. The optimized catalyst was shown to give the desired cyclopropylester with very good yield and both high diastereo and enantioselectivity. The ester was readily reduced to the corresponding alcohol which has previously been converted to levomilnacipran in two steps (Angew. Chem., Int. Ed. 2014, 53, 6810−6813).

The power of TAs for the synthesis of chiral amines is wellillustrated in a recent report by Limanto et al. documenting the synthesis of antiarrhythmic agent Vernakalant. As part of the synthesis the trans-amino alcohol motif was created using an enzyme-catalyzed dynamic asymmetric-transamination (DATA). The starting material for this process is the α-keto ether, which is then treated with the transaminase and amine donor at high pH (>9). The amine is stereoselectively introduced by the TA, while under the basic reaction conditions the α-chiral center is equilibrated. Using an enzyme engineered to be both highly selective and tolerant of high pH, the desired transdiastereoisomer was formed in high yield and selectivity. The product was isolated as the malate salt as this offered greater physical and chemical stability as well as the opportunity to upgrade the purity (Org. Lett. 2014, 16, 2716−2719).

Typically, biocatalysis uses biological tools (enzymes) in either a biological environment (a cell) or a chemical environment (a flask), and by definition organic chemistry uses chemical tools in a chemical environment. The remaining combination is to use chemical tools in a biological environment, and Sirasani et al. have demonstrated this concept by reporting an alkene hydrogenation process which works in a biological environment. In this system, engineered E. coli produces hydrogen gas as a metabolite via a pathway involving a hydrogenase enzyme and redox partners. The hydrogen thus produced is used by a palladium catalyst to hydrogenate a range of cinnamic acids in excellent yield. The reaction was most

The development of broadly applicable catalytic methods for the sustainable production of chiral amines is a research priority for the pharmaceutical industry and transaminases (TAs) have been shown to be excellent biocatalysts for this purpose. There are, however, challenges to developing efficient TA catalyzed processes such as displacing the unfavorable equilibrium position with respect to product formation and the limited availability of simple high-throughput screening methods to identify new enzymes or evaluate large libraries of engineered G




chemoselectivities that might offer advantages in specific cases especially if instances of reagent poisoning can be overcome. Chusov and List have published an interesting report of a catalytic process where carbon monoxide can be used as the reducing agent in place of hydrogen. An initial screen of Pd, Ru, and Rh catalysts showed that only Rh supported reduction of the intermediate imines with Rh2(OAc)4 and Rh/C as preferred options. A variety of aryl functional groups were supported, e.g., −OMe, −CN, −NO2, −Cl, and N−Bn groups were not cleaved or reduced. The potential for in situ hydrogen formation via the water gas shift process was investigated and shown to be minimal in the case of Rh2(OAc)4. Omitting carbon monoxide and operating with deuterium gas led to only 11% incorporation of deuterium. Mechanistic studies with Rh2(OAc)4 showed minimal reaction from an added hydrogen atmosphere and also downplayed the involvement of formate to generate hydride species. While rhodium itself might not suggest the basis for a sustainable process, the approach does offer a number of real and potential benefits. First, hydrogen production requires greater energy and material consumption than carbon monoxide. As with the tris(pentafluorophenyl)borane examples presented, there is also the opportunity to conduct reductive aminations in the presence of on otherwise susceptible functionality offering potential for shorter routes and reduction in materials consumption improving the green credentials of a route (Angew. Chem., Int. Ed. 2014, 53, 5199−5201).

successful when using palladium on polyethylenimine/silica gel (Royer catalyst), and it was speculated that increased cellcatalyst contact could be occurring as E. coli is known to absorb on the polyethylene support. Interestingly, this hydrogenation catalyst appears to be biocompatible, with the cells surviving the reaction. This led the authors to suggest that the hydrogenation is likely to occur outside of the cells, although further work is required (Angew. Chem., Int. Ed. 2014, 53, 7785−7788).

9. REDUCTIONS The use of readily handled silane reducing agents in the presence of Lewis acids continues to be of interest for amide reduction. Chadwick et al. have reported on the combination with tris(pentafluorophenyl)borane to reduce secondary and tertiary amides in cases where the previously reported Zn(OTf)2 does not work. A variety of functional groups were tolerated including nitro, furan, and halide although nitriles underwent competitive reduction forming numerous products. Some secondary amides also gave a variety of side reactions. One limitation of the methodology is the propensity for tris(pentafluorophenyl)borane to form adducts with amines. This is especially favorable as amine basicity increases and where N−H bonds are present. This explains the lack of turnover with N-alkyl secondary amides relative to N-aryl or tertiary analogues (J. Org. Chem. 2014, 79, 7728−7733).

Similar conditions to those above were published almost simultaneously by Blondiaux and Cantat. Many of the same substrates were included but there were some interesting extensions also reported. First, the approach was extended to primary amides which are notoriously difficult to reduce through silane approaches. This was achieved in high yield through initial N-silylation (two examples), which also probably served to provide steric inhibition of coordination of the product amine with tris(pentafluorophenyl)borane. Next, tandem 1,4- and 1,2-reductions of cinnamides could be achieved although the reaction did appear to stall during the subsequent amide reduction. Finally there was also a single report of an aryl methyl ester being reduced to a methyl group in high selectivity depending on the nature of the silane used (Chem. Commun. 2014, 50, 9349−9352).

10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT Wang et al. have combined a previously reported hydrogen borrowing alkylation procedure with a reaction to form primary amides from nitriles using aldoximes as a water surrogate. They determined that a single iridium based catalyst ([Cp*IrCl2]2) at 1 mol % loading was capable of producing the primary amide from nitrile and aldoxime in toluene at 100 °C, then carrying that on directly through the alkylation of the amide nitrogen with an alcohol in the presence of less than stoichiometric base (0.2 equiv Cs2CO3) at 130 °C to provide elaborated amides directly. A range of predominantly aromatic nitriles and benzyl alcohols afforded amides in 80 ± 5% yield with aliphatic reactants performing similarly (Chem. Commun. 2014, 50, 8303−8305).

Oldenhuis et al. utilize Ellman’s sulfinamide in a RuMACHO (A) catalyzed coupling with racemic secondary alcohols via hydrogen borrowing coupling to provide output of enantiomerically enhanced amines. They propose that the alcohol is oxidized to the ketone by the catalyst in the presence

These methods using strong Lewis acids based on boron do serve to avoid platinum group metals in reduction processes, but this must be balanced against the synthesis of the reagents themselves. However, they provide alternative methods with H




alcohol was used as solvent. Alkylation with 2-butanol required longer reaction times and alkylation of aniline with benzyl alcohol was only achieved in high yield by heating in a microwave reactor. Further studies showed that iridium was not leached from the catalyst, to the limit of detection, demonstrated that the catalyst system was heterogeneous through the hot filtration test and studied the reuse of the catalyst over six cycles. The authors argue that the catalytic cycle occurs entirely within the pores of the catalyst with the Lewis acidic sites provided by the zirconium promoting the formation of the intermediate imine (ChemCatChem 2014, 6, 1794−1800).

of the sulfinamide which couples to form the sulfinylimine. This imine moiety is in turn diastereoselectively reduced by the Ru hydride form of the catalyst (B) to form the α-chiral sulfinylamine. This then leads to the chiral amine. Most alcohols shown as examples had one methyl β-substituent relative to the amine and this methodology is superior to organometallic approaches to α-chiral amines bearing a βmethyl substituent. The authors note that larger accompanying β-substituents on the alcohols hindered the overall diastereocontrol of the process (J. Am. Chem. Soc. 2014, 136, 12548−12551).

Tang et al. report the use of a bis-alkoxyphosphorane to facilitate a redox-free Mitsunobu reaction. Treatment of activated and unactivated secondary alcohols with 1 equiv triphenyl bis(2,2,2-trifluoroethoxy)phosphorane, prepared from triphenyl-phosphine oxide (TPPO), and 2 equiv benzoic acids in ethyl acetate affords the corresponding ester with clean inversion at the alcohol center. Acetic acid could also be used but gave lower yields, as did menthol. No net phosphorus waste is generated as the reagent is derived from triphenylphosphine oxide which was also recovered in 86% yield from one reaction and the protocol avoids the use of diazobased oxidants. Multinuclear NMR studies support the formation of intermediate alkoxytriphenyl-phosphonium benzoate upon addition of benzoic acid, which subsequently forms the ester and triphenylphosphine oxide via an Arbuzov collapse (Chem. Commun. 2014, 50, 7340−7343).

Enyong and Moasser have developed a ruthenium catalyst system which enables alkylation of amines under the mildest reaction conditions known for Ru at the time of publication. A 2:2:1 mixture of amino-amide ligand: potassium tert-butoxide: ruthenium source is premixed and then used to alkylate primary and secondary aliphatic amines and anilines with primary alcohols. Reactions using the alcohol as solvent are typically run at 55−65 °C affording primarily monoalkylated products in good yield. 1,4- and 1,5-Diols and primary aliphatic amines afford cyclic products and some secondary amines could be alkylated at room temperature using a higher catalyst loading. A stoichiometric amount of alcohol could be used with toluene as solvent at 110 °C, and further study showed that a 3:7 mixture of alcohol−toluene allowed a reduction in catalyst loading and reaction temperature. Reactions are conducted in degassed solvent, under dry nitrogen, and in the presence of 3 Å molecular sieves (J. Org. Chem. 2014, 79, 7553−7563).

A notable aspect of the last three publications is the use of chlorinated solvents in the preparation of the catalysts.

11. FRIEDEL−CRAFTS CHEMISTRY A group from the Vietnam National University and Roskilde University (Denmark) have reported the use of bismuth triflate in the Friedel−Crafts benzoylation of a variety of unactivated and activated arenes using microwave irradiation. Previous reports have employed bismuth triflate but under a conventional heating regime. The authors investigated 14 commercially available triflates. Surprisingly, the more Lewis acidic metal triflates, e.g., Eu(OTf)3, Tm(OTf)3, and Yb(OTf)3 are not efficient at effecting good conversions; the authors do not offer further explanation of this phenomenon. Among the examples of unactivated arenes they provide, the conversion of

Rasero-Almansa et al. report the use of a bifunctional iridium−zirconium metal−organic framework (MOF), prepared from UIO-66-NH2, as a heterogeneous catalyst for the alkylation of amines with alcohols. Catalyst screening studies performed on the alkylation of primary amines with alcohols under 1−6 bar hydrogen showed superior reactivity of the heterogeneous catalyst over the equivalent homogeneous catalyst when the BF4− counterion was used. Monoalkylation of primary and secondary amines with ethanol or benzyl alcohol was also achieved in the absence of hydrogen; the I




fluorobenzene to the corresponding p-benzoylated product in excellent yield and the selectivity is notable. Moreover, these reactions are run neat, although solvent is used in the workup. In the example with anisole, the authors demonstrated that bismuth triflate was easily recovered and reused five times without any loss of catalytic activity (Synth. Commun. 2014, 44, 2921−2929).

Liu et al. described the ligandless [bmim]PF6 promoted Suzuki−Miyaura coupling of potassium aryltrifluoroborates with aryl bromides in water at 80 °C, using palladium acetate as catalyst and sodium bicarbonate as base (under air). While using water as a solvent for the Suzuki−Miyaura coupling of potassium organotrifluoroborates had been previously reported, these examples were limited to −OH/−COOH containing substrates or 5-iodo-1,3-dioxin-4-ones. The use of ionic liquids in metal mediated couplings has also been reported in the literature; however, only one previous report described the Suzuki−Miyaura coupling of potassium organotrifluoroborates in ionic liquids. The authors initially observed poor reactivity of aryl bromides in either pure water or [bmim]PF6, but attenuation of the water:[bmim]PF6 ratio provided a significant increase in yield. The coupling conditions tolerated a broad range of functional groups and aromatic substitution patterns, including polybromo-substrates to generate polyaryls in high yield. Coupling of iodoanisole provided a moderate yield of the desired product (48%), while the attempted couplings of an aryl chloride and aryl triflate were not successful. The ionic liquid/catalyst system was successfully recycled through five iterations to produce the desired product in decreasing yields of 99%, 95%, 90%, 81%, and 64%, respectively (J. Org. Chem. 2014, 79, 7193−7198).

Li et al. have reported on the copper catalyzed enantioselective Friedel−Crafts alkylation of pyrrole with isatins. In this paper, a catalyst using a chiral tridentate Schiff’s base/metal was developed. The authors propose a transition state where the isatin is activated by chelation of the metal center in the complex, while the NH in pyrrole serves as a hydrogen bond donating group to direct the alkylation to the Si face of isatin. In addition, the authors optimized and improved the conversion of unprotected isatins (R2 = H) by developing a method to release isatin in low concentrations to avoid the racemic background reaction. They accomplished this by using nitromethane to effect a Henry/retro Henry reaction to modulate the concentration of the isatin into the reaction. They also point out that the addition of hexafluoroisopropanol (HFIP) boosted the enantioselectivity. Although the exact role of HFIP was unknown, it is postulated that the weak acidity of HFIP favors the hydrogen bond of isatin with the catalyst in the transition state. In this way, HFIP can promote the enantioselectivities in the reaction. The scope of this transformation is demonstrated with various substituted isatins and an example where indole is used as the electrophile instead of pyrrole (Org. Lett. 2014, 16, 3192−3195).

Zhao et al. reported the development of a method to oxidize heteroaromatic amines to the corresponding nitro-substituted heteroaromatic. The report focused on nitrogen-rich heteroaromatics, and the method employed the use of oxone (2KHSO3·KHSO4·K2HSO4) in water as a green alternative to electrophilic nitrations or oxidation methods employing metal catalysts or dangerous reagents (i.e., concentrated H2O2) in organic solvents. The authors found that amino pyrazoles with various functional groups were oxidized in good yields. While nitration of pyrazoles with electron-withdrawing groups can be difficult, the oxidation of the corresponding amine was successfully demonstrated using this method. The mild reaction conditions (40 °C, 18 h), environmental friendliness, and operationally safe nature of the oxidant in this work present a safe and scalable method for the oxidation of heteroaromatic amines (Org. Process Res. Dev. 2014, 18, 886−890).

12. CHEMISTRY IN WATER Mandha et al. have published the solvent-free, noncatalytic formation of α-aminophosphonates from the three component condensation of aldeydes, amines, and trimethylphosphite at ambient temperature (58−88% yield). The authors hypothesize that the water generated from the condensation of the amine and aldehyde catalyzes the subsequent turnover of the phosphonium intermediate into the aminophosphonate. This hypothesis was tested by isolating and subjecting the imine to trimethylphosphite under both anhydrous and aqueous conditions. The anhydrous conditions did not produce the desired aminophosphonate, while stoichiometric water effectively promoted the reaction. Aromatic and aliphatic aldehydes, as well as anilines and primary/secondary amines were welltolerated (J. Chem. Sci. 2014, 126, 793−799). J




Hu et al. describe the silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary carboxylic acids. High yields for this Hunsdiecker-type reaction are obtained in emulsions of sodium dodecyl sulfate (SDS) in water, while reaction in organic solvents results in yields lower than 12%. The reaction can be performed under mild conditions using 1.5 equiv of the electrophilic SCF3 reagent (1) (i.e., a CF3 substituted thioperoxide), 30 mol % AgNO3, and 1 equiv of K2S2O8 as the oxidant. The silver-mediated oxidative decarboxylation proceeds through a radical mechanism and is, in contrast with electrophilic trifluoromethylthiolation reactions, compatible with arene, alkene, and alkyne groups. Yields up to 90% are obtained for secondary and tertiary carboxylic acids, but primary and aromatic carboxylic acids give low yields or no conversion under these reaction conditions (Angew. Chem., Int. Ed. 2014, 53, 6105−6109).

Lipshutz and Ghorai have reviewed the various organic reactions that have been performed under micellar conditions in water. In addition to the known micelle-forming surfactants PTS and TPGS-750-M based on α-tocopherol (vitamin E), a third generation surfactant SPGS-550-M based on the inexpensive phytosterol β-sitosterol is reviewed. A general experimental procedure is given for most of the reactions described. An overview of the various techniques for product isolation is provided as well as a brief evaluation of the impact of the approach based on E-factors (Green Chem. 2014, 16, 3660−3679).

13. GENERAL GREEN CHEMISTRY Sheldon has published an excellent review “Green and sustainable manufacture of chemicals from biomass: state of the art”. Examples of complete deoxygenation of biomass materials to give hydrocarbons are presented as well the more redox economical approach of direct conversion of carbohydrates to commercially important oxygenates. In addition three potential bio-based routes for producing polyethylene terephthalate (PET) are analysed. PET is a high volume polymer (>50 million tonnes per annum) used for soft drinks and drinking water bottles among other applications (Green Chem. 2014, 16, 950−963). Jimenez-Gonzalez and Overcash have published a perspective on the evolution of life cycle assessment (LCA) in pharmaceutical and chemical applications. The perspective captures many of the life cycle assessments for pharmaceutical products that have currently been published (a relatively small number). Timelines for historical evolution of life cycle assessments are presented; so, for example, the Coca Cola company performed its first LCA in 1969. Dow Chemical started a Life Cycle program in 1990, and GSK and Pfizer both started their first life cycle programs in 1997 (Green Chem. 2014, 16, 3392−3400). 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 Andrew Cosbie Amgen, Thousand Oaks, California 91320, United States Louis Diorazio AstraZeneca, Macclesfield, SK10 2NA, U.K. Peter Dunn Pfizer Global Supply, Ramsgate Road, Sandwich, 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*

Rate enhancement of the Darzens reaction in aqueous media has been described by Li and Li. The Darzens reaction between halo-ketones and aldehydes have been carried out in water under PTC conditions using LiOH or Li2CO3 as base and mechanical stirring in the presence of granular polytetrafluoroethylene (PTFE sand). Reaction times of a few minutes to 5 h are needed for complete conversion, which is much faster than reaction in organic solvents. Best results for aromatic aldehydes are obtained with Aliquat 336 as phase transfer catalyst, while sodium dodecyl sulfate works best for aliphatic aldehydes. In addition, a high diastereoselectivity in the synthesis of steroidal epoxyketones is obtained through kinetically controlled reaction (J. Org. Chem. 2014, 79, 8271−8277).

Tomás -Mendivil et al. have developed an efficient ruthenium(IV) catalyst for the hydration of nitriles to amides under mild aqueous conditions, as illustrated for the antiepileptic drug rufinamide. The new bis(allyl)-Ru(IV)phosphinous acid catalysts were readily prepared from commercially available dimeric {RuCl(μ-Cl)(η3:η3-C10H16)}2 complex and 2 equiv dimethyl- or diphenyl-phosphinoxide. Compared to known ruthenium catalysts (optionally with hydrophilic phosphine ligands) a lower catalyst loading of the new catalyst is needed and reactions can be performed under milder conditions (60 °C vs ≥100 °C). Under these conditions almost complete conversion to the amide was obtained with moderate to high TOF values up to >1000 h−1. In addition, the aqueous solution containing the Ru(IV) catalyst could be reused several times. The mild reaction conditions even made it possible to convert cyanohydrins quantitatively to hydroxyl amides (Chem. Commun. 2014, 50, 9661−9664). K




GlaxoSmithKline, Stevenage, Hertfordshire, U.K.

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

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

Luke Humphreys GlaxoSmithKline, Stevenage, Hertfordshire, U.K.

Bernard Kaptein DSM Ahead R&D Innovative Synthesis, P.O. Box 18, 6160 Maryland Geleen, The Netherlands

Lynette Oh GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States

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

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

Timothy White Eli Lilly, Indianapolis, Indiana 46225, 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]. Notes

The authors declare no competing financial interest.

L


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