The Green Chemistry Articles of Interest - Organic Process Research

Green Chemistry Highlights pubs.acs.org/OPRD

The Green Chemistry Articles of Interest 1. INTRODUCTION The American Chemical Society’s (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable (PR) was developed in 2005 to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The Roundtable currently has 16 member companies as compared to three in 2005. The membership scope has also broadened to include contract research/manufacturing organizations, generic pharmaceuticals, and related companies. Members currently include ACS GCI, Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Codexis, Dr. Reddy’s, DSM Pharmaceutical Products, Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, Pfizer, Inc., Roche, 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 2013−September 2013. These articles of interest represent the opinions of the authors and do not necessarily represent the views of the member companies. Some articles are included because, whilst not currently being regarded as green, the chemistry has the potential to improve the current state of the art if developed further. The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures.

An application of this new solvent in hydride reduction reactions is reported, and a specific new process for the reduction of nitriles to amines in 2-MeTHF and in 1,2,3-TMP in using 1,1,3,3-tetramethyldisiloxane (TMDS) in combination with copper triflate Cu(OTf)2 is developed and described (Green Chem. 2013, 15, 3020−3026). McGonagle et al. have published a solvent selection guide for aldehyde-based direct reductive amination processes. A SciFinder survey indicated that 25% of published reductive aminations use either dichloromethane (DCM) or dichloroethane (DCE) as solvent. In the study three commonly used reagents are examined, sodium cyanoborohydride, sodium triacetoxyborohydride (STAB), and picoline−borane complexes. The results for reactions with DCM and DCE are compared with greener solvents such as ethyl acetate, IPA, and certain ethers. The results of the study show that chlorinated solvents are not required, particularly when using STAB as the reducing agent (Green Chem. 2013, 15, 1159−1165).

3. AMIDE FORMATION Kang et al. have reported on the reaction of nitriles and alcohols under ruthenium-catalyzed conditions to generate amides in a redox-neutral single step with complete atom economy. The reaction differentiates itself from previous amidation reactions utilizing these components in that the carbon of the nitrile is not the carbonyl source in the reaction, and instead the reaction proceeds through hydrogen transfer from the alcohol to nitrile with the subsequent C−N bond formation between the nitrogen of the nitrile and the α-carbon of the primary alcohol. Screening studies on a model system indicated that RuH2(CO)(PPh3)3 with an NHC precursor (1,3-diisopropylimidazolium bromide) as ligand were the optimal catalyst system with toluene at reflux as the solvent and sodium hydride added as base. A range of both aliphatic and aromatic nitriles were successful substrates with the main limitation being functional groups that were unable to tolerate the basic reaction conditions. Similarly, good substrate scope was observed with respect to the primary alcohol employed. Given the relative ease of accessing isotopelabelled nitriles, this methodology was demonstrated to be effective for the synthesis of labelled-amides with complete isotope incorporation. Deuterium labelling at the α-CH2 of the alcohol demonstrated unequivocally that hydrogen generated from alcohol oxidation is responsible for the reduction of the nitrile, and NMR studies confirmed the involvement of imine intermediates (J. Am. Chem. Soc. 2013, 135, 11704−11707).

2. SOLVENTS A special issue of Current Organic Chemistry was dedicated to green solvents in the synthesis of pharmaceuticals (Curr. Org. Chem. 2013, 17, 1131). Next to articles on biocatalysis and dynamic kinetic resolution, a review paper on green solvents in organic synthesis is included, covering several main classes of environmentally benign solvents, namely water, fluorous solvents, ionic liquids, organic carbonates, scCO2, and biosolvents. The focus of the article is on new evolutions in the last 15 years and on the complementarity of these alternatives (Curr. Org. Chem. 2013, 17, 1179−1187). Liu et al. published a communication on catalysts and additive-free synthesis of disulfides in the biobased green solvent ethyl lactate. This solvent was compared to traditional solvents like DMF and toluene and showed an interesting promotion effect of ethyl lactate on this thiol-coupling reaction (RSC Adv. 2013, 3, 21369−21372). Sutter et al. evaluated the toxicological profile of the glycerolbased 1,2,3-trimethoxypropane. It is proposed by the authors to be an alternative green solvent as it gives a negative result in the Ames test, has low acute toxicity, relatively high flashpoint (45 °C), and low ecotoxicity in an aquatic environment. © XXXX American Chemical Society

Received: May 27, 2014 Accepted: June 5, 2014

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dx.doi.org/10.1021/op500167y | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Green Chemistry Highlights

long-chain monocarboxylic acids are not good substrates. A plausible mechanism is provided in which the nano-MgO activates the carboxylic acid on its surface throughout the amide bond formation (Appl. Catal., A 2013, 456, 118−125).

Sun et al. have reported on the formation of amides from aromatic amines utilizing 1,3-diketones as the acylating agent. The reaction proceeds via a novel C−C bond cleavage under oxidative metal-free conditions with water as the solvent. Initial screening indicated 30% hydrogen peroxide to be the optimal oxidant. Various anilines were successful substrates for the reaction though those bearing electron-withdrawing substituents required elevated reaction temperatures. Aliphatic amines failed to react under the reaction conditions. Various diketones were also evaluated as acylating agents, and steric hindrance was demonstrated to be a critical factor in the efficiency of the acyl transfer. Control experiments to determine the mechanism suggest that the reaction proceeds through an enamine intermediate via a radical mechanism (Green Chem. 2013, 15, 3289−3294).

Two groups have published on the oxidative amidation of benzylic alcohols catalyzed by iron salts in the presence of an oxidant. Gaspa et al. have utilized FeCl3·6H2O with 70% aqueous TBHP as the oxidant. Initially the amine is reacted with NCS to generate the N-chloroamine in situ, which can then be consecutively treated with the alcohol, catalyst, and oxidant. Electronic or steric effects on the aromatic ring of the benzylic alcohol were shown to have little influence on the reaction, and both primary and secondary amines were well tolerated. A radical-type mechanism is proposed (Org. Biomol. Chem. 2013, 11, 3803−3807). The system of Ghosh et al. utilizes Fe(NO3)3·9H2O as the catalyst, and the reaction proceeds in a tandem fashion. Initially, the alcohol is oxidized in the presence of catalytic amounts of the iron salt and TEMPO with air as the stoichiometric oxidant. After 2 h, the amine hydrochloride salt, calcium carbonate, and 70% aqueous TBHP are added, and the reaction is heated to 60 °C for 16 h to form the amide. Again, a range of primary and secondary amines were well tolerated, and little effect was noted based on the electronic properties of the benzylic alcohol. In the case of chiral amine salts, no racemization was detected during the amidation, and again a radical-type mechanism is proposed (Tetrahedron Lett. 2013, 54, 4922−4925).

Lanigan et al. have published on the use of B(OCH2CF3)3 to promote the reaction between carboxylic acids and amines to generate the corresponding amides. An alternative scalable synthesis of the reagent from B2O3 is described, and the compound can be stored at room temperature under nitrogen for ∼4 months without decomposition. In addition, a novel work-up has been developed using a series of commercially available scavenger resins to enable isolation of the pure amide directly from the reaction mixture. The scope of the amidation process is also evaluated. In examples with acids with adjacent chiral centres, no significant racemization was involved, and the protocol was extended to the formation of dipeptides. B(OCH2CF3)3 was also demonstrated to be an effective reagent for the formylation of both primary and secondary amines with DMF (J. Org. Chem. 2013, 78, 4512−4523).

4. OXIDATIONS C−H functionalization is an important area for green chemistry since it offers opportunities for shorter synthetic routes with reduced waste. Roduner et al. reviewed recent advances in C−H oxidations using molecular oxygen, covering both organometallic and biocatalytic approaches. The authors address a critical aspect of reactions using oxygen that is not often addressed in publications: safety. Two ways of safely using oxygen are reviewed, including supercritical CO2 and water as solvents, and flow chemistry in microreactors (ChemCatChem 2013, 5, 82−112). Use of biocatalysis for oxidations is an area of growing interest and application in the pharmaceutical industry. The Turner group at Manchester pioneered the use of engineered monoamine oxidases (MAO) for the preparation of chiral amines. The latest paper from this group describes the development of a number of variants of MAOs derived from Aspergillus niger

Das et al. have published on the use of nano magnesium oxide (MgO) to promote the formation of amides under solvent-free reaction conditions. The reactions took place at 70 °C with the catalyst being recovered by centrifugation, and able to be recycled through 5 reactions without loss of activity. The optimum catalyst load was 5 mol %, with a loss of activity noted at higher loadings, which is believed to be due to a decrease in surface area due to particle aggregation. The catalyst was characterized by numerous techniques such as EDX, FTIR and SEM micrographs, and changes observed as the catalyst lost activity. The activity of the catalyst system is attributed to its enhanced basicity, and this is correlated against yield over a range of catalyst loadings. Numerous carboxylic acids and amines are reported to couple in good to excellent yields under the optimized conditions, though aliphatic dicarboxylic and B




in water at 100 °C, a reaction that produces only water and t-BuOH as waste. The reaction is tolerant of a number of functional groups and also is effective with substrates containing pyridines and thiophenes. The authors propose a mechanism in which the alcohol is first oxidized to the aldehyde, which then forms a hemiaminal with ammonia, followed by oxidation to the primary amide. The drug piracetam was prepared using this methodology as the final step in the synthesis (Green Chem. 2013, 15, 1956−1961).

having broad substrate scope and applications in deracemization reactions of substrates of pharmaceutical interest. The deracemization process consists of a cycle in which an MAO selectively oxidizes one enantiomer of a racemic amine to an imine, with BH3−NH3 converting the resulting imine back to the racemic amine. Repeated cycles thus provide a single enantiomer of the amine with high yield and ee.

Particularly noteworthy was the application of this methodology to the synthesis of (R)-harmicine using the oxidase enzyme for two transformations. First, an indole intermediate is nonselectively oxidized to an iminium ion which is trapped by the nucleophilic indole to afford racemic harmicine. Next, deracemization in the same reaction vessel via the oxidation/ reduction sequence using borane−ammonia produces (R)harmicine in overall 83% yield and >99% ee (J. Am. Chem. Soc. 2013, 135, 10863−10869).

Elimination of highly toxic metals is a goal of green chemistry. However, when these metals are required for a particular transformation, immobilization is an excellent way to minimize exposure and permit reuse. Basavaraju et al. report the immobilization of OsO4 by construction of a flow reactor with the wall surface modified with a nanobrush polymer coating of poly(4-vinylpyridine) used to immobilize OsO4 via ligation to the pyridine units (Angew. Chem. 2013, 52, 6735−6738).

5. ASYMMETRIC HYDROGENATIONS Liu et al. have developed an enantioselective metal-free hydrogenation of imines by using simple chiral boranes as catalyst. The active catalyst was generated in situ from hydroboration of chiral dienes with HB(C6F5)2, thus allowing a wide range of catalysts to be evaluated. Once an optimal catalyst structure was identified, temperature and solvent effects were evaluated. Temperatures between 30 and 0 °C had little impact on enantioselectivity. Solvent effects were pronounced, and mesitylene was identified as optimum. Using optimized conditions of 2.5 mol % diene and 5 mol % HB(C6F5)2 in mesitylene at 25 °C, a variety of biaryl substituted imines were screened. Substitution was limited primarily to the carbon-bound aryl group, and alteration of the methyl group of the imine had little effect on

Base metal catalysis is an area of renewed interest given the inherent lack of sustainability for processes based on precious metals. Iron is a preferred metal catalyst, not only due to its abundance but also for its low toxicity. Regarding oxidants, H2O2 is a preferred green oxidant since the only waste produced is water. Lenze and Bauer combine both these green aspects for the oxidation of 1,2-diols catalyzed by iron(II) complexes using H2O2 in MeCN, finding that the secondary alcohol is selectively oxidized vs the primary alcohol. Five amine ligands were studied, with the symmetrical bis-pyridyl amine (1) as the most effective. The authors conducted preliminary studies to delineate the mechanism but did not draw firm conclusions. Regardless of whether the reaction proceeds via hydride- or hydrogen-atom abstraction, or via electron transfer, the stability of the incipient secondary α-hydroxy carbon radical, cation, or radical cation, over the primary species is likely to be responsible for the observed selectivity. It is also worth noting that the 1,2-diol substrates do not suffer from C−C bond cleavage which is the most common outcome with the majority of strong oxidizing agents (Chem Commun. 2013, 49, 5889−5891).

Continuing with the theme of alcohol oxidations, Wu et al. report a metal-free oxidation of primary and benzylic alcohols to primary amides using tert-butylhydroperoxide and ammonia C




be effective, although with inferior yields and enantioselectivities (Angew. Chem. Int. Ed. 2013, 52, 1−5). An Ir(I)phosphine−phosphite complex has been developed and employed in the asymmetric reduction of various imine hetereocyles, i.e. benzoxazines, benzoxazinones, benzothiazinones, and quinaxalinones for the first time. The catalyst loading was found to be in the order of 0.5−2 mol %. This catalytic system works at room temperature and affords the product in excellent yields (94−99%) and enantioselectivities (94−99% ee). Mechanistically, stepwise proton and hydride transfers are thought to be the favored pathways to afford products (Org. Lett. 2013, 15, 2066−2069).

enantioselectivity. Under mild reaction conditions asymmetric reduction is achieved up to 99% yield and 89% ee (J. Am. Chem. Soc. 2013, 135, 6810−6813). Continuous flow technology is considered to be one of the best alternatives to batch mode operations in R&D and manufacturing. Duque et al. have developed a continuous-flow, solvent-free asymmetric hydrogenation strategy to reduce dibutyl itaconate to (S)-dibutyl 2-methylsuccinate at room temperature under 5 bar H2 pressure in the presence of Rh−MeDuPHOS catalyst immobilized on alumina using phosphotungstic acid as the anchor. The conversion and enantioselectivity were found to be up to 99% and 98%, respectively. The low operating pressure utilized in this protocol allows for a more efficient use of hydrogen, and the product can be accessed without decompression. Leaching of Rh is very low, allowing for extended run times; however, the ee began to decrease after 23 h, and conversion began to decrease after 47 h continuous reaction time (Angew. Chem. Int. Ed. 2013, 52, 9805−9807).

The potential of BIPI (phosphinoimidazole) ligands in combination with Ir(cod)BArF have been exploited in the asymmetric reduction of difficult substrates, i.e. dimethylindene and dimethyldihydronaphthalene. Screening identified ligand 2, having the fluoride substituent, as extremely effective. A brief screen of solvents was conducted, and dichloromethane gave higher conversion compared to methanol or toluene. Various tetrasubstituted olefin substrates have been tested, and the conversion and enantioselectivities of these were found to be excellent under optimized conditions, consisting of 2 mol % catalyst, in dichloromethane at 0 °C (Adv. Synth. Catal. 2013, 355, 1455−1463).

Ru/SNNS [N,N-bis(2-tert-butylthiobenzylidene)-1,3propanediamine] systems are analogous to chiral PNNP and salen Ru complexes and are found to have potential similar to that of Ru diphosphine complexes. This is the first catalyst of its kind that has been tested for asymmetric hydrogenation of simple to hindered/unsaturated ketones in high yields (98%) and enantioselectivity (95% ee). The substrate/base/catalyst ratio was found to be in the order of 2000/100/1; in some cases it was as high as 29300/1083/1. This system has better features as it can tolerate air and moisture. Catalysts based on Ru/SNNS show excellent chemoselectivity in the reduction of unsaturated ketones and aldehydes with S/C ratios up to 106/1. In situ formation of the catalyst without base was also found to

6. C−H ACTIVATION Huang et al. have developed an iron-catalyzed oxidative radical cross-coupling/cyclization to synthesize dihydrobenzofurans. A combination of 10 mol % FeCl3 and 1.2 equiv DDQ are used to couple electron-rich phenols and napthols with styrene or styrene derivatives. The reaction is initiated through DDQ-promoted oneelectron phenol oxidation. Iron coordination of the oxidized phenol stabilizes the carbon−centred radical which then undergoes addition with styrene followed by C−O bond formation. While the chemistry is quite mild and uses iron as a green catalyst, one drawback is that 2 equiv of olefin are required to obtain high yields (Angew. Chem. Int. Ed. 2013, 52, 7171−7155). D




ionic strength of the reaction, a pH-dependent Brønsted acidcocatalyzed reaction was discovered where 1 equiv of TFA provided the best yield. These conditions decrease reaction time significantly to 5 h (23 without TFA) and improve yield to 90% (60% without TFA). Substitution on the amine−phenyl ring was well tolerated as well as on the aromatic positions of the tetrahydroisoquinoline. A small sampling of other Michael acceptors also resulted in good yields. The authors present a significant amount of detail into the mechanistic understanding of the reaction and studies to optimize the pH for this process, highlighting the benefit this genre of Brønsted acid-cocatalyzed reaction systems may have on other radical processes (J. Org. Chem. 2013, 78, 4107−4114).

A C−H lactonization method has been developed which efficiently constructs biaryl lactones via carboxylic acid-directed C−H functionalization/C−O bond reductive elimination. The reaction uses a simple catalyst system, 5 mol % Pd(OAc)2 and 15 mol % N-acetylated glycine, for C−H functionalization of 2-aryl carboxylic acids. The terminal oxidant is (diacetoxyiodo)benzene which is believed to generate a palladium(IV) intermediate that can more readily undergo C−O reductive elimination. The reaction scope is broad; however, ortho-substituted biaryl acids couple in moderate yields (∼50%) with >30% recovered starting material. The authors demonstrate the utility of the method through the synthesis of cannabinol which requires two successive C−H lactonization steps (Org. Lett. 2013, 15, 2574−2577).

7. GREENER FLUORINATION Mazzotti et al. reported a robust, scalable, and practical palladium-catalyzed fluorination of arylboronic acids. Prior to this work, the catalytic alternatives providing such functionalized aryl fluorides consisted of Pd-catalyzed fluorination of aryl triflates, or the silver-catalyzed fluorination of stannanes. The current work constitutes an obvious improvement from an environmental standpoint. The Pd-catalyzed fluorination uses terpyridyl Pd (II) complex as a precatalyst. It proceeds in DMF or acetonitrile and converts aryl trifluoroborates, or even their boronate esters or boronic acids, both electron−rich and poor, into their corresponding fluorides. The methodology is compatible with a wide range of functional groups (ketones, amides, carboxylic acids, esters, bromides, heterocycles) and results in yields ranging from 63% to 99%. The paper comprises useful mechanistic considerations which should further help in optimization specific to a substrate in the future (J. Am. Chem. Soc. 2013, 135, 14012−14015).

Pirnot et al. have developed a method for direct activation at the β-position to a carbonyl via photoredox activation. The system they optimized takes advantage of a common household compact fluorescent bulb and a commercially available catalyst with only 1 mol % loading. An amine cocatalyst facilitates enamine formation with the aldehyde, followed by enamine oxidation and the subsequent nucleophilic radical coupling with the arene at the β-position. Good yields from 44−86% for a variety of aldehydes and ketones in a cyclic 6-membered ring system when X = C and EWG = CN are reported. Also, a variety of electron-withdrawing groups including pyridine systems where X = N delivers good yields, with the best yields provided by esters and sulfones at the ortho and para positions. The real highlight of this methodology may be the ability to use a cinchona-based amine catalyst to deliver chiral products. At this time they only highlight one example with cyclohexanone delivering 50% ee, but studies are ongoing. The authors do highlight the unfortunate formation of an equivalent of cyanide during the course of the reaction, generating an aqueous waste stream which must be treated accordingly. Finally, another drawback to consider is reaction time, with most reactions requiring times in the 48 h range (Science. 2013, 339, 1593−1596).

Bloom et al. reported an elegant iron-catalyzed benzylic fluorination method as a synthetic equivalent to 1,4-conjugate addition of fluoride. Iron(II) acetylacetonate was demonstrated to catalyze effectively the net conjugate fluorination formally carried out with Selectfluor. While a large excess of fluoride source is still being used, the ability to derivatize an activated but unfunctionalized benzylic position offers an interesting alternative in terms of feedstock. In addition, it enlarges the scope and utility of iron as a catalyst. The methodology was demonstrated on a wide range of aromatics and proceeded in modest yields (38% to 75%) with improved reactivity on esters and carboxylic acids. Although still suffering from modest yields, the mild conditions combined with an operationally simple and robust process makes this chemoselective transformation highly

In another example of photocatylzed C−H activation, Yoon and co-workers have developed a Brønsted acid-cocatalyzed radical photocatalytic C−H activation at the α-amino site of tertrahydroisoquinolines. First, conditions were optimized with the use of a 23 W compact fluorescent lamp and the commercially available Ru(bpy)3Cl2 catalyst. During the course of investigations to improve the reaction rate by increasing the E




attractive, and prone to future development (J. Org. Chem. 2013, 78, 11082−11086).

Terpenoid products obtained from the cyclisation of a polyisoprene backbone have important applications from chiral building blocks in synthesis to therapeutic compounds such as taxol and artemisinin. Seitz et al. demonstrated that triterpene cyclases can be used to generate di- and triheterocycles from functionalized, shortened polyisoprene units. This highlights the versatility and flexibility of these enzymes to act as general Brønsted acid catalysts. Using a cyclase from Zymomonas mobilis, a range of terminal nucleophiles could be used to produce cyclic ethers, enol ethers, and lactones in reasonable yields (ChemBioChem 2013, 14, 436−439).

8. BIOCATALYSIS Many enzyme-catalysed reactions such as ketoreduction, transamination, and monooxygenation are showing increasing use in chemical synthesis. Whilst the development of naturally occurring reaction types is continuing, it is not necessary to limit biocatalysis to reactions which have natural precedents. Coelho et al. demonstrated this concept by altering the activity of cytochrome P450BM3 from Bacillus megaterium from oxygenation to cyclopropanation. By substituting a cysteine thiolate ligand with a weakly donating serine, the authors raised the FeIII/II potential and allowed the enzyme to facilitate an NAD(P)H-driven reaction. This mutation also removed monooxygenation activity from the protein. The engineered enzyme was shown to work in vivo for the cyclopropanation of styrene under anaerobic conditions. Despite the use of ethyldiazoacetate which is a drawback, the product was formed in good yield and with high diastereo- and enantioselectivity (Nat. Chem. Biol. 2013, 9, 485−487).

Conducting more than one reaction in the same vessel can make processes much more sustainable as it can reduce cycle times and energy consumption, as well as minimise both yield loss and waste. Enzymatic processes in particular have great potential for one-pot cascades as reaction conditions tend to be more similar than for chemical reactions. Liu and Li have shown this approach is possible for the synthesis of (R)-2-alkylδ-lactones from 2-alkylidenecyclopentanones. This system uses an enoate reductase from Acinetobacter sp. RS1 and a Baeyer− Villiger mono-oxygenase expressed in E. coli. The whole cells expressing each enzyme are added sequentially to a single pot, and the product lactones are produced in good yields and high enantioselectivity (ACS Catal. 2013, 3, 908−911).

To further expand the transformations catalysed by the engineered P450BM3 enzyme, McIntosh et al. reported an intramolecular C−H amination. Using E. coli cells in vivo under anaerobic conditions, high yields, total turnover numbers (TTN), and ee could be achieved. These results compare favorably with those previously reported for this transformation by chemical methods (Angew. Chem. Int. Ed. 2013, 52, 9309−9312).

One of the more aspirational transformations in the ACS Green Chemistry Institute Pharmaceutical Roundtable’s 2007 paper was the asymmetric hydrogentation of unfunctionalized olefins, enamines, and imines. The reduction of this last class of substrates has recently been reported by Rodriguez-Mata et al. Using an (R)-selective imine reductase (IRED), Q1E1E0 from Streptomyces kanamyceticus, 2-methyl-1-pyrroline could be reduced to (R)-2-methylpyrrolidine in low yield but excellent ee. Moreover, the crystal structure of the protein was solved, and it is hoped that this may help deduce the mechanism of this reaction and provide a basis for rational engineering of the enzyme (ChemBioChem 2013, 14, 1372−1379).

Interestingly, the ee of the product is higher than that observed in the initial reduction reaction, indicating possible F




degradation of the product lactone. It was found that hydrolysis of the (S)-2-alkyl-δ-lactone was being catalysed by Acinetobacter sp. RS1, causing the ee of the (R)-δ-lactone to be upgraded. As more and more novel biocatalysts and enzyme-catalysed reactions are discovered, this brings into focus the need to think differently about the way molecules could be constructed. To assist in this regard, Turner and O’Reilly have proposed that new guidelines for “biocatalytic retrosynthesis” should be developed for future training and education of synthetic chemists (Nat. Chem. Biol. 2013, 9, 285−288).

substrate to generate a relatively stable tertiary cation. In the absence of Et2O, dimerization of the substrate occurs (Angew. Chem., Int. Ed. 2013, 52, 7492−7495).

9. REDUCTIONS It has long been known that hot, alkaline conditions decompose sugars to hydrogen and a variety of low-molecular weight organic species, e.g. lactate, formate, and acetate. Kumar et al. have exploited this and used D-glucose as the sole reducing agent in a catalyst-free process. There are some deficiencies in the system at the present time. There is a requirement for an extended hold at elevated temperatures, but at present, substrate concentrations are only 0.25 M, and there is clear scope for optimisation. Nonetheless, impressive chemoselectivity was reported with halide, vinyl, carbonyl, and even additional nitro substituents remaining unaffected by the conditions. Yields were in the range 47−99% across a total of 22 substrates (RSC Adv. 2013, 3, 4894−4898).

One crucial aspect to be considered for industrial application of FLPs (and indeed other novel research technologies) is the tolerance towards impurities. Cost concerns typically mean that solvents and other reagents are used at lower specification than in a research environment where prepurification is common. In the FLP-catalyzed hydrogenation of imines, residual amounts of aldehyde and water can lead to catalyst poisoning. Thompson et al. have explored the use of scavengers with common FLP systems and shown that small amounts of tri-isobutylaluminum (TIBAL) or triethylsilane can prevent poisoning and can even restore activity in a stalled reaction. Seven substrates were considered in this work, although chemoselectivity was not broadly investigated apart from the presence of aryl halides. One aspect of this work is that typical catalyst loadings are already around 0.5−2.5 mol % with the potential to reduce further although loadings are higher for some electron-rich systems (Org. Process Res. Dev. 2013, 17, 1287−1292).

Possibly the most studied of the metal−free reducing agents are the frustrated Lewis pairs (FLP). These systems deliver both hydrogen activation and subsequent reduction of organic compounds via noninteracting Lewis acid/base centres. A common component in such systems is tris(pentafluorophenyl)borane. Now Nicasio et al. have shown that related boranes showing reduced Lewis acidity can also function effectively in the reduction of electron-deficient olefins. They determined that the rate-limiting step in such reductions was the transfer of hydride from an intermediate borohydride species [e.g., (F5Ph)3BH−]. Moderating the Lewis acidity of the borane species facilitated subsequent hydride transfer while still allowing heterolytic hydrogen cleavage. Control experiments showed that both components were necessary for reaction to occur, applying the isolated borohydride reagent followed by a DABCO·H+ quench was not successful. Optimal conditions were reached using (2,4,6-F3Ph)3B as Lewis acid. A range of substrates could be reduced using this system where the olefin was activated by ester, sulfonyl, and nitro groups. However, apart from the nitroolefins, it was necessary for >1 electronwithdrawing group to be present (RSC Adv. 2013, 3, 21369−21372. Chem. Eur. J., 2013, 19, 11016−11020). Generally FLP systems utilize a P- or N-centred Lewis base, Hounjet et al. have now shown that even simple ethers can function as promoters in certain situations and have demonstrated the hydrogenation of 1,1-diphenylethylene with >95% conversion. It appears that the critical aspects of this approach are the Lewis basicity of the ether and the ability of the

The above FLP cases might be viewed as niche examples that require lengthy reaction times and whose green credentials are limited to avoiding the use of endangered metals. As the field develops, however, the scope for optimising Lewis acid/base partners and additives will increase and limitations of substrate range and catalyst activity will reduce. We are beginning to see that these approaches do show the potential for more tailored systems to be developed that offer scope for competitive metalfree reductions. Base metal catalysis has gained in popularity as an alternative to the use of precious metal catalysts. Typically having lower toxicity and greater abundance, this strategy is a green approach to catalytic methodologies. Four papers that demonstrate the power of this strategy using iron catalysts were published during the current review period. One strategy using in situ formed iron heterocyclic carbene complexes was reported by Volkov et al. Using N,N-dimethylbenzamide as a model substrate, conditions G




sufficient to warrant strong consideration of this iron-catalyzed alternative of a very common transformation (Eur. J. Org. Chem. 2013, 2061−2065).

were refined that produced both high activity and selectivity for the amine, versus formation of the aldehyde and alcohol products. Iron(II) acetate and the ionic liquid [Ph-HEMIM][OTf] were used under further refinement of silane and solvent. Using these results, a mechanism was proposed that led to the final optimized conditions. The reduction was reported with aryl or heteroaryl tertiary amides, using 1 mol % iron(II) acetate, 1.1 mol % [Ph-HEMIM][OTf], 2.2 mol % n-BuLi, 1 mol % LiCl, and 3 equiv polymethylhydrosiloxane (PMHS) in THF at 65 °C, affording the tertiary amine product in high yield with relatively short reaction time. Reactions using primary or secondary amides failed to produce product (Eur. J. Org. Chem. 2013, 2066−2070).

Another publication focussing on reduction of carboxylic esters and amides was reported by Fernández-Salas et al. In this paper, the reduction of esters to alcohols was first approached using silane-mediated reduction, catalyzed with potassium hydroxide. After a screen of both silane and base catalyst, conditions for the reduction of methyl benzoate were identified. Using 1.1 equiv of phenylsilane with 4 mol % potassium hydroxide under solvent-free conditions at room temperature reduction reactions were complete within 1 h. A variety of esters were reduced under these conditions, some required 60 °C to achieve complete reduction, and some required the use of a small amount of THF. Additional solvents were not screened, as the authors appeared to prefer solvent-free conditions for this transformation. When applied to amides, these conditions provided the amines in high yield, though longer reaction times were required. Again, heating or the use of THF was required in certain cases. Primary and secondary amides returned only starting materials; thus, this methodology is currently limited only to tertiary amides (Chem. Commun. 2013, 49, 9758−9760).

Selective reduction of conjugated α,β-unsaturated aldehydes to provide allylic alcohols is a challenging problem in chemical synthesis. Wienhöfer et al. published a paper using iron catalysis to address this. Extending the use of an iron complex previously identified by the Beller group for hydrogenation of carbon dioxide and bicarbonate, they endeavoured to selectively reduce the model system of cinnamaldehyde. They quickly identified the need of an acidic cocatalyst and found that cinnamaldehyde can be reduced selectively without reducing the olefin. A solvent screen identified isopropyl alcohol as the optimum solvent, as lower-chain alcohols lead predominately to formation of acetals. High temperatures are required, the optimum being 140 °C, at which temperature catalyst loading can be reduced to 0.05 mol %. However, for practicality temperatures of 120 °C were chosen for additional optimization. The optimum reaction conditions are 0.2 to 0.4 mol % [FeF(L)[BF4], 20 bar H2, 120 °C, trifluoroacetic acid (2 mol %) in isopropyl alcohol. These conditions were demonstrated on a number of conjugated aldehyde systems and showed high functional group tolerance providing the allylic alcohols in >95% yield in most cases. Additionally, a very nice mechanistic investigation was conducted and reported in detail (Chem. Eur. J. 2013, 19, 7701−7707).

10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT Two groups have published studies into the N-alkylation of heterocyclic amines with alcohols, in particular various benzazoles, a common motif in pharmacophores. Bala et al. report on the effectiveness of an iron catalyst for the transformation. Fe(II)phthalocyanine (FePc), an inexpensive catalyst the group has developed for other chemistries, was found to provide good yield (92%) in a model reaction of 2-aminobenzothiazole with benzyl alcohol in toluene with sodium tert-butoxide at 100 °C; the reaction did not proceed in the absence of catalyst. This protocol provides moderate to very good yields with a wide array of variously substituted heterocycles as well as providing various benzazoles via ring closures of ortho-substituted anilines reacting with alcohols and 2 equiv base at 120 °C. The typical hydrogentransfer mechanism of alcohol oxidation, imine coupling, and reduction was confirmed by intermediate trapping with modified reaction conditions (Green Chem 2013, 15, 1687−1693).

Junge et al. published an iron-catalyzed reduction of carboxylic ester to alcohols. After a brief screen of iron and ligand options, an ideal combination was realized that used 5 mol % Fe(stearate)2 with 10 mol % 1,2-diaminoethane. The reductant, polymethylhydrosiloxane (PMHS) was used in 3.0 equiv in toluene at 100 °C. There was no mention of modifying the solvent for this transformation. Using these optimized conditions, the reaction produced moderate and variable yields of the alcohol products, and showed poor tolerance for other reducible functionalities. Keto, nitro, and amide groups were fully reduced under the reaction conditions, while the ester remained largely intact. Nonetheless, the number of compatible functionalities is H




Shimizu et al. prepared heterogeneous nickel nanoparticles supported on θ-alumina for the N-alkylation of anilines and some primary and secondary amines with a range of alcohols. Reactions were conducted base free using 1 mol % of catalyst (5 wt % Ni on θ-alumina) in o-xylene at 144 °C, with 33 h−1 turnover frequency, comparing favorably to other heterogeneous systems. Two mol % catalyst was used for the reaction of aliphatic amines and alcohols. The catalyst was prepared by reduction of supported nickel oxide under a flow of hydrogen at 500 °C prior to use. The catalyst was readily separated from the reaction mixture by centrifugation and could be reused at least 3 times after regeneration under the reducing conditions. Mechanistic studies support the hydrogen-borrowing mechanism, and catalyst characterization studies led the authors to conclude that the metal/support interface is probably the active site of the catalyst (ACS Catal. 2013, 3, 998−1005).

In contrast, Donthiri et al. describe a metal-free N-alkylation of 2-amino-substituted benzothiazoles, thiazoles, pyridine, pyrazine, and pyrimidine with benzyl alcohols. The reaction is conducted in toluene at 120 °C with 20 mol % sodium hydroxide as catalyst. The reaction does not proceed in DMF, DMSO, glycerol, or water, whilst chlorobenzene gives a lower yield in the model alkylation of 2-aminobenzothiazole with 4-chlorobenzyl alcohol. Weaker bases (Na2CO3, K2CO3) and lower temperatures (e.g., 100 °C) give lower yields, whereas KOH, NaOtBu, and KOtBu are good (yield >85%), but not as effective as NaOH. The yield of the reaction is independent of electron-donating or -withdrawing substituents in either the benzyl alcohol or 2-aminobenzothiazole with isolated yields in the range 80−96%. N-benzyl 2-aminothiazole is obtained in 96% isolated yield, comparable to Bala et al. at a higher temperature without catalyst. The reaction only proceeds with benzyl alcohols and pyridinemethanol (J. Org. Chem. 2013, 78, 6775−6781).

Continuing the heterogeneous catalyst theme, Yamada et al. report the use of polyspiroborate iridium catalysts for the alkylation of amines and ammonia in water. The insoluble polymeric catalysts were prepared by treating a soluble linear catecholborate polymer with an iridium species in a mixture of DME−acetonitrile. Spectroscopic analysis of the resulting insoluble product shows a material composed of anionic spiroborate polymer with dicationic Ir2+, the iridium acting as a crosslinker in the polymer. The catalyst (1 mol % Ir) was used for the alkylation of anilines, benzylamine, dibenzylamine, morpholine, and 4-hydroxymethylpiperidine with benzyl alcohols in water at 100−150 °C for 24 h. Tribenzylamines could be prepared in 57−95% yield by heating aqueous ammonia with benzyl alcohol and the catalyst in pH 4 buffer at 150 °C in a microwave reactor for 24 h; ethyl acetate was used to extract the product during the work-up. The catalyst was removed by decantation and reused three times (Synthesis 2013, 45, 2093−2100).

The authors in both publications present studies to support in situ oxidation of the benzylalcohol to the corresponding benzaldehyde as the first stage of the mechanism, facilitated by FePc in the first paper and oxygen in the second. These findings are consistent with the literature and may account for the differences in reactivity highlighted here. Heterogeneous catalysts are attractive for their ease of separation and potential for reuse; however, they can require extended reaction times at high temperature. Wang et al. have developed an N-heterocyclic carbene−iridium complex supported on a mesoporus silica (SBA-15) which was successfully used to catalyse the N-alkylation of anilines, benzylamine, cyclohexylamine, and 2-aminopyrimidine and the β-alkylation of 2° alcohols with benzyl alcohols (hexylalcohol was used in one example of each transformation). The heterogeneous catalyst was found to give a superior yield to the corresponding homogeneous analogue in both transformations. The substrates were mixed with the catalyst (1.5 mol % Ir), base and heated in toluene at 110 °C. N-Alkylation reactions were run for 48 h with NaHCO3 (0.5 equiv) and β-alkylation reactions 24 h with KOH (1 equiv). The catalyst could be recovered and reused 8 times for β-alkylation and 12 times for amine alkylation. The authors argue that the SBA-15 support plays an active role in the reactions by providing a water sink (Adv. Synth. Catal. 2013, 355, 1117−1125).

Putra et al. have combined two hydrogen-transfer reactions for the enantioselective preparation of β-aminoalcohols from racemic diols. Treatment of excess 1-phenyl-1,2-ethanediol with secondary amines in the presence of [RuCl2(p-cymene)]2 and (S,R-Josiphos) for 24 h in toluene at 100 °C affords the amino alcohol in good to high yield (99% by 1H NMR, 87% isolated in 1 example) with moderate ee (up to 77%). Mechanistic studies show that the diol is oxidised to the corresponding ketoaldehyde which undergoes reductive amination of the aldehyde followed by asymmetric hydrogenation of the ketone (Eur. J. Org. Chem. 2013, 6146−6151) (Scheme 1). Three publications describe the use of CO2 as a C1 building block for amine methylation. Jacquet et al. utilise phenylsilane (2 equiv) and a mixture of an N-heterocyclic carbene and zinc chloride (5 mol %) in THF for N-methylation of I




great influence. Not surprisingly, electron-donating groups enhance the reactivity over substrates bearing electron-withdrawing groups. The mechanism is presumed to proceed via addition of the 1,3-dicarbonyl compound to an N-acyliminium ion intermediate (from the initial dehydration of the hydroxyl group) followed by ring closure via Friedel−Crafts alkylation (J. Heterocycl. Chem. 2013, 50, 501−505).

Scheme 1

N-methylanilines. N,N-dimethylaniline was obtained in 95% yield after 20 h at 100 °C, under 1 bar CO2. The influence of electron-donating and -withdrawing substituents and their substitution position were explored, and the reaction was extended to 1° amines and anilines with variable results; treatment of aniline for 72 h afforded a mixture of N,N-dimethylaniline (79%) and N-methyl-N-phenylformamide (21%) (Chem. Sci 2013, 4, 2127−2131). Li et al. have found a ruthenium-based catalyst system for use with phenylsilane (4 equiv) in toluene at 100 °C, under 30 bar CO2 for the N-methylation of a wider range of 2° amines; there are 22 examples with isolated yields ranging from 61−99% (Angew. Chem. Int. Ed. 2013, 52, 9568−9571). Beydoun et al. use molecular hydrogen (60 bar) as the reductant in the presence of a ruthenium catalyst in THF at 150 °C, under 20 bar CO2 (Angew. Chem. Int. Ed. 2013, 52, 9554−9557). There is some overlap of examples with the previous paper and neither method is superior in all cases. Anilines and primary amines are dimethylated using both methods. All three groups present studies that support a formamide intermediate.

12. CHEMISTRY IN WATER Chou and Raines describe the conversion of azides into diazo compounds in water. By the use of water as solvent the applicability of this conversion in chemical biology can become of potential interest. The process is illustrated for the synthesis of various diazoacetic acid esters and amides, and a wide range of functional groups are tolerated.

The authors report the design and optimization of a watersoluble activated phosphinoester used in stoichiometric quantities to mediate the azide to diazo conversion in a phosphate buffer solution of pH 7. Especially, the reaction almost exclusively produced the diazo compound without side-product formation of Staudinger ligation if the conjugated acid of the leaving group in the phosphinoester has a pKa < 7 (J. Am. Chem. Soc. 2013, 135, 14936−14939). By the developments in modern click chemistry the 1,2,3triazole group has become a privileged scaffold in many bioactive molecules. An alternative preparation of these triazoles is by an organocatalyzed 1,3-dipolar cycloaddition reaction of ketones and azides. However, the reported reactions are restricted to the use of organic solvents. Yeung et al. now describe the use of water as solvent for this 1,3-dipolar cycloaddition using 20 mol % of proline N,N-dioctylamide as organocatalyst. This reaction in water at 80 °C is applied to a wide range of ketones and aromatic azides (Green Chem. 2013, 15, 2384−2388).

11. FRIEDEL−CRAFTS CHEMISTRY Wang et al. have demonstrated a one-pot synthesis of pyrrolo[1,2-a]quinolin-1-ones from the reactions of 5-hydroxy-1arylpyrrolidin-2-ones with 1,3-dicarbonyl compounds using H3PO4/P2O5 or HOAc/H2SO4. The examples utilizing ethyl acetoacetate and acetylacetone were generally high yielding; however, when ethyl benzoyl acetate was employed, lower yields were obtained. Presumably this is due to the steric hindrance of final cyclization. The substituents on the phenyl ring also have a

A new method for aroylation with CO and aryl iodides via ruthenium-catalyzed C−H activation of (hetero)arenes bearing J




In another interesting article by Grego et al., details of a catalytic fixed bed continuous process for the synthesis of methyl phenylcarbamate by carbamoylation of aniline by dimethyl carbonate in the presence of zinc carbonate catalyst has been reported. Detailed studies on parametric effects influencing this phosgene-free process showed high conversions (∼98% at 200 °C) and selectivity (97%) without any significant catalyst deactivation even after 180 h despite a reaction stoppage and restart in between (Org. Process Res. Dev. 2013, 17, 679−683).

ortho-directing groups is described by Beller and co-workers. Remarkably, the reactivity of this carbonylative C−C coupling was dramatically increased by changing the organic solvent to water. The best reaction conditions identified are 5 mol % of RuCl2(cod) catalyst and 0.2 equiv of KOAc as additive, using NaHCO3 (2 equiv) as base and 30 bar CO at 120 °C for 20 h. Pyridine-2-yl, N-pyrazole, and pyrimidine-2-yl have been used as ortho-directing groups (Angew. Chem. Int. Ed. 2013, 52, 6293−6297).

Pedersen et al. made use of a setup where a continuous stirred tank reactor (CSTR) and static mixer reactor were connected in series to overcome challenges associated with impurity formation and handling of suspended solids in plug flow reactors for the Grignard alkylation reaction of 2-chlorothioxanthen-9-one with allylmagnesium chloride. The CSTR was used to generate and retain the solid phase, whereas an outward line fitted with a filter was used to transfer the homogeneous liquid phase into plug flow static mixer reactor to achieve higher conversions of the unreacted ketone (Org. Process Res. Dev. 2013, 17, 1142−1148).

The iron(III)-catalyzed direct nucleophilic substitution of allylic (benzylic) alcohols with a wide range of nucleophiles has been described by Trillo et al. Although the application of FeCl3 Lewis acid-catalyzed processes in water have been known for some time (e.g. in Mukiyama aldol reactions) examples of direct substitution of free allylic alcohols in water are rare. Various sulfonamides and anilines, as well as benzyl carbamate, benzamide, benzotriazole, and TMSN3 can be used as nitrogen nucleophiles, but no conversion was observed with tert-butyl carbamate and basic amines (benzylamine, butylamine, ammonia). Also carbon nucleophiles such as allyltrimethylsilane, TMSCN, anisole, indole, or diethyl malonate can be used. Use of FeO(OH)·2H2O instead of FeCl3 as the catalyst worked equally well or even slightly better for less acidic sulfonamides, anilines, and indole. The low toxicity of FeCl3, the use of water, and the lack of leaving group activation makes this conversion of special interest (ChemCatChem 2013, 5, 1538−1542).

Lehmann et al. carried out an inverse-electron-demand Kondrat’eva reaction to generate cycloalka[c]pyridines from unactivated oxazoles and cycloalkenes in a continuous tubular reactor under conditions of elevated temperature and pressure. Continuous flow reactor characteristics offer much better control and efficiency over batch reactors under the required extreme operating conditions (230 °C and 750 psi), and the process offers easy access to annulated pyridines (Org. Lett. 2013, 15, 3550−3553).

In recent years various successful examples of sp2 C−H bond activation in water and the application in a variety of catalytic cross-coupling reactions have been described in the literature. These cross-coupling reactions and the role of water as a solvent have been reviewed in a recent paper by Li and Dixneuf (Chem. Soc. Rev. 2013, 42, 5744−5767). Tomasek and Schatz review recent developments of olefin metathesis in aqueous media. The two main strategies are discussed: design and application of water-soluble catalysts and the use of commercial catalysts under heterogeneous micellar conditions (Green Chem. 2013, 15, 2317−2338).

14. GENERAL GREEN CHEMISTRY Adams et al. from GSK have published an article on GSK’s reagent guide which has the objective of embedding sustainability into reagent selection. The assessment includes a combined environmental score, heath score, and safety score, a chemistry score which takes into account factors such as work-up, stoichiometry, and atom efficiency. Three of the reagent guides are published in the paper with a further 12 shared in the Supporting Information. The format is impactful and easy to use (Green Chem 2013, 15, 1542−1549). Leahy et al., have published an article proposing seven key elements of an effective Green Chemistry program with examples from several pharmaceutical companies. The seven key elements are (i) empowered Green Chemistry teams with management support, (ii) metrics and targets, (iii) resources and tools, (iv)

13. CONTINUOUS PROCESSING AND PROCESS INTENSIFICATION Yoshida et al. published a featured article on the use of micro reactors to enable flash chemistry (i.e., chemistry that is unsuitable for batch/semibatch processing) involving extremely fast reactions (

The Green Chemistry Articles of Interest - Organic Process Research

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