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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., Genentech, GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, Pfizer, Inc., and Sanofi. One of the strategic priorities of the Roundtable is to inform and influence the research agenda. Two of the first steps to achieve this objective were to publish a paper outlining key green chemistry research areas from a pharmaceutical perspective (Green Chem. 2007, 9, 411−420) and to establish annual ACS GCIPR research grants. This document follows on from the Green Chemistry paper and is largely based on the key research areas though new sections have been added. The review period covers October 2014 to March 2015. These articles of interest represent the opinions of the authors and do not necessarily represent the views of the member companies. Some articles are included because, while not currently being regarded as green, the chemistry has the potential to improve the current state of the art if developed further. The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures.

substrates. The reaction was performed at 35 °C with the products being isolated without chromatography after extractive workup. A range of functional groups were well-tolerated by the reactions, and aromatic heterocycles were also successful substrates including furans which are often prone to oxidation. The reaction with 2-nitropyridine provided a low yield of the desired amide, and no examples of couplings with aliphatic aldehydes are reported (Synthesis 2015, 47, 949−954).

Hummel and Ellman have described a heterocycle directed C−H amidation with isocyanates using Co(III) for the preparation of a range of functionalized benzamides. The optimal conditions utilize the air- and moisture-stable cationic preformed complex [Cp*Co(C6H6)][PF6]2 as the catalyst with 1,4-dioxane as the solvent. Reactions were performed at 120 °C with the addition of catalytic potassium acetate shown to be the key for success. Lowering the catalyst loading to 2.5 mol % had a minimal effect on isolated yield, and reactions were typically run at 2.0 M concentration to minimize solvent volumes. A range of aromatic isocyanates were successfully coupled with electronic and steric effects having negligible impact on the reaction efficiency. Alkyl isocyanates were also successful coupling partners, though in some of these instances, higher catalyst loading (10 mol %) was required to obtain high yields. Good functional group tolerance was observed enabling either further functionalization of the product or late stage introduction of the amide to be achieved. A number of nitrogen-based heterocycles (pyrazoles, pyrimidines, and pyridines) were shown to be effective directing groups, and a gram-scale example of the reaction is also described. This is also the first example of this transformation that does not require a precious metal catalyst (Org. Lett. 2015, 17, 2400−2403).

2. SOLVENTS γ-Valerolactone (GVL) is a solvent which has attracted much interest in the green chemistry literature as it is relatively polar and biomass derived. Strappaveccia et al. have successfully used GVL in the Heck reaction using a Pd/C catalyst and found that in addition to giving excellent yields, GVL leached less palladium from the solid support than DMF or NMP (Green Chem. 2015, 17, 365−372). 3. AMIDE FORMATION Sheng et al. have reported on the synergistic operation of an oxidant and a reductant in a one-pot synthesis of amides directly from nitro-arenes and aldehydes, thus potentially reducing the number of operations to access this moiety. Model studies indicated that zinc with acetic acid was the optimal reducing agent with sodium chlorate performing best as the oxidant from a range of reagents screened. Stoichiometry proved critical to success with a ratio of 1:1.4:4:1:2 (nitroarene−aldehyde−zinc powder−sodium chlorate−acetic acid) providing the highest yields. A 3:1 ratio of ethanol to water was employed as the solvent system to ensure dissolution of the © XXXX American Chemical Society

Numerous reaction conditions have been disclosed for the classical Beckmann rearrangement although these are often accompanied by drawbacks such as harsh reagents, forcing conditions, multistep sequences, or use of excess organic solvents. Mahajan et al. have described a one-step method to directly convert ketones to amides in the presence of hydroxylamine hydrochloride under solvent-free conditions. Received: February 12, 2016 Revised: February 19, 2016 Accepted: February 24, 2016

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DOI: 10.1021/acs.oprd.6b00042 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Green Chemistry Highlights

atures leading to decomposition of the N-formylated products. Primary and secondary aliphatic, aryl and heteroaryl amines were all successful substrates with electron donating substituents being shown to accelerate the reaction. α-Amino acid derivatives could also be utilized without racemization. Replacing formic acid with other acids accompanied by a slight increase in temperature led to formation of the corresponding amides. The high water solubility of the catalyst made product workup and isolation facile through an extractive workup, and the HPAIL could be recovered and recycled through the reaction four times with a minimal loss of activity (Tetrahedron 2014, 70, 2237−2245). Fu et al. have expanded this reaction manifold to the transamidation of nonactivated carboxamides with amines. In this case, model studies indicated that 2 mol % of the pyridinebased HPAIL [PyPS]3PW12O40 was the optimal catalyst with the reaction being carried out at 120 °C. Again, solvent-free conditions were employed, and it was demonstrated that microwave irradiation had a significant positive effect on the rate and yield of the reaction. Aromatic, heteroaryl, primary and secondary aliphatic amines could all be successfully utilized with aliphatic amines showing higher reactivity. Steric hindrance was shown to be a critical parameter with sterically encumbered secondary amines showing longer reaction times and poorer yields. For the amide component, a wide substrate scope was demonstrated, and the reaction was extended to phthalimide to access N-substituted phthalimides. Again, the products could be easily isolated through extractive-workup, and the catalyst recycled five times with little loss of catalytic efficiency (Tetrahedron 2014, 70, 9492−9499).

Model studies on the conversion of the intermediate oxime to the amide with toluene as the solvent indicated that FeCl3· 6H2O (10 mol %) was the optimal catalyst. Application of these conditions to the direct conversion of the ketone lead to stalled reactions, though it was found that this problem could be overcome by running the reaction at 130 °C under solvent-free conditions. A range of ketones were successfully transformed to the corresponding amides in the presence of 1.5 equiv hydroxylamine hydrochloride with preferential aryl group migration being observed exclusively across a series of alkyl, arylketones. Several heterocyclic systems were also successful substrates though in some cases led to tautomeric product mixtures (Tetrahedron Lett. 2015, 56, 1915−1918).

Previously, Bao et al. have described the palladium-mediated aminolysis of esters with tertiary amines by C−O and C−N bond activations and have now extended this work to be catalyzed by supported gold nanoparticles. A series of both Au and Pd nanoparticles (NPs) were prepared and evaluated in a model reaction, which demonstrated that not only were AuNPs capable of catalyzing the reaction, but also gave significantly higher yields than either PdNPs or the previously disclosed homogeneous Pd(OAc)2 conditions. An optimal catalyst loading of 3 wt % Au/Al2O3 avoided particle aggregation from higher loadings and a significant decrease in catalytic efficiency for lower loadings. A range of esters were evaluated in a comparative study of the Pd(OAc)2 and Au/Al2O3 aminolysis reactions. Interestingly, when N,N-diethylaniline was employed as the amine, the Pd-mediated system provided higher yields. However, when less active esters such as phenyl esters were employed, the AuNP-mediated system was able to give high yields of the desired amide product even at 25 °C, whereas the Pd-system required elevated temperatures (115 °C) to display reactivity. Scope studies demonstrated that the reaction was not applicable to alkyl esters and that enhanced yields were obtained either when electron-withdrawing groups were present on the aryl ester, or with N-containing heteroaryl esters (for example pyridines), which were shown to be capable of directing the cleavage through coordination to the metal. Further studies showed that it was possible to recycle the AuNPs five times in the reaction without any loss of catalytic performance (J. Org. Chem. 2014, 79, 6715−6719).

Though there have been a number of reports on the metalmediated N-alkylation of amides with alcohols, these suffer from drawbacks such as high reaction temperatures and extended reaction times as well as the limitation that only primary alcohols can be utilized as substrates. Apsunde and Trudell have reported on a solvent-free iridium-mediated Nalkylation which allows the utilization of secondary alcohols. During optimization studies, it was noticed that the reaction still proceeded in the absence of base, and thus running the reaction at 160 °C with 2 equiv of the alcohol over 3 h with 5 mol % of (Cp*IrCl2)2 led to the optimum yield. A range of benzylic and aliphatic alcohols were successfully utilized in coupling reactions with a range of benzamides and acetamide. The reaction also showed good functional group tolerance, and could be extended to cyclic and acyclic secondary alcohols with little deterioration of yield noted even in the case of sterically demanding secondary alcohols (Synthesis 2014, 46, 230−234).

Heteropolyanion-based ionic liquids (HPAILs) are hybrid materials prepared from Keggin heteropolyanions and “taskspecific ionic liquids” (TSILs), which show high thermal and chemical stability due to extended hydrogen bonding networks between the anion and cation, and have emerged as novel environmentally benign catalysts. Chen et al. have described an N-formylation of a range of amines under solvent-free conditions with 1.5 equiv formic acid using 2 mol % of the imidazole-based HPAIL [MIMPS]3PW12O40 as the catalyst. An optimal temperature of 70 °C was determined, with lower temperatures leading to attrition in rate, and higher temperB




racemization particularly in the coupling of α-amino acids. El Dine et al. have reported on a series of sulfur-containing aryl boronic acids with the hypothesis that the sulfur would both assist in the formation of the initial acyloxy boron intermediate and facilitate the collapse of the tetrahedral intermediate formed after amine attack, which is the rate-determining step. Model studies across a series of catalysts provided key learnings regarding the orientation, electronic, and steric environment of the sulfur as well as the optimal spacing between this atom and the boronic acid. With a lead catalyst identified, the reaction conditions were refined to identify the best solvent (DCM), drying reagent (activated 5 Å molecular sieves, which are believed to also act as a water reservoir), as well as the optimal loading of the catalyst (10 mol %). The substrate scope was evaluated, and many primary, secondary, aliphatic, and heterocyclic amines were successfully coupled at room temperature. Introduction of steric hindrance around the amine necessitated gentle heating of the reaction to 45 °C. Aromatic carboxylic acids were difficult coupling partners and required a solvent switch to toluene to obtain a moderate yield of the desired amide. With respect to the coupling of α-amino acid derivatives, model studies revealed fluorobenzene as the optimum solvent with an increased catalyst loading of 25 mol % being employed. Using these conditions, a number of α-amino acid couplings (including a dipeptide example) are demonstrated at 65 °C with formation of less than 3% racemization product (J. Org. Chem. 2015, 80, 4532−4544).

Direct amidation of an aldehyde with an amine represents an attractive alternative for the synthesis of amides due to the ready availability of the aldehydes and the fact that this approach avoids the isolation and subsequent activation of a carboxylic acid. Chen et al. have reported on the use of a welldefined N-heterocyclic carbene (NHC)-based Ru catalyst to mediate this transformation. Optimization studies demonstrated that addition of 40 mol % of NaH to the reaction was critical to facilitate binding of the in situ generated hemiaminal intermediate to the Ru species through formation of the corresponding alkoxide. The reaction scope was also evaluated with aromatic aldehydes providing better yields than aliphatic aldehydes. Heteroaromatic aldehydes also provided the desired product in moderate to good yields. For the amine component, reduced yields were observed for sterically encumbered amines and less basic amines such as aniline (Org. Chem. Front. 2015, 2, 241−247).

Leow has reported a mild and benign oxidative lightmediated amidation of aromatic aldehydes using a phenzinium salt as the catalyst and air as the terminal oxidant. Screening a series of common photocatalysts demonstrated that the inexpensive metal-free phenazine ethosulfate was the most efficient, with 1 mol % being the optimal loading, with the reaction being carried out in inhibitor-free THF. A range of aromatic and heteroaromatic aldehydes were demonstrated to react successfully with pyrrolidine and electron-withdrawing substituents were beneficial for the reaction. Steric hindrance near the reacting center led to diminished yields. Primary aliphatic and aromatic amines lead to the imine as the major product. Six-membered cyclic and acyclic amines showed lower reactivity though good yields could still be obtained by using an alternative photocatalyst. A model reaction was demonstrated on 1 mmol scale, though the catalyst decomposed under the reaction conditions, and as such was not recyclable (Org. Lett. 2014, 16, 5812−5815).

Due to their ordered structures, high surface areas and large pore volumes, metal−organic frameworks (MOFs) have emerged as useful materials in a number of fields including heterogeneous catalysis, though at this time their use in liquid phase organic synthesis is seldom documented. Bai et al. have prepared and fully characterized a series of Co-based MOFs, and reported on their ability to mediate amide formation through the C−H functionalization of aldehydes and subsequent oxidative amidation with formamides. Of the series of Co-MOFs prepared, optimal catalytic efficiency was identified for the material pyrolyzed at 600 °C (Co@C− N600), which contains 35.8 wt % Co. Model studies indicated DMF was the optimal solvent at 80 °C using 5 equiv TBHP as the oxidant and 10 mol % Co as the catalyst. Interestingly, increasing the temperature to 100 °C led to a significant decrease in yield, and other sources of Co (both homogeneous and other nanomaterials) also showed diminished catalytic efficiencies. A wide variety of benzaldehydes were successfully converted with electron-donating substituents shown to have a minor positive influence on rate, whereas sterically encumbered substrates led to slightly lower yields. Heteroaryl and aliphatic aldehydes were also shown to be successfully converted, though in the latter case toluene was used as the solvent. A range of formamides were also successfully converted, and the sequential amidation of piperazine-1,4-dicarbaldehyde was also demonstrated. The catalyst could easily be recovered through

Boronic acid catalysis for the direct formation of amides from amines and carboxylic acids is well-established, but challenges still exist in this area in terms of general reactivity and C




amine had a deleterious effect on the reaction yield though a similar effect was not observed at the reacting acid. The complex was noted to have no tolerance to hydroxyl groups, and as such did not mediate the analogous esterification reactions. Similarly, esters were inert under the reaction conditions enabling them to be utilized as protecting groups in amide couplings using this protocol. A number of rate and mechanistic studies are provided examining the effects of pKa of both reacting species as well as the induction period for the reactions and the role and stoichiometry of the molecular sieves (ACS Catal. 2015, 5, 3271−3277).

application of a magnet close to the reactor wall, and successful recycling through five reactions with only minimal loss of activity was demonstrated (ACS Catal. 2015, 5, 884−891).

Bechi et al. have reported on a series of tandem-cascade reactions employing oxidative enzymes under aqueous conditions for the direct conversion of aryl alcohols to amides and carboxylic acids as well as the conversion of cyclic amines to lactams. With aryl alcohols as starting materials, two enzyme systems (galactose oxidaseGOaseand laccase with the redox mediator TEMPO) were identified for the initial conversion to the intermediate aldehyde. Both enzymatic systems use oxygen (air) as the terminal oxidant. Due to enzymatic inhibition by the amine and TBHP, the reactions were run as a one-pot−two-step process with the required chemical reagents being added to drive conversion to the desired amides. In general, the laccase−TEMPO combination gave higher conversions because this system was able to tolerate higher initial concentrations of the substrate. Coupling of the GOase system to a second oxidative enzyme transformation (xanthine dehydrogenase, XDH) enables isolation of the carboxylic acids in a one-pot manner. For conversion of cyclic amines, a monoamine oxidase (MAO) was identified from a screen as the optimal enzyme for the initial conversion of the cyclic amine to the intermediate imine, which could then be converted to the desired lactam in one-pot using either chemical (CuI, H2O2) or enzymatic (XDH) methods (Green Chem. 2014, 16, 4524−4529).

Metal-mediated aminocarbonylation represents an attractive alternative for the synthesis of aryl amides, but is under-utilized on laboratory scale owing mainly to the hazards of handling CO gas particularly at elevated pressures. Gaudino et al. have described a microwave-mediated protocol, which employs CO at 1 bar pressure diluted with nitrogen to facilitate the reaction. In addition, a new heterogeneous catalyst system was developed featuring Pd(II)-triphenylphosphine embedded in cross-linked β-cyclodextrin (CβCAT). Model studies on 4iodoanisole showed acetonitrile to be the optimal solvent (in contrast to initial studies on a homogeneous system, which utilized toluene) with triethylamine as the base and 0.01% of catalyst at 125 °C for 90 min. A control reaction performed in a Parr reactor showed the clear advantages to using the microwave for this process (94% vs 28% yield). A range of aryl iodides were successfully aminocarbonylated though yields were adversely affected by steric bulk at the ortho-position. Primary amines also provided higher yields than secondary amines. Aryl bromides and chlorides were unreactive under the reaction conditions. The catalyst could be easily recovered by filtration, and reused in the reaction up to five times with only a minimal loss in reactivity (Org. Process Res. Dev. 2015, 19, 499−505).

Lundberg and Adolfsson have reported on a protocol for direct amidation of carboxylic acids at room temperature utilizing the Lewis acidic metal sandwich complex bis(dicyclopentadienyl)hafnium dichloride [Hf(Cp)2Cl2] identified through a solvent/catalyst screen. Further model studies indicated that a ratio of 2:1 of amine to acid was optimal with 0.75 g of activated 4 Å molecular sieves per 0.5 mmol of substrate in diethyl ether as the solvent. The acid concentration (0.05−0.4 M) and catalyst loading (2−20 mol %) were optimized for each individual substrate. An evaluation of the scope was carried out, which showed that benzoic, cinnamic, and electron-poor acids were all successful substrates as well as a range of protected amino acids. Benzyl and aliphatic amines also worked well, though anilines and acyclic secondary amines were unsuccessful coupling partners though this did enable selective couplings to be achieved in the case of 2-aminobenzylamine. Increasing steric hindrance around the reacting

Sarkar et al. have reported on an amidation reaction of aryl halides (iodides, bromides) with isocyanides (aryl, alkyl) mediated by a heterogeneous nanodomain copper(I) oxide catalyst in aqueous media. The nanoparticles are easily synthesized by reduction of cupric chloride dihydrate in water at 60 °C using fructose as both the reducing and capping agent. FT-IR analysis demonstrated the absence of even trace Cu(II) contamination in the particles. Other sources of Cu(I) showed no catalytic activity in a model reaction, and the optimal conditions utilized 10 mol % of the catalyst at 80 °C for 1 h in water with lutidine as the base, and sonication being shown to D




be critical for optimal efficiency. The catalyst could be easily recovered by centrifugation, washed, and reused up to four times with only a minimal loss of activity (Tetrahedron Lett. 2015, 56, 623−626).

Molecular oxygen is also an attractive green reagent for the oxidation of Csp3-H bonds. However, direct oxidation of heteroaryl benzylic methylene groups is challenging due to the low reactivity and potential coordination of the heterocycle to the metal catalyst. Liu et al. reported the use of ethyl chloroacetate to activate the heterocycle and thus the benzylic position while avoiding the catalyst poison at the same time. A large variety of alkyl heteroarenes including pyridines, benzothiazoles, benzimidazoles and quinolines are converted to the corresponding ketones with 10% CuCl2 dihydrate catalyst, 1 atm of O2, and 1 equiv of ethyl chloroacetate. Electron paramagnetic resonance (EPR) experiments were carried out to confirm the involvement of an organic radical intermediate (Angew. Chem., Int. Ed. 2015, 54, 1261−1265).

4. OXIDATIONS Selective oxidation of aliphatic alcohols to access esters under environmentally benign conditions remains challenging and attracts a significant amount of interest. Xiao et al. report a onepot process under mild and base-free conditions with molecular oxygen, visible light and heterogeneous photocatalysts of gold− palladium alloy nanoparticles on a phosphate-modified hydrotalcite support. The aliphatic alcohol is first selectively oxidized to the aldehyde, which then oxidatively couples with the unreacted alcohol to provide the ester product. The photocatalysis arises from activation of the adsorbed reactant molecules by the light-excited metal electrons on the surface of metal nanoparticles. Various aliphatic alcohols were converted to the esters in moderate to good yields. Use of benzyl alcohol and an aliphatic alcohol solvent led to various benzoates. Aliphatic secondary alcohols were converted to corresponding ketones in high yields under these conditions (J. Am. Chem. Soc. 2015, 137, 1956−1966).

Sagadevan et al. reported a visible-light initiated, Cu(I) catalyzed oxidative C−N coupling for a highly efficient one-step synthesis of α-ketoamides. A wide range of aryl and alkyl terminal alkynes were coupled with electron-rich or deficient anilines with 5% of CuCl as catalyst at room temperature in the presence of blue LEDs and 1 atm of O2 to provide αketoamides in good-to-excellent yields. No ligands or bases were required for the coupling. Two epoxide hydrolase inhibitors were prepared via this method in one step and high yields from commercially available starting materials. Mechanistic studies suggested that the Cu(I) acetylide intermediate is excited by visible-light and oxidized to Cu(II) by O2 to trigger the oxidative coupling (Green Chem. 2015, 17, 1113−1119).

High valent Pd centers have been used to enable unique catalytic activity such as olefin difunctionalization. However, stoichiometric, wasteful, and high-energy oxidants such as PhI(OAc)2 are typically required due to the high kinetic barrier to access high valent Pd centers. Wickens et al. report the use of environmentally benign O2 as the terminal oxidant for Pdcatalyzed olefin dioxygenation. The key is the presence of a catalytic amount of nitrite, which generates NO2 as the active oxidant under the reaction conditions. Various functional groups were well-tolerated to provide diacetoxy products in up to 94% yield. This is a green alternative to the toxic OsO4 catalyst, which was typically used for olefin dihydroxylation (Angew. Chem., Int. Ed. 2015, 54, 236−240).

5. ASYMMETRIC HYDROGENATIONS Yan et al. report a new, efficient, and highly enantioselective direct asymmetric hydrogenation of α-keto acids into optically active α-hydroxy acids by employing the Ir/SpiroPAP catalyst. A series of Ir/SpiroPAP catalyst derivatives [C(1−4)] having differing substitution patterns on the pyridine ring of the ligand were investigated. Reduction of α-keto acids with hydrogen, using 0.1 mol % of this catalyst system at room temperature afforded product in high yields (92−98%), turn over number (TON, up to 50 000) and ee (up to 99.2%). Catalyst C-3 was demonstrated in the synthesis of a clopidogrel precursor in 95% yield and 91% ee (99.1% ee after crystallization) (Chem. Commun. 2014, 50, 15987−15990). E




6. C−H ACTIVATION Wagner and Ofial have developed an oxidative α-cyanation of tertiary amines which forms α-amino nitriles using nontoxic potassium thiocyanate. The reaction is typically run in water with tert-butyl hydrogen peroxide oxidant and generates innocuous byproducts. The authors propose that both the tertiary amine and potassium thiocyanate are oxidized in situ to form an electrophilic iminium species and nucleophilic cyanide anion, respectively. Tertiary alkyl amines, N,N-dimethylanilines, and tetrahydroisoquinolines are all viable substrates for the reaction. In cases where there are multiple types of C−H bonds, the primary −NCH3 position is oxidized over secondary or tertiary C−H bonds. A secondary alcohol group in one substrate was converted to the corresponding ketone during the α-cyanation (J. Org. Chem. 2015, 80, 2848−2854).

Pauli et al. report the development of efficient iridium catalysts derived from chiral pyridine−phosphinite ligands for the asymmetric hydrogenation of 2- and 3-substituted furans and benzofurans. The catalyst containing a six-membered carbocyclic ring and a methyl group next to the pyridine nitrogen atom gave the best results for the hydrogenation of 3methyl substituted benzofurans. This catalyst was successfully applied in the hydrogenation of a bromobenzofuran derivative to give an intermediate used in the synthesis of (−)-thespesone (1) (Chem.Eur. J. 2015, 21, 1482−1487).

Yu et al. have developed a substrate-directed system for C−H cyanation, halogenation, and allylation using base metal catalysis. Notably, the reactions use a cobalt(III) catalyst and do not require stoichiometric Grignard reagents to generate a reactive low-valent cobalt species. The reactions demonstrate high arylation regioselectivity based on sterics. Pyrimidines, pyridines, and amides successfully promote the directed C−H arylation and alkenylation. The allylation is particularly efficient for forming C2-allylated indoles as only 0.2 mol % catalyst is required and undergoes room temperature coupling with very high turnover numbers. N-Cyano-N-phenyl-p-toluenesulfonamide, N-iodosuccinimide, and allyl methyl carbonate are the electrophiles used for the reaction in 1.2−2.5 equiv, forming the products in 54−97% yield. Bromination is promoted using Nbromophthalimide; however, the yields are modest (45−48%). One current drawback of the method is the use of 1,2dichloroethane as reaction solvent (J. Am. Chem. Soc. 2014, 136, 17722−17725).

Kuwano et al. have shown that a combination of an [IrCl(cod)]2 catalyst (cod = 1,5-cyclooctadiene), Josiphos derived ligand (L), iodine, and a lanthanide triflate can be used for the asymmetric hydrogenation of 2,4-disubstitutedpyrimidines affording chiral 4-substituted amidines in high yield and enantioselectivity. The lanthanide triflate additive plays a pivotal role in activating the pyrimidine and achieving high enantioselectivity. The scope of the reaction was examined using ytterbium triflate as additive which included the formation of a cyclic guanidine (in 87% yield, 91% ee) when the C-2 substituent was a dimethylamino group. The authors used deuteration studies to probe the mechanism of the reduction (Angew. Chem.. Int. Ed. 2015, 54, 2393−2396).

Wang et al. have disclosed a copper catalyzed formation of imidazo[1,5-a]pyridines in the presence of air from arylpyridine ketones and benzyl amines. The steric hindrance of the R1 aryl group contributed to slightly lower yields, while methyl, trifluoromethyl, methoxy, chloride, and fluoride substitutions were all well-tolerated (65−97% yield). Similar functionality was explored on the R2 aryl moiety, and good yields were again observed with the exception of heteroaromatic furan and pyridine amines which resulted in the desired product but in lower yield. Unfortunately, no desired product was formed when aliphatic amines were utilized (J. Org. Chem. 2015, 80, 2431−2435).

Wu et al. have published the synthesis of 2-quinolinones from anilines and ethylpropenoates in the presence of sodium F




persulfate. Screening a variety of acids revealed that ptoluenesulfonic acid provided the best conversion. A wide range of anilines showed good conversion to the desired product with ethyl acrylate (53−98% yields). In addition, metasubstituted anilines showed reactivity exclusively at the site para to the substitution. While anilines with electron-donating groups at the para position provided good conversion, para electron-withdrawing functionality did not generate the desired quinolinone. Aryl functionality was well-tolerated on the propenoate with electron-rich substrates exhibiting higher conversion than electron-poor compounds. Alkyl-substituted propenoates could be utilized to generate the desired product, but yields were significantly lower (37% for ethyl crotonate and 58% for methacrylate). Finally, a very high yielding formal synthesis of tipifarnib by generating the key quinolinone core in 95% yield was reported (Org. Lett. 2015, 17, 222−225).

Rapid and efficient introduction of trifluoromethyl groups onto olefins in a selective manner remains a challenge to the chemical community. Current practices rely on olefination methodologies or transition-metal-mediated trifluoromethylation of functionalized olefins, for example, but suffer from limited selectivity. Schweizer et al. reported an unprecedented stereodivergent hydrogermylation of easily obtained trifluoromethylated alkynes that can subsequently be engaged in a cross-coupling transformation in a selective manner. The nontoxic organogermanium hydride reacted with α-trifluoromethylated alkynes in the presence of peroxydisulfate as radical initiator undergo smooth transformation in a mixture of acetonitrile and water or DMF at room temperature and under air atmosphere to give rise to the (Z)-isomers selectively in good yields (71−87% yields). The stereocomplementary outcome would come from palladium-catalyzed hydrogermylation in THF, usually requiring higher activation energy, with temperatures ranging from 20 to 100 °C, giving rise in modest to good yields (43−91%) to the E-isomers in a fully selective fashion. The resulting products can then be used as valuable fluorinated building blocks. The corresponding trichlorogermanes can easily be generated and subsequently undergo a smooth cross-coupling (Org. Lett. 2015, 17, 1794−1797).

7. GREENER FLUORINATION Incorporation of trifluoromethylthio groups has been developing very rapidly in the past few years as a means to improve permeability of the drug candidates and metabolic stability. Most reported methodologies rely on the use of the toxic gaseous trifluoromethylsulfenyl chloride or variants thereof and display poor substrate scope or suffer from low overall mass efficiency. Honecker et al. reported a robust transition metalfree protocol for trifluoromethylthiolation. The methodology is illustrated on a variety of N-heteroarenes, such as pyrroles, indoles, azaindoles, and indolizines. It proceeded under thermal conditions in DMF (typically at 90 °C), with 2[(trifluoromethyl)thio]isoindoline-1,3-dione as the electrophilic reagent delivering the trifluoromethylthio group and sodium chloride as the activator. Moderate-to-good yields were reported for a variety of pyrroles and indoles (yields ranging from 54% to 94%). A remarkable functional group tolerance was observed with electron-rich or poor substrates. In the case of 3-substituted indoles, additional chloride source was required to allow for the introduction of the desired functional group. The chloride ions are proposed to act as a Lewis base leading the formation of the highly reactive trifluoromethylsulfenyl chloride that undergoes the desired electrophilic aromatic substitution (Chem.Eur. J. 2015, 21, 8047−8051).

8. BIOCATALYSIS Bromination was one of the reaction types highlighted in the key green chemistry research areas publication (Green Chem. 2007, 9, 411−420) as “reactions currently used but better reagents preferred”. Biocatalysis offers a potential alternative to chemical processes, but these reactions have only been carried out on a milligram scale. Frese and Sewald have demonstrated the regioselective synthesis of C7-brominated tryptophan on a gram scale using sodium bromide as the bromine source. This is carried out using RebH, a tryptophan-7-halogenase, combined with an alcohol dehydrogenase and a flavin reductase. By immobilizing several enzymes and then crossG




certed, highly asynchronous Diels−Alder mechanism, nonDiels−Alder routes (for example, dipolar and biradical) are not easily disproven and therefore cannot be ruled out at present (Nature Chem. Biol. 2015, 11, 256−258).

linking them, a solid, scalable multifunctional biocatalyst can be produced (Angew. Chem., Int. Ed. 2015, 54, 298−301).

One limitation of biocatalysis is that the enzymatic equivalent of many important or useful organic chemistry transformations has not been developed. In an effort to address this, Hammer et al. have sought to develop a biocatalyst platform for carrying out Brønsted acid catalysis under aqueous conditions. By using a highly evolvable squalene hopene cyclase (SHC), protein engineering of the active site gave a catalyst capable of activating a range of functional groups such as alkenes, epoxides, and carbonyls. Using this methodology a range of cyclohexanoids were prepared with high stereoselectivity (Nature Chem. Biol. 2015, 11, 121−126).

Despite belonging to the same family of flavoenzymes, nitroreductases and enoate reductases perform different reactions reducing aromatic nitro groups and CC double bonds, respectively. In addition, these classes of enzymes have pronounced differences in their structures, sharing no structural homology. In an attempt to understand the governing factors in this functional selectivity, Park et al. mutated an enoate reductase KYE1 to produce nitro-reductase activity. To achieve this, the authors used iterative site-directed mutagenesis based on rational design and on literature data assuming that increasing the active site would eliminate the ER activity. The ratio of enoate reductase and nitroreductase activity of the mutants was measured using the reduction of ketoisopherone and 4-nitrobenzenesulfonamide. One of the designed mutants (H191A/F296A/Y375A) showed an increase in nitroreductase activity by 100-fold compared to the wild-type while losing all enoate reductase activity. In this case a least, there appears to be a strong trade off for evolving nitroreductase activity: the complete loss of enoate reductase function (ChemBioChem 2015, 16, 811−818).

Hydroxynitrile lyases are valuable tools in the biocatalytic toolbox due to their ability to make α-cyanohydrins via C−C bond formation. However, their use industrially can be limited due to the availability of sufficient quantities of protein with consistent quality at low cost. Weidner et al. report the expression of a manganese dependent hydroxynitrile lyase (HNL) from Granulicella tundricola in Escherichia coli. In addition the authors engineered the protein to improve its activity and stability at low pH as well as to broaden its substrate scope. Several mutants obtained by random and sitesaturation mutagenesis of the active site showed improved HNL activity with triple mutant GtHNL A40H/V42T/Q110H identified to have 490-fold higher activity than wild type and high enantioselectivity (ChemCatChem 2015, 7, 325−332).

9. REDUCTIONS While the reduction of amides to amines is well-demonstrated, the same cannot be said of the corresponding reduction of esters to ethers. Li et al. have demonstrated the catalytic hydrogenation of esters using Ru(acac)3 and triphos in the presence of catalytic Al(OTf)3. A variety of cyclic and acyclic esters could be reduced in yields ranging from 30 to 96%. Strong Lewis acid additives were critical in order to polarize the CO/C−OH bond. Although protic acids are often beneficial for Ru/triphos reductions, only TfOH gave any of the desired fully reduced products, albeit in low yield. Similarly only Lewis acids bearing OTf ligands were successful, it was not clear from the studies whether these acted as a source of TfOH although the effect of the Lewis acid was far greater than that of the acid itself. A pathway involving a cationic Ru complex was proposed, supported by the inhibitory effect of halide. It was also shown to be possible to reductively couple carboxylic acids and alcohols although only a few examples were reported (Angew. Chem., Int. Ed. 2015, 54, 5196−5200).

Iterative polyketide synthases (PKSs) are able to generate a variety of polyketides often producing a carbocycle (generated by the reactive poly β-keto intermediates produced), while processive polyketide synthases typically do not. However, the spinosyn biosynthetic pathway appears to be an exception to this as the synthesis is catalyzed by a processive PKS but produces a carbocyclic structure. An enzyme in the biosynthesis, SPnF, appears to catalyze a [4 + 2] cycloaddition on a 22-membered macrolactone, perhaps via a Diels−Alder mechanism. Fage et al. investigated this enzyme by determining the 1.50-Å-resolution crystal structure of SpnF bound to Sadenosylhomocysteine for a better understanding of the reaction. Although computational studies supported a conH




stabilize active species, but these were found to inhibit the process. It was shown to be possible to reduce any of catalyst loading, CO pressure, or temperature by corresponding increases in the other two. In the most extreme example, raising the temperature to 180 °C allowed catalyst loadings to be reduced to 0.008 mol % (Org. Lett. 2015, 17, 173−175).

Catalytic reduction using nonprecious metals is an area of growing interest. Gieshoff et al. have shown that treatment of iron(II) or iron(III) chloride with lithium aluminium hydride gave a catalytic species that can promote olefin and acetylene reduction under 1 atm of hydrogen at 20 °C. Previous examples required excess LiAlH4 or NaBHEt3 as the reducing agent. A variety of functional aromatic groups are tolerated, e.g., aryl halide, ester, amide, and aniline although few aliphatic groups were included, mainly amides. Mechanistic studies under hydrogenation conditions suggest that transferred hydrogens are not derived from the aluminium reagent and that the transformation follows a nonradical pathway (Green Chem. 2015, 17, 1408−1413).

10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT There have been two complementary reports of iron catalyzed C−N bond formation via a hydrogen autotransfer pathway between amines and alcohols. Yan et al. relayed the use of iron cyclopentadienone 1 as a catalyst (Nat. Commun. 2014, 5, 5602), while Rawlings et al. focused on catalyst 2 (Org. Lett. 2015, 17, 1086−1089). Both publications report specific classes of substrate for which the individual catalyst system is preferred, with only one product (N-benzyl-4-methoxyaniline) in common to both publications. The scope across both manuscripts includes aliphatic and aromatic amines and alcohols with Yan et al. describing a broader scope of aliphatics, including diols to form 5−7 membered heterocycles and with CPME as the solvent. They also include an exemplar synthesis of piribedil in 54% yield, comparing reasonably with reported ruthenium based syntheses of >85% (Haniti, et al. J. Am. Chem. Soc. 2009, 131, 1766−1774 and Shan, et al. ChemCatChem 2014, 6, 808−814). Both publications state that further work is underway to establish the scope and applications of the catalyst system.

Ketone reduction is another area where Fe-based catalysts are of great interest. Bigler and Mezzetti have reported on asymmetric transfer hydrogenation of aryl ketones using chiral N2P2 macrocycles as ligands. Conventional acetophenones were readily reduced in high yield with good ee; unsurprisingly those bearing ortho-substituents provided the best results. Of greater interest was the performance with more hindered alkyl substitutents, where good enantioselectivity was seen (85− 90% ee), although yields were lower. In addition, the authors were able to demonstrate through doping studies that the complex seems to operate via a homogeneous pathway. This has been a major barrier for use of Fe-based systems where stability has been a concern and ligand dissociation rapidly leads to Fe(0) nanoparticles. The initially investigated nitrile ligands were exchanged for more strongly coordinating isonitrile ligands, and the resulting precatalysts were isolated as brightly colored, air-stable solids. This also resulted in a change of ligand geometry as the nitrile adducts were mainly trans-coordinated (cis−trans 1:3), while the isonitriles favored a cis arrangement (cis−trans 93:7). The authors acknowledge the modest reactivity of the catalyst system, but this demonstrates that such species are viable candidates for optimization in asymmetric, homogeneous catalysis (Org. Lett. 2014, 16, 6460−6463).

Jumde et al. report a ruthenium based catalyst system for the alkylation of anilines and cross coupling of primary and secondary alcohols under mild conditions. Utilizing 1,3,5-triaza7-phosphaadamantane (PTA, 5 mol %) as ligand, [Ru(cod)Cl2] (2.5 mol %) and potassium tert-butoxide (1 equiv), effective monoalkylation of anilines could be achieved in toluene at 55 °C in less than 24 h. Typically >90% conversion was achieved with >80% isolated yields. These may be the mildest ruthenium catalyzed hydrogen autotransfer reaction conditions reported at the time of this review period. The same catalyst system could be used to alkylate 1-phenylethanol with benzyl alcohol or nhexanol to afford α-alkylated acetophenones in 76 and 78% yield, as determined by GC-MS. Reactions were run in air, but this was not a requirement for successful outcome with one

The use of CO as reducing agent has previously been applied to reductive amination using rhodium catalysis. Kolesnikov et al. report the use of ruthenium as an alternative to rhodium in a simple process based on catalytic RuCl3. A wide variety of substrates were successful, and both aldehydes and ketones could be used including less reactive examples such as 2adamantanone. Initially phosphine additives were included to I




always compatible with pharmaceutical substrates (Catal. Sci. Technol. 2015, 5, 1412−1427). Conversion of alcohols into nitrogen containing heterocycles via a sequence of hydrogen transfer reactions has been demonstrated for three classes of heterocycle. Two publications use variations of RuH2CO(PPh3)3/Xantphos, piperidinium acetate, and crotonitrile (as hydrogen acceptor) developed by Williams (Adv. Synth. Catal. 2008, 350, 1973−1978). Schmitt et al. replaced the piperidinium acetate with 15 mol % acetic acid in the reaction of 2-substituted 1,3-diols with aryl hydrazines to produce 1,4-disubstituted pyrazoles in 60−75% isolated yield (Org. Lett. 2015, 17, 1405−1408).

example giving comparable conversion when run under nitrogen (Eur. J. Org. Chem. 2015, 1829−1833).

In an extension of previous work, Shen et al. introduce the concept of interrupted hydrogen borrowing in the α-alkylation of ketones with methanol. Using the bulky cataCXium A ligand with [Ir(cod)Cl]2 and potassium hydroxide in an oxygen atmosphere, the initial alkylation reaction can be stopped at a mixture of methylene and methoxymethyl intermediates without the “hydrogen returning” step of the hydrogen borrowing sequence. Addition of a metal scavenger, followed by base and a nucleophile results in 1,4-nucleophilic addition to prepare more elaborate ketones. Alternatively the alkene could be converted to the epoxide. Further elaboration of 1,5diketones thus prepared to tetra-substituted pyridines is demonstrated. The requirement for an oxygen atmosphere for the initial reaction in boiling methanol means this approach will not be appropriate for scale-up in batch scale chemistry (Angew. Chem., Int. Ed. 2015, 54, 1642−1645).

Mura et al. applied the same (RuH2CO(PPh3)3/Xantphos, crotonitrile) catalyst system to the sequential reaction of an aniline and benzyl alcohol to form the corresponding imine which was further reacted with an alkyl alcohol in the presence of TFA to prepare 2-phenyl-3-alkyl-substituted quinolines in 40−70% yields. Reactions were conducted neat in a sealed tube using microwave heating at 130 °C for 1 h to form the imine, followed by addition of the alcohol, TFA, additional crotonitrile, and further heating for 3 h; the products were obtained after column chromatography. The reaction showed some sensitivity to electronic effects with generally electron withdrawing groups on the benzyl alcohol and electron donating substituents on the aniline giving a slightly higher yield; 4-cyano and 4-nitro-anilines failed to react (Adv. Synth. Catal. 2015, 357, 576−582).

Jumde et al. used a ruthenium catalyst and Xantphos in the preparation of a series of 3-(alkyl or phenyl)-substitutedtetrahydro-1,4-benzodiazepines from o-aminobenzylalcohols and 1,2-aminoalcohols. The reactions were run in toluene at 160 °C in a sealed system for up to 16 h. Isolated yields ranged from 36−69%, and further substitution of the benzyl alcohol did not influence the yield, with 3-methyl and 4-chloro substituents examined (Eur. J. Org. Chem. 2015, 1068−1074).

Two complementary reviews include the use of alcohols in the alkylation of ketones. Obora has reviewed α-alkylation reactions using alcohols. The review covers the literature to mid 2014 and considers the use of both homogeneous and heterogeneous catalyst systems for the α-alkylation of activated methylene and methyl groups. The review includes methodology for carbon methylation using either DMF or methanol (ACS Catal. 2014, 4, 3972−3981). Shimizu has surveyed the use of heterogeneous catalysts for hydrogen transfer chemistry involving alcohols. The review covers the Meerwein−Pondorf− Verley reduction of carbonyl compounds, N-alkylation of amines, ammonia, or urea; N-alkylation of acidic methylene and methyl groups, self-and cross alkylation of alcohols via aldol chemistry, N or C-3 alkylation of indoles, the synthesis of quinolines, and thio-ethers. The review charts the progress in each area and highlights the challenges of progressing from homogeneous transition metal catalysis to heterogeneous catalysis, sometimes using base metals, where the advantages of catalyst recovery are somewhat offset by harsher reaction conditions, high temperature and reaction time, which are not

An alternative to the formation of C−N and C−C bonds with alcohol activation is using the activation to form ethers among other bonds. Zhang et al. relay the use of alcohols for intramolecular etherification by exploiting the SN1 hydrolysis of allylic and benzylic alcohols in water and 1,1,1,3,3,3-hexafluoro2-propanol (HFIP) under thermal conditions. In this report, they were able to generate a diverse array of products from chromenes to spirocyclic ethers in water alone to di- and J




tricyclizations in mixtures of water and HFIP in moderate to excellent yield. HFIP is a better hydrogen-bond donor and has higher ionizing power than water, as well as helping to solubilize organic compounds (J. Org. Chem. 2015, 80, 1107−1115).

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

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

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

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

Gheorghe-Doru Roiban

11. GENERAL GREEN CHEMISTRY Roschanger and Senanayake from the Boehringer Ingelheim Company along with Sheldon from Delft University have introduced a new metric, namely, the Green Aspirational Level (GAL). The new metric suggests a target of what pharmaceutical process chemists should be aspiring to in their process chemistry work. It is calculated by the following formula

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

Timothy White Eli Lilly, Indianapolis, Indiana United States

Stijn Wuyts Janssen Pharmaceutical Companies of Johnson and Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium

Jingjun Yin

GAL = (no. of construction steps + no. of strategic redox reactions) × factor

■

The idea is that redundant steps, e.g., protections, deprotections, or nonstrategic redox reactions, do not count toward target setting. Factors are given for both phase I and for commercial products. The paper uses Pfizer’s published Viagra synthesis as a worked example and calculates its GAL and compares with the actual results. The Viagra synthesis is significantly better than the GAL, and the authors hence conclude that “the commercial Viagra process is indeed very green” (Green Chem. 2015, 17, 752−768). Henderson et al. from GSK have published their acid and base selection guide. The guide which has been used internally at GSK for the last 10 years contains approximately 90 acids and bases and are ranked based on their EHS properties, clean chemistry assessment, and greenness (Green Chem. 2015, 17, 945−949). Green Chemistry Articles of Interest are produced on behalf of The ACS GCI Pharmaceutical Roundtable.

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.

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

Marian C. Bryan Genentech, Inc., 1 DNA Way, MS 18B, South San Francisco, California 94080, 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* K


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