Some Items of Interest to Process R&D Chemists and Engineers

Highlights from the Literature Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Some Items of Interest to Process R&D Chemists and Engineers

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PHOTOREDOX-CATALYZED DEUTERATION AND TRITIATION OF PHARMACEUTICAL COMPOUNDS

scale deuteration (gram scale, >4 deuteriums per molecule, 15 Ci/mmol, total radioactivity >10 mCi) labeling suitable for ligand binding studies to be achieved. Again, despite the use of smaller excesses of T2O, it proved possible to successfully tritiate all 13 of the drugs selected through judicious selection of the catalyst(s) and conditions. The tritiation protocol was extended to a series of GPR-40 target molecules to determine both binding and metabolite identification.

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BIOCATALYTIC SITE-SELECTIVE AND ENANTIOSELECTIVE OXIDATIVE DEAROMATIZATION OF PHENOLS Although, a number of chemical methods have been developed for the oxidative dearomatization of phenol derivatives, several major issues exist not only with site selectivity and product isolation but also with the development of an asymmetric variant of these processes. Narayan and co-workers have studied the substrate promiscuity and selectivity of several isolated flavin adenine dinucleotides (FAD)-dependent monooxygenases known from secondary metabolite pathways across a series of small molecule resorcinol derivatives (Nature Chemistry 2017, DOI: 10.1038/NCHEM.2879). The three mono-oxygenases studied (TropB, AzaH, and SorbC) were each shown to have a unique footprint from a substrate scope perspective with AzaH even shown to be effective for the oxidative dearomatization of less electron-rich substrates. From these initial analytical scale reactions, the substrates displaying the highest turnover numbers were repeated on milligram scales with an NADPH recycling system employed to mitigate costs associated with the cofactor. From these experiments, both TropB and AzaH show a preference for (R)-C3 hydoxylation, whereas SorbC shows altered facial selectivity for the (S)-C5 products (typically >99% ee for all three enzymes). For convenience, the authors demonstrate that the reactions can also be carried out with identical results on preparative scale using lyophilized whole cell preparations of the expressed proteins, and these preparations can be stored at −80 °C for 6 months without any impact on reactivity. Several one-pot cascade reactions triggered by these biocatalytic oxidative enzymes are also reported demonstrating the ease with which structural complexity can rapidly be established through these processes.

Direct hydrogen isotope exchange (HIE) of C−H bonds represents the most efficient method for the introduction of either deuterium (for ADME studies) or tritium (for ligand binding studies) into drug candidate molecules. Although several transition-metal-based methodologies have been disclosed to achieve this, they are typically limited to aromatic C− H moieties, while HIE methods targeting aliphatic C−H bonds remain a challenge. MacMillan and co-workers have described a photoredox-catalyzed approach that relies on the activation of tertiary amines via single electron oxidation to give an amine radical cation, which after deprotonation provides an α-amino radical that can be intercepted by a hydrogen atom transfer (HAT) catalyst (in equilibrium with D2O or T2O) thus leading to the labeled products (Science 2017, 358 (6367), 1182). Successful realization of this goal would lead to labeling of alkyl amine moieties, which are present in greater than 50% of commercial drugs. Model studies on the deuterium labeling of the antidepressant clomipramine hydrochloride demonstrated that not only was selection of the photocatalyst important, but also the use of the sterically hindered triisopropylsilanethiol as the HAT catalyst critical to avoid a deleterious thiol-substrate coupling pathway. Extension of these conditions for program © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.7b00390 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

position of a range of cyclic amines. Typically, benzophenone or tert-butyl phenyl ketone were the hydride acceptors of choice though trifluoroacetophenone was used for substrates with attenuated reactivities. For substrates with an existing αsubstituent, functionalization took place at the electronically less activated and sterically more accessible position leading generally in a highly trans-selective fashion to the α,α′disubstituted amines. Control studies on the rates of the various steps led to a simplified protocol being developed in which n-BuLi was added to a mixture of the cyclic amine and the carbonyl compound followed by addition of the desired organolithium nucleophile. These studies demonstrate that the rate of both deprotonation and nucleophilic addition greatly exceed the known addition of an organolithium reagent to the carbonyl compound.

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DIRECT α-C−H BOND FUNCTIONALIZATION OF UNPROTECTED CYCLIC AMINES The most attractive method for the synthesis of functionalized saturated nitrogen heterocycles involves the modification of C− H bonds. Although a number of methods to achieve this have been reported, these are typically limited to protected or tertiary amines, with the aforementioned protecting groups, which can be difficult to remove, typically also acting as directing groups. Seidel et al. have described new methodology to enable α-C−H functionalization of unprotected secondary cyclic amines through initial lithiation followed by hydride transfer to a suitable acceptor (a carbonyl compound) to generate a cyclic imine, which can be subsequently trapped by an organolithium compound to generate the functionalized amines (Nature Chemistry 2017, DOI: 10.1038/ NCHEM.2871). Although the method is seemingly conceptually simple, challenges exist to realize this transformation with conditions needing to be identified in which both rate of hydride transfer must significantly exceed imine deprotonation, as well as trimerization, and the rate of nucleophilic addition has also to exceed these two nonproductive processes. Optimization studies allowed a three-step protocol to initially be developed, which allowed the efficient introduction of a range or aryl, alkenyl, and heteroaryl substituents to the α-

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DIRECT DEHYDROXYTRIFLUOROMETHOXYLATION OF ALCOHOLS Trifluoromethyl ethers are of interest in medicinal chemistry due to not only the strong electron-withdrawing effect of this group but also the highly lipophilic nature of this moiety. However, methods to access this functionality are limited primarily due to the reversible decomposition of the trifluoromethoxide anion, with the methods reported possessing drawbacks such as needing a large excess of the alcohol substrates, showing limited substrate scope, or requiring stoichiometric quantities of additional reagents. Tang and coworkers have reported on the first dehydrotrifluoromethoxylation of alcohols, exploiting the decomposition of the trifluoromethoxide anion (generated from a trifluoroaryl sulfonate (TFMS) derivative) to produce fluorophosgene, which reacts with the alcohol to form an intermediate fluoroformate that can be displaced with an additional equivalent of trifluoromethoxide to generate the desired products (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/ B




activated phenyl boronic ester indicated that choice of ligand was crucial for successful reaction with the N,N′-diarylsubstuted NHC precursors (specifically IPr and SIPr) proving to be the best. For the activator, nBuLi was equally efficient as t BuLi, and surprisingly in contrast to the Pd-mediated transformation, the aryl bromides were inferior substrates to the aryl chlorides. From a scope perspective, numerous functional groups were tolerated though not nitro, cyano, or carbonyl substituents. Heterocyclic halides could also be employed though they led to relatively poor yields. The utility of the method was extended to the derivatization of an Edaravone (used as a treatment for brain ischemia) derivative, though only the ortho-chloride was a successful substrate (even without the NHC ligand). Initial mechanistic studies indicate the intermediacy of a zerovalent cobalt complex, with a bimetallic radical-centered process proposed to potentially account for the preference for aryl chlorides.

anie.201711050). Model studies utilizing 4-phenyl-1-butanol as the substrate demonstrated that both the aryl substituent of the TFMS derivative (4-methylbenzyl) and the nature of the fluoride activator (CsF) were key to obtain optimal yields with TMABr as an additive. A 9/1 mixture of DMA/HMPA was the best solvent system, though the HMPA could be omitted with only a slight drop in yield for certain substrates. From a scope perspective, both primary and secondary alcohols were effective substrates with excellent functional group tolerance. Tertiary alcohols were unaffected by the reaction conditions enabling selective trifluoromethoxylation to be achieved. From a mechanistic perspective 19F NMR confirms the intermediacy of the fluoroformate, while both 18O-labeling studies and the significant racemization of enantiopure alcohols during the reaction suggest an SN1-type nucleophilic trifluoromethoxylation.

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SITE-SELECTIVE AND STEREOSELECTIVE FUNCTIONALIZATION OF NONACTIVATED TERTIARY C−H BONDS

COBALT-CATALYZED SUZUKI BIARYL COUPLING OF ARYL HALIDES

Typically, the site selectivity of the rhodium-mediated insertion of carbenes into nonactivated bonds takes place based on the preference of the substrate. However, a more versatile methodology herein would be if these processes could take place in a catalyst-controlled manner. Following on from their report detailing the use of a sterically demanding Rh-based catalyst (featuring TPCP ligands) to preferentially insert into the most accessible secondary C−H bond of n-alkanes (Nature 2016, 533, 230), Davies et al. have reported on the ability of a modified carbene reagent and Rh2(S-TCPTAD)4 to achieve high site selectivity for nonactivated tertiary C−H bonds (Nature 2017, 551, 609). Selecting the reaction of methyl-2(4bromophenyl)-2-diazoacetate with 2-methylpentane as the model system, the authors demonstrated that judicious selection of the catalyst (Rh2(S-TCPTAD)4) and the use of the trifluoroethyl ester of the carbene were necessary for the best selectivity (96/4) and ee (86%). Although, this optimal

Despite the widespread use and versatility of the palladiummediated Suzuki reaction, there is growing interest to develop similar coupling methodologies based on more sustainable earth-abundant metals (EAMs). Bedford and co-workers have described a method to achieve this utilizing simple cobalt-based catalysts prepared in situ from commercially available precursors (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201710053). Model studies on the reaction between 4-chlorotoluene and an C




result was obtained at −40 °C, subsequent scope studies were initially conducted in refluxing CH2Cl2 to enhance the rate of the desired reaction. An investigation on the scope of the reaction indicated that the optimal catalyst system consistently led to highly selective C−H functionalization at a tertiary center with good yields (64−93%) and enantioselectivity (72−92% ee). If the environment around the tertiary center became sterically encumbered, then an alternative tertiary or secondary site is preferred. The reaction was shown to tolerate a range of functional groups, and heterocycles, and was successfully extended to a range of more complex substrates using an equimolar amount of the two reagents. Structural studies on the Rh2(S-TCPTAD)4 catalysts show that it adopts close to a C4symmetric shape featuring a shallow pocket that enables the most accessible tertiary C−H bond to approach the rhodiumbound carbene on the phthalimido face of the dirhodium complex.

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alkynyl Grignard or zinc species, as coupling partners. Bao and co-workers at University of Chinese Academy of Sciences have described a copper-catalyzed decarboxylative alkylation of terminal alkynes with alkyl diacyl peroxides as the alkyl source (Adv. Synth. Catal. 2017, 359, 3720). CuCl with dtbpy as ligand and NEt3 as base catalyze the decarboxylation of acyl peroxides, which are easily formed by DCC mediated dehydrative coupling with hydrogen peroxide, and can be used directly after filtration. Aryl, heteroaryl, and alkyl terminal alkynes are successfully coupled, including substrates with chloro, hydroxyl, and amine functionality. A low reaction concentration in acetonitrile is required for useful results. Of note, short alkyl chain diacyl peroxides were not tested due to their known shock-sensitivity. Secondary and tertiary acyclic alkyl diacyl peroxides also cannot be used due to their instability.

EFFICIENT COBALT-CATALYZED METHYLATION OF AMINES USING METHANOL

N-Methyl amines are common motifs in pharmaceutical and agrochemical products. The methylation of amines often requires hazardous methylating agents such as dimethyl sulfate or methyl iodide, or formaldehyde when reductive amination is used. Other strategies using more environmentally friendly methyl sources such as CO2, dimethyl carbonate, and formic acid have been developed, but can require the use of expensive reducing agents or precious metals. Liu and co-workers at Beijing National Laboratory for Molecular Sciences have developed a cobalt-catalyzed methylation of amines using methanol as the methyl source (Adv. Synth. Catal. 2017, DOI: 10.1002/adsc.201701044). Co(acac)2 was chosen as the commercially available Co-precursor for the majority of the study, but several other Co-catalysts are also useful. The use of the tetradentate phosphine ligand, P(CH2CH2PPh2)3 (PP3), is crucial for activity, along with a basic potassium salt, with K3PO4 providing the best results. High temperatures in methanol are required (140 °C). Lowering the reaction temperature to 120 °C drastically reduced the catalytic efficiency. Secondary aliphatic amines are methylated in excellent yield, as are benzyl amines containing both electrondonating and electron-withdrawing functional groups. Dimethylation occurs with primary aliphatic and benzyl amines. Interestingly, only monomethylation occurs with aromatic amines, even with 2 equiv of base and extended reaction times. Control and deuterium-labeling experiments suggest the dehydrogenation of methanol to form formaldehyde, followed by hydrogen transfer from a cobalt hydride to be the reaction pathway.

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DIRECT ARYL C−H AMINATION WITH PRIMARY AMINES USING ORGANIC PHOTOREDOX CATALYSIS

C−H functionalization of arenes is a more atom-economical method than well-known cross-coupling methodologies that require preoxidized substrates, but C−H amination of arenes with aliphatic amines is uncommon. Nicewicz and co-workers at the University of North Carolina have described a photoredox catalysis strategy for direct C−H amination of arenes with primary amines (Angew. Chem., Int. Ed. 2017, 56, 15644). The single electron transfer (SET) approach utilizes an acridinium photoredox catalyst capable of oxidizing primary

COPPER-CATALYZED DECARBOXYLATIVE ALKYLATION OF TERMINAL ALKYNES Alkyl halides are the most frequently used alkyl source for the formation of C(sp3)−C(sp) bonds and are generally coupled with alkynes using Pd or Ni for the well-known Sonogashira cross-coupling. More readily available carboxylic acids, or their activated form, can be used as alkylating reagents after decarboxylation, but require alkynyl metal reagents, such as D



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amines that are subsequently trapped with electron-rich aromatics and heteroaromatics. The ortho/para regioselectivity is low for many instances, but can be improved by increasing the steric size of the substituent on the phenolic ether (leading to improved para selectivity) or blocking competing reactive sites. The reaction requires 455 nm LEDs and oxygen as an oxidant and tolerates a wide range of primary amines, including a variety of amino acids and complex amines. The reaction was successfully performed using a flow apparatus, increasing the possibility of application to scale up.

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STEREOSPECIFIC ALLYLIC FUNCTIONALIZATION: THE REACTIONS OF ALLYLBORONATE COMPLEXES WITH ELECTROPHILES

PALLADIUM-CATALYZED REGIODIVERGENT HYDROAMINOCARBONYLATION OF ALKENES TO PRIMARY AMIDES WITH AMMONIUM CHLORIDE

Allylboronic esters are readily available and configurationally stable and react reliably with π-electrophiles; however, they are unreactive toward a range of other electrophiles. Aggarwal and co-workers from University of Bristol, in a collaboration with Mayr and Berionni from Ludwig-Maximilians-Universität München, have described the addition of aryllithium species to allylboronic esters to enhance their nucleophilicity, enabling addition to a range of electrophiles (J. Am. Chem. Soc 2017, 139, 15324). The reaction of an electron-deficient aryllithium species (3,5-(CF3)2C6H3Li or NaphthylLi) with a chiral allylboronic ester promotes a highly regio- and diastereoselective addition of the activated boronate species to a range of electrophiles, selectively reacting at the γ-position. Electrophiles such as tropylium, benzodithiolylium, activated pyridines, Eschenmoser’s salt, Togni’s reagent, Selectfluor, DIAD, and MeSX react in good to moderate yields. Of note, this method provides access to challenging chiral quaternary allylic fluoride and trifluoromethyl compounds. The addition of the aryllithium was found to increase the nucleophilicity of the allylboronic ester by 7 to 10 orders of magnitude.

Among the many ways to synthesize aliphatic amides, transition-metal-catalyzed hydroaminocarbonylation of alkenes is one of the most economical and efficient methods, requiring simple alkenes, CO, and amines. For the synthesis of primary amines, ammonia is required, which can lead to complications due to its ability to disrupt metal-catalyzed processes. Huang and co-workers at the University of Science and Technology of China have developed a palladium-catalyzed hydroaminocarbonylation of alkenes using ammonium chloride as an ammonia surrogate that, with the correct choice of ligand, can be selective for either branched or linear primary amides (Chem. Sci. DOI: 10.1039/c7sc04054g). Branched regioselectivity is observed with a variety of styrenes using Pd(t-Bu3P)2 as catalyst. Pd(PPh3)4 also provided good reactivity but with lower regioselectivity. Only 2 equiv of ammonium chloride are required. NMP is crucial as the solvent, as is high pressures of CO (30 atm) as other solvents or lower pressures resulted in unsatisfactory results. To obtain the linear primary amide, the bidentate ligand, Xantphos, along with PdI2 was utilized. For this system, both aryl and aliphatic alkenes provide the linear product in good to moderate regioselectivity. Further, by switching the catalyst to Pd(COD)Br2 along with Xantphos as ligand, 1,1-disubstituted alkenes are successfully hydroaminocarbonylated with linear selectivity, expanding the scope of this method to provide a broad range of amides. 15NH4Cl can be used as a convenient method to incorporate 15N into amides. A series of mechanistic studies suggest the direct reaction of NH4Cl with an acylpalladium species generated after hydropalladation and CO insertion.

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LIGAND−SUBSTRATE DISPERSION FACILITATES THE COPPER-CATALYZED HYDROAMINATION OF UNACTIVATED OLEFINS In spite of the plethora of ligand effects in metal mediated catalysis, very little is known about the temporary attractive forces between ligand and the substrate. Lambrecht and Liu at the University of Pittsburgh, Pennsylvania, Buchwald at the Massachusetts Institute of Technology, Cambridge, and coworkers have reported the subtle effect of ligand−substrate attractions facilitated by the copper-catalyzed hydroamination of unactivated olefins (J. Am. Chem. Soc. 2017, 139, 16548). The team quantified the different catalyst−substrate interactions based on reactivity by using computational analysis, which were validated by experimental findings. Their studies revealed that the hydroamination of the challenging unactivated aliphatic olefins were effectively catalyzed by the catalyst generated from the bulky bidentate phosphine ligands such as DTBM-SEGPHOS, due to the stabilizing ligand−substrate E




synthesized oxazolines in clean and high yielding processes. This report may help in the development of telescopic reaction protocols that accommodate incompatible reagents or solvent systems.

interaction. This report may help in the design and development of more effective ligands in metal-mediated catalysis.

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RING-FUSED CYCLIC AMINALS FROM TETRAHYDRO-β-CARBOLINE-BASED DIPEPTIDE COMPOUNDS Indole-based structures are present in a number of biologically active natural alkaloids, and their synthesis has continued to be of immense interest. In their report, Bifulco, Gomez-Monterrey et al. have reported the synthesis of fused-ring cyclic aminals from tetrahydro-β-carboline-based dipeptides (J. Org. Chem. 2017, 82, 12014). The team evaluated various conditions and found perbenzoic acid in the presence of trifluoroacetic acid led to exclusive formation of functionalized polycyclic indole derivatives in good yields. However, when bulky nitrogen protecting groups such N-Fmoc were used, it resulted in a lower yield of cyclized product. Furthermore, initial in silico investigations of the synthesized compounds showed some promise for potential use as peptidomimetics.

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CATALYTIC HYDROALKYLATION OF ALLENES The use of substoichiometric reagents in reductive crosscoupling reactions often provide an alternate to the traditional cross-coupling of organometallic reagents. In their report, Lalic et al. at the University of Washington, Seattle have reported on a catalytic method for the hydroalkylation of allenes (Angew. Chem. Int., Ed. 2017, 56, 15703). The team found suitable conditions, which included alkyl triflates as electrophiles, SIPrCuF as catalyst, (Me2HSi)2O as hydride donor, and CsF as turnover reagent. The reaction tolerated a wide range of functional groups such as aryl boronic esters, alkyl tosylates, alkyl bromides, esters, and so forth. In addition, high yields of products were obtained, even with silyl-substituted allenes. In a preliminary investigation of the reaction mechanism, the team suggested a highly reactive dinuclear copper allyl complex as the key intermediate in the reaction. However, a more detailed mechanistic study is required to fully ascertain the true mechanism of the efficient cross-coupling reaction.

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AN INTEGRATED CONTINUOUS-FLOW SYNTHESIS OF A KEY OXAZOLIDINE INTERMEDIATE TO NOROXYMORPHONE FROM NATURALLY OCCURRING OPIOIDS Flow chemistry continues to garner attention due to potential advantages over batch reactors, such as the rapid integration of uninterrupted multistep reactions and enhanced diffusion mixing, which allows only a small amount of a hazardous intermediate to be present at any instant, and so forth. Cantillo, Kappe and co-workers have reported on the use of continuous flow chemistry to synthesize key oxazolidine intermediates leading to opioid antagonists such as naltrexone, naloxone, and so forth (Eur. J. Org. Chem. 2017, 44, 6505). The team telescoped and integrated three synthetic steps: C14 hydroxylation, hydrogenation, and aerobic oxidation. Starting from the naturally occurring oripavine and thebaine alkaloids, the team

PALLADIUM-CATALYZED ORTHO C−H HYDROXYLATION OF BENZALDEHYDES USING A TRANSIENT DIRECTING GROUP Selective activation of a C−H bond poses a great challenge in synthetic organic chemistry. Sorensen and co-workers at Princeton University have reported an unusual ortho C−H functionalization of benzaldehydes using 4-chloroanthranilic acid as a transient directing group (Org. Lett. 2017, 19, 6280). By carefully choosing the requisite oxidant, the team prevented overoxidation of the benzaldehydes, suppressed side reactions, and allowed compatibility of the reagents and reactants. Various electron-withdrawing groups and electron-donating groups in the benzaldehydes were well tolerated at the ortho, para, or meta positions. In addition, a plausible mechanism involving a Pd(IV) complex was postulated. This report sheds further light F




Na2SO4 additive was found to be beneficial for the reaction. Promising yields in the upper 30% range (with 98% linear aldehyde) were obtained. The authors propose a mechanism for the reaction observed.

on the expanding application of C−H functionalization in organic synthesis.

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STOCHASTIC NUCLEATION OF POLYMORPHS: EXPERIMENTAL EVIDENCE AND MATHEMATICAL MODELING Reproducibility of published experimental results is a topic widely discussed; the reproducibility of obtaining a certain polymorph as a result of a crystallization process is very important both scientifically (as proof of process understanding) and from a business perspective (including possible intellectual property consequences). The problem is that todate our detailed understanding of crystallization mechanisms is very limited, with no reliable deterministic models that can be used to predict crystallization outcomes (polymorph). Part of the explanation of this difficulty in understanding crystallization is its stochastic nature (i.e., random probability distribution or pattern that may be analyzed statistically but may not be predicted precisely). A report from Professor Mazzotti’s group at ETH Zurich (Maggioni, G. M. et al. Cryst. Growth Des. 2017, 17, 6703) provides insight into this challenge. Specifically, the authors demonstrate experimentally, and with process modeling, the stochastic nature of polymorph nucleation. The model compound was isonicotinamide, which exhibits several polymorphs. Both (nucleation) detection times and the polymorphs observed in a large number of repetitions of the same experiments were statistically distributed. Concentration and temperature were identified to be the most influential process parameters determining which polymorph nucleates first. Experiments were conducted at two scales (Crystal16 and EasyMax) using XRPD off-line to determine the type of polymorphs obtained in both cases; with the EasyMax, online monitoring was conducted using a Raman spectrometer. A mathematical model describing the crystallization studied is presented, with good corroboration with the experimental results found. A critical comparison with certain literature data is presented.

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MICROMIXING IN A ROTOR-STATOR SPINNING DISC REACTOR Developing sustainable processes has been the focus of chemical engineering research for decades, often under the umbrella of “process intensification”. Through process intensification, heat and mass transfer occur with high efficiency, using less energy, and minimizing the negative impact on the environment. A team from the Eindhoven University of Technology reported the reduction by more than 1 order of magnitude of the micromixing time in a wellresearched scheme, the Villermaux-Dushman parallel-competitive reaction system (Mananzo Martinez, A. N., et al. Ind. Chem. Eng. Res. 2017, 56, 13454) using a rotor-stator spinning disc reactor. Micromixing times (describing the mixing at molecular level, an important parameter especially for the scaleup of fast reactions) were found to be in the range of 0.1 to 9 ms, compared to 10−100 ms in other mixing devices. The reactor consists of a rotating disc enclosed by a fixed cylindrical housing, separated only by a few millimeters. The disc can rotate at high speed (up to 2000 rpm) creating high local shear rates. Good selectivity control in fast parallel-competitive reactions requires mixing times shorter than reaction times. Correlations of the micromixing times measured with the energy dissipation rate are also presented, together with a theoretical background regarding micromixing and the Villermaux−Dushman test reactive system.

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PROBABILITY OF NUCLEATION IN A METASTABLE ZONE: COOLING CRYSTALLIZATION AND POLYTHERMAL METHOD One of the tools available for the development of a crystallization process is the metastable zone width (MSZW). Ample experimental evidence accumulated over the years indicates that the width measured for the metastable zone in a crystallization is impacted by the equipment and operating conditions used in the measurement. It was known that the MSZW (polythermal method) is not a deterministic property of a solute, and therefore it does not scale-up “as is”. A report from a collaboration between Eastman Chemical and the Universities of Buffalo and of Illinois at Urbana−Champaign (Bhamidi, V. et al. Cryst. Growth. Des. 2017, 17, 5823) analyzes in detail MSZW measurements executed by the team and by different groups as reported in the literature. Among the systems investigated were: paracetamol−water, salicylamide− methanol, isonicotinamide−ethanol, and ascorbic acid−water. A critical assessment of certain (crystallization) MSZW “dogmas” is provided; for example, it is widely accepted that the MSZW depends on the cooling rate employed in the measurement. The authors carefully explain that it is the change

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UNDERSTANDING THE ROLE OF NONIONIC SURFACTANTS DURING CATALYSIS IN MICROEMULSION SYSTEMS Water was proved to be a possible solvent for several organic reactions, however less so for transition-metal-catalyzed reactions. A team from Technische Universität Berlin reported their success for a case of a rhodium catalyzed hydroformylation in water (Pogrzeba, T., et al. Ind. Eng. Chem. Res. 2017, 56, 9934). The model substrate was 1-dodecene; the catalyst precursor was [Rh(acac)(CO)2], using a water-soluble ligand, SulfoXantphos (2,7-bissulfonate-4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). Several technical grade surfactants from the Marlipal 24 series exhibiting various degrees of ethoxylation were used. The influence of temperature, phase behavior, and surfactant on the reaction were carefully investigated. Typical reaction conditions were 15 bar syngas pressure, temperatures between 65−120 °C, and a ratio of 1/4/2500 for rhodium/ligand/alkene. The amount of surfactant was in the 1−16% range, and the use of 1% G




chloro-N-hydroxyphthalimide (TCNHPI) esters with a number of different nucleophiles under nickel catalysis. However, the necessary redox-active esters must be prepared from carboxylic acidstypically using TCNHPI and a coupling agent such as DICprior to coupling. Unfortunately, in many cases large excesses of both reagents are required, along with extended reaction times. In an effort to address this drawback, the Baran group now reports the use of tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) as a new reagent for the in situ activation of carboxylic acids for nickel-catalyzed cross-couplings without the need for isolation (Org. Lett. 2017, 19, 6196). In most cases, the reaction efficiency with CITU is comparable to the older two-reagent protocol, although a number of significant disadvantages exist, including the need for a vast excess of the organometallic coupling partner (often 20 equiv), as well as mediocre yields in many cases. Additionally, the reaction is limited to organozinc nucleophiles when CITU is used; it is incompatible with the decarboxylative Suzuki reaction due to suspected inhibition by the hexafluorophosphate counterion. In addition to nickel-catalyzed cross-couplings, it was also found that CITU can be used as a new peptide coupling agent, as the activated TCNHPI esters react rapidly with amines to form amides. In this role, it has a number of advantages over traditional coupling agents such as HATU and PyBop, including low epimerization where acids with adjacent stereogenic centers are used, and an improved safety profile over the notoriously energetic benzotriazole and azabenzotriazole agents. Its use in multistep solid-phase peptide synthesis was demonstrated with several complex examples. The CITU reagent is easily prepared from inexpensive materials and is now also commercially available.

in the driving force of the crystallization that mostly impacts the MSZW: d[ln(S(t)]/dt, where S is the system saturation. However, systems will behave differently at high vs low cooling rates. Another such “dogma” challenged in this report is the explanation why MSZW measured at higher cooling rates are wider than those measured at slow cooling rates. The authors show why the simplistic explanation that at high cooling rates the system spends less time at intermediate supersaturation may be misleading. As discussed in the above Highlight, it is the stochastic nature of nucleation that complicates our attempts to develop a workable, deterministic description of crystallization phenomena.

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ELUCIDATING THE MECHANISM OF THE LEY−GRIFFITH (TPAP) ALCOHOL OXIDATION The Ley−Griffith protocol for the oxidation of alcohols with tetra-n-propylammonium perruthenate (TPAP) has been used by chemists for over 30 years, and was among the first general methods for the catalytic oxidation of alcohols to aldehydes. However, despite this long history, the reaction is more complicated than it appears due to the fact that multiple oxidation states of ruthenium are capable of effecting the desired transformation, and several key details remain unknown. A comprehensive study from Williams and Bernhardt at the University of Brisbane now sheds light on the mechanism of this venerable reaction, revealing several interesting details (Chem. Sci. 2017, 8, 8435). As expected, the rate-determining step was found to be the oxidation of a single molecule of alcohol by a single perruthenate anion; the stoichiometric oxidant NMO does not appear in the rate law. Crucially, it was found that, in anhydrous solvents, the reaction initially proceeds slowly until the buildup of watera byproduct of the oxidationleads to the formation of RuO2. This insoluble species functions as a highly active heterogeneous catalyst, greatly accelerating the rate of the reaction. For freshly prepared or recrystallized TPAP, this process manifests itself as a significant induction period. Ironically, slightly impure commercial samples usually function more predictably without the delay in activity observed for higher quality material, although the yield was found to be similar regardless of the catalyst source or delay in initiation.

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RUTHENIUM(II)-CATALYZED OLEFINATION VIA CARBONYL REDUCTIVE CROSS-COUPLING Olefination reactions remain a crucial weapon in the arsenal of carbon−carbon bond forming reactions. However, recent advances in metathesis chemistry notwithstanding, phosphorus-based reactions such as the Wittig and Horner−Wads-

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CITU: A PEPTIDE AND DECARBOXYLATIVE COUPLING REAGENT Since their seminal publication in 2016, the Baran group has reported the decarboxylative coupling of redox-active tetraH




context of flow chemistry. Importantly from a process standpoint, the authors report initial studies on the reaction mechanism as well as on the degree of metal leaching from the catalyst particles.

worth−Emmons reactions are still among the most commonly used reactions, despite their drawbacks. A new ruthenium(II)mediated catalytic olefination was recently reported by Li and co-workers at McGill University (Chem. Sci. 2017, 8, 8193). The reaction uses hydrazones as the nucleophilic component, and these can be coupled with aryl ketones and aldehydes generating water and nitrogen as the only stoichiometric byproducts. Although the carbonyl acceptors are generally limited to nonenolizable ketones, the reaction conditions are mild, and the functional group tolerance is fairly good. One drawback is the generally poor control over double bond geometry, but in intramolecular cases, or where diastereoselectivity is not important, this reaction could provide a useful and green alternative to more classical olefination methods.

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RHODIUM-CATALYZED ASYMMETRIC 1,4-ADDITION REACTIONS OF ARYL BORONIC ACIDS WITH NITROALKENES: REACTION MECHANISM AND DEVELOPMENT OF HOMOGENEOUS AND HETEROGENEOUS CATALYSTS The rhodium-catalyzed asymmetric conjugate addition of aryl boronic acids to nitroalkenes is undoubtably a valuable reaction in organic synthesis. To date, this reaction has typically been achieved using a rhodium precatalyst and a chiral diene in a homogeneous catalytic system (albeit often in a biphasic solvent mixture). A recent study from Kobayashi and coworkers at the University of Tokyo reports the first heterogeneous catalytic system for this reaction, using mixed metal Rh/Ag Polymer Incarcerated Carbon Black (PI/CB) nanoparticles (Chem. Sci. 2017, 8, 8362). In practice, the combination of silver and rhodium salts with carbon black and polystyrene derived monomers gives an immobilized catalyst that in conjunction with a chiral diene ligand is able to perform the same reactions as the homogeneous system with comparable yields and enantioselectivities. Although the parent reaction works well with as little as 0.1 mol % rhodium, the heterogeneous system requires 1 mol %, presumably due to the fact that only the small fraction of the rhodium at the surface of the particles is able to react. Despite this apparent disadvantage, this immobilization technique may be of general interest in the field of rhodium catalysis, particularly if it could be used in the

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ELECTROPHILIC AMINATION WITH NITROARENES

The use of an aromatic nitro group as a versatile precursor to the streamlined synthesis of N-alkylated anilines is hampered by the excessive reactivity of the initial product of nitro reduction, the nitroso compound (Angew. Chem., Int. Ed. 2017, 56, 11570). To overcome this, Rauser et al. have instead successfully developed a nitrenoid (ArN(OBpin)Bpin) arising from partial nitro reduction. The nitrenoid is reacted with diaryl or dialkylzinc compounds to form an aminoborane product which can be acylated, sulfonylated, or alkylated further. Aromatic nitro compounds bearing unprotected hydroxyl or amino groups react successfully, and OTBS, alkyne, alkene, keto, carboxylate, and ester groups also remain intact. There is no indication as to how heteroaromatic nitro compounds react under the reaction conditions.

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LEARNING TO PLAN CHEMICAL SYNTHESES

ANALYTICAL METHODOLOGY FOR CHARACTERIZATION OF REACTIVE STARTING MATERIALS Scientists at Genentech have reviewed the utility of analytical techniques that can be used to quantify residual levels of reactive materials that commonly feature in synthetic routes to small molecule pharmaceuticals (S. Stowers et al. Am. Pharmaceut. Rev. 2017, 20 (5), 76). The classes of material covered are sulfonate acids and esters, hydrazines, amines, boronic acids and esters, aldehydes, and acid halides. As such materials can display genotoxicity, control to ppm levels accentuates the challenge posed by their reactivity. The article focuses on strategies for leveraging normal phase and reversedphase HPLC, supercritical fluid chromatography, and gas chromatography. These strategies include eliminating or reducing components of the mobile phase known to react with the analyte of interest and selecting a stationary phase that minimizes reaction with the analyte. The strategies are exemplified with examples from the authors’ collective experience. The article contains 104 references.

The use of computer-assisted synthesis planning is often criticized for suggesting chemically unreasonable steps. This deficiency is reported to be addressed by Segler et al. using an algorithm that uses three neural networks combined with a Monte Carlo Tree Search (see arXiv:1708.04202). The neural networks were trained on 12 million reactions extracted from the Reaxys database. The resulting 3N-MCTS algorithm was faster (

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