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

Highlights from the Literature pubs.acs.org/OPRD

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

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A NITROGEN-ASSISTED ONE-POT HETEROARYL KETONE SYNTHESIS FROM CARBOXYLIC ACIDS AND HETEROARYL HALIDES

Zeng and co-workers have described an alternative synthesis of aryl ketones starting from carboxylic acids through Suzuki coupling of the triazine ester (J. Org. Chem. 2016, 10.1021/ acs.joc.6b02667). Although this reaction requires transformation to the ester through reaction with CDMT, the whole sequence can be conducted in a single pot, and the strongly polar nature of the triazine facilitates the difficult cleavage of the C−O bond, while its leaving group potentially accelerates the transmetalation process. Screening a model Suzuki coupling indicated that judicious selection of the Pd source (Pd(PPh3)2Cl2), solvent (toluene), and base (K3PO4) were all important to realize the optimal yields. For the acid, the scope indicated that both electron-rich and electron-poor substituents both worked well, with the yield being negatively influenced by substituents in the ortho-position. Aliphatic and heteroaryl carboxylic acids were also acceptable coupling partners. For the boronic acids, again both electron-rich and electron-poor substituents were acceptable, and for this component the effect of sterics was negligible.

Typically, the preparation of heteroaryl ketones involves a reaction between an organometallic reagent and a carboxylic acid derivative with direct conversion from the parent carboxylic acid being less commonly employed, though potentially being more attractive. Mineno and co-workers at Takeda have described a direct synthesis utilizing the acid and 2-iodopyridine as the coupling partner (J. Org. Chem. 2016, 10.1021/acs.joc.6b00194). Model studies utilizing benzoic acid indicated that the optimum conditions featured initial treatment with iPrMgBr to generate the carboxylate, which was treated with 2-iodopyridine. Treatment of the reaction with iPrMgCl·LiCl promoted halogen-metal exchange followed by addition to the carbonyl to provide the desired ketone. The reaction was carried out in one-pot at ambient temperature with no tertiary alcohol being observed. Reversing the coupling partners and starting with iodobenzene and picolinic acid led to a significantly depressed yield indicating the importance of the position of the nitrogen substituent in the heteroaryl halide, and this was confirmed by the failure of both 3- and 4-iodopyridine to react. However, a range of other heteroaryl halides were successful substrates with the iodides being better coupling partners than the corresponding bromides. For the carboxylic acid component, a range of functional groups were tolerated (nitrile, ester), though both ketones and nitro groups led to a complicated reaction mixture. A mechanistic hypothesis is proposed with the carboxylate and second equivalent of Grignard reagent forming an aggregated species which chelates to the pyridine nitrogen thus promoting halogen-metal exchange. Addition into the carbonyl forms a dimagnesiated tetrahedral intermediate, thus preventing further Grignard addition to form the tertiary alcohol. © XXXX American Chemical Society

ONE-POT SYNTHESIS OF ARYLKETONES FROM AROMATIC ACIDS VIA PALLADIUM-CATALYZED SUZUKI COUPLING

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AN UPDATED SYNTHESIS OF THE DIAZO-TRANSFER REAGENT IMIDAZOLE-1-SULFONYL AZIDE HYDROGEN SULFATE

Diazo transfer reagents are extremely useful for the conversion of amines to azides, though there are safety concerns regarding both the stability of these reagents as well as the processes utilized to prepare them. The hydrochloride salt of imidazole-1-sulfonyl azide was promoted as a “shelf-stable” reagent, but concerns over its hygroscopicity, shock sensitivity, and gradual decomposition over time to release HN3 as well as the report of an explosion during its formation while concentrating mother liquors following crystallization have seriously questioned this claim. Gardiner and co-workers have reported on the increased stability of the hydrogen sulfate salt of this reagent, demonstrating its

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DOI: 10.1021/acs.oprd.6b00149 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

into the aryne. Although simpler to perform than the corresponding Pd- and Cu-mediated C−O bond formations, the latter reactions have a significantly wider substrate scope.

insensitivity to drophammer impact as well as its low electrostatic discharge and friction sensitivities (J. Org. Chem. 2016, 10.1021/ acs.joc.6b00177). This salt both functions as a diazo transfer reagent and is stable at ambient temperature for several months with no discoloration, which would suggest HN3 release. The original synthesis required isolation of the hydrochloride salt, though the initial new synthesis involves the addition of sodium azide (Caution: blast shields should be used with any azide-based reagent) to sulfuryl chloride in acetonitrile followed by imidazole to generate imidazole-1-sulfonyl azide in solution. Aqueous bicarbonate wash (thus neutralizing any HN3) followed by extraction with ethyl acetate and addition of H2SO4 led to precipitation of the hydrogen sulfate salt in 60% yield on a 25 g scale. The synthesis was further optimized by carrying out the whole process in ethyl acetate, thus replacing the extraction with a washing process, increased the yield to 78%.

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PALLADIUM-CATALYZED BENZYLIC ARYLATION OF PYRIDYLMETHYL SILYL ETHERS: ONE-POT SYNTHESIS OF ARYL(PYRIDYL)METHANOLS

Walsh and co-workers have reported on a deprotonative crosscoupling process (DCCP) of 2-pyridylmethyl silyl ethers with aryl bromides to form either the arylated silyl ethers or the free alcohols in a one-pot process (Org. Lett. 2016, 10.1021/ acs.orglett.6b00450). Model studies indicated that use of 3 equiv of LiN(SiMe3)2 in DME with Pd(OAc)2 and NIXANTPHOS at 85 °C were the optimum conditions. Both electrondonating and electron-withdrawing substituents were tolerated on the aryl bromide. The reactions of the corresponding 4-pyridylmethyl silyl ether took place at room temperature, suggesting the greater reactivity of these substrates, which is consistent with the greater acidity of 4-methylpyridine over 2-methylpyridine and also demonstrates that chelation is not crucial for reactivity. For the more reactive systems, sterically encumbered aryl bromides as well as heteroaryl bromides were successful coupling partners. The size of the silyl group was also shown not to be an issue as TBS, TMS, and TIPS groups could all be utilized, though in the case of the bulkier variants, higher catalyst loadings were required. Direct treatment of the reaction mixtures with TBAF led to the isolation of the corresponding alcohols in excellent yields.

REGIOSELECTIVE, TRANSITION METAL-FREE C−O COUPLING REACTIONS INVOLVING ARYNE INTERMEDIATES

The utilization of aryne intermediates in synthesis is often hampered not only by the forcing conditions typically required to generate them but also the poor regioselectivities often observed in the subsequent reactions. During a screening campaign to identify new catalysts for C−O bond formation, Tilley and co-workers observed that 3-haloanisoles efficiently couple with KOtBu at 90 °C in THF in the absence of transition metal catalysts (Org. Lett. 2016, 10.1021/acs.orglett.6b00183). Interestingly, no coupling product was observed under the same conditions using NaOtBu. In probing the effect of the cation, it was also found that incorporation of 18-crown-6 into the KOtBumediated reaction led to a boost in reactivity, enabling the reaction to take place at ambient temperature. Mechanistic studies demonstrated that no trace transition metal impurities were present, and that the reaction only took place in cases where the methoxy group was meta to the bromide, indicating the requirement for a doubly activated proton to be present to generate the intermediary aryne. The high regioselectivity observed was explained through analysis of the deviations from 120° of the C−C−C bond angles with displacement preferentially occurring at the site of the largest deviation. This is further confirmed through analysis of the reaction products obtained from 2-bromo-4-fluoroanisole and 3-bromo-4-fluoroanisole, which should give the same product distribution due to the same aryne intermediate being formed. A series of successful substrates are demonstrated with only catalytic quantities of the crown ether being shown to be required, and as expected iodides and bromides reacted significantly more rapidly than the corresponding chlorides. Alternative alcohols including sterically encumbered examples could also be incorporated, and preliminary results demonstrated that an amine could also be added

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HSiCl3-MEDIATED REDUCTION OF NITRO-DERIVATIVES TO AMINES: IS TERTIARY AMINE-STABILIZED SiCl2 THE ACTUAL REDUCING SPECIES?

Recently, a reduction of both aromatic and aliphatic nitro groups using HSiCl3 under metal-free conditions has been reported. While further investigating the chemoselectivity of this transformation, Benaglia and co-workers showed that the addition of DMF enabled selective reduction of an imine in the presence of a nitro group whereas addition of Hunig’s base preserved the imine while the nitro group was reduced (J. Org. Chem. 2016, 10.1021/ acs.joc.6b00191). Prompted by these findings, the group sought to elucidate the reaction mechanism initially utilizing the HSAB (hard and soft acids and bases) to explain these observations. Herein, soft Lewis bases like DMF preferentially react at the soft B




analysis shows the four-membered ring to be planar providing a relatively rigid structure. Further transformations of the products are demonstrated either through ring cleavage or functional group transformation of the nitrile moiety.

oxophilic silicon atom forming a hypervalent silicon species capable of reducing imines, while Brønsted bases (like tertiary amines) react at the hard acidic site leading to proton abstraction and formation of R3NH+/−SiCl3. In the latter case, equilibration to SiCl2 is possible, and alternate methods to form this material and subsequently use it in the reduction as well as studies of the potential transition states of the reaction suggest that a SiCl2:amine adduct generated in situ is the actual reducing agent. Further evidence is provided by the fact that electron-poor nitroarenes are reduced faster, and computational studies indicate a three-step mechanism involving initial conversion of the nitro to a nitroso species, which is converted through a cyclic hydroxylamine to give the silylated amine, which is hydrolyzed on workup.

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TWO SCALABLE SYNTHESES OF (S)-2-METHYLAZETIDINE

N-ARYLAZETIDINES: PREPARATION THROUGH ANIONIC RING CLOSURE Workers from Pfizer have provided a further example of the current interest in azetidines being presented with the challenge to develop a route to provide multihundred gram quantities of (S)-2-methylazetidine with >98% ee (J. Org. Chem. 2016, 10.1021/acs.joc.6b00149). Although several potential routes had previously been reported, none were deemed suitable for scaleup due to moderate yields, poor availability of starting materials, chromatographic separations or the use of cryogenic conditions. The team initially utilized (R)-(−)-1,3-butanediol and cyclized the bis-mesylate with benzylamine, though column chromatography was required to remove polymeric impurities at this stage. Despite a slight erosion of the ee during this step, a key observation was found that not only could the ee be upgraded by formation of the (R)-(−)-CSA salt, but also that this material was isolated as a bench-stable crystalline material. Switching to the bis-triflate, it was found that cyclization with benzyhydrylamine in the presence of Hunig’s base provided the azetidine in 91% ee. Washing with water removed excess Hunig’s base, and formation again of the CSA-salt allowed an upgrade of the ee to >99%. Hydrogenolysis cleanly removed the benzyhydryl group allowing isolation of the desired (S)-2-methylazetidine as a stable, crystalline CSA-salt, and this procedure allowed production of 200 g of the desired material. A second route to the desired compound was also developed starting from Boc-protected (R)-2-azetidine carboxylic acid. Reduction by borane generated in situ afforded the corresponding alcohol, which was activated as the mesylate, and reduced using super-hydride. Due to volatility concerns, the material was not isolated at this point, but the Boc group directly cleaved by treatment with (R)-(−)-CSA in refluxing 2-MeTHF to provide the desired material after reslurry in 49% overall yield as a white solid in four steps (three of which were telescoped).

There is a growing interest in azetidines as privileged scaffolds in medicinal chemistry, and with this a need for new synthetic approaches particularly to functionalized versions of this heterocycle. Couty et al. have described an approach to a series of N-arylated azetidines through a key anionic ring closure, which has previously only been investigated for the N-alkyl variants (J. Org. Chem. 2016, 10.1021/acs.joc.6b00169). Starting from β-aminoalcohols, arylation is achieved through copper catalysis with the desired aryl iodide either with or without a ligand. N-Cyanomethylation proved challenging owing to the lower nucleophilicity of the N-aryl compounds. A two-step sequence featuring intermediate oxazolidine formation followed by opening with cyanide under a variety of conditions solved this issue. For the ring closure, treatment with mesyl chloride allowed isolation of the crude mesylates, which were cyclized to the desired azetidines through treatment with t-BuOK. In the case of the N-alkyl azetidine intermediates, the corresponding mesylation leads to isolation of the corresponding chloride via an intermediate aziridinium ion. In the case of substituted azetidines, the ratio of isomers isolated generally agrees with computational predictions indicating that the diastereoselectivity originates from rapidly attained thermodynamic control. X-ray

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HOFMANN REARRANGEMENT OF CARBOXAMIDES MEDIATED BY N-BROMOACETAMIDE




significant factor; for quadratic cooling, cooling duration was the most statistically significant factor. Irrespective of the cooling protocol employed, gassing was found to increase the particle d50 size (when compared with the crystallization conducted without gassing). Future work will look at scale-up strategies of gassing crystallization.

Many reagents have been developed for the conversion of primary carboxamides to amines possessing one less carbon (Hofmann rearrangement) though often low yields owing to side reactions, and poor functional group tolerance are observed. Ivanovic et al. have disclosed a one-pot procedure using the easily prepared N-bromoacetamide (NBA) to mediate this transformation (Synthesis 2016, 10.1055/s-0035-1561405). Optimization studies looking at an intramolecular version of the reaction for the formation of a cyclic urea indicated that excess NBA (3 equiv) with LiOH (6 equiv) as a base in methanol provided the best yields. Replacing LiOH with KOH resulted in a very poor reaction indicating the critical role that the cation is playing in the reaction. With NBA compared to the analogous transformation using NBS, no brominated side products were observed. The reaction was extended to a range of primary amides trapping with both MeOH and BnOH to provide the amine products protected as carbamates. The benzyl carbamates are easily cleaved by hydrogenolysis, though cannot be formed in the reactions using NBS owing to oxidation/bromination of BnOH. Initial experiments utilized a gradual addition of NBA and base, but addition of the reagents in one portion was equally effective.

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WHY DO CHEMICALLY SIMILAR PHARMACEUTICAL MOLECULES CRYSTALLIZE IN DIFFERENT STRUCTURES: A CASE OF DROPERIDOL AND BENPERIDOL For many years, significant effort was made to develop crystal structure predictive methods, and whereas some progress was achieved, typically it is still not possible to rationalize different crystal structures observed for similar molecules. An in-depth analysis attempting to explain the different crystal structures of two similar API’s, droperidol, and benperidol (a and b respectively, below) was reported by a team from the University of Latvia (Berzins, A., et al. Cryst. Growth Des. 2016, 10.1021/ acs.cgd.5b01736). The two molecules differ in the saturation of the C8−C9 bond: it is unsaturated in droperidol, but it is saturated in benperidol as shown in the figure below. Detailed investigations of the contributions of various structural motifs were conducted, and theoretical calculations were executed. Comparison of the crystal structures of the two API’s did not find any mutually isostructural phases. When cross-seeding crystallizations were performed, three new droperidol phases were obtained, including a new polymorph, all isostructural with known benperidol phases. This paper has 67 references.

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INTEGRATION OF IN SITU IMAGING AND CHORD LENGTH DISTRIBUTION MEASUREMENTS FOR ESTIMATION OF PARTICLE SIZE AND SHAPE Crystallization monitoring using various PAT (process analytical technology) tools such as the FBRM (focused beam reflectance method) and PVM (particle vision measurement) can significantly contribute to process understanding from the semiquantitative measurements made. An important challenge addressed by many research groups over the years is the possibility to determine the particle size distribution from the chord length distribution measured by the FBRM. In a significant effort made by teams at the University of Strathclyde and MettlerToledo Ltd. (Agimelen, O. S., et al. Chem. Eng. Sci. 2016, 144, 87) the authors have developed methodologies that lead to both particle size and shape when both the FBRM and imaging data are used. The methods are not straightforward, and it is hoped that at the appropriate time they will be incorporated in the instruments’ software. Three compounds were used to prove the concept of the method: polystyrene microspheres, cellobiose octaacetate particles, and glycine. Excellent agreement was obtained between the measured and the calculated particle size and shape. There are 11 coauthors on this paper, and the Supporting Information is 30 pages long.

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REVISION OF THE CRYSTAL STRUCTURE OF THE FIRST MOLECULAR POLYMORPH IN HISTORY Polymorphism is older than it seems: the first example was published by Liebig and Wohler in 1832 for benzamide. The crystal structure of the stable polymorph, form I, was established in 1959, whereas that of the metastable polymorph, form II has not been established yet. Form II could not be adequately characterized using XRPD, solid state NMR, IR, or Raman spectroscopy especially because form II could be produced only as a mixture with form I. A collaboration between the University of Copenhagen and Goethe University, Frankfurt focused on a computational crystal structure prediction for benzamide form II (Johansson, K. E., et al. Cryst. Growth Des. 2016, 10.1021/acs.cgd.5b01495). Using a highly validated computational crystal structure prediction method based on dispersion-corrected density functional theory, the authors were able to propose a revised structure for benzamide form II. The revised crystal structure presents catemers rather than dimers, and possesses the rare space group symmetry Fdd2 with two molecules in the asymmetric unit. The structural search considered 230 space groups with one or two molecules in the asymmetric unit. When experimental data becomes available, it is hoped that the predicted structure will be confirmed, even though it is presented now with a “fair degree of certainty”.

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DESIGN OF MEDIAN CRYSTAL DIAMETER USING GASSING CRYSTALLIZATION AND DIFFERENT PROCESS CONCEPTS Recently, Wohlgemuth’s group at TU Dortmund University developed gassing crystallization as an alternative to sonocrystallization and as an expansion of airlift crystallizer technology. In a paper from the TU Dortmund University team (Kleetz, T., et al. Cryst. Growth Des. 2016, 10.1021/acs.cgd.5b01428), additional process characterization is reported, including the impact of different cooling protocols (linear and quadratic) is analyzed. The model system used was succinic acid/water. Statistical design of experiments (DoE) was employed to develop this process understanding, with the median particle diameter as a key process result. It was found that for linear cooling, the supersaturation when gassing was started was the most statistically D



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POLYFUNCTIONAL LITHIUM, MAGNESIUM, AND ZINC ALKENYL REAGENTS AS BUILDING BLOCKS FOR THE SYNTHESIS OF COMPLEX HETEROCYCLES

catalyst promotes the addition of the sulfoximine to a nitrocinnamaldehyde derivative, used to increase both reactivity and selectivity. MnO2 or a quinone derivative can both be used as oxidant. Lowering the temperature to −60 °C provided the best selectivities, but moderate to good selectivities are observed at −20 °C and −40 °C. For most cases, both enantiomers can be isolated in good ee and yield, and the reacted enantiomer can be readily hydrolyzed in aqueous HCl. The reaction was performed on gram scale to provide an intermediate in the synthesis of a compound known for its FXa inhibitory activity and anticoagulant effects.

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Knochel and co-workers at Ludwig-Maximilians-Universität München have described the synthesis and utility of an easily accessible and versatile β-silylated alkenyl-metal lynchpin for the synthesis of a variety of complex heterocycles (Angew. Chem., Int. Ed. 2016, 10.1002/anie.2016200961). The reagent contains an electrophilic acetal along with a 1,1-bimetallic nucleophilic moiety of well-differentiated reactivity. In three efficient steps starting from a trialkylsilyl-substituted propargyl alcohol, an alkenyl iodide precursor is prepared, that is then converted into either a lithium, magnesium, or zinc reactive organometallic reagent. The magnesium reagent, when added to aryl or heteroaryl aldehydes, will spontaneously cyclize after an acid-mediated deacetalization to form 1,2-disubstituted furans. The lithium reagents are similarly used, but with N-sulfonylaldimines, to form 1,2-disubstitued pyrroles. The zinc reagents participate in Pd-catalyzed Negishi cross-couplings to form intermediates that are easily transformed into interesting heterocycles. In all cases, the silyl group can be converted to a vinyl iodide for further manipulation.

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ASYMMETRIC SYNTHESIS OF ALLYLIC AMINES VIA HYDROAMINATION OF ALLENES WITH BENZOPHENONE IMINE

A variety of methods have been developed for the synthesis of allylic amines, using various types of starting materials and nitrogen sources. The addition of ammonia to allenes would be a very atom economical method but is very challenging because of the ability of ammonia to shut down catalytic cycles and the difficulties associated with its handling. Breit and co-workers at Chemie Albert-Ludwigs-Universität Freiburg have developed an asymmetric hydroamination of allenes using commercially available and easily prepared benzophenone imine as the ammonia carrier (Chem. Sci. 2016, 10.1039/C5SC04984A). The highly enantioselective and regioselective hydroamination uses a rhodium/Josiphos catalyst system and requires an acid additive, such as TFA or PPTS. Terminal allenes containing alkyl substituents as well as ether, thioether, phthalimide, and sulfone functional groups are well tolerated. The allylic amine products are isolated as either the HCl salt, amide, carbamate, or tosylate via a one-pot treatment with the corresponding acyl- or sulfonyl chorides or anhydrides. The released benzophenone can be recycled after hydrolysis in good yield.

ORGANOCATALYTIC KINETIC RESOLUTION OF SULFOXIMINES

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CHEMOSELECTIVE REDUCTION OF TERTIARY AMIDES UNDER THERMAL CONTROL: FORMATION OF EITHER ALDEHYDES OR AMINES

Kinetic resolution is a common strategy to obtain enantioenriched material on a large scale, especially if multistep syntheses or expensive catalysts/ligands are required for other methods. Bolm and co-workers at RWTH Aachen University have described a NHC-catalyzed kinetic resolution of sulfoximines, the monoaza analogues of sulfones, to resolve both enantiomers of the challenging substrate class in good to excellent enantioselectivities (J. Am. Chem. Soc. 2016, 138, 2166). The bulky NHC E




There is a large variety of methods for the reduction of amides, but many reducing agents are intolerant to other functional groups and lack chemoselectivity. Adolfsson and co-workers at the University of Stockholm have developed a Mo-catalyzed reduction of tertiary amides with unprecedented chemoselectivity, allowing for amide reduction in the presence of many reducible functional groups, including aldehydes and imines (Angew. Chem., Int. Ed. 2016, 55, 4562). The Mo(CO)6 catalyzed process utilizes inexpensive 1,1,3,3-tetramethyldisiloxane (TMDS) as reducing agent, in THF, or 2-methyl THF, which was used for a 10 mmol scale reaction. Different products can be obtained by changing the temperature. At lower temperatures (−5 to 65 °C) the aldehyde is formed, while higher temperatures (65−80 °C) produce the amine. Substrates with electron-withdrawing groups require higher temperatures and longer reaction times but are still reduced in good yields. Substrates with other reducible functional groups, such as nitro-, vinyl-, nitrile-, carboxylic acid-, ester-, ketone-, aldehyde-, and imine-functionality, are all tolerated. Tertiary amides are required, as silylated amides are formed with primary and secondary amides.

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The reactions are tolerant of functionality in either crosscoupling partner as well as being insensitive to being run under air. Aryl chlorides can be used, as well as bromides and iodides, though the use of the chlorides requires mild heating in order to push the reactions to completion. The boronic acid coupling partner can also take the form of Bpin or B(MIDA) derivatives, as well as BF3K salts. The method if further illustrated by making congested biaryl bonds that would be difficult under more conventional reaction conditions, even with much higher catalyst loadings. An example of a palladium-catalyzed Sonogashira coupling that proceeds in the absence of a copper cocatalyst is also provided.

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PALLADIUM-CATALYZED N-ARYLATION OF CYCLOPROPYLAMINES

PALLADIUM-CATALYZED CROSS-COUPLINGS IN WATER AT ROOM TEMPERATURE

Introducing a cyclopropyl group to an aromatic amine through alkylation is challenging on account of its partial double bond-like character. A method for forging such bonds by arylating cyclopropylamine instead has been described by T. J. Colacot and co-workers at Johnson Matthey (Org. Lett. 2016, 18, 1442). When [(tBuBrettPhos)Pd(allyl)]OTf is used, the aryl halide can be either a bromide or a chloride, though the reactions of the latter require heating above ambient temperatures, a characteristic that can be exploited in substrates bearing both potential sites of reaction. Where there is a substituent ortho to the site of reactivity, recourse to the use of the less sterically demanding [(BrettPhos)Pd(crotyl)]OTf is required. The arylation of aryl cyclopropylamines, so as to form diaryl cyclopropylamines, is also described using (tBu3P)Pd(crotyl)Cl as precatalyst and aryl bromides. The application of the conditions to a range of aromatic and heteroaromatic substrates proceeds in good-to-excellent yields. Notably, the palladium precatalysts are all commercially available and air-stable.

The Lipshutz group have described palladium-catalyzed crosscouplings to forge sp2−sp2, sp2−sp3, and sp2−sp bonds using a catalyst formed from palladium acetate and HandaPhos, a novel monophosphine ligand which will soon become commercially available (Handa, S., et al. Angew. Chem., Int. Ed. 2016, 55, 10.1002/anie.201510570). By harnessing their amphiphile methodology, such that the reactions are performed within micelles, catalyst loadings of no more than 0.1 mol % palladium are possible. This is at least an order of magnitude lower than conventional unoptimized loadings for palladium-catalyzed cross-couplings. The authors speculate that the incorporation of the HandaPhos ligand into a palladacycle would open the door to further reductions in catalyst loading. The use of the micelle technology goes hand in hand with the use of water as the bulk solvent for the reactions. The addition of further water at the end of the reaction may precipitate the product, in which case the involvement of an organic solvent is avoided completely, and the reaction liquors recycled. Alternatively, the product can be extracted into an organic solvent, and this phase filtered through silica gel, reducing the palladium content of the product to 99% enantiomeric excess. After extensive mechanistic investigations, a plausible mechanistic pathway which involves an unusual C−H activation leading to a carbo-palladation followed by either an anti-βhydride elimination or a more likely base-assisted E2 elimination. Kinetic isotope effect (KIE) measurements as well as density functional theory (DFT) calculations supported the pro posed pathway. The 13C and 2H KIE values and a free energy barrier of 22.4 kcal/mol were consistent with a carbo-palladation step. The systematic research reported could lead to the understanding and the development of new regioselective methodologies.

The replacement of expensive rare earth reagents with less expensive and more sustainable catalysts is very important for the future of catalysis. Consequently, nickel, the fifth most abundant element by weight after iron, oxygen, magnesium, and silicon, has received wide attention in catalysis. Zhou et al. (J. Am. Chem. Soc. 2016, 138, 2957) have reported the first nickel-catalyzed intermolecular hydroacylation reaction of alkenes and simple aldehydes. This cross-coupling reaction involves nickel-catalyzed activation of a C−H bond and the addition of aldehyde to the alkene to form a new C−C bond. The optimized protocol provided selective preparation of branched ketones in high yields (up to 99%) and selectivities (up to 99:1). To understand the mechanism of the reaction, they embarked on several experiments in association with density functional theory (DFT) calculations which showed evidence for reversible formation of acyl−nickel−alkyl intermediate and the transfer of the aldehyde C−H bond to a coordinated alkene without involving oxidative addition. The hydrogen transfer referred to as ligand-to-ligand hydrogen transfer (LLHT) was determined to be the turnover-limiting step of the overall process. In addition, the aldehyde C−H bond site selectivity was to the electron-deficient carbon atom of the styrene H



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ORGANOCATALYTIC ASYMMETRIC BIGINELLI-LIKE REACTION INVOLVING ISATIN

ring. The photophysical properties of the prepared polycyclics were measured by UV−vis absorption photoluminescence in dichloromethane at room temperature. To expand the substrate scope of the reaction, they synthesized derivatives involving pyrrole, indole, and thiophene which underwent the reaction smoothly. However, both primary and secondary α−bromoalkyl esters underwent the protocol in lower yields. Also, only a trace amount of product was detected with tertiary ethyl 2-bromo-2-methylpropanoate. A plausible reaction mechanism was proposed which involved radical species reacting via a Heck-type insertion and trapping by an o-aryl C(sp2)−H bond which led to the formation of the quaternary carbon center.

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The Biginelli reaction have undergone several variations since its discovery over 120 years ago. This multicomponent reaction provides valuable frameworks for compounds that can be used in research programs with good atom efficiency. Silvani and co-workers J. Org. Chem. 2016, 81, 1877) have for the first time carried out an asymmetric, Brønsted acid catalyzed Biginelli-like reaction employing N-substituted isatins, urea, and alkyl acetoacetates. Optimal conditions reported involved the use of a BINOL-derived phosphoric acid which has recently received increased attention in catalysis. In addition, the Biginelli-like compounds reported were useful key intermediates for further transformations. The absolute configuration at the oxindole C3 quaternary center was determined by quantum mechanical methods and NMR spectroscopy. Furthermore, density functional theory (DFT) measurements were in satisfactory agreement with the experimentally observed enantiomeric excess.

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Pd(II)-CATALYZED C3-SELECTIVE ARYLATION OF PYRIDINE WITH (HETERO)ARENES

The direct arylation of unactivated pyridine with both unactivated and activated arenes has received increased interest due to the ability to circumvent the problem of functional group compatibility and the potential of further transformation. However, this poses great challenge in controlling regioselectivity and reactivity. Jain, Yu and co-workers (Org. Lett. 2016, 18, 744) reported a highly C3-selective arylation of pyridines affording various 3,3′-bypyridines and 3-arylpyridines. The optimal conditions were found to be Pd(OAc)2, 1,10phenanthroline (phen), Ag2CO3, K2CO3, pyridine as additive, and 130 °C. The TON (turnover number) was determined by the amount of palladium which was characterized by 1H NMR using CH2Br2 as an internal standard or by isolated yield of product. The reaction conditions tolerated both electron-rich as well as electron-deficient pyridines.

PALLADIUM-CATALYZED CYCLIZATION OF ALKENES WITH ORGANOHALIDES

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MECHANISM-BASED SCREENING OF PHOTOCATALYTIC REACTIONS Glorius and co-workers at Westfälische Wilhelms-Universität Münster describe the discovery of photocatalytic reactions through a mechanism-based screening strategy (Angew. Chem., Int. Ed. 2016, 55, 4361). The methodology aims to accelerate the occurrence of serendipitous observations by examining different reaction components with a focus on isolated mechanistic steps. Efforts toward the invention of photocatalytic transformations began with a luminescence quencher screen against the Ir(III) complex [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 to identify prospective substrates. Next, the lead substrates were submitted to a second step that examined their quenching ability relative to the excited states of visible light active complexes. The experimental sequence accelerated the selection of substrate−catalyst combinations that could result in efficient

Fluorene, one of the most important polycyclic aromatic hydrocarbons (PAHs), have offered exciting prospects in current material science, nanotechnology, and biological and pharmaceutically relevant compounds. A commonly employed strategy that imparts the desired redox-activity for certain applications is to have electron donors and/or acceptors either appended to the side chain or placed directly in a repeating unit. Consequently, a driving force for research involves development of materials that are inexpensive and tunable and that are easily mass-produced. Xu and co-workers (Org. Lett. 2016, 18, 776) have reported a palladium-catalyzed tandem C−Br/C−H functionalization and cyclization of alkenes with organohalides. The reaction was tolerant of substrates containing substituents of varying electronic character (withdrawing or donating) and steric factors on the aromatic I




quenching and advanced mechanistic understanding, and enabled the development of new reactions. For example, a mechanism-based screening uncovered the oxidative quench capacity of benzotriazole derivatives and led to the finding of a denitrogenation pathway that could be exploited to generate anilides in the presence of anhydrides. Further optimization resulted in a general method for the preparation of a variety of anilides using a range of benzotriazole and benzoyl substrates.

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ENANTIOSELECTIVE α-FUNCTIONALIZATION OF AZAARENES

Although several methods exist for the enantioselective

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functionalization of 2-substituted azaarenes in the α-position,

DEVELOPMENT OF NEW IMAGING PROBES: INCORPORATION OF A FLUOROGENIC AMINO ACIDS IN PEPTIDES Advances in biology, chemical synthesis, and drug product development have fueled interest in modified peptides containing unnatural amino acid residues. While their excellent target selectivities and structural adaptability have captured the imagination of drug discovery groups, their modular synthesis and improvements in downstream purification methods have opened a door to commercially viable processes. Collaborative work between European chemists and biologists has resulted in the development of fluorescent antimicrobial peptides for realtime imaging of fungal infections (Nat. Commun. 2016, 7, 10940; 10.1038/ncomms10940). A Trp-BODIPY amino acid with a spacer-free C−C linkage between Trp and the BODIPY fluorogen was prepared via arylation of Fmoc-Trp-OH. Process optimization and the use of microwave irradiation facilitated further scale-up and isolation of the Trp-BODIPY residue to afford multigram quantities of a stable solid that could be used in solid phase peptide synthesis (SPPS). Cyclic analogues of an antimicrobial hexapeptide with high affinity for the membrane of fungal cells were prepared via SPPS using 2-chlorotrityl polystyrene resin followed by acidic cleavage and cyclization in solution with HATU as the coupling reagent. The remarkable fluorogenic properties of a lead peptide for the visualization

none of them qualify for the generation quaternary centers. Claudio Palomo and co-workers at Universidad del Paiś Vasco describe a mild enantioselective carbo- and hetero-αfunctionalization of 2-cyanomethylazaarene N-oxides in J. Am. Chem. Soc. 2016, 138, 3282. A range of N-oxide substrates reacted with an acrylate surrogate in the presence of a cinchona-based bifunctional catalyst to afford the desired adducts in good yields and enantioselectivities. Interestingly, similar conditions enabled the α-amination of pyridine N-oxides with azodicarboxylates. The adducts formed in these reactions can be elaborated into different compounds via (a) reduction of the N-oxide, (b) oxidative conversion of the ketol moiety to the corresponding carbonyl group (NaIO4, MeOH/H2O, rt), or (c) transformation of the α-nitrile function. Control experiments indicate that both the N-oxide and its ortho orientation relative to the cyanoalkyl substituent are essential to the success of the reaction. J




of A. f umigatus in human tissue highlights the power of a methodology that could transform current procedures for the preparation of peptide-based imaging probes.

Robert Ely

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Onyx Pharmaceuticals, 249 E. Grand Ave., South San Francisco, California 94080, United States. E-mail: [email protected].

SYNTHESIS OF ARYL NITRILES FROM METHYLARENES

Antonio Ramirez Bristol-Myers Squibb, Chemical Development, One Squibb Drive, New Brunswick, New Jersey 08903, United States. E-mail: [email protected].

Kang and co-workers described a single step transformation of

Paul Richardson

methylarenes to aryl nitriles in J. Am. Chem. Soc. 2016, 138, 3294.

Pfizer, Chemistry, 10578 Science Center Drive, San Diego, California 09121, United States. E-mail: paul.f.richardson@ pfizer.com.

The reaction, which is transition metal- and cyanide-free, uses

Andrei Zlota

substoichiometric amounts of AlCl3 and N-hydroxyphthalimide (NHPI) in the presence of excess t-BuONO in wet acetonitrile.

The Zlota Company, LLC 15, Fairbanks Road, Sharon, Massachusetts 02067-2858, United States. E-mail: andrei. [email protected].

A range of methylarenes afforded the corresponding nitriles in

Robert Kargbo

high yields, including electron-rich and electron-deficient

AMRI Chemistry, Lilly Corporate Center Indianapolis, Indiana 46285, United States. E-mail: robert.kargbo@ amriglobal.com.

variations. The methodology could be extended to chiral

Alan Steven

binaphthyls toward the synthesis of nitriles with excellent ee

Chemical Development, AstraZeneca, Cambridge CB4 0FZ, U.K.. E-mail: [email protected].

John Knight*

retention. Notably, chemoselectivities can be controlled to

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prepare mono- or dinitriles from dimethylarenes by submitting the resulting mononitriles to a second reaction cycle. The

JKonsult Ltd, Meadow View, Cross Keys, Hereford, HR1 3NT, U.K.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

research group demonstrated that citalopram could be prepared on gram scale and in good yields from commercially available m-xylene using the selective mononitrile functionalization. K


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

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