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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PALLADIUM-CATALYZED α,β-DEHYDROGENATION OF ESTERS AND NITRILES α,β-Unsaturated carbonyls are useful intermediates in organic synthesis, leading to several methods for their construction.

procedure starts with the addition of TFAA to N,N,N′,N′tetramethylmethanediamine (TMDAM) to form Tietze’s imminum salt (Me2NCH2+CF3COO−), which can react with deprotonated secondary amines to form mixed aminals. TFAA is again added, adding to the least sterically hindered amine of the mixed aminal, leading to a selective elimination to form a new reactive imminium ion. This imminium ion can react with aryl, benzylic, or allylic zinc or Grignard reagents to form a variety of tertiary amines, including difficult to prepare sterically hindered amines. The synthesis of a nitrile containing phenethylamine was demonstrated on gram scale in good yield.

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SILYLATION OF C−H BONDS IN AROMATIC HETEROCYCLES BY AN EARTH-ABUNDANT METAL CATALYST Mild and inexpensive methods for C−H functionalization of arenes are extremely valuable for pharmaceutical and material The dehydrogenation of carbonyls is commonly employed, generally involving the use of stoichiometric oxidants like IBX or SeO2. While there are examples of catalytic methods, they are only applicable to relatively acidic aldehydes and ketones. Newhouse and co-workers at Yale University have described a Pd-catalyzed α,β-dehydrogenation of the less acidic substrates, esters, and nitriles (J. Am. Chem. Soc. 2015, 137, 5875). The strategy involves deprotonation of the ester or nitrile with LiTMP, transmetalation to a zinc enolate, followed by addition to the Pd-catalyst. β-Hydride elimination provides the product and an allylpalladium hydride species which reductively eliminates to form propene and Pd(0). Allyl pivalate is the best oxidant for esters, while allyl acetate provides better results for nitriles. The zinc enolate is required to suppress direct addition of the lithium enolate to the allyl oxidant. Heterocycles including protected piperidines, furan, and indole are welltolerated, as are sulfonamides, ethers, acetals, and aryl chlorides. Substitution at the β-position is required, and amino acids and α-aryl-substituted nitriles are not tolerated. Kinetic isotope effect studies suggest that β-hydride elimination is reversible, followed by a turnover-limiting reductive elimination.

sciences. Grubbs, Stoltz, and co-workers at California Institute of Technology have described a powerful method for the silyation of C−H bonds in aromatic heterocylces without the use of arene prefunctionalization or precious metals (Nature 2015, 518, 80). The method utilizes readily available and inexpensive potassium tert-butoxide as a catalyst with a variety of hydrosilanes. No hydrogen acceptors, ligands, or additives are required, and the reaction proceeds at moderate temperatures in ethereal solvents or neat. A variety of indoles, furans, and other N-, O-, and S-containing heteroarenes are regioselectively silylated in moderate to excellent yield. The reaction was scaled to over 100 g without loss in efficiency, and the catalyst loading could be dropped to as low as 1.5%. The reaction is not applicable to electron deficient substrates, and carbonyl groups, Ar−Br, Ar−I, Ar−CN, and Ar−NO2 groups shut down the reaction. Experiments described in the thorough Supporting Information seem to rule out a silyl anion mechanistic route, as well as an elementary radical generation/ addition mechanism; although, silyl radical species do appear to play an important role.

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PREPARATION OF TERTIARY AMINES BY THE REACTION OF IMMINIUM IONS DERIVED FROM UNSYMMETRICAL AMINALS WITH ZINC AND MAGNESIUM ORGANOMETALLICS Knochel and co-workers at Ludwig-Maximilians-Universität have described the preparation of tertiary amines via the addition

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PALLADIUM-CATALYZED OXIRANE-OPENING REACTION WITH ARENES VIA C−H BOND ACTIVATION C−H functionalization of arenes is an ideal reaction to build up molecular complexity; thus identifying new conditions and of organometallic reagents to imminium ions derived from unsymmetric aminals (Org. Lett. 2015, 17, 2026). The one-pot © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.5b00202 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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compatible electrophiles is important. Kanai and co-workers at the University of Tokyo have described the first broadly

Highlights from the Literature

PRACTICAL OLEFIN HYDROAMINATION WITH NITROARENES

The synthesis of complex amines represents a key transformation for the pharmaceutical industry and is typically

applicable Pd-catalyzed opening of oxiranes with arenes via C−H activation (J. Am. Chem. Soc. 2015, 137, 6140). The Pd(OAc)2 catalyzed reaction requires a directing group, generally a pyridine ring or other nitrogen containing functional group, to direct an ortho C−H insertion, followed by a regioselective opening of terminal epoxides. Simple alkylsubstituted epoxides do not react, instead requiring a functional group that can coordinate to palladium, such as a variety of ethers, carbonyls, or even a phenyl ring. When N-methoxybenzamide was used as a substrate, coupling followed by cyclization provided 3-substituted isochroman-1-ones. Importantly, when enantiomerically pure epoxides were used, complete stereoretention was observed in the products. Kinetic isotope experiments suggest C−H activation to be the ratedetermining step.

accomplished through classical reaction manifolds such as reductive amination, alkylation or C−N cross-coupling processes. Baran and co-workers have reported on a new orthogonal approach for the synthesis of secondary amines through a radical-mediated formal hydroamination of olefins with nitroarenes (Science 2015, 348, 886). Model studies indicated that Fe salts are unique in their ability to catalyze the reaction with PhSiH3 being the most effective silane for facilitating the reaction. The process is run at 60 °C in EtOH with an excess of the olefin employed, and a Zn/HCl-mediated reduction of the N,O-alkylated adduct introduced into the same flask to optimize the yield. Examples utilizing 27 olefins are provided with reactivity trends following those known for Fe-based olefin functionalization with reaction taking place at the more substituted-carbon of the olefin. Given the radical nature of the reaction, a wide range of sterically demanding products can be accessed which would be difficult to obtain by more classical methods. In addition, sterically demanding amines are valuable within drug discovery as a means of blocking metabolism. Excellent functional group tolerance is shown for the nitroarene component, and nitro-heteroarenes are also effective substrates. Numerous reactions have been performed on decagram scale, and initial calorimetry studies show no induction period for the reaction. Examples applied to medically relevant targets as well as isotopic labeling are also presented as well as substrate limitations of the methodology. Initial mechanistic studies indicate the reaction proceeds through initial reduction of the nitroarene to the corresponding nitrosoarene, which forms an adduct with alkyl radicals formed from the donor olefin. Cleavage of the N−O σ bond provides the secondary amine product.

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CATALYTIC CHEMICAL AMIDE SYNTHESIS AT ROOM TEMPERATURE: ONE MORE STEP TOWARD PEPTIDE SYNTHESIS Boron-catalyzed amide bond formation has been known since 1970, but despite the achievements over the years, only a few

catalysts have been described that promote amide bond formation under mild conditions and, importantly, avoid racemization when α-amino acids are involved. Blanchet and co-workers have described a heterocyclic boronic acid catalyst that promotes amide bond formation at room temperature and shows minimal to no epimerization for chiral substrates (J. Org. Chem. 2015, 80, 4532). Inspired by successful catalysts designed by Hall and Whiting, o-substituted arylboronic acid catalysts with sulfur moieties were synthesized and screened. A thiophene provided the best results and is anticipated to assist with initial acyloxyboron formation and breakdown of the tetrahedral intermediate. A variety of aryl and alkyl carboxylic acids were coupled with primary and secondary amines in moderate to excellent yields at room temperature in DCM. Some sterically hindered substrates required heating. Most importantly, several epimerizable acids and amines were coupled with minimal to no racemization. These reactions required fluorobenzene as solvent at 65 °C. One example of dipeptide formation was shown, proceeding in >98:2 dr.

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Bi(OTf)3-CATALYZED MULTICOMPONENT α-AMIDOALKYLATION REACTIONS Multicomponent reactions represent atom-efficient methods of rapidly constructing arrays of potentially bioactive molecules. Manolikakes and Schneider have reported on a Bi(OTf)3mediated reaction of amides, aldehydes, and (hetero)arenes to form α-substituted amides with only water formed as a byproduct (J. Org. Chem. 2015, 10.1021/acs.joc.5b00662). Model studies on the reaction between benzamide, paraformaldehyde, and m-xylene showed Bi(OTf)3 (commercially available, nontoxic, air, and moisture stable) to be uniquely effective (2.5 mol %) at promoting the reaction in solvents such as DCE or CH3NO2 B




of both HBr (48% aq) and DMSO in EtOAc at 60 °C to give 2,4-dimethoxybromobenzene in 94% yield. A range of arene and heteroarene substrates were effectively brominated using the new protocol with the reaction being successfully demonstrated on kilogram scale. Functional group tolerance was good, and the reaction was regioselective for the paraposition when both ortho- and para-positions were unsubstituted. With alkyl substituents no benzylic bromination was observed unlike other oxidative halogenation reactions. Electron-poor substrates did not react under the new conditions. The methodology was extended to a series of natural products to demonstrate its applicability for late stage halogenation. Screening studies enabled the reaction to be developed for iodination using NH4I (1.4 equiv), H2SO4 (1.8 equiv), and DMSO (3.6 equiv) in EtOAc to generate the reactive species. The authors speculate that the slow generation of X2 in situ is the key element leading to the highly regioselective nature of the halogenations reported.

leading to the product as a 15:1 mixture of regioisomers (ortho/ para vs ortho/ortho). A wide range of primary amides were

tolerated with no secondary amides reacting under the present conditions with the exception of oxazolidin-2-one. For the arene/heteroarene component, electon-rich arenes were suitable substrates though in some cases, the temperature had to be carefully controlled to prevent direct addition of the heteroarene to formaldehyde. In some cases, judicious choice of the formaldehyde source (aq. formalin vs paraformaldehyde) was shown to be key to obtain the optimized yields. Electronpoor aromatics did not react even under forcing conditions. From a mechanistic perspective, the bis-amide was shown to be a stable and isolable intermediate, which can decompose under the reaction conditions to provide the reactive acylimine. Studies replacing formaldehyde with aliphatic aldehydes demonstrated that the reactions should be conducted at ambient temperature to prevent formation of the enamide with slow addition of the nucleophile being required for optimum yields. Only electron-rich arenes/heteroarenes are suitable substrates though very reactive substrates fail due to competing direct addition to the aldehyde. For arylaldehydes, slightly higher catalyst loadings are required with the addition of a catalytic amount of TfOH being shown to elevate the yields in some cases.

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OXALYL CHLORIDE AS A PRACTICAL CARBON MONOXIDE SOURCE FOR CARBONYLATION REACTIONS Despite its significant utility as a synthetic building block in organic synthesis, the routine use of carbon monoxide (CO) is

still uncommon on laboratory scale due to the hazards associated with the gas. Although several solutions have been developed for the in situ generation of CO, these often suffer drawbacks such as harsh reaction conditions to generate the gas or the high cost of the precursors utilized. Hansen and Ulven have reported on the generation of CO through the NaOHmediated hydrolysis of oxalyl chloride (Org. Lett. 2015, 10.1021/acs.orglett5b01252). The low aqueous solubility of CO and the fact that the byproducts CO2 and HCl are quenched by hydroxide enables CO gas to be generated with 97% efficiency. The hydrolysis reaction is both fast and exothermic though can be controlled by the dropwise addition of oxalyl chloride to the aqueous solution. The CO-generated was initially used in a hydroxycarbonylation reaction using a two-chamber system but could more conveniently be collected and transferred using a balloon. The CO-generated is slightly wet (200 ppm water), and although suitable for most uses, the gas could be easily dried by passing through a short plug of CaCl2. A diverse range of synthetic examples are provided demonstrating the utility and ease of this method for the generation of high-quality CO gas.

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EFFICIENT AND PRACTICAL OXIDATIVE BROMINATION AND IODINATION OF ARENES AND HETEROARENES WITH DMSO AND HYDROGEN HALIDE: A MILD PROTOCOL FOR LATE-STAGE FUNCTIONALIZATION Oxidative halogenation of arenes using HX (X = Br, I) represents an attractive alternative to the use of X2, which is the

current dominant industrial approach to access aryl halides. Numerous oxidizing agents have been used though all are accompanied by drawbacks (poor regioslectivity, low atom economy). The combination of DMSO and HBr has been reported though often low reactivity and use of excess reagents precludes the use of this methodology. Jiao and co-workers hypothesized that in these previous reports using DMSO as both oxidant and solvent strongly reduced the reactivity of X+, and as such employing stoichiometric DMSO would not only boost the reactivity of the system but enable stoichiometric amounts of HX to be utilized as well (Org. Lett. 2015, 10.1021/ acs.orglett5b00932). Using m-dimethoxybenzene as the model substrate, bromination proceeded within 15 min using 1.1 equiv

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PRACTICAL CONTINUOUS-FLOW TRAPPING METALATIONS OF FUNCTIONALIZED ARENES AND HETEROARENES USING TMPLi IN THE PRESENCE OF Mg, Zn, Cu, OR La HALIDES In situ trapping transmetalations provide a useful synthetic methodology for the formation of various functionalized substituted aromatic systems though the utility is mitigated by the need for cryogenic temperatures as well as extensive C




controlled by steric effects forming the meta and para isomers as major products with a degree of benzylic borylation also observed. Disubstituted benzenes were less reactive, and anisole, in sharp contrast to previously reported homogeneous systems (Ir, Fe, Co), provided the ortho-isomer as the major product. A number of functional groups were incompatible owing to competing reactions with the Ni catalyst under the reaction conditions. Numerous heteroarenes were demonstrated not to be suitable substrates, though a series of indoles were shown to be exceptionally reactive substrates providing the 2-borylated indoles in good to excellent yields regardless of electronic or steric factors. Switching the Ni precursor to Ni(OAc)2 enabled this borylation to be performed on the gram scale. Initial mechanistic studies indicate that the reaction is probably mediated by a heterogeneous Ni species.

optimization often being required to scale-up these processes. Becker and Knochel have reported on a practical solution to

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LIGAND-ENABLED STEREOSELECTIVE β-C(sp3)−H FLUORINATION: SYNTHESIS OF UNNATURAL ENANTIOPURE ANTI-β-FLUORO-α-AMINO ACIDS The introduction of fluorine represents a key strategy for blocking metabolism as well as modulating a number of these limitations by performing the reactions under continuous flow conditions at 0 °C (Angew. Chem., Int. Ed. 2015, 10.1002/ anie.201502393). A solution of the substrate and metal salt are combined in flow with a solution of TMPLi to carry out the “in situ metalation” with the product being quenched in a batch reaction with a suitable electrophile to provide the desired product. The metalation process is complete within 40 s and is demonstrated for Mg, Zn, Cu, and La species. Use of continuous flow also enables unique regioselectivities to be accessed owing to the metalations taking place under kinetically controlled reaction conditions. In addition, side reactions such as benzyne-formation can be avoided, and substrates which fail under batch conditions such as 2-fluoropyridine also work successfully in flow. The reactions also provide enhanced regioselectivities particularly in the case of furans and are easily scaled simply by extending the reaction time with the examples provided being demonstrated on up to a 12 mmol scale.

physical properties of a bioactive molecule. Yu and co-workers have reported on the synthesis of a series of anti-β-fluoro-α-amino acids formed initially by a direct arylation followed by a second C−H activation to introduce the fluorine in a stereoselective manner (J. Am. Chem. Soc. 2015, 10.1021/ jacs.5b04088). Selectfluor was chosen as the preferred fluoride source due to relatively low cost and the low likelihood of it deactivating the Pd-catalyst. Sterically hindered ligands were evaluated as it was anticipated that these would promote the C(sp3)−F bond forming reductive elimination from a Pd(IV) center. Model studies using a phenylalanine-derived amide as the substrate showed 1,4-dioxane to be the preferred solvent and the presence of Ag2CO3 crucial for reactivity with the optimization of the quinolone-based ligand (both the aryl and aliphatic components) being the key parameter for optimal reactivity. In addition, the controlled stoichiometry and concentration of the reaction were also shown to be important. The reaction showed a broad range of functional group compatibility for substituents on the aryl ring and also tolerated pyridines substituted in the 2-position. The reaction was then extended to aliphatic substrates such as the parent L-alanine with minor variations in the reaction conditions being employed to optimize yields. Mechanistically the reaction is proposed to proceed through a Pd(II)/Pd(IV) catalytic cycle with the stereogenic center built during the C(sp3)−H activation step being controlled by the favorable nature of a trans-substituted fiv-membered palladacycle. The antistereochemistry of the products was confirmed by X-ray crystallography, and notably no products arising from β-hydride elimination were detected.

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NICKEL-CATALYZED BORYLATION OF ARENES AND INDOLES VIA C−H BOND CLEAVAGE C−H borylation of arenes and heteroarenes represents a key synthetic methodology for the late stage elaboration of

aromatic molecules. Although methods utilizing precious metals such as Ir are well-established, there is a drive to develop similar reactions based on abundant base-metals like Co, Fe, and Ni. Chatani and co-workers have reported on a Ni-mediated borylation using Ni(cod)2 with an N-heterocyclic carbene ligand (ICy·HCl) using NaOtBu as the base (Chem. Commun. 2015, 51, 6508). Either HBPin or B2Pin2 could be used as the boron source with the reaction being run at elevated temperature (80−100 °C) either in neat substrate or using methylcyclohexane as the solvent. For simple substituted benzene derivatives, the borylation was found to be primarily D



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DEVELOPMENT OF A MODULAR, AIR-STABLE NICKEL PRECATALYST

indicated that critical parameters for success were a large bite angle of the phosphine ligand as well as the presence of an acid.

Precatalysts that are air-stable and cheap are extremely attractive for large scale synthesis, but often are either not

Using DPPPen as the ligand, an amino hydrochloride as the acid, the reaction proceeded efficiently under 10 atm CO pressue at 120 °C in anisole with 0.55 equiv of H2O and Pd(TFA)2 as the catalyst. The reaction gave a high degree of regiolselectivity for the linear product, which further increased with increase of steric bulk of the substrate, and both amino moieties of the aminal were incorporated in the product. The reaction was shown to be applicable for a wide range of aromatic and aliphatic terminal alkenes with good functional group tolerance, though internal alkenes were unreactive under the current conditions. A range of aminals were also successfully transformed with a model reaction being demonstrated on gram scale. Examination of the proposed mechanism suggested that cooperative catalysis using an acid and paraformaldehyde could promote the desired reaction using free primary or secondary amines, and using 10 mol % of each, this was shown to be the case. Again, a range of successful examples are provided with it being noted that in the case of anilines, it is not necessary to add paraformaldehyde to the system. A gram scale example is also shown with the major regioisomer being confirmed in the case of both reaction protocols by small molecule X-ray crystallography.

compatible with a variety of ligand classes, require reducing conditions for activation, or do not display general reactivity. Doyle and co-workers at Princeton University have described the synthesis and applicability of a practical, air-stable Ni(II) precatalyst (Org. Lett. 2015, 17, 2166). Using TMEDA and a hindered aryl substituent to shield nickel from associative substitution, the group found that a (TMEDA)Ni(o-tolyl)Cl catalyst is stable to air and ambient temperature for three months on the benchtop with no detectable decomposition. The catalyst crashes out of the reaction conditions as a crystalline, square planar complex and was used as a substitute for Ni(cod)2 or other Ni(II) catalysts in several reactions, including Suzuki−Miyaura, Buchwald−Hartwig, and oxidative and dehydrogenative coupling reactions. In most cases, with the addition of K3PO4, the precatalyst was found to be equivalent or superior to the literature report. Reaction observations suggest that either nickel−boron or nickel−nickel transmetalation are possible mechanisms for precatalyst activation, but the reaction must be heated to at least 60 °C for this to occur. Workers at Pfizer have also reported on this catalyst describing the synthesis on multigram scale under neat conditions using Ni(cod)2 as the precursor (ACS Catal. 2015, 5, 3120). They also comment on the stability of the catalyst and note its applicability for use in HTE (high throughput experimentation) campaigns based on its solubility, stability in solution over 24 h, and the ease of ligand exchange. Again, a comparison is carried with Ni(cod)2 and NiCl2(dme) over a range of reactions including cross-electrophile and Songashira couplings, and from these results the authors note the importance of utilizing the appropriate Ni source to maximize the learnings from HTE screening studies.

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COPPER-CATALYZED AMINOBORATION OF ALKENES Sakae, Hirano, and Miura (Osaka University) report a ligandcontrolled regiodivergent aminoboration of terminal alkenes in J. Am. Chem. Soc. 2015, 137, 6460. The Cu-catalyzed aminoboration enables the preparation of β-borylalkylamines regiodivergently by the appropriate choice of ancillary ligands.

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PALLADIUM-CATALYZED HYDROAMINOCARBONYLATION OF ALKENES WITH AMINES: A STRATEGY TO OVERCOME THE BASICITY BARRIER IMPARTED BY ALIPHATIC AMINES Hydroaminocarbonylation of olefins offers an alternative approach for amide synthesis, and although systems to achieve this have been reported, they suffer from drawbacks such as harsh reaction conditions and only being applicable for aromatic amines. Huang and co-workers have hypothesized that this substrate limitation is due to the fact that the intermediate palladium-hydride species can only be formed under relatively acidic conditions (Angew. Chem., Int. Ed. 2015, 10.1002/anie.201502405). To circumvent this substrate inhibition, they evaluated aminals as aliphatic amine surrogates in the Pd-catalyzed hydroaminocarbonylation. Model studies E




An ingenious application of the inability of MIDA boronates to stabilize an adjacent radical enabled the development of a new

Whereas a xantphos-CuCl complex affords terminal borylation (conditions A), N-heterocyclic carbene ligands favor the opposite regioisomer (conditions B). Extensive screening of catalysts, bases, and borylating reagents guided the finding of optimal reaction conditions that facilitated the functionalization of an assortment of unactivated terminal alkenes. The transformation tolerates oxygen- and silicon-based functional groups, and the use of different hydroxylamine derivatives opens a window to the synthesis of a variety of aminoborated products bearing cyclic amines. The authors propose a mechanism in which the migratory insertion of the terminal alkene into an intermediate borylcopper species controls the regioselectivity of the reaction.

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NICKEL-CATALYZED BORYLATION OF ARYL ETHERS Martin and co-workers at ICIQ (Tarragona, Spain) describe a Ni-catalyzed ipso-borylation of aryl ethers via C−OMe bond

route to highly functional MIDA boronates via radical addition of xanthates to vinyl MIDA boronates (Quiclet-Sire and Zard in J. Am. Chem. Soc. 2015, 137, 6762). In general, additions of radicals to simple vinyl boronates afford adducts with an unpaired electron stabilized by delocalization onto the empty p-orbital of the boron atom. In contrast, radical additions to vinyl MIDA boronates where the empty p-orbital is filled by the lone pair of the nitrogen originate radical adducts with limited stability and increased reactivity. For this reason, the addition to vinyl MIDA boronates can be positioned last in a sequence of additions to successfully propagate processes in which the MIDA boronate radical initiates the subsequent step. Intermolecular addition of xanthates to vinyl MIDA boronates were initiated by lauroyl peroxide (DLP) in refluxing EtOAc to provide a highyielding entry to densely functionalized MIDA derivates.

cleavage in J. Am. Chem. Soc. 2015, 137, 6754. The reactions, which are compatible with a wide variety of substrates, require the use of a cocktail containing catalytic amounts of Ni(COD)2 and PCy3 in the presence of borylating reagent B2(nep)2 and base. The transformation is not precluded by the presence of substituents in the ortho position, and the conditions are mild enough to promote the borylation of enantioenriched benzyl esters without compromising the optical purity of the substrates. Notably, replacement of the stoichiometric reagents with B2(pin)2 and CsF expands the scope of the borylation to benzylic C(sp3)−OMe bonds including benzyl methyl ethers with β-hydrogens. This procedure complements classical orthoborylation methods obtained via ortho-metalation or by electrophilic aromatic substitution. (Bnep = 5,5-dimethyl1,3,2-dioxaborolane).

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STAPLED PEPTIDES VIA PALLADIUM-CATALYZED C−H ACTIVATION Stapled peptides are peptide-like compounds designed to adopt locked shapes. Their conformational rigidity is intended to withstand proteolytic degradation and optimize peptide-target binding in drug discovery. A consortium of scientists from Barcelona (Spain) and Yachai Tech (Ecuador) describe the synthesis of constrained peptides facilitated by a C−H activation step in Nat. Commun. 2015, 6, 1. The reaction between Trp and iodo-Phe (or iodo-Tyr) residues is promoted by combinations of acid, stoichiometric AgBF4, and catalytic Pd(OAc)2, and takes place in a MW reactor at 90 °C for 20 min. Under these conditions, formation of the stapled

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RADICAL ADDITION OF XANTHATES TO VINYL BORONATES The distinctive properties of N-methyl imidodiacetic acid (MIDA) boronates have fueled their use in organic synthesis. F




(72−95%). The catalyst is synthesized in a single step from commercially available s-triazene and trifluoroethanol.

peptide is compatible with standard SPPS procedures enabling on-resin C−H activation between consecutive SPPS elongation steps. The protocol is general and can be efficiently used to staple a variety of linear precursors, including biologically relevant peptides. Remarkably, the intermolecular version of the procedure opens a new entry to couple peptides and generate C−C conjugates.

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A TUNED BICYCLIC PROAZAPHOSPHATRANE FOR CATALYTICALLY ENHANCED N-ARYLATION REACTIONS WITH ARYL CHLORIDES Amines are found in many valuable compounds, and as a result the development of methods to forge the carbon−nitrogen

bond has proliferated. The Pd-catalyzed Buchwald−Hartwig amination (BHA) has become the most widely used method to make the C−N bond. The searches for better and more robust catalyst/ligand for the BHA reaction continue to be reported. Kim and co-workers now report their development of a proazaphosphatrane ligand that in the presence of Pd2(dba)3 as palladium source couples aryl chlorides with amines with enhanced reaction rate and yield (Eur. J. Org. Chem. 2015, 1954). The reaction uses sodium tert-butoxide (tBuONa) as the base and toluene as the solvent to afford upon heating to 80 °C various amines in good to excellent yields (80−97%). The catalyst can also be used to make carbazoles from 2,2′-dichlorobiphenyl in a similarly high yield (83−98%).

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S-TRIAZENE BASED FLUOROUS COUPLING REAGENT FOR DIRECT AMIDE SYNTHESIS The amide bond is widely found in biologically active molecules and various polymers. Many methods to construct the amide

EFFICIENT AND VERSATILE BUCHWALD−HARTWIG AMINATION OF (HETERO)ARYL CHLORIDES USING THE Pd−PEPPSI-IPr(NMe2)2 PRECATALYST IN THE PRESENCE OF CARBONATE BASE In another report dealing with the Buchwald−Hartwig amination (BHA) reaction, Lavigne and co-workers report

bond have been developed over the years. However, most methods used today are limited by cost, low yields, or difficult isolation procedures. In a new report, Awasthi and co-workers report their development of an s-triazene fluorous catalyst to make the amide bond (Tetrahedron Lett. 2015, 56, 1960). The fluorous based catalyst was used to catalyze the amidation of various carboxylic acids with primary and secondary alcohols. The reaction is carried out using 5 mol % of catalyst and uses acetonitrile as the optimal solvent and requires heating to 60 °C. The reaction goes to full conversion in under 4 h of reaction time to furnish amides in good to excellent yields

their development of a Pd-PEPPSI-IPr(NMe2)2 precatalyst (PEPPSI = pyridine-enhanced precatalyst preparation stabilization and initiation). The Pd-PEPPSI-IPr(NMe2)2 precatalyst shows high catalytic efficiency in BHA of aryl chlorides and G




amines (Eur. J. Org. Chem. 2015, 2042). The reaction, using the mild base cesium carbonate (Cs2CO3), affords various aryl amines in 52−99% yield. The precatalyst was also used to successfully couple aryl chlorides and primary alkyl amines. High selectivity was observed when the ortho position of the aryl chloride had a substituent; otherwise formation of bisarylated products was observed.

zinc bromide (ZnBr2) and dichloromethyl methyl ether to make in situ the (dichloromethyl)arene, that then reacts with aq. ammonia and iodine to make the nitrile. The electron-rich aromatic nitriles are formed in moderate-to-high yields (59−94%). They demonstrate usefulness of this reaction by synthesizing febuxostat.

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ORTHOGONAL TANDEM CATALYSIS Recent (since 2011) developments in orthogonal tandem catalysis have been reviewed by the Marks group at Northwestern University in a Nature Perspective (Lohr, T. L., et al. Nat. Chem. 2015, 7, 477). Orthogonal tandem catalysis is a one-pot reaction in which sequential catalytic processes occur through two or more functionally distinct and noninterfering catalytic cycles. This perspective discusses the application of orthogonal tandem catalysis to several synthetically complex processes such as hydrocarbon upgrading. Mechanistic investigations were conducted to confirm that there was no catalyst “cross-talk”. One method used to prevent catalyst interaction has been the use of a physical barrier placed between the catalysts. Another important application of tandem catalysis was developed for the conversion of biomass to the important chemical intermediate 5-hydroxymethylfurfural (HMF). Typically, such processes require two steps because the enzymes used must be separated from organic solvents and aqueous acidic solutions. A one-step tandem catalysis process uses an immobilized enzyme and a solid acid catalyst. The design of noninterfering catalytic cycles remains to be a significant challenge for the widespread use of tandem catalysis. Future work might focus on the possibility of using tandem catalysis for an endothermic process coupled with an exothermic one, rendering the combined process thermodynamically favorable. This perspective has 55 references.

IODINE-CATALYZED OXIDATIVE AMINATION OF SODIUM SULFINATES: A CONVENIENT APPROACH TO THE SYNTHESIS OF SULFONAMIDES UNDER MILD CONDITIONS The sulfonamide bond is a common motif in biologically active compounds. Sulfonamide is also used as a nitrogen-protecting

group. Consequently many methods to make the sulfonamide bond have been developed. However, most of the current methods are limited because of the harsh reaction conditions employed or they exhibit poor functional group compatibility. Recently Jiang et al. had previously reported a Cu-catalyzed oxidative coupling reaction of amines and sodium sulfinates to make sulfonamides (Chem. Commun. 2013, 49, 6102). Yotphan and co-workers have now developed a metal free variant of this reaction that uses molecular iodine (I2) as a catalyst and sodium percarbonate (Na2CO3·1.5H2O2) as a source of hydrogen peroxide (Eur. J. Org. Chem. 2015, 1575). The reaction is carried out in a MeCN/DCE solvent mixture and affords various sulfonamides in moderate to good yields (40−84%). Attempts to couple aromatic amines (anilines) failed. They propose a reaction mechanism that proceeds either via a direct displacement of sulfonyl iodide or a radical substitution pathway.

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CONTROL OF HETEROGENEOUS NUCLEATION VIA RATIONALLY DESIGNED BIOCOMPATIBLE POLYMER SURFACES WITH NANOSCALE FEATURES Effective control of the nucleation/growth balance for particle engineering in a crystallization process remains to be a challenge. Available approaches for this control, such as seeding, have certain limitations. Heterogeneous nucleation on foreign surfaces has been shown to alter nucleation rates of small molecules and proteins, however with very limited industrial applications. Progress in this area has been reported by an MIT team including members of the Novartis-MIT Center for Continuous Manufacturing (Tan, L., et al. Cryst. Growth Des. 2015, 10.1021/cg501823w). In this work, heterogeneous nucleation control was achieved through the use of a rationally designed biocompatible polymer, poly(vinyl alcohol), PVA. The design was based on computations of the angles between the largest faces of 13 model compounds selected from the Cambridge Structural Database. Using the most prevalent angles thus calculated (40, 60, 65, 80, 85, and 90°) PVA films were fabricated with nanoscale features matching the calculated angles. Prior to the crystallization experiments, to prevent primary heterogeneous nucleation on their surface, the vials were carefully cleaned, activated under oxygen plasma, and a FOTS (trichloro-(1H,1H,2H,2H-perfluorooctyl)-silane) monolayer was deposited on their surface. The model compounds used in this study were aspirin and indomethacin. Nucleation times were then measured for homogeneous nucleation, and for heterogeneous nucleation for the cases of flat and round PVA

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FACILE ONE-POT TRANSFORMATION OF ARENES INTO AROMATIC NITRILES UNDER METAL-CYANIDE-FREE CONDITIONS The nitrile moiety is an important group that is found in pharmaceuticals and agrochemicals. In addition the nitrile can

serve as a stable intermediate for amides, carboxylic acids, ketones, aldehydes, etc. As a result, many methods to make nitriles have been reported. In a new publication Togo et al. report their development of a one-pot metal-cyanide-free protocol to make electron-rich aromatic nitriles (Eur. J. Org. Chem. 2015, 2023). The reaction first reacts arenes with H




2014, 26, 6213), who used organic phase droplets in a hydrogel matrix to crystallize API’s. The model compound used in the study was fenofibrate, a hydrophobic drug substance, which was crystallized in a hydrophilic hydrogel matrix. The composite hydrogels were prepared in four steps: (i) dissolution of the API in the organic phase (anisole); one of the parameters used to control API loading was the concentration of the API in the dispersed phase (anisole); (ii) emulsification in an aqueous continuous phase containing alginate (2%) and a surfactant (5% pluronic surfactant F68); emulsification was accomplished at three different levels of energy input: high pressure homogenization (nanoemulsions), millifluidics (macroemulsions), and magnetic stirring to make large macroemulsions; (iii) cross-linking with CaCl2; (iv) controlled evaporative crystallization. The dried composite can also be compressed into a tablet. DSC and XRD were used to characterize the API in the dry composite. The average particle size of the fenofibrate thus crystallized was 330 nm, exhibiting a dissolution rate comparable to that of the state-of-the-art commercially formulated fenofibrate (found in TriCor). The API in the latter has an estimated average particle size of approximately 400 nm, obtained by nanomilling. Interestingly, confining the API molecules in the matrix influences both particle size as well morphology. When crystallized in bulk, fenofibrate tends to form needles, whereas the API molecules crystallized in the droplet “crystallizer” adopt other morphologies. Future work could lead to composite hydrogels designed as the final formulation, to be manufactured in a combined crystallization/ drug product manufacturing process. This article has 49 references, and its Supporting Information has 21 pages.

films, as well as for PVA films exhibiting nanoscale features with the six characteristic angles mentioned above. In general, heterogeneous induction times on PVA films were found to be one or 2 orders of magnitude shorter than the corresponding homogeneous nucleation times. This increase in nucleation rates is explained by the favorable interactions between certain functional groups on the API’s and the PVA side chains. In addition to the PVA film geometry, as expected, nucleation times were also influenced by the solution supersaturation. For indomethacin, heterogeneous nucleation on PVA films produced mostly the thermodynamically stable γ-polymorph (up to 97%), whereas homogeneous nucleation produced mostly the metastable α-indomethacin (76% by Raman spectroscopy).

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CRYSTAL GROWTH RATE DISPERSION VERSUS SIZE-DEPENDENT CRYSTAL GROWTH: APPROPRIATE MODELING FOR CRYSTALLIZATION PROCESSES A fundamental understanding of crystal growth rate dispersion is lacking; growth rate dispersion refers to the fact that in a uniform particle population, under identical fluid dynamics conditions, crystals do not grow at the same rate, but rather a range of growth rates is observed. Similarly, crystal growth rate exhibits a random fluctuation over time. Part of this insufficient understanding relates to the possible confusion of growth rate dispersion with size-dependent crystal growth. The latter refers to the monotonous increase of crystal growth rate with crystal size. Shedding some light on this topic is research that resulted from a collaboration between Suranaree University of Technology in Thailand and the Martin Luther University in HalleWittenberg (Srisanga, S., et al. Cryst. Growth Des. 2015, 10.1021/cgd5b00126). This work aims to prove that size dependent crystal growth is actually an artifact of growth rate dispersion and occurs primarily with submicron particles. From a theoretical standpoint, it is only possible to postulate that crystal growth dispersion is due to the existence of a range of internal lattice perfection and/or to surface effects as a result of crystals’ growth history. The authors also explain that crystal growth dispersion cannot be considered an intrinsic property of the molecule, but it also depends on the crystallization method, and on the type of seed used. Experimentally, the team executed new crystallization experiments (with hexamethylenetetramine) and repeated several previously reported (with D-fructose), in both cases using seeds with bimodal distributions. If size dependent crystal growth operated, then smaller crystals would grow slower, and the distance between the size distribution peaks should change over time. These experiments showed that the distance between the peaks remained constant during the growth experiments, and the peak widths increased, supporting the crystal growth mechanism. Population balance simulations were also conducted. A 30 year old quote from Berglund sums it up: “Crystals don’t grow faster because they are larger, but rather they become larger because they grow faster”.

Robert Ely Onyx Pharmaceuticals, 249 E. Grand Ave., South San Francisco, California 94080, United States. E-mail: REly@ onyx.com.

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

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

Joseck Muhuhi The Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States. E-mail: jmuhuhi@dow. com.

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

John Knight*

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J-KONSULT Ltd, 1 Beechwood Lane, Heathfield, East Sussex, TN21 8QQ, U.K.

AUTHOR INFORMATION

Corresponding Author

COMPOSITE HYDROGELS LADEN WITH CRYSTALLINE ACTIVE PHARMACEUTICAL INGREDIENTS OF CONTROLLED SIZE AND LOADING A creative solution for a well-controlled “crystallizer” was identified by a team from MIT (Eral, H. B., et al. Chem. Mater.

*E-mail: john@scientificupdate.co.uk.

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