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

Some Items of Interest to Process R&D Chemists and Engineers■ Ni-CATALYZED BORYLATION OF

HALIDES AND PSEUDOHALIDES WITHTETRAHYDROXYDIBORON [B2(OH)4]

Arylboronic acids are of high importance as reagents in thesynthesis of pharmaceuticals. Recently, the Pd-catalyzed synthesisof arylboronic acids employing the atom-economical tetrahydroxy-diboron (BBA) reagent was reported by the Molander group. Thehigh cost associated with palladium, combined with several limi-tations of both Pd- and Cu-catalyzed processes, prompted thesame group to develop an alternative method (J. Org. Chem.2013, 78, 6427). Thus, the Ni-catalyzed borylation of aryl andheteroaryl halides and pseudohalides using BBA was demon-strated using a readily available Ni complex in conjunction withtriphenylphosphine ligand, Hunig’s base, and EtOH solvent.The reaction is widely functional group tolerant, is applicableto a number of heterocyclic systems, and even operates at roomtemperature in certain cases. Moreover, the increased reac-tivity of Ni towards oxidative insertion (relative to Pd) allowsmesylates to participate effectively in this borylation.

■ SYNTHESIS OF ENANTIOPURE FLUOROHYDRINSUSING ALCOHOL DEHYDROGENASES AT HIGHSUBSTRATE CONCENTRATIONS

Fluorinated compounds have a central role in pharmaceuticals,agrochemicals, radiotracers, and high-performance materials. Inparticular, vicinal fluoro alcohols (fluorohydrins) also presentinteresting properties as liquid crystals and as precursors ofnatural product analogues, such as steroids or carbohydrates,since it is well-known that the introduction of C−F bonds canmodulate their physicochemical properties, including bioavail-ability, lipophilicity, and oxidative stability. The use of purifiedand overexpressed alcohol dehydrogenases to synthesize enantio-pure fluorinated alcohols is reported by Lavandera and Gotore(J. Org. Chem. 2013, 78, 7312). When the bioreductions were

performed with ADH-A from Rhodococcus ruber overexpressed inE. coli, no external cofactor was necessary to obtain the enantiopure(R)-derivatives. By employing Lactobacillus brevis ADH, it waspossible to achieve the synthesis of enantiopure (S)-fluorohydrins ata 0.5 M substrate concentration. Furthermore, due to the activatedcharacter of these substrates, a huge excess of the hydrogen donorwas not necessary.

■ SELECTIVE OLEFIN NITRATION WITH Fe(NO3)3AND TEMPO

Nitro compounds, particularly conjugated nitroolefins, havegreat importance in synthetic organic chemistry. Although thereare many reported methods for their synthesis, these methodsare often limited by a number of serious drawbacks: harshconditions, limited scope, and poor control of the geometricisomer obtained. Now, Maiti and co-workers report that ferricnitrate with catalytic TEMPO is a useful reagent for regio- andstereoselective nitration of a wide variety of aromatic, aliphatic,and heteroaromatic olefins (J. Org. Chem. 2013, 78, 5949). Thisreaction provides nitroolefins in preparatively useful yields withexcellent (E)-selectivity.

■ Pd-CATALYZED ADDITION OF POTASSIUMARYLTRIFLUOROBORATES TO ALIPHATICNITRILES: SYNTHESIS OF ALKYLARYL KETONES, DIKETONE COMPOUNDS,AND 2-ARYLBENZO[b]FURANS

A Pd-catalyzed addition of potassium aryltrifluoroborates toaliphatic nitriles has been developed by Wu, Chen, and co-workers(J. Org. Chem. 2013, 78, 5273). Following a large screening

Published: September 12, 2013

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effort, the authors identified the optimal conditions as catalyticPd(TFA)2 together with the bipyridine ligand (bipy) and TFA asadditives. Depending upon the exact nitrile substrate employed, avariety of products can be derived. For example, simple nitriles canafford alkyl aryl ketones, and these can be labeled if isotopicallyenriched water is used for the reaction. Several dinitriles (e.g.,malononitrile, glutaronitrile, and adiponitrile) were applicable inthis process for the construction of 1,3-, 1,5-, or 1,6-dicarbonylcompounds. Additionally, when appropriate 2-hydroxyphenylace-tonitrile substrates are used, the process leads to 2-arylbenzo[b]-furans via sequential addition and intramolecular annulationreactions in a single pot. The authors also propose a plausiblemechanism for this catalytic cycle.

■ SOLVENT-FREE METHALLYLATION OF KETONESACCELERATED BY tert-ALCOHOLS

Over the past two decades, numerous efforts have been directedtoward the synthesis of tertiary homoallylic alcohols via theallylation of ketones. In particular, allyl organoboron reagents havebeen extensively employed for this process, but typically a metalcatalyst is required to affect the allylation (In, Cu, Ir, Zn, Ni).Alternatively, the direct metal-free allylation of ketones representsthe most simple, convenient, and economical method for thesynthesis of tertiary homoallylic alcohols. Now Zhang and co-workers at Boehringer Ingelheim report a solvent- and metal-free process for the direct methallylation of ketones, employingthe stable B-methallylborinane (J. Org. Chem. 2013, 78, 5775).Interestingly, this reaction was found to be accelerated bytertiary alcohols such as tertiary amyl alcohol. In the presenceof 2.0 equiv of tert-amyl alcohol, the methallylation productswere prepared at room temperature in excellent yields.The salient features of the described process include simpleoperation, high efficiency, and mild reaction conditions.

■ ONE-POT SYNTHESIS OF 2,5-DISUBSTITUTEDPYRIMIDINES FROM NITRILES

Substituted pyrimidines are found in a wide variety of naturalproducts and are also used as building blocks for a number ofactive pharmaceutical ingredients (APIs) present in prominentcommercial drugs such as Crestor, Gleevec, and Aggrenox. Anattractive and well-known approach to access 2,5-disubstituted

pyrimidines involves the condensation of malondialdehydes ortheir equivalents, such as vinamidinium salts, with amidines. Inparticular, the condensation of thermally stable vinamidiniumhexafluorophosphate salts with amidines is an efficient andversatile strategy since a variety of these species are nowcommercially available, even in bulk. On the other hand, typicalliterature procedures for this pyrimidine synthesis involveisolation of the intermediate imidates prior to conversion intothe required amidines. Now Frutos, Wei, and co-workers atBoehringer Ingelheim report a practical, one-step process forthe synthesis of 2,5-disubstituted pyrimidines (J. Org. Chem.2013, 78, 5880). The protocol proved to be general for thesynthesis of a variety of pyrimidine-containing compoundsbearing an assortment of functional groups.

■ ASYMMETRIC SYNTHESES OFSEROTONIN/NOREPINEPHRINE REUPTAKEINHIBITORS: ADDITIVES PROMOTE NOYORI-TYPEREDUCTIONS OF A β-KETO-γ-LACTAM

Magnus and co-workers at Eli Lilly describe efforts towardsthe synthesis of a serotonin/norepinephrine reuptake inhibitor(J. Org. Chem. 2013, 78, 5768). Access to the two contiguousstereocenters in this target was achieved via a dynamic kineticresolution (DKR) with enantio- and diastereoselective hydro-genation on a β-keto-γ-lactam to afford a β-hydroxy-γ-lactamwith 96% ee and 94% de. Reduction of lactam to the pyrro-lidine and purification via the dibenzoyl-(L)-tartaric acid dia-stereomeric salt enriched the ee and de to 100%, and this wastaken forward to the final API structure. While screeninghydrogenation reaction systems with ruthenium BINAPcatalysts, it was found that silica column-purified substrate didnot give full conversion. Analysis of the crude substrate prior tochromatographic purification suggested that small amounts ofinorganics and/or acidic residue may have been involved inearlier successful reactions. On the basis of these observations,continued additive screening revealed that catalytic HCl andLiCl enabled higher yields for this particular DKR hydro-genation. In addition, the rate and equilibrium of the DKRhydrogenation was studied by online NMR and chiral HPLC,which indicated that one of the enantiomers was reducing fasterthan the equilibration of the stereocenter.

■ SYNTHESIS OF ARYL SULFONAMIDES VIAPALLADIUM-CATALYZED CHLOROSULFONYLATIONOF ARYLBORONIC ACIDS

Buchwald and co-workers at MIT have described the synthesisof aryl sulfonamides (J. Am. Chem. Soc. 2013, 135, 10638) froma readily available [SO2]

+ synthon, phenyl chlorosulfate. Thestrategy utilizes a regioselective Suzuki−Miyaura cross-couplingbetween phenyl chlorosulfate and aryl boronic acids (1.5 equiv)with 2 mol % palladium catalyst and 5 mol % Na2CO3 in dryacetone. These conditions provide access to a variety of electronically

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and sterically diverse sulfonyl chlorides, some of which cannot beaccessed by common methods such as electrophilic aromatic sub-stitution. Boronic acids derived from nitrogen heterocycles were notcross-coupled under these conditions due to deboronation of thestarting materials and/or the instability of the corresponding sul-fonyl chlorides. A one-pot procedure to produce aryl sulfonamidesis achieved by simply adding in the corresponding primary orsecondary amine (1.2−3 equiv) to the crude reaction mixture.

■ DIRECT CATALYTIC CROSS-COUPLING OFORGANOLITHIUM COMPOUNDS

Organolithium reagents are common intermediates in thesynthesis of various organometallic reagents used in catalyticcarbon−carbon cross-couplings. The direct use of organo-lithium reagents as the organometallic partner in cross-couplingreactions has been a challenging problem because lithium−halogenexchange is faster than oxidative addition leading to homocouplingbyproducts. Feringa and co-workers at University of Grøngingen(Nat. Chem. 2013, 5, 667) have reported palladium-catalyzedconditions that suppress this side reaction and result in thedirect coupling of easily accessible alkyl- and (hetero)aryl-lithium reagents with alkenyl or (hetero)aryl-bromides. Theuse of toluene as solvent, dilute reaction conditions (0.45 M),and slow addition of the organolithium reagent discourageslithium−halogen exchange. Bulky trialkyl phosphine ligandson the palladium catalyst accelerate reductive elimination, sup-pressing β-H elimination, leading to highly selective cross-couplings. The mild reaction conditions (room temperaturefor 1 h) allow for the use of several functional groups includingaryl chlorides, alcohols, acetals, aryl ethers, amines, and com-pounds with acidic protons. Electrophilic functional groupssuch as ketones and nitriles are not compatible; however, estersare tolerated if the corresponding aryl iodide is used and thereaction temperature is lowered (−10 °C). Only 1.2 equiv ofthe organolithium reagent is required with 5 mol % catalyst.

■ CATALYTIC ENANTIOSELECTIVE ONE-POTAMINOBORYLATION OF ALDEHYDES:A STRATEGY FOR CONSTRUCTION OFNONRACEMIC α-AMINO BORONATES

Hong and Morken of Boston College have developed aplatinum-catalyzed enantioselective one-pot aminoborylation ofaldehydes to construct α-amino boronates (J. Am. Chem. Soc.

2013, 135, 9252). The strategy involves in situ silyl imineformation from aromatic aldehydes with LiHMDS (1.05 equiv)in THF at room temperature, followed by enantioselective Pt-catalyzed diboration with B2(pin)2 (1.2 equiv). The diborationutilizes a commercially available Pt-catalyst and readily availableTADDOL-based phosphonite ligands. The diborated intermediatecan be acylated with pivaloyl chloride (1.2 equiv) and the additionof pivaloyl acid (1.0 equiv) to presumably aid in protoborona-tion and/or protodesilylation. The diboron intermediate can alsobe acylated with α-amino acid fluorides to produce peptidic aminoboronates. Aromatic aldehydes with various electronic groupswere tolerated, while ortho-substituted aromatic aldehydes ledto nearly racemic products. Examples of aliphatic aldehydes werenot shown. The amino boronate products can be hydrolyzed tothe boronic acid or cross-coupled with stereoinverstion to providebenzylhydryl amines.

■ MILD AND HIGHLY SELECTIVEPALLADIUM-CATALYZED MONOARYLATIONOF AMMONIA ENABLED BY THE USEOF BULKY BIARYLPHOSPHINE LIGANDS ANDPALLADACYCLE PRECATALYSTS

Buchwald and co-workers at MIT have developed an atomeconomical synthesis of primary aryl amines using ammoniaand aryl halides (Org. Lett. 2013, 15, 3734). The convenientglovebox and high-pressure-free procedure utilizes bulky biaryl-phosphine ligands and a palladium precatalyst to provide moderateto excellent yields in high selectivity for monoarylation of a broadrange of structurally diverse 5- and 6-membered heteroaryl halides.Several base-sensitive groups, including ketones, esters, and cyanogroups, were surprisingly tolerated despite the use of stoichiometricNaOtBu, as were sterically hindered aryl halides. This methodprovides the first example of Pd-couplings between ammonia and5-membered heteroaryl halides.

■ Pd(II)-CATALYZED C−H IODINATION USINGMOLECULAR I2 AS THE SOLE OXIDANT

Yu and co-workers at The Scripps Research Institute along withcollaborators at Bristol-Myers Squibb have described a directedPd(II)-catalyzed C−H iodination of aryl amides using I2 asthe sole oxidant (J. Am. Chem. Soc. 2013, 135, 103326). Thisprocedure avoids the use of expensive or strong oxidants toachieve halogenation. The ortho-iodination of aryl amides and



benzamides utilized 2% Pd(OAc)2 and could be lowered to 0.5%catalyst when run on gram scale. Monoselective iodinationoccurred when one of the ortho-positions of the aryl ring wassubstituted. Ortho-unsubstitued substrates resulted in di-iodina-tion in high yields. Substrates bearing meta- and para-substitutionresulted in selective iodinations in good yields, and both electron-withdrawing and -donating groups were tolerated. A α-methyl onthe directing group hampered the di-iodination, resulting in selec-tive mono-iodination in a substrate derived from naproxen.The iodination of benzamides required the addition of K2S2O8(0.2 equiv) and DMSO as solvent to suppress dimerization.Iodination of several pyrazoles, oxazoles, thiazoles, and pyridineswas achieved in N-methylformamide (NMF) as solvent,representing the first example of directed Pd(II)-catalyzed C−Hactivation of a broad range of heterocycles.

■ Rh(III)-CATALYZED AMINATION OF ARENES WITHALKYL AZIDES

Researchers at the Korea Advance Institute of Science andTechnology reported the direct C−H amination of arenes withalkyl azides as the nitrogen source in Angew. Chem., Int. Ed. 2013,52, 8031. The procedure, which relies on the use of a Rh(III)catalyst generated from (RhCp*Cl2)2 and AgSbF6 as a silveradditive, displayed a broad substrate generality and high func-tional group tolerance. Thus, benzamides, aryl ketones, arylketoximes, and flavones underwent directed amination at theortho position with a variety of benzyl and alkyl azides togive the corresponding N-alkyl aniline products in good yields.The interjection of reactive intermediates and the existence ofa significant kinetic isotope effect in the reaction of deuterium-labeled substrates support a mechanism involving the irre-versible cleavage of the C−H bond promoted by a cationicRh(III) species. An intermediate rhodacycle would react with

the azide to form the Rh(III) amido complex that delivers thedesired product following nitrogen release and protonolysis.The amination does not proceed through a SNAr pathway sinceelectron-rich substituents in the arene accelerate the process.

■ Pd(II)-CATALYZED HALOGENATION OF ARENES

The limitations of current methodologies for the preparation of arylhalides continue to challenge chemists disposed to develop generalapproaches that avoid impractical reaction conditions. Rao and co-workers at Tsinhua University report a Pd(II)-catalyzed procedurefor the regio- and chemoselective chlorination and brominationof electron-deficient arenes (Angew. Chem., Int. Ed. 2013, 52,4440). Under acidic conditions, benzoates, benzamides, aro-matic sulfonamides, ketones, and esters undergo directed ortho-metalation mediated by the weakly coordinating oxygen atomsof these functional groups. Subsequent reaction with chlorineor bromine sources in the presence of a co-oxidant forms thedesired C−halogen bonds through reductive elimination from aPd(IV) species and regeneration of the Pd(II) catalyst. Optimalreaction conditions involve the use of Pd(OAc)2 as catalyst,stoichiometric amounts of NCS or NBS as halogenating re-agents, Na2S2O8 as the co-oxidant, and TfOH as the key acidiccomponent that accelerates the process by generating theelectron-deficient Pd complex Pd(OTf)2. The scalability of thehalogenations was demonstrated on a gram scale without anyneed for air- or moisture-free reaction conditions. Competitionexperiments between different directing groups indicated thefollowing order of ortho-directing ability: NHAc > CONHR >CO > SO2NHR > CO2Et, CONR2, SO2NR2. Moreover,kinetic isotope effect studies indicated that the cleavage of theC−H bond is involved in the rate-limiting step of the reaction.

■ SYNTHESIS OF N-BOC IMINES FROM N-BOCAMINALS

Maruoka and co-workers at Kyoto University describe theacid-catalyzed generation of N-Boc imines from their aminal



cousins in Angew. Chem., Int. Ed. 2013, 52, 5532. The value ofN-Boc imines resides on their reactivity towards 1,2-additions,which lead to a variety of N-Boc amines of synthetic interest. Themethodology avoids the accumulation of unstable N-Boc iminesduring the reactions by slowly generating them in situ from N-Bocaminals, and subsequently promoting their consumption bycommon nucleophiles. The aminals could be readily obtained aswater-, air-, and light-stable white solids from aldehydes bearingalkynyl, alkenyl, alkyl, or aryl substituents attached to the carbonylgroup. A variety of nucleophiles reacted in Mannich-type addi-tions, including diethyl malonate, ketoesters, acetyl acetone, andsilyl enol ethers to give the desired adducts. Mechanistic studiesconfirmed that the elimination of BocNH2 is reversible and onlytrace amounts of N-Boc imine are generated under the reactionconditions. The acid catalyst plays a dual role mediating the imineformation and accelerating the addition step.

■ Ag-CATALYZED NITROGENATION OF ALKYNES

Jiao and co-workers at Peking University describe a directprocedure to prepare nitriles from alkynes (Angew. Chem., Int.Ed. 2013, 52, 6677). Inspired by the metal-catalyzed CCbond cleavage that occurs in alkyne metatheses, the authorsenvisioned that the right combination of a transition metal anda nitrogen source could facilitate the nitrogenation process.Following an extensive screening of potential catalysts, nitrogensources, and solvents, optimal conditions were identified thatcomprised the use of Ag2CO3, TMSN3, and air in DMSO. Thus, arange of terminal alkynes substituted with diverse functional groupsafforded their corresponding nitrile derivatives in good yields.The addition of TEMPO or BHT did not affect the outcome ofthe transformations, indicating that a radical mechanism is unlikely.In addition, control experiments that submitted potential aziridineand tetrazole intermediates to the reaction conditions were un-successful. The isolation of a productive vinyl azide intermediateand the requirement of 2 equiv of TMSN3 to transform thisintermediate into the desired nitrile shed light into the mechanismof the complex sequence. HN3 and CH2N2 are process byproductsthat could be detected by GC−MS.

■ CATALYTIC ASYMMETRIC α-ALKYLATIONS OFN-BOC-PYRROLIDINE

Chiral pyrrolidines substituted at the 2-position are valuableintermediates in the synthesis of bioactive compounds as wellas efficient organocatalysts in asymmetric transformations. Cordier,Lundgren, and Fu described the development of a one-potmethod for the preparation of a variety of 2-alkylpyrrolidines fromN-Boc-pyrrolidine (J. Am. Chem. Soc. 2013, 135, 10946).Treatment of racemic α-zincated N-Boc-pyrrolidineprepared

in situ from commercially available N-Boc-pyrrolidine, s-BuLi,TMEDA and ZnI2with a chiral Ni catalyst and inactivatedalkyl electrophiles afforded enantioenriched 2-alkylpyrrolidinesresulting from an enantioconvergent Negishi-type cross-coupling. The chiral Ni catalyst results from the combinationof NiCl2·glyme and a C2-symmetric 1,2-diamine ligand.Secondary alkyl iodides and alkyl bromides yielded the desiredproducts with high enantioselectivities, whereas their primarycongeners cross-coupled with lower ee. Control experimentsdemonstrated that the configuration of the product dependslargely on the configuration of the ligand rather than thestereochemistry of the organozinc nucleophile.

■ SYNTHESIS OF ENANTIOMERICALLY PUREα-FUNCTIONALIZED GRIGNARD REAGENTS

Rayner, O’Brien, and Horan report a novel strategy for thepreparation of enantiomerically pure α-functionalized Grignardreagents in J. Am. Chem. Soc. 2012, 135, 8071. The process,which does not require (−)-sparteine, involves the asymmetricdeprotonation of O-alkyl carbamates with s-BuLi in thepresence of a chiral diamine and the trapping of the lithiatedspecies with Andersen’s chiral sulfinate. Succeeding stereo-specific sulfoxide/Mg exchange at room temperature generates



the chiral Grignard reagents in enantiomeric ratios ≥99:1.Reaction of the chiral Grignards with aldehydes yielded protecteddiols with anti diastereoselectivity in good yields and enantiose-lectivities (99:1 er). Similarly, the Aggarwal-type rearrangementpromoted by treatment of a chiral Grignard with i-BuB(pin), andsubsequent oxidation afforded the desired alcohol in 94:6 er. Thestereochemical outcome of this rearrangement could be improvedto 99:1 er by incorporating an alternative sulfoxide/Li exchange.Careful study of a α-alkoxy-substituted Grignard reagent revealedits configurational stability at room temperature for 30 min.

■ PALLADIUM-CATALYZED HIGHLY SELECTIVEORTHO HALOGENATION (I, Br, Cl) OFARYLNITRILES VIA sp2 C−H BOND ACTIVATIONUSING CYANO AS DIRECTING GROUP

C−H functionalization has emerged as a valuable and atom-economical tool in organic synthesis wherein the use of weaklycoordinating directing groups enable higher reactivity throughcyclopalladated intermediates, and exquisite selectivity to beobtained. In this respect, the cyano group is particularly usefulas it can subsequently be transformed into a range of differentfunctional groups. Sun and co-workers have reported on theortho-selective halogenations of aryl nitriles under palladium-mediated conditions (J. Org. Chem. 2013, 78, 2786). Screeningstudies on the reaction of benzonitrile with N-iodosuccinimide(NIS) indicated that Pd(OAc)2 was the optimal palladiumsource with a loading of 5% with an acidic additive such asp-toluenesulfonic acid (PTSA) essential for a successful reac-tion. DCE was shown to be the best solvent, although the reactiondid progress in other solvents, and the ideal temperature wasshown to be 70 °C. Alternative iodic sources such as iodine led tomixtures of products. The scope of the reaction was demonstratedto be broad with neither electronic nor steric effects of the sub-strates playing a significant role. For meta-substituted aromatics,the iodination did not occur between the two substituents butat the other ortho position. The conditions were also extended tobromination and chlorination simply by switching the succinimide.Again, excellent yields, high regioselectivity, and good func-tional group tolerance were demonstrated. The chemistry wasdemonstrated on 20 mmol scale with only a minor erosion ofyield, and applied as a key step in the syntheses of the naturalproducts paucifloral F, and its regioisomer isopaucifloral F. Amechanistic rationale is provided, invoking cyano coordinationto the palladium using its π-electrons to direct the generation ofthe aryl palladium species. The acid additive is believed to benecessary to protonate the N-halosuccinimide (NXS) to make ita more effective X+ source.

■ PALLADIUM-CATALYZED CROSS-COUPLINGREACTION OF FUNCTIONALIZED ARYL- ANDHETEROARYLBISMUTHANES WITH 2-HALOOR (2-TRIFLYL)-AZINES AND -DIAZINES

Metal-catalyzed coupling reactions between halogenatedelectrophiles and organometallic reagents represent afundamental approach for the installation of aromatics andheteroaromatics into organic molecules. However, for

2-haloazines or diazines, only limited examples of this approachhave been reported for the synthesis of 2-arylheterocycles, andthese suffer from drawbacks such as modest substrate scope, limitedfunctional group tolerance, or the need to work under strictlyanhydrous and inert conditions. Gagnon and Petiot have reportedon the use of organobismuthanes to circumvent many of theselimitations (Eur. J. Org. Chem. 2013, 5282). These reagents areeasily prepared, can be chromatographed and stored in air atroom temperature, and show low toxicity. In addition, unlikeother organometallic reagents, all three aryl groups can betransferred from the organobismuthane to the electrophile,making these reagents significantly more atom economical. Amodel reaction between triphenylbismuth and a chloropyr-idazine showed Pd(PPh3)4 to be the optimal palladium sourceat a loading of 5 mol % in DMF at 130 °C. The addition of abase such as cesium carbonate was shown not to be essential forreaction to occur but was necessary to obtain the best yields. Awide range of azines and diazines were evaluated in the reac-tion with chlorides, bromides, and triflates all being demon-strated as being effective coupling partners. In contrast to thecorresponding organomagnesium reagents, a wide variety offunctional groups were also tolerated in the reaction. Studyingthe regioselectivity in a 2,4-dichloropyrimidine showed it waspossible to obtain the 4-substituted product in good yield byadjusting the amount of organobismuthane employed. The scopeof organobismuthanes was also examined, and again good yieldswere obtained in the coupling reaction except in the case ofortho-substituted aryl groups. Additionally, a range of functionalgroups were tolerated on the organobismuthane, and it wasdemonstrated that it was possible to cleave an acetal withoutcleaving the C−Bi bond to provide the corresponding formyl-substituted reagent, which was then utilized in a couplingreaction.

■ CHIRAL N-HETEROCYCLIC CARBENE/PYRIDINELIGANDS FOR THE IRIDIUM-CATALYZEDASYMMETRIC HYDROGENATION OF OLEFINS

Chiral iridium catalysts have considerably expanded the scopeof asymmetric olefin hydrogenation by obviating the need fora coordinating group next to the CC bond. The majorityof iridium catalysts feature chiral bidentate N,P-ligands witha heterocycle as a coordinating unit and, although effective ina range of cases, are not suitable for the hydrogenation of acid-sensitive substrates. Burgess and co-workers developed a catalystsystem to overcome this by replacing the phosphine with anN-heterocyclic carbene (NHC), and Pfaltz and co-workers have



reported on a new ligand system in which the oxazoline unit hasbeen replaced with a bicyclic pyridine backbone to the molecule(Angew. Chem., Int. Ed. 2013, 52, 7422). Comparison of theX-ray structure of the new ligand with the original phosphiniteanalogue showed a similar orientation of the tetrahydroquino-line, and a boat conformation of the chelate ring in both cases.Further modeling studies indicated the similarity of the twoligand systems, leading to the expectation that the new systemswould perform in a similar manner in an asymmetric hydro-genation reaction. The new NHC-based catalysts were evaluatedagainst six typical test substrates and compared with theanalogous pyridine−phosphinite catalysts. All three of the newcomplexes evaluated generally showed high catalytic activity withfull conversion being obtained after 2 h with 1 mol % catalyst.With the exception of terminal olefins, high enantioselec-tivities were observed for all substrates, and the new catalystswere shown to be complementary to the Burgess system. Fur-ther studies also demonstrated the new NHC-based catalyststo perform in a superior manner in the hydrogenation of acid-sensitive substrates.

■ NICKEL-CATALYZED SUZUKI−MIYAURACOUPLINGS IN GREEN SOLVENTS

Transition-metal-catalyzed couplings are widely used in thepharmaceutical industry, and the search for more cost-effectivecatalysts that enable these reactions to take place under moreenvironmentally friendly conditions is an important goal today.Garg and co-workers have reported on the use of the commerciallyavailable Ni(Cl)2(PCy3)2 as a precatalyst to mediate this trans-formation (Org. Lett. 2013, 15, 3950). The model reactionbetween a napthyl sulfamate and phenylboronic acid usingpostassium phosphate as the base with 5 mol % catalyst wasexamined in >30 solvents to potentially identify greener alter-natives. From these reactions over half the solvents provided aquantitative yield with tert-amyl alcohol and 2-MeTHF beingselected for further studies. Several other electrophilic partnerswere evaluated and shown to be effective under the optimalreaction conditions. The scope of the reaction was also exa-mined with numerous heterocyclic halides being shown tocouple in high yield. In addition, a range of bis-heterocyclicscaffolds was synthesized, exploiting this new methodology.Finally, two examples are provided on gram scale with a loweringof the catalyst loading to 0.5 mol %.

■ LIGAND-DEPENDENT SITE-SELECTIVE SUZUKICROSS-COUPLING OF3,5-DICHLOROPYRIDAZINES

The ability to differentiate between identical halogens in themetal-catalyzed couplings of heteroarenes is a valuable goal inrapidly expanding SAR space in a lead series. Generally, steric

effects, electronic effects, and directing groups are all exploitedto obtain site selectivity. Workers at Merck have studied a rangeof catalyst systems in the Suzuki-coupling of 3,5-dichloropyr-idazine (J. Org. Chem. 2013, 78, 7758). They found that theligand utilized has a profound effect on the chemoselectivityof the coupling. In general, electron-deficient bidentate ligandspromoted coupling at C-3 with DPPF being identified as theoptimum ligand. This selectivity could be essentially reversedby using an electron-rich monodentate ligand with Q-Phosgiving the highest selectivity for the C-5 position. Each of thesystems were then optimized through screening studies toidentify the best catalyst/ligand loadings, solvent, and base. Awide range of examples using aryl, heteroaryl, and alkenylboronic acids are provided for both the C-3- and C-5-selectivesystems leading to the desired products in good yield. Thechemistry was further extended to 2,4-dichloropyridine, andagain by simply switching the ligand employed, selectivity foreither the C-2 or C-4 position was demonstrated.

■ AMIDE ACTIVATION BY TMSCl: REDUCTION OFAMIDES BY LiAlH4 UNDER MILD CONDITIONS

The reduction of amides and lactams to the correspondingamines still represents a contemporary synthetic challenge.Although a number of methods have been identified, there areconsiderable drawbacks and limitations to many of these.Bandichhor and co-workers have developed a system for the effec-tive reduction of secondary and tertiary amides using a combi-nation of LAH and TMS-Cl (Tetrahedron Lett. 2013, 54, 4908).Model studies indicated that a reverse mode of addition wascritical for reaction success with the amide being treated withTMS-Cl prior to addition of the reducing agent. Both THF andDCM were shown to be suitable solvents with the reactionstypically being completed within 1 h at 0−5 °C using a TMS-Clto LAH ratio of 1.2/1.4. With the optimized conditions inhand, a range of both secondary and tertiary amides andlactams were successfully reduced. In the cases of enantiopureamides, no racemization was observed under the reactionconditions. A mechanism for the transformation was proposedon the basis of initial activation of the amide by TMS-Cl.

■ SILVER-MEDIATED TRIFLUOROMETHYLATIONOF ARYLDIAZONIUM SALTS: CONVERSION OFAMINO GROUP INTO TRIFLUOROMETHYL GROUP

Much progress has been made in developing methods for theinstallation of the CF3 moiety into an aromatic ring. However,



there are still a number of drawbacks with the methods thus fardeveloped such as limited substrate scope, harsh reactionconditions, or expensive reagents. Wang and co-workers havereported a silver-mediated method to convert aryl diazoniumsalts, which are obtained from readily available anilines, into thecorresponding trifluoromethyl compounds (J. Am. Chem. Soc.2013, 135, 10330). The initial experiment imitated the classicSandmeyer conditions but utilized AgCF3 (freshly preparedfrom AgF and Me3SiCF3) as the source of the trifluoromethylgroup and led to a 41% yield of the desired product.Optimization studies led to the discovery that EtCN was thebest solvent, and addition of an excess (3.5 equiv) of AgCF3 at−78 °C led to an 80% isolated yield. Further work alsodemonstrated that the counterion of the diazonium salt has asignificant effect on the reaction with Br−, Cl−, and CF3CO2

−

being the counterions of choice. The reaction was demon-strated for a range of anilines bearing both electron-with-drawing and -donating groups as well as sterically demandingsubstrates. A number of oxidation-sensitive functional groupswere also well tolerated. For heterocyclic substrates, moderateyields could be obtained aside from pyridine, which performedpoorly. The reaction was successfully performed on morecomplex molecules (demonstrating the potential for its use forlate-stage trifluoromethylation) and was also shown to work ongram scale. The authors also demonstrated the reaction intandem with their previously disclosed metal-free borylationprocedure. Initial mechanistic studies suggest that the reactiondoes not proceed through a radical species, but instead anoxidative addition−reductive elimination pathway involving ahigh-valent silver species is proposed.

■ SOLVENT-CONTROLLED COPPER-CATALYZEDOXIDATION OF BENZYLIC ALCOHOLS TOALDEHYDES AND ESTERS

The ester functional group is found widely in pharmaceuticals,agrochemicals, and polymers. Consequently there is con-tinuous research to discover better methods to make thisgroup without having to go through an activated carboxylicacid intermediate. Wei and co-workers report a solvent-controlled protocol that uses copper as catalyst to selectivelyoxidize benzylic alcohols to make either aldehydes or esters ingood yields (Eur. J. Org. Chem. 2013, 4503). The reaction doesrequire a bis-amine ligand (L) and di-tert-butyl peroxide(DTPB) as the oxidant. When the reaction is run, neat estersare formed in good yields (71−91%). The use of a polar sol-vent such as DMF on the other hand leads to formationof aldehydes in good yields (83−93%). They propose amechanism for the two processes that proceed via a commonalkoxy copper complex.

■ THE FIRST ZnII-CATALYZED OXIDATIVEAMIDATION OF BENZYL ALCOHOLSWITH AMINES UNDER SOLVENT-FREECONDITIONS

There is currently a need for methods that can form the amidebond that do not have to go through a carboxylic acid pre-activation. Most of the known non-activating protocols requireeither expensive catalysts (Ru or Rh) or some form of aheterogeneous catalyst. Ideally the synthesis of amides witha cheaper metal that is widely available would be the best.Now in a new report, Beller et al report a zinc-catalyzedoxidative amidation of benzyl alcohols (Eur. J. Org. Chem.2013, 2783). The procedure is carried out in air using acatalytic amount (5 mol %) of ZnI2 and tert-butyl hydro-peroxide (TBHP) as the oxidant. With this protocol theyare able to make aryl amides from aryl benzylic alcohols inmoderate to good yields (46−85%); however, the synthesis ofheteroarylamides from heterobenzylic alchols gave low yields(23−48%).

■ SUCCESSFUL SCALE-UP OF AN INDUSTRIALTRICKLE BED HYDROGENATION USINGLABORATORY REACTOR DATA

Catalytic hydrogenation processes can be a challenge to scale-up, and when the need is to scale-up by a factor larger than amillion in one step, the challenge is quite significant. Runningthe process continuously contributes to the success of such ascale-up task, and a team from Dow reports, albeit in limiteddetail, about the successful scale-up of a proprietary hydro-genation over a palladium catalyst by a factor of 3 × 10 6

(Hickman, D. A., et al. Ind. Eng. Chem. Res. 2013, 52, 10.1021/ie4005354). After a suitable catalyst formulation (inert fines)was identified for the design of the commercial reactor, theteam generated the necessary kinetic data using a small-scale(continuous) reactor. Three important problems had to besolved during this work: suitable catalyst wetting, produc-tivity, and deactivation. Careful physical characterization ofthe catalyst particles was conducted using X-ray photo-electron spectroscopy and transmission electron micros-copy. Four distinct catalyst deactivation mechanisms wereconsidered: sintering, iron poisoning, palladium loss,and fouling. Experiments were conducted for up to 3600 h(five months) in order to develop the necessary processunderstanding for effective process design. A suitablecatalyst bed aspect ratio solved the catalyst wetting problem,and optimized catalyst particle size led to an economicallyattractive productivity. For meaningful process understanding,the team used raw materials representative for commercialmanufacturing. Support from the Oak Ridge NationalLaboratory is acknowledged by the Dow team.



■ EFFECT OF WATER ON THE CHEMICAL STABILITYOF AMORPHOUS PHARMACEUTICALS: I. SMALLMOLECULES

Whereas qualitative impact of water on the stability ofpharmaceuticals is reasonably well understood, quantificationof such impact is an ongoing effort. A recent report from Pfizerand Allergan (Ohtake, S., et al. J. Pharm. Sci. 2013, 102, 1139)reviews the state-of-the-art in the understanding of theinteraction between water and amorphous pharmaceuticals,focusing on small molecules. There are several reasons why thequantitative understanding of such impact has not progressedwell: the interactions at stake are compound specific, they are verycomplex, and water can play several roles (plasticizer, reactant,product, or a reaction media modifier). Several case studies ofinvestigating the impact of water on lyophilized amorphouscephalosporins are discussed. For a meaningful comparisonbetween different compounds, the degradation rates measuredare normalized, being expressed as the ratio between the rate at agiven water content and that at near zero water content. Becauseof the similarity in the reaction rates observed in solution andwith amorphous solids, it is proposed that solution chemistryknowledge could be better leveraged to understand the behaviorof amorphous solids interacting with water. In all the casesanalyzed in this review, the compounds remained amorphousthroughout the range of water content considered. More compli-cated cases, where phase changes or crystallization occurs werenot discussed. This review has 81 references.

■ THE ASSESSMENT OF IMPURITIES FORGENOTOXIC POTENTIAL AND SUBSEQUENTCONTROL IN DRUG SUBSTANCE AND DRUGPRODUCT

Because of the unusually high toxicity of genotoxic impurities(GTI), the associated control strategies are addressed in dedi-cated regulatory guidelines issued by EMA (2006), FDA(2008), and ICH (2013). The industry presented their opinionsince 2006 in several position papers. Among others, the industryrecommendation for a staged threshold of toxicological con-cern (TTC) aimed at striking a balance between the duration ofclinical trials, availability of analytical methods, maturity ofsynthetic processes, and potential risk is worth noting. A recentreview describes the strategies implemented at Eli Lilly andCompany to address the EMA and FDA control strategies forGTI (Dow, L. K., et al. J. Pharm. Sci. 2013, 102, 1404).Particularly challenging is the assessment of the potential GTI,and to date there has not been a consistent approach across theindustry to address such genotoxic potential. This reviewdescribes the conservative approach taken by Lilly for GTI riskassessment (GRA).Because ICH guidelines do not directly apply to clinical

phases of development, Lilly has developed a phase-appropriatestrategy for GTI identification threshold in drug substance. TheLilly GRA includes, besides the assessment of the impuritiesassociated with the synthetic route, the evaluation of actual andpotential degradation impurities. Stress testing is used for thedevelopment of a “degradation knowledge space”, based on theQbD paradigm. The control strategies employed are describedvery clearly by using flowcharts and decision trees. This reviewhas 55 references

Mark McLaughlinMerck & Co. Inc., Rahway, New Jersey 07065, UnitedStates. E-mail: [email protected].

Robert ElyOnyx Pharmaceuticals, 249 East Grand Avenue, South SanFrancisco, California 94080, United States E-mail: [email protected] RamirezBristol-Myers Squibb, Chemical Development, OneSquibb Drive, New Brunswick, New Jersey 08903, UnitedStates. E-mail: [email protected] RichardsonPfizer, Chemistry, 10578 Science Center Drive, San Diego,California 09121, United States. E-mail: [email protected] MuhuhiThe Dow Chemical Company, 1710 Building, Midland,Michigan 48674, United States E-mail: [email protected] ZlotaThe Zlota Company, LLC 15, Fairbanks Road, Sharon,Massachusetts 02067-2858, United States. E-mail: [email protected] Knight*Scientific Update LLP, Maycroft Place, Stone CrossMayfield, East Sussex TN20 6EW, United Kingdom

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected]



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

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