Some Items of Interest to Process R&D Chemists ... - ACS Publications

Highlights from the Literature pubs.acs.org/OPRD

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

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COPPER-CATALYZED AMIDATION OF ALKYL BORONIC ESTERS

The combination of photoredox and metal catalysis has been demonstrated to offer alternatives for forging under mild conditions new C−C bonds. Rueping’s group from Aachen in Germany recently expanded the scope of this type of methodology to the creation of C(sp2)−C(sp3) bonds by crosscoupling reaction of aryl- and vinylsulfonates (Chem. Eur. J. 2016, 22, 16437). While an iridium photoredox catalyst promotes the formation of a radical from the N-arylglycine derivative, a nickel catalyst is required to cleave the C−O bond and allow the formation of the new C−C bond. Optimization work focused on the nickel source and ligand and led to the identification of Ni(II) trifluoromethanesulfonate and tris(4-methoxyphenyl)phosphine as the most efficient catalytic system. As usual for this kind of reaction, it is performed at room temperature and tolerates most of the common functional groups on both reaction partners. Although aromatic bromides and chlorides could both be present in the arylglycine substrate, the presence of the former in the triflate coupling partner is not tolerated leading to bis-alkylated product.

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RUTHENIUM-CATALYZED α-METHYLATION OF CARBONYL COMPOUNDS USING METHANOL

Despite its operational simplicity, amide alkylation with alkyl (pseudo)halides suffers from drawbacks such as overalkylation and toxicity of the reagents. Watson and co-workers from University of Delaware recently succeeded in developing an alternative based on oxidative cross-coupling of boronic esters (Chem. Eur. J. 2016, 22, 15654). Building upon their previous work with alkyl boronic acid, the authors were able to identify exogenous ligands (NacNac, see scheme above) that allow the desired reaction to take place in good to high yields. The optimal conditions use copper acetate as catalyst and tertbutylhydroperoxide (DTBP) as oxidant in tert-butanol as solvent. Protodeborylation of substrate could be avoided through the addition of molecular sieves. A wide range of functionalized primary and secondary alkyl pinacol esters are tolerated under the reaction conditions, and the alkylation of aryl- as well as alkylamides was demonstrated.

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DECARBOXYLATIVE AMINOMETHYLATION OF ARYL- AND VINYLSULFONATES

α-Methylation of carbonyl compounds with environmentally benign methanol through borrowing hydrogen methodology has Published: December 16, 2016 © 2016 American Chemical Society

2019

DOI: 10.1021/acs.oprd.6b00413 Org. Process Res. Dev. 2016, 20, 2019−2027

Organic Process Research & Development

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been demonstrated with expensive rhodium or iridium based catalysts. Seayad and co-workers from Singapore have recently disclosed that cheaper ruthenium catalysts were also competent for promoting such reactions (Adv. Synth. Catal. 2016, 358, 3373). Crucial for the success of the reaction is the nature of the ligand with DPEPhos performing best. A catalytic amount of lithium tert-butoxide and high temperatures (ranging from 100 to 160 °C) are also required for the reaction to take place efficiently. In accordance with the borrowing hydrogen mechanism, the substrate scope is large with free phenols and amines being tolerated but nitro functional group being partially reduced. Worthy of note is the fact that methyl ketones led to doubly methylated compounds. It allows the authors to realize a one-pot sequential α-alkylation-α-methylation of aromatic methyl ketone substrates by performing the reaction under the same conditions with a higher alcohol and adding methanol subsequently. A few examples of α-methylation of esters and nitriles are also provided with the former requiring more forcing conditions (160 °C under microwave irradiation for 8 h).

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Highlights from the Literature

SYNTHESIS OF AROMATIC AZACYCLES VIA HFIP-CATALYZED AZADIENE CYCLOADDITIONS

Glinkerman and Boger report the remarkable effect of HFIP as a solvent in enabling the cycloaddition reaction between azadienes and enamines to form annulated aromatic azacycles (J. Am. Chem. Soc. 2016, 138, 12408). The reaction proceeds via a three-step sequence of [4 + 2]-cycloaddition, retro-[4 + 2]cycloaddition extruding N2 (or HCN in the case of 1,3,5triazines), and aromatization through the elimination of pyrrolidine. A range of annulated pyridines were accessed in good-to-excellent yields, furnished with ester, aromatic, and heteroatom substituents. Pyrimidines could also be accessed from 1,3,5-triazines and isomeric pyridines from 1,2,4-triazines, respectively. The authors applied this methodology to the synthesis of methoxatin, and it offers an alternative, simple process for the late-stage installation of heteroaromatic ring systems.

RUTHENIUM-CATALYZED C−H FUNCTIONALIZATIONS ON BENZOIC ACIDS

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Although much progress has been made in the past decade in the field of ruthenium-catalyzed C−H functionalization of aromatic substrates, this type of reaction is limited to strongly coordinating nitrogen-containing directing groups which can be difficult to remove and modify. Ackermann and co-workers from Gottingen in Germany have recently addressed this issue by finding conditions that allow the C−H arylation of weakly coordinating benzoic acids (Chem. Commun. 2016, 52, 13171). The C−H functionalization of this versatile class of substrates can be achieved through the use of tricyclohexylphosphine-modified ruthenium(II) bis-carboxylate catalyst in N-methylpyrrolidinone at high temperature. The scope of the reaction is relatively large regarding the benzoic acid coupling partner with ortho- and meta-substituted substrates providing the monoarylated products in good-to-high yields, while parasubstituted ones led to bis-arylation products. A variety of aryl bromides proved to be competent reaction partners as well as a limited number of alkenyl and alkynyl halides.

COPPER-CATALYZED HYDROXYLATION OF (HETERO)ARYL HALIDES

Ma and co-workers report a Cu(II)-catalyzed synthesis of phenols and hydroxylated heteroaromatics from the respective halides demonstrating a broad substrate scope and high efficiency (J. Am. Chem. Soc. 2016, 138, 13493). The choice of ligand was found to be key for successful reaction as even slight modification through removal or protection of the phenol substituent resulted in low yields of the hydroxylated product, perhaps owing to higher solubility of the phenolic ligand in the basic reaction medium. Copper(I) and (II) salts both promoted the reaction with Cu(acac)2 giving the best yields. The reactivity of the (hetero)aryl halides follows the expected pattern with chlorides requiring relatively harsh conditions to achieve high conversions (130 °C), while bromides and iodides could be transformed at 80 or 60 °C, respectively. A broad range of substituents are tolerated, including electron-rich and -poor (hetero)aromatic substrates. The reaction does not appear to 2020




generates the intermediate oxalate that can be submitted to the cross-coupling reaction without further purification. A wide range of aryl bromides were incorporated including pyridyl bromides. Primary and secondary alcohols could be coupled successfully, with moderate-to-high diastereoselectivities achievable for alcohols furnished with additional chiral centers. This development significantly widens the range of sp3 moieties that can be coupled via this methodology.

require an oxidant for turnover and offers an alternative to carrying reactive phenolic moieties through multistep syntheses by enabling late-stage functionalization of stable (hetero)aryl halides.

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SELECTIVE FUNCTIONALIZATION OF PYRIDINES VIA PHOSPHONIUM SALTS

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TERMINAL-SELECTIVE FUNCTIONALIZATION OF ALKYL CHAINS BY REGIOCONVERGENT CROSS-COUPLING Baudoin et al. has reported a method for regioconvergent n-alkylation of aryl triflates starting from either a single secondary alkyl halide or organometallic derivative thereof or a starting mixture of either of these kinds of species (Angew. Chem., Int. Ed. 2016, 55, 14793). Because β-hydride elimination and hydropalladation are fast relative to cross coupling and further that linear σ-alkyl Pd species undergo cross-coupling faster than isomeric branched complexes, the predominant products obtained are n-alkylated arenes. The process was found to be general with respect to both the structure of the alkyl bromide used as well as the substitution of the aryl triflate. Various functional groups were tolerated. Aryl triflates derived from simple heterocycles and estrone were demonstrated along with a vinyl triflate. Overall this method would probably be best suited for n-alkylation of early intermediates of a fine chemical synthesis, since rigorous purging would be required to remove any traces of the branched isomer.

McNally and co-workers report the regioselective functionalization of pyridines with nucleophiles via the formation of phosphonium salts (J. Am. Chem. Soc. 2016, 138, 13806). The sequential reaction of pyridines with triflic anhydride, triphenylphoshine, and an amine base in cold CH2Cl2 furnishes pyridyl phosphonium salts exclusively substituted at the 4-position or the 2-position if the former is blocked by a substituent. Pyrimidine and pyrazine substrates were also functionalized at the 4- and 2-positions, respectively. The isolable phosphonium salts can be substituted with a wide range alcohols, thiols, azide, or lithiated aromatics. The authors demonstrated the late-stage functionalization of multiple natural products and pharmaceuticals, exemplifying the functional group tolerance and selectivity of this methodology. It offers an interesting alternative to classical electrophilic or nucleophilic aromatic substitution and cross-coupling methodologies.

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PHOTOREDOX sp3−sp2 CROSS-COUPLING OF OXALATES WITH ARYL HALIDES

Zhang and MacMillan report an extension to the well-developed photoredox methodology for sp3−sp2 cross-coupling employing oxalates as an alternative to boronic or carboxylic acids (J. Am. Chem. Soc. 2016, 138, 13862). The activation of abundant primary and secondary alcohols as the oxalate derivative enables the formation of secondary radicals via iridium photoredox catalysis. These radicals are cross-coupled with aryl bromides via a second catalytic mechanism involving a nickel catalyst. Simply reacting the requisite alcohol with oxalyl chloride 2021



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CATALYTIC ALKYLATION OF REMOTE C−H BONDS ENABLED BY PROTON-COUPLED ELECTRON TRANSFER


AMIDE-DIRECTED PHOTOREDOX-CATALYZED C−C BOND FORMATION AT UNACTIVATED sp3 C−H BONDS

Rovis and co-workers have also published chemistry for the alkylation of remote, unactivated C−H bonds under photoredox catalysis (Nature 2016, 10.1038/nature19810). Much like the Knowles work above, the premise of their reaction rests on an N-centered radical performing intramolecular 1,5-hydrogen atom abstraction and the interception of the newly formed radical by an electron-deficient alkene. Similarly, the reaction conditions employ an Ir-based photocatalyst under basic conditions. However, at first glance, the Rovis work appears more user-friendly and geared toward use in multistep organic synthesis. For instance, both the base and the catalyst are more readily available than the corresponding reagents in the Knowles work. Additionally, a wider scope of electron-deficient olefins is accommodated. Finally, the acyl group on the substrate nitrogen atom, trifluoroacetyl, is an easily removed protecting group. Still, given the success of both developed chemistries, the interested chemist should evaluate parameters broadly for maximum efficiency in their own work.

Knowles and co-workers have published a method for alkylation of otherwise unactivated C−H bonds remote from a secondary amide under photocatalytic reaction conditions that proceeds via proton-coupled electron transfer (Nature, 10.1038/nature19811). The method bears some resemblance to the Hofmann−Lö ffler−Freytag reaction, except that (1) no halogenation of a secondary amide is required and (2) the carbon-centered radical that results from 1,5-hydrogen atom abstraction is intercepted by an enone, acrylate, or other good radical acceptor. In several cases, the site of new C−C bond formation was either a secondary or tertiary center. Other aromatic N-acyl groups could be used with varying success, but a Boc carbamate performed poorly as a directing group/precursor to an N-centered radical. Also, although methyl vinyl ketone itself could be used to trap the carbon-centered radical, simple acrylates did not. However, by using alkenes bearing two electron-withdrawing groups, trapping with nonenone substrates could be achieved.

2022



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ENANTIOSELECTIVE FORMATION OF ALL-CARBON QUATERNARY STEREOCENTERS VIA C−H FUNCTIONALIZATION OF METHANOL: IRIDIUM-CATALYZED DIENE HYDROHYDROXYMETHYLATION

Krische and co-workers have reported a fascinating method for enantioselective functionalization of 1,3-dienes with methanol using relatively simple Ir-based catalysts (J. Am. Chem. Soc. 2016, 138, 14210). The authors stumbled onto this unique reactivity when studying the coupling of 2-phenyl-1,3-butadiene with ethanol. Whereas this reaction resulted in C−C bond formation at the 3-position of the diene starting material, when methanol was used, C−C bond formation at the 2-position was observed, leading to the generation of an all-carbon quaternary stereocenter, and the authors chose to follow and optimize this lead. In examining the reactivity of 2-aryl-1,3-dienes, the authors observed the addition of methanol across the 1,2-π-bond of the diene system and observed no products of allyl cation trapping, a much more common mode of reactivity between dienes and methanol.

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Pd-CATALYZED γ-C(sp3)−H ARYLATION OF FREE AMINES USING A TRANSIENT DIRECTING GROUP

FORMAL TOTAL SYNTHESIS OF IVORENOLIDE A BY CATALYTIC MACROCYCLIZATION IN FLOW

A formal total synthesis of Ivorenolide A has been developed recently by employing a Z-selective olefin cross metathesis and a macrocyclic Glaser−Hay coupling as key steps (J. Org. Chem. 2016, 81, 6750). As shown in the graphic, the key precursor cisolefin before the macrocyclization was obtained in high yield by metathesis using the Ru type of Grubbs catalyst. Moreover, the macrocyclic Glaser−Hay coupling was realized by a phase separation/continuous flow manifold in 52% yield, with multiple advantages such as catalysis (CuCl2 and Ni(NO3)2), fast reaction times (2 h), and high concentration as well as facile scale-up.

The Yu group has reported a method for the arylation of γ-C(sp3)−H bonds in acyclic and cyclic systems (J. Am. Chem. Soc. 2016, 138, 14554). As one might expect, a Pd(II) catalyst is used; however, the most interesting facet of this chemistry is the use of 2-hydroxy-3-nicotinaldehyde as a transient scaffolding element. In the absence of this additive, no products of siteselective C−H arylation are observed, and the use of other aldehydes has a dramatic effect on reaction efficiency, though none are as effective as the given aldehyde. The authors opine that the imine forms between the amine substrate and the aldehyde and that this transient construct directs C−H palladation, leading to productive C−C bond formation. The authors demonstrated the broad applicability of their reaction to numerous aryl iodide and amine cosubstrates.

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2023

ELECTROPHILIC AMINATION OF ARENES AND SCHMIDT REACTION OF CARBOXYLIC ACIDS IN FLOW




flow process gave better results in terms of yield and selectivity in comparison to the corresponding batch counterpart.

A continuous flow protocol for the direct stoichiometric electrophilic amination of arenes and the Schmidt reaction of aromatic carboxylic acids was developed recently (Kappe, O., et al. J. Org. Chem. 2016, 81, 9372). As shown in the graphic, the reactants (either arene and TMS-azide for the amination reaction or arenecarboxylic acid and triflic acid for the Schmidt reaction) are combined in the reaction segment. The direct amination of arenes was achieved within 2−5 min at 90 °C after an intensified protocol at elevated temperatures. Alternatively, aromatic carboxylic acids were additionally chosen as substrates via a Schmidt reaction employing similar flow reaction conditions (

Some Items of Interest to Process R&D Chemists ... - ACS Publications

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