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

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

pubs.acs.org/OPRD

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

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CATALYTIC REDUCTION OF ALKYL AND ARYL BROMIDES USING ISOPROPANOL

fragrances Pelargene,Verdirosa, and Doremox were all demonstrated with high enantioselectivity.

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PALLADIUM-CATALYZED DIRECT C3-SELECTIVE ARYLATION OF N-UNSUBSTITUTED INDOLES WITH ARYL CHLORIDES AND TRIFLATES

Grubbs and co-workers report the use of Milstein’s complex to reduce primary, secondary, tertiary, and aryl halides using 2-propanol as the hydride source (Angew. Chem. Int. Ed. 2017, 56, 15123). Reduction of C−X bonds is a challenging transformation often requiring activated substrates and/or harsh reagents including, but not limited to, LiAlH4, silanes, or HSnBu3/AIBN. The combination of Milstein’s ruthenium PNN pincer complex and a stoichiometric amount of base (NaOtBu) enabled reduction of a range of primary, secondary, tertiary, and both aryl and heteroaryl bromides in isopropanol at 100 °C. Yields were typically >70% with reaction on up to 10 mmol scale demonstrated. Three examples of alkyl chlorides were also demonstrated in 52−99% yield, whereas a primary alkyl tosylate proved unreactive under these conditions.

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CATALYTIC ASYMMETRIC [4 + 2]-CYCLOADDITION OF DIENES WITH ALDEHYDES List and co-workers report the development of a highly acidic and confined chiral Brønsted acid catalyst for the asymmetric [4 + 2]-cycloaddition of unactivated dienes with aldehydes (J. Am. Chem. Soc. 2017, 139, 13656). [4 + 2]-Cycloadditions often require electron-deficient dienophiles and/or electron-rich dienes. The authors reasoned that a strong Brønsted acid would be required to sufficiently lower the LUMO of the aldehyde to allow reaction with simple dienes and that a highly confined chiral environment would be necessary to enable high levels of stereoinduction. An imidodiphosphoramidate was successful in catalyzing the highly enantioselective [4 + 2]-cycloaddition of a range of aryl and alkyl aldehydes with substituted dienes in up to >99% ee. The reaction was scaled to 10 mmol aldehyde using only 0.2 mol % catalyst, and the syntheses of the commercialized © XXXX American Chemical Society

Manabe and co-workers report the direct C3-arylation of N-unprotected indoles with aryl chlorides and triflates (Org. Lett. 2017, 19, 5388). A terphenyl phosphine ligand substituted with phenols allows for directed arylation at the C3-position of indoles without recourse to protection of the indole nitrogen.

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DOI: 10.1021/acs.oprd.7b00371 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

attacking nucleophilic arene. Yields for this transformation range from modest to excellent, and typical substrates contain pendant free indoles, phenols, and naphthols. The base used is either K2HPO4 or K2CO3, depending on the nature of the leaving group on nitrogen, and in all cases, the reaction is conducted above ambient temperature. While the finer details of reaction mechanism were not determined, the transformation was proven to be intramolecular, as no crossover products were observed in relevant control experiments, and pre-existing literature points to a direct displacement at the electrophilic nitrogen.

Electron-rich and -neutral arenes coupled in generally high yields, whereas reduced yields were observed for electron-poor and heteroaromatics. Indoles substituted in 5- or 7-positions followed the same trend for coupling with 4-tolyl chloride where electron-rich and -neutral reactants performed best. C2-Substituted indoles coupled in low yield and N-methylation shut down reactivity. Interestingly, a C3-substituted indole underwent dearomatization to form a 3,3-disubstituted indolenine in moderate yield.

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HETEROCYCLIC SULFINATES AS GENERAL NUCLEOPHILIC COUPLING PARTNERS IN PALLADIUM CATALYSIS

Willis and co-workers report updated conditions for the crosscoupling of heteroaryl sulfinates with chlorides and bromides that greatly improves the functional group tolerance of the reaction (Org. Lett. 2017, 19, 6033). Heteroaromatics are rarely employed as nucleophiles in palladium-catalyzed cross-couplings as the corresponding boronates, stannanes, zincates, magnesates, or lithiates are often poorly stable and/or challenging to prepare. However, hetereoaryl sulfinates are bench stable and straightforward to prepare, thereby overcoming these limitations. The newly developed conditions allow for the coupling of a wide range of substituted heteroaromatics with chlorides and bromides in 1,4-dioxane at 100 °C. The demonstrated scope of hetereoaromatics includes 2- and 3-pyridyl, pyrazine, pyridazine, 2- and 4-pyrimidines, quinolone, 3-indazole, 4-pyrazole, 2-imidazole, and 5-indole. A wide range of functional groups were also tolerated including, but not limited to, phenol, carboxylic acid, nitrile, and pentafluorosulfide.

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SELECTIVE RADICAL FLUORINATION OF TERTIARY ALKYL HALIDES AT ROOM TEMPERATURE Yu, Li, and co-workers have published a paper documenting the use of Selectfluor (1-chloromethyl 4-fluorodiazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) to convert only tertiary alkyl bromides or iodides into the corresponding tertiary alkyl fluorides (Angew. Chem. Int. Ed. 2017, 56, doi: 10.1021/ anie.201708197). Although the authors initially expected to achieve the given transformation with Selectfluor under Ag(I) catalysis based on prior work, control experiments reveal that mere stirring of substrates with the reagent in CH3CN at ambient temperature led to productive replacement of the starting halogen with fluoride. Most tert-alkyl bromide substrates examined led to tert-alkyl fluorides in good yields and without harm to common functional groups. Moreover, side reactions typically observed with C−H fluorination or hydrofluorination of alkenes−such as solvolysis, elimination, or destructive participation by nucleophilic groups or anions−were minimized or simply not observed. In addition, tert-alkyl iodides behaved similarly. Remarkably, less hindered alkyl bromides and chlorides

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A SIMPLE AND BROADLY APPLICABLE C−N BOND FORMING DEAROMATIZATION PROTOCOL ENABLED BY BIFUNCTIONAL AMINO REAGENTS Bower and co-workers have reported N,O-doubly protected hydroxylamine reagents for the overall 4C + N1 formation of pyrrolidines via dearomatization of substituted γ-aryl-1-propanol fragments (Angew. Chem. Int. Ed. 2017, 56, 14531). The report builds on similar electrophilic nitrogen chemistry reported by the group (J. Am. Chem. Soc. 2017, 139, 14005) that differs in that it operates in acidic media. In this latest advance, the doubly protected reagents are used to transform primary alcohols into doubly protected hydroxylamine-bearing substrates. In turn, these new substrates undergo cyclization at nitrogen with lysis of the weak N−O bond and concomitant dearomatization of the B




The chemistry was applied to protected amino acids (e.g., histidine, tyrosine) as well as small drug-like molecules, establishing the potential of the method for the late-stage functionalization of privileged architectures.

in the starting substrate were spared, providing proof-of-concept for site- and halogen-selective fluorination. Basic mechanistic experiments point to a radical-based mechanism for the substitution.

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LEWIS ACID ENHANCEMENT BY HYDROGEN-BOND DONORS FOR ASYMMETRIC CATALYSIS Chiral nonracemic H-bond donors continue to serve as reliable molecular scaffolds for enantioselective catalysis, with the discovery and invention of new modes of substrate activation comprising a fertile area of research. Jacobsen and his group, who have been pioneers in this pursuit, have reported a pathway by which achiral trialkylsilyl triflatespopular reagents for Lewis acid-catalysis and mediation of numerous racemic transformationscan be activated by chiral nonracemic squaramide-based dual H-bond donors, and the resulting complexes catalyze Lewis acid catalyzed reactions currently not accelerated or mediated by existing H-bond catalysts (Science 2017, 358, 761). As a starting point, the authors examined the Mukaiyama aldol reaction between a benzaldehyde acetal and an enol silyl ether in the presence of substoichiometric quantities of TBSOTf and dual H-bond donors. Squaramide-based catalysts led to the most efficient reactions and the most highly enantioenriched products. A squaramide-based “catalyst” unable to H-bond was found to inefficiently catalyze the reaction and furnished essentially racemic product, implicating H-bonding as a crucial element of catalysis; moreover, essentially no reaction was observed with just TBSOTf or in the presence of other H-bond catalysts under the reaction conditions (−78 °C, MTBE solvent). In addition to the aforementioned reaction, related reactions with silyl ketene acetals and allyl silanes proved amenable to enantioselective catalysis in this regime, as did the (4 + 3) union of furans with

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CATION RADICAL ACCELERATED NUCLEOPHILIC AROMATIC SUBSTITUTION VIA ORGANIC PHOTOREDOX CATALYSIS Tay and Nicewicz have described a method for nontraditional SNAr reactions of alkoxyarenes wherein the alkoxy group serves as the leaving group (J. Am. Chem. Soc. 2017, 139, doi: 10.1021/ jacs.7b10076). The chemistry is conducted under irradiation from 455 nm LEDs and catalyzed by a purely organic (metalfree) acridinium dye. While a traditional SNAr reaction with alkoxy leaving groups is prohibitively endergonic, in the present context, single electron oxidation of the alkoxyarene substrate permits soft nitrogen nucleophiles (imidazoles, benzimidazoles, and triazoles) to attack a transiently formed cation radical of the arene, after which loss of methanol with concomitant aromatization leads to product. Notably, the strategy of single-electron oxidation in advance of nucleophilic attack reverses the expected trends of leaving group ability; many of the substrates tested bear one or more chlorine atoms that are left unscathed.

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catalyzed by Cu(I) bisphosphine complexes. In their current report, they describe the use of substoichiometric quantities of each Cu(OAc)2 and DTBM-SEGPHOS and excess (EtO)3SiH to achieve the titled transformation under just 1 atm of CO2 at 60 °C. Yields for the process are generally good while enantioselectivities are typically excellent. A variety of common functional groups were tolerated including aryl ethers, aryl halides, aryl fluorides, trifluoromethyl groups, furans and thiophenes, and esters. In addition, 1-aryl-1,3-butadienes could also be enantioselectively hydroxymethylated such that the new C−C bond was generated at the benzylic carbon and a new Z-configured alkene was generated across the 2,3-position of the former, starting butadiene. Simple mechanistic experiments appear to rule out silyl formates as intermediates, since, when these species were stoichiometrically generated and subjected to the standard reaction conditions but without CO2, no hydroxymethylated products were observed. Alternatively, a stoichiometrically generated benzylic Cu(I)-bisphosphine complex underwent complete conversion to a Cu(I) carboxylate complex when exposed to CO2, suggesting such reactivity is catalytically relevant.

oxyallyl cation precursors. In-depth mechanistic studies were conducted on the (4 + 3) reaction, including the determination that the reaction is first order in acetal-bearing substrate and catalyst, but zero-order in furan and that squaramide-based H-bond catalysts bind to silyl triflates in 1:1 stoichiometry and much more strongly than do N-methylated squaramide catalyst analogs or Bu4NOTf. The overall mechanistic picture that emerges is that the squaramide dual H-bond catalyst induces a pre-equilibrium heterolytic dissociation of triflate counterion from the starting trialkylsilyl triflate, leaving the silyl cation to bind either solvent or one of the squaramide carbonyls. In the rate-determining step, the silyl cation induces ionization of the acetal-based substrate, leading to enantioselective trapping by the nucleophilic substrate organized by a network of noncovalent stabilizing interactions between electrophile and the squaramide−triflate anionic complex.

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HIGHLY REGIO- AND ENANTIOSELECTIVE COPPER-CATALYZED REDUCTIVE HYDROXYMETHYLATION OF STYRENES AND 1,3-DIENES WITH CO2 A team of chemists at Sichuan and Chengdu Universities led by Yu have reported the highly regio- and enantioselective hydroxymethylation of conjugated unsaturated substrates using CO2 as the source of carbon and oxygen (J. Am. Chem. Soc. 2017, 139, doi: 10.1021/jacs.7b10149). The authors have had a continuing interest in the synthetic chemistry of CO2 and harnessed recent observations on enantioselective hydrocupration of styrenes

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DIPHENYLSILANE-PROMOTED AMIDE BOND COUPLING

Sayes and Charette reported a method for coupling carboxylic acids and amines using diphenylsilane, a tertiary amine base, and an additive such as DMAP (Green Chemistry 2017, 19, 5060). The byproducts of the reaction are hydrogen and the corresponding siloxane that can be separated via filtration. Standard reaction conditions employed for screening substrates included heating at 80 °C in acetonitrile for 42 h. The method was applied to peptide bond formation from amino acids bearing pendant hydrophobic side chains with minimal epimerization.

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AMIDATION VIA COUPLING OF ALKYLSILICATES AND ISOCYANATES

Zheng, Primer, and Molander reported a nickel-photoredox dual catalyst system for the synthesis of amides (ACS Catalysis 2017, 7, 7957). The method does not require a stoichiometric D




imidozapyrimidines, and imidazopyrazines. This operationally simple, copper-catalyzed, formal aza-[3 + 2] cycloaddition reaction afforded a range of N-heterobicyclic compounds in good yield.

reductant and featured mild conditions permitting tolerance of heterocycles and several functional groups such as amide, nitrile, fluoride, enolizable ketone, and ester. The use of photocatalyst for radical generation and completion of the nickel catalytic cycle made it possible to achieve redox neutral conditions.

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DIRECT ALDEHYDE C−H ARYLATION AND ALKYLATION VIA THE COMBINATION OF NICKEL, HYDROGEN ATOM TRANSFER, AND PHOTOREDOX CATALYSIS Ketones are important and ubiquitous structural motifs found in natural products, pharmaceuticals, photosensitizers, flavors, fragrances, and organic materials. The merger of photoredox and transition metal catalysis has enabled the invention of a large and varied range or cross-coupling reactions. MacMillan and his co-worker from Princeton University extended their previous research in this area to report a metallophotoredox-mediated aldehyde C−H arylation, vinylation, or alkylation (J. Am. Chem. Soc. 2017, 139, 11353). This novel ketone synthesis was catalyzed by a combination of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (Ir photocatalyst), NiBr2·dtbbpy, quinuclidine, potassium carbonate, and visible light. Control experiments revealed that all of these components were essential for the new aldehyde C−H arylation reaction. The highest yields were obtained in 1,4-dioxane solvent. Electron-donating and -withdrawing groups on the aryl bromide coupling partner exhibited equal efficacy in the reaction. Vinyl and alkyl bromides were also effective coupling partners in this novel ketone synthesis. A broad range of ketones were synthesized in one step in generally high yields by this synthetic methodology, under mild reaction conditions.

CATALYTIC, ENANTIOSELECTIVE α-ALKYLATION OF ALDEHYDES USING OLEFINS

MacMillan and colleagues reported a catalytic method to gain access to chiral α-alkyl aldehydes without the need for stoichiometric oxidants or reductants (Nature Chemistry 2017, 9, 1073). The central concept in this work was the coupling of photoredox, organo- and hydrogen atom transfer catalytic cycles to afford an overall redox neutral process. A chiral amine organocatalyst was employed to generate an enamine intermediate, which upon oxidation and Si-face addition to the olefin substrate led to C−C bond formation. The substrate scope was explored in intra- and intermolecular reactions.

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SYNTHESIS OF IMIDAZOPYRIDINES VIA COPPER-CATALYZED, FORMAL AZA-[3 + 2] CYCLOADDITION REACTION OF PYRIDINE DERIVATIVES WITH α-DIAZO OXIME ETHERS N-Containing heterocyclic compounds are extremely important in the study of biological activity and for pharmaceutical utilization. Imidazopyridines, which contain both pyridine and imidazole moieties, comprise a privileged scaffold due to the extensive range of biological activity exhibited. Lee and co-workers from the Kangwon National University reported an efficient, modular synthetic method for the one-step construction of imidazopyridines (J. Org. Chem. 2017, 82, 10209). The methodology was predicated on the copper-catalyzed formal aza-[3 + 2] cycloaddition reaction of pyridine derivatives with α-diazo oxime ethers. Optimization studies indicated that copper(II) hexafluoroacetylacetonate [Cu(hfacac)2] was the most effective catalyst and that trifluoroethanol (TFE) was the optimal solvent. Generally good to excellent yields were obtained, irrespective of the electronic nature of the aryl substituent on the α-diazo oxime ether component. A variety of functional groups were tolerated, including: halo, nitro, ether, and ketone. In some of the examples reported, transesterification with the solvent was observed, to afford the corresponding trifluoroethyl ester. The transesterification was minimized by utilization of the corresponding tert-butyl ester. The methodology was extended to the preparation of related N-heterobicyclic compounds, such as imidazopyridazines,

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ONE-POT SYNTHESIS OF 1,2-DISUBSTITUTED 4-, 5-, 6-, AND 7-AZAINDOLES FROM AMINO-O-HALOPYRIDINES VIA N-ARYLATION/SONOGASHIRA/CYCLIZATION REACTION Azaindoles are bioisosteres of the indole scaffold, a privileged structure, and have been used in diverse areas of research, such as materials and medicinal chemistry due to their physiochemical and pharmacological properties. Substituted azaindoles are interesting drug discovery scaffolds because their properties can be mediated by changing the substitution pattern or the position of the endocyclic nitrogen. Marques and co-workers at the Universidade Nova de Lisboa detailed an efficient protocol to attain 4-, 5-, 6-, and 7-azaindoles in one pot (Org. Lett. 2017, 19, 5118). The described protocol consists of sequential N-arylation of amino-o-halopyridines, Sonogashira reaction, and cyclization to the desired product. When the Sonogashira reaction was performed at 110 °C, spontaneous cyclization to the desired azaindole was observed. Aryl iodides were preferred for the palladium catalyzed N-arylation. The reaction sequence was E




analogues are difficult to access. Lautens and co-workers reported an extension of their previous research on multicatalytic reactions to novel syntheses of the N-alkylated and N-H pyridobenzazepine motifs (J. Org. Chem. 2017, 82, 6089). The two building blocks are o-aminophenylboronic esters and o-vinyl chloropyridines. A rhodium catalyst facilitates the 1,4-arylation reaction followed by a palladium catalyzed C−N coupling between a secondary amine and an aryl chloride. Extensive optimization experiments revealed that the multicatalytic reaction could be performed in one pot. The methodology was applicable to the synthesis of N-alkyl and N-H pyridobenzazepines with comparable yields. Ring closure did not occur in the absence of the palladium catalyst, which demonstrated that the C−N bond formation occurred via palladium catalysis and not through an SNAr mechanism. An electron-withdrawing group is required at the 5-position of the pyridine component. This novel Rh/Pd-catalyzed two-component protocol afforded functionalized pyridobenzazepines in one-pot under mild conditions.

compatible with both electron-donating and electron-withdrawing substituents on both the phenylacetylene and aryl iodide. The reaction was extended to include alkyl substituted acetylenes in the Sonogashira reaction. Slightly higher yields were obtained when the reaction sequence was performed in one pot. This report consists of one of the first reports of a one-pot method to synthesize the four azaindole isomers.

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SITE-SELECTIVE COPPER-CATALYZED AMINATION AND AZIDATION OF ARENES AND HETEROARENES VIA DEPROTONATIVE ZINCATION The development of general and rapid access to diversely functionalized aminoarenes is important, as they are highly valuable skeletons widely found in ligands, natural products, and pharmaceuticals. Lithium amidodialkylzincate complexes are known to promote directing-group-mediated ortho-zincation of unactivated arenes. Wang and co-workers at Duke University extended this finding into a detailed methodology for the amination of (hetero)arenes via a site-selective C−H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines (J. Am. Chem. Soc. 2017, 139, 11622). Optimization of the C−H zincation indicated that a catalytic amount of LiTMP significantly improved the zincation reaction with Li[ZnEt2(TMP)]. The most effective source of copper for the subsequent amination was copper(II) 2-ethylhexanoate (Cu(eh)2). Highly electrophilic moieties such as a nitro group, aldehydes, and ketones are not compatible with the zincate intermediate. The zincate intermediates also reacted with azido iodinane to afford the corresponding (hetero)aryl azides in good yields. This methodology was widely applicable to a diverse array of (hetero)arene scaffolds with predictable regioselectivity, and excellent functional group compatibility.

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RUTHENIUM-CATALYZED TANDEM C−H FLUOROMETHYLATION/CYCLIZATION OF N-ALKYLHYDRAZONES WITH CF3BR: ACCESS TO 4-FLUOROPYRAZOLES The importance of fluorine-containing pyrazoles to the pharmaceutical and agrochemical industries has been steadily increasing in recent years. As a consequence, the development of methods suitable for the incorporation of fluorine or fluoroalkyl groups into the pyrazole ring continues to be the subject of intense research. Predicated on their previous copper-catalyzed synthesis of 4-substituted pyrazoles, Bouyssi, Monteiro and their co-worker from the Institut de Chemie et Biochemie Moléculaires et Supramoléculaires reported a ruthenium-catalyzed synthesis of substituted-4-fluoropyrazoles (J. Org. Chem. 2017, 82, 3311). The requisite starting materials, aldehyde derived N,N-dialkylhydrazones, were readily synthesized. Tribromofluoromethane served as the source of fluorine. The commercially available and inexpensive ruthenium complex, RuCl2(PPh3)3, was discovered to be a very effective catalyst for this transformation. Diglyme was the

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SYNTHESIS OF PYRIDOBENZAZEPINES USING A ONE-POT Rh/Pd-CATALYZED PROCESS The nitrogen-containing dibenzazepine structural unit can be found in many pharmaceutically relevant compounds, including tricyclic antidepressants and an anticancer agent. While the core structures of these tricyclic motifs are readily available, substituted F




three-membered heterocycles such as sulfonamides or carbamates. Kürti and co-workers from Rice University described a protocol that offers a direct entry to unsubstituted or alkyl substituted aziridines (Angew. Chem. Int. Ed. 2017, 56, 9886). The authors succeeded in refining a previously described method by using hydroxylamine-O-sulfonic acid (HOSA) as a safe replacement for O-(2,4-dinitrophenyl)hydroxylamine. Thorough investigation of reaction conditions led to the identification of Bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)] (DuBois catalyst) as the preferred catalyst and pyridine as the optimal base in 1,1,1,3,3,3-hexafluoro-2-propanol as solvent. The key features of the developed protocol are its tolerance toward numerous functional groups (alkynes, esters, five- and six-membered heterocycles) combined with a good selectivity for the most electron-rich alkene and a high stereospecificity. The authors extend the methodology to N-alkyl aziridination although the yields are slightly reduced compared to the N−H aziridination process probably because of the increased steric hindrance.

preferred solvent for the reaction. The reaction displayed good tolerance for a variety of functional groups, including cyano, ester, formyl, and halide. In general, higher yields were obtained with electron-withdrawing substituents. This novel methodology affords substituted-4-fluoropyrazoles in good yields in one step from readily available starting materials.

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NICKEL-CATALYZED CYANATION OF ARYL CHLORIDES AND TRIFLATES USING BUTYRONITRILE: MERGING RETRO-HYDROCYANATION WITH CROSS-COUPLING

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With few exceptions, metal-catalyzed cyanations of aryl (pseudo)halides rely on the use of toxic cyanide salts. Only recently safer alternatives such as potassium hexacyanoferrate(III) have been introduced that left the issue of poor salt solubility in organic solvent unaddressed. Morandi and Yu from Max Planck Institute in Germany have overcome this problem by developing a protocol that takes advantage of the retro-hydrocyanation of alkyl nitriles to generate HCN in situ (Angew. Chem. Int. Ed. 2017, 56, doi: 10.1002/anie.201707517). Butyronitrile was elected as an inexpensive cyanating agent, and optimization studies demonstrate that aryl chlorides and triflates require different conditions in terms of temperature, optimal nickel source, and base. In both cases, the reactions rely on the same ligand (Xantphos) in toluene and the presence of an aluminum cocatalyst was necessary to achieve high yields. The scope is large regarding the functional groups tolerated in the electrophile, and vinyl triflates were demonstrated to be suitable substrates too.

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PALLADIUM-CATALYZED 2,2,2-TRIFLUOROETHOXYLATION OF AROMATIC AND HETEROAROMATIC CHLORIDES UTILIZING BORATE SALT

As with many other fluoroalkyl functional groups, the 2,2,2-trifluoroethyl ether moiety can be found in a number of drug molecules and agrochemicals. It is perhaps surprising that only few methods exist for its introduction on (hetero)aromatic compounds. Novak and co-workers from Budapest have recently described a palladium-catalyzed 2,2,2-trifluoroethoxylation of chloroarenes which relies on the use of tetrakis(2,2,2-trifluoroethoxy) borate salt (Chem. Eur. J. 2017, 23, 15628). The key

DIRECT AND STEREOSPECIFIC SYNTHESIS OF N−H AND N-ALKYL AZIRIDINES FROM UNACTIVATED OLEFINS USING HYDROXYLAMINE-O-SULFONIC ACIDS Aziridine is a prominent heterocyclic moiety either as a synthetic intermediate or as part of a biologically active compound. Most of the procedures to date provide only access to the N-protected G




finding was that mixed borate salts formed by ligand exchange reactions at the boron atom were more reactive than the initial reagent. Consequently, performing the reaction in alcohols that are sufficiently hindered not to react with the aryl halides allows the reaction to take place efficiently without needing a base. tert-Amyl alcohol was elected as the optimal solvent with a catalytic system being composed of tris(dibenzylideneacetone)dipalladium(0) and t-BuXPhos. A variety of (hetero)aryl chlorides were found to be competent substrates under the developed reaction conditions with carbonyl (aldehyde and ketones) and benzylic halides being well tolerated.

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An example of multigram scale synthesis with reduced catalyst loading is also provided.

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CONTINUOUS SELECTIVE INTERMOLECULAR BUCHNER RING EXPANSIONS

A PRACTICAL AND SCALABLE SYSTEM FOR HETEROARYL AMINO ACID SYNTHESIS

A continuous flow regioselective and enantioselective intermolecular Buchner ring expansion has been reported recently (Beeler, A. B. et al. Org. Lett. 2017, 19, 5268). Compared with the batch counterpart, the practicality and scope (22 examples) of the reaction were greatly improved under flow conditions. As shown in the graphic, cycloheptatrienes were generated from the reactions of ethyl diazoacetate with symmetric and nonsymmetric arenes in good yield and excellent regioselectivity, without thermodynamic isomerization. In addition, the asymmetric catalysis of intermolecular Buchner reaction was demonstrated with disubstituted diazo esters in good to excellent enantioselectivity, affording cycloheptatrienes with an all-carbon quaternary center.

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Mainly because of their improved physicochemical properties, heteroarene-containing unnatural amino acids are sought after compounds in the field of discovery chemistry. Jui and co-workers from Emory University in Atlanta have developed a photoredox mediated catalytic conjugate addition of heteroaryl halides on dehydroalanine derivatives that provide a straightforward access to β-heteroaryl α-amino acids (Chem. Sci. 2017, doi: 10.1039/C7SC03612D). The developed conditions employ [Ir(ppy)2(dtbbpy)]PF6 as catalyst and Hantzsch ester as a stoichiometric reductant in aqueous dimethyl sulfoxide at room temperature. Under blue LED irradiation, a number of halogenated pyridines were found to react in good to high yields with a variety of Michael acceptors providing the racemic compounds with modest to high diastereoselectivity in the case of β-substituted substrates. Worthy of note is that the extension of the method to a chiral dehydroalanine substrate deriving from cysteine led to the expected amino acids with almost perfect selectivity.

CONTINUOUS SYNTHESIS OF STEREOSELECTIVE DIFLUOROMETHYLATED STYRENES VIA VISIBLE-LIGHT PHOTOCATALYTIC DECARBOXYLATION

A continuous stereoselective synthesis of difluoromethylated styrenes via visible-light photocatalytic decarboxylation of feed stock cinnamic acids was developed from the reaction with an inexpensive CF2 source (Noël, T. et al. ACS Catal. 2017, 7, 7136). The photoredox catalyst fac-Ir(ppy)3 could afford a broad substrate scope toward an operationally simple and stereoselective synthesis under visible light, without additional reagent for CO2 extrusion. High E-selectivity was realized when meta- and para-substituted cinnamic acids were applied, while high Z-selectivity (less stable Z product) for ortho-substituted substrates under batch conditions. However, ortho-substituted H



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substrates afforded the E-isomer via continuous-flow processing through accurate control of the reaction time.

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CONTINUOUS CHEMOSELECTIVE HYDROGENATION OF ALDEHYDES CATALYZED BY PLATINUM NANOPARTICLE DISPERSION


A DUAL PALLADIUM AND COPPER HYDRIDE CATALYZED APPROACH FOR ALKYL−ARYL CROSS-COUPLING OF ARYL HALIDES AND OLEFINS

A chemoselective flow hydrogenation of aldehydes catalyzed by a dispersion of platinum nanoparticles in an amphiphilic polymer (ARP-Pt) has been developed (Uozumi, Y. et al. ACS Catal. 2017, 7, 7371). It is worthwhile mentioning the nice chemoselectivity between aldehyde and other reducible functional groups, such as keto, ester, or amide moieties, which were inert under this catalysis (ARP-Pt) in the flow conditions. Both substituted aromatic and aliphatic aldehydes readily underwent flow hydrogenation in aqueous solutions within 22 s to give the corresponding primary benzylic or aliphatic alcohols in up to 99% yield with excellent chemoselectivity. In addition, the total turnover number of the catalyst reached 997 for benzaldehyde substrate, although a long-term continuous-flow hydrogenation for 8 days was necessary.

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Two basic synthetic methods that have been developed for the construction of Csp2−Csp3 bond include palladium-catalyzed cross-coupling of aryl halides with alkylboron reagents (Suzuki reaction) and reaction using a stoichiometric alkyl metal reagent. A complementary approach for the Csp2−Csp3 cross-coupling reactions using α-olefins as starting materials is disclosed from Buchwald’s laboratory of Massachusetts Institute of Technology (Angew. Chem. Int. Ed. 2017, 56, 7242). The Buchwald research team developed a dual palladium and copper hydride catalytic system, in which the first Cu-catalytic cycle consists of the conversion of the olefin into an alkylcopper(I) complex via an olefin insertion with an in situ formed CuH. The second catalytic cycle could involve an oxidative addition, a transmetalation between the aryl Pd(II) complex and the alkylcopper(I) complex, and a reductive elimination to generate the Csp2−Csp3 cross-coupling product. The protocol shows tolerance of a broad range of functional groups and heterocycles, providing the crosscoupling products in good yields.

CONTINUOUS VISIBLE-LIGHT-MEDIATED SELECTIVE ARYLATION OF CYSTEINE

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A continuous visible-light-mediated selective arylation of cysteine has been developed recently relying on the use of eosin Y as a metal-free photocatalyst and aryldiazonium salts as arylating agents (Noël, T. et al. Angew. Chem. Int. Ed. 2017, 56, 12702). The reaction can be significantly accelerated in a microflow reactor (flow for 30 s vs batch for 2 h), allowing the in situ formation of the required diazonium salts followed by selective arylation of cysteine to give various arylated cysteine derivatives (11 examples, 45−89% yield) as well as arylated cysteine-containing dipeptides (12 examples, 32−86% yield). Moreover, the method was applied to the chemoselective arylation of a model peptide in biologically relevant conditions (room temperature, phosphate-buffered saline) within 30 min. In general, this one-pot protocol with in situ formation of diazonium salts starting from readily available anilines reduces the risks associated with the handling of potentially explosive aryl diazonium intermediates and also affords easy scale-up under flow conditions (atmospheric conditions, visible light irradiation, short reaction time).

SYNERGISTIC VISIBLE-LIGHT PHOTOREDOX/NICKEL-CATALYZED SYNTHESIS OF ALIPHATIC KETONES VIA N−C CLEAVAGE OF IMIDES A dual catalytic system, iridium-based photoredox catalysis and transition metal nickel-catalyzed Csp2−Csp3 cross-coupling, is developed from Molander’s laboratory at University of Pennsylvania to access aliphatic ketones (Org. Lett. 2017, 19, 2426). For the nickel-catalyzed Csp2−Csp3 cross-coupling reaction, one of the well-conceived reaction pathways involves a reductive elimination of Ni(III) complex, such as B, which is formed from Ni(II) complex A through a coordination with the radical R2. The oxidative addition of amides to generate an acylnickel(II) complex is challenging due to the less reactive C−N bond in the amides. The team led by Professor Molander identified N-acylpyrrolidine-2,5-diones as the electrophilic partner in an SET photoredox/Ni cross-coupling protocol. These imides are highly stable and easily accessed from the corresponding carboxylic acids. The alkyl radical would be generated via a single electron transfer (SET) oxidation of alkyltrifiuoroborates by photoexcited Ir*. This synthesis is operationally simple and I




performed at ambient temperature with tolerance for a variety of functional groups.

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Another favorable feature is that the reaction could be carried out under mild conditions.

DIRECT CATALYTIC DESATURATION OF LACTAMS ENABLED BY SOFT ENOLATION

Carbon−carbon double bond formation can be achieved by an elimination reaction, a strategy that is often used to prepare α,β-unsaturated compounds. The strategy, however, requires derivatization of the α-position, e.g., installation of a leaving group on the α-position. Dong and co-worker of University of Chicago, Illinois, developed a direct catalytic α,β-desaturation of lactams under mild conditions (J. Am. Chem. Soc. 2017, 139, 7757). The new approach relies on the merging “soft enolization” with palladium-catalyzed enolate oxidation. With a Lewis acid and a weak base the enolization of the amide would generate enolate A in situ, which would subsequently undergo transmetalation to give a palladium complex B. Finally, β-hydride elimination of the complex B would deliver the α,β-unsaturated lactam product. DIPEA was selected as base to facilitate the β-hydride elimination process. To close the catalytic cycle, the Pd(II) catalyst is regenerated by the oxidation of Pd(0) with 2,5-di-tert-butylbenzoquinone.

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HYPERVALENT IODINE(III)-CATALYZED FORMAL [2 + 2 + 1] CYCLOADDITION REACTION FOR METAL-FREE CONSTRUCTION OF OXAZOLES

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SYNTHESIS OF DIFLUOROALKYLATED TETRACYCLIC COMPOUNDS VIA VISIBLE-LIGHT-INDUCED RADICAL CYCLIZATION The photoredox-catalyzed reaction is a versatile and prevalent approach in organic synthesis. As one of its applications, visiblelight-induced single electron transfer (SET) reaction is utilized to generate free radicals. Li and co-worker of Fuzhou University, China reported a visible-light-induced difluoroalkylation and cyclization cascade reaction of 1,8-enynes (J. Org. Chem. 2017, 82, 4449). The reaction includes two SET steps: the initial SET step to generate difluoroalkyl radical and the second SET step to oxidize a π-radical to its corresponding cation B. The radical addition of the initially formed difluoroalkyl radical starts the radical cascade cycloaddition process involving a rearrangement. Using this method, a range of functionalized difluoroalkylated tetracycles could be synthesized in high to excellent yields.

Transition-metal-catalyzed cyclization of alkynes with nitriles is frequently used to synthesize oxazoles. Although useful, this method has limitations, such as the lack of diversity and potential product contamination with the residual transition metal. In order to address the product contamination issues, various reactions were developed under metal-free conditions. Saito and co-workers of Tokyo University of Agriculture and Technology, Japan developed an iodine(III)-catalyzed formal [2 + 2 + 1] cycloaddition reaction for metal-free construction of oxazoles (Org. Lett. 2017, 19, 2506). The hyperiodine(III) catalyst is J




generated in situ by oxidation of iodoarene precatalyst with mCPBA. It was hypothesized that the oxazole product is formed via a reductive elimination of alkenyl(phenyl)iodonium intermediate A, releasing iodoarene precatalyst at the same time. An alternative pathway to the oxazole product would involve a reductive elimination of B to C followed by keto−enol tautomerization and cyclization.

Wenyi Zhao Jacobus Pharmaceutical Co. Inc., Princeton, New Jersey 08540, United States

Dongbo Zhao ChulanST Wuhan Co. Limited, 3-4-5 Wangjiadun, Xudong Avenue, Wuchang District, Wuhan 430063, Hubei Province, P. R. China

Sylvain Guizzetti NovAlix, Building A: Chemistry, Bioparc, Bld Sébastien Brant BP 30170, F-67405 Illkirch Cedex, France

James A. Schwindeman Rohner Inc., 4066 Belle Meade Circle, Belmont, North Carolina 28012, United States

David S. B. Daniels Pfizer Chemical Research & Development, IPC533, B530/1.158F, Ramsgate Road, Sandwich, Kent CT13 9NJ, U.K.

Carlos A. Guerrero Bristol-Myers Squibb Co., Chemical and Synthetic Development, One Squibb Drive, New Brunswick, New Jersey 08901, United States

Arjun Raghuraman Polyurethane Process R&D, The Dow Chemical Co., Freeport, Texas 77541, United States

John Knight*

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

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

David S. B. Daniels: 0000-0002-9092-1377 Carlos A. Guerrero: 0000-0002-2377-1102 Arjun Raghuraman: 0000-0002-9843-0441 Notes

E-mail: [email protected]; [email protected]; [email protected]; [email protected]; david.daniels@pfizer.com; [email protected]; [email protected].

K


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