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Highlights from the Literature Cite This: Org. Process Res. Dev. 2019, 23, 1107−1117

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

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ASYMMETRIC SYNTHESIS OF ALKYL FLUORIDES: HYDROGENATION OF FLUORINATED OLEFINS

Because of their unique properties, stereodefined alkyl fluorine atoms are increasingly incorporated into pharmaceutical compounds. Their synthesis, however, especially at large scale, can be a significant obstacle because of the limited commercial availability of chiral fluorinated building blocks coupled with the unsolved challenges of asymmetric synthesis and stereoretentive alcohol substitution. Asymmetric hydrogenation is an effective and well-established method on scale, but the direct translation of this to fluorine-containing substrates can be hampered by defluorination. A recent advancement in this area from Andersson and co-workers (Angew. Chem., Int. Ed. 2019, DOI: 10.1002/anie.201903954) reports an effective method for the asymmetric hydrogenation of trisubstituted vinyl fluorides in typically excellent yield and enantioselectivity. A range of N,P iridium catalysts were prepared and evaluated, leading to typically no detectable amounts of the defluorinated side products during the asymmetric hydrogenation. A range of either unsaturated ketones or styrenyl vinyl fluorides performed well, giving excellent yields and enantioselectivities (generally >90% yield and >95% ee), and the reaction was shown on a gram scale. The only reported heterocyclic system was a thiazolecontaining substrate, and in selected cases requiring increased H2 pressure (20 bar) some defluorination was observed (83% recovery of the auxiliary in all cases. Finally, the authors demonstrated the synthesis of BCP analogues of phenylglycine and tarenflurbil, replacing benzene rings in both cases.

GENERAL CYCLOPROPANE ASSEMBLY BY ENANTIOSELECTIVE TRANSFER OF A REDOX-ACTIVE CARBENE TO ALIPHATIC OLEFINS

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Because of their intrinsic high strain and unique bonding, cyclopropanes are of great interest in organic chemistry, asymmetric catalysis, and medicinal chemistry. In order to contribute to this area, Mendoza and co-workers at Stockholm University have reported a general method for the enantioselective preparation of cyclopropanes via a redox-active carbene transfer to aliphatic olefins (Angew. Chem., Int. Ed. 2019, 58, 5930). The methodology is based on the use of Nhydroxyphthalimidoyl diazoacetate reagent, which is reported to be more stable than the benchmark ethyl diazoacetate. After a screening of catalysts, an electron-rich metallacyclic ruthenium catalyst showed its superiority for the cyclopropanation reaction. This system was used on an impressive scope of olefins. Styrenes, nucleophilic or aliphatic alkenes, and electrondeficient olefins led to the desired cyclopropanes in excellent yields (>80% in most cases) with good diastereo- and enantioselectivities. In a later part, the authors described the successful preparation of chiral cyclopropanes of interest for the preparation of drugs, natural products, and fragrances.

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HYDRODIFLUOROMETHYLATION OF ALKENES WITH DIFLUOROACETIC ACID

Incorporation of fluorine can modulate physicochemical properties and impact bioavailability as well as adsorption. Therefore, new fluorination methods represent an invaluable tool for drug discovery, as 20% of new drugs contain at least one fluorine atom. As a continuation of their research expertise on fluorination, Gouverneur and co-workers at the University of Oxford described an operationally simple and scalable method for the hydrodifluoromethylation of alkenes using inexpensive difluoroacetic acid (Angew. Chem., Int. Ed. 2019, DOI: 10.1002/ anie.201903801). After optimization of the reaction conditions, which focused on solvents and oxidants, the methodology was applied to a scope of alkenes in moderate to good yields, proving the tolerance of this process to functional groups such as esters, amides, and halides. One example using an alkyne led to the corresponding difluoromethylated alkene. This method was also successfully applied to complex molecules such as steroids, dipeptides, and drugs. Finally, the successful scale-up of highly valuable building blocks up to the 10 g scale was described.

ENANTIOENRICHED α-SUBSTITUTED BICYCLO[1.1.1]PENTANES

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DOI: 10.1021/acs.oprd.9b00250 Org. Process Res. Dev. 2019, 23, 1107−1117

Organic Process Research & Development

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COPPER-CATALYZED TRIFLUOROMETHYLATION OF ALKYL BROMIDES

Highlights from the Literature

LIGANDLESS IRON-CATALYZED AROMATIC CROSS-COUPLING DIFLUOROMETHYLATION OF GRIGNARD REAGENTS WITH DIFLUOROIODOMETHANE

Fluorine plays a key role in the pharmaceutical and agrochemical industries because of its particular chemical and physical properties. Among them, the difluoromethyl group is regarded as an essential function, as it can be considered a bioisostere of an alcohol and as a lipophilic hydrogen-bond donor. Mikami and co-workers at the Tokyo Institute of Technology described a ligandless iron-catalyzed aromatic cross-coupling difluororomethylation reaction using Grignard reagents (J. Org. Chem. 2019, 84, 6483). After a screening of ligands and optimization of the reaction conditions, the authors highlighted that the reaction is most effective without any ligands and were able to optimize the model reaction to provide up to 92% yield under very mild conditions. They subsequently applied this methodology to a variety of aryl Grignards in good conversions but with sometimes quite low isolated yields. Another limitation might be the absence of heteroaromatic Grignards in the substrate scope.

New approaches using copper-catalyzed processes have been disclosed in recent years that have enabled new disconnections within organic synthesis, such as highly challenging sp3−sp3

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bond formations. MacMillan and co-workers at the Merck Center for Catalysis at Princeton University recently reported a

ASYMMETRIC CATALYSIS USING AROMATIC ALDEHYDES AS CHIRAL α-ALKOXYALKYL ANIONS

method for the copper-catalyzed trifluoromethylation of alkyl bromides (J. Am. Chem. Soc. 2019, 141, 6853). After a set of control reactions highlighted that previously described conditions are optimal for this transformation, the authors disclosed an impressive scope, from activated to unactivated as well as heterocycle-containing scaffolds. Free alcohols, esters, protected

Transition-metal-catalyzed C−C bond formation is a standard method in organic synthesis. Generally, aromatic aldehydes are used as electrophiles to participate in reactions with nucleophiles. Recently, Ohmiya and co-workers at Kanazawa University in Japan disclosed a new umpolung strategy for the catalytic formation of a chiral α-alkoxyalkyl anion from an aromatic aldehyde for use in the synthesis of chiral silylprotected secondary alcohols (J. Am. Chem. Soc. 2019, 141, 113). The chiral α-alkoxyalkyl anion (existing as its copper(I) complex) is obtained in situ from the aldehyde through the addition of a silylcopper(I) species followed by a 1,2-Brook rearrangement. Subsequent transmetalation between the alkoxyalkylcopper(I) (A) and oxidative addition palladium complex (B) delivers the desired cross-coupling product. Because of the mild reaction conditions and high enantioselectivity and yield, this synthetic method can be useful for latestage functionalization of pharmaceutical intermediates.

amines, and terminal amides are tolerated, with yields of 61− 83%. Allylic and benzylic bromides can also be used for this reaction and lead to the trifluoromethylated products in modest to excellent yields. In a later part, heteroarenes were used as substrates and proved to be good candidates for this transformation. Indeed, heterocycles prone to N−O or N−N bond cleavage, like pyrazoles, isoxazoles, and oxadiazoles, or those known to be problematic in metal-catalyzed protocols, such as imidazoles, are tolerated. Finally, in order to demonstrate the utility of this method, the authors undertook the efficient preparation of trifluoromethylated analogues of the drugs celecoxib and ticagrelor in good yields. 1115



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REDUCTIVE COUPLING BETWEEN AROMATIC ALDEHYDES AND KETONES OR IMINES BY COPPER CATALYSIS

To meet increasing demands from the chemical, agrochemical, and pharmaceutical industries, many new synthetic methods have been developed during the last two decades, in which transition-metal-catalyzed reactions play an indispensable role. Copper, as an inexpensive, earth-abundant transition metal, is utilized in various catalytic reactions. Recently, Ohmiya and coworkers at Kanazawa University in Japan developed a coppercatalyzed reductive coupling reaction to access 1,2-diols ( J. Am. Chem. Soc. 2019, 141, 3664). Both aldehydes and ketones are electrophiles and are unreactive toward each other under conventional reaction conditions. The Japanese team exploited an umpolung strategy by converting the aldehyde electrophiles into nucleophilic silyloxyalkylcopper(I) species C in situ via a 1,2-Brook rearrangement of α-silyl-substituted copper(I) alkoxides B.

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PHOTOSENSITIZED ENERGY-TRANSFER-MEDIATED CYCLIZATION OF 2-(1-ARYLVINYL)BENZALDEHYDES TO ANTHRACEN-9-(10H)-ONES

One of the desired features of visible-light-induced photocatalyzed reactions is mild reaction conditions that would allow a process to proceed with good selectivity and great functional group tolerance. Most visible-light-induced transformations proceed under photoredox catalysis via a pathway involving single electron transfer (SET) between an excited-state photocatalyst and a substrate. Recently, Yoshikai and coworkers at Nanyang Technological University in Singapore developed a photosensitized energy-transfer catalysis for cyclization of 2-(1-arylvinyl)benzaldehydes (Org. Lett. 2019, 21, 1202). This new process is preferred over the traditional strong Brønsted acid- or Lewis acid-mediated Friedel−Crafts acylation in the synthesis of anthracen-9-(10H)-ones. The researchers hypothesized a reaction pathway that contains a triplet biradical A (generated from an energy-transfer process) followed by a 1,5-hydrogen shift to form biradical B. Subsequent intersystem crossing and isomerization would form o-quinodimethane-type intermediate C.

ALIPHATIC RADICAL RELAY HECK REACTION AT UNACTIVATED C(sp3)−H SITES OF ALCOHOLS

■ Traditionally, radical reactions have limited applications in organic synthesis because of their innate nature of high reactivity and poor chemoselectivity. The combination of radical chemistry with transition metal catalysis can alter the radical reactivity, which allows the radical reaction to occur in a controlled manner. A typical example of a transition-metalmediated radical reaction is the nickel-catalyzed cross-coupling reaction between aryl halides and in situ-formed radicals. Gevorgyan and co-workers at the University of Illinois at Chicago developed an aliphatic radical relay Heck reaction of alcohols at unactivated C(sp3)−H sites (Angew. Chem., Int. Ed. 2019, 58, 1794). This reaction is arguably an attractive approach because of the use of inexpensive, easily accessible alcohols and olefins as the starting materials. In this protocol, a Si-based auxiliary has to be installed on the hydroxy group to enable selective I atom/radical translocation events at remote C−H sites followed by Heck reaction. Thus, the reaction proceeds through three putative Pd(I)/radical species (A, B, and C).

ALKENYL EXCHANGE OF ALLYLAMINES VIA NICKEL(0)-CATALYZED C−C BOND CLEAVAGE

Usually a reversible reaction is unable to reach complete conversion because of the equilibrium between the starting materials and products, unless a gas or precipitate forms as a driving force. Recently, Zhou and co-workers at Nankai University in Tianjin, China, disclosed an alkenyl group exchange strategy to prepare allylamines utilizing the reversibility of nickel(0)-catalyzed hydroalkenylation of imines (J. Am. Chem. Soc. 2019, 141, 2889). The catalytic cycle involves migratory insertion of the C−C double bond in the allylamine starting material into in situ-formed nickel(II) hydride A to give nickelacycle B. Alkenyl group exchange takes place through the transformation of nickelacycle B into E, which is driven by the formation and loss of the ethylene gas byproduct via intermediates C and D.

Wenyi Zhao 1116




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

Sylvain Guizzetti NovAlix, Building A: Chemistry, Bioparc, Bld. Sébastien Brant BP 30170, Illkirch F-67405 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, Discovery Park House, IPC 533, Sandwich, Kent CT13 9NJ, U.K.

Sylvain Petit Chemical Process Research & Development, UCB Pharma SA, Chemin du Foriest, B-1420 Braine-L’Alleud, Belgium

James J. Douglas Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield SK10 2NA, U.K.

Antonio Ramirez Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, 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 Sylvain Petit: 0000-0002-9198-8602 James J. Douglas: 0000-0002-9681-0459 Antonio Ramirez: 0000-0003-2636-6855 Notes

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

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