Organic Process Research & Development - 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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RUTHENIUM(II)-CATALYZED META C−H MONO- AND DIFLUOROMETHYLATIONS BY PHOSPHINE/CARBOXYLATE COOPERATION

methods to access densely functionalized chiral aziridines. Trost and co-workers have reported a protocol to access enantiopure trisubstituted aziridines utilizing α-chloro-β-aminoketones as the key intermediates, which are derived in turn from a Mannich reaction between an α-chloroketone and an imine (Angew. Chem., Int. Ed. 2017, 56, 2440). Although model studies indicated that use of a noncoordinating solvent was important, the critical optimization parameter was shown to be the nature of the ligand with the use of a non-C2 symmetric ProPhenol ligand key to obtaining high diastereo- and enantioselectivities. The protocol was successfully applied to the reaction of a range of chloro-indanones and -tetralones with a range of N-Boc imines and subsequently extended to seldom used α-bromoketones. Two methodologies were then developed to convert the intermediates to the desired aziridines by either treatment with Cs2CO3 in acetonitrile or alternatively NaH in THF in cases when chloride elimination competed with the desired cyclization. The practicality of the approach was demonstrated by combining the two reactions into a one-pot method, though the addition of Florisil was necessary when Cs2CO3 was used in order to scavenge the Zn-ProPhenol catalyst prior to the cyclization.

Whereas a number of ortho-selective directing group trifluoromethylations have been reported, mono- and difluoromethylations have proven more elusive, as have positional selective C−H transformations to the more remote meta- and parapositions. Ackermann and co-workers have reported on an efficient meta-selective Ru(II)-mediated difluoromethylation directed by various heteroarenes using difluoroacetates (Angew. Chem., Int. Ed. 2017, 56, 2045). Model studies using 2-phenylpyridine as the substrate demonstrated that a single component catalyst featuring a carboxylate ligand in the presence of an exogenous phosphine ligand performed best with Na2CO3 as the base and 1,4-dioxane as the optimal solvent. The variation of the phosphine indicated that electron-deficient ligands performed best with the synergy between the phosphine/carboxylate key for reaction success. The reaction was shown to not only be directed by a range of pyridines featuring a variety of synthetically useful functional groups, but also by alternative heterocycles such as pyrimidines, indazoles, and pyrazoles. In several cases, the addition of Ni(PPh3)2Cl2 as an additive led to improved outcomes either due to low concentrations of free phosphine or a heterobimetallic effect. The reaction was then extended to a series of aryl purines with high levels of meta-selectivity being maintained and no reaction being observed at the kinetically more acidic C-8 position of the purine motif. Key mechanistic findings showed electron-rich substrates to be more reactive while the reaction was also tolerant of water, though completely inhibited in the presence of a radical scavenger. The removal of the ester group provided the difluoromethylated compounds, while the reaction conditions were also shown to be applicable for the synthesis of the analogous monofluoromethylated materials.

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ENANTIOSELECTIVE SYNTHESIS OF CHIRAL OXIME ETHERS: DESYMMETRIZATION AND DYNAMIC KINETIC RESOLUTION OF SUBSTITUTED CYCLOHEXANONES

There is a growing interest in compounds possessing axial chirality (atropisomers) given their occurrence in natural products and application as chiral ligands. Antilla and co-workers have reported on the enantioselective synthesis of a series of oxime ethers through the reaction of 4-substituted cyclohexanones with phenoxyamines promoted by a chiral BINOLderived phosphate complex (Angew. Chem., Int. Ed. 2017, 56, 2454). Initial model studies demonstrated that DCM as the optimal solvent with low temperature and the use of a Sr complex being necessary to obtain the best enantioselectivity. For substrate scope, it was demonstrated that it was absolutely necessary to have a phenyl group on the oxyamine, though both alkyl and aryl groups were well-tolerated on the substituted cyclohexanone. The original hypothesis envisioned that the oxime ethers would serve as intermediates for the preparation of chiral benzofurans, though extending the chemistry to obtain these heterocycles led to a complete erosion of enantioselectivity. Calculations on the transition state structures were utilized to

EFFICIENT ACCESS TO CHIRAL TRISUBSTITUTED AZIRIDINES VIA CATALYTIC ENANTIOSELECTIVE AZA-DARZENS REACTIONS

Despite their utility as synthetic intermediates, and their presence in numerous biologically active molecules, there are limited © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.7b00057 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

biological activities and is increasingly used as a tool compound to study endocytotic processes. Three total syntheses of this molecule have been reported with the longest linear sequences ranging from 27 to 32 steps and a total yield in each case of 60%). Finally, the group showed a third catalytic cycle could be added to the current two-cycle system; this was realized through the cyclization of 2-(phenylbuta-1,3diyn-1-yl)aniline with PdCl2 (5 mol %) affording the starting arylethynyl indole.

IRON(II) CHLORIDE-PROMOTED RADICAL CASCADE METHYLATION/α-CHLORO-β-METHYLATION OF N-ARYLACRYLAMIDES

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SONOGASHIRA DIVERSIFICATION OF UNPROTECTED HALOTRYPTOPHANS

Goss and co-workers from the University of St. Andrews have reported for the first time the Sonogashira coupling of free unprotected halotryptophans utilizing the water-soluble ligand sXPhos (Chem. Sci. 2017, 10.1039/C6SC04423A). The diversity of this transformation was exemplified through modification at the 5-, 6-, or 7- position on the tryptophan backbone and the successful incorporation of a variety of aliphatic and aromatic derived alkynes. The application of microwave-assisted heating was found to greatly reduce reaction times in comparison to conventional heating. Moreover, the reaction could be conducted under aqueous conditions; copper salts were not needed, and the process works exceptionally well without the need for amino acid protection. In two examples, the procedure was shown to proceed well on tripeptide substrates, an exciting finding as this opens the possibility for late stage labeling of peptides. Finally, the group successfully biosynthesized a new-tonature cyclic lipopeptide incorporating a 6-bromo functionality, that under the optimized reaction conditions afforded the desired cross-coupled product.

The research groups of Li and Yan from Hebei University, China, have developed radical based methylations with the advantage of utilizing common and economical methyl sources/oxidants (Adv. Synth. Catal. 2017, 359, 246). Either oxindoles or chlorinated amides could be formed depending on the nitrogen substituents of the arylacrylamide starting materials. In both cases, the reaction utilizes dimethyl sulfoxide as the methyl source. Iron(II) chloride acts as a reaction catalyst (50 mol % in the case of oxindole synthesis) and as a chloride source in the synthesis of chlorinated amides (100 mol %). In one highlighted case, the gram-scale synthesis of 1-benzyl-3-ethyl-3methylindolin-2-one was successful (62% yield, see scheme above). The radical based mechanism proposed was supported by control experiments, in which TEMPO was found to halt the reaction. D



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DIVERGENT SYNTHESIS OF INDANES AND TETRALINS

set two stereocenters and also generates a synthetically versatile B(pin) group. The initial copper boration is most efficient with cis-alkenes, providing >20:1 dr for most substrates. Previously described Cu-NHC complexes were found to provide the highest enantioselectivity, even near room temperature, which is required for the palladium coupling step. The Pd-Ruphos G3 coupling step occurs with excellent stereoretentive selectivity in a toluene/MeCN solvent mixture. Antidiasteromers can be formed by simply switching to a Pd-XPhos catalytic system. Electron-rich and fluorinated styrene derivatives, along with strained alkyl alkenes, participate in the dual catalytic system. Styrenes with sterically hindered β-substituents are ineffective substrates, as are sterically hindered aryl bromide coupling partners. The synthetic utility of the arylboration products was demonstrated by the efficient construction of two pharmaceutically relevant compounds.

■ Thomson and co-workers at Northwestern University have recently disclosed their findings on the Brønsted acid-catalyzed synthesis of indanes and tetralins (Chem. Sci. 2017, 10.1039/ C6SC04762A). The best catalyst for the transformation was identified as bis(trifluoromethanesulfonyl)imide (10 mol %; other catalysts screened included CF3CO2H, FeCl3, and TMSOTf) when conducted in nitromethane as a reaction solvent. There are a number of key advantages associated with this transformation; first, the reaction is conducted at room temperature (heating the reaction was found to have an adverse effect on the product yield). Second, each reaction was completed in 2 h, and finally, the reaction tolerates a range of benzyl alcohol precursors. The choice of the correct allylsilane dictates the product formed; in some cases, up to three stereocenters were generated in one step. The authors utilized this methodology where R4 = CH2OH to access lignan natural products, including sacidumlignan B and pycanthuligene C in good yields.

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FRUSTRATED LEWIS ACID/BRØNSTED BASE CATALYSTS FOR DIRECT ENANTIOSELCTIVE α-AMINATION OF CARBONYL COMPOUNDS

α-Amination of carbonyl compounds is an economical synthetic approach to useful compounds in organic chemistry. Wasa and co-workers at Boston College have discovered a frustrated Lewis acid/Brønsted base catalytic system for the α-amination of a variety of carbonyl compounds, including examples of enantioselective amination of cyclic aromatic ketones (J. Am. Chem. Soc. 2017, 139, 95). The dual catalytic system utilizes highly Lewis acidic B(C6F5)3 to activate carbonyls for deprotonation by a bulky amine base. The generated boron enolate forms a tightly bound ionic pair with the amine salt, which also activates dimethyl azodicarboxylate (DMAD) as a nitrogen electrophile for α-amination. Using pentamethylpiperidine (PMP) as a base, cyclic and acylic ketones, as well as esters and thioesters, are aminated in moderate to good yields under mild conditions. The amination of amides requires the more basic Barton’s base. The reaction was rendered highly enantioselective for cyclic aromatic ketones with a derivative of 1,2-diphenylethylenediamine as catalyst. Unfortunately, this catalyst is not sufficiently basic for deprotonation of esters, amides, or thioesters. Conditions to reduce the N−N bond in the product were not shown.

CATALYTIC ENANTIOSELECTIVE ARYLBORATION OF ALKENYLARENES

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Brown and Logan at Indiana University have developed a Cu/Pd-catalyzed enantioselective arylboration of alkenylarenes, representing a powerful method for the construction of 1,1-diarylalkanes from simple precursors (Angew. Chem., Int. Ed. 2017, 56, 851). This dual catalytic method builds on previously reported Pd/Cu carboborations but, importantly, is the first to

DICHLOROMETHYLLITHIUM: SYNTHESIS AND APPLICATION IN CONTINUOUS FLOW MODE

Dichloromethyllithium, synthesized by deprotonation of dichloromethane, is an extremely useful intermediate; however, E




its synthesis requires very low temperatures (−78 to −100 °C) in order to avoid carbene formation and degradation. This makes it a great candidate for flow chemistry. Hafner, Sedelmeier, and co-workers at Novartis in Basel, have described a simple and robust method for the synthesis and use of dichloromethyllithium in continuous flow (Org. Lett. 2017, 19, 786). Using simple PTFE T-pieces (i.d. = 0.5 mm) as mixing elements and PFA tubing as tubular reactors (i.d. = 0.8 mm), a solution of DCM in THF (0.3 M) was mixed with commercial n-BuLi (1.6 M in hexanes) at −30 °C with a 0.5 s residence time to generate dichloromethyllithium. This freshly prepared solution was then mixed in a second reactor with either an aldehyde or boronic pinacol ester electrophile (1.0 M in THF). The β,β-dichlorocarbinol products were quenched into a citric acid solution, and the products were isolated in excellent yield and purity after only a simple workup. These crude products could be used after evaporation to synthesize aminothiazoles. The α-chloroboronic esters were purified by filtration through a plug of silica or directly quenched with Grignard reagents to form the alkylated boronic esters. This method greatly enhances the synthetic utility of DCMLi for large-scale operations.

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on reactions performed in water with Lipshutz’s TPGS-750-M designer surfactant (Org. Lett. 2017, 19, 194). Notably, 5−20% by volume of the right cosolvent is reported to either improve the solubility of the reaction components or to produce stable suspensions. This increases the applicability of the technology for substrates whose crystallinity would otherwise slow the entry of the molecules into the micelles. Examples of the impact of the cosolvent are provided for Suzuki cross-couplings, Miyaura borylations, SNAr reactions, amide bond formations, C−H activation reactions, and the reduction of nitroaromatics. Apart from improving solubility, the cosolvent also reduces the surface tension of the reaction solvent such that any gaseous byproducts do not result in excessive foaming. An extractive workup with a water-immiscible cosolvent is required as part of the reaction workup, though after the addition of fresh cosolvent, the aqueous raffinate can often be productively recycled. In spite of its use of organic solvents as reaction cosolvent and for extractive purposes, this technology is reported to still have the potential for the development of processes with low process mass intensities and provides a candidate for the replacement of a dipolar aprotic solvent that may have unfavorable safety credentials.

A GENERAL, MODULAR METHOD FOR THE SYNTHESIS OF ALKYLBORONATE ESTERS

■ A wide range of stereospecific transformations can be applied to alkylboronate esters, making them valuable synthetic intermediates. Fu and co-workers at Caltech have described a powerful alkyl−alkyl coupling of racemic α-haloboronates with alkylzinc reagents to provide alkylboronate esters in good enantioselectivites and yield (Science 2017, 354, 1265). Importantly, this reaction utilizes a chiral catalyst to transform racemic reagents to enantioenriched products, rather than using stoichiometric chiral reagents. The α-haloboronate starting materials are generally synthesized by a Matteson homologation of commercially available dichloromethylboronate ester and organolithium reagents. The nickel catalyst, along with a chiral diamine ligand, is responsible for establishing the stereocenter, likely through a radical generated from homolytic cleavage of the C−Cl bond. Organozinc reagents with functional groups such as acetals, esters, primary alkyl chlorides, silyl ethers, and cyano groups were all well-tolerated. The mild reaction conditions allow the use of sensitive functional groups such as epoxides, aldehydes, and ketones. A variety of C−C, C−N, C−O, and C-halogen bond formation reactions were achieved with the enantioenriched alkylboronate ester products.

A ROBUST AND BROADLY APPLICABLE COBALT-CATALYZED CROSS-COUPLING OF FUNCTIONALIZED BENCH-STABLE ORGANOZINC PIVALATES WITH UNSATURATED HALIDES

The Knochel group have reported a means of cross-coupling functionalized (hetero)aryl zinc pivalates with (hetero)aryl halides (Angew. Chem., Int. Ed. 2017, 56, 1092). Its use of cobalt(II) chloride as a catalyst has appeal on cost and toxicity grounds, versus analogous palladium-based methods, and does not require an exogenous base. The pivalate coupling partners, prepared by transmetallating the corresponding Grignard with zinc pivalate, offer functional group compatibility, high levels of reactivity, what is typically a solid form, handleability in air, and compatibility with undried technical-grade solvents. Reported results are restricted to electron-deficient (hetero)aryl halides, though they are all high-yielding and include challenging substrates like 2-chloropyrazine. The method also allows (hetero)zinc pivalates to be cross-coupled with alkynyl bromides

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EFFECTS OF COSOLVENTS ON REACTIONS RUN UNDER MICELLAR CATALYSIS CONDITIONS Novartis scientists have looked at the effect of certain organic cosolvents, specifically THF, acetone, PEG-200, and toluene, F




product using 0.1 mol % of an iridium catalyst and a ligand developed in-house. Catalytic iodine was used to enhance both the reactivity and enantioselectivity. This reduction includes the stereoselective delivery of hydrogen to a tetrasubstituted alkene. Although the enantiomeric excess was only 70%, a downstream diastereomeric salt resolution upgraded this to over 99.5%, completing the synthesis with an overall yield of 38% over seven steps.

and bromo- or iodoalkenes, with complete retention of the double bond geometry.

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SUZUKI−MIYAURA CROSS-COUPLING OPTIMIZATION ENABLED BY AUTOMATED FEEDBACK Researchers at the Novartis-MIT Center for Continuous Manufacturing have developed a droplet microfluidic system to optimize Suzuki reactions (Buchwald, S. L., et al. React. Chem. Eng. 2016, 1, 658). The DoE-based algorithm used starts off with initial fractional factorial designs and initial refining of a quadratic response surface associated with continuous process parameters. Discrete variables such as the precatalyst and ligand are then whittled down, before the optimal set of such variables is used to further refine the response surface. Optimal conditions were validated by repeating some of them in batch mode. A general finding arising from the study is that the dialkylbiarylphosphines class of ligands is particularly suitable for the coupling of aryl chlorides with unstable boronic acids. Second, the work provides further evidence that optimal conversions with a catalyzed transformation require a ligand that matches the rates of the individual steps as closely as possible. Recognizing that optimization can refer to different reaction characteristics, the authors also demonstrate the use of their setup to rapidly establish a ligand− precatalyst ratio that balances catalyst stability and activity for a particular cross-coupling.

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A DATA-DRIVEN STRATEGY FOR PREDICTING GREENNESS SCORES Optimizing the manufacture of a target compound with respect to process mass intensity can ignore potentially superior alternatives using completely different synthetic sequences, because information on the latter is scant at the time of route selection or reevaluation (Eastgate, M. D., et al. Green Chem. 2017, 19, 127). To address this, researchers at BMS have developed a predictive analytics approach that estimates the potential PMIs of different unoptimized route options. The approach evaluates “probable” ranges for the PMI and yield of a particular transformation using an algorithm that starts from actual data associated with BMS’s use of the particular type of chemistry (e.g., amide bond formation) concerned, in a scale-up setting over the past decade. Limitations with the accuracy of the predictions stem from the limited size of this database of scale-up reactions. A comparison of the PMIs of four compounds within the portfolio with the average PMI range data generated by the tool is used to validate the approach. The authors point out that the tool could be expanded to evaluate the PMI associated with all process inputs, including reagents and solvents, so that the PMI of a target molecule across its entire supply chain can be evaluated.

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CHEMOSELECTIVE ACYLATION OF PRIMARY AMINES AND AMIDES WITH POTASSIUM ACYLTRIFLUOROBORATES UNDER ACIDIC CONDITIONS

A novel method for the coupling of amines, amides and other nitrogen nucleophiles with potassium acyltrifluoroborates (KATs) was introduced by Bode et al. (J. Am. Chem. Soc. 2017, 139, 1826). The reaction proceeds in an aqueous solvent system in the presence of an inexpensive chlorinating agent such as DCH or TCCA with near-equimolar amounts of the nucleophile, KAT, and activator. The scope is broad with respect to the type of nitrogen-containing component and amines, amides, carbamates, ureas, guanidines, and sulfonamides are all competent coupling partners in the reaction. Despite this generality, the reaction is at present limited to primary amines and amides and does not tolerate substitution on other nitrogen nucleophiles. Interestingly, this stricture is not a consequence of the mechanism which is thought to proceed via N-chlorinationbut is attributed

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SEQUENTIAL C−H ARYLATION AND ENANTIOSELECTIVE HYDROGENATION Scientists at Boehringer Ingelheim have reported an efficient multikilogram synthesis of an 11β-HSD-1 inhibitor (Wei, X., et al. J. Am. Chem. Soc. 2016, 138, 15473). Efficient access to a tricyclic indenopyridine structure was possible using an intramolecular Heck-like C−H arylation. The successful development of this reaction required the alkylation of the pyridine nitrogen to prevent it from participating in a competing C−N bond formation. The stereogenic centers of the target structure were installed by an asymmetric hydrogenation of the arylation G




group’s previously published photoredox-nickel catalyzed etherification reaction (Nature 2015, 524, 330) it in fact operates through a distinct and novel mechanism. In contrast to the etherification reaction, in this case the iridium photocatalyst does not modulate the oxidation state of the nickel; rather, an isohypsic energy transfer between the photoexcited iridium(III) catalyst and the nickel(II) carboxylate is the key event that allows the otherwise thermodynamically unfavorable C−O bondforming reductive elimination to occur at room temperature. Although triplet sensitization by energy transfer is well-known in organic photochemistry, it is rarely invoked in photocatalyzed organometallic chemistry, and until this study, convincing experimental evidence for its existence had been lacking. It is interesting to note that, although an iridium photocatalyst was found to be optimal, classic triplet sensitizers like benzophenone and Michler’s ketone could also significantly accelerate the reaction compared to the background process. The scope of the carboxylic acid component is broad, and both aliphatic, alicyclic, and aryl carboxylic acids work well, as do amino acids. Some variation is tolerated in the aryl bromide component and a number of heteroaromatic examples are given, but examples of ortho-substituted and electron rich arenes are lacking. Although this particular reaction may find limited application in chemical processes, it is likely that the concept of photosensitized transition metal catalysis will lead to more powerful and useful transformations in time.

to steric sensitivity, as one secondary amine could be forced to couple under harsher conditions. However, this property leads to some surprising reactivity differences that would be difficult to achieve with other reagents, e.g., the selective acylation of a primary amide in the presence of an unprotected piperidine. The reaction also shows remarkable chemoselectivity and tolerates some surprising functional groups such as carboxylic acids, alcohols, and pyridines, which might be expected to interfere with many classical amide-forming reactions. Due partly to the nature of their synthesis, a somewhat limited range of acylating agents is used, and mainly aryl KAT reagents are demonstrated. Indeed, the greatest drawback to this methodology is perhaps the availability of the potassium acyltrifluoroborates.

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RHODIUM-CATALYZED DECARBONYLATIVE BORYLATION OF AROMATIC THIOESTERS FOR FACILE DIVERSIFICATION OF AROMATIC CARBOXYLIC ACIDS

Although a number of new methodologies for the decarboxylative functionalization of alkyl carboxylic acids have been presented in recent years, the more challenging decarboxylation of aryl- and heteroaryl-carboxylic acids remains underexplored. Hosoya and co-workers recently reported a new method for the decarbonylative borylation of aryl thioesters that provides an important link between stable, abundant aryl carboxylic acids and the corresponding readily diversifiable aryl boronate esters (Angew. Chem., Int. Ed. 2017, 56, 2482). The use of thioesters as activating groups allows the reaction to take place at significantly lower temperatures than the previously reported nickel-catalyzed reactions that employ esters and amides in this role. The reaction conditions are relatively mild and anilines, heterocycles, and ortho-substituents are tolerated on the thioester component. Furthermore, the proof of concept was also achieved for vinyl and alkyl carboxylic acids, which are often difficult to decarboxylate via metal-mediated processes. Finally, the reaction was also demonstrated on four carboxylic acid-containing pharmaceuticals, underscoring its applicability for the late-stage functionalization and diversification of drug-like molecules. From a process standpoint, it is noteworthy that, although the reaction was typically demonstrated with 5 mol % of rhodium catalyst, the authors show that as little as 0.05 mol % could be used, albeit with significantly longer reaction times.

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PHOTOSENSITIZED, ENERGY TRANSFERMEDIATED ORGANOMETALLIC CATALYSIS THROUGH ELECTRONICALLY EXCITED NICKEL(II) A unique set of photochemical conditions for the coupling of carboxylic acids with aryl bromides was disclosed by MacMillan, McCusker, and co-workers (Science 2017, 355, 380). Although this report appears to describe an extension of the MacMillan

NUCLEOPHILIC DEOXYFLUORINATION OF PHENOLS VIA ARYL FLUOROSULFONATE INTERMEDIATES

The synthesis of aryl fluoride-containing molecules is a familiar challenge to process chemists in the pharmaceutical industry. Although the direct deoxyfluorination of phenols is an appealing reaction that has been known for a number of years, the use of this tactic in drug manufacture has been hampered by the complex and expensive reagents that are typically required. H




tetra-substituted rings. Exhaustive hydrogenation of the products was also demonstrated, giving rise to unusual chiral enantioselective amine synthesis that would be difficult to achieve by other means.

Sanford and her collaborators at the Dow Chemical Company report a new method that achieves this important transformation using a combination of sulfuryl fluoride and tetramethylammonium fluoride in a new two-step one-pot protocol (J. Am. Chem. Soc. 2017, 139, 1452). It is noteworthy that a preliminary computational study of the reaction mechanism suggests that the reaction does not proceed via Meisenheimer-type intermediate. Instead, initial addition of fluoride to the aryl fluorosulfonate intermediate occurs at sulfur, forming a pentacoordinate species that undergoes concomitant C(sp2)−O cleavage and C(sp2)−F formation. In keeping with this proposed mechanism, the reaction proceeds even for electron neutral and some electronrich phenols, albeit at somewhat higher temperatures and with a larger excess of fluoride in difficult cases. In contrast, for electrondeficient phenols, the reaction often occurs at or only slightly above room temperature. The one-pot deoxyfluorination protocol is demonstrated on a number of phenol-containing drugs and on up to 13 g scale. One major disadvantage of this methodology is that sulfuryl fluoride is a toxic gas (bp 55 °C), although the authors are able to circumvent this problem by preparing a dilute solution (1−2 wt %) in dioxane. Sulfuryl fluoride is used as a fumigant, so it will remain to be seen if this readily available material will find alternate applications on scale.

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THE EVOLUTION OF Pd0/PdII-CATALYZED AROMATIC FLUORINATION

ENANTIOSELECTIVE NARASAKA−HECK CYCLIZATIONS: SYNTHESIS OF TETRASUBSTITUTED NITROGEN-BEARING STEREOCENTERS

Starting materials to prepare aromatic fluorides are limited despite their importance to the pharmaceutical, agrochemical, material industries, and so forth. In addition, general protocol to prepare unactivated aryl and heteroaromatic fluorides remain very challenging. The Buchwald group (Acc. Chem. Res. 2016, 49, 2146) has provided an insightful and systematic account on the discovery and development of a Pd-catalyzed C−F crosscoupling technology. A key to overcoming the once hypothetical fluorination of heteroaryl was the “observation”; a precipitated bright yellow solid from a reaction mixture when dissolved in CD2Cl2 became dark red. The color change was due to the formation of a new complex. The unusual substituted complex prompted the group to carry out further ligand modifications, which led to the readily available AlPhos ligand. The Pd−AlPhos catalyst recipe was very effective in the fluorination of the once challenging five-membered heterocycles. In addition, the group discussed the Pd-ligand recipes that allowed the directed regioisomeric aryl fluorination, room temperature fluorination, glovebox-free fluorination of aryl triflate, and so forth. It must be noted that, despite these advances, the general and truly practical fluorination protocol has enormous room for improvement. However, these discoveries may provide a bed rock for further development.

Even within the privileged class of nitrogen-containing hetereocycles, pyrrolidines are a particularly common motif in bioactive molecules. However, they are often formed using classic condensation and reductive amination chemistry, or brought in as commercial building blocks rather than being synthesized de novo. Bower and co-workers along with collaborators at AstraZeneca report an improved protocol for the enantioselective preparation of α,α-disubsituted pyrroldines using the little-known Narasaka modification of the Heck cyclization (Chem. Sci. 2017, 10.1039/c6sc04466b). Although the group had previously published a version of this reaction using a ligand based on the TADDOL scaffold (Chem. Commun. 2013, 49, 1521), levels of enantioinduction were too low to be useful. However, after extensive catalyst synthesis and screening, a bespoke SPINOL-derived P,N-ligand emerged that can now deliver consistently high enantiomeric ratios for a number of different substrates. The reaction was demonstrated with the variation of substitution around the alkene component, including a number of alkyl and aryl groups; however, the effect of substitution on the linking carbon chain was not reported. It is noteworthy that the formation of imine-containing products allows an opportunity for further functionalization of the ring system, potentially allowing access to quite densely tri- or

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SCALABLE SYNTHESIS OF (−)-THAPSIGARGIN The simplified synthesis of complex natural and unnatural product is still faced with mammoth difficulties including synthetic and economic challenges. The Baran group in collaboration with Leo Pharma (ACS Cent. Sci. 2017, 3, 47) have reported the scalable synthesis of the complex and highly oxygenated sesquiterpene (−)-thapsigargin. The team transformed the once 36−46 step process to an 11-step synthesis. The cradle to this I




elaboration of the synthesized morpholines and piperazines via reductive amination, sulfonation, acylation, and urea formation.

new remarkable route was the effective two-phase terpene strategy, a cyclization followed by precise choreographic installation of multiple atomic oxygen in sequential oxidations. The synthesis began with the cyclization of the readily available ethyl vinyl ketone and (+)-dihydrocarvone. This provided the skeletal framework which allowed sequential oxidative steps, which was followed by the formation of the serendipitous major dihydronaphthalenone diastereomer. Thus, the photochemical rearrangement followed by further synthetic manipulations led to the synthesis of (−)-thapsigargin and (−)-nortrilobolide sesquiterpenes. It must be noted that (−)-thapsigargin has promising therapeutic potential; however, it is also known to be highly toxic at very low concentrations.

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PALLADIUM-CATALYZED ENANTIOSELECTIVE C−H ACTIVATION OF ALIPHATIC AMINES USING CHIRAL ANIONIC BINOL−PHOSPHORIC ACID LIGANDS

Aliphatic C−H bonds are ubiquitous in nature and readily provide starting material for synthetic transformations. However, a dichotomy exists in their functionalization since they are intrinsically less reactive. Gaunt et al. (J. Am. Chem. Soc. 2017, 139, 1412) have reported an enantioselective Pd(II)-catalyzed C−H amination reaction that produced chiral aziridines and are also amenable to further elaboration to potentially useful heterocyclic chiral building blocks. After initial experimentations, an example of reaction conditions the group settled on was the use of BINOL derived phosphoric acid, Pd(OAc)2, I2, AgOAc, EtOAc, and a 90 °C temperature. The reaction conditions tolerated a wide range of substrates possessing variable electronic and steric properties, which provided aziridines in good yields and high enantiomeric ratios (e.r.’s). The group presented a preliminary pathway for the Pd(II)−catalyst coordination. It involves coordination of the Pd(II)−nitrogen lone pair in the pseudoaxial position which activates the C−H bond on the methyl group that is syn to the coordinated metal. This probably led to a four-membered cyclopalladated complex and the subsequent formation of the aziridine ring.

DE NOVO ASSEMBLY OF HIGHLY SUBSTITUTED MORPHOLINES AND PIPERAZINES

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ENANTIOSELECTIVE NiH/Pmrox-CATALYZED 1,2-REDUCTION OF α,β-UNSATURATED KETONES The use of first-row transition metals in catalysis has attracted increasing attention due to their low cost and sustainability. Unlike CuH reduction, very few reports exist for the use of NiH in enantioselective reactions. Zhu and co-workers have reported a mild and effective enantioselective NiH catalyzed 1,2-reduction of α,β-unsaturated ketones (Angew. Chem., Int. Ed. 2017, 56, 2022). The group found (S)-4-tert-butyl-2-(pyrimidin-2-yl)-4,5dihydrooxazole [(S)-t-Bu-Pmrox] ligand, which was readily prepared from the corresponding chiral amino alcohol, provided a general substrate scope, and delivered high levels of 1,2-selectivity and high enantioselectivities. The protocol tolerated sensitive functional groups such as iodo, boronic acid pinacol ester, triflate, and so forth. Thus, these intermediates also

The pharmacokinetic benefits of introducing morpholine or piperazines in drug molecules have rendered their widespread use and are referred to as privileged structures in medicinal chemistry. Unlike their unsubstituted congeners, substituted morpholine and piperazines are not only difficult to introduce, but their synthesis involves elaborate synthetic design. Dömling and co-workers (Org. Lett. 2017, 19, 642) have reported a versatile de novo synthesis of substituted morpholine and piperazine via a multicomponent reaction sequence. This useful multicomponent strategy involved the formation of the Ugiadduct followed by sequential cyclization to the morpholine. A slight modification of the protocol with the use of diamine, TMSN3, and trifluoroacetic acid at low or elevated temperatures gave the piperazine derivatives. The group also highlighted the J




a three-component trifluoromethylation of boronic esters with furans in Angew. Chem., Int. Ed. 2017, 56, 1810. The methodology involves the reaction of a furan-2-yllithium with a boronic ester to form a boronate complex that reacts with a trifluoromethyl radical and triggers a 1,2-metallate rearrangement upon single electron oxidation. Optimized conditions using Umemoto’s reagent as the CF3 radical source work for an assortment of boronic esters to give the corresponding furan derivatives in good yields. Interestingly, secondary boronic esters react with essentially complete enantiospecificity. EPR spectroscopic studies of mixtures containing a spin trap reveal that the CF3 radical is formed in the reaction. The oxidative medium (K2CO3, I2) promotes the formation of the final products by rearomatization of intermediate species. The three-component coupling is not restricted to furan-2-yllithium, and successful table entries are shown for lithiated thiophene and N-Bocpyrrole.

provide various synthetic handle for further manipulations. Furthermore, the group reported a one-pot, gram-scale protocol, which gave acetyl-protected allylic ester in high yield, 1,2-selectivity, and high enantioselectivity.

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A MILD AND LIGAND-FREE NICKEL-CATALYZED SILYLATION VIA C−OMe CLEAVAGE

Aryl methyl ethers, unlike their activated C−O electrophilic congeners such as aryl carbamates, sulfonates, triflates, and so forth, have a very low propensity to undergo C−OMe cross coupling reactions. Consequently, very few protocols exist for their use in metal catalyzed cross-coupling reactions. Martin and co-workers (J. Am. Chem. Soc. 2017, 139, 1191) have reported a mild and effective Ni-catalyzed C−OMe cleavage. The unprecedented protocol involves an ipso-silylation of aryl methyl ethers and extensive substrate scope, which included benzyl methyl ethers, anisole derivatives, and vinyl ethers. Noteworthy was the low catalytic loading that effected silylation at room temperature, suggesting the generation of a very reactive Ni-catalyst. Furthermore, the group showed a circumstantial evidence involving Ni(0)-ate complex, which probably facilitated the transformation. On the other hand, it was clear that more mechanistic studies are warranted to fully understand the mechanism of the reaction. The mild reaction conditions, wide substrate scope, and the orthogonal silylation technique exemplified in this report could foster C−OMe scission in the design of new C-heteroatom bond formation.

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NICKEL-MEDIATED DECARBONYLATION OF KETONES Relative to aldehydes, the decarbonylation of ketones offers unique challenges owing to the compulsory activation of two inert C−C bonds. Chemists at Osaka University report a Ni/ N-heterocyclic carbene-mediated decarbonylation of simple unstrained ketones that opens a new route to biaryl compounds (Tobisu, M. et al. J. Am. Chem. Soc. 2017, 139, 1416). Screening studies identified that pairing stoichiometric amounts of Ni(cod)2 with an IMesMes ligand enables the decarbonylation of a variety of diaryl ketones. Remarkably, optimized conditions give the desired biaryl product and unreacted starting material with little or no byproducts formed. Intermolecular crossover experiments demonstrate the absence of mixed biaryls, indicating that the process occurs through an intramolecular mechanism. In addition, ketones containing both electron-donating and electron-withdrawing substituents display accelerations suggestive of electronic push−pull effects. A mechanistic hypothesis considers the irreversible formation of an aroyl-Ni(II) intermediate via oxidative addition and subsequent decarbonylation to generate a diaryl-Ni complex. Reductive elimination from the latter affords the desired biaryl product along with a Ni-carbonyl species that can be observed by IR spectroscopy.

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CF3 RADICAL-INDUCED COUPLING OF BORONIC ESTERS Trifluoromethylated heteroaromatics are common substructures in the notebook of development chemists striving to introduce the CF3 substituent at a given stage of the synthesis. The group of Prof. Aggarwal at University of Bristol describes the discovery of K




deuteration, which uses sodium dispersion in ethanol-d1, affords satisfactory deuterium incorporation across a variety of esters, is operationally simple, and constitutes an affordable option to pyrophoric alkali metal deuterides such as LiAlD4. Control experiments support a single electron transfer (SET) mechanism that tolerates potentially sensitive functional groups such as F, OMe, and SMe. The first electron transfer can be reversible and occurs even in the absence of a proton, whereas the second electron transfer only takes place in the presence of a proton donor. The anionic intermediates are deuterated by the deuterium donor.

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THE LOGIC BEHIND A PHYSICAL−ORGANIC CHEMIST’S RESEARCH TOPICS Modern chemical development exploits components from multiple disciplines to enable the safe, environmentally benign, timely, and economical manufacturing of quality organic compounds. While process development strategies vary among practitioners contingent on the nature of the deliverable, physical organic principles constitute an underlying guide to all approaches. Distinguished Professor Charles L. Perrin publishes an especially engaging Perspective in J. Org. Chem. 2017, 82, 819, which describes the diverse areas of his research career. The use of NMR methods to measure proton exchange rates (e.g. saturation transfer, 2D-EXSY), studies of the origins of stereochemical and anomeric effects, or the application of isotopic perturbation to probe energy potentials are just a few examples of meticulous, fundamental research in the field of structure−reactivity relationships.

SYNTHESIS OF α,α-DIDEUTERIO ALCOHOLS

Robert Ely Pharmaceutical Operations, Pfizer, San Francisco, California 94105, United States

Paul Richardson Pfizer, Chemistry, 10578 Science Center Drive, San Diego, California 09121, United States

Andrei Zlota The Zlota Company, LLC 15, Fairbanks Road, Sharon, Massachusetts 02067-2858, United States

Deuterated drug candidates continue to attract the interest of the pharmaceutical industry due to the kinetic endurance of C−D bonds towards metabolic transformations. However, such a simple alteration brings about multiple challenges. While synthetic chemists hinge on a limited number of methodologies to introduce deuterium, CMC professionals strive to bring into line the peculiarities associated with isotopologue impurities. J. An et al. from China Agricultural University in Beijing report the development of a selective synthesis of α,α-dideuterio alcohols from esters in J. Org. Chem. 2017, 82, 1285. The reductive

Alan Steven Chemical Development, AstraZeneca, Cambridge CB4 0FZ, U.K.

David Day Department of Chemistry, University of Warwick, Coventry, CV4 7AL, U.K.

Robert Kargbo Department of Process Chemistry, AMRI, 26 Corporate Circle, Albany, New York 12212, United States L




Christopher Nawrat Merck & Co., Rahway, New Jersey 07065, United States

Antonio Ramirez Bristol-Myers Squibb, Chemical Development, 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]. Notes

E-mail: [email protected]; paul.f.richardson@pfizer. com; [email protected]; alan.steven@ astrazeneca.com; [email protected]; christopher.nawrat@ merck.com; [email protected].

M


Organic Process Research & Development - ACS Publications

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