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

Highlights from the Literature pubs.acs.org/OPRD

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

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ON THE DESIGN OF COMPLEX DRUG CANDIDATE SYNTHESES IN THE PHARMACEUTICAL INDUSTRY

A review from process chemists Martin Eastgate and Michael Schmidt at Bristol-Myers Squibb and Keith Fandrick at Boehringer Ingelheim highlights the importance of synthetic strategy and the need for the development of new chemistry during process development (Nat. Rev. Chem. 2017, 1 (16), 1). Arguing strongly in favor of “disruptive innovation”, the authors highlight examples from their respective companies where the development of new reactions and processes resulted in a step change in synthetic efficiency compared to previous routes. Detailed case studies include JAK2 inhibitor BMS-911543, NRTI BMS-986001, HIV attachment inhibitor BMS-663068, and Pfizer’s smoothened inhibitor PF-04449913. The review contains 55 references.

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Given the unquestionable value of functionalized nucleosides as prodrugs for the treatment of HIV, HCV, and cancer in recent years, the ability to selectively perform chemistry at the desired positions on the ribose ring has become increasingly important. A report from chemists at Merck Process Research & Development describes the selective 3′-phosphoramidation, phosphorylation, and acylation of nucleosides with a seemingly more reactive free 5′-hydroxyl group (Chem. Sci. 2017, 8, 2804). Although strong bases such as organometallics and phosphazenes are known to favor 5′-phosphorylation, it was reported that use of a milder base such as DBU shifted selectivity to strongly favor 3′-functionalization. It was shown through NMR studies and intermolecular NOE correlations that DBU forms a 1:1 complex with substrate, and an intramolecular hydrogen bond is responsible for deactivation of the 5′-position. Furthermore, the computational prediction of the success of the method was possible. Owing to the simple conditions and ability to assess the feasibility of the reaction in silico, this method could be generally useful for the synthesis of 3′-functionalized nucleosides without the need for protection of the typically more reactive 5′-position.

CONVERSION OF tert-BUTYL ESTERS TO ACID CHLORIDES USING THIONYL CHLORIDE

Sammakia and co-workers at the University of Colorado at Boulder have described the direct conversion of tert-butyl esters into acid chlorides using thionyl chloride (J. Org. Chem. 2017, 82, 3245). The reaction is clean and high yielding, and other esters even isopropyl and benzylare unreactive under the conditions. Although 10−20 equiv of thionyl chloride were required, the reaction could generally be performed at room temperature, and the acid chloride can be obtained as a toluene solution after azeotropic removal of the unreacted thionyl chloride. A number of different functional groups and protecting groups were tolerated, and the reaction could also be performed on an amino acid derivative with minimal erosion of the enantiopurity. The method was developed when an acid chloride was required whose parent carboxylic acid was difficult to isolate, and it is potentially useful in similar cases or in telescoped reaction sequences. © XXXX American Chemical Society

PROTECTING-GROUP FREE SELECTIVE 3′-FUNCTIONALIZATION OF NUCLEOSIDES

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ALKYL-(HETERO)ARYL BOND FORMATION VIA DECARBOXYLATIVE CROSS-COUPLING: A SYSTEMATIC ANALYSIS

A recent publication from the Baran group provides a user-guide to the decarboxylative coupling of activated esters with a variety of organometallic nucleophiles (Angew. Chem., Int. Ed. 2017, 56, 3319). Exploiting the recently discovered ability of activated carboxylic acids to stand in for alkyl halides in cross-coupling reaction, a range of organozinc, organomagnesium, and boronic acids were cross-coupled under nickel and iron catalysis. Primary,

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DOI: 10.1021/acs.oprd.7b00163 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

This makes the emerging field of C(sp2)-O bond activation through nickel catalysis for cross-coupling chemistry an intriguing methodology. Rueping and co-workers at RWTH Aachen University have described the synthesis of primary aryl amines from readily available aryl esters with benzophenone imine as the nitrogen source (Org. Lett. 2017, 19, 1788). The Ni(0)-catalyzed reaction is highly ligand dependent, requiring 1,2-bis(dicyclohexylphosphino)ethane as a ligand. Other common phosphine ligands, as well as an NHC ligand, provided only trace product. Several bases were also examined, with Cs2CO3 providing the best yields. Naphthyl esters are more reactive than phenyl esters. Phenyl substrates required sulfamate activation, while naphthyl carbonates, pivalates, carbamates, and sulfamates provide the aryl amine in good yields. The benzophenone imine is a convenient nitrogen source that provides the primary amine after acid hydrolysis; however, the secondary amine can be isolated after sodium borohydride reduction of the ketimine intermediate.

secondary, and tertiary carboxylic acid derivatives were crosscoupled in synthetically useful yields, and the reaction was found to be generally insensitive to adventitious water and oxygen. Although the use of inexpensive iron and nickel catalysts is attractive for scale up, as is the ability to utilize activated carboxylic acids generated in situ, the current low reaction concentration (0.1−0.2 M) and requirement for excess nucleophile (typically 3 equiv) could be potentially problematic from a PMI standpoint.

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3-AMINODEOXYPYRANOSES IN GLYCOSYLATION: DIVERSITY-ORIENTED SYNTHESIS AND ASSEMBLY IN OLIGOSACCHARIDES

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3-Aminodeoxypyranoses are valuable intermediates for the synthesis of oligosaccharides, which are prevalent in important antibiotics. Zeng, Wan, and co-workers at Huazhong University of Science and Technology have described the synthesis and utility of a cyclic sulfamidate imine as a useful lynchpin for a variety of 3-amino- and 3-nitro sugars that can be used in glycosylation chemistry (Angew. Chem., Int. Ed. 2017, 56, 5227). The strategy utilizes the cheap and commercially available deoxy sugar, rhamnose, to access a useful precursor to aminosugar building blocks. Simple reduction and oxidation chemistries can provide glycosyl donors. The efficiency of several different glycosyl donors was investigated to provide disaccharides with α-selectivity in good yields. In addition, the use of DMF was found to change the selectivity of gold-catalyzed glycosylation to favor the β-linkage. The synthesis of a tetrasaccharide containing four different 3-aminosugars displays the utility of this method.

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C−O FUNCTIONALIZATION OF α-OXYBORONATES: A DEOXYGENATIVE GEM-DIBORYLATION AND GEM-SILYLBORYLATION OF ALDEHYDES AND KETONES

NICKEL-CATALYZED SYNTHESIS OF PRIMARY ARYL AND HETEROARYL AMINES VIA C−O BOND CLEAVAGE

Several examples of the utility of gem-diboryl compounds have been published recently, making the synthesis of these compounds increasingly important. Liu and co-workers at Lanzhou Institute of Chemical Physics and Lan and co-workers at Chongqing University have described a convenient method to synthesize gem-diboryl and gem-silylboryl compounds from aldehydes and ketones, utilizing Cu-catalyzed borylation, followed by the first example of a 1,2-metalate rearrangement with OB(pin) as a leaving group (J. Am. Chem. Soc. 2017, 139, 5257). The Cu-catalyzed borylation of aldehydes and ketones has been well-studied and proceeds with ICyCuCl (ICy = 1,3-dicyclohexylimidazol-2-ylidene) as catalyst to generate α-oxyboronic esters. These intermediates can now be activated with NaOtBu as a base for nucleophilic displacement by either B2(pin)2 or B(pin)-SiMe2Ph to generate gem-diboryl or gem-silylboryl compounds. Labeling studies, as well as DFT calculations, suggest a five-membered transition state boryl

The synthesis of aryl amines via aryl halides is well-known, but sometimes access to the aryl halide takes several steps. B




migration, followed by a 1,2-metalate rearrangement with OB(pin) as the leaving group. By using an enantioenriched α-oxyboronic ester, the reaction was shown to proceed with inversion at the carbon center in a stereospecific manner. Starting from a variety of aldehydes or ketones, the Cu-catalyzed borylation and base-promoted C-OBpin borylation can be achieved in a single operation. To obtain the gem-diboryl compounds, two equivalents of B2(pin)2 and base is simply added in along with the reagents for carbonyl borylation. For gem-silylboryl compounds, the Cu-catalyzed borylation with one equivalent of B2(pin)2 is first carried out, followed by the addition of base and B(pin)-SiMe2Ph.

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The late-stage installation of phenols is an important process due to their prevalence in pharmaceuticals as well as their sensitivity to a variety of transformations. The hydroxylation of aryl halides is an attractive method for the installation of phenols but generally requires strong base and/or harsh reaction conditions. Fier and Maloney at Merck Process have described the utility of benzaldehyde oxime as a convenient hydroxide surrogate for a Pd-catalyzed hydroxylation of aryl halides (Angew. Chem., Int. Ed. 2017, 56, 4478). Using an aryl bromide containing an aliphatic methyl ester and an aryl fluoride, several highthroughput experiments were carried out to find conditions for a Pd-catalyzed hydroxylation without ester hydrolysis or SNAr displacement side reactions. With the conditions identified, less than 1% of ester hydrolysis or SNAr displacement occurred, providing the phenol in excellent yield. 2-MeTHF is also a competent solvent, as is K3PO4 as base. The mild conditions allow for the construction of highly functionalized phenols, demonstrated by an impressive additive screen as well as testing 18 polyfunctional drug-like aryl halides as part of a chemistry informer library. Mechanistic studies support an initial Pd-catalyzed O-arylation of benzaldoxime, followed by base-induced elimination to provide the phenol and an equivalent of benzonitrile.

SELECTIVE REDUCTIVE REMOVAL OF ESTER AND AMIDE GROUPS FROM ARENES AND HETEROARENES THROUGH NICKEL-CATALYZED C−O AND C−N BOND ACTIVATION

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The Chan-Lam coupling is a widely known method to make aryl amines but has major limitations when it comes to reactivity using aryl pinacol boronic esters, especially with aryl amines. Common side reactions such as protodeborination, oxidative homocoupling, and oxidation to the phenol can decrease the yield and make purification difficult. To improve the utility of this important reaction, Watson of University of Strathclyde and Miras and co-workers of University of Glasgow, in a collaboration with GSK, studied the coupling in great mechanistic depth to discover simple improvements to enhance utility of this reaction (J. Am. Chem. Soc. 2017, 139, 4769). The full article focuses on the differences between using pinacol boronic esters and boronic acids, as well as aliphatic amines vs aryl amines. Using EPR analysis, HRMS, and UV−vis spectroscopy, as well as 11 B NMR, several requirements to improve the reaction were determined: (1) sequestration of AcO−/AcOH; (2) removal of free pinacol; and (3) promotion of Cu(I) oxidation. To accomplish this, commonly used NEt3 was replaced with B(OH)3, and the organoboron−amine stoichiometry was reversed, increasing the amount of amine. These changes provided a generally effective catalytic Chan-Lam coupling, with a shorter reaction time, and lower quantities of byproducts.

Readily available esters and amides are useful directing groups for manipulation of aryl and heteroaryl compounds, allowing access to structural patterns that could be difficult to access without their directing ability. If the ester of amide is not desired, selective reduction of carboxylic acid derivatives have been developed but usually provide the alcohol, ether, aldehyde, or amine. Reductive cleavage of the ester or amide is less known. Rueping and co-workers at RWTH Aachen University have described a Ni-catalyzed selective reduction of aryl/heteroaryl esters and amides with polymethylhydrosiloxane (PMHS), an inexpensive, nontoxic, and air-stable hydrosilane (Angew. Chem., Int. Ed. 2017, 56, 3972). Importantly, the process utilizes a cheap, air-stable Ni(II) salt, and when run on 1 g scale, the catalyst loading could be lowered to 5 mol %. The reduction is selective for phenyl esters in the presence of methyl esters and is tolerant of a variety of functional groups including alkenes, ketones, acetals, and methylthiols. The reduction of activated amides requires longer reaction times.

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SPECTROSCOPIC STUDIES OF THE CHAN-LAM AMINATION: A MECHANISM-INSPIRED SOLUTION TO BORONIC ESTER REACTIVITY

SYNTHESIS OF COMPLEX PHENOLS ENABLED BY A RATIONALLY DESIGNED HYDROXIDE SURROGATE

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CRYSTALLIZATION FROM THE AMORPHOUS STATE OF A PHARMACEUTICAL COMPOUND: IMPACT OF CHIRALITY AND CHEMICAL PURITY An amorphous drug substance is sometimes obtained by design; other times amorphous material is undesirably formed during certain operations such as milling. In all cases, controlling the crystallization from such amorphous state is necessary, including preventing or delaying crystallization. A team from the Universities of Rouen and Coimbra reports their results on the C




transformation presumed to be a key process in the preferential enrichment observed with certain chiral organic compounds (Takahashi, H., et al. Cryst. Growth Des. 2017, 17, 671). Preferential enrichment is a spontaneous enantiomeric resolution of certain chiral racemic crystals. The monitoring of the polymorphic transition was accomplished using in-house built instruments for temperature controlled video-microscopy and time-resolved in situ XRPD, as well as in situ ATR-FTIR. Details about and images of the in-house built devices are included in the paper. The pictures and the movies recorded during the crystallization experiments are quite fascinating to see.

behavior of amorphous diprophylline (7-(2,3-dihydroxypropyl)1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione, DPL), a chiral compound, in the presence of theophylline (TPH) impurity (Viel, Q., et al. Cryst. Growth Des. 2017, 17, 337). Amorphous samples were prepared by fast cooling from the melt, and two protocols were designed to induce crystallization. Only purified material was used. Racemic and enantiopure DPL were crystallized, and crystallization conducted from amorphous material of various degrees of optical purity showed no impact of the enantiomeric composition of the DPL. On the other hand, the amount of theophylline impurity does impact the morphology of the crystals obtained from the supercooled melt of DPL. Extensive solid state characterization was conducted, using DSC, hot stage optical microscopy, XRPD, and Raman spectroscopy. A mechanism is proposed to explain the experimental observations, involving the formation of primary crystals by homogeneous nucleation and growth, followed by the formation of secondary nuclei of metastable solid solutions with faster growth rates. Such process understanding can contribute to the better management of the stability of amorphous drug substances. This paper has 60 references.

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USE OF BOX BEHNKEN DESIGN OF EXPERIMENTS (DOE) FOR THE DEVELOPMENT OF HIGH-THROUGHPUT QUANTITATIVE PROTON NUCLEAR MAGNETIC RESONANCE (QHNMR) EXPERIMENTS FOR INDUSTRIAL APPLICATIONS The use of statistical design of experiments (DoE) for analytical method development is well-established, and many chromatographic methods (HPLC in particular) are routinely developed using DoE. A team from the Indian Defense R&D Establishment and the Indian Institute of Technology (Roorkee) reported the use of DoE for high throughput 1H NMR quantitative measurements in an industrial context (Kumar, A., et al. Ind. Eng. Chem. Res. 2017, 10.1021/acs.iecr.6b04097). To develop a reliable 1H NMR method needed for the quantification of the components of a chemical weapon decontamination mixture, a Box-Behnken design was used, investigating seven parameters: flip angle (P0), central frequency (O1P), number of scans (NS), sample temperature (T), acquisition time (AQ), line broadening function (LB), and interscan delay (D). A total of 62 measurements were conducted to determine that three of the seven factors evaluated were statistically significant: flip angle (P0), number of scans (NS), and interscan delay (D). Fourteen verification experiments were executed to find good agreement with the results of a classical analytical method used for the same mixtures. A Bruker 600 MHz instrument was used, with suitable hardware and software. Method suitability, linearity, and repeatability were determined, and limits of detection and quantification were established. Method optimization was executed to minimize the measurement time. The method was also automated to allow for high throughput use. This paper has 45 references.

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RAPID PRODUCTION OF SUBMICRON DRUG SUBSTANCE PARTICLES BY SUPERSONIC SPRAY DRYING Certain drug formulations require the use of the submicron particles, which can be produced for example, by nanomilling, nanoprecipitation, or spray drying. Nanomilling challenges include material loss, high energy consumption, and possible changes of the API crystal structure. Batch-to-batch variability is a challenge upon scale-up of nanoprecipitation processes. A team from Harvard University and Ecole Polytechnique Federale de Lausanne reported the use of a supersonic spray drying method to produce submicron drug substance particles (Eggersdorfer, M. L., et al. Cryst. Growth Des. 2017, 17, 2046). In contrast to known spray drying techniques, the process developed by the team involves the design of a novel apparatus capable of relatively rapid production of submicron particles by making use of a unique geometry of the nozzle of the spray dryer. The model compound used in these studies was the synthetic steroid danazol (17α-ethynyl-17β-hydroxy-4-androsten-[2,3-d]isoxazole). The smallest particles obtained exhibited a Sauter mean diameter of 188 nm and could be produced at 200 mg/h. Higher productivity (1.5 g/h) produced relatively larger particles, of a mean Sauter diameter of 772 nm. The particles thus obtained are approximately an order of magnitude smaller than those obtained in commercially available spray dryers. The novel spray dryer was designed using CAD (computer aided design) and 3D-printing, employing specially treated materials of construction, exhibiting a supersonic nozzle. The spray drying process developed does not require heating the gas used, thus allowing the processing of thermolabile substances. Colleagues of the authors from Novartis Pharma AG and from BASF SE are acknowledged for their contributions to this project.

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C3-ARYLATION OF INDOLES WITH ARYL HALIDES Chen and Wu from Dartmouth College, Hanover, USA describe a transition metal-free coupling of unprotected indoles with aryl halides in Angew. Chem., Int. Ed. 2017, 56, 3951. Excess t-BuOK promotes the direct introduction of an aromatic substituent at the position 3 of indole in degassed DMSO. The method tolerates alkoxy, nitro, or amine groups on the electrophile and a variety of substituents on different positions of the indole nucleophile. When coupled with N-alkylation in the presence of MeI or BnBr, the transformation enables a modular synthesis of C3-arylated, N-alkylated indoles of potential interest to medicinal chemists. Control experiments revealed the coexistence of electron transfer processes and aryne intermediates during the arylation: (a) EPR analysis of incomplete reactions confirmed the existence of free radicals, (b) the presence of radical scavengers resulted in lower yields, (c) o- and p-substituted phenyl iodides afforded cine-substitution products, and (d) benzyne intermediates could be trapped with external nucleophiles.

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IN SITU OBSERVATION OF POLYMORPHIC TRANSITION DURING CRYSTALLIZATION OF ORGANIC COMPOUNDS SHOWING PREFERENTIAL ENRICHMENT A team from Kyoto and Meijgakuin Universities in Japan and Universite Rouen and Aix-Marseille University reported the in situ observation of a solvent-assisted solid-to-solid polymorphic D




electrophilic amide precursors to afford the desired products in good yields. Remarkably, the methodology can be extended to the amidation of pyrroles when the amidation step is performed at room temperature. C-3 amidations can be purposefully redirected to N-1 aminal formation with the appropriate N-[(benzenesulfonyl)oxy]amide, in the absence of a transmetalation reagent and using DMSO as the solvent.

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FRIEDEL−CRAFTS C−H BORYLATION The importance of borylated aromatics in modern organic synthesis cannot be overstated. In fact, attempts to prepare borylated aromatics from arenes has fueled the development of transition-metal-catalyzed C−H activation as well as the advancement of aromatic substitution methods with electrophilic boron reagents. Yin, Klare, and Oestreich (Technische Universität Berlin) disclose the use of B(C6F5)3 as an activator for hydroboranes toward the electrophilic C−H borylation of electron-rich arenes in Angew. Chem., Int. Ed. 2017, 56, 3712. Under optimized conditions, catalytic B(C6F5)3 promotes the para-borylation of a series of N,N-disubstituted anilines with excess catechol borane in refluxing toluene. In situ transesterification of catechol to pinacol affords the arylboronates that are less susceptible to protodeborylation. While the substrate scope of the reaction is remarkable, substitution at the aniline nitrogen is crucial, and monoalkylated anilines and their alkyl phenyl cousins are not sufficiently nucleophilic. Mechanistic studies support a SEAr sequence with the formation of a borenium ion and subsequent dihydrogen release. Substoichiometric amounts of alkenes accelerate the reaction and facilitate the borylation at room temperature.

3-AMIDATION OF INDOLES WITH AN ELECTROPHILIC NITROGEN AGENT

The implementation of electrophilic aminations remains a challenge in pharmaceutical development. Ortiz, Hemric, and Wang at Duke University report a direct and selective 3-amidation of indoles using electrophilic nitrogen in Org. Lett. 2017, 19, 1314 N-[(Benzenesulfonyl)oxy]amides promote the C-3 amidation of deprotonated indole in the presence of excess ZnCl2 as transmetalating agent in DMF. The three-step protocol (i.e., deprotonation, transmetalation, amidation) enables the functionalization of a series of substituted indoles with different

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ADDITION OF ALLYL-SODIUM SPECIES TO ALDIMINES Electrophilic and nucleophilic allyl palladium intermediates have expanded the versatility of the allyl synthon by adding multiple options for the synthetic chemist. Bao, Kossen, and Schneider at the University of Edinburgh report the use of catalytic NaN(TMS)2 in the allylic C(sp3)−H bond activation of alkenes E




(J. Am. Chem. Soc. 2017, 139, 4362). Substoichiometric amounts of NaN(TMS)2 deprotonate the allylic position of a series of alkenes and react regioselectively with PMP-protected benzaldehyde-derived imines to afford the corresponding 1,2-adducts in excellent E:Z stereoselectivities (>49:1). Interestingly, the regioselectivity of the NaN(TMS)2-mediated addition differs from the connectivity obtained in related imino−ene reactions and Pd-catalyzed cross-couplings mediated by superstoichiometric lithium amides. Studies on the scope of alkene and imine structures demonstrate that a variety of functional groups are tolerated in both partners. Mechanistic studies confirm the requirement of a sodium amide by inductively coupled plasma (IPC) metal analysis and 23Na NMR spectroscopy, which connects the structure of the observable intermediates with the desired reactivity. The manuscript adds to a revived interest in the use of sodium amides as Brønsted bases (see Collum et al. J. Org. Chem. 2016, 81, 11312 and Mulvey et al. Angew. Chem., Int. Ed. 2013, 52, 11470).

that enable the formation of carbon-CHF2 bonds. The current state of the art methods involve cross-couplings between aryl electrophiles with nucleophilic “CHF2” reagents, which are typically catalyzed/mediated by copper, and believed to proceed through the formation of (L)Cu(CHF2) intermediates, which until now have not been isolated. Sanford and co-workers hypothesized that, by employment of a sterically encumbered N-heterocyclic carbene (NHC) ligand to protect the Cu center, it might be possible to not only inhibit the typical bimolecular decomposition of these complexes, but also to isolate and investigate their reactivity (Organometallics 2017, 36, 1220). This proved to be the successful, and both the IPr and SiPr complexes formed and isolated as neutral monomeric species, which was confirmed by small molecule X-ray crystallography. Furthermore, the stoichiometric reaction of the IPr complex was demonstrated with a series of aryl iodides to successfully form the difluoromethyl derivatives in moderate (electron-rich) to excellent (electrondeficient) yields. The electron-rich iodides also required more forcing conditions due to a slower oxidative addition. Initial investigations to utilize the complex in a catalytic cycle simply by merging the transmetalation step in the synthesis of the complexes with the difluoromethylation reaction provided complex mixtures due to the tert-butoxide bases used in the former being too reactive. To mitigate this, the ability of fluoride salts to promote the transmetalation from fluoroalkyl silicon species was exploited, and these proved to be more compatible with the reaction conditions leading to a Cu-catalyzed difluoromethylation, which proved successful for electron-rich, -neutral, and -deficient aryl iodides. Substrates bearing either aldehydes or ketones were not tolerated with addition of CHF2 to the carbonyl completing with the desired product, though this limitation could be overcome by acetal-protection of the carbonyl moiety.

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REMOTE SITE-SELECTIVE C−H ACTIVATION DIRECTED BY A CATALYTIC BIFUNCTIONAL TEMPLATE

SYNTHESIS, REACTIVITY, AND CATALYTIC APPLICATIONS OF ISOLABLE (NHC)Cu(CHF2) COMPLEXES

One of the major drawbacks of many directed C−H activation approaches is the need for a functional group handle through which to covalently attach the directing group to the substrate of interest. To avoid this limitation, Yu and co-workers have

The increasing propensity of difluoromethyl substituents in pharmaceuticals has led to a desire for new synthetic methods F




which an aryl group was close to the NH motif, the more facile ortho-sp2 C−H alkenylation took place. Other α,β-unsaturated systems were also reactive substrates though both simple olefins and styrenes failed to react. X-ray crystallography confirmed that the N−H function was directing the C−H bond cleavage, while kinetic isotope studies indicate that, whereas in the absence of ligand the C−H bond cleavage is irreversible, once the ligand is added reprotonation becomes possible through the proximity of the ligated protonated amide. A number of functional group transformations of the products are demonstrated, and a modest amount of enantioselectivity (12% ee) is reported for the process in the presence of an enantiopure ligand.

reported on the design of a bifunctional U-shaped template capable of binding both Pd(II) and Cu(II) for the meta-selective monoalkenylation of a variety of 3-phenylpyridines (Nature 2017, 543, 538). The template is based on a bis-sulfonamide scaffold with the optimal ligand featuring a rigid backbone, cisorientation of the sulfonamides, and pendant C-3 pyridine group side arms as the directing groups. Control experiments confirm that the remote directing effect controls the meta-selectivity on the basis of both geometry and distance. The addition of AgBF4 to the reaction is crucial for success, and this is hypothesized to be due to a potential Pd−Ag heterodimer in the transition state. From a scope perspective, a range of substitution patterns and functional groups are tolerated though meta-substitution leads to both poor yields and loss of selectivity due to steric effects. In addition, other N-containing heterocycles can replace the pyridine. Extending this bimetallic catalysis to the olefination of quinolines led to the need to design a different molecular scaffold with nitrile-based templates in which the metal is anchored through tridentate coordination being successfully employed though under stoichiometric conditions. The selective alkenylation of quinolones took place in the 5-position, and the reaction extended to other bicyclic systems such as quinoxalines and benzothiazoles as well as the late-stage modification of the antitumor alkaloid (+)-camptothecin. In both systems, the template could be recovered with >95% efficiency.

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LIGAND-ASSISTED PALLADIUM-CATALYZED C−H ALKENYLATION OF ALIPHATIC AMINES FOR THE SYNTHESIS OF FUNCTIONALIZED PYRROLIDINES

VISIBLE-LIGHT-INDUCED C-2 ALKYLATION OF PYRIDINE N-OXIDES

There are a limited number of methods available for the C−H alkylation of abundantly available pyridine-N-oxides with the more recent both involving the intermediacy of alkyl radicals. Recognizing the potential to generate these from potassium alkyltrifluoroborates using photoredox catalysis, Xu and co-workers have reported on a mild method for the C-2 alkylation of pyridine-N-oxides (J. Org. Chem. 2017, 82, 2059). Model studies on the alkylation of 2-methylpyridine-N-oxide with potassium cyclohexyltrifluoroborate highlighted the importance of both 1-acetoxy-1,2-benziodoxol-3-(1H)-one (BIOAc) as the oxidant and TFA as an acidic additive for optimal yields with the reactions being run in CH2Cl2/water at room temperature with 36 W blue LED irradiation and a Ru-based photocatalyst. A range of pyridine N-oxides could be transformed with ortho-, meta-, and para-substitution all tolerated, and a range of functional groups (ether, amide, etc.) compatible with the reaction conditions. Other N-containing heterocycles could also be employed, while a range of functional groups (halide, cyano, etc.) also tolerated on the alkyltrifluoroborate. The methodology was applied to the synthesis of the antifungal agent, ciclopirox. Radical trapping and completion reaction studies indicate that the reaction proceeds through a SEAr mechanism, while kinetic isotope measurements suggest that the C−H bond cleavage is not the rate-determining step with the quantum yield indicating a chain reaction.

C−H Functionalization of aliphatic amine derivatives represents a powerful methodology for the rapid assembly of potentially bioactive molecular scaffolds. Gaunt and He have reported on a synthesis of complex pyrrolidines via a cascade C−H alkenylation, aza-Michael addition of differentially substituted morpholinones (Chem. Sci. 2017, 10.1039/c7sc00468k). Stoichiometric studies on the palladation of these substrates indicated an intriguing ligand-based (with a protected aminoacid being employed as the ligand) effect in which addition of a ligand to the system channels the ligand to the 5-membered palladacycle as opposed to the favored 4-membered palladacycle in the absence of the ligand. The use of AgOAc as a stoichiometric oxidant with catalytic Pd(OAc)2 and ligand in HFIP in the presence of acrylate led to exclusive formation of the desired pyrrolidine derived from the 5-membered palladacycle strongly suggesting the reversibility of the palladacycle formation under ligand-mediated conditions with the product acting as a kinetic trap for the reaction. Scope studies demonstrated that a wide range of α,α′-morpholinones were successful substrates with high regio- and diastereo-selectivity being observed and a range of remote functional groups also tolerated. In cases in

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THREE-COMPONENT ONE-POT REACTIONS OF 2-TRIFLUOROMETHYL-N-NOSYLAZIRIDINE, PRIMARY AMINES, AND VINYLSULFONIUM SALTS FOR CONVENIENT ACCESS TO CF3-CONTAINING PIPERAZINES Piperazine derivatives are the third most-common nitrogencontaining heterocycle in FDA-approved drugs today, while the beneficial effects of fluorine substitution on biological activity, and both chemical and metabolic stability have been welldocumented. Hanamoto and co-workers from Saga University G




could be replaced by other electron-rich heterocycles such as pyrroles and thiophenes, while the variation of the aldehyde enables both indole-benzothiophenes and indole−indoles to be accessed.

have reported on a facile regioselective substitution of CF3containing piperazines exploiting the highly regioselective ringopening of 2-trifluoromethyl-N-nosyl aziridine by primary amines under neutral conditions (Synthesis 2017, 10.1055/s0036-1558963). This reaction is thermally promoted and proceeds in near quantitative yield. To form the desired piperazines in a one-pot process, optimization studies involving the addition of a suitable two-carbon electrophile, a base, and a second solvent were carried out. Although no reaction was observed with 1,2-dibromoethane, a vinyl sulfonium salt proved to be the optimal electrophile with either EtOAc or acetone as solvent using K2CO3 as the base. From a scope perspective, the first step showed few limitations though the second cyclization step showed a sensitivity to both sterics (ortho-substitution inhibits the reaction) and electronics (electron-withdrawing groups retard the reaction) indicating the importance of the inherent nucleophilicity of the intermediate CF3-1,2-diethylenediamine. The report also demonstrated that the N-Ns bond could be easily cleaved under standard conditions.

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FOUR-COMPONENT SYNTHESIS OF PHOSPHONIUM SALTS: APPLICATION TOWARD AN ALTERNATIVE APPROACH TO CROSS-COUPLING FOR THE SYNTHESIS OF BIS-HETEROARENES There are a number of limitations of classical cross-coupling approaches, and in particular reactions involving a pair of heteroarenes still represent a considerable challenge. For this transformation, Lin and co-workers have reported on a novel alternative which utilizes the intermediacy of phosphonium salts to promote the formal coupling reaction (Angew. Chem., Int. Ed. 2017, 56, 5106). Initially, the synthesis of these salts is developed through a model four-component reaction of N-methylindole, salicylaldehyde, an acid, and a phosphine. These studies indicated that triflic acid or HBF4 in THF were the best acids, with acetonitrile leading to a slight enhancement of rate. Numerous phosphines worked well, but PBu3 proved optimal in the crosscoupling step. Crucially, the addition sequence was important to avoid the formation of byproducts with the sequential addition of the acid followed by the phosphine to a solution of the reagents proving to be best. A range of protected indoles as well as substituted salicylaldehydes were successfully utilized though tosyl-protection on the indole shut down the reaction due to reduced nucleophilicity. The treatment of the phosphonium salts with an acyl chloride in the presence of base (DBU) led to the formation of indole-benzoxazoles through an acylation/ intramolecular Wittig reaction. Further studies showed the indole

MULTICOMPONENT REACTIONS WITH CYCLIC TERTIARY AMINES ENABLED BY FACILE C−N BOND CLEAVAGE

Multicomponent reactions (MCRs) represent an efficient method to rapidly assemble relatively complex structures from simple starting materials. Key to the success of such a reaction is the identification of an active intermediate species, which can react further to trigger several multiple bond formations with a number of discrete reactants. Zhu, Huang, and co-workers have developed an MCR, which employs a cyclic tertiary amine as the H




challenges stemming from their intermediate size: they have historically been treated on a case-by-case basis as to whether regulations for small molecules or biologics are more appropriate. Considerations when evaluating the qualities of amino acid monomers, reagents, and solvents and control strategies for coupling, deprotection, cleavage from a resin, and postcleavage workups are all described, as are factors that can affect the API quality during secondary manufacture. Establishing linkages between material attributes and process parameters whose variation affects the critical quality attributes of the drug substance and product is supported. The authors finish by concluding that peptide products should be developed using a risk-based approach commensurate with the complexity of the product and that they will be assessed on a case-by-case basis. The article contains 154 references.

pivotal reagent, which after reaction with a (hetero)aryl halide undergoes facile C−N bond cleavage to initiate the cascade reaction (Angew. Chem., Int. Ed. 2017, 56, 5101). Model studies on the reaction of 2-bromopyridine with DABCO and Na2S in a three-component process demonstrated that DMSO was the optimal solvent at a temperature of 120 °C with none of the potential diaryl thioether byproduct being observed. Under these conditions, a range of heterocycles were also demonstrated as successful substrates. To further increase the utility of the reaction was extended to a four-component process utilizing both a (hetero)aryl halide, which undergoes the initial reaction with DABCO as well as an electron-deficient aryl halide, which forms the thioether in situ to subsequently react with the activated intermediate through C−N bond cleavage. Fine-tuning of the electrophilicity of the reacting (hetero)aryl species was shown to be crucial in a one-pot process, though if a substantial difference in reactivity was observed, the desired product could be obtained through a two-step sequential process involving premixing of a reactant with Na2S. Utilizing this approach, the product structure could be controlled through addition order of the reagents. Other cyclic tertiary amines were also demonstrated as successful reagents, and the reaction was extended to phenolates as nucleophiles in the three-component process. Preliminary mechanistic studies confirmed the intermediacy of the thiolate species, and the reaction demonstrated for the onepot synthesis of the analgesic ruzadolane.

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DESIGN OF EXPERIMENTS (DOE) IN PHARMACEUTICAL DEVELOPMENT The role that a Design of Experiments (DoE) approach can play in the development of a pharmaceutical product using the principles of Quality by Design has been reviewed (Drug Dev. Ind. Pharm. 2017, 10.1080/03639045.2017.1291672). The different phases that need to be considered as part of the planning and execution of a DoE are described, together with a general series of experimental tips. Examples of mixture and factorial designs performed in a pharmaceutical development setting are worked through. The article contains 70 references.

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CONTAINMENT CHALLENGES IN HPAPI MANUFACTURE FOR ADC GENERATION The payloads of antibody−drug conjugates are high potency APIs (HPAPIs) (Drug Discov. Today 2017, 10.1016/j.drudis.2017.02.003). A recent article commissioned by Pfizer provides an overview of considerations, regulatory guidelines, and in-house practices that protect both operators and the environment during the manufacture of a payload, its conjugation, analytical activities, and the disposal of waste streams. Since manufacturers have hitherto been allowed to selfregulate themselves when establishing an appropriate level of containment, they have each adopted different containment classification systems for their payloads. Details of the categories used by SafeBridge, Lonza, Merck, Alkermes, SAFC, and Carbogen Amcis are provided. A successful containment strategy is described as considering: (i) occupational hygiene monitoring, (ii) staff training, (iii) site safety culture, (iv) continuous improvement, and (v) engineering controls. A manufacturing control strategy that uses process analytical technology where possible is advocated in order to avoid unnecessary sampling and operator exposure. The risk of cross-contamination in a multipurpose facility that handles payloads is a concern due to their potency. In the absence of specific regulatory guidance for HPAPIs, existing regulatory guidance is provided on the topic of API cross-contamination in manufacturing facilities.

MEASUREMENT AND ACCURATE INTERPRETATION OF THE SOLUBILITY OF PHARMACEUTICAL SALTS Accurately evaluating the solubility of a salt can be challenging due to solid state phase transformations in the material that remains out of solution and the potential of the dissolved species to alter the solution pH (J. Pharm. Sci. 2017, 10.1016/ j.xphs.2017.01.023). As a result, the correct interpretation of measurements of the solubility of a salt relies on an appropriate experimental design, understanding the kinetics, accurate measurements of pH and concentration, and the analysis of the form of the material that remains out of solution. A review by authors from Sanofi and Prescient discusses the experimental complexities associated with the measurement of salt solubilities, techniques that improve experimental data quality and detect changes in the solid phase, and illustrates the how best to interpret salt solubility data. The authors recommend the development of a harmonized approach for reporting salt solubility measurements given that it is often not clear if such data refer to the salt itself or the active moiety. The review contains 55 references.

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BIOPRIVILEGED MOLECULES: CREATING VALUE FROM BIOMASS Authors from Iowa State University have produced a perspective article on what they are describing as bioprivileged molecules (Green Chem. 2017, 10.1039/c7gc00296c). These are intermediates derived from biomass that can be converted into chemicals with multiple downstream applications, including some that are currently derived from petrochemicals. The authors point out that understanding the target applications arising from the derivatization of a candidate molecule is vital for understanding if it is truly bioprivileged or not. Muconic acid, 5-hydroxymethylfurfural, and triacetic acid lactone are proposed as bioprivileged molecules and disparate products arising from their diversity-oriented downstream processing are provided.

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BUILDING PARITY BETWEEN BRAND AND GENERIC PEPTIDE PRODUCTS: REGULATORY AND SCIENTIFIC CONSIDERATIONS FOR QUALITY OF SYNTHETIC PEPTIDES The FDA’s Centre for Drug Evaluation has summarized the different aspects of quality that are relevant to the development, manufacture, and regulatory assessment of peptidic pharmaceutical products (Int. J. Pharm. 2017, 518, 320). The authors point out that bringing a peptide to market creates regulatory I



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GREENING OF PEPTIDE SYNTHESIS Researchers from the University of York have found that propylene carbonate, a nontoxic, comparatively cheap, and nonhygroscopic material, is a potential replacement for reprotoxic DMF as part of the coupling step of solution and solid phase peptide syntheses (Green Chem. 2017, 10.1039/C7GC00247e). No significant racemization of the activated amino acid coupling partners is observed. While a standard Merrifield resin did not swell adequately in the solvent, a cross-linked polyethylene glycol was able to be used for work on a support. The utility of this solvent for a multistep peptide synthesis is demonstrated with the preparation of the nonapeptide bradykinin in a similar purity to material prepared using DMF as solvent. Coupling transformations apart, the utility of propylene carbonate as solvent when removing an N-terminal protecting groups so as to allow a subsequent chain elongation is also demonstrated.

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product. One drawback to the reported protocol is the requirement of a relatively high catalyst loading; nonetheless, it replaces existing stoichiometric intramolecular reactions and provides a starting point for the catalytic development of related transformations.

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SYNTHESIS OF 3-SUBSTITUTED 2-ARYLPYRIDINES VIA Cu/Pd-CATALYZED DECARBOXYLATIVE CROSS-COUPLING OF PICOLINIC ACIDS WITH (HETERO)ARYL HALIDES

CATALYTIC ASYMMETRIC DIAMINATION OF STYRENES

The preparation of 2-aryl-3-fluoropyridine via decarboxylative cross-coupling reaction has been very challenging despite the advantages of stability, atom-economy, and the readily availability of the carboxylic acids as coupling partners. A collaborative work by L. J. Goossen et al. at Ruhr University in Germany and the Pfizer group in Groton, USA (J. Org. Chem. 2017, 82, 3917) have reported a decarboxylative Cu/Pd-catalyzed cross-coupling of 3-substituted picolinic acid with (hetero)aryl halides. The team carried out a systematic experimentation and discovered optimal conditions for the reaction. The use of Pd(COD)Cl2 (5 mol %), DavePhos (15 mol %), and Cu2O (5 mol %) in DMSO at 130 °C provided a wide range of reactivity with various substituted aryl bromides and chlorides. The chloro-substituted substrate, in general, gave lower yields compared to the aryl bromides. However, the greater structural diversity of chlorides coupled with their generally being less expensive commercially than their bromide counterparts, provides more utility to the reported protocol. In addition, modified conditions were necessary for other less reactive substrates such as 3-methoxy- and 3-unsubstituted-picolate. Likewise, picolinic acids that were substituted at the 4-, 5-, and 6-positions were unreactive to the standard conditions. Nonetheless, the protocol gives convenient access to 3-substituted arylpyridines, which provide synthetic hubs for further derivatization.

Metal-catalyzed asymmetric vicinal diamination reactions suffers from the strong binding affinity of the diamine product to the metal center, which deactivate the catalyst and renders the process noncatalytic in the metal center. To circumvent this problem, Muñiz and co-workers (J. Am. Chem. Soc. 2017, 139, 4354) have reported an enantioselective catalytic vicinal diamination of styrenes, catalyzed by iodine(I/III) reagent, and 3-chloroperbenzoic acid (m-CPBA) as a terminal oxidant. The use of m-CPBA maybe unattractive at first sight; however, the combination with nonchlorinated solvents renders the process more benign and attractive. After establishing the optimal conditions for the reaction, the group explored 30 styrene cores with different substitution patterns. The unprecedented intermolecular difunctionalization reaction resulted in 40−87% isolated yields, high asymmetric inductions (91−98% ee), and included the challenging internal alkene substrates. The team proposed the generation of a chiral bissulfonimide−iodine(III) center, which efficiently differentiates the enantiotopic face of the styrene substrate. Enantioselective monoamination was followed by a cyclic sulfonimide intermediate, which forms the second C−N bond via nucleophilic ring opening of the cyclic intermediate that eventually gives the desired diaminated

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DEVELOPMENT OF A PALLADIUM-CATALYZED TANDEM ADDITION/CYCLIZATION FOR THE CONSTRUCTION OF INDOLE SKELETONS The Fischer indole synthesis, discovered over a 130 years ago, has undergone many impressive modifications due in part to the wide range of targets containing the indole structure including therapeutic agents, bioactive natural and synthetic products, and other functional molecules. Wu and co-workers (J. Org. Chem. J




2017, 82, 3631) have reported the first palladium-catalyzed tandem addition and subsequent intramolecular cyclization of 2-(2-aminoaryl)acetonitriles with arylboronic acids, for the direct construction of 2-substituted indole skeletons. The inherently inert nature of the aliphatic acetonitriles has limited their use in metal-catalyzed reactions. This protocol, on the other hand, provided sufficient activation of the aliphatic nitriles, which led to good functional group tolerance, and remarkable chemoselectivity. However, very bulky substituents such as 2,6-dimethylphenylboronic acid afforded lower yields. In addition, strongly electron-withdrawing groups such as trifluoromethyl and acetyl, afforded decreased yields of 29 and 47% respectively. Aryl boronic acids with moderate electron-withdrawing substituents such as halogens, gave slightly higher yields of product. The group proposed a plausible mechanism; transmetalation between the Pd(II) catalyst and arylboronic acid leads to a Pd-aryl species, which activate the nitrile followed by intramolecular carbopalladation. The ketimine or ketone intermediate formed, subsequently cyclized to afford the desire indole product.

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protocol, commencing with a photooxygenation of the readily available furan substrates, followed by the treatment with Me2S and primary amines. The intermittent 2-pyrrolidinone serves as an electron rich dienophile, which undergoes an inverse electrondemand hetero-Diels−Alder reaction with the electron poor α,β-unsaturated enones. The proposed concerted [4 + 2] cycloaddition, possibly driven by the relief of ring strain on the pyrrolidinone, was followed by acid-catalyzed rearrangement which gave the tetrahydropyranopyrrolone (THPP). Exposure of THPP to Brønsted acids such as TFA at room temperature afforded up to 81% yield of the diene. On the other hand, exposure to reductive condition such as Et3SiH and TFA, afforded the fully saturated THPP product in 67−73% yields with high diastereoselectivity. Furthermore, the reductive condition of BF3·OEt2 and Et3SiH gave the cis-fused THPP in 62−73% as a single diastereomer.

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OLEFINATION WITH SULFONYL HALIDES AND ESTERS: SCOPE, LIMITATIONS, AND MECHANISTIC STUDIES OF THE HAWKINS REACTION

ONE-POT TRANSFORMATION OF SIMPLE FURANS INTO OCTAHYDROINDOLE SCAFFOLDS

There have been many modification to the Julia olefination; however, very few reports exist on the use of nonstabilized carbanion precursors. Barbasiewicz and et al. (Org. Lett. 2017, 19, 1756) have reported the olefination of carbanions of alkanesulfonyl halides and esters, with nonenolizable carbonyl compounds. Preliminary investigation on the character of the leaving group, found that trifluoroethoxide was superior to chloride, and the nature of the leaving group influences both the carbanion stability and the rate of olefination. Various aliphatic aldehydes with electron-donating group afforded the corresponding alkenes in high yields (65−85%). However, the presence of acceptor groups such as o-Br and p-CF3 led to significant decreased in yields. A plausible mechanism involves a pentacoordinated sulfur intermediates, which can be stabilized by an electronegative ligand at the apical position. The group demonstrated the scalability of the protocol by carrying out a large-scale olefination on a 100 mmol scale, using commercial starting material, and the relatively cheaper lithium tert-amoxide instead of t-BuOLi.

Vassilikogiannakis and co-workers from the University of Crete (Angew. Chem., Int. Ed. 2017, 56, 4020) have reported a one-pot innovative methodology that synthesize diverse array of tetrahydropyrano-pyrroles and di- and hexa-hydroindolones. These molecules were constructed using the highly efficient K



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ENANTIOSELECTIVE PALLADIUM-CATALYZED CARBENE INSERTION INTO THE N−H BONDS OF AROMATIC HETEROCYCLES

In a drug discovery program, the nature of productive interactions with the binding pockets on protein surfaces constitutes wide range of interactions via hydrophobic contacts to hydrogen bonds. A very important class of compounds are those with rotatable bonds in either linear or hub scaffolds, capable of interacting with the grooves of protein/binding surfaces. However, the construction of the “hub” scaffolds in a simple and regiochemical fashion utilizing readily assessable reagents continue to be challenging. To address these problems, Yudin and co-workers (Angew. Chem., Int. Ed. 2017, 10.1002/ anie.201611006) have reported a flexible approach to synthesize the hub-based scaffolds using oxalyl MIDA (N-methyliminodiacetic acid) boronates. The simple protocol merged the boronate and the diketone functionalities in the same molecule. The aromatic and aliphatic oxalyl boronates were prepared from the corresponding vinyl MIDA boronates by dihydroxylation and oxidation. When the oxalyl boronates where exposed to NH4OAc, and benzaldehyde in the presence of acetic acid, they were smoothly converted to the corresponding 2,4,5trisubstituted borylate imidazoles. Standard cross-coupling conditions with aryl bromides afforded the densely functionalized imidazoles. One major drawback to the protocol was the significant protodeboration byproducts. However, the protocol was utilized to rapidly synthesize a series of serine/threonineprotein kinase 10 (STK10). These kinases are well-known drug targets due to their roles in regulating cellular and pathological functions.

Chiral C3-substituted indoles and carbazoles are commonly assessed via challenging and inefficient substitution reactions, chiral resolution, enantioselective reductive amination and so forth. Van Vranken and co-workers (Angew. Chem., Int. Ed. 2017, 56, 4156) have reported the first example of palladium-catalyzed carbene insertion into the N−H bonds of aromatic heterocycles using α-aryl-α-diazoesters as palladium carbene precursors, and chiral bis(oxazoline)-ligand, affording high enantioselectivity (up to 99% ee). The group demonstrated the sensitivity of the diazo compounds to electronic factors. While electron-donating groups accelerated the reaction; electron-withdrawing groups, on the other hand, slowed the reaction significantly. In addition, the indole substrates gave lower ee compared to the carbazole substrates. Furthermore, other heterocycles with sp2 lone pairs such as imidazole, indazole, and pyrazole were poor substrates for the reaction conditions. Nonetheless, the method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.

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SYNTHESIS OF 1,5-BENZOAZASILEPINES

OXALYL BORONATES ENABLE MODULAR SYNTHESIS OF BIOACTIVE IMIDAZOLES

Doye and co-workers from Oldenburg, Germany, have recently disclosed their findings on the synthesis of 1,5-benzoazasilepines (Chem. Eur. J. 2017, 23, 4197). This work builds upon their previous reporting of a one-pot methodology to access 1,5-benzodiazepines (Chem. Eur. J. 2017, 23, 1237), of which the privileged scaffold has been utilized in a number of important pharmaceuticals. Initially, the group show that allylsilanes undergo a regioselective, intermolecular alkene hydroaminoalkylation with secondary amines catalyzed by 10 mol % of titanium mono(formamidinate) complex while heated to 140 °C for 24 h. The reaction was shown to tolerate alkyl, ether, and halide substitution on the aromatic ring; the latter of which presented an opportunity to exploit a Buchwald−Hartwig amination to access 1,5-benzoazasilepines. This was realized in a one-pot fashion affording 11 examples in yields ranging from 47 to 84%. L



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ACCESSING CYCLOPENTADIENE DERIVATIVES THROUGH GOLD CATALYSIS

include mild reaction conditions, in which an alcohol is used as the reaction solvent and that O2 is used as oxidant, while warmed to 60 °C. Alternative oxidants were trialed, including TBHP and DTBP as suitable replacements, yet O2 proved optimum. Mechanistically, the reaction was proposed to proceed first through an imine (isolated in control experiments in 15% yield), while the gold was not thought to be playing a role in its formation. However, the authors show that the gold catalyst was crucial for the reaction between the isolated imine intermediate and styrene, generating the quinoline product. If oxygen was replaced for nitrogen, no product was observed, showing that oxygen is indispensable in their synthetic protocol.

Gold-catalyzed enyne cycloisomerizations have been welldocumented in the literature to date, and latest research from Huang and co-workers from Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences have expanded the scope of this strategy to access substituted cyclopentadiene derivatives (Chem. Commun. 2017, 53, 3745). The key feature of this article shows that strained cyclopropenes are activated in preference to alkynes, more specifically ynamides, by the gold catalysts. Optimization studies showed that one equivalent of ynamide and five equivalents of cyclopropene (excess required to prevent self-reaction side products), in acetonitrile, at 100 °C, in the presence of 5 mol % of gold(I) catalyst. The methodology tolerates modification of multiple positions with over 20 examples reported in yields up to 99%. Most interestingly, the mechanism was postulated to proceed through a gold-carbene formed through activation of the cyclopropene by gold(I); a cyclopropane product was isolated when styrene was added to the reaction mixture.

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CONSTRUCTION OF FUNCTIONALIZED AZA-BENZOBICYCLO[4.3.0] DERIVATIVES

The Huang group from Nankai University, China, have showcased the synthesis of structurally complex azabenzobicyclo[4.3.0] ring systems from 2-tosylamino chalcones and Morita−Baylis−Hillman (MBH) carbonates (Chem. Commun. 2017, 53, 3974). Triphenylphosphine was used as a stoichiometric reagent in the process; the procedure utilizes chloroform as the optimum solvent of choice while heated to 60 °C. The protocol proceeded well for over 20 examples, with yields reaching up to 94%; incorporation of a broad variety of both electron donating and withdrawing substituents across the scaffold was tolerated. The group successfully report a gram scale synthesis of bromo analogue 1 in 81% yield and highlight subsequent transformations on the privileged scaffolds including a tosyl deprotection, ester reduction, and palladium-catalyzed cross-coupling. With the aid of control experiments, the authors provide evidence of key intermediates that could be isolated after just 20 min. Moreover, deuterium labeling studies were conducted that support the postulated mechanism.

GOLD-CATALYZED CROSS-DEHYDROGENATIVE COUPLING

The groups of Feng and Zhang from Jiangnan University, China, have recently disclosed their findings of a goldcatalyzed dehydrogenative Povarov/oxidation tandem reaction (Adv. Synth. Catal. 2017, 359, 824). Their methodology has allowed access to a library of quinolines that incorporate functionalization at three key positions; reactions yields can reach up to 98% when only 5 mol % of gold(III) catalyst is employed in the reaction. The catalytic systems’ benefits M



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COBALT-CATALYZED C−H CARBONYLATIVE CYCLIZATION OF ALIPHATIC AMIDES

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]; [email protected]; [email protected]; [email protected].

The Gaunt group from Cambridge University, UK, have recently discovered a cobalt-catalyzed C−H carbonylation reaction to access substituted succinimides from aliphatic carboxamides under atmospheric carbon monoxide pressures (Chem. Sci. 2017, 8, 2588). The reaction utilizes earth abundant metals and is guided by a pyridyl-derived auxiliary. Over 15 examples are presented in yields ranging from 49 to 89%; those examples containing alkyl substituents were well-tolerated in the transformation. Substrates containing both an sp2 (phenyl) and sp3 (methyl) substituent showed a rare example of aliphatic C−H activation over traditionally more reactive sp2-hybridized C−H bonds. Other functionalities that were successfully incorporated include spirocycles, ester functionalities, and trifluoromethyl groups. A gram scale synthesis on their test substrate was realized without sacrificing product yield. The succinimide products were later ring-opened under three separate conditions to access useful derivatives.

Robert Ely Achaogen, Inc., 7000 Shoreline Ct. #371, South San Francisco, California 94080, 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

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

David Philip 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

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

Antonio Ramirez N


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