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

Highlights from the Literature pubs.acs.org/OPRD

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

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GENERATION AND RING OPENING OF AZIRIDINES IN TELESCOPED CONTINUOUS FLOW PROCESS

with catalytic base such as NaOEt or KHMDS, presumably forms a double-deprotonated monoanionic Co(I) complex that provides superior conversion and selectivity for the primary amine. The primary amine is generated in excellent yields for arenes with electron-donating groups at 135 °C under 30 bar of H2 pressure. The use of benzene resulted in the cleanest reaction, while solvents such as toluene, THF, and 1,4-dioxane provide similar yields but with slightly higher amounts of secondary amine. Arenes with electron-withdrawing groups in the para-position resulted in poor yields and furnish higher amounts of the secondary amine. Halides, ethers, amines, and trifluoromethyl groups were all tolerated, while a para-nitro group shut down the reaction. Two examples of the reduction of arenes with ortho-substitution and one pyridine substrate were reported in excellent yields. More challenging benzyl and alkyl nitriles proved to be good substrates, providing the primary amine products in good-toexcellent yields.

Aziridines are powerful building blocks in organic synthesis because of their efficiency as an electrophile, but their high reactivity makes them possible cytotoxins. Shipman and co-workers at the University of Warwick have described a flow process for the generation and opening of aziridines starting from amino alcohols that circumvents the isolation of the reactive material (Org. Lett. 2015, 17, 3632). The formation of aziridines via a twoinput flow process, followed by isolation, was demonstrated with tosyl (Ts), methanesulfonyl (Ms), and 4-nitrobenzenesulfonyl (Ns) groups using the sulfonyl chloride. Triethylamine (4.5 equiv) with DMAP (0.5 equiv) was generally used, except for N-Ms derivatives where DBU with methanesulfonyl anhydride was more successful. To avoid reactor blockages, chloroform was used as solvent to keep the formed hydrochloride salt in solution. To reduce reaction time, larger quantities of reagents and slightly elevated temperatures (30 °C) were used. Ring opening of the aziridines with oxygen-, fluoride-, chloride-, and carbon-based nucleophiles was also achieved under flow conditions in goodto-excellent yields. Importantly, the formation and opening of the aziridines could be done without isolation of the aziridines, using a three-input microreactor. The use of the sulfonic acid anhydrides with DBU gave the best results, requiring only 16 and 12 min residence times for the aziridine formation and ring opening, respectively.

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There are many excellent transition-metal catalyzed methods for the synthesis of aryl sulfides; however, there are far fewer reports of metal-free sulfenylations. Cossy and co-workers at the Institute of Chemistry, Biology, and Innovation (CBI) in France have described a metal-free sulfenylation of electron-rich arenes using N-thiosuccinimides as electrophilic sulfur sources (Org. Lett. 2015, 10.1021/acs.orglett.5b01889). The sulfenylating reagent is synthesized and isolated after reaction of an aryl or alkyl thiol with sulfuryl chloride and base, followed by addition of succinimide and base. The reagent reacts with electron-rich arenes in a regioselective manner that is in accord with electrophilic aromatic substitution, in the presence of TFA (15 equiv) at rt. Dropping the TFA equivalents slowly (5−10) results in similar yields, but no product is observed with only one equivalent of TFA. Oxygen or carbon substitution on the arene nucleophile is required for good yield. Halide substitution is tolerated, but electron-withdrawing groups either dramatically lower the yield or shut down the reaction completely. Examples of both alkyl and aryl N-thiosulfinimides are reported.

SELECTIVE HYDROGENATION OF NITRILES TO PRIMARY AMINES CATALYZED BY A COBALT PINCER COMPLEX

Catalytic reduction of nitriles to primary amines is an attractive method due to the availability of starting materials, high atom efficiency, and the possibility of high selectivity for the primary amine. While several heterogeneous catalytic systems are known, homogeneous systems require precious metals, except for a recent Fe-catalyzed report from the Beller lab. A welcomed addition comes from Milstein and co-workers at the Weizmann Institute of Science who have reported the first homogeneous Co-catalyzed hydrogenation of nitriles to primary amines (J. Am. Chem. Soc. 2015, 137, 8888). The PNNH ligand, that along © XXXX American Chemical Society

SYNTHESIS OF ARYL SULFIDES: METAL-FREE C−H SULFENYLATION OF ELECTRON-RICH ARENES

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DOI: 10.1021/acs.oprd.5b00266 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Highlights from the Literature

HYDROXYL-DIRECTED CROSS-COUPLING: A SCALABLE SYNTHESIS OF DEBROMOHAMIGERAN E AND OTHER TARGETS OF INTEREST

promotes the oxidative addition of Selectfluor. One difference between this report and Yu’s is the addition of catalytic Fe(OAc)2. The iron additive drastically increases the yield, presumably aiding in catalyst turnover, and could explain the lack of need for a bulky ligand for palladium as required in the Yu report. Also, the amide-directing group, 2-(pyridine-2-yl)isopropyl amine (PIP), was chosen since the more commonly used 8-aminoquinoline directing group did not promote the coupling. A variety of amino acid derivatives, as well as nonamino acid aliphatic amides, were demonstrated, including substrates with aryl halides, phthalimides, and nitro groups. Importantly, the reaction is very site-selective, only fluorinating the β-position even in the presence of more acidic benzylic γ-C−H bonds.

Alkene diboration provides useful intermediates for organic synthesis, especially as new methods to selectively manipulate alkyl boronates are discovered. Blaisdell and Morken of Boston College have described a β-hydroxyl-directed Suzuki−Miyaura cross-coupling of 1,2-bis(boronate) species that is site-selective for the proximal boron, increasing the utility of alkene diboration products (J. Am. Chem. Soc. 2015, 137, 8712). Directed crosscoupling only occurs when boron is β to the hydroxyl group. Diborylated products of α- or γ-hydroxyl olefins result in selective cross-coupling of the terminal boron for steric reasons. The data suggest the formation of a substrate-derived Pd(alkoxide), followed by an inner-sphere stereoretentive transmetalation that ultimately provides the 1,3-syn relative stereochemistry. Starting from a homoallylic alcohol, metal-free directed diboration and Pd-catalyzed directed cross-coupling, followed by silyl or acetate protection, can be accomplished in a one-pot operation. Aryl, heteroaryl, and alkenyl halides or triflates are well-tolerated as cross-coupling partners, as are terminal, internal, and trisubstituted alkenes as diboration substrates. The solvent combination of THF/toluene/H2O is important to minimize elimination byproducts. The tandem directed diboration/cross-coupling was used to prepare two pharmaceutically relevant intermediates as well as the natural product debromohamigeran E.

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TRANSNITRILATION FROM DIMETHYLMALONONITRILE TO ARYL GRIGNARD AND LITHIUM REAGENTS: A PRACTICAL METHOD FOR ARYL NITRILE SYNTHESIS

The installation of cyano functional groups is a common obstacle in the pharmaceutical industry because of the safety concern with using highly toxic cyanide salts on a large scale, and the lack of commercial availability of many of the cyanide reagents. Much progress has been made with transition metal catalyzed cyanations, but the binding affinity of cyanide makes reaction stalling due to catalyst poisoning a risk. Reeves and co-workers at Boehringer Ingelheim Pharmaceuticals have developed the use of dimethylmalononitrile as an effective reagent for cyanation of aryl Grignard and aryllithium reagents (J. Am. Chem. Soc. 2015, 137, 9481). The reagent is a commercially available, bench stable solid that is less toxic than other commercially available cyanide sources. The reagent reacts with aryl Grignard or lithium nucleophiles under mild conditions and releases isobutyronitrile as a byproduct. A range of aryl Grignard substrates, either commercially available or generated in situ, reacted efficiently with the reagent, including substrates with esters, amides, amines, ethers, thioethers, halides, and several heterocylces. Importantly, the reaction also works with sterically hindered substrates under the same mild conditions. Lithiated nucleophiles, either generated from lithium-halogen exchange or directed ortho-lithiation, worked as efficiently as the Grignard nucleophiles.

PALLADIUM-CATALYZED SITE-SELECTIVE FLUORINATION OF UNACTIVATED C(sp3)−H BONDS

The Pd-catalyzed ligand-directed C−H functionalization of unactivated β-sp3 carbons of amides has become an increasingly popular method to functionalize amino acid and aliphatic acid derivatives. The challenging introduction of fluorine to these sp3 carbons has only been recently achieved recently by Yu at Scripps and in this highlight by Ge and co-workers at Purdue University (Org. Lett. 2015, 10.1021/acs.orglett.5b01710). Similar to the work by Yu, Ge’s method utilizes Selectfluor as the fluorine source and silver carbonate as an additive. No product was observed with other fluorine sources or in the absence of a silver source. The exact role of silver is not known, but it is speculated that it acts as a base, aiding in C−H abstraction, and/or B



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REGIOSELECTIVE CONTROL OF THE SNAR AMINATION OF 5-SUBSTITUTED2,4-DICHLOROPYRIMIDINES USING TERTIARY AMINE NUCLEOPHILES


PALLADIUM-CATALYZED ARYLATION OF FLUOROALKYLAMINES

Anilines present issues within medicinal chemistry due to their propensity for oxidation, which can be mitigated by substitution with electron-withdrawing groups. In this regard, fluoroalkylsubstituted anilines are attractive, though have not been widely studied as there are only limited methods to access this structural motif. Hartwig and Brusoe have reported on a general Pdcatalyzed reaction to access these molecules directly from the trifluoroethylamine and the aryl halide (J. Am. Chem. Soc. 2015, 137, 8460). Key to the development of the reaction was the selection of KOPh as the base with the realization that the desired products could be decomposed with stronger bases. Given that KOPh is not a typical base for C−N bond forming reactions, a series of ligands were evaluated, and it was found that sterically hindered monophosphine ligands (AdBippyPhos) were able to successfully mediate the coupling with extremely low loadings (0.05 mol % Pd/0.2 mol % ligand). Typically, Pd/ligand ratios of 1:2 enabled lower loadings of catalyst to be used. In addition, it was shown that, although KOPh is not widely commercially available, the reaction worked in an identical manner when the base was generated in situ from phenol and KOtBu. A wide range of aryl halides (chloride or bromide) were successfully transformed under the standard conditions with good functional group tolerance being displayed, though some variation of ligand was required to obtain optimal yields, particularly for sterically encumbered systems. Heteroaryl halides were also successful substrates though five-membered rings and systems containing acidic N−H groups did not react under the reaction conditions. The reaction could also be extended to a range of different fluoroalkylamines including both enantiopure branched and cyclic systems which react without any erosion of optical purity. Further derivatization of the coupled products through C−N bond formation (at ambient temperature to avoid base-promoted decomposition) is also demonstrated. Detailed mechanistic and kinetic analyses are also provided showing the resting state of the catalyst to be [(tBuBippyPhos)Pd(Ar) (OPh)], which is unique for the coupling to form an arylamine.

SNAr reactions of halopyridimines offer diverse options for the preparation of densely functionalized biologically active compounds, and as such methods which offer predictable substitution patterns for what might otherwise be difficult to access compounds are of significant value to the medicinal chemistry community. Mobashery and co-workers have reported on the regioselective amination of a variety of 5-substituted (nitro, cyano, trifluoromethyl)-2,4-dichloropyrimidines using tertiary amine nucleophiles (J. Org. Chem. 2015, 10.1021/ acs.joc.5b01044). The reaction of 2,4-dichloro-5-nitropyrimidine with diethylamine under standard conditions predominantly led as expected to the 4-substituted pyrimidine derivative. Utilizing trimethylamine under the same reaction conditions gave a 91% yield of the 2-substituted derivative with the N-dealkylation taking place from a cationic quaternary amine intermediate presumably involving the liberated halide. None of the 4-substituted or the 2,4-disubstituted amine products were detected by NMR. The product structures were indisputably confirmed by NMR and X-ray crystallography. The scope of the reaction was evaluated using 14 trialkylamines with yields of the 2-amino product ranging from 25 to 91% with general C-2 regioselectivity being observed. It is important to note that the products in themselves are potentially reactive compounds, and as such efficient purification and prompt use in subsequent reactions is advised. For unsymmetrical trialkylamines, the trend emerges that the smaller N-alkyl group is typically lost in the dealkylation reaction though this is not strictly adhered to, particularly when a benzyl group is present and is preferentially cleaved, or in some cases where a pyrrolidine ring is present in the incumbent nucleophile and ring cleavage occurs instead. Sterically encumbered trialkylamines are unsuccessful in this chemistry. The reaction is further extended to the 5-cyano- and 5-trifluoromethyl-substituted pyrimidines, and the utility of the methodology demonstrated through the concise-syntheses of several biologically relevant compounds. C



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P2Et PHOSPHAZENE: A MILD, FUNCTIONAL GROUP TOLERANT BASE FOR SOLUBLE, ROOM TEMPERATURE PALLADIUM-CATALYZED C−N, C−O, AND C−C CROSS-COUPLING REACTIONS


CHLOROFORM AS A CARBON MONOXIDE PRECURSOR: IN OR EX SITU GENERATION OF CO FOR PALLADIUM-CATALYZED AMINOCARBONYLATIONS

Despite its significant utility as a synthetic building block in organic synthesis, the routine use of carbon monoxide (CO) is still uncommon on laboratory scale due to the hazards associated with the gas. Several surrogate reagents have been developed for the in situ generation of CO, though these often suffer drawbacks such as harsh reaction conditions to generate the gas or the high cost of the precursors utilized. Gockel and Hull have exploited the use base-mediated hydrolysis of chloroform to achieve this transformation recognizing that for this method to be synthetically practical, the hydrolysis has to both be rapid, and mediated by a heterogeneous base (Org. Lett. 2015, 17, 3236). Initial focus on the hydrolysis reaction indicated that CsOH was the optimal base with the analogous Li, Na, and K bases all performing significantly worse. Combining this procedure with a Pd-mediated aminocarbonylation indicated that this was an effective method for the in situ generation of CO and the reaction was both scaled to 10 mmol and utilized for 13C labeling through the employment of isotopically enriched 13CHCl3. A range of aryl and heteroaryl halides were successfully employed in the reaction with electronrich anilines providing higher yields than their electron-poor counterparts. The reaction showed good functional group tolerance and was demonstrated for several pharmaceutically relevant substrates, though yields were shown to deteriorate with steric hindrance around the aryl halide. Dichlorocarbene is a known intermediate in the hydrolysis of chloroform, and a series of model reactions were performed to demonstrate that this intermediate is short-lived under the reaction conditions, and as such does not participate significantly in side reactions.

Improvements in Pd-mediated cross-coupling reactions over the past two decades have largely focused on enhanced reactivity of the ligand systems enabling milder conditions to be employed and consequently a wider tolerance in terms of substrate scope as well as the now commonplace use of Pd-precatalysts. In contrast, very little attention has been paid to the nature of the base, and typically strong inorganic bases are utilized, which leads to both issues with reproducibility linked to solubility as well as a limited substrate scope with regard to base-sensitive substrates. Workers at Merck have reported on the use of P2Et as a soluble base to promote these transformations (Org. Lett. 2015, 17, 3370). Initial investigations on a range of strong organic soluble bases in a series of Pd-mediated transformations indicated that P2Et showed higher reactivity than other bases and in conjunction with tBuXPhos and tBuBrettPhos G3 precatalysts showed strong reactivity across the range of nucleophiles evaluated in a diverse array of solvents. Furthermore, this reactivity was upheld with various electrophiles in both DMSO and t-amyl alcohol. Robustness tests were conducted with a variety of bases typically used for C−N coupling reactions as well as P2Et by carrying out the reaction in the presence of an aryl or alkyl ester. In the majority of cases, poor yields were observed with side reactions of the ester predominating, and although Cs2CO3 was observed to protect the ester, a diminished yield of the desired coupling product (41%) was obtained when compared to using P2Et as the base (97%). Further experiments showed clear advantages of utilizing this base in the synthesis of a pharmaceutical target containing base-sensitive groups and also illustrated the negative impact that heating can have on such complex substrates. A kinetic analysis of the range of organic bases investigated in this report confirmed the enhanced reactivity of the P2Et based system, and the authors postulate that in many cases, although the base (e.g., MTBD) can promote the catalysis, the reaction is inhibited by Lewis basic catalyst inhibition. In the case of P2Et and the hindered Pd−phosphine complex, this does not occur as a high level of steric congestion would result from the base binding to the catalyst. This hypothesis is to some degree confirmed by P2Et being unsuccessful with less sterically encumbered precatalyst systems.

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PHOTOREDOX CROSS-COUPLING: Ir/Ni DUAL CATALYSIS FOR THE SYNTHESIS OF BENZYLIC ETHERS

Exploitation of visible-light mediated photoredox catalysis for the controlled generation of radical species has led to a renaissance in the use of such species for C−C bond formation. Molander and co-workers have reported on a Ni-mediated method for the generation of benzylic ethers through the coupling of α-alkoxymethyl radicals with aryl-/heteroaryl-bromides (Org. Lett. 2015, 17, 3294). The radicals are generated in a facile fashion D




from α-alkoxymethyltrifluoroborates under Ir-catalysis and then investigated in a model coupling system. An extensive solvent screen was conducted with a focus on maintaining homogeneity throughout the reaction and a cosolvent system of dioxane and DMA (5:1) was identified as being optimal in terms of balance between reactivity and solubility. Early reactions were observed to stall presumably due to the generation of BF3 during the trifluoroborate oxidation, and this issue was mitigated through addition of K2HPO4. Evaluation of the potential catalysts/ligands led to the selection of NiCl2·dme/dttbbpy (owing to its low cost, superior performance in the model system and commercial availability) as the system to pursue in the evaluation of the scope of the reaction. From the aryl bromide perspective, a range of substrates were successfully coupled, though slightly depressed yields were obtained for electron-rich and sterically encumbered systems. Good functional group tolerance was observed including an aldehyde and an acetophenone-based substrate demonstrated on gram scale. A range of heteroaryl bromides were also effective substrates, though protection was required for systems such as indazoles and azaindoles. 5-Bromopyrimidine was selected as the model substrate to evaluate the scope of the α-alkoxymethyltrifluoroborate reagent, and a range of functionalized ethers were successfully incorporated including one featuring a PEG-like linker. Several also featured ether protecting groups enabling the facile preparation of benzylic alcohols without reductive sequences relying on the availability of the corresponding esters or aldehydes.

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increased. From a pharmaceutical perspective, trifluoromethylated carboxylic acids also provided the aniline coupling products in moderate yields. Control experiments to determine the mechanism indicate that the reaction is unlikely to proceed through an amide intermediate, which is subsequently reduced, and the methodology was further demonstrated for the metal-free syntheses of a series of three commercialized drug molecules.

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LIGAND-FREE COPPER-CATALYZED NEGISHI COUPLING OF ALKYL-, ARYL-, AND ALKYNYLZINC REAGENTS WITH HETEROARYL IODIDES

Despite the versatility of the Negishi coupling in constructing carbon−carbon bonds, alkylzinc reagents (due to their penchant for β-hydride elimination after transmetalation) and heteroaryl halides (due to their ability to bind to the catalysts in a competitive manner to the ligands) still present significant challenges as coupling partners. Giri and co-workers have reported on an alternative ligand-free, copper-mediated reaction protocol to overcome these issues (Angew. Chem., Int. Ed. 2015, 54, 8236). Model studies on the reaction of cyclohexylmethylzinc bromide with 7-chloro4-iodoquinoline indicated that 2 mol % of copper iodide in the presence of lithium chloride (1 equiv) in DMF led to almost quantitative conversion to the desired product after 3 h at room temperature. No product was obtained in the absence of CuI, while the use of LiCl is believed to generate a more reactive organozinc species thus overcoming a mild product inhibition effect observed in its absence. Only trace products are observed utilizing known Ni and Pd-based Negishi coupling systems, and other dipolar aprotic solvents can also be utilized for the reaction. Scope studies indicate that a wide range of primary, secondary, and tertiary alkylzinc reagents (including β-hydrogen atoms) can be effectively coupled with a range of iodides of nitrogen-containing heterocycles (pyridines, pyrazines, quinolones, etc., though no examples of 5-membered or heterocycles incorporating other heteroatoms are included). Excellent functional group tolerance is observed, and the protocol can be further extended to aryl- and alkynyl−zinc reagents if elevated temperatures are employed.

BORON-CATALYZED N-ALKYLATION OF AMINES USING CARBOXYLIC ACIDS

Typically, the alkylation of amines is achieved either through nucleophilic substitutions using hazardous alkyl halides or reductive aminations with air-sensitive aldehydes. Fu and coworkers have reported on a catalytic system for the N-alkylation of amines using stable, and readily available carboxylic acids as the alkylating reagents (Angew. Chem., Int. Ed. 2015, 10.1002/ anie.201503879). Their rationale was based on the ability of a boron-based catalyst to mediate efficient reductive C−N formation in the presence of a silane reducing agent in preference to direct reduction of the carboxylic acid. Optimization studies using N-methylaniline as the substrate with formic acid as the alkylating agent indicated that B(C6F5)3, which is capable of forming a frustrated Lewis pair (FLP) is the essential catalyst for the transformation with a variety of silanes being effective reductants with PMHS being preferred due to its low cost, environmentally friendly nature and stability. The effective nature of the specific catalyst is hypothesized to be due to its ability to form a FLP with carbonyl groups to activate the silane and thus induce reductive C−N bond formation. Catalyst loadings of 0.5−1 mol % were optimal with ethers and arenes shown to be suitable solvents. Under the optimal conditions, a range of N-alkylated anilines were successfully methylated with the reaction displaying both a good functional group tolerance and negligible effects based on the electronics of the aromatic ring. Heteroaromatic amines are also successful substrates, and in the cases of primary amines, it was shown that the degree of methylation can be controlled through tuning of the stoichiometry of the reagent. Various carboxylic acids were also demonstrated to be effective coupling partners, and in the case of primary amines as substrates, the amount of monoalkylation was shown to increase as the length of the carboxylic acid side chain

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[2 + 2] PHOTOCYCLOADDITION OF CINNAMATES IN FLOW AND DEVELOPMENT OF A THIOUREA CATALYST

Cyclobutanes can be found in a range of biologically active natural products and are most commonly accessed through a [2 + 2] E




organometallic species and preventing overalkylation and thus preserving the ketone oxidation state during the second organometallic addition. Initial studies focused on the addition of the first organometallic at −78 °C to provide the Weinreb amide, which in themselves are synthetically useful intermediates, and showed that both a range of lithiated- and Grignard-reagents (Grignard additions took place at 0 °C) were competent nucleophiles. Switching to the second addition at room temperature indicated that the nature of the second nucleophile does not strongly influence the overall ketone yield, though there are a couple of specific cases in which reversal of the order of organometallic addition has a significant effect on overall yield. Utilizing sp2-hybridized Grignard reagents as the first nucleophile leads to poor selectivity and adding a Grignard prior to an organolithium species inhibits the second reaction. With the optimal conditions in hand, the one-pot synthesis of a range of densely functionalized unsymmetrical diketones was demonstrated, and the methodology extended to telescoped syntheses and the synthesis of natural products. React IR studies were carried out to show the stability of the tetrahedral intermediate at depressed temperature and its controlled collapse upon warming.

photocycloaddition of cinnamic acid derivatives. Although this reaction is highly attractive from an atom-efficiency standpoint, challenges arise through competing olefin isomerization, and often only modest yields and selectivities of the desired products are obtained after extended reaction times. Beeler and co-workers have reported on an alternative approach utilizing a flow chemistry platform developed in their laboratory, which features a xenon(Hg) beam, filtered utilizing a range of filters focused on a cone reactor allowing even irradiation of the reaction (Angew. Chem., Int. Ed. 2015, 10.1002/anie.201504454). Highly efficient temperature control of the cone reactor can be achieved using a chiller as the FEP tubing sits in small grooves promoting heat transfer, and the photochemical setup can be easily modified to promote batch reactions in a vial, again with controlled cooling. Model studies on the [2 + 2]-photocycloaddition of methyl cinnamate indicated that control of the wavelength was crucial for optimum reactivity with a further small increase in efficiency being noted utilizing the platform in flow mode (29% conversion). To further promote the transformation, the authors postulated that a dual-hydrogen bonding catalyst may be capable of templating the two substrates and thus facilitate dimerization. This hypothesis led to the development of a thiourea-based catalyst, which under optimized flow conditions led to 76% conversion to the desired dimeric product accompanied by an increase in diastereoselectivity. Wavelength was again a crucial parameter, but unlike the uncatalyzed reaction, control of the power of the UV source was now also shown to have a significant effect, suggesting a potential triplet-sensitization process in the thiourea-mediated reaction. A series of NMR studies were carried out to probe the role of the thiourea catalyst, and the optimal reaction conditions were applied to a series of cinnamate derivatives with, in all cases, the thiourea-catalyzed reaction in flow leading to both higher conversions and enhanced diastereoselectivities.

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ONE-POT UNSYMMETRICAL KETONE SYNTHESIS EMPLOYING A PYRROLE-BEARING FORMAL CARBONYL DICATION LINCHPIN REAGENT

DESIGN OF NEW LIGANDS FOR THE PALLADIUM-CATALYZED ARYLATION OF α-BRANCHED SECONDARY AMINES

Although Pd-catalyzed carbon−nitrogen bond formation has become a powerful tool in organic synthesis, there are rare examples in which α-branched secondary amine nucleophiles have been successfully exploited in this methodology. Poor nucleophilicity due to steric hindrance leads to competing reactions with the alkoxide base being observed while β-hydride elimination for the intermediate PdII-amido complex leads to the oxidized amine. Buchwald and co-workers have reported on the rational design of ligands to facilitate this transformation (Angew. Chem., Int. Ed. 2015, 54, 8259). They hypothesized that use of ligands based on the CPhos scaffold featuring less electron-rich biaryl phosphines would not only be able to increase the rate of C−N reductive elimination but also increase the rate of transmetalation. Incremental ligand modifications led to the identification of a precatalyst (P7), which was able to promote C−N bond formation in a range of aryl systems. In some cases, excess amine needed to be used, and steric hindrance on the aryl halide led to slightly lower yields of the desired product with increased formation of the reduced arene. Switching to heteroaryl halides, which are important within the scope of pharmaceutically relevant substrates, P7 was again shown to be a successful precatalyst in promoting C−N bond formation. However, in more activated systems, increasing amounts of byproduct arising from displacement with alkoxide base were observed with P7 leading to the design of P8, which provided high yields in these cases. In cases where enantiopure amines were used, a degree of epimerization was observed in the coupled products,

Several retrosynthetic approaches exist for the synthesis of unsymmetrical ketones though all essentially feature the elaboration of a linchpin carbonyl synthon on which two carbon groups are appended. Within this reactivity paradigm, a general carbonyl dication reagent has not been disclosed until now. Sarpong and co-workers have addressed this, and disclosed N-methoxyN-methyl-1H-pyrrole-1-carboxamide (CLAmP) as a versatile reagent able to react sequentially with two different organometallic reagents to generate unsymmetrical ketones (Angew. Chem., Int. Ed. 2015, 10.1002/anie.201502894). The key to the success of this methodology is the modulation of the reaction conditions to enable controlled collapse of the intermediary tetrahedral species allowing monoaddition of the initial F



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though these two new systems offer both unprecedented scope and reactivity in the Pd-mediated coupling of α-branched secondary amines.

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HIGHLY ENANTIOSELECTIVE NUCLEOPHILIC DEAROMATIZATION OF PYRIDINES BY ANION-BINDING CATALYSIS

IRIDIUM-CATALYZED DYNAMIC KINETIC ISOMERIZATION: EXPEDIENT SYNTHESIS OF CARBOHYDRATES FROM ACHMATOWICZ REARRANGEMENT PRODUCTS

The asymmetric addition of a nucleophile to a pyridinium salt represents an attractive method for the formation of a range of enantioenriched piperidine scaffolds, which occur widely in biologically active compounds. However, this approach presents a number of challenges including harsh conditions to break the aromaticity of the ring system, C-2/C-4 selectivity issues as well as catalyst deactivation through coordination to the substrate. Mancheño and co-workers have reported on a highly enantioselective dearomatization of pyridines with silylketene acetals as the nucleophile utilizing triazole-based C−H hydrogen donor catalysts (Angew. Chem., Int. Ed. 2015, 54, 8823). Model studies on 2-picoline were carried out through a two-step protocol involving in situ quaternization with TrocCl at 0 °C followed by treatment with the catalyst and nucleophile at a range of temperatures. The optimal system utilized diethyl ether as the solvent with the addition taking place at −78 °C and led to both high enantioselectivity (98:2) and a high level of selectivity for the C-2 product (94:6). In the absence of the catalyst, it should be noted that a background reaction was observed leading to the C4 product. The optimal conditions were applied to a range of differentially substituted pyridines, and the reaction was also scaled to 2 mmol with effective recovery and reuse of the catalyst being demonstrated. Substitution in 2- and 4-positions of the pyridines led to formation of the corresponding C2-substituted products with high enantioselectivity, though systems featuring electron-donating groups in the C4-position displayed lower reactivity and as such the reaction was carried out at −60 °C. Remarkably, in the case of C-3-substituted pyridines, the regioselectivity was reversed in favor of the 1,4dihydropiperdines with the products again being isolated in high ee. Unsubstituted pyridines provide the C-2 product in high ee though a competitive C-2/C-4 addition was observed. Finally, a range of derivatization reactions of the products were carried out to both confirm the absolute stereochemistry and to demonstrate their synthetic versatility.

Efficient processes for the transformation of sustainable raw materials into high value fine chemicals is an important area of chemical research. From this perspective, the Achmatowicz rearrangement has been widely studied to enable the transformation of furans into dihydropyranones, which are building blocks for the synthesis of carbohydrates. The major drawback of this transformation is that, despite many studies being carried out, most of the transformations involving the anomeric center suffer from low stereoselectivity. Tang and co-workers have reported on an iridium-catalyzed dynamic kinetic isomerization to enable the stereoselective synthesis of lactones from the epimeric mixture of Achmatowicz rearrangement products through an internal redox isomerization process (Angew. Chem., Int. Ed. 2015, 54, 8756). The keys to the success for this approach are that both the rate of equilibration between the cis/trans hemiacetals has to be faster than the isomerization, while the rate of redox isomerization has to be faster for one hemiacetal than the other. Model studies using the substrate prepared from reduction and rearrangement of 2-acetylfuran indicated that iridium-based catalysts were uniquely effective in promoting isomerization to the lactone with [{Ir(cod)Cl}2] being the best. With this catalyst, the lactone was formed in quantitative yield as a 3:1 mixture in favor of the cis isomer, which is identical to the ratio of the starting hemiacetals, indicating isomerization takes places at a much faster rate than equilibration. Screening Brønsted acids demonstrated that the rate of hemiacetal equilibration could be accelerated through an acid additive with 2,6-dichlorobenzoic acid being shown to be optimal with the cis isomer formed exclusively. The generality of the protocol was demonstrated for a range of the hemiacetals with neither electronics nor sterics significantly impacting the outcome of the reaction. The utility of the products was illustrated through concise syntheses of noviose and a range of deoxysugars. The reaction was successfully demonstrated on multigram scale, and a mechanistic hypothesis involving a stereoselective internal hydrogen transfer is provided.

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STRUCTURE-POLYMORPHISM STUDY OF FENAMATES: TOWARD DEVELOPING AN UNDERSTANDING OF THE POLYMORPHOPHORE As part of the ongoing effort to understand polymorphism, Adam Matzger’s group at the University of Michigan (Ann Arbor) discusses their approach using the concept of pharmacophore to correlate chemical structure with polymorphic propensity (Lopez-Mejias, V., et al. Cryst. Growth Des. 2015, 10.1021/ acs.cgd.5b00570). A polymorphophore is defined using an analogy with a pharmacophore: “a collective ensemble of structural motifs that renders a compound to be polymorphic”. The model molecule for the study is tolfenamic acid, 2-[(3-chloro-2-methylphenyl) amino] benzoic acid (TA), a pentamorphic system, used G



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DESIGNING ROBUST CRYSTALLIZATION PROCESSES IN THE PRESENCE OF PARAMETER UNCERTAINTY USING ATTAINABLE REGIONS Over 50 years ago, Horn introduced the concept of attainable regions for the process design of chemical reactors. Such attainable regions describe all possible outcome states of a system of chemical reactors, with the “only” knowledge required for their determination being the chemical reaction network, the associated chemical kinetics, and the feed composition. When sufficient resources are available, this methodology could be used to define a design space in accordance with the Quality by Design (QbD) requirements. The concept has been used in various scenarios with the exception of the case where significant parameter uncertainty is present, specifically the kinetic parameters are not precisely known for all the reactions in the network at stake. A collaboration from Eli Lilly, University of Manchester, and University of California (Santa Barbara) discusses a methodology to develop a robust crystallization process using uncertainty-adjusted attainable regions (Vetter, T., et al. Ind. Eng. Chem. Res. 2015, 10.1021/ acs.acs.iecr.5b00693). The crystallization process used to demonstrate the concept was that of paracetamol in ethanol. The population balance equation framework was used to model this crystallization process under a variety of scenarios, both batch and continuous. In order to maintain manageable modeling, only one of the four possible sources of uncertainty is tackled, parameter uncertainty. The other three sources of uncertainty that were not included in this work were: structural uncertainty (model bias), measurement errors and variability in operating conditions. A significant amount of crystallization process information was available, including primary and secondary nucleation and growth kinetics. Two sets of specifications were used: desired mean particle size of 200 μm or of 400 μm (and a desired yield of 98%). Simulations of crystallization outcomes were executed for batch, plug-flow and a cascade of three mixed suspension mixed product removal crystallizer (MSMPRC). For continuous processes executed in MSMPRC’s, longer residence times and more crystallizers can increase the robustness of the crystallization process. In this particular case it was possible to determine that growth rate is more important than nucleation rate in achieving the desired particle size distribution. This paper has 50 references.

as an NSAID in Europe. Six TA analogues (some newly synthesized) were systematically investigated using a combined experimental and computational approach to understand the structure-polymorphism relationship. They included fenamic acid (2-phenylamino benzoic acid, FA) and mefenamic acid, 2-[(2,3dimethyl) phenyl] aminobenzoic acid, MA. These analogues exhibit a monocarboxylated diphenylamine nucleus, while having different substituents on the noncarboxylated phenyl ring. Because solvent based methods were not productive enough to generate new forms, polymer-induced heteronucleation was employed, a method developed also in the Metzger lab. Several polymorphs were obtained for these TA analogs, and they were compared (XRPD, X-ray crystal structure where possible) with the TA polymorphs. Certain similarities were observed between some of the polymorphs examined. In addition, conformational analysis was executed, to find that some of the polymorphs of TA analogs did resemble certain TA polymorphs. From these comparisons it was concluded that substitution on the noncarboxylated ring leads to polymorphs, whereas the diphenylamine moiety did not appear to lead to multiple crystalline phases. The team is attempting to develop a protocol that allows for structure-polymorph correlations once one compound in a series is experimentally available. The hypothesis that needs to be further verified is that “a collective ensemble of conformational, steric and electronic features is responsible for the adoption of multiple packing modes in molecular compounds” (the” polymorphophore”).

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CONTROL OF POLYMORPHISM IN CONTINUOUS CRYSTALLIZATION VIA MIXED SUSPENSION MIXED PRODUCT REMOVAL SYSTEMS CASCADE DESIGN

A collaboration from the Massachusetts Institute of Technology (MIT) and The Swiss Federal Institute of Technology (ETH) (Lai, T.-T. C., et al. Cryst. Growth Des. 2015, 10.1021/ acs.cgd.5b00466) addresses the challenge of polymorphic control when converting a batch crystallization process to a continuous process. The model compound used in the study was para-aminobenzoic acid, exhibiting two polymorphs, α and β. The polymorphic system is enantiotropic: form α is the commercial form, stable at temperatures above the transition temperature of 15 °C; form β, typically difficult to obtain in batch crystallizations, is stable at temperatures below the transition temperature of 15 °C. The goal was to define operating conditions for the continuous process leading to the desired polymorph, to be obtained in high yield (future objectives would include particle size distribution optimization). A careful investigation of the crystallization kinetics and thermodynamics in different regimes was conducted. Operating conditions of temperature and residence time were defined for high polymorphic purity (>95%) and high yield were established. A single stage Mixed Suspension Mixed Product Removal system (MSMPR) operated at 5 °C was polymorph β specific. A carefully designed two-stage MSMPR system was capable of producing 75% polymorph α. A creative approach was used for seeding: the first stage was operated at 30 °C producing polymorph α which was then continuously fed to the second reactor operating at 5 °C. Mathematical models were developed for the MSMPR’s analyzed, and an operating window was defined based on these calculations.

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TRANSFORMATION OF ACIDIC POORLY WATER SOLUBLE DRUGS INTO IONIC LIQUIDS A team from Novartis and the University of Wurzburg (Balk, A., et al. Eur. J. Pharm. Biopharm. 2015, 94, 73) reported a detailed study of the improved physical properties of several BCS Class II compounds (low solubility, high permeability) upon their transformation to the corresponding tetrabutylphosphonium (TBP) salts. The model compounds employed in the study were: diclofenac, ibuprofen, ketoprofen, naproxen, sulfadiazine, sulfamethoxazole, and tolbutamide. The seven TBP salts thus obtained were either low melting (

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