OPRD - American Chemical Society

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

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

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CONTROL STRATEGY FOR SMALL MOLECULE IMPURITIES IN ANTIBODY−DRUG CONJUGATES A white paper authored by scientists from a cross-pharma impurities working group argue that current ICH guidelines do not adequately address how to handle small-molecule impurities arising from the payload, linker, or linker-payload of antibody− drug conjugates (Jones, M. T.; et al. AAPS PharmSciTech 2018, 10.1208/s12249-017-0943-6). A decision tree is presented that indicates a proposal for setting control limits on the basis of whether the impurity is conjugatable, contains the payload, or is unusually potent. A formula for daily impurity dose is presented, and the figures it generates indicate that small-molecule impurities should pose little risk to patient safety.

FAST AND ACCURATE PREDICTION OF THE REGIOSELECTIVITY OF ELECTROPHILIC AROMATIC SUBSTITUTION REACTIONS Chemists will be interested in a semiempirical quantummechanical method developed by the University of Copenhagen for predicting the preferred site of electrophilic aromatic substitution (EAS) (Jørgensen, M.; et al. Chem. Sci. 2018, 9, 660). The method, named RegioSQM, relies on identifying the aromatic carbon with highest proton affinity on the basis that such a protonated species resembles the intermediate of EAS. The calculations successfully predicted the observed regioselectivity (including examples of bisbromination) with a success rate of 81% when 525 brominations found in the literature were retrospectively analyzed. This figure rose to 96% after correction for cases in which the experimentally observed site of reaction was not where it was predicted to be computationally but was within 3.0 kcal/mol of the latter. While the method is presented as being generally applicable to electrophilic aromatic substitutions, the only validation data presented are for these bromination reactions. The method requires only the SMILES string of the reaction substrate and has been made freely available to the chemistry community.

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EVOLVING GREEN CHEMISTRY METRICS INTO PREDICTIVE TOOLS FOR DECISION MAKING AND BENCHMARKING ANALYTICS BMS scientists have provided more details about their Monte Carlo simulation-based methodology for using the historical yield and process mass intensity (PMI) of a class of reactions as a guide as to the probable efficiency, if a member of that reaction class is taken into development (Eastgate, M. D.; et al. ACS Sustainable Chem. Eng. 2018, 6, 1121). This initiative is driven by the opportunity to improve the chance of selecting a route during a route identification exercise, that when fully developed, offers the most efficiency versus alternative route options. Its use is demonstrated through a prediction of the efficiencies of different route options for the synthesis of fostemsavir, a potential HIV treatment. The authors stress the importance of not pushing the unfavorable environmental credentials of a reactant, reagent, and solvent outside of the consideration of the environmental footprint of the process, just because they feature outside of the GMP synthesis of the API. The article points out that the precompetitive sharing of PMI data between companies is required if this approach is to deliver an inflection point in its potential value to the wider community.

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Recent interest in couplings mediated by Pd(I) dimer complexes continues with the disclosure that they can be precatalysts for the amination of aryl halide electrophiles with both aliphatic and aromatic amines (Spokoyny, A. M.; et al. Dalton Trans. 2018, DOI: 10.1039/C8DT00119G; ChemRxiv preprint server, https:// doi.org/10.26434/chemrxiv.5758551.v1). The Pd(I) dimer complexes examined all showed excellent stability toward storage in air. The article also provides an operationally straightforward synthesis of [PdI2(MeCN)6][BF4]2, a convenient precursor to airstable Pd(I) dimer complexes bearing biaryl phosphine ligands.

PROCESS DEVELOPMENT AND ROBUST CONTROL OF PHYSICAL ATTRIBUTES OF AN AMORPHOUS DRUG SUBSTANCE Merck scientists have shared the development and rationale behind the isolation process for boceprevir, an API isolated in an amorphous state, whose surface area was highly dependent on the processing conditions (Zarkadas, D.; et al. J. Pharm. Sci. 2018, 107, 217). Heating a suspension in a reactor and using FBRM to monitor the kinetics of agglomeration of the suspended particles is reported to generate glass transition temperature data that allow better predictions of surface area than the data produced by DSC measurements. The isolation process involved two discrete stages. The first used a continuous tee mixer precipitation process, and in-line chord length distribution measurements were used to help with its successful scale-up. The second stage involved a dynamic vacuum distillation step. The process has delivered control over the API surface area, a quality attribute critical for bioavailability and drug product manufacture, with a capability in excess of six sigma. © XXXX American Chemical Society

BUCHWALD−HARTWIG AMINATION USING PALLADIUM(I) DIMER PRECATALYSTS SUPPORTED BY BIARYL PHOSPHINE LIGANDS

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MODELING OLANZAPINE SOLUTION GROWTH MORPHOLOGIES Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine) is a successful antipsychotic drug first patented in 1971. However, because of its complex molecular structure, the mechanism of crystal growth of olanzapine is

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DOI: 10.1021/acs.oprd.8b00061 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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not well understood. Olanzapine exhibits approximately 60 solid forms, of which 56 are solvates and one is an amorphous compound. As a result, manufacturing of olanzapine is complex, and a fundamental understanding of its crystal growth mechanism can support the development of a robust crystallization process. A collaboration from Prof. Doherty’s group at the University of California, Santa Barbara, Eli Lilly Co., and Shanghai Jiao Tong University led to the successful prediction of olanzapine form I crystals (Sun, Y.; et al. Cryst. Growth Des. 2018, 18, 905; M. F. Doherty, corresponding author). Spiral crystal growth of stable olanzapine form I from five (nonsolvating) solvents (acetone, ethyl acetate, toluene, methyl isobutyl ketone, and n-butyl acetate) was modeled using a dimeric growth unit. These dimeric units are considered to be stabilized by multiple C−H···π contacts. The predicted morphologies align well the experimentally observed crystals.

Highlights from the Literature

DIRECT α-C−H BOND FUNCTIONALIZATION OF UNPROTECTED CYCLIC AMINES

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RATIONAL SOLVENT SELECTION FOR PHARMACEUTICAL IMPURITY PURGE Solvent selection for impurity purge in a (re)crystallization process is typically done empirically using either a traditional trial-and-error approach or a statistical design of experiments (DoE) approach, and either can be a time-consuming activity. Because of the recent progress with computational methods used for solid-state characterization, such tools could assist in a (re)crystallization solvent selection. A report from Pfizer (Abramov, Y. A. Cryst. Growth Des. 2018, 18, 1208) describes the success with such an approach. Three impurity purge factors are proposed on the basis of the impurity partition coefficient between the solvent and the crystalline API and the thermodynamic solubility of the API. Among others, the chemical structure of the impurity must be known in order to be able to calculate such purge factors. Compared with previously developed genotoxic impurity purge factors, which are semiquantitative risk factors, the computational purge factors proposed in this work are computed on the basis of thermodynamic considerations. In addition to several software platforms necessary in the computation of the purge factors, the main calculations were run in COSMOtherm (executing thermodynamic calculations of chemical potentials). A limited comparison of the proposed factors against experimental data for published compounds was conducted, showing that one of the three factors proposed exhibits superior predictive properties.

Cyclic amines are among the most commonly recurring motifs in bioactive natural product and drug structures. A new method for the C−H functionalizion of unprotected cyclic amines via their transiently generated imines, reported by Daniel Seidel and co-workers (Nat. Chem. 2018, 10, 165), represents a novel approach to the modification of these key fragments. Although the addition of organometallic nucleophiles to cyclic imines is well-established, Siedel’s methodology couples this to a new protocol for in situ imine generation through deprotonation and treatment with a hydride acceptor such as benzophenone. The lowtemperature in situ generation of the imine electrophiles sidesteps common side reactions of these species such as trimerization or aza-enolate formation, enabling the one-pot amine α-functionalization to be easily accomplished without the need for transition metals or amine protecting groups. A range of alkyl, vinyl, and aryl organolithium nucleophiles are demonstrated on a broad array of differently sized rings. Although the stereochemical outcome of the addition is controlled by the substrate, the reaction was found to be highly diastereoselective (for trans addition) where existing stereocenters are present. Moreover, existing stereocenters next to nitrogen do not suffer from erosion of enantiopurity under the reaction conditions. Although the use of ether as a solvent and the requirement for cryogenic temperatures are problematic in a process chemistry setting, this approach represents an original and inexpensive alternative to many existing methods for amine C−H functionalization.

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RACEMIC AND ENANTIOPURE CAMPHENE AND PINENE STUDIED BY THE CRYSTALLINE SPONGE METHOD Growing crystals suitable for single-crystal X-ray analysis is challenging. Recently, Fujita developed a method for the absolute structure determination of chiral guests that involves the use of chiral crystalline sponges. A collaboration between DSM and Radboud University (de Poel, W.; et al. Cryst. Growth Des. 2018, 18, 126; R. de Gelder, corresponding author) applied this methodology using a porous metal−organic framework consisting of ZnI2 and 2,4,6-tris(pyridin-4-yl)-1,3,5-triazine as a “sponge” for crystal structure determination of camphene and pinene. Because of the molecular freedom, camphene’s crystal structure cannot be resolved using classical X-ray diffraction, and pinene is a liquid at room temperature. XRPD was used to monitor the host−guest interaction and to define an end point for the formation of the molecular complex. Future work will evaluate the capability of this method to assist with chiral resolutions.

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CHIRAL AUXILIARY RECYCLING IN CONTINUOUS FLOW: AUTOMATED RECOVERY AND REUSE OF OPPOLZER’S SULTAM Despite the advances in asymmetric catalysis that recent decades have brought, covalently linked chiral auxiliaries are still a relatively common sight in organic synthesis, even in the pharmaceutical industry. Although many popular auxiliaries such as Oppolzer’s sultam can be recycled, their reuse typically adds several operations to a batch process, leading to increased cycle time B

DOI: 10.1021/acs.oprd.8b00061 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Highlights from the Literature

GREEN AND SUSTAINABLE SOLVENTS IN CHEMICAL PROCESSES Solvents constitute a major part of waste streams from the execution of chemical processes and therefore have the potential to have a major impact on the environmental burden of a chemical reaction. Thus, judicious choice of the solvent for a reaction can be as important in minimizing cost, energy usage, and waste generated with a particular chemical step as the selection of the reagents and conditions themselves. New developments in the availability of renewable organic solvents as well as more specialized alternatives such as ionic liquids, liquid polymers, deep eutectic solvents, and supercritical fluids are summarized in a recent review by Jason Hallett and co-workers (Chem. Rev. 2018, 118, 747). The performance of each class of solvent is outlined with respect to the chemistry for which it is suitable, its extraction properties, its environmental impact, and the wider context of the types of processes where it may be useful. The review contains 498 references and serves as an excellent introduction to solvents beyond those commonly found in a standard organic chemistry laboratory.

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OXIDASE CATALYSIS VIA AEROBICALLY GENERATED HYPERVALENT IODINE INTERMEDIATES

and cost. In contrast, a recent paper by Sullivan and Newman (Chem. Sci. 2018, DOI: 10.1039/c7sc05192a) describes the design of a continuous flow process that allows for the recycling of a chiral auxiliary without isolation, rendering the reaction “pseudocatalytic”, as multiple equivalents of product can now be produced for a single equivalent of chiral auxiliary. Although the reaction studiedthe asymmetric reduction of α,β-unsaturated carbonyl compoundshas been reported using many varied catalytic systems, certain substrate classes remain problematic even for modern transition metal catalysis. For the system studied, the entire process could be accomplished with a total residence time of 30 min in flow, compared with around 22 h required to run the three steps in batch. Moreover, both the yield and diastereoselectivity were also improved in flow. Beyond this reaction, the design and engineering principles of this system may be applicable to other cases where no acceptable catalytic alternative is available or where increased efficiency is sought.

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ENZYMATIC ASYMMETRIC SYNTHESIS OF CHIRAL AMINO ACIDS Chiral amino acids are of huge importance to the field of organic synthesis in catalysis, for the preparation of chiral auxiliaries, and as building blocks themselves. This broad utility has driven the development of numerous approaches to their synthesis. However, with the ever-increasing accessibility of the tools of chemical biology, biocatalytic and enzymatic methods have moved to the fore. A recent review by Yu-Guo Zheng and coworkers (Chem. Soc. Rev. 2018, DOI: 10.1039/c7cs00253j) provides a useful overview of the numerous enzymatic reactions that can be used to synthesize nonracemic chiral amino acids, with a focus on unnatural substrates. The review focuses on four main categories of enzymatic reactions: asymmetric reductive amination of keto acids catalyzed by amino acid dehydrogenases (AADHs), asymmetric transfer of an amino group to keto acids by aminotransferases, enantioselective addition of ammonia to α,β-unsaturated acids by ammonia lyases, and aldol-type condensation of amino acids with aldehydes enabled by aldolases and hydroxymethyltransferases.

Iodine(III) reagents such as diacetoxyiodobenzene, iodosobenzene, and Koser’s reagent are capable of performing unique and powerful transformations in organic synthesis. However, the use of these reagents on a large scale is limited by their high cost, a lack of large-scale suppliers, and the high PMI associated with their use. Although catalytic systems based around these reagents have been reported for some time, to date no system that make uses of the simplest oxidantmolecular oxygenhas been reported. Now, David Powers and co-workers have disclosed a system that harnesses intermediates in the oxygen-driven autoxidation of simple aldehydes to achieve both the synthesis of iodine(III) reagents and catalytic versions of some of their best known reactions (Nat. Chem. 2018, 10, 200). With acetaldehyde as the aldehyde reagent, combined with 1 mol % CoCl2 as an initiator, a number of popular hypervalent iodine reagents can be C

DOI: 10.1021/acs.oprd.8b00061 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

prepared in high yield using only oxygen as the terminal oxidant. Furthermore, these reagents can also be generated and used in situ to accomplish the oxygen-driven oxidation of a number of classes of organic molecules. This provides an interesting and novel oxidase catalysis platform with fairly broad applicability. Clearly, the use of pure oxygen as an oxidant is impractical in a process setting, but the authors show that air can also be used, albeit in lower yield. Although the majority of reactions are reported in DCE, which is unappealing because of its toxicity, other solvents such as MeCN and AcOH were also demonstrated to be competent in the reaction.

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DEVELOPMENT OF A SCALABLE, CHROMATOGRAPHY-FREE SYNTHESIS OF t-Bu-SMS-Phos AND APPLICATION TO THE SYNTHESIS OF A CHIRAL CF3-ALCOHOL DERIVATIVE WITH HIGH ENANTIOSELECTIVITY USING RHODIUM-CATALYZED ASYMMETRIC HYDROGENATION

with 1-octene demonstrated the requirement to add p-TsOH as a cocatalyst to ensure sufficient reactivity. A range of bidentate phosphines were evaluated because of their known propensity to form linear over branched products, with Xantphos emerging as the best, providing a 92% yield with excellent selectivity for C-3 (>20:1) of the heteroarene and a good linear/branched ratio of products (88:12). From the olefin perspective, steric bulk increased the linear selectivity, while 1,1-disubstituted, internal (leading to branched products), tetrasubstituted, and cyclic olefins were all well-tolerated. In the case of (−)-β-citronellene, the terminal olefin was selectively carbonylated to give the linear ketone. Indoles, pyrroles, furans, thiophenes, and electron-rich arenes were all successful substrates. If C-3 of the indole is blocked, the reaction takes place at C-2, and the C2/C3 selectivity for pyrrole could be controlled by changing the steric bulk of the N substituent. Mechanistic and DFT studies suggest that the reaction proceeds through a Pd−hydride complex, with the regioselectivity determined by the strain energy in the transition state.

Although the synthesis of enantioenriched trifluoroisopropanol via the Noyori-type Ru-mediated reduction of trifluoroacetone has been reported, the high hydrogen pressure required and the potential for runaway decomposition of the thermally unstable ketone starting material cause serious safety concerns for the use of this process on scale. In order to enable the efficient kilogramscale preparation of chiral nonracemic trifluoroisopropanol, Chris Senanayake and co-workers at Boehringer Ingelheim have studied the asymmetric hydrogenation of the corresponding enol acetate under rhodium catalysis (J. Org. Chem. 2018, 83, 1448). A highly efficient and enantioselective process was developed using the C2-symmetric P-chiral diphosphine ligand t-Bu-SMS-Phos, but it was difficult to prepare the quantities needed using the published chemistrydespite the low loading and ligand recycling used. Thus, the authors report a much improved chiralauxiliary-based approach that was used to prepare over 4 kg of the ligand, eliminating the numerous chromatographic purifications required in the original route. The hydrogenation itself was demonstrated on a 1 kg scale, and 97% of the ligand could be recovered and recycled.

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DIRECT ASYMMETRIC MICHAEL REACTION OF α,β-UNSATURATED ALDEHYDES AND KETONES CATALYZED BY TWO SECONDARY AMINE CATALYSTS There are a number of challenges inherent in the development of a direct asymmetric Michael reaction between an α,β-unsaturated aldehyde and an unactivated ketone, including control of 1,2versus 1,4-selectivity and generation of a suitable intermediate chiral species to control the enantioselectivity. Hayashi and Umekubo have reported on this reaction mediated by pyrrolidine accompanied by a chiral silyl ether to provide the product in 74% yield with 91% ee (syn/anti = 5:1) (Angew. Chem. Int. Ed. 2018, 57, 1958). To explain the success of the reaction, labeling studies were carried out to determine the relative rates of formation of both the intermediate iminium ion and the enamine. These showed that both possible iminium species were formed from the aldehyde, with pyrrolidine reacting slightly faster, though only pyrrolidine reacts with the ketone to form the enamine. In order to rationalize the high levels of enantioselectivity observed, the chiral iminium ion must react preferentially with the racemic enamine, and this is postulated to occur because of its higher electrophilicity. Replacing pyrrolidine with L-trans-4-hydroxyproline led to higher levels of diastereoselectivity but had no impact on the enantioselectivity, while the addition of both water and p-nitrophenol is critical for reactivity. A range of aromatic

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TOWARD GREEN ACYLATION OF (HETERO)ARENES: PALLADIUM-CATALYZED CARBONYLATION OF OLEFINS TO KETONES The synthesis of ketones through carbonylation of organometallic reagents as the C-nucleophiles is well-established, but it suffers from the drawback of generating stoichiometric amounts of metal salts as waste. Beller and co-workers have reported a Pd-mediated, directing-group-free C−H carbonylation of a range of (hetero)arenes with readily available olefins (ACS Cent. Sci. 2018, 4, 30). Model studies on the reaction of N-methylindole D

DOI: 10.1021/acs.oprd.8b00061 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

the solvent with a catalytic amount of acetyl chloride added in order to generate HCl in situ (Eur. J. Org. Chem. 2018, 306). Control studies showed no conversion in either neat acetyl chloride or HFIP alone, and although other fluorinated solvents were somewhat effective, HFIP proved to be superior, in some part because of its ability to solubilize the starting materials. A range of examples are provided, including electron-rich phenols and a number of phenol-containing natural products. Electronrich cinnamic acids performed in a superior manner to electronically neutral derivatives, and a number of heterocyclecontaining cinnamic acids are also reported. Mechanistic studies by NMR clearly demonstrate the development of a hydrogen bond between HFIP and the cinnamic acid, and the reaction is believed to proceed via 1,4-addition of the ortho carbon of the phenol followed by cyclization.

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REGIOSELECTIVE HALOGENATION OF ARENES AND HETEROCYCLES IN HEXAFLUOROISOPROPANOL

and heteroaromatic moieties are tolerated at the β-position of the aldehyde, though alkyl groups are not. In addition, six- and seven-membered cyclic ketones give high yields and enantioselectivities, though both suffer in the case of the analogous fivemembered rings.

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Aryl and heteroaryl halides are important building blocks in medicinal chemistry because of their propensity to participate in a variety of metal-mediated coupling reactions. However, their preparation is often complicated by the need to use either corrosive reagents or the requirement to add Lewis or Brønsted acids as activators of NXS-based reagents. Crousse and co-workers have reported a mild regioselective halogenation using HFIP as the solvent with the rationale that an activator would not be required because NXS would be activated in an electrophilic manner through hydrogen bonding to the solvent (J. Org. Chem. 2018, 83, 930). A range of electron-rich arenes and heteroarenes were successfully brominated using NBS, primarily at the para position, with the reactions generally occurring at room temperature in an hour. Less electron-rich arenes than toluene were not successful substrates, and no benzylic bromination was observed. The methodology was extended to the use of both NIS and NCS, though the latter had a slightly narrower substrate scope. The reaction was also demonstrated on a gram scale and applied to one-pot sequential halogenations and halogenation/ Suzuki cross-couplings.

HEXAFLUOROISOPROPANOL AND ACETYL CHLORIDE PROMOTED CATALYTIC HYDROARYLATION WITH PHENOLS

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A PLATFORM FOR AUTOMATED NANOMOLE-SCALE REACTION SCREENING AND MICROMOLE-SCALE SYNTHESIS IN FLOW The application of high-throughput experimentation for medicinal chemistry reaction optimization is to some degree limited by material availability, particularly for complex advanced intermediates. Whereas employing high-throughput screening-based instrumentation has enabled reactions to be performed on the submilligram scale in well plates, there are limitations in the range of solvents that can be used as well as the real-time resolution of the analysis. Workers at Pfizer have disclosed a flow-based screening platform that enables >1500 reactions to be evaluated in 24 h using

Coumarins and dihydrocoumarins are prevalent scaffolds in both natural products and bioactive compounds and can be accessed through the hydroarylation of α,β-unsaturated acids with substituted phenols. Currently reported conditions utilize TFA to achieve this transformation, with electron-rich phenols being significantly preferred. Aubé and co-workers have developed a mild alternative protocol for this transformation using HFIP as E

DOI: 10.1021/acs.oprd.8b00061 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Highlights from the Literature

issues and utilizes Ph3PO as a catalyst (Org. Lett. 2018, 20, 728). Model studies using benzamide as the substrate indicated that as little as 1 mol % Ph3PO was effective, though the stoichiometries employed for oxalyl chloride (2 equiv) and Et3N (3 equiv) were critical for complete conversion. Several solvents were able to mediate the reaction, with MeCN shown to be the best. From a scope perspective, aryl, heteroaryl, and aliphatic amides were all successful substrates, though aliphatic amides displayed lower reactivity. Phthalimide-protected amino acid amides were also successfully dehydrated, though the corresponding Boc-protected substrates led to multiple side products. Two potential mechanistic pathways were proposed, and the one featuring the intermediacy of an N-acyltriphenylphosphine imide (originally rejected by Appel) was shown to be highly probable through control studies.

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