Pharmaceutical Process Chemistry: Evolution of a Contemporary Data-Rich Laboratory Environment
An excellent “perspective” on process chemistry was recently published by a team of Pfizer process scientists (Caron, S., et
al. J. Org. Chem. 2015
, in press, DOI: 10.1021/jo502879m
). The sections are Introduction, Discussion, Process Optimization, Technology transfer and Scale-up, and Conclusions. The Discussion section covers route selection, laboratory experimentation, defining the proposed regulatory strategy and defining the API final form. The Process Optimization section reviews the attributes of a good process, Quality by Design (QbD) and data rich experimentation, purification and impurity control, understanding solubility to aid design, reaction kinetics, process modeling, batch and flow, and statistical design of experiments (DoE).
The authors list several criteria met by “good processes”: safety, robustness, (crystalline) intermediate stability, the use of a small number of unit operations and pieces of equipment, avoiding large volume swings, and being capable of tolerating “typical” variability in the starting materials and solvents employed. QbD implementation enables the systematic generation of process understanding of the quantitative relationship between API quality attributes and process parameters, allowing for the development of a meaningful control strategy in a prospective manner. In the QbD subsection the authors briefly describe the Pfizer “Lab of the Future” initiative which encourages the replacement of round-bottom flasks with automated lab reactors (ALRs) of similar configuration with the plant reactors. Such ALRs have monitoring and control capabilities for temperature, agitation, pH, and dosing, as well as reaction calorimetry (in some cases). These ALR’s can be easily interfaced with Process Analytical Technology (PAT) tools for particle size measurement, Raman and IR spectroscopy, and they can be also fitted with autosampling capabilities (allowing for LC of unattended reactions).
Because of the monitoring capabilities of ALR’s, scale-dependent parameters can be studied and modeled in order to reduce the risk during process scale-up. Multivariate processes are best studied using multivariate experimental methods such as DoE. The Technology Transfer and Scale-Up section addresses process safety, predictive tools and process fit, and data management. Perhaps due to legal considerations, eight of the figures in the review depict lab instrumentation without indicating the names of the manufacturers of the equipment. Several case studies are included to support some of the points made in the paper which is a very good read for both experienced and less-experienced process development scientists.
Interesting Morphological Behavior of Organic Salt Choline Fenofibrate: Effect of Supersaturation and Polymeric Impurity
In a collaboration between AbbVie and the University of California (Santa Barbara) (Bordawekar, S., et al. Cryst. Growth Des. 2014, 14, 3800) an in-depth process understanding of the crystallization process for choline fenofibrate (the API in Triplix used to treat mixed dyslipidemia) was achieved. During the development of the crystallization process, three morphologies were identified: thin plates, thick plates, and prisms. Due to the high solubility of the API, efficacy was not impacted by crystal morphology. However, when nine versions of the API produced with the three morphologies in three different particle sizes (small, medium, large) were submitted to wet granulation, only the thick plates and the prisms of medium size formulated well. A cooling seeded crystallization process was developed leading to relatively large API particles which were later milled to produce the drug substance of suitable crystal morphology and size.
First, a crude isolation was employed (evaporative crystallization) followed by a recrystallization to control the habit. The initial solvent mixture employed was MeOH/IPA; however, one plant preferred not to use MeOH, and hence an EtOH crystallization process was developed. The seed employed was milled API, at 1% level (API) added as a slurry. During the development of the crystallization process, a strong dependency of the crystal habit on supersaturation was noticed, and a preliminary mechanistic explanation is proposed. When the team attempted to remove the recrystallization step, only thin plates were obtained. Careful process analysis led to the observation that a very low level of an impurity may impact the crystal habit. It was established that the impurity was poly(isopropyl methacrylate), formed from isopropyl-2-bromo-methylpropionate, one of the starting materials in the synthesis of choline fenofibrate. Even at levels of 0.1%, this polymeric impurity appeared to inhibit the growth of the most dominant crystal face. The crude isolation step could not remove the polymeric impurity to sufficiently low levels so that prisms or thick plates would be obtained. As a result, the recrystallization step could not be eliminated. Scanning electron microscopy and atomic force microscopy provided valuable insights into the growth mechanisms of the choline fenofibrate crystals.
Crystallization Optimization of Pharmaceutical Solid Forms with X-ray Compatible Microfluidic Platforms
For various considerations, some companies prefer to conduct their crystallization screening studies in-house. Building on prior work, and based on recent progress in microfluidics, a team from AbbVie and the University of Illinois at Urbana–Champaign report on the development of a microfluidic crystallization optimization method (Horstman, E. M., et al. Cryst. Growth Des. 2015
, in press, DOI: 10.1021/cg5016065
). The crystallization processes designed were seeded, with seeds obtained “off-chip” by conventional evaporative crystallization. The 72-well microfluidic platform was designed such that it fits the goniometer (at Argonne National Lab). However, since the chips were still too large to fit cryostreams, the single crystal X-ray measurements were conducted at room temperature. Crystallization processes were monitored with optical microscopy. The model compounds used in the work were three API’s (piroxicam, piracetam, and carbamazepine) as well as the cocrystal carbamazepine/4-hydroxybenzoic acid. In two cases (carbamazepine and the cocrystal carbamazepine/4-hydroxybenzoic acid) the structures obtained with the microfluidic platform were solved at a similar resolution as the previously reported structures which were obtained at low temperature. Among the advantages of this new method: the possibility of using very small amounts of API (5 μg per well), the capability of collecting X-ray data “on-chip”, without the need to harvest the crystals, and the possibility of obtaining a certain polymorph (with control via seeding). Future work will cover temperature control and the possibility of using additives in the crystallization.
As part of their ongoing work in sonochemistry, the Suslick group at the University of Illinois at Urbana–Champaign reports a novel sonocrystallization method for the production of pharmaceutical nanocrystals (Kim, H. N., et al. Cryst. Growth Des. 2015
, in press, DOI: 10.1021/acs.cgd5b00072
). The device used is comprised of a flow-through ultrasonic horn through which the API solution is pumped as a fine droplet spray, flowing in countercurrent with an antisolvent. The API used in the experiments reported was carboxyphenyl salicylate (CPS, salsalate). Submicron particles with a narrow particle size distribution could be obtained (in a range of 75–175 nm). Surfactants added to the antisolvent increased the stability of the dispersions produced. For both nonionic (polyvinylpyrrolidone) as well for anionic (sodium dodecyl sulfate) surfactants, the explanation for increased dispersion stability is based on the capability of these surfactants to reduce nanoparticle agglomeration.
The stability of the nanocrystals was monitored with XRPD for a period of 10 m, and zeta potentials were also measured upon particle formation. In control experiments where no ultrasound was used, under high agitation rates (900 rpm, magnetic stir bar) much larger crystals were obtained (100 μm). Formation of nanoparticles under sonication may be explained, among others, by the very energetic local conditions generated by ultrasound: temperatures higher than 5000 K, pressures above 105 kPa, and heating/cooling rates over 1010 K/s. Several process parameters were investigated for their impact on particle size: ultrasound power, temperature, flow rates (of the solute, and of the antisolvent), and API concentration. Of those, API concentration was found to have the highest impact on particle size. Future work will include scale-up investigations, expected to be successful due to the relatively low ultrasonic power needed (20 kHz). This communication has 40 references.
Asymmetric Hydrogenation of Enamines and Imines
As the result of a collaboration between University of Helsinki and the Hungarian Academy of Sciences, Pápai and Repo report the asymmetric hydrogenation of enamines and unhindered imines catalyzed by a chiral binaphtyl-linked aminoborane ( J. Am. Chem. Soc. 2015
, 4038). The combination of a hindered Lewis acid and a base in the structure of the catalyst originates a “frustrated Lewis pair” (FLP) system that promotes the heterolysis of molecular hydrogen under mild reaction conditions. A variety of enamines and imines undergo hydrogenation at room temperature with high enantioselectivities using MTBE as solvent and 2 bar of H2
. Computational studies suggest that hydrogen transfer from the FLP catalyst to the enamine is initiated by protonation of the substrate and followed by a rate-determining hydride transfer. The catalyst can be easily prepared from commercially available starting materials with high optical purity.
Iron-Catalyzed Borylation of Aryl C–H Bonds
Bontemps, Sortais, Sabo-Etienne, and Darcel developed a new borylation of aryl and heteroaryl C–H bonds ( J. Am. Chem. Soc. 2015
, 4062). The reactions, which are mediated by an iron bis(dimethylphosphinoethane) complex and UV irradiation (350 nm) in the presence of pinacolborane, occur regioselectively (meta > para ≫ ortho) at room temperature, afford the corresponding borylated compounds in moderate to good yields, and tolerate ether and amine substituents. Spectroscopic and mechanistic studies support the formation of a productive trans
-hydrido(boryl)iron intermediate, Fe(H)(Bpin)(dmpe)2
that equilibrates with a highly reactive Fe (0) bis (diphosphine) complex and reacts with the arene substrate to yield the borylated product.
Automated Synthesis of Small Molecules
The group of Prof. Martin Burke at University of Illinois reported the use of an automated building block-based platform to prepare 14 different families of small molecules ( Science 2015
, 1221). The synthetic strategy uses iterative cycles of deprotection (D), coupling (C), and purification (P) analogous to those employed in the coupling of amino acids to assemble peptides. This approach exploits the versatility and commercial availability of N
-methyliminodiacetic acid (MIDA) boronates as building blocks that integrate the functional groups and stereochemical elements required to synthesize the target molecule. The MIDA boronates enable the implementation of a catch-and-release chromatographic purification based on their minimal mobility on silica gel when eluting with MeOH–Et2
O mixtures (catch) relative to the rapid elution observed with THF (release). A series of carbon-heteroatom bond formations should be added to the same platform owing to the stability of MIDA boronates toward different reaction conditions, including O-alkylation, Buchwald–Hartwig amination, and amide bond formations. Remarkably, the new technology was used to stereoselectively cyclize modular precursors connected via automated Csp2
couplings and generate polycyclic natural products.
Iron-Catalyzed N-Arylsulfonamide Formation through Directly Using Nitroarenes as a Nitrogen Source
Nitroarenes are easily synthesized and stable precursors to aromatic amines, which are the most common nitrogen starting material for the synthesis of arylsulfonamides. Luo and co-workers from Sichuan University have developed a convenient Fe-catalyzed synthesis of arylsulfonamides using nitroarenes as the nitrogen source, bypassing the need for the occasionally troublesome reduction of nitroarenes to aromatic amines ( J. Org. Chem. 2015, 80 (7), 3504). The reaction requires the addition of NaHSO3 as the reductant, while catalytic FeCl2, FeCl3, or Cu(OAc)2 lead to significant yield increases. Further yield enhancement was observed upon the addition of diamine ligands, such as trans-N,N′-dimethyl-1,1-dicyclohexane (DMDACH). A variety of functional groups were tolerated on both the nitroarene and the sodium arylsulfinate including aryl halides, esters, aldehydes, carboxylic acids, nitriles, and interestingly, amino groups. Neither nitromethane nor alkyl sulfonates reacted under the conditions. Mechanistic studies suggest that the reaction does not proceed through common nitroarene reduction intermediates, such as a nitrosobenzene-, N-phenylhydroxylamine-, or aniline-species, but instead by the nucleophilic addition of an Fe-activated arylsulfinate on the nitroarene, followed by bisulfite reduction.
Catalytic Chemo-, Regio-, and Enantioselective Bromochlorination of Allylic Alcohols
Alkene dihalogenation is a common method to functionalize alkenes to make versatile synthetic intermediates, as well as halogenated natural products. While there are a few examples of enantio- and regioselective dihalogenation reactions, the catalyst controlled addition of two different halogens across an alkene is unprecedented. Burns and co-workers at Stanford have developed a highly chemo-, regio-, and enantioselective bromochlorination of allylic alcohols using practical reagents to form highly functionalized dihalogenated products ( J. Am. Chem. Soc. 2015, 137, 3795). The two halogen sources, used in only slight excess, are cheap and commercially available. The chiral catalyst is an easily accessible Schiff base.
The key observation was the drastic improvements in enantio- and regioselectivity with the use of nonpolar solvents, such as hexanes, which, following bromonium formation, favors chloride addition to the olefinic carbon closest to the alcohol. 1,1-Disubstituted, trisubstituted, and cis-disubstituted alkene substrates are bromochlorinated with excellent selectivities, while trans-disubstituted alkenes react with poor regioselectivity. Allylic oxygen functionality is required for useful enantio- and regioselectivity. The conditions were also amendable to dichlorination or dibromination by simply replacing NBS with tert-butyl hypochlorite, or ClTi(O-iPr)3 with BrTi(O-iPr)3, respectively.
Palladium-Catalyzed Aerobic Oxidative Dehydrogenation of Cyclohexenes to Substituted Arene Derivatives
A variety of classical methods exist for the synthesis of substituted arenes by sequential installation of functional groups around the aromatic ring; however, certain substitution patterns can be difficult to access or require several synthetic manipulations. Iosub and Stahl at the University of Wisconsin-Madison have described an alternative arene synthesis approach, utilizing a Pd-catalyzed dehydrogenation of cyclohexenes ( J. Am. Chem. Soc. 2015, 137, 34544). The cyclohexene starting materials are accessible via Diels–Alder cycloadditions, and the quinone cocatalyst, sodium anthraquinone-2-sulfonate, is cheap and commercially available.
The cocatalyst is used to avoid competing disproportionation of the cyclohexene into the corresponding cyclohexane and arene. The reaction is competent in both chlorobenzene and trifluorotoluene, and reactions with catalyst loadings as low as 1 mol % were demonstrated. Oxygen was the only terminal oxidant described. Substrates containing esters, ketones, imides, nitriles, aryl chlorides, and cyclic anhydrides proceeded well under the reaction conditions. Admirably, a list of unsuccessful substrates was also listed, including cyclohexenes containing a diacid, a N-aryl amide bearing a bromide, a thiophene, and N-heterocycles, including pyridine and benzimidazole. A phthalimide containing TFPA1 modulator was efficiently synthesized using this oxidative dehydrogenation methodology.
Efficient Asymmetric Synthesis of Structurally Diverse P-Stereogenic Phosphinamides for Catalyst Design
Efficient and reliable methods for the synthesis of new chiral ligands make asymmetric catalysis much more attractive for industrial processes. Han and co-workers at Boehringer Ingelheim Pharmaceuticals have developed the first general method for the synthesis of P-stereogenic phosphinamides, a class of phosphine ligand that remains relatively unexplored, and displayed the use of these catalysts in an asymmetric 1,4-reduction of α,β-unsaturated ketones ( Angew. Chem., Int. Ed. 2015, 54 (18), 5474).
These organocatalysts are prepared via a method similar to one the same group used to synthesize P-stereogenic phosphine oxides, which utilizes a readily available chiral phenol scaffold to synthesize cyclic 1,3,2-benzoxazaphosphinine 2-oxide intermediates. An aryl nucleophile is then added to break the P–N bond, followed by the addition of an N-nucleophile to release the chiral scaffold and produce the phosphinamide in good yields and excellent enantioselectivities. The tunable synthesis allows for the synthesis of a range of diarylphosphinamides or methyl-substituted arylphosphinamides. The chiral phenol scaffold can be electronically adjusted to allow for the addition of more challenging nucleophiles in good conversion and without overaddition. This method was used to synthesize a modular family of P-stereogenic phosphinamide-based bidentate phosphine oxide Lewis base catalysts for a silane mediated 1,4-reduction of chalcone derivatives. All catalysts furnished the product in high yields and the more sterically congested catalysts delivered high enantioselectivities, demonstrating the high potential for these catalysts in asymmetric catalysis.
Catalytic Enantioselective Allenoate–Alkene [2 + 2] Cycloadditions
Despite the prevalence of cyclobutanes in medicinally relevant molecules, as well as their importance as synthetic intermediates, the synthesis of cyclobutanes by catalytic enantioselective methods remain limited to a few intramolecular [2 + 2] photochemical reactions. Brown and co-workers at Indiana University have described a catalytic enantioselective [2 + 2] cycloaddition between allenoates and a variety of alkenes, including weakly and nonpolarized alkenes ( J. Am. Chem. Soc. 2015, 137, 3482). The process utilizes an oxazaborolidine catalyst that is available in one step from commercially available materials, and the reaction does not require cryogenic temperatures. While the reaction is restricted to α,β-unsubstituted allenoates, a variety of alkenes react in good-to-moderate yield and in high enantioselectivity, including terminal alkenes, cis- and trans-disubstituted alkenes, and unactivated terminal alkenes.
Terminal, unactivated alkenes require the use of the more electrophilic trifluoroethylallenoate to obtain higher yields however, this represents a rare example of an enantioselective catalytic reaction with a terminal unactivated alkene. The geometry of the alkene is conserved in the product, suggesting a concerted cycloaddition, and nonsymmetric alkenes react with moderate regioselectivity.
Rhodium (III)-Catalyzed Decarboxylative ortho-Heteroarylation of Aromatic Carboxylic Acids by Using the Carboxylic Acid as a Traceless Directing Group
Direct C–H/C–H cross-coupling between a simple arene and a heteroarene is the most attractive method to achieve a key bond formation found prevalently within the pharmaceutical approach. However, regioselectivity issues and the need for a large excess of the arene have plagued many approaches with the more recently, use of directing groups to promote selective cleavage of the arene C–H bond has emerged as a viable strategy to overcome these limitations.
You and co-workers have reported on a Rh(III)-mediated cross-coupling utilizing a carboxylic acid as a directing group ( Org. Lett. 2015
). Key advantages of this approach are that this moiety is found in numerous readily available substrates and can be tracelessly removed by protodecarboxylation to provide the ortho
-functionalized products. Extensive optimization studies on the reaction between 2-methoxybenzoic acid and benzothiophene showed, that although palladium catalysis was ineffective, the reaction could be successfully mediated at 150 °C in NMP using [Cp·RhCl2
(2.5 mol %), AgSbF6
(20 mol %), K2
(2 equiv), and Ag2
(3 equiv) with an 83% yield being obtained after 24 h.
The reaction was further demonstrated for a range of functionalized electron-rich heteroarenes (furans, indoles, etc.), as well as electron-deficient systems such as thiazoles and caffeine. For the acid component, ortho- and para-systems were effective substrates with little effect on the electronic nature of the substituent being observed, while meta-substituted substrates reacted at the less hindered site. Mechanistic studies indicated that the C–H bond breaking of the benzoic acid was the rate-limiting step, and the higher reactivity of an electron-rich acid suggests that the cyclometalation proceed through an electrophilic C–H bond activation.
Iridium-Catalyzed Selective Hydrogenation of 3-Hydroxypyridinium Salts: A Facile Synthesis of Piperidin-3-ones
Numerous biologically active compounds feature the piperidin-3-one fragment, and this moiety also serves as a desirable synthetic intermediate for further elaboration. The most conceptually simple approach to this class of molecule is through hydrogenation of the corresponding pyridine-3-ols, which are readily available. However, this approach is hampered by a number of challenges including over-reduction and catalyst deactivation through substrate coordination.
Zhou and co-workers have reported on an efficient solution to this through the hydrogenation of the corresponding 3-hydroxypyridinium salts ( Org. Lett. 2015
). Initial studies showed that, although ineffective at reducing 2-phenylpyridin-3-ol, the homogeneous catalyst [Ir(COD)Cl]2
in conjunction with a phosphine ligand was able to reduce the corresponding N
-benzylpyridinium salt exclusively to the piperidin-3-one albeit initially in modest yield (27%). Optimization of the reaction indicated that PPh3
was the best ligand with NaHCO3
employed as an inorganic base and DCE as the solvent. Temperature had little influence on the outcome of the reaction, and catalyst loadings could be lowered to 1 mol % with no negative effect on the yield. A range of functionalized substrates were successfully demonstrated with the electronics having little impact, though sterically encumbered substrates required higher catalyst loadings, and 2-alkyl substituted substrates needed a higher reaction temperature to reach completion (60 as opposed to 50 °C).
The method was extended to 4-substituted-3-hydroxypyridinium salts and applied to an intermediate in the synthesis of Pfizer’s rheumatoid arthritis drug, Xeljanz. Selective hydrogenation was also demonstrated on the gram scale with the subsequent utility of the products shown though hydrogenolysis to remove the benzyl group as well as enantioselective ketone reduction. A mechanism is proposed, and the low activity of the iridium catalyst for C═O provided as the rationale for why the ketone remains intact.
Chemoselective Formation of Unsymmetrically Substituted Ethers from Catalytic Reductive Coupling of Aldehydes and Ketones with Alcohols in Aqueous Solution
Reductive coupling of carbonyl compounds with alcohols represents an alternative to classical methods for the synthesis of unsymmetrical ethers. Yi and Kalutharage have reported on a method utilizing [(C6
as an effective catalyst for this reaction using hydrogen as the stoichiometric reductant and water as the solvent ( Org. Lett. 2015
). The reaction scope indicated that both aryl- and aliphatic aldehydes were successful substrates. For alcohols, primary and secondary alcohols were also utilized, and in the case of a 1,2-diol, exclusive selectivity for the primary alcohol was observed.
When two aliphatic substrates were employed, slightly lower yields were observed with no significant yield improvements observed on extending the reaction time. In many cases, hydrogen was replaced, and two equivalents of the alcohol were utilized with the second equivalent serving as the hydrogen donor. For ketones, benzylic systems exhibited faster reaction rates than aliphatic substrates, and the methodology was extended to several more complex, biologically relevant substrates. In many cases, poor substrate solubility in purely aqueous media entailed the use of toluene as a cosolvent or alternatively chlorobenzene as solvent. Kinetic isotope effects and labeling studies indicate the key involvement of the water in the C–O bond cleavage and hydrogenolysis steps, and a mechanistic hypothesis is provided for the reaction.
Condensed-Phase, Halogen-Bonded CF3I and C2F5I Adducts for Perfluoroalkylation Reactions
Despite its potential to be a useful and economical source of CF3
, the use of the reagent CF3
I is challenging due to its low boiling point (−22.5 °C) and the difficulty in accurately dispensing small volumes. Ritter and co-workers have demonstrated that CF3
I forms a 1:1 halogen-bonded adduct with tetramethylguanidine (TMG), which is liquid at ambient temperature, and can be stored at 0 °C for 2 months with no sign of decomposition, loss of CF3
I content, or pressure build-up ( Angew. Chem., Int. Ed. 2015
). In a similar manner, a stable 2:1 adduct with DMSO could be formed. In addition, CF3
I also forms stable 1:1 adducts with both TMG and DMSO, and these four formulations are commercially available from Sigma-Aldrich.
A novel direct aryl trifluoromethylation was developed using the TMG-adducts in conjunction with K2S2O8 and Cu(OAc)2·H2O in acetic acid at 90 °C. The reaction was demonstrated to be effective for electron-neutral and electron-rich arenes (including highly substituted arenes) as well as electron-deficient heterocycles. Although positional selectivities are modest, this method is operationally simple and proceeds under an ambient atmosphere without the rigorous exclusion of moisture. These adducts were also shown to be effective as a straight replacement for gaseous CF3I in a range of synthetic protocols. Though judicious selection of the adduct to be utilized is required as in some cases given the ability of TMG to also serve either as a one-electron reductant or a H atom donor leading to side-reactions occurring. The adduct stoichiometries were established by NMR, with X-ray crystallography and DFT calculations providing a deeper insight into the bonding interaction.
Synthesis of Acyl Carbamates via Four Component Palladium-Catalyzed Carbonylative Coupling of Aryl Halides, Potassium Cyanate, and Alcohols
Classical methods to access N-acyl carbamates typically suffer from several drawbacks including a lack of functional group compatibility, or the need to synthesize labile intermediates such as isocyanates or acyl chlorides. Skrydsrup and co-workers have reported on an alternative approach utilizing a four-component coupling approach utilizing aryl halides as substrates, and featuring their previously developed COgen setup for the in situ generation of CO ( Org. Lett. 2015, 17, 1248). Model studies on 4-bromoanisole using isopropyl alcohol as the substrate showed that optimum yields were obtained using 5 mol % of both Pd(cod)Cl2 with Xantphos as the ligand with the use of KOCN as the source of cyanate. The reaction was complete after 8 h at 70 °C with only 1.1 equiv of CO being required. From a substrate perspective, the reaction displayed good functional group tolerance for a range of aryl and heteroaryl bromides with the yields being shown to be somewhat sensitive to steric hindrance.
Various other alcohols were shown to be competent nucleophiles running the reactions with 2 equiv of the alcohol in dioxane at 70 °C, though using either amines or thiols led to either direct aminocarbonylation or no conversion, respectively. Two methods were devised to obtain the primary amide either through a one-pot two step reaction using t-BuOH followed by TFA cleavage, or by utilizing water as the nucleophile with the former providing slightly higher yields. This methodology was extended to provide 13C labeled primary amides, and a mechanistic hypothesis for the transformation is provided.
Access to Nitriles from Aldehydes Mediated by an Oxoammonium Salt
A range of versatile methods exist to access nitriles though drawbacks with these still exist such as use of toxic cyanide sources, harsh reaction conditions, or concerns with the stability of intermediates. Leadbeater and co-workers have reported on an oxidative synthesis of nitriles from aldehydes utilizing HMDS as a nitrogen source and mediated by Bobbitt’s salt ( Angew. Chem., Int. Ed. 2015
). The initial reaction was accompanied by an observed exotherm postulated to occur during oxidation of the intermediate imine, and this was successfully mitigated through use of CH2
as a solvent at up to 0.5 M scale. Pyridine was initially incorporated in the reaction system and while demonstrated to be unnecessary from a mechanistic standpoint was retained to sequester BF3
generated during the reaction.
The loadings of the oxoammonium salt and HMDS provided critical mechanistic insight enabling subsequent optimization and a plausible mechanism to be provided. A range of aryl and heteroaryl aldehydes are provided as successful substrates with electron-rich systems reacting at a significantly faster rate, and in some cases electron-poor systems gave the primary amide as a byproduct. Aliphatic aldehydes were also successful substrates though it was necessary to add the HMDS slowly to avoid side reactions, and obtain good yields.
α,β-Unsaturated aldehydes in which the double bond is not in further conjugation with an aromatic system led only to polymerization. The methodology was extended to utilize alcohols as substrates with oxidation to the aldehyde and subsequent formation of the nitrile taking place in a two-step one-pot approach.
Significant Enhancement in the Efficiency and Selectivity of Iron-Catalyzed Oxidative Cross-Coupling of Phenols by Fluoroalcohols
The iron-mediated oxidative cross-coupling of phenols is a useful reaction to access advanced phenol-based materials from simple building blocks. This method relies on the generation of high valent iron species, which induce a single electron transfer to generate an intermediate radical cation. Typically, these reactions are carried out in 1,2-dichloroethane (DCE) under forcing conditions, which leads to a deterioration in the yields and selectivity of the process.
Pappo and co-workers have reported on the use of fluorinated solvents for these processes, which are capable of reducing the oxidation potential of the phenols, and hence enable the reactions to take place under milder conditions ( Angew. Chem., Int. Ed. 2015
). Initial studies on the homocoupling of 2-naphthol showed that switching to 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) provided complete conversion to BINOL in 1 h, as opposed to 9% conversion after 24 h under the classical conditions with DCE as solvent. In addition, use of HFIP as solvent provided a system with superior oxidizing power enabling phenols with higher oxidation potentials to be used as substrates as evidenced by a range of examples featuring reactions with β-ketoesters. Furthermore, use of the new system enabled selective phenol oxidation in the presence of arenes followed by subsequent cross-coupling with only minimal amounts of the homocoupling products being observed which had hindered previous attempts to utilize this reaction as a viable synthetic process.
A range of examples are provided coupling phenols with both 1,3,5-trimethoxybenzene and polycyclic aromatic hydrocarbons (PAHs). The effects of fluorinated alcohols on other iron-mediated oxidative cross-couplings is also investigated with a coupling between β-diketones and phenols being developed, which was then highlighted as the key step in the total synthesis of 2‴-dehydroxycalodenin B.
In Situ Generation of Difluoromethyl Diazomethane for [3 + 2] Cycloadditions with Alkynes
The use of trifluoromethyl diazomethane in synthesis has enjoyed a renaissance in the past 5 years. However, despite the potential utility particularly in both the agrochemical and pharmaceutical field, the analogous difluoromethylated reagent has remained unknown. Mykhailiuk has reported on the generation and in situ utilization of this reagent and its subsequent use in a [3 + 2] cycloaddition with a range of alkynes ( Angew. Chem., Int. Ed. 2015
). A study of the degradation products when attempting to generate CF2
under classical conditions led to the conclusion that any successful synthesis would need to be conducted under both nonaqueous and nonbasic conditions. It was noticed that a colorless chloroform solution of trifluoroethyl amine, tert
-butylnitrite, and a catalytic amount of acetic acid changed to a strongly yellow color after 15 min at reflux. Addition of an alkyne and stirring at room temperature overnight led to the isolation of the desired pyrazole in 76% yield. This one-pot procedure does not require an inert atmosphere, was scaled to gram quantities, and does not involve the isolation of the potentially toxic and explosive CF2
The scope of the reaction indicate that the reaction is a type 1 [3 + 2] cycloaddition in that it is accelerated by electron-withdrawing groups on the alkyne, with unactivated alkynes demonstrated to be unsuccessful substrates. Furthermore, a correlation was observed between both the yield and rate and the strength of the electron-withdrawing group on the alkyne. In general, the reaction was regioselective with the electron-withdrawing alkyne substituent occupying the 5-position on the product pyrazole, though in one case steric effects were shown to override this electronic preference.
Alkyl Aryl Ether Bond Formation with Phenofluor
Although well-established methods exist for the synthesis of ethers, there are a number of issues with each of these particularly in terms of limited substrate scopes based on reactivity requirements. Ritter and co-workers have reported on a PhenoFluor-mediated aryl-alkyl ether synthesis, which represents a shift in terms of reactivity and enables gaps in terms of substrate scope of classical methods to potentially be addressed ( Angew. Chem., Int. Ed. 2015
The hypothesis behind the approach relied on diverting the typical deoxyfluorination reaction profile of PhenoFluor through trapping of the fluoride ions by silanes and utilizing alcoholates or phenolates as nucleophiles. Model studies indicated that this was possible with the optimal conditions utilizing PhenoFluor and TMS-imidazole (2 equiv) in dioxane at 60 °C. Using both the silyl ethers of the alcohol and phenol substrates led to higher yields, though the reaction scope was demonstrated without this modification to illustrate the operational simplicity. Electron-rich and electron-poor phenols were successful substrates including substituted-salicylaldehydes, which do not work in Mitsunobu reactions. Primary and secondary alcohols are within scope with 2,2,2-trifluoroethanol being utilized to access aryl trifluoroethers. The reaction proceeds with inversion at the alcohol center, and mechanistic/labeling studies indicate that the ether oxygen originates from the phenol and that tight ion pairs are of key relevance to the observed reactivity.
Nickel-Catalyzed Monofluoromethylation of Aryl Boronic Acids
Introduction of monofluoromethyl groups represents a novel strategy in modulating the biological, and physical properties of pharmaceutically relevant substrates, and as such new synthetic methods to achieve this transformation are of significant value. Several coupling approaches have been reported though suffer from limitations in terms of catalyst loadings and large excesses of substrates being required. Wang and co-workers have reported on a nickel-mediated approach in which the fluoromethyl groups contain either a phenylsulfone or ethoxycarbonyl substituent ( Angew. Chem., Int. Ed. 2015
Model studies using phenylboronic acid as the substrate with PhSO2CFHI indicated that Ni(acac)2 in conjunction with phosphine ligands (PPh3 was optimum) using K2CO3 as the base in CH2Cl2 at 100 °C were the optimum conditions. Switching to either the boronate ester or trifluoroborate led to no conversion. Good functional group tolerance was noted for both electron-donating and electron-withdrawing systems, though in the latter case, higher loadings of both catalyst and ligand were typically required. The optimized reaction conditions could then be extended using ethyl-2-bromo-2-fluoroacetate as the coupling reagent. Mechanistic studies indicate oxidative addition through a radical pathway with a catalytic cycle featuring Ni(I)/Ni(III) intermediates. Reductive desulfonylation was achieved using Na(Hg) for several examples, and this methodology demonstrated for the late stage fluoromethylation of ezetimibe.
“Reductive Addition” of a Boron–Boron Sigma-Bond to 4,4′-Bipyridine toward Organocatalytic Diboration
A 4,4′-bipyridine as an organocatalyst system for diboration of pyrazine derivatives was recently developed, with the formation of of E1–[cat]–E2 as a key catalyst intermediate via reductive addition of nonpolar E1–E2 bond to unsaturated substrates such as 4,4′-bipyridines. As shown in the graphic, there are two steps for the whole catalyst cycle: (1) reductive addition of the boron–boron bond of bis(pinacolato)diboron to 4,4′-bipyridine to form N,N′-diboryl-4,4′-bipyridinylidene and (2) oxidative boryl transfer from the intermediate to pyrazine to give N,N′-diboryl-1,4-dihydropyrazine with regeneration of 4,4′-bipyridine ( J. Am. Chem. Soc. 2015, 137, 2852−2855). The success of diboration to sterically hindered pyrazines demonstrated the remarkable catalyst efficiency of 4,4′-bipyridines and the mechanism involving organocatalytic σ-bond activation would be a new tool for organic transformations as an alternative to transition metal-catalyzed reactions.
Copper-Catalyzed Enantioselective Propargylic Etherification of Propargylic Esters with Alcohols
The first example of successful enantioselective propargylic etherification was developed recently in the presence a copper-Pybox complex catalyst ( J. Am. Chem. Soc. 2015, 137, 2472−2475). Not only aliphatic alcohols (such as methanol and ethanol) but also phenols could be applied to this transformation with propargylic esters to give the corresponding propargylic ethers in good to high yields with a high-to-excellent enantioselectivity (up to 99% ee). Propargylic carbonate was revealed to be a substrate of choice. It is noteworthy that a variety of propargylic carbonates bearing an alkyl substituent at the propargylic position are applicable as substrates in the present reaction system.
Cooperative Photoredox and Lewis Acid Catalysis for Enantioselective Conjugate Additions of α-Amino Radicals
A dual-catalyst protocol that combines transition metal photoredox catalysis with chiral Lewis acid catalysis was reported recently, targeting the highly enantioselective addition of photogenerated α-amino radicals to Michael acceptors ( J. Am. Chem. Soc. 2015, 137, 2452−2455). As shown in the graphic, up to 21 successful examples demonstrated the effective, general strategy to generate and control the reactivity of photogenerated reactive intermediates such as α-amino radicals as well as to efficiently transfer the chirality (up to 96% ee). It is also expected that the combination of photoredox and chiral Lewis acid catalysis could provide an approach to control the stereochemistry of a wide variety of photoinitiated organic reactions.
Relay Iron/Chiral Brønsted Acid Catalysis: Enantioselective Hydrogenation of Benzoxazinones
A relay iron/chiral Brønsted acid-catalyzed asymmetric hydrogenation of benzoxazinones was reported recently ( J. Am. Chem. Soc. 2015, 137, 2763−2768). As shown in the graphic, this approach provides a variety of chiral dihydrobenzoxazinones (23 examples) in good to high yields (75–96%) and enantioselectivities (up to 98:2 er) via in situ generation of organic reducing agents. The present methodology makes use of a simple iron carbonyl complex and proceeds with molecular hydrogen, which makes the overall process more atom-efficient compared to transfer hydrogenations. In addition, this catalytic reduction could generate interesting chiral building blocks from easily available starting materials in good to excellent isolated yields and chiral outcome. It is noteworthy that challenging 3-alkyl-substituted benzoxazinones underwent highly enantioselective reduction. A key to success is the utilization of a nonchiral phosphine ligand to decrease unselective background reductions through tuning the catalytic activity of Fe3(CO)12.
Catalyst-Free and Metal-Free Electrophilic Bromoamidation of Unactivated Olefins
An efficient, catalyst-free, and metal-free bromoamidation of unactivated olefins has been recently developed by using the N- bromosuccinimide/sulfonamide protocol ( J. Org. Chem. 2015, 80, 2815−2821). As shown in the graphic, 4-(trifluoromethyl)benzenesulfonamide and N-bromosuccinimide (NBS) were used as the nitrogen and halogen sources, respectively. It is worthwhile to mention that both cyclic and aliphatic olefins undergo this transformation. Mechanistic studies suggest that 4-CF3C6H4SO2NBr2 was generated in situ and might be the active halogenating species.
Renewable Polymers from Itaconic Acid by Polycondensation and Ring-Opening-Metathesis Polymerization
It is well-known that biobased raw material is a better alternative for polymer production in order to reduce the carbon footprint for industrial process. As a renewable feedstock obtained by fermentation of carbohydrates, itaconic acid is used as a key substrate to produce polynorbornenes as well as aliphatic unsaturated polyesters. For example, the solvent-free and straightforward Diels–Alder reaction of dimethyl itaconate (DMI) and cyclopentadiene was used to prepare a partially renewable norbornene monomer, which was used in the ring-opening-metathesis polymerization (ROMP) with different catalysts to prepare polymers with low dispersities and adjustable molecular weights. As shown in the graphic, ROMP of a DMI derived norbornene led to polynorbornenes, whereas renewable unsaturated polyesters were prepared by direct polycondensation of DMI with diols ( Macromolecules 2015, 48, 1398−1403). With tin(II) ethylhexanoate as catalyst, 4-methoxyphenol as a radical inhibitor, the direct polycondensation of DMI and different diols yielded linear unsaturated polyesters with a molecular weight up to 11 500 Da without isomerization or cross-linking of the vinylic double bond. Further modification of the unsaturated polyesters by thia-Michael addition gave polysulfides, which were subsequently oxidized to polysulfones. In addition, the therefrom derived unsaturated and functionalized renewable polynorbornenes could be further modified by hydrogenation to give better thermal properties, due to lower glass transitions as consequence of the increased flexibility of the polymer backbone.
Hydrosilylation Using a Neutral Silicon Lewis Acid
Tilley and co-workers reported the hydrosilylation of aromatic aldehydes using a neutral organosilicon Lewis acid ( J. Am. Chem. Soc. 2015, 137, 5328−5331). The reaction conditions typically involved treatment of the aldehyde substrate with 5 mol % of the Lewis acid in deuterated dichloromethane at 25 °C, and the reaction times were 0.5–2 h. The reported reaction conditions tolerated a variety of silane substituents including sec-alkyl, tert-alkyl, aryl, and dimethylamido groups. The effect of various electron withdrawing groups on the aromatic aldehyde on reaction yield was reported. The Lewis acidity of the silicon catalyst was explored by complexation with Lewis bases such as triphenylphosphine oxide, trans-crotonaldehyde, and N,N′-diisopropylbenzamide; weak affinity to aldehydes and strong affinity to benzamides and triphenylphosphine oxide was observed. Stereochemical retention was predominantly observed with a chiral silane and a mechanism was proposed based on the effect of retention on solvent polarity and salt.
Manganese-Catalyzed C–H Azidation
Groves and co-workers reported a novel Mn-catalyzed azidation reaction using aqueous sodium azide that can be applied to late-stage functionalization of complex substrates ( J. Am. Chem. Soc. 2015, 137, 5300−5303). The standard conditions described above were used to transform a variety of cycloalkyl, aromatic, heteroaromatic, and fused cyclic substrates, as well as clinical drugs and/or drug analogs to the corresponding azides in moderate-to-good yields. Mn-porphyrins as well as Mn-salen complexes were found to be good catalysts for this transformation, and the reaction could be conducted in air. Kinetic isotope effect studies, azidation of chiral substrates, and DFT calculations were used to propose a mechanism involving formal oxidation to a Mn(V)═O complex bearing an axial azide which abstracts a H atom resulting in a Mn(IV)–N3 complex that leads to C–N3 bond formation and regeneration of the Mn(III) catalyst.
Synthesis of Tertiary Carbamates Using Copper Catalysis
Kanai and co-workers reported the synthesis of tertiary carbamates from isocyanates and hydrocarbons using tetrakis(acetonitrile)copper(I) tetrafluoroborate ( Chem. Sci. 2015, 6, 3195−3200). Aromatic isocyanates bearing electron-withdrawing and donating substituents, aliphatic and cycloaliphatic isocyanates all gave moderate-to-good yields of the tert-butylcarbamate product. The reaction had a broad substrate scope with respect to the hydrocarbon, and the observed selectivity was 3° > 2° > 1°. A series of control reactions, kinetic isotope studies, and kinetic studies using in situ FT-IR spectroscopy were used to propose a mechanism involving rate-determining cleave of the C(sp3)–H bond.
Photoinitiated Living Radical Polymerization of Acrylates, Acrylamides, and Vinyl Acetate
Fu and co-workers reported a controlled living polymerization methodology using a Co(salen) catalyst and visible light photoinitiator ( Chem. Sci. 2015, 6, 2979−2988). Several acrylates, acrylamides, and vinyl acetate were polymerized using the Co(salen) complex as both the initiator and polymerization mediator to obtain polymers with average molecular weights in the range 14000–68000 with polydispersity indices of <1.25. The addition of 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TPO) improved the polymerization efficiency, and it was shown that polymerization could take place using a household compact fluorescence lamp or sunlight. The light source was essential for initiation but not required for chain propagation. Analysis of the polymer structures using NMR spectroscopy, GPC, and MALDI-MS revealed that ω and α chain ends were capped with Co(salen) and −CO2Me, respectively, and it was shown that the ω end could be functionalized to −OH by oxygenation followed by hydrolysis.
Palladium-Catalyzed Amination of Aryl Sulfides
Aryl sulfides represent an interesting but challenging class of electrophiles in cross-coupling reactions. Yorimitsu, Osuka, and co-workers from Kyoto, Japan, have recently extended the scope of their previously described amination of aryl sulfides with anilines ( Angew. Chem., Int. Ed. 2015, 53, 9329) to encompass aliphatic amines as substrates ( Eur. J. Org. Chem. 2015, 2678). The optimized conditions use precatalyst SingaCycle-A1 in combination with potassium hexamethyldisilazide at 60 °C in apolar solvents, with toluene being the best. A variety of substituted aryl sulfides react with primary and secondary alkylamines and anilines to furnish the amination product in moderate-to-high yields. Examples of the reaction of a selection of (hetero)aryl sulfides under the same conditions but without recourse to any palladium source are also provided.
Palladium-Catalyzed Csp2–H Functionalization of Heteroarenes via Isocyanide Insertion
Although isocyanides have found numerous applications as versatile C1 synthons in transition-metal catalysis, their use in C–H activation processes under intermolecular conditions have rarely been explored. Van der Eycken and Xu’s groups have recently reported a methodology for the synthesis of a di(hetero)aryl framework through the insertion of an isocyanide into an aryl halide bond followed by the attack of a heterocycle via C–H activation ( Chem. Eur. J. 2015, 21, 4908). Ketones and benzylic amines can be synthesized in this fashion by reacting a heteroarene, an isocyanide, and an aryl halide in the presence of palladium acetate, XantPhos, and cesium carbonate in acetonitrile at 110 °C. While ketones are obtained by silica gel promoted hydrolysis of the imines, zinc-mediated reduction provides the corresponding amines. A large substrate scope was demonstrated regarding the heterocycle and (hetero)aryl halide coupling partners (with most functional groups being tolerated excepted nitro), but only secondary and tertiary alkyl substituted isocyanides were found to provide the desired products under the developed conditions.
Palladium-Catalyzed Synthesis of 3-Bromosubstituted Pyrroles
Pyrroles represent an interesting class of heterocycle that exhibit diverse biological and therapeutic activities. Jiang’s group from Guangzou, China, have recently disclosed a new strategy for the synthesis of 3-bromopyrroles that relies on a palladium-catalyzed intermolecular oxidative cyclization of bromoalkynes with N-allylamines ( Chem. Commun. 2015, 51, 5894). The reaction is best carried out in toluene/DMF mixture with palladium dichloride as catalyst and benzoquinone as oxidant. An array of bromoalkynes and N-allylamines are tolerated under the reaction conditions, but only aryl groups can be introduced efficiently at the 1- and 2-position of the pyrrole ring. Moreover, branched allylamines failed to provide the desired products. The reaction was successfully extended to propargyl esters to give pyrroles substituted in the 3-position with an ester.
Palladium-Catalyzed Aminocarbonylation of N-Chloramines with Boronic Acids
Palladium-catalyzed aminocarbonylation of aryl halides has evolved into a reliable tool for amide bond formation since its discovery by Schoenberg and Heck, but the related transformation of N–X bond was unknown until Wu and Li from Rostock, Germany, succeeded in developing the aminocarbonylation of N-chloramines with boronic acids ( Chem. Eur.—J. 2015, 21, 7374). A mechanistic study reveals that a hybrid organometallic-radical process is involved instead of the expected oxidative carbonylation process. Interestingly, Pd/C is used as a ligand-free and recyclable catalyst for this transformation which is best performed in tert-butyl methyl ether with sodium hydrogen carbonate as base. N-Chloramines are generated in situ from the corresponding amines by reaction with N-chlorosuccinimide. A large substrate scope was demonstrated for the boronic acid coupling partner with aliphatic, aromatic, and alkenyl amides being accessible with this methodology. Worthy of note, bromide and iodide substituted aryl boronic acids also provide the corresponding products in moderate-to-high yields. However, it should be noted that this process is limited to secondary and sterically nonhindered amines.
Palladium-Catalyzed Acylative Suzuki Coupling of Amides
Transition metal-catalyzed cross-coupling of aryl boronic acids with carboxylic acid derivatives represents of interesting alternative to the traditional Friedel–Craft acylation and the nucleophilic addition of organometallics to carbonyl derivatives for the synthesis of aryl ketones. Zou and Li from China have disclosed the unprecedented use of amides as electrophiles in this type of coupling ( Chem. Commun. 2015, 51, 5089. The authors observed that in the presence of potassium carbonate a catalytic system composed of tricyclohexylphosphine and dichlorobis(tricyclohexylphosphine)palladium(II) was able to promote the reaction of various N-phenyl-N-tosyl amides with boronic acids. Whereas the electronic effects seem to have only marginal influence on the outcome of the reaction, the steric hindrance on both coupling partners significantly hampers the yield. Indeed, ortho-substituted phenyl boronic acids and bulky alkyl amides (such as adamantyl) led to decreased yields. The authors demonstrated that this limitation can be overcome by replacing the N-phenyl group of the amide by a more electron-deficient N-(3,5-bis(trifluoromethyl)phenyl) moiety.
One-Pot Synthesis of Chiral Lactones
In searching for efficient and economical synthesis, chemists are constantly exploring various opportunities to conduct multicomponent reactions in one-pot. Recently, a one-pot process was developed (Riguet, E., et al. J. Org. Chem. 2014, 79, 10881) for the synthesis of chiral γ-lactones. This process involves a sequential enantioselective organocatalytic Michael addition of boronic acid and diastereoselective intramolecular Passerini reaction. An “ate complex”, formed from the carboxylate group in the iminium ion and boronic acid, facilitates the aryl migration followed by the intramolecular Passerini reaction with isocyanide to furnish the desired chiral lactones. Water was chosen as an additive to improve the overall reaction. The solvent effect was also observed, using nitrile solvents gave good product yields with high enantiopurity. Other solvents, such as ethyl acetate, dichloromethane, ethanol, etc., required longer reaction times and gave inferior results. Reactions in DMF or DMSO were not complete even after prolonged reaction times.
Diastereo- and Enantioselective Synthesis of 1,2-Dihydronaphthalenes
Besides optical resolution, asymmetric synthesis has been increasingly utilized to access chiral compounds. Generally, synthesis of chiral dihydronaphthalenes by metal-catalyzed dearomatization of electron-deficient naphthalenes requires either chiral auxiliary or ligands. With a view of developing metal-free asymmetric synthesis, Sun and co-workers of Hong Kong University of Science and Technology disclosed an organocatalytic enantio- and diastereoselective synthesis of 1,2-dihydronaphthalenes ( J. Am. Chem. Soc. 2015, 137, 560). The reaction was proposed to proceed through an isobenzopyrylium, generated in situ from the corresponding acetal, whose reaction with vinylboronic acid occurs to form [4 + 2] cycloaddition bicyclic zwitterionic intermediate in a highly diastereo- and enantioselective manner. The subsequent intramolecular elimination gives the observed dihydronaphthalene product.
Regiospecific Synthesis of N-Substituted Indoles
Indoles are valuable intermediates in organic synthesis and various synthetic methods, including metal-catalyzed and metal-free reactions, have been developed. The metal-catalyzed synthesis is generally started with halogen-substituted aromatic substrates in order to achieve C–C bond formation via C–X bond oxidative insertion. Recent-developed C–H bond activation strategy allows the C–C bond coupling directly without resorting aromatic halogenation to access C–X functionality. In order to achieve the C–H bond activation in a catalytic fashion, an external oxidant is usually needed to regenerate the catalytic species. A report by Huang and co-workers, published in Org. Lett. 2014, 16, 5976, revealed a ruthenium-catalyzed redox-neutral C–H activation in which “an oxidative functional group serves as both a directing group (DG) and an internal oxidant” without using the external oxidant. In the presence of alkynes, including both internal and terminal alkynes, the subsequent C–C bond coupling followed by cyclization afforded the desired indoles in good yields. This protocol tolerated a wide range of functional groups, which is not common as the reactions were conducted at 110 °C. For asymmetric alkyl aryl alkynes, “single regioisomers (2-aryl-3-alkylindoles) were obtained exclusively.”
Metal-Free Synthesis of 1,3-Oxazinen-4-ones
Generally, most chemical reactions generate byproducts in addition to the desired products, which have to be separated. Those byproducts may have environmental issues associated with their disposal. Catalytic reactions have been widely utilized in chemical and pharmaceutical industries to address the cost and environmental impact. Hawkins and co-workers developed a metal-free and atom-economic protocol for the synthesis of 1,3-oxazinen-4-ones ( Org. Lett. 2015, 17, 234). The synthesis started with a transformation of cyclopropyl carboxylic acids to the corresponding acid chlorides, followed by a reaction with imines. The resulting N-acyliminium cyclopropane intermediates underwent a nucleophilic cyclopropane ring-opening and cycloaddition cascade to provide the products. Such cascade process is highly desired as it generates no process wastes.
A Bioinspired Rearrangement
Access to a molecule with complex structure via rearrangement is a common approach in organic synthesis, which represents an atom- and step-economic synthesis as per green chemistry. The marine natural product (+)-aureol is biologically active, containing a compact tetracyclic ring system with four contiguous stereocenters and a cis-relationship between the two cyclohexane rings. Recently, a biosynthetic strategy was disclosed (Rosales, A. and Oltra, J. E., et al. Org. Chem. 2015, 80, 1866), involving a stereospecific rearrangement of a tricycle with exo-olefin moiety into a tetrasubstituted olefin. This BF3·Et2O-mediated rearrangement proceeds through a coordination-activation of the exo-olefin moiety by the Lewis acid, which would lead to an intermediate (I). The subsequent cascade stereospecific 1,2-H shift and stereospecific 1,2-Me shift sequence delivers the desired tetrasubstituted olefin efficiently.
Synthesis of Tetrahydrofuran Lignans via Oxidative Ring-Opening of Diarylcyclobutane
Lignan natural products comprise a broad spectrum of biologically active secondary metabolites. Lignan biosynthesis occurs through a putative bis-para-quinone methide as a key intermediate. Inspired by the biosynthesis, Lumb and Albertson developed a total synthesis of tetrahydrofuran lignans ( Angew. Chem., Int. Ed. 2015, 54, 2204). To access the bis-para-quinone methides, I and II, the researchers identified the reaction conditions (FeCl3·6H2O/acetone–water, 0 °C) that allowed an oxidative ring-opening of diarylcyclobutanes. Depending on the inherent stereoselectivity of the resulting I and II, (±)-tanegool and (±)-pinoresinol were obtained in 59% and 48% yields, respectively. This approach allowed to access tanegool in four steps from ferulic acid, which provides an alternative approach to the tetrahydroguran lignans.
Metal-Free Synthesis of Indole via NIS-Mediated Cascade C–N Bond Formation/Aromatization
Indoles are basic structural elements in a wide range of naturally occurring biologically important compounds and are widely utilized in chemistry, biology, and material sciences. As such, novel and robust indole syntheses are of interest. Deng and co-workers at Tianjin University reported a practical and metal-free rapid synthesis of indoles under mild conditions via an NIS-mediated cascade C–N bond formation/aromatization of N-Ts-2-alkenylanilines ( J. Org. Chem. 2015, 80, 3841). Protection of the aniline nitrogen with a tosyl group and two equivalents of NIS were required to obtain the maximum yields. Methylene chloride and 1,2-dichloroethane were the most efficacious solvents. A variety of functional groups were tolerated in the synthesis. The yield was only minimally impacted by the electronic nature of the substituents.
Selective Synthesis of Alkylboronates by Copper (I)-Catalyzed Borylation of Allyl or Vinyl Arenes
Alkylboronates have demonstrated utility in traditional Suzuki–Miyaura cross-coupling reactions and alkylation regents in oxidative cross-coupling reactions. Further, alkylboronates exhibit superior shelf stability versus other C(sp3) organometallics. Wen and co-workers at Guangdong Ocean University described a new borylation reaction which exhibits both high activity and excellent regioselectivity for allyl and vinyl arenes ( J. Org. Chem. 2015, 80, 4142). The reaction is operationally simple to perform–equimolar quantities of the allyl or vinyl arene and Pin2B2, catalytic copper (1) chloride, and a slight molar excess of base. The reaction does not proceed without either the copper catalyst or the base. Markovnikov regioselectivity was observed in the reactions, resulting in addition of the boron atom to the internal carbon of allyl arenes. In stark contrast, anti-Markovnikov regioselectivity was observed in the reactions involving styrene derivatives. The authors propose a mechanism to explain this dichotomy of results.
Catalytic Domino Reaction of Ketones/Aldehydes With Me3SiCF2Br for the Synthesis of α-Fluoroenones/α-Fluoroenals
Installation of fluorine into organic molecules has become a powerful strategy in drug discovery and new material design. Zhu, Liu, and Wang at Northeast Normal University detailed a unique catalytic, domino reaction for the synthesis of α-fluoroenones and α-fluoroenals ( Org. Chem. 2015, 17, 1712). The key to this cascade reaction sequence is the reagent Me3SiCF2Br, which serves as a source of the corresponding silyl enol ether and difluorocarbene. The reaction cascade was triggered by catalytic amounts of both tetrabutylammonium bromide (TBAB) and tetrabutylammonium fluoride (TBAF). Toluene was found to be the optimal reaction solvent; 110 °C was the optimal reaction temperature. The reaction tolerated a variety of functional groups, including ether, ester, nitro, halo, and nitrile.
Synthesis of Vinyl Boronates from Aldehydes by a Practical Boron–Wittig Reaction
Vinyl boronic esters are broadly useful functional motifs in organic synthesis. They possess high chemical stability and yet participate in a variety of transformations, including Suzuki–Miyaura couplings and Petasis reactions. Morken and co-workers at Boston College reported a novel, transition-metal-free synthesis of these important building blocks ( Org. Lett. 2015, 17, 1708). The methodology was predicated on a highly stereoselective boron–Wittig reaction between stable 1,1-bis(pinacolboronates) and aldehydes. The reactions were high yielding and afforded high selectivity for the E isomer. The methodology was further extended to afford 1,1-disubstituted and trisubstituted vinyl boronates.
Transition-Metal-Free Access to Primary Anilines from Boronic Acids and a Common +NH2 Equivalent
The formation of C–N bonds constitutes one of the most important transformations in organic synthesis, due primarily to the large proportion of biologically relevant structures, dyes, and materials that contain amines. Consequently, convenient, high-yielding synthetic methods for anilines are of continued interest. McCubbin and co-workers at the University of Winnipeg reported a transition-metal-free, operationally simple aniline synthesis from arylboronic acids ( J. Org. Chem. 2015, 80, 2545). The source of nitrogen is hydroxylamine-O-sulfonic acid (HSA), which was previously reported not to react with boronic acids. A 1:1 mixture of acetonitrile and water was found to be the optimal solvent system. Sodium hydroxide was the optimal base. The reaction was incompatible with nitro, ketones, esters, and nitriles, although arylboronic acids containing amines, phenols, ethers, and halogens were suitable substrates. The free boronic acid was required.
Copper-Mediated Trifluoromethylation Using Phenyl Trifluoromethyl Sulfoxide
Organofluorine compounds have been the subject of increasing research activity in recent years, since the incorporation of fluorine into bioactive compounds can enhance their lipophilicity and metabolic stability. In this context, aromatic compounds bearing a −CF3 group(s) are frequently utilized in medicinal and agricultural chemistry. Wang, Hu, and their co-workers from the Shanghai Institute of Organic Chemistry described a mild method for the generation of “CuCF3” and its utility in the trifluoromethylation of aryl halides, terminal alkynes, and arylboronic acids ( Org. Lett. 2015, 17, 298). Commercially available phenyl trifluoromethyl sulfoxide was converted in essentially quantitative yield to CuCF3; the conversion of the corresponding sulfone was much less efficient. CuCF3, stabilized with Et3N·HF, reacted efficiently, with a variety of (hetero)aryl bromides and iodides to afford the corresponding trifluoromethylated (hetero)arenes in good yields. No external ligands were required to promote this coupling. The reaction was further extended to the trifluoromethylation of terminal alkynes and arylboronic acids.
Organocatalytic Synthesis of Benzoxazoles and Benzothiazoles Using Aryl Iodide and Oxone via C–H Functionalization and C–O/S Bond Formation
The construction of benzoxazole and benzothiazole structural motifs has been a topic of immense interest in recent years due to their presence in a number of natural products and biologically active compounds. Punniyamurthy and co-workers at the Indian Institute of Technology Guwahati reported an organocatalytic protocol for the synthesis of substituted benzoxazoles and benzothiazoles ( J. Org. Chem. 2014, 79, 7502). Aryl-alkyl(thio)anilides were the starting materials; 4-iodonitrobenzene was the catalyst, and oxone was the oxidant. The reaction was conducted in hexafluoro-2-propanol (HFIP) as the solvent at room temperature. Good yields were obtained with electron donating or mildly electron withdrawing substituents. Low yields were obtained with strongly electron withdrawing substituents (e.g., nitro, nitrile, ester).
Correction: Updated Reference
The Highlights published in Org. Process Res. Dev. 2015, 19 (3), 389–398 contained an error in the reference so the highlighted article is repeated below with the correct reference.
Hydrogenations at Room Temperature and Atmospheric Pressure with Mesoionic Carbene-Stabilized Borenium Catalysts
The development of new catalysts for hydrogenation based on frustrated Lewis pairs (FLPs) is a challenge due to the difficulty in accessing or preparing analogues of B(C6
that are still Lewis acidic enough to heterolytically cleave hydrogen to enable the desired reaction to take place. Crudden and co-workers have prepared a series of electronically unique catalysts through reaction of a deprotonated triazolium salt (easily accessed by a Huisgen cycloaddition) and 9-BBN under noncryogenic conditions ( Angew. Chem., Int. Ed. 2015
). These mesoionic N
-heterocyclic carbenes (MIC) not only have greater hydricity to their NHC congeners but are also predicted to be more stable and accessible with varying degrees of steric hindrance based on their simple synthesis. For hydrogenation, an in situ protocol for generation of the borenium ions was developed by hydride abstraction prior to addition of the substrate and exposure to hydrogen. Reactivity comparisons in the reduction of aldimines indicated that the MIC-stabilized borenium ions showed enhanced reactivity compared to their NHC-stabilized counterparts with an increase in reactivity being observed with decreased steric crowding around the boron atom. This enabled reactions to be carried out under ambient hydrogen pressures in regular glassware. Electronic factors and remote steric factors also played a role in dictating the reactivity, and the reaction was shown to be sensitive to catalyst inhibition by imines and product amines lacking steric bulk. A range of quinolines and pyridines were successfully hydrogenated though more forcing conditions were required for the latter. Mechanistic studies indicated that hydrogen activation is likely to be the rate-limiting step.
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