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

Highlights from the Literature pubs.acs.org/OPRD

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

■

COBALT-CATALYZED CROSS-COUPLINGS OF BENCH-STABLE ARYLZINC PIVALATES WITH (HETERO)ARYL AND ALKENYL HALIDES

Fasan and co-workers report the use of engineered myoglobin expressed in bacteria for catalysis of the diastereo- and enantioselective transfer of the carbene generated from 1,1,1trifluoromethyl-2-diazoethane to olefins (J. Am. Chem. Soc. 2017, 139, 5293). The gaseous 1,1,1-trifluoromethyl-2-diazoethane is generated ex situ from the diazotization of 2,2,2-trifluoroethylamine with NaNO2 and bubbled through the mixture of olefin and whole cells expressing the myoglobin with the aid of argon as a carrier gas. The generation of the diazo species ex situ overcomes the incompatibility of such reaction conditions with proteins. Although the scope of olefins is limited to a range of styrenes and a single thiophene derivative, the isolated yields are good and the stereoselectivities remarkable.

■

Nonprecious metal-catalyzed cross-coupling reactions have attracted great interest in recent times. Especially of interest are those methodologies that use simple metal salts without the need for an (often expensive) added ligand. Knochel and co-workers report the cobalt(II) chloride catalyzed cross-coupling of arylzinc pivalates with sp2-halides under mild conditions (Synthesis 2017, 10.1055/s-0036−1588986). Zinc pivalates have been demonstrated as bench-stable solids for Negishi-type cross-couplings and by employing catalytic amounts of CoCl2 (≤5 mol %) in THF at a slightly elevated temperature (40 °C) the authors successfully couple heteroaryl chlorides and bromides, aryl bromides and iodides, and alkenyl bromides with these pivalates. Yields are generally good (>60%) and unaffected by increasing scale between 1 and up to 20 mmol of halide. The cross-coupling of nitrogen heterocycles was demonstrated, including pyridines, quinolines, pyrimidines, and triazines. When cross-coupling nitrogen heterocycles at the 2-position, the catalyst loading could be lowered to 1 mol % without loss of efficiency. Alkene geometry is also retained during cross-coupling of alkenyl bromides.

■

USE OF A TRACELESS ACTIVATING AND DIRECTING GROUP FOR THE CONSTRUCTION OF TRIFLUOROMETHYLPYRAZOLES: ONE-POT TRANSFORMATION OF NITROOLEFINS AND TRIFLUORODIAZOETHANE

The 3-trifluoromethylpyrazole is a key structural motif found in many agrochemical and pharmaceutical active substances. Ma and co-workers from Tianjin in China have recently extended the scope of the cyclo-addition of 2,2,2-trifluorodiazomethane to the regioselective synthesis of 4-substituted 3-trifluoromethylpyrazoles by using nitroolefins as dipolarophiles (Angew. Chem., Int. Ed. 2017, 56, 4569). They found that a combination of silver(I) oxide and sodium phosphate efficiently mediates the desired reaction where the nitro group acts as a traceless activating and directing group which is removed in situ by elimination. The reaction performed well producing the 3-trifluoromethylpyrazoles in good-to-high yields regardless of the nature of the nitroolefin substrates, with heteroaryl moieties such as pyridines and furans being tolerated. Two protocols were developed, one of them relying on the in situ generation of the diazonium obviating the need for its isolation. Examples of the use of other perfluorinated diazoniums and a brief mechanistic study are also provided.

MYOGLOBIN-CATALYZED DIASTEREO- AND ENANTIOSELECTIVE SYNTHESIS OF CF3−CYCLOPROPANES

Published: June 8, 2017 © 2017 American Chemical Society

789

DOI: 10.1021/acs.oprd.7b00193 Org. Process Res. Dev. 2017, 21, 789−799

Organic Process Research & Development

■

Highlights from the Literature

AEROBIC OXIDATION OF METHYLARENES TO BENZALDEHYDES CATALYZED BY COBALT(II) ACETATE AND N-HYDROXYPHTHALIMIDE (NHPI) IN HEXAFLUOROISOPROPANOL (HFIP)

nitrile-based solvents (J. Org. Chem. 2017, 82, 4044). Lossen rearrangements are often challenging to perform on scale owing the large exothermic potential of the activated hydroxamic acid intermediates typically used and isocyanates generated from their rearrangement. During the development of a route to BMS-955176 the authors discovered an unusual synergy between nitrile-based solvents and DBU for the rearrangement without need to activate the hydroxamic acid. Through mechanistic investigations they elucidated a pathway whereby the nitrile activates the hydroxamic acid followed by rearrangement to the isocyanate. This isocyanate reacts rapidly with another molecule of hydroxamic acid to generate a dimer that breaks down to a carbamic acid and regenerates isocyanate, hence the pseudocatalytic nature of this species. The carbamic acid gives the final amine product by decarboxylation. The optimized reaction was performed on 55 kg scale giving 99.8% conversion and 95.5% isolated yield after crystallization.

■

SYNTHESIS OF PYRROLES VIA A SILVER-CATALYZED 1,3-DIPOLAR CYCLOADDITION/OXIDATIVE DEHYDROGENATIVE AROMATIZATION TANDEM REACTION Pyrroles are an important class of aromatic heterocyclic compounds that can be found in a large number of natural products. Synthetic pyrrole derivatives have found important applications in biology, medicine, material science and the dye industry. Despite their demonstrated importance, there are few reports pertaining to the one-pot synthesis of pyrroles from simple alkenes. Hu and co-workers from Huaiyin Normal University and Southwest University of Science and Technology described an operationally simple synthesis of pyrroles from readily available alkenes and imines (J. Org. Chem. 2017, 82, 4194). The initial [1,3] dipolar cycloaddition between an imine and an alkene was catalyzed by silver carbonate. The resultant pyrrolidines were oxidized in situ with benzoyl peroxide (BPO) to afford the corresponding pyrroles in good overall yields. The reaction was tolerant of a variety of functional groups on the phenyl ring of the imine, including halide and ether; nitro substitution was not tolerated however. Alkenes bearing a broad range of electron withdrawing groups reacted smoothly. This methodology affords a practical synthetic method for the preparation multisubstituted pyrroles.

The oxidation of methylarenes to benzoic acids catalyzed by Co(OAc)2/NHPI has been broadly studied and proceeds well with acetic acid as solvent. Pappo and co-workers report the use of HFIP as a solvent for this transformation that inhibits autoxidation of benzaldehydes to the corresponding benzoic acids, thereby enabling the synthesis of benzaldehydes from methylarenes with high selectivity (Angew. Chem., Int. Ed. 2017, 56, 5912). Interestingly, when o-, m-, pxylene or mesitylene were employed only a single methyl group undergoes oxidation giving o-, m-, p-tolualdehyde or 3,5-dimethylbenzaldehyde. A wide range of functional groups are tolerated under the reaction conditions including halides, esters, ethers, amides, alkenes, and carboxylic acids. Unprotected phenols are not tolerated as they interrupt the radical chain reaction. A 20 mmol scale reaction with 4-tert-butyl toluene was demonstrated, generating the corresponding aldehyde in 75% yield with 85% of the expensive HFIP solvent recovered by distillation.

■

A NITRILE INITIATED LOSSEN REARRANGEMENT “PSEUDO-CATALYTIC” IN ISOCYANATE

■

DECARBOXYLATIVE BORYLATION Boronic acids and their esters are of paramount importance to all facets of chemical science. Although their popularization has largely been spurred by the incredible utility of the Suzuki coupling, boronic acids have, to date, found countless applications in fields far outside of cross-coupling, such as materials science, chemosensor development, and

Strotman and co-workers from Bristol-Myers Squibb report the discovery and development of a mild Lossen rearrangement of hydroxamic acids to amines mediated by DBU in 790




drug discovery. Baran and co-workers at the Scripps Research Institute and Calibr reported a simple and practical method to rapidly access densely functionalized alkyl boronate esters from abundant carboxylic substituents (Science 2017, 10.1126/science.aam7355). The alkyl carboxylic acids were converted into the redox-active N-hydroxyphthalimide ester. Inexpensive NiCl2·6H20 and the bipyridyl compound L1 were found to be the optimal catalyst and ligand for the decarboxylative borylation. A binary solvent mixture of THF and DMF afforded the optimal yields omission of DMF afforded significantly lower yields. In the absence of MgBr2· OEt2, virtually no product was obtained. The reaction conditions tolerated a variety of functional groups, including: ethers, esters, amides, ketones, olefins, and alcohols. The described simple method for nickel-catalyzed decarboxylative borylation proved general for a range of primary, secondary, tertiary, and peptide derived structures.

■

■

DECARBOXYLATIVE ALKENYLATION

The Baran laboratory, in conjunction with chemists at BristolMyers Squibb and Asymchem, have developed and reported a method for decarboxylative alkenylation of aliphatic carboxylic acids (Nature 2017, 10.1038/nature22307). The chemistry follows in the footsteps of previous reported chemistry from the group, using redox-active esters (RAEs) as intermediates that permit the lysis of a weak N−O bond and generation of a carboxy radical; decarboxylation ensues followed by the interception with Ni prior to cross-coupling. The coupling partners are alkenylzinc species, available by a wide variety of protocols, and most conveniently accessed by metal−halogen exchange followed by simple transmetalation. The general reaction conditions are surprisingly simple: once the RAE is obtained (either exogenously generated or synthesized in situ), the treatment of it with alkenylzinc reagent and substoichiometric quantities of both Ni(acac)2·xH2O and 2,2′-bipyridine in a THF/DMF solvent mixture at ambient temperature leads to the product. The chemistry is sufficiently general that the authors were able to couple all classes of carboxylic acids (whether they led to primary, secondary, or tertiary radicals) to all classes of alkenylzinc species (whether they led to mono-, di-, tri-, or tetrasubstituted alkenes). The chemistry is robust, as it could be applied to polyfunctional molecules, including peptides, and opens up nonintuitive possibilities, examples of which can be found in the article. Lastly, it should be noted that the chemistry has been scaled up to the mole scale.

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

Difluoromethyl substituents are increasingly common components of pharmaceuticals and agrochemicals. Therefore, there is significant demand for synthetic methods that enable the formation of carbon−CHF2 bonds. Sanford and co-workers at the University of Michigan detailed the preparation, isolation, and utility of N-heterocyclic carbene [(NHC)Cu(CHF2)] complexes in organic synthesis (Organometallics 2017, 36, 1220). Copper(I) compounds bearing the bulky IPr [(1,3bis(2,6-disopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene] ligand exhibited a high stability in solution at room temperature. The isolated complex (IPr)Cu(CHF2) reacted stoichiometrically with aryl iodides at an elevated temperature. Further, the synthetic methodology was extended to a (IPr)CuCl-catalyzed difluoromethylation of aryl iodides. The reaction tolerated a wide variety of additional substituents, including acetal, carbonyl, nitro, nitrile, ether, and halides, but was particularly effective for electron-rich aromatic substrates. This methodology should find wide applicability in the arenas of agrochemicals, materials science, and pharmaceuticals. 791




preferred catalyst, and a mixed solvent system of DMPU/THF was optimal. The amount of Ti(OEt)4 was optimized at 0.4 equiv. This biaryl coupling proved to be quite general both activated and unactivated aryl fluorides afforded uniformly high yields. The reaction was highly selective for C−F bond activation, in the presence of C−Br and C−Cl bonds.

■

C(SP2)−H BORYLATION OF FLUORINATED ARENES USING AN AIR-STABLE COBALT PRECATALYST: ELECTRONICALLY ENHANCED SITE SELECTIVITY ENABLES SYNTHETIC OPPORTUNITIES The direct, selective C−H functionalization of organic molecules in the absence of directing groups is a grand challenge in modern catalysis. Fluorinated arenes are prominent targets given the prevalence of this subunit in pharmaceuticals, agrochemicals, and organic materials. Chirik and co-workers at Princeton University reported a general cobalt-catalyzed method for the ortho-tofluorine-selective borylation of a wide range of fluorinated arenes (J. Am. Chem. Soc. 2017, 139, 2825). The reaction of cobalt(II) pivalate with the pincer ligand 4-Me-(iPrPNP) afforded the airstable precatalyst 4-Me-(iPrPNP)Co(O2CtBu)2 precatalyst (A). Catalytic C−H borylation was accomplished with a catalytic amount of A and one equivalent of B2pin2 in THF at 80 °C. The activity and selectivity with A proved quite general among a range of fluorinated arenes. High isolated yields and ortho-tofluorine selectivity were observed regardless of the substituents on the arene or the substitution pattern. The reaction displayed excellent functional group tolerance on the fluoroarene; however, bromo and chloro substituents were not tolerated. This simple synthetic procedure afforded fluorinated aryl boronate esters in good yield, with the site selectivity different from that obtained with iridium catalysts.

■

IODINE-MEDIATED INTRAMOLECULAR C−H AMIDATION FOR THE SYNTHESIS OF N-SUBSTITUTED BENZIMIDAZOLES C−N bond formation via direct oxidative coupling of C−H and N−H bonds features atom- and step-economy and as such has received considerable attention in recent years. Benzimidazole is a privileged structural unit present in many biologically active compounds. Yu and co-workers at Zhenghou University have extended their previous work in the field to the intramolecular synthesis of benzimidazoles (J. Org. Chem. 2017, 82, 3152). The imine intermediate (A) was readily prepared from N-tosyl-1,2phenylenediamine and the corresponding aromatic aldehyde in ethanol. Extensive studies were performed to optimize the intramolecular cyclization. The preferred solvent for the cyclization was methylene chloride. Therefore, it is imperative to remove the ethanol prior to the cyclization step. A portion of 1.2 equiv of the oxidant iodine afforded the highest yield, and excess potassium carbonate was required. The method is compatible with a variety of electron-donating or electronwithdrawing groups on the phenyl ring of the aldehydes; uniformly high yields were obtained. This synthetic methodology was extended to aliphatic aldehydes, substituted 1,2-phenylenediames, and other protecting groups on the aromatic amine. The mild reaction conditions and readily available raw materials translate into a very practical synthetic procedure to produce this important class of heterocycles.

■

COBALT-CATALYZED BIARYL COUPLINGS VIA C−F BOND ACTIVATION IN THE ABSENCE OF PHOSPHINE OR NHC LIGANDS Fluorine-containing organic compounds have become increasing important in a wide range of areas such as medicine, agrochemistry, catalysts, materials science, and biochemistry. Numerous transition-metal-catalyzed cross-couplings of fluorinated compounds with organometallic reagents have been developed recently. These cross couplings typically require a phosphine or N-heterocyclic carbene (NHC) ligands. Duan and co-workers at Beijing Normal University described a general cobalt catalyzed cross-coupling of aryl fluorides with aryl Grignard reagents in the presence of substoichiometric Ti(OEt)4 (J. Org. Chem. 2017, 82, 1291). Cobalt(II) chloride was the

■

MERGING PHOTOREDOX WITH 1,2-METALLATE REARRANGEMENTS: THE PHOTOCHEMICAL ALKYLATION OF VINYL BORONATE COMPLEXES Silvi et al. have reported a novel method for triggering 1,2-metalate rearrangement under either purely photochemical or metalaphotoredox conditions (J. Am. Chem. Soc. 2017, 139, 5736). In this report, they generate anionic boronates bearing at least one vinyl group (typically the starting materials are pinacol 792




heterocyclic ring, diastereoselective cyclizations are observed. Finally, given that commercially available, linear unsaturated organozinc species also participate in the reaction, there may be more than one mechanistic mode of cyclization.

esters of vinylboronic acids that are treated with an alkyllithium) and expose them to α-iodoacetophenones. In most cases, irradiation with light from a blue LED source results in alkyl iodide homolysis. The carbon radical adds to the distal terminus of the vinyl boronate, generating a carbon-centered radical at the boron-bearing carbon. Upon intermolecular SET transfer of this unpaired electron to another molecule of alkyl iodide, 1,2-metalate rearrangement ensues (either to neutralize the carbocation formed or in concert with electron transfer). The chemistry is quite general for a variety of phenacyl iodides. In addition, phenacyl bromides could either be converted to iodides in situ using 20 mol % NaI or a Ru-based photocatalyst could be used to reduce outright the alkyl bromide and thus initiate the radical chain process. The authors note that, although there are now reliable ways to generate β-boryl carbonyl compounds, the current method offers a unique approach to γ-boryl carbonyl compounds.

■

COPPER-CATALYZED DICARBOFUNCTIONALIZATION OF UNACTIVATED OLEFINS BY TANDEM CYCLIZATION/CROSS-COUPLING Thapa and co-workers have reported a method for 1,2-dicarbofunctionalization of alkenes bearing a pendant alkyl or aryl bromide or iodide (J. Am. Chem. Soc. 2017, 139, 5700). The method differs from prior work from the Brown and Fu groups, where related processes were carried out under reaction conditions involving both Cu- and Ni-based catalysts. In the present work, which describes a two-stage process, an organozinc halide is generated by the action of activated Zn on an alkyl bromide/iodide or an aryl halide. However, because the substrates are suitably structured, they undergo fast 5-exo-trig cyclization after radical formation but before recombination with Zn(I). The newly formed, cyclized organozinc is then solvent swapped (from THF to DMF) and subjected to cross-coupling with electron-deficient aryl iodides with substoichiometric CuI in warm DMF. A range of five-membered rings, both carbocyclic and hetereocyclic (pyrrolidinyl, tetrahydrofuranyl), are thus formed (in the first stage) along with incorporation of an electron-deficient arene (in the second stage). Similarly, aryl iodides, instead of alkyl bromides/iodides, can be cyclized to organozinc intermediates and then cross-coupled with separate electron-deficient aryl iodides. In cases where the starting alkyl halide is part of a conformationally flexible carbocyclic or

■

DEVELOPMENT OF CHIRAL, BIFUNCTIONAL THIOSQUARAMIDES: ENANTIOSELECTIVE MICHAEL ADDITIONS OF BARBITURIC ACIDS TO NITROALKENES

Rawal and co-workers have reported a new class of squaramidebased H-bonding organocatalysts (J. Am. Chem. Soc. 2017, 139, 5297). This group has pioneered the use of squaramides, based on squaric acids, for catalytic, enantioselective transformations. However, this established class of organocatalysts suffer from limited solubility, especially in the nonpolar solvents often deployed for H-bond catalysis, and the limits of their acidity have been reached. By analogy to the superiority of thioureas versus 793




optimal reaction conditions, which include substoichiometric quantities of both Ni(OAc)2·4H2O and bathophenanthroline (BPhen), primary amines bearing a primary or secondary alkyl group may be cross-coupled to a variety of boronic acids. The yields are moderate to good; however, the loading of boronic acid coupling partner is somewhat high. With regard to mechanism, while Ni catalysts are known to shuttle between Ni(0) and Ni(II) or Ni(I) and Ni(III), three experiments suggest the latter is operative: (i) a pyridinium salt coupling partner derived from a chiral primary amine led to racemic product after coupling; (ii) the use of cyclopropylmethylpyridinium salt led to ring opening followed by coupling; and (iii) the inclusion of TEMPO into a typical reaction led to TEMPO-bearing adducts that were diverted from cross-coupling.

simple ureas in this arena of catalytic chemistry, Rawal and co-workers have sought to generate thio- and dithiosquaramides, where one or both carbonyls are replaced by thionyls. The solution was to convert the carbonyls into thionyls on a mixed ester−amide substrate prior to the incorporation of the second chiral amine. The dithiosquaramides so generated are more acidic than simple squaramides by 4−5 orders of magnitude and, gratifyingly, are significantly more soluble (>3.0 mg/mL compared to

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

Recommend Documents