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■ ANAPHYLAXIS INDUCED BY PEPTIDE COUPLING

AGENTS
Universität München performed an in-depth determination of
the basicities of 32 pyrrolidines and imidazolidinones in
acetonitrile as well as rate constants for reactions with
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reference electrophiles and nucleophilic reactivities (J. Am.

Chem. Soc. 2020, 142, 1526). They were able to determine that
pyrrolidines are more basic than imidazolidinones in most
cases; moreover, the pKaH values are significantly higher in
Downloaded via 95.85.70.35 on February 7, 2020 at 12:35:33 (UTC).

acetonitrile than in aqueous solution. The reactivities with

reference electrophiles were determined photometrically and
followed second-order kinetics (first-order in the amine and
Nowick and co-workers at the University of California, Irvine
first-order in the electrophile). It is important to highlight that
reported the development of life-threatening anaphylaxis in the
substitution at the 2-position with bulky groups led to more
lead author (K. J. McKnelly) after repeated exposure to
complex kinetics. The thermodynamic and kinetic data
uronium coupling agents such as HATU, HBTU, and HCTU
determined in this study may now be used to optimize the
(J. Org. Chem. 2019, DOI: 10.1021/acs.joc.9b03280).
conditions for reactions catalyzed by secondary amines.
Uronium coupling agents are used extensively in the solid-
phase synthesis of peptides and in medicinal and process
chemistry to make amide bonds. They are occasionally
employed on larger scales, so exposure of manufacturing
■ IDENTIFICATION OF ALCOHOL ABSOLUTE
STEREOCHEMISTRY
technicians is also a possibility. There have been only limited
reports prior to this one regarding sensitization by uronium
reagents, with nine reports concerning HATU and HBTU and
none concerning HCTU. The material safety data sheets for
these reagents highlighted only HBTU, which is reported to
“cause respiratory sensitization”. The sensitization grew
steadily over the course of years of exposure to the reagents
and, after multiple minor reactions (wheezing, coughing, runny
nose, etc.), resulted in a potentially fatal throat-closing
anaphylactic reaction that was successfully treated with
diphenylhydramine. Skin-prick tests confirmed allergic reac-
tions to HATU, HBTU, and HCTU and ruled out other
reagents that the lead author had used extensively (Fmoc- Kolis, Whitehead, and co-workers from Clemson University in
protected amino acids). She must now carry an epinephrine South Carolina reported the determination of alcohol absolute
autoinjector (generic EpiPen) whenever she is close to stereochemistry through single-crystal X-ray diffraction
researchers actively working with these agents. The develop- (SXRD) after simple derivatization (Org. Lett. 2019, 21,
ment of allergic reactions to these reagents is not unexpected, 9622). There are numerous spectroscopic methods for the
as they are able to modify proteins, and this report should identification of absolute stereochemistry, oftentimes coupled
serve as a public service announcement (PSA) that care should with theoretical methods to predict chiroptical properties to
be taken by anyone using these reagents to avoid and/or infer the absolute configuration. Chiral derivatizing agents
minimize exposure. (e.g., Mosher esters) allow for determination of absolute

■ BASICITIES AND NUCLEOPHILICITIES OF

PYRROLIDINES AND IMIDAZOLIDINONES USED
configuration through NMR analysis but require both
diastereomers to be synthesized from enantiopure reagents.
Direct measurement of absolute stereochemistry is possible for
AS ORGANOCATALYSTS
Chiral pyrrolidines and imidazolidinones play a key role as
organocatalysts in modern organic synthesis. Whereas some of
these compounds were studied for their respective basicities in
aqueous solution, investigations of protonation equilibria are
very rare. Mayr and co-workers from Ludwig-Maximilians-

© XXXX American Chemical Society https://dx.doi.org/10.1021/acs.oprd.0c00027

A Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Highlights from the Literature

crystalline materials that contain a heavy atom (Z > 14) omatization of B followed by protodemetalation furnished the
through measurement of anomalous dispersion. The work desired meta-alkylated products.

■
reported here builds upon previous reports on the highly
crystalline nature of guanidinium salts of organosulfates to NUCLEOPHILIC IMINES AND ELECTROPHILIC
develop a simple procedure for the identification of alcohol o-QUINONE METHIDES: THREE-COMPONENT
absolute stereochemistry. The alcohol of interest is simply ASSEMBLY OF ASSORTED
allowed to react with a slight excess of sulfur trioxide pyridine 3,4-DIHYDRO-2H-1,3-BENZOXAZINES
complex in dry DCM, and the conversion is monitored by
NMR spectroscopy. Once the reaction is complete, exposure
to an equimolar amount of guanidinium chloride in methanol
followed by slow evaporation often gives crystals that are of
suitable quality for SXRD. The inclusion of a sulfur atom (Z =
16) on the organosulfate allows for absolute stereochemical
assignment. Crystals of 16 primary and secondary alcohols
were successfully grown using this methodology alongside a
single example of a primary amine (1-phenylethylamine).
Tertiary alcohols are currently unsuitable, as incomplete
sulfation was observed. One primary alcohol ((−)-citronellol)
failed to generate crystals of suitable quality for SXRD.
Precious alcohol substrates can be recovered through
hydrolysis of the organosulfate by refluxing in wet THF.

■ THREE-COMPONENT RUTHENIUM-CATALYZED
DIRECT META-SELECTIVE C−H ACTIVATION OF
ARENES: A NEW APPROACH TO THE
ALKYLARYLATION OF ALKENES
Quinone methides are reactive intermediates that are
commonly encountered in many areas of chemistry and
biology. Both reductive and oxidative metabolisms from
quinine methides have become a very important topic in
drug design as well as drug safety. o-Quinone methides can
readily engage in [4 + 2] cycloadditions with electron-rich
dieneophiles, leading to rearomatization of the ring. To access
the o-quinone methide, a common method involves heating a
Mannich base of the corresponding polycyclic o-phenolic
compound, which yields a stable polyaryl o-quinone methide.
Recently, Pettus and co-workers at the University of California,
Santa Barbara realized a three-component assembly of assorted
3,4-dihydro-2H-1,3-benzoxazines via a reaction between
nucleophilic imines and electrophilic o-quinone methides
(Org. Lett. 2019, 21, 7746). The team prepared o-quinone
methides C in situ at low concentration via addition of
Grignard reagents onto salicyladehyde followed by intra-
molecular Boc group migration. In the presence of imines, 1,4-
conjugate addition occurs, followed by intramolecular
cyclization of the developing phenoxide zwitterions onto the
resulting iminium species, providing an assortment of N-
substituted 3,4-dihydro-2H-1,3-benzoaxines in a single pot.

■
Despite advances in transition-metal-mediated C−H function-
alization in the past decades, meta C−H functionalization of
OPTICALLY PURE N-HETEROCYCLIC CARBENE
aromatic rings remains a formidable challenge. The use of a
directing group during the C−H activation of aromatic METAL COMPLEXES
compounds leads often to ortho-C−H-functionalized products.
In order to address this issue, a strategy of combining ortho
C−H activation with a selective radical addition was developed
by Liang and co-workers at Lanzhou University in China (J.
Am. Chem. Soc. 2019, 141, 13914). Initial ortho C−H
functionalization of 2-phenylpyridine leads to ruthenated Mauduit, Clavier, and co-workers from Aix Marseille
complex A. A subsequent single electron transfer process University and the University of Rennes in France reported
between A and ethyl bromodifluoroacetate generates a radical the synthesis of optically pure N-heterocyclic carbene (NHC)
(·CF2CO2Et) whose addition to the alkene affords a carbon metal complexes from prochiral NHC precursors and
radical (·CR2CHRCF2CO2Et). The newly formed radical speculated on their potential use in asymmetric catalysis (J.
undergoes selective radical addition at the position para to Am. Chem. Soc. 2020, 142, 93). Chiral NHCs are well-studied
the C−Ru bond, leading to species B. Subsequent rear- in asymmetric catalysis, and there are numerous examples of
B https://dx.doi.org/10.1021/acs.oprd.0c00027
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development

■
pubs.acs.org/OPRD Highlights from the Literature

such complexes. However, these rely on optically pure starting VISIBLE-LIGHT-INDUCED, METAL-FREE CARBENE
materials for the synthesis of NHCs, thereby increasing both INSERTION INTO B−H BONDS BETWEEN
the cost and complexity. The authors exploited the robustness ACYLSILANES AND PINACOLBORANE
of copper−NHC complexes toward silica gel to allow the chiral
resolution of racemic mixtures formed from prochiral NHC
precursors by preparative chiral HPLC. Once separated, the
chiral copper−NHC complexes are stable toward epimeriza-
tion at room temperature (t1/2 = 22 days at 40 °C). The
complexes were readily transmetalated with both gold and
palladium with retention of configuration of the NHC ligand
through a proposed associative mechanism. The gold and
palladium complexes demonstrated enhanced stabilities (t1/2 =
2 years and 15 days, respectively, at 80 °C). Both the copper
and palladium complexes were tested in asymmetric catalysis
and generated enantioenriched products in asymmetric allylic
alkylation (copper, up to 90% ee) and asymmetric intra-
molecular α-arylation (palladium, up to 98% ee). These novel
catalysts offer more opportunities in asymmetric synthesis, and
further applications should be forthcoming. Carbenes are versatile synthetic intermediates that can engage

■ HOUSANES: BICYCLO[2.1.0]PENTANE
CARBOXYLIC ACIDS
in a variety of chemical transformations, such as carbene
insertion reactions, to form C−X bonds, including C−N, C−
O, C−S, and C−Si bonds. Carbenes are commonly generated
from diazo compounds via photolytic, thermal, or transition-
metal-catalyzed routes. Diazo compounds are generally
unstable and potentially explosive; synthetically useful diazo
compounds usually require electron-withdrawing groups to
improve their stability. Recently, Glorius’s laboratory at
Westphalian Wilhelms University in Germany developed a
protocol for the visible-light-induced generation of α-siloxy
carbenes and their insertion into B−H bonds to provide direct
access to valuable α-alkoxy organoboronate esters (J. Am.
Chem. Soc. 2019, 141, 16227). The metal-free reaction
proceeds under mild reaction conditions that are operationally
simple, atom-economical, and tolerant of a broad substrate
scope. Many examples gave quantitative yields. Density
functional theory (DFT) calculations suggested that the
Grygorenko and co-workers from Enamine Ltd. reported the siloxycarbene is generated from the T1 state of the acylsilane
and that the insertion of the carbene into the B−H bond
synthesis of 1,3-disubstituted bicyclo[2.1.0]pentane derivatives
occurs in a concerted manner.
(J. Org. Chem. 2019, DOI: 10.1021/acs.joc.9b03044). The
“escape from flatland” concept in molecular design has driven
the need for compounds with greater sp3 character but with
retention of the geometric constraint afforded by the aromatic
■ SITE-SELECTIVE C−H OXYGENATION VIA ARYL
SULFONIUM SALTS
systems they replace. Bicyclo[2.1.0]pentane derivatives (so-
called housanes) contain a cyclobutane fused to a cyclo-
propane and can be considered as constrained surrogates of
cyclopentanes. Prior to the reported work, access to these
scaffolds has been limited, restricting their inclusion in drug
discovery efforts. The authors exploited the intramolecular
anionic cyclization of a cyclopentyl ester with a leaving group
at the 3-position, and the diastereoselective installation of
substituents at the 4-position was also demonstrated.
Substituents at the 4-position include fluorine, hydroxyl,
methyl ether, alkyl, aromatic, and amine. The authors
synthesized both diastereomers of the amine substituent and
isolated the single enantiomers by preparative chiral HPLC,
thereby giving access to four isomers of the γ-amino acid. The Phenols and aryl ethers are useful organic intermediates, and
synthesis of all derivatives was demonstrated on at least the the synthesis of these compounds generally requires a
gram scale, with up to 100 g of some derivatives synthesized in prefunctionalization step, in which achieving synthetically
a single run. useful site selectivity can be challenging. Recently, Ritter and
C https://dx.doi.org/10.1021/acs.oprd.0c00027
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Organic Process Research & Development
co-workers at Max Planck Institute for Coal Research in
Germany developed a two-step process for the formation of
arene C−O bonds with excellent site selectivity at a late stage
(Angew. Chem., Int. Ed. 2019, 58, 16161). The researchers
prepared the thianthrenium salt intermediates with high para
selectivity by the reaction of arenes with thianthrene oxide in
the presence of trifluoroacetic acid (TFAA) and HBF4 (Angew.
Chem., Int. Ed. 2019, 58, 14615). Subsequent hydroxylation of
the arylthianthrenium salts was accomplished with water as the
nucleophile under photoredox conditions. The in situ-formed
thianthrene byproduct plays a key role in this catalytic process,
allowing the combination of the two catalytic cycles: the Ir-
mediated photoredox process and the Cu-catalyzed cross-
coupling process.
■
IRON-CATALYZED CROSS-COUPLING OF
FUNCTIONALIZED BENZYLMANGANESE HALIDES
WITH ALKENYL IODIDES, BROMIDES, AND
TRIFLATES
As a method that is complementary to the currently available
transition-metal-catalyzed C−C bond cross-coupling reactions,
Knochel and co-workers at Ludwig-Maximilians-Universität
München in Germany developed an iron-catalyzed cross-
coupling reaction of functionalized benzylmanganese halides
with alkenyl iodides, bromides, and triflates (Org. Lett. 2019,
21, 8684). The benzylic manganese chlorides were prepared by
a two-stage reaction involving Grignard formation with benzyl
chlorides followed by a reaction with MnCl2. In the presence
of a catalytic amount of FeCl2, the reaction of benzylic
manganese chlorides proceeds through highly reactive iron ate
complex A. The subsequent coupling reaction of A with
electrophiles occurs via either one-electron reduction/radical
recombination or two-electron oxidative addition of electro-
philes onto the FeII species followed by reductive elimination.
The mild reaction conditions tolerate various functional
groups, which makes this method a valuable approach in
organic synthesis.
■ REDUCTIVE sp3−sp2 COUPLING REACTIONS
ENABLE LATE-STAGE MODIFICATION OF
PHARMACEUTICALS
Late-stage functionalization has been a hot topic for a few years
now, as it provides the opportunity to prepare complex
compounds from the same scaffold at the penultimate step.
D https://dx.doi.org/10.1021/acs.oprd.0c00027
pubs.acs.org/OPRD Highlights from the Literature
Moreover, introduction of sp3 moieties has proven to enhance
the pharmacokinetic and physicochemical properties of drug
candidates. Levi and co-workers at Merck combined these two
topics and reported that reductive sp3−sp2 coupling reactions
enable late-stage modification of pharmaceuticals (Org. Lett.
2020, 22, 556). After optimization (product yield, chemo-
selectivity, dehalogenation, ligands, and solvents) of the
reductive coupling reaction on a nitrogen-rich 5-chloroamino-
pyrimidine, the authors applied these conditions to a range of
primary and secondary halides. The products were isolated in
low to moderate yields, and the conditions were compatible
with ethers, protected amines, esters, acetals, and phospho-
nates. Finally, they applied this methodology on a millimolar
scale without any notable deviations in reactivity or chemo-
selectivity.
■ REDUCTIVE CLEAVAGE OF SECONDARY
SULFONAMIDES: CONVERTING TERMINAL
FUNCTIONAL GROUPS INTO VERSATILE
SYNTHETIC HANDLES
The ability to selectively modify single sites of complex
molecules is a powerful and efficient tool in drug discovery, as
single-point modifications can have profound impacts on
biological and physicochemical properties. Sulfonamides and
related bioisosteres are prevalent in medicines across all
therapeutic areas. Fier, Kim, and Maloney at Merck described a
method for the late-stage functionalization of secondary
sulfonamides via reductive cleavage of the N−S bond to
generate sulfinates and amines (J. Am. Chem. Soc. 2019, 141,
18416). Secondary sulfonamides reacted rapidly and chemo-
selectively with the combination of ethyl benzoylformate and
tris(dimethylamino)phosphine in THF at ambient temperature
to afford N-sulfonyl phenylglycine ester intermediates.
Addition of tert-butyl tetramethylguanidine (BTMG) resulted
in clean fragmentation and concomitant generation of the
desired sulfinate and imine products, both of which could be
refunctionalized in situ. The free amine was liberated from the
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Highlights from the Literature

imine in quantitative yield via the addition of aqueous
hydroxylamine. Similarly, the sulfinate species reacted with
exogenous electrophiles to form a variety of S(VI) functional
groups. The reaction conditions were chemoselective for N−S
cleavage of secondary sulfonamides containing ketone, ester,
triflate, halide, and various heterocyclic functional groups. The
detailed methodology serves as a general platform for the late-
stage functionalization of secondary sulfonamides under
exceedingly mild conditions.
organic chemistry. As a continuation of their research program
focused on activation of unreactive C−H bonds, Gaunt and co-
workers at the University of Cambridge reported an elegant
functionalization of γ-C(sp3)−H bonds with palladium
catalysis (Nat. Chem. 2020, 12, 76). By taking advantage of
the formation of a five-membered palladacycle helped by the
presence of the tertiary amine, the authors were able to
selectively insert various aromatics at the γ-position by reaction
with boronic acids. The scope of the reaction is very wide, as

■
the reaction is tolerant of ketones, esters, ethers, protected
A MODULAR AND DIASTEREOSELECTIVE [5 + 1] amines, and heteroaromatics, and the products are obtained in
CYCLIZATION APPROACH TO N-(HETERO)ARYL moderate to excellent yields with perfect regioselectivity. In a
PIPERIDINES latter part, the functionalization of drug analogues was
described, as well as an enantioselective version of the reaction
using prochiral reagents.

■ IRON-CATALYZED ROOM-TEMPERATURE
CROSS-COUPLINGS OF BROMOPHENOLS WITH
ARYL GRIGNARD REAGENTS

Because of the importance of piperidines in drug discovery and

FDA-approved pharmaceuticals, many methods have been
reported for the stereoselective synthesis of this class of
compounds. Moreover, N-(hetero)arylation of piperidines has
emerged as crucial in drug discovery. In order to contribute to
this field, Sather and co-workers from Merck reported a
diastereoselective reductive amination/aza-Michael synthesis
of functionalized N-(hetero)aryl piperidines (J. Am. Chem. Soc.
2020, 142, 726). After optimization of the reaction conditions
for the cyclization, focused on the temperature and mixtures of
alcohols and water as solvents, the authors applied this optimal
setup to explore the scope of ketones, aldehydes, and
nucleophiles. The reaction is very tolerant of many functional
groups such as alkenes, protected amines and alcohols, acetals,
nitrile, nitro esters, and heterocycles. In most cases, the
products were obtained in good to excellent yields with
moderate to good diastereoselectivities. DFT computational
studies concluded this excellent paper, which opens new
opportunities for the preparation of N-aryl piperidines.

■ CATALYTIC C(sp3)−H BOND ACTIVATION IN

TERTIARY ALKYLAMINES

Biphenols and their analogues are well-known in the field of

Tertiary amines are very important in drugs and agrochemicals,
with around 26% containing this moiety. Moreover, function-
alization of unactivated C−H bonds remains a challenge in
E https://dx.doi.org/10.1021/acs.oprd.0c00027
bioactive (natural) products, but their synthesis largely relies
on protecting group chemistry. Duan and co-workers from
Beijing Normal University in China solved this issue by
achieving the direct cross-coupling of bromophenols and aryl
Grignard reagents (Adv. Synth. Catal. 2019, 361, 5421). The
catalytic system is composed of tri-n-butylphosphine and
iron(III) acetylacetonate, and titanium(IV) ethoxide is
required to overcome the debromination and catalyst
complexation issues. Under the best conditions, bromophenols
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
containing functional groups such as ketone, nitrile, or ester
could be cross-coupled to aryl organomagnesium reagents in
good to high yields. The acidic hydroxyl proton of the phenol
could be masked by the in situ reaction with isopropylmagne-
sium chloride or by engaging the preformed sodium or
potassium phenolate. The methodology was extended to
functionalized organometallic reagents prepared by the
Knochel turbo-Grignard protocol and was applied to the
gram-scale synthesis of a natural product, garcibiphenyl C.
■
AN AIR-STABLE BINARY NICKEL(0)−OLEFIN
CATALYST
Nickel catalysis is used in important industrial processes at
large scales, such as the polymerization of butadiene or
ethylene. Its use in the pharmaceutical, agrochemical, and fine
chemical industries is less widespread, with a contributing
factor being the limited availability of stable Ni(0) catalysts.
Ni(COD)2 (COD = 1,5-cyclooctadiene) is typically the
precursor of choice because of its stability, but it still requires
handling under an inert atmosphere at low temperatures to
prevent oxidation. A long-standing challenge in nickel catalysis
has been the identification of stable Ni(0) catalysts that can
still participate in a range of important nickel-catalyzed
reactions. In this setting, Cornella and co-workers (Nat.
Catal. 2020, 3, 6) recently reported the preparation and
isolation of the air-stable Ni(0)−alkene complex Ni(Fstb)3,
where (Fstb)3 = trans-1,2-bis(4-(trifluoromethyl)phenyl)-
ethene. The complex can be conveniently prepared from the
stable commercially available precursor Ni(acac)2 and displays
stability for several days under ambient conditions. The utility
of the new complex was shown via its application to many
frequently encountered nickel-catalyzed processes for which
Ni(COD)2 has previously been used. For example, the
complex was competent in heteroaryl Suzuki cross-couplings
and C−N bond-forming reactions between aryl chlorides and
either secondary amines or anilines. Furthermore, it was
F https://dx.doi.org/10.1021/acs.oprd.0c00027
pubs.acs.org/OPRD Highlights from the Literature
effective in the synthesis of an ester from the N-Boc amide as
well as an alkyl−alkyl Negishi coupling. Some limitations of the
new complex were observed, with the latter two reactions
requiring increased temperature to fully generate the active
catalyst from Ni(Fstb)3 compared with using the more
coordinatively labile Ni(COD)2.
■ IMIDAZOTETRAZINES AS WEIGHABLE
DIAZOMETHANE SURROGATES FOR
ESTERIFICATIONS AND CYCLOPROPANATIONS
Although a number of protocols have been designed to
generate and use in situ the extremely dangerous diazo-
methane, all have specific limitations that could only be
overcome through recourse to flow chemistry or specialized
settings. Svec and Hergenrother recently disclosed that
temozolomide (TMZ), an imidotetrazine drug, could be
repurposed to effect esterification and cyclopropanation, the
standard transformations requiring diazomethane (Angew.
Chem., Int. Ed. 2020, 59, 1857). The authors took advantage
of the easy generation of methyl diazonium from TMZ in an
aqueous basic medium to develop conditions for both
reactions. Esterification was carried out in a solvent mixture
composed of dioxane and water with sodium carbonate as the
base and was high-yielding for a large range of acids, including
sensitive and complex ones. A few examples of iron-catalyzed
cyclopropanation were provided but required the use of
concentrated aqueous potassium hydroxide, thus limiting the
usefulness of the protocol. Although both protocols require an
excess of the high-molecular-weight diazonium source (3−4
equiv), these drawbacks are compensated by the stability and
low toxicity of TMX compared with other diazomethane
surrogates. The methodology was extended to the formation of
other esters (trideuteromethyl and ethyl) by replacing TMZ
with other easily accessed N3-alkylated imidotetrazines.
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
■
pubs.acs.org/OPRD
DEOXOFLUORINATION OF ALIPHATIC
CARBOXYLIC ACIDS: A ROUTE TO
TRIFLUOROMETHYL-SUBSTITUTED DERIVATIVES
More than 20% of all modern pharmaceuticals and up to 30%
of agrochemicals contain at least one fluorine atom. Aliphatic
carboxylic acids are among the most available chemical
compound classes, and it would be highly desirable to have a
practical method to convert them into the corresponding
trifluoromethyl-substituted derivatives. Mykhailiuk and co-
workers from Enamine Ltd., the Institute of Organic
Chemistry NAS of Ukraine, and Taras Shevchenko National
University of Ukraine detailed the fluorination of aliphatic
carboxylic acids with sulfur tetrafluoride under mild conditions
(J. Org. Chem. 2019, 84, 16105). The experimental protocol
requires no irradiation or metal-containing reagents or
additives. The key observation was that the addition of water
at the beginning of the reaction generated HF in situ, which
catalyzed the desired reaction. The reaction was performed
neat in a Hastelloy autoclave. Diverse primary, secondary,
tertiary, and α-amino acids afforded the corresponding
trifluoromethylated products in good yields. A variety of
functional groups, including ester, cyclopropyl, halo, amino,
and nitro, were compatible with the reaction protocol. The
reaction proceeded with full retention of the stereochemistry
and absolute configuration of chiral centers. This reported
protocol provides a practical synthesis of functionalized
trifluoromethyl-substituted aliphatic derivatives from readily
available aliphatic carboxylic acids.
■ DIASTEREOSELECTIVE FeCl3·6H2O/NaBH4
REDUCTION OF OXIME ETHER FOR THE
SYNTHESIS OF THE β-LACTAMASE INHIBITOR
RELEBACTAM
The β-lactamase inhibitor relebactam has been approved in
combination with Primaxin for the treatment of serious
antibiotic-resistant bacterial infections. Its structure comprises
a key chiral piperidine fragment that was recently synthesized
via a diastereoselective FeCl3·6H2O/NaBH4 reduction of an
oxime ether (Chung, J. Y. L.; et al. J. Org. Chem. 2020, 85,
994). Previous synthetic efforts toward this piperidine core
G https://dx.doi.org/10.1021/acs.oprd.0c00027
Highlights from the Literature
proceeded via oxime reduction of a benzyl ester analogue,
resulting in modest diastereoselectivity (3:1 dr). The current
approach began with investigations of the carboxylic acid
directly, hoping that it could function as an additional binding
point to selectively deliver the hydride reagent. Following an
initial screen of a wide variety of reduction protocols, the
FeCl3/NaBH4 combination proved to be a uniquely effective
mixture, giving the desired product with 95:5 dr. The process
was found to be robust and operational on a large scale below
−25 °C, with a requirement for water (introduced via the
FeCl3·6H2O) as well as the addition of NaBH4 as a solution in
triglyme. Under these conditions the reaction proceeded after
16 h to >99% conversion with approximately 95:5 dr in an
assay yield of 82−87%. After investigations of the isolation
procedure, the final product was obtained via the formation of
the bisulfate salt, allowing effective removal of the iron salts.
Detailed mechanistic studies were also undertaken and
suggested that the highly diastereoselective reduction occurs
via a bicyclic iron complex.
■ ANNULATION CHEMISTRY BASED ON TANDEM
MICHAEL ADDITION−ENAMINE FORMATION: AN
IMPROVED METHOD FOR THE PREPARATION OF
1-SUBSTITUTED
2,3,5,6,7,8-HEXAHYDROQUINOLIN-4(1H)-ONES
Tandem reaction methodology has witnessed enormous
growth recently, due in no small part to the atom-economical
nature of the process. The utility of the Michael reaction as
one of the featured steps in such methodology has been
demonstrated. As an extension of their investigation of such
methodology, Hunt and co-workers at the College of New
Jersey reported the utilization of 2-(but-2-enoyl)cyclohexan-1-
one (A) as a Michael acceptor (Tetrahedron Lett. 2019, 60,
151). The starting material was readily prepared in good yield
by acylation of the lithium enolate of cyclohexanone with
crotonyl chloride. The desired 1-substituted 2,3,5,6,7,8-
hexahydroquinolin-4(1H)-ones were prepared in one pot by
the addition of a stoichiometric amount of the corresponding
amine to A. The reaction kinetics was significantly improved
by the addition of molecular sieve powder. Dichloromethane
and toluene were suitable solvents for the reaction. The
proposed mechanism involved an initial Michael reaction of
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
the amine with the enone, followed by intramolecular enamine
formation. This tandem methodology proved to be an
effective, facile, one-pot, one-step synthesis of this class of
nitrogen heterocycles under exceedingly mild conditions.
■ LIGAND-CONTROLLED REGIODIVERGENT
HYDROALKYLATION OF PYRROLINES
In the absence of a directing group, hydrocarbonation of an
alkene usually leads to the linear isomer whatever the position
of the starting unsaturation. Qian and Hu from EPFL in
Switzerland recently reported that in the case of pyrrolines the
regioselectivity of alkylation can be controlled by the ligand
(Angew. Chem., Int. Ed. 2019, 58, 18519). Extensive
optimization of the reaction parameters led to the
identification of two different pyridine−pyrazoline ligands,
L8 and L10 (see the scheme), that under the same conditions
provided the C2- or C3-alkylated derivatives of N-protected
pyrrolines, respectively, in high yields and regioselectivity. The
reaction is carried out in dimethylacetamide at room
temperature and tolerates a wide range of primary and
secondary alkyl iodides as coupling partners containing ether,
carbamate, sulfonamide, and ester functional groups. The
reaction was successfully applied to complex natural derivatives
of cholestanol and ibuprofen, but limitations were observed
with tertiary alkyl iodides and non-benzylic bromides.
■ COBALT-CATALYZED CROSS-COUPLING
REACTIONS OF ARYL TRIFLATES AND LITHIUM
ALKYLBORATES
The Suzuki−Miyaura cross-coupling is currently one of the
most important synthetic tools for carbon−carbon bond
formation and is widely used in the production of fine
H https://dx.doi.org/10.1021/acs.oprd.0c00027
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chemicals, pharmaceuticals, and materials. There is strong
interest in replacing the traditional palladium catalyst with a
more highly abundant and cost-effective first-row transition
metal, such as nickel, iron, or cobalt. Duong and co-workers at
the Agency for Science, Technology and Research (A*STAR)
reported a cobalt catalyst system for the coupling of a broad
array of aryl triflates and arylboronic esters activated by n-
butyllithium (J. Org. Chem. 2019, 84, 12686). Extensive
optimization of the reaction variables was performed to
maximize the yield of the desired cross-coupling product.
Cobalt(II) chloride was the most effective catalyst. N-
Heterocyclic carbenes (NHCs) were examined as ligands for
cobalt, and the highest yields were obtained with bulky
substituents on both nitrogens. IAd·HBF4 was more efficient
than IAd·HCl in the reaction, which suggested a dependence
of the catalyst generation efficiency on the NHC counterion.
The cross-coupling reaction did not proceed in the absence of
the cobalt catalyst. The reaction was tolerant of a variety of
substituents on the triflate coupling partner, including nitrile,
ester, amide, and trifluoromethyl. The cobalt catalyst system
was also amenable to the coupling of arylboronic acid esters
with either electron-withdrawing or electron-donating sub-
stituents. The described cobalt catalyst system afforded good
yields of biaryls featuring different functional groups and
substitution patterns.
■ SEQUENTIAL XANTHALATION AND
O-TRIFLUOROMETHYLATION OF PHENOLS: A
PROCEDURE FOR THE SYNTHESIS OF ARYL
TRIFLUOROMETHYL ETHERS
Organic molecules containing fluorine are common in
pharmaceutical, agrochemical, and materials science because
of their unique physical properties and bioactivities. The
−OCF3 group is of particular interest to pharmaceutical
research because of its high electronegativity, unique
orthogonal conformation to the aromatic ring, high lip-
ophilicity, and high metabolic stability. Londregan at Pfizer,
Hartwig at the University of California, Berkeley, and their co-
workers reported a novel method for the synthesis of aryl and
heteroaryl trifluoromethyl ethers via the corresponding aryl
and heteroaryl xanthates (J. Org. Chem. 2019, 84, 15767). The
xanthates were prepared in quantitative yield using the novel
imidazolium reagent 1 irrespective of the electronic nature of
the aryl or heteroaryl alcohol. XtalFluor-E afforded the highest
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■
pubs.acs.org/OPRD Highlights from the Literature

yields of the trifluoromethyl ethers from the xanthates of the ONE AMINE, THREE TASKS: REDUCTIVE
plethora of fluorinating agents tested. Trichloroisocyanuric COUPLING OF IMINES WITH OLEFINS IN BATCH
acid (TCCA) or NFSI as an additive increased the yield of the AND FLOW
trifluoromethyl ethers. Heteroaromatic xanthates afforded
lower yields of the corresponding trifluoromethyl ethers. The
two-step trifluoromethylation of phenols via xanthate inter-
mediates proceeded in good yields under mild conditions with
easily handled reagents.

■ POT AND TIME ECONOMIES IN THE TOTAL

SYNTHESIS OF COREY LACTONE

Although the area of photoredox coupling reactions is

Prostaglandins are a group of physiologically active compounds
with important roles in biology. Their non-natural analogues
have been used in a wide range of medicines and have
subsequently attracted significant interest from synthetic
chemists. The most well studied intermediate is the Corey
lactone, introduced in the landmark 1969 synthesis of
expanding rapidly, the generation of α-amino radicals from
imines remains difficult because of their high reduction
potentials. Rueping’s group at RWTH Aachen in Germany
recently demonstrated that the strategic choice of the reductive
quencher can overcome this limitation (Chem.Eur. J. 2019,
DOI: 10.1002/chem.201904483). Tributylamine was found to
be a uniquely efficient additive that could play a triple role:
reducing the excited-state catalyst, activatiing the imine
substrate via hydrogen-bond formation, and serving as the
hydrogen transfer agent. The use of ethanol as the solvent
greatly enhanced the yields of addition of variously substituted
N-benzylideneanilines to electron-poor olefins. In addition to
acrylates, the radical acceptors tolerated encompassed
acrylonitriles, vinyl sulfones, and acrylamides. Worthy of note
is the fact that the translation of the batch protocol under flow
conditions afforded a drastic decrease in the reaction time (24
to 4 h) without compromising the yield.

■
prostaglandin F2α by E. J. Corey. Significant work in the
following years has led to new more efficient routes to Corey ASYMMETRIC HYDROBORATION OF
lactone, but a practical and efficient asymmetric synthesis is HETEROARYL KETONES BY ALUMINUM
still desirable. A recent report by Hayashi and co-workers CATALYSIS
(Chem. Sci. 2019, DOI: 10.1039/c9sc05824a) details a
synthesis of Corey lactone that applies many principles of
efficient large-scale chemistry, i.e., pot economy via telescoped
processes and isolations as well as minimization of the
reaction/manufacturing time. The synthesis is reliant on a
key asymmetric organocatalyzed [3 + 2] cycloaddition that
provides the cyclopentanone core as a single isomer on a gram
scale with >99% ee. Subsequent reduction of both the
aldehyde and ketone groups with LiAlH(tBuO)3 and an acidic
quench of the reaction with HBF4 leads to cyclization and
generation of the intermediate lactone. During the subsequent
removal of the THF reaction solvent, the silicon group is
attacked by residual fluoride to ultimately provide the Corey
lactone framework after Tamao−Fleming oxidative conditions.
The final product is obtained after column chromatography in
50% overall yield through the seven-reaction sequence in one Many biologically relevant heterocyclic compounds contain a
pot. chiral 2-pyridyl alcohol motif, typically prepared via the
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reduction of the corresponding ketone. Numerous methods

have been developed to achieve this transformation, such as
biocatalytic, transition-metal-catalyzed, and organocatalyzed
reduction protocols. Significant challenges remain, and a recent
advancement was reported by Rueping, Lebedev, and Cavallo
(J. Am. Chem. Soc. 2019, 141, 19415) who disclosed an
aluminum-catalyzed asymmetric hydroboration of 2-acetylpyr-
idine and related structures. After identification of a
trifluoromethyl-BINOL ligand in combination with pinacol-
borane and AlMe3 that provided excellent yield and selectivity,
the method was applied to a range of pyridyl ketones. The
procedure typically gave >70% yield with >90% ee and could
be scaled to 10 mmol using a 0.2 mol % loading of the catalyst.
The reaction conditions were also applied to related pyrazine,
imidazole, and thiazole heterocycles but were not effective
when acetophenone was used. Extensive and detailed
mechanistic investigations were also conducted, as well as
the isolation of many synthetically important reaction
intermediates.
Wenyi Zhao
Sylvain Guizzetti
James A. Schwindeman
David S. B. Daniels orcid.org/0000-0002-9092-1377
James J. Douglas orcid.org/0000-0002-9681-0459
Sylvain Petit orcid.org/0000-0002-9198-8602
John Knight

■ AUTHOR INFORMATION
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00027
Notes
E-mail addresses: Wenyi38@hotmail.com; sguizzetti@novalix.
com; james.schwindeman@olonricerca.com; david.daniels@
pfizer.com; james.douglas1@astrazeneca.com; sylvain.petit@
ucb.com; john@jkonsult.co.uk.

J https://dx.doi.org/10.1021/acs.oprd.0c00027
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