ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review)
1-Substituted-2,2,2-trifluoroethylamines have emerged as structurally distinct and pharmacologically potent motifs in modern drug design, contributing to enhanced metabolic stability, target selectivity, and bioactivity across various therapeutic classes. This review provides a comprehensive account...
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| author | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_facet | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim |
| author_institution_txt_mv | [
{
"author": "Alicja Wzorek",
"institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland"
},
{
"author": "Taizo Ono",
"institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan"
},
{
"author": "Daniel Baecker",
"institution": "Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany"
},
{
"author": "Wei Zhang",
"institution": "Department of Chemistry, University of Massachusetts Boston, Boston MA 02125, Unites States;"
},
{
"author": "Vadim Soloshonok",
"institution": "University of Basque Country"
}
] |
| author_sort | Wzorek, Alicja |
| baseUrl_str | https://ucj.org.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-22T08:23:57Z |
| description | 1-Substituted-2,2,2-trifluoroethylamines have emerged as structurally distinct and pharmacologically potent motifs in modern drug design, contributing to enhanced metabolic stability, target selectivity, and bioactivity across various therapeutic classes. This review provides a comprehensive account of their catalytic enantioselective synthesis, encompassing chiral auxiliary-based methods and a wide array of asymmetric catalytic strategies — including hydrogenation, [1,3]-proton shift reactions, nucleophilic additions, and cycloadditions. Emphasis is placed on the stereochemical outcomes achieved with ruthenium, palladium, phosphoric acid, borane, and squaramide-based catalysts, many of which routinely deliver an enantiomeric excess (ee) exceeding 90–99%. Despite these advances, the phenomenon of self-disproportionation of enantiomers (SDE) remains critically underreported, casting doubt on the veracity of ee values in the literature. This review highlights the pronounced SDE behavior of fluorinated amines and underscores the need for rigorous stereochemical validation. By integrating synthetic innovation with epistemic scrutiny, this work aims to guide future research toward more reliable, efficient, and stereochemically sound methodologies for the synthesis of fluorinated amine derivatives. |
| doi_str_mv | 10.33609/2708-129X.91.12.2025.33-72 |
| first_indexed | 2026-03-19T02:00:18Z |
| format | Article |
| fulltext |
33
UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.91.12.2025.33-72
ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS
OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).
Alicja Wzorek1, Taizo Ono2, Daniel Baecker3, Wei Zhang4, Vadim A. Soloshonok5*
1 Institute of Chemistry, Jan Kochanowski University in Kielce,
Uniwersytecka 7, 25-406 Kielce, Poland;
2 National Institute of Advanced Industrial Science and Technology (AIST),
2266-98, Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-8560, Japan;
3 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy,
Freie Universität Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany;
4 Department of Chemistry, University of Massachusetts Boston,
Boston MA 02125, Unites States;
5 IKERBASQUE, Basque Foundation for Science,
María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain
e-mail: vadimsoloshonok@gmail.com
1-Substituted-2,2,2-trifluoroethylamines have emerged as structurally distinct and phar-
macologically potent motifs in modern drug design, contributing to enhanced metabolic sta-
bility, target selectivity, and bioactivity across various therapeutic classes. This review provides
a comprehensive account of their catalytic enantioselective synthesis, encompassing chiral
auxiliary-based methods and a wide array of asymmetric catalytic strategies — including hydro-
genation, [1,3]-proton shift reactions, nucleophilic additions, and cycloadditions. Emphasis
is placed on the stereochemical outcomes achieved with ruthenium, palladium, phosphoric
acid, borane, and squaramide-based catalysts, many of which routinely deliver an enantio-
meric excess (ee) exceeding 90–99%. Despite these advances, the phenomenon of self-dis-
proportionation of enantiomers (SDE) remains critically underreported, casting doubt on the
veracity of ee values in the literature. This review highlights the pronounced SDE behavior of
fluorinated amines and underscores the need for rigorous stereochemical validation. By inte-
grating synthetic innovation with epistemic scrutiny, this work aims to guide future research
toward more reliable, efficient, and stereochemically sound methodologies for the synthesis
of fluorinated amine derivatives.
Keywords: fluorinated amines, catalytic enantioselective synthesis, medicinal chemistry,
self-disproportionation of enantiomers, epistemic scrutiny.
34 ISSN 2708-129X. Укр. хім. журн., 2025
ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
INTRODUCTION.
Amino compounds, such as amines and
amino acids, are foundational to both natural
biochemistry and modern drug design [1–4].
Amines are ubiquitous in nature — from neu-
rotransmitters such as dopamine and serotonin
to alkaloids in plants and signaling molecules
in animals. Their basicity, hydrogen-bonding
capacity, and structural versatility make them
essential for molecular recognition and biolo
gical activity. Amino acids, the building blocks
of proteins, are a specialized class of amines
that orchestrate nearly every cellular function,
from enzymatic catalysis to structural sup-
port and immune signaling. Beyond their role
in protein biosynthesis, amino acids serve as
precursors for hormones, metabolic interme
diates, and redox regulators. Most endogenous
amines in biological systems are derived from
amino acids through enzymatic decarboxyla-
tion or other transformations [5].
In drug design, amino compounds are
prized for their ability to engage biological
targets through ionic and hydrogen-bond-
ing interactions. Many small-molecule drugs
incorporate primary, secondary, or tertiary
amines, as well as amino acids and derivatives
such as 2-hydroxyamines and 1,2-diamines, to
enhance solubility, receptor binding, and phar-
macokinetics [6–9]. Amino acid derivatives,
including peptidomimetics and β-amino acids,
offer tunable scaffolds for modulating bioavai
lability and selectivity. The strategic incorpora-
tion of amine and amino acid motifs continues
to drive innovation in medicinal chemistry,
enabling the design of therapeutics that mimic,
modulate, or disrupt biological processes with
precision [10–13].
Besides natural and tailor-made amino com-
pounds, modern drug design is characterized
by strategic fluorination to achieve enhanced
pharmacokinetic profiles, metabolic stability,
and target selectivity [14–16]. The introduc-
tion of fluorine atoms or fluorinated groups
into bioactive molecules profoundly influen
ces their physicochemical properties — mo
dulating lipophilicity, acidity, and membrane
permeability [17]. The high electronegativity
of fluorine and its small size allow it to mimic
hydrogen while altering electronic distribu-
tion, often improving binding affinity through
dipolar interactions or conformational control.
In metabolic terms, C–F bonds resist oxidative
degradation, extending drug half-life and re-
ducing off-target effects [18, 19]. Fluorination
can also block metabolic hotspots or redirect
biotransformation pathways, contributing to
safer and more efficacious therapeutics [20, 21].
Notably, fluorinated motifs such as trifluo-
romethyl, difluoromethylene, and aryl fluo-
rides [22–24] are now commonplace in ap-
proved drugs across oncology, neurology, and
infectious diseases. The precision with which
fluorine modulates molecular behavior makes
it indispensable in lead optimization, enabling
medicinal chemists to fine-tune activity and
ADME properties without compromising scaf-
fold integrity. As synthetic methodologies ad-
vance [25–38], the role of fluorine continues to
expand, driving innovation at the interface of
chemistry and biology.
Fluorine-containing amino compounds
represent a powerful class of molecular tools
in contemporary drug design. Incorporation
of fluorine into amine-bearing scaffolds —
such as trifluoroethylamines, difluoromethyl-
amines, and fluorinated anilines — can mo
dulate basicity, enhance metabolic stability, and
improve target engagement through altered
hydrogen-bonding profiles and dipolar inte
35https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
ractions. Fluorinated amino acids, including
α-trifluoromethylated and β-fluorinated ana-
logs, offer conformational rigidity and proteo-
lytic resistance, making them valuable in pep-
tidomimetics and protein–protein interaction
inhibitors [39–41]. These modifications often
lead to improved pharmacokinetic properties,
such as increased membrane permeability and
reduced clearance. Strategically placed fluo-
rine atoms can also influence stereoelectro
nic effects, guiding molecular recognition and
selectivity. As synthetic access to fluorinated
building blocks expands, their integration into
drug candidates enables fine-tuning of bioac-
tivity without compromising scaffold integrity.
Fluorine-containing amines and amino acids
thus serve as versatile elements in lead opti-
mization, bridging structural innovation with
functional precision across therapeutic areas
[42–44].
Building on our long-standing interest in
the asymmetric synthesis of fluorine-contain-
ing amines [45–48] and amino acids [49–54],
we have focused this review on the catalytic
enantioselective synthesis of 1-substituted-
2,2,2-trifluoroethylamines — a structurally
distinct class of compounds with growing
relevance in modern drug design. The article
encompasses: (i) an overview of marketed
pharmaceuticals and bioactive molecules fea-
turing the 2,2,2-trifluoroethylamine motif;
(ii) a detailed account of catalytic asymmet-
ric methodologies for their synthesis; and (iii)
a discussion of the self-disproportionation of
enantiomers (SDE) phenomenon [55], which
is particularly pertinent to fluorinated amines
and their derivatives.
We anticipate that this compilation will
serve not only as a practical reference for re-
searchers working with fluorine-containing
amino compounds, but also as a conceptual
springboard for innovation in synthetic and
medicinal chemistry. In particular, it aims
to support those exploring the strategic role
of fluorine in the design and optimization of
pharmaceutical agents.
Recent advances in 2,2,2-trifluoroethyl-
amine-containing pharmaceuticals.
In recent years, the incorporation of
2,2,2-trifluoroethylamine residues into bio-
active compounds has garnered significant
attention for its ability to modulate biological
activity, pharmacokinetics, and other drug-
like properties. These efforts have culminated
in the approval of two drugs approved by the
US-American Food and Drug Administration
(FDA) and the identification of two additional
compounds that have served as indispensable
structural leads in drug development.
The most recent FDA-approved drug in
this class is Vorasidenib 1 (Fig. 1), marketed
under the brand name Voranigo. Developed
by Servier Pharmaceuticals, Vorasidenib is
a brain-penetrant, dual inhibitor of mutant
isocitrate dehydrogenase-1 (IDH1) and IDH2.
It received FDA approval on August 6, 2024,
becoming the first systemic therapy for Grade 2
astrocytoma or oligodendroglioma harboring
a susceptible IDH1 or IDH2 mutation.
The drug emerged from efforts to target
metabolic vulnerabilities in gliomas, where
IDH mutations lead to the accumulation of
2-hydroxyglutarate (2-HG) — an oncometa
bolite that disrupts cellular differentiation and
promotes tumorigenesis. Vorasidenib works
by selectively inhibiting mutant IDH enzymes,
thereby reducing 2-HG levels and slowing tu-
mor progression. Its efficacy was demonstra
ted in the Phase III INDIGO trial, where it
36 ISSN 2708-129X. Укр. хім. журн., 2025
ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
significantly extended progression-free survi
val and delayed the need for further interven-
tion.
Interestingly, although racemic Vorasidenib
exhibits comparable nanomolar-level bioacti
vity, the enantiomer with R,R absolute confi
guration demonstrates approximately ten-fold
greater potency in cellular assays [56].
The therapeutic profile of Vorasidenib is
notable for its oral bioavailability, central ner
vous system penetration, and targeted mecha
nism, making it particularly suited for low-
grade gliomas post-surgery. It is administered
once daily, with dosing adjusted for pediatric
patients based on body weight [57–60].
While the full particularities have not been
publicly disclosed in detail, fluorinated mo-
tifs—such as trifluoroethylamine or related
groups — are often employed in IDH inhibi-
tors to enhance lipophilicity, metabolic stabi
lity, and binding affinity to the mutant enzyme
pocket. The electron-withdrawing properties
of fluorine can fine-tune the pharmacodyna
mics and improve central nervous system
(CNS) penetration, which is critical for brain
tumor therapeutics. In general, Vorasidenib
represents a paradigm shift in glioma treat-
ment, combining precision oncology with stra-
tegic fluorine chemistry to address a previously
underserved patient population.
Another notable drug incorporating a
2,2,2-trifluoroethylamine residue is Pirtobruti-
nib 2 (Fig. 1), marketed as Jaypirca. Developed
by Loxo Oncology, a subsidiary of Eli Lilly and
Company, Pirtobrutinib is a next-generation,
non-covalent inhibitor of Bruton’s tyrosine
kinase (BTK). It received accelerated FDA ap-
proval on January 27, 2023, for the treatment
of relapsed or refractory mantle cell lympho-
ma (MCL) following at least two prior lines of
systemic therapy, including a BTK inhibitor.
A subsequent approval in December 2023 ex-
panded its indication to chronic lymphocytic
leukemia (CLL) and small lymphocytic lym-
phoma (SLL) in patients previously treated
with both a BTK and a Bcl-2 inhibitor [61, 62].
The therapeutic profile of Pirtobrutinib is
distinguished by its reversible binding to BTK,
unlike earlier covalent inhibitors such as Ibru-
tinib. This allows it to re-establish BTK inhibi-
tion in patients who have developed resistance
to covalent BTK inhibitors. It is administered
orally at 200 mg once daily, offering a con
venient and targeted approach to B-cell malig
nancies.
Mechanistically, Pirtobrutinib binds to the
ATP-binding site of BTK, blocking down-
stream signaling that promotes B-cell prolife
ration and survival. Its non-covalent interac-
tion enables sustained inhibition even in the
presence of BTK mutations that impair cova-
lent binding [63–65].
While the full details are proprietary, fluori-
nated motifs—particularly trifluoroethylamine
or trifluoromethyl groups — are commonly
employed in kinase inhibitors to enhance li-
pophilicity, metabolic stability, and selectivity.
In Pirtobrutinib, fluorine likely contributes to
CNS penetration, binding affinity, and phar-
macokinetic optimization, reinforcing its effi-
cacy in hematologic malignancies. Pirtobruti-
nib represents a significant advance in preci-
sion oncology, offering renewed therapeutic
options for patients with limited alternatives.
Another notable fluorinated drug is Ina-
volisib 3 (Fig. 1), a PI3Kα-selective inhibitor de-
veloped by Genentech, a member of the Roche
Group. The approved molecule incorporates a
2,2-difluoroethylamine residue. Interestingly,
a related drug candidate—compound 4, fea-
37https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
turing a 2,2,2-trifluoroethylamine fragment—
played a pivotal role in optimizing the pharma-
cological profile of Inavolisib. Substitution with
a trifluoromethyl group in compound 4 yield-
ed a α isoform of phosphatidylinositol 3-kinase
(PI3Kα) IC₅₀ of 0.095 nM and a PI3Kδ/PI3Kα
selectivity ratio of 171, indicating reduced iso-
form selectivity. In contrast, Inavolisib, bearing
a difluoromethyl group, achieved a PI3Kα IC₅₀
of 0.034 nM and a PI3Kδ/PI3Kα ratio of 361,
demonstrating markedly enhanced selectivity
for the α isoform.
Marketed under the brand name Itovebi,
Inavolisib received FDA approval in May 2024
for use in combination with Fulvestrant ±
Palbociclib in patients with hormone recep-
tor-positive (HR+), HER2-negative, PIK3CA-
mutated advanced or metastatic breast cancer
who have progressed following prior endo-
crine therapy. The therapeutic profile of Ina-
volisib is defined by its high selectivity for the
PI3Kα, a frequently mutated oncogenic driver
in breast cancer [66]. Unlike earlier pan-PI3K
inhibitors, Inavolisib exhibits improved tolera-
bility and reduced off-target toxicity, owing in
part to its rational design and physicochemical
optimization [67–70].
Mechanistically, Inavolisib binds to the
ATP-binding pocket of PI3Kα, inhibiting
downstream protein kinase B and mammalian
target of rapamycin (AKT/mTOR) signaling
and promoting degradation of mutant p110α
protein. This dual action not only suppresses
tumor cell proliferation but also enhances sen-
sitivity to endocrine therapy, particularly in
tumors harboring PIK3CA mutations [70–73].
Structurally, Inavolisib incorporates a dif-
luoroethylamine, a fluorinated motif that con-
tributes to its metabolic stability, target selec-
tivity, and oral bioavailability. The role of fluo
rine in modulating lipophilicity and binding
kinetics is well-established in kinase inhibitor
design, and in Inavolisib, it likely enhances
CNS penetration and pharmacokinetic perfor-
mance.
Administered orally at 30 mg once daily,
Inavolisib offers a convenient and targeted ap-
proach to overcoming endocrine resistance in
breast cancer. Common adverse effects include
hyperglycemia, rash, diarrhea, and stomati-
tis, consistent with PI3K pathway inhibition
[74–76].
Inavolisib represents a refined evolution in
PI3K-targeted therapy, balancing potency with
precision and reaffirming the value of fluori-
nated scaffolds in modern oncology.
Finally, we would like to mention Odana-
catib 5 (MK-0822) featuring 2,2,2-trifluoro-
ethylamine residue. It was a promising inves-
tigational drug developed by Merck & Co.,
discovered at Merck Frosst in Montreal in the
early 2000s. It was designed as a selective in-
hibitor of cathepsin K (CTSK), a cysteine pro-
tease critical for osteoclastic bone resorption.
By targeting CTSK, Odanacatib aimed to treat
osteoporosis and bone metastases by reducing
bone degradation while preserving bone for-
mation — an advantage over traditional bis-
phosphonates.
Merck advanced Odanacatib into Phase III
clinical trials, and by 2014, the company an-
nounced plans to seek FDA approval based on
strong efficacy and a favorable safety profile.
However, in 2016, Merck discontinued its de-
velopment after post-trial analysis revealed an
increased risk of stroke, halting its regulatory
submission [77, 78].
The fluorinated motif, 2,2,2-trifluoroethyl
amine, plays a pivotal role in enhancing
metabolic stability, lipophilicity, and target
38 ISSN 2708-129X. Укр. хім. журн., 2025
ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
binding affinity. The CF₃ group contributes
strong electron-withdrawing effects, which
modulate the basicity of the adjacent amine
and improve pharmacokinetic properties.
Additionally, the trifluoroethylamine unit
helps fine-tune the interaction of the molecule
with the cathepsin K active site, contributing
to its selectivity and potency. Furthermore,
Odanacatib features residues of fluoroleucine
and nitrile of aminocyclopropane carboxylic
acid, underscoring the role of tailor-made ami-
no acids in modern drug design [79–81].
Though never approved, Odanacatib re-
mains a notable example of how fluorinated
amine motifs can be leveraged in drug design
to achieve precise biological effects and favora-
ble drug-like properties.
Fig. 1. Representative examples of fluorinated drug scaffolds
containing the CF₃–CH(NR₂) moiety.
Brief Overview of Chiral Auxiliary-Based
Approaches for the Synthesis of the 2,2,2-Tri
fluoroethylamine Moiety.
Considering the critical role of enantiomeric
purity in the development of chiral pharmaceuti-
cals [82–84], chiral auxiliary-assisted asymmet-
ric synthesis of 2,2,2-trifluoroethylamines has
garnered significant attention. Most research in
this area centers on the use of chiral derivatives
of industrially available trifluoroacetaldimines 6
and 7 (Fig. 2). p-Toluenesulfinimine 6, derived
from Davis’ p-toluenesulfinamide [85–88], is
a cost-effective, readily accessible, and opera-
tionally reliable reagent. It exhibits high reac-
tivity toward nucleophilic additions, furnishing
1-substituted 2,2,2-trifluoroethylamines 8 in
chemical yields and diastereoselectivities ex-
ceeding 90% [89–92]. Ellman’s tert-butanesul-
finamide-derived imine 7 has proven even
more prolific, inspiring a substantial body of re-
search [93–102]. It enables the synthesis of tar-
get trifluoroethylamines 8 with excellent yields
(>95%) and virtually complete diastereoselec-
tive control (>98%) [103–109].
39https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
Fig. 2. Chiral auxiliary-based approaches to trifluoroethylamines.
Enzymatic resolution of racemic 2,2,2-tri
fluoroethylamines 8 remains relatively under-
explored. Nonetheless, the use of penicillin
acylase (penicillin amidase, EC 3.5.1.11) [110]
offers a practical and efficient route to both
enantiomers, delivering products of excep-
tionally high enantiomeric purity (>99% ee)
[111–113].
Catalytic enantioselective Approaches for the
Synthesis of the 2,2,2-Trifluoroethylamine Moiety
Reduction of C=N Bond.
Catalytic enantioselective hydrogenation
of imines is a well-established methodology,
supported by a rich arsenal of chiral catalysts,
optimized reaction conditions, and broad sub-
strate scope. Its application to the reduction of
fluorinated imines is generally straightforward,
albeit with occasional complications. The key
distinction of fluorine-containing imines lies
in their heightened reactivity, which can in-
fluence both selectivity and reaction kinetics.
Nonetheless, the enantioselective reduction of
fluoroimines remains a robust and extensively
studied domain of synthetic chemistry [114].
A representative example is the work by
Wu et al. (Scheme 1) [115], who achieved the
enantioselective transformation of α-trifluoro
methylimines 9 into α-trifluoromethylamines
11 via asymmetric transfer hydrogenation. The
reaction employed a ruthenium catalyst 10
(2 mol%) derived from (1S,2S)-1,2-diphenyl
ethane-1,2-diamine, with sodium formate
serving as the hydrogen source and a water–
dimethylformamide mixture as the cosolvent.
Conducted at 40 °C, the process afforded the
desired amines in excellent chemical yields
(>90%) and high enantioselectivity (>95% ee),
highlighting the efficiency and practicality of
this catalytic system.
Scheme 1. Hydrogenation of N-aryl aryl/CF3-ketimines using Ru(II) catalyst 10.
Dai and Cahard (Scheme 2) [116] reported
the in situ generation of catalyst 13 (2 mol%),
derived from dichloro(para-cymene)rutheni
um(II) dimer [(RuCl₂(η⁶-arene))₂] and (1S,2R)-
1-amino-2,3-dihydro-1H-inden-2-ol, in the
presence of isopropyl alcohol. This protocol
40 ISSN 2708-129X. Укр. хім. журн., 2025
ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
enables the formation of a bifunctional chiral
catalyst directly in the reaction medium, which
efficiently promotes the asymmetric transfer
hydrogenation of trifluoromethyl ketimines
12, affording the corresponding amines 14 in
excellent yields (>95%) and high enantioselec-
tivities (up to 93% ee). The reactions are per-
formed under ambient temperature conditions
in the presence of a base (t-BuOK), highlight-
ing the operational simplicity and stereoche
mical efficiency of this catalytic system.
Scheme 2. Hydrogenation of N-PMP aryl/CF3-ketimines using Ru(II) catalyst 13.
While the methods outlined in Schemes 1
and 2 yield excellent results for trifluorome-
thyl and aryl imines, their application to alkyl
ketimines proves ineffective, often resulting
in low reactivity and/or poor enantioselecti
vity. This diminished performance may be at-
tributed to imine–enamine tautomerism via
a 1,3-proton shift reaction (vide infra) [117],
and/or the presence of a mixture of Z/E imine
geometric isomers.
Abe et al. (Scheme 3) [118] demonstrated
that under hydrogen pressure, a catalytic sys-
tem comprising palladium(II) trifluoroacetate
and 2,2′-bis(diphenylphosphino)-1,1′-binaph-
thyl (BINAP) 16 (2 mol%) effectively promotes
the asymmetric hydrogenation of α-fluorina
ted iminoesters 15, yielding highly enantioen-
riched β-fluorinated α-amino esters 17. Both
yield and enantioselectivity were significant-
ly enhanced by employing fluorinated alco-
hols — notably 2,2,2-trifluoroethanol, which
enabled enantioselectivities of up to 91% ee.
It is noteworthy that imines derived from
trifluoropyruvic acid, serving as versatile syn-
thons for the general synthesis of α-trifluo-
romethyl amino acids, were first introduced
in 1986 by the Kukhar – Yagupolskii group
[119–122].
Scheme 3. Hydrogenation of fluoroalkyl-substituted α-iminoesters.
41https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
Chen et al. (Scheme 4) [123] demonstrated
that the use of Cl-MeO-BIPHEP 19 (2 mol %)
as a catalyst effectively generalizes the previous-
ly discussed approach to the hydrogenation of
aryl- and alkyl-substituted imines 18, afford-
ing the corresponding amines 20 in excellent
chemical yields (>95%) and with enantioselec-
tivities of up to 94% ee. Notably, the presence
of 2,2,2-trifluoroethanol was found to be crucial
for achieving high stereochemical fidelity.
Scheme 4. Hydrogenation of alkyl- and aryl-substituted CF3-imines.
It is important to recognize that while certain
perfluorinated compounds have valuable ap-
plications in life sciences and materials chemi
stry, many members of this class — collectively
known as per- and polyfluoroalkyl substances
(PFAS) — pose significant environmental risks
due to their persistence and bioaccumulative
potential [124–126]. Consequently, the synthe-
sis and use of such substances should be subject
to strict regulatory oversight and pursued only
when no suitable alternatives are available.
Henseler et al. (Scheme 5) [127] repor
ted the metal-free synthesis of optically active
α-CF₃ amines 14 under mild catalytic condi-
tions. The reactions were carried out in reflux-
ing dichloromethane for 24 hours, employing
chiral phosphoric acid 21 (10 mol %) as the
catalyst and benzothiazoline 22 (1.2 equiv.) as
the reducing agent. The method afforded the
desired amines in yields ranging from 70%
to 90%, with enantioselectivities exceeding
95% ee.
Scheme 5. Hydrogenation of aryl-substituted CF3-imines using chiral phosphoric acid 21.
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ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
Chen et al. (Scheme 5) [128] applied the
same catalytic protocol to the reduction of
trifluoromethyl alkynyl ketimines 23, afford-
ing the corresponding amines 24 with yields
and enantioselectivities reaching up to 98%
and 98% ee, respectively. Notably, the alkyne
moiety remained intact, with no reduction of
the triple bond observed under the reaction
conditions.
In the methods discussed above for hyd
rogenation of trifluoromethyl-substituted
imines, application of N-PMP is a common
feature of the starting compounds. Stereoelec-
tronic properties of the PNP group provides for
proper reactivity of the C=N bond and its more
stable geometric configuration. Furthermore,
this group can be conveniently removed under
the standard conditions shown in Scheme 6. Its
cleavage via oxidative hydrolysis — commonly
using harsh oxidants such as ceric ammonium
nitrate (CAN), as illustrated in Scheme 6 —
enables access to the free amine. Alternative
strategies for PMP deprotection similarly rely
on strongly acidic and oxidizing conditions to
unveil the primary amine functionality. The
conditions outlined in Scheme 6 preserve the
enantiomeric integrity of the compounds and
afford consistently high yields (>70%).
Scheme 6. Deprotection of PMP group.
Gosselin et al. (Scheme 7) [129] developed
a catalytic enantioselective strategy for the di-
rect synthesis of trifluoromethylated amines
30. The sequence begins with the addition of
lithium bis(trimethylsilyl)amide to trifluo-
romethyl/aryl ketones 25, generating (E)-N-
TMS-ketimines. Subsequent treatment with
methanol induces solvolysis of the N–Si bond,
yielding bench-stable, isolable N–H imines
26 as Z/E isomer mixtures, along with a side
product, aminoalcohol 27. These three-com-
ponent mixtures are then subjected to enanti-
oselective reduction using catalyst 28 (2 mol%)
and catecholborane 29 as the reducing agent,
affording the desired CF₃-amines 30 in 72–
95% yields and with enantioselectivities rang-
ing from 75% to 98% ee. The reactions are con-
ducted in toluene at –15 °C for 18 hours, and
upon completion, the mixtures are quenched
with 2.0 M HCl in diethyl ether, furnishing the
products as hydrophilic acid salts.
Scheme 7. Chiral borane-catalyzed reductions of NH imines.
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Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
[1,3]-Proton Shift Reaction.
The discovery of biomimetic reductive ami-
nation of fluorinated carbonyl compounds dates
back to 1986 [119, 130], when the Kukhar –
Yagupolskii group attempted a Staudinger re-
action between keto-ester 31 (Scheme 8) and
phosphazene 32. Unexpectedly, the reaction
yielded Schiff base 34 as the sole product. It is
reasonable to assume that the intended in-
termediate 33 underwent irreversible in situ
isomerization to imine 34, which was subse-
quently hydrolyzed with ease, affording tri
fluoroalanine 35 in high yield.
Scheme 8. Staudinger reaction followed by the irreversible [1,3]-proton shift.
The [1,3]-proton shift reaction has emerged
as a synthetically versatile and broadly applica-
ble transformation [131], enabling the efficient
and practical conversion of various fluorinated
carbonyl substrates — including CF₃-aldehydes
[132, 133], CF₃-ketones [134, 135], as well as α-
[136] and β-ketoacids [137, 138] — into their
corresponding biologically relevant amino de-
rivatives under a wide range of reaction condi-
tions [139–141]. Notably, the reaction can pro-
ceed through two consecutive [1,3]-proton shift
steps, further expanding its synthetic utility and
enabling access to more complex molecular ar-
chitectures [142, 143]. While the transforma-
tion is typically base-catalyzed [144], it can also
occur under thermal conditions [145], under-
scoring its operational flexibility.
Moreover, the use of chiral phenylethyl-
amine introduces a stereochemical dimen-
sion to the process, allowing for asymmetric
[1,3]-proton shift transfer and affording enan-
tiomerically enriched CF₃-amino compounds
with enantiomeric excesses reaching up to
90% ee [146–149].
The first catalytic enantioselective [1,3]-pro-
ton shift reaction, reported in 1994, is illustrat-
ed in Scheme 9 [150]. In this pioneering study,
N-benzylenamines 36, prepared from β-poly-
fluoroalkyl-β-ketocarboxylic esters and ben-
zylamine, underwent a [1,3]-proton shift cata-
lyzed by (–)-cinchonidine 37 (5–13 mol%). The
transformation afforded N-benzylidene deri
vatives 38 in good yields (67–89%) and with
moderate enantioselectivity — up to 36% ee.
Scheme 9. Cinchonidine-catalyzed [1,3]-proton shift reaction.
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ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
Subsequent hydrolysis of the products 38
proceeded smoothly, delivering the corre-
sponding optically active (R)-β-polyfluoro-
alkyl-β-amino acids in excellent yields (87–
93%). This work represents a foundational
example of asymmetric proton shift catalysis
and laid the groundwork for future develop-
ments in enantioselective synthesis of fluori-
nated amino acid derivatives.
Scheme 10 [151] illustrates the catalytic
enantioselective synthesis of α-(trifluorome-
thyl)benzylamine Schiff base 41 employing
chiral base 40. In this transformation, imine
39 undergoes isomerization to form Schiff
base 41, catalyzed by 50 mol% of cinchonidine
derivatives 40 in various solvents, including
chloroform, methanol, and acetonitrile. When
cinchonidine 40 (R = H) was used as the cata-
lyst in chloroform, the reaction achieved 79%
conversion of imine 39, yielding Schiff base 41
with (R)-absolute configuration and 35% ee.
Remarkably, the product was obtained as a
single compound, free from detectable bypro
ducts.
Scheme 10. Catalytic enantioselective synthesis
of α-(trifluoromethyl)benzylamine Schiff base.
This transformative line of research —
centered on chiral base-catalyzed [1,3]-pro-
ton shift transfer—was originally pioneered
by Ukrainian chemists, whose foundational
contributions have since inspired widespread
optimization efforts and the development of
more efficient catalytic systems. Building on
this groundwork, Wu and Deng introduced
several key modifications, including the use
of synthetically tailored cinchona alkaloid 44
and benzylamine derivatives 42 bearing elec-
tron-withdrawing substituents on the aroma
tic ring (Scheme 11). The latter strategy was a
direct extension of earlier findings [139–141],
which demonstrated that the electrophilic na-
ture of the benzene ring significantly facilitates
the [1,3]-proton shift, enabling isomerization
under milder conditions. Equally important,
their work [152, 153] underscored the criti-
cal role of catalyst structure in achieving high
levels of stereocontrol, with enantiomeric ex-
cesses of products 43 reaching up to 90% ee.
In a parallel development, Liu et al. [154]
reported comparable results using an even
more structurally elaborate designer catalyst
45 (Scheme 11). Notably, both catalytic sys-
tems are effective at low loadings (as little as
10 mol%), highlighting their practical utility in
asymmetric synthesis.
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Scheme 11. Synthetic cinchona derivatives as catalysts for enantioselective [1,3]-proton shift.
Since the pioneering work of the Kukhar –
Yagupolskii group in 1986 [119, 130], a fun-
damentally new dimension has emerged in
the chemistry of the [1,3]-proton shift reac-
tion—specifically involving the trapping of
the intermediate 1,3-azaallylic anion by vari-
ous electrophiles. For instance, Li et al. [155]
(Scheme 12) demonstrated that β-isocu-
preidine 50, a cinchonine-derived alkaloid
used at 10 mol% loading, effectively catalyzes
an asymmetric SN2′–SN2′ reaction between
N-2,2,2-trifluoroethylisatin ketimines 46 and
Morita – Baylis – Hillman (MBH) type car-
bonates 47. This transformation proceeds via
selective trapping of the intermediate anion
48, affording synthetically valuable CF₃-sub-
stituted amino compounds 49 with high enan-
tioselectivity and efficiency. A series of chiral
α-trifluoromethylamines were obtained in
excellent yields (70–90%) and ee (~90%). No-
tably, despite the presence of two potentially
reactive sites on anion 48, the reaction occurs
exclusively at the α-position relative to the CF₃
group.
Scheme 12. Coupling of CF3-imines with Morita−Baylis−Hillman allylic carbonates.
Shi et al. (Scheme 13) [156] reported an
Ir/phosphoramidite 55-catalyzed enantiose-
lective cascade transformation involving a
[1,3]-proton shift, allylation, and subsequent
aza-Cope rearrangement of trifluoroethylisa
tin-derived imines 51 with allylic carbonates
52, ultimately furnishing CF₃-substituted ami-
no derivatives 54. Notably, the initial product
53 arises from allylation of the [1,3]-proton
shift intermediate, despite the steric hindrance
associated with the corresponding anion. This
intermediate 53 then undergoes a spontaneous
aza-Cope rearrangement, delivering the net
γ-allylation product 54. The rearrangement is
driven by steric relief from the adjacent tet-
ra- and trisubstituted stereogenic centers, and
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ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
is likely further facilitated by conjugation of
the resulting olefin with the aromatic system.
A broad array of derivatives bearing various
(hetero)aryl substituents can be accessed, with
most examples exhibiting excellent yields (up
to 95%) and high enantioselectivity (~90% ee).
Scheme 13. Ir − phosphoramidite-catalyzed cascade reactions of CF3-imines.
Wang et al. (Scheme 14) [157] reported the
Pd-catalyzed trapping of 1,3-azaallyl anions
derived from fluorenyl imine 56 with allyl-
ic acetates 57. The transformation employs a
Pd(dba)₂ complex in conjunction with a PHOX
ligand 59, using Cs₂CO₃ as the base in THF.
The reaction proceeds with high enantioselec-
tivity (~90% ee) and modest to good diastereo-
selectivity (up to 8:1 dr). Although conceptual-
ly related to the Ir-catalyzed cascade described
in Scheme 13, this process diverges mechanis-
tically: it involves direct allylation at the least
sterically hindered site of the azaallyl anion,
rather than proceeding through a rearrange-
ment pathway. This distinction underscores
the complementary nature of Pd and Ir cata
lysis in accessing structurally and stereoche
mically diverse azaallyl-derived products.
Scheme 14. Pd-catalyzed trapping of 1,3-azaallyl anions derived from fluorenyl imine.
Onyeagusi et al. (Scheme 15) [158] intro-
duced an alternative strategy for the enantiose-
lective allylation of CF₃-substituted imines 60,
catalyzed by a chiral Pd complex. In this proto-
col, imines 60 react with terminal dienes 61 in
the presence of 5 mol% Pd–DTBM-SEGPHOS
catalyst 63. The reaction is carried out in 1,4-di-
oxane using 2.0 equivalents of triethylamine to
generate the corresponding 1,3-azaallyl anion
under mild heating over 12 hours. The inter-
mediate anion undergoes selective allylation
at the least sterically hindered site, affording
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products 62 in yields of up to 86%, with ex-
cellent enantioselectivity (~95% ee) and good
diastereoselectivity (up to 10:1 dr). This me
thod highlights the versatility of Pd catalysis
in accessing highly enantioenriched CF₃-con-
taining amines through direct functionaliza-
tion of azaallyl intermediates.
Scheme 15. Pd–DTBM-SEGPHOS-catalyzed reactions with dienes.
Liu et al. (Scheme 16) [159] described an
enantioselective Michael/aza-Henry cycload-
dition between trifluoromethyl-substituted
iminomalonate 64 and nitroalkenes 65, cata-
lyzed by 10 mol% of a quinine-derived squar-
amide catalyst 67. This transformation enables
the efficient synthesis of highly functionalized
pyrrolidine derivatives 66 bearing 5-trifluo-
romethyl and 3-nitro substituents, along with
three contiguous stereogenic centers. The re-
action proceeds with excellent stereoselectivi-
ty (>20:1 dr, 99% ee) and very good yields (up
to 82%).
Mechanistically, the corresponding 1,3-aza-
allylic anion undergoes regioselective attack at
the α-position relative to the trifluoromethyl
group, followed by nucleophilic addition of
the nitro-stabilized anion to the C=N dou-
ble bond. Analogous to amino malonate che
mistry, one of the carboxyl groups in products
66 can be selectively removed via decarbo
xylation, granting access to polysubstituted,
CF₃-containing proline derivatives — a class of
tailor-made amino acids with significant bio-
medical relevance [160].
Scheme 16. Enantioselective Michael/aza-Henry cycloaddition reactions.
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ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
You et al. (Scheme 17) [161] reported an
enantioselective [3+2]-cycloaddition between
N-2,2,2-trifluoroethylisatin ketimines 68 and
β-trifluoromethyl enones 69, catalyzed by chi-
ral bifunctional squaramide–tertiary amine or-
ganocatalysts. This transformation affords a di-
verse array of 3,2′-pyrrolidinyl spirooxindoles
70 featuring a vicinal bis(trifluoromethyl)-sub-
stituted pyrrolidine core and up to four con-
tiguous stereocenters. The protocol is notable
for its exceptional efficiency in constructing
structurally complex spirocyclic oxindoles, de-
livering products in high yields (75–99%) and
excellent enantioselectivities (92–99% ee). Re-
actions are performed in dichloromethane at
0 °C using only 5 mol% of organocatalyst 67.
Scheme 17. Reactions of CF3-imines catalyzed by bifunctional squaramide.
Huang et al. (Scheme 18) [162] reported an
enantioselective, exo′-selective [3+2]-cycload-
dition between CF₃-containing isatin-derived
azomethines 68 and methyleneindolinones
71. Catalyzed by 10 mol% of a cinchona-de-
rived bifunctional squaramide organocatalyst
73, this transformation efficiently delivers a
series of trifluoromethylated 3,3′-pyrrolidi-
nyl-dispirooxindoles 72 — compounds of
potential biological relevance—with excellent
stereocontrol (84–99% yields, >20:1 dr, and
>99% ee). The reaction proceeds at room tem-
perature in chloroform and constructs four
contiguous stereogenic centers, including two
adjacent spiro quaternary stereocenters. Nota-
bly, the catalytic performance closely parallels
that observed in Scheme 17, indicating that
minor structural variations in the organoca
talyst framework exert negligible influence on
the reaction outcome.
Scheme 18. Exo′-selective [3+2] cycloaddition reactions of CF3-imines.
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Zhi et al. (Scheme 19) [163] reported the
use of a distinct class of catalysts 76 to pro-
mote reactions virtually identical to those
previously described. Specifically, a domino
Michael – Mannich [3+2]-cycloaddition pro-
ceeds efficiently between isatin ketimines 68
and Boc-protected isatin-derived enoates 74,
affording spiro-compounds 75 of potential
medicinal relevance. The transformation de-
livers products in good yields (60–92%) and
with excellent stereoselectivity (72–93% ee).
Reactions are typically carried out in mildly
polar solvents at ambient temperature using
10 mol% of catalyst 76. Notably, this protocol
offers a direct and practical route to structu
rally complex spirooxindoles bearing multiple
stereocenters, reinforcing the versatility of this
catalytic strategy.
Scheme 19. Bifunctional thiourea-catalyzed domino Michael–Mannich [3+2]-cycloadditions.
Su et al. (Scheme 20) [164] reported the
enantioselective introduction of a trifluorome-
thyl group at the 2′-position of spiro-pyrroli-
dine-3,3′-oxindoles 78 using 1 mol% of a qui-
nine-derived squaramide catalyst 79. Under
ambient conditions in toluene, the 2,2,2-trif-
luoroethylamine-derived ketimine 64 under-
went a base-catalyzed [1,3]-proton shift to ge
nerate the corresponding trifluoromethylimine
intermediate. This species then participated in
a 1,3-dipolar cycloaddition with dipolarophile
77, affording pharmaceutically relevant spiro-
cyclic products in excellent yields (>80%) and
outstanding enantioselectivities (up to 99% ee).
Scheme 20. Enantioselective synthesis of spiro CF3-compounds catalyzed
by quinine-derived squaramide catalyst.
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ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
Yi et al. (Scheme 21) [165] reported a co-
operative Brønsted base–Lewis acid catalyzed
1,3-dipolar cycloaddition employing chiral
dinuclear zinc catalyst 83. This system enables
an asymmetric, exo′-selective [3+2]-cycload-
dition of CF₃-containing, N-unprotected isat-
in-derived azomethine ylides. In the presence
of 10 mol% catalyst, ylides 80 react efficiently
with methyleneindolinones 81 to afford a series
of trifluoromethyl-substituted 2,3-pyrrolidinyl
dispirooxindoles 82, exhibiting excellent enan-
tioselectivity (up to 99% ee) and exo′-diastere-
oselectivity (>20:1 dr). Remarkably, up to four
contiguous stereogenic centers—including two
adjacent spiro quaternary stereocenters — are
constructed in a single step. The use of a bi-
functional, metal-based catalyst stands out in a
domain largely dominated by organocatalysts.
Scheme 21. Zn/chiral ligand catalyzed reaction of isatin-derived ylides with oxindoles.
Nucleophilic additions to C=N bond.
Zhang et al. (Scheme 22) [166] repor
ted a highly enantioselective organocatalytic
Friedel – Crafts aminoalkylation of indoles
85 with imines 84, achieved by chiral phos-
phoric acid 87 catalysis. This approach ena-
bled the synthesis of novel chiral trifluorome-
thyl-containing compounds 86 in high yields
and with excellent enantioselectivities. The
methodology was further extended to the
corresponding imines derived from difluoro
acetaldehyde, demonstrating a broad substrate
scope. Reactions were typically carried out in
dichloromethane with 4 Å molecular sieves at
ambient temperature over one to three days.
Reported yields approached quantitative levels
(up to 99%), with enantioselectivities consis
tently exceeding 95% ee.
Scheme 22. Organocatalytic enantioselective Friedel–Crafts aminoalkylation of indoles.
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Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
Husmann et al. (Scheme 23) [167] reported
a highly enantioselective Friedel–Crafts reac-
tion catalyzed by chiral phosphoric acid 87.
In this transformation, N-Boc-protected ethyl
trifluoropyruvate imine 88 was activated by
6 mol% of catalyst and reacted with a broad
range of indole derivatives 85 to furnish qua-
ternary α-amino acids 89 in excellent yields
(up to 99%) and high enantioselectivities (up
to 98:2 er). The reactions were typically con-
ducted in toluene at −78 °C for approximately
3 hours.
It is worth noting that N-activated imines of
trifluoropyruvic acid were first developed by the
Yagupolskii group in 1986 [119,121,122,168].
Their work pioneered the use of these inter-
mediates in the general synthesis of α-trifluo-
romethyl amino acids [169,170].
Scheme 23. Friedel−Crafts reactions of N-Boc-protected ethyl trifluoropyruvate imines.
Mannich addition reactions involving fluo
rinated imines and diverse nucleophiles repre-
sent one of the most reliable strategies for syn-
thesizing fluorine-containing amines and ami-
no acids [171–173]. The strong electron-with-
drawing effect of fluorine enhances the electro-
philicity of the imine moiety, enabling these re-
actions to proceed under mild conditions with
excellent stereocontrol over the resulting ami-
no compounds [174–176]. A catalytic enantio
selective variant of the Mannich reaction was
reported by Fustero et al. (Scheme 24) [177],
who described a concise two-step synthesis of
optically pure fluorinated β-alkyl γ-amino al-
cohols 92. This method employs proline catal-
ysis and utilizes inexpensive, readily available
starting materials, such as imine 90 and alde-
hydes 91. However, closer examination of the
reaction conditions reveals significant limita-
tions: the process requires three days to com-
plete, yields of 92 are modest (approximately
40%), and the protocol is labor-intensive, in-
volving incremental temperature increases of
10 °C per day starting from −20 °C.
Scheme 24. Proline-catalyzed Mannich reactions of CF3-imines.
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ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
You and Luo (Scheme 25) [178] reported
a Mannich-type addition of malonyl-derived
nucleophiles 94 to N-Cbz trifluoromethyl al-
dimines, which were generated in situ from
N,O-acetals 93. This transformation affords
dicarbonyl trifluoromethylamines 96 as the
final products. The reaction employs a chiral
diamine catalyst 95 in its triflic acid salt form,
used at a relatively high loading of 20 mol%.
Reactions are carried out at 60 °C over a two-
day period. Despite the extended reaction time
and elevated catalyst loading, the authors re-
port excellent outcomes, with yields reaching
up to 99% and enantioselectivities exceeding
99% ee.
Scheme 25. Chiral amine-catalyzed Mannich addition reactions.
Amination.
Kawatsura et al. (Scheme 26) [179] repor
ted a palladium-catalyzed, regio- and enan-
tioselective allylic amination of trifluorome-
thyl-substituted, racemic, and unsymmetrical
1,3-disubstituted allylic esters 97 using secon
dary amines 98. The transformation proceeds
via a two-step sequence. In the first step, a
conventional allylic substitution occurs, af-
fording racemic allylic amines 99. Subsequent
treatment of these intermediates with the same
palladium catalyst in the presence of AgPF₆
triggers a dynamic kinetic asymmetric trans-
formation (DYKAT), furnishing the target al-
lylic amines bearing a trifluoromethyl group
at the α-position relative to the amino moiety.
The reactions are typically carried out in di
oxane at 60 °C for up to 96 hours, delivering
the desired products in yields exceeding 80%
and with ee of approximately 90%.
Scheme 26. Allylic amination and dynamic kinetic asymmetric transformation.
Zhu et al. (Scheme 27) [180] developed an
organocatalytic asymmetric strategy for syn-
thesizing 2-trifluoromethyl-substituted tetra
hydroquinolines 103 via an addition–cycliza-
tion cascade between 2-aminochalcones 101
and trifluoromethyl-containing nitroalkenes
102. The transformation is catalyzed by
thiourea 104, employed at a 10 mol% loading.
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Reactions are carried out in toluene at 0 °C over
approximately 24 hours. This cascade process
efficiently furnishes tetrahydroquinolines 103
bearing three contiguous stereogenic centers,
with excellent yields (~90%), high diastereose-
lectivity (>20:1), and notable enantioselectivity
(~90% ee).
Scheme 27. Chiral thiourea-catalyzed additions to CF3-nitroalkenes.
Takata et al. (Scheme 28) [181] introduced
a copper-catalyzed electrophilic amination
strategy as a general approach for synthesiz-
ing α-trifluoromethylamines. Their method
involves a regioselective net hydroamination
of 1-trifluoromethylalkenes 105 using hydro-
silanes and hydroxylamines 106. A carefully
optimized combination of ligand and additive
was critical to suppress the otherwise prevalent
β-fluoride elimination from the α-CF₃-sub-
stituted organocopper intermediate, thereby
enabling efficient formation of the desired α-tri-
fluoromethylamines. The reaction proceeds
in good yields (>70%) with excellent regiose-
lectivity. Furthermore, by employing a chiral
bisphosphine ligand 108, the transformation
can be rendered enantioselective, affording op-
tically pure α-trifluoromethylamines with ee
exceeding 98%. These fluorinated amines hold
significant promise for applications in medici-
nal and pharmaceutical chemistry.
Scheme 28. Electrophilic amination 1-trifluoromethylalkenes.
Self-disproportionation of enantiomers and
its impact on assessing the stereochemical out-
come of enantioselective reactions.
SDE is a stereochemical phenomenon in
which a non-racemic mixture of enantiomers
spontaneously separates into fractions with
differing ee when subjected to achiral physical
processes such as distillation, sublimation, or
chromatography [182–184]. Remarkably, even
in the absence of a chiral selector, a scalemic
mixture can yield one fraction enriched in
a single enantiomer and another closer to
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ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
racemic composition. This behavior has far-
reaching implications for enantiopurity as-
sessment, enantiomer separation strategies,
and even hypotheses concerning the origin of
biological homochirality. Among the various
theories proposed to explain the emergence
and persistence of enantiomerically pure or
highly enriched samples, SDE remains the only
mechanism that has been experimentally vali-
dated [185–187].
Mechanistically, SDE arises from subtle dif-
ferences in intermolecular interactions that
favor either homochiral or heterochiral aggre-
gation. These aggregation preferences lead to
distinct physicochemical properties—such as
solubility, volatility, and retention behavior —
enabling spontaneous enantiomeric enrich-
ment or depletion under entirely achiral con-
ditions. Given that intermolecular interactions
are intrinsic to all chemical compounds, it fol-
lows that SDE is a fundamental property of all
chiral substances.
Although recognized conceptually earlier,
systematic investigation into SDE began only
about two decades ago, yielding a rich body
of data across diverse chemical scaffolds and
all major types of chirality. These include he
lical, axial [188–194], central chirality on car-
bon [195–197] and sulfur [198–201], as well
as compounds featuring multiple stereogenic
centers and C₂ symmetry [202]. The phenome-
non has been observed across a broad spectrum
of separation techniques, including crystalliza-
tion [203,204], sublimation [205–208], distil-
lation [209–211], density gradient ultracentri
fugation [212], suspension precipitation [213],
and various chromatographic methods—ran
ging from gravity-driven columns [214–216]
and flash chromatography to medium pres-
sure liquid chromatography (MPLC) [217–
219], high pressure / high performance liquid
chromatography (HPLC) [188], size-exclusion
chromatography (SEC) [211], and even gas
chromatography (GC) [220].
The pervasive nature of spontaneous dera
cemization events carries significant impli-
cations for the accurate reporting of enanti-
omeric purity in chiral compounds, whether
derived from natural sources or synthesized in
the laboratory [221–223]. As a phenomenon
deeply intertwined with chirality and asym-
metric synthesis, SDE demands careful scru-
tiny. A thorough understanding of its mecha-
nisms is essential for reliably characterizing the
stereochemical outcomes of enantioselective
reactions. Despite its relevance, fewer than 5%
of published studies in catalytic asymmetric
synthesis explicitly verify ee using SDE con-
trol experiments, relying instead on standard
chiral analysis that may overlook subtle but
consequential artifacts. These underreporting
risks compromising reproducibility and me
chanistic interpretation. Far from being a mere
complication, SDE represents both a challenge
and an opportunity — one that calls for deli
berate methodological control to prevent mis-
interpretation and ensure the integrity of ex-
perimental data [224–226].
For example, compounds 109–112 (Fig. 3)
exhibited pronounced SDE under routine
gravity-driven column chromatography — an
everyday method used in laboratories for pro
duct purification and isolation. Starting from
moderately enriched samples (60–70% ee), the
ee varied dramatically across collected frac-
tions, ranging from 99% to as low as 10% ee.
This highlights that a randomly selected frac-
tion could misleadingly report the enantiose-
lectivity of the reaction anywhere between 99%
and 10% ee.
55https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
The data reported to date on the SDE be-
havior of various chiral compounds strong-
ly suggest that derivatives of amines, amino
acids, amides, esters, ketones — and especial-
ly fluorinated analogs — exhibit pronounced
SDE effects [227–238]. This casts a shadow of
doubt over literature reports of ee that lack spe-
cific SDE controls. Accordingly, the ee values
cited in the papers reviewed here should be
interpreted with caution. It is highly plausible
that some reported data deviate substantially
from the true enantioselectivities and warrant
a healthy degree of skepticism.
Fig. 3. Routine CF₃-amines with pronounced SDE.
CONCLUSIONS.
1-Substituted-2,2,2-trifluoroethylamines
represent a structurally distinct and pharma-
cologically potent class of fluorinated amines,
increasingly recognized for their role in modu-
lating bioactivity, metabolic stability, and mo-
lecular recognition. Their incorporation into
drug scaffolds — whether in kinase inhibitors,
metabolic modulators, or protein–protein in-
teraction disruptors — has yielded clinically
validated therapeutics and inspired new direc-
tions in medicinal chemistry.
Synthetic access to these motifs has expan
ded considerably, with catalytic enantioselec-
tive methods now complementing traditional
chiral auxiliary-based approaches. Among the
most broadly adopted strategies are asymmetric
hydrogenation and transfer hydrogenation of
trifluoromethyl imines, often employing ruthe-
nium, palladium, or organocatalytic systems.
Chiral phosphoric acids and borane-based
catalysts have also demonstrated high stereo
chemical fidelity, enabling reductions with
enantiomeric excesses routinely exceeding 90–
95%. Despite the diversity of reaction types —
ranging from metal-catalyzed hydrogenation
to [1,3]-proton shift transformations — the
stereochemical outcomes are generally robust,
provided that substrate geometry and tauto-
meric equilibria are properly managed.
However, the widespread neglect of self-
disproportionation of enantiomers (SDE) in
stereochemical reporting casts a troubling sha
dow over the veracity of published enantio
meric excess (ee) values. Numerous studies
have demonstrated that routine purification
methods, such as gravity-driven column chro-
matography, can induce pronounced SDE
effects — especially in fluorinated amines —
leading to misleading ee values across collec
ted fractions. Yet, fewer than 5% of papers in
the field explicitly account for this phenome-
non, raising concerns about reproducibility
and mechanistic interpretation.
Moving forward, the field must embrace
SDE-aware methodologies as a standard com-
ponent of stereochemical analysis. This includes
implementing control experiments, validating
56 ISSN 2708-129X. Укр. хім. журн., 2025
ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES (review).ORGANIC CHEMISTRY
ee across multiple fractions, and critically re-
assessing legacy data. As synthetic access to
CF₃-amines continues to evolve, so too must
our epistemic rigor. The convergence of cata-
lytic innovation, fluorine chemistry, and ste-
reochemical integrity offers fertile ground for
future breakthroughs — provided that we re-
main vigilant against the subtle distortions that
SDE can introduce.
ACKNOWLEDGMENTS:
We gratefully acknowledge the finan
cial support from IKERBASQUE,
Basque Foundation for Science (for
Soloshonok). The authors acknow
ledge the assistance of Microsoft
Copilot and Google Gemini for their
support in translating to Ukrainian.
ЕНАНТІОСЕЛЕКТИВНИЙ КАТАЛІЗ
ДЛЯ СИНТЕЗУ 1-ЗАМІЩЕНИХ-2,2,2-
ТРИФТОРЕТИЛАМІНІВ (огляд)
Аліція Взорек,1 Таїзо Оно,2 Даніель Беккер,3
Вей Чжан,4 Вадим А. Солошонок,5*
1 Хімічний інститут,
Університет Яна Кохановського в Кельці,
вул. Університетська 7, 25–406 Кельце,
Польща;
2 Національний інститут передової науки
та технологій (AIST),
2266–98, Анагахора, Шімошідамі, район
Моріяма, Нагоя, 463–8560, Японія;
3 Відділ фармацевтичної та медичної хімії,
Фармацевтичний інститут,
Вільний університет Берліна,
Кьоніґін-Луїзе-Штрасе 2+4, 14195 Берлін,
Німеччина;
4 Хімічний факультет,
Університет Массачусетса в Бостоні,
Бостон, Массачусетс 02125,
Сполучені Штати Америки;
5 ІКЕРБАСКЕ, Баскська наукова фундація,
вул. Марія Діас де Харо 3, Площа Бізкая,
48013 Більбао, Іспанія
e-mail: vadimsoloshonok@gmail.com
1-Заміщені-2,2,2-трифторетиламіни за
рекомендували себе як структурно уні-
кальні та фармакологічно потужні мотиви
в сучасному дизайні ліків, що сприяють
підвищенню метаболічної стабільності,
селективності до мішеней та біоактивнос-
ті в різних терапевтичних класах. У цьому
огляді представлено вичерпний опис їх-
нього каталітичного енантіоселективного
синтезу, що охоплює методи на основі хі-
ральних ауксиліаріїв та широкий спектр
стратегій асиметричного каталізу, вклю-
чаючи гідрування, реакції [1,3]-протонно-
го зсуву, нуклеофільне приєднання та ци-
клоприєднання. Особливу увагу приділено
стереохімічним результатам, отриманим
за допомогою каталізаторів на основі руте-
нію, паладію, фосфорної кислоти, борану
та скварамідів, багато з яких стабільно за-
безпечують енантіомерний надлишок (ee),
що перевищує 90–99%. Незважаючи на ці
досягнення, явище самодиспропорціону-
вання енантіомерів (СДЕ) залишається
критично недостатньо висвітленим, що
ставить під сумнів достовірність наведених
у літературі значень ee. Цей огляд підкрес-
лює виражену схильність фторованих амі-
нів до СДЕ та наголошує на необхідності
ретельної стереохімічної валідації. Поєд-
57https://ucj.org.ua
Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim A. Soloshonok UCJ № 12 / Vol. 91
нуючи синтетичні інновації з епістемічним
аналізом, ця робота має на меті спрямува-
ти майбутні дослідження на розроблення
більш надійних, ефективних та стереохі-
мічно обґрунтованих методологій синтезу
похідних фторованих амінів.
Ключові слова: фторовані аміни, каталі-
тичний енантіоселективний синтез, медич-
на хімія, самодиспропорціонування енан-
тіомерів, епістемологічна перевірка.
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Cтаття надійшла 20.10.2025.
|
| id | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-761 |
| institution | Ukrainian Chemistry Journal |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-23T01:14:04Z |
| publishDate | 2026 |
| publisher | V.I.Vernadsky Institute of General and Inorganic Chemistry |
| record_format | ojs |
| resource_txt_mv | ucjorgua/c6/b54e5db8484cbc38ea211ae108d50bc6.pdf |
| spelling | oai:ojs2.1444248.nisspano.web.hosting-test.net:article-7612026-07-22T08:23:57Z ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review) Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim fluorinated amines, catalytic enantioselective synthesis, medicinal chemistry, self-disproportionation of enantiomers, epistemic scrutiny. 1-Substituted-2,2,2-trifluoroethylamines have emerged as structurally distinct and pharmacologically potent motifs in modern drug design, contributing to enhanced metabolic stability, target selectivity, and bioactivity across various therapeutic classes. This review provides a comprehensive account of their catalytic enantioselective synthesis, encompassing chiral auxiliary-based methods and a wide array of asymmetric catalytic strategies — including hydrogenation, [1,3]-proton shift reactions, nucleophilic additions, and cycloadditions. Emphasis is placed on the stereochemical outcomes achieved with ruthenium, palladium, phosphoric acid, borane, and squaramide-based catalysts, many of which routinely deliver an enantiomeric excess (ee) exceeding 90–99%. Despite these advances, the phenomenon of self-disproportionation of enantiomers (SDE) remains critically underreported, casting doubt on the veracity of ee values in the literature. This review highlights the pronounced SDE behavior of fluorinated amines and underscores the need for rigorous stereochemical validation. By integrating synthetic innovation with epistemic scrutiny, this work aims to guide future research toward more reliable, efficient, and stereochemically sound methodologies for the synthesis of fluorinated amine derivatives. V.I.Vernadsky Institute of General and Inorganic Chemistry 2026-01-25 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/761 10.33609/2708-129X.91.12.2025.33-72 Ukrainian Chemistry Journal; Vol. 91 No. 12 (2025): Ukrainian Chemistry Journal; 33-72 Украинский химический журнал; ##issue.vol## 91 ##issue.no## 12 (2025): Ukrainian Chemistry Journal; 33-72 Український хімічний журнал; Том 91 № 12 (2025): Ukrainian Chemistry Journal; 33-72 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/761/396 Copyright (c) 2026 Alicja Wzorek, Taizo Ono, Daniel Baecker, Wei Zhang, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0 |
| spellingShingle | Wzorek, Alicja Ono, Taizo Baecker, Daniel Zhang, Wei Soloshonok, Vadim ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review) |
| title | ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review) |
| title_full | ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review) |
| title_fullStr | ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review) |
| title_full_unstemmed | ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review) |
| title_short | ENANTIOSELECTIVE CATALYSIS FOR THE SYNTHESIS OF 1-SUBSTITUTED-2,2,2-TRIFLUOROETHYLAMINES(Review) |
| title_sort | enantioselective catalysis for the synthesis of 1-substituted-2,2,2-trifluoroethylamines(review) |
| topic_facet | fluorinated amines catalytic enantioselective synthesis medicinal chemistry self-disproportionation of enantiomers epistemic scrutiny. |
| url | https://ucj.org.ua/index.php/journal/article/view/761 |
| work_keys_str_mv | AT wzorekalicja enantioselectivecatalysisforthesynthesisof1substituted222trifluoroethylaminesreview AT onotaizo enantioselectivecatalysisforthesynthesisof1substituted222trifluoroethylaminesreview AT baeckerdaniel enantioselectivecatalysisforthesynthesisof1substituted222trifluoroethylaminesreview AT zhangwei enantioselectivecatalysisforthesynthesisof1substituted222trifluoroethylaminesreview AT soloshonokvadim enantioselectivecatalysisforthesynthesisof1substituted222trifluoroethylaminesreview |