Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів
The review covers the latest achievements in the application of N-(tert-butylsulfinyl)polyfluoroalkyl imines in the asymmetric synthesis and summarizes stereochemical observations of their behavior in different types of reactions (reduction of the C=N bond, addition reactions with organometallic rea...
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Journal of Organic and Pharmaceutical Chemistry| _version_ | 1874273847529701376 |
|---|---|
| author | Cherednichenko, Alona S. Rassukana, Yuliya V. |
| author_facet | Cherednichenko, Alona S. Rassukana, Yuliya V. |
| author_institution_txt_mv | [
{
"author": "Alona S. Cherednichenko",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
},
{
"author": "Yuliya V. Rassukana",
"institution": "Institute of Organic Chemistry of the National Academy of Sciences of Ukraine",
"orcid": ""
}
] |
| author_sort | Cherednichenko, Alona S. |
| baseUrl_str | https://ophcj.nuph.edu.ua/oai |
| collection | OJS |
| container_end_page | 22 |
| container_issue | 2 |
| container_start_page | 3 |
| container_title | Журнал органічної та фармацевтичної хімії |
| container_volume | 23 |
| datestamp_date | 2026-08-22T19:54:27Z |
| description | The review covers the latest achievements in the application of N-(tert-butylsulfinyl)polyfluoroalkyl imines in the asymmetric synthesis and summarizes stereochemical observations of their behavior in different types of reactions (reduction of the C=N bond, addition reactions with organometallic reagents, C-H acids, etc.). Fluorinated N-(tert-butylsulfinyl) imines are convenient substrates for obtaining enantiomerically enriched derivatives of polyfluoroalkyl amines, amino alcohols, amino acids, and heterocyclic systems. In recent decades, various approaches to their functionalization have been proposed. With this in mind, important aspects of their reactivity, regio- and stereochemistry have been systematized in this paper. |
| doi_str_mv | 10.24959/ophcj.25.321224 |
| first_indexed | 2025-07-23T04:43:37Z |
| format | Article |
| fulltext |
ISSN 2308-8303 (Print) / 2518-1548 (Online) 3
Review Article
http://ophcj.nuph.edu.ua
UDC 542.913+547-304.2+547.478.92
A. S. Cherednichenko, Yu. V. Rassukana
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Academik Kukhar str., 02094 Kyiv, Ukraine
Recent advances in the asymmetric functionalization
of N-(tert-butylsulfinyl)polyfluoroalkyl imines
Abstract
The review covers the latest achievements in the application of N-(tert-butylsulfinyl)polyfluoroalkyl imines in the asymmetric
synthesis and summarizes stereochemical observations of their behavior in different types of reactions (reduction of the C=N
bond, addition reactions with organometallic reagents, C-H acids, etc.). Fluorinated N-(tert-butylsulfinyl) imines are conveni-
ent substrates for obtaining enantiomerically enriched derivatives of polyfluoroalkyl amines, amino alcohols, amino acids,
and heterocyclic systems. In recent decades, various approaches to their functionalization have been proposed. With this in
mind, important aspects of their reactivity, regio- and stereochemistry have been systematized in this paper.
Keywords: tert-butylsulfinyl; polyfluoroalkyl imines; asymmetric synthesis; aldimines; ketimines; stereoselectivity
А. С. Чередніченко, Ю. В. Рассукана
Інститут органічної хімії Національної академії наук України,
вул. Академіка Кухаря, 5, м. Київ, 02094, Україна
Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів
Анотація
Огляд охоплює найновіші здобутки в застосуванні N-(трет-бутилсульфініл)поліфтороалкілімінів в асиметричному синтезі,
а також узагальнює стереохімічні закономірності їхньої поведінки в різних типах реакцій (відновлення C=N зв’язку,
приєднання металоорганічних реагентів, С-Н кислот тощо). Фторовмісні N-(трет-бутилсульфініл)іміни є зручними
субстратами для одержання на їх основі енантіомерно збагачених похідних поліфтороалкілімінів, аміноспиртів, амі-
нокислот і азотовмісних гетероциклів. За останні десятиліття було запропоновано різноманітні підходи до їх функціо-
налізації. З огляду на це важливі аспекти щодо їхньої реакційної здатності, регіо- і стереохімії систематизовано в цій
роботі.
Ключові слова: трет-бутилсульфініл; поліфтороалкіліміни; асиметричний синтез; альдиміни; кетиміни; стереоселективність
Citation: Cherednichenko, A. S.; Rassukana, Yu. V. Recent advances in the asymmetric functionalization
of N-(tert-butylsulfinyl)polyfluoroalkyl imines. Journal of Organic and Pharmaceutical Chemistry 2025, 23 (1), 3 – 22.
https://doi.org/10.24959/ophcj.25.321224
Received: 26 January 2025; Revised: 28 March 2025; Accepted: 1 April 2025
Copyright© 2025, A. S. Cherednichenko, Yu. V. Rassukana. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0).
Funding: The work was supported by the National Academy of Sciences of Ukraine (grant No. 0124U002052).
Conflict of interests: The authors have no conflict of interests to declare.
■ Introduction
Since Ellman’s group introduced chiral N-tert-
butylsulfinyl amides into synthetic practice [1],
the corresponding N-sulfinyl imines have also
found a wide application in organic synthesis,
providing access to a variety of optically active
amines [2]. Among different N-sulfinyl imines,
compounds with a polyfluoroalkyl substituent at
the imine carbon atom deserve special attention.
On the one hand, the introduction of a powerful
electron-withdrawing polyfluoroalkyl group sig-
nificantly increases the imine electrophilicity,
promoting reactions with nucleophilic reagents.
On the other hand, the presence of fluorine atoms
can lead to significant changes in the physico-
chemical and biological properties of molecules
compared to their non-fluorinated analogs [3 – 9].
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Thus, N-(tert-butylsulfinyl)polyfluoroalkylimines
can be convenient precursors of enantiomerical-
ly pure α-polyfluoroalkylamines, important chi-
ral substrates for the preparation of different non-
racemic fluorine-containing compounds. Great in-
terest in this type of imines is confirmed by dozens
of works in this area over the past decades, which
were described, in particular, in reviews by prof.
Soloshonok and co-authors in 2016 – 2018 [10, 11].
In the present review, we attempt to systema-
tize and generalize the regularities of the asym-
metric functionalization of N-(tert-butylsulfinyl)
polyfluoroalkyl imines, including the experimen-
tal data obtained in recent years, which will al-
low for an effective prediction of the configura-
tion of the newly created stereocenter and should
stimulate the further development of this area
of organic chemistry.
■ Results and discussion
1. Reduction of the azomethine bond of
N-(tert-butylsulfinyl)polyfluoroalkyl imines
A stereoselective reduction of non-fluorinated
N-(tert-butylsulfinyl)ketimines with sodium and
lithium borohydrides was first determined in the
late 2000s in the works of Ellman et al. [12, 13].
However, the possibility of involving α-polyfluo-
roalkyl imines in this reaction was demonstra-
ted only a decade later on the example of α,β-
unsaturated N-(tert-butylsulfinyl)ketimines 1 bear-
ing a trifluoromethyl group (Scheme 1) [14].
The screening of the spectrum of sodium or li-
thium borohydrides and aluminum hydrides (NaBH4,
LiBH4, NaBH3CN, CatBH, LiAlH4, Red-Al, LiBHEt3,
L-Selectride) showed that the highest diastereo-
selectivity (90 – 99 %) could be achieved when us-
ing DIBAL-H in THF and L-Selectride in a mix-
ture of THF/HMPA (5:1) at –78°С.
N-(tert-butylsulfinyl)imines of trifluoroaceto-
ne and trifluoroacetophenones generated in situ
were subjected to reduction, skipping the isola-
tion step. According to this procedure, a series
of imines of α-trifluoromethyl aryl and alkyl ke-
tones were reduced with sodium borohydrides
and L-Selectride with de up to 98 % (Scheme 2,
Table 1) [15 – 17].
Most likely, metal hydrides (NaBH4, LiBH4,
NaBH3CN, LiAlH4, DIBAL-H) and organoboron
compounds (CatBH) coordinate with the oxygen
atom of the sulfinyl group, forming a closed tran-
sition state A, which results in (R,R)-diastereo-
mers of sulfinamides 4. In turn, L-Selectride dis-
plays a worse propensity for the coordination and
attack over the imine C=N bond occurs through
the open transition state B, leading to (S,R)-ste-
reoisomer of sulfinamides 4 (Scheme 3) [15, 18].
The screening of reducing agents for chemo-
and stereoselective reduction of the azomethine
bond of N-tert-butylsulfinyl trifluoromethylimi-
noesters 5 also revealed similar dependence of
the stereochemical outcome of the process on the
nature of the reductant (Scheme 4, Table 2).
The best results in terms of both chemo- and ste-
reoselectivity were achieved when 9-borabicyclo-
nonane (9-BBN) was used as a reducing agent [19].
The hydrolysis of N-(sulfinyl)aminocarboxy-
late 6 gave an optically pure stereoisomer of
F3C N
S
O
F3C N
H
S
O
F3C N
H
S
O
( )-R 1 ( )-R,R 2( )-S,R 2
R RR
R = C6H5, 4-MeO-C6H4, 4-Me-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 2-MeO-C6H4,
3-Br-C6H4, 1-naphtyl, 2-furyl, C6H5C C, Cn 8H17, C6H5(CH2)3
DIBAL-HL-Selectride
THF/HMPA,
-78°C
THF,
-78°C
de 90 98 %– de 92 99 %–
60 99 %– 81 99 %–
Scheme 1. A stereoselective reduction of α,β-unsaturated N-(tert-butylsulfinyl)ketimines
Table 1. The reduction of trifluoromethyl ketimines 3
R [H] Yield ( %) Product de ( %)
Ar
NaBH4 66 – 85 (S,S)-4 90 – 98
L-Selectride 60 – 84 (R,S)-4 92 – 98
Alk
NaBH4 52 – 79 (S,S)-4 96 – 98
L-Selectride 22 – 84 (R,S)-4 92 – 98
9-anthrylа LiBH4 71 (S,S)-4 97
Note: a The intermediate imine was chromatographically isolated in the individual state before the reduction
ISSN 2308-8303 (Print) / 2518-1548 (Online) 5
Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
3,3,3-trifluoroalanine 7 – a biologically promis-
ing α-amino acid. The (R)-isomer of trifluoroala-
nine 7 was obtained similarly from sulfinamide
(R,R)-6, the product of imine 5 reduction in (R)-
configuration.
On the other hand, the reduction of imines 5
with a complex of borane with dimethyl sulfide
proceeded with the involvement of the carboxy-
late function, in addition to the C=N bond [19].
It enabled a stereospecific preparation of synthe-
tically attractive trifluoromethyl aminoethanols
with either protected 8 or free amino group 9
(Scheme 5).
Thus, the ability to control chemo- and stereo-
selectivity by selecting the appropriate reducing
agent allows for the synthesis of both stereoisomers
F3C N
S
O
F3C N
H
S
OR
F3C N
H
S
OR
+
R
( )-S 3 ( )-S,S 4 ( )-R,S 4
S
O
H2N
CF3
R
O
+
[H]Ti(O Pr)i 4
or
Zr(O Bu)t 4
R = C6H5, 4-MeO-C6H4, 4-Me-C6H4, 4-Br-C6H4, C6H5(CH2)3, Cn 8H17 [15], 9-anthryl [16], Me [17]
Scheme 2. The reduction of aryl- and alkyl trifluoromethyl ketimines
R
N
F3C
S
O
R
NH
F3C
S
O
N
S
O M
H
R
tBu
CF3
N
F3C
R
O tBu
H M
R
NH
F3C
S
O
MBH4
L-Selectride
( )-R 3
( , )-R R 4
( , )-S R 4
TS A
TS B
Scheme 3. Possible mechanisms of the reduction of the C=N bond of N-tert-butylsulfinyl trifluoromethyl ketimines
1. HCl (conc), 90oC
2. propylene oxide NH2F3C
CO2H
( )-S 85 %7( )-S 5 ( )-S,S 6
N
F3C
MeO2C S
O
9-BBN
NH
F3C
MeO2C S
O
THF, 0oC
Scheme 4. A stereoselective reduction of the C=N bond of N-tert-butylsulfinyl trifluoromethyl iminopyruvates
Table 2. Reaction conditions for the reduction of C=N bond of iminopyruvate (S)-5
№ [H] Conditions (S,S)/(R,S)-6
1 NaBH4 THF, –78оС 1:1.1
2 NaBH(OCOCH3)3 THF, rt 1:2
3 LiBH4 THF, –78оС 1:2.4
4 CatBH THF, –78оС 2.4:1
5 9-BBN THF, 0оС >99:1a
Note: a (R,S)-6 is absent according to 1H and 19F NMR data
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Журнал органічної та фармацевтичної хімії 2025, 23 (2)
of various β-polyfluoroalkylamines, starting from
one enantiomer of N-(tert-butylsulfinyl)polyfluo-
roalkyl imines.
2. Reactions of N-(tert-butylsulfinyl)po-
lyfluoroalkyl imines with organometallic
compounds
The addition of Li- and Mg-organic com-
pounds to the azomethine bond of imines, includ-
ing N-(tert-butylsulfinyl)imines, is a convenient
method for forming a new C-C bond with the con-
current generation of a new stereogenic carbon
atom. The interaction of imine of fluoral (S)-10
(generated in situ) with phenylmagnesium bro-
mide allowed one to obtain amines (S,S)-11 with
diastereoselectivity of 70 % (Scheme 6). The se-
lectivity increased with the addition of Lewis
acids (AlMe3, AlEt3, BF3•Et2O, TiCl4, Mg(OTf)2),
but it led to a general decrease in yields [20].
The addition of phenyl lithium (2.5 equiv., 2.5M
solution in THF) to trifluoroacetaldimine (S)-10
resulted in the formation of α-trifluoromethyl ben-
zylamine (S,S)-11 in the yield of 66 % and with a
significantly improved diastereomeric ratio (98:2)
compared to the reaction with phenyl magnesium
bromide. Various aryl lithium reagents were suc-
cessfully involved in the reaction with imine 10
under optimal conditions (THF, –78°C) (Scheme 6).
Later, it was shown that N-(tert-butylsulfinyl)
imine of fluoral 10 purified by vacuum distilla-
tion demonstrated better yields (83 % compared
to 64 %) in the reaction with PhLi [21]. The au-
thors [20] attributed the stereochemical result
obtained in both reactions to the formation of open
transition state A in the course of the reactions
(Scheme 6).
Similarly to aldimines, α,β-unsaturated N-(sul-
finyl)ketimines (R)-12 successfully reacted with
aryl, alkyl, and alkynyl lithium reagents to pro-
vide α-polyfluoroalkyl allylamines (S,R)-13 with
good yields (48 – 99 %) and diastereoselectivities
(70 – 98 %) (Scheme 7) [22].
The addition of (trimethylsilyl)ethynyl lithi-
um to trifluoroacetaldimine (S)-10 occurred with
sufficiently high diastereoselectivity (de 86 %),
however, the yield of propargylamine (R,S)-14 was
only 33 % [23]. At the same time, when N-(tert-
butylsulfinyl)imine of fluoral (R)-10 interacted with
lithium arylacetylides generated in the presence
of LiHMDS, the diastereomeric ratio varied from
52:48 to 70:30 (Scheme 8) [24].
Significantly better results were obtained in
the reaction of lithium acetylides (including those
with a trimethylsilyl substituent) with α-trifluoro-
methylketimines 3 in the presence of titanium
tetraisopropylate (Scheme 9). The correspond-
ing α-trifluoromethyl-α-propargylamines (R,S)-16
were obtained with yields from 56 to 97 % and
the diastereoselectivity of 98 % [25].
The stereochemical result of the reaction
of polyfluoroalkylaldimines 18 with propargyl
HCl
HCl
HCl/Et2O
( )-S 9
( )-R 9
NH2F3C
HO
NH2F3C
HO
rt, 1 h
Me2S BH3
THF, -20 C
o
90 %
( )-S 5
( )-R 5 ( )-R,R 8
( )-S,S 8
N
F3C
MeO2C S
O
N
F3C
MeO2C S
O
N
H
F3C
S
O
HO
N
H
F3C
S
O
HO
95 %
*
Scheme 5. The complete reduction of N-tert-butylsulfinyl trifluoromethyl iminopyruvates
F3C N
S
O
F3C N
H
S
ORH
( )-S 10 ( , )-S S 54 66 %11, –
RLi, THF, -78 oC
de 70 99 %–
or
Ph
DCM, -78oC
R = C6H5, 4-MeO-C6H4, 4-MeS-C6H4, 4-F-C6H4, 3,5- -F-Cdi 6H3,
2-Me-C6H4, pyridin-2-yl
N
F3C H
MR
TS A
O
tBu
M = Li, Mg
Scheme 6. The addition of propargyl magnesium bromide to N-(tert-butylsulfinyl)polyfluoroalkyl imines
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
magnesium bromide was found to be crucially de-
pendent on the nature of the solvent, variating
from de 12 % (in DCM) to de 92 – 98 % (in THF).
α-Propargylamines (S,S)-19 were used for further
transformation into derivatives of terpene alka-
loids 21 by the synthesis of enynes 20 and their sub-
sequent cyclization by the Pauson-Khand reaction
scheme [26]. Additionally, enynes 20 were intro-
duced into the ruthenium-catalyzed metathesis
yielding tetrahydropyridines 22 [27] (Scheme 10).
Lithiated thiazoles turned out to be conveni-
ent reagents for the nucleophilic addition to the
azomethine bond of N-(sulfinyl)imine (S)-10.
The optimal conditions (1.1 equiv. of LDA, THF,
–78°С) were suitable for thiazoles annulated with
an imidazole or 1,2,4-triazole ring and provided
reaction products (R,S)-23 with the yields of
61 – 72 % and stereoselectivities reaching 99 %
(Scheme 11) [28, 29].
N-Sulfinyl imine of fluoral (S)-10 also under-
goes a zinc-initiated reaction with allyl and alkyl
bromides to form the corresponding enantiome-
rically enriched sulfinamides (S,S)-24 and (S,S)-
25 (Scheme 12) [21, 30]. The stereochemical re-
sult of the reaction is consistent with the open
transition state previously proposed, which is si-
milar to reactions with organomagnesium and
organolithium reagents.
The interaction of α,β-unsaturated N-(tert-
butylsulfinyl)ketimines (R)-26 with ethyl bromo-
acetate in the presence of zinc occurred with a high
regio- and chemoselectivity (Scheme 13) [31].
RF N
S
O
RF
N
H
S
O
( )-R 12 ( , )-S R 48 99 %13, –
Ph Ph
R
RLi
Et2O, -40oC
RF = CF3, CHF2, CClF2, C3F5, C5F11
R = C6H5, 4-F-C6H4, 4-Cl-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 3-Me-C6H4,
2-Me-C6H4, naphtyl, PhC C, Bun
de 70 98 %–
Scheme 7. The addition of Li-organic reagents to α,β-unsaturated N-(sulfinyl)ketimines
HN
F3C
S
O
Ar
H
N
F3C
S
O
de 4 40 %–
H Ar
LiHMDS, -78°C
DCM
Ar = C6H5, 4-Me-C6H4, 4-MeO-C6H4, 4-EtO-C6H4, 3-Me-C6H4, 4-Me-C6H4, 4- Bu-Ct 6H4,
4-( -pentyl)-Cn 6H4, 3-F-C6H4, 4-F-C6H4, 4-Cl-C6H4, 3-Br-C6H4, 4-Br-C6H4, 3-O2N-C6H4
( )-R 10( , )-R R 15 31 87 %–
HN
F3C
S
O
( , )-R S 14
TMS
H
N
F3C
S
O
( )-S 10
de 86 %
33 %
AlMe3, toluene
-78°C...rt
H TMS
Scheme 8. N-(tert-butylsulfinyl)imine of fluoral in the reactions with Li-acetylides
R
N
F3C
S
O
( )-S 3
HN
F3C
S
O
( , )-R S 16
Li R'
R'R
HCl
NH2
F3C
R'R
( )-R 17
56 97 %–
87 97 %–
de 98 %
R = C6H5, 4-MeO-C6H4, 4-Cl-C6H4, Cn 6H11; R' = Bu, Hex, cyclopropyl, TMS, Cn n 6H5, CF3
Ti(O Pr)i 4, -78oC
Scheme 9. N-(tert-butylsulfinyl)trifluoromethyl ketimines in the reaction with Li-acetylides
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Журнал органічної та фармацевтичної хімії 2025, 23 (2)
H
N
RF
S
O
(S)-18
HN
RF
S
O
( , )-S S 19
N
RF
( )-S 20
R1
Bus
N
O
R2
RF
R1
R2
Bus
H
RF = CF3, CHF2, C2F5, C3F7, C4F9, CF2Cl; R1 2 = H, Me, C6H5
42 81 %–
( )-S 21
92 98 %de –
33 76 %–
N
Bus
RF
( )-S 22
THF, -78oC
60 87 %–
86 92 %–
MgBr
Scheme 10. The addition of propargyl magnesium bromide to N-(tert-butylsulfinyl)imine of fluoral
F3C N
S
OH
( )-S 10 ( , )-R S 23
+ X
N
N
S
R'
R
X
N
N
S
R'
R
HN
CF3
S
OX = CH, N
X = N: R = H; R' = Me, Ph, 4-Cl-C6H4, 4-Br-C6H4, 4-F-C6H4, 3-Cl-C6H4, 3-Br-C6H4, 3,4- -Cl-Cdi 6H3, 2-naphtyl
X =CH: R' = Me; R = Ph, 4-Cl-C6H4, 4-Br-C6H4, 4-F-C6H4, 4-Me-C6H4, 4-MeO-C6H4, 3-Cl-C6H4, 3-Br-C6H4,
3-MeO-C6H4, 2-MeO-C6H4, 3,4- -Cl-Cdi 6H3, 2-naphtyl
40 78 %–
de 96 99 %–
LDA, THF, -78 oC
Scheme 11. The reaction of N-(tert-butylsulfinyl)imine of fluoral with lithiated thiazoles
F3C N
S
O
N
H
S
OCF3H
( )-S 10 ( , )-S S 24
Zn, DMF, 0°C
52 86 %–
de 6 96 %–
R2
R1Br
R1
R2
N
H
S
OCF3
( , )-S S 25
DMF, 0°C
Zn, TMSCl
65 %
de 91%
EtO
O
R1 = R2 =R1 = R2 = H,
R2 = H: R1 = CO2Et, Me
R1 = H: R2 = Ph, CO2Et, Me
Br CO2Et
Scheme 12. N-(tert-butylsulfinyl)imine of fluoral in the Zn-mediated reactions with allyl and alkyl bromides
N
RF
S
O
R
Zn, THF
40 60– oC, 3 h
HN
S
O
R
RF
EtO2C
de 70 90 %–
RF = CF3, CClF2, Cn 3F7, Cn 5F11
R = Ph, 4-F-C6H4, 4-Cl-C6H4, 4-Me-C6H4,
4-MeO-C6H4, 2-Me-C6H4, 3-Me-C6H4,
1-naphtyl, 2-thienyl, C6H5(CH2)3
( )-R 26 ( )-R,R 27
26 76 %–
Br CO2Et
Scheme 13. N-(tert-butylsulfinyl)trifluoromethyl ketimines in the Zn-mediated reaction with ethyl bromoacetate
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
3. Reaction of N-(tert-butylsulfinyl)poly-
fluoroalkyl imines with CH-acids
The reaction of polyfluoroalkyl imines with
esters of carboxylic acids is a convenient method
for the synthesis of fluorine-containing com-
pounds with a β-aminocarboxylic acid fragment.
Thus, β-aminomalonates 28 were synthesized by
the interaction of N-(tert-butylsulfinyl)imine of
fluoral (S)-10 with a number of dialkylmalonates
(Scheme 14). The highest stereoselectivities were
observed in the presence of nBuLi or sterically
hindered phosphazene bases (P2-Et). The products
of the Mannich reaction with diethylmalonate
were successfully transformed into optically pure
β-trifluoromethyl-β-alanine enantiomers (R)- and
(S)-29 [32, 33].
Esters of β-trifluoromethyl-β-amino acids
can be obtained directly, without an additional
decarboxylation step, by the reaction of imines
with alkyl acetates in the presence of LDA. (S,S)-
diastereomer 30 was formed stereospecifically
(de>99 %). The removal of the sulfinyl group and
the subsequent cyclization with a substituted thio-
urea yielded tetrahydro-6-oxo-pyrimidine (S)-31,
a potential β-secretase inhibitor currently studied
as a medicine for the treatment of Alzheimer’s
disease (Scheme 15) [34].
Derivatives of methylsulfonic and phospho-
nic acids also undergo the reaction with N-(tert-
butylsulfinyl)imines 10 in the presence of strong
bases (Scheme 16) [35, 36].
N-tert-butylsulfinyl polyfluoroalkyl aldimi-
nes 18 were successfully involved in the aza-Henry
reaction with nitromethane under mild condi-
tions. The study of various factors, such as the
nature of the base, solvent, temperature and the
F3C N
S
O
N
H
S
OCF3
H
F3C
NH2
+
nBuLi
(10 mol%)
R2O2C
R2O2C
R1 CO2H
R1 = H, Me, F; R2
95 %
( )-S 10
( , )-R S 28 ( )-R 29
P2-Et
(10 mol%)
N
H
S
OCF3
F3C
NH2
R2O2C
R2O2C
R1
CO2H
96 %
( , )-S S 28 ( )-S 29
de 16 84 %–
de 84 98 %–
80 99 %–
22 98 %–
H
H
N
P
P
NMe2
Me2N NMe2
EtN NMe2
NMe2
P2-Et
R1CH(CO2R2)2
for R1=H
Scheme 14. The reaction of N-(tert-butylsulfinyl)imine of fluoral with dialkylmalonates
F3C N
S
OH
+
LDA
N
NO
CF3
NHBoc
de 80 99 %–
R = H, Me, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2-, -CH2CH=CHCH2-
2Ph, allyl, CH2C6H4Me, CH2C6H4OMe
N
H
S
OCF3
OAlk
O
AlkO
OR
R
RR
( )-S 10 ( )-S,S 30 ( )-S 31
toluene, -78°C
44 99 %–
Scheme 15. The reaction of N-(tert-butylsulfinyl)imine of fluoral with alkyl acetates
F3C N
S
O
N
H
S
OCF3H
75 %de
LiHMDS
( )-S 10 ( , )-R S 32
S
O
O
Ph
N
H
S
OCF3
95 %de
nBuLi, THF
CH3P(O)(OR)2
P
RO
O
RO
( , )-R S 33
PhSO2CH3
75 %53 76 %–
Scheme 16. The reaction of N-(tert-butylsulfinyl)imine of fluoral with derivatives of sulfonic and phosphonic acids
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sequence of the reagent addition, showed that the
best chemo- and stereoselectivity of the reaction
with imine of fluoral were achieved when the re-
action was carried out in DMSO in the presence
of 0.1 equiv. of Hünig’s base (Scheme 17) [37].
The reaction of N-(tert-butylsulfinyl)imines of
trifluoropyruvate 5 with nitromethane in the pre-
sence of quinine allowed for obtaining enantiome-
rically pure α-trifluoromethyl substituted α-amino-
β-nitrocarboxylates 34 (Scheme 18) [19].
The study of the effect of the reaction condi-
tions on the stereoselectivity of the process sho-
wed that the nature and amount of the base had
a crucial impact on the diastereomeric excess of
the products. In particular, the transition from
stronger (Hünig’s base) to weaker (quinine) bas-
es led to a complete reversal of the stereochemi-
cal outcome of the reaction explained by the oc-
currence of two different mechanisms with open
and closed transition states (Scheme 19).
The addition of ketones to fluorinated N-(tert-
butylsulfinyl)imines provides access to another
class of optically active compounds – β-amino-
ketones 35 – precursors of nitrogen-containing
heterocycles, 1,3-diamines, γ-aminoalcohols, and
other polyfunctional compounds. However, the
yields and diastereomeric excess vary widely
depending on the nature of the substituents in
the aromatic ring of both imines and ketones
(Scheme 20) [38].
Recent experimental data have shown that
the nature of an organometallic base and a sol-
vent has a significant influence on the result
of the addition of ketones to the azomethine.
The best results in terms of yields and stere-
oselectivity in the reaction of trifluoromethyl
ketimine (S)-3 with p-tolylethan-1-one and me-
thyl acetate were achieved when using KHMDS
(Scheme 21) [39].
However, it turned out that the addition of
tert-butyl acetate and tert-butyl acetoacetate to
N-(sulfinyl)-α-fluoromethylaryl imines (R)-38
led to the opposite stereochemical result, and in
the case of the reaction with (R)-imine 38, the
newly created stereocenter has (S)-configuration
(Scheme 22) [40 – 42].
RF N
S
O
RF N
H
S
O
O2N
( )-R 18
DIPEA
DMSO, 15oC
RF = CF3, C2F5, HC2F4, CF2Br
CH3NO2
( )-R,R 33
N
RF H
O
tBu
TS A
CH2NO2
66 86 %–
de >99 %
Scheme 17. The addition of nitromethane to N-(tert-butylsulfinyl)polyfluoroalkyl aldimines
( )-S 5 ( )-S,S 34
N
F3C
MeO2C S
O
N
H
F3C S
O
O2N
CH3NO2
quinine
(0.1 equiv)
MeO2C
N
H
F3C S
O
O2N
MeO2C
( )-R,S 34
de 90 %
+
Scheme 18. The addition of nitromethane to N-tert-butylsulfinyl trifluoromethyl iminoesters
N
CF3MeO2C
O
CH2NO2
tBu
TS A
S
O
H
N
CO2Me
F3C tBu
O2N
N
δ+
δ-
TS B
( , )-S S 34
O2NCH2
( , )-R S 34
Scheme 19. Possible transition states of the nitromethane addition to N-tert-butylsulfinyl imines of trifluoropyruvate
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
The reaction of imine 10 with β-ketoacids in
the presence of Lewis acids makes it possible to
obtain a wide range of products 40 with alkyl,
cycloalkyl, aryl, and hetaryl substituents at-
tached to the oxo-group. The decarboxylation of
the intermediate adduct A at the last step of the
process was confirmed by a mass spectrometric
study of the reaction mixture (Scheme 23) [43].
In 2019, the addition of a derivative of boro-
nic acids – benzylboropinacolate – to the C=N bond
of N-(tert-butylsulfinyl)imine of trifluoroacetophe-
none (R)-41 (Scheme 24) was reported for the
first time [44, 45]. Similarly to other classes of
esters, anion was generated in the presence of
a strong base (nBuLi) [46]. The reaction pro-
ceeded with a good yield, but with a low stereo-
selectivity (de 26 %), and unfortunately, the con-
figuration of the major diastereomer was not de-
termined.
The interaction of imine (S)-10 with the lithi-
um enolate of indanone apparently occurred as
a nucleophilic attack in the open transition state
(Scheme 25, TS A), which was consistent with
previous observations for aldimines [47].
The reaction of aldimine 10 with indanone con-
taining a thiocyanate group led to the formation
of both the product of the conventional Man-
nich nucleophilic addition 44 and the spirocyclic
F3C N
S
O
N
H
S
OCF3R
+
R1 CH3
O LDA
R1
O
10 86 %de –
R = Ph, 4-MeO-C6H4, 4-Cl-C6H4
R1 = Ph, 4-MeO-C6H4, 4-Cl-C6H4, 4-Me-C6H4, 2-Me-C6H4
R
O
LiN
R' S(O) -But
R
F3C
TS A( )S -3 ( , )-S S 35
29 91 %–
THF, -78oC
Scheme 20. The reaction of N-tert-butylsulfinyl trifluoromethyl ketimines with ketones
F3C N
S
O
N
H
S
OCF3R
Tol Me
O
KHMDS, Et2O
Tol
O
de 94 %
R
-78oC
R = C6H4O(CH2)3CF3
N
H
S
OCF3
Me OMe
O
KHMDS, THF
MeO
O
R
-78oC
de 95 %
R = 4-MeO-C6H4
( )-S 3( , )-S S 36 ( , )-S S 37
Scheme 21. The reaction of N-tert-butylsulfinyl trifluoromethyl ketimines with p‑tolylethan-1-one and methyl acetate
N
S
OAr
N
H
S
O
R
O
de >95 %
Ar
R = O Bu, CHt 2CO2tBu; Ar = 2-F-C6H4, 2-F-4-Br-C6H3
LDA
+
Me R
O TiCl(O Pr)i 3
( )-R 38 ( , )-S R 39
F
F
Scheme 22. The reaction of N-tert-butylsulfinyl fluoromethyl ketimines with ketones and alkyl acetates
F3C N
S
O
N
H
S
OCF3
H
+
OH
O
R
O
de 90 98 %–
R
O
Ni(SO3CF3)2
(10 mol%)
THF, rt, 24 h
N
H
S
OCF3
R
O
HO2C
( )-S 10 ( , )-R S 40
A
70 99 %–
Scheme 23. The Lewis acids-mediated addition of β-ketoacids to N-tert-butylsulfinyl imine of fluoral
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Журнал органічної та фармацевтичної хімії 2025, 23 (2)
aziridine 45, which was the result of nucleo-
philic substitution of the thiocyanate group.
The screening of various bases showed that the
percentage of aziridine 45 increased with the in-
crease in basicity of the inorganic salt. Replacing
the solvent with a more polar DMF facilitating
the intramolecular nucleophilic cyclization gave
the cyclic product 45 with high chemoselectivity.
It is also important that mild conditions for the
removal of the sulfinyl group enabled the synthe-
sis of the unprotected aziridine 47 without the
destruction of the spirocyclic part of the molecu-
le (Scheme 26) [48].
The possibility of using cyclic amides (indol-
2-ones) in the Mannich reaction with trifluoro-
acetaldimine 10 was demonstrated in 2014.
The nature of the base has a decisive influence
on conversion rates and diastereomeric excess,
and lithium bases (LDA, LiHMDS, nBuLi) pro-
vide the best results (Scheme 27) [49].
Stabilized α,α-difluoroenolates obtained by the
cleavage of the C-C bond of the corresponding
α-fluorinated gem-diols reacted with imine (S)-10
under mild conditions with a high chemo- and ste-
reoselectivity with the formation of optically acti-
ve β-amino ketones (S,S)-49 (Scheme 28) [50, 51].
This method has been proven to be effective
for the synthesis of optically pure quaternary
α-fluoro-β-ketoamines containing a C-F stereoge-
nic center (Scheme 29) [52].
The asymmetric addition of trifluoromethyl
gem-diols to chiral imines (R)-18 also provided
α-difluoroalkyl-β-aminosulfones (S,R)-51. A de-
tailed screening of the reaction conditions showed
F3C N
S
OPh
+
-78 C, THF
o
de 26 %
Ph Bpin F3C N
H
S
OPh
Ph
( )-R 41 ( , )/( , )-R R S R 42
nBuLi
62 %
Scheme 24. Boropinacolates as CH-acids in the addition reaction with N‑tert‑butylsulfinyl trifluoromethyl ketimines
F3C N
S
O
N
H
S
OCF3
+
LDA
de 93 98 %–
O
R
-78o
O
R
N
O
tBu
CF3H
OLi
H
TS A
H
( )-S 10 ( , , )-S S S 43
85 95 %–
Scheme 25. The addition of ring-substituted indanones to N-tert-butylsulfinyl imine of fluoral
HN S
O
CF3
NaOAc, THF
de 82 %
O
O
SCN
NCS
N
S
O
O
CF3
Na2CO3, DMF
de 80 %
( )-R 10
( )-S 10
NH2
CF3
O
SCN
73 %
H
N
O
CF391 %
(2 ,1` ,R S RS)-44
(2 ,2` ,S S SS)-45
(2 ,1` )-R S 46
(2 ,2` )-S S 47
H
H
84 %
67 %
Scheme 26. Different pathways of the N-(tert-butylsulfinyl)trifluoroacetaldimine reaction with 2-thiocyanoindanone
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
that the optimal values of yields and diastereo-
meric excess were achieved only when the reaction
time was extended to 4 hours (Scheme 30) [53].
A similar method was applied to 3-fluoroindo-
line-2-one derivatives, which also formed fluori-
nated enolates under the action of a mixture of
Hünig’s base and lithium bromide (Scheme 31) [54].
It is known that 2-alkylpyridines can be used as
CH-acids in functionalizations with carbonyl com-
pounds and imines under catalysis by Brønsted or Le-
wis acids [55 – 57]. The use of optically active N-(tert-
butylsulfinyl)polyfluoroalkyl imines (S)-18 allowed
for the preparation of enantiomerically enriched
functionalized pyridines (S,S)-53 (Scheme 32) [58].
F3C N
S
O
+
LDA
de 38 88 %–
N
R2
-78oC, DCM
O
R1 N
R2
O
R1
CF3
N
H
S
O
R1
R2
2Me, Me, OMe, CF3
N
OR Li
CF3
N H
S
O
TS A
H
( )-S 10 ( , , )-S S S 48
79 98 %–
Scheme 27. The addition of indol-2-ones to N-tert-butylsulfinyl imine of fluoral
de 94 98 %–( )-S 10
R
O HO
CF3
OH
Et3N, LiBr
THF, 0°C
- CF3CO2
R
O
F
F
R
O CF3
N
H
S
O
FF
FF
F3C N
S
OH
( , )-S S 49
30 min
83 98 %–
Scheme 28. N-(tert-butylsulfinyl)trifluoroacetaldimine in the detrifluoroacetylative Mannich reaction
RF N
S
O
de 84 96 %–
RF = CF3, C2F5, C3F7, C4F9, CF2Cl, CF2Br
X = -(CH2)n-, n = 1, 2, 3; -(CH2O)-
Et3N, LiBr
2-MeTHF, -40oCR
+
X
R
X
O
F
CF3
OH
OH
CF3
N
H
S
OO
F
( )-S 18 ( , , )-S S S 50
79 97 %–
Scheme 29. The detrifluoroacetylative Mannich reaction in the synthesis of quaternary α‑fluoro-β-ketoamines
de 72 99 %–
RF = CF3, CF2H, C2F5, C3F7, C4F9, CF2Cl
Et3N, LiBr
-78oC, 4 h
R
R
S
O
O
FF
CF3
OH
OH
CF3
N
H
S
O
S
FF
O
O
RF N
S
O
+
( )-R 18 ( , )-S R 51
37 86 %–
Scheme 30. The detrifluoroacetylative Mannich reaction in the synthesis of α‑difluoroalkyl-β-aminosulfones
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N-(tert-Butylsulfinyl)imine of fluoral 10 suc-
cessfully reacted with enolates of glycine esters
in the presence of organic (Et3N, DMAP, DBU,
LiHMDS, tBuOLi) and inorganic (K2CO3 and
Cs2CO3, NaOH) bases. The best yields (49 – 87 %)
and diastereoselectivity (84 – 98 %) were achieved
when using 0.1 equiv. of Cs2CO3 in THF at room
temperature (Scheme 33, path a) [59]. Another
approach to compound 54 involves obtaining Schiff
bases in situ by the interaction between lithium
2,2-diphenylglycine carboxylate and aldehydes
(Scheme 33, path b). In the next step, interme-
diate A reacts with trifluoroacetaldimine 10 under
the catalysis by p- or m-nitrobenzoic acid with the
formation of the corresponding diamines [60].
β-Trifluoromethyl-α,β-diamino acid (S,S)-56
was synthesized by the reaction of N-(sulfinyl)
imine of fluoral (S)-10 with the nickel complex
of Schiff bases and the subsequent destruction
of the resulting complex 55 by hydrochloric acid
(Scheme 34) [61].
N-(tert-Butylsulfinyl)polyfluoroalkylaldimi-
nes (S)-18 entered the Lewis acid catalyzed re-
action with vinylogous carbonyl compounds – si-
lylated dienolates, and the regiochemistry of the
addition depended on the nature of the catalyst.
Thus, when AgBF4 was used, the Mannich reac-
tion in the α-position of the enolate occurred, giv-
ing β-amino-β-fluoroalkyl-α-vinyl esters (R,S)-57.
The stereochemical result of the process can be
RF N
S
O
de 84 96 %–
RF = CF3, C2F5, C3F7, CF2Cl, CF2Br
DIPEA, LiBr
2-MeTHF, -40oC
N
O
R1
R2
F
HO
CF3
OH
+
N
O
R1
R2
F
F3C
N
H
S
O
( )-S 18 ( , , )-S S S 52
79 97 %–
Scheme 31. Fluoroindolinones in the detrifluoroacetylative Mannich reaction with N-tert-butylsulfinyl polyfluoroalkyl aldimines
RF N
S
O
N
R1
R2
N
R2
R1
N
H
RF
S
OTi(O Pr)i 4, BuLin
THF, -42oC
de 60 94 %–
RF = CF3, CHF2
( )-S 18 ( , )-S S 53
31 84 %–
+
Scheme 32. 2-Alkylpyridines as CH-acids in the addition reaction with N-tert-butylsulfinyl polyfluoroalkyl aldimines
89 98 %–
CO2R
N
PhPh
a
R1
O CO2LiH2N
PhPh
R1 H
N
O
Li Ph
Ph
O
MeOH, rtb
N
CF3
HN S
Ph
Ph
O
( )-S 10
49 87 %–
( , , )- 84 99 %S S S de54 –
A
( )-S 10
CO2R, R1
R1
Scheme 33. N-tert-butylsulfinyl imine of fluoral in the synthesis of trifluoromethyl-substitured vicinal diamines
N N
Ph
Ni
OO
O
N
+
de 88 %
( )-S 10 N N
Ph
Ni
OO
O
N
CF3
H
N
H
S
O
DBU
MeCN, rt
BuBu BuBu
COOH
NH2
NH2
F3C
1M HCl
86 %
( , , )-S S S 55 ( , )-S S 56
77 %
Scheme 34. N-tert-butylsulfinyl imine of fluoral in the synthesis of β-trifluoromethyl-α,β-diamino acids
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
related to the formation of chelated TS A, in which
the metal atom is coordinated with two oxygen
atoms (of enolate and sulfinyl groups) and a nitro-
gen atom, and as a result, an “α-product” with the
(R,S)-configuration is formed. In the case of the ca-
talysis by TMSOTf, the γ-addition takes place, re-
sulting in α,β-unsaturated aminoesters (S,S)-58.
Assumably, the oxygen atom of the sulfinyl group
coordinates with the sterically hindered trimethylsilyl
cation forming an open TS B (Scheme 35) [62, 63].
3-Alkenyl-2-oxoindoles reacted with polyfluo-
roalkylaldimines (S)-18 under the catalysis by
organometallic bases (LDA, KНMDS), thus giv-
ing γ-addition products 59 in the (S,S)-configu-
ration (Scheme 36) [64].
In contrast to reactions with silyldienolates
and oxoindoles, the interaction of imines (S)-18
with α,α-dicyanoalkenes led to (R,S)-isomers of
γ-products 60. This is explained by the formation
of TS A, in which the metal atom of the enolate
chelates with the nitrogen atom of the aldimine,
leading to the Re-face addition (Scheme 37) [65].
The use of heterocyclic siloxides (furan and
pyrrole derivatives) in the addition reactions to
imines (S)-18 resulted in non-racemic γ-bute-
nolides 62 and γ-butyrolactams 61 It was found
that when the reaction was carried out in a low
polar solvent (DCM) in the presence of TMSOTf,
the process occurred regio- and stereoselectively
(Scheme 38) [62, 66].
The reaction of aldimines (S)-18 with indo-
les occurred chemo- and stereoselectively in the
presence of BF3•Et2O (in DCM) or LDA (in THF)
and led to compounds 63 bearing an indole nu-
cleus and the pharmacophoric 2,2,2-trifluoro-
1-aminoethyl function (Scheme 39) [67 – 69].
OTMS
OR
+
RF N
S
O
RF
NH
S
O O
OR
RF
NH
S
O O
OR
AgBF4 TMSOTf
DCM, -78oCDCM, -50oC
��
�
RF = CF3, CHF2, CF2Br; R = Et, But
de 84 98 %–
de 86 98 %–
N
O
tBu
RFH
Nu
TS A
LA
AgO
N
RF
RO Si
S
O
BF4
TS B
( )-S 18
( , )-R S 57
( , )-S S 58
89 94 %–62 85 %–
�
Scheme 35. Different pathways of the silylated dienolates addition to N‑tert‑butylsulfinyl polyfluoroalkyl aldimines
+
RF N
S
O
KHMDS
THF, -78oC
de 68 96 %–
N
O
R1
R3
N
O
R1
R3
R2
R2
NH
S O
RF
Ti(O Pr)i 4
( )-S 18 ( , )-S S 59RF = CF3, CHF2; R1 = Boc, Moc, Bn, Me
R2 = H, Me, OMe, Cl
R3 = Me, Ph, 4-MeO-C6H4 4-Cl-C6H4
55 92 %–
,
Scheme 36. The vinylogous Mannich reaction of 3-alkenyl-2-oxoindoles with N‑tert‑butylsulfinyl polyfluoroalkyl aldimines
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The aza-Corey-Chaykovsky reaction is a con-
venient method for the construction of an aziri-
dine ring, which is an important moiety in syn-
thetic chemistry. Thus, cyclization of a series of
trifluoromethyl ketimines 3 with dimethylsul-
foxonium methylide occurred successfully with
both alkyl and aryl ketimines, and with a high
stereoselectivity led to (R,S)-2-trifluoromethyl-
aziridines 64 [70]. The introduction of N-(tert-
butylsulfinyl)imine of trifluoropyruvate into the
aza-Corey-Chaykovsky reaction allowed to syn-
thesize 2-trifluoromethyl-2-ethoxycarbonylazi-
ridine (S,S)-65, an interesting substrate for the
synthesis of α-aminocarboxylic acid derivatives
(Scheme 40) [71].
4. Other types of reactions using N-(tert-
butylsulfinyl)polyfluoroalkyl imines
The aza-Baylis-Hillman reaction is a conve-
nient method for the preparation of α-methylene-
β-amino acids. The introduction of N-(tert-butyl-
sulfinyl)imine of fluoral (R)-10 in the reaction pro-
vided high yields and diastereoselectivity (>90 %)
even with 10 mol % of a catalyst (Scheme 41) [72].
It is worth noting that the stereochemical result,
namely the (R)-configuration of the new stereocen-
ter, differs from the reaction with non-fluorinated
+RF N
S
O
RF = CF3, CHF2, C2F5, C3F7, C4F9, CF2Cl, CF2Br
R = Me, OMe, Br
tBuOK
CNNC
CNNC
N
H
RF
S
OR
R
de >99 %
K
N
F3C
H
S
O
H
CN
CN
TS A
( )-S 18
( , )-R S 60
39 95 %–
Scheme 37. α,α-Dicyanoalkenes in the vinylogous Mannich reaction with N‑tert‑butylsulfinyl polyfluoroalkyl aldimines
RF = CF3, CHF2, C2F5, C3F7, C4F9, CF2Cl, CF2Br45 80 %–
de 30 96 %–
RF N
S
O OR OTMS
TMSOTf
DCM, -78°C O
O
R
RF
HN S
O
N
OTBS
Boc
TMSOTf
DCM, -78°CN
O
RF
HN
S
O
Boc
R = H: , 70 92 %67 95 % de– –
R = Me: , > 99 %47 89 % de–
( )-S 18
( , , )-S S S 62( , , )-S S S 61
Scheme 38. Siloxy-derivatives of furan and pyrrole in the addition reaction with N‑tert‑butylsulfinyl polyfluoroalkyl aldimines
RF N
S
OH
+
BF3*Et2O, DCM
or
LDA, THF HN
CF3
S O
N
R
R1
R1
N
R
R1
R1
2 2Ph
R1 = H, 2-Me, 4-CN, 4-MeO, 5-CN, 5-MeO, 5-Me, 5-CO2H, 5-CO2 2 6-Cl,
RF = CF3 , 54 98 %36 96 % de– –
RF = CF2P(O)(OEt)2 , >96 %49 81 % de–
( )-S 18
( , )-S S 63
,
Scheme 39. The reaction of N‑tert‑butylsulfinyl polyfluoroalkyl aldimines with functionalized indoles
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
analogs [73, 74], which supports the conclusion that
the process proceeds as an attack in the open TS A
as in most reactions with polyfluoroalkyl aldimines.
Several enantiomerically enriched α-(trifluoro-
methyl)tryptamines were synthesized by the “ene”
reaction with imine (R)-10. The reaction pro-
ceeded with a high stereoselectivity regardless
of the substituents in the indole ring and led to
the predominant formation of the (R,R)-stereoi-
somer 67 (Scheme 42) [75].
Lithiated ethyl and butyl vinyl ethers success-
fully reacted with polyfluoroalkyl aldimines (S)-18
giving optically enriched amines 68 with a high
diastereoselectivity (Scheme 43). The configura-
tion of the product was assumed to be (S,S) based
on previous observations for these types of in-
teractions [76].
The addition of hydrophosphoryl compounds
to optically pure N-(tert-butylsulfinyl)imines of
fluoral or trifluoromethyl ketones leads to deri-
vatives of polyfluoroalkyl-substituted α-amino-
phosphonic acids. Thus, the reaction of diethyl phos-
phite and imine (S)-10 occurred in the presence
of potassium carbonate to give products 69 with
good yields (65 %) and stereoselectivity (de 76 %).
Replacing hydrophosphoryl compounds with their
synthetic equivalents, trimethylsilyldialkylphos-
phites generated in situ allowed to significantly
improve diastereoselectivity (68 – 88 %), while
the diastereomeric ratio increased in the series
R = Me < Et ≈ Pr < i-Pr (Scheme 44) [77].
Trifluoromethylketimines (R)-70 also enter
the reaction with phosphites under catalysis by
Ti(OiPr)4 [78]. The reaction is effective for both
CF3
N
S
O
R
-45oC, DMF
R = CH2(CH2)9CH3, Ph, 4-MeOC6H4, 4-ClC6H4, 4-CF3C6H4, C C-1-(5-MeO)naphtyl, C C-1-(3,4-ClC6H3)
de 72 99 %–
S O
CH2
TMSOI
NaH, DMF, rt
N
F3C R
S
t-Bu
O
0oC, toluene
S O
CH2
TMSOI
NaH BuOKor t
DMSO, rt
N
F3C CO2Et
S
t-Bu
O
R = CO2Et
24 %
de >99 % ( )-S 3 ( , )-R S 64( , )-S S 65
45 93 %–
Scheme 40. The aza-Corey-Chaykovsky reaction of N‑tert‑butylsulfinyl trifluoromethyl ketimines in the synthesis
of 2-trifluoromethylaziridines
+
F3C N
S
O
rt, neat
de >90 %
N
CF3H
TS A
DABCO
EWG
CF3
NH
S
O
EWG
S
O
H
N
ORO
( )-R 10 ( , )-R R 66
EWG = CO2Me, CO2tBu, C(O)Me, CN
85 98 %–
Scheme 41. The aza-Baylis-Hillman reaction of activated alkenes with N‑(tert‑butylsulfinyl)imine of fluoral
+
F3C N
S
O
neat, 80oC
de 66 76 %–
N
Boc N
Boc
HN S
O
CF3
R R
( )-R 10
( , )-R R 67
R = 5-H, 5-Me, 5-OMe, 5-Cl, 5-F, 5-CF3, 6-CF3
47 71 %–
Scheme 42. The uncatalyzed diastereoselective “ene” reaction of N‑(tert‑butylsulfinyl)trifluoroacetaldimine
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Журнал органічної та фармацевтичної хімії 2025, 23 (2)
alkyl and aryl ketimines and leads to the for-
mation of α-trifluoromethylaminophosphonates
(S,R)-71 with a stereoselectivity from 87 to 99 %.
Although, in contrast to the reaction with imine
of fluoral, the use of K2CO3 in the reaction with
polyfluoroalkyl ketimines did not lead to the de-
sired product, its replacement with stronger in-
organic bases, in particular rubidium and cesi-
um carbonates, was proved to be more successful
[79]. As a result, non-racemic adducts (S,R)-72
were obtained with yields from 56 to 88 % and a
high diastereoselectivity (Scheme 45).
By the addition of dimethylphosphine oxide
to imines (R)-and (S)-18 in the presence of Ti(OiPr)4,
enantiomerically pure α-amino-α-polyfluoroalkyl
dimethylphosphine oxides 73 were synthesized
in high yields and an excellent stereoselectivity.
Upon deprotection, water-soluble optically pure
amino-substituted dimethylphosphine oxides 74
were isolated in the form of hydrochloride salts
(Scheme 46) [80].
Functionalized pyrrolones (S,S)-75 were ob-
tained from the imine of trifluoropyruvate (S)-5
by the cyclocondensation with various push-pull
+
RF N
S
O
tBuLi, THF
70 96 %de –
14 85 %–
( )-S 18 ( , )-S S 68
RF = CF3, CHF2
R = Et, Bu, -(CHn 2-CH2)-
-78..0oC
OR
RF N
H
S
O
O
R
Scheme 43. The reaction of lithiated vinyl ethers with N‑tert‑butylsulfinyl polyfluoroalkyl aldimines
F3C N
S
O
N
H
S
OCF3H
56 83 %–
de 68 88 %–
HP(O)(OEt)2
P
RO
O
OR
or
Me3SiOP(OR)2
DCM, 0oC
K2CO3, DCM, rt
( )-S 10 ( , )-S S 69
Scheme 44. N-(tert-butylsulfinyl)imines of fluoral in the asymmetric synthesis of α‑trifluoromethyl α-aminophosphonic acids
RF N
S
OR
HP(O)(OEt)2
Hex/Tol, -40oC
Ti(O Pr)i 4
N
H
S
ORF
48 90 %–
de 87 99 %–
P
EtO
O
OEt
RF = CF3,
R = Ph, 4-Me-C6H4, 4-MeO-C6H4,
4-Cl-C6H4, Cn 6H13
DCM, rt
N
H
S
ORF
56 88 %–
de 50 84 %–
P
R1O
O
OR1
M2CO3
M = Rb, Cs
HP(O)(OR1)2
RF = CF3, CF2Cl, CF2H
R1 = Me, Et, Ph
( )-R 70 ( , )-S R 71( , )-S R 72
R R
Scheme 45. The addition of phosphites to N‑tert‑butylsulfinyl trifluoromethylketimines
RF N
S
O
>99 %de
( )-S 18 ( , )-S S 73
RF = CF3, CHF2, CF2Ph
RF N
H
S
OP
Ti(O Pr)i 4
Et2O, 0oC
P H
O
O
80 95 %– ( )-S 74
RF NH2
P OHCl
dioxane
HCl
75 89 %–
>99 %de
Scheme 46. The Ti-mediated addition of dimethyl phosphine oxide to N‑tert‑butylsulfinyl polyfluoroalkyl aldimines
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Journal of Organic and Pharmaceutical Chemistry 2025, 23 (2)
enamines, with diastereoselectivity dependent on
the nature of substituents in the enamine mol-
ecule (Scheme 47) [19].
A series of optically pure cyclic sulfoximines
78 was obtained by the interaction of ArSO2CF2-
sulfinyl imines (S)-76 with trimethylsilylphenyl
triflates 77, the cycloaddition occurred stereo-
specifically to give diastereomer in (R,SS)-confi-
guration, meaning that the configuration of the
stereogenic sulfur atom was preserved [81, 82]
(Scheme 48).
■ Conclusions
The analysis of the asymmetric functionali-
zation of the azomethine bond of N-(tert-butyl-
sulfinyl)polyfluoroalkyl imines allows us to con-
clude that the stereoresult of the reactions is
determined both by the structure and geometry
of the imine and by the reaction conditions (the
nature of the solvent, the catalyst, and the tem-
perature conditions of the process). The steric
and electronic properties of polyfluoroalkyl sub-
stituents affect the conformational state of imi-
nes (the polyfluoroalkyl substituent is located in
the trans position relative to the sulfinyl group),
as well as the geometry of the transition state
(polyfluoroalkyl substituents usually occupy the
equatorial position). However, aldimines are
more prone to form the open transition state in
the addition reactions to the C=N bond, and the
result of the process is therefore regulated by
steric factors. While polyfluoroalkyl ketimines
are more likely to form transition states with a
closed geometry. In the latter case, the sulfinyl
group usually participates in regulating the di-
rection of the addition due to the ability of the
oxygen atom to form coordination bonds.
The review demonstrates that N-(tert-butyl-
sulfinyl)polyfluoroalkyl imines are versatile sub-
strates, which easily interact with different
types of nucleophiles, providing access to a wide
range of optically pure derivatives of polyfluoro-
alkyl-substituted amines, amino alcohols and
amino acids.
■ Acknowledgments
The authors express their gratitude to the
National Academy of Sciences for funding this
work (grant No. 0124U002052) and to all the
brave defenders of Ukraine.
F3C
N
S
O
( )-S 5
MeO2C
N
R
O Me
EWGNH CF3
( , )-S S 75a c–
S
O
Me
NHR
EWG
H
+
Et2O THFor
rt, 3-7 d
a: EWG = CO2Et, R = H; : EWG = COb 2Me, R = Me;
c: EWG = CN, R = H
de 70 90 %–
75 80 %–
Scheme 47. Push-pull enamines in the reaction with N‑tert‑butylsulfinyl trifluoromethyl iminopyruvates
R CF2SO2Ar
N
S
O
tBu +
Me3Si
TfO
R1
R2
S
N
R1
R2
ArO2SF2C R
tBu O
CsF, MeCN
rt, 12 h
Ar = Ph: R = Ph, 3-Me-C6H4, 4-Me-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 3-MeO-C6H4, 4-MeO-C6H4, 4-CF3-C6H4,
6-Br-2-naphtyl, ( )-styryl, Pr; RE i 1, R2 = H, Me, MeO; R2+R3 = -(CH2)3-; R2 = Me, R3 = H
Ar = 2-pyridyl: R = Ph, 3-Me-C6H4, 4-Me-C6H4, 3-MeO-C6H4, 4-MeO-C6H4, 4-CF3-C6H4, 4-F-C6H4,
4-Cl-C6H4, 4-Br-C6H4, 4-Ph-C6H4, naphtyl, ( )-styryl, Pr; RE i 1, R2 = H; R2 = Me, R3 = H; R2 = H, R3 = Me;
R2+R3 = naphtyl
de >99 %( )-S 76 ( , )-R S 78
36 90 %–
77
Scheme 48. The stereoselective [3+2] cycloaddition of N‑tert‑butylsulfinyl ketimines to arynes
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Журнал органічної та фармацевтичної хімії 2025, 23 (2)
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Information about the authors:
Alona S. Cherednichenko (corresponding author), PhD in Chemistry, Junior Researcher of the Department of Organoelement Chemistry,
Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; https://orcid.org/0009-0001-7159-6898;
e-mail: alyonachered@gmail.com.
Yuliya V. Rassukana (corresponding author), Dr. Sci. in Chemistry, Professor, Deputy Director for Scientific Work in Institute
of Organic Chemistry of the National Academy of Sciences of Ukraine; https://orcid.org/0000-0003-3101-9911;
e-mail for correspondence: juvivi@ukr.net.
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| id | oai:ojs.journals.uran.ua:article-321224 |
| institution | Journal of Organic and Pharmaceutical Chemistry |
| issn | 2518-1548 |
| keywords_txt_mv | |
| language | English |
| last_indexed | 2026-08-23T01:00:30Z |
| publishDate | 2025 |
| publisher | National University of Pharmacy |
| record_format | ojs |
| resource_txt_mv | ophcjnupheduua/94/5e8e7f5541d71c0e0b765bdbf7357394.pdf |
| spelling | oai:ojs.journals.uran.ua:article-3212242026-08-22T19:54:27Z Recent advances in the asymmetric functionalization of N-(tert-butylsulfinyl)polyfluoroalkyl imines Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів Cherednichenko, Alona S. Rassukana, Yuliya V. трет-бутилсульфініл поліфтороалкіліміни асиметричний синтез альдиміни кетиміни стереоселективність tert-butylsulfinyl polyfluoroalkyl imines asymmetric synthesis aldimines ketimines stereoselectivity The review covers the latest achievements in the application of N-(tert-butylsulfinyl)polyfluoroalkyl imines in the asymmetric synthesis and summarizes stereochemical observations of their behavior in different types of reactions (reduction of the C=N bond, addition reactions with organometallic reagents, C-H acids, etc.). Fluorinated N-(tert-butylsulfinyl) imines are convenient substrates for obtaining enantiomerically enriched derivatives of polyfluoroalkyl amines, amino alcohols, amino acids, and heterocyclic systems. In recent decades, various approaches to their functionalization have been proposed. With this in mind, important aspects of their reactivity, regio- and stereochemistry have been systematized in this paper. Огляд охоплює найновіші здобутки в застосуванні N-(трет-бутилсульфініл)поліфтороалкілімінів в асиметричному синтезі, а також узагальнює стереохімічні закономірності їхньої поведінки в різних типах реакцій (відновлення C=N зв`язку, приєднання металоорганічних реагентів, С-Н кислот тощо). Фторовмісні N-(трет-бутилсульфініл)іміни є зручними субстратами для одержання на їх основі енантіомерно збагачених похідних поліфтороалкілімінів, аміноспиртів, амінокислот і азотовмісних гетероциклів. За останні десятиліття було запропоновано різноманітні підходи до їх функціоналізації. З огляду на це важливі аспекти щодо їхньої реакційної здатності, регіо- і стереохімії систематизовано в цій роботі. National University of Pharmacy 2025-04-11 Article Article application/pdf https://ophcj.nuph.edu.ua/article/view/321224 10.24959/ophcj.25.321224 Journal of Organic and Pharmaceutical Chemistry; Vol. 23 No. 2 (2025); 3-22 Журнал органической и фармацевтической химии; Том 23 № 2 (2025); 3-22 Журнал органічної та фармацевтичної хімії; Том 23 № 2 (2025); 3-22 2518-1548 2308-8303 en https://ophcj.nuph.edu.ua/article/view/321224/320261 Copyright (c) 2025 Alona S. Cherednichenko, Yuliya V. Rassukana http://creativecommons.org/licenses/by/4.0 |
| spellingShingle | трет-бутилсульфініл поліфтороалкіліміни асиметричний синтез альдиміни кетиміни стереоселективність Cherednichenko, Alona S. Rassukana, Yuliya V. Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів |
| title | Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів |
| title_alt | Recent advances in the asymmetric functionalization of N-(tert-butylsulfinyl)polyfluoroalkyl imines |
| title_full | Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів |
| title_fullStr | Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів |
| title_full_unstemmed | Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів |
| title_short | Нові досягнення в асиметричній функціоналізації N-(трет-бутилсульфініл)поліфтороалкілімінів |
| title_sort | нові досягнення в асиметричній функціоналізації n-(трет-бутилсульфініл)поліфтороалкілімінів |
| topic | трет-бутилсульфініл поліфтороалкіліміни асиметричний синтез альдиміни кетиміни стереоселективність |
| topic_facet | трет-бутилсульфініл поліфтороалкіліміни асиметричний синтез альдиміни кетиміни стереоселективність tert-butylsulfinyl polyfluoroalkyl imines asymmetric synthesis aldimines ketimines stereoselectivity |
| url | https://ophcj.nuph.edu.ua/article/view/321224 |
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