Asymmetric trifluoromethylthiolation of azlactones under chiral phase transfer catalysis

Article abstract of DOI:10.1039/d0ob00476f

The first enantioselective method for the installation of the SCF₃ group at the C-4 position of azlactones is described in the present communication under quinidinium phase transfer catalysis. The higher performance of substrates containing electron-rich 2-aryl groups at the azlactone was rationalized using DFT calculations.

Full text of DOI:10.1039/d0ob00476f

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DOI: 10.1039/D0OB00476F
ARTICLE
Asymmetric Trifluoromethylthiolation of Azlactones under Chiral
Phase Transfer Catalysis
Marina Sicignano,a Ricardo I. Rodríguez,b Vito Capaccio,b Fabio Borello,a Rafael Cano,b Francesco De
Received 00th January 20xx,
Accepted 00th January 20xx
Riccardis,a Luca Bernardi,c Sergio Díaz-Tendero,d Giorgio Della Sala, a* and José Alemánb*
DOI: 10.1039/x0xx00000x
The first enantioselective method for the installation of the SCF3 group at the C-4 position of azlactones is described in the
present communication under quinidinium phase transfer catalysis. The higher performance of substrates containing
electron-rich 2-arylgroups at the azlactone was rationalized using DFT calculations.
direct asymmetric functionalization of reactive α-carbon in
weakly acidic carbonyl compounds, with electrophilic SCF3
sources. However, only a limited set of carbonyl substrates has
been explored to date, being mainly comprised by β-keto
Introduction
Over the last recent years, the design of new organofluorinated
compounds has become one of the trending topics in the
agrochemical and medicinal chemistry field, due to their
peculiar physicochemical and biological features, leading to a
plethora of reports on innovative fluorine-based drug
candidates.1 Worldwide research groups have thus focused
their efforts in the development of diverse synthetic
methodologies aimed to the asymmetric incorporation of
fluorine atoms or fluoroalkyl groups into organic molecules.2 In
esters,6 α -thioketones,7 and oxindoles,7,8 and isoxazolidin-5-
ones.9 (Scheme 1).
Previous works:
R
*
O
*
O
O
SCF3
SCF3
SCF3
O
N
SCF3
SPh
cyclic -thioketones 7
G
O
G
G
CO2R
*
*
R
N
1,2
Boc
Boc
-ketoesters 6
isoxazolidin-5-ones 9
oxindoles 7,8
this
regard,
bioactive
compounds
bearing
the
This work: Unprecedented synthesis of SCF3-azlactones
trifluoromethylthio group (SCF3) have shown a remarkably
improved metabolic stability and transmembrane permeability,
thanks to both its lipophilic and electron-withdrawing nature
(Hansch parameter π= 1, 44).3 Unsurprisingly, a powerful
arsenal of strategies enabling the introduction of this group
onto various scaffolds is now available at the synthetic
chemist’s tool box. Among them, the formation of C(sp2)- and
C(sp)-SCF3 bonds has been satisfactorily achieved through
either transition-metal-promoted couplings, organocatalyzed
reactions or radical processes.4 Nevertheless, the direct
stereocontrolled nucleophilic or electrophilic installation of the
SCF3 group at C(sp3) centres remains as a challenging task.5,6
The most common approach to fulfil this challenge relies on the
O
O
O
R
SCF3
O
PTC
O
SCF3
*
N
N
+
R
Ar
N
Ar
O
Scheme 1.
Carbonyl compounds used in the previous asymmetric
trifluoromethylthiolation reactions and our working plan with azlactones
In this context, azlactones drew our interest because of their
synthetic and biological significance, thanks to the wide range of
attractive pharmacological activities displayed, as their high
versatility as building blocks, arising from presence of both
nucleophilic and electrophilic sites.10 In the light of this, we were
intrigued by the possibility of incorporating the SCF3 group into the
azlactone core in an enantioselective fashion, through a phase
transfer catalysed process (bottom, Scheme 1).
Initially, aiming to test the feasibility of our idea, azlactone 1a was
chosen as a model substrate, N-(trifluoromethylthio)phthalimide 2
as SCF3 source,11 in dichloromethane at –20 °C and in the presence
of catalytic amount of K3PO4.12 A wide family of different phase
transfer catalysts (Table 1. Selected examples taken from ESI) was
tested. Derived from this first screening, it was notorious that O-
alkylated and O-acylated forms of the phase-transfer catalyst (I-III)
were unsuitable for this transformation, leading to good yields but
low stereocontrol (entries 1-3). A modest enantioselectivity was
a. Dipartimento di Chimica e Biologia “A. Zambelli”, Università degli Studi di Salerno,
Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy,
b. Organic Chemistry Department, Módulo 1, Universidad Autónoma de Madrid,
28049 Madrid, Spain.
c. Department of Industrial Chemistry ‘‘Toso Montanari’’ & INSTM RU Bologna,
Alma Mater Studiorum University of Bologna, Viale del Risorgimento 4, 40136
Bologna, Italy.
d. Chemistry Department, Módulo 13, Universidad Autónoma de Madrid, 28049
Madrid, Spain.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Journal Name
achieved with cinchoninium bromide (IV) (entry 4). Additionally, entry 8) affording complex mixtures and degradation VoifewthAerticslteaOrtnilninge
DOI: 10.1039/D0OB00476F
although the presence of electron-rich aromatic rings at the N-benzyl materials. Aiming to increase both, yield and enantiomeric ratio of
moiety (catalyst V) provided a good yield of 3a, it turned out to be 3a, we then decided to properly modify the substrate structure,
detrimental for the stereocontrol (entry 5). Conversely, electron- surveying various substituent at its C-2 position, in the reaction
poor N-benzyl groups (catalysts VI-VII) brought to
a slight catalysed by VIII (see Table 2). It was found that the electronic nature
improvement of the e.r. (entries 6-7). It should be highlighted the of the C-2 substituent was highly relevant, as the reaction did not
importance of the free hydroxyl group by directing/assisting the take place when electron poor aromatic rings were used, even after
electrophilic attack of 2 on one of the two enantiotopic faces of 1a extended reaction times, as complete degradation of the starting
(compare entries 1-7).13 It is noteworthy that, upon switching from azlactones was only observed (Table 2, entries 1 and 2). Interestingly,
the cinchonine to a quinidine core, the enantiomeric ratio was when a chlorine atom was placed in the para-position of the
further improved albeit with a decay of the yield (entry 8), leading to aromatic ring, the reaction proceeded smoothly, with better yield
the identification of VIII as the most suitable phase-transfer catalyst. and shorter time compared to the unsubstituted phenyl ring, but the
A wide array of parameters was further studied (temperature, enantioselectivity was lower (Table 2, entries 3 and 4). Finally, when
solvent, base and catalyst loading) confirming as optimal the an electron donating group was introduced at the para-position of
preliminarily chosen reaction conditions, as reported in Table 1, the 2-aryl group (Table 2, entry 5), full conversion was accomplished
entry 8.14
in very short reaction time (1h), displaying excellent yield and high
enantiomeric ratio (Table 2, entry 5).
Table 1. Screening of phase transfer catalysts
O
O
O
Table 2. Screening of C-2 substituent
PTC (20 mol%)
K3PO4 (10 mol%)
Ph
O
Ph
SCF3
O
N
SCF3
+
N
N
Ph
Ph
O
O
O
DCM, -20°C, 4 days
PTC-VIII (20 mol%)
K3PO4 (10 mol%)
O
Ph
O
Ph
SCF3
O
3a
1a
2
N
SCF3
+
N
N
R
R
DCM, -20°C
O
3
1
2
AdCOO
AllylO
N
BnO
N
N
N
Br
Br
Br
Entry
R
Time
Conv./Yield (%)a
er b
N
N
-
1
2
3
4
5
4-CN(C6H4)
1b
7 days
5 days
19 h
Degradation
Degradation
100/83
III
I
II
-
4-CF3(C6H4) 1c
4-Cl(C6H4) 1d
C6H5 1a
HO
HO
HO
70:30
82:18
94:6
N
N
N
Br
Br
Br
4 days
1 h
50/49
N
N
N
NO2
100/84
OMe
4-OMe(C6H4)
1e
VI
IV
V
Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), 0.1 M. aIsolated yield. bThe
values of er were determined by HPLC.
HO
HO
MeO
N
N
Br
Br
CF3
CF3
Subsequently, with the optimized reaction scenario, the reaction
scope was carried out (Scheme 2), showing that both electron-
donating and electron-withdrawing groups at the benzyl substituent
of the azlactone core (3h, 3i and 3j) allowed the incorporation of the
SCF3 group without dramatically altering the good enantioselectivity
and excellent yield. The substrate containing a β-naphthylmethyl
side chain also reacted successfully under the standard conditions
without losing quality in the results (3f). Good yield and
enantioselectivity were also obtained upon replacing PMP with 3,5-
(MeO)2C6H3 at the C-2 position of the core (cf. 3e and 3g). Gratefully,
the presence of an arylmethyl sidechain proved to be not mandatory
to achieve good results. For instance, a homobenzylsubstituted
azlactone was smoothly transformed into the corresponding
thiofluorinated compound 3k in good yield and enantiomeric ratio. A
similar result was obtained with a methionine derivative, affording 3l
albeit requiring a longer stirring time. Moreover, the reaction of
substrates containing moderately sterically hindered cyclohexyl, sec-
butyl and isopropyl chains, occurred smoothly, delivering the desired
products 3m, 3n and 3o respectively with e.r.’s from moderate to
excellent. In particular, an outstanding result was achieved with the
N
N
CF3
CF3
VII
VIII
b
Yield (%)a
Entry
e
r
Catalyst
1
2
3
4
5
6
7
8
80
86
72
91
78
57
74
49
I
II
51:49
52:48
51:49
72:28
53:47
77:23
72:28
82:18
III
IV
V
VI
VII
VIII
Reaction conditions: 1 (0.10 mmol), 2 (0.12 mmol), 0.1 M. aIsolated yield. bThe
values of er were determined by HPLC.
Attempting to use different SCF3-sources such as N-
(trifluoromethylthio)saccharin
(trifluoromethylthio)succinimide under the best conditions (Table 1,
and
N-
2 | J. Name., 2012, 00, 1-3
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valine-derived azlactone, that was transformed into the the anions derived from azlactones 1a-e and tetrabutylammonium
View Article Online
DOI: 10.1039/D0OB00476F
corresponding trifluoromethylthiolated product 3o as a single ion (see structures in the ESI). In all cases, the obtained stabilization
enantiomer. During our investigation, we encountered some energy of the resulting complex between the azlactone anion and the
+
limitations in the scope of this methodology, as outlined in the NBu4 , compared to the separated compounds, oscillated around
bottom of Scheme 2. The configuration assignment of the resulting ~21 kcal·mol-1. The nature of the simulated interaction is
trifluoromethylthiolated azlactones was described as
comparison of simulated and experimental electronic circular positively charged ammonium species and the negatively charged
dichroism spectra of compound 3k (see ESI for details).
R
by
a
rationalised by considering Coulomb attraction forces between the
azlactone, as well as Van der Waals forces between the azlactone
phenyl rings and the ammonium aliphatic chains. Since this
interaction is very similar in all cases, we concluded that it does not
have major influence on the observed reactivity. In a second step of
our simulations, the highest occupied molecular orbitals of the
enolates – HOMO – were analysed (Scheme 3). These molecular
orbitals show  character and are localized only in the azlactone ring,
particularly, higher electron density is observed in the azlactones
molecular region between the carbonyl oxygen atom and C-4,
consistently with the observed electrophilic attack of SCF3 at the
latter position (see a.u. values in Scheme 3 and ESI for different
representations and a deeper analysis of the HOMO orbital). The
orbital energy increases across the substituent series CN < CF3 < Cl <
H < OCH3, which is roughly in accordance with the experimental
reactivity behaviour. In an effort to obtain the atomic population,
and thus the charges located on each atom, a Natural Bond Orbital
(NBO) analysis17 was lastly performed. This final study was mainly
focused on the previously identified two key atoms, the carbonyl
oxygen and C-4, unveiling a partial negative charge in both sites. This
data suggested an excess of electron density and was consistent with
the higher electron density associated to these atoms in the HOMO
orbital, displaying a clear charge trend (see Z values in Scheme 3).
These computational data reflect very well the observed reactivity
trend, wherein enolates with lower electron density at C-4 do not
react or react very slow compared to enolates with higher electron
density. However, the higher reactivity of the p-chloro substrate 1d
compared to its unsubstituted counterpart 1a is not reproduced by
the calculated electron densities, thus suggesting that other factors
may work in these borderline cases. In summary, a simple electron
density analysis offers an explanation to the general reactivity trend,
with more reactive substrates characterized by larger accessibility
(higher energy) of the HOMO orbital and enhanced electron density
at C-4, suggesting that the rate-determining step is the reaction of
azlactone anion with the electrophilic SCF3 source.
O
O
O
PTC VIII (20 mol%)
K3PO4 (10 mol%)
O
O
R
N
SCF3
R
+
N
PMP
SCF3
N
DCM, -20°C
PMP
O
3e-o
1e-o
2
O
O
O
O
O
O
MeO
N
SCF3
N
SCF3
PMP
N
SCF3
PMP
3e 1h, 84% yield
94:6 er
3f 19h, 98% yield
85:15 er
3g 1h, 72% yield
86:14 er
OMe
OMe
Cl
Cl
OMe
Cl
O
O
O
O
O
O
N
SCF3
N
SCF3
N
SCF3
PMP
PMP
PMP
3j 2h, 89% yield
81:19 er
3i 2h, 90% yield
81:19 er
3h 2h, 98% yield
75:25 er
O
O
O
O
O
O
SMe
SCF3
N
SCF3
N
SCF3
PMP
PMP
N
PMP
3l 19h, 85% yield
74:26 er
3m 4h, 92% yield
91:9 er
3k 5h, 88% yield
80:20 er
O
O
O
O
N
SCF3
N
SCF3
PMP
PMP
3o 2h, 88% yield
>99:1 er
3n 2h, 87% yield
72:28 er
Limitations of the reaction
O
O
O
O
O
O
O
O
t-Bu
Ph
N
N
N
N
PMP
PMP
PMP
PMP
no reaction
decomp. of starting material
Scheme 2. Azlactone scope: yields of isolated products are given. HPLC was use
for er meassurements. Reactions conditions: 1 (0.1 mmol), 2 (0.12 mmol), 0.1 M
In the quest for finding a plausible explanation to the relationship
observed between the reactivity and the para-substituent at the 2-
aryl moiety of azlactone, which showed the high efficiency of the p-
OMe group (See Table 2 and Scheme 3), we performed reactions of
azlactones 1a-e with NBu4Br as PTC, confirming the same reactivity
order (CN < CF3 < H < Cl < OCH3). This experimental result suggest
that such trend is not due to an interaction between the chiral and
non-chiral catalyst and the different substrates, but rather it is solely
dependent on the electronic nature of the azlactone. This
information realigned our efforts to carry out a theoretical study
based on Density Functional Theory (DFT) calculations.15,16 As a
starting point in our simulations, we located the minima in the
potential energy surface corresponding to the interaction between
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
N
N
N
N
N
NC
F3C
Cl
H
MeO
1b
1c
1d
1e
1a
4 days, 49% yield
No reaction
No reaction
9 h, 83% yield
1h, 84% yield
Scheme 3. Reactivity and comparison of the different aryl groups at the azlactones
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J. Name., 2013, 00, 1-3 | 3
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4-(3,4-dimethoxybenzyl)-2-(4-methoxyphenyl)-4-
DOI: 10.1039/D0OB00476F
((trifluoromethyl)thio)oxazol-5(4H)-one (3h): Obtained after 2 h as
a yellow solid (43.2 mg, 98% yield), mp 107-108 °C. H NMR (300
MHz, CDCl3) δ 7.87 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 6.77–
6.67 (m, 3H), 3.86 (m, 3H), 3.79 (s, 3H), 3.68 (s, 3H), 3.42 (d, J = 13.2
Hz, 1H), 3.26 (d, J = 13.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 174.7,
164.1, 162.3, 148.9, 148.5, 130.3, 128.8 (q, J = 310.1 Hz), 123.7,
122.6, 116.8, 114.4, 113.5, 111.0, 76.8 (q, J = 1.1 Hz), 55.7, 55.7, 55.6,
Experimental section
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General
procedure
for
the
enantioselective
1
trifluoromethylthiolation of azlactones
In a 4 ml vial, to a mixture of the selected azlactone (1.0 eq., 0.10
mmol), N-(trifluoromethylthio)phthalimide 2 (1.2 eq., 0.12 mmol,
29.7 mg), catalyst VIII (0.20 eq., 0.02 mmol, 12.6 mg), and K3PO4 (0.1
eq., 0.01 mmol, 2.1 mg) dichloromethane (1.0 mL) was added and
the reaction mixture was stirred for the indicated time at -20 °C.
Then, the mixture was filtered and concentrated in vacuo. The crude
residue was purified by chromatography (10 g silica gel cyclohexane-
ethyl acetate, 99/1 to 80/20) to afford the corresponding product.
[휶]ퟐퟎ
42.1 (q, J = 1.1 Hz). 19F NMR (282 MHz, CDCl3) δ -37.5.
= -40.2°
푫
(c = 0.80, CHCl3). Enantiomeric ratio 75:25 determined by HPLC
analysis (CHIRALPAK® AS-H column (ϕ 0.46 cm x 25 cm), n-hexane:i-
PrOH = 80:20, 0.5 mL/min, tminor = 11.1 min, tmajor = 12.1 min). HRMS
(ESI) [M + H+] calcd for C20H19F3NO5S+ 442.0931, found 442.0930
4-benzyl-2-(4-methoxyphenyl)-4-(trifluoromethyl)thio)oxazol-
5(4H)-one (3e): Obtained after 1 h as a yellow solid (32.0 mg, 84%
yield), mp 115-116 °C. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 8.9 Hz,
2H), 7.21 (m, 5H), 6.94 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 3.47 (d, J = 13.1
Hz, 1H), 3.32 (d, J = 13.1 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 174.7,
164.0, 162.2, 131.4, 130.8, 130.4, 128.7 (q, J = 311.1 Hz), 128.5,
4-(3,4-dichlorobenzyl)-2-(4-methoxyphenyl)-4-(trifluoromethyl)-
thio)oxazol-5(4H)-one (3i): Obtained after 2 h as a yellow solid (40.5
mg, 90% yield), mp 109-110 °C. 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J
= 8.9 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.06 (dd,
J = 8.2, 2.0 Hz, 1H), 6.97 (d, J = 8.9 Hz, 1H), 3.88 (s, 3H), 3.43 (d, J =
13.4 Hz, 1H), 3.28 (d, J = 13.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ
174.3, 164.3, 162.7, 132.6, 132.6, 132.5, 131.8, 130.5, 130.4, 129.8,
128.6 (q, J = 310.0 Hz), 116.4, 114.5, 76.2 (q, J = 1.1 Hz), 55.6, 41.5 (q,
128.2, 116.8, 114.4, 76.8 (q, J = 1.1 Hz), 55.6, 42.5 (q, J = 1.1 Hz). 19
[휶]ퟐ푫ퟎ
F
NMR (282 MHz, CDCl3) δ -37.5.
= -65.5° (c = 0.80, CHCl3).
Enantiomeric ratio 94:6 determined by SFC analysis (CHIRALPAK® AS-
H column (ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH = 95:5, 0.5 mL/min,
tminor = 7.2 min, tmajor = 8.1 min). HRMS (ESI) [M + H+] calcd for
C18H15F3NO3S+ 382.0719, found 382.0710.
[휶]ퟐퟎ
J = 1.1 Hz). 19F NMR (282 MHz, CDCl3) δ -37.3.
= -53.8° (c = 0.80,
푫
CHCl3). Enantiomeric ratio 81:19 determined by HPLC analysis
(CHIRALPAK® IB column (ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH = 99:1,
0.5 mL/min, tmajor = 17.9 min, tminor = 20.9 min). HRMS (ESI) [M + H+]
calcd for C18H13Cl2F3NO3S+ 449.9940, found 449.4942.
2-(4-methoxyphenyl)-4-(naphthalen-2-ylmethyl)-4-
((trifluoromethyl)-thio)oxazol-5(4H)-one (3f): Obtained after 19 h as
a yellow solid (42.3 mg, 98% yield), mp 119-120 °C. H NMR (300
MHz, CDCl3) δ 7.87–7.81 (m, 2H), 7.77–7.71 (m, 2H), 7.71–7.65 (m,
2H), 7.49–7.37 (m, 2H), 7.35 (dd, J = 8.6, 1.7 Hz, 1H), 6.94–6.87 (m,
2H), 3.83 (s, 3H), 3.65 (d, J = 13.1 Hz, 1H), 3.51 (d, J = 13.1 Hz, 1H). 13
1
4-(4-chlorobenzyl)-2-(4-methoxyphenyl)-4-
(trifluoromethyl)thio)oxazol-5(4H)-one (3j): Obtained after 2 h as a
yellow solid (37.0 mg, 89% yield), mp 100-101 °C. 1H NMR (300 MHz,
CDCl3) δ 7.87 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.14 (d, J =
8.6 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H), 3.44 (d, J = 13.3 Hz,
1H), 3.30 (d, J = 13.3 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 174.6, 164.2,
162.4, 134.3, 131.9, 130.5, 130.0, 128.7, 128.7 (q, J = 310.0 Hz),
116.6, 114.5, 76.5 (q, J = 1.1 Hz), 55.6, 41.7 (q, J = 1.1 Hz). 19F NMR
[휶]ퟐퟎ
C
NMR (75 MHz, CDCl3) δ 174.7, 164.0, 162.4, 133.1, 132.8, 130.4,
129.9, 129.1, 128.8 (q, J = 309.8 Hz), 128.1, 128.0, 127.6, 126.3,
126.2, 116.8, 114.4, 76.9 (q, J = 1.1 Hz), 55.5, 42.7. 19F NMR (282 MHz,
[휶]ퟐퟎ
CDCl3) δ -37.5.
= -47.6° (c = 0.80, CHCl ). Enantiomeric ratio
3
푫
85:15 determined by HPLC analysis (CHIRALPAK® AS-H column (ϕ
0.46 cm x 25 cm), n-hexane:i-PrOH = 98:2, 0.5 mL/min, tminor = 14.7
min, tmajor = 17.3 min). HRMS (ESI) [M + H+] calcd for C22H17F3NO3S+
432.0876, found 432.0873.
(282 MHz, CDCl3) δ -37.4.
= -52.0 ° (c = 0.80, CHCl ).
3
푫
Enantiomeric ratio 81:19 determined by HPLC analysis (CHIRALPAK®
IB column (ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH = 99:1, 0.5 mL/min,
tmajor = 15.1 min, tminor = 16.2 min). HRMS (ESI) [M + H+] calcd for
C18H14ClF3NO3S+ 416.0330, found 416.0335.
4-benzyl-2-(3,5-dimethoxyphenyl)-4-((trifluoromethyl)thio)oxazol-
5(4H)-one (3g): Obtained after 1 h as a white solid (33.3 mg, 81%
yield), mp 117118- °C. 1H NMR (300 MHz, CDCl3) δ 7.22 (m, 5H), 7.02
(d, J = 2.3 Hz, 2H), 6.65 (t, J = 2.3 Hz, 1H), 3.81 (s, 6H), 3.48 (d, J = 13.2
Hz, 1H), 3.33 (d, J = 13.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 174.4,
162.4, 161.0, 131.2, 130.5, 128.7 (q, 310.2 Hz), 128.6, 128.3, 126.2,
106.6, 105.9, 76.7 (q, J = 1.1 Hz), 55.7, 42.4 (q, J = 1.1 Hz). 19F NMR
[휶]ퟐ푫ퟎ
2-(4-methoxyphenyl)-4-phenethyl-4-((trifluoromethyl)thio)oxazol-
5(4H)-one (3k): Obtained after 5 h as a white solid (34.8 mg, 88%
yield), mp 103-104 °C. 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz,
2H), 7.34-7.13 (m, 5H), 7.05 (d, J = 8.8 Hz, 2H), 3.93 (s, 3H), 2.78 (m,
1H), 2.65 (m, 1H), 2.56-2.33 (m, 2H). 13C NMR (75 MHz, CDCl3) δ
175.2, 164.2, 162.7, 138.9, 130.6, 128.8 (q, J = 309.5 Hz), 128.7,
128.4, 126.7, 116.9, 114.5, 75.9 (q, J = 1.1 Hz), 55.6, 38.4 (q, J = 1.1
(282 MHz, CDCl3) δ -37.5.
= -51.0° (c = 0.80, CHCl3).
Enantiomeric ratio 86:14 determined by HPLC analysis (CHIRALPAK®
AS-H column (ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH = 99:1, 0.5
mL/min, tminor = 21.4 min, tmajor = 22.2 min). HRMS (ESI) [M + H+] calcd
for C19H17F3NO4S+ 412.0825, found 412.0826.
[휶]ퟐퟎ
Hz), 30.1. 19F NMR (282 MHz, CDCl3) δ -37.7.
= -58.8° (c = 0.80,
푫
CHCl3). Enantiomeric ratio 80:20 determined by HPLC analysis
(CHIRALPAK® AS-H column (ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH =
98:2, 0.5 mL/min, tminor = 13.2 min, tmajor = 16.2 min). HRMS (ESI) [M
+ H+] calcd for C19H17F3NO3S+ 396.0876, found 396.0870.
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
4-benzyl-2-phenyl-4-((trifluoromethyl)thio)oxazol-5(4H)-one (3a):
View Article Online
DOI: 10.1039/D0OB00476F
2-(4-methoxyphenyl)-4-(2-(methylthio)ethyl)-4-
Obtained after 19 h as a white solid (17.2 mg, 49% yield), mp 104-
((trifluoromethyl)thio)oxazol-5(4H)-one (3l): Obtained after 19 h as 105 °C. 1H NMR (300 MHz, CDCl3) δ = 7.90 (dd, J = 8.4 Hz, 1.4 Hz, 2H),
a pink solid (31.0 mg, 85% yield), mp 97-98 °C. H NMR (300 MHz, 7.59 (t, J = 7.4 Hz, 1.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.24-7.18 (m,
1
CDCl3) δ 8.02 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 3.92 (s, 3H), 5H), 3.49 (d, J = 13.2 Hz, 1H), 3.35 (d, J = 13.2 Hz, 1H). 13C NMR (300
2.67-2.41 (m, 4H), 2.09 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 175.2, MHz, CDCl3) δ = 174.5, 162.5, 133.7, 131.3, 130.6, 129.2 (q, J = 298
164.3, 159.7, 130.7, 116.9, 128.8 (q, = 310.0 Hz), 114.5, 75.3 (q, J = Hz), 128.9, 128.5, 128.34, 128.27, 124.7, 42.5. 19F NMR (300 MHz,
19
[
[휶]ퟐퟎ
= -41.1° (c = 0.80, CHCl ). Enantiomeric
푫
1.1 Hz), 55.6, 35.8, 28.4, 15.2. F NMR (282 MHz, CDCl3) δ -37.5.
휶]ퟐ푫ퟎ
CDCl3): δ = -37.51 (s, 3 F).
ratio 82:18 determined by HPLC analysis (CHIRALPAK® AS-H column
(ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH = 90:10, 0.5 mL/min, tminor
3
= -29.4° (c = 0.50, CHCl3). Enantiomeric ratio 74:26 determined
by HPLC analysis (CHIRALPAK® AS-H column (ϕ 0.46 cm x 25 cm), n-
hexane:i-PrOH = 98:2, 0.5 mL/min, tminor = 15.5 min, tmajor = 17.9 min).
=
9.3 min, tmajor = 11.1 min). HRMS (ESI) [M + H+] calcd for
C17H13F3NO2S+ 352.3174, found 352.3170.
HRMS (ESI) [M + H+] calcd for C14H15F3NO3S2 366.0440, found
+
366.0447.
4-benzyl-2-(4-chlorophenyl)-4-((trifluoromethyl)thio)oxazol-5(4H)-
one (3d): Obtained after 19 h as a white solid (32.0 mg, 83% yield),
mp 118-119 °C. 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J = 6.9 Hz, 2H),
7.44 (d, J = 6.9 Hz, 2H), 7.21 (s, 5H), 3.48 (d, J = 13.2 Hz, 1H), 3.34 (d,
J = 13.2 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 174.2, 161.7, 140.3,
131.1, 130.5, 129.6, 129.4, 128.7 (q, J = 309.9 Hz), 128.5, 128.3,
4-(cyclohexylmethyl)-2-(4-methoxyphenyl)-4-
((trifluoromethyl)thio)oxazol-5(4H)-one (3m): Obtained after 4 h as
a white solid (35.6 mg, 92% yield), mp 114-115 °C. 1H NMR (300 MHz,
CDCl3) δ 8.00 (d, J = 8.9 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H),
2.10 (dd, J = 14.0, 5.3 Hz, 1H), 1.96 (dd, J = 14.0, 6.6 Hz, 1H), 1.78–
1.52 (m, 5H), 1.50 – 1.38 (m, 1H), 1.29 – 1.08 (m, 3H), 1.08 – 0.87 (m, 123.0, 77.2, 42.4 (q, J = 1.1 Hz). 19F NMR (282 MHz, CDCl3) δ -37.5.
[
2H). 13C NMR (75 MHz, CDCl3) δ 176.0, 164.1, 162.1, 130.5, 128.8 (q, 휶]ퟐ푫ퟎ
= -38.2° (c = 0.80, CHCl3). Enantiomeric ratio 70:30 determined
by HPLC analysis (CHIRALPAK® AS-H column (ϕ 0.46 cm x 25 cm), n-
J = 310.1 Hz), 117.1, 114.5, 76.1 (q, J = 1.1 Hz), 55.6, 43.8, 34.4, 34.2,
33.6, 26.0, 25.9. 19F NMR (282 MHz, CDCl3) δ -37.9.
[휶]ퟐퟎ
= -43.3° (c = hexane:i-PrOH = 99:1, 0.5 mL/min, tminor = 13.3 min, tmajor = 17.5 min).
푫
0.60, CHCl3). Enantiomeric ratio 91:9 determined by HPLC analysis HRMS (ESI) [M + H+] calcd for C17H12ClF3NO2S+ 386.0224, found
(CHIRALPAK® AS-H column (ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH = 386.0228.
99.5:0.5, 0.3 mL/min, tminor = 17.3 min, tmajor = 18.8 min). HRMS (ESI)
[M + H+] calcd for C18H21F3NO3S+ 388.1189, found 388.1193.
Conclusions
4-isobutyl-2-(4-methoxyphenyl)-4-((trifluoromethyl)thio)oxazol-
5(4H)-one (3n): Obtained after 2 h as a white solid (30.2 mg, 87%
yield), mp 102-103 °C. 1H NMR (300 MHz, CDCl3) δ 8.07–7.93 (m, 2H),
In conclusion, we have developed the first enantioselective
direct installation of SCF3 group at the C-4 position of azlactones
by employing
a phase transfer catalyzed methodology,
7.07–6.95 (m, 2H), 3.90 (s, 3H), 2.14 (dd, J = 13.8, 5.6 Hz, 1H), 1.98 affording a wide array of products with benzyl, homobenzyl and
(dd, J = 13.8, 6.9 Hz, 1H), 1.88–1.68 (m, 1H), 1.00–0.86 (m, 6H). 13C
NMR (75 MHz, CDCl3) δ 175.9, 164.1, 162.1, 130.5, 128.8 (q, J = 309.7
aliphatic α-side chains with high yields and good
enantioselectivity. The most effective cinchona alkaloid derived
catalyst is characterized by the electron poor nature of N-benzyl
group and the presence of a free hydroxyl moiety. The absolute
configuration of products has been determined by circular
dichroism. In addition, DFT calculations gave interesting
mechanistic insights and provided an explanation for the best
performance achieved with substrates containing an electron-
rich 2-aryl group. Further investigation aimed to expand the
scope of enantioenriched trifluoromethylthiolated aza-
compounds are currently under way.
Hz), 117.1, 114.5, 76.1 (q, J = 1.1 Hz), 55.6, 45.0, 25.4, 23.8, 23.0. 19
F
[휶]ퟐ푫ퟎ
NMR (282 MHz, CDCl3) δ -37.9.
= -39.9 ° (c = 0.80, CHCl3).
Enantiomeric ratio 72:28 determined by HPLC analysis (CHIRALPAK®
IB column (ϕ 0.46 cm x 25 cm), n-hexane:i-PrOH = 99.2:0.8, 0.35
mL/min, tmajor = 17.8 min, tminor = 19.1 min). HRMS (ESI) [M + H+] calcd
for C15H17F3NO3S+ 347.0803, found 347.0800.
4-isopropyl-2-(4-methoxyphenyl)-4-((trifluoromethyl)thio)oxazol-
5(4H)-one (3o): Obtained after 19 h as a white solid (29.3 mg, 88%
1
yield), mp 98-99 °C. H NMR (300 MHz, CDCl3) δ 8.06–7.96 (m, 2H),
7.04–6.96 (m, 2H), 3.89 (s, 3H), 2.39 (hept, J = 6.5 Hz, 1H), 1.20 (d, J
= 6.8 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
174.4, 163.0, 161.2, 129.5, 128.0 (q, 309.7 Hz), 116.0, 113.4, 79.1 (q,
Conflicts of interest
The authors declare no conflict of interest.
J = 1.1 Hz), 54.6, 34.8, 16.2, 15.8. 19F NMR (282 MHz, CDCl3) δ -37.5.
[
휶]ퟐ푫ퟎ
Acknowledgements
= -61.3° (c = 0.80, CHCl3). Enantiomeric ratio >99:<1 determined
by HPLC analysis (CHIRALPAK® AS-H column (ϕ 0.46 cm x 25 cm), n-
hexane:i-PrOH = 99.5:0.5, 0.3 mL/min, tmajor = 16.8 min. HRMS (ESI)
[M + H+] calcd for C14H15F3NO3S+ 334.0719, found 334.0714.
We are grateful to the Spanish Government (RTI2018-095038-
B-I00, CTQ, CTQ2016-76061-P), “Comunidad de Madrid” and
European Structural Funds (S2018/NMT-4367). R.I.R thanks
Fundación Carolina for a graduate fellowship. G.D.S and M.S.
thank the University of Salerno for financial support (FARB). We
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ARTICLE
Journal Name
9
(a) V. Capaccio, M. Sicignano, R. I. Rodríguez, G. Della Sala and
acknowledge the generous allocation of computer time at the
Centro de Computación Científica (CCC-UAM). We thank Irene
Tozio for experimental work.
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12 Our preliminary experiments demonstrated that the use of
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13 The presence of a free OH group proved to be a key
requirement
also
in
the
quinidine
catalyzed
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6 | J. Name., 2012, 00, 1-3
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