Trifluorosulfonylation Cascade in Allenols: Stereocontrolled Synthesis of Bis(triflyl)enones

Article abstract of DOI:10.1002/chem.202001236

Herein, we report investigations embodying the first example of reversal of the native regioselectivity in the reaction of allenols with electrophiles. The effortlessness of C?C bond formation, mild reaction conditions, neither catalysts nor light irradiation, and exquisite selectivity, both in terms of functional-group tolerance and chemo-, site-, and stereo-selectivity, converts this trifluorosulfonylation-rearrangement sequence into an appealing protocol for the preparation of novel functionalized enones. The synthetic utility of this method has been validated by the conversion of the initially prepared bis(triflyl)enones into a variety of bis(triflyl)-functionalized molecules such as 1,3-dienes, allylic alcohols, pyrroles, pyrazoles, and chromenes. Besides, DFT calculations have provided a reliable understanding of observed selectivity.

Full text of DOI:10.1002/chem.202001236

Accepted Article
Accepted Article
Title: Trifluorosulfonylation Cascade in Allenols: Stereocontrolled
Synthesis of Bis(triflyl)enones
Authors: Pedro Almendros, Carlos Lázaro-Milla, Jon Macicior, and
Hikaru Yanai
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.202001236
Link to VoR: https://doi.org/10.1002/chem.202001236
01/2020

10.1002/chem.202001236
Chemistry - A European Journal
Full Paper
Trifluorosulfonylation Cascade in Allenols: Stereocontrolled
Synthesis of Bis(triflyl)enones
Carlos Lázaro-Milla,[a] Jon Macicior,[a],[b] Hikaru Yanai,[c] and Pedro Almendros*[b]
Abstract: Herein, we report investigations embodying the first
example of reversal of the native regioselectivity in the reaction of
allenols with electrophiles. The effortlessness of C–C bond formation,
mild reaction conditions, neither catalysts nor light irradiation,
exquisite selectivity, both in terms of functional group tolerance and
chemo-, site-, and stereo-selectivity, converts this fluorosulfonylation-
rearrangement sequence into an appealing protocol for the
preparation of novel functionalized enones. The synthetic utility of this
method has been validated by the conversion of the initially prepared
bis(triflyl)enones into a variety of bis(triflyl)-functionalized molecules
such as 1,3-dienes, allylic alcohols, pyrroles, pyrazoles, and
chromenes. Besides, DFT calculations have provided a reliable
understanding of observed selectivity.
(Scheme 1a).[7] Taking into account the analogies in the reactivity
between allenes and alkynes,[8] we decided to examine a similar
reaction with allenes (Scheme 1b). Herein, we report that the
reaction of allenols with Yanai’s reagent selectively gives
bis(triflyl)enones through electrophilic attack of Tf2C=CH2 on the
terminal sp2-hybridized C4 atom of the allene moiety (Scheme 1c).
It should be noted that common electrophiles react with allenols
at the central sp-hybridized C3 atom to generate cationic
intermediates taking place further cyclization or rearrangement
processes (Scheme 1d).[9],[10] The current protocol constitutes the
first example of reversal of the native regioselectivity in the
reaction of allenols with electrophiles.
(a) Previous literature
Tf
Introduction
Tf2C CH2
2-FPy
Tf
R2
R1
+
F
N
The functionalized α,β-unsaturated ketone moiety is the key
core of naturally occurring compounds which display various
biological activities.[1] Besides, the use of α,β-unsaturated
ketones as building blocks in organic synthesis is well
developed.[2] The traditional routes for the preparation of α,β-
unsaturated ketones, namely, aldol condensation and Wittig
reaction, are associated to the use of harsh reaction conditions
and the generation of harmful waste by-products. As a result of
these drawbacks, new methods for their stereoselective synthesis
are necessary.[3] On the other hand, the presence of fluorine-
containing groups in an organic compound confers it unique
chemical and pharmaceutical properties.[4] In this context,
increasing attention is being given to the SO2CF3 (Tf) group due
to its strong electron-withdrawing ability coupled to a mild
lipophilicity, which resulted in a bioavailability improvement.[5] We
have recently reported that the reaction of alkynes with 2-(2-
ref. 7
R1
R2
CTf2
1
(b) Initial aim of the project
Tf
Tf
R2
Tf
Tf
R2
Tf2C CH2
in situ generated
•
+
or
R2
R1
R1
R1
1
from
(c) Current work
OH
R3
R2
O
R2
C4
Tf2C CH2
+
R1
R1
CHTf2
C3
C4
R4
•
R4
R3
R5
in situ generated
from 1
R5
(d) Classical reactivity
fluoropyridinium-1-yl)-1,1-bis(triflyl)ethan-1-ide
1
(Yanai’s
reagent),[6] which serves as potent precursor of outstandingly
electrophilic Tf2C=CH2, selectively yields bis(triflyl)cyclobutenes
OH
R3
R5
R5 R4
R4
O
R2
E
O
C3
E
R1
E
or
C3
•
C3
R1
R2
ref. 9
C4
R3
R1
R2
R3
R4
R5
[a]
[b]
[c]
Dr. C. Lázaro-Milla, J. Macicior
Grupo de Lactamas y Heterociclos Bioactivos, Unidad Asociada al
CSIC, Departamento de Química Orgánica, Facultad de Ciencias
Químicas
Universidad Complutense de Madrid, E-28040 Madrid (Spain)
J. Macicior, Prof. Dr. P. Almendros
Instituto de Química Orgánica General, IQOG
Consejo Superior de Investigaciones Científicas, CSIC,
Juan de la Cierva 3, 28006 Madrid (Spain)
E-mail: palmendros@iqog.csic.es
Scheme 1. Background, initial aim and current proposal.
Results and Discussion
Synthesis and Synthetic Transformations of Bis(triflyl)enones
Dr. H. Yanai
We initiated our study using 3-methylbuta-1,2-diene 2 as
starting allene and employing previous alkyne to cyclobutene
formation conditions,[7] with the use of 2-(2-fluoropyridinium-1-yl)-
1,1-bis(triflyl)ethan-1-ide 1. Disappointingly, the reaction did not
School of Pharmacy, Tokyo University of Pharmacy and Life
Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392 (Japan)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.202001236
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proceed either in the absence or presence of Lewis acids such as
AgOTf, [(Ph3P)AuNTf2], or In(OTf)3 (Scheme 2a). Allenamide 3
was too reactive and failed to give a clean reaction (Scheme 2b).
Given these results, we decided to move to a different type of
substituted allenes, such as allenols, which could be efficient in a
cycloetherification reaction. Fortunately, the reaction of allenol 4a
with reagent 1 proceeded in acetonitrile at room temperature
smoothly, but neither cyclobutane nor cyclized product were
formed. To our surprise, the obtained product 5a was an (E)-α,β-
unsaturated ketone bearing a CH2CHTf2 substituent, which may
be considered to be a product through electrophilic attack of
Tf2C=CH2 on the terminal sp2-hybridized carbon atom of the
starting allene (Scheme 2c).[11] Notably, in this case, the (Z)-
isomer was not obtained. Due to the strongly acidic character of
the hydrogen in Tf2CH-bearing compounds,[12],[13] adduct 5a was
isolated as the corresponding sodium salt after chromatographic
purification with silica gel.[14] Afterwards, the ratio of starting
materials, the temperature and the solvent were evaluated. The
conclusion of this survey was that the best performance occurred
running the reaction at room temperature in acetonitrile and using
equimolar amounts of 4a and 1.
optimized conditions. Nearly total selectivity in favor of the (E)-
isomer 5a–i was observed in all cases. The ease with which the
bis(triflyl)-α,β-unsaturated
ketones
can
be
prepared
stereoselectively is remarkable. The results presented in Scheme
3 demonstrate that this novel fluorosulfonylation-rearrangement
cascade is receptive towards steric and electronic effects.
OH
R2
R1
R2
O
CH3CN
rt
+
F
N
R1
CHTf2
•
CTf2
5a–j
1
4a–j
[isolated yield, E/Z %, t]
O
O
CTf2
CTf2
Na
S
Na
R
5e (64%, 97, 3 h)[a]
5a
R = H (80%, >99, 45 min)
5b R = NO2 (31%, >99, 5 h)
5c R = MeO (45%, >99, 30 min)[a]
5d
R = Cl (48%, 97, 1 h)
O
CTf2
O
Na
Tf2C
Na
CTf2
(a)
O
Na
Me
CH CN X
3
5f
(39%, >99, 6 h)
F
N
•
+
2 recovered
5g
(90%, 20 min)
rt
Me
CTf2
2
Br
1
O
O
O
CTf2
CTf2
(b)
(c)
CTf2
O
O
Na
Na
Na
CH3CN
rt
complicated
mixture
N
F
N
+
5j
5h (59%, 1 h)
(68%, 88, 5 h)
5i (84%, 40 min)
•
CTf2
3
1
HO
N
•
•
non-productive
precursors
OH
O
O
N
CH3CN
rt
OH
Me
Me
5-oxindole
F
N
+
CTf2 Na
5-indole
•
CTf2
5a
(75%)
4a
1
Scheme 3. Controlled synthesis of bis(triflyl)-functionalized enones 5a–j. [a]
The reaction was initiated at –40 oC.
Scheme 2. Impact of the allene substitution on the reaction of functionalized
allenes with Yanai’s reagent 1.
After exploring the scope at the carbinol moiety, the
compatibility of this transformation with the presence of
substituents at the allene functionality was studied. Pleasantly,
allenols 4k–m bearing alkyl, aryl or ethoxycarbonyl substitution at
the allene end undertook the reaction with reagent 1 to afford the
desired bis(triflyl)enones 5k–m in fair yields (Scheme 4). Even
sterically hindered allenols 4n and 4o having gem-disubstitution
at the distal allene carbon were well accommodated under the
optimized conditions (Scheme 4). Unfortunately, the introduction
of substitution at the proximal allene carbon such as in allenols 4p
and 4q resulted in a messy reaction. We next studied the
chemoselectivity of this fluorosulfonylation-rearrangement
sequence, and a variety of unsaturated functional groups were
evaluated. The results in Scheme 4 revealed lower reactivity of
alkene, alkyne, isolated allene, and azide groups in comparison
with the allenol moiety in precursors 4r–x. This exquisite
chemoselectivity of the allenol moiety, might grant a strategy for
orthogonal functionalization of these initially unaltered functional
Next, we surveyed the scope of the reaction between
diversely substituted allenols 4 and reagent 1 under the above
conditions. Allenols 4a–d having substituted aromatic rings of
different electronic nature were converted to the corresponding
bis(triflyl)enones 5a–d in reasonable yields (Scheme 3). A
heteroaromatic scaffold such as in 5e, was also well
accommodated. However, when the protocol was applied to
allenol-tethered heterocycles 5-indole and 5-oxindole,
complicated mixtures were obtained and enone formation could
not be accomplished (Scheme 3), likely due to off-target reactions
between the arene moiety and Tf2C=CH2.[15] Besides, starting
from the bis(allenol) 4f, the two-fold sequence smoothly yielded
the double functionalized enone 5f. Noteworthy, allenols bearing
a quaternary carbinolic center were also competent starting
materials, delivering the required bis(triflyl)enones 5g–j in
reasonable yields (Scheme 3). Interestingly, allenols 4i and 4j
bearing alkyl moieties were suitable reaction substrates under the
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10.1002/chem.202001236
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OH
groups in α,β,γ,δ-unsaturated ketone 5r, dienone 5s, enallenone
5t, enynones 5u–w, and azidoenone 5x.
Ph
(D)H
Ph
O
H(D)
H(D)
(D)H H(D)
CH3CN
rt
+
(D)H
F
N
CHTf2
•
(D)H
(D)H
(D)H H(D)
(D)H
OH
CTf2
R2
R1
R2
O
R3
(D)H
[D]-5a–[D5]-5a
CH3CN
rt
+
F
N
[Dn]-4a
1 or [D2]-1
[isolated yield, E/Z %, t]
R1
CHTf2
•
R5 R4
R3
5k–x
CTf2
R4
D
O
O
O
R5
1
D
D
4k–x
[isolated yield, E/Z %, t]
Ph
Ph
Ph
CTf2
CTf2
Na
[D']- (62%, >99, 1 h)
CHTf2
Na
D
Na
O
R
O
OH
R
5a
5a
5a
[D]- (61%, >99, 95 min)
[D2]- (72%, >99, 1 h)
Ph
Ph
Ph
CTf2
CTf2
Me Me
R
•
Na
R = Et (54%, 97, 1 h)
5l R = Ph (43%, >99, 1 h)
Na
O
D
O
O
D
D
D D
5k
5n R = H (41%, >99, 2 h)
5o R = Me (78%, >99, 2 h)
4p R = Me
4q R = Ph
Ph
Ph
Ph
CTf2
Na
[D2']- (66%, >99, 80 min)
CHTf2
Na
[D3]- (60%, >99, 1.5 h)
CTf2
Na
[D3']- (59%, >99, 1 h)
D
D
D
R
5m R = CO2Et (39%, >99, 7 h)
enone formation
suppressed
5a
5a
5a
O
O
O
D
O
O
D
O
CTf2
CTf2
Ph
CTf2
D
D
D
D D
Na
Na
O
Na
Ph
Ph
Ph
CTf2
Na
5a (73%, >99, 70 min)
CTf2
Na
CTf2
Na
5a (83%, >99, 75 min)
O
5r
(67%, >99 (E,E), 1 h)
D
D
D
D D
•
5s (50%, >99, 1 h)
5a (63%, >99, 80 min)
[D3'']-
[D4]-
[D5]-
5t (58%, 93, 1 h)
O
O
O
Scheme 5. Controlled synthesis of deuterated enones [D]-5a–[D5]-5a.
CTf2
Na
CTf2
CTf2
Na
O
Na
O
Ph
Ph
The obtained products 5 which hold up transformable
functional groups would be readily derivatized and thus may be
converted into a versatile platform for further elaboration. To
exemplify the utility of functionalized enones 5, we were motivated
to pursue a few functional group modifications. As depicted in
Scheme 6a, the α,β-unsaturated ketone moiety of 5a was readily
converted in a two-step process, via N-tosylhydrazone 6, into
bis(triflyl)propyl-decorated pyrazole 7. The chemoselective
reduction of the carbonyl group in enone 5a was also
accomplished to furnish the bis(triflyl)alkylated allylic alcohol 8
(Scheme 6a). The alkenylation of the ketone moiety in adduct 5a
was addressed using standard Wittig olefination conditions to
provide bis(triflyl)ated 1,3-diene 9 (Scheme 6a). A radical
procedure involving 1,4-addition of benzenethiol to enone 5a
provided the functionalized thioether 10 (Scheme 6a). We also
accomplished the efficient preparation of bis(triflyl)propyl-pyrrole
11 starting from functionalized enone 5j and p-anisidine (Scheme
6b). Besides, the alkyne and azide groups in substrates 5w and
5x can be selectively modified keeping unaltered the enone
moiety (Schemes 6c and 6d). A temperature-controlled divergent
reaction of the alkyne moiety in adduct 5w was successfully
performed, selectively delivering the cyclobutene 12 and the
chromene derivative 13 (Scheme 6c); while the intermolecular
heterocyclization of the azide group in compound 5x resulted in
the formation of triflyl-triazole 14 (Scheme 6d).
5v (54%, >99, 1.5 h)
5u
(64%, 88, 1 h)
OMe
O
CTf2
5w (47%, >99, 3h)[a]
Na
N3
[a]
5x
(73%, >99, 1.5 h)
Scheme 4. Controlled synthesis of bis(triflyl)-functionalized enones 5k–x. [a]
The reaction was run at 0 oC.
Organic compounds bearing C−D bonds are important
molecules from a chemical perspective, among other reasons,
kinetic isotope experiments can be developed. Taking into
account that replacing H for D should make alterations to the
pharmacological properties, deuterated compounds are also
relevant in the pharmaceutical field. Bearing in mind the
significance of deuterated scaffolds,[16] we considered that the
above sequence could be useful for the preparation of deuterated
bis(triflyl)-functionalized enones. Initially, the reaction between
allenol 4a and deuterated Yanai’s reagent [D2]-1 was tested.
Notably, bis(triflyl)ated α,β-enone [D2]-5a was smoothly obtained
in 72% yield (Scheme 5). Taking into account that strict choice of
the deuterium-labeled position is critical for the progress of a
prosperous deuterated drug, we decided to embark on the
preparation of differently labeled deuterated enones 5a. When
easily available D-labeled alenols [D]-4a, [D’]-4a, [D2]-4a, and
[D3]-4a were used as precursors under standard reaction
conditions, the desired deuterated bis(triflyl)enones [D]-5a, [D’]-
5a, [D2’]-5a, [D3]-5a, [D3’]-5a, [D3’’]-5a, [D4]-5a and [D5]-5a were
achieved in fair yields and with the same high level of deuteration
as in the starting materials (Scheme 5).
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(a)
H
N
fluoropyridine (2-FPy) in a reversible fashion. Subsequent
electrophilic attack of Tf2C=CH2 on the C4 atom in 4 led to the
formation of vinyl cation intermediates INT-1, which rapidly
undergoes an addition of water molecule to give oxonium
intermediates INT-2. Proton-mediated elimination of a water
molecule via proton-transferred intermediates INT-3 should
produce intermediates INT-4, which are the protonated form of
the final α,β-unsaturated ketones 5. Possibly, in such system,
weakly basic 2-FPy promotes proton transfer and deprotonation
processes.
K2CO3
HN
N
Ts
N
Ph
Ph
CH3CN, 130 ºC
microwave, 2 h
CTf2 Na
Ph
CTf2 Na
6 (77%)
7
(69%)
TsNHNH2
I2, K2CO3
EtOH
75ºC, 3 h
O
OH
Ph3PMe
Br
NaBH4
Ph
CTf2 Na
CTf2
Na
Ph
CTf2 Na
CeCl3ꞏ7H2
O
tBuOK, THF
5a
9 (47%)
8
MeOH, rt, 2 h
0º C to rt, 5 h
(93%)
PhSH
CH3CN
CAN 80ºC, 6 h
SPh
O
Ph
CTf2
Na
10 (74%)
(b)
OMe
Br
O
N
p-anisidine
CTf2,Na
OH
1
CTf2 Na
MeOH,
80 ºC
OH
OH
5j
11 (87%)
microwave, 1 h
R3
C1
R3
R4
R2
R1
R3
R2
R1
R2
R1
O
(c)
O
H2O
Tf
Tf
O
C
CTf2
CTf2
Na
Na
1
1
C3
•
CTf2 Na
(57%)
CH3CN
CH3CN
O
H2O
O
CTf2
CTf2
5w
O
R5
12
(63%)
80ºC, 2 h
rt, 2 h
13
R5
R4
C4
R5
R4
Tf
Tf
Na Tf2
C
OMe
2-FPy
4
INT-1
INT-2
OMe
proton
transfer
MeO
(d)
O
O
1
CTf2 Na
CTf2 Na
R2
O
H
H
CH3CN
N3
N
O
Tf
5x
14 (92%)
rt, 5 h
N
R2
N
O
R3
R1
H
–
H2O
R3
R2
R1
R1
CHTf2
Scheme 6. Synthetic transformations of bis(triflyl) enones 5.
CTf2
R3 R5 R4
H
O
CTf2
R4
R5
R4
R5
5
INT-4
INT-3
Mechanistic Study
Scheme 8. Tentative pathway for the formation of bis(triflyl)enones 5.
To find out some details concerning the provenance of the
oxygen atom of the newly formed ketone group in bis(triflyl)
enones 5, labeling and control experiments were designed. When
the reaction of allenol 4a was carried out in anhydrous acetonitrile
but with the addition of H218O (2 equiv), the obtained product was
the labeled 18O-5a in which the carbonyl oxygen atom was
specifically replaced by its isotope 18O (Scheme 7a). On the other
hand, the reaction of allenol 4a with Yanai’s reagent 1 was not
affected by the presence of molecular oxygen (Schemes 7b and
7c). Such experiments evidence that H2O existing in the reaction
system supplies the oxygen atom of the enone moiety.
Concerning the unusual regioselectivity in the initial
electrophilic attack of Tf2C=CH2 on the allene functionality, we
conducted a DFT modelling at PCM(MeCN)-M02-6X/6-31+G(d)
level of theory. To evaluate favorable approaching direction of
sterically bulky Tf2C=CH2 to allenic C4 and C3 atoms in 4a,
respectively, preliminary calculations were conducted (see
Supporting Information) and the hydrogen bond-assisted
orthogonal transition state (TS-1a) with 24.5 kcal mol–1 of G298
was found (Figures 1c). Here, a sum of global minimum Gibbs
energies of allenol 1a and Tf2C=CH2 is used as a reference. After
considering conformational varieties of starting molecules,[17] nine
transition states TS-1a–c, TS-2a–c, and TS-3a–c with similar
approaching direction were computed (Figures 1a and 1c).
Among these, TS-3b is the most favorable (G298 = 22.7 kcal mol–
1) and G298 values of others are below 25.0 kcal mol–1 as well.
On the other hand, TS-4b is the most likely transition state for the
C3 attack (G298 = 23.3 kcal mol–1), while the G298 values of
conformationally isomeric TS-4a,c TS-5a,b and TS-6 are higher
than 25.0 kcal mol–1 (Figures 1b and 1c). The Boltzmann
distribution considering these 15 transition states suggests a
kinetic ratio of 87:13 for the C4-/C3-attacks. This ratio was not
changed in a considerable magnitude, even when more than 40
transition states were considered (see Supporting Information).
This fact implies that the congested C3 atom allows only limited
approaches of Tf2C=CH2. In other words, the observed C4-
selectivity can be attributed with the steric bulkiness of the
electrophilic alkene.
(a)
OH
18O
CH3CN, rt
F
N
N
N
+
CTf2 Na
H218O (2 equiv)
•
•
CTf2
18O-5a (76%)
4a
OH
1
1
(b)
(c)
O
CH3CN, rt
F
CTf2 Na
+
Ar atmosphere
CTf2
5a
5a
(71%)
O
4a
OH
CH3CN, rt
O2 balloon
F
CTf2 Na
+
•
CTf2
(73%)
4a
1
Scheme 7. Labeling and control experiments.
A reasonable pathway for the formation of bis(triflyl)enones 5
from allenols 4 and reagent 1 is shown in Scheme 8. Initially, the
reagent 1 releases electrophilic alkene Tf2C=CH2 and 2-
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10.1002/chem.202001236
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Full Paper
For C4 addition
For C3 addition
Ph
H
O
Ph
Ph
H
H
H
H
H
Ph
Ph
O
H
Ph
H
O
Tf
O
H
H
H
H
H
H
H
H
H
H
H
H
Tf
Tf
Tf
O
O
H
H
H
H
Tf
Tf
H
Tf
Tf
Tf
Tf
H
H
H
H
H
H
H
H
H
Tf
Tf
H
H
H
H
H
H
H
H
TS-1
TS-2
TS-3
TS-4
TS-5
TS-6
up
down
190.9 pm
(+24.4)
189.7 pm
190.5 pm
194.6 pm
192.0 pm
down
191.2 pm
195.6 pm
up
TS-1a
TS-1b
TS-1c
TS-2a
TS-2b
TS-2c
TS-3a
(+24.5)
(+23.0)
(+23.5)
(+24.3)
(+23.5)
(+23.7)
183.0 pm
190.9 pm
(+22.7)
189.5 pm
192.3 pm
(+27.5)
194.5 pm
(+23.3)
193.1 pm
(+25.3)
193.3 pm
198.4 pm
(+31.9)
TS-3b
TS-3c
TS-4a
TS-4b
TS-4c
TS-5a
TS-5b
TS-6
(+25.9)
(+23.7)
(+33.0)
Conclusion
Figure 1. Hydrogen bond-assisted orthogonal transition states. G298 values (in
parentheses) are given in kcal mol–1
.
In summary, we have implemented a novel rearrangement
protocol in allenols granting the preparation of bis(triflyl)ethyl-
decorated α,β-unsaturated ketones. The sequence comprises
three processes: nucleophilic attack of the allene moiety to in situ
generated Tf2C=CH2, water addition to the so-formed zwitterion,
and final dehydration. Remarkably, the process shows great
chemo-, site-, and stereo-selectivity. The mild reaction conditions,
neither catalysts nor light irradiation, confers the transformation
outstanding functional group tolerance and wide scope. Briefly,
the first example of reversal of the native regioselectivity in the
reaction of allenols with electrophiles as a novel functionalization
reaction of the allene scaffold has been achieved.
A reaction pathway via energetically most likely TS-3b was
also calculated. As shown in Figure 2, vinyl cation intermediate
INT-1 (also see, Scheme 8) was found after intrinsic reaction
coordinate (IRC) and geometry optimization calculations. The
following addition of water is highly exothermic and INT-3 is
thermodynamically more stable than INT-2. The overall profile is
consistent with experimental observations in the reaction of 4a
with Tf2C=CH2 in situ generated from 2-fluoropyridinium salt 1.
TS-3b
+22.7
Acknowledgements
INT-1
+19.4
This work was supported in part by AEI (MICIU) and FEDER
(Project PGC2018-095025-B-I00) and KAKENHI (17K08224). C.
L.-M. thanks MICIU and UCM for a postdoctoral contract. We are
grateful to Prof. B. Alcaide for continued support.
H2O
INT-1
INT-3
0
INT-2
4a
+
–5.9
INT-3
–12.0
Tf2C=CH2
H2O
Conflict of interest
The authors declare no conflict of interest.
–29.2
INT-2
INT-4
INT-4
Figure 2. A reaction path through TS-3b. G298 values are given in kcal mol–1
.
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10.1002/chem.202001236
Chemistry - A European Journal
Full Paper
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Keywords: allenes
• fluorine • metal-free reactions •
selectivity synthetic methods
•
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10.1002/chem.202001236
Chemistry - A European Journal
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This article is protected by copyright. All rights reserved.

10.1002/chem.202001236
Chemistry - A European Journal
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Entry for the Table of Contents
Research Article
Carlos Lázaro-Milla, Jon Macicior,
Hikaru Yanai, and Pedro Almendros*
Page No. – Page No.
Trifluorosulfonylation Cascade in
Allenols: Stereocontrolled Synthesis
of Bis(triflyl)enones
This study provided the first example of reversal of the native regioselectivity in the
reaction of allenols with electrophiles as a novel functionalization reaction of the
allene scaffold.
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